Clopidogrel and Gemfibrozil Strongly Inhibit the CYP2C8-Dependent Formation of 3-Hydroxydesloratadine and Increase Desloratadine Exposure In Humans.

A recent in vitro study suggested that CYP2C8 is essential in the metabolism of desloratadine, an H1 receptor antagonist. If the proposed biotransformation mechanism takes place in vivo in humans, desloratadine could serve as a selective CYP2C8 probe substrate in drug-drug interaction studies. Glucuronide metabolites of clopidogrel and gemfibrozil act as time-dependent inhibitors of CYP2C8, but they have not been compared clinically. We conducted a randomized crossover study in 11 healthy subjects to characterize the involvement of CYP2C8 in desloratadine metabolism and to compare the CYP2C8 inhibitory strength of clopidogrel (300 and 75 mg on two following days) with that of gemfibrozil (600 mg BID for 5 days). Compared with placebo (control), clopidogrel increased the area under the plasma concentration-time curve (AUC0-∞) and peak plasma concentration (C max) of desloratadine to 280% (P = 3 × 10-7) and 165% (P = 0.0006), respectively. The corresponding increases by gemfibrozil were to 462% (P = 4 × 10-7) and 174% (P = 0.0006). Compared with placebo, clopidogrel and gemfibrozil decreased 3-hydroxyloratadine AUC0-71h to 52% (P = 5 × 10-5) and 6% (P = 2 × 10-8), respectively. Moreover, the 3-hydroxydesloratadine:desloratadine AUC0-71 h ratios were 21% (P = 7 × 10-10) and 1.7% (P = 8 × 10-11) of control during the clopidogrel and gemfibrozil phases. Our results confirm that CYP2C8 plays a critical role in the formation of 3-hydroxydesloratadine in humans, making desloratadine a potential CYP2C8 probe substrate. Furthermore, the findings corroborate the previous estimates that clinically relevant doses of clopidogrel cause strong CYP2C8 inhibition, whereas those of gemfibrozil almost completely inactivate the enzyme in humans.

Pharmacological evaluation of Convolvulus pluricaulis as hypolipidaemic agent in Triton WR-1339-induced hyperlipidaemia in rats.

OBJECTIVE: The aim of the study was to evaluate the effect of Convolvulus pluricaulis (CP; C. pluricaulis) methanolic extract on Triton WR-1339-induced hyperlipidaemia in rats. METHODS: The study comprised of six groups namely normal control, experimental control and treatment groups (100, 200 and 400 mg/kg of C. pluricaulis, and 65 mg/kg of Fenofibrate). Hyperlipidaemia was induced by a single intraperitoneal injection of Triton WR-1339 400 mg/kg in rats. Parameters such as lipid profile, oxidative stress, histological analysis and atherogenic index were evaluated. The plant extract was further studied by HPLC and LCMS, for analyses of active phytochemicals. KEY FINDINGS: The result of the study showed that C. pluricaulis significantly decreased total cholesterol, triglycerides, LDL-c, MDA levels and atherogenic index while the levels of HDL-c and GSH were found to be raised. Plant extract at the dose of 400 mg had a consistent effect on all lipid profile parameters. Lower doses (100 and 200 mg) did not produce a statistically significant reduction in LDL-c. In addition, the protective effect of C. pluricaulis was confirmed by histological analysis. Further, the findings of the study were found to be comparable with fenofibrate. CONCLUSIONS: Therefore, the present study suggests that C. pluricaulis has the potential for the treatment of hyperlipidaemia.

Adult prescription drug use and pediatric medication exposures and poisonings.

BACKGROUND AND OBJECTIVES: Nontherapeutic medication ingestions continue to be a major pediatric health problem, with recent increases in ingestions despite a number of public health interventions. It is unknown how changes in adult prescription drug use relate to pediatric medication poisonings. The objective of the study was to measure the association between changing adult prescription drug patterns and pediatric medication exposures and poisonings and identify high-risk classes of medications and pediatric age groups. METHODS: We measured monthly pediatric exposures and poisonings using the National Poison Data System and prescriptions written for adults using the National Ambulatory Medical Care Surveys for 2000 through 2009. Associations between adult prescriptions for oral hypoglycemics, antihyperlipidemics, ß-blockers, and opioids and exposures and poisonings among children 0 to 5, 6 to 12, and 13 to 19 years were analyzed by using multiple time-series analysis. Emergency department visits, serious injuries, and hospitalizations stemming from these associations were described. RESULTS: Adult medication prescriptions were statistically significantly associated with exposures and poisonings in children of all ages, with the strongest association observed for opioids. Across medications, the greatest risk was among children 0 to 5 years old, followed by 13- to 19-year-olds. Rates of emergency department visits were highest for events related to hypoglycemics (60.1%) and ß-blockers (59.7%), whereas serious injuries and hospitalizations occurred most frequently with opioids (26.8% and 35.2%, respectively) and hypoglycemics (19.5% and 49.4%, respectively). CONCLUSIONS: Increasing adult drug prescriptions are strongly associated with rising pediatric exposures and poisonings, particularly for opioids and among children 0 to 5 years old. These associations have sizable impacts, including high rates of serious injury and health care use.

Gemfibrozil ingestions reported to Texas poison control centers, 2000-2005.

Review of the literature failed to identify any information on potentially adverse ingestions of the cholesterol-lowering drug gemfibrozil (GEM) reported to poison control centers. Data from Texas poison control centers were used to describe the pattern of isolated GEM ingestions reported during 2000-2005. A total of 118 cases were identified. The mean maximum dose ingested was 2407 mg (range 300-18,000 mg) or 3.3 tablets/capsules (range 1-30 tablets/capsules). The patient was male in 55% of the cases. The most common circumstances of the exposure were unintentional therapeutic error (49%), general unintentional (34%), and suspected attempted suicide (11%). The management site was on site (84%), already at/en route to a health care facility (10%), referred to a health care facility (5%), and other (2%). The ingestion considered potentially toxic in 3% of the cases and no deaths were reported. A specific adverse clinical effect was listed for 9% of the cases, being gastrointestinal (5%), neurological (3%), or cardiovascular (1%). A specific treatment was listed for 54% of the cases, most frequently decontamination by dilution (39%) or food (15%). Potentially adverse isolated GEM ingestions reported to poison control centers generally do not involve serious medical outcomes and are successfully managed at home with a favorable outcome.