ARTICLE
Aphthous stomatitis and to a lesser extent other oral ulcerations are
uncommon among adverse effects of drugs. Patients with aphthous stomatitis
are often disabled. Its pathogenesis remains unclear but is probably multifactorial.
Nonsteroidal anti-inflammatory drugs are most commonly the cause but other
molecules contained in some anti-infectious drugs (griseofulvin, isoniazid),
antihypertensive drugs (captopril), interleukin-2, gold, D-penicillamin
and of course antimetabolites may also play a role [1].
Here, we report 2 cases of major aphthous stomatitis following therapy
with nicorandil, a potassium-channel activator. Nicorandil is a new treatment
for angina pectoris. Its main adverse effects include: headache, postural
hypotension, nausea and vomiting, abdominal pain and cutaneous erythema
related to its vasodilatory effects [2]. As far as we know, no previous
cases of major aphthous stomatitis related to nicorandil have been reported
in the literature.
Case reports
Case 1
An 80-year-old woman was admitted to the dermatology department, complaining
of major aphthous stomatitis. She was discovered to have a history of
minor aphthous stomatitis with 1 or 2 small aphthae per year, healing
within 10 days. Because of severe coronaropathy, she had been treated
with furosemide, potassium chloride, atenolol, lysin acetylsalicylate,
molsidomin, simvastatin, allopurinol and perhexilin maleate. Treatment
with nicorandil was then started (2 x 10 mg/day). Fifteen days after the
dose was increased (2 x 20 mg/day), the patient developed chronic major
aphthous stomatitis which led to her admission 3 months after the onset.
Nicorandil could not be withdrawn because of her severe coronaropathy.
Colchicine treatment (1 mg/day) was then started and with a decrease in
the nicorandil dosage (2 x 10 mg/day), total recovery was observed. As
a result, colchicine was able to be withdrawn after 5 weeks.
Case 2
A 61-year-old man was admitted after a 6 month history of major aphthous
stomatitis involving the tongue (Fig.
1), the lips, the hard palate and the inner side of his cheeks.
The patient's medical history included myocardial infarction for which
he had been treated with lysin acetylsalicylate and atenolol without any
complications. Three weeks after the administration of nicorandil (2 x
20 mg/day) and enalapril, he developed chronic and extensive ulcerations
of the mouth, without genital lesions, inducing a weight loss of 6 kg
over a period of 6 months. At this point, nicorandil was stopped whilst
continuing the administration of enalapril. The patient recovered within
5 weeks, no relapse was experienced in the 6 months that followed.
Comment
In these two cases the sequence of events suggests a drug-induced mucosal
disease: in the first case, major aphthous stomatitis occured two weeks
after a dosage increase. It then completely disappeared after a nicorandil
dosage decrease associated with colchicine. In the second case, major
aphthous stomatitis began three weeks after a high dose (40 mg/day) of
nicorandil had been administered. The patient recovered 5 weeks after
nicorandil was stopped. In both patients we were able to exclude other
causes of aphthous stomatitis such as Behcet's disease, inflammatory bowel
disease, iron deficiency or cyclic neutropenia, so that the responsibility
of nicorandil in these two cases of major aphthous stomatitis seems likely.
No similar case has been reported in the literature
but the two pharmaceutical firms co-marketing nicorandil have been informed
of one such case since its commercialization.
The pathogenesis of aphthous stomatitis remains unknown [3]. Hypersensitivity
reactions to exogenous antigens could play a role in aphthous stomatitis.
Trauma may initiate ulcers in predisposed people. In addition, there is
a clear variability in host susceptibility with a polygenic inheritance,
but a variable penetrance. In nicorandil-induced major aphthous stomatitis,
a dosage increase or a high-dose treatment as well as a history of minor
aphthous stomatitis can be considered as important cofactors.
CONCLUSION
Nicorandil, like many other drugs, may cause aphthous ulcerations. The
risk is unknown; nevertheless, the diagnosis of drug-induced major aphthous
stomatitis should be considered in patients who develop extensive oral
ulcerations while receiving this drug. In addition, particular care must
be taken while treating patients having a history of minor aphthae.
Acknowledgements
We would like to thank the Roger-Bellon and Merck-Clevenot pharmaceutical
laboratories for their kind cooperation.
REFERENCES
1. Zelickson BD, Rogers RS III. Oral drug reactions. Dermatol Clin
1987; 5: 695-708.
2. Frampton J, Buckley MM, Fitton A. Nicorandil: a review of its pharmacology
and therapeutic efficacy in angina pectoris. Drugs 1992; 44: 625-55.
3. Scully C, Porter S. Recurrent aphthous stomatitis : current concepts
of etiology, pathogenesis and management. J Oral Pathol Med 1989;
18: 21-7.
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