The role of CYP2C and CYP3A in the disposition of 3-keto-desogestrel after administration of desogestrel

AIMS: Our objective was to study in vivo the role of CYP2C and CYP3A4 in the disposition of 3-keto-desogestrel after administration of desogestrel, by using the selective inhibitors fluconazole (CYP2C) and itraconazole (CYP3A4). METHODS: This study had a three-way crossover design and included 12 healthy females, the data from 11 of whom were analyzed. In the first (control) phase all subjects received a single 150 microg oral dose of desogestrel alone. In the second and third phases subjects received a 4 day pretreatment with either 200 mg fluconazole or 200 mg itraconazole once daily in a randomized balanced order. Desogestrel was given 1 h after the last dose of the CYP inhibitor. Plasma 3-keto-desogestrel concentrations were determined for up to 72 h post dose. RESULTS: Pretreatment with itraconazole for 4 days significantly increased the area under the plasma concentration-time curve (AUC) of 3-keto-desogestrel by 72.4% (95% confidence interval on the difference 12%, 133%; P = 0.024) compared with the control phase, whereas fluconazole pretreatment had no significant effect (95% CI on the difference -42%, 34%). Neither enzyme inhibitor affected significantly the maximum concentration (95% CI on the difference 14%, 124% for itraconazole and -23%, 40% for fluconazole) or elimination half-life (95% CI on the difference -42%, 120% for itraconazole and -24%, 61% for fluconazole) of 3-keto-desogestrel. CONCLUSIONS: According to the present study, the biotransformation of desogestrel to 3-keto-desogestrel did not appear to be mediated by CYP2C9 and CYP2C19 as suggested earlier. However, the further metabolism of 3-keto-desogestrel seems to be catalyzed by CYP3A4.     

伊曲康唑与氟康唑在重症监护室早期经验性治疗真菌感染的疗效比较

目的比较伊曲康唑和氟康唑在重症监护室早期经验性治疗中的有效性和安全性。方法采取随机、对照、开放的临床试验，入选的40例患者具有真菌感染的高危因素，均出现不明原因发热，广谱抗生素治疗3～7 d无效。将入选患者随机分配为伊曲康唑治疗组和氟康唑治疗组各20例。伊曲康唑治疗组给予伊曲康唑注射液200 mg，q12 h，先治疗2 d，随后给予200 mg，qd，共5 d，再改用伊曲康唑口服液口服，每次200 mg，bid，治疗14 d；氟康唑治疗组给予氟康唑注射液400 mg静脉滴注，qd，共治疗21 d。观察患者体温变化、真菌感染情况、药物相关的不良反应和疗效。结果伊曲康唑组总有效率65.0%，不良反应率30.0%；氟康唑组总有效率50.0%，不良反应率5.0%，但两组总有效率和不良反应发生率均差异无显著性（均P＞0.05）。治疗过程中，氟康唑组出现2例深部真菌感染。结论伊曲康唑和氟康唑均可作为现阶段重症监护室早期经验性治疗的一线药物，但伊曲康唑疗效更佳。     

Gender differences in the adverse events associated with cardiovascular drugs in a spontaneous reporting system in South Korea

Background Studies on disease-related gender differences in pharmacodynamics and pharmacokinetics are prevalent; however, gender differences in the drug-related adverse events have not been systemically described. Objective To explore gender differences in the adverse events associated with cardiovascular drugs using a spontaneous reporting system. Setting This study was conducted using the Korea adverse event reporting system and national health insurance databases. Methods The number of reported adverse events was divided by the number of patients diagnosed with cardiovascular diseases (Korean Standard Classification of Disease, 7th Revision, I05–I70) and prescribed cardiovascular drugs. We calculated adverse event reporting rates per 100,000 persons and the reporting ratio for women, compared with men. Main outcome measures Reporting ratios across the groups of adverse events and cardiovascular drugs. Results We identified 27,533 adverse events associated with cardiovascular drugs and 9,413,666 patients with cardiovascular disease. Compared with men, reporting ratios of women were higher in the following categories: Overall (1.09, 95% CI, 1.06–1.11), beta blockers (1.20, 95% CI, 1.05–1.39), and calcium channel blockers (1.14, 95% CI, 1.03–1.27). For the adverse events, the reporting ratio was 1.34 (95% CI, 1.14–1.58) for musculoskeletal disorders and 2.54 (95% CI, 2.10–3.07) for oedema in women. Conclusion Our findings on differential adverse events reporting rates associated with the cardiovascular drugs between women and men provide an evidence on possible gender differences in wide range of pharmacotherapy. A clear understanding of the relationship between drug-induced adverse events and gender will aid in the development of therapeutic interventions being tailored to the individual patients.

