OBJECTIVE: To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin.

DATA SOURCES: A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well.

STUDY SELECTION AND DATA EXTRACTION: Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials.

DATA SYNTHESIS: Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies.

CONCLUSIONS: While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

OBJECTIVE: To report 3 cases of immediate hypersensitivity reactions to moxifloxacin in patients who tolerated ciprofloxacin.

CASE SUMMARIES: A 71-year-old man, a 44-year-old woman, and a 70-year-old woman with a history of a moxifloxacin reaction developed an immediate hypersensitivity reaction upon oral challenge with moxifloxacin in our Drug Safety Clinic. The reaction was mainly characterized by pruritus and urticaria, although dyspnea and hypotension were noted in the first and second patient, respectively. Two of the patients had negative oral challenge tests with ciprofloxacin and all 3 patients tolerated full treatment courses of oral ciprofloxacin. In all 3 cases, use of the Naranjo probability scale indicated a highly probable adverse drug reaction.

DISCUSSION: Moxifloxacin, similar to other fluoroquinolones, can cause immediate hypersensitivity reactions. Previous publications have reported both cross-reactivity and a lack of cross-reactivity among various fluoroquinolones. The 3 patients discussed demonstrated a lack of cross-reactivity between moxifloxacin and ciprofloxacin since they tolerated oral challenge tests and full treatment courses of ciprofloxacin. Moxifloxacin has unique side chains at positions 7 and 8 on its bicyclic ring structure. Antigenic specificity to particular side chains at positions 7 and 8 on the bicyclic ring structure of moxifloxacin may explain this lack of cross-reactivity. Higher reporting rates of anaphylaxis to moxifloxacin compared to other fluoroquinolones may also be related to side chain specificity, although definitive evidence for this is lacking.

CONCLUSIONS: Based on our experience, patients who develop immediate hypersensitivity reactions to moxifloxacin may receive ciprofloxacin therapy in an appropriately monitored setting if they have previously tolerated full treatment courses of ciprofloxacin. Research into whether there is a specific side chain reaction unique to moxifloxacin is warranted.

BACKGROUND: Adverse drug events (ADEs) occurring in the community and treated in emergency departments (EDs) have not been well studied.

OBJECTIVE: To determine the prevalence, severity, and preventability of ADEs in patients presenting at EDs in 2 university-affiliated tertiary care hospitals in the Canadian province of Newfoundland and Labrador.

METHODS: A retrospective chart review was conducted on a stratified random sample (n = 1458) of adults (≥18 y) who presented to EDs from January 1 to December 31, 2005. Prior to the chart review, the sample frame was developed by first eliminating visits that were clearly not the result of an ADE. The ED summary of each patient was initially reviewed by 2 trained reviewers in order to identify probable ADEs. All eligible charts were subsequently reviewed by a clinical team, consisting of 2 pharmacists and 2 ED physicians, to identify ADEs and determine their severity and preventability.

RESULTS: Of the 1458 patients presenting to the 2 EDs, 55 were determined to have an ADE or a possible ADE (PADE). After a sample-weight adjustment, the prevalence of ADEs/PADEs was found to be 2.4%. Prevalence increased with age (0.7%, 18-44 y; 1.9%, 45-64 y; 7.8%, ≥65 y) and the mean age for patients with ADEs was higher than for those with no ADEs (69.9 vs 63.8 y; p < 0.01). A higher number of comorbidities and medications was associated with drug-related visits. Approximately 29% of the ADEs/PADEs identified were considered to be preventable, with 42% requiring hospitalization. Cardiovascular agents (37.4%) were the most common drug class associated with ADEs/PADEs.

CONCLUSIONS: Adult ADE-related ED visits are frequent in Newfoundland and Labrador, and in many cases are preventable. Further efforts are needed to reduce the occurrence of preventable ADEs leading to ED visits.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of rufinamide in the treatment of epileptic seizures and describe its potential place in therapy.

