29 Ocak 2009 Perşembe

References

• Ackey D, Walton TE. Liquid-phase study of ozone inactivation of Venezuelan Equine Encephalomyelitis virus. Appl Environ Microbiol 1985; 50:882-886
• Armstrong. Infectious Diseases, First Ed. Mosby, Philadelphia, 2000
• Babior BM. Phagocytes and oxidative stress. Am J Med 2000; 109:33-44
• Bocci V. Ozone: A New Medical Drug. Springer, 2005
• Bocci V. Oxygen-Ozone Therapy: A Critical Evaluation. Kluwer Academic Publishers, Dordrecht, 2002
• 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
• Cann AJ. Principles of Molecular Virology, Second Edition. Academic Press, New York, 1997
• 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
• Cech T. RNA as an enzyme. Scientific American 1986 Nov; 255(5): 64-76
• Clamann H. Physical and medical aspects of ozone. In: Physics and Medicine of the Atmosphere and Space. John Wiley and Sons, New York, 1960, p 151
• Dailey JF. Blood. Medical Consulting Group, Arlington MA, 1998
• Dawson TM, et al. Gases as biological messengers: Nitric oxide and carbon monoxide in the brain. J Neuroscience 1994; 14:5147-5159
• Delves PJ, Roitt IM. Encyclopedia of Immunology. Academic Press: San Diego, 1998
• Di Paolo N. Extracorporeal blood oxygenation and ozonation (EBOO) in man. Preliminary report. Int J Artif Organs 01 Feb 2000; 23(2): 131-141
• Dulak J, Jozkowicz A. Carbon monoxide: A “new” gaseous modulator of gene expression. Acta Biochimica Polonica 2003; 50(1): 31-47
• Dyas A, Boughton B, Das B. Ozone killing action against bacterial and fungal species: Microbiological testing of a domestic ozone generator. J Clin Pathol (Lond) 1983; 36(10): 1102-1104
• Evans AS, Kaslow RA (Eds). Viral Infections in Humans: Epidemiology and Control, Fourth Edition, Plenum, New York, 1997
• Gumulka J, Smith L. Ozonation of cholesterol. J Am Chem Soc 1983; 105(7): 1972-1979
• Hurst CJ. Viral Ecology. Academic Press, New York, 2000
• Ignarro LJ (Ed). Nitric Oxide: Biology and Pathobiology. Academic Press, 2000
• Ishizaki K, Sawadaishi D, Miura K, Shinriki N. Effect of ozone on plasmid DNA of Escherichia coli in situ. Water Res 1987; 21(7): 823-828
• Ivanova O, Bogdanov M, Kazantseva V, et al. Ozone inactivation of enteroviruses in sewage. Vopr Virusol 1983; 0(6): 693-698
• Knipe DM, Howley PM. Fundamental Virology, Fourth Edition. Lippincott Williams & Wilkins, Philadelphia, 2001
• Laskin JD, Laskin DL. Cellular and Molecular Biology of Nitric Oxide. Marcel Dekker, 1999
• Lincoln J, Hoyle CH, Burnstock G. Nitric Oxide in Heath and Disease. Cambridge University Press, 1997
• Lohr A, Gratzek J. Bactericidal and paraciticidal effects of an activated air oxidant in a closed aquatic system. J Aquaric Aquat Sci 1984; 4(41/2): 1-8
• Matus V, Nikava A, Prakopava Z, Konyew S. Effect of ozone on survivability of Candida utilis cells. Vyestsi AkadNavuk Bssr Syer Biyal Navuk 1981; 0(3): 49-52
• Matus V, Lyskova T, Sergienko I, Kustova A, Grigortsevich T, Konev V. Fungi; growth and sporulation after a single treatment of spores with ozone
• Max J. Antibodies kill by producing ozone. Science 15 Nov 2002; 298: 1319
• Mudd JB, Leavitt R, Ongun A, McManus T. Reaction of ozone with amino acids and proteins. Atmos Environ 1969; 3:669-682
• Menzel D. Ozone: An overview of its toxicity in man and animals. Toxicol and Environ Health 1984; 13:183-204
• Olinescu R, Smith TL. Free Radicals in Medicine. Nova Science Publishers, Inc. Huntington, New York, 2002
• Paulesu L, Luzzi L, Bocci V. Studies on the biological effects of ozone: Induction of tumor necrosis factor (TNF-alpha) on human leucocytes. Lymphokine Cytokine Research 1991; 5:409-412
• Razumovskii SD, Zaikov GE. Ozone and Its Reactions With Organic Compounds. Elsevier, New York, 1984
• Rilling S, Veibahn R. The Use of Ozone in Medicine. Haug, New York, 1987
• Rilling S. The basic clinical applications of ozone therapy. Ozonachrichten 1985; 4:7-17
• Smith LL. Cholesterol autoxidation of lipids. Chemistry and Physics of Lipids. 1987; 44:87-125
• Snyder S. Drugs and the Brain. Scientific American Library Series, 1996
• Rice RG. Century 21 – Pregnant with ozone. Ozone Science and Engineering 2002; 24: 1-15
• Riesser V, Perrich J, Silver B, McCammon J. Possible mechanism of poliovirus inactivation by ozone. In: Forum on Ozone Disinfection. Proceedings of the International Ozone Institute. Syracuse, NY, 1977:186-192
• Roy D, Wong PK, Engelbrecht RS, Chian ES. Mechanism of enteroviral inactivation by ozone. Appl Envir Microbiol 1981; 41:718-723
• Roy D, Engelbrecht RS, Chian ES: Comparative inactivation of six enteroviruses by ozone. Am Water Works Assoc J 1982; 74(12): 660-664
• Sunnen G. Ozone in Medicine. Journal of Advancement in Medicine. 1988 Fall; 1(3): 159-174
• Sunnen G. Possible mechanisms of viral inactivation by ozone. Townsend Letter for Doctors. Ap 1994: 336
• Sweet J, Kao MS, Lee D, Hagar W. Ozone selectively inhibits growth of human cancer cells. Science 1980; 209:931-933
• Thanomsub B. Effects of ozone treatment on cell growth and ultrastructural changes in bacteria. J Gen Appl Microbiol 01 Aug 2002; 48(4): 193-199
• 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. Odrei Publishers, Iffezheim, 1999
• Wells KH, Latino J, Gavalchin J, Poiesz BJ. Inactivation of human immunodeficiency virus Type 1 by ozone in vitro. Blood 1991 Oct; 78(7): 1882-1890
• Wentworth P, McDunn JE, Wentworth AD, et al., Evidence for antibody-catalysed ozone formation in bacterial killing and inflammation. Science 13 Dec 2002; 298: 2195-2199
• Wink DA, Grisham MB, Mitchell JB, Ford PC. Direct and indirect effects of nitric oxide in chemical reactions relevant to biology. Methods Enzymol 1996; 268:12-31
• Wolcott J, Zee YC, Osebold J. Exposure to ozone reduces influenza disease severity and alters distribution of influenza viral antigens in murine lungs. Appl Environ Microbiol 1982; 443:723-731
• Yu BP. Cellular defenses against damage from reactive oxygen species. Physiological Reviews 1994 Jan; 74(1): 139-162

