Dr.Levent KARAFAKI (Tel:0312 431 12 38)

LEVOLİFT

2011-10-18T06:27:00.000-07:00

LEVOLİFT

Levolift 2006 yılında Dr.Levent KARAFAKI tarafından geliştirilen bir mezolift uygulamasıdır. İçeriği sadece Dr.Levent KARAFAKI tarafından bilinmekte ve uygulanmaktadır.

Uygulama şekline gelince iyi bir cilt muayenesi sonrasında karışım kişiye özel hazırlanmakta ve uygulanmaktadır. Uygulama 9 ay boyunca toplamda 14 seans yapılmaktadır. İlk ay haftada bir dört kez sonra 15 günde bir 4 kez ve sonrasında ayda bir şeklinde devam edilmektedir. Uygulamadan sonra 8 saat boyunca terlemek, duş almak ve aşırı aktivasyon yapılmamalıdır.

Doğal bir uygulama olan levolifting işlemi sadece Dr.Levent KARAFAKI tarafından uygulanmaktadır. Uygulama işmi zaten levo (Levent) isminden gelmekte ve uygulama yaptığımız bir hasta tarafından esinlendirilmiştir. Uygulamanın keşfinin üzerinden 5 yıl gibi süre geömesine rağmen halen hastalarda etkileri sürmekte veya bir kaç uygulama sonrasında beş yıl önceki hale dönülmektedir. Herhangi bir şekilde alerji veya yan etki riski mevcut değildir.

Esen kalın

Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.Ankara ozon , ozon ankara , alternatif kanser tedavisi , dmso , integratif tıp , akupunktur ,

LIVER & GALLBLADDER

2011-03-24T12:11:00.001-07:00

Abstract The purpose of this article is to demonstrate Liver/
Gallbladder zangfu disharmony as a possible
aetiological manifestation of erectile dysfunction.
This is done by the examination of ancient Chinese medical
theory in conjunction with the latest research from China.
One of the goals of this article is to dislodge the fixed notion
that erectile dysfunction is synonymous with Kidney yang
deficiency; it is just one of many pattern differentials that
must be considered. The Liver/Gall Bladder organ pair
was selected, as there are several erectile dysfunctioncausing
disorders that affect these zangfu.
Part One of this article examines the physiology and
pathology of the erection process from both the biomedical
and Chinese medicine (CM) perspectives. The Chinese
medicine pattern differentiation examines all of the various
patterns associated with erectile dysfunction. Part Two of this
article (to be published in JCM 69) will focus on treatment,
including acupuncture, dietetics and herbal therapies, with
special attention paid to individual herbs well known for
their beneficial effects in treating impotence.
The two appendices examine the more commonly understood
Chinese medicine aetiological patterns of impotence
and the Daoist theory of semen retention.
Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.Ankara ozon , ozon ankara , alternatif kanser tedavisi , dmso , integratif tıp , akupunktur ,

İNATÇI FİSTÜL TEDAVİSİ VE CERRAHİ YARA İYİLEŞMESİNDE OZONİZE ZEYTİNYAĞININ ETKİLERİ

2010-10-13T06:52:00.000-07:00

Therapeutic Effects of Ozonized Olive Oil in the Treatment of Intractable Fistula and Wound after Surgical Operation

Akiyo Matsumoto1, Shotaro Sakurai2, Nariko Shinriki3,

Shigeru Suzuki4 and Toshiaki Miura5

1Department of Surgery, Chiba-Tokushukai Hospital,

Narashino-dai, Funabashi, 274-8503, Japan

2Department of Pharmacy, Kashiwa Municipal Hospital, Fuse, Kashiwa, 277-0825, Japan

3Tsukuba Materials Information Laboratory, Sapporo Branch, Sapporo, 062-0906, Japan

4Nippon Ozone Co. Ltd., Arakawa 7-4-3, Tokyo, 116-0002, Japan

5College of Medical Technology, Hokkaido University, Kita-ku, Sapporo, 060-0812, Japan

Abstract

20 patients at several hospitals who underwent surgical operation between August

1998 to August 2000 had ozonized olive oil applied to their intractable fistula or

wounds. The ozonized olive oil treatment was fully effective in 19 of the cases. The

one exception was for a case of pilonidal sinus. Ozonized olive oil was especially

effective in treating intractable abdominal fistula to digestive tract after surgical

operation. No adverse side effects were observed in the administration of the

ozonized olive oil. It was fully effective for a discharge of pus and the formation of

granulation.

Introduction

There have been many cases of intractable fistula forming after surgical operations. In Europe

ozonized olive oil has been used to treat serious wounds and good results have been achieved,

however it has almost never been used in clinical applications in Japan. We started to test

ozonized olive oil by treating intractable wound which resulted in a cure. Since then we have

applied it for many kinds of cases, e.g., intractable fistula, decubitus anal fistula, pilonidal

sinus and so on. We will report good results we achieved.

Materials and Methods

The main component of ozonized olive oil was found to be triolein triozonide as explained in

the proceeding presentation..

Refrigerated ozonized olive oil which was obtained from Pharmoxid, Germany was brought

to a viscous state at room temperature before use.

20 patients who had been treated unsuccessfully for intractable fistulas and wounds were

selected. These patients had previously been treated by curettage, saline deterge, antibiotic

ointment and/or drainage. Before treatment with ozonized olive oil an informed consent form

was obtained.
Pus from the intractable fistulas and wounds was discharged and the ozonized oil was

administered to the opening by a 1.0 or 3.0 ml syringe. After the application of the ozonized

oil the fistula or wound was loosely covered by gauze. In some cases excess pus was

produced so a saline deterge was used, and debridement was done in cases of necrosis. There

was no administration of antibiotics either externally or orally, nor were the fistulas or wounds

stuffed with gauze or drained.

Results

20 cases are shown in Table 1. The number of other treatments before the ozonized oil (saline

deterge, antibiotic ointment, curettage and drainage) and the interval between treatments is

shown on the center. In the right columns we show the number of treatments of the ozonized

oil, dosage volume and intervals of application until the patient was cured.

There were three cases of intractable fistula after operation for inguinal hernia, including one

case of intractable fistula with infected mesh (case 2), which was cured by only 5 applications

of the ozonized oil.

Four cases of intractable fistula after operation for acute appendicitis with peritonitis (case 4

to 7) had difficulty in closing the opening, but after using the ozonized oil for only 3 to 10

applications they were cured. Photo.1 shows case 4 pre and post the ozonized oil treatment.

Five cases of intractable wound after operation for infected epidermal cyst were also shown.

Case 11 needed 24 applications but the others soon recovered. Photo. 2 shows case 10 pre and

post the ozonized oil treatment.

One case (case 13) was fistula after incision to treat an infected urachal cyst. Excretion of pus

was limited but the incision wound did not easily close after the operation. However after

only 3 treatments with the ozonized oil it closed.

We treated three cases of fistula after incision and drainage for infected pilonidal sinus. In

case 19 the number of treatments was higher than usual but a cure was effected. Case 17 had a

3 cm diameter abscess cavity under the skin that was not cured despite many applications of

the ozonized oil.

In a case of lower limb ulceration due to sunburn (case 20), a patient had a 3.0cm diameter

blister . Following usual practice the blister was pricked and treated, however the abscess

belaque at the bottom of the ulcer did not disappear. After application of the ozonized oil pus

solidification and a drying up at the ulcer bottom started and epithelization appeared, and then

the ulcer cured. This is shown in Photo. 3.

We treated three cases of fistula after incision and drainage for perianal abscess (cases 14 to

16), including one case for periviorectal abscess (case 15). We showed the cure proceedings

of case 15 in Photo. 4. Abscess cavities were formed in the range of 1) ischiorectal fossa on

the right, 2) internal and external obturator muscles on the left, 3) piriform muscles, 4) a part

of maximum gluteal muscle. A patient had a fever over 38°C and an increase of leukocyte

(15,200/mm3). After repeated incisions and drainage for perianal abscess, a decrease of

excretion of pus occurred and on the 8th day from the operation the patient started to eat.

However he again had a fever of 38°C and an increase in the amount of pus. We were forced
operation we started to treat his fistula with the ozonized oil, then the administration of oral

antibiotics became unnecessary. On the 14th day of treatment with the ozonized oil he started

to have meals without a fever nor an increase in leukocyte although a small amount of pus

was excreted. Photo. 4-B is a X-ray using diatorizonate sodium and shows the intractable

fistula at the start for the ozonized oil treatment. Photo. 4-D shows the fistula after 18

applications of the ozonized oil, and only ramiform fistula remained in the range of 1)

ischiorectal fossa on the right and the back of the rectum. In the CTs (4-E1~E3) abscess

formation could not be found. On the incised part of the right side around the anus a fistula

into which a sonde could only be inserted 2 cm remained and there was no excretion of pus.

From then the patient became an outpatient and until now there has been no sign of

recurrence.

Discussion and Conclusion

We often see intractable fistulas and wounds as a result of surgical operation. In the treatment

of intractable fistulas, use of local applications of Picibanil, fiblin paste and/or medicine made

from human blood coagulation factor 8, high oxygen pressure treatment and laser beam

irradiation method have been reported.1)-5) Operation for inguial hernia often gives rise to

infected mesh ( case 2 ) resulting in the need for a second operation. The infection is initially

cured but soon gets re-infected causing a repeat hernia. In operations for acute appendicitis

with diffuse peritonitis the formation of intractable fistula is often seen6). Even in cases of

relatively simple fistula observed by X-ray diatorizoate sodium treatment becomes very hard

due to the difficulty in overcoming infection and the elimination of bad granulation. In cases

of infected epidermal cyst, incision to eliminate pus often causes the infection to spread and

consequently subcutaneous tissue is lost, increasing the difficulty in curing the wound.

We tried treating intractable fistulas and wounds with the ozonized oil, which is especially

easy to apply without any special instrument. The application of the ozonized oil decreased the

excretion of pus along with a corresponding increase in granulation at the rim of the wound.

Then the opening reduced to a pin point or line state, and finally the excretion of pus stopped

and the fistula closed. In cases of fistula with minimal excretion of pus, epithelization of the

opening parts and subsequent closing were rapid. Infected urachal cysts and infected pilonidal

sinuses which are not cured by antibiotics7) usually need radical operations, however in our

study they were seen to be effectively cured by the ozonized oil. Anal fistulas, which are

easily formed after incision and drainage for perianal abscesses often need a radical operation,

but cases 14 and 16 soon healed after application of the ozonized oil, and there has been no

sign of recurrence. In case 15 a periviorectal abscess showed a rapid reduction of fistula size

and a tendency to heal. Until now, after debriedment intractable fistulas and wounds were

classified by their conditions and their treatment was carried out according to this

classification. Wounds with large amounts of pus had saline deterge, drainage and local

application of antibiotics. After the granular formation some drugs which promote the

formation of granulation was used. Using the ozonized oil by itself resulted in pus

solidification, an ocurrence of drying, the appearance of epithelization and a decrease in the

size of abscesses. The fistulas and wounds had a tendency to cure; therefore the ozonized oil

itself can cure these independently. Intractable wounds that had a certain degree of

granulation after debriedment of the parts of necrosis and abscess had the ozonized oil applied

and this resulted in rapid epithelization and a closing of the opened wounds.
The disinfection effect of ozonized olive oil has already been reported8). On the other hand the

stimulation mechanism of the ozonized oil to the tissue (e.g., granulation and epithelization

etc.) has not been clarified enough. However, in ozone treatment (e.g., autohemotherapy)

ozone has been recognized to have some stimulating effects on leukocytes, e.g., induction of

many cytokines was clearly confirmed by Bocci9,10). In ozone gas rinsing of ulcers caused by

arterial circulation disorders (diabetes), increases of granulation tissue and epidermal

epithelium were observed by Rokitansky11). Also in the case of ozonized olive oil some active

oxygen species which are considered to be generated from the breakdown of triolein

triozonide will be able to react and/or stimulate the cells. About this point more study will be

needed.

In conclusion we think that because of its good results with no side effects and ease of

application ozonized olive oil should be used for the treatment of intractable fistulas and

wounds after surgical operations.

References

1) Nakanishi Y, Nakajima T, Yoshimura Y et al.: Nihon Keisei-geka Gakkai Kaishi (J. Japan

Soc. Plastic and Reconstructive Surgery) 17: 428-433, 1997

2) Hiraguchi E, Miyake Y, Sunaga M et al.: Nihon Rinsyo-geka Gakkaishi (J. Japan Surgical

Assoc.) 53: 209-214, 1992

3)Usui A, Kubota M, Ohkita J et al.: Hinyouki-geka (Japanese J. Urological Surgery) 6 : 373-

376, 1993

4) Kawashima M, Tamura H, Takao K et al.: Nihon Iji Shinpou (Japan Medical Journal)

No.3525 : 43-45, 1991

5) Suguro M, Ejiri S, Sakashita T : Shohkaki Naishikyo (Endoscopia Digestiva) 9 : 411-416,

1997

6) Yamamoto S, Watabe T, Matsumoto Y et al.: Geka (Surgery) 57 : 149-154, 1995

7) Lundhus E, Gottru F : Outcome at three to five years of primary closure of perianal and

pilonidal abscess. A randomised, double-blind clinical trial with a complete three-year

follow up of one compared with four days’ treatment with ampicillin and metronidazole.

Eur. J. Surg. 159 : 555-558, 1993

8) Lezcano I, Nuñez N, Espino M, Gómez M : Antibacterial activity of ozonized sunflower

oil, Oleozón, against Staphylococcus aureus and Staphylococcus epidermidis. Ozone Sci.

Eng. 22 : 207-214, 2000

9) Bocci V, Paulesu L : Studies on the biological effects of ozone. 1; Induction of interferon

γ on human leucocytes. Haematologica 75 : 510-515, 1990

10) Paulesu L, Luzzi E, Bocci V: Studies on the biological effects of ozone. 2; Induction of

tumor necrosis factor (TNF-α) on human leucocytes. Lymphokine Cytokine Res. 10, 409-

412, 1991

11) Werkmeister H : Subatomospheric O2/O3-treatment of therapy-resistent wounds and

ulcerations. OzoNachrichten 3/4, 53-59, 1985

Photo. 1 Case 4: Formation of intractable fistula after operation for acute appendictis

A: Wound before medication of ozonized olive oil
B: X-ray with diatorizoate sodium (X-ray) of intractable fistula
C: Wound after one application of the ozonized oil
D: Wound after 6 applications of the ozonized oil

Photo. 2 Case 10: Formation of intractable fistula after operation for infected epidermal cyst

A: Wound before medication
B: Wound after one application of the ozonized oil
C: Wound after 4 applications of the ozonized oil

Photo. 3 Case 20: Debriedment of lower limb ulceration

A: Wound before medication
B: Wound after 2 applications of the ozonized oil
C: Wound after 7 applications of the ozonized oil
D: Wound after 16 applications of the ozonized oil

Photo. 4 Case 15: Formation of intractable fistula after incision and drainage for perianal abscess

A: Wound before medication B: X-ray of intractable fistula C1, C2: CT with diatorizoate sodium (CT) of intractable fistula

D: X-ray of intractable fistula after 18 applications of the ozonized oil. E1, E2, E3: CT of intractable fistula after 18 applications of the ozonized oil. Before medication, abscess cavities were formed in the range of 1), 2), 3) and 4) in the pictures. After 18 applications, only ramiform fistula remained in the range of 1) and the back of the rectum, and abscesses in other parts were not detected by CT. 1) ischiorectal fossa on the right 2) internal and external obturator muscles on the left 3)piriform muscle 4) a part of maximum gluteal muscle

Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.Ankara ozon , ozon ankara , DMSO , C Vitamini , PRP ,

Ozonun cilt üzerine etkileri

2010-08-31T09:35:00.000-07:00

The dual action of ozone on the skin

G. Valacchi,* V. Fortino* and V. Bocci*

*Department of Physiology, University of Siena, Siena 53100, Italy

Department Internal Medicine, School of Medicine, University of California Davis, Davis, CA 95616, U.S.A.

Correspondence

G. Valacchi.

Summary

The aim of this brief review is to summarize the recent literature on the effect of ozone (O3) on cutaneous tissues. Recently it has been reported that a chronic contact with O3 can be deleterious for the skin. Our group and others have shown a progressive depletion of antioxidant content in the stratum corneum and this can then lead to a cascade of effects resulting in an active cellular response in the deeper layers of the skin. Using an in vivo model we have shown an increase of proliferative, adaptive and proinflammatory cutaneous tissue responses. On the other hand the well known activity of O3 as a potent disinfectant and oxygen (O2) donor has been also studied for therapeutic use. Two approaches have been described. The first consists of a quasi-total body exposure in a thermostatically controlled cabin. This treatment has proved to be useful in patients with chronic limb ischaemia. The second approach is based on the topical application of ozonated olive oil in several kinds of skin infection (from soreness to diabetic ulcers, burns, traumatic and surgical wounds, abscesses and skin reactions after radiotherapy). We and other authors have observed a striking cleansing effect with improved oxygenation and enhanced healing of these conditions. It is now clear that, on the skin, O3, like other drugs, poisons and radiation, can display either a damaging effect from a long exposure or a beneficial effect after a brief exposure to O2 and O3 or to the application of ozonated oil to chronic wounds. Christian Friedrich Schonbein discovered ozone (O3) in 1839 and in 1853 he made the first measurement of O3 in the Austrian mountains. Today, we know that some gases such as O3, carbon monoxide, nitric oxide and carbon dioxide can have dual actions, behaving either as useful or as harmful agents.1 The O3 layer is located at an altitude of about 22 km. Approximately 90% of the O3 in the atmosphere resides in the stratosphere. The O3 concentration in this region is about 10 parts per million by volume. O3 absorbs the bulk of solar ultraviolet (UV) radiation in the wavelengths from 290 to 320 nm. These wavelengths are harmful to life because they can be absorbed by the nucleic acid in cells and damage it.

Increased penetration of UV radiation to the planet’s surface would damage plant life and have harmful environmental consequences. Appreciably increased amounts of solar UVradiation at the Earth’s surface would result in a host of biological effects, such as a dramatic increase in cancer; it seems that a 10% drop in the level of the O3 layer may cause a 25% increase in skin carcinoma and melanoma.2 Moreover this risk has recently been enhanced by excessive pollution with O3 in the troposphere, particularly evident during summertime in large cities.3 Thus the strong oxidative power of O3 in association with other contaminants, can be harmful for plants and animals. The human bronchopulmonary system and the

skin are the most accessible targets; they are vulnerable owingto the paucity of local antioxidant defences. O3 toxicity for the pulmonary system has been extensively examined while attention to the skin problem is more recent but no less important.

An interesting difference that we would like to point out here is that while the pulmonary system is absolutely intolerant to O3 and this gas should never be inhaled, the skin, forbanatomical and biochemical reasons, is somewhat more resistant. Recent literature points out that although a long exposure is certainly deleterious, transitory exposure at low and precisely controlled O3 concentrations can have useful effects.
The damage to the respiratory tract by oxidative environmental pollutants such as O3 and nitrogen oxides have already been reviewed4 while recent literature has focused only on the damaging interaction between long exposures to O3 and cutaneous tissues.5–10

We believe that it is now also correct to discuss the unexpected herapeutic effect of a brief exposure of patients to O3 or the use of ozonated oil for cutaneous infections. 1096 2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp1096–1100

Skin responses to environmental stress The skin consists of two main layers, the epidermis and the dermis, of which the latter is superficial to the subcutaneous fat tissue. Dermal fibroblasts synthesize a complex extracellular matrix containing collagenous and elastic fibres. Blood capillaries reach the upper part of the dermis. The epidermis contains mostly keratinocytes that rise to the skin surface as they differentiate progressively to form the non-nucleated corneocytes that comprise the superficial part of the epidermis, the stratum corneum (SC).

The skin, as an interface between the body and the environment, is chronically exposed to stress from both UV radiation and environmental oxidative pollutants such as diesel fuel exhaust, cigarette smoke, halogenated hydrocarbons, heavy metals and O3 (one of the most toxic of these compounds).11
The skin is protected against oxidative stress by a variety of antioxidants; these include enzymatic antioxidants such as glutathione peroxidase, superoxide dismutase, catalases and nonenzymatic low-molecular weight antioxidants such as vitamin E isoforms, vitamin C, glutathione (GSH), uric acid and ubiquinol. 7 Recently, the presence of a- and c-tocopherol, ascorbate, urate and GSH has been shown also in the SC.10 Interestingly, the distribution of antioxidants in the SC follows a gradient with higher concentrations in deeper layers.12 This may be explained by the fact that SC layers move up in time as a part of the physiological turnover of skin cells and are replaced by freshly differentiated keratinocytes. Therefore, the superficial layer is exposed to chronic oxidative stress for a longer time than the deep layer. Compared with the SC, the surface lipids contain high levels of a- and c-tocopherol because of the secretion of vitamin E by sebaceous glands.13 Eventually, the uppermost layer of the SC will desquamate and the remaining antioxidants and reacted products will be eliminated from the body.

In general the outermost part of the skin, the epidermis, contains lower concentrations of antioxidants than the dermis. In the lipophilic phase, a-tocopherol is the most prominent antioxidant, while vitamin C and GSH are the most abundant in the aqueous phase. Skin responses to ozone It is generally understood that the toxic effects of O3 are mediated through free radical reactions, although O3 is not a radical species per se.14 They are achieved either directly by the oxidation of biomolecules to give classical radical species (hydroxyl radical) or by driving the radical-dependent production of cytotoxic, nonradical species (aldehydes).15

Furthermore, the formation of the oxidation products characteristic

of damage from free radicals has been shown to be

prevented by the addition of the antioxidants vitamin E and C,

though the mechanism is not fully understood. The target specificity

of O3 towards specific compounds together with its

physicochemical properties of fairly low aqueous solubility

and diffusibility, must be taken into account when a target tissue

(lung and skin) is exposed to O3.16

Polyunsaturated fatty acids

Cell membranes and their lipids are relevant potential targets

of environmental stressors such as UV and O3. Using a spin

trapping technique, the formation of radicals in the SC upon

exposure to O3 and ⁄or UV was detected (L. Packer, unpublished

observation).

The spin adduct could arise from an alkoxyl radical formed

during lipid peroxidation. Furthermore, lipid radicals (LÆ) are

generated in epidermal homogenates that have been exposed

to environmental stressors. The organic free radical LÆ reacts

with O2, forming peroxyl radical LOOÆ and hydrolipoperoxides

(LOOH). Transition metals and in particular iron, play a

key role in the reactions of LOOH and in the subsequent generation

of alkoxyl radicals (ROÆ can amplify the lipid peroxidation

process).

The stratum corneum as the first target of environmental

stressors

Within the skin, the SC has been identified as the main target

of oxidative damage.17,18 As the outer skin barrier, the SC has

important functions, limiting transepidermal water loss and

posing a mechanical barrier to penetration by exogenous

chemicals and pathogens. It comprises a unique two-compartment

system of structural, non-nucleated cells (corneocytes)

embedded in a lipid enriched intercellular matrix, forming

stacks of bilayers that are rich in ceramides, cholesterol and

free fatty acids.19,20

The effects of O3 on cutaneous tissues have recently been

evaluated using a murine model. While no effect of O3 on

endogenous antioxidants was observed in full thickness skin

(dermis, epidermis and SC), it could be demonstrated that a

single high dose of O3 (10 lg g)1 · 2 h) significantly depleted

topically applied vitamin E.21 When the skin was separated

into upper epidermis, lower epidermis and papillary dermis,

and dermis, O3 induced a significant depletion of tocopherols

and ascorbate followed by an increase in the lipid peroxidation

measured as malondialdehyde (MDA) content. O3 is

known to react readily with biomolecules and does not penetrate

through the cells; therefore, it was hypothesized that O3

mainly reacts within the SC.17 This hypothesis was supported

by further experiments, where hairless mice were exposed to

varying levels of O3 for 2 h. Depletion of SC lipophilic (tocopherols)

as well as hydrophilic (ascorbate, urate, GSH) antioxidants

was detected upon O3 exposure and it was

accompanied by a rise in lipid peroxidation as an indicator of

increased oxidative stress.22 Furthermore, a recent study has

shown the increase of 4-hydroxylnonenal (4-HNE) content in

murine SC using both Western blot and immunohistochemical

analysis.23

Skin cellular responses to ozone exposure

As mentioned above, O3 exposure was shown to induce antioxidant

depletion as well as lipid and protein oxidation in the

2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp1096–1100

Ozone on the skin, G. Valacchi et al. 1097

SC. Recent studies have investigated the effects of O3 in the

deeper functional layers of the skin.23–25

To evaluate the effect on cutaneous tissues of O3 exposure,

hairless mice were exposed for 6 days to 0Æ8 lg g)1 for

6 h day)1 and the homogenized whole skin was analysed.

Under these experimental conditions an increase of proinflammatory

marker cyclooxygenase-2 (COX-2) expression was

detected confirming the role that O3 can play in skin inflammation.

This induction was accompanied by an increase in the

protein level of heat shock protein (HSP)32, also known as

haem oxygenase-1 (HO-1), confirming that HSPs are sensitive

markers of O3-induced stress in cutaneous tissues.

Our group was the first to document the upregulation of

HSPs 27, 32 and 70 in homogenized murine skin upon O3

exposure (8Æ0 lg g)1 for 2 h).25 HSP27 showed the earliest

(2 h) and highest (20-fold) response to O3 compared with

the delayed induction (12 h) of HSP70 and HO-1. Increased

expression of HSP27 has been demonstrated following heating

of both keratinocyte cell lines and organ-cultured human

skin.26,27 HSP27 is expressed predominantly in the suprabasal

epidermis in human skin,28 whereas HSP70 predominates in

the dermis compared with the epidermis. These differences in

location between HSP27 and HSP70 might explain the different

time course of induction of these stress proteins upon O3

exposure. Interestingly, O3 induction of HO-1 showed a

delayed time course compared with that for HSP27 and 70, in

line with a previous study, which showed a peak of HO-1

induction at 18–24 h in rat lungs after O3 treatment.29 It is

therefore possible that bioactive compounds generated by

products of O3 exposure may be responsible for the induction

of HO-1 as was also shown after UV irradiation.30,31

As HSPs are involved in cell proliferation, apoptosis and

inflammatory response, O3-mediated HSPs induction can affect

normal skin physiology. Thus, HSPs might provide an adaptive

cellular response to O3; enhancing the expression of HSPs

might turn out to be a new way to deal with the immediate

and long-term consequences of O3 exposure. A prerequisite

for the utilization of this concept is the development of nontoxic

HSP inducers and their evaluation for clinical efficacy

and safety.

Furthermore, increased levels of metalloproteinase-9

(MMP-9; mRNA and activity) was observed after O3 exposure

(0Æ8 lg g)1 for 6 h).24 MMPs have been associated with the

degradation of the basal membrane and play important roles

in wound healing and in tumour development. In addition,

MMPs may contribute to the enhancement of skin ageing and

formation of wrinkles.32

O3 is also able to modulate proliferative responses in mouse

skin.23 Proliferating cellular nuclear antigen (PCNA) is a protein

identified as the polymerase-associated protein synthesized

in the early G1 and S phases of the cell cycle involved in DNA

replication and repair. PCNA is induced by stress responses that

cause DNA damage;33 it has been reported that PCNA gene

expression can be induced in the lungs by diesel exhaust particles,

another form of oxidative lung damage,34 suggesting that

oxidation can affect proliferative behaviour in target tissues.

O3 exposure can also affect cell differentiation. In skin tissue,

we detected an increase of keratin 10 (K10) production

after O3 treatment;23 K10 is a keratin produced in well differentiated,

suprabasal keratinocytes; O3-induced changes in K10

suggest that O3 (at levels of 0Æ8 lg g)1) induces keratinocyte

proliferation and differentiation.35 It is not clear how O3 displays

its effects, but recent studies have shown that it is able

to induce the activation of the transcription factor, NF-jB, by

phosphorylation of the kinase, IjBac.23

Changes in the redox state have been shown to activate the

NF-jB intracellular signalling pathway; this cascade includes

several kinases and transcription factors. NF-jB-mediated signal

transduction has been implicated in the regulation of viral

replication, autoimmune diseases, tumorigenesis and apoptosis,

and in the inflammatory response. In this regard, the activation

of NF-jB is known to play a crucial role in COX-2

gene activation,36 suggesting that O3 plays a role in the

expression of numerous proinflammatory and adaptive inflammatory

responses.

It is not surprising that exposure of the skin to O3 can trigger

several biochemical pathways leading to inflammation and

affecting skin biology. On the other hand basic and clinical

work developed during the last 15 years has shown that transient

treatment and small O3 doses can reactivate useful body

functions and might display therapeutic activity.37

Is a brief application of ozone on the skin medically

useful?

This question may be surprising but important anatomical and

functional aspects can explain how a very brief exposure of the

skin to O3 may display systemic activity with no toxicity. First,

the layer of lipids overlying the SC consists of an unusual oily

material derived from sebum,38,39 that is the external line of

defence against O3 and UV irradiation. Secondly, O3 cannot

penetrate into the cutaneous tissues because it immediately

reacts with the polyunsaturated fatty acids and traces of water

overlaying the SC, generating reactive oxygen species (ROS) and

lipooligopeptides (LOP), among which are hydrogen peroxide,

peroxyl radicals and 4-HNE. Thus, only newly generated ROS

and LOPs can be either partly reduced by the skin antioxidants

or partly absorbed via the venous and lymphatic capillaries.

Quasi-total body exposure (excluding the neck and head to

avoid breathing O3) to O2 and O3 is performed in a tightly

closed cabin, thermostatically controlled at about 40 C and

saturated with water vapour. As the time spent in the cabin is

only 15–20 min, the skin is exposed to progressively increasing

O3 concentrations of no more than 0Æ9 lg mL)1 for only

a few minutes. In human volunteers several parameters such as

variation of total antioxidants, peroxidation products, protein

thiol groups and cytokine plasma levels were examined after

the constant introduction of 1 L min)1 volume of O2 and O3

(98% and 2%) into a 440-L cabin. A significant increase of

pO2 and of peroxidation products in venous plasma was detected,

indicating a systemic effect of absorbed O2 and O3-

derived compounds from the skin. Negligible variations of the

2005 British Association of Dermatologists • British Journal of Dermatology 2005 153, pp1096–1100

1098 Ozone on the skin, G. Valacchi et al.

plasma antioxidant capacity and other haematochemical and

enzymatic components assured lack of toxicity and all volunteers

reported a feeling of well-being in the next few days.40

This approach appears to help patients with chronic limb ischaemia

and deserves to be pursued scientifically.37

Topical application

Interestingly, in spite of its instability, the O3 molecule can be

stabilized as an ozonide between the double bonds of a

monounsaturated fatty acid such as oleic acid.37 As a consequence,

ozonated olive oil remains stable for 2 years at 4 C.

This preparation is proving to be ideal for the topical use of

O3 in the treatment of chronically infected cutaneous and

mucosal areas of the body.

O3 is widely recognized as one of the best bactericidal, antiviral

and antifungal agents and therefore it is profitably and

practically employed as ozonated olive oil with well defined

peroxide contents. The ozonated oil is now used topically for

the treatment of war wounds, anaerobic infections, herpetic

infections (HHV I and II), trophic ulcers and burns, cellulitis,

abscesses, anal fissures, decubitus ulcers (bed sores), fistulae,

fungal diseases, furunculosis, gingivitis and vulvovaginitis.41

Matsumoto et al. tested the efficacy of the ozonated oil in the

treatment of fistulae and chronic surgical wounds and, in a

series of 28 patients, the ozonated oil was fully effective in 27

cases without side-effects.42 Even radiodermatitis lesions in

patients with cancer have been found to be beneficially influenced

by exposure to O3

43 but far better results could be

achieved with the simple application of ozonated oil.

Conclusions

Biological and clinical studies on the effects of O3 on the skin

have shown that O3 can be either toxic, or safe at the point of

use as a real drug, depending upon its dosage, length of exposure

and the antioxidant capacity of the tissue exposed.

The ambivalent character of O3 has been likened to the

Latin god Janus;44 indeed O3 is useful in the stratosphere but

is toxic in the troposphere because of its chronic effects on

the respiratory system, skin and mucosae.45

On the other hand, it has recently been observed that olive

oil, which during ozonation traps O3 in the form of a stable

ozonide, when applied to all sorts of acute and chronic cutaneous

infections, slowly release O3 which, in comparison with

conventional creams, displays effective disinfectant and stimulatory

activities that lead to rapid healing. The dual behaviour

of O3 fits well the concept of ‘hormesis’ that says the exposure

of a living organism to a very low level of an agent

harmful at high or chronic levels induces an adaptive and

beneficial response.46,47

Acknowledgments

The authors thank Italian MIUR Project ‘Rientro dei Cervelli’

for partial financial support.

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1100 Ozone on the skin, G. Valacchi et al.Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.

HASTALAR İÇİN OZON BİLGİSİ

2010-06-28T07:50:00.000-07:00

Information for patients

What is Ozone ?
What is Ozone Therapy ?
In what diseases is ozone therapy usually applied ?
What should I know as a patient ?
Ozone fingerprint
Where can I obtain information ?
What is Ozone ?

     Ozone is a chemical compound consisting of three oxygen atoms O3 (ie triatomic oxygen), a highly energetic form of normal (diatomic) atmospheric oxygen (O2). Thus, the molecules of these two forms are different in structure, ie:

     At room temperature, O3 is a colorless gas with a characteristic odor (eg after thunderstorms, at high altitudes or near the sea etc). Its name is from the Greek ozein (ozein) meaning “to smell”, and it was discovered in 1840 by the German chemist Christian Friedrich Schönbein (1799-1868). Closer to ground level it can occur in the form of smog at concentrations of 1 part O3 per 10 million parts air (= 0.1 ppm = 200 µg/m³); at a height of 2,000 meters (or 6,561.6 feet), however, it is much less, as a rule only 0.03 - 0.04 ppm.

     Due to its being an extremely powerful oxidizing agent and a highly effective disinfectant, it is used throughout the world to destroy germs in water treatment installations supplying drinking water. What is Ozone Therapy ?

Ozone as a therapeutic

Medical ozone is always a mixture of purest ozone and purest oxygen.

