Population pharmacokinetics of mefloquine in military personnel for prophylaxis against malaria infection during field deployment.

OBJECTIVE: The purpose of this study was to determine the population pharmacokinetics of mefloquine in healthy military personnel during prophylaxis for malaria infections. METHODS: The subjects were 1,111 Australian soldiers participating in two studies: a randomised double-blinded study (group A, 161 subjects) and an open-label study (group B, 950 subjects). Following a loading dose (250 mg mefloquine base daily, 3 days), subjects received an oral weekly maintenance dose of 250 mg over 6 months. Blood was collected after the last split loading dose then at weeks 4, 8 and 16 for group A, and at weeks 13 and 26 for group B. Plasma mefloquine concentrations were measured by high-performance liquid chromatography (HPLC). Pharmacokinetic modelling was performed using NONMEM. RESULTS: A two-compartment model with inter-occasion variability (IOV) for clearance satisfactorily described the pharmacokinetics. Typical values were clearance (CL/F, 2.09 l/h), central volume of distribution (V1/F, 528 l), absorption rate constant (KA, 0.24 h(-1)), inter-compartmental clearance (Q/F, 12.5 l/h), peripheral volume of distribution (V2/F, 483 l) and elimination half-life (t (1/2), 14.0 days). Weight had a positive influence on central volume but was insufficient to warrant dosage adjustments. The inter-individual variability (coefficient of variation, CV%) for CL/F and V1/F was 24.4% and 29.6%, respectively. The IOV for CL/F was 17.8%. The proportional residual error (CV%) for groups A and B was 11.5% and 19.5%, respectively, and the additive error standard deviation (SD) was 57 ng/ml and 149 ng/ml, respectively. CONCLUSION: The typical parameter values were comparable with those estimated in much smaller cohorts of healthy subjects and in malaria patients treated with single-dose mefloquine. The lower unexplained variability in the blinded study suggested these subjects may have been more compliant in taking their medication than soldiers in the open-label study.

Use of the GnRH analogue, deslorelin acetate, in a slow-release implant to accelerate ovulation in oestrous mares.

In two separate controlled clinical trials, the efficacy and safety of 2.2 mg of the GnRH analogue deslorelin, administered subcutaneously as a short-term implant to normally cycling mares in oestrus with a dominant ovarian follicle more than 30 mm in diameter, were evaluated, using a placebo as a negative control. The oestrous cycle of each mare was followed by teasing, palpation per rectum and transrectal ultrasonography. Follicles were monitored every 24 hours by ultrasonography until ovulation occurred. The mares were either mated naturally or inseminated artificially. In trial 1, 174 mares were treated at six locations in Canada, and in trial 2, 98 mares were treated at three locations in the USA. In trial 1, the treatment with deslorelin reduced the mean (sd) time to ovulation from 84.2 (48.4) hours to 50.2 (19.6) hours (P < 0.001) and in trial 2 it reduced it from 88.8 (40.3) hours to 54.1 (26.5) hours (P < 0.001). In trial 1, the percentage of mares ovulating within 48 hours increased from 37.7 per cent in control mares to 86.1 per cent in treated mares (P < 0.001) and in trial 2 the percentage increased from 26.5 to 80.9 per cent (P < 0.001). In trial 2, the duration of oestrus in the deslorelin-treated mares was reduced from 6.1 days to 4.3 days and the number of matings or artificial inseminations was reduced from 2.5 to 1.7 (P < 0.001). In trial 1, days 12 to 20 pregnancy rates for matings at the treatment oestrus were not different for deslorelin-treated (75.6 per cent) and placebo-treated (66.1 per cent) mares. In trial 2, days 12 to 20 pregnancy rates from matings at the treatment oestrus were lower for deslorelin-treated (58.7 per cent) than for placebo-treated (83.3 per cent) mares (P < 0.05), although pregnancy rates were similar for deslorelin-treated (97.1 per cent) and placebo-treated (95.0 per cent) mares after mating at the second oestrus. In both trials, pregnancy losses due to early or late abortions were within the normally expected range and similar for deslorelin-treated (3.6 and 3.7 per cent, respectively) and placebo-treated (13.4 and 7.5 per cent) mares. The treatments did not cause systemic side effects and local reactions at the implantation sites were slight and of short duration.

Synchronization of estrus after treatment with Luprostiol in beef cows and in beef and dairy heifers.

Four trials were conducted to study synchronous estrous response in beef cows and in beef and dairy heifers to Luprostiol (13, thia-PG-F(2)alpha analog) in comparison with other prostaglandin products. In Trial 1, 60 virgin beef heifers were observed for estrus for 5 d and artificially inseminated. Heifers not observed in estrus within 5 d were randomly assigned to receive 15 mg Luprostiol or 25 mg Lutalyse. In Trial 2, 75 multiparous, lactating beef cows were randomly assigned to receive either 15 mg Luprostiol, 25 mg Lutalyse or 500 mcg Estrumate. All cows received a second injection of the respective treatment 11 d later. In Trial 3, 96 multiparous, lactating beef cows were randomly assigned to receive 15 mg Luprostiol or 25 mg Lutalyse. All cows received a second injection of the respective treatment 11 d later. In Trial 4, virgin dairy heifers were palpated per rectum. Seventy-seven heifers with a palpable corpus luteum (CL) were randomly assigned to receive 15 mg Luprostiol or 500 mcg Estrumate. In all trials animals were artificially inseminated 12 h following observed estrus. Estrous response during the 5-d synchronized period was 44% for Luprostiol and 42% for Lutalyse treated heifers in Trial 1. It was 52, 56 and 60%, respectively, for Luprostiol, Lutalyse and Estrumate treated cows in Trial 2; 23% for Luprostiol and 19% for Lutalyse treated cows in Trial 3; and 68% for Luprostiol and 70% for Estrumate treated heifers in Trial 4. Treatment with Luprostiol results in a similar synchronous estrous response as with the other prostaglandin products used in these studies.