Literature Review Summary
Coronary artery disease (CAD) is the most common form of cardiovascular disease and the leading cause of morbidity and mortality in many parts of the world including Malaysia.
Current therapy for myocardial ischemia relies on drug that reduces myocardial oxygen demand, mechanical endovascular revascularization procedures (angioplasty) or bypass surgery.
However recent advances in the management of coronary artery disease include what is known as therapeutic angiogenesis.
Although Folkman1 had identified the therapeutic and pathologic implications of neovascularization due to antigenic growth factors almost 30 year ago, it is not until recently that therapeutic angiogenesis emerged as a clinically feasible modality in the management of cardiovascular diseases and has generated considerable interest.
Angiogenesis, the process of new blood vessel formation from pre-existing fully differentiated endothelial cells is comprised of several discrete steps. These include dissolution of matrix, endothelial cell migration, proliferation and organization into a network structure, followed by lumen formation. In therapeutic angiogenesis, exogenous antigenic growth factors or genes encoding these growth factors are used to stimulate the growth of collateral vessels to ischemic tissues.
In all the above-mentioned process, derived nitric oxide (NO) has been implicated3,4. NO is an endothelial survival factor, inhibition apoptosis and enhancing endothelial cells proliferation. NO is generated from a reaction catalyzed by the enzyme nitric oxide synthase (NOS).5 It is also noted that vascular endothelial growth factor (VEGF) which is considered to be the most important antigenic growth factor, stimulates the release of NO and up regulates the expression of nitric oxide synthase (NOS).6 It binds to receptors on endothelial cells, resulting in their growth, proliferation and migration.
Other factors that are known to regulate angiogenesis are transforming growth factor beta (TGF-beta) and tumor necrosis factor alpha (TNF-alpha). Both TGF-beta and TNF-alpha are antigenic in vivo. It has been demonstrated that these cytokines induce angiogenesis indirectly by stimulating that production of direct-acting positive regulators from stromal and rh noattracted inflammatory cells. In this context then, TGF-beta and TNF- ;ha are considered to be indirect positive regulators.'
Apart from the mentioned angiogenic growth factors, a few others have been identified. Among them are fibroblast growth factor, pleteled derived growth factors and interleukin 8.8 It is also imperative to know that expression of the growth factors and the receptors is upregulated by hypoxia and ischemia, allowed a targeted therapeutic response and also limiting the potential for the pathologic angiogenesis.9
A large body of evidence shows that administration of angiogenic growth factors can augment nutrient perfusion through neovascularization. Theoretically, angiogenesis can be achieved either by the use of grows factor proteins or by the introduction of genesencoding these proteins (protein versus gene therapy).
Hence trials have been carried out to determine the efficacy of such methods in the treatment of ischaemic heart disease. Proof of concept in humans was initially established in severely symptomatic patients with critical limb ischaemia.10
Shortly thereafter; clinical investigations were extended to severely symptomatic patients with coronary artery disease. Within the same framework, we shall now try to explore other frontiers that may share the same premise of scientific ingenuity. Could therapeutic angiogenesis be triggered by other mechanisms than protein or gene therapy?
Researchers at the Second University of Naples conducted a study to evaluate the effect of oxygen-ozone therapy upon haemorheological parameters and haemoglobin-oxygen affinity in patients with peripheral occlusive arterial disease 11
They concluded that ozonized auto transfusions improved the viscosity of blood and its ability to deliver oxygen to tissues in patient suffering from occlusive arterial disease.
Ozone therapy has also been shown to reduce scavenger enzyme activity in patients with cardiovascular disease, which seems to be a critical fact into pathogenesis of the disease 12
It is also reported that ozone can reduce the blood cholesterol level 13 Anecdotal evidence showed marked improvement clinically and new collaterals angiographic ally in patients treated with ozone. Could there be a scientific explanation to this phenomenon?
Research carried out at the Institute of General Physiology, University of Siena have shown that the treatment of human endothelial cells with ozonated serum yielded a significant and steady increase of nitric oxide (NO).14 This observation is extremely important in view that as we had mentioned earlier, NO plays a crucial role in every steps of angiogenesis.
We hypothesized that this then could be the link to the observed antigenic phenomenon. It should also noted that ozone therapy would also result in increase in levels of a few biological factors namely transforming growth factor beta 15 tumor necrosis factor alpha 16 interleukin 817 and platelet derived growth factor beta 18 All of these factors as mentioned earlier are antigenic growth factors.
Furthermore ozone has also been shown to increase nitric synthase (NOS) activity 19 the enzyme catalyzing the production of NO.
The only thing at this moment in time we cannot say is whether azonated serum is able to increase gene expression of VEGF. However, Chua et al. has clearly shown that VEGF mRNA was expressed in a dose and time dependent manner when rat endothelial cells were exposed to 0.5 - 1 mM H2O2.20 It is a known fact that human serum exposed to biologically active ozone concentration incubated with human endothelial cells will induce H2O2 production 14
Therefore there seem to be an apparent correlation in terms of gene expression of VEGF mediated by a known active compound triggered by ozone in human blood.
We feel that the only way to prove or disprove our hypothesis would be to conduct a randomized controlled trial. Ozone treatment via Eboo, RHP and Safe has been used for four decades but owing to the lack of clinical studies, it has not been adopted by orthodox medicine 21 With the advent of precise medical ozone generators, it is now possible to evaluate this mechanism of action, therapeutic dose and possible toxicity.