According to its application, the ozone concentration can vary between 1 and 100 µg/ml (0.05 – 5 % O3). The ozone therapist, a trained physician, determines the complete dosage according to the medical indication and the patient's condition.

Properties and effect

     Medical ozone has highly pronounced bactericidal, fungicidal and virostatic properties, and is thus widely used in disinfecting infected wounds, as well as in bacterially and virally produced diseases.

     Its ability to stimulate the circulation is used in the treatment of circulatory disorders and makes it valuable in revitalizing organic functions.

     When administered at low concentrations, the organism's own resistance is mobilized, ie ozone (re)activates the immune system.

     As a response to this activation through ozone, the body's immune cells produce special messengers called cytokins (including important mediators such as interferones or interleukins). These inform other immune cells, setting off a cascade of positive changes throughout the immune system, which is stimulated to resist diseases for example. This means that the application of medical ozone is extremely useful for immune activation in patients with a low immune status and/or immune deficit.

     Small quantities of ozone applied in what is called “major autohemotherapy” (external treatment of the patient's blood before reinfusion) consequently activate the body's own antioxidants and radical scavengers.

     It is thus possible to understand why ozone is used in diseases which involve chronic inflammation.

     Indications

    Thanks to its selective properties, medical ozone is used in three principal fields of indication: The treatment of circulatory disorders, also in the field of geriatrics, and The treatment of diseases produced by viruses such as liver diseases (hepatitis) and herpes The treatment of infected, badly healing wounds and inflammatory processes, such as for example Open ulcers on the legs (ulcus cruris) Inflammatory intestinal conditions (Colitis, Proktitis), Burns, scalds and infected wounds, fungus infections and others

     As an additive or complementary therapy in various types of cancer, ozone is applied for general immunoactivation at low dosages in the form of "major autohemotherapy" (reinfusion) or "minor autohemotherapy" (reinjection) via the intramuscular route.
Forms of application

NOTE: In any form of ozone therapy, the breathing in of ozone gas is forbidden.

     Many decades of experience and a number of recent clinical studies have shown that the following five application methods are valid for ozone:

     Major autohemotherapy (treatment of the patient's blood outside the body before reinfusion) in geriatrics (age-related conditions), for revitalization, in the treatment of circulatory disorders and virus-produced diseases, and for general immunoactivation. By this method, 50 to 100 ml of the patient's own blood is withdrawn in the normal manner, enriched externally with an exactly defined quantity of ozone (with disposable sterile material and containers!). The ozone reacts completely - ie at a rate of 100 % - with specific substances making up the red and white blood cells and thereby activates their vital activities = metabolism. It is this activated blood (not ozone or oxygen!) that is immediately reintroduced into the patient's system using a normal drip unit.

     Using the same principle, minor autohemotherapy is an application, via the intramuscular route, of O3 treated blood for unspecific immunoactivation revitalization: it can be used in allergic diseases or in a general way to improve the body's inherent resistance.

     External treatment is primarily achieved through a closed system using O3 gas fed into special plastic “boots” (for the legs and feet) or bags, foils etc fitting various parts of the body. These are of course made of ozone-resistant materials. The parts of the body treated have previously been moistened with water, as ozone cannot act on dry areas. This method is highly effective in treating ulcers, sores, open wounds, postoperative lesions, shingles (herpes) and infected areas etc. Other forms are ozonized pure water (eg in dental treatments) and ozonized pure medical olive oil (for skin eruptions such as eczemas and conditions involving molds, funguses and lichens etc).

     O3 gas application via the rectal route is not as inconvenient or unpleasant as it sounds (medically, it is called insufflation). In fact, the patient feels absolutely nothing, as the O3 gas is directly absorbed by the sensitive intestinal membranes; in addition, the specially designed disposable tube is lubricated, which makes the method totally hygienic - and practical, as a patient can apply it himself/herself. This method is primarily indicated for inflammatory conditions of the intestinal tract, but is finding increasing use for general revitalization processes.

     Injection of ozone into the joints (ie via the intraarticular route); as the term implies, ozone is carefully injected - by a trained specialist - in the treatment of inflamed and painful joints (arthritis, recurrent arthrosis, general pathological stiffness). This is a must in many orthopedic practices.
In what diseases is ozone therapy usually applied ?

     A whole number of pathological conditions exist which can be influenced positively or even healed by ozone. This is a fact which has been confirmed by a wide series of scientific investigations and medical publications. As a rule, medical ozone is applied in addition to other therapeutic methods ie it belongs to the field of complementary medicine.

     For all patients, men and women, to know about the latest developments in ozone therapy – and as quickly as possible – a large number of therapists (in Europe) got together and founded the (legally registered) Medical Society for Ozone Application in Prevention and Therapy, formerly called the Medical Society for Ozone Therapy, with the aim of providing basic information to doctors/therapists and patients alike. This important information exchange function has increased over the years.

     As to how far your physician is able to inform and help you depends on the country you are in and the current status of medical ozone. All should know, however, that medical ozone, when properly and responsibly handled (and the correct indication has been established), is safe, practical, effective and – as a preventive at least - low in cost.

     Naturally, in spite of this , as with all other forms of medical treatment, no 100 % guarantee can be given that ozone therapy will alleviate the condition it has been applied for. Success will vary according to the patient's state of health, the frequency of ozone treatment, the doses and concentrations applied, and a number of other factors.

Circulatory disorders

     Arterial circulatory disorders, for which, among other symptoms, a feeling of coldness in the legs or pains after walking only short distances ("short cut" syndrome) are alarming signs, have been a classical indication for ozone therapy for over 40 years now. Its success has been confirmed by a large number of clinical trials. Ozone is applied as a complement to and in combination with other methods in classical and complementary medicine.

Regeneration and revitalisation

     Stress situations on the job or conditions of excessive mental and physical tension respond particularly well to O3 application. Its ability to activate red and white blood cell metabolism produces an improvement in general wellbeing, and brings about a general revitalisation. Professional sportsmen and -women profit greatly from this fact as well. Although ozone does not give its user a higher performance level, it does improve physical output during the endurance phase, ie just below maximum exertion. In addition, the regeneration phase is measureably shortened in endurance sports.

     The elderly patient. Prevention and therapy

     Elderly patients respond very well to medical ozone therapy, as it is here possible to make use of all its clinical advantages, such as that of making an improved supply of oxygen accessible to all tissues, mobilising the immune system, and activating the body's own supply of antioxidants and radical scavengers. Furthermore, we have its positive influence in cerebral circulatory disorders - a condition characterized by a general reduction in physical performance, insecurity in walking, and feelings of dizziness. In addition to other measures applied in complementary medicine, medical ozone is also used as a preventive, contributing to a marked increase in life quality.

Diseases of the eye

     Circulatory disturbances due to old age also affect the eye with atrophic and degenerative changes. For example, senile macular degeneration is well known, occurring at the center of the retina - the point where visual focus is at its sharpest. Its sequels are thus able to influence the optic nerve to varying degrees, producing what is called optic nerve atrophy. Results obtained from a clinical trial carried out at the University of Siena show, in addition to reports from practical applications, improvements in vision lasting for 6 to 8 months after ozone- autohaemotransfusion. Continuing the series of treatments can produce further improvement in visual performance or prevent it from worsening.

Malignant disease (cancer)

     Ozone-autohaemotransfusion can be applied with great profit in the form of an additional, biological, therapy in malignant conditions. We here make use of ozone's immunoactivating property, produced when it is applied at a low dose. Immune cells - such as lymphocytes, helper and suppressor cells, natural killer cells - are activated via biological reactions induced by ozone to respond by producing messenger proteins called cytokines to which, for example, the interferons belong. In fact, ozone makes the body produce increased quantities of its own interferons and interleukins. On reintroduction of the ozonized blood, a cascade of positive immune reactions are set off, also contributing to general resistance and wellbeing.

Fungal skin infections and infected skin lesions

     The fungicidal and bactericidal properties of ozone have been successfully in use for over 100 years in the treatment of water for drinking. They make medical ozone an effective therapeutic agent in combating persistent skin moulds and fungi, especially those of the feet with bacterial infections, fungal infections of the trunk or against fungal/mycotic infections of the mucous membranes.

Infected wounds

     The local treatment of infected wounds, such as may easily occur with open bed sores (decubitus), ulcers of the lower leg (ulcus cruris), diabetic gangrene or delayed/disturbed wound healing processes, belong to the classical application fields of medical ozone. We here primarily make use of its disinfectant, ie bactericidal and fungicidal, effects, to obtain a germ-free and clean wound. Once this has been achieved, we then apply lower doses of O3 gas to accelerate/improve wound healing.

Intestinal diseases: proctitis and colitis

     In the case of inflammatory intestinal processes, particularly during their early stages, the local application of ozone in the form of rectal O3 gas insufflation has been proved very useful. A series of 10 ozone applications is sufficient in most cases. Several such series are only necessary in about 10 % of the patients (from a proctitic clinical study on O3 involving 248 patients).

Viral diseases

Herpes simplex (facial herpes), herpes zoster (shingles)

     Both types of herpes are caused by viruses. Herpes of the lips (H. labialis), a frequently recurring condition and a highly unpleasant disease, can be treated very successfully with ozone in combination with other medical methods. In the case of herpes zoster or shingles, the complementary application of ozone is useful, both in the form of ozonized water compresses and O3 autohaemotransfusions.

Inflammatory processes of the liver

     Inflammatory diseases of the liver are counted among the classical indications for medical ozone. Whereas the treatment of hepatitis A (HVA = hepatitis virus A) is relatively unproblematic and produces complete healing, another form, hepatitis B (HVB = hepatitis virus B), frequently takes a chronic course. Here, in addition to classical medical treatment methods, we find that ozone autohaemotransfusion or the rectal insufflation of controlled ozone/oxygen gas quantities can be successful. This also applies to the treatment of hepatitis C which, due to an incubation period capable of lasting for a number of years, is generally not diagnosed as a liver disease until it has become a chronic condition.

Inflammatory and degenerative joint conditions

     When we divide inflammatory diseases of the joints into three phases, it is particularly stages 1 and 2, ie those not yet involving a severe bone deformation, that are responsive to medical ozone application. This applies to gonarthritis (inflammation of the knee joint) or the active arthritic form in knee and shoulder joints. Here, intraarticular ozone injections applied in addition to basic standard medical methods - in this case specific exercise therapy measures - are of great use. We here make full use of the antiinflammatory effects of ozone, in addition to its immunomodulatory properties and its ability to activate cartilage metabolism.

Arthritic/rheumatic conditions

Chronic polyarthritis

     The term arthritic/rheumatic conditions includes various painful diseases of the skeletal or muscular system, partly also involving functional restrictions. In general, the application of medical ozone can here be regarded as being a complementary measure only, combined with a basic classical method and corresponding physiotherapy. In the case of rheumatic arthritis (chronic polyarthritis), our experience shows that ozone autohaemotherapy is a very useful complementary form when given during the non-acute phases. Its immunomodulatory and antiinflammatory properties are here its basic principle of action. What should I know as a patient ?

     Before undergoing any form of ozone therapy, you should inform your doctor about any medication or special dietary measures you are taking or have been taking recently. You should only discontinue a regimen of this kind if your doctor advises you to do so. He or she should also know about allergies, inherited diseases or other complaints, and how they have been treated.

     In many countries, especially outside Europe, ozone therapy is not always covered by health insurance policies or employers' medical benefit schemes.. You should also try to find out where ozone units exist in your country, what trained specialists are available, and how much treatment costs. Most ozone applications are in series of up to 10 sessions, and a second or even third series may be necessary in some indications. Nevertheless, you should always remember that a little prevention can save a much more expensive full-scale treatment later on.

     Ozone therapy is low risk and usually applied as a complementary, additive or restorative method, ie in accompaniment of standard medical treatments. OZONE fingerprint

Natural occurrence

     Ozone is one of the most important gases in the stratosphere surrounding our planet (at a height of 10 - 50 kilometers / 6 - 30 miles). At a height of 20 - 30 kilometers (12 - 18 miles), its maximum concentration is 1 part O3 per 100,000 parts air (10 ppm) and thus much greater than at ground level (0.03 - 0.04 ppm).

The ozonosphere

     This protective layer of ozone acts as a filter against the otherwise highly destructive hard radiation in the form of ultraviolet (UV) energy coming from the sun, thus helping to maintain the biological balance on our planet Earth.

The ozone gap

     Due to a complicated process caused by industrial gases (containing FCKW`s and other halogens), the O3 in our protective ozonosphere is caused to break down. As there is then not enough ozone to act as a filter, this causes an increasingly large gap through which UV rays (which are capable of causing skin cancer and influencing genetic processes) can penetrate without hindrance.

Smog alarm

     However, much closer to the ground, as in large cities, ozone can be produced via waste or exhaust gases (eg from automobiles and factories) and the interaction of nitrogen oxide and sulfur oxides, and from oxygen through ultraviolet radiation.

     As we are able to measure O3 very accurately, it is therefore used and quoted as an indicator for environmental pollution, though it does not cause it.

    Maximum worksite concentration (MWC) The maximum permissible worksite concentration (MWC) for ozone is 200 µg/m³ or 0.1 ppm, and must not be exceeded during an 8 hours' working day and 40 hours per week, as ozone is capable of causing damage to the respiratory tract and mucous membranes. Values vary from one country to another and are not always obligatory (in Germany for example, this was reversed as a legal regulation in 1995 and is now a recommendation).

Technical ozone

     Technical ozone (TechO3) is a mixture of ozone and air prepared from atmospheric air which is used all over the world, principally for sterilizing water (city installations) and in chemical bleaching processes etc.

Medical ozone

     Contrary to technical ozone, the medical form is prepared from pure medical oxygen (MedO2) via silent electrical discharge for use as an ozone/oxygen mixture at an exact concentration and dosage.

     Its concentration ranges from 1 to 100 micrograms per milliliter (µg/ml), corresponding to an ozone/oxygen mixture at ratios between 0.05 % O3 to 99.95 % O2 and 5 % O3 to 95 % O2. As the ozone molecule is not stable, its medical form is always freshly prepared on site (in a special generator) for immediate use ie administration. (This is because, after about 1 hour, only half the original ozone is still present, the rest having decomposed to become oxygen again.)

Ozone therapy - a quick survey EFFECT MEDICAL USES
Activation of red blood cell metabolism
improved oxygen supply arterial circulatory disorders (peripheral and cerebral in particular);
Revitalization
Activation of immune cells
(the body releases is own vital cytokins, such as interferones and interleukins add. / complementary therapy in various kinds of cancer)
Revitalization;
General immune weakness.
Increase and activation of the body's own antioxidants and radical scavengers Inflammatory processes, eg arthritis, reactivated arthrosis, vascular conditions;
Age-related processes.

Where can I obtain information ?

Depending on what country you are in, your physician and/or pharmacist may know about medical ozone and its uses in therapy. However, basic information in all fields can be obtained from the:

Medical Society for Ozone Application
in Prevention and Therapy

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Oksijen ve Kanser

2010-06-10T08:45:00.000-07:00

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N C Med J. 1997 Mar-Apr;58(2):140-3.

Oxygen and cancer.
Dunn T.

Abstract
Tumor hypoxia results from multiple pathophysiologic interactions. Abnormalities in tumor vessel structure and function lead to decreased oxygen delivery relative to normal tissue. Furthermore, a relatively high rate of tumor cell proliferation increases oxygen consumption by tumor tissue. The net result of decreased oxygen supply and increased oxygen demand is hypoxia. Hypoxia makes tumors resistant to radiation and some chemotherapy, and it induces expression of growth factors, angiogenic factors, and cell cycle regulatory proteins that affect tumor phenotype. Recent attempts to make tumors more sensitive to radiation and chemotherapy by reducing hypoxia (by increasing tumor blood flow, the use of oxic gases, and blood substitutes) have been ineffective. Future research may be directed more toward decreasing oxygen consumption or actually exploiting the hypoxic environment to achieve a therapeutic benefit.

PMID: 9088144 [PubMed - indexed for MEDLINE]
http://www.ncbi.nlm.nih.gov/pubmed/9088144

Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.

2010-06-04T12:53:00.000-07:00

Bel ağrısında ozon tedavisi

Ağırlıklı olarak major otohematorapi amaçlı kullanılan medikal ozonun lokal uygulamalarına olan tıbbi ilgi gün geçtikçe artmaktadır. Artan bu ilgi literatürde yayımlanan randomize çalışmaların sayısı ile de paralellik göstermektedir. Alanının saygın dergisi Spine’da (Tübitak A grubu) yayımlanan yeni bir klinik çalışma etkileyici sonuçlar ortaya koydu (Intramuscular Oxygen-Ozone Therapy in the Treatment of Acute Back Pain With Lumbar Disc Herniation A Multicenter, Randomized, Double-Blind, Clinical Trial of Active and Simulated Lumbar Paravertebral Injection; SPINE, 2009: 34 (13); 1337–1344).

Disk hernisine bağlı akut bel ağrısı şikayeti ile başvuran 60 hasta üzerinde yapılan bu çift-kör çalışmanın sonuçlarına göre paravertebral bölgeye intramusküler olarak uygulanan ozon-oksijen enjeksiyonlarının hastaların %61’inde ağrıyı tamamen geçirdiği rapor edilmiştir. Anti-inflamatuar ilaçların verildiği kontrol grubunda iyileşme oranı %33’te kalmıştır.

İntradiskal ve intraforaminal ozon uygulamalarının akut bel ağrısında yararlı sonuçlar verdiği uzun zamandır bilinmektedir. Ancak görece invaziv olan bu yöntemlerle karşılaştırıldığında paravertebral kaslara ozon-oksijen karışımı enjeksiyonu uygulaması son derece kolay ve ucuz bir yöntemdir. Skopi ve ameliyathane şartları gerektirmemesi, yan etki profilinin çok düşük olması ve kolay uygulanabilmesi bu tedavi yöntemini öne çıkaran diğer unsurlardır.

Paravertebral intramusküler ozon enjeksiyonlarının etkin tedavi edici özelliği, disk hernisi vakalarının yaygınlığı düşünüldüğünde son derece önemli bir kazanım olarak durmaktadır. Ülkemizde bilinilirliği ve uygulama merkezleri hızla artan ozon tedavisinin disk hernilerine bağlı akut bel ağrısında da kullanılabileceğine dair yeterli bilimsel ve klinik kanıt oluşmuştur. Bel ağrısı ile uğraşan merkez ve kliniklerin hastalarına ozon tedavisini de önermeleri birkaç nedenle önem arz etmektedir.

Tedavinin maliyeti oldukça düşük ve uygulaması kolaydır. Minimal invaziv bir tedavi yöntemidir. Hastaların ağrı kesici ve NSAID kullanma ihtiyaçlarını anlamlı derecede düşürmektedir. Sadece kronik böbrek yetmezliği vakalarının %15’inden kontrolsüz ağrı kesici ve NSAID ilaç kullanımının sorumlu olduğu düşünüldüğünde, bu yeni yaklaşımın önemi daha da artmaktadır.

Kaynak:
Intramuscular Oxygen-Ozone Therapy in the Treatment of Acute Back Pain With Lumbar Disc Herniation A Multicenter, Randomized, Double-Blind, Clinical Trial of Active and Simulated Lumbar Paravertebral Injection; SPINE, 2009: 34 (13); 1337–1344

Kaynak: allturk.com

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2010-06-04T12:52:00.000-07:00

Ozon tedavisi ile zayıflama

Ozon tedavisi pek çok hastalıkta yararlı sonuçlar doğuran, yüzyılı aşkın süredir bilinen ve kullanılan yardımcı bir tedavi yöntemidir. Bu tedavi ile insan vücuduna hiçbir ilaç verilmez; vücutta mevcut mekanizmalar güçlü bir şekilde uyarılır. Ozon tedavisi ile elde uyarılan mekanizmalara göz atıldığında, vücuttan yağ kaybının artırılması ve selülitlerin ortadan kalkması gibi yararlar elde edilebileceği açıktır. Ancak hiç kimse sadece ozon tedavisi alarak kilolarından kurtulamaz. Kurtulamaz çünkü gerçek anlamda yağ kaybetmek için harcanan kalori miktarından daha az kalori almak gerekir. Bu basit ancak temel mantık ile rahatlıkla kilo verebilirsiniz. Pekiyi bu kurala uymak kolay mıdır? Tabii ki değildir; öyle olsaydı kilo vermek bu kadar büyük bir toplumsal sorun haline gelmezdi. Hemen her gün internette yayına başlayan yeni siteler ne oldukları, hangi mekanizma ile zayıflattıkları hatta içinde ne olduğu bile bilinmeyen bitkisel ürünlerle insanları garantili zayıflattıklarını iddia ediyorlar.

Vücudun sesini dinlemeyen hiçbir zayıflatma yöntemi çalışmaz

Bu nedenle ben bu iddiaların hiçbirine katılmıyorum. Hatta bitkisel bazı ürünlerle gerçekten zayıflayanlar olsa bile, bu etkinin kalıcı olmadığını biliyorum. Eğer vücudunuzu aldatırsanız kesinlikle sizden intikamını alacaktır. Sizin nefret ettiğiniz göbek, kalça vs. yağların nedeni sizsiniz. Nasıl onları vücudunuza sokarken onun sesini dinlemediniz, ihtiyacınız olmadığı halde aşırı kalorili beslendiniz; şimdi sıra vücudunuzda. O da yağlarını size kolayca vermeyecektir. Çünkü yağ dokusu olarak kilo alan insanların metabolizmaları bozulur. Başta karbonhidrat (şeker) metabolizması olmak üzere dengeler alt üst olur. Kilo alan kişi bunu fark edemeyebilir. Ancak glikoz-insülin ilişkisi hemen tüm şişmanlarda bir şekilde bozuktur. Bu bozukluğun önemli bir kriteri atıştırma ya da açlık krizleridir. Öğünler arasında ortaya çıkan halsizlik ve yorgunluk ile karakterize bu durum aslında hiç de enerjiye ihtiyacınızın olmadığı dönemlerde ortaya çıkar. Çünkü kısa bir süre önce ana öğünlerden bir tanesini (öğlen veya akşam) yemişsinizdir.

Metabolizmanızı önemsemelisiniz

Ancak bozulmuş metabolizmanız kan şekerini sağlıklı bireylerdeki gibi düzenleyemediği için şişmanların çoğu öğünlerden sonra kan şekerinin yükselmesi, buna yanıt olarak biraz fazla insülin salgılanması ve ardından kan şekerinin düşmesi şeklinde ortaya çıkan bir döngüye sahiptirler. İşte kan şekerinin düştüğü bu dönemde atıştırma krizleri ortaya çıkar. Bu dengesizliği düzeltmedikten sonra dilediğiniz kadar destek tedavi görebilirsiniz; sonucu çok fazla değiştiremeyeceğiniz açıktır. Bu bölümde anlatılan ve başka nedenlerle aslında çoğu şişman kişi diyabet değilse bile pre-diyabetiktir. Yani gelecekte büyük olasılıkla şeker hastası olacaktır. Bu kişilerin sabah açlık kan şekerlerinin normal olmasının anlamı büyük değildir. Çünkü bizleri asıl hasta eden post-prandial dediğimiz yemeklerden sonra ortaya çıkan yüksek kan şekeri ve onu takip eden olaylardır.

Altın kurallar

Böylece metabolizmanızın sesini dinlemek durumundasınız; bu sese kulak verdiğinizde üç altın kural duyarsınız. Birinci altın kural “makul, mantıklı ve yaşam tarzına dönüştürülebilecek beslenme alışkanlığı”, ikinci altın kural “makul, mantıklı ve yaşam tarzına dönüştürülebilecek hareket alışkanlığı” ve üçüncü altın kural ise “karbonhidrat krizlerinin önlenmesi”dir. Gümüş ve bronz kurallara geçmenin pratikte anlamı yoktur; zira pek çok insan bu üç kurala uyum sağladığında diğerleri çok daha kolay uygulanabilir prensiplerdir.

İşte bu üç altın kurala uyumunuzu kolaylaştıran ozon terapi zayıflamak isteyenleri çok mutlu edecek sonuçlar doğurabilir. Ozon tedavisi zayıflamaya kararlı ancak diyet yapmakta zorlanan, harekete isteksiz ve açlık krizleri yaşayan kişilerde etkileyici metabolik değişimlere neden olur. Diyet yapmakta zorlanan insanlardaki en temel sorunlardan bir tanesi diğer iki kural konusunda sıkıntı yaşamalarıdır. Bu insanlar diyetin yanında bir de hareket programı takip etmek istemezler. Hatta çoğu kişi vücudun çalışma prensiplerine tamamen ters olarak akupunktur gibi iştahı merkezi olarak kesen yöntemleri tercih ederler. Sonuç genellikle kısa vadede memnuniyet verici, uzun vadede ise (genellikle üzerinden bir sonbahar-kış dönemi geçtiğinde) faciadır. Oysa uygun bir diyet ile beraber hareket miktarınızı artırdığınız sürece kan şekeriniz düzenlenir, insülinin gücü artar ve açlık krizlerinin şiddeti azalır. Açlık krizlerinin şiddeti azaldıkça “atıştırma” ve “kaçak” miktarı azalır.

Ozon tedavisi zayıflamanıza yardımcı olur

Ozon tedavisi, bireylerin metabolik hızını artırmanın en iyi yollarından bir tanesidir. Çoğu kişide kan şekerinin düzenlenmesine destek olur ve açlık krizlerini önler. Organizmanın yağlardan enerji üretmesi için gerekli hücresel düzenlemeleri kuvvetlendirir. Başta cilt olmak üzere, beyin ve kasların kan dolaşımını artırarak vücudun daha iyi oksijenlenmesine, enerjiye daha kolay ulaşmasına yardımcı olur. Pek çok bilim insanı asıl doyması gerekenin midemiz değil beynimiz ve algılarımız olduğunu kabul eder. Ozon tedavisi ile desteklenen metabolizma sonucu beynimiz ve algılarımız enerji krizine girmez, yağların enerji amaçlı kullanımı artar ve hem diyete hem de egzersize uyum desteklenir. Birkaç seans ozon tedavisinden sonra ortaya çıkan “artmış iyilik ve zindelik hali” vücut tarafından son derece olumlu algılanır. Böylece birbirini pozitif olarak etkileyen, “metabolizmanın hızlanması” “yağlardan elde edilen enerji oranının artması” “artmış zindelik ve iyilik hali” “beynin ve algıların bu durumu onaylaması” süreci kazan-kazan modeli olarak ifade edilen ve kilo vermeyi adeta eğlenceye döndüren bir döngü oluşturur.

Bu açıklamalardan sonra ozon tedavisinin zayıflamanıza paralel olarak cilt ve cilt altı dolaşımını düzenleyerek selülit sorununu da kolaylıkla çözeceğini söyleyebiliriz.

