Chapter 9 THE CLINICAL APPLICATION OF OZONETHERAPY The reader may be eager to examine in which diseases ozonetherapy can be proficiently used and she/he will be amazed by the versatility of this complementary approach (Table 5). The fact that the medical applications are numerous exposes the ozonetherapist to medical derision because superficial observers or sarcastic sceptics consider ozonetherapy as the modern panacea. This is so because ozone, like oxygen, is a molecule able to act simultaneously on several blood components with different functions. The ozone messengers ROS and LOPs can act either locally or systemically in practically all cells of an organism. In contrast to the dogma that “ozone is always toxic”, three decades of clinical experience, although mostly acquired in private clinics in millions of patients, have shown that ozone can act as a disinfectant, an oxygen donor, an immunomodulator, a paradoxical inducer of antioxidant enzymes, a metabolic enhancer, an inducer of endothelial nitric oxide synthase and possibly an activator of stem cells with consequent neovascularization and tissue reconstruction. Table 5. Ozone therapy can be used in the following medical specialities Angiology Gynaecology Pneumology Cardiology Hepatology Rheumatology Cosmetology Infectivology Stomatology Dentistry Intensive therapy Surgery Dermatology Neurology Urology Gastroenterology Oncology Gerontology Orthopaedics Figure 2 (Chapter 4) has tried to give a comprehensive idea of how ozonated blood cells and LOPs interact with a number of organs after the initial reaction of ozone with plasma components. One of the substantial differences between classical pharmacology and ozonetherapy is that this approach generates a heterogeneous number of compounds, which, in 97 98 Chapter 9 submicromolar concentrations, can trigger a variety of functional activities, hence multiple therapeutic responses rarely obtainable with a single drug. We know that chronic diseases are the result of a number of dysfunctions and the use of a reductionist approach can be disadvantageous. Indeed atherosclerotic patients often complain that during the day they must remember to take six or seven drugs such as a statin, folic acid, antioxidants, an antiplatelet agent, an anticoagulant, an ACE-inhibitor etc., to keep the disease at bay. This example is mentioned not for disregarding conventional medicine but to point out a reality that presents some problems with compliance and eventual outcome. Actually statins produce pleiotropic effects thus resembling ozone because, by inhibiting 3-hydroxyl-3- methylglutaryl coenzyme A reductase, an enzyme crucial to cholesterol and nonsteroidal isoprenoid compounds biosynthesis, they have antiatherosclerotic and surprising immunosuppressive effects (Mach, 2003; Vollmer et al., 2004; McCarey et al., 2004). On the other hand also ozonetherapy has drawbacks: ozone is a gas intrinsically toxic that cannot be breathed, cannot be stored and must be used with caution and competence. Thus ozonetherapy can be performed only by physicians after an appropriate training in ozonetherapy using a precise ozone generator equipped with a well-calibrated photometer. It is disgraceful that it is also performed with unprecise ozonators by charlatans and speculators without a medical qualification and this very fact compromises the credibility of ozonetherapy in the medical field. Hopefully this drawback will be overcome when ozonetherapy will become part of official medicine and all public hospitals will have an appropriate service. In the future, with medical supervision and a suitable ozonator, it will be possible to do, at least in part, some automedication using either rectal insufflation or/and body exposure (BOEX). This will represent a big step ahead because chronic patients will treat themselves comfortably at home with the result of maintaining a good quality of life. The main problem remains the scarcity of clinical trials and the difficulty of knowing and organizing reliable clinical results obtained by individual ozonetherapist. As a consequence, referees have been keen to suggest doing first animal studies. This suggestion is unrealistic because, beside rectal insufflation or intraperitoneal administration of gas (with obvious problems), laboratory animals are not suitable for examining the value of prolonged AHT. Moreover as millions of AHTs carried in humans have already proved their efficacy and atoxicity, why should we waste time with animal models? Too often it has happened that, even extremely successful results with human tumour transplanted in mice (see the clamour of “tumour infiltrating lymphocytes” and the media frenzing unleashed by the New York Times’ article reporting the antiangiogenetic effect of “endostatin”) have not been reproduced in the clinical setting! The Clinical Application of Ozone 99 While I admire some important and clear-cut results achieved with randomized clinical trials, all of us have to consider that behind such studies there are thousands of biochemists, immunologists, pharmacologists, clinical scientists, statisticians and, even more important, giant pharmaceutical industries providing huge fundings for the research. Even so, because of always being in a hurry to sell the new drug, they commit mistakes and recently a statin had to be withdrawn because of deadly effects. Thus, it is unfair when referees disregard our almost “heroic” efforts to do a clinical study without a sponsor and no other professional help. From the height of their chairs, they disdain to read or to have the referees’ comments regarding papers dealings with ozonetherapy, by solemnly declaring that “the topic is under-researched, the quality is very poor and the theme is not of wide interest to an international readership”. Nothing could be more false than those statements because we address critical issues where official medicine fails to be satisfactory, such as chronic limb and heart ischaemia, ARMD and chronic cutaneous wounds and ulcers that never heal. While it is true that some ozonetherapists treat the trivial cellulite for earning a living, this topic is certainly irrelevant but it is unfair drawing negative conclusions on the whole approach. Italian Health Authorities, well supported by conventional clinicians, who do not know anything about ozonetherapy, are also disdainful of our work: during the last 12 years they have done their best in rejecting our efforts by obstructing to perform ozonetherapy in public hospitals with the usual excuse that ozone is toxic or that is used badly owing to the lack of precise regulations. Thus, not only there is no financial support but what is more indecent is that these supreme judges are full of prejudices and refuse to understand even the simplest concepts of this therapy. However I am not begging indulgence because any complementary approach must accept and undergo the regulations endorsed by conventional medicine and must clarify whether a treatment is really effective and atoxic. I will then describe the results so far achieved by either presenting either data of any available clinical trial, or a “best case series” or anecdotal, yet reliable results. It will be shown that in many diseases, conventional medicine is quite adequate and ozonetherapy does not necessarily represent the first choice treatment. Indeed the competent physician-ozonetherapist must know all the conventional “gold standard” therapies and use them. Only when the best standard treatment is not satisfactory, the ozonetherapist may propose the option of ozonetherapy, only if he is sure of its efficacy. It is also possible that in some diseases, ozonetherapy may complement the conventional treatment and accelerate the resolution of the disease. I would also state that the term “alternative medicine” must be rejected because ozonetherapy is still an experimental approach and cannot be antithetical but only complementary. In spite of important 100 Chapter 9 progresses, conventional medicine is still unable to provide a significant improvement in some diseases. Thus it is ethically correct to take advantage of ozonetherapy when the best orthodox treatment has failed. In the next eighteen sections, the biological and clinical effects of oxygen-ozone therapy will be discussed and it will become apparent that this approach can be of critical importance in some diseases, useful if combined to orthodox medicine in others and, so far, useless in a few. 1. INFECTIOUS DISEASES (BACTERIAL, VIRAL, FUNGAL, PARASITIC) There is no doubt that ozone can have an important therapeutic role in x- x x various types of infections because it generates ROS (O2 , OH , H2O2, NO and HOCl), also produced by granulocytes and macrophages during an infectious process (Badwey and Karnowsky, 1980; Chanock et al., 1994; Anderson et al., 1997; Saran et al., 1999; Titheradge, 1999; Babior, 2000). Moreover, neutrophils have a wealth of antimicrobial proteins in their granules and release proinflammatory cytokines which, by exerting a variety of effects, cause tissue damage as well (Witko-Sarsat et al., 2000). Nieva and Wentworth (2004) have entertained the possibility that ozone may be produced in vivo via the antibody-catalyzed water-oxidation pathway through a postulated dihydrogentrioxide (H2O3) intermediate. To our surprise, it appears that Nature is able to generate gaseous and reactive x molecules (CO, NO and O3), which, in trace amounts, may display critical physiological roles, while, during inflammation, excessive amounts cause