1Onkoderma - Clinic for Dermatology, Venereology and Dermatologic Surgery, Sofia; 2Department of Dermatology and Venereology, Medical Institute of Ministry of Interior Sofia, Bulgaria.
3Department of Dermatology and Venereology, Military Medical Academy, Sofia, Bulgaria.
Georgian Med News. 2024 Mar(348):132-143.
Changing the vision, understanding, interpretation and analysis of certain data or scientific dilemmas is what is able to change the status quo and revitalize a mission, an impulse or important thoughts, thus creating the conditions for it to increase immensely the chances of bringing it to success. Or, following Albert Einstein's postulate: ˝We cannot solve our problems with the same thinking we used when we created them˝, we should think: ˝Where does the road to success start? How do we solve or neutralize a problem? ˝ And the answer is: ˝ By taking a consistent and systematic approach, analyzing each component! And we eliminate every possibility of negative influence.˝ These thoughts apply with full force to cancer rates in general, but also to melanoma rates in particular: the murderous tempo of globalization and modernization in medicine has not yet led to the desired decrease in these rates; on the contrary, they are rising headlong and remain largely unpredictable and difficult to regulate. The conclusion is that a solution should be sought by refracting light through another prism: that of Nitrosogenesis and Pharmaco-Oncogenesis. A step-by-step and systematic approach to solving a problem requires patience, determination, and perseverance. As this perseverance is needed mainly to overcome the general ignorance, neglect, disinterest, uneducation and uncertainty of others, rather than doubt in one's own thesis, analysis, and the need for an active approach. Careful analysis of concepts such as ˝Drug Mediated Nitrosogenesis˝ and ˝Onco-pharmacogenesis/Pharmaco-oncogenesis˝ of skin cancer would certainly contribute to the elucidation of skin carcinogenesis in the context of polymedication of the contamination and polymorbidity worldwide. The FDA has already in 2019 taken this much needed first step of universal awareness and its ˝arm˝ has been taken seriously and responsibly solely by dermatologists and dermatosurgeons. It was this guild and only this guild that launched its independent, never-ending observations, logically grounded (hypo)theses, remaining to date confirmatory, unshakable, and enigmatic regarding the unit: intake of potentially contaminated medication and subsequent development of melanomas. It is this and only this branch of the medical guild that has also become the guarantor of safety and objectivity in science, and thus of safety in the fight for survival of a huge number of skin cancer patients. Contaminated oral antidiabetic drugs in the face of Metformin and Sitagliptin do not make an exception in this respect. Similarly to cutaneous melanomas occurring (and published in the scientific literature) after combined intake (or monomedication) of/ between ranitidine, valsartan, olmesartan, candesartan, telmisartan, irbesartan, losartan, enalapril, lisinopril, perindopril, hydrochlorothiazide, nifedipine, amlodipine, propafenone, bisoprolol, nebivolol, melitracen and a number of others, we inform about another rare but not unexpected clinical observation: occurrence of cutaneous melanomas after taking another class of drugs- oral antidiabetic ones. Or after the intake of nitrosamine-contaminated antidiabetic drugs. And whether this contamination is "real or potential" is left to regulators and manufacturers to decide. We accept it as real-potential' or
potentially-real' because of the fact that neither the regulators nor the manufacturers know what it is or whether it is there or how it arose. The data shared in patients one and two in the presented scientific work are confirmatory in relation to the potential pathogenetic action of nitrosamine contaminated drugs such as 1) bisoprolol/ nebivolol/ candesartan/ hydrochlorothiazide and amlodipine, as well as 2) furosemide in the direction of cutaneous melanoma. Patient 3 in fact also represents the first formally described patient with subsequent melanoma development worldwide, having developed it following intake of potentially/actually nitrosamine-contaminated metformin and metformin/sitagliptin (both drugs are themed in the FDA's Potentially Contaminated Drug Bulletin: 1) metformin, multiple times between 2020-21, due to its contamination with NDMA and 2) sitagliptin, as of September 2022, due to its contamination with NTTP). It should not be seen as surprising to anyone that the intake of relatively similar carcinogens/nitrosamines or NDSRIs, but as an unofficial component of heterogeneous drugs, produces a relatively monomorphic clinical picture- that of cutaneous melanoma. Or to put it metaphorically: ˝The wolf changes its hair, but not its mood˝. A carcinogen remains a carcinogen, regardless of whether it is ingested in a lemonade, a tablet, a sandwich, or a bonbon. Similarly to the intake of nitrosamines in food. Future studies should address the important tasks/dilemmas to elucidate 1) the phototoxic/photocarcinogenic effect of unmetabolized nitrosamines identified in drug formulations; 2) the phototoxic/photocarcinogenic effect of DNA adducts generated after their metabolization, and 3) the availability of specific DNA adducts in lesional/tumor tissue and blood of patients after ingestion of nitroso-containing drug formulations. This level of evidence is likely to lead to a reconsideration of the arguments for the introduction of permanent elimination regimes for nitrosamines in medicines. Metabolic reprogramming (and its relationship to UVB radiation) due to the availability of nitrosamines in cigarette smoke is also currently a proven reality. Based on the available clinicopathological correlations, we believe that nitrosamines in drugs have a similar effect and are part of the key pathway activating skin carcinogenesis under the influence of solar radiation. Intake of contaminated medication is associated with skin cancer generation and progression. It is up to regulators and manufacturers to justify the merits and benefits of the self-imposed presence of carcinogens in drugs or the benefits of such drugs. Apart from the "cancer-generating benefit", of course, which is already widely known. And let us not forget that: "A lie stops being a lie and becomes a truth the moment it is officially refuted".
