TERAIH,YAMANISHIH,SHIMAHARAM.Nicorandil-in-duced tongue ulceration with or without fungal infection[J].Odontology,2012,100(1):100-103.
Oral ulceration is one of the common adverse effects of nicorandil in European countries. In Japan, however, only 9 cases of nicorandil-induced oral ulceration have been reported. Here, we report 3 cases of nicorandil-induced oral ulceration, one of which exhibited a unique clinical course associated with Candida infection. In this case, the initial discontinuation of nicorandil failed to ameliorate the lesion. However, the second discontinuation of the drug after the control of the Candida infection overlying the surface of the ulcer produced a favorable effect. This patient was diagnosed with nicorandil-induced tongue ulceration with Candida infection.
YAMAMOTOK,MATSUSUEY,HORITAS,et al.Nicoran-dilinduced oral ulceration:report of 3 cases and review of the Japanese literature[J].Oral Surg Oral Med Oral Pathol Oral Radiol Endod,2011,112(6):754-759.
Nicorandil-induced oral ulceration in 3 Japanese patients is reported. The patients were men aged 86, 81, and 91 years. Ulcers of 15, 10, and 12 mm in diameter, respectively, were observed at the border of all of the patients' tongues. These were painful and persistent but not indurated. Irritation by the teeth or dentures was not evident. They had been administered nicorandil at a dose of 15 mg for 22, 54, and 90 months, respectively; therefore, ulceration induced by nicorandil was suspected. In consultation with the doctor, nicorandil was withdrawn. The ulcers disappeared 5, 8, and 9 weeks, respectively, after the cessation of nicorandil. No relapse of the ulcer was noted. The findings suggest that these were the examples of nicorandil-induced oral ulceration.
CAMPOLMIN,GUYC,CINOTTIE,et al.Corneal perfora-tion:another side effect of nicorandil[J].Cutan Ocul Toxicol,2014,33(2):96-98.
Context: Nicorandil is an antianginal drug used for 20 years in Japan and introduced in France in 1994. Since 1997, side effects such as mucocutaneous ulcerations have regularly been reported.<br/>Objective: To describe the first case of a patient with a spontaneous corneal perforation associated with mucocutaneous ulcerations while taking Nicorandil.<br/>Materials and methods: A 81-year-old patient, with no past history of ocular disease but a long past history of cardiovascular disease, presented with a spontaneous paracentral corneal perforation. This was consecutive to 5 months of recurrent keratoconjunctivitis and mucocutaneous ulcerations resistant to conventional therapy. (He was taking nicorandil for 5 years.) A penetrating keratoplasty was performed in emergency.<br/>Results: Inflammatory and infectious causes of spontaneous corneal perforation were ruled out. After initial uneventful post-operative wound healing, an epithelial ulcer appeared on the graft. Dermatologists suggested the iatrogenic role of nicorandil and the drug was discontinued. Both mucocutaneous and corneal ulcerations resolved rapidly.<br/>Discussion: Although mucocutaneous ulcerations have been attributed several times to nicorandil, this is, to our knowledge, the first major corneal damage due to this antianginal drug. Timing, pattern of illness, absence of other aetiology, recurrence of epithelial ulceration on the corneal graft and its spontaneous healing after nicorandil discontinuation make it highly apparent probable that nicorandil was directly involved in this corneal perforation.<br/>Conclusion: Ophthalmologists and dermatologists should be aware of the risk of severe but reversible corneal ulcerations in patients treated with nicorandil. A pharmacovigilance warning statement should be compulsory.
TRECHOTP,BAZARD MC,PETITPAINN,et al.Conjun-ctival and corneal ulcerations:keep a sharp eye on nicorandil[J].Br J Ophthalmol,2012,96(3):463-464.
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SHAPEY IM,AGBAMUD,NEWALLN,et al.Nicorandil-associated ulceration of the gastrointestinal tract:side effects requiring surgical intervention[J].Int J Colorectal Dis,2015,30(8):1143-1145.
Author information: (1)Department of Colorectal Surgery, Wirral University Teaching Hospital NHS Foundation Trust, Arrowe Park Hospital, Arrowe Park Road, Wirral, Merseyside, CH49 5PE, UK, i.m.shapey@doctors.org.uk.
KING PM,SUTTIE SA,JANSEN JO,et al.Perforation of the terminal ileum:a possible complication of nicorandil therapy[J].Surgeon,2004,2(1):56-57.
Recent reports have implicated nicorandil as a possible causative agent in the pathogenesis of anal and oral ulceration. We report a case of ulceration and perforation of the terminal ileum in a patient taking nicorandil. The possibility of an association between nicorandil therapy and gastrointestinal ulceration is discussed.
