Spontaneous reports of hypertension leading to hospitalisation in association with rofecoxib, celecoxib, nabumetone and oxaprozin

BACKGROUND AND OBJECTIVE: Data on file with the US FDA, and other published studies, suggest that the selective cyclo-oxygenase (COX)-2 inhibitor NSAID rofecoxib has a greater hypertensive adverse effect than other NSAIDs, including celecoxib. In this study we describe a pharmacoepidemiologic analysis of spontaneous adverse event reports of acute, clinically serious hypertension (as defined by hospitalisation) reported in association with rofecoxib, celecoxib, nabumetone and oxaprozin. The objective of this analysis is to assess whether postmarketing data are consistent with results of clinical trials. We also collapse cases into series for the identification of possible risk factors for clinically severe, NSAID-associated hypertension. METHODS: Domestic (US) cases of apparently unconfounded, acute hypertension leading to hospitalisation were collected and reviewed from the spontaneous adverse events database of the FDA for rofecoxib, celecoxib, nabumetone and oxaprozin for the initial 3 years of marketing. Drug use data for the same intervals enabled calculation of reporting rates. RESULTS: In an analysis of reporting rates, hospitalisation for acute blood pressure (BP) elevation was reported more frequently (3.8-fold) for rofecoxib compared with celecoxib. A total of 34 cases are collapsed into case series. No cases were identified for either nabumetone or oxaprozin. Inspection of reviewed cases for celecoxib and rofecoxib suggest that these patients (average age 72 years) were potentially high-risk candidates for NSAID therapy. DISCUSSION AND CONCLUSION: During early marketing, hospitalisation for acute BP elevation appears to have been reported more frequently for rofecoxib compared with celecoxib. This is consistent with clinical trial data on file with the FDA, and other published studies that found rofecoxib to have a greater effect on BP than other NSAIDs, including celecoxib. This finding may be particularly relevant in older patients given the prevalence of hypertension and cardiovascular disease in this age group.     

选择性COX-2抑制剂的心血管安全性评价

目的：研究以罗非昔布、塞来昔布、伐地昔布、鲁米昔布为代表的选择性COX-2抑制剂在临床应用的安全性。方法：查询国内外相关文献资料并结合临床实践进行回顾性研究。结果：罗非昔布、塞来昔布、伐地昔布、鲁米昔布等都有增加心血管不良事件的危险,同时罗非昔布的心血管风险要高于塞来昔布。结论：心血管危险是COX-2抑制剂的“类效应”,所以在临床应用这类药物时．应当加强合理的监管措施;仍需对COX-2抑制剂在心血管系统的安全性进行深入研究。     

Fluconazole-associated Stevens-Johnson syndrome

Fluconazole uncommonly causes Stevens-Johnson syndrome. A young Indian man who developed this adverse effect after his second dose of fluconazole is described. The characteristics of previously reported individuals with fluconazole-associated Stevens-Johnson syndrome and toxic epidermal necrolysis are also summarized: three out of five of the patients were immunocompromised, five out of five were hospitalized, and all had complete resolution of this drug-induced condition.     

Practical considerations for carbamazepine use in bipolar disorder

Carbamazepine (CBZ) has a long history of successful use in epilepsy and, therefore, has a safety profile that is well characterised. Additionally, an extended-release formulation of CBZ (CBZ-ERC; Equetro, Shire US) has recently been approved for use in bipolar disorder. The most frequent adverse events associated with CBZ are somnolence, fatigue, dizziness and headache. Rash and leukopoenia may occur in approximately 10% of patients, but are benign and transient in most cases. Rare serious adverse effects include agranulocytosis, aplastic anaemia, Stevens-Johnson syndrome and toxic epidermal necrolysis. Although changes in lipid profiles have been noted, hyperglycaemia does not occur with CBZ, and clinically significant weight gain is uncommon. Proper monitoring and careful titration of the extended-release formulation should allow for successful use of CBZ in psychiatric patients.     

Cutaneous reactions to non-steroidal anti-inflammatory drugs

We retrospectively reviewed the records of 195 patients with suspected cutaneous reactions from NSAIDs. Two hundred and six different non-steroidal anti-inflammatory drugs (NSAIDs) were suspected of causing cutaneous reactions, and the most frequent suspected causative NSAID was ibuprofen (25.7%). Angioedema and/or urticaria were the most frequent cutaneous reactions (54.4%), and the foremost suspected causative drug for these reactions was ibuprofen. The second most frequently found cutaneous reaction was maculopapular eruption (26.2%), and celecoxib was the most commonly suspected causative NSAID for it. The primary suspected NSAIDs causing fixed drug eruption were in enolic acid group. Furthermore, drug hypersensitivity syndrome was diagnosed in five patients, and Stevens-Johnson syndrome and toxic epidermal necrolysis were detected in five patients.     