Doç.Dr. Ahmet KORKMAZ

Kaynak: allturk.com

Ozone Therapy on Cerebral Blood Flow: A Preliminary Report

2010-04-14T07:39:00.000-07:00

Ozone Therapy on Cerebral Blood Flow: A Preliminary ReportBernardino Clavo1,2,7, Luis Catalá3,7, Juan L. Pérez2,4,7, Victor Rodríguez5 and
Francisco Robaina2,6,7
Departments of 1Radiation Oncology and 2Research Unit, 3Radiology, 4Medical Physics and 6Chronic Pain Unit,
Dr Negrín Hospital, 5La Paterna Medical Center and 7Canary Islands Institute for Cancer Research (ICIC),
Las Palmas (Canary Islands), Spain
Ozone therapy is currently being used in the treatment of ischemic disorders, but the underlying mechanisms
that result in successful treatment are not well known. This study assesses the effect of ozone
therapy on the blood flow in the middle cerebral and common carotid arteries. Seven subjects were
recruited for the therapy that was performed by transfusing ozone-enriched autologous blood on 3 alternate
days over 1 week. Blood flow quantification in the common carotid artery (n 14) was performed
using color Doppler. Systolic and diastolic velocities in the middle cerebral artery (n 14) were estimated
using transcranial Doppler. Ultrasound assessments were conducted at the following three time
points: 1) basal (before ozone therapy), 2) after session #3 and 3) 1 week after session #3. The common
carotid blood flow had increased by 75% in relation to the baseline after session #3 (P 0.001) and by
29% 1 week later (P 0.039). In the middle cerebral artery, the systolic velocity had increased by 22%
after session #3 (P 0.001) and by 15% 1 week later (P 0.035), whereas the diastolic velocity had
increased by 33% after session #3 (P 0.001) and by 18% 1 week later (P 0.023). This preliminary
Doppler study supports the clinical experience of achieving improvement by using ozone therapy in
peripheral ischemic syndromes. Its potential use as a complementary treatment in cerebral low perfusion
syndromes merits further clinical evaluation.
Keywords: color Doppler – ischemia – low perfusion – transcranial Doppler
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access
version of this article provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original
place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a
derivative work this must be clearly indicated.
For reprints and all correspondence: Bernardino Clavo, MD, Department of
Radiation Oncology and Research Unit, Dr Negrín Hospital, C/ Barranco la
Ballena s/n, 35020 Las Palmas (Canary Islands), Spain. Fax: 34 928
449127; Tel: 34 928 450284. E-mail: bernardinoclavo@terra.es
involved in the investigation. The study included 5 males and
2 females with a mean age of 58 years (range, 34–78).
Informed consent was obtained from all the participants prior
to inclusion in the study. The study was approved by the
Institutional Ethical Committee. Table 1 summarizes the
details of the subjects that participated in this study.
Ozone Therapy
Ozone therapy was administered by autologous blood transfusion
on 3 alternate days over 1 week. The procedure involved
the collection of 200 ml venous blood into a blood bag containing
heparin (25 IU/ml) and CaCl2 (5 mM). The O3/O2 gas
mixture was prepared from clinical-grade O2 using the OZON
2000 medical device (Zotzmann Stahl GmbH, Plüderhausen,
Germany). The blood was mixed with 200 ml of O3/O2 gas
mixture at a concentration of 60 g/ml in a sterile single-use
300 ml container. Subsequently, the blood was slowly
re-introduced into the patient via the antecubital vein, after
being passed through a sterile 0.20 m filter. The blood
remained outside the body for approximately 15–30 min, and
no adverse reactions were observed.
Doppler studies were conducted on the following three
occasions: 1) before session #1; 2) after session #3; and 3)
1 week after session #3.
Transcranial Doppler Velocimetry
Systolic and diastolic velocities (in cm/s) were measured in the
MCA by the transtemporal approach using a transcranial
Doppler (TCD) with a 2 MHz probe from an Angiodine-2
Fluo-Link 300® device. The patient was alert, relaxed and
seated when the absence of stenoses was confirmed. The
Doppler insonation angle was 60 .
Common Carotid Blood Flow Quantification
Blood flow quantification of CCA was performed using
a color Doppler, Philips Ultrasound P-800 unit®, with timedomain
processing. This technique simultaneously evaluates
the velocity and the vessel diameter, and the data is presented
in terms of ml/min. The usefulness and validity of this technique
has been previously described (4,5). The patient was
alert, relaxed and in the supine position when the absence of
significant stenoses in the extracranial carotid arteries was
confirmed. A 7.5 MHz linear high-definition probe with a
Doppler insonation angle of 60 was used. We obtained
information regarding the volume of blood flow (in ml/min) in
both CCAs at 2 cm prior to the carotid bifurcation.
All ultrasound studies were performed bilaterally by the
same radiologist in order to minimize interobserver variability
(6). When an optimal image of stable blood flow was obtained,
recordings over at least three cardiac cycles were made. This
was repeated at least three times in order to preclude operatorinduced
or technical inaccuracies. The median values that
were obtained were used in the statistical analyses.
Neither blood pressure nor hemoglobin levels were measured.
Statistical Analysis
The SPSS 7.0 for Windows software package (SPSS-Ibérica,
Madrid, Spain) was used throughout the study. The normality
of distribution of data was assessed by the Kolmogorov–
Smirnov test. Two-sided tests were applied. The data are
expressed as mean SD. The paired t-test was used to compare
differences between the baseline and the two time-point
measurements following the ozone therapy. Linear correlation
was assessed by the Pearson’s r test. The differences were
considered to be significant when P 0.05.
316 Ozone therapy on cerebral blood flow
Table 1. Patients and control subjects included in the study
Patient Age (years) Characteristics
#1 67 aComplementary treatment during radiochemotherapy for advanced carcinoma of hypopharynx.
bArterial hypertension under drug treatment and hyperglycemia under dietary treatment.
#2 74 aComplementary treatment during radiochemotherapy for advanced carcinoma of base of tongue.
bChronic obstructive bronchitis (COB) under treatment with bronchodilator inhalers.
#3 63 aComplementary treatment during radiochemotherapy for advanced carcinoma of supraglottis.
bHyperuricemia treated with allopurinol. Multiple sclerosis treated with baclofen.
#4 51 aRadiation-induced necrosis of thyroid cartilage (radiotherapy was administered for carcinoma of glottis several years ago).
bTreatment with corticosteroids.
#5 78 aChronic ulceration with calcaneous exposure and transplant failure.
bInsulin-dependent diabetes, arterial hypertension under drug treatment. Stroke 1 year ago. Duodenal ulcers.
#6 43 Healthy subject.
#7 34 Healthy subject.
aReason for ozone therapy. bConcomitant diseases or treatments (no changes were made in the medications during the period of Doppler evaluation). The study
was planned with three ozone therapy sessions to evaluate the initial effects under the same conditions. Patient #1, #2 and #3 (cancer patients) were required to
commence their scheduled radiochemotherapy after session #3; therefore, ethical considerations precluded delay in the cancer treatment. Ozone therapy was
continued during the radiochemotherapy; however, radiotherapy of the cervical and carotid areas altered the subsequent Doppler evaluations. Patient #4 suffered
from hemorrhage of the larynx. Ozone therapy was stopped after session #3 to enable the patient to undergo surgery. The usual complications associated with the
surgical treatment of this radiation-induced necrosis were absent. Patient #5 who suffered from several vascular diseases was treated with systemic and local
ozone therapy for a chronic wound. Patient #6 and #7 (healthy subjects recruited from among the hospital staff) also received 3 sessions of ozone therapy to
evaluate the Doppler Effect. Further sessions were neither scheduled nor administered.
eCAM 2004;1(3) 317
Results
Transcranial Doppler Velocimetry
The baseline systolic velocity in MCA was 90.9 6.1 cm/s.
After session #3, it increased to 111 7.3 cm/s (increase 22%,
P 0.001), and 1 week later, it was 104.3 8 cm/s (increase
15%, P 0.035). The baseline diastolic velocity in MCA was
41.1 4.4 cm/s. After session #3, it increased to 54.6 4.6 cm/s
(increase 33%, P 0.001), and 1 week later, it was 48.6
5 cm/s (increase 18%, P 0.023) (Fig. 1).
Common Carotid Blood Flow Quantification
The baseline CCA blood flow was 233 19 ml/min. After
session #3, it increased to 407 38 ml/min (increase 75%,
P 0.001), and 1 week later, it was 301 22 ml/min
(increase 29%, P 0.039) (Fig. 2).
The baseline CCA blood flow directly correlated with the
MCA diastolic velocity (r 0.557; P 0.039) and inversely
correlated with age (r 0.825; P 0.001) (Fig. 3). The percentage
increase in CCA blood flow 1 week after session #3
was directly correlated with age (r 0.735; P 0.004)
(Fig. 4) and inversely correlated with the initial values of the
CCA blood flow (r 0.691; P 0.009). In older patients, the
increase in CCA blood flow was higher and that in basal perfusion
was lower (Fig. 5) (Note: in Figs 4 and 5, the Doppler
data for the left arteries of one patient 1 week after session #3
were not available due to technical reasons).
Discussion
Although biomedical applications of ozone therapy can be
traced back to the end of the 19th century, numerous aspects of
the effects of the therapy remain unexplored.
The airways are precluded in this therapy, which uses ozoneenriched
autologous blood transfusion; therefore, lung toxicity
resulting from oxidative stress is avoided. Ozone, per se, does
not enter the organism; the effects that are observed are mediated
0
20
40
60
80
100
120
pre-1 post-3 1 week
* *
0
10
20
30
40
50
60
70
pre-1 post-3 1 week
*
*
MCA diastolic velocity - cm/s
MCA systolic velocity - cm/s
Figure 1. Transcranial Doppler during ozone therapy. Left. Diastolic velocity (in cm/s) in the middle cerebral artery (MCA) increased by 33% at the end of session
#3 (P 0.001), and an 18% increase persisted for 1 week after session #3 (P 0.023). Right. Systolic velocity in MCA increased by 22% at the end of session #3
(P 0.001), and a 15% increase persisted for 1 week after session #3 (P 0.035). The error bars are the 95% confidence intervals. Significant differences
(P 0.05) are indicated with an asterisk (*).
0
50
100
150
200
250
300
350
400
450
pre-1 post-3 1 week
*
*
CCA blood flow - ml / min
Figure 2. Carotid blood flow during ozone therapy. Blood flow quantification
(in ml/min) in the common carotid artery (CCA) increased by 75% at the end
of session #3 (P 0.001), and a 29% increase persisted for 1 week after
session #3 (P 0.039). The error bars are the 95% confidence intervals.
Significant differences (P 0.05) are indicated with an asterisk (*).
0
10
20
30
40
50
60
70
80
90
100 150 200 250 300 350
Basal CCA blood flow - ml/min
Age
Figure 3. Relationship between baseline blood flow and age. Baseline values
of the common carotid artery (CCA) blood flow were inversely correlated with
the age of the patients (r 0.825; P 0.001). A lower blood flow was
observed in older patients.
by the rapid oxidation of certain substances in the blood in the
transfusion recipient. In appropriate concentrations, this can
up-regulate the synthesis of antioxidants in blood (7). This
property has been very actively investigated with respect to the
protection against free radical damage associated with heart
(8), kidney (9) and liver (10) disorders. The mechanisms
proposed to explain the vascular effects include the liberation
of vasoactive substance as well as the improvement in erythrocyte
flexibility and blood rheology (1,11,12).
Several studies that included control subjects have indicated
that when ozone-free oxygen is used, the beneficial biochemical
(7,10) and rheological (1) responses are not observed. The
changes in the MCA and/or CCA blood flow occurring during
ozone therapy were assessed in the present study that did not
include non-ozonized blood transfusion and each patient was
his/her own control.
As indicated by the CCA measurements, the increase in
diastolic velocity in the MCA is compatible with a decrease
in vascular resistance, a rheological improvement (1,12) and
an overall increase in blood flow. The inverse correlation
between the percentage increase in CCA blood flow and the
initial values is compatible with a microvascular redistribution
resulting in better oxygenation in tissues with poor blood supply.
This was tentatively demonstrated in our previous studies
by the direct measurement of muscle and tumor oxygenation
using polarographic electrodes (13,14).
These rheological and vascular effects suggest that coadjuvant
ozone therapy could decrease the vasoconstriction that is secondary
to hyperoxia. Techniques such as carbogen breathing or
hyperbaric chambers are used to increase the amount of O2 dissolved
in arterial blood. However, when prolonged for 15–30
min, these therapies can lead to an increase in peripheral vascular
resistance along with a generalized vasoconstriction in most
organs (15). Decreased cerebral blood flow secondary to hyperoxia
has indeed been documented in humans by transcranial
Doppler (16) and magnetic resonance (17) studies.
The above-mentioned effects of ozone therapy and data from
the present study, especially the potentially greater effect in
older patients or in those with lower initial blood flow, augur
well for its use in cerebral low perfusion syndromes and stroke.
This is further supported by the clinical experience gained in a
study that assessed 150 patients with ischemic cerebrovascular
disease treated with prolonged ozone therapy (18).
The present Doppler study was planned with only three
ozone therapy sessions for several reasons. Firstly, we wanted
to evaluate the effect of ozone therapy and to observe whether
the effect could be maintained for a prolonged period, which
has been suggested by the clinical experience gained from its
use in sessions widely separated over several days. Hence, we
decided to perform the third session approximately 1 week
later without any intervening sessions. Secondly, we wanted to
administer the same number of sessions to all the patients in
the study. However, some of them were cancer patients who
needed to commence their scheduled radiochemotherapy.
Therefore, in order to avoid interference with the scheduled
radiochemotherapy, the present ozone study was performed
during the period when oncologic staging and planning of the
radiotherapy were carried out. Hence, the number of ozone
therapy sessions for Doppler evaluation was less than that
considered necessary for a full-fledged ozone therapy, which
usually lasts for several weeks or even months. The Doppler
Effect after several additional sessions could indeed be higher
than that currently observed. Data on the optimal separation
between the ozone therapy sessions are not currently available.
Further, the schedule could vary depending on the desired
clinical effect (antioxidant, enhancing the immune or vascular
system, etc.). Nevertheless, the current study supports the
clinical experience gained in the treatment of vascular disorders,
318 Ozone therapy on cerebral blood flow
0
50
100
150
200
250
300
350
0 10 20 30 40 50 60 70 80
Age
% increase in CCA blood flow
1 week after ozone therapy
Figure 4. Relationship between age and blood flow increase post-ozone
therapy. The percentage increase in CCA blood flow 1 week after session #3
was directly correlated with age (r 0.735; P 0.004). A higher increase
was observed after ozone therapy in older patients.
0
50
100
150
200
250
300
350
100 150 200 250 300 350
Basal CCA blood flow - ml/min
% increase in CCA blood flow
1 week after ozone therapy
Figure 5. Relationship between the baseline blood flow and its increase post
ozone therapy. The correlation in CCA blood flow between baseline values
and the percentage increase 1 week after session #3 was highly significant
(r 0.691; P 0.009), i.e., there is a higher percentage increase in CCA
corresponding to a lower initial blood flow. Note: the percentages under 100%
indicate a decrease in blood flow at this time point.
eCAM 2004;1(3) 319
employing widely separated sessions over extended periods
(2,3). Two or three applications per week appear to be sufficient
in providing significant vascular improvement. However,
changes observed over a mere 1 or 2 weeks are usually not
sufficient to improve chronic clinical conditions. The current
findings regarding a residual effect, which is still significantly
elevated over baseline 1 week after the last session, support
our postulation that one or two additional sessions per week
can be effective during the initial maintenance period. The
mode and timing of administration of additional sessions over
a period of months need to be explored for the optimization of
the sessions.
In the course of this study, our hospital facilities were transferred
to a different location in our city, and we were unable to
conduct further Doppler studies using the same equipment.
Therefore, we decided to increase the study sample by including
two healthy subjects from our hospital. We could not evaluate
the differences between patients and healthy subjects due to
the scarcity of patients. Only patient #5 had suffered a
CVA/stroke that may modify the Doppler evaluation in the
carotid and middle cerebral arteries. However, patients with
localized tumors do not appear to have a systemic vascular
alteration or an altered vascular response. Therefore, we
assumed that the effect observed in these arteries is a general
effect, which does not differ from that observed in the healthy
subjects or the patients that were studied.
Further studies, which include new technologies such as
interstitial multichannel laser Doppler used to quantify fluctuations
in microvascular perfusion during ozone therapy, are in
progress in order to ascertain some of the remaining doubts
regarding the efficacy of ozone therapy.
In conclusion, this preliminary Doppler study demonstrates,
albeit in a small number of subjects, that ozone therapy
increases blood flow in CCA and MCA with a prolonged
effect such that it can be very easily assessed by TCD and
carotid ultrasound. These data support the clinical experience
of achieving improvement using ozone therapy in peripheral
ischemic syndromes. Its potential use as a complementary
treatment in cerebral low perfusion syndromes warrants
further clinical investigation.
Acknowledgements
The study was supported in part by a grant (FUNCIS 98–31)
from the Health and Research Foundation of the Autonomous
Government of the Canary Islands, Spain.
We wish to thank Dr R. Reyes (Department of Interventional
and Vascular Radiology) and Dr G. Rovira-Dupláa (Ozone
therapy Unit of the Quirón Clinic, Barcelona, Spain) for their
valuable advice in conducting this study. We also thank
R. Martin-Oliva (Head of Department of Medical Physics) and
Dr M. A. Hernández (Head of Department of Radiation
Oncology) for their administrative and clinical support with
the equipment. Editorial assistance was provided by
Dr Peter R. Turner, t-SciMed, Reus, Spain.
Conflict of Interest
The study was supported in part by a grant (FUNCIS 98–31)
from the Health and Research Foundation of the Autonomous
Government of the Canary Islands, Spain.
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Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.

Beyin TÜMÖRLERİ

2010-02-05T04:05:00.000-08:00

What is Brain Cancer?

The brain and spinal column make up the central nervous system (CNS), where all vital functions of the body are controlled. When tumors arise in the central nervous system, they are especially problematic because a persons thought processes and movements can be affected. These tumors can also be difficult to treat because the tissues surrounding a tumor that may be affected by surgery or radiation may play a vital role in functioning.

There are two broad types of cancers occurring within this system. Primary tumors originate in the central nervous system, whereas secondary tumors migrate from cancers located elsewhere in the body, such as breast cancers. Secondary, or metastatic, brain tumors, are more common than primary brain cancers. This section focuses on primary brain cancers.

What is the brain?

Together, the brain and spinal cord form the central nervous system. This complex system is part of everything we do. It controls the things we choose to do,like walk and talk,and the things our body does automatically,like breathe and digest food. The central nervous system is also involved with our senses; seeing, hearing, touching, tasting, and smelling, as well as our emotions, thoughts, and memory.

The brain is a soft, spongy mass of nerve cells and supportive tissue. It has three major parts: the cerebrum, the cerebellum, and the brain stem. The parts work together, but each has special functions.

The brain is composed of:

A. The cerebrum, which is divided into two cerebral hemispheres. The cerebrum is the largest part of the brain and is divided into lobes where discrete functions occur. Higher reasoning takes place in the cerebrum.

B. The cerebellum, or little brain, located beneath the cerebrum. The cerebellum controls coordination and balance.

C. The brain stem, which is the lowest portion of the brain and connects to the spinal cord, controls involuntary functions essential for life, such as the beating of the heart and breathing.

D. The meninges, membranes that surround and protect the brain and spinal cord. There are three meninges.

The types of primary brain cancers are classified according to the type of cells from which they originate. Oncologists describe the tumor based on its characteristics. For example, a noninfiltrating tumor can be expected to grow slowly and not invade surrounding structures. A well-differentiated tumor is also slow growing, but has the potential to be invasive. Anaplastic tumors are generally more aggressive.

Gliomas - Most brain tumors are gliomas, which originate in the glial cells (the supportive cells of the nervous system). Gliomas can be described as low-grade (slow-growing); intermediate-grade (more aggressive); or high-grade (very aggressive).

There are many different types of gliomas:

E. Astrocytoma, the most common type of glioma, which usually begin in cells called astrocytes within the cerebrum, or the cerebellum. Glioblastoma multiforme is a form of very aggressive astrocytoma.

F. Oligodendroglioma, a tumor that develops from oligodendrocytes. These cells are responsible for producing the myelin that surrounds nerves.

G. Brain stem glioma, which begins in the glial cells in the brain stem.

H. Ependymoma, which begins in the ependyma, the cells that line the passageways in the brain where cerebrospinal fluid is made and stored.

I. Mixed tumors, which are composed of more than one of the glial cell types.

Nonglial tumors include:

J. Acoustic schwannoma, which occurs in the vestibular nerve.

K. Craniopharyngioma, which begins near the pituitary gland.

L. Meningiomas, which originate in the meninges surrounding the brain and spinal column. Even though these tumors are generally benign, they may cause significant symptoms as they grow and press on the brain or spinal cord.

M. Medulloblastoma, which arises from granular cells in the cerebellum.

N. Primary CNS lymphoma.

O. The pineal and pituitary glands, located near the base of the brain, can also be the source of tumors.

Since brain and spinal cord tumors behave somewhat differently than tumors arising in other parts of the body, they are often referred to as low and high grade, rather than benign and malignant. Oncologists assign the terms low, intermediate, or high grade to a patient’s tumor based on parameters that predict how quickly the tumor can grow and its potential to spread to other parts of the brain.

Treating brain and spinal cord tumors can be difficult. The blood-brain barrier, which normally serves to protect the brain and spinal cord from damaging chemicals getting into those structures, also keeps out many types of potentially beneficial chemotherapy drugs. Surgery can be difficult if the tumor is near a delicate portion of the brain or spinal cord and radiation therapy can damage healthy tissue. However, research in the past two decades has improved the survival rates of patients with brain tumors. More refined surgeries, a better understanding of what types of tumors respond to chemotherapy, and precise delivery of radiation have resulted in longer life span and better quality of life for people with brain cancers.

As we well know, there are many kinds of cancer; unfortunately they all come about because of the out-of-control growth of abnormal cells.

Healthy Cells vs. Cancer Cells

Healthy cells are like a cat. They need structure to determine the size of bones and shape of the body, tail and whiskers. The DNA in genes and chromosomes determine this. They need energy to play and prowl and sustain life. This is derived from chemicals in food. Cats need a system to deliver chemicals (food nutrients like amino acids, carbohydrates, fats, vitamins and minerals) to all parts of their body. These are the blood vessels. Growth factors take a kitten into a lazy old cat, all the while helping it to function normally.

The body and its cells are mostly made up of protein. The building blocks of proteins are substances called amino acids that in the form of enzymes and hormones literally control every chemical reaction within the cells. When these are modified, different messages are sent to a complex control system that can alter their function. There are twenty different kinds of amino acids that are essential to life. Twelve of these can be synthesized within the body however; eight must be supplied by the daily diet.

Structure

Normal Cells

Cancer Cells

DNA in genes and chromosomes go about their business in a normal way.

Cancer cells develop a different DNA or gene structure or acquire abnormal numbers of chromosomes.

Cells divide in an orderly way to produce more cells only when the body needs them.

Cells continue to be created without control or order. If not needed, a mass of tissue is formed which is called a tumor.

Energy

Normal Cells

Cancer Cells

Cells derive 70% of their energy from a system called the “Krebs Cycle.”

Cells have a defective “Krebs Cycle” and derive little or no energy from it.

Cells derive only 20% of their energy from a system called “Glycolosis.”

Cancer cells derive almost all their energy from “Glycolosis.”

Cells derive most of their energy with the use of oxygen.

Cells derive most of their energy in the absence of oxygen.

Blood Vessels

Normal Cells

Cancer Cells

Cells have a built-in blood vessel system.

Cells do not have a built-in blood vessel system. They require more of certain amino acids to grow.

Growth Factors

Normal Cells

Cancer Cells

While similar to cancer cells, the amount of them is more in balance to produce a more normal level of activity.

These cells have over produced, require more chemicals (food) and are over active.

Functions

Normal Cells

Cancer Cells

The enzymes and hormones go about business in a normal balanced manner.

The enzymes and hormones are either over active or under active.

Tumors are Different

Benign

Malignant

Benign tumors are not cancerous. They do not invade nearby tissues nor spread to other parts of the body. They can be removed and are not a threat to life.

Malignant tumors are cancerous. They can invade and damage nearby tissues and organs and they can break away and enter the blood stream to form new tumors in other parts of the body. The spread of cancer is called metastasis.

What causes brain tumors?

The causes of brain tumors are not known. Researchers are trying to solve this problem. The more they can find out about the causes of brain tumors, the better the chances of finding ways to prevent them.

Doctors cannot explain why one person gets a brain tumor and another doesn't, but they do know that no one can "catch" a brain tumor from another person. Brain tumors are not contagious.

Although brain tumors can occur at any age, studies show that they are most common in two age groups. The first group is children 3 to 12 years old; the second is adults 40 to 70 years old.

By studying large numbers of patients, researchers have found certain risk factors that increase a person's chance of developing a brain tumor. People with these risk factors have a higher-than-average risk of getting a brain tumor. For example, studies show that some types of brain tumors are more frequent among workers in certain industries, such as oil refining, rubber manufacturing, and drug manufacturing. Other studies have shown that chemists and embalmers have a higher incidence of brain tumors. Researchers also are looking at exposure to viruses as a possible cause. Because brain tumors sometimes occur in several members of the same family, researchers are studying families with a history of brain tumors to see whether heredity is a cause. At this time, scientists do not believe that head injuries cause brain tumors to develop.

In most cases, patients with a brain tumor have no clear risk factors. The disease is probably the result of several factors acting together.

What are primary brain tumors?

Tumors that begin in the brain tissue are known as primary brain tumors. Secondary tumors are those that develop when cancer spreads to the brain. Primary brain tumors are classified by the type of tissue in which they begin. The most common brain tumors are gliomas, which begin in the glial (supportive) tissue. There are several types of gliomas:

Astrocytomas arise from small, star-shaped cells called astrocytes. They may grow anywhere in the brain or spinal cord. In adults, astrocytomas most often arise in the cerebrum. In children, they occur in the brain stem, the cerebrum, and the cerebellum. A grade III astrocytoma is sometimes called anaplastic astrocytoma. A grade IV astrocytoma is usually called glioblastoma multiforme.

Brain stem gliomas occur in the lowest, stemlike part of the brain. The brain stem controls many vital functions. Tumors in this area generally cannot be removed. Most brain stem gliomas are high-grade astrocytomas.

Ependymomas usually develop in the lining of the ventricles. They also may occur in the spinal cord. Although these tumors can develop at any age, they are most common in childhood and adolescence.

Oligodendrogliomas arise in the cells that produce myelin, the fatty covering that protects nerves. These tumors usually arise in the cerebrum. They grow slowly and usually do not spread into surrounding brain tissue. Oligodendrogliomas are rare. They occur most often in middle- aged adults but have been found in people of all ages.

There are other types of brain tumors that do not begin in glial tissue. Some of the most common are described below:

Medulloblastomas were once thought to develop from glial cells. However, recent research suggests that these tumors develop from primitive (developing) nerve cells that normally do not remain in the body after birth. For this reason, medulloblastomas are sometimes called primitive neuroectodermal tumors (PNET). Most medulloblastomas arise in the cerebellum; however, they may occur in other areas as well. These tumors occur most often in children and are more common in boys than in girls.

Meningiomas grow from the meninges. They are usually benign. Because these tumors grow very slowly, the brain may be able to adjust to their presence; meningiomas often grow quite large before they cause symptoms. They occur most often in women between 30 and 50 years of age.

Schwannomas are benign tumors that begin in Schwann cells, which produce the myelin that protects the acoustic nerve, the nerve of hearing. Acoustic neuromas are a type of schwannoma. They occur mainly in adults. These tumors affect women twice as often as men.

Craniopharyngiomas develop in the region of the pituitary gland near the hypothalamus. They are usually benign; however, they are sometimes considered malignant because they can press on or damage the hypothalamus and affect vital functions. These tumors occur most often in children and adolescents.

Germ cell tumors arise from primitive (developing) sex cells, or germ cells. The most frequent type of germ cell tumor in the brain is the germinoma.

Pineal region tumors occur in or around the pineal gland, a tiny organ near the center of the brain. The tumor can be slow growing (pineocytoma) or fast growing (pineoblastoma). The pineal region is very difficult to reach, and these tumors often cannot be removed.

What are secondary brain tumors?

Metastasis is the spread of cancer. Cancer that begins in other parts of the body may spread to the brain and cause secondary tumors. These tumors are not the same as primary brain tumors. Cancer that spreads to the brain is the same disease and has the same name as the original (primary) cancer. For example, if lung cancer spreads to the brain, the disease is called metastatic lung cancer because the cells in the secondary tumor resemble abnormal lung cells, not abnormal brain cells.

Treatment for secondary brain tumors depends on where the cancer started and the extent of the spread, as well as other factors, including the patient's age, general health, and response to previous treatment.

What are adult brain tumors?

Adult brain tumors are diseases in which cancer (malignant) cells begin to grow in the tissues of the brain. The brain controls memory and learning, senses (hearing, sight, smell, taste, and touch), and emotion. It also controls other parts of the body, including muscles, organs, and blood vessels. Tumors that start in the brain are called primary brain tumors.

What are metastatic brain tumors?

Often, tumors found in the brain have started somewhere else in the body and spread (metastasized) to the brain. These are called metastatic brain tumors.

What are the symptoms of an adult brain tumor?

A doctor should be seen if the following symptoms appear:

Frequent headaches.

Vomiting.

Loss of appetite.

Changes in mood and personality.

Changes in ability to think and learn.

Seizures.

What is the treatment for brain tumors?

Treatment for a brain tumor depends on a number of factors. Among these are the type, location, and size of the tumor, as well as the patient's age and general health. Treatment methods and schedules often vary for children and adults. A treatment plan is developed to fit each patient's needs.

The patient's doctor may want to discuss the case with other doctors who treat brain tumors. Also, the patient may want to talk with the doctor about taking part in a research study of new treatment methods. Such studies are called clinical trials.

Many patients want to learn all they can about their disease and their treatment choices so they can take an active part in decisions about their medical care. A person with a brain tumor will have many questions, and the doctor is the best person to answer them. Most patients want to know what kind of tumor they have, how it can be treated, how effective the treatment is likely to be, and how much it is likely to cost.

Many people find it helpful to make a list of their questions before they see the doctor. Taking notes can make it easier to remember what the doctor says. Some patients also find that it helps to have a family member or friend with them when they talk with the doctor,either to take part in the discussion or just to listen.

Patients and their families have a lot to learn about brain tumors and their treatment. They should not feel that they need to understand everything the first time they hear it. They will have other chances to ask the doctor to explain things that are not clear.

What tests are used to find and diagnose adult brain tumors?

Tests that examine the brain and spinal cord are used to detect (find) adult brain tumor. The following tests and procedures may be used:

CT scan (CAT scan): A procedure that makes a series of detailed pictures of areas inside the body, taken from different angles. The pictures are made by a computer linked to an x-ray machine. A dye may be injected into a vein or swallowed to help the organs or tissues show up more clearly. This procedure is also called computed tomography, computerized tomography, or computerized axial tomography.

MRI (magnetic resonance imaging): A procedure that uses a magnet, radio waves, and a computer to make a series of detailed pictures of the brain and spinal cord. A substance called gadolinium is injected into the patient through a vein. The gadolinium collects around the cancer cells so they show up brighter in the picture. This procedure is also called nuclear magnetic resonance imaging (NMRI).

Adult brain tumor is diagnosed and removed in surgery. If a brain tumor is suspected, a biopsy is done by removing part of the skull and using a needle to remove a sample of the brain tissue. A pathologist views the tissue under a microscope to look for cancer cells. If cancer cells are found, the doctor will remove as much tumor as safely possible during the same surgery. An MRI may then be done to determine if any cancer cells remain after surgery. Tests are also done to find out the grade of the tumor.

What is the grade of a tumor?

The grade of a tumor refers to how abnormal the cancer cells look under a microscope and how quickly the tumor is likely to grow and spread. The pathologist determines the grade of the tumor using tissue removed for biopsy. The following grading system may be used for adult brain tumors:

Grade I

The tumor grows slowly, has cells that look similar to normal cells, and rarely spreads into nearby tissues. It may be possible to remove the entire tumor by surgery.

Grade II

The tumor grows slowly, but may spread into nearby tissue and may become a higher-grade tumor.

Grade III

The tumor grows quickly, is likely to spread into nearby tissue, and the tumor cells look very different from normal cells.

Grade IV

The tumor grows very aggressively, has cells that look very different from normal cells, and is difficult to treat successfully.

The chance of recovery (prognosis) and choice of treatment depend on the type, grade, and location of the tumor and whether cancer cells remain after surgery and/or have spread to other parts of the brain.

How are adult brain tumors treated?

Different types of treatment are available for patients with adult brain tumor. Some treatments are standard (the currently used treatment), and some are being tested in clinical trials. Before starting treatment, patients may want to think about taking part in a clinical trial. A treatment clinical trial is a research study meant to help improve current treatments or obtain information on new treatments for patients with cancer. When clinical trials show that a new treatment is better than the standard treatment, the new treatment may become the standard treatment.

Three types of standard treatment are used.

1. Surgery

Surgery is used, when possible, to treat adult brain tumor

2. Radiation therapy

Radiation therapy is a cancer treatment that uses high-energy x-rays or other types of radiation to kill cancer cells. There are two types of radiation therapy. External radiation therapy uses a machine outside the body to send radiation toward the cancer. Internal radiation therapy uses a radioactive substance sealed in needles, seeds, wires, or catheters that are placed directly into or near the cancer. The way the radiation therapy is given depends on the type and stage of the cancer being treated.

3. Chemotherapy

Chemotherapy is a cancer treatment that uses drugs to stop the growth of cancer cells, either by killing the cells or by stopping the cells from dividing. When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body (systemic chemotherapy). When chemotherapy is placed directly into the spinal column, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas (regional chemotherapy). A dissolving wafer may be used to deliver an anticancer drug directly into the brain tumor site after the tumor has been removed by surgery. The way the chemotherapy is given depends on the type and stage of the cancer being treated.

How metastatic brain tumors are treated?

Tumors that have spread to the brain from somewhere else in the body are usually treated with radiation therapy and/or surgery. Chemotherapy may be used if the primary tumor is the kind that responds well to chemotherapy. Clinical trials are under way to study new treatments.

Brain Stem Gliomas

Treatment of brain stem gliomas may include the following:

Hyperfractionated radiation therapy.

A clinical trial of new anticancer drugs and/or biologic therapy.

Pineal Astrocytic Tumors

Treatment of pineal astrocytic tumors may include the following:]

Surgery and radiation therapy, with or without chemotherapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs and biologic therapy following radiation therapy.

] Pilocytic Astrocytomas

Treatment of pilocytic astrocytoma is usually surgery with or without radiation therapy.

Diffuse Astrocytomas

Treatment of diffuse astrocytoma may include the following:

Surgery, usually with radiation therapy.

A clinical trial of surgery and radiation therapy with or without chemotherapy for tumors that cannot be completely removed by surgery.

A clinical trial of radiation therapy delayed until the tumor progresses.

A clinical trial comparing high-dose and low-dose radiation therapy.

Anaplastic Astrocytomas

Treatment of anaplastic astrocytoma may include the following:

Surgery plus radiation therapy, with or without chemotherapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs and biologic therapy following radiation therapy.

A clinical trial of chemotherapy combined with different methods of delivering radiation therapy.

Glioblastoma

Treatment of glioblastoma may include the following:

Surgery plus radiation therapy, with or without chemotherapy.

A clinical trial of chemotherapy placed into the brain during surgery.

A clinical trial of radiation and concurrent chemotherapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs and biologic therapy following radiation therapy.

A clinical trial of chemotherapy and new methods of delivering radiation therapy.

Clinical trials of new treatments.

Oligodendroglial Tumors

Treatment of oligodendrogliomas may include the following:

Surgery, usually with radiation therapy.

A clinical trial of surgery and radiation therapy with or without chemotherapy for tumors that cannot be completely removed by surgery.

Treatment of anaplastic oligodendroglioma may include the following:

Surgery plus radiation therapy with or without chemotherapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs and biologic therapy following radiation therapy.

Mixed Gliomas

Treatment of mixed gliomas may include the following:

Surgery plus radiation therapy with or without chemotherapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs or biologic therapy following radiation therapy.

Ependymal Tumors

Treatment of grade I and grade II ependymomas is usually surgery with or without radiation therapy.

Treatment of anaplastic ependymoma may include the following:

Surgery plus radiation therapy.

A clinical trial of surgery followed by chemotherapy before, during, and after radiation therapy.

A clinical trial of chemotherapy and/or biologic therapy.

Medulloblastoma

Treatment of medulloblastomas may include the following:

Surgery plus radiation therapy to the brain and spine.

A clinical trial of surgery and radiation therapy to the brain and spine for tumors that are more difficult to treat successfully.

A clinical trial of chemotherapy.

Pineal Parenchymal Tumors

Treatment of pineal parenchymal tumors may include the following:

Surgery plus radiation therapy with or without chemotherapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs and biologic therapy following radiation therapy.

Meningeal Tumors

Treatment of meningiomas may include the following:

Surgery with or without radiation therapy.

Radiation therapy for tumors that cannot be removed by surgery.

Treatment of malignant meningioma may include the following:

Surgery plus radiation therapy.

A clinical trial of external radiation therapy plus hyperthermia therapy or new methods of delivering radiation therapy.

A clinical trial of new anticancer drugs and/or biologic therapy following radiation therapy.

Germ Cell Tumors

Treatment of central nervous system germ cell tumors depends on the type of cancer cells, the location of the tumor, whether the cancer can be removed in an operation, and other factors.

Craniopharyngioma

Treatment of craniopharyngiomas may include the following:

Surgery to remove the entire tumor.

Surgery to remove as much of the tumor as possible, followed by radiation therapy.

Recurrent Adult Brain Tumor

Treatment of recurrent adult brain tumors may include the following:

Surgery with or without chemotherapy.

Radiation therapy, if not used during previous treatment, with or without chemotherapy.

Internal radiation therapy.

Chemotherapy.

A clinical trial of new anticancer drugs.

A clinical trial of chemotherapy placed into the brain during surgery.

A clinical trial of biologic therapy.

Metastatic Brain Tumors

Treatment of a single metastatic brain tumor is usually surgery followed by radiation therapy to the brain.

Treatment of more than one metastatic brain tumor may include the following:

Radiation therapy to the brain.

Surgery, for large tumors that are pressing on areas of the brain and causing symptoms.

What are the side effects of treatment for brain cancer?

Cancer treatment often causes side effects. These side effects occur because treatment to destroy cancer cells damages some healthy cells as well.

The side effects of cancer treatment vary. They depend on the type of treatment used and on the area being treated. Also, each person reacts differently. Attempts are made to plan the patient's therapy to keep side effects to a minimum. Patients are very carefully watched so that any problems which occur can be addressed.

A craniotomy is a major operation. The surgery may damage normal brain tissue, and edema may occur. Weakness, coordination problems, personality changes, and difficulty in speaking and thinking can result. Patients can also have seizures. In fact, for a short time after surgery, symptoms may be worse than before. Most of the side effects of surgery lessen or disappear with time.

Most of the side effects of radiation therapy go away soon after treatment is over. However, some side effects may occur or persist long after treatment is completed.

Some patients have nausea for several hours after treatment. Patients receiving radiation therapy may become very tired as treatment continues. Resting is important, but doctors usually advise their patients to try to stay reasonably active. Radiation therapy to the scalp causes most patients to lose their hair. When it grows back, the new hair is sometimes softer and may be a slightly different color. In some cases, hair loss is permanent.

Skin reactions in the treated area are common. The scalp and ears may be red, itchy, or dark. These areas may look and feel sunburned. The treated area should be exposed to the air as much as possible but should be protected from the sun. Patients should not wear anything on the head that might cause irritation. Good skin care is important at this time. The doctor may suggest certain kinds of soap or ointment, and patients should not use any other lotions or creams on the scalp without the doctor's advice.

Sometimes, brain cells killed by radiation form a mass in the brain. The mass may look like a tumor and may cause similar symptoms, such as headaches, memory loss, or seizures. Doctors may suggest surgery or steroids to relieve these problems. About 4 to 8 weeks after radiation therapy, patients may become quite sleepy or lose their appetite. These symptoms may last several weeks, but they usually go away on their own. Still, patients should notify the doctor if they occur.

Children who have had radiation therapy for a brain tumor may have learning problems or partial loss of eyesight. If the pituitary gland is damaged, children may not grow or develop normally.

The side effects of chemotherapy depend on the drugs that are given. In general, anticancer drugs affect rapidly growing cells, such as blood cells that fight infection, cells that line the digestive tract, and cells in the hair follicles. As a result, patients may have a lowered resistance to infection, loss of appetite, nausea, vomiting, or mouth sores. Patients also may have less energy and lose their hair. These side effects usually go away gradually after treatment stops.

Some anticancer drugs can cause infertility. Women taking certain anticancer drugs may have symptoms of menopause (hot flashes and vaginal dryness; periods may be irregular or stop). Some drugs used to treat children and teenagers may affect their ability to have children later in life.

Certain drugs used in the treatment of brain tumors can cause kidney damage. Patients are given large amounts of fluid while taking these drugs. Patients also may have tingling in the fingers, ringing in the ears, or difficulty hearing. These problems may not clear up after treatment stops.

Treatment with steroids to reduce swelling in the brain can cause increased appetite and weight gain. Swelling of the face and feet is common. Steroids can also cause restlessness, mood swings, burning indigestion, and acne. Patients should not stop using steroids or change their dose without consulting the doctor, however. The use of steroids must be stopped gradually to allow the body time to adjust.