Abstract An 82-year-old woman was admitted with feculent vaginal discharge and bleeding per vagina. Investigations revealed the presence of a rectovaginal fistula with no obvious etiology. Due to the surgical team's previous experience with nicorandil-induced ulceration, the drug was stopped. The rectovaginal fistula healed completely within 6 months. Copyright 漏 2011 Mosby, Inc. All rights reserved.
CHAUDHERYB,NEWMAN PA,LYONSA.De novo rectovaginal fistulation and multisite ulceration as a consequence of nicorandil therapy[J].Int J Colorectal Dis,2014,29(3):415-416.
Dear Editor: Nicorandil has been implicated with multisite ulceration, gastrointestinal perforation and fistulation in the presence of diverticular disease. We describe a case rectovaginal fistulation and vulval ulceration in a patient who was taking nicorandil who did not have diverticular disease. A 77-year-old Caucasian lady was referred to the colorectal outpatient clinic with perineal pain, rectal bleeding and vaginal discharge. She had six per vaginal deliveries without obstetric complications and described no additional gastrointestinal or gynaecological symptoms. Her past medical history included ischaemic heart disease for which she was on nicorandil (30聽mg twice daily) for the last 8聽years. Examination revealed bilateral punched out vulval ulcers and possible rectovaginal fistulation; further examination was not possible due to patient discomfort. Examination under anaesthesia confirmed a rectovaginal fistula. There was a small 0.5-cm-diameter rectal opening above the sphincter ...
WILLIAMSC,TAMUNOP,SMITH AJ,et al.Perianal ulceration and other cutaneous ulcerations complicating nicorandil therapy[J].J Am Acad Dermatol,2007,56(5 Suppl):116-117.
Williams C, Tamuno P, Smith AJ, Walker SL, Lyon CC.
GOHC,WONG SC,BORLANDC.Persistent orocutaneous and anal fistulae induced by nicorandil:a case report[J].J Med Case Rep,2009,12(3):119.
Introduction Although nicorandil is prescribed widely, awareness of its potential to cause serious complications to the gastrointestinal tract mucosa is limited. Whilst nicorandil-induced oral and anal ulceration is well documented in the literature, nicorandil-induced fistulation is not. This is the first report in the literature of a single patient demonstrating simultaneous orocutaneous and anal fistulae during nicorandil therapy. Two separate cases of orocutaneous and anal fistulae associated nicorandil usage have previously been documented in specialist journals. Case presentation A 71-year-old Caucasian man presented with a 3-year history of concurrent orocutaneous and anal fistulae. He had been exposed to 30 mg twice-daily nicorandil therapy for 4 years. Both fistulae responded poorly to intensive and prolonged conventional treatment but healed promptly on reduction and eventual withdrawal of nicorandil therapy. Conclusion Management of resistant cases of orocutaneous and anal fistulae in patients on high-dose nicorandil therapy may be impossible without reduction or even withdrawal of nicorandil.
MOSLEYF,BHASINN,DAVIES JB,et al.Life-threatening haemorrhage secondary to nicorandil-induced severe peri-anal ulceration[J].Ann R Coll Surg Engl,2010,92(6):39-40.
Nicorandil-induced ulceration is rare but has been reported at multiple sites throughout the gastrointestinal tract. We report a life-threatening complication of such ulceration - catastrophic per-rectal haemorrhage requiring emergency surgery with no prior symptoms. Whilst nicorandil should be considered in cases of chronic peri-anal and peristomal ulceration which fail to respond to conventional treatments, this case highlights its importance in the setting of acute surgical presentations.
THRUMURTHY SG,DATE RS,OWA OS,et al.Nicorandil-induced colonic ulceration:an unusually delayed presentation of a rare complication[J].Int J Colorectal Dis,2011,26(12):1631-1632.
Dear Editor: Nicorandil is a potassium-channel activator used widely as a third-line treatment for ischaemic heart disease. Its action of relaxing vascular smooth muscle causes both arterial and venous dilatation, consequently enhancing cardiac perfusion. Its rare side effect of gastrointestinal ulceration manifests mainly in the oro鈥揳nal regions, although involvement of other parts of the gut have been described. The exact pathogenesis of these ulcers remains unknown but they appear to be related to the dose of Nicorandil, and resolve upon withdrawal of the drug, with a median healing time of 12聽weeks. Two proposed pathogenic mechanisms are vascular steal phenomenon and the direct local effect of either Nicorandil or its metabolite. This article describes the first reported instance of late-onset colonic ulceration induced by Nicorandil, and adds to the growing evidence of this idiopathic side effect in susceptible patients. An 82-year-old woman presented with a 3-month history of progr ...