DATA SOURCES: MEDLINE (1966-January 2010) and PubMed (1966-January 2010) literature searches were conducted to identify primary literature investigating rufinamide. References from selected publications discussing rufinamide, as well as the package insert, were reviewed.

STUDY SELECTION AND DATA EXTRACTION: Published controlled trials describing the efficacy and safety of rufinamide were given preference. Available abstracts were also reviewed. Four published trials were identified and included and a retrospective review of the clinical use of rufinamide was also analyzed. The remainder of the information described is from 4 abstracts.

DATA SYNTHESIS: Rufinamide is a new antiepileptic agent that differs structurally from other antiepileptic drugs and is approved as adjunctive therapy for Lennox- Gastaut syndrome (LGS). It presumably provides its antiseizure activity by prolonging sodium channel inactivity, stabilizing cell membranes. It is absorbed and metabolized extensively, then excreted renally as an inactive metabolite. Clinical trials show that adjunctive rufinamide is effective at reducing seizure frequency in patients with LGS and refractory partial seizures. Rufinamide showed no effect on cognitive function in patients with refractory partial seizures. Short-term adverse event rates were similar to those of placebo. Safety data from long-term studies show that rufinamide is well tolerated, causing headache, dizziness, and fatigue at rates of >10%. Rufinamide has few clinically relevant drug interactions, although it does increase phenytoin serum concentrations, while valproate increases rufinamide serum concentrations.

CONCLUSIONS: Data show that rufinamide is safe and effective as an adjunctive agent for LGS and may be used to treat partial seizures. The benefits of rufinamide include its pharmacokinetics, limited drug interactions, and lack of effect on cognitive function, but its use is limited by the rarity of LGS and the lack of comparative data with other antiepileptic agents.

OBJECTIVE: To review the literature describing the efficacy of metformin and topiramate for the treatment of second-generation antipsychotic-induced weight gain.

DATA SOURCES: Articles were identified by searching the MEDLINE database (from 1949 through January 2010) using the key words metformin, topiramate, antipsychotic, weight, weight gain, and obesity.

STUDY SELECTION AND DATA EXTRACTION: All randomized, placebo-controlled trials of metformin and topiramate were selected for review.

DATA SYNTHESIS: Weight gain due to second-generation antipsychotic use is a concern due to the risk of long-term metabolic and cardiovascular effects with these agents. These effects include obesity, hyperglycemia, and insulin resistance, all of which may contribute to diabetes and cardiovascular disease. Second-generation antipsychotics vary in the degree to which they cause weight gain, and dietary and lifestyle changes may not be feasible or sufficient in counteracting this weight gain. Although other pharmacologic agents may be beneficial to prevent and treat antipsychotic-induced weight gain, metformin and topiramate have been the most extensively studied in this setting. Metformin acts peripherally to cause weight loss, while topiramate acts centrally. Review of 11 randomized, controlled trials demonstrates beneficial effects of metformin and topiramate in prevention and treatment of weight gain. Metformin is generally well tolerated and has been studied in pediatric patients, while topiramate is associated with more drug interactions and may possibly interfere with control of schizophrenia.

CONCLUSIONS: Data for the use of metformin and topiramate in the treatment and prevention of second-generation antipsychotic-induced weight gain are limited. Both may be effective in helping patients lose weight via mechanisms that have yet to be clearly defined. The use of metformin results in greater weight loss than topiramate, and topiramate is associated with more risks and may compromise the treatment of schizophrenia. Treatment of antipsychotic-induced weight gain with metformin may be an option after lifestyle and dietary changes have failed.

OBJECTIVE: To examine the pharmacokinetic implications and potential clinical effects of tobacco smoking cessation in patients on stable clozapine or olanzapine treatment.

DATA SOURCES: A literature search of MEDLINE (1950-November 2009) and EMBASE (1980-November 2009) was conducted using the search terms smoking, tobacco, cigarette, cannabis, smoking cessation, cytochrome P450, antipsychotic, clozapine, and olanzapine. In addition, reference lists from publications identified were searched manually.