Loss of appetite can be a problem for patients during therapy. People may not feel hungry when they are uncomfortable or tired. Some of the common side effects of cancer treatment, such as nausea and vomiting, can also make it hard to eat. Yet, good nutrition is important because patients who eat well generally feel better and have more energy. In addition, they may be better able to withstand the side effects of treatment. Eating well means getting enough calories and protein to help prevent weight loss, regain strength, and rebuild normal tissues. Many patients find that eating several small meals and snacks during the day works better than trying to have three large meals.

Patients being treated for a brain tumor may develop a blood clot and inflammation in a vein, most often in the leg. This is called thrombo-phlebitis. A patient who notices swelling in the leg, leg pain, or redness in the leg should notify the doctor right away.

Doctors, nurses, and dietitians can explain the side effects of cancer treatment and can suggest ways to deal with them.

INTEGRATIVE THERAPY

4. THE SCIENTIFICALLY FORMULATED AMINO ACID THERAPY

(Keep in mind, CAAT is much more than just a “diet”; it is an amino acid, carbohydrate, & glucose REDUCTION protocol which strategically uses the chemical reactions of amino acids, foods, and nutritional supplements to impair the development of cancer cells, thus starving them to death.) Clinical trials have already been done with humans using amino acid depravation formulas, and with much success. (Journal American Medical Association. 1967; 200:211)

CAAT is a course of therapy to control a patient’s amino acid intake. This is achieved by taking certain foods out of a persons’ daily food plan for a short time and by replacing them with a scientifically supported formula of amino acids. It is also important to emphasize that the food plan that accompanies the amino acid formula needs to be followed so not to offset any of the benefits we are creating by depriving the cancer cells the nutrients they need to grow. Also, it is important to realize that the patient does not need to abandon their conventional cancer treatment, (surgery, chemotherapy, radiation, hormone treatments) nor is it recommended that they do so unless it has already failed them. CAAT works synergistically with chemotherapy and/or radiation to enhance their benefits (see study by Dr. Marco Rabinowitz of the National Cancer Institute). His report on amino acid deprivation, such as with Controlled Amino Acid Therapy (CAAT), proven to inhibit phosphofructokinase which shuts down the energy supply to cancer cells, simultaneously enhancing the benefits of chemotherapy while lessening their toxic side effects. CAAT has also proven to work successfully alone.

Phase 1: CAAT Formulation

The most important component of CAAT is the scientifically formulated amino acids. Based on the specific formula for each cancer, it consists of separate amino acids, citric acid, and small amounts of sodium benzoate. Each formula replaces most of the regular daily proteins found in meats, dairy, fish, beans and nuts, which cancer cells can derive their energy from. The CAAT formula taken two times per day will nourish the healthy cells while causing the cancer cells to starve to death. Of course each individual has specific needs concerning their diet, and this is explained in the second phase of the protocol as well as with a specialist at the Institute when beginning the CAAT therapy.

Phase 2: Daily Food Intake

DISCLAIMER: The following food program SHOULD NOT be consumed without the amino acid formula and without consent from your doctor and our Institute.

Breakfast:

*1/2 Grapefruit or 1-orange or 6-ounces of fresh orange juice.

Whey Enhanced Protein (Vanilla Flavor – Vitamin Shoppe Brand) approximately

10 – 12 grams of protein – read label carefully, based on 150 lb. person ].

A serving of Grits (Butter, cinnamon and other spices are okay).

1 cup of green or black tea (Fructose is sweetener of choice).

* Do Not have ½ grapefruit if taking Chemotherapy

Explanation: ½ Grapefruit or 1 orange or 6 ounces of fresh orange juice are rich in the natural nutrients called Limonene and Citric Acid. Limonene helps shut down the Ras cancer gene which is over active in 90 percent of all cancers. Citric Acid helps shut down glycolosis which in turn helps starve cancer cells to death.

Whey Enhanced Protein (Vanilla Flavor – Vitamin Shoppe Brand) Phosphorus is a nutrient that cancer cells must utilize in order to grow and reproduce. This brand of whey protein is very low in phosphorous and contains no additional vitamins, so when using approximately 10 – 12 grams of protein per 150 lb. person, it helps to protect normal cells, maintain a normal appetite, and also helps to fight edema. (Edema is the swelling or water build up in the legs or other sites in the body)

Whey protein is included in the daily menu of all advanced or metastatic cancer patients. When treating cancers that are stable or have regressed in size, patients then have the option of including other protein foods at their breakfast meals such as cottage cheese, yogurt, or soy foods. Eggs are allowed in the diets of patients with lymphoma and brain cancers.

Grits or Cream of Wheat or 1 slice of white toast or ½ plain bagel or ½ English muffin (Butter is okay)

Grits or white rice is the preferred carbohydrate food at each meal. The other choices are options once the patient’s cancer is stable or reduced in size. Unrefined carbohydrates are included in the CAAT menu instead of whole grains to deprive cancer cells of a certain B-complex vitamin called Pyridoxine (Vitamin B-6). Cancer cells require this vitamin to manufacture certain amino acids that we keep away from through CAAT’s amino acid reduction formula and diet. Grits is the preferred carbohydrate food at all meals instead of rice, corn, or pasta because it helps deplete Tryptophan in the body, which is essential for the growth and spreading of cancer cells.

1 cup of green or black tea, using fructose as the sweetener of choice. These teas are rich sources of several compounds that help shut down glycolosis and cut off the energy supply to cancer cells. Also, green or regular tea helps to prevent certain hormones and tumor growth factors from stimulating cancer cells to grow and metastasize to other parts of the body. Brassica teas can also be taken because they contain sulphorane, a nutrient that inhibits cancer growth, and also shuts down the cancer genes.

* Why we use fructose as the sweetener of choice will be explained in detail at the end of this phase of the CAAT protocol.

Lunch:

Amino acid formula (4 level plastic scoops) mixed with any of the following: Water & Fructose; Sugar free Kool-Aid; Diet ginger ale; Fresh lemonade & Fructose; Chicken or Beef broth; V8 juice.

Generous amounts of One cooked vegetable or a combination of the following: asparagus, broccoli, cabbage, brussell sprouts, spinach, squash, string beans.

One serving (1/2 cup)of fresh fruit. Choice of: pear, orange, blueberries, raspberries, strawberries.

1 serving (moderate) of grits or corn or rice or pasta (Add tomato sauce or butter)

1 tablespoon of coconut oil

8 to 10 black or green olives

2 tablespoons of vinegar (minimum of 5% acidity) add to vegetables or food

1 cup of green or black tea (Fructose as desired)

Explanation:

This Amino Acid Reduction Formula (4 level plastic scoops may vary) combined with the special diet, allows the CAAT Protocol to reduce certain amino acids in the daily diet of the cancer patient, and is designed to replace most of the animal protein in the diet. Cancer cells require the amino acids glycine, serine, glutamic acid, and aspartic acid to synthesize DNA, build new blood vessels or duplicate its entire contents of proteins. Also, cancer cells require these and certain other amino acids in order to synthesize other proteins that act as growth promoting hormones or tumor growth factors. CAAT impairs the synthesis of a protein called elastin, which is absolutely essential to the manufacture of new blood vessels. The Amino Acid Reduction Formula, diet, certain phytochemicals and herbs work efficaciously to attack cancer cells at each and every biological front.

The generous amounts of one cooked vegetable or a combination of such helps keep normal cells healthy. They are low in carbohydrates and proteins, and high in phytochemicals, compounds which help fight cancer. Patients are allowed to eat these vegetables and salads whenever desired.

The 8 to 10 olives are rich in squalene and oleic acid, nutrients that have been reported to inhibit certain cancer growth factors. The calories in olives also help control body weight and increases ketones in the blood. Ketones help fight cancer by impairing glycolosis – a process in which cancer cells depend almost exclusively upon for their daily supply of energy. Vinegar (and fructose) are two natural products that increase the production of both ACETIC ACID and CITRIC ACID in the body.

Acetic acid and citric acid also help fight cancer by shutting down the process of glycolosis.

Normal cells derive most of their daily energy supply from acetic acid and citric acid, where as cancer cells derive most of their daily energy from glycolosis.

Dinner:

Amino acid formula (4 plastic level scoops) mixed with any of the following: Water & fructose; Sugar free Kool–Ade; Diet Ginger Ale; Fresh lemonade & Fructose; Chicken or Beef broth; V8 Juice.

Generous amounts of One cooked vegetable or a combination of the following: asparagus, broccoli, cabbage, brussel sprouts, spinach, squash, string beans.

One serving (1/2 cup) of stewed plums with fresh cream & fructose; use 4-ounces of orange juice if plums are not in season.

Avacado salad with lettuce, tomatoes, celery, onions, with lemon juice and coconut oil or olive oil.

2 tablespoons of vinegar (minimum of 5% acidity) add to vegetables or food.

1 serving of grits or corn or pasta or rice (Add garlic and butter or tomato sauce)

1 cup of green or black tea (Fructose as desired)

Mid Evening Snack: Ketogenic Cocktail – 2 ounces of fresh cream, ½ ounce each of both coconut & olive oil, 1 tablespoon of Fructose.

Sugar free Jell-O with whipped cream & Fructose or 1 plum or 4 ounces of orange juice.

Explanation: The sugar free jell-o helps to appease the appetite. Plums contain quinlic acid, which is converted into benzoic acid in the body and which in turn helps to deplete the availability of the amino acid Glycine (Glycine is essential to the synthesis of DNA for cancer cells) and the proteins that cancer cells require to build new blood vessels and their tumor growth factors. If underweight take two ounces of light cream and one ounce of olive oil/coconut oil as needed to maintain weight.

Optional Meal:

3 to 4 ounces of Veal, Fish of choice, Beef, Chicken breast, and 1-slice of white bread.

Consume this meal with a minimum of 3 hours before or after taking the amino acids.

Explanation: If the patient is 10 or more pounds underweight or if their albumin levels are below normal is when the optional meal is allowed. This meal should be eaten a minimum of 3 hours before or after taking the amino acids. CAAT provides sufficient protein to maintain the health of normal cells and adequate amounts of calories to maintain desired body weight. Any proteins taken in excess of amounts recommended in the diet will counter act the benefits of the CAAT protocol.

Special Diets: A special diet will be created for any cancer patient whose ability to consume food and liquids has placed them in a critical situation. When a patient is using a feeding apparatus, or they have become too weak or lethargic to eat and drink the daily minimum amount for survival, we will break up the total breakfast, lunch, and dinner over a period of every 2 hours during the entire day until the patient is capable of returning to a daily diet as outlined above.

Carbohydrate and glucose reduction in this diet: CAAT’S dietary menu provides approximately 20 percent of its calories in the form of carbohydrates. Calories need not be a focal point or counted daily. It is recommended that all patients combat their cancers by keeping their body weight at normal or slightly below normal levels. A patient’s desired body weight is regulated by their rate of metabolism, which in turn is regulated by their blood levels of thyroxine, cortisone, insulin, and the amounts of fats and oils in the diet. Studies with human cancer patients and laboratory animals show that reducing the calories of carbohydrates (glucose) in their daily diet by only 10 percent reduced the size of cancerous tumors. When carbohydrate (glucose) calories were reduced 40 percent, the cancers disappeared. It is recommended that those patients who are obese gradually and systematically lose their excess weight to increase the efficiency of the CAAT protocol. Those patients who are underweight shoudn’t gain weight unless they are more than 10 pounds below normal levels. When a patient is underweight due to anorexia or cachexia, such illnesses must be addressed before the CAAT protocol can begin.

Why we use Fructose and Vinegar to treat cancer:

Nobel Prize winner Dr. Otto Warburg discovered more than 50 years ago that all cancer cells produce inordinate amount of lactic acid but he couldn’t explain why.

In 2001 our Institute published the first study to show that cancer cells produce excess amounts of lactic acid because they could not access the oxygen in compartments in the cells called the mitochondria. This provided evidence that cancer cells depend almost exclusively upon glycolosis or the metabolism of glucose as their major source of energy.

Dr. Spitz and Dr. Lee with other cancer researchers published studies showing that when cancer cells are deprived glucose, their energy supply is cut off which causes these cancer cells to commit suicide.

Therefore shutting down glycolosis would be one means of destroying cancer cells because energy can only be derived from glucose through the metabolic process called glycolosis.

Recently our Cancer Institute discovered that both acetic acid and citric acid could inhibit the activity of a key enzyme in glycolosis called phosphofructokinase, which in turn shuts down the process of glycolosis. Our cancer Institute is the first to introduce both fructose and vinegar as treatments for cancer because they either contain or produce acetic acid.

In conclusion, fructose and vinegar are added as supplements to the CAAT protocol because of their acetic acid properties that help shut down glycolosis, shutting off cancer cells energy supply and causing them to die off.

Phase 3: Nutritional Supplements

Nutritional supplements are based on each unique situation. For example, slow growing cancers produce low levels of toxic free radicals. Tumor cells that grow aggressively produce large amounts of toxic free radicals. The patient will be instructed whether or not to take anti-oxidants (in a nutritional supplement) and at what dosage, according to the levels of toxic free radicals produced in the cancerous cells.

An example of how nutritional supplements can help manipulate cancer cells involves vitamin B-6 (pyroxidine) There are four amino acids essential to the synthesis of DNA. However, those amino acids cannot be synthesized without a certain enzyme, which includes vitamin B-6 among other components. Any supplement containing vitamin B-6 SHOULD NOT be taken during the first 2 months of the CAAT protocol.

The patient will be instructed as to which nutritional supplements or phytochemicals should be purchased and at what dosage strength. Keep in mind that each supplement only complements the CAAT protocol. However, when they are combined they augment the therapeutic benefits of the aminoacid, carbohydrate, and glucose reduction diet.

Parsley: Contains ingredients that can help shut down certain enzymes called Epithelial Growth Factors, which stimulate the growth and spread of cancer. ( CAAT’S amino acid reduction diet works in the same manner )

Vitamin D: Helps activate in many kinds of cancers enzymes called Phosphotases, which literally shut down the activities of other enzymes called Kinases, which are essential to the growth and reproduction of cancer cells.

Green Tea Extract: Phytochemicals in tea help shut down glycolosis (cancer cell’s main supplier of energy) and thereby help to starve cancer cells to death. These effects help complement the effects of CAAT’S carbohydrate reduction.

Anti-Oxidants: The controversy as to whether or not to treat cancer with anti-oxidants is slowly resolving with the current understanding of how they affect the activity of genes and enzymes in cancer cells. The prevailing data shows that the benefits or lack of benefits depend upon the oxidative state the cancer cells are in. Anti-oxidants taken when the cells are in a very high oxidative state may prevent cancer cells from entering apoptosis ( apoptosis is when a cancer cell commits suicide) When oxidative stress in cancer cells is only slightly above normal, anti-oxidants are then expected to stop their growth and reproduction.

Blood Chemistry: Blood tests are usually taken every 6 to 8 weeks, depending upon the results of each test. Not only is it important to monitor the tumor markers but equally important to keep abreast of the overall health of normal tissues and organs. For example, it is important to learn of the health of the kidneys and liver, whether the body is producing sufficient red and white blood cells, etc. Low albumin levels most often indicate insufficient intake of proteins in the diet and this problem would have to be addressed. CAAT is designed to attack cancer but keep the normal cells and tissues functioning harmoniously.

Whey Protein: This protein food is recommended at the breakfast meal to help meet the daily needs of amino acids for the normal cells of the body, and to help keep albumin levels normal and to help prevent edema. We recommend Whey protein purchased from the Vitamin Shoppe because it is the only brand that we have seen with no phosphorous or additional vitamins added to it.

Grits: Grits are also recommended at the breakfast meal in place of whole grains because it is low in vitamin B-6. Cancer cells require B-6 to manufacture the amino acid Glycine, which is required for DNA synthesis. Grits, instead of whole grains, therefore helps prevent cancer cells from manufacturing DNA and building new blood vessels.

Calcium D-Glucurate: This phytochemical helps the body to retain a compound called Glucuronic acid. This is necessary to eliminate both estrogen and testosterone from the body. This is why Calcium D-Glucurate is added to the regiments of patients with breast & prostate cancers. Calcium D-Glucurate is not to be confused with calcium carbonate, which is nothing more than a calcium supplement.

D-Limonene: This phytochemical found mostly in citrus fruits blocks the process called Isoprenylation, which is necessary for tumor growth factors such as the RAS gene, Epithelial Growth factor, Tyrosine Kinase, and Insulin-Like-Growth-factor, to send their signals into the nucleus of a cancer cell and directs them to grow and divide into more cancer cells.

Tocotrienols: This member of the Vitamin E family also helps shut down Isoprenylation and assists D-Limonene in blocking the actions of the various tumor growth factors. More specifically, tocotrienols shut down an enzyme called HMG-2, which is essential to the synthesis of the building blocks that form the Isoprenylation process.

Niacin: This B-Complex vitamin works with D-limonene and the Tocotrienols to shut down the process of Isoprenylation, which as mentioned above prevents the cancer promoting RAS genes from sending signals into the nucleus of the cell. Niacin also helps deplete thee amino acid Glycine, which cancer cells need to synthesize DNA. And by reducing cholesterole in the body, Niacin helps lower the production of estrogen and testosterone.

Choline: This B-complex vitamin is included in our supplement list to help the liver metabolize Niacin and other compounds and to help fight fatigue that accompanies most forms of cancer.

Selenium: Numerous studies show that this mineral can interfere with the activity of certain genes that promote the growth of cancer and to induce cancer cells to commit suicide (apoptosis)

Perilla Oil: This oil is rich in Alpha Linolenic Acid which can inhibit the growth of cancer cells in several ways. One way is to inhibit the synthesis in the body of a tumor growth promotin hormone called Prostaglandin-2, also, Alpha Linolenic Acid inhibits the actions of certain genes that promote the growth of cancer cells. Linolenic acid is not to be confused with linoleic acid, which is a bad fat that stimulates the growth of cancer cells. This bad fat, linoleic acid, is found in all vegetable oils and nuts (With the exception of coconut oil). Olive oil has the least amount of this bad fat.

Super Miraforte: This herb impairs the synthesis of estrogen from testosterone in the body and is included in the regiments of women with breast cancer.

Licorice Root Extract & Pantothenic Acid: This herb and vitamin are added to the regiment when it is desirable to produce steroid like actions in the body. Also used to help patient’s gain weight and to inhibit the growth of lymphomas and leukemia’s.

Resveratrol: This phytochemical blocks the actions of a number of a number of cancer promoting genes thereby causing cancer cells to enter into apoptosis (cell death) and is included in the treatment of all cancers.

Indole-3 Carbinol & D.I.M.: These two phytochemicals block the actions of both estrogen and testosterone and are included in the regiments of both breast and prostate gland cancer.

Melatonin: Numerous studies show that this hormone blocks the synthesis of the cancer promoting chemicals in the body called Leukotrienes, and is included in the treatment of all cancers.

Artho Pro System: This combination of herbs and phytochemicals inhibits the synthesis of the cancer promoting hormone called Prostaglandin-2 and the Leukotriens and replaces the drug celebrex when liver problems are present. The Prostaglandin hormone is over active in most cancers and stimulates cancer growth. The body manufactures the Prostaglandin hormone from the bad fat, Linoleic acid, mentioned above.

Licorice Root Extract & Pantothenic Acid: This HERB and VITAMIN are added to the regiment when it is desirable to produce steroid like actions in the body. Used also to help patients gain weight and ti inhibit the growth of Lymphomas and Leukemias.

CAAT is designed to attack cancer, while keeping normal cells and tissues functioning harmoniously.

Orijinal sayfa: http://www.apjohncancerinstitute.org/cancer/brain.htm

Ozone Therapy on Cerebral Blood Flow: A Preliminary Report

2009-08-08T01:22:00.000-07:00

Ozone Therapy on Cerebral Blood Flow: A Preliminary Report
Bernardino Clavo1,2,7, Luis Catalá3,7, Juan L. Pérez2,4,7, Victor Rodríguez5 and
Francisco Robaina2,6,7 Departments of 1Radiation Oncology and 2Research Unit, 3Radiology, 4Medical Physics and 6Chronic Pain Unit, Dr Negrín Hospital, 5La Paterna Medical Center and 7Canary Islands Institute for Cancer Research (ICIC), Las Palmas (Canary Islands), Spain

Introduction
Cerebral low perfusion syndromes have significant clinical
and social repercussions. An important field in neurological
research includes the search for more effective drugs and other
methods in order to ameliorate this problem. Ozone therapy is
a non-conventional therapy that has been used for several years
in the treatment of ischemic disorders, particularly of the
lower limbs (1–3). However, to date, very few studies have
systematically evaluated blood flow changes resulting from
ozone therapy.
With regard to this, the effect of ozone therapy on the blood
flow in the middle cerebral artery (MCA) and the common
carotid artery (CCA) was investigated in the current study.
Subjects and Methods Patients In this study, the blood flow in 28 arteries (14 MCA and
14 CCA) was evaluated in 7 subjects—5 patients and 2 healthy
volunteers. The subjects were from our university hospital.
The patients who underwent elective ozone therapy, which was
unrelated to the treatment of their cerebral vascular diseases,
were from the Radiation Oncology department. Their scheduled
medication was not modified during the study period. The volunteers
were members of the clinical staff of the departments
Advance Access Publication 6 October 2004 eCAM 2004;1(3)315–319
doi:10.1093/ecam/neh039
© 2004, the authors
Evidence-based Complementary and Alternative Medicine, Vol. 1, Issue 3 © Oxford University Press 2004; all rights reserved
Original Article
Ozone Therapy on Cerebral Blood Flow: A Preliminary Report
Bernardino Clavo1,2,7, Luis Catalá3,7, Juan L. Pérez2,4,7, Victor Rodríguez5 and
Francisco Robaina2,6,7
Departments of 1Radiation Oncology and 2Research Unit, 3Radiology, 4Medical Physics and 6Chronic Pain Unit,
Dr Negrín Hospital, 5La Paterna Medical Center and 7Canary Islands Institute for Cancer Research (ICIC),
Las Palmas (Canary Islands), Spain
Ozone therapy is currently being used in the treatment of ischemic disorders, but the underlying mechanisms
that result in successful treatment are not well known. This study assesses the effect of ozone
therapy on the blood flow in the middle cerebral and common carotid arteries. Seven subjects were
recruited for the therapy that was performed by transfusing ozone-enriched autologous blood on 3 alternate
days over 1 week. Blood flow quantification in the common carotid artery (n 14) was performed
using color Doppler. Systolic and diastolic velocities in the middle cerebral artery (n 14) were estimated
using transcranial Doppler. Ultrasound assessments were conducted at the following three time
points: 1) basal (before ozone therapy), 2) after session #3 and 3) 1 week after session #3. The common
carotid blood flow had increased by 75% in relation to the baseline after session #3 (P 0.001) and by
29% 1 week later (P 0.039). In the middle cerebral artery, the systolic velocity had increased by 22%
after session #3 (P 0.001) and by 15% 1 week later (P 0.035), whereas the diastolic velocity had
increased by 33% after session #3 (P 0.001) and by 18% 1 week later (P 0.023). This preliminary
Doppler study supports the clinical experience of achieving improvement by using ozone therapy in
peripheral ischemic syndromes. Its potential use as a complementary treatment in cerebral low perfusion
syndromes merits further clinical evaluation.
Keywords: color Doppler – ischemia – low perfusion – transcranial Doppler
The online version of this article has been published under an open access model. Users are entitled to use, reproduce, disseminate, or display the open access
version of this article provided that: the original authorship is properly and fully attributed; the Journal and Oxford University Press are attributed as the original
place of publication with the correct citation details given; if an article is subsequently reproduced or disseminated not in its entirety but only in part or as a
derivative work this must be clearly indicated.
For reprints and all correspondence: Bernardino Clavo, MD, Department of
Radiation Oncology and Research Unit, Dr Negrín Hospital, C/ Barranco la
Ballena s/n, 35020 Las Palmas (Canary Islands), Spain. Fax: 34 928
449127; Tel: 34 928 450284. E-mail: bernardinoclavo@terra.es
involved in the investigation. The study included 5 males and
2 females with a mean age of 58 years (range, 34–78).
Informed consent was obtained from all the participants prior
to inclusion in the study. The study was approved by the
Institutional Ethical Committee. Table 1 summarizes the
details of the subjects that participated in this study.
Ozone Therapy
Ozone therapy was administered by autologous blood transfusion
on 3 alternate days over 1 week. The procedure involved
the collection of 200 ml venous blood into a blood bag containing
heparin (25 IU/ml) and CaCl2 (5 mM). The O3/O2 gas
mixture was prepared from clinical-grade O2 using the OZON
2000 medical device (Zotzmann Stahl GmbH, Plüderhausen,
Germany). The blood was mixed with 200 ml of O3/O2 gas
mixture at a concentration of 60 g/ml in a sterile single-use
300 ml container. Subsequently, the blood was slowly
re-introduced into the patient via the antecubital vein, after
being passed through a sterile 0.20 m filter. The blood
remained outside the body for approximately 15–30 min, and
no adverse reactions were observed.
Doppler studies were conducted on the following three
occasions: 1) before session #1; 2) after session #3; and 3)
1 week after session #3.
Transcranial Doppler Velocimetry
Systolic and diastolic velocities (in cm/s) were measured in the
MCA by the transtemporal approach using a transcranial
Doppler (TCD) with a 2 MHz probe from an Angiodine-2
Fluo-Link 300® device. The patient was alert, relaxed and
seated when the absence of stenoses was confirmed. The
Doppler insonation angle was 60.
Common Carotid Blood Flow Quantification
Blood flow quantification of CCA was performed using
a color Doppler, Philips Ultrasound P-800 unit®, with timedomain
processing. This technique simultaneously evaluates
the velocity and the vessel diameter, and the data is presented
in terms of ml/min. The usefulness and validity of this technique
has been previously described (4,5). The patient was
alert, relaxed and in the supine position when the absence of
significant stenoses in the extracranial carotid arteries was
confirmed. A 7.5 MHz linear high-definition probe with a
Doppler insonation angle of 60 was used. We obtained
information regarding the volume of blood flow (in ml/min) in
both CCAs at 2 cm prior to the carotid bifurcation.
All ultrasound studies were performed bilaterally by the
same radiologist in order to minimize interobserver variability
(6). When an optimal image of stable blood flow was obtained,
recordings over at least three cardiac cycles were made. This
was repeated at least three times in order to preclude operatorinduced
or technical inaccuracies. The median values that
were obtained were used in the statistical analyses.
Neither blood pressure nor hemoglobin levels were measured.
Statistical Analysis
The SPSS 7.0 for Windows software package (SPSS-Ibérica,
Madrid, Spain) was used throughout the study. The normality
of distribution of data was assessed by the Kolmogorov–
Smirnov test. Two-sided tests were applied. The data are
expressed as mean SD. The paired t-test was used to compare
differences between the baseline and the two time-point
measurements following the ozone therapy. Linear correlation
was assessed by the Pearson’s r test. The differences were
considered to be significant when P 0.05.
316 Ozone therapy on cerebral blood flow
Table 1. Patients and control subjects included in the study
Patient Age (years) Characteristics
#1 67 aComplementary treatment during radiochemotherapy for advanced carcinoma of hypopharynx.
bArterial hypertension under drug treatment and hyperglycemia under dietary treatment.
#2 74 aComplementary treatment during radiochemotherapy for advanced carcinoma of base of tongue.
bChronic obstructive bronchitis (COB) under treatment with bronchodilator inhalers.
#3 63 aComplementary treatment during radiochemotherapy for advanced carcinoma of supraglottis.
bHyperuricemia treated with allopurinol. Multiple sclerosis treated with baclofen.
#4 51 aRadiation-induced necrosis of thyroid cartilage (radiotherapy was administered for carcinoma of glottis several years ago).
bTreatment with corticosteroids.
#5 78 aChronic ulceration with calcaneous exposure and transplant failure.
bInsulin-dependent diabetes, arterial hypertension under drug treatment. Stroke 1 year ago. Duodenal ulcers.
#6 43 Healthy subject.
#7 34 Healthy subject.
aReason for ozone therapy. bConcomitant diseases or treatments (no changes were made in the medications during the period of Doppler evaluation). The study
was planned with three ozone therapy sessions to evaluate the initial effects under the same conditions. Patient #1, #2 and #3 (cancer patients) were required to
commence their scheduled radiochemotherapy after session #3; therefore, ethical considerations precluded delay in the cancer treatment. Ozone therapy was
continued during the radiochemotherapy; however, radiotherapy of the cervical and carotid areas altered the subsequent Doppler evaluations. Patient #4 suffered
from hemorrhage of the larynx. Ozone therapy was stopped after session #3 to enable the patient to undergo surgery. The usual complications associated with the
surgical treatment of this radiation-induced necrosis were absent. Patient #5 who suffered from several vascular diseases was treated with systemic and local
ozone therapy for a chronic wound. Patient #6 and #7 (healthy subjects recruited from among the hospital staff) also received 3 sessions of ozone therapy to
evaluate the Doppler Effect. Further sessions were neither scheduled nor administered.
eCAM 2004;1(3) 317
Results
Transcranial Doppler Velocimetry
The baseline systolic velocity in MCA was 90.9 6.1 cm/s.
After session #3, it increased to 111 7.3 cm/s (increase 22%,
P 0.001), and 1 week later, it was 104.3 8 cm/s (increase
15%, P 0.035). The baseline diastolic velocity in MCA was
41.1 4.4 cm/s. After session #3, it increased to 54.6 4.6 cm/s
(increase 33%, P 0.001), and 1 week later, it was 48.6
5 cm/s (increase 18%, P 0.023) (Fig. 1).
Common Carotid Blood Flow Quantification
The baseline CCA blood flow was 233 19 ml/min. After
session #3, it increased to 407 38 ml/min (increase 75%,
P 0.001), and 1 week later, it was 301 22 ml/min
(increase 29%, P 0.039) (Fig. 2).
The baseline CCA blood flow directly correlated with the
MCA diastolic velocity (r 0.557; P 0.039) and inversely
correlated with age (r 0.825; P 0.001) (Fig. 3). The percentage
increase in CCA blood flow 1 week after session #3
was directly correlated with age (r 0.735; P 0.004)
(Fig. 4) and inversely correlated with the initial values of the
CCA blood flow (r 0.691; P 0.009). In older patients, the
increase in CCA blood flow was higher and that in basal perfusion
was lower (Fig. 5) (Note: in Figs 4 and 5, the Doppler
data for the left arteries of one patient 1 week after session #3
were not available due to technical reasons).
Discussion
Although biomedical applications of ozone therapy can be
traced back to the end of the 19th century, numerous aspects of
the effects of the therapy remain unexplored.
The airways are precluded in this therapy, which uses ozoneenriched
autologous blood transfusion; therefore, lung toxicity
resulting from oxidative stress is avoided. Ozone, per se, does
not enter the organism; the effects that are observed are mediated
0
20
40
60
80
100
120
pre-1 post-3 1 week
* *
0
10
20
30
40
50
60
70
pre-1 post-3 1 week
*
*
MCA diastolic velocity - cm/s
MCA systolic velocity - cm/s
Figure 1. Transcranial Doppler during ozone therapy. Left. Diastolic velocity (in cm/s) in the middle cerebral artery (MCA) increased by 33% at the end of session
#3 (P 0.001), and an 18% increase persisted for 1 week after session #3 (P 0.023). Right. Systolic velocity in MCA increased by 22% at the end of session #3
(P 0.001), and a 15% increase persisted for 1 week after session #3 (P 0.035). The error bars are the 95% confidence intervals. Significant differences
(P 0.05) are indicated with an asterisk (*).
0
50
100
150
200
250
300
350
400
450
pre-1 post-3 1 week
*
*
CCA blood flow - ml / min
Figure 2. Carotid blood flow during ozone therapy. Blood flow quantification
(in ml/min) in the common carotid artery (CCA) increased by 75% at the end
of session #3 (P 0.001), and a 29% increase persisted for 1 week after
session #3 (P 0.039). The error bars are the 95% confidence intervals.
Significant differences (P 0.05) are indicated with an asterisk (*).
0
10
20
30
40
50
60
70
80
90
100 150 200 250 300 350
Basal CCA blood flow - ml/min
Age
Figure 3. Relationship between baseline blood flow and age. Baseline values
of the common carotid artery (CCA) blood flow were inversely correlated with
the age of the patients (r 0.825; P 0.001). A lower blood flow was
observed in older patients.
by the rapid oxidation of certain substances in the blood in the
transfusion recipient. In appropriate concentrations, this can
up-regulate the synthesis of antioxidants in blood (7). This
property has been very actively investigated with respect to the
protection against free radical damage associated with heart
(8), kidney (9) and liver (10) disorders. The mechanisms
proposed to explain the vascular effects include the liberation
of vasoactive substance as well as the improvement in erythrocyte
flexibility and blood rheology (1,11,12).
Several studies that included control subjects have indicated
that when ozone-free oxygen is used, the beneficial biochemical
(7,10) and rheological (1) responses are not observed. The
changes in the MCA and/or CCA blood flow occurring during
ozone therapy were assessed in the present study that did not
include non-ozonized blood transfusion and each patient was
his/her own control.
As indicated by the CCA measurements, the increase in
diastolic velocity in the MCA is compatible with a decrease
in vascular resistance, a rheological improvement (1,12) and
an overall increase in blood flow. The inverse correlation
between the percentage increase in CCA blood flow and the
initial values is compatible with a microvascular redistribution
resulting in better oxygenation in tissues with poor blood supply.
This was tentatively demonstrated in our previous studies
by the direct measurement of muscle and tumor oxygenation
using polarographic electrodes (13,14).
These rheological and vascular effects suggest that coadjuvant
ozone therapy could decrease the vasoconstriction that is secondary
to hyperoxia. Techniques such as carbogen breathing or
hyperbaric chambers are used to increase the amount of O2 dissolved
in arterial blood. However, when prolonged for 15–30
min, these therapies can lead to an increase in peripheral vascular
resistance along with a generalized vasoconstriction in most
organs (15). Decreased cerebral blood flow secondary to hyperoxia
has indeed been documented in humans by transcranial
Doppler (16) and magnetic resonance (17) studies.
The above-mentioned effects of ozone therapy and data from
the present study, especially the potentially greater effect in
older patients or in those with lower initial blood flow, augur
well for its use in cerebral low perfusion syndromes and stroke.
This is further supported by the clinical experience gained in a
study that assessed 150 patients with ischemic cerebrovascular
disease treated with prolonged ozone therapy (18).
The present Doppler study was planned with only three
ozone therapy sessions for several reasons. Firstly, we wanted
to evaluate the effect of ozone therapy and to observe whether
the effect could be maintained for a prolonged period, which
has been suggested by the clinical experience gained from its
use in sessions widely separated over several days. Hence, we
decided to perform the third session approximately 1 week
later without any intervening sessions. Secondly, we wanted to
administer the same number of sessions to all the patients in
the study. However, some of them were cancer patients who
needed to commence their scheduled radiochemotherapy.
Therefore, in order to avoid interference with the scheduled
radiochemotherapy, the present ozone study was performed
during the period when oncologic staging and planning of the
radiotherapy were carried out. Hence, the number of ozone
therapy sessions for Doppler evaluation was less than that
considered necessary for a full-fledged ozone therapy, which
usually lasts for several weeks or even months. The Doppler
Effect after several additional sessions could indeed be higher
than that currently observed. Data on the optimal separation
between the ozone therapy sessions are not currently available.
Further, the schedule could vary depending on the desired
clinical effect (antioxidant, enhancing the immune or vascular
system, etc.). Nevertheless, the current study supports the
clinical experience gained in the treatment of vascular disorders,
318 Ozone therapy on cerebral blood flow
0
50
100
150
200
250
300
350
0 10 20 30 40 50 60 70 80
Age
% increase in CCA blood flow
1 week after ozone therapy
Figure 4. Relationship between age and blood flow increase post-ozone
therapy. The percentage increase in CCA blood flow 1 week after session #3
was directly correlated with age (r 0.735; P 0.004). A higher increase
was observed after ozone therapy in older patients.
0
50
100
150
200
250
300
350
100 150 200 250 300 350
Basal CCA blood flow - ml/min
% increase in CCA blood flow
1 week after ozone therapy
Figure 5. Relationship between the baseline blood flow and its increase post
ozone therapy. The correlation in CCA blood flow between baseline values
and the percentage increase 1 week after session #3 was highly significant
(r 0.691; P 0.009), i.e., there is a higher percentage increase in CCA
corresponding to a lower initial blood flow. Note: the percentages under 100%
indicate a decrease in blood flow at this time point.
eCAM 2004;1(3) 319
employing widely separated sessions over extended periods
(2,3). Two or three applications per week appear to be sufficient
in providing significant vascular improvement. However,
changes observed over a mere 1 or 2 weeks are usually not
sufficient to improve chronic clinical conditions. The current
findings regarding a residual effect, which is still significantly
elevated over baseline 1 week after the last session, support
our postulation that one or two additional sessions per week
can be effective during the initial maintenance period. The
mode and timing of administration of additional sessions over
a period of months need to be explored for the optimization of
the sessions.
In the course of this study, our hospital facilities were transferred
to a different location in our city, and we were unable to
conduct further Doppler studies using the same equipment.
Therefore, we decided to increase the study sample by including
two healthy subjects from our hospital. We could not evaluate
the differences between patients and healthy subjects due to
the scarcity of patients. Only patient #5 had suffered a
CVA/stroke that may modify the Doppler evaluation in the
carotid and middle cerebral arteries. However, patients with
localized tumors do not appear to have a systemic vascular
alteration or an altered vascular response. Therefore, we
assumed that the effect observed in these arteries is a general
effect, which does not differ from that observed in the healthy
subjects or the patients that were studied.
Further studies, which include new technologies such as
interstitial multichannel laser Doppler used to quantify fluctuations
in microvascular perfusion during ozone therapy, are in
progress in order to ascertain some of the remaining doubts
regarding the efficacy of ozone therapy.
In conclusion, this preliminary Doppler study demonstrates,
albeit in a small number of subjects, that ozone therapy
increases blood flow in CCA and MCA with a prolonged
effect such that it can be very easily assessed by TCD and
carotid ultrasound. These data support the clinical experience
of achieving improvement using ozone therapy in peripheral
ischemic syndromes. Its potential use as a complementary
treatment in cerebral low perfusion syndromes warrants
further clinical investigation.
Acknowledgements
The study was supported in part by a grant (FUNCIS 98–31)
from the Health and Research Foundation of the Autonomous
Government of the Canary Islands, Spain.
We wish to thank Dr R. Reyes (Department of Interventional
and Vascular Radiology) and Dr G. Rovira-Dupláa (Ozone
therapy Unit of the Quirón Clinic, Barcelona, Spain) for their
valuable advice in conducting this study. We also thank
R. Martin-Oliva (Head of Department of Medical Physics) and
Dr M. A. Hernández (Head of Department of Radiation
Oncology) for their administrative and clinical support with
the equipment. Editorial assistance was provided by
Dr Peter R. Turner, t-SciMed, Reus, Spain.
Conflict of Interest
The study was supported in part by a grant (FUNCIS 98–31)
from the Health and Research Foundation of the Autonomous
Government of the Canary Islands, Spain.
References
1. Giunta R, Coppola A, Luongo C, Sammartino A, Guastafierro S, Grassia
A, et al. Ozonized autohemotransfusion improves hemorheological
parameters and oxygen delivery to tissues in patients with peripheral
occlusive arterial disease. Ann Hematol 2001;80:745–8.
2. Romero A, Menéndez S, Gómez M, Ley J. La Ozonoterapia en los estadios
avanzados de la aterosclerosis obliterante. Angiología 1993; 45:146–8.
3. Rovira G, Galindo N. La ozonoterapia en el tratamiento de las úlceras
crónicas de las extremidades inferiores. Angiología 1991;2:47–50.
4. Maulik D, Kadado T, Downing G, Phillips C. In vitro and in vivo validation
of time domain velocity and flow measurement technique.
J Ultrasound Med 1995;14:939–47.
5. Westra SJ, Levy DJ, Chaloupka JC, Hill JA, Robert JM, Sayre JW, et al.
Carotid artery volume flow: in vivo measurement with time-domain processing
US. Radiology 1997;202:725–9.
6. Schoning M, Scheel P. Color duplex measurement of cerebral blood flow
volume: intra- and interobserver reproducibility and habituation to serial
measurements in normal subjects. J Cereb Blood Flow Metab
1996;16:523–31.
7. León OS, Menéndez S, Merino N, Castillo R, Sam S, Pérez L, et al.
Ozone oxidative preconditioning: a protection against cellular damage by
free radicals. Mediators Inflamm 1998;7:289–94.
8. Hernández F, Menéndez S, Wong R. Decrease of blood cholesterol and
stimulation of antioxidative response in cardiopathy patients treated with
endovenous ozone therapy. Free Radical Biol Med 1995; 19:115–9.
9. Barber E, Menendez S, Leon OS, Barber MO, Merino N, Calunga JL,
et al. Prevention of renal injury after induction of ozone tolerance in rats
submitted to warm ischemia. Mediators Inflamm 1999;8:37–41.
10. Peralta C, León OS, Xaus C, Prats N, Jalil EC, Sala-Planell E, et al.
Protective effect of ozone treatment on the injury associated with hepatic
ischemia reperfusion: antioxidant-pro-oxidant balance. Free Rad Res
1999;31:191–6.
11. Bocci V. Autohaemotherapy after treatment of blood with ozone: a
reappraisal. J Int Med Res 1994;22:131–43.
12. Verrazzo G, Coppola L, Luongo C, Sammartino A, Giunta R, Grassia A,
et al. Hyperbaric oxygen, oxygen-ozone therapy, and rheologic parameters
of blood in patients with peripheral occlusive arterial disease.
Undersea Hyperb Med 1995;22:17–22.
13. Clavo B, Pérez JL, Catalá L, López L, Suárez G, Lloret M, et al. Effect of
ozone therapy on muscle oxygenation. J Altern Complem Med
2003;9:251–6.
14. Clavo B, Perez JL, Lopez L, Suarez G, Lloret M, Rodriguez V, et al.
Ozone therapy for tumor oxygenation: a pilot study. Evid Based
Complement Alternat Med 2004;1:93–8.
15. Bergo GW, Tyssebotn I. Cardiovascular effects of hyperbaric oxygen with
and without addition of carbon dioxide. Eur J Appl Physiol
1999;80:264–75.
16. Omae T, Ibayashi S, Kusuda K, Nakamura H,Yagi H, Fujishima M. Effects
of high atmospheric pressure and oxygen on middle cerebral blood flow
velocity in humans measured by transcranial Doppler. Stroke 1998;29:94–7.
17. Watson NA, Beards SC, Altaf N, Kassner A, Jackson A. The effect of hyperoxia
on cerebral blood flow: a study in healthy volunteers using magnetic
resonance phase-contrast angiography. Eur J Anaesthesiol 2000;17:152–9.
18. Rodriguez MM, Garcia JR, Menéndez S, Devesa E, Valverde S.
Ozonoterapia en la enfermedad cerebrovascular isquémica. Revista Cenic
Ciencias Biológicas 1998;29:145–8.
Received February 29, 2004; accepted August 20, 2004