Tıbbın açan gülü,

Tamamlayıcı ve palyatif uygulamalar. Dünyada hızlı bir gelişme gösteren tamamlayıcı tıp uygulamaları ve palyatif uygulamalar Türkiye'de yeterli seviyeye bir türlü gelememiştir. Ancak son yıllarda tıpta ve iletişim araçlarındaki gelişmeler bu uygulamaların da yaygınlaşmasına ve tercih edilmeye başlanıyor.

26 Ocak 2009 Pazartesi

Sağlık Ne Demek?
Günümüzde sağlığın tanımı yapılırken sanırım yanlış bazı şeyler yapıyoruz. Sağlık hastalıksızlık hali midir? yoksa hastalık varlığında dahi kaliteli yaşamak mıdır?

12 Ocak 2009 Pazartesi

OZON YAYIN

Tumor Hypoxia and Ozone Therapy
Author: Kornel Kusznieruk
Affiliation: University of Western Ontario
Date Published: Tuesday October 24th, 2006 @ 23:30:29 EST

Abstract
This paper describes the importance of increasing oxygen content in tumors and provides some possible ways of doing this.
Introduction

Tumors are a rapidly expanding mass originating from one transformed cell. This rapid
expansion does not allow for proper vascularization to occur. At the size of 2-3 mm3 the
tumor would hypothetically stop growing because of its need for a blood supply to
provide oxygen and nutrients (1). Unfortunately, the tumor can coerce the host
endothelial cells to enter the growing mass and provide life support. This is
accomplished, in part, by release of chemoattractant compounds from the growing tumor
or from immune system cells which have entered the growing tumor. These compounds
activate neighboring endothelial cells to migrate to the tumor, to cut through host tissue so that they can arrive at the tumor, and to start proliferating and forming new blood vessels for the tumor. This process is called angiogenesis (2).

Although the host-derived endothelium allows the tumor to grow, its vascular structure is
much different from that of normal tissue. The tumor has no intratumor lymphatics, this
does not permit fluid draining from tumour tissue and as a result high interstitial fluid
pressure develops (3). The high interstitial pressure inhibits drugs from penetrating the
whole tumor tissue, as well as forcing death of some tumor cells. This alteration of
interstitial pressure combined with the rapid rate of tumor cell proliferation ends up
forming a situation where the growing tumor is vascularized, but only to the limited
extend that it needs for it’s own survival. Tumor blood vessels do not contain smooth
muscle lining, are resistant to control by the nervous system, and grow in a disorganized manner compared to vasculature in non-tumor tissue (3). An example of the difference between tumor and non-tumor vasculature is that the former relies on tumor secretion of vascular endothelial growth factor (VEGF) for its survival, whereas the former is insensitive to withdrawl of VEGF (4).