AL-HILLIZ,PRITCHARDR,ROCHE-NAGLEG,et al.Nicorandil related anal ulcer[J].Br J Dermatol Ir J Med Sci,2006,175(3):62-63 .
BACKGROUND: Anal ulceration is uncommon. Patients are typically referred because of severe anal pain, bleeding, discharge, and ulceration. It is important to exclude anal carcinoma, and to consider more unusual causes. METHODS: A 74-year-old lady presented with severe anal pain and ulceration. This was subsequently noted to be related to nicorandil, a potassium channel activator used in the treatment of angina. Discontinuation of nicorandil and faecal diversion allowed symptom relief and ulcer healing. CONCLUSION: Knowledge of the association between nicorandil and anal ulceration is essential in order to appropriately diagnose and manage this condition.
Nicorandil is a vasodilator used to control severe angina. It has been associated with oral and anal ulceration that resolves upon withdrawal of the drug. We report a series of four patients, all of whom were receiving nicorandil therapy and developed nonspecific para-stomal ulcerations of similar clinical and histological appearance. All ulcers healed on withdrawal of nicorandil with no relapse. To the best of our knowledge, nicorandil-associated para-stomal ulcers have not been reported before. It is imperative to be aware of this association to prevent the persistence of these extremely painful ulcerations, and to avoid unnecessary and inappropriate interventions with substantial morbidity in a group of high-risk patients.
LEE MT,LIN HY,LEE SH,et al.Risk of skin ulcera-tions associated with oral nicorandil therapy:a population-based study[J].Br J Dermatol,2015,173(2):498-509.
Although healthcare products regulatory agencies have issued warnings on risk of ulceration associated with the use of nicorandil, a population-based study has not been carried out.To determine the relationship between use of nicorandil and skin ulceration.We carried out a population-based study using a cohort of 1 million people assembled from Taiwan's national health insurance database. The association between nicorandil use and skin ulcers was estimated by a Cox proportional hazards regression model adjusting for a nicorandil-specific propensity score (PS) comprising of 86 potential predictors (c-statistic = 0·91).The prospective cohort was longitudinally followed from January 2005 to December 2009, during which 1268 new users of nicorandil and 771 136 nonusers were identified. A higher frequency of skin ulcers (29 of 1268; 2·3%) was observed for users of nicorandil compared with nonusers (3231 of 771 136; 0·4%). Compared with nonusers, the crude hazard ratio (HR) associating nicorandil use with skin ulcers was 5·52 [95% confidence interval (CI) 3·82-7·95] and the PS-adjusted HR was 1·85 (95% CI 1·27-2·69). A risk period analysis showed that the risk of skin ulceration among users of nicorandil was greatest in the first year. Subgroup analysis found that the interaction term reached statistical significance (P < 0·05) for age and diabetes.Use of nicorandil was found to be associated with an increased risk for skin ulceration, especially in the first year after incident exposure. We suggest that regulatory agencies re-evaluate the risk for skin ulceration associated with use of nicorandil.
LEE CC,CHANG SS,LEE SH,et al.Use of nicorandil is associated with increased risk for gastrointestinal ulceration and perforation- a nationally representative population-based study[J].Sci Rep,2015,29(5):11495.
Nicorandil is a vasodilatory drug used to relieve angina symptoms. Several healthcare products regulatory agencies have issued a warning associating the use of nicorandil and gastrointestinal (GI) ulceration. We aimed to evaluate the association between use of nicorandil and GI ulceration/perforation. A population-based cohort study involving 1 million randomly sampled participants in Taiwan鈥檚 National Health Insurance Research Database was carried out. We estimated the association between use of nicorandil and GI ulceration/perforation by a Cox proportional hazards regression model. A nicorandil-specific propensity score (PS) was also created for adjustment of 75 covariates and matching. 25.8% (183/710) of nicorandil-treated patients developed new GI ulcer events and 1.6% (20/1254) developed new GI perforation events in the three-year follow-up period, as compared to 9.3% (61,281/659,081) and 0.3% (2,488/770,537) in the general population comparator cohort. Patients treated with nicorandil were at significantly increased risk of GI ulcer (PS adjusted hazard ratio 1.43, 95% CI, 1.23 to 1.65, 6848 excess cases per 100,000 person years) or GI perforation (aHR 1.60, 95% CI 1.02鈥2.51, 315 excess cases per 100,000 person years) compared with the nicorandil unexposed population. Our finding may warn the clinicians to weigh the overall risk-benefit balance of nicorandil treatment in patients.
PISANOU,DEOSARANJ,LESLIE SJ,et al.Nicorandil,gastrointestinal adverse drug reactions and ulcerations:a systematic review[J].Adv Ther,2016,33(3):320-344.
