Nicorandil-induced ulcerations: a 10-year observational study of all cases spontaneously reported to the French pharmacovigilance network.

Nicorandil-induced ulcers remain often poorly recognised, with a late diagnosis and an inadequate management. We aimed to provide a clinical overview of the 148 spontaneously reported cases of nicorandil-induced ulcers to the French pharmacovigilance network between 2005 and 2014 and to complete this picture with worldwide published cases over the same period. Spontaneously reported nicorandil-induced ulcers were mainly mucosal (oral and anal) with a previous trauma in 23·0% of patients, revealed by a severe complication in 12·8% of cases. The mean cumulative dose of nicorandil was higher in serious cases. The median delay between the start of nicorandil use and the onset of the ulcer was 23·4 months, and after the ulcer was diagnosed, the median time to incriminate nicorandil was still 3·3 months, being shorter for mucosal ulcerations than for cutaneous ulcerations (5·2 versus 14·0 months, P = 0·001). The anatomic distribution in the 199 published cases differed slightly, but delays were similar. The hypothesis of mechanism becomes more precise, leaving no doubt about the necessity to discontinue the treatment. Practitioners need to be aware that nicorandil-induced ulcers can occur in many locations, possibly multiple and complicated, and should be simply managed by discontinuing treatment with no further reintroduction of nicorandil.

[Counterfeit and Falsified Drugs: an Overview]. / Trafic de faux médicaments : panorama 2014.

If the traffic of fake medicines may represent an economic threat for the pharmaceutical industry, it can also be responsible of safety concerns for patients. Despite fake drugs represent a real threat for public health, the intended punishments are until now only based on intellectual property rights. Estimated to generate more than 55 billion euros per year, the traffic of falsified drugs varies from a country to another one. Indeed, the proportion of falsified drugs ranges from 1% in industrialized countries with a regulated and controlled distribution system to 60% of medicines in some developing countries. Currently, the measures developed to limit this traffic concern five main areas: legislation / regulation, cooperation, enforcement, technology and communication. Communication actions should be performed to inform health professionals as the populations about the risks of using drugs purchased outside the legal drug market.

Role of nicotinic acid and nicotinamide in nicorandil-induced ulcerations: from hypothesis to demonstration.

Nicorandil, a nicotinamide ester, was first reported to be involved in the induction of oral ulcers in 1997. Since then, many reports of single or multiple nicorandil-induced ulcerations (NIUs) have been reported. We hypothesised that in the case of high-dosage nicorandil or after an increased dosage of nicorandil, nicotinic acid and nicotinamide (two main metabolites of nicorandil) cannot appropriately merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate, which leads to abnormal distribution of these metabolites in the body. In recent or maintained trauma, nicotinamide increases blood flow at the edge of the raw area, inducing epithelial proliferation, while nicotinic acid ulcerates this epithelial formation, ultimately flooding the entire scar. We demonstrate, by comparison to a control patient non-exposed to nicorandil, an abnormal amount of nicotinic acid (×38) and nicotinamide (×11) in the ulcerated area in a patient with NIUs. All practitioners, especially geriatricians, dermatologists and surgeons, must be aware of these serious and insidious side effects of nicorandil. It is critical to rapidly reassess the risk-benefit ratio of this drug for any patient, and not only for those with diverticular diseases.

Targeting solid tumours with potassium channel activators. A return to fundamentals?

From a pharmacological point of view nicotinamide and minoxidil are potassium channel activators. Nicotinamide is used as a radiosensitizer in ARCON (accelerated radiotherapy combined with carbogen breathing and nicotinamide) therapeutic strategy with promising results but not confirmed so far. Minoxidil has never been considered by radiotherapists. Based from recent pathophysiological considerations we suggest a new perspective for the use of these two "old" molecules in order to target solid tumours.

A case of nicorandil-induced unilateral corneal ulceration.

Nicorandil, a second-generation nitro derivative, has been reported to induce single or multiple ulcerations in many locations, including oral, anal, perianal, vulvovaginal, perivulval, penile, gastrointestinal, colic, peristomal and skin locations. Ocular locations are now highly suspected. Herein, we report the case of a 78-year-old woman who experienced corneal ulceration at second cataract surgery (right eye) while being treated with nicorandil for 3 years. Four years before, she had had an uneventful first cataract surgery (left eye). The ulcers healed within 6 weeks after simple withdrawal of nicorandil, an expected delay for this type of chemical ulcer. The substitution of nicorandil with classic nitric oxide donors has already been done without complication. Surgical intervention is unnecessary and inappropriate. Case reports of ocular side effects induced by nicorandil are rare and probably underestimated.

Hypersensitivity and vaccines: an update.