Tumors contain areas of hypoxia (4a). The cause of this is multifactorial and includes poor tumor perfusion by the blood (5), clotting of tumor blood vessels due to activated clotting factors on tumor endothelium (6), and the rapid rate of tumor growth. Hypoxia,and poor perfusion have been shown to negatively correlate with prognosis (7, 8).
Cancer cells under hypoxic environments secrete matrix metalloproteases, which allow
them to metastasize (9). In addition, hypoxia programs cancer cells and macrophages to
secrete VEGF, a protein that stimulates angiogenesis as well as immune suppression (10).
Hypoxia activates hypoxia inducible factor (HIF-1) a nuclear transcription factor which is important in promotion of angiogenesis (11). Besides local hypoxia, late stage cancer patients have lower systemic hemoglobin levels compared to healthy controls, this is due in part to lower renal production of erythropoietin (11a). Lower hemoglobin implies less oxygen transport and therefore reduced tumor oxygenation. Studies aimed at increasing hemoglobin levels by administration of erythropoietin have shown increased efficacy of radiotherapy and chemotherapy (11b).


An important consideration of tumor hypoxia is the role it plays in protection of tumorsfrom anti-tumor defense systems. For example, tumor necrosis factor alpha (TNF-α) is acytokine secreted by activated macrophages and T cells, which as the name implies has antitumor activity. Interestingly, the cytotoxicity of TNF-α to tumor cells is reduced under hypoxic conditions (12). Hypoxia also stimulates production of soluble TNF-α receptors which hypothetically may block systemic activities of this cytokine (13). This may explain the poor efficacy of systemic TNF-α therapy which was attempted in the
1980s (reviewed in 13a). If TNF-α can not kill cancer cells, then it is possible that
immune effectors which use intracellular signalling similar to TNF-α will not be able to work either. Such mediators include the Fas signalling pathway (13b). Since Fas ligand and TNF-α are used by T cells in killing of target cells, the poor efficacy of immunotherapy may be explained by hypoxia.

In accordance with the above point: lymphokine activated killer (LAK) cells are effective in killing certain types of tumor cells in vitro and in vivo but the ability to generate these cells is depressed under conditions of hypoxia. Furthermore, the ability of estabilished LAK cells to kill tumor targets is decreased under conditions of hypoxia similar to those found inside the tumor (14). Proliferation of lymphocytes in response to interleukin-2 is also inhibited during hypoxia (15).

In 1953 the impact of tumor oxygenation on efficacy of radiation therapy was described by Gray et al (16). Since then a great number of studies confirming that tumor sensitivity to radiotherapy positively correlates with tumor oxygenation (reviewed in 17). Several other interventions such as etoposide, doxorubicin, camptothecin and vincristine therapy are oxygen dependent (17a).

The Problem
Tumor hypoxia:
1. Stimulates angiogenesis
2. Suppresses immune function by:
a) Blocking TNF-α toxicity
b) Blocking systemic TNF-α activity by shed receptors
c) Blocking lymphocyte proliferation
d) Blocking LAK cell generation and activity
e) Induces production of the immune-suppressive cytokine VEGF
3. Stimulates resistance to radio- and chemotherapy.

Available Solutions

Hyperbaric Chambers

Methods of increasing tumor oxygenation have been described. One such method
involves exposing a patient to higher oxygen tension by use of a hyperbaric chamber.
This approach has shown marginal increases in oxygenation of some tumors although
clinical efficacy is a matter of debate. A randomized trial of squamous cell sarcoma
patients treated with radiotherapy in the presence of air or hyperbaric oxygen
demonstrated a significantly greater number of patients achieving clinical response in the hyperbaric oxygen group (18). Another randomized study assessing the ability of hyperbaric oxygen to increase efficacy of radiotherapy in cervical carcinoma patients demonstrated no beneficial effects (19). In addition to questionable clinical efficacy hyperbaric oxygen is a costly and sometimes dangerous procedure, which is not commonly used.

Carbogen

Inhalation of carbogen, a mixture of 95% oxygen and 5% carbon dioxide has also been
shown to increase tumor oxygenation both in animal models (20,21) and in the clinical
situation (22-24). An explanation for this effect is that carbon dioxide has vasodilatory functions in this setting which allows for better tumor perfusion of the high concentration of inhaled oxygen (25). Therapeutic benefits of carbogen therapy are mixed although some radiosensitizing effects have been observed alone (26-28), or in combination with nicotinamide in Phase I/II trials (29). Phase III trials are needed.

Proposed Solutions

Hypertonic Saline

Patients suffering from hemorragic shock often incur organ failure due to hypo-perfusion and lose of oxygen. Hypertonic solutions have originally been found useful in the treatment of traumatized patients with hemorrhagic shock. In 1980 Velasco et al demonstrated that an injection of 7.5% NaCl in hemorrhaged dogs restored arterial pressure and cardiac output while increasing survival compared to dogs receiving isotonic saline (30). In the same year, his group published human study in which 12 patients with hypovolaemic shock refractory to volume replacement, corticosteroid and dopamine infusions were administered a bolus of 100-400 ml of 7.5% NaCl. 11 of the 12 patients responded with rise in arterial pressure and the resumption of urine flow, the effects lasting for several hours (31). This treatment has been shown to increase oxygen content of organs in part by causing intratissue fluid to enter blood vessels, and increase blood vessel volume. These effects were postulated to be due to the temporary disruption of osmotic balance, as well, as erythrocytes losing their volume and being able to squeeze through areas which previously have not been perfused. Hypertonic saline therapy has not been associated with toxicity and has been used extensively in the clinical setting (33,34). The hemodynamic-stabilizing effects of saline have even been shown benefitial a hamster model of endotoxemia (35).

