DEVELOPMENT AND VALIDATION OF DESLORELIN ACETATE ASSAY AND A PILOT STUDY ON THE PHARMACOKINETICS OF DESLORELIN ACETATE IMPLANTS AND FECAL HORMONE MONITORING IN THE DOMESTIC GOAT (CAPRA HIRCUS).

Short-term clinical and hormonal effects of a deslorelin implant on late-prepubertal bitches – Based on flare-up signs

Male cownose rays (Rhinoptera bonasus) can display aggressive behaviors toward other conspecifics. This can lead to accidental, self-inflicted trauma to the subordinate ray attempting to flee, such as rostral or ocular abrasions and ulcerations. Gonadotropin releasing hormone (GnRH) agonists, such as deslorelin acetate (Suprelorin®), are commonly used among mammals for both reproductive management and behavioral mitigation, such as aggression in males. However, limited work has been done to advance our understanding of GnRH agonists in elasmobranchs. In an attempt to mitigate aggression, the use of deslorelin was investigated in three adult male cownose rays, that were implanted with either one (two rays) or two (one ray) 9.4 mg deslorelin implants. Another male ray was not implanted and used as the "control" male. Blood was collected from each ray prior to implantation, and then at various timepoints over 24 months, to evaluate plasma testosterone concentrations. Plasma testosterone was measured via enzyme immunoassay which was validated for this species. Behavior was monitored daily. The three males that received implants all had higher testosterone concentrations than the control animal two weeks to 24 months post-implantation. The ray that received two 9.4 mg implants displayed dose-dependent 50 to 100% higher concentrations compared to the two rays that received only one 9.4 mg implant. Testosterone concentrations in the control male were similar to previous published results. Implanted rays displayed increased aggressive and reproductive behaviors, that were not suppressed throughout the study. Female rays continued to be chased throughout the year, with some sustaining self-inflicted rostral abrasions requiring medical management. The deslorelin implants produced a persistent stimulation of testosterone production with no sign of suppression after two years. Based on the continued and sometimes enhanced unwanted aggressive behaviors, and failure of testosterone suppression, deslorelin is not recommended in male cownose rays for aggression and reproductive behavior mitigation.

Hormonal contraception is being increasingly used to manage captive animals in zoological collections. Many of the animals placed on contraception are of genetic importance within captive breeding programs; therefore, it is imperative that the application of contraceptive products minimize potential side effects and facilitate a return to fertility if required. Deslorelin acetate implants (Suprelorin®) are one example of a hormonal contraceptive that is frequently used in captivity as they are easy to use and effective in most species. It is hypothesized that removing implants may hasten reversal of contraception treatment; therefore, placement in a location where they can easily be recovered is advocated. In this report, the efficacy and safety of Suprelorin implants placed in their recommended site between the scapulae is compared with alternative placement sites where implants can more easily be located for removal. Using the European Association of Zoos and Aquariums (EAZA) Group on Zoo Animal Contraception (EGZAC) Contraception Database, rates of success, failure, and reversal in 561 records of Suprelorin use in European collections are compared. Of these, 357 have information relating to the location of implant placement. When correctly applied, rates of efficacy were high (>99%) irrespective of placement site. Rates of reversal were 33.3% higher in alternative placement sites, although in most cases it is unknown whether implants were removed or not. In conclusion, the placement of Suprelorin implants in alternative sites does not negatively affect the efficacy, facilitating at the same time implant removal, minimizing potential side effects, and reducing reversal time, allowing for effective use in captive conservation breeding programs.

Vasopressin (AVP) and corticotropin-releasing factor (CRF) are key mediators in the organism's neuro-adaptive response to stress. Through pituitary and central vasopressin V(1b) receptors, AVP participates in the control of the hypothalamic-pituitary-adrenal axis (HPA) and is involved in various emotional processes. SSR149415 is the first selective, orally active vasopressin V(1b) receptor antagonist yet described. It is a competitive antagonist with nanomolar affinity for animal and human V(1b) receptors and displays a highly selective profile with regard to a large number of receptors or enzymes. In vitro, SSR149415 potently antagonizes functional cellular events associated with V(1b) receptor activation by AVP, such as intracellular Ca(2+) increase or proliferation in various cell systems. Pharmacological studies, performed by measuring ACTH secretion induced by various stimulants such as hormones (AVP or AVP + CRF) or physical stress (restraint or forced swimming stress and dehydration) in conscious rats or mice, confirm the antagonist profile of SSR149415 and its efficacy in normalizing ACTH secretion in vivo. SSR149415 is active by the oral route, at doses from 3 mg/kg, it potentiates CRF effect and displays a long-lasting oral effect in the different models. At 10 mg/kg p.o. its duration of action is longer than 4 h. This molecule also decreases anxiety and exerts marked antidepressant-like activity in several predictive animal models. The anxiolytic effects of SSR149415 have been demonstrated in various Generalized Anxiety Disorders (GAD) models (four-plate, punished drinking, elevated plus-maze, light dark, mouse defense test battery, fear-potentiated startle and social interaction tests). It is as effective as the benzodiazepine diazepam in the acute stress exposure test. SSR149415 has similar efficacy to the reference antidepressant drug, fluoxetine, in acute (forced-swimming) and chronic (chronic mild stress and subordination stress) situations in rodents. SSR149415 also reduces offensive aggression in the resident-intruder model in mice and hamsters. Depending on the model, the minimal effective doses are in the range of 1-10 mg/kg i.p. or 3-10 mg/kg p.o. SSR149415 is devoid of adverse effects on motor activity, sedation, memory or cognitive functions and produces no tachyphylaxis when administered repeatedly. It is well-tolerated in animals and humans and exhibits an adequate ADME profile. Thus, SSR149415 is a new dual anxiolytic/antidepressant compound, which appears to be free of the known side effects of classical anxiolytic/antidepressant drugs. Clinical trials are in progress, they will hopefully demonstrate its therapeutical potential for treating stress-related disorders.