Abstract INTRODUCTION: Nicorandil is a popular anti-anginal drug in Europe and Japan. Apart from some common adverse drug reactions (ADR), its safety is satisfactory. Several reports have suggested a link between nicorandil, gastrointestinal (GI) ulceration and fistulas. The review aims to critically appraise, synthesize and present the available evidence of all known GI ADR per anatomical location. METHODS: The study complied with the PRISMA statement. Literature and pharmacovigilance databases were used to provide rate and/or calculate parameters (median age, median dose, history of symptoms, length of therapy and healing time after withdrawal of the drug). Differences in distribution of quantitative variables were analyzed via Mann-Whitney test. Correlation between quantitative variables was assessed with a Spearman's correlation coefficient. A p value <0.05 was significant. RESULTS: Oral ulcerations occur in 0.2% of the subjects, anal ulcerations are present between 0.07% and 0.37% of patients. Oral and distal GI involvements are the most common ADR (28-29% and 27-31% of all GI ADR, respectively). The hepatobiliary system, the pancreas and salivary glands are not affected by nicorandil exposure. The time to develop oral ulcerations is 7402weeks among people on <3002mg/day compared to only 7.502weeks in individuals on higher regimens (p02=020.47). There is a significant correlation between dose and ulcer healing time (Spearman's 0.525, p02<020.001). CONCLUSIONS: Ulcerative disease is a very commonly reported GI ADR. A delayed ulcerative tendency supports the hypothesis of an ulcerogenic metabolite. Nicorandil seems to act as a cause of the ulcerations, but appears to also work in synergy with other promoting factors. Whether the action of the metabolites relies on a specific mechanism or a simple chemical ulceration is still to be established.
FRASER SJ,PINION SB,ADAMSONB,et al.Vulval ulceration induced by the potassium-channel activator nicorandil:a case series of five patients[J].BJOG,2009,116(10):1400-1402.
KATORYM,DAVIESB,KELTYC,et al.Nicorandil and idiopathic anal ulceration[J].Dis Colon Rectum,2005,48(7):1442-1446.
Abstract PURPOSE: Several reports have implicated nicorandil as a reversible cause of anal ulceration. We have recently commenced a specialist clinic for patients presenting with severe anal ulceration to assess treatment in this difficult group. Recognition of this association may avoid unnecessary surgery. METHODS: Twenty-six patients treated with nicorandil had severe painful anal ulceration. Examination under anesthesia was required to biopsy the lesions to exclude neoplasia or inflammatory bowel disease. In total, three patients had proximal diverting stomas without subsequent ulcer resolution, two had perineal debridement with one requiring subsequent skin grafting, and one had an abdominoperineal excision for unremitting pain. RESULTS: The association of perianal ulceration with nicorandil became apparent only in the latter part of this series. Ten ulcers successfully re-epithelialized when nicorandil was stopped. Nine patients reported anal pain relief and partial healing on clinical examination at two months but failed to show subsequent complete resolution. One patient agreed to nicorandil cessation and reported symptomatic anal pain relief at two weeks but subsequently developed unstable angina requiring hospital admission. Nicorandil was recommenced with anal pain relapse. CONCLUSIONS: Failure to recognize nicorandil as an etiologic factor in the development of anal ulceration, when other potential underlying well-recognized inflammatory or neoplastic processes have been excluded, may lead to unnecessary surgical intervention in a group of high-risk patients. One of our patients had a potentially avoidable abdominoperineal resection. Pharmaceutical manipulation with alternative antiangina medication may induce healing. Pharmacologic manipulation should be coordinated with a physician to minimize precipitation of unstable angina.
TRECHOTP,BARBAUDA,PETITPAIN NB,et al.Nico-randil and ulcerations:a NAD/NADP and nicotinic acid-dependent side-effect?[J].Br J Dermatol,2008,158(5):1150-1151.
Sir, Nicorandil is a vasodilator used to control angina by decreasing cardiac preload and afterload. Since our initial case report in 1997 of nicorandil-induced major aphthous stomatitis, many authors have described single and multiple localizations of similar nicorandil-induced ulcerations in anal, perianal, vulval, perivulval, intestinal, colonic and peristomal locations. Cutaneous ulcerations have recently been reported, sometimes even at a distance from mucosal ulcerations, and the theoretical link between fistulating bowel disease and nicorandil therapy is currently being investigated.Today, the mechanism of these adverse drug reactions remains unknown but is thought to involve the toxicity of the drug or its metabolites as well as vascular steal phenomenon in vulnerable sites.The hypothetical interaction between the metabolic pathways of nicorandil and the endogenous pool of nicotinamide adenine dinucleotide/phosphate (NAD/NADP) is proposed here for the first time.
Use of nicorandil is associated with increased risk for gastrointestinal ulceration and perforation- a nationally representative population-based study