This stimulates the question of whether infusions of hypertonic saline may be used in
conjunction or alone for increasing tumor oxygenation. An added benefit to this
approach is immunostimulation! It has been demonstrated in mouse and human that
hypertonic saline therapy increases T cell proliferation and IL-2 production, while
suppressing production of PGE-2 and also suppresses IL-4 production (36-40). IL-4 and
PGE-2 have both been shown to suppress antitumor immune responses (41,42).
Another interesting approach to cancer therapy, which has not been attempted is the
combination of hypertonic saline infustion with systemic interleukin-2. One of the big
problems with clinical administration of IL-2 is induction of a shock-like state called the vascular-leak syndrome (43). Along these lines, a randomized trial was conducted examining crystalloid vs colloid resuscitation. No clear benefitial effect was demonstrated (44).

Although therapy with hypertonic saline seems absurdly simple, we must not forget that cisplatin therapy would have most likely been abandoned had Cvitkovic et al not found that rapid fluid administration can spare the host of this drug’s nephrotoxic effects
(45,46).

Ozone Therapy/Stressed Cell Therapy

Introduction

There are some areas in which ideas practiced in alternative medicine may have clinical
relevance, I believe the area of ozone therapy is one of them.

Ozone therapy is administered through several routes:
1. Directly intravenously,
2. Intrarectally,
3. Exposing patient blood to ozone ex-vivo followed by subsequent re-infusion
(Autohematherapy).

The first method was described by Lacoste in 1951 who used it to treat vascular
insuffiency and gangrene (47). Intravenous administration of ozone is possible since
both ozone and oxygen are very soluble in blood (48), however this technique is
considered out-dated and is hardly used today. Rectal administration has been used with
some efficacy for AIDS associated diarrhea (49), although, by far, the safest and most
widely method of ozone therapy is the third one mention: autohematherapy.

Vasocare therapy, invented by Anthony Bolten of Vasogen, is analogous to
autohematherapy, with the exception that UV irradation and/or heat is added to the
patient cells before reintroduction. In contrast to traditional ozone therapy, the effects of Vasocare have been extensively analysized scientifically with several patents and papers available in the public domain. I will clump together Vasocare and traditional autohematherapy for purposes of this discussion.

Clinical Effects

Reports of ozone therapy are largely anectodal due to it being primarily practiced in
alternative medicine. In this field it is a panacea, irresponsibly claimed by detractors to be a cure for everything from AIDS to diabetes (50,51). Reports such has these have
severely damaged the credibility of ozone therapy, even placing it on the National Cancer
Institute’s list of questionable treatments for cancer (52).

With that said, I will examine the credible literature on this topic. Anacedotally reported, treatment of peripheral limb ischemia has been successful with autohematherapy (53,54).

Recently, Tylicki et al treated 12 patients with lower limb atherosclerotic ischemia. Of these, 11 had prolonged ability to walk on a threadmill post-treatment (55). In another pilot study symptoms of atherosclerotic vasculopathy were improved (56). Utility of Vasocare treatment was demonstrated in peripheral vascular disease in a two centered double-blind study by Baird and Belch in the United Kingdom where the treatment group reported a greater than 50% increase in walking distance compared to controls (57). Vasogen has currently received approval for a Phase III pivotal trial in peripheral arterial disease (58).

Vasogen has also demonstrated efficacy of Vasocare therapy in autoimmune diseases
both in animal models and in humans, unfortunately, these studies have not been
published in the peer reviewed literature but only as patents (59-61). More relevant to our discussion, Vasogen noticed some anti-leukemia effects in its trial on graft versus host disease, this is the basis for an ongoing trial of Vasocare in chronic lymphocytic leukemia (62).

Mechanisms

It is postulated that these effects are mediated in part by the ability of the treatment to increase tissue oxygenation, while at the same time having an anti-inflammatory effect(reviewed in 63). Erythrocytes in patients receiving autohematherapy are postulated to be better oxygen carriers than controls due to an increase in 2,3 diphosphoglycerate (64). A randomized trial comparing autohematherapy to hyperbaric oxygen demonstrated that only autohematherapy decreases blood viscosity while increasing erythrocyte filterability
(65). Both of these changes would hypothetically increase tumor oxygenation. Another
mechanism of ozone therapy may be induction of nitric oxide (NO). NO possesses many
effects, but one of the well known ones is vasodilation (66). In Vasogen mentions in two of their patents, that Vasocare blocks platelet aggregation and induces NO (67,68).
Once again, these effects could hypothetically increase tumor oxygenation.
Ozone therapy may also have direct effects on cancer cells. In the 1920s Warburg
postulated cancer cells preferentially utilize anaerobic metabolism (69). Others after him have claimed that high concentrations of oxygen can specifically kill tumor cells, although this was for the most part proven wrong. Interestingly, ozone can preferentially inhibit various primary human tumor cells while sparing normal tissue, in vitro (70).
Similar results were obtained in leukemic cell lines (71).