Allergic reactions to vaccines can be classified as sensitivity to one of the vaccine components, pseudo-allergic reactions, often after hyperimmunization, and exacerbation of atopic symptoms or vasculitis. Pseudo-allergic reactions, some possibly due to hyperimmunization, are probably more common than true allergies. Atopic reactions should not be confused with the "flash" phenomenon, defined as an exacerbation of an allergic reaction due to a reduction in the allergic reactivity threshold following the vaccine injection. BCGitis occurs frequently, and for this reason, guidelines for Bacillus Calmette-Guérin (BCG) have been modified. The vaccine is now reserved for people at risk of exposure to Mycobacterium tuberculosis. This review provides an update on the vaccination modalities for people allergic to eggs, on the assessment that should be performed when a reaction occurs due to tetanus vaccination, on the urticaria after hepatitis vaccination, on an aluminum granuloma, which is more and more frequent in young children, and vasculitis after flu vaccination and BCGitis. The side effects associated with new, recently released vaccines, such as anti-influenza A H1N1 or anti-human papilloma virus (HPV) will also be presented.

Nicorandil: from ulcer to fistula into adjacent organs.

Nicorandil is an original vasodilatator used to control angina by decreasing cardiac preload and afterload. Since 1997, many reports of single or multiple nicorandil-induced ulcerations have been published. To date, eight cases of nicorandil-induced fistula into adjacent organs have been described. The pathogeneses of nicorandil-induced ulceration and fistula into adjacent organs are not yet elucidated. The two main hepatic biotransformation pathways of nicorandil are denitration and reduction of the alkyl chain leading to nicotinamide and niconitic acid which merge into the endogenous pool of nicotinamide adenine dinucleotide/phosphate. This merging which is known as saturable, may contribute to a slow and abnormal distribution of nicotinamide and nicotinic acid out of the endogenous pool. Under these special conditions, providing these two molecules in situ, nicotinic acid associated with nicotinamide may ulcerate rather recent or maintained trauma. Ulcers and fistulae induced by nicorandil heal after withdrawal. Surgical intervention is unnecessary and inappropriate as it is ineffective and exacerbates morbidity. All practitioners should be correctly informed about these serious but preventable nicorandil side effects, which mostly occur in the elderly and fragile population. In the absence of corrective measures, withdrawal of this original and active drug should be considered.

Misuse of acetaminophen in the management of dental pain.

PURPOSE: We highlight the risk associated with acetaminophen misuse in patients having dental pain in France based on a series of cases of unintentional acetaminophen overdose reported by the Emergency Dental Service of Nancy over a 9-month period. METHODS: Data were collected by querying the French Pharmacovigilance database. Each retrieved clinical data were reviewed by a clinician. RESULTS: Thirteen cases of acetaminophen overdose were reported to the Regional Pharmacovigilance Center of Lorraine, Nancy, France. Most cases (10/13) concerned men aged 20-40 years old. Mild, unspecific clinical symptoms were observed in seven of 13 patients. The median value of the supposed ingested dose was 137 mg/kg/24 h. Liver enzyme activity was tested in 10 patients and was abnormal in four patients. N-acetylcysteine treatment was administered to four patients. CONCLUSIONS: We propose that even patients with mild clinical symptoms with a supposed ingested dose of acetaminophen greater than 150 mg/kg/24 h should be referred to an emergency department and that liver enzyme activity should be analyzed. No case of liver failure was observed during our short survey. However, hepatotoxicity of repeated supratherapeutic ingestion of acetaminophen was suspected in four patients. Patients and practitioners should thus be better informed about the risk of unintentional acetaminophen overdose following supratherapeutic acetaminophen ingestion.

Anaphylaxis during anesthesia in France: an 8-year national survey.

BACKGROUND: More attention should be paid to rare serious adverse events such as anaphylaxis to increase the safety of anesthesia. OBJECTIVE: To report the results of an 8-year survey of anaphylaxis during anesthesia in France. METHODS: Data from patients who experienced anaphylaxis between January 1, 1997, and December 31, 2004, were analyzed. Estimated incidences were obtained by combining this database with data from the French pharmacovigilance system by using a capture-recapture method. The number of patients exposed to the offending agents was obtained from data collected during the national survey of anesthesia practice. RESULTS: A total of 2516 patients was included. A diagnosis of IgE-mediated reaction was established in 1816 cases (72.18%). The most common causes were neuromuscular blocking agents ([NMBAs]; n = 1067; 58.08%), latex (n = 361; 19.65%), and antibiotics (n = 236; 12.85%). The median annual incidence per million procedures was higher for females 154.9 (5th-95th percentile, 117.2-193.1) than for males 55.4 (5th-95th percentile, 42.0-68.0). It reached 250.9 (5th-95th percentile, 189.8-312.9) for women in cases of allergic reactions to NMBAs. In children, a diagnosis of IgE-mediated reactions was obtained in 122 cases (45.9%). The most common causes were latex (n = 51; 41.8%), NMBAs (n = 39; 31.97%), and antibiotics (n = 11; 9.02%). In contrast with adults, no female predominance was observed. CONCLUSION: The incidence of allergic reactions during anesthesia, estimated on a national basis, is higher than previously estimated. These results should be taken into account in the evaluation of the benefit-to-risk ratio of the various anesthetic techniques in individuals. The similar incidence of reactions according to sex before adolescence suggests a role for sex hormones in the increase of anaphylaxis observed in women.