STUDY SELECTION AND DATA EXTRACTION: English-language articles and human studies were identified, yielding 111 returns. Articles that reported clinical outcomes following smoking cessation were selected. Pharmacokinetic data for these drugs were reviewed and articles that provided relevant background information were also included.

DATA SYNTHESIS: Pharmacokinetic studies have demonstrated more rapid clearance of olanzapine and lower clozapine and norclozapine (desmethylclozapine) concentrations in smokers compared to nonsmokers. These studies also found that smokers require higher doses of these agents than nonsmokers. There are case reports of adverse clinical outcomes following smoking cessation in patients being treated with olanzapine and clozapine. Reports that included serum concentrations consistently found elevations following smoking cessation, and dosage reductions of 30-40% were required to achieve pre-cessation concentrations. Worsening psychiatric symptoms, somnolence, hypersalivation, extreme fatigue, extrapyramidal effects, and seizures have all been reported following smoking cessation in this patient group.

CONCLUSIONS: Pharmacists need to be aware of potential risks associated with smoking cessation in patients stabilized on clozapine or olanzapine. Toxicity as a result of recent smoking reduction or cessation may be a reason for hospital admission. For hospitalized patients, pharmacists should obtain information concerning smoking status, including cessation attempts. Nonspecific signs and symptoms of elevated clozapine or olanzapine concentrations should be considered in relation to clinical status while the patient is hospitalized. Measurement of baseline serum clozapine concentrations and/or empiric dosage adjustment in patients expected to have a prolonged hospital stay with forced smoking cessation may be appropriate.

BACKGROUND: The benefits of inhaled corticosteroids (ICS) in reducing the mortality related to chronic obstructive pulmonary disease (COPD) are controversial.

OBJECTIVE: To estimate whether ICS in monotherapy or in combination with long-acting β₂-agonists (LABA) reduces the mortality rate among COPD patients compared to those treated with LABA monotherapy.

METHODS: Using data from the Canadian province of Quebec's health administrative databases, a nested case-control study was conducted. A cohort of COPD patients aged 50 years and over between 1996 and 2000 was initially formed. Patients were included if they filled at least 6 prescriptions of an inhaled bronchodilator, received at least 1 medical service for COPD, and did not receive any diagnosis of asthma over a 12-month period. For each case of death identified in the cohort, up to 37 controls were time matched. For cases and controls, the exposure to ICS and LABA was assessed within the 3 months prior to the date of death for cases and date of selection for controls. Adjusted mortality rate ratios were estimated by conditional logistic regression comparing patients using ICS monotherapy or ICS/LABA combination therapy with patients using LABA monotherapy.

RESULTS: This study included 5996 cases of death and 54,750 controls. The mortality rates were found to be lower among users of ICS monotherapy than users of LABA monotherapy (OR 0.69; 95% CI 0.53 to 0.88) and lower among users of an ICS/LABA combination than users of LABA monotherapy (OR 0.73; 95% CI 0.56 to 0.96). No significant differences were observed between users of ICS/LABA combination therapy and users of ICS monotherapy (OR 1.07; 95% CI 0.93 to 1.23).

CONCLUSIONS: ICS were found to be associated with a reduction in mortality rate when compared to LABA among patients with COPD. However, the ICS/LABA combination therapy did not provide any additional benefit on mortality when compared to ICS monotherapy.

BACKGROUND: Several clinical studies have suggested that the overuse of shortacting β-agonists (SABAs) and the underuse of inhaled corticosteroids are prevalent and may compromise patient health and increase the use of scarce health-care resources.

OBJECTIVE: To examine the impact of an intervention designed to reduce SABA metered-dose inhaler (MDI) overdispensing on asthma-related drug and healthcare utilization endpoints in a mail order pharmacy benefit population.