Conclusion

Ozone therapy has been used for millions of treatments without toxicity (cited in 72).
Under a different form (Vasocare) ozone therapy is now entering Phase III trials. The
combination of ozone therapy with radio, chemo and immune therapies should increase
efficacy of these treatments by overcoming tumor hypoxia. Future studies in this area are
definitely warranted.
________________________________________
References
1. Folkman J. Tumor angiogenesis. Adv Cancer Res. 1985;43:175-203

2. Tumour angiogenesis / edited by Roy Bicknell, Claire E. Lewis, and Napoleone
Ferrara. Oxford, [England] ; New York : Oxford University Press, 1997.

3. Jain RK. Haemodynamic and transport barriers to the treatment of solid tumours.
Int J Radiat Biol. 1991 Jul-Aug;60(1-2):85-100

4. Benjamin LE, Golijanin D, Itin A, Pode D, Keshet E. Selective ablation of immature
blood vessels in established human tumors follows vascular endothelial growth factor
withdrawal. J Clin Invest. 1999 Jan;103(2):159-65.

4a. Williams KJ, Cowen RL, Stratford IJ. Hypoxia and oxidative stress. Tumour
hypoxia—therapeutic considerations. Breast Cancer Res. 2001;3(5):328-31

5. Fenton BM, Lord EM, Paoni SF. Intravascular HBO saturations, perfusion and
hypoxia in spontaneous and transplanted tumor models.
Int J Cancer. 2001 Sep 1;93(5):693-8.

6. Gouin-Thibault I, Achkar A, Samama MM. The thrombophilic state in cancer patients.
Acta Haematol. 2001;106(1-2):33-42

7. Dunst J, Ahrens S, Paulussen M, Burdach S, Jurgens H. Prognostic impact of tumor
perfusion in MR-imaging studies in Ewing tumors. Strahlenther Onkol. 2001
Mar;177(3):153-9.

8. Rudat V, Stadler P, Becker A, Vanselow B, Dietz A, Wannenmacher M, Molls M,
Dunst J, Feldmann HJ. Predictive value of the tumor oxygenation by means of pO2
histography in patients with advanced head and neck cancer. Strahlenther Onkol. 2001
Sep;177(9):462-8.

9. Canning MT, Postovit LM, Clarke SH, Graham CH. Oxygen-mediated regulation of
gelatinase and tissue inhibitor of metalloproteinases-1 expression by invasive cells. Exp
Cell Res. 2001 Jul 1;267(1):88-94.

10. Semenza GL. HIF-1: using two hands to flip the angiogenic switch.
Cancer Metastasis Rev. 2000;19(1-2):59-65

11. Pugh CW, Gleadle J, Maxwell PH. Hypoxia and oxidative stress in breast cancer.
Hypoxia signalling pathways. Breast Cancer Res. 2001;3(5):313-7.
21

11a. Kurzrock R. The role of cytokines in cancer-related fatigue. Cancer. 2001 Sep
15;92(6 Suppl):1684-8.

11b. Littlewood TJ. The impact of hemoglobin levels on treatment outcomes in patients
with cancer. Semin Oncol. 2001 Apr;28(2 Suppl 8):49-53.

12. Naldini A, Cesari S, Bocci V. Effects of hypoxia on the cytotoxicity mediated by
tumor necrosis factor-alpha. Lymphokine Cytokine Res. 1994 Aug;13(4):233-7.

13. Scannell G, Waxman K, Kaml GJ, Ioli G, Gatanaga T, Yamamoto R, Granger GA.
Hypoxia induces a human macrophage cell line to release tumor necrosis factor-alpha and
its soluble receptors in vitro. J Surg Res. 1993 Apr;54(4):281-5.

13a). Balkwill FR. Tumour necrosis factor and cancer. Prog Growth Factor Res.
1992;4(2):121-37.

13b) Natoli G, Costanzo A, Guido F, Moretti F, Levrero M. Apoptotic, non-apoptotic,
and anti-apoptotic pathways of tumor necrosis factor signalling. Biochem Pharmacol.
1998 Oct 15;56(8):915-20.

14. Ishizaka S, Kimoto M, Tsujii T. Defect in generation of LAK cell activity under
oxygen-limited conditions. Immunol Lett. 1992 May;32(3):209-14.

15. Loeffler DA, Juneau PL, Masserant S. Influence of tumour physico-chemical
conditions on interleukin-2-stimulated lymphocyte proliferation. Br J Cancer. 1992
Oct;66(4):619-22.

16. Gray LH, Conger AD, Ebert M, Hornsey S, Scott OC. The concentration of oxygen
dissolved in tissues at the time of irradiation as a factor in radiotherapy. Br J Radiol
26:638-48, 1953.

17. Hill RP. Cellular basis of radiotherapy. In: Tannock IF, Hill RP, editors. The basic
science of oncology. 2nd ed. New York: McGraw-Hill; pp259-275, 1992.