Carbamazepine, HLA-B*1502 and risk of Stevens-Johnson syndrome and toxic epidermal necrolysis: US FDA recommendations

Recently, the USA FDA has made a labeling change to the drug information contained in carbamazepine. Owing to recent data implicating the HLA allele B*1502 as a marker for carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in Han Chinese, the FDA recommends genotyping all Asians for the allele. This allele is seen in high frequency in many Asian populations other than Han Chinese, but there are few data on whether the allele is a marker for this severe outcome in anyone other than Han Chinese. In fact, the association has not been found in Caucasian patients. We review the data that prompted this recommendation, list data for other ethnic groups, both Asian and non-Asian, and briefly discuss the implication of this recommendation for clinical practice.     

Valdecoxib (Pharmacia)

Pharmacia (formerly Searle), in collaboration with Pfizer and Yamanouchi, has developed valdecoxib, a second-generation cyclooxygenase (COX)-2 inhibitor as a follow-up to celecoxib, for the treatment of arthritis. Pharmacia filed an NDA with the FDA in March 2001 for the treatment of acute pain, dysmenorrhea, osteoarthritis (OA) and rheumatoid arthritis (RA). At this time, Pharmacia anticipated a 12-month review [402883]. In June 2001, launch was anticipated in 2002 [412616], and in November 2001, valdecoxib was granted FDA approval [429715]. The company claims that valdecoxib has improved potency and broader therapeutic range than other COX-2 inhibitors including celecoxib, and has the potential for once-daily dosing [287279], [313957]. By 1999, due to the poor water solubility of valdecoxib, Searle was also developing the prodrug parecoxib [324667]. Valdecoxib has been described by Searle as almost superimposable at the site critical for COX-2 inhibition, a structural side pocket in the enzyme which coincides with the sulfonamide group of the drug [324667]. In April 2000, Morgan Stanley Dean Witter estimated sales would be US $400 million in 2003, rising to US $750 million in 2004 [375906]. In April 2001, Merrill Lynch predicted world sales of US $460 million in 2002, rising to $1,065 million in 2005 [420574]. In September 2000, Merrill Lynch reported that additional pain data were being accumulated for this drug, the possible inclusion of which could push filing back to later in the first half of 2001 [382577]. In May 2001, Merrill Lynch expected launch in 2002 [411811]. In August 2001, Lehman Brothers predicted that launch would take place in thefirst half of 2002 and the product would make peak sales of US $1,500 million [420809]. Credit Suisse predicted in this month that total sales would reach US $330 million in 2002, rising to US $1832 million in 2004 [422318]. In September 2001, Morgan Stanley expected launch in the first half of 2002 [427113]. By October 2001, Credit Suisse had revised its sales predictions to US $180 million in 2002, US $790 million in 2003 and US $1,430 in 2004 [427185].     

Acetylsalicylic acid and other salicylates in relation to Stevens-Johnson syndrome and toxic epidermal necrolysis

AIMS: Various nonsteroidal anti-inflammatory drugs are known to increase the risk of Stevens-Johnson syndrome and toxic epidermal necrolysis. The relationship between salicylate treatment and these conditions is not known. METHODS: A case-control study was conducted in four countries in Europe from 1989 to 1995. RESULTS: Among 373 cases and 1720 controls, the multivariate relative risk estimate for any salicylate use in the previous week was 1.3 (95% confidence interval, 0.8-2.2); no statistically significant elevations were observed for single ingredient preparations or for salicylate-containing combination products. CONCLUSIONS: Acetylsalicylic acid and other salicylates are not associated with a measurable increase in the risk of these rare but severe reactions.     

实例探讨药物引起SJS或TEN的评分方法——Naranjo评分与ALDEN评分比较

药物引起的史蒂文斯-约翰逊综合征（SJS）和中毒性表皮坏死松解症（TEN）是一种罕见严重的不良反应,其特征是广泛性的皮肤表皮剥离和黏膜侵犯。当评估可疑药物和SJS或TEN之间的因果关系时,除了Naranjo评分外,最近根据两个大型的病例对照研究结果所衍生的ALDEN评分也提供了新思路。本文结合1例同时服用对乙酰氨基酚和头孢拉定导致中毒性表皮坏死综合征的案例,应用ALDEN评分及Naranjo评分分析两种药物与ADR间的关联性,并讨论此两种评分方法的差异性及适宜性。     

Treatment of epidermal necrolysis with high-dose intravenous immunoglobulins (IV Ig): clinical experience to date