METHODS: Retrospective pre- and postintervention analysis was conducted on all new SABA prescriptions indicating a quantity more than 1 SABA MDI per month and on asthma patients who were continuously enrolled in the Medco Health Solutions prescription benefit program from July 1, 2006, to June, 30, 2007 (preintervention), and July 1, 2007, to June 30, 2008 (postintervention). The intervention involved a written or verbal request to the prescriber to reduce the quantity of SABA MDIs dispensed to less than 1 SABA MDI per month if determined appropriate by the prescriber. Effectiveness of the intervention on asthma-related drug and health-care utilization outcomes were measured in the overall Medco pharmacy population and in asthma patients receiving more than 1 SABA MDI per month.

RESULTS: The percentage of new SABA prescriptions dispensed for more than 1 SABA MDI per month was significantly reduced during year 2 (22.9% vs 9.7%, p < 0.01). Of the 1835 asthma patients who received more than 1 SABA MDI per month in year 1, 1230 (67%) received fewer than 1 SABA MDI per month during year 2. The incidence of asthma-related hospitalizations, emergency department visits, and oral corticosteroid use did not significantly change from year 1 to year 2.

CONCLUSIONS: This analysis shows that an intervention can succeed in reducing the overdispensing of quick-relief medication without compromising asthma control. Further investigation is warranted to better understand the interplay between reduction in excessive SABA use and improved clinical outcomes.

OBJECTIVE: To determine the relationship between doses of gemcitabine and absolute neutrophil count and thrombocytopenia in patients with severe hepatic dysfunction (total bilirubin ≥4.5 mg/dL), and the relationship between doses of gemcitabine in patients with severe hepatic dysfunction and nonhematologic toxicity.

CASE SUMMARY: A retrospective chart review was conducted for patients receiving gemcitabine at the Medical University of South Carolina from October 2006 through October 2008. Seven patients were identified who had an elevated total bilirubin level (≥4.5 mg/dL) at the time they were receiving gemcitabine. All 7 patients received gemcitabine 1000 mg/m² throughout their treatment, regardless of liver function. Six patients did not experience significant hematologic toxicity warranting a dose reduction or a dose being held. One patient developed thrombocytopenia, warranting a dose being held.

DISCUSSION: Gemcitabine is a chemotherapy agent frequently used for the treatment of pancreatic cancer as well as metastatic breast, lung, and ovarian cancer. To date there is limited information on dosing of gemcitabine in patients with an elevated total bilirubin. A previous study looking at lower grades of liver dysfunction suggested empiric dose reductions be made in these patients because of increased incidence of toxicity.

CONCLUSIONS: These results indicate the possibility that no initial dose reduction is necessary for patients with liver dysfunction receiving gemcitabine; however, close monitoring of these patients is required.

OBJECTIVE: To evaluate the use of recombinant factor VIIa (rFVIIa) to reverse major bleeding from newer parenteral anticoagulant therapy.

DATA SOURCES: MEDLINE/PubMed was searched from January 2000 through December 2009 using the terms recombinant factor VIIa, rFVIIa, NovoSeven, enoxaparin, argatroban, fondaparinux, lepirudin, bivalirudin, idraparinux, nadroparin, hirudin, and desirudin. References of identified articles were reviewed.

DATA SYNTHESIS: Data evaluating the role of rFVIIa to reverse major bleeding from newer parenteral anticoagulant therapy is limited to case reports and small laboratory investigations. Laboratory investigations suggest that rFVIIa may be effective in reversing the hemostatic effects of newer parenteral anticoagulants. In most case reports analyzed, standard interventions for bleeding (eg, fresh frozen plasma, packed red blood cells) were attempted prior to using rFVIIa. Sixteen published cases describe the use of rFVIIa to reverse major bleeding from low-molecular-weight heparins, synthetic pentasaccharides, and direct thrombin inhibitors. Initial doses ranged from 20 to 120 µg/kg. rFVIIa was considered effective or partially effective based upon clinical response in 13 cases. Use was not effective in 3 cases because of a thrombotic event, no change in hemostasis, and death from bleeding complications. As thrombosis is the major safety concern, an individualized risk-benefit assessment is required prior to the use of rFVIIa therapy to restore hemostasis.