17a). Tomida A, Tsuruo T. Drug resistance mediated by cellular stress response to the
microenvironment of solid tumors. Anticancer Drug Des. 1999 Apr;14(2):169-77.

18. Haffty BG, Hurley R, Peters LJ. Radiation therapy with hyperbaric oxygen at 4
atmospheres pressure in the management of squamous cell carcinoma of the head and
neck: results of a randomized clinical trial. Cancer J Sci Am. 1999 Nov-Dec;5(6):341-7.

19. Dische S, Saunders MI, Sealy R, Werner ID, Verma N, Foy C, Bentzen SM.
Carcinoma of the cervix and the use of hyperbaric oxygen with radiotherapy: a report of a
randomised controlled trial. Radiother Oncol. 1999 Nov;53(2):93-8.

20. Hartmann KA, van der Kleij AJ, Carl UM, Hulshof MC, Willers R, Sminia P. Effects
of hyperbaric oxygen and normobaric carbogen on the radiation response of the rat
rhabdomyosarcoma R1H.
Int J Radiat Oncol Biol Phys. 2001 Nov 15;51(4):1037-44.

21. Horsman MR, Khalil AA, Nordsmark M, Grau C, Overgaard J. Relationship between
radiobiological hypoxia and direct estimates of tumour oxygenation in a mouse tumour
model. Radiother Oncol. 1993 Jul;28(1):69-71.

22. Powell ME, Collingridge DR, Saunders MI, Hoskin PJ, Hill SA, Chaplin DJ.
Improvement in human tumour oxygenation with carbogen of varying carbon dioxide
concentrations. Radiother Oncol. 1999 Feb;50(2):167-71.

23. Aquino-Parsons C, Green A, Minchinton AI. Oxygen tension in primary
gynaecological tumours: the influence of carbon dioxide concentration. Radiother Oncol.
2000 Oct;57(1):45-51.

24. Partridge SE, Aquino-Parsons C, Luo C, Green A, Olive PL. A pilot study
comparing intratumoral oxygenation using the comet assay following 2.5% and 5%
carbogen and 100% oxygen. Int J Radiat Oncol Biol Phys. 2001 Feb 1;49(2):575-80.

25. Griffiths JR, McIntyre DJ, Howe FA, McSheehy PM, Ojugo ASE, Rodrigues LM,
Wadsworth P, Price NM, Lofts F, Nicholson G, Smid K, Noordhuis P, Peters GJ, Stubbs
M. Issues of normal tissue toxicity in patient and animal studies—effect of carbogen
breathing in rats after 5-fluorouracil treatment.
Acta Oncol. 2001;40(5):609-14.

26. Martinez JC, Villar A, Cabezon MA, de Serdio JL, Fuentes C, Espineira M, Perez
MD, Gil J, Artazkoz JJ, Borque C, Suner M, Saavedra JA. Hyperfractionated
chemoradiation with carbogen breathing, with or without erythropoietin: a stepwise
developed treatment schedule for advanced head-and-neck cancer.
Int J Radiat Oncol Biol Phys. 2001 May 1;50(1):47-53.

27. Marcial VA, Pajak TF, Kramer S, Davis LW, Stetz J, Laramore GE, Jacobs JR, Al-
Sarraf M, Brady LW. Radiation Therapy Oncology Group (RTOG) studies in head and
neck cancer. Semin Oncol. 1988 Feb;15(1):39-60.

28. Dische S, Rojas A, Rugg T, Hong A, Michael BD. Carbogen breathing: a system for
use in man. Br J Radiol. 1992 Jan;65(769):87-90.

29. Hoskin PJ, Saunders MI, Dische S. Hypoxic radiosensitizers in radical radiotherapy
for patients with bladder carcinoma: hyperbaric oxygen, misonidazole, and accelerated
radiotherapy, carbogen, and nicotinamide. Cancer. 1999 Oct 1;86(7):1322-8.

30. Velasco IT, Pontieri V, Rocha e Silva M Jr, Lopes OU. Hyperosmotic NaCl and
severe hemorrhagic shock. Am J Physiol. 1980 Nov;239(5):H664-73.

31. de Felippe J Jr, Timoner J, Velasco IT, Lopes OU, Rocha-e-Silva M Jr. Treatment of
refractory hypovolaemic shock by 7.5% sodium chloride injections. Lancet. 1980 Nov
8;2(8202):1002-4.

32. Mazzoni MC, Borgstrom P, Intaglietta M, Arfors KE. Capillary narrowing in
hemorrhagic shock is rectified by hyperosmotic saline-dextran reinfusion. Circ Shock.
1990 Aug;31(4):407-18.

33. Shires, G. T., A. E. Barber, H. P. Illner. 1995. Current status of resuscitation:
solutions including hypertonic saline. Adv. Surg. 28:133

34. Wade, C. E., G. C. Kramer, J. J. Grady, T. C. Fabian, R. N. Younes. 1997. Efficacy of
hypertonic 7. 5% saline and 6% dextran-70 in treating trauma: a meta-analysis of
controlled clinical studies. Surgery 122:609.