     

Hospitalization for serious blood and skin disorders following co-trimoxazole

Aims To quantify the risk of serious blood and skin disorders requiring hospitalization among otherwise healthy users of co-trimoxazole
Methods We conducted a population-based cohort study at Group Health Cooperative of Puget Sound (GHC).
Results During the years 1987 to 1993 we found six cases of co-trimoxazole-associated blood disorders and three cases of co-trimoxazole-associated skin disorders yielding risks of 5.6/100,000 (95% CI 2.6–12.2) and 2.8/100,000 (95% CI 0.9–8.2) respectively. In all cases found there was prompt recovery after discontinuation of co-trimoxazole. We found no cases of toxic epidermal necrolysis.
Conclusions We conclude that the risk of blood and skin disorders associated with the use of co-trimoxazole leading to hospitalization is low.     

Systematic review and meta-analysis: D-Penicillamine vs. placebo/no intervention in patients with primary biliary cirrhosis--Cochrane Hepato-Biliary Group

BACKGROUND: D-Penicillamine is used for patients with primary biliary cirrhosis due to its ability to decrease hepatic copper and modulate the immune response. The results on effects of D--penicillamine in randomized-clinical trials of primary biliary cirrhosis patients are inconsistent. AIM: To systematically evaluate the benefits and harms of D-penicillamine for patients with primary biliary cirrhosis. METHODS: We have performed a systematic review with meta-analyses of randomized-clinical trials to evaluate the effects of D-penicillamine for primary biliary cirrhosis. The primary outcomes are mortality and mortality or liver transplantation. We analysed the data by fixed-effect and random-effect models. RESULTS: Seven randomized trials including 706 patients were analysed. d-Penicillamine was without significant effects on mortality (RR 1.08, 95% CI: 0.82-1.43, P = 0.56), mortality or liver transplantation (RR 1.11, 95% CI: 0.74-1.68, P = 0.62), pruritus, liver complications, progression of liver histological stage and liver biochemical variables. D--Penicillamine significantly decreased serum alanine aminotransferase activity (weighted mean difference -45 IU/L, 95% CI: -75 to -15, P < 0.05) and led to significantly more adverse events (RR 4.18, 95% CI: 1.38-12.69, P = 0.01). CONCLUSION: D-Penicillamine did not appear to reduce the risk of mortality or morbidity, and led to more adverse events in patients with primary biliary cirrhosis.     

Hepatic effects of lovastatin exposure in patients with liver disease: a retrospective cohort study.

BACKGROUND: Little is known about the potential adverse hepatic effects of HMG-CoA reductase inhibitors ('statins') in patients with existing liver disease; therefore, we examined the risk of liver toxicity with lovastatin exposure in these patients. METHODS: A retrospective cohort study was performed using data from a large integrated health plan in Northern California, USA. Patients with laboratory or clinical evidence of liver disease were identified and their exposure to lovastatin was determined. The primary outcome was a pattern of liver-test abnormalities associated with a poor prognosis among patients with drug-induced liver disease, based on Hy's Rule. Secondary outcomes included liver injury (defined as moderate or severe, depending on the degree of ALT level elevations) or the development of either clinical cirrhosis or liver failure. Incidence rate ratios (IRRs) were calculated and multivariate analyses conducted using extended Cox models. RESULTS: A total of 93 106 patients met the entry criteria. Lovastatin exposure was associated with a lower incidence of all endpoints, including the primary outcome (IRR = 0.28, 95% CI 0.12, 0.55), moderate liver injury (IRR = 0.56, 95% CI 0.47, 0.65), severe liver injury (IRR = 0.50, 95% CI 0.29, 0.81) and the occurrence of either cirrhosis or liver failure (IRR = 0.29, 95% CI 0.21, 0.38); adjustment for age and sex resulted in some attenuation of this reduction in incidence. The observed effects were generally consistent across a range of baseline liver-disease diagnoses and greater cumulative lovastatin exposure was associated with fewer outcome events for some endpoints. CONCLUSIONS: In this retrospective analysis, exposure to lovastatin was not associated with an increased risk of adverse hepatic outcomes. These results do not support concern regarding lovastatin-related hepatotoxicity in patients with existing liver disease.     

