The pharmacokinetics and safety of desvenlafaxine in subjects with chronic renal impairment.

BACKGROUND: Desvenlafaxine (administered as desvenlafaxine succinate), the major active metabolite of venlafaxine, is a new serotonin-norepinephrine reuptake inhibitor (SNRI) approved for the treatment of major depressive disorder (MDD). OBJECTIVE: To assess the pharmacokinetics, safety, and tolerability of desvenlafaxine in healthy volunteers vs. those with renal impairment. MATERIALS AND METHODS: A single, oral, 100 mg dose of desvenlafaxine was administered to healthy subjects (n = 8) and subjects with mild (n = 9), moderate (n = 9), or severe (n = 7) renal impairment (24-h creatinine clearance, ml/min: 50 - 80, 30 - 50, or < 30 ml/min, respectively) or end-stage renal disease (ESRD; on dialysis.

Chiral bioequivalence: effect of absorption rate on racemic etodolac.

BACKGROUND: For many racemic drugs, bioequivalence assessment based on isomer-nonspecific assays is appropriate because enantiomeric area under the concentration-time curve (AUC) exposure ratios are close to unity. Use of nonspecific methods in cases in which the ratio is substantially greater or less than 1, however, may obscure real therapeutic differences among formulations, especially if the enantiomers exhibit differing pharmacological potencies. OBJECTIVE: To examine the influence of absorption rate on etodolac bioequivalence as measured by total [(R,S)-] and (S)-etodolac. DESIGN: Single dose, 3-period, crossover, pharmacokinetic study in 24 healthy volunteers in which the administration rate of etodolac was varied. METHODS: Participants received etodolac 400mg in solution, given as a single dose over 1 minute or as divided doses over 30 and 90 minutes. Unresolved and enantiomer concentrations of etodolac were measured by a validated HPLC assay. The enantiomer ratio was similarly measured by HPLC. RESULTS: Bioequivalence parameters derived for both unresolved and (S)etodolac indicate that peak plasma drug concentration (Cmax) was not bioequivalent. By delaying absorption, bioequivalence was lost. CONCLUSIONS: Collectively, these data demonstrate that bioequivalence between 2 products of etodolac based on enantiomerically nonspecific criteria alone may not generalise to the pharmacologically relevant (S)-enantiomer. This suggests that enantiospecific assays are necessary for bioequivalence assessments.

Pharmacokinetics of etodolac in patients with stable juvenile rheumatoid arthritis.

This was a single-center, open-label, single-dose pharmacokinetic study of etodolac in pediatric and adolescent patients with stable juvenile rheumatoid arthritis (JRA). Eleven male and female patients with JRA (8.1 to 14.8 years of age, weighing 26.4 to 59.5 kg) received a single oral dose of etodolac (200, 300, or 400 mg based on body weight). Clinical laboratory measurements, measurement of vital signs, and physical examinations were performed to monitor safety. Concentrations of etodolac were determined in plasma using high-performance liquid chromatography with ultraviolet detection with a limit of quantitation of 0.2 mg/L and were analyzed using a noncompartmental pharmacokinetic method. Pharmacokinetic parameters observed were consistent in magnitude and degree of variability with data from healthy adult subjects receiving a single 400- or 600-mg dose of etodolac. Although the mean fraction of unbound drug in patients with JRA was higher than in healthy adults, the oral clearance was independent of age. No serious adverse events occurred during this study. Etodolac yielded consistent pharmacokinetic values among stratified dose subgroups. Single doses of all etodolac treatments were well tolerated in both pediatric and adolescent patients.

The anthelmintic efficacy of netobimin against experimental infections of Fasciola hepatica in sheep.

Netobimin (coded SCH 32481, Schering Corporation), a new broad-spectrum anthelmintic having both fasciolicidal and nematocidal properties was evaluated for efficacy against mature Fasciola hepatica infections in sheep. The trial was conducted with 30 cross-bred spring lambs, each experimentally infected with 250 F. hepatica metacercariae. A single treatment of netobimin was administered at 17 weeks post-infection (PI) by oral drench at 7.5 or 20 mg kg-1 body weight while 10 animals remained as untreated controls. At necropsy (either 1 or 2 weeks post-treatment), the mean number of adult flukes recovered from the control, 7.5 and 20 mg kg-1 groups were 94.7, 35.9 and 8.8, respectively. The resulting efficacies were 62% (P less than or equal to 0.05) and 90.7% (P less than or equal to 0.01), respectively. No clinical signs of fascioliasis were noted in any sheep during the trial. No signs of toxicosis nor any adverse reactions to the drug were observed.