High-dose human intravenous immunoglobulins (IV I ) have now been used as a treatment for epidermal necrolysis for several years.We have reviewed all series involving more than nine patients treated with high-dose IV Ig for toxic epidermal necrolysis (TEN) or Stevens-Johnson syndrome (SJS) published in indexed journals. Nine series included a total of 156 patients; among the 156 reported cases, 32 patients died (20.5%). When the analysis was restricted to the five series that included some comparison with expected deaths, the mortality rate observed in patients treated with IV Ig was 27% versus an expected rate of 30%. Because of high diversity in study designs and dosages of IV Ig used, and because several series included duplicate cases, it was not possible to make more detailed statistical analyses, including individual prognostic factors and IV Ig dosages.In the absence of randomised controlled trials, this review does not provide a definite conclusion on the usefulness of IV Ig in SJS or TEN; however, the analysis of published data does not suggest a dramatic efficacy.We conclude that, in the absence of further studies, IV Ig cannot yet be considered the standard of care for SJS or TEN.     

Extent of renal effect of cyclo-oxygenase-2-selective inhibitors is pharmacokinetic dependent

Non-steroidal anti-inflammatory drugs (NSAIDs) cause renal side-effects. In the present study, we tested the hypothesis that the extent of the renal effects of cyclo-oxygenase (COX)-2-selective NSAIDs is linked to their pharmacokinetics. A single oral dose of rofecoxib (10 mg/kg), celecoxib (40 mg/kg), meloxicam (3 mg/kg) or placebo was administered to rats. Urinary excretion of electrolytes, a marker of renal effects, and plasma and kidney concentrations of NSAIDs were measured. Rofecoxib and celecoxib, but not meloxicam, significantly decreased urinary sodium and potassium excretion. There was a significant correlation between the area under the 24 h plasma concentration-time curve (AUC0-24) of rofecoxib and the change in sodium (r = -0.65; P < 0.02) and potassium (r = -0.82; P < 0.0006) excretion. The AUC0-24 of celecoxib was correlated with sodium (r = -0.80; P < 0.05) but not potassium excretion. The ratios of kidney to plasma drug concentrations were 1.72, 3.16 and 0.17 for rofecoxib, celecoxib and meloxicam, respectively. The renal effect of the COX-2-selective NSAIDs examined, marked by their ability to reduce the excretion of electrolytes, is influenced by systemic exposure to the drugs. The relatively higher distribution into the kidneys of rofecoxib and celecoxib compared with meloxicam suggests involvement of direct drug exposure in the kidneys in the adverse renal effect.     

196例儿童抗癫痫药物高敏反应综合征临床分析并文献复习

目的:探讨抗癫痫药物导致的儿童高敏反应综合征的特征及规律,为抗癫痫药物应用提供参考.方法:筛选和分析国内外公开发表的抗癫痫药物在儿童临床治疗中致高敏反应的文献,对患儿抗癫痫药物高敏反应综合征的临床特点及规律进行分析.结果:共筛选出196例儿童高敏反应综合征病例,临床表现为发热、皮肤损害、淋巴结肿大,重症病例会损伤其他器...     

Asplenic fulminant sepsis secondary to a dog bite complicated by toxic epidermal necrolysis/Stevens-Johnson syndrome

We report a case of asplenic fulminant sepsis in Australia following a dog bite which was complicated by toxic epidermal necrolysis/Stevens-Johnson syndrome (TENS/SJS). Capnocytophaga canimorsus, the infective organism, is a rare cause of septicaemia: a high degree of suspicion of this unusual organism and its early aggressive management is paramount. The diagnostic and management difficulties of TENS/SJS in the context of a patient with fulminant sepsis, DIC and on inotropes are also highlighted.     

Stevens-Johnson syndrome/toxic epidermal necrolysis in a patient receiving concurrent radiation and gemcitabine

A patient with stage IV malignant melanoma treated with daily radiotherapy and low-dose (100 mg/m2) daily gemcitabine developed a blistering skin eruption, fever and neutropenia consistent with overlap Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). The diagnosis was confirmed by skin biopsy of an affected area. The case history is described, and the literature relating to the development of SJS/TEN in association with chemotherapy and radiotherapy administration is reviewed. This report describes a serious potential complication of concurrent gemcitabine and radiotherapy.     