With regard to ozonated blood, no risks have been demonstrated, provided that ozone concentration is no higher than 80 Gamma. There is no evidence that EBOO, RHP and SAFE produce acute or chronic side effects, even after 60 sessions, and most patients reports a feeling of well- being 22
Besides showing therapeutic effects, results from research done on human subjects after successful attempts on sheep indicate that EBOO, RHP and Safe are clinically valid, without side-effects and worthy of testing in various diseases 23
In the age of molecular medicine it is real 'act of faith' to believe that ozone therapy might be a valid therapeutic option, but the history of medicine teaches us that we should not disregard any possibility.
In a superbly written article entitled "Complementary medicine: from quackery to science?" Prof Edzard Ernst24 has pointed out that time has come "to submit to scientific scrutiny treatments that appear potentially useful. The obvious way to do this is to conduct randomized controlled trials taking into account the peculiarities of the remedies that are being tested"..
1. Folkman J. Tumuor angiogenesis: therapeutic implications. N Eng J Med. 1971; 285: 1182-6/
2. Takeshita S, Zheng LP, Brogi E et al. Therapeutic angiogenesis. A single intraarterial bolus of vascular endothelial growth factor augments revascularization in a rabbit ischaemic hind limb model. J Clin Invest. 1994; 93:662-70.
3. Morbidelli L, Chang CH, Douglas HJ, Granger FL and Ziche M. Nitric Oxide mediates mitogenic effect of VEGF on coronary venular endothelium. Am J Physiol 1996; 270: H411 -H415.
4. Ziche M, Morbidelli L, Masini S et al. nitric oxide mediates angiogenesis in vivo and endothelial cell growth and migration in vitro promoted by substance P. J Clin Invest. 1994; 94: 2036 - 2044.
5. Moncada S, Palmer RM and Higgs EA. Nitric oxide: physiology, pathophysiology and pharmacology. Pharmacol Rev. 1991; 43: 109 - 142.
6. Hood JD, Meininger CJ, Ziche M et al. VEGF upregulates ecNOS message, protein and NO production in human endothelial cells. Am J Physiol. 1998; 274 (3 pt 2): H1054 - H1058.
7. Pepper MS, Mandriota S, Vassali JD et al. Angiogenesis regulating cytokines: activities and interactions. Cum Top Microbiol lmmunol.1996] 213: 31 -67.
8. Henry TD. Science, Medicine, and the future: Therapeutic angiogenesis. BMJ 1999; 318: 1536 - 1539.
9. Isner JM. Tissues responses to ischaemia: local and remote responses for preserving perfusion in ischaemia muscle. J Clin Invest. 2000; 106: 615-619.
10. Freedman SB, Isner JM. Therapeutic angiogenesis for coronary artery disease. Ann Intern Med 2002; 136: 54 - 71.
11. Giunta R. Ozonized antohaemotransfusion improves haemorheological parameters and oxygen delivery to tissues in patients with peripheral acclusive disease. Ann Hematol 2001; 80: 745 - 748.
12. Hernandez F, Menendez S and Wang R. Decrease of blood cholesterol and stimulation of antioxidative response in cardiopathy patients treated
with endovenous ozone therapy. Free Radic Biol. Med. 1995,19: 115 -
13. Rilling S. The basic clinical applications of ozone therapy. Sci. Eng. 1985; 7: 259-274.
14. Valacchi G and Bocci V. Studies on the biologicaleffects of ozone: 11. Release of factors from human endothelial cells. Mediat Inflamm 2000; 9: 271 -276.
15. Bocci V, Luzzi E, Corradeschi F et al. Studies on the biological effects of ozone: 6. Production of transforming growth factor 1 by human blood after ozone treatment. J Biol Regular Homeost Agent 1994; 8: 108 — 112.
16. Paulesu L, Luzzi E and Bocci B. Studies on the biological effects of ozone: 2. Induction of tumor necrosis factor (TNF - alpha) on human leukocytes. Lymphokine and Cytokine Research 1991; 10: 409 - 412.
17. Bocci V, Valacchi G, Corradeschi F et al. Studies on the biological effects of ozone:8. Effects on the total antioxidant status and in interleukin - 8 production. Mediat Inflamm 1998; 7: 313 - 317.
18. Valacchi G and Bocci V. Studies on the biological effects of ozone: 10. Release of factors from ozonated human platelets. Mediat Inflamm 1999; 8: 205-209.
19. Laskin DL, Heck DE and Laskin JD. Role of inflammatory cytokines and nitric oxide in hepatic and pulmonary toxicity. Toxicol Lett 1998; 102 - 103: 289-293
20. Chua CC, Hamdy RC and Chua BHC. Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells. Free Rad Biol Med 1998; 25: 891 - 897.
21. Bocci V. Biological and clinical effects of ozone. Has ozone therapy a future in medicine? BrJBiomed Sci 1999: 56: 270 - 279.
22. Bocci V. Ozone as a bioregular. Pharmacology and Toxicology of ozone therapy today. J Biol Homeost Agents 1996; 10: 31 -53.
23. Di Paolo N, Bocci V, Garosi G et al. Extracorporeal blood oxygenation and ozonation in man. Preliminary report. Int J Artif Organs 2000; 23: 131 - 141.
24. Ernst E. Complementary medicine: from quackery to science? J Lab Clin Med 1996; 127: 244-5.
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