Absence of clinically relevant drug interactions following simultaneous administration of didanosine-encapsulated, enteric-coated bead formulation with either itraconazole or fluconazole

This open-label, two-way crossover study was undertaken to determine whether the enteric formulation of didanosine influences the pharmacokinetics of itraconazole or fluconazole, two agents frequently used to treat fungal infections that occur with HIV infection, and whose bioavailability may be influenced by changes in gastric pH. Healthy subjects were randomized to Treatment A (200-mg itraconazole or 200-mg fluconazole) or Treatment B (same dose of itraconazole or fluconazole with 400 mg of didanosine as an encapsulated, enteric-coated bead formulation). In the itraconazole study, a lack of interaction was concluded if the 90% confidence interval (CI) of the ratio of the geometric means of log-transformed C(max) and AUC(0-T) values of itraconazole and hydroxyitraconazole, the active metabolite of itraconazole, were contained entirely between 0.75 and 1.33. In the fluconazole study, the equivalence interval for C(max) and AUC(0-T) was 0.80-1.25. The data showed that for itraconazole the point estimate and 90% CI of the ratios of C(max) and AUC(0-T) values were 0.98 (0.79, 1.20) and 0.88 (0.71, 1.09), respectively; for hydroxyitraconazole the respective values were 0.91 (0.76, 1.08) and 0.85 (0.68, 1.06). In the fluconazole study, the point estimate and 90% CI of the ratios of C(max) and AUC(0-T) values were 0.98 (0.93, 1.03) and 1.01 (0.99, 1.03), respectively. The T(max) for itraconazole, hydroxyitraconazole, and fluconazole were similar between treatments. Both studies indicated a lack of clinically significant interactions of the didanosine formulation with itraconazole or fluconazole. These results showed that the encapsulated, enteric-coated bead formulation of didanosine can be concomitantly administered with drugs, such as the azole antifungal agents, whose bioavailability may be influenced by interaction with antacids.     

Hepatic adverse drug reactions: a case/non-case study in Italy

OBJECTIVE: Adverse drug reactions (ADRs) can involve all tissues and organs. Liver injuries are considered among the most serious and are a cause for concern among physicians and patients. To assess the extent of drug-induced liver injuries in Italy we compared the number of cases of hepatic ADRs with reports of all other drug-related reactions present in the same database. METHODS: Spontaneous reports from six Italian Regions collected from January 1990 to May 2005 were analysed. Adverse reactions were classified according to WHO Adverse Reaction Terminology for causality assessment, and only those with "certain", "probable" or "possible" causality assessment were included. Association between drugs and hepatic ADRs was assessed using the case/non case method, calculating the ADR reporting odds ratio (ROR) as a measure of disproportionality. RESULTS: On May 2005, the database contained 35,767 ADR reports, of which 11,829 were excluded because they were unclassifiable or unlikely in terms of causality assessment. Therefore, the analysis was carried out on 23,938 reports, of which 1,069 concerned hepatic ADRs (cases) and 22,869 concerned non-cases. The proportion of serious ADRs was about 40% in the overall database, and about 74% among cases. The drug classes with the highest number of cases were statins (ROR = 2.9, 95% CI 2.4-3.5), antiplatelet agents (ROR = 3.5; 95% CI 2.6-4.6), NSAIDs (ROR = 2.9; 95% CI 2.1-3.9) and macrolides (ROR = 1.7; 95% CI 1.2-2.3). CONCLUSION: Hepatic adverse drug reactions remain a serious concern for several drugs widely used in clinical practice. Monitoring hepatic enzymes on a monthly basis for the first 6 months of treatment has been suggested for patients taking medications known to be hepatotoxic. A better knowledge of the epidemiology and mechanisms of hepatic ADRs may contribute to minimising their occurrence.     

The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis

Abstract

Background: Novel oral anticoagulants, including direct factor Xa inhibitors and direct factor IIa inhibitors, have been used to prevent stroke in patients with atrial fibrillation (AF) for a decade. In this study, the efficacy and safety of the novel oral anticoagulants were assessed in AF patients.

Methods: No language restrictions were applied. Study selection and data extraction were carried out by searching PubMed, EMBASE, OVID, the BIOSIS, the Web of Science, Clinical Trials Registers, Cochrane Central Register of Controlled Trials and the China Academic Library and Information System. Each database was searched from its inception date to June 2013. Using odds ratio (OR) as an indicator, we systematically evaluated the primary efficacy endpoints and safety endpoints, as well as 10 secondary endpoints.

