Pharmacokinetics and pharmacodynamics of the injectable formulation of methadone hydrochloride and methadone in lipid nanocarriers administered orally to horses

We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated‐measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed‐rank, adjusted by Bonferroni tests. Blood samples were also collected up to 6 h after dosing for plasma drug quantification by LC‐MS/MS. Methadone pharmacokinetic parameters were determined by noncompartmental and compartmental approaches. There were no differences in pharmacodynamic parameters. No statistical differences were observed in the pharmacokinetic parameters from noncompartmental analysis for both groups, except a significant decrease in peak plasma concentration, increase in apparent volume of distribution per fraction absorbed (Vd_ss/F) and increased mean residence time (MRT) for NANO. One‐compartment open model with first order elimination best described the pharmacokinetic profiles for both groups. Neither ORAL nor NANO administered orally to horses produced antinociception. The nanoencapsulated formulation of methadone given orally to horses did not improve methadone pharmacokinetic parameters or increased systemic body exposure to methadone.     

Lamprey GnRH‐III Releases Luteinizing Hormone but not Follicle Stimulating Hormone in Pigs

The effect of exogenous administration of lamprey GnRH‐III (IGnRH‐III) on gonadotropin secretion was evaluated in pigs. Six crossbred barrows (82.4 ± 3.5 kg body weight) were assigned randomly to a replicated 3 × 3 Latin square design to evaluate the effect of 0.1, 1.0 or 10.0 μg/kg body weight of exogenous IGnRH‐III on LH and FSH secretion. To facilitate blood collection and infusion of IGnRH‐III, barrows were catheterized in the jugular vein 1 day before initiation of experiments. Blood samples were taken at 10‐min intervals for 6 h, starting 2 h before treatments were applied. Relative concentrations of LH and FSH were calculated by obtaining the ratio of the average concentration of each hormone 2 h after infusion divided by the average concentration during the 2 h before infusion. Relative concentrations of FSH after IGnRH‐III infusion did not influence mean concentration of FSH at any of the doses; yet 10.0 μg/kg body weight had a significant effect on LH secretion (p < 0.01). Relative concentrations of LH averaged 1.2, 1.0 and 3.0 ng/ml (for doses of 0.1, 1.0 and 10.0 μg/kg body weight of IGnRH‐III respectively). Only a dose of 10 μg/kg body weight elicited a significant LH increase that was associated with exogenous IGnRH‐III infusion. We conclude that IGnRH‐III is a weak GnRH agonist and at high doses, IGnRH‐III has the ability to release LH but not FSH in barrows.     

Effects of methadone on the minimum alveolar concentration of isoflurane in dogs

ObjectiveTo investigate the effects of methadone on the minimum alveolar concentration of isoflurane (ISO_MAC) in dogs.Study designProspective, randomized cross-over experimental study.AnimalsSix adult mongrel dogs, four males and two females, weighing 22.8 ± 6.6 kg.MethodsAnimals were anesthetized with isoflurane and mechanically ventilated on three separate days, at least 1 week apart. Core temperature was maintained between 37.5 and 38.5 °C during ISO_MAC determinations. On each study day, ISO_MAC was determined using electrical stimulation of the antebrachium (50 V, 50 Hz, 10 mseconds) at 2.5 and 5 hours after intravenous injection of physiological saline (control) or one of two doses of methadone (0.5 or 1.0 mg kg^?1).ResultsMean (±SD) ISO_MAC in the control treatment was 1.19 ± 0.15% and 1.18 ± 0.15% at 2.5 and 5 hours, respectively. The 1.0 mg kg^?1 dose of methadone reduced ISO_MAC by 48% (2.5 hours) and by 30% (5 hours), whereas the 0.5 mg kg^?1 dose caused smaller reductions in ISO_MAC (35% and 15% reductions at 2.5 and 5 hours, respectively). Both doses of methadone decreased heart rate (HR), but the 1.0 mg kg^?1 dose was associated with greater negative chronotropic actions (HR 37% lower than control) and mild metabolic acidosis at 2.5 hours. Mean arterial pressure increased in the MET1.0 treatment (13% higher than control) at 2.5 hours.Conclusions and clinical relevanceMethadone reduces ISO_MAC in a dose-related fashion and this effect is lessened over time. Although the isoflurane sparing effect of the 0.5 mg kg^?1 dose of methadone was smaller in comparison to the 1.0 mg kg^?1 dose, the lower dose is recommended for clinical use because it results in less evidence of cardiovascular impairment.     

Complex interplay between intrinsic and extrinsic drivers of long-term survival trends in southern elephant seals

Background  

Determining the relative contribution of intrinsic and extrinsic factors to fluctuations in population size, trends and demographic composition is analytically complex. It is often only possible to examine the combined effects of these factors through measurements made over long periods, spanning an array of population densities or levels of food availability. Using age-structured mark-recapture models and datasets spanning five decades (1950–1999), and two periods of differing relative population density, we estimated age-specific probabilities of survival and examined the combined effects of population density and environmental conditions on juvenile survival of southern elephant seals at Macquarie Island.     

Heterozygote detection for maple syrup urine disease in cattle

SUMMARY The clinical, pathological and biochemical manifestations of maple syrup urine disease (MSUD) are similar in Poll Hereford and Poll Shorthorn X Poll Hereford calves. No significant differences were observed in branched-chain amino acid concentrations in plasma, or of branched-chain keto acid dehydrogenase activity in fibroblasts, between Poll Herefords homozygous normal and heterozygous for the mutation responsible for MSUD. Haemopoietic chimerism resulted in incorrect diagnosis of the MSUD genotype in 30% of non-identical twins when blood DNA was analysed using allele-specific amplification. Hair roots are shown to be a suitable source of target DNA for genotyping Poll Hereford cattle for the MSUD mutation. Twelve of 203 (5.8%) aged Poll Hereford bulls, sampled at saleyards during the last 4 months of 1993, were found to be heterozygous for the mutation. In contrast, the mutant sequence was detected in only 1 of 150 (0.7%) 2- and 3-year-old Poll Hereford bulls offered for sale at 2 stud sales held during 1993, suggesting that the prevalence of the disease may decline over the next few years.     

Progressive ethmoidal haematoma in horses

Progressive ethmoidal haematoma was diagnosed in 12 Thoroughbreds, 1 part- Arab and 1 stock horse. Ages ranged from 3 to 18 years and both males and females were affected. Diagnosis was based on history, clinical signs, endoscopic and radiographic findings, and was confirmed histologically in 10 cases. Eleven (78%) of the lesions were unilateral and 3 (22%) were bilateral. Two horses were euthanased on diagnosis, 4 were treated conservatively. Of the latter, 3 were euthanased 6 to 24 months after diagnosis, due to progression of the lesions, while 1 case resolved completely within 13 months. Eight horses were treated by surgical excision of the lesion. Three died in the post-operative period, 3 were euthanased within 48 months after recurrence of the condition, and 2 had no recurrence within 60 and 72 months, respectively.