CONCLUSIONS: rFVIIa may be considered to manage major refractory bleeding from newer parenteral anticoagulant agents when the benefit is thought to outweigh the thrombotic risk.

OBJECTIVE: To describe the case of a patient who developed symptomatic bradycardia upon initiation of oral ziprasidone and later with oral aripiprazole, both of which resolved shortly after discontinuation of therapy.

CASE SUMMARY: An 18-year-old female with bipolar disorder was started on oral ziprasidone 80 mg at night and the dose was subsequently increased to 120 mg for management of acute mania and delusions. The patient developed symptomatic bradycardia (heart rate 31-35 beats/min), which resolved after ziprasidone was decreased to 80 mg. Three months later, the patient was readmitted for treatment of bipolar mania with psychotic features in the context of medication nonadherence. She was started on oral aripiprazole 15 mg daily (subsequently increased to 20 mg) in conjunction with 600 mg lithium carbonate twice daily. The patient again developed symptomatic bradycardia that resolved after discontinuation of aripiprazole.

DISCUSSION: This is the first case report of symptomatic bradycardia associated with the use of ziprasidone or aripiprazole. The Naranjo probability scale suggests that the likelihood of the atypical antipsychotic as the cause of bradycardia is probable for both ziprasidone and aripiprazole. Symptomatic bradycardia with the use of other atypical antipsychotics has been reported in the literature. Little is known about the mechanisms that contribute to the antipsychotic-associated bradycardic response.

CONCLUSIONS: Further studies are needed to better determine the relationship between antipsychotics and reflex bradycardia. Although bradycardia remains a relatively uncommon phenomenon seen with the use of these medications, the severity of this potential adverse effect warrants consideration when initiating antipsychotic therapy.

OBJECTIVE: To review literature regarding the effect of diabetes medications as a contributing risk for falls and fall-related morbidity in elderly patients with type 2 diabetes.

DATA SOURCES: Primary literature was identified through PubMed MEDLINE (1966-November 2009) using the search terms elderly, aged, older adults, diabetes type 2, diabetes mellitus, falls, fractures, medication, hypoglycemia, and vitamin B₁₂ deficiency. Each drug class and the individual agents within the classes were also included in the search. Additional references were obtained through review of references from articles obtained.

STUDY SELECTION AND DATA EXTRACTION: Clinical studies evaluating diabetes medications and their association with falls, as well as studies evaluating their association with the complications of falls, were considered for inclusion. Selection emphasis was placed on randomized studies evaluating diabetes medications and falls.

DATA SYNTHESIS: There is no direct link between metformin and falls; however, an indirect association caused by neuropathy secondary to vitamin B₁₂ deficiency may be of concern. Although hypoglycemia is a risk factor, to date, there are no trials specifically linking insulin secretagogues to falls. Insulin use has been demonstrated to increase the risk of falls in the elderly. Thiazolidinediones increase fracture risk and thus may worsen fall-related outcomes. There are no studies to date linking other agents to an increased risk of falls.

CONCLUSIONS: Special considerations should be made when treating elderly patients with diabetes. At this time, a patient's functional level and risk factors for falls should weigh into decision-making regarding drug selection. The risk of falls and fall-related complications associated with diabetes medications should not be ignored.

BACKGROUND: Six pioneer physicians-pharmacists quality circles (PPQCs) located in the Swiss canton of Fribourg (administratively corresponding to a state in the US) were under the responsibility of 6 trained community pharmacists moderating the prescribing process of 24 general practitioners (GPs). PPQCs are based on a multifaceted collaborative process mediated by community pharmacists for improving compliance with clinical guidelines within GPs' prescribing practices.

OBJECTIVE: To assess, over a 9-year period (1999-2007), the cost-containment impact of the PPQCs.