Effect of various psychotropic drugs on the performance of avoidance and escape behaviors in rats

Naltrexone is used to antagonise etorphine immobilisation, but a safe and effective dose for this purpose has not been objectively determined. Eight domestic goats were immobilised with etorphine (0.07 mg/kg)...

Indacaterol is a novel, inhaled, once-daily, ultra-long-acting β2-adrenoceptor agonist that has been approved in the EU for the treatment of chronic obstructive pulmonary disease (COPD). Ethnic differences may influence the pharmacokinetics and pharmacodynamics of a drug, and it is therefore important to compare these parameters in different populations. To compare the efficacy, safety and pharmacokinetics of indacaterol between Caucasian and Japanese patients with COPD. Data from two randomized, double-blind, single-dose crossover, placebo-controlled studies in Caucasian and Japanese patients with moderate-to-severe COPD were compared. The two studies were similar in terms of study design, study population (inclusion/exclusion criteria), parameters examined and the indacaterol doses (150, 300 or 600 μg) tested. Efficacy (primary endpoint: 24-hour post-dose [trough] forced expiratory volume in 1 second [FEV1]), pharmacokinetics, and safety were assessed for 24 hours post-dose in each treatment period. Fifty-one Caucasian (86.3% male; mean age 61.8 years) patients were randomized into the first study and 50 Japanese (92.0% male; mean age 67.2 years) patients were randomized into the second study; ≥90% of patients completed the studies. In both studies, 24-hour post-dose trough FEV1 was significantly higher for all indacaterol doses versus placebo (p<0.001), with clinically relevant differences of 140 and 130 mL for the lowest (150 μg) dose in the Caucasian and Japanese studies, respectively. In both studies, single doses of indacaterol provided improvements in FEV1 that were sustained for 24 hours (p<0.001 vs placebo at all time points). In both populations, the average maximum serum concentration (Cmax) of indacaterol was observed at the first sampling time point and pharmacokinetic profiles were similar between populations. The increase in exposure (Cmax and area under the serum concentration-time curve from time zero to 24 hours) with increasing indacaterol dose was similar in both populations. All indacaterol doses in both studies demonstrated similar safety profiles. Indacaterol provided 24-hour bronchodilation with a fast onset of action and similar pharmacokinetic and safety profiles in Caucasian and Japanese patients. These findings suggest that ethnic factors do not influence the treatment of COPD with indacaterol.

Metabolism and pharmacokinetics of the combination Zidovudine plus Lamivudine in the adult Erythrocebus patas monkey determined by liquid chromatography-tandem mass spectrometric analysis

Long-term suppression of fertility in female giraffe using the GnRH agonist deslorelin as a long-acting implant

The effect of small intravenous doses (0.025 and 0.05 mg) of glucagon was evaluated in 22 patients. All 12 patients given 0.05 mg demonstrated by hypotonicity of the stomach and duodenum at 1 min and beginning return of peristalsis at 2 1/2 min. Subsequently, 100 patients with radiographically normal upper gastrointestinal examinations who received 0.05 mg of glucagon intravenously were compared to 100 patients with normal examinations without it. Comparison was made to determine the effect of glucagon on gastric mucosal coating and distention of the stomach and duodenum. In all areas of the stomach, mucosal coating was significantly improved in the glucagon group. There was also increased distention of the distal antrum, duodenal bulb, and duodenal loop. No adverse effects were reported. Because of the short duration of action of glucagon, the examination needs to be coordinated and done rapidly. The routine use of a small dose of glucagon increased the performance time slightly with small additional cost but was compensated for by the increased diagnostic quality of the examination.

Minimum effective dose of spinal ropivacaine with and without fentanyl for postpartum tubal ligation