Unexpected nanomolar inhibition of carbonic anhydrase by COX-2-selective celecoxib: new pharmacological opportunities due to related binding site recognition

By optimizing binding to a selected target protein, modern drug research strives to develop safe and efficacious agents for the treatment of disease. Selective drug action is intended to minimize undesirable side effects from scatter pharmacology. Celecoxib (Celebrex), valdecoxib (Bextra), and rofecoxib (Vioxx) are nonsteroidal antiinflammatory drugs (NSAIDs) due to selective inhibition of inducible cyclooxygenase COX-2 while sparing inhibition of constitutive COX-1. While rofecoxib contains a methyl sulfone constituent, celecoxib and valdecoxib possess an unsubstituted arylsulfonamide moiety. The latter group is common to many carbonic anhydrase (CA) inhibitors. Using enzyme kinetics and X-ray crystallography, we demonstrate an unexpected nanomolar affinity of the COX-2 specific arylsulfonamide-type celecoxib and valdecoxib for isoenzymes of the totally unrelated carbonic anhydrase (CA) family, such as CA I, II, IV, and IX, whereas the rofecoxib methyl sulfone-type has no effect. When administered orally to glaucomatous rabbits, celecoxib and valdecoxib lowered intraocular pressure, suggesting that these agents may have utility in the treatment of this disorder. The crystal structure of celecoxib in complex with CA II reveals part of this inhibition to be mediated via binding of the sulfonamide group to the catalytic zinc of CA II. To investigate the structural basis for cross-reactivity of these compounds between COX-2 and CA II, we compared the molecular recognition properties of both protein binding pockets in terms of local physicochemical similarities among binding site-exposed amino acids accommodating different portions of the drug molecules. Our approach Cavbase, implemented into Relibase, detects similarities between the sites, suggesting some potential to predict unexpected cross-reactivity of drugs among functionally unrelated target proteins. The observed cross-reactivity with CAs may also contribute to differences in the pharmacological profiles, in particular with respect to glaucoma and anticancer therapy and may suggest new opportunities of these COX-2 selective NSAIDs.     

Lamotrigine-induced toxic epidermal necrolysis in three patients treated for bipolar disorder

Exfoliative dermatitis, including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), is a mild-to-life-threatening process that has been described after exposure to many antiepileptic drugs. The increased use of antiepileptic drugs for treatment of bipolar disorder and neurologic disorders has extended the risk of exfoliative disorder to this population of patients, and these patients and their health care providers may not be familiar with the risks involved with these drugs. We describe the cases of a 28-year-old woman with bipolar 1 disorder initially treated with lamotrigine, and two adolescent girls with bipolar 2 disorder treated with lamotrigine after poor responses to other drug regimens. In all three patients, rashes progressed to toxic epidermal necrolysis in spite of treatment with corticosteroids at their local hospitals; thus, they were transferred to our burn treatment center. Response to early corticosteroid treatment in suppressing progression of exfoliation was variable in these patients. Ultimately, two of the three required ventilatory support; their conditions improved within 8-32 days of treatment, and they were discharged from the hospital. Case reports of lamotrigine-induced exfoliative disorder in patients with bipolar disorder have been published. However, these three patients were admitted to our burn treatment center within a 12-month period. Our institution admits approximately 10-12 patients with TEN/year, and the increased use of lamotrigine for treatment of bipolar disorder is likely to result in more patients with TEN. Therefore, health care professionals need to be aware of the early signs and symptoms of exfoliative dermatotoxicity when treating patients with lamotrigine.     

奥卡西平致癫痫患儿皮疹12例临床分析及药学监护建议

目的 分析12例奥卡西平引起皮疹患儿的临床特点,为临床合理用药提供参考。方法 收集新疆维吾尔自治区人民医院儿科2014年1月至2017年1月奥卡西平引起皮疹的患儿资料。对患儿的性别、年龄、临床表现、奥卡西平的用法用量、皮疹出现的时间和严重程度以及转归进行调查分析。结果 共收集到12例皮疹患儿,其中10例为轻度斑丘疹,2例为药物超敏综合征,未收到史蒂文斯—约翰逊综合征、中毒性表皮坏死松解症病例。1例人类白细胞抗原基因药物基因检测结果阳性,11例为阴性。12例皮疹患儿经糖皮质激素等药物治疗后好转出院。结论 针对皮疹患儿的相关临床资料并结合文献,制定奥卡西平在临床使用过程中的药学监护建议,避免严重不良反应的发生。     

Valdecoxib-induced toxic epidermal necrolysis in a patient allergic to sulfa drugs

A 55-year-old Caucasian woman with a previously documented sulfa allergy was admitted to the hospital after she developed toxic epidermal necrolysis; she had been taking valdecoxib for 8 days for knee pain. Four days later, her bullous lesions had progressed to 45-50% of her body surface area. She was transferred to a burn unit for aggressive wound care and fluid hydration. Valdecoxib, a cyclooxygenase-2 inhibitor, is a benzenesulfonamide prescribed for arthritis pain and inflammation, and dysmenorrhea. Clinicians should exercise caution when prescribing valdecoxib to patients who are allergic to sulfa drugs.