Effect of butafosfan supplementation during oocyte maturation on bovine embryo development.

Around 60-80% of oocytes maturated in vivo reached competence, while the proportion of maturation in vitro is rarely higher than 40%. In this sense, butafosfan has been used in vivo to improve metabolic condition of postpartum cows, and can represent an alternative to increase reproductive efficiency in cows. The aim of this study was to evaluate the addition of increasing doses of butafosfan during oocyte maturation in vitro on the initial embryo development in cattle. In total, 1400 cumulus-oocyte complexes (COCs) were distributed in four groups and maturated according to supplementation with increasing concentrations of butafosfan (0 mg/ml, 0.05 mg/ml, 0.1 mg/ml and 0.2 mg/ml). Then, 20 oocytes per group were collected to evaluate nuclear maturation and gene expression on cumulus cells and oocytes and the remaining oocytes were inseminated and cultured until day 7, when blastocysts were collected for gene expression analysis. A dose-dependent effect of butafosfan was observed, with decrease of cleavage rate and embryo development with higher doses. No difference between groups was observed in maturation rate and expression of genes related to oocyte quality. Our results suggest that butafosfan is prejudicial for oocytes, compromising cleavage and embryo development.

Safety and efficacy of GSK2248761, a next-generation nonnucleoside reverse transcriptase inhibitor, in treatment-naive HIV-1-infected subjects.

GSK2248761 is a novel, once-daily (QD), next-generation nonnucleoside reverse transcriptase inhibitor (NNRTI) with activity against efavirenz-resistant strains. Two phase I/IIa, double-blind, randomized, placebo-controlled studies investigated the antiviral activity, safety, and pharmacokinetics (PK) of several doses of GSK2248761 monotherapy in treatment-naive HIV-infected subjects. In the initial study, 10 subjects (8 active and 2 placebo) per dose received sequentially descending GSK2248761 monotherapy regimens of 800, 400, 200, and 100 mg QD for 7 days. Because a dose-response relationship was not identified, a second study examined a lower, 30-mg QD dose in 8 subjects (6 active and 2 placebo). Adverse events, viral load (VL), PK, and reverse transcriptase mutations were assessed and combined for analysis. Treatment with GSK2248761 for 7 days was well tolerated with no serious adverse events or discontinuations. The mean VL reductions from baseline on day 8 were 0.97, 1.87, 1.84, 1.81, and 1.78 log(10) copies/ml for GSK2248761 doses of 30, 100, 200, 400, and 800 mg QD, respectively. GSK2248761 PK (maximum drug concentration in serum [C(max)], area under the plasma concentration-time curve from 0 h to the end of the dosing interval [AUC(0-τ)], and concentration at the end of the dosing interval [C(τ)]) increased proportionally over the dose range of 30 to 800 mg QD. The relationship between short-term VL change and GSK2248761 PK was best described by a maximum-effect (E(max)) model using C(τ) (E(max) = 2.0; 50% effective concentration [EC(50)] = 36.9 ng/ml). No NNRTI resistance mutations emerged during the study. GSK2248761 at 100 to 800 mg QD for 7 days was well tolerated, demonstrated potent antiviral activity in treatment-naive HIV-infected subjects, and had favorable PK and resistance profiles. GSK2248761 is no longer in clinical development.

GABA(A) ρ receptor mechanisms in the rat amygdala and its role in the modulation of fear and anxiety.

RATIONALE: Accumulating evidence for the presence of GABA(A) ρ receptors within the amygdala which differ from other members of the GABA(A) receptor family in both subunit composition and functional properties has been recently obtained. OBJECTIVES: This work was conducted to study whether GABA(A) ρ receptors may have a putative role in the amygdaloid modulation of fear and anxiety. RESULTS: It was found that the bilateral intra-amygdaloid administration (6-240 pmol/side) of (1,2,5,6-tetrahydropyridine-4-yl)methylphosphinic acid, a selective GABA(A) ρ receptor antagonist, reduced dose-dependently the exploration