Ozone Therapy and Its Use in Medicine
We have recently read the report by üreyen et al.  on a possible side effect which, by just reading the title, seems unwisely linked to ozone therapy. We feel this report is problematical because of the publication of significant incomplete information and an improper conclusion to wit: ‘…ozone ther-apy in our case could be the possible etiol-ogy of the index myocardial infarction’.
This paper does not give us any infor-mation about the technique used, the ozone concentration, the total weight of ozone, the volume of blood, and any other relevant data regarding the administration of this gas. Such factors, analogous to dose and mode of administration of any drug, would be of great importance. The major autohemotherapy technique, in our opin-ion, is the safest method when compared to other therapeutic approaches. Usually, a standard autohemotherapy is done using citrate as an anticoagulant and with the concentration ranging between 20 and 40 μg/ml or, with heparin, 5,000 units per 200 ml of blood.
Moreover, in one of the papers cited by Bocci et al.  regarding the platelet activa-tion, the authors report ‘we were not sur-prised to observe a rapid platelet aggrega-tion in heparinized plasma particularly at the highest concentration’. Bocci et al. re-ported on in vitro samples in a format to-tally foreign to in vivo ozone delivery. Wa-ter poured on isolated (in vitro) cells can cause them to explode.
This is not relevant to in vivo water con-sumption. Furthermore, the authors may not have been aware that ozone therapy en-hances prostacyclin synthesis and improves the prostacyclin/thromboxane ratio . These effects stand in direct contradiction to the conclusion rendered by the authors of the single report, wherein an improve-ment in prostacyclin would be expected to have cardioprotective effects: ‘We assume that PGI2 stimulation may contribute to the beneficial effects of ozone treatment.’
Finally, Sroczynski et al.  again re-ported the opposite of the conclusion of üreyen et al. , finding that intra-arterial ozone gas ‘…showed a significant im-provement in both groups [atherosclerotic and diabetic patients] manifested by an in-crease in ankle-arm index, and prolonga-tion of the intermittent claudication dis-tance by more than twice’. The treatment of atherosclerotic ischemia of the lower ex-tremities with O 3 is both valuable and safe. Surely, if ozone therapy could incite patho-logical thrombosis, these authors should have seen problems with direct gas admin-istration to an artery!
Our past experience in the Pharmacol-ogy Department following the Pharmaco-Epidemiological Surveillance Program in agreement with WHO standards, and, in extensive clinical practice, gave us enough experience to observe and catalog side ef-fects. Following the WHO definitions , one event candidate, as a potential side effect, is classified as unlikely when in rela-tion to the time elapsed since the event, a relationship has become improbable (but not impossible). In the same document, an adverse event is defined as a medical occur-rence temporally associated with the use of a medicinal product or procedure, but not necessarily causally related.
In the case reported by the authors, the time from the treatment (morning) to the first symptoms (3 h before midnight) seems to be too long to rationally explain them as a consequence of the ozone treatment. The authors did not disclose other potential in-citing factors such as a fat-laden meal (free fatty acids increase risk ), event or stress, etc.
In our opinion, it is not easy to under-stand how a thrombotic lesion could pro-duce symptoms 12 h later, long after the al-leged instigating event had occurred. Or if it did, the authors need to explain with well-documented data that the ozone treatment can delay action in instigating thrombosis.
In the last 30 years, two of the authors, Dr. Rowen and Dr. Re, have executed about 60,000 major autohemotherapies on hu-mans without any side effects. Human studies  have been performed to evaluate some interesting metabolic pathways acti-vated by a correct administration of ozone doses using the most appropriate tech-nique. We imagine that very many major autohemotherapies must have been ad-ministered so far all around the world by the thousands of physicians working in this field. Needless to say that only in a few cas-es could we observe mild reactions such as redness.
We agree with the authors that unfortu-nately, like every other therapy, ozone ther-apy has side effects. Fortunately, the num-ber of adverse drug reactions reported for ozone therapy that we could find in the lit-erature is negligible when compared to those produced by surgery or pharmaco-logical treatments, particularly in the elder-ly [8, 9]
We believe your readers should be aware of the significant flaws in the report-ing of this case and the conclusions, whichfly in the face of years of experience and hundreds of thousands of ozone treat-ments. We believe it is far more likely that other factors in the unfortunate case might have been the cause of the heart attack and that a 12-hour separation from an unde-scribed ozone treatment is simply coinci-dental.
1 üreyen ?M, Ba? CY, Arslan ?: Myocardial in-farction after ozone therapy: is ozone therapy Dr. Jekyll or Mr. Hyde? Cardiology 2015; 132: 101–104.
2 Bocci V, Valacchi G, Rossi R, Giustarini D, Paccagnini E, Pucci AM, Di Simplicio P: Stud-ies on the biological effects of ozone. 9. Effects of ozone on human platelets. Platelets 1999; 10: 110–116.
3 Schulz S, Ninke S, Watzer B, Nüsing RM: Ozone induces synthesis of systemic prosta-cyclin by cyclooxygenase-2 dependent mech-anism in vivo. Biochem Pharmacol 2012; 83: 506–513.
4 Sroczynski J, Antoszewski Z, Matyszczyk B, Krupa G, Rudzki H, Zbrońska H, Skowron J: Clinical assessment of treatment results for atherosclerotic ischemia of the lower extrem-ities with intraarterial ozone injections. Pol Tyg Lek 1992; 47: 964–966.
5 WHO. http://www.who.int/medicines/areas/ quality_safety/safety_efficacy/trainingcours-
6 Oliver MF: Metabolic response during im-pending myocardial Infarction – II. Clinical implications. Circulation 1972; 45: 491–500. http://circ.ahajournals.org/content/45/2/491. full.pdf.
7 Re L, Martínez-Sánchez G, Bordicchia M, Malcangi G, Pocognoli A, Morales-Segura MA, Rothchild J, Rojas A: Is ozone pre-con-ditioning effect linked to Nrf2/EpRE activa-tion pathway in vivo? A preliminary result. Eur J Pharmacol 2014; 742: 158–162.
8 Laroche ML, Charmes JP, Nouaille Y, Picard N, Merle L: Is inappropriate medication use a major cause of adverse drug reactions in the elderly? Br J Clin Pharmacol 2007; 63: 177– 186.
9 Lazarou J, Pomeranz BH, Corey PN: Inci-dence of ADR in hospitalized patients: a me-ta-analysis of prospective studies. JAMA 1998; 279: 1000–1005.
Lamberto Re a Robert Rowen b Valter trUNK li c