35. de Carvalho H, Matos JA, Bouskela E, Svensjo E. Vascular permeability increase
and plasma volume loss induced by endotoxin was attenuated by hypertonic saline with
or without dextran.
Shock. 1999 Jul;12(1):75-80.

36. Coimbra R, Junger WG, Hoyt DB, Liu FC, Loomis WH, Evers MF. Hypertonic
saline resuscitation restores hemorrhage-induced immunosuppression by decreasing
prostaglandin E2 and interleukin-4 production. J Surg Res. 1996 Aug;64(2):203-9.

37. Junger WG, Coimbra R, Liu FC, Herdon-Remelius C, Junger W, Junger H, Loomis
W, Hoyt DB, Altman A. Hypertonic saline resuscitation: a tool to modulate immune
function in trauma patients?
Shock. 1997 Oct;8(4):235-41.

38. Coimbra R, Junger WG, Liu FC, Loomis WH, Hoyt DB. Hypertonic/hyperoncotic
fluids reverse prostaglandin E2 (PGE2)-induced T-cell suppression. Shock. 1995
Jul;4(1):45-9.

39. Junger WG, Hoyt DB, Hamreus M, Liu FC, Herdon-Remelius C, Junger W, Altman
A. Hypertonic saline activates protein tyrosine kinases and mitogen-activated protein
kinase p38 in T-cells. J Trauma. 1997 Mar;42(3):437-43;

40. Junger WG, Liu FC, Loomis WH, Hoyt DB. Hypertonic saline enhances cellular
immune function.
Circ Shock. 1994 Apr;42(4):190-6.

41. Lucey DR, Clerici M, Shearer GM. Type 1 and type 2 cytokine dysregulation in
human infectious, neoplastic, and inflammatory diseases. Clin Microbiol Rev. 1996
Oct;9(4):532-62.

42. Young MR. Eicosanoids and the immunology of cancer. Cancer Metastasis Rev.
1994 Dec;13(3-4):337-48.

43. Cotran RS, Pober JS, Gimbrone MA Jr, Springer TA, Wiebke EA, Gaspari AA,
Rosenberg SA, Lotze MT. Endothelial activation during interleukin 2 immunotherapy. A
possible mechanism for the vascular leak syndrome. J Immunol. 1988 Mar
15;140(6):1883-8.

44. Pockaj BA, Yang JC, Lotze MT, Lange JR, Spencer WF, Steinberg SM, Topalian
SL, Schwartzentruber DJ, White DE, Rosenberg SA. A prospective randomized trial
evaluating colloid versus crystalloid resuscitation in the treatment of the vascular leak
syndrome associated with interleukin-2 therapy. J Immunother. 1994 Jan;15(1):22-8.

45. Cvitkovic E, Spaulding J, Bethune V, Martin J, Whitmore WF. Improvement of cisdichlorodiammineplatinum
(NSC 119875): therapeutic index in an animal model.
Cancer. 1977 Apr;39(4):1357-61.

46. Gonzales-Vitale JC, Hayes DM, Cvitkovic E, Sternberg SS. The renal pathology in
clinical trials of cis-platinum (II) diamminedichloride. Cancer. 1977 Apr;39(4):1362-71.
47. Lacoste: Traitement des insuffisances vascuilaires pa l’ozone. Gaz med de France
1951;315

48. Rokitansky O: Klinik und biochemie der ozon therapy. Hospitals 1982;52:643 nd
711.

49. Carpendale MT, Freeberg J, Griffiss JM. Does ozone alleviate AIDS diarrhea?
J Clin Gastroenterol. 1993 Sep;17(2):142-5.

50. www.trunkerton.fsnet.co.uk/ozone_cure_for_aids.htm

51. missoula.bigsky.net/ravaids/Myths.htm

52. www.bccancer.bc.ca/pg_g_05.asp?PageID=1702&ParentID=4

53. Rokitansky O. Klinik und Biochemie der Ozontherapie. Hospitalis 1982;52643-7.

54. Werkmeister H. Dekubitalgeschwure und die Behandlung mit der Ozon-
Unterdruckbegasung. In: Beck, Viebahn-hnsler eds. Ozon-Handbuch. Grundlagen.
Pravention. Therapie. Landsberg/Lech: Ecomed, 1995, V-7-7.1 1-V-7.1, 22.

55. Tylicki L, Niew glowski T, Biedunkiewicz B, Burakowski S, Rutkowski B.
Beneficial clinical effects of ozonated autohemotherapy in chronically dialysed patients
with atherosclerotic ischemia of the lower limbs--pilot study. Int J Artif Organs. 2001
Feb;24(2):79-82.

56. Di Paolo N, Bocci V, Garosi G, Borrelli E, Bravi A, Bruci A, Aldinucci C,
Capotondo L. Extracorporeal blood oxygenation and ozonation (EBOO) in man.
preliminary report. Int J Artif Organs. 2000 Feb;23(2):131-41.