Result: Compared to the control drugs, the novel oral anticoagulants showed an OR decreased by 26% (OR: 0.74, 95% confidence interval (CI): 0.62–0.88) for stroke or systemic embolism, decreased by 24% (OR: 0.76, 95% CI: 0.64–0.90) for major bleeding, decreased by 10% (OR: 0.90, 95% CI: 0.84–0.95) for death from any cause, decreased by 27% for disabling or fatal stroke (OR: 0.73, 95% CI: 0.54–0.97), decreased by 31% (OR: 0.69, 95% CI: 0.60–0.8) for fatal bleeding, and decreased by 8% (OR: 0.92, 95% CI: 0.88–0.95) for serious adverse events. However, there was no significant difference in acute myocardial infarction, systemic embolism, major bleeding or clinically relevant non-major, all bleeding events, all adverse events and liver function disorder, between the novel oral anticoagulants and control drugs (p?>?0.05).

Conclusions: Compared to the control drugs, the novel oral anticoagulants showed higher efficiency and safety in patients with AF, as evidenced by their superior performance not only in reducing the risk of stroke or systemic embolism with a lower risk of major bleeding but also in decreasing the incidence of death from any cause, disabling or fatal stroke, serious adverse events and fatal bleeding.     

Safety of fluconazole in paediatrics: a systematic review

Purpose

To determine the safety of fluconazole in neonates and other paediatric age groups by identifying adverse events (AEs) and drug interactions associated with treatment.

Methods

A search of EMBASE (1950–January 2012), MEDLINE (1946–January 2012), the Cochrane database for systematic reviews and the Cumulative Index to Nursing and Allied Health Literature (1982–2012) for any clinical study about fluconazole use that involved at least one paediatric patient (≤17 years) was performed. Only articles with sufficient quality of safety reporting after patients’ exposure to fluconazole were included.

Results

We identified 90 articles, reporting on 4,209 patients, which met our inclusion criteria. In total, 794 AEs from 35 studies were recorded, with hepatotoxicity accounting for 378 (47.6 %) of all AEs. When fluconazole was compared with placebo and other antifungals, the relative risk (RR) of hepatotoxicity was not statistically different [RR 1.36, 95 % confidence interval (CI) 0.87–2.14, P?=?0.175 and RR 1.43, 95 % CI 0.67–3.03, P?=?0.352, respectively]. Complete resolution of hepatoxicity was achieved by 84 % of patients with follow-up available. There was no statistical difference in the risk of gastrointestinal events of fluconazole compared with placebo and other antifungals (RR 0.81, 95 % CI 0.12–5.60, P =?0.831 and RR 1.23, 95 %CI 0.87–1.71, P?=?0.235, respectively). There were 41 drug withdrawals, 17 (42 %) of which were due to elevated liver enzymes. Five reports of drug interactions occurred in children.

Conclusion

Fluconazole is relatively safe for paediatric patients. Hepatotoxicity and gastrointestinal toxicity are the most common adverse events. It is important to be aware that drug interactions with fluconazole can result in significant toxicity.     

Prolongation of the QT interval and cardiac arrhythmias associated with cisapride: limitations of the pharmacoepidemiological studies conducted and proposals for the future

Not all hazards can be identified from clinical studies prior to marketing of medicinal products. Pre-marketing large-scale trials for cisapride did not report any serious cardiac arrhythmias. After a long period of availability in several countries it was withdrawn in 2000 because of reports of serious, and in many cases fatal, cardiac events. Whilst spontaneous reporting systems for adverse drug reactions (ADRs) have limitations such as under-reporting, they are an effective system for signal generation, particularly of rare ADRs. Pharmacoepidemiological studies aim to identify and calculate the incidence of adverse reactions, with increased sensitivity to less common ADRs compared to randomised controlled trials, yet cohort sizes may be insufficient to detect very rare ADRs such as drug-induced Torsade de Pointes, with an estimated incidence of the order of 1 per 12,000 to 1 per 120,000 patients. Several pharmacoepidemiological studies investigated adverse events associated with cisapride, one of which specifically examined the association between serious cardiac arrhythmias and cisapride. These observational studies were conducted using large population databases, but each failed to identify sufficient cases to establish a causal relationship. Explanations include that the cohort sample sizes were too small, and either under-, or mis-reporting of events of interest may have occurred. To estimate the risk of very rare adverse events, pharmacoepidemiological studies require very large numbers. Furthermore, the events in question need to be clinically recognisable by doctors and adequately documented in patients' notes, computer records, or on study questionnaires. The establishment of a national registry for drug-induced QT prolongation to identify cases and correlate clinical information may help to better identify these rare ADRs earlier. Such proactive surveillance could avoid unnecessary delays for other drugs where QT prolongation and serious cardiac arrhythmias may be an issue.