METHODS: The key elements of PPQCs are a structured continuous quality improvement and education process; local networking; feedback of comparative and detailed data regarding costs, drug choice, and frequency of prescribed drugs; and structured independent literature review for interdisciplinary continuing education. The data are issued from the community pharmacy invoices to the health insurance companies. The study analyzed the cost-containment impact of the PPQCs in comparison with GPs working in similar conditions of care without particular collaboration with pharmacists, the percentage of generic prescriptions for specific cardiovascular drug classes, and the percentage of drug costs or units prescribed for specific cardiovascular drugs.

RESULTS: For the 9-year period, there was a 42% decrease in the drug costs in the PPQC group as compared to the control group, representing a $225,000 (USD) savings per GP only in 2007. These results are explained by better compliance with clinical and pharmacovigilance guidelines, larger distribution of generic drugs, a more balanced attitude toward marketing strategies, and interdisciplinary continuing education on the rational use of drugs.

CONCLUSIONS: The PPQC work process has yielded sustainable results, such as significant cost savings, higher penetration of generics and reflection on patient safety, and the place of "new" drugs in therapy. The PPQCs may also constitute a solid basis for implementing more comprehensive collaborative programs, such as medication reviews, adherence-enhancing interventions, or disease management approaches.

BACKGROUND: Gastrointestinal (GI) adverse effects are common with oral opioid treatment.

OBJECTIVE: To estimate the costs associated with GI events after oral short-acting opioid treatment, from the payer perspective.

METHODS: Medical and pharmacy claims from the PharMetrics' Patient-Centric Database were used to identify opioid-naïve patients who received a new prescription for oxycodone- or hydrocodone-containing immediate-release oral products between 2002 and 2006. Health-care resource use and costs were determined for patients with claims associated with ICD-9 CM (International Classification of Diseases-9th Clinical Modification) codes for nausea/vomiting (787.0x), constipation (564.0x), bowel obstruction (560, 560.1, 560.3, 560.39, 564.81), or antiemetic and laxative prescriptions during the 3 months after opioid index prescription and compared with patients without these GI event medical or prescription claims. Resource use data were compared using negative binomial regression and cost data were compared using ordinary least squares confirmed by generalized gamma regression analysis while controlling for demographics, treatment duration, and comorbidities.

RESULTS: Data from 237,447 patients were analyzed. Patients with GI event claims had significantly more hospitalizations (adjusted mean 0.20 to 0.97 vs 0.17, respectively, p < 0.001), days in the hospital (1.12 to 12.05 vs 1.00 days, p < 0.001), emergency department visits (0.36 to 1.44 vs 0.25 visits, p < 0.001), outpatient office visits (5.68 to 11.81 vs 4.11 visits, p < 0.001), and prescription claims (7.46 to 8.21 vs 6.06 claims, p < 0.001) than did patients without any GI event claims in the 3 months after index opioid prescription. Compared with patients without any GI event claims, incremental adjusted mean total health-care costs for patients with any of the GI event claims ranged from $4,880 to $36,152 and were significant (p < 0.001).

CONCLUSIONS: The economic burden of GI events coincident with opioid treatment is significant for patients with a GI event recorded in claims. Reducing GI adverse effects has potential cost savings for the health-care system.

OBJECTIVE: To report on 6 weeks of daptomycin treatment for tricuspid valve endocarditis caused by Staphylococcus aureus in a pregnant female in her second trimester.

CASE SUMMARY: A 24-year-old, 14-week pregnant patient with no significant medical history, but with a history of intravenous drug abuse presented with tricuspid valve endocarditis caused by methicillin-sensitive S. aureus. After initial treatment with vancomycin, the patient continued to have fever and bacteremia and was initiated on daptomycin 6 mg/kg for 6 weeks of therapy. The treatment resulted in the resolution of the endocarditis, and no adverse sequelae were identified in the mother or baby.

