Ozone Therapy and Its Use in Medicine
We have recently read the report by üreyen et al. [1] 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. [2] 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 [3]. 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. [4] again re-ported the opposite of the conclusion of üreyen et al. [1], 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 [5], 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 [6]), 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 [7] 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.
Reference
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-
es/definitions.pdf.
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.
同文翻译：
臭氧疗法及其在医学中的应用
Lamberto Re a Robert Rowen b Valter trUNK li c
意大利安科纳医学院的药理学和毒理学;美国加利福尼亚州圣罗莎私人诊所;生物技术学院，化学与药剂科，锡耶纳大学，锡耶纳，意大利。我们最近阅读了尿素等[1]的报告，其可能的副作用是，通过阅读标题，似乎不明智地将其与臭氧治疗联系在一起。我们觉得这报告是有疑问的,因为重要的出版不完整的信息和一个结论即:在我们的例子中可以看到不当的臭氧治疗，从病原学指数中可引起心肌梗塞的可能。
这篇论文没有给我们任何关于使用的技术、臭氧浓度、臭氧总重量、血液总量以及其他有关该气体管理的相关数据的信息。这些因素，类似于任何药物的剂量和管理方式，将是非常重要的。与其他治疗方法相比，我们认为，主要的自体血液治疗技术是最安全的方法。标准的自血疗法通常使用柠檬酸作为抗凝剂，浓度范围20至40μg /ml或肝素,5000单位每200毫升于血液中。
此外，Bocci等[2]在其中一篇论文中提到了血小板的激活，作者报告说:“我们并没有在肝磷化血浆中观察到快速血小板聚集现象，特别是在浓度最高的时候。”Bocci等人在体外样本中以一种形式重新移植到体内的臭氧输送中。水分在分离(体外)细胞中大量注入，会导致细胞爆炸。
这与体内水分的吸收无关。此外，作者可能还没有意识到臭氧治疗提高了环前列腺素的含量，合成并改善了环前列腺素/血栓素比率[3]。这些效应与单一报告的作者得出的结论有直接的矛盾，其中，环前列腺素的改进将会有心血管保护效应:“我们假设PGI2刺激可能有助于臭氧治疗的有益效果。”
最后，[4]我们得到了相反的结论，两组实验对象的静脉和动脉内的臭氧气体的都有显著提升((动脉粥样硬化和糖尿病患者)，体现的支出踝动脉压力指数和环前列腺素的含量间歇性跛行距离都增加了两倍以上。由此可得出结论：治疗动脉粥样硬化性缺血时，O 3是有价值且安全的;当然，如果臭氧疗法能够刺激病理的血栓形成，那么作者也应该看到了臭氧气体的直接作用。
关于药物流行病学监测项目，我们药学部门的经验与世卫组织的标准是一致的，并在广泛的临床实践中，给了我们足够的前车之鉴来观察和编录副作用。 根据世界卫生组织的定义[5]，判断一个疗法是否可行的重要标准是：这个疗法的潜在副作用，随着时间的流逝能否被忽略不计。在同一份文件中，不良事件被定义为一种医学上的发生，与使用药物或程序有关，但不一定是因果关系。
在作者报告的病例中，从治疗(早晨)到第一个症状(午夜前3小时)的时间似乎太长，不能理性地解释它们是臭氧治疗的结果。作者没有透露其他潜在的潜在因素，如脂肪含量高的食物(游离脂肪酸增加风险[6])，事件或压力等。
在我们看来，不太容易理解血栓形成的病变如何能在事后12小时，在事件发生后很长一段时间。如果是这样的话，作者需要解释清楚的数据，即臭氧治疗可以延缓血栓形成的作用。
在过去的30年里，两位作者，罗文博士和雷博士，已经在没有任何副作用的情况下，执行了大约60000个主要的自体血液疗法。人类研究[7]已经通过使用最合适的技术来评估一些有趣的代谢途径，这些代谢途径是通过正确的臭氧剂量管理来实现的。
我们可以想象到，在世界范围内，成千上万的医生在这一领域工作的时候，已经有了很多主要的自体血液疗法。不用说，只有在极少数情况下，我们才能观察到一些反应，如发红。
我们同意作者的观点，与其他疗法一样，像其他疗法一样，臭氧也有副作用。幸运的是，我们在文献中发现的臭氧治疗药物不良反应的数量在医学统计时可以忽略不计。