XP Tonics

2009-07-27T07:04:00.000-07:00

Xp Tonik Sls

Giriş:

Bilindiği üzere kanser yaş, cinsiyet, ekonomik sınıf tanımayan ve hayatın hangi döneminde karşı karşıya kalınabileceğinin bilinmediği bir hastalıktır. Özellikle son yıllarda erken tanı yöntemlerinin bu kadar gelişmiş olmasına rağmen önlenemez bir artış gösteren kanser, ölümle sonuçlanan bir hastalık olması nedeniyle sadece hastalar değil hasta yakınlarının da oluşturduğu geniş bir populasyonu etkileyen, toplum üzerine sosyolojik ve psikolojik travmalar oluşturan son derece önemli bir hastalıktır.

Özellikle gelişmiş ülkelerde kanser üzerine yapılan çalışmalar hız kazanmış ikinci dünya savaşı ile birlikte kullanılmaya başlanan kemoterapi ve radyoterapi yöntemlerinin sınırlı sonuçları sebebi ile tıbbın temelini oluşturan ve alternatif tedavi yöntemleri içerisinde sayılan bitkisel druglar üzerine eğilmeye başlanmıştır. Yapılan binlerce çalışma geleceğe umutla bakmamızı sağlarken bu konuda bu eşsiz coğrafyada yaptığımız ve yapacağımız çalışmaların sonucunda elde ettiğimiz ve edeceğimiz sonuçlar ülkemizin dünya literatüründeki yerini daha yükseklere taşıyacak ve atalarımızdan bize miras kalan tıbbın öncüleri olma vasfını devam ettirmemizi sağlayacaktır.

Bilinen tedavi yöntemleri ile mümkün olması oldukça zor bir olasılık olsa da, bazı kanser türlerinin tedavisinde, erken teşhise bağlı kemoterapi, radyoterapi bazen da cerrahi tedaviler ile olumlu sonuçlar elde edildiği bilinmektedir. Viral sebeplerin (HPV) çok önemli bir rol oynadığı Rahim ağzı kanseri için geliştirilen aşı gibi diğer kanser türleri içinde çeşitli koruyucu yöntemleri ortaya koymaya çalışmak, akademisyenler ve bilim adamlarını son derece meşgul eden ve ne yazık ki çok fazla ilerleme kaydedilemeyen bir konudur.

Klinik ve laboratuar çalışmalarında kanser tedavisinde hatırı sayılır sağlık örgütleri ve bilim adamlarının ne kadar özveri ve gayretle çalıştıklarını unutmamak gerekir. Klasik tedavi yöntemleri dışında kalan alternatif tedavi yöntemleri ile kanserden kurtulmaya çalışan pek çok hastanın olduğu bilinmektedir. Modern tıp uygulamaları içerisinde yer almadığından profesyonel yardım almadan yapılan bu tedavilerle çok sınırlı sonuçlar alınabilmektedir.

Mevcut durumda modern tıpta uygulanabilecek her türlü tedavi yöntemi uygulandıktan sonra, artık başka şans kalmayıp hastalar kendi başlarına kaldıkları zaman alternatif tedavi yöntemlerine yönelmekte ancak çoğu kez geç kalınmaktadır. Özellikle bitkilerle tedavi iletişim olnaklarının en üst düzeyde olduğu içerisinde olduğumuz bilişim çağında tecrübelerin daha çok ve sıklıkla paylaşılmasına olanak sağlaması nedeniyle yaygınlaşmaya ve popülaritesini kazanmaya başlamıştır. Son çare olarak başvurulan bitkisel tedaviler aslında modern tedavil protokolleri içerisinde yer alması gereken tedaviler oldukları düşünülmektedir. Kanser erken teşhis, uygun tedavi ve hastanın tedavi aşamasında yapılan değerlendirilmesi ile yeni tedavi stratejilerinin de geliştirilmesi gereken bir hastalıktır. Herbalist Adnan Akar tarafından geliştirilen çeşitli bitkisel kombinasyonları içeren tedavi yöntemleri ile özellikle beyin tümörlerinde elde ettiği başarılar internet ortamında kolaylıkla takip edilmektedir. Xp Tonik Sls adı verilen özel kombinasyon tedavi ile elde edilen başarı, düzenli yapılan tetkikler ile ortaya konulmaktadır. Bu sonuçlar siz veya uzmanlarınız tarafından değerlendirilerek söz konusu dinamik, kombine tedavinin geliştirilmesine katkılarınız ümit edilmektedir.

Dr.Levent KARAFAKI 27/07/2009

Kanserde Ozon Tedavisinin Yeri

2009-07-04T06:35:00.000-07:00

Kanser tedavisine ozonun katkısı

Kanser toplumların korkulu rüyası olmaya devam eden, tedavisi oldukça zahmetli ve uzun süreli bir hastalıktır. Günümüzde belirli türlerine karşı önemli başarılar elde edilse de halen kanserin tedavisinde alınması gereken büyük mesafe olduğu açıktır. Ülkemizde her yıl 100.000’in üzerinde ölümden sorumlu olan kanserin tedavisinde en yaygın kullanılan iki yöntem ilaç (kemoterapi) ve ışın (radyoterapi) tedavileridir. Hastalığın ve hastanın durumuna göre her iki tedavi yöntemi ayrı ayrı veya birlikte kullanılabilir.

Kanser ile ilgili önemli sorunlardan bir tanesi nüks ve metastazların görülmesi bir diğeri de uygulanan tedavilerden kaynaklanan yan etkilerdir. Nüks bazı tür kanserlerde daha yaygın görülür ve hastanın tedavisi bittikten sonra uzun süre takibini gerektirir. Hastalığın tedavisi boyunca ve tedavi bittikten sonra ortaya çıkan yan etkiler ise bazen öyle şiddetli olur ki, hastanın yaşam konforunda büyük bozulmaya ve hatta hastalığın kendisinden daha büyük sorunlara kaynak teşkil eder. Günümüzde kanser tedavisinde kullanılan ilaçların insan vücudundaki normal hücreleri de etkilemesi, karaciğer ve böbrek gibi yaşamsal organlar üzerinde uzun süreli hasara neden olmaktadır.

Kanser korkutucu bir hastalık olduğu için, pek çok hasta ve hasta yakını mevcut tedavilere ek veya yardımcı yollar araştırmaktadırlar. Günümüzde bitkisel ilaçlar başta olmak üzere kanseri tedavi ettiği iddia edilen onlarca ürün hastalar tarafından yaygın olarak kullanılmaktadır. Hekimlerin önemli bir kısmı bu ürünlerin kullanılmasına karşıdır ancak çoğu vakada bu tür ilaçlar hekimin bilgisine başvurulmadan tedaviye dâhil edilmektedir. Fayda gördüğünü söyleyen onlarca hasta olmakla birlikte genel olarak kemoterapi ve radyoterapi ile birlikte kullanıldığı için, yararlı etkilerin hangi tedavi yönteminden kaynaklandığı çoğu zaman tespit edilemez. Her ne olursa olsun, hastalara mutlaka tedaviyi takip eden hekime danışmaları ve ilgili hekimin onayı ile bu tür ilaçları kullanmaları önerilir.

Hastalar ve hasta yakınları tarafından sıkça başvurulan yardımcı tedavi yöntemlerinden bir tanesi de ozon tedavisidir. Ozon tedavisinin kanser tedavisinde etkinliğinin olup olmadığı gün geçtikçe daha çok sorgulanmaktadır. Ozon tedavisinin etki mekanizması göz önüne alındığında, özellikle kemoterapi ve radyoterapi gören hastalara ozon uygulamasının birkaç yönden hasta yararına sonuçlar doğuracağı açıktır. Birincisi ozon tedavisi immun sistemi destekleyerek insan vücudunun kanser hücreleri ile savaşma kapasitesini ciddi düzeyde artırır. İkincisi, dokuların kanlanmasını ve dolaşımını düzenleyerek kemoterapi ve radyoterapinin etkinliğini artırır. Bilindiği gibi her iki tedavi yönteminin etkili olabilmesi için kanser dokusunun iyi düzeyde kanlanması gerekmektedir. Üçüncüsü, kanser dokusunda ortaya çıkan (hipoksi-oksijen yetersizliği) sorununun çözümüne yardımcı olarak kanser hücrelerinin metastaz (başka bölgelere göç etme) kapasitelerini düşürür. Dördüncüsü kemoterapi ve radyoterapiden kaynaklanan yan etkilerin (yorgunluk, bitkinlik, saç dökülmesi, karaciğer hasarı, radyoterapiden kaynaklanan yara ve cilt yanıkları vb.) azalmasına destek olur.

İtalya ve Almanya’da tek başına ozon ile kanser hastalarını tedavi eden pek çok merkez bulunmaktadır. Ülkemizde hekimler tarafından yeni tanınmaya başlayan bu destekleyici tedavinin bilinen yan etkisinin olmaması, kanser tedavisine yüksek miktarda ek yük getirmemesi ve pek çok hastanın yaşam konforunu ve tedavi etkinliğini artırması ümit vericidir. Yine de hastalarımızın tek başına ozon tedavisini değil, uygulanan kemoterapi ve radyoterapi kürleri ile bu tedaviyi almaları hem hastalar hem de hasta yakınları için yüz güldürücü sonuçlar doğuracaktır.

Doç.Dr.Ahmet KORKMAZ

Ozon Terapisinin Ülseratif Kolit Üzerine Etkileri

2009-07-01T11:36:00.000-07:00

Positive Effects of Oxygen-Ozone Therapy in
Chronic Ulcerative Rectocolitis
A Case Report
SUMMARY. This case report deals with a 45-year woman who suffered from chronic ulcerative rectocolitis, initially treated by allopathic drugs and subsequently only by holistic natural therapy. Whereas no satisfactory results were obtained with the first treatment, the second therapeutic approach was entirely successful. As is known, rectocolitis is a chronic pathology characterized by inflammatory and degenerative lesions of the bowel mucosa. Although its aetiology is still unknown, genetic, immunologic and environmental factors have been implicated. From September 1997 to February 2000 the patient was treated in different hospitals and at home with numerous drugs including anti-inflammatory medication, antibiotics, immunosuppressive, cortisone-like and anti-depressive substances. Since no acceptable positive effects were obtained, she opted for natural holistic therapy. The following clinical picture was recorded by us: 1) rectocolitis with ulcers, characterized by 20-30 bloody diarrhoeal bowel discharges per day; 2) severe anemia, hemoglobin being 5.2 g%; 3) severely imbalanced water status; 4) joint pain in numerous regions; 5) cough with abundant transparent catarrh, particularly the during night; 6) sleep loss due to cough and bowel discharges; 7) variable intensity fever; 8) depression due to home confinement; 9) no possibility of work; 10)total discouragement with physicians and official therapy. The holistic natural therapy consisted in two different modalities of oxygen-ozone therapy: a) rectal insufflation of a mixture of oxygen-ozone with a low concentration of ozone (10-12 mg of ozone in 1 mL of oxygen) 2-3 times a week for a long period; b) major ozonated autohemotransfusion with the addition of homotoxicological drugs once a week for a long period. At the end of July 2000, patient decided to stop treatments because she was healthy. She then continued with treatments every month up to the month of July 2001. After that no further therapy was given up to the last check-up in October, 2003, the patient being in good health.

TSK Koruyucu Hekimlik Bülteninde Ozon Tedavisi

2009-06-10T07:00:00.000-07:00

Yazar: Özler M, Öter Ş, Korkmaz A. Ozon Gazının Tıbbi Amaçlı Kullanılması. TAF Prev Med Bull. 2009; 8(1): 69-74.
TAF Preventive Medicine Bulletin, 2009: 8(1)
Derleme/Review Article TAF Prev Med Bull 2009; 8(1):59-64

Ozon Gazının Tıbbi Amaçlı Kullanılması
[The Use of Ozone Gas for Medical Purposes]

ÖZET

Ozon (O3) üç oksijen atomundan oluşan renksiz, keskin kokulu doğal bir gazdır. Yer yüzeyi yakınlarında toksik ve kirletici olan ozon, stratosfer tabakasında zararlı ultraviyole ışınları süzücü rolüyle hayati önem taşır. Keşfinden sonraki ilk yıllarda dezenfeksiyon amacıyla kullanılırken yıllar içerisinde yapılan çalışmalar medikal kullanımını gündeme getirmiştir. Ozon tedavisi belirli bir miktarda ozon/oksijen karışımının vücut boşluklarına ya da dolaşım sistemine uygulanması olarak özetlenebilir. Ozon/oksijen gaz karışımı intravenöz, intramuskuler, intraartiküler, intraplevral, intrarektal ve intradiskal uygulanabildiği gibi topikal de uygulanabilir. En yaygın ozon uygulanma şekli majör otohemoterapidir. Bu yöntemde hastadan özel bir şişe içerisine alınan 50–270 ml kan ozon/oksijen karışımı ile belirli bir süre temas ettirilir ve daha sonra tekrar vücuda geri verilir (reinfüzyon). Ozon uygulaması esnasında oksidatif stres ve lipid oksidayonu sonucu oluşan hidrojen peroksit ikincil haberci gibi davranarak ozon tedavisinin biyolojik etkilerine aracılık eder. Tekrarlayan ozon uygulamaları sonucunda antioksidan sistem uyarılarak oksidatif strese karşı direnç gelişir. Ayrıca hücre membranında bulunan yağ asitlerinin oksidasyonuna bağlı olarak çeşitli sitokin düzeyleri de artar. Ozon tedavisi özellikle inflamatuar sürecin yoğun olarak yaşandığı ve immün sistemin ön planda yer aldığı fizyopatolojik durumlarda yardımcı tedavi yöntemi olarak kullanılmaktadır. Bu durumlardan bazıları yara iyileşmesi, yaşa bağlı makuler dejenerasyon, iskemik ve infeksiyöz hastalıklardır.

SUMMARY

Ozone (O3) is a colorless and sharp odorous natural gas that is composed of three oxygen atoms. Ozone, that is toxic and pollutant near earth’s surface, it is vital in stratosphere by absorbing harmful ultraviolet radiation. Although initial years after being discovered it was used for disinfection, studies conducted have come into question for medical usage of ozone. Ozone therapy may be summarized as administering a particular amount of ozone/oxygen mixture into body cavities or circulation. Ozone/oxygen gas mixture can be applied via intravenous, intramuscular, intraarticular, intrapleural, intrarectal and intradiscal as well as topically. Most frequent ozone administration is major autohemotherapy. In this method, 50-270 ml blood of patient is taken into a special bottle and after contacting with ozone/oxygen mixture for a particular duration, it is re-infused. During this period, hydrogen peroxide produced by oxidative stress and lipid oxidations mediates the biological effects of ozone therapy by acting as a second messenger. Repetition of ozone administration creates resistance against oxidative stress via inducing antioxidative system. Moreover, levels of several cytokine are increased depending on the fatty acid oxidation in cell membranes. Ozone therapy is used as an adjuvant therapeutic modality in the pathophysiological conditions where severe inflammatory processes and immune activation are involved. Some of the examples are wound healing, age-dependent macular degeneration, ischemic and infectious disorders.

Mehmet Özler, Şükrü Öter, Ahmet Korkmaz
GATA Fizyoloji AD
Anahtar Kelimeler: Ozon, ozon tedavisi, lipid peroksidasyonu.
Key words: Ozone, ozone therapy, lipid peroxidation.
Sorumlu yazar/ Corresponding author: Mehmet Özler.
GATA Fizyoloji AD Etlik, Ankara, Türkiye.
fizyomehmet@gmail.com
GİRİŞ
Ozon üç oksijen atomundan oluşan gaz halinde bir moleküldür. Oksijen molekülünün (O2) kararlı haline karşın, ozon (O3), kararsız bir moleküldür. Ozon gazını alman kimyacı Christian Friedrich Schönbein 1839 yılında keşfetmiştir. Ozon renksiz ve keskin kokulu bir gazdır. Keşfinden sonraki ilk yıllarda dezenfeksiyon amacıyla kullanılmıştır. 1860 yılında Monaco şehrinin su arıtma tesisinde dezenfeksiyon amacıyla ozon kullanılmaya başlanmıştır. Ozonun bu dezenfekte edici etkisi güçlü okside edici özelliğinden kaynaklanmaktadır. Sadece virüs ve bakterileri öldürmekle kalmaz tüm mikroorganizmalar ve toksinlerini de okside edebilir. Ozon ayrıca fenolleri, pestisitleri, deterjanları, kimyasal atıkları ve aromatik bileşikleri de etkili şekilde nötralize edebilir (1,2). Ozon kimyasal yapısı itibariyle radikal özelliği taşımamakla birlikte, florin ve persülfattan sonra, bilinen üçüncü en güçlü oksidan maddedir (3).

Ozon özellikle atmosferin üst tabakalarında oldukça bol bulunan bir moleküldür. Atmosferdeki ozonun %90’ına yakını, yer yüzeyinden yaklaşık 20–50 km yüksekte bulunan stratosfer tabakası içinde yer alır. Geri kalan %10’luk ozon miktarı ise 10–15 km’ler arasındaki troposfer tabakası içinde bulunmaktadır. Atmosferde stratosfer tabakası içerisinde bulunan ozon, ultraviyole radyasyonunun etkisiyle bir taraftan oluşurken, öbür taraftan da yok edilmektedir. Bu işlem ultraviyole radyasyonun değişik frekanslarında meydana gelir (4).

Ozon oluşumunu gösteren tepkime aşağıda gösterilmiştir.
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Çok reaktif bir gaz olan ozon canlılar için toksiktir. Akciğer ve gözler ozonun toksik etkisine en hassas organlardır. Gözdeki irritasyonu ve akciğere etkileri konsantrasyon, sıcaklık, nem ve maruz kalınan süreye bağlı olarak değişir. Düşük konsantrasyonda ozon inhalasyonu, boğazda irritasyon ve buna bağlı öksürüğe neden olabilir. Yüksek konsantrasyonlardaki inhalasyon ise bronşiyal mukoza ve pnömosit hücresi hasarına bağlı akciğer ödemine kadar varabilir (5,6).

Medikal Ozon ve Etki Mekanizması

Ozonun tıbbi amaçla kullanımının ilk olarak 1880 yılında Dr. John Harvey Kellogg (Battle Creek/Michigan/ABD) tarafından gerçekleştirildiğini yazan kaynaklar bulunmakla birlikte daha yaygın görüşe göre kabul edilen ilk tıbbi kullanımı Birinci Dünya Savaşı sırasında Alman askerlerinin kangren ve benzeri ciddi yaralanmalarını tedavi eden Dr. Albert Wolff’a dayanır. Bilimsel bir toplantıda ozonun tedavi edici bir ajan olarak gündeme alındığı ilk önemli organizasyon ise 1935 yılında Berlin’de toplanan 59uncu Alman Cerrahi Birliği (59th Meeting of the German Surgical Society) toplantısı olup, burada Dr. Erwin Payr “Cerrahi’de Ozon Uygulamaları” başlığı altında kendi vakalarından oluşan derleme türünde bir sunum yapmıştır (7,8). Bu tarihten sonra 80’li yıllara kadar, ozon tedavisini münferit olarak uygulayan çeşitli hekimler ve araştırmacılar bulunmaktadır. 1980’li yıllardan itibaren ise tıbbi amaçla ozon kullanımına yönelik gerek bilimsel çalışmalar, gerekse vaka serileri literatürde artmaya başlamıştır. Ozon tedavisi belirli bir miktarda oksijen/ozon karışımının vücut boşluklarına ya da dolaşım sistemine uygulanmasıdır; bu karışım intravenöz, intramuskuler, intraartiküler, intraplevral, intrarektal ve intradiskal uygulanabildiği gibi topikal de uygulanabilir (3). Ozon tedavisinin klasik uygulaması haline gelmiş olan yöntem 1974 yılında Wolff tarafından tarif edilmiştir. Bu yöntemde; bir miktar kan (50–270 ml) vücut dışına alınarak, ozona dayanıklı bir şişede 5-10 dakika oksijen/ozon karışımıyla temas ettikten sonra tekrar aynı kişiye geri verilir (ototransfüzyon) (3,9). Bu uygulama şekli majör otohemoterapi (HT) olarak adlandırılmaktadır. Bu tarihten günümüze, daha çok Avrupa’da olmak üzere milyonlarca ozon ototransfüzyon tedavisi yapılmıştır (10).

Ozon reaktif bir molekül olduğu için tıbbi amaçlı kullanımında dikkat edilmesi gereken bazı durumlar vardır:

Ozon, hiçbir zaman saf olarak verilmemeli ve belli oranda oksijenle karıştırılarak uygulanmalıdır. Bu karışımda oksijen %95’den az ozon %5’ten fazla olmamalıdır. Normal atmosfer havasının bu karışıma girmesi engellenmelidir. Çünkü ozonun reaktif özelliğinden dolayı hava ile teması sonucu toksik bir gaz olan nitrojen dioksit (N2O2) oluşabilmektedir. Ayrıca emboliye sebep olmaması için ozon gaz olarak damar sistemi içerisine verilmemelidir. Tüm işlemler sırasında ozona dayanaklı malzemenin (paslanmaz çelik, nötral cam ve teflon) kullanılması gerekmektedir (3).

Ozon, diğer gazlar (O2, CO2) gibi suda çözünebilir. Ozon oksijene göre 1,6 kat daha yoğun ve suda çözünürlüğü 10 kat daha fazla olan bir moleküldür. Saf suda diğer gazlar gibi Henry kanununa göre çözünür. Çözünmesi ısıya, basınca ve konsantrasyonuna bağlıdır. Biyolojik sıvılarda ise ozon oksijenden farklı olarak hızlıca biyomoleküller ile reaksiyona girer.

OzonPlazmaROTLOPTrombositLökositEritrositDiğer organlarKemik iliğiendotelBüyüme faktörlerinin salınmasıİmmünsistem uyarılmasıDokulara daha kolay Oksijen bırakma Antioksidan enzim miktarında artmaOksidatifstrese dirençli eritrosit yapımıve artmışkök hücre aktivasyonuNO salgılanmasında artma

Şekil 1. Ozon tedavisinin etkileri. (ROT: Reaktif oksijen türevleri, LOP: Lipit oksidasyon ürünü (Lipid oxidation products))
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Dolayısı ile HT esnasında uygulanan ozon/oksijen karışımındaki ozon afinite sırasıyla çoklu doymamış yağ asitleriyle, antioksidanlarla ve sistein gibi sülfhidril (SH) grubu taşıyan tiyol bileşikleri ile reaksiyona girer. Ozonun miktarına bağlı olarak karbonhidratlar, proteinler (dolayısıyla da enzimler), DNA ve RNA da bu reaksiyondan etkilenebilir. Tüm bu bileşikler ozon karşısında elektron donörü gibi davranarak oksitlenirler. Sonuçta süperoksit (O2-), hidrojen peroksit (H2O2) ve hipoklorik asit(HClO) gibi reaktif oksijen türevleri (ROT) oluşur. Bu reaksiyonlardan en önemlisi doymamış yağ asitlerinin oksidasyonudur. Ana reaksiyon aşağıdaki gibidir (3).

R-CH=CH-R’+O3+H2O→R-CH=O+R’-CH=+H2O2

Bu reaksiyonda her hidrojen peroksit ile birlikte iki de lipit oksidasyon ürünü (lipid oxidation products; LOP) oluşmaktadır (11,12). Lipit oksidasyon ürünleri için iyi bilenen örnekler şunlardır; lipoperoksil radikalleri, hidroperoksitler, malondialdehit, izoprostan, alkenaller ve 4-hidroksi-2,3-trans nonenal (HNE) (13-16).

Görülüyor ki, ozonun biyolojik etkilerinin ortaya çıkması için serbest radikallerin varlığı önemlidir. Serbest radikaller, çeşitli patolojik süreçlerin gerek başlatıcısı, gerek ara basamaklarda işe karışabilen, gerekse sonucunda ortaya çıkabilen reaktif maddelerdir. Bunlar, organizmada aerobik solunum sırasında mitokondride ve fagositlerde solunum patlaması gibi çeşitli fizyolojik durumlarda da oluşabilmektedir (17). Aerobik canlılar serbest radikallerin toksik etkilerinden korunmak için antioksidan sistemler geliştirmişlerdir. Non enzimatik olanlar; ürik asit, askorbik asit, protein (özellikle albumin), protein olmayan tiyoller, vitamin E ve biluribindir. Enzimatik olanlar ise süperoksit dismutaz (SOD), katalaz (CAT) ile glutatyon peroksidaz (GPx) glutatyon transferaz (GST), glutatyon (GSH) ve glutatyon redüktazdan (GR) oluşan glutatyon sistemidir (12). Son zamanlara kadar oksidatif stresin hücre hasarındaki rolü ve hastalıkların altında yatan patolojik süreçlere etkileri konusuna odaklanılmıştı. Patolojik süreçlerde oksidatif stresin artış mekanizmaları ve etkilerini açıklayan yüzlerce çalışma yapılmıştır (18-23). Yakın zamanda yapılan çalışmalarda ise oksidatif stresin bilinenin tersi etkilerinin de olabileceği görülmüştür. Bu çalışmalarda oksidasyon/redüksiyon (redox) reaksiyonlarının başta hücre içi haberleşme olmak üzere biyolojik mekanizmalarda rol aldığı gösterilmiştir. Artık açık olarak biliniyor ki gerek reaktif moleküller gerekse bunların çeşitli biyolojik moleküllerle reaksiyona girmesi sonucu ortaya çıkan oksidasyon ürünleri düşük konsantrasyonlarda (fizyolojik düzeylerde) hücrede önemli roller üstlenmektedir (23-26).