Anthelmintic efficacy of netobimin against naturally acquired gastrointestinal nematodes in yearling heifers.

The efficacy of netobimin (Coded SCH 32481, Schering Corporation) in removing naturally acquired gastrointestinal nematode infections was evaluated in 10 treated and 10 untreated (control) yearling beef heifers. The anthelmintic was administered as an oral drench at a dose level of 7.5 mg kg-1 body weight. Fecal egg per gram (EPG) counts were reduced with netobimin by 98% (P less than or equal to 0.01) at both 1 and 2 weeks post-treatment (PT). The compound was highly effective in removing Oesophagostomum radiatum (100% at P less than or equal to 0.01), Cooperia spp. (97.66% at P less than or equal to 0.01) and Nematodirus helvetianus (100%, although not significant), but was ineffective against immature Ostertagia ostertagi (3.19%) and only moderately effective against adult forms (66.14% at P less than or equal to 0.05). The low efficacy against adult O. ostertagi was partially attributed to the maturation of fourth-stage larvae, not removed by the 7.5 mg kg-1 treatment, during the 14-day treatment-slaughter interval. Efficacy against Trichuris spp. could not be evaluated due to low levels and unequal numbers of worms recovered in the groups. The overall efficacy against adult species, excluding Trichuris spp., was 67.40% (P less than or equal to 0.05). No adverse reactions or signs of toxicosis were observed in heifers treated with netobimin.

The anthelmintic efficacy of netobimin against naturally acquired gastrointestinal nematodes in sheep.

The broad-spectrum anthelmintic efficacy of netobimin (SCH 32481, Schering Corporation) was evaluated using 30 cross-bred spring lambs with naturally acquired infections of gastrointestinal nematodes. Three groups of 10 animals each were allotted into either control (given a tap water drench as a placebo) or 7.5 and 20 mg kg-1 dosage groups (given the netobimin as an oral drench). Seven to fourteen days post-treatment, animals were necropsied and nematodes recovered by standard techniques. Examination of fecal samples taken on dates of necropsy showed median egg production was reduced in treated animals (61.98% with 7.5 mg kg-1 and 100% with 20 mg kg-1). The compound was highly effective in removal of adult nematodes representing a number of genera and species of trichostrongyloids at the 7.5 and 20 mg kg-1 dose levels (shown, respectively, below). These included Ostertagia spp., with O. circumcincta, O. trifurcata, O. ostertagi and Teladorsagia davtiani (96.20%; 100%), Trichostrongylus spp., with T. axei, T. vitrinus and T. colubriformis (100%; 98.72%), Nematodirus spp., with N. spathiger, N. filicollis and N. battus (100% both levels) and Haemonchus contortus (100% both levels). High efficacies against other species of nematodes (at both dose levels) were not statistically significant (Cooperia spp., Chabertia ovina and Oesophagostomum venulosum). At 20 mg kg-1, netobimin significantly reduced populations of early and late fourth stage larvae of Ostertagia spp. by 100%. The overall efficacy (all life stages included) was 90.16% at 7.5 mg kg-1 and 98.77% at 20 mg kg-1 dose levels. No adverse reactions or signs of toxicosis were observed.

Techniques for observing fetal behavior in utero: a comparison of chemomyelotomy and spinal transection.

Two procedures--chemomyelotomy and spinal transection--have been utilized to chemically block or physically sever the spinal cord of pregnant rats, enabling direct observation of fetal behavior without the use of anesthesia. The effect of each procedure on fetal behavior was studied at four gestational ages (Days 17, 18, 19, and 20). Substantial differences in fetal activity were found between chemomyelotomy and spinal transection groups, including differences in the overall level of activity as well as the pattern of developmental change of behavior. Such differential effects indicate that chemomyelotomy and spinal transection are not equivalent maternal preparations in the study of fetal behavior.