改变对某些数据或科学难题的看法、理解、解释和分析,正是能够改变现状、振兴一项使命、一个冲动或重要思想的原因,从而为提高成功的机会创造条件。或者,按照阿尔伯特·爱因斯坦的假设:“我们不能用创造问题时的同一思维来解决问题”,我们应该思考:“成功的道路从哪里开始?我们如何解决或中和一个问题?”答案是:“通过采取一致和系统的方法,分析每个组成部分!我们消除了一切负面影响的可能性。”这些想法完全适用于癌症的总体发病率,但也适用于黑色素瘤的发病率:全球化和医学现代化的致命节奏尚未导致这些发病率的下降;相反,它们正不顾一切地飙升,而且在很大程度上是不可预测的,难以控制。结论是,应该通过折射另一个棱镜来寻找解决方案:即亚硝胺生成和药物致癌发生。解决问题的逐步和系统方法需要耐心、决心和毅力。因为这种毅力主要需要克服他人的普遍无知、忽视、不感兴趣、未受教育和不确定性,而不是对自己的论文、分析和积极方法的怀疑。仔细分析“药物介导的亚硝胺生成”和“皮肤癌的药物致癌发生/药物致癌发生”等概念,将有助于阐明多药物污染和多疾病的全球背景下皮肤癌的致癌机制。FDA 已经在 2019 年迈出了这一急需的普遍意识的第一步,其“手臂”已被皮肤科医生和皮肤科医生认真负责地采取。正是这个公会,而且只有这个公会,发起了独立的、永无止境的观察、合乎逻辑的(假设)假说,至今仍然证实、不可动摇,并且对单位:摄入潜在污染药物和随后黑色素瘤的发展具有神秘感:摄入潜在污染药物和随后黑色素瘤的发展。正是这个医学公会的分支,也成为了科学安全和客观性的保障,从而成为大量皮肤癌患者生存斗争的保障。受污染的口服抗糖尿病药物在二甲双胍和西他列汀的情况下也不例外。同样,在联合摄入(或单药治疗)雷尼替丁、缬沙坦、奥美沙坦、坎地沙坦、替米沙坦、厄贝沙坦、氯沙坦、依那普利、赖诺普利、培哚普利、氢氯噻嗪、硝苯地平、氨氯地平、普罗帕酮、比索洛尔、奈比洛尔、美替拉秦和许多其他药物后发生的皮肤黑色素瘤(并在科学文献中发表)之后,我们报告了另一种罕见但并非出乎意料的临床观察结果:另一种口服抗糖尿病药物的发生。或者在摄入含亚硝胺的抗糖尿病药物之后。而这种污染是“真实的还是潜在的”,则留给监管机构和制造商来决定。我们接受它是“潜在的真实”或“潜在的真实”,因为监管机构和制造商都不知道它是什么,是否存在,以及它是如何产生的。在本文所介绍的科学工作中,患者 1 和 2 所共享的数据与亚硝胺污染药物如 1)比索洛尔/奈比洛尔/坎地沙坦/氢氯噻嗪和氨氯地平,以及 2)呋塞米的潜在致病作用在方向上具有确认性,以皮肤黑色素瘤。事实上,患者 3 也代表了全球第一个正式描述的随后发展为黑色素瘤的患者,他在摄入潜在/实际含亚硝胺的二甲双胍和二甲双胍/西他列汀(这两种药物都在 FDA 的潜在污染药物公告中列出:1)二甲双胍,在 2020-21 年期间多次因含有 NDMA 而受到污染,以及 2)西他列汀,自 2022 年 9 月以来,由于其含有 NTTP 而受到污染)。任何人都不应感到惊讶的是,摄入相对相似的致癌物/亚硝胺或 NDSRIs,但作为异质药物的非官方成分,会产生相对单态的临床图像-即皮肤黑色素瘤。或者用比喻的说法:“狼改变了它的毛,但没有改变它的心情”。致癌物质仍然是致癌物质,无论它是在柠檬汁、片剂、三明治还是糖果中摄入的。就像在食物中摄入亚硝胺一样。未来的研究应该解决阐明 1)药物制剂中鉴定的未代谢亚硝胺的光毒性/光致癌作用;2)其代谢产物产生的 DNA 加合物的光毒性/光致癌作用;以及 3)患者摄入含硝基药物制剂后病变/肿瘤组织和血液中特定 DNA 加合物的可用性的重要任务/难题。这种证据水平很可能导致重新考虑引入永久性消除药物中亚硝胺的论点。由于香烟烟雾中存在亚硝胺,代谢重编程(及其与 UVB 辐射的关系)目前也是一个已被证实的现实。基于现有的临床病理相关性,我们认为药物中的亚硝胺具有类似的作用,是在太阳辐射影响下激活皮肤致癌机制的关键途径的一部分。受污染药物的摄入与皮肤癌的发生和进展有关。监管机构和制造商有责任证明药物中存在致癌物质的优点和好处,或者证明此类药物的优点和好处。当然,除了“致癌生成的好处”之外,这已经广为人知。让我们不要忘记:“谎言一旦被正式反驳,就不再是谎言,而是成为事实。”