Ozonun biyolojik etkilerini açıklamak için yapılan çalışmalarda daha çok HT tedavisi model alınmıştır (27-30). HT esnasında uygulanan ozon/oksijen karışımındaki ozon plazmada hızla çözünür. Daha önce bahsedildiği gibi sıvılardaki çözünürlüğü fazla olan ozonun bir kısmı plazmada bulunan antioksidanlar ile reaksiyona girerek bunların miktarlarını azaltır. Bu anlık olaylar sırasında çeşitli ROT de oluşabilmektedir. Bu radikallerin yarı ömrü çok kısa olduğu için, daha kan hastaya geri verilemeden, yani ototransfüzyondan önce bunlar ortadan kalkarak yerlerini lipit oksidasyon ürünlerine bırakırlar. Bu ürünler, büyük oranda kandaki hakim hücre olan eritrositlerin membranlarının oksidasyonu ile ortaya çıkar. Eritrosit membranındaki doymamış yağ asitleri oksidasyona çok duyarlıdır. Yukarıda formülünü de gösterdiğimiz üzere, bu reaksiyonlar sırasında ortaya çıkan hidrojen peroksit, molekül yapısı itibariyle radikal olmayan oksitleyici bir moleküldür (3,12,31).

Hidrojen peroksitin ozonun tedavi edici etkinliklerinin en azından bir kısmından sorumlu - ikincil habercisi gibi davrandığı kabul edilmektedir. İlk etkilerinden biri eritrositlerde 2,3-difosfogliserat düzeyini artırma yoluyla hemoglobin-oksijen ayrışma eğrisinin sağa kaymasına ve böylece oksijenin dokulara daha kolay bırakılmasına neden olmasıdır. Plazmada konsantasyonu artan hidrojen peroksit kolayca hücrelerin içine diffüze olarak; lökosit ve endotelial hücrelerde çeşitli interferon, interlökin ve transforme edici büyüme faktörü (TGF) yapımını da artıran uyarıları tetikler (32). Lipit oksidasyon ürünlerinin yarı ömürleri ise saatlere varabilmekte, dolayısıyla ömrü çok kısa olan ROT’lerin ilk etkileri sonrasında ozonun gecikmiş etkilerinden sorumlu tutulmaktadır. Uzun yarı ömürlerinden dolayı bu ürünler ototransfüzyon ile vücuda verilmiş olur ve dolaşım yoluyla dokulara ulaşarak buralarda çeşitli biyolojik etkiler gösterirler (31,33,34).

HT tedavisi yapılmadan önce kanın antikoagülan verilerek hazırlanması gerekir. Çünkü ozon doza bağlı olarak trombosit fonksiyonlarının artışına neden olmaktadır. Trombosit fonksiyonlarındaki artışın bazı yararlı sonuçları da olmaktadır. Aktive olmuş trombositler içlerinde bulunan büyüme faktörlerini salarak iskemi ve ülserli hastalarda iyileşmeye olumlu katkı sağlar (12). HT sonrası ozonlanmış kanın vücuda verilmesi ile oluşan terapötik etkileri şekil 1’de gösterilmiştir (31).

Ozonun konsantrasyonuna bağlı olarak artan kuvvetli okside edici özelliği nedeniyle belli bir
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orandan sonra vücut için de toksik etkisi olabileceği gerçeğini unutmamak gerekmektedir. Doğal olarak, organizmadaki antioksidan savunma sistemleri ozon oksidasyonuna karşı koyacaktır. Plazmanın sahip olduğu geniş antioksidan kapasite ve eritrositlerdeki antioksidan enzimler nedeniyle, kan ozon toksisitesine karşı en dirençli dokudur. HT uygulamaları sırasında plazmada çözünen ozonun burada bulunan antioksidanlar (bilirubin, askorbik asit, SH grubu taşıyan glutatyon ve albumin) ile reaksiyona girerek bunların konsantrasyonunu azaltmaktadır (31). Öte yandan, HT sonucu ortaya çıkan ROT artışı ve antioksidanların azalması geçici bir durumdur. Bocci ve Carlo, yaptıkları çalışmada değişik dozlarda (20,40,60,80 μg/ml) ozon uygulanmış kanlarda dozla doğru orantılı olarak glutatyon ve total antioksidan seviyesinde azalma, lipit peroksidasyonu ve okside glutatyon düzeyinde artma olduğunu göstermiş, uygulamanın 20 dakika sonrasında ise antioksidan düzeylerinin eski haline döndüğünü tespit etmişlerdir (30).

Denilebilir ki, HT uygulaması sırasında tedavinin etkinliğini kanın toplam antioksidan gücü belirlemektedir. Kanın antioksidan kapasitesi düşük, ozonun konsantrasyonu fazla olursa şiddetli membran oksidasyonu sonucu eritrositler hemolize olur, tam tersi olduğunda ise ozondan beklenen ROS ve hidrojen peroksit yanıtı yeterli olmayabilir ve arzulanan terapötik etki görülemeyebilir. Ozon uygulamaları sonucunda oluşması beklenen ROT ve lipit oksidasyon ürünlerinin terapötik etki gösterebilmesi için belli bir konsantrasyonda olması gerekir (3). Bu açıdan, kanda bulunan antioksidanların önemi yapılan bir çalışma ile gösterilmiştir. Bu çalışmada eritrositler yıkanarak plazmadan uzaklaştırılmış ve değişik konsantrasyonlarda ozon uygulanmıştır. Yapılan değerlendirmelerde düşük 10-20 μg/ml ozon konsantrasyonlarındaki uygulamalarda bile eritrositlerin çoğunda hemoliz olduğu görülmüştür (28). Yapılan çalışmalarda ozonun terapötik konsantrasyonu 10-80 μg/ml olarak belirlenmiştir. Bu ozon konsantrasyonu Rice-Evans’ın tarif ettiği total antioksidan kapasiteyi %25’den fazla düşürmediği gibi azalan antioksidanlar 20 dakika sonra eski haline gelmektedir. (27,28,35,36).

Ozon uygulaması ile hem oksijenaz-1 (HO-1) enziminin de uyarıldığı bildirilmiştir. Bu enzimin artışından gerek ROT, gerekse yukarıda sözü edilen ılımlı eritrosit hemolizi sorumlu olabilir. HO-1, hem halkasının yıkım yolunda görev alan mikrozomal bir enzimdir ve yapımı oksidatif stres artışı, proinflamatuvar sitokinler ve nitrik oksit (NO) ile uyarılabilmektedir Bu enzim hem molekülünü biliverdin ve karbon monoksite (CO) parçalar. Son yıllarda HO-1 ile yapılmış birçok çalışmada bu enzimin; antioksidan antiapopitotik antiinflamatuar etkilerinin olduğu gösterilmiştir. Ozon uygulaması sonucu görülen en etkin HO-1 artışının aynı zamanda ozonun terapötik doz aralığı olarak da vurgulanan 20-80 μg/ml arasında ortaya çıktığı gösterilmiştir. Yine HO-1’in yanında ısı şok protein-70’in de arttığı gösterilmiştir (36-38).

Ozonun diğer bir uygulama şekli olan minör hemoterapide ise hastadan alınan 5 ml kan ile aynı miktarda 80-100 μl/ml konsantrasyonundaki oksijen/ozon karışımı bir dakika inkübe edilir. Bu süre zarfında ozonunun, yine aynı şekilde kanda önce çözünüp sonra da biyolojik moleküller ile reaksiyona girmesi beklenir. Sonrasında bu kan, gluteus kasına yavaşca enjekte edilir. Bu uygulama sonrasında kas içine enjekte edilen kanın doku derinliklerine ilerlerken pıhtılaşmasına rağmen hastalardan çok azı hafif şişme ve ağrıdan yakınmaktadır. Bu işlem esnasında anesteziye gerek yoktur. Tartışmalı olmakla birlikte, bu uygulamanın immünmodülatuar bir etkisinin olduğu iddia edilmekte ve etki mekanizması şu şekilde açıklanmaktadır: Enjeksiyon yerinde hafif derecede steril inflamasyon meydana gelmekte, bölgeye nötrofil ve monositler gelerek denatüre proteinleri ve parçalanmış eritrositleri fagosite etmektedir. Eğer kan içinde HCV, HBV ve HIV gibi virüsler var ise ozon tarafından inaktive edilip parçalanmış bu virüs atıkları bölgeye gelen bu immün hücreler tarafından ortadan kaldırılır. Böylece bu işlem bir çeşit aşı etkisi yaratır ve immün sistemi bu antijenlere karşı uyarır (3).

Medikal Ozon Tedavisinin klinik uygulamaları

Ozon tedavisinin özellikle inflamatuar sürecin yoğun olarak yaşandığı ve immün sistemin ön planda yer aldığı fizyopatolojik durumlarda tedavi edici etkisi şaşırtıcıdır. Ozon uygulamaları yara iyileşmesi, yaşa bağlı makuler dejenerasyon, iskemik ve infeksiyöz hastalıklarda yapılan vaka analiz çalışmalarında olumlu etkiler göstermiştir. Bunun yanında basit diş ve ağız enfeksiyonlarından hepatitlere kadar uzanan geniş bir aralıktaki çeşitli enfeksiyon hastalıklarında etkin olarak uygulanmaktadır (39-41). Martinez-Sanchez ve arkadaşları diyabetik ayak gelişmiş hastalarda yaptıkları çalışmada ozon tedavisinin etkinliğini değerlendirmişlerdir. Bu çalışmada ozon tedavisi uygulanan hastalarda antibiyotik tedavisi alanlara göre yara iyileşmesi hızlanmış, hastanede kalma süreleri kısalmış, kan şekeri düzeyleri daha iyi kontrol edilebilmiş ve antioksidan enzim düzeyleri artmış olarak bulunmuştur (42). Ayrıca çeşitli 62 www.korhek.org

TAF Preventive Medicine Bulletin, 2009: 8(1)

derecelerde artrit ve artroz vakaları ile romatizmal hastalıkları da kapsayan ortopedik hastalıklarda da faydalı etkiler rapor eden araştırmalar dikkat çekmektedir. Buna örnek olarak Mutu ve arkadaşlarının lomber disk hernisi olan hastalarda yaptığı çalışmayı gösterebiliriz. Bu çalışmada lomber disk hernisi olan hastalara oksijen/ozon karışımı disk içine enjeksiyonla uygulanmıştır ve gerek hasta memnuniyeti gerekse medikal olarak yapılan değerlendirmede bu tedavinin yararlı olduğu görülmüştür (43).

Medikal Ozon Tedavisinin Yan Etki ve Kontrendikasyonları

Ozon tedavisinin yan etkisi yok denecek kadar azdır. Şimdiye kadar bildirilen yan etkiler uygulama hatalarına bağlı lokal komplikasyonlardır. Bazı durumlarda ozon terapisi uygulanması sakıncalı olabilir. Bu durumlar: glukoz 6 fosfat dehidrogenaz enzim eksikliği (favizm), özellikle erken dönem olmak üzere hamilelik, anjiotensin çevirici enzim (ACE) inhibitörü tedavisi görenler, hipertiroidi, kanama bozukluğu, kontrol altına alınamayan kardiyovasküler hastalıklar ve ozona reaksiyon gösteren astım hastaları olarak sıralanabilir (44).

SONUÇ VE ÖNERİLER

Ozon tedavisinin tarihi süreci incelendiğinde ilginç bir gelişme gösterdiği ortaya çıkar. Bu molekül keşfedildikten bir müddet sonra sonra tıbbi amaçlı kullanılmaya başlanmıştır. Ozon tedavisinin ilkeleri bilimsel olarak belirlenmeden birçok klinik uygulama yapılmıştır. Yakın zamanda doz ve etki çalışmaları yapılmış uygulamalar daha bilimsel bir temele oturmuştur. Bununla birlikte halen ozon tedavisinin etki mekanizmasının birçok yönden açıklanmaya ihtiyacı vardır. Tüm dünyada devam eden deneysel ve klinik ozon tedavisi çalışmaları, yakın gelecekte mekanizmanın daha ayrıntılı açıklanmasına katkıda bulunacaktır. Ülkemizde pekçok uzmanlık alanından hekimin kullandığı ozon tedavisi ile ilgili deneysel çalışmalar özellikle hiperbarik oksijen tedavisi ile karşılaştırmalı olarak GATA Fizyoloji AD. Başkanlığı araştırma laboratuvarında devam etmektedir (45-48).

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19. Oter S, Korkmaz A, Topal T, Ozcan O, Sadir S, Ozler M, Ogur R, Bilgic H. Correlation between hyperbaric oxygen exposure pressures and oxidative parameters in rat lung, brain, and erythrocytes. Clin Biochem. 2005; 38(8): 706-11.
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42. Martínez-Sánchez G, Al-Dalain SM, Menéndez S, Re L, Giuliani A, Candelario-Jalil E, Alvarez H, Fernández-Montequín JI, León OS. Therapeutic efficacy of ozone in patients with diabetic foot. Eur J Pharmacol. 2005; 523(1-3): 151-61.
43. Muto M, Ambrosanio G, Guarnieri G, Capobianco E, Piccolo G, Annunziata G, Rotondo A. Low back pain and sciatica: treatment with intradiscal-intraforaminal O2-O3 injection. Our experience. Radiol med. 2008; 113: 695-706.
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48. Özler M, Ersöz N, Özerhan İH, Harlak A, Sadır S, Topal T, Öter Ş, Korkmaz A. Sıçanlarda oluşturulmuş peritoneal adezyon üzerine ozon tedavisinin etkisi. 2009; in press.
64 www.korhek.org

Yazının PDF Formatı http://www.korhek.org/khb/khb_008_01-69.pdf

Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.

Kanserin Metabolik süreci

2009-05-28T10:19:00.000-07:00

KANSERİN METABOLİK SÜRECİ

Boston'daki Beth Israel Hastanesi şef patoloğu Dr. Harold Dvorak, 'Gerçekte hiç kimse kanserden ölmez' diyor. Çoğunlukla organ iflası sonucunda hastalar kaybedilmektedir. Kanser hücresi normal hücrelerden 10 ila 15 kat daha hızlı çoğalır. Bunun sonucunda da fazla miktarda glukoza ihtiyaç duyar. Normal hücreler gibi glukozu yakmayan kanser hücresi glukozu fermente (oksijen kullanmadan yıkım) eder ve sonuç olarak ortama laktik asit salınımına ve aşırı metabolik yüke sebep olur. Laktik asit karaciğere giderek sitrik asit siklusu ile glukoza dönüşür ve karaciğerde glikojen olarak depo edilir.

Karaciğer ve tümör arasındaki bu kısır döngü sonucu oluşan metabolik yük ve enerji kaybı, karaciğerin aşırı çalışarak belirli bir zaman sonra kendisini tüketmeye başlaması ve bu durumun devam etmesi sonucu tükenmesi ile sonuçlanır.

Karaciğerin kanserde üstlendiği görev yukarıda da anlattığımız şekliyle hayati öneme haizdir ve önemi kesinlikle göz ardı edilmemelidir. Başarılı bir kanser tedavisi ancak sağlıklı ve fonksiyonlarını eksiksiz yerine getirebilen bir karaciğerle yapılabilir. Bu nedenledir ki karaciğerin üzerindeki yükü almamızı sağlayan, onun iş yükünü hafifleten ve bunun yanı sıra kanserde yine önemi kaçınılmaz olan amino asit içeriği ile genlerin tamirinde görev alan XP Tonics SLS’nin neden kullanılması gerektiğini açıkça, tartışmasız gözler
Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir.

KANSER METABOLİZMASI

2009-05-17T10:09:00.000-07:00

KANSERİN METABOLİK SÜRECİ

Kanserden kimse ölmez, kanserin oluşturduğu ve çoğunlukla organ iflası sonucunda hastalar kaybedilmektedir. Kanser hücresi normal hücrelerden 10 ila 15 kat daha hızlı çoğalır. Bunun sonucunda da fazla miktarda glukoza ihtiyaç duyar. Normal hücreler gibi glukozu yakmayan kanser hücresi glukozu fermente (oksijen kullanmadan yıkım) eder ve sonuç olarak ortama laktik asit salınımına ve aşırı metabolik yüke sebep olur. Laktik asit karaciğere giderek sitrik asit siklusu ile glukoza dönüşür ve karaciğerde glikojen olarak depo edilir.

Karaciğer ve tümör arasındaki bu kısır döngü sonucu oluşan metabolik yük ve enerji kaybı, karaciğerin aşırı çalışarak belirli bir zaman sonra kendisini tüketmeye başlaması ve bu durumun devam etmesi sonucu tükenmesi ile sonuçlanır.

Karaciğerin kanserde üstlendiği görev yukarıda da anlattığımız şekliyle hayati öneme haizdir ve önemi kesinlikle göz ardı edilmemelidir. Başarılı bir kanser tedavisi ancak sağlıklı ve fonksiyonlarını eksiksiz yerine getirebilen bir karaciğerle yapılabilir. Bu nedenledir ki karaciğerin üzerindeki yükü almamızı sağlayan, onun iş yükünü hafifleten ve bunun yanı sıra kanserde yine önemi kaçınılmaz olan amino asit içeriği ile genlerin tamirinde görev alan XP Tonics SLS’nin neden kullanılması gerektiğini açıkça, tartışmasız gözler önüne sermektedir.

Hepatit C ve Ozone Therapy

2009-05-07T08:09:00.000-07:00

Hepatitis C and Ozone Therapy
by Gérard V. Sunnen, M.D.

Abstract
Hepatitis C (HCV) is a global disease with an expanding incidence and prevalence base. Of massive public health importance, hepatitis C presents supremely challenging problems in view of its adaptability and its pathogenic capacity. The unique strategies that HCV utilizes to parasitize its host make it a formidable enemy and therapeutic interventions need considerable honing to counter its progress. Ozone, because of its special biological properties, has theoretical and practical attributes to make it a potent HCV inactivator.

History of the virus A form of hepatitis became recognized in the 1970's that resembled hepatitis B, serum hepatitis, and to a lesser extent hepatitis A, infectious hepatitis. It had, however, novel features, amongst them, a distinctive serological profile. In 1989, the genome of hepatitis C (HCV) was deciphered.

It is possible, by means of extrapolation from the genetic evolution of a virus, to approximate its age. Sequence genetic analysis points to the diversification of different HCV genotypes 200 to 400 years ago. Ancestors to these genotypes probably date back 100,000 or so years when viruses co-evolved with modern humans. Further analysis of genetic viral trees and Old and New World primates take the primordial forms of these viruses to primate speciation periods some 35 million years ago.

Today, in the context of human population growth, migration, and global travel, the hepatitis C virus has expanded its territories, geographically, and demographically. There is every indication that the evolution of this virus, in all its forms, is currently manifesting an accelerated phase.

Virion architecture and molecular biology The HCV particle is composed of a nucleocapsid containing its genome, an RNA single strand composed of approximately 9600 nucleotides, and its protein coating. The nucleocapsid is surrounded by an envelope which allows attachment and penetration into host cells. The genome encodes structural proteins designated as core (C), envelope 1 (E1), envelope 2 (E2), and P7 (unknown function), providing for virion architecture, and nonstructural proteins, mainly enzymes essential to the virion's life cycle, designated as NS2, NS3, NS4A, NS4B, NS5A, and NS5B. Proteases release structural and nonstructural proteins. Helicases unwind viral nucleic acid. Polymerases replicate RNA. Within this genome is located a hypervariable region implying an area of intensive genetic fluidity and mutational potential. HCV displays great genotypic flexibility which makes for sophisticated evasiveness to host defenses.

The nucleocapsid is surrounded by an envelope, a lipid bilayer associated with a union of carbohydrates and proteins, glycoproteins. Up to 60% of the lipid component of the envelope is phospholipid and the remainder is mostly cholesterol. It possesses projections called peplomers which facilitate attachment to host cells. One protein on peplomers of the HCV particle which is thought to be instrumental in the attachment process is designated CD-81.

The sequence of nucleotides within the HCV genome shows significant variations. Strains obtained from different parts of the world, for example, may differ substantially in their structural and nonstructural protein compositions. This has lead to a system of classification of the HCV family into 6 genotypes (1 to 6), and approximately 100 subtypes (designated a, b, c, ect.). Genotypes vary from each other by a factor of 30% over the entire genome. Subtypes vary by about 20%. Genotypes 1 to 3 have global distribution, while genotype 4 and 5 are found mainly in Africa, and 6 is distributed in Asia. Importantly, genotype and subtype differences have shown varying susceptibility to antiviral therapy.

Within any one afflicted individual, HCV particles do not show a homogeneous population. Instead, they function as a pool of genetically variant strains known as quasispecies. This is due to the high replication error inherent in the function of the polymerase enzymes. Herein lies one of the important armaments of HCV. Continuously generated genetic diversity gives it great advantage in negotiating and conquering immune defense and therapeutic strategies. Furthermore, the antigenic differences between genotypes may have implications regarding the proper evaluation and the therapeutic regimen of patients.

Viral life cycle A freely circulating virion enters a host cell by binding to a cell surface receptor. In the case of HCV the host cell is a hepatocyte. However, bone marrow, kidney cells, macrophages, lymphocytes, and granulocytes may also be trespassed.

Once cell entry is achieved, the virion sheds its envelope to commence its replication. It binds to cellular ribosomes and released viral polymerase begins the RNA replication cycle. Newly formed nucleocapsids continue their assembly with the acquisition of new envelopes by means of budding through membranes of the cell's endoplamic reticulum. Newly formed virions may number in the range of 10 billion daily. The average life span of virions is in the order of a few hours.

Virions are then released into the general blood and lymphatic circulation, ready to infect new cells, re-infect already diseased cells, or a new host, mainly through bodily fluid transmission pathways. HCV RNA, as measured by polymerase chain reaction (PCR) may show 10 million or more virions per ml. As little as 0.0001 ml of blood may be sufficient to impart infection. The evolution of hepatitis C is characterized by phases of accentuated viremia punctuated by periods of relative quiescence. The presence and timely detection of these viremic waves may offer novel therapeutic considerations.

Clinical and laboratory manifestations Hepatitis, from anyone of the several viruses capable of inducing liver inflammation, produce a spectrum of clinical and laboratory manifestations. Hepatitis C distinguishes itself by the low incidence of acute phases and by the high incidence of progression to chronicity. Acute hepatitis C progresses from exposure, to incubation, to pre-icteric, icteric, and convalescent phases. With an incubation period of about 6 weeks, the first and sometimes only symptoms include weakness, fatigue, indolence, headache, nausea, poor appetite, and vague abdominal pain. The pre-icteric period extends from the onset of symptoms to the appearance of jaundice, ranging usually from 2 to 12 days. The icteric phase corresponds to the declaration of jaundice and darkened urine. The convalescent phase is marked by the gradual disappearance of symptoms.

Chronic hepatitis C is characterized by the presence of HCV RNA and the elevation of liver enzymes for 6 months or longer. Patients may be asymptomatic, or at times suffer an acute exacerbation with a return of symptoms. Approximately 75% of acutely ill patients continue into a chronic phase evidenced by parameters of viral presence.

Hepatitis C can only be distinguished from other viral hepatic conditions by serological and virological determinations. Liver enzymes characteristically affected by HCV infection include serum alanine transfesferase (ALT), aspartate aminotransferase (AST), gamma- glutamyl transpeptidase (GGTP), and alkaline phosphatase; in addition, there may be abnormalities in bilirubin, serum albumin, prothrombin time, and platelet density.

Cirrhosis, a diffuse disruption of liver tissue architecture with regenerative nodules surrounded by fibrosis, is an important sequel to hepatitis C. Within 20 years post HCV infection 20 to 25% of patients will develop cirrhosis. Hepatic decompensation ensues with ascites as the salient marker.

Hepatocellular carcinoma, another notable outcome of HCV infection is present in approximately 5% of patients post infection. The presence of cirrhosis is central to its genesis. Although the mechanisms by which cirrhosis ushers carcinoma are unknown, it is likely that chronic inflammation and the sustained pressure of cellular regeneration play important roles.

Up to 10% of patients appear to have fully conquered the disease. HCV antibodies are undetectable, as is HCV RNA. Liver enzymes are fully normalized, but liver biopsy may show lingering areas of stagnant inflammation and spotty necrosis. It is thus possible for host immunocompetence to vanquish HCV infection and therapeutic strategies aim to assist the host immune system to achieve this goal.

Immunological response to the virus HCV particles are detected early in the infection, usually 1 to 2 weeks following exposure. Antibodies to HCV core, nonstructural, and envelope elements appear about 6 weeks after exposure. A broad range of cytokines are mobilized. Cellular immunity is activated with broad recruitment of neutrophils, natural killer (NK), macrophages, and CD4 and CD8 T helper cells.

Current and experimental treatment strategies As of this date the main treatment strategies for hepatitis C include interferon and ribavirin. Interferons are natural cellular products which activate macrophages, neutrophils and natural killer cells. There is controversy as to interferon's biological effects, be they mostly immunoregulatory or directly antiviral. Ribavirin is a guanosine analog that represses messenger RNA formation thus inhibiting the replication of many DNA and RNA viruses. It is, however, mutagenic to mammalian cells. Ribavirin and interferon have significant medical and psychiatric side effects.

Treatment response is defined as undetectable viral load 6 months following therapy. Contemporary detection methods of quantitative HCV RNA determinations are capable of detecting approximately 1000 viral copies per serum ml.

Resistance to antiviral therapies is a particularly vexing problem in anti HCV treatment. Novel and experimental antiviral compounds include inhibitors of protease, polymerase and helicase.

Vaccine development needs to take into account HCV's antigenic rainbow and its high mutability. High mutation rates in this condition implies a dauntingly diverse and variable array of viral antigenic components. It is estimated, for example, that HCV mutates significantly in its own host approximately a thousand times a year. This implies that within any one afflicted individual there exists an awesomely large array of viral quasispecies, which in turn creates commensurate difficulties in the creation of effective vaccines.

Ozone: Physical and physiological properties Ozone (O3) is a naturally occurring configuration of three oxygen atoms. With a molecular weight of 48, the ozone molecule contains a large excess of energy. It has a bond angle of 127° and resonates among several forms. At room temperature, ozone has a half life of about one hour, reverting to oxygen. A powerful oxidant, ozone has unique biological properties which are being investigated for applications in various medical fields. Basic research on ozone's biological dynamics have centered upon its effects on blood cellular elements (erythrocytes, leucocytes, and platelets), and to its serum components (proteins, lipoproteins, lipids, carbohydrates, electrolytes). Administrating increaing dosages of ozone to whole blood shows that beyond a certain threshold there is a rise in the rate of hemolysis. This threshold, depending upon various parameters, begins to be reached at 40 to 60 micrograms per milliliter, and becomes significant when higher levels are attained. Precise ozone dosing capacity is therefore essential in clinical practice and research.

Leucocytes show good resistance to ozone because they have enzymes which protect them from oxidative stress. These enzymes include superoxide dismutase, glutathione, and catalase. Research has shown that platelets also maintain their integrity after ozone administration. In ozone therapy, the doses applied to blood are gauged to avoid disruption of its cellular elements. Serum components remain viable during ozone therapy. Lipid and protein peroxides, produced in small amounts by ozonation, have demonstrable antiviral properties. Interestingly, ozone tends to stimulate leucocyte function and cytokine production. Ozone increases the oxygen saturation (p02) in erythrocytes and enhances their pliability so that capillary circulation is facilitated.

Ozone: Antiviral properties Recently, there has surged renewed interest in the potential of ozone for viral inactivation. It has long been established that ozone neutralizes bacteria, viruses, and fungi in aqueous media. This has prompted the creation of water purification processing plants in many major municipalities worldwide.

Ozone's antiviral properties may also be applied to the treatment of biological fluids, albeit in technologically and physiologically appropriate ways. Indeed, it is noted that ozone, administered in such dosages designed to respect the integrity of blood's cellular and constituent elements, is capable of inactivating a spectrum of viral families.

Some viruses are much more susceptible to ozone's action than others. It has been found that lipid-enveloped viruses are the most sensitive. This group includes, amongst others, HCV, Herpes 1 and 2, Cytomegalus, HIV1 and 2.

The envelopes of viruses provide for intricate cell attachment, penetration, and cell exit strategies. Peplomers, finely tuned to adjust to changing receptors on a variety of host cells, constantly elaborate new glycoproteins under the direction of E1 and E2 portions of the HCV genome. Envelopes are fragile. They can be disrupted by ozone and its by-products.

In HCV, viral load appears to be a major factor in the invasiveness and virulence of the disease process. Preliminary research has shown that reduction of viral load in Hepatitis C by means of ozone therapy can significantly normalize hepatic enzymes and improve measures of global patient health. Volunteers administered ozone therapy according to the method outlined below achieved a viral load reduction in the order of 5 log, or 99.9%, along with a normalization of liver enzyme levels.

Ozone: Clinical methodology Ozone may be utilized for the therapy of a spectrum of clinical conditions. Routes of administration are varied and include external and internal (blood interfacing) methods. In the technique of ozone major autohemotherapy for hepatitis C, an aliquot of blood is withdrawn from a virally-afflicted patient, anticoagulated, interfaced with an ozone/oxygen mixture, then re-infused. This process is repeated serially until viral load reduction is documented.

The aliquots of blood range from 50 ml. to 300 ml. Ozone dosages and treatment frequency vary according to treatment protocols. The reason aliquots of blood are treated and not, as one would propose, the entire blood volume, is that in the latter case the total ozone dosage administered would exceed toxic limits.

The average adult has 4 to 6 liters of blood, accounting for about 7% of body weight. How can the viral load reduction observed via ozone therapy be explained in the face of a technique that treats relatively small amount of blood, albeit serially?

Ozone: Possible mechanisms of anti-viral action
The viral culling effects of ozone in infected blood may recruit the following mechanisms:

Denaturation of virions through direct contact with ozone. Ozone, via this mechanism, disrupts viral envelope proteins, lipoproteins, lipids, and glycoproteins. The presence of numerous double bonds in these unsaturated molecules makes them vulnerable to the oxidizing effects of ozone which readily donates its oxygen atom and accepts electrons in these redox reactions. Double bonds are thus reconfigured, molecular architecture is disrupted and widespread breakage of the envelope ensues. Deprived of an envelope, virions cannot sustain nor replicate themselves.

Ozone proper, and the peroxide compounds it creates, may directly alter structures on the viral envelope which are necessary for attachment to host cells. Peplomers, the viral glycoproteins protuberances which connect to host cell receptors are likely sites of ozone action. Alteration in peplomer integrity impairs attachment to host cellular membranes foiling viral attachment and penetration.

Introduction of ozone into the serum portion of whole blood induces the formation of lipid and protein peroxides. While these peroxides are not toxic to the host in quantities produced by ozone therapy, they nevertheless possess oxidizing properties of their own which persist in the bloodstream for several hours. Peroxides created by ozone administration show long-term antiviral effects which serve to further reduce viral load. This factor may explain in part the reason for the fact that ozonated blood in the amount processed in usual treatment protocols is able to reduce viral load values in the total blood volume.

Immunological effects of ozone have been documented. Cytokines are proteins manufactured by several different types of cells which regulate the functions of other cells. Mostly released by leucocytes, they are important in mobilizing the immune response. It has been found that ozone induces the release of cytokines which in turn activate a spectrum of immune cells. This is likely to constitute a significant avenue for the reduction of circulating virions.

Ozone action on viral particles in infected blood yield several possible outcomes. One outcome is the modification of virions so that they remain structurally grossly intact yet sufficiently dysfunctional as to be nonpathogenic. This attenuation of viral particle functionality through slight modifications of the viral envelope, and possibly the viral genome itself, modifies pathogenicity and allows the host to increase the sophistication of its immune response. The creation of dysfunctional viruses by ozone offers unique therapeutic possibilities. In view of the fact that so many mutational variants exist in any one afflicted individual, the creation of an antigenic spectrum of crippled virions could provide for a unique host-specific stimulation of the immune system, thus designing what may be called a host-specific autovaccine.

Summary
Viruses are far from being static entities. As quintessential intracellular parasites they have developed, through millions of years of cohabitation with their hosts, astoundingly sophisticated structures, survival, and propagation mechanisms. They have adapted, modified their biological strategies, and evolved impressive genetic diversity and mutational capacity to cope with the changing ecology of planetary life.

HCV has an extremely high rate of mutation and within any one individual there may exist millions of antigenic quasispecies. The disease process is marked by periods of viral quiescence alternating with viremic waves whereby billions of virions are poured into the blood and lymphatic reservoirs. Their astounding numbers stress the immune system relentlessly and produce an inexorable compromise in all parameters of its functioning.

Viral load reduction by means of ozone blood treatment alleviates immune system fatigue. Ozone-mediated viral culling may be achieved by anyone of a number of possible mechanisms. Direct virion denaturation, peplomer alteration, lipid and protein peroxide formation, cytokine induction, host pan-humoral activation, and host-specific autovaccine creation are suggested mechanisms. Due to the excess energy contained within the ozone molecule, it is theoretically likely that ozone, unlike antiviral options available today, will show effectiveness across the entire genotype and subtype spectrum.

Ozone embodies unique physico-chemical and biological properties which suggest an important role in the therapy of hepatitis C, either as a monotherapy, or as an adjunct to standard treatment regimens.

