NITROSAMINES IN METFORMIN AND HYDROCHLOROTHIAZIDE: "HUMAN SAFE PHOTOCARCINOGENS" WITHIN THE POLYPHARMACY AS GENERATOR FOR PHOTOTOXICITY/ PHOTOCARCINOGENICITY AND THE SUBSEQUENT DEVELOPMENT OF MULTIPLE KERATINOCYTE CARCINOMAS. DOUBLE HATCHET FLAP AS OPTIMAL AND NECESSARY DERMATOSURGICAL DECISION IN TWO NEW PATIENTS.

The issues that have been identified to date as potentially pivotal in relation to skin cancer in general, but also keratinocytic cancer in particular, mainly concern the permanent potentiation of concepts such as phototoxicity and hence its subsequent photocarcinogenicity over time. Studies by scientific teams dating back more than 50 years have defined the phototoxicity of nitrosamines as a rather non-specific property, regardless of whether the last mentioned have a carcinogenic effect or not. Recently or in 11/ 2024, hydrochlorothiazide was officially declared by the IARC/ International agency on cancer research as carcinogenic to humans due to its phototoxicity. Similar to sartans, metformin, beta blockers and calcium antagonists, hydrochlorothiazide are also associated with contamination from nitrosamines and all of them are scientifically and pathogenetically linked to phototoxicity and carcinogenicity in humans. The photocarcinogenic risk of those drugs in humans based on availability of nitrosamines in drugs seems to remain in all likelihood uncalculated by the regulators' tests, which are tailored to assess the purely carcinogenic risk, which in practice is also inaccurately calculated for a number of points. The cumulative phototoxicity and subsequent photocarcinogenicity in humans differ from pure carcinogenicity in bacteria and rodents. According to a number of international clinical observational studies, concomitant use of more than 1 antihypertensive drug is also associated with a significantly higher risk of developing skin cancer, and in patients with diabetes mellitus this risk is further increased. Polymedication of potentially contaminated drug production is logically associated pathogenetically with the intake of a larger amount of photocarcinogens and/or mutagens in parallel. The present article highlights and is indicative of the following facts: nitroso (photo)carcinogenesis is an undeniable fact that is integral to photocarcinogenesis and skin cancer pathogenesis. Nitrosogenesis of skin cancer is mediated and regulated most likely by the nitrosamine content of drugs. Drug-mediated Photo nitroso genesis/ Carcinogenesis of skin cancer accounts for the occurrence and progression of a significantly greater number of tumors compared to pure Photocarcinogenesis. Permanent intake of potentially contaminated polymedication leads to clinical manifestation of multiple skin tumors. We present two cases of patients who developed scalp tumors treated successfully with double hatchet flap. One of them developed a scalp tumor but also an additional auricular tumor in the context of a potential nitrosamine-contaminated polydrug regimen including 1) metformin, 2) bisoprolol, 3) amlodipine/valsartan/hydrochlorothiazide. The double hatchet flap technique and the role of drug-induced Nitroso Carcinogenesis/Photo Nitroso Carcinogenesis/Oncopharmacogenesis due to the permanent intake of phototoxic, genotoxic substances (within drugs), also known as nitrosamines, is commented. Complete elimination regimens of nitrosamines in drugs appear to be the safest solution to this global problem concerning skin cancer and cancer in general worldwide.