Secondary/Tertiary Amines in Generic Drug Structure in the Context of Polypharmacy as Main Source for Photocarcinogenicity in Humans and Subsequent Melanoma Development and Progression: Spotlight on Two New Cases

The dilemma regarding the sporadic phototoxicity and carcinogenicity of certain drugs is on the verge of being definitively resolved. New models of photocarcinogenicity associated with the use of a specific drug or a group of drugs from diverse classes have for decades been linked to the generation of a range of diverse side effects in the skin area. Some of these effects are heterogeneous in nature and are primarily driven by drug bioavailability in the skin. Nitroso contamination, recently announced in 2018 by regulators such as the FDA and EMA, does not actually exist or remains incorrectly defined as contamination. There is conclusive evidence of nitroso formation/synthesis of photocarcinogens in medicinal products containing secondary or tertiary amino groups. In practice, it turns out that the active ingredient in a diverse class of medications is associated with the endogenous or exogenous generation of nitrosamines, which have been known for decades as photocarcinogens. The presence of certain amines whether inside or outside the human body is considered an essential requirement for these processes. Literature data on drug-induced photocarcinogenicity and phototoxicity exist for nearly every class of the aforementioned medications, such as: Beta Blockers (bisoprolol), ACE inhibitors (ramipril), Diuretics (spironolactone), Calcium Channel Blockers (amlodipine), Statins (atorvastatin, simvastatin), NSAIDs (acetylsalicylic acid), Antidiabetics (glimepiride, vildagliptin, metformin), Alpha-1 blockers (tamsulosin), and Proton Pump Inhibitors (omeprazole). However, there are currently no logical models to explain the sporadic nature of these adverse drug reactions, which is due to several key factors, such as: 1) The number of medications containing secondary/tertiary amino groups taken by patients (polypharmacy); 2) The extent of exogenous nitration/nitrosation during the manufacturing process; 3) The acidic gastric environment, which catalyzes the reaction of nitration or nitrosation, which is predominantly endogenous in nature; 4) The rate of metabolism of nitroso medications by the liver; 5) Competitive inhibition of receptor enzyme systems in the liver by a specific class of drugs and the increase in the concentration of another class of drug (plasma and tissue, respectively); 6) Exposure to solar radiation, etc. Since all or nearly all of these factors are environmental factors, they may vary further. The pharmacokinetics and pharmacodynamics of affected patients vary within a single ethnic group, race, region, or latitude, similar to dietary habits. Regardless of all the aforementioned variations, the occurrence of the same skin tumors in the context of taking generics with a similar structure (which contain secondary or tertiary amine groups subject to nitrosation) is associated, according to scientific data and publications from around the world, with the subsequent occurrence of skin tumors. This association could be described as strongly pathogenic, but with slight percentage differences across different geographic regions. Drug- and nutritionally-mediated processes involving concepts such as nitrosogenesis, photo nitroso carcinogenesis, or the formation of photocarcinogens have been found to be key determinants in the development and progression of melanoma and skin cancer in general.