BIBLIOGRAPHY

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* Bocci V. Ozonation of blood for the therapy of viral diseases and immunodeficiencies. A hypothesis. Medical Hypotheses 1992 Sept; 39(1):30-34
* Bolton DC, Zee YC, Osebold JW. The biological effects of ozone on representative members of five groups of animal viruses. Environmental Research 1982; 27:476-48
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* Cardile V, et al. Effects of ozone on some biological activities of cells in vitro. Cell Biology and Toxicology 1995 Feb; 11(1):11-21
* Carpendale MT, Freeberg JK. Ozone inactivates HIV at noncytotoxic concentrations. Antiviral Research 1991; 16:281-292
* Dailey JF. Blood. Medical Consulting Group, Arlington MA, 1998
* Di Bisceglie AM, Bacon BR. The unmet challenge of hepatitis C. Scientific American 1999; 281:58-63
* Dienstag JL. Sexual and perinatal transmission of hepatitis C. Hepatology 1997; 26: 66S-70S
* Dieperink E, Willenbring M, Ho SB. Neuropsychiatric symptoms associated with hepatitis and interferon alpha: A review. Am J Psychiatry 2000 June; 157(6):867-876
* Evans AS, Kaslow RA (Eds). Viral Infections in Humans: Epidemiology and Control, Fourth Edition, Plenum, New York, 1997
* Gonzalez-Peralta RP, Qian K, She JY, et al. Clinical implications of viral quasispecies heterogeneity in chronic hepatitis C. J Med Virology 1996; 49:242-24
* Harrison TJ, Zuckerman AJ (Eds). The Molecular Medicine of Viral Hepatitis. Molecular Medical Science Series. John Wiley & Sons, New York, 1997
* Konrad H. Ozone therapy for viral diseases. In: Proceedings 10th Ozone World Congress 19-21 Mar 1991, Monaco. Zurich: International Ozone Association 1991:75-83
* Liang TJ, Hoofnagle JH, (Eds). Hepatitis C. Academic Press, San Diego, 2000
* Maggi F, Fornai C, Morrica A, et al. Divergent evolution of hepatitis C virus in liver and peripheral blood mononuclear cells of infected patients. J Med Virology 1999; 57:57-63
* Major ME, Feinstone SM. The molecular virology of hepatitis C. Hepatology 1997; 25: 1527-1538
* Maertens G, Stuyver L. Genotypes and genetic variation of hepatitis C virus. In: The Molecular Medicine of Viral Hepatitis. John Wiley $ Sons Ltd., London, 1997: 225-227
* Monjardino J. Molecular Biology of Hepatitis Viruses, Imperial College Press, London, 1998
* Par A, et al. Hepatitis C virus infection: pathogenesis, diagnosis and treatment. Scandinavian Journal of Gastroenterology. 1998 Suppl; 228: 107-114
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* Pawlotsky J. Hepatitis C virus resistance to antiviral therapy. Hepatology Nov. 5, 2000; 32: 889-89
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* Sunnen GV. Ozone in Medicine. Journal of Advancement in Medicine. 1988 Fall; 1(3): 159-174
* Trivedi M. Newly diagnosed hepatitis C: Lack of symptoms doesn't mean lack of progression. Postgraduate Medicine 1997; 102: 95-98
* Valentine GS, Foote CS, Greenberg A, Liebman JF (Eds). Active Oxygen in Biochemistry. Blackie Academic and Professional, London, 1995
* Vaughn JM, Chen Y, Linburg K, Morales D. Inactivation of human and simian rotaviruses by ozone. Applied Environmental Microbiology 1987; 48:2218-2221
* Viebahn R. The Use of Ozone in Medicine. Haug, Heildelberg, 1994
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http://www.triroc.com/sunnen/topics/hepc.htm sayfasından alınmıştır.

KANSERLE YAŞAM

2009-04-14T06:00:00.000-07:00

Zaman hızla geçip gidiyor ve kanser hastalığı yol almaya devam ediyor. Kanserojen maddelerdeki artış, genetik hasar konusundaki başarımız insanlığın en büyük ve en kötü illetini besleyip duruyor. Dr.Levent KARAFAKI
Bize kalan ise batıda geliştirilecek tedavileri bekleyerek umudumuzu korumaya çalışmak. Bu arada unuttuğumuz en önemli kavram ise yaşamak. Nasıl olmalı da kanserle yaşamayı öğrenmeliyiz. Hastalrımın büyük kısmında gördüğüm etki bıkkınlık, bitkinlik ve en sonunda ne olacaksa bir an önce olsun da kurtulayım psikolojisi.Dr.Levent KARAFAKI
Bu dünya hiçbirimize kalmayacak. Ama yaşamı zenginleştirmek ve haz almak bizim elimizde. Özellikle kanser hastalarında ki aslında tüm hastalarda en önemli olan yaşam sevgisi. Bu olmadan gribi bile atlatabilme gücüne sahip değiliz. Atatürk'ün bir sözü geliyor aklıma muhcat olduğunuz kudret damarlarınızdaki asil kanda mevcuttur. Asıl anlamı farklı olsa da sağlık için de bu cümlenin çok önemli olduğunu düşünüyorum. Yani hastalıkları iyileştirme gücü aslında kanımızda yani vücudumuzda mevcut. Sadece bizler bu gücü nasıl ortaya çıkarabileceğimizi bilmiyoruz. Asıl tedavi yolu buradan geçtiği halde biz bütün yükü ilaçların üzerinde bırakarak kendi bağışıklık sistemimiz ile iyileştirebilme gücümüzü ortaya çıkarmıyoruz.
Bu gücü nasıl kullanabilirz; Öncelikle desteğe ihtiyacımız olduğumuz olduğunu söylemem gerekiyor, eş, çocuk, anne, baba bazen arkadaş ne kadar faydalı olur bu yorucu yolculukta tahmin edemzsiniz. Nereden başlamalıyız, öncelikle vücudumuzu güçlü tutmanın anahtarı doğru beslenmeden geçer. Ne kadar az kimyasal madde o kadar çok mücadele, neler yemeliyiz veya neler yememeliyizden daha çok nasıl yemeliyiz daha önemli bir konu olarak karşımıza çıkıyor.

Şimdilik esen kalın yazının devamı nisanın son haftasında devam edecek.......

Dr.Levent KARAFAKI

Mevcut yazılı metin bilgilendirme amaçlıdır. Bilimsel verilerden elde edilmiş bilgilerdir. Konu hakkında uzman kişiler tarafından yönlendirilmeniz ve tedaviye yönelik işlemleri bir hekim kontrolünde uygulamanız veya uygulatmanız önerilir. Bu yazı Dr.Levent KARAFAKI tarafından kaleme alınmıştır. Lütfen kopyalerken de saygı duyalım ve en azından alıntı yapılan site veya yazan kişiyi belirtelim. Teşekkür ederim.