DISCUSSION: Infective endocarditis is a common infection encountered in the hospital setting and represents an increased cost burden to institutions due to prolonged lengths of treatment. Antimicrobial resistance, antimicrobial failure, inadequate attainment of effective drug concentrations, drug allergies, and adverse reactions may be factors that limit the use of commonly utilized antimicrobial agents. Therefore, newer therapies like daptomycin may need to be employed in these situations. Although daptomycin is pregnancy category B, limited case reports with neonatal outcomes are reported.

CONCLUSIONS: This case provides further support for the safety of daptomycin in pregnancy with the dose of 6 mg/kg, the extended duration of therapy (6 weeks), and the primary exposure in the second trimester.

OBJECTIVE: To report a case of clinically significant hypoglycemia attributed to the concomitant use of trimethoprim/sulfamethoxazole (TMP/SMX) and repaglinide by a diabetic patient.

CASE SUMMARY: A 76-year-old diabetic patient with impaired renal function and no history of hypoglycemia was receiving treatment with repaglinide 1 mg 3 times daily. Five days after TMP/SMX therapy was started for a urinary tract infection, the man developed symptomatic hypoglycemia. Repaglinide and TMP/SMX were stopped and intravenous D-glucose was administered to normalize glucose levels. Repaglinide, but not TMP/SMX, was reintroduced 5 days later and no other hypoglycemic episode occurred. Objective causality assessments revealed that the interaction was probable (World Health Organization-Uppsala Monitoring Centre) or possible (Horn Drug Interaction Probability Scale).

DISCUSSION: This interaction between TMP/SMX and repaglinide was predictable according to available pharmacokinetic data in healthy subjects. Trimethoprim induced CYP2C8 inhibition, thus increasing the plasma concentration of repaglinide. This interaction is mentioned in the repaglinide product information. To our knowledge, however, no case of symptomatic hypoglycemia associated with a combination of repaglinide and trimethoprim has been described before. This discrepancy may be explained by the subtherapeutic dosage used in the pharmacokinetic study. Moreover, our patient had impaired renal function, which may have led to trimethoprim accumulation and potentiated its interaction with repaglinide. A direct lowering of blood glucose levels due to sulfamethoxazole, also potentiated by renal failure, could also be involved in triggering hypoglycemia.

CONCLUSIONS: This interaction between TMP/SMX and repaglinide may have involved inhibition of CYP2C8 by trimethoprim. Clinicians should be aware that this association may lead to symptomatic hypoglycemia, particularly in patients with renal dysfunction.

OBJECTIVE: To report a case of hypertrophic cranial pachymeningitis (HCP) associated with the long-term administration of nonsteroidal antiinflammatory drugs (NSAIDs).

CASE SUMMARY: A 23-year-old man presented with recurrent headaches as the primary clinical manifestation. After the administration of the NSAIDs indomethacin and aceclofenac for 2 years, he developed signs of progressive cranial polyneuropathies (eg, II, III, V, VI, and VII palsy) and damage to the brainstem. Cranial contrast-enhanced magnetic resonance imaging (MRI) revealed curvilinear subdural enhancement and significant tentorium cerebelli and falx cerebri enhancements. Since antituberculosis treatment combined with corticosteroid therapy and analgesia with celecoxib for 40 days had not achieved satisfactory results, NSAIDs were discontinued and a single oral dose of a corticosteroid was given. No headaches were reported at a 6-month follow-up appointment. In addition, his cranial polyneuropathy improved significantly. Reexamination by contrast-enhanced MRI scan demonstrated that tentorial enhancement and thickening of the falx cerebri were markedly alleviated.

DISCUSSION: No additional causes of HCP were found during systematic investigation in this patient. In addition to headache, cranial polyneuropathy and thickened cerebral dura mater appeared after administration of NSAIDs for 2 years. The symptoms that appeared during the NSAID therapy were remarkably alleviated 5 months after medication discontinuation. Adverse drug reaction (ADR) assessment revealed that long-term administration of NSAIDs may be associated with the occurrence and development of HCP.

CONCLUSIONS: Long-term administration of NSAIDs is a probable cause of HCP. Clinicians should be aware of this ADR and avoid prescribing NSAIDs for an extended period.