57. www.vasogen.com/112900.html

58. Visioli F. VasoCare. Vasogen.
Curr Opin Investig Drugs. 2001 Sep;2(9):1247-9.

59. US Patent # 6,258,357

60. US Patent # 6,204,058

61. US Patent # 5,980,954

62. www.vasogen.com/040501.html

63. Bocci V. Ozone as a bioregulator. Pharmacology and toxicology of ozonetherapy
today. J Biol Regul Homeost Agents. 1996 Apr-Sep;10(2-3):31-53.

64. Viebahn-Hansler R. Einfluss auf den rythrozytenstoffwechsel. In: Ozon-Handbuch.
Grundlagen-Prevention-Therapie. Landsberg/Lech:Ecomed, 1995, 1-15.

65. Verrazzo G, Coppola L, Luongo C, Sammartino A, Giunta R, Grassia A, Ragone R,
Tirelli A.Hyperbaric oxygen, oxygen-ozone therapy, and rheologic parameters of blood
in patients with peripheral occlusive arterial disease.
Undersea Hyperb Med. 1995 Mar;22(1):17-22.

66. Lind L. Evaluation of endothelium-dependent vasodilation in humans. Blood Press.
2001;10(3):124-30.

67. US Patent # 5,834,030

68. US Patent # 5,591,457

69. Warburg, O. (1924) Biochem Z. 152, 319-344.

70. Sweet F, Kao MS, Lee SC, Hagar WL, Sweet WE. Ozone selectively inhibits growth
of human cancer cells. Science. 1980 Aug 22;209(4459):931-3.

71. Canadian Patent # 2192602

72. Bocci V. Biological and clinical effects of ozone. Has ozone therapy a future in
medicine? Br J Biomed Sci. 1999;56(4):270-9.

Ozon Tedavisi Genel Bilgi




3 Major Effects of Ozone on the Body by Dr. Frank Shallenberger
1. Ozon beyaz kan hücreleri üretimini stimüle eder. Bu hücreler vücudu virüs, bakteri, mantar ve kansere karşı koruyan hücrelerdir. Bu hücrelerin oksijenden yoksun kalması sonucunda fonksiyonlarını tam olarak yerine getiremezler. Eğer bu mekanizma düzgün olarak çalışmaz ve tehditleri ortadan kaldıramazsa normal hücrelere karşı da reaksiyon gösterebilir ve sonuç olarak alerjik reaksiyonlar ortaya çıkar. Ozon oksijen seviyelerini normal sınırlara çekerek desentizasyonu ortadan kaldırır.

2. İnterferon bağışıklık sistemini bir orkestra gibi yöneten çok önemli bir maddedir. Bazı interferonlar virüsle enfekte olmuş hücreler tarafından üretilirler. Bu interferonlar komşu hücreleri uyarır infekte hücrelere karşı kensini savunur ve virüs replikasyonunu engeller (çoğalmasını). Diğer interferonlar, kas, bağ dokusu ve beyaz kan hücreleri tarafından salgılanır. İnterferon gamma düzeyleri ozon tedavisi ile %400-900 arasında artırılır. Bu interferon fagositik hücrelerin patojenler ve anormal hücreleri öldürmesi ve fagosite etmesindeki karışıklıkları giderir. İnterferonlar kronik hepatit B ve C, genital siğil (papilloma virüs sebepli), Hairy cell lösemi, kaposi sarkomu, relapsing-remitting multiple sclerosis ve kronik granülomatoz hastalıklarda kullanımı FDA tarafından onaylanmıştır. İnterferon güncel çalışmalarında ağız içi siğilleri (papilloma virüs kaynaklı), HIV enfeksiyonu, kronik myeloid lösemi, non-hodkin lenfoma, kolon tümörleri, böbrek tümörleri, mesane kanseri, malign melanom, bazal cell karsinoma ve leishmaniazis tedavisinde interferon kullanımını araştırmaktadır. İnterferonun dışarıdan verilmesi toksik etkiler yaparken ozon tedavisi ile vücutta güvenli bir şekilde yükseltilebilir.

     3. Tümör büyümesi esnasında vücut tümör necrosis faktörü üretir. Ozon tedavisi de TNF’nin üretimini artırır. Tümör ne kadar büyürse o kadar TNF üretilir. Tümör ne zaman metastatik hale gelirse, kanser hücreleri lenf ve kan damarları vasıtasıyla taşınırlar. Vücudun başka yerlerine ulaşır ve yerleşerek orada çoğalmaya başlar ve TNF üretilmesine sebep olur bu madde de orijinal tümörü baskılar. Ne zaman ki tümör cerrahi olarak çıkarılırsa TNF seviyesi dramatik olarak düşer ve sağlıklı dokuda yeni tömör görülür.
      4. Ozon IL-2 salgılanmasına neden olur. IL-2 bağışıklık sistemin temel taşıdır. T-Helper hücreler tarafından salınır. Bu süreç otostimülasyon olarak bilinir. IL-2 T-helperlar üzerindeki reseptörleri bir araya toplar ve bunların daha fazla IL-2 salınımı sağlamasına neden olur. Bu lenfositlerin değişimine ve hızla çoğalmasına neden olur, T-helpers, T-supressors, sitotoksik T’s, T-delayed ve T-memory hücrelerinin artışı meydana gelir.