C VİTAMİNİNİN T HÜCRELER ÜZERİNE İMMÜNOMODÜLATÖR ETKİSİ

2009-04-14T04:57:00.000-07:00

Immunology Letters 98 (2005) 63–72
Mega-dose Vitamin C modulates T cell functions in Balb/c mice only
when administered during T cell activation
Kahwa Noha,b, Hyunja Lima,b, Sung-kyu Moona,b, Jae Seung Kanga,b, Wang Jae Leea,b,
Dongsup Leeb, Young-il Hwanga,b,∗
a Tumor Immunity Medical Research Center, Seoul National University College of Medicine, Seoul 110-799, South Korea
b Department of Anatomy, Seoul National University College of Medicine, 28 Yongon-Dong, Chongno-Gu,
Seoul 110-799, South Korea
Received 5 August 2004; received in revised form 20 October 2004; accepted 21 October 2004
Abstract
Previously we reported that a mega-dose of Vitamin C enhanced the initial stage of delayed-type hypersensitivity reaction in Balb/c mice.
In this study its effects were further evaluated as follows. Mice were administered Vitamin C intraperitoneally at 0.625 mg/day or at 5 mg/day
for variable days before, during, or after being sensitized with DNFB. T cells were isolated in each group and examined. When stimulated
antigen-specifically or non-specifically in vitro, mice showed elevated thymidine uptake and a shift of cytokine secretion profiles toward Th1,
i.e., elevated levels IL-2, TNF-, and IFN-, and lowered level of the Th2 cytokine IL-4, only when Vitamin C was administered during
sensitization. T cells from those mice administered Vitamin C before sensitization or after challenge showed the same T cell properties as those
from PBS-treated mice. Mice were also given 0.625 mg/day of Vitamin C during primary and/or secondary immunizations with KLH and
secondary specific antibody titers in sera were measured. The total specific antibody titer was lowered in Vitamin C-treated animals whenever
treatments were administered, and this was entirely attributed to decreased levels of IgG1 and IgE antibodies. Based on these results, we
suggest that an exogenously administered mega-dose of Vitamin C shifts immunity in Balb/c mouse toward Th1 and that these affects occur
only when Vitamin C is administered during T cell activation.
© 2004 Elsevier B.V. All rights reserved.
Keywords: Mega-dose; Vitamin C; Th1 polarization; Delayed type hypersensitivity; T cell activation; Isotype
1. Introduction
Vitamin C acts as an electron donor for many kinds of human
enzymes, facilitates iron transport, and is regarded as one
of the most important physiological antioxidants [1,2].In addition,
VitaminCexerts several diverse effects on the immune
system. It increases neutrophil motility [3,4] and phagocytic
function [5] in human. Macrophage functions in mice such as
chemotaxis, phagocytosis, and superoxide anion production
are enhanced by several antioxidants including Vitamin C
[6]. Increased proliferation of T cells [7,8], and inhibition of
∗ Corresponding author. Tel.: +82 2 740 8209; fax: +82 2 745 9528.
E-mail address: hyi830@snu.ac.kr (Y.-i. Hwang).
various forms of T cell death [9] and Fas-induced apoptosis
of monocytes [10] by Vitamin C have also been reported. The
increased cytotoxic activity of natural killer cells in humans
is another example of an effect ofVitamin C supplementation
[11,12].This biologically important micronutrient should be
exogenously administered in diets or as tablets to those, including
human, that lack terminal enzyme l-gulonolactone
oxidase in the Vitamin C synthetic pathway [13], and thus
cannot make Vitamin C themselves.
The recent recommended daily allowance (RDA) for
ascorbic acid by National Academy of Sciences is 75 mg and
90 mg per day for women and men, respectively. Nevertheless,
several authors have claimed that this dose is inadequate
and have suggested that the RDA be increased. For example,
0165-2478/$ – see front matter © 2004 Elsevier B.V. All rights reserved.
doi:10.1016/j.imlet.2004.10.012
64 K. Noh et al. / Immunology Letters 98 (2005) 63–72
Levine et al. [14] suggested 200 mg/day to maintain optimal
blood concentrations. Considering that low concentrations of
serum ascorbate are related to increased mortality [15,16], the
recent RDA could be below that actually needed to maintain
health.
Meanwhile, despite many controversies about its beneficial
effects, the usage of even higher doses of Vitamin C at
the level of grams per day has been suggested for both preventative
and therapeutic purposes in a number of diseases,
including cancer [17], atherosclerosis [18], viral infections
[19], H. pylori infection [20], and acute pancreatitis [21]. In
addition, supplement users regularly consume more than 1 g
of Vitamin C per day [22]. However, the effects and mechanisms
of such ‘mega-doses’ of Vitamin C have not been well
defined.
Previously we reported that exogenously given megadose
of Vitamin C augment the initial stage of delayedtype
hypersensitivity (DTH) response against 2,4-dinitro-1-
fluorobenzene (DNFB) in Balb/c mice [23]. In this study, we
further analyzed the ways in which mega-dose Vitamin C
modifies the functions of T cells in mice. When mega-dose
Vitamin C was administered during sensitization, activated
and memory T cells were rendered more vulnerable to both
ex vivo antigen-specific and non-specific stimuli and their
cytokine secretion profiles were shifted to Th1. Furthermore,
vitamin C also affected humoral immune response against
keyhole limpet hemagglutinin (KLH), by critically lowering
specific serum IgG1 and IgE levels.
2. Materials and methods
2.1. Mice
Seven-week-old male Balb/c mice were purchased from
BioLink (Seoul, Korea) and housed in animal facilities at
Seoul National University, College of Medicine (Seoul, Korea).
They were kept under a 12 h light–dark cycle and all
the animals were given mice chow and tap water ad libitum
through the experimental period.
Experimental groups were administered Vitamin C
(Sigma, St. Louis, MO) intraperritoneally at a daily dose
of 0.625 mg or 5mg freshly dissolved in 200l of PBS.
The durations of the injections varied in each experimental
group. An equal volume of PBS was given to control
animals.
2.2. Induction of delayed type hypersensitivity (DTH)
reaction
To induce DTH response, animals were shaved on the
dorsum (approximately 1 cm×1 cm). Sensitizationwas done
for two consecutive days by applying 25 l of 0.5% DNFB
solution gradually onto the shaved skin. DNFB (Sigma, St.
Louis, MO) solutionwas freshly prepared in acetone:olive oil
(4:1) just before use. On variable days after the last sensitization,
DTH was induced by the topical application of 20l
of 0.2% DNFB solution on the dorsal surface of the right
pinna [24]. The interval between sensitization and challenge
varied depending on the experiments. The left pinna was left
untreated or treated with vehicle only. The thickness of both
pinnae were measured with a constant-loading micrometer
(Mitutoyo, Japan) once just before sensitization (designated
as basal thickness) and for 7–10 days after challenge at the
same time of the day. The magnitude of DTH response was
expressed as the percentage of pinna swelling compared to
its basal thickness.
2.3. T lymphocyte proliferation assay
To assess the effect of mega-dose Vitamin C on na¨ıve,
act¨ıvated, and memory T cells, mice were administered
0.625 mg of Vitamin C for various days before, during, or
after sensitization with DNFB. Splenocytes were isolated
using Ficoll-Hypaque (Amersham Pharmacia Biotech, Sweden)
density gradient and incubated at 37 ◦C for 2 h to remove
adherent monocytes and macrophages, and then in
a dish coated with 10 ml of 2 g/ml anti-NK1.1 antibody
(Pharmingen, San Diego, CA) for another 2 h to eliminate
NK cells. T cells were further purified by negative selection
using Dynabeads® Mouse pan B (Dynal Biotech, Oslo, Norway)
by following the manufacturer’s instructions. Briefly,
4×107 Dynabeads were added to 107 cells in a 1.5 ml microcentrifuge
tube, mixed well, and incubated at 4 ◦C for 40 min.
The tubes were then placed in a Dynal MPC (magnetic particle
concentrator) for 2 min. Un-bound cells were collected
by washing with PBS containing 0.1% fetal bovine serum.
The purity of T cells was assessed by FACS analysis using
PE-conjugated hamster anti-CD3 antibody (Pharmingen, San
Diego, CA).
Non-specific T cell activation was determined using hamster
anti-CD3 antibody (Pharmingen, San Diego, CA) or
PMA/ionomycin (Calbiochem, San Diego, CA). Ninety sixwell
plates were coated with 100l of 1g/ml anti-CD3
antibody in each well at 4 ◦C for 24 h. T cells were plated
in coated wells (at 2×105/well), or were cultured in the
presence of 100 ng/ml PMA and 500 ng/ml ionomycin. Incubation
was carried out for 24 h in Dulbeco’s minimum
essential medium (DMEM) supplemented with 10% fetal
bovine serum (Gibco BRL, Carlsbad, CA), 100 U/ml
of penicillin and 100g/ml of streptomycin (Gibco BRL,
Carlsbad, CA) at 37 ◦C in an atmosphere supplemented
with 5% CO2. DNFB-specific T cells were also stimulated.
T cells, 2×105/well, were co-cultured in 96-well
plates with 5×105 mitomycin-treated syngeneic spleen
cells pulsed with 2,4-dinitrobenzenesulfonic acid (DNBS;
Aldrich, Milwaukee, WI), a water-soluble DNFB analogue
[25]. After 24 h, cells were pulsed with 1Ci/well of [3H]
thymidine (Amersham Pharmacia Biotech, Oslo, Norway)
for 18 h, and then harvested using a cell harvester (Skatron
Instrument, Lier, Norway) on glass-fiber filters. Radioactivity
was counted in a scintillation counter (WalK.
Noh et al. / Immunology Letters 98 (2005) 63–72 65
lac, Fort Wayne, IN) and all samples were prepared in
triplicate.
2.4. Cytokine detection
To determine the effect of a mega-dose Vitamin C on
cytokine secretion profiles, T cells were purified as described
above. T cells, 3×106/well, were plated in six-well plates
and stimulated with anti-CD3 antibody, PMA/ionomycin,
or DNBS, as described above. After 24 h incubation,
supernatants were collected. Cytokines in the cell-free
supernatants were detected using commercial quantitative
sandwich immunoassay kits for IL-2, IFN-, TNF- (R&D
Systems, Minneapolis, MN), and IL-4 (Biosource, Nivelles,
Belgium) by following the manufacturer’s manual.
2.5. Immunization with keyhole limpet hemocyanin
(KLH) and specific antibody titration
To assess the effects of Vitamin C on humoral immune
response, we immunized mice twice, on days 1 and 21, with
an intraperitoneal injection of 100g KLH (Calbiochem, La
Jolla, CA) in 200l PBS. Control mice were injected with
PBS only. Blood samples were drawn from the orbital plexus
on days 11 and 31, sera were obtained and stored at 4 ◦C until
used.
To titrate KLH-specific antibodies in sera, 96 well-ELISA
plates (Nunc, Rochester, NY) were coated with 100l of
4g/ml KLH/well for 2 days at 4 ◦C. Plates were then briefly
washed and blocked with 1% skim milk in PBS for 1 h at
room temperature. Serum samples were diluted 1:100 in 1%
skim milk/PBS containing 0.05% Tween 20, applied to the
first row of ELISA plate, and were four-fold serially diluted.
All samples were prepared in duplicate. After incubation
for 2 h at room temperature, plates were washed with
a PBS-0.05% Tween 20 mixture, and alkaline phosphataseconjugated
secondary antibodies for each isotype were added
and incubated for 60 min at room temperature. Plates were
washed three times, and p-nitrophenyl phosphate substrate
(Amresco, Solon, OH) solution was added. OD values were
measured at 405 nm. The secondary antibodies used were
as follows; goat anti-mouse polyvalent immunoglobulins
(1:1000 diluted, Sigma), goat anti-mouse IgM, IgG1, IgG2a,
IgG2b, IgG3, and IgE antibodies (1:1000 diluted, Southern
Biotech, Birmingham, AL). KLH-specific anti-sera obtained
from other experiments were collected in a tube and used as
a standard serum in every ELISA plate. Titers are expressed
as relative to standard serum values.
2.6. Statistical analysis
Statistical analysis was performed by one-way ANOVA
with Student–Newman–Keuls post-hoc analysis using
PRISM software (GraphPad, San Diego, CA). Significance
was set at p < 0.05.
3. Results
3.1. Vitamin C pre-treatment before challenge enhances
the initial stage of DTH response, but suppresses overall
inflammation accompanying DTH response
Mice were treated intraperitoneally with a daily dose of
0.625 mg or 5mg of Vitamin C, or 200 l of PBS for 26 days,
during which sensitization (on days 4 and 5) and challenge
(on day 16) with DNFB were done. Each group consisted
of eight mice. After inducing DTH response, pinna thickness
was measured and the % increment calculated versus
basal thickness (Fig. 1A). Because, in pilot tests, ears treated
with vehicle only (acetone:olive oil) showed just slight and
transient thickness increases (data not shown), we left con-
Fig. 1. The effect of Vitamin C injected during or after the induction of
skin DTH response against DNFB. Mice were intraperitoneally injected
with daily doses of 0.625 or 5mg of Vitamin C for whole 26 days of experiment
(A) or only after challenge, (B) respectively. Sensitization was
done with DNFB on days 11 and 12. Control groups were injected with
200l of PBS. The thickness of pinna was measured after challenge as
indicated, and the percentage thickness increment vs. basal thickness was
calculated. When Vitamin C was administered all through the experimental
days (A), the pinnae of experimental groups on the first day after challenge
were dose-dependently thicker than those of the control groups (p < 0.001).
Subsequently, from the second day, this situation reversed. When Vitamin C
was administered only after challenge (B), the profile was nearly the same
as that shown by Panel A, except on the first day, when the values do not
reveal statistically significant differences. Data represent mean ear swelling
(±S.D.) of eight mice per group.
66 K. Noh et al. / Immunology Letters 98 (2005) 63–72
trol pinnae untreated (even by vehicle). Pinna thickness in all
groups peaked 2 days after challenge (32.8, 24.4, and 18.6%
increment in control, 0.625 mg-, and 5 mg-treated groups,
respectively) and then gradually decreased; control group
values were highest and those of the 5 mg-treated group
lowest. However, the values were reverse 1 day after challenge,
the initial stage of DTH response. The control group
showed the lowest increment (12.7%) and the 5 mg-treated
group showed the highest (17.9%). These differences between
the three groups were statistically significant. This pattern
was exactly the same to as that reported previously [23].
Thus, Vitamin C treatment seemed to accentuate the initial
stage of DTH response on the one hand, and to exert antiinflammatory
effects on an initiated DTH response on the
other.
Considering that intraperitoneally injected exogenous vitamin
C accumulates in several tissues of the body [23], the
observed initial accentuation of DTH response by Vitamin
C treatment could be the result of accumulated tissue Vitamin
C, or the result of any alterations of immune components
before challenge. To clarify this issue, we induced DTH response
in another set of experimental groups, which were
injected with a daily dose of 0.625 mg or 5mg of Vitamin C,
or 200l of PBS for 10 days from the day of challenge, and
then measured the pinna thickness (Fig. 1B). The overall profile
was similar to the results of the groups in Fig. 1A, except
that the increment on the first day after challenge was lowest
in the 5 mg-treated group (12.4 compared to 14.4% both in
the control and in the 0.625 mg-treated groups) even though
thiswas not statistically significant. These results suggest that
pre-treating with Vitamin C before and during sensitization
affects those immune components that induce an increase
in the early DTH response. Of course, the inflammatory response
itself seemed to be suppressed by the presence of
exogenous Vitamin C alone when the inflammation was proceeding.
3.2. Vitamin C treatment only during sensitization
enhanced the initial stage of DTH
We further divided the experimental group in Fig. 1A into
“before sensitization” and “during sensitization” subgroups.
In this case, challenge was done at 38 days, instead of at 6
days after sensitization to allow the activated immune cells to
become quiescent. Thus, four groups were given a daily dose
of 0.625 mg of Vitamin C, (1) during all experimental days
(60 days; () in Fig. 2), (2) for 7 days before sensitization
(() in Fig. 2), (3) for 10 days during sensitization (() in
Fig. 2), or (4) for 10 days after challenge ((♦) in Fig. 2). The
control group received PBS on all experimental days (() in
Fig. 2). As is shown in Fig. 2, two groups injected during the
sensitization period showed a greater pinna thickness increment
on the first day after challenge than the other groups,
including the control group (p < 0.01). Injection of Vitamin C
before sensitization or after challenge failed to augment the
initial DTH response.
Fig. 2. The effect of Vitamin C treatment before sensitization, during sensitization,
and after challenge on DTH response was further analyzed. Mice
were intraperitoneally injected with 0.625 mg of Vitamin C for all days of
the experiment (), for 7 days before sensitization (), for 10 days during
sensitization (), for 10 days after challenge (♦), or injected with 200 l
PBS during the experiment (). DTH response was induced with DNFB 38
days after sensitization to allow the T cells activated during sensitization
to become quiescent. Only the groups administered with Vitamin C during
sensitization (and on the graph) showed an initial accentuation of DTH
response as shown in Fig. 1A. The data represent mean ear swelling (±S.D.)
of eight mice per group.
3.3. Vitamin C enhanced T cell proliferation
The next task was to identify which of the immune components
was most probably affected by Vitamin C during
sensitization, and responsible for the accentuation of the initial
stage of DTH response. We thought that T cells were
the most probable candidate, because T cells, especially Th1
cells, are the prime responders during sensitization and the
initiation of DTH response by antigen challenge [26]. Therefore,
we evaluated the functional differences of T cells from
mice treated and not treated with Vitamin C.
Mice were administrated 0.625 mg of Vitamin C or 200 l
of PBS (A) for 10 days without sensitization (na¨ıve T cells;
equivalent to () in Fig. 2), or (B) for 16 days with sensitization
at days 11 and 12 (activated T cells; equivalent to ()
in Fig. 2), or (C) for 54 days with sensitization on days 10
and 11 (memory T cells; equivalent to () in Fig. 2). At the
end of the Vitamin C administration, mice were sacrificed
and T cells were obtained as described in Section 2. Purity of
isolated T cells was over 90% as assessed by FACS analysis
(data not shown).
Na¨ıve T cells (Fig. 3A) proliferated in the presence of
anti-CD3 antibody and PMA/I, but were not proliferated by
DNBS and without stimulation (“control” in the graph). Furthermore,
the magnitude of thymidine incorporation was the
same in both the Vitamin C-treated and PBS-treated groups.
These results imply the absence of both active T cells and
DNFB-specific memory T cells. After sensitization (Fig. 3B),
T cells proliferated in the absence of any kind of proliferative
stimulus (‘control’ in the graph) implying T cell activation in
K. Noh et al. / Immunology Letters 98 (2005) 63–72 67
Fig. 3. The effect of exogenously administered mega-dose Vitamin C on
T cell proliferative activities. Mice were treated with 0.625 mg of Vitamin
C for 10 days without sensitization (A), for 16 days with sensitization on
days 11 and 12 (B), or for 54 days with sensitization on days 11 and 12 (C).
Control groups were injected with 200l of PBS. T cells were isolated and
cultured for 24 h with a DNFB-specific or non-specific stimuli (anti-CD3
antibody or PMA/I). Tritiated thymidine was pulsed for an additional 18 h
and radioactivities were measured. The filled bar () and the unfilled bar ()
represent the Vitamin C-treated and PBS-treated groups, respectively. The
proliferation of T cells from Vitamin C-treated mice exceeded that of the
control groups only when the mice were sensitized. Values are the average
cpm±S.D. of triplicates.
vivo by sensitization. When stimulated with anti-CD3 antibody
or PMA/I, thymidine uptake was elevated more in the
Vitamin C-treated group than in the PBS-treated group. To
be noticed in these groups is that DNBS also enhanced T cell
proliferation in contrast to the na¨ıve T cell groups, implying
the presence of DNFB-specific activated T cells. T cells
from mice 42 days after sensitization (Fig. 3C) revealed similar
results to those in Fig. 3B. However, the control group
showed minimal uptake indicating the absence of activated T
cells. Meanwhile, proliferation was induced by DNBS both
in Vitamin C-treated and PBS-treated groups, which implies
the presence of DNFB-specific memory T cells. However,
the magnitude of thymidine uptake in the Vitamin C-treated
group was double that of the PBS-treated group.
Besides the status of the T cells isolated, another possible
factor that could elicit differences among groups in Fig. 3
is the duration of Vitamin C treatment (10, 16, and 54 days,
respectively). Therefore, we repeated the T cell proliferation
assay with some modification and examined the effect
of the duration of Vitamin C treatment. Mice were treated
with a daily dose of 0.625 mg Vitamin C (A) for 43 days
with sensitization on days 4 and 5, or (B) for 43 days without
sensitization, or (C) treated with Vitamin C only for 10 days
during sensitization 38 days before T cell isolation. Thymidine
uptake assays were done in the same way as in Fig. 3;
the results are shown in Fig. 4. Results for the 43 day-treated
and sensitized groups (Fig. 4A) were the same as those of
the groups in Fig. 3C, which were treated for 54 days and
sensitized. Despite long-term treatment of Vitamin (for 43
days), if sensitization was not carried out during Vitamin
C treatment (Fig. 4B, similar to Fig. 3A), T cells showed
unaltered thymidine uptake compared to the corresponding
PBS-treated group. Meanwhile, those treated with Vitamin
C only during sensitization (Fig. 4C) elicited similar results
to the sensitized 43-day Vitamin C-treated group (Fig. 4A),
suggesting that sensitization in the presence of exogenously
administered mega-dose Vitamin C results in an increase
in T cell response to both antigen-specific and non-specific
stimuli.
3.4. T cells treated with Vitamin C shifted their cytokine
secretion profiles from Th2 to Th1
The enhanced initial stage of DTH response could be regarded
as an outcome of the shift of general immune response
from Th2 to Th1 [27]. Thus, changes in the cytokine secretion
profiles of T cells could be expected. Mice were treated with
Vitamin C or PBS and T cells were isolated as in Fig. 3. After
the ex vivo stimulation of T cells for 24 h, supernatants were
collected and titers of Th1 cytokines including IL-2, TNF-
, and IFN- and the Th2 cytokine IL-4 were measured by
ELISA.
Without sensitization (left column in Fig. 5), Vitamin C
treatment did not alter the cytokine secretion profiles of T
cells versus those of PBS-treated mice, at least with respect
to the four cytokines tested. T cells not-stimulated or stimulated
with DNBS secreted no detectable cytokines. In contrast,
T cells from sensitized mice, regardless of their being
activated (middle column in Fig. 5) or memory (right column
in Fig. 5) cells, showed elevated IL-2, TNF-, and IFN- secretions
in Vitamin C-treated mice, whereas the secretion of
IL-4 decreased.
68 K. Noh et al. / Immunology Letters 98 (2005) 63–72
Fig. 4. The effect of the duration of Vitamin C treatment on T cell proliferative
activities. Mice were injected with 0.625 mg of Vitamin C for 43 days
with sensitization on days 4 and 5 (A), for 43 days without sensitization (B),
or for the first 10 days of the 43 days with sensitization on days 4 and 5 (C).
Control groups were injected with 200l of PBS. T cells were isolated and
cultured for 24 h with DNFB specific or non-specific stimuli (anti-CD3 antibody
or PMA/I). Tritiated thymidine was pulsed for an additional 18 h, and
radioactivities were measured. Filled bar () and unfilled bar () represent
Vitamin C-treated and PBS-treated groups, respectively. Even though mice
were treated with Vitamin C for 43 days, T cells show no difference in their
proliferative activity vs. those of PBS-treated mice if they were not sensitized
during Vitamin C treatment (B). In contrast, only a 10-day Vitamin C
treatment affected T cell proliferation when the treatment was done during
sensitization (C). Values are the average cpm±S.D. of triplicates.
3.5. Vitamin C decreased anti-KLH IgG1 and IgE
antibody responses in vivo
Because cytokine profiles were shifted toward Th1, it
could be predicted that humoral response would be attenuated
[27]. To verify this, we injected mice with Vitamin C
or PBS, immunized them withKLHtwice, and then measured
the serum KLH specific antibody titers by ELISA. A daily
dose of 0.625 mg Vitamin C was intraperitoneally administered;
(1) on all experimental days, or (2) during the primary
immunization for 7 days, or (3) during the secondary immunization
for 7 days. The control group was treated with PBS
on all experimental days.
The results shown in Fig. 6 are for secondary immune
sera. Whole specific titer (IgM, IgG, and IgA) was reduced
in Vitamin C-treated mice regardless of treatment time, and
this seemed to be mainly due to reduced IgG1 and IgE titer,
which are typical Th2-driven isotypes in mice. Other isotypes
were unaffected in terms of KLH specific titer.
4. Discussion
In this study, we examined the effects of Vitamin C on
immune response in Balb/c mice. Previous results that an
exogenously administered mega-dose of Vitamin C accentuated
the initial stage of DTH response [23] were reproduced
in the present experiment. When sensitization was carried
out with the administration of exogenous mega-dose Vitamin
C, the resulting in vivo activated and memory T cells
showed increased proliferative activities in response to ex
vivo antigen-specific and non-specific stimuli, and shifted
cytokine secretion profiles from Th2 to Th1. When immunizationwas
done in the presence of an exogenous mega-dose
of Vitamin C, the titer of whole antigen-specific antibodies in
secondary sera was reduced, and this reduction was mainly
attributed to decreased titers of the Th2-driven isotypes, IgG1
and IgE.
DTH response to skin sensitizer molecules such as DNFB
was used as an experimental model to evaluate cell-mediated
immune function [24]. When memory T cells against an antigen
are exposed to the same antigen again (challenge), they
are reactivated (initial stage of DTH response) to secrete cytokines
like IL-2 and IFN-, which in turn activate tissue
macrophages (cognition and activation). These events occur
within 24 h [28]. Activated macrophages again secrete inflammatory
cytokines and reactive oxygen radicals to propagate
and maintain inflammation [29].
UV irradiation [30,31] and burn stress [32] suppress DTH
response in skin by producing reactive oxygen species (ROS).
Topically or orally administered Vitamin C protects against
this suppression, probably by acting as an antioxidant. In this
experiment, we examined the effect of Vitamin C on DTH
response in normal mice, not from the aspect of protection
against DTH suppression. When injected intraperitoneally,
Vitamin C showed biphasic effect on DTH response. The
thickness of pinnae on the first day increased in a Vitamin C
dose-dependent manner. However, this thickness increment
was inversely related to the amount of Vitamin C administered
from the second day on (Fig. 1). We thought that the
Vitamin C altered T cell function and thus augmented initial,
and cognition and activation stages of DTH response, whereK.
Noh et al. / Immunology Letters 98 (2005) 63–72 69
Fig. 5. The effect of Vitamin C on cytokine secretion by T cells. Mice were treated with 0.625 mg of Vitamin C for 10 days without sensitization (left column),
for 16 days with sensitization on days 11 and 12 (middle column), and for 54 days with sensitization on days 11 and 12 (right column). Control groups were
injected with 200l of PBS. T cells were isolated and cultured for 24 h with DNFB specific or non-specific stimuli. ELISA was done on the supernatants for
the cytokines. In general, Vitamin C elevated the secretion of Th cytokines (IL-2, TNF-, IFN-) and lowered Th2 cytokine (IL-4) secretion by T cells. Filled
bars () and unfilled bars () represent Vitamin C-treated and PBS-treated groups, respectively. Values are the average±S.D. of triplicates.
upon it performed a role as an anti-inflammatory agent from
the second day on.
The anti-inflammatory effects of Vitamin C have already
been suggested. It exerts these effects by scavenging ROS
that is produced by macrophages, destroys tissues and activates
macrophages and neutrophils to progress inflammation
[33,34]. It inhibits the activation of transcription factor NF-
B, which plays a critical role in the production of inflammatory
cytokines such as TNF-, IL-1, and IL-6 [35–37].
Actually, patients with cystic fibrosis with high plasma Vitamin
C levels had lower inflammation indexes than those with
low Vitamin C levels [34]. Based on such results, we suggest
that the dose-dependent suppression of ear thickening in Vitamin
C-treated mice is due to the anti-inflammatory effect
of Vitamin C. This explanation is further supported by the
finding in Fig. 2. Challenged ears were thinner from day 2
after challenge in groups which were administeredVitamin C
during active inflammation (() and () in Fig. 2) than in the
other groups not givenVitamin C at the time of inflammation.
Even though we measured changes in ear thickness for 10
days, we focused on the first day of DTH response. To explain
the augmentation of the initial stage of DTH response,
70 K. Noh et al. / Immunology Letters 98 (2005) 63–72
Fig. 6. The effect of Vitamin C treatment upon humoral immune response.
Mice were treated with 0.625 mg of Vitamin C for 41 days during primary
and secondary immunization ( ), for 10 days after primary immunization
( ), or for 10 days after secondary immunization (). Control group mice
were injected with 200 l of PBS during the experiment (). Ten days after
secondary immunization, sera were obtained and ELISA was performed
for whole and each isotype of KLH-specific antibody. Titers are expressed
relative to standard serum. In all experimental groups, whole KLH-specific
antibody titers were reduced vs. the control group. Among isotypes, the titers
of IgG1 and IgE were markedly reduced in all experimental groups, and thus,
contributed to the reduction in whole antibody titer. Each group consisted of
eight mice. Values are the average±S.D. **p < 0.001 vs. control. *p < 0.01
vs. control.
we analyzed the effect of Vitamin C on T cells, the initial
effector cells in this response.We found that an exogenously
administered Vitamin C mega-dose affected T cell functions,
such as proliferative activity and cytokine secretion profiles.
Furthermore, these effects occurred only when Vitamin C
was given during the sensitization period, i.e., when na¨ıve T
cells become activated and memory T cells begin to emerge.
It is notable that the duration of Vitamin C treatment did
not significantly influence these effects. For example, though
mice were treated with Vitamin C for as much as 43 days, no
change in T cell proliferation was observed in the absence of
sensitization (Fig. 4B). On the other hand, when mice were
treated withVitamin C for only10 days, changes in T cell proliferative
activity was observed if the treatment was applied
during sensitization (Fig. 4C).
T cells obtained 43 days (Fig. 3C) and 38 days (Fig. 4A
and C) after sensitization showed minimal thymidine uptake
without any ex vivo stimulation. This implies that almost
all T cells activated through sensitization were deactivated.
Actually, in vivo activated T cells cease proliferation within
1 week of antigen challenge [38,39]. However, when nonspecifically
stimulated with anti-CD3 antibody or PMA/I,
Vitamin C-treated T cells showed more uptake of thymidine
than PBS-treated T cells, a different feature from the na¨ıve
T cells in which there was no difference of thymidine uptake
between the Vitamin C-treated and the PBS-treated groups
(Fig. 3A and B). T cells in Figs. 3 and 4A and C were composed
of not only na¨ıve T cells but memory T cells, and it
can be presumed that the difference between the Vitamin Ctreated
and the PBS-treated groups is due to the activation
of memory T cells. Indeed, when these cell compartments
were stimulated with DNBS, a vivid difference in thymidine
uptake was observed between the Vitamin C-treated and the
PBS-treated groups.We do not know whether this difference
be the result of either a difference in the number of memory
cells or a difference in the vulnerability of memory T cells to
proliferative stimuli or both. Since it has been reported that
Vitamin C inhibits the apoptosis of activated T cells [9] and
increases the number of plasma T cells in elderly patients
[40], an increased number of DNFB-specific memory T cells
in theVitamin C-treated group can be expected. However, the
increased number of memory cells cannot simply explain the
increased thymidine uptake in Vitamin C-treated T cells in
Figs. 3 and 4A and C by non-specific stimulations, which are
presumably independent of specific memory T cells. Further
studies are needed to solve this issue.
The cytokine secretion profiles of T cells were also
changed in addition to and in parallel with changes in proliferative
activities (Fig. 5); that is, the increased secretion of
Th1 cytokines (IL-2, IFN- and TNF-) and the decreased
secretion of Th2 cytokine (IL-4). These results are similar to
the increased IL-2 and IFN- production of T cells by supplementary
Vitamin E in patients with advanced colorectal
cancer [41]. Since the elevated Th1 cytokines are involved
in cell-mediated immune responses [42,43], these results explain,
in part, the augmented initial stage of DTH response
observed in the present study.
Another point is that, since IL-4 is involved in humoral
immunity [42,43], we expected to observe reduced serum
immunoglobulin levels, and in fact this was the case. In Vitamin
C-treated groups during sensitization, total KLH-specific
antibody titers were reduced. In particular, specific IgG1 and
IgE levels were less than a tenth of those of the PBS-treated
group, markedly contributing to a reduced total specific antibody
titer. These results are in accordance with lower IL-4
secretion by Vitamin C-treated T cells, since IL-4 is known
to induce isotype switching to IgG1 and IgE [44].
Some contradictory results have been reported with respect
to the effects of Vitamin C on humoral response. Longterm
treatment of Vitamin C increased serum IgA and IgM,
but not IgG levels in humans [45]. In guinea pigs, Vitamin
C administration during immunization enhanced specific humoral
responses [46]. Many others have reported unaltered
humoral responses in Balb/c mice [8], humans [47], and in
guinea pigs [48]. These discrepancies could be the results of
differences in the Vitamin C dose and administration routes,
the co-administration of other nutrients, and species used, or
on the presence of T cell stimulation. Meanwhile, in situations
such as chronic granulomatous disease, in which we
could expect the persistent activation of T cells in vivo, longterm
treatment of Vitamin C lowered plasma Ig levels [3].
Vitamin C also reduced serum total IgE levels in asthma patients
[49].
It remains to be elucidated how the two groups treated
with Vitamin C, i.e., during primary or secondary immunization,
had the same secondary antibody secretion profiles.
Those treated only during secondary immunization would
K. Noh et al. / Immunology Letters 98 (2005) 63–72 71
have the same repertoire of memory B cells as the control
group, we would expect a higher titer of IgG1 and IgE
in this group than in the group treated during primary immunization.
However, the titers of both groups showed no
differences. The possibilities are that the isotype-switched
memory B cells during the primary response either underwent
apoptosis or isotype-switched once again during the
secondary response probably due to decreased IL-4 production
by T cells. In this experiment we obtained no data on
this issue, and a search of the literatures provided no clear
suggestions.
To summarize, mega-dose Vitamin C altered the proliferative
capacity of T cells against specific and non-specific
stimuli, and changed cytokine profiles toward Th1, and finally
resulted in an increase in the onset of DTH response and a
decrease in the total specific antibody titer in serum. This
Th1 polarization of immune response by Vitamin C has been
mentioned of its possibility [50]. What is important is that
these effects of exogenous Vitamin C occurred only when it
was administered during sensitization. Thus, we suggest that,
only activated T cells are vulnerable to changes by exogenous
mega-dose Vitamin C. It is not known whether this effect occurs
due to the intracellular accumulation of Vitamin C or
to the ligation of putative Vitamin C membrane receptors,
which have not yet been identified.
Acknowledgement
This work was supported by the Korea Science & Engineering
Foundation (KOSEF) through the Tumor Immunity
Medical Research Center (TIMRC) at Seoul National University,
College of Medicine.
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Ozone In Medicine
V. Bocci a; C. Aldinucci a; E. Borrelli b; F. Corradeschi a; A. Diadori c; G. Fanetti d; G. Valacchi a
a Institute of General Physiology, University of Siena, Siena b Institute ofThoracic and Cardiovascular Surgery,
c Department of Ophthalmology of the University of Siena, d Servizio Trasfusionale, Azienda Ospedaliera Senese, Siena, Italy
Online Publication Date: 01 January 2001
To cite this Article Bocci, V., Aldinucci, C., Borrelli, E., Corradeschi, F., Diadori, A., Fanetti, G. and Valacchi, G.(2001)'Ozone In Medicine',Ozone: Science & Engineering,23:3,207 — 217
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OZONE SCIENCE & ENGINEERING 0191-9512101 53.00 + .OO
Vol. 23. pp. 207-217 lntcrnational Ozone Association
Rintcd in the U.S.A. Copright @ 2001
Ozone In Medicine
V.Bocci4, C.Aldinucci, E.Borrelli,' F.Corradeschi, ~ . ~ i a d o r iG' ,.F anetti3 and G.Valacchi
Institute of General Physiology, University of Siena, Via A. Moro, 53100 Siena, Tel: 0039 0577 234226;
Fax: 0039 0577 234219 ; email: Fisaen@unisi.it
'1 Institute of Thoracic and Cardiovascular Surgery
Department of Ophthalmology of the University of Siena
') Servizio Trasfusiodale, Azienda Ospedaliera Senese, Siena. Italy, Tel: 0039 577 585070, Fax: 0039 577 5861 67
') Corresponding author
Received for Review: 9 March 2000
Accepted for Publication: 6 December 2000
Abstract
Ozone therapy has been used as a complementary medical approach for half a century but it has
encountered skepticism by orthodox medicine because, particularly in the past, it has been used by
practitioners and others without a rational basis and appropriate controls. With the advent of modem
medical ozone generators incorporating a photometer, it has become possible to obtain precise ozone
concentrations and to evaluate some mechanisms of action and possible toxicity. In contrast with the
respiratory tract, human blood exposed to appropriate ozone concentrations is able to tame its strong
oxidant properties and neither acute, nor chronic side effects have ensued in millions of patients treated
with ozonated autohaemotherapy (0,-AHT). This review summarizes our studies aimed at clarifying
biological effects, defining any possible damage, the therapeutic window and suitable doses able to express
a therapeutic activity. A very interesting and promising aspect is the induction of the so-called heat stress
proteins (HSP) leading to adaptation to a chronic oxidative stress. The use of ozone in human therapy has
been reviewed but so far very few controlled clinical studies have been reported. Mostly on the basis of
anecdotal results, ozone therapy appears usehl in infectious diseases, immune depression, vascular
disorders, degenerative diseases and orthopedics.
Key Words
Ozone; Medical Applications; Reactive Oxygen Species; Antioxidants; Hemotherapy; Ozone Tolerance;
Introduction
Although ozone has been used as a potent
disinfectant since the first World War (I), its
validity in medicine still remains controversial, even
though the National Health Institutes of several
countries, namely Germany, Italy, Austria, Russia
and some of the United States now include ozone
therapy and bio-oxidative therapy among the
pharmacological approaches of complementary
medicine. In most of the United States, the problem
of ozone, as one of the worse pollutants in large
cities, has acquired such a preeminent consideration that
it practically denies its use in medicine. Studies in vitro
and in vivo (2-5), confirming its toxicity for the
respiratory tract have led to the co.nclusion that ozone is
"always" toxic for humans, animals and plants. The
authors believe that the generalization of this conclusion
is, at least in part, unjustified because ..we have
demonstrated that judicious use of ozone can be
therapeutically useful and atoxic (6-10). There is no
doubt that ozone is intrinsically toxic (1 I ) , but as any
other drug, when used properly, has a definite
therapeutic window. Moreover, every year millions of
207
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208 V. Bocci et al.
patients all over the world undergo some sort of
ozone therapy and minimal, if any, side effects have
been noted. Some charlatans, mostly without any
medical qualifications, have caused a few deaths
because they inject directly the gas intravenously, a
procedure prohibited since 1986 in Europe (7;8; 10).
It is unfortunate that even today a few physicians
and many naturopaths and others, owing to the fact
that they cannot practice the classical hemotherapy,
predicate that intravenous injection of oxygen-ozone
is "the only effective way". This crucial problem
will be discussed in order to clarify the danger and
its basic irrationality.
The purpose of this brief review is four fold: firstly,
to present data from our Laboratory that show how
ozone, coming in contact with biological fluids,
decomposes and generates reactive oxygen species
(ROS), secondly, to define how ozone's messengers
can activate biochemical and immunological
mechanisms leading to biological effects, thirdly, to
show that we are now able to determine a
therapeutic window or, in other words, a range of
biologically active concentrations below which
ozone is practically inactive and above which can be
toxic. Fourthly, we will attempt to analyze the
results regarding therapeutic efficacy in five main
areas: infectious diseases, immune depression,
vascular disorders, degenerative diseases and
orthopedics. The breadth of ozone therapy, rather
than arising the suspicion of a "panacea", ought to
be envisaged as due to the multiform action of
ozone on cells with different functions.
The knowledge recently acquired allows one today
to plan rational clinical applications in different
diseases and to evaluate the therapeutic activity and
side effects. Future breakthroughs can be achieved
only if we are able to grasp firstly, the biological
activity of lipid oxidation products (LOPS),
secondly, the practical implications of the ozone
tolerance by clarifying the role of heat-stress
proteins (HSP) and, thirdly, if we will be able to
cany out randomized, double blind clinical trials
possibly performed in several medical centers.
The present paper intends to give a general
overview of the results so far achieved and therefore
technical details can be found in previous papers
(I 2- 15).
Ozone Mechanism
Progress in this field is expected only if we are able to
clarify precisely the mechanisms of action because it
will allow defining the therapeutic dose and possible
toxicity. We will examine separately the possible
mediators broadly defined as reactive oxygen species
(ROS) and the cell targets that are ultimately responsible
for the therapeutic response.
Ozone's active messengers
Both oxygen (about 97%) and ozone (no more than 3%)
dissolve in biological fluids according to their solubility,
relative concentrations, partial pressure and temperature
(1). However, there is a critical 'difference between these
two gases because oxygen is fairly stable in solution
while ozone decomposes immediately by avidly reacting
with polyunsatured fatty acids (PUFA) (1 1). This
implies that ozone does not obey Henry's law and
therefore an extremely dynamic equilibrium arises
between the ozone in the gas phase and the ozone
reacting and disappearing in the aqueous solution. Thus,
we can envisage a continuous flow of ozone into the
solution from the gas phase until the latter is exhausted.
It is felt that this crucial instability has not been fully
appreciated by cell biologists, who examine ozone
toxicity in tissue cultures maintained in a gas phase
where concentration of ozone, although very low (0.2 -
1 pprn), remains stable for several hours or days of
incubation. The final results are misleading because it is
obvious that overall cell toxicity cannot be simply
attributed to the low ozone concentration, but to the
uncalculated total sum of ozone that during every
millisecond has passed into the solution. In other words,
a cell layer in culture exposed to an ozone concentration
as low as 0.1 ppm may not be damaged if the exposure
lasts only ten min whereas total cell death may ensue
after 60 min exposure because ozone will continue to
dissolve during the following 50 min reaching the lethal
amount.
It has been shown (1 1) that the reaction between a mole
of an unsaturated fatty acid containing a cis-double bond
and 0, in water generates two moles of aldehyde and
one mole of hydrogen peroxide (H20,).
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Ozone in Medicine 209
H20, is also generated when O, reacts with
physiological saline.
The reduction potential is smaller (0.682 volt) in the
semireaction towards H,02 than directly towards
H20 (1.229 volt). Indeed we have demonstrated (14)
that after ozonation of either saline or human
plasma, H,02 is formed in both liquids with the
important difference that H,O, in the plasma has a
very short half-life (about 2.5 min) due to the
presence of traces of enzymes such as glutathione
peroxidase (GSH-Px) and catalase, which are able to
degrade H202. Appropriate enzyme inhibitors are
able to prolong the lifetime of H20, while addition
of catalase, as it was expected, accelerates its decay
(14). The other important reaction is that 0,, by
reacting with PUFA, will generate a number of
LOPs such as hydroperoxides, isoprostanes,
platelet-activating factor (PAF) and terminal
products such as malondialdehyde and 4-
hydroxyponenal (HNE) (162 1 ) The latter
compound is becoming particularly interesting
because, depending upon its final concentration
(>lo ph4 or < I pM), may either be harmful or act
as a physiological messenger, respectively (22;23).
Owing to the wealth and heterogeneity of PUFA,
several types of LOPs may be generated and their
biological activities, including potential toxicity,
remain to be explored in vivo. Once again,.results
obtained in vitro by using apparently toxic LOPS
may not be applicable in vivo owing to their rapid
turnover and, as an example, enzymes such as
glutathione transferases and aldehyde
dehydrogenases are involved in the metabolism of
HNE (16). Phospholipases and sphyngomyelinase
are likely to be activated by LOPs and this may lead
to an amplification of some biological processes.
Furthermore LOPS have a short half-life but, upon
reinfusion of ozonated blood, may reach specific
sensors situated in critical organs such as bone
marrow, spleen, liver and other sectors of the
immune system. If this is true, .LOPS may be
responsible for transmitting the information of
peroxidative stress and possibly inducing the
upregulation of antioxidant enzymes, hence the
tolerance to 0,. This dubbed as
"oxidative stress adaptation" or oxidative
preconditioning (7;24-26) is extremely interesting
because it could allow a reversal of chronic
oxidative stress typical of degenerative diseases. We
have already demonstrated an increase of
antioxidant enzymes (7) and we are examining.
levels of heme oxygenase (HO) activity. The
isoform 1 of the latter enzyme (HO-I), also known as
heat shock protein 32 @sp 32), is inducible and is
responsible for the conversion of heme into biliverdin,
carbon monoxide (CO) and free iron (27-29). ,
Cytochrome P450 constitutes another source of heme
undergoing degradation via HO-1. We would like to
emphasize that the above products, until recently
regarded as toxic waste destined only for excretion, are
compounds with great physiological and a possible
therapeutical role: bilirubin (via biliverdin reductase) is
a crucial lipophylic antioxidant and CO may function as
a gaseous regulator of endothelial tone in synergy with
nitric oxide (NO). Indeed we have just demonstrated
that human endothelial cells exposed to ozonated
plasma increase the release of NO (30). Nitrosothiols
such as S-nitrosocysteine, S-nitrosoglutathione and Snitrosoalbumin,
formed in human plasma to buffer NO'S
concentration, have physiological significance because
function as a reservoir for NO (31). Another important
mechanism of activation that has been partly clarified
(13) is the opening of Ca2' channels somehow related to
ROS acting on the external part of the cell membrane
leading to a sudden increase of intracellular Cal'
concentration with consequent enzymic activation. So ,
far we have only indirect evidence of this phenomenon
by either chelating tjle extracellular Ca2+ with citrate
used as a blood anticoagulant or by adding from 5 up to
25 rnM Ca2+ in heparinized blood (13) but obviously it
will be important to measure the actual intracellular
increase of Ca2+
Effectors and the biochemical targets
It is now clear that ozone works indirectly in different
ways: owing to' the fact that H,O, is an unionized
molecule and its passage through the cell membrane is
free, its sudden increase in the extracellular water is
immediately transferred into the intracytoplasmic water,
but the intracellular environment counteracts this
potentially toxic increase by quenching it with reduced
glutathione (GSH) coupled to GSH peroxidase. This
causes an increase of oxidized glutathione (GSSG) and a
decrease of the GSWGSSG ratio, which is rapidly
reconstituted by the action of GSH reductase in turn
exploiting the NADPWNADP reservoir. Lowering the
NADPH level enhances the activity of glucose 6
phosphate dehydrogenase (G6PD) that, particularly in
the erythrocytes, leads to the activation of. the hexose
monophosphate shunt. When necessary an excessive
increase of intracytoplasmic Y,02 is also double
checked by catalase. There is a concomitant activation
of glycolysis with increased ATP and a still
controversial increase of 2-3 diphosphoglycerate (2-3
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210 V. Bocci et al.
DPG) production as key enzymes involved in this
process have not yet been shown to be activated
(32;33). Obviously the shift to the right of the HbO,
dissociation curve would favor an increased oxygen
delivery to hypoxic tissues (7;lO). It has also been
claimed (34) that the erythrocytic membrane
becomes more fluid and more negatively charged,
that blood viscosity decreases due to
hypofibrinogenemia and to a decreased level of low
density lipoproteins (LDL). However Morgan et al.
(35) found that erythrocytes from ozone-exposed
mice exhibited decreased deformability and
therefore all of these claims must be controlled
because we must be sure if indeed ozone can
improve, blood rheology in ischemic diseases.
As far as the activation of cytokine synthesis in
leukocytes is concerned, it is now well accepted that
the sudden surge of intracytoplasmic H,O, is finally
responsible for the activation of the nuclear
transcription factor (NF-kl3). Briefly, H20,, by
activating specific protein kinases, would
phosphorylate the I-KB subunits that detach from
the NF-k8 complex. The free heterodimer (p50-p6S
proteins) can then move into the nucleus where,
after binding to DNA control elements, activates
gene expression and the successive synthesis of
interferons and interleukins as shown by us (12-
15;36) and others (37;38).
The transient rise of intracytoplasmic H,O, prompts
a few considerations: the first one is that the 0,
concentration must be adequate to allow a sufficient
H,O, generation for the activation of transducer
molecules and to counteract, the simultaneous
degradation, and the second is that H,02
concentration must reach a critical threshold. If it is
below the liminal value, activation will not occur
but if it is excessive, damage may result implying
the relevance of having identified the therapeutic
window between about 20 and 80 pglml of gas per
ml of blood. If the 0, concentration is below 20
pglml, 'most of the oxidant power of 0, will be
quenched by the natural antioxidants (between 1.28
and 1.83 mM plasma) (39) and therefore the
necessity of measuring precisely the 0,
concentration to avoid either a placebo or a toxic
effect is of crucial importance. On the experimental
basis of progressively increased hemolysis, ozone
concentrations higher than 80 pglml are more likely
detrimental than beneficial.
Little is known about the biological activity of LOP
such as hydroperoxides, isoprostanes, malondialdehyde
and 4-hydroxyalkenals produced during blood
ozonation. Aggregation of platelets, as we have
observed in platelet rich plasma anticoagulated with
heparin (40), is at least in part attributable to released
PAF (21). While some of these can act as physiological
messengers (18;20-23) they appear to be, particularly in
vitro, very toxic (17;22;23). Their production and
consequent plasma levels are somewhat related to the
ozone dose and it is conceivable that in vivo a low
ozone dose may express a more favorable
activityltoxicity ratio than a higher ozone dose. Thus,
once again, we should aim to define in different
pathologies the optimal dose that may be either in the
low (20-40 pg/ml per ml of blood), or in the mediumhigh
range (30-80 pglml per ml of blood).
Moreover LOPS may exert the overlooked and yet
crucial function for transmitting the information of on
ongoing peroxidative stress to distant organs with the
purpose of inducing the "oxidative stress adaptation" or
ozone tolerance (24-26;41-48). This can be achieved
only by slowly activating gene expression towards the
synthesis of heat-shock proteins, antioxidants enzymes
(GSH-Px, catalase, superoxide dismutases etc), DNA
repair enzymes and, most important, heme-oxygenase
(27-29). This may lead to increased bilirubin levels (49)
and local release of CO that, associated to increased
endothelial production of NO (30) may well explain the
vasodilation and consequent clinical improvement
observed in limb ischemia treated with 0, AHT. It is
almost needless to say that upregulating the production
of antioxidant enzymes in patients with degenerative
diseases (favored or caused by a life-long oxidative
stress) is the simplest way to readjust the redox balance,
possibly leading to a stabilization of the disease.
Administration of antioxidant compounds may be
helpful (50;Sl) but, most likely, not so effective for
neutralizing ROS as the intracellular increase of
antioxidant enzymes.
Applications of Ozone Therapy in Medicine
Today, a better understanding of the basic reactions of
ozone able to activate different biological functions
allows the dispelling of skepticism surrounding ozone
therapy. Although its application is extremely versatile
there are two important limitations: firstly, ozone should
never be inalated as the fluid film lining the tracheobronchial
mucosa is too thin to protect it from the .
oxidative insult (11) and secondly, the gas mixture of
OJO, should never be injected intravenously (IV) either
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Ozone in Medicine 211
because it can cause oxygen embolism and because
no meaningful blood /ozone ratio can be ever
calculated. We will never get tired of repeating that
human organism, although composed of almost 66%
water should not be compared and treated as a water
sterilization plant. Were we to allow the IV gas
administration, it would cause severe side effects
and many deaths each year.
On the other hand the approach consisting in the
exposure of a precisely measurable volume of the
patient's blood (200-250 ml) to an equal volume of
gas (1 to l), of which the ozone concentration can
be accurately measured in real time by photomeby,
is by far the most scientific, simple, inexpensive and
side-effects free procedure. Most of the merit goes
to Wolff (52) who applied the ozonated
autohemoterapy (0,-AHT) in the late 70s. The
optimized procedure that must be can-ied out in
neutral glass and ozone-resistant tubing where the
inlet is separated from the outlet equipped with a
standard blood, filter has been recently described in
detail (53). Standard autotransfusion bags made of
polyvinyl chloride (PVC) additioned with about
40% additives have been banned by the Italian
Ministry of Health after our demonstration (53) that
ozone causes the release of significant amounts of
plastic microparticles and phthalates into the blood.
Other routes of administration of ozone can be
allowed for selected applications: the subcutaneous
(SC) route for treating lipodistrophy; the
intramuscular (LM) route into the paravertebral
muscles aAer locating the point(s) triggering low
back pain; the intradiscal- intraforaminal andfor the
epidural route for treating a herniated disc; the
intraarticular or periarticular route for treating acute
and chronic arthrosis. Knoch et al. (54), Carpendale
et al. (55) and ourselves (56) have evaluated pros
and cons of the rectal insufflation of 0,-0, as a
possible option when 0,-AHT cannot be used for
difficult venous access. This route has been used in
human. immunodeficiency virus (HIV) infection
( 5 9 , chronic hepatitis, ulcerative colitis and
Crohn's disease with apparently satisfactory results
(54) using up to 800 ml of 0,-0, at a maximal 0,
concentration of 40 pg/rnL administered within 5
minutes. In the case of chronic bacterial and
parasitic infections becoming resistant to antibiotics,
low 0, concentration (3-5 pg/mL) have been also
insufflated into the oral, nasal, tuba1 (during 30 sec
apnea), vaginal, urethral, vesical, pleural and
peritoneal cavities. Obviously the technique of gas
insufflation is a very empirical and approximate one but
it can be useful, as ozone does not allow bacterial
resistance.
Which are the diseases likely to benefit from the
application of ozone therapy? It appears reasonable and
ethical to use ozone especially when conventional
therapies are ineffective or not available as too often
occurs in poor countries. Obviously, by considering the
potent disinfectant action of 03, top priority goes to all
sorts of bacterial, viral and fungal infections. Either gas,
or ozonated water, or ozonated oil display a cleansing
and disinfectant effect (1 ;57-63).
Moreover 03-mT, combined with topic therapy, can be
helpful because, as previously ,discussed, it activates cell
metabolism and the immune system. Indeed various
immunodeficiencies associated with chronic viral
diseases and metastatic cancer, particularly after highintensity
chemotherapy, may benefit from a long cycle
(about 50 treatments, twice weekly for six months) of
0,-AHT that, in comparison to interferon, highly active
antiretroviral therapy (HAART) and cytostatics does not
procure acute or chronic side effect (64;65). Actually
the majority of patients reports an unusual feeling of
well-being that should not be neglected.
Unfortunately, for the time being, we have to rely on
anecdotal reports (65). One clinical study in HIV
infection (66) yielded doubtful results because blood
was badly mistreated by heat, W irradiation and 0, in
unknown concentration.
In western countries several circulatory disturbances
,bind-limb ischemia, heart-brain-retinal ischemia) due
to atherosclerosis, diabetes, smoking, aging and a too
intense lifetime oxidative damage represent a
formidable medical problem that cannot. be entirely
coped by orthodox medicine.
0,-AHT has shown therapeutic effects particularly in
patients refractory to conventional treatments because,
as it has been mentioned, expresses multiple actions
such as vasodilation, increased delivery of oxygen in
hypoxic tissues and release of wound healing factors
(67). Clinical results in acute cerebro-vascular disorders,
chronic ischemic cardiopathy and even in the 111--1V
stages of hind-limb ischemia have been remarkable,
particularly, when a systemic treatment was combined
with a topical one on torpid ulcers and incipient necrosis
(33; 68-70). Two randomized, placebo controlled (0,-
AHT) cross-over studies have been performed to
evaluate the efficacy of 0,-AHT in patients with age-
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212 V. Bocci et al.
related macular degeneration (ARMD) (33) and
with mild hypertension (71). Significant clinical
improvement was achieved in both trials although it
faded 2-4 months after the end of the treatment.
However, as it happens with other medications, this
is to be expected and can be minimized by
continuing the treatment at a slow pace.
As far as degenerative diseases are concerned,
preliminary studies by using 0,-AHT and 0, rectal
insufflation cairied out in patients with cardiac
infarction (72), neurodegenerative disease (73) and
ARMD (33) have shown clinical improvement and
interestingly a progressive increase in GSH Px,
glucose-6-phosphate dehydrogenase and superoxide
dismutase in erythrocytes. However there is an
urgent need for programming controlled studies in
order to show that ozone therapy can induce a state
of oxidative stress adaptation, possibly capable of
stabilizing the disease.
Finally injections of small volumes of 0,-0, at a 0,
concentration below 30 'pg/ml ire being used in
orthopedic pathology, via peri, or intrarticular, or
intradiscal injection (74; 75). It appears that the
treatment that is occasionally painful for a few
minutes has no side effects and in about 70 % of
patients allows pain relief, decongestion,
reabsorption of edema and improved mobility (74;
75). How ozone works remains hypothetical: after
intradiscal injection, ozone generates hydrbxyl
radicals (OH') measured by electron spin resonance
(Bocci et al, manuscript in preparation) that can
degrade proteoglycans in the degenerate nucleus
pulposus leading to its reabsorption with consequent
reduction of herniated material responsible for
radicular pain. In the synovial membrane ozone
therapy may either induce the release of
immunosuppressive cytokines andlor
proinflammatory cytokine antagonists as well as the
over-expression of antioxidant enzymes able to
block excessive ROS formation. In regard to the
injection of 5-10 mL 0, -0, (15-20 pg/ml) into the
trigger points of paravertebral muscles
correspondent to the metamers of the hernial disc,
we have proposed (76) that the "chemical
acupuncture" due to the needle and ozone inhibits
amyelinic nociceptors fibers and activate the
antinociceptive system. This explanation appears
plausible because the successive analgesia permits
muscle relaxation and vasodilation with consequent
improvement of local muscular physiology and
disappearance of pain. Brayda-Bruno and Cinnella
(77) have reported that about 70 % of patients improve
after a few session of this easy, risk free procedure. It is
worth noting that lower back pain syndrome is very
common and it is advantageous to try this minimally
invasive treatment. However, as it was proposed in 1998
(76), it is impellent to compare this procedure against a
wait-list control, two placebo controls (one with 0,
alone and another without any gas) and a standardtreatment
control.
Conclusions and Perspective
On the basis of experimental results obtained in the last
decade (6;7;91;2 - 15;24-26;36-38;40), we have selected
a range from 20 up to 80 pg/ml of ozone per ml of blood
to be used for different pathologies, within which, no
damage to blood components has been noticed. An
orientative scheme of dosages has been previously
reported for different diseases (10) depending upon
whether the therapeutic activity is mainly exerted by
either erythrocytes or leukocytes (7; 8;10). In order to
avoid toxicity and allow oxidative stress adaptation, we
are applying the "start low, go slow" principle: that is
0,-AHT is performed starting with very low ozone
concentrations (20-25pg/mL per ml of blood) to be
increased in single steps of 5 pg/mL to the highest level
between 40 and 80 pglmL depending upon the disease
and the state of the patient (10).
Although we do not yet have unequivocal clinical data
based upon controlled double-blind studies, we have
encouraging evidence suggesting that ozone therapy can
be useful in vascular, infectious and degenerative
diseases (1;7;10;34;55;57-63;68-73). Whether ozone,
therapy can be useful in metastatic cancer (65) and
surprisingly in orthopedics (74-77), respiratory and
immune diseases remains to be seen and it should be
ascertained starting with cautious and controlled
experimentation.
Even if, theoretically, ozone therapy implies always an
oxidative insult, this must be carefully calculated on the
basis of a precise ozone dose and brief time of exposure.
Luckily this is possible owing to the large antioxidant
potential of blood (39;40;50;5 1). that is practically
impossible to overwhelm with the indicated ozone
concentrations. Moreover, during the course of therapy
the total antioxidant status must be sustained. by daily
administration of antioxidant vitamins (0.5 g of vit C, 10
mg vit E, Se, etc and at least 0.6 g of N-acetylcysteine as
a precursor of GSH) accompanied by a diet rich in fresh
vegetables and fruits.
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Ozone in Medicine 213
The concept of "oxidative stress adaptation" must
be thoroughly evaluated because it is expected to
lead to great improvements. If this idea will prove to
be correct against all the most pessimistic views of
ozone as a therapeutic agent (ll), we will have
demonstrated that ozone is indeed a paradoxical
molecule and that prejudices are the worst foes of
biology and medicine. In order to achieve a suitable
and smooth adaptation, the best strategy seems to
start with low and slowly increasing ozone dosages.
Two to three weeks may be necessary before
measuring a substantial increase of antioxidant
enzymes in erythrocytes. One must also take into
account that erythrocytes have a fairly slow turnover
(78) and therefore it takes a few weeks before the
newly "super-gifted" erythrocytes, released from
the bone marrow, can progressively substitute the
old ones. Thus the application of the "start low, go
slow" principle (10) appears reasonable for
demonstrating the validity of the concept.
In conclusion, in spite of our efforts during the last
decade to give a solid scientific basis to ozone
therapy, much work remains to be done. Ozone
therapy is in the middle of a schizophrenic situation:
on one hand, if one reads the weekly reports in the
oxgists, one remains appalled by wonderful
therapeutic achievements obtained in most cases by
charlatans without any medical qualification. This is
very detrimental for the real progress of ozone
therapy as desperate patients searching a hopeful
treatment are not in the position to distinguish
between the truth and the fake. On the other hand, in
the age of molecular medicine and gene therapy,
ozone therapy appears at best as an obsolete,
empirical and still doubtful approach. It reminds the
well-hown Indian story about the blind men and
the elephant. We touch it, we smell it but we still do
not see it. However, as-it happens in Science, even
gene therapy that seemed so promising present great
problem (79). Against all the odds, I firmly believe
that if we can continue with an appropriate
biological and clinical experimentation, ozone can
become an important therapeutic agent because it
can reactivate a variety of biological hctions
crucial for regaining health and is very cheap, easy
to use, versatile and atoxic, if used properly.
Acknowledgements
This work was partly supported by MURST grants
(ex40%). The editorial assistance of Mrs. Helen Carter
and Patrizia Marrocchesi is gratefully acknowledged.
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