Dear Sirs,
We read with great interest the case reported in this journal by Salim et al.Reference Salim, Joshi and Hopkins1 concerning the ulceration of the nasal dorsum in a 64-year-old man treated with nicorandil (a medical treatment for stable angina). We would like to contribute to the topic confirming a very likely diagnosis of a drug-induced adverse effect, and put forward for consideration two remarks regarding this serious and yet to be sufficiently recognised adverse effect.
The first commentary refers to the conditions of occurrence of ulcers induced by nicorandil, and the second one to their preferential location.
Nicorandil, a nicotinamide ester (N-(2-hydroxyethyl) nicotinamide-nitrate ester), is the first and only association between nitrate and potassium channel activators. Studies on animals have shown that nicorandil is as effective as cimetidine at treating experimentally induced gastric ulceration. In one experiment, Sakai et al.Reference Sakai, Akima and Katsuyama2 demonstrated that nicorandil (3 and 10 mg/kg, orally), like cimetidine (50 mg/kg, orally), protected against acute gastric damage in water immersion plus restraint stress- and aspirin-induced gastric ulcer models of rats. However, after intravenous pre-treatment with an antagonist of ATP-sensitive potassium channels (glibenclamide), the ulcer lesions were increased. Ironically, nicorandil was found to be involved in the induction of oral ulcers in 1997 by Reichert et al.Reference Reichert, Antunes, Trechot, Barbaud, Weber and Schmutz3 Since then, cases of single or multiple nicorandil-induced ulcerations have been reported, including ulcers at gastrointestinal locations.Reference Egred, Andron and Morrison4
According to Trechot et al.,Reference Trechot, Barbaud, Petitpain, Claeys and Schmutz5 in the particular configuration of high-dosage nicorandil, nicotinamide and nicotinic acid derivatives (two main metabolites of nicorandil) may be unable to merge into the endogenous pool of nicotinamide adenine dinucleotide and nicotinamide adenine dinucleotide phosphate, leading to abnormal in situ distribution of these molecules in the body. Additionally, in the case of recent or maintained trauma, nicotinamide increases blood flow at the edge of the raw area, while nicotinic acid (pKa = 4.8) ulcerates the new epithelial formation. The results of the Sakai et al.Reference Sakai, Akima and Katsuyama2 study are not disputed. However, extrapolation of the animal experiments to humans cannot be considered as the animals were killed 5 hours after the administration of a single oral dose of nicorandil. This renders such examination of a delayed adverse effect of nicotinic acid, and study of the metabolite responsible for ulcers, impossible in humans.
Considering that one of the clinical particularities of nicorandil-induced ulcerations is a typical location pattern in areas of trauma, it is necessary to investigate the cause of trauma. In the case reported by Salim et al.,Reference Salim, Joshi and Hopkins1 the use of a full-face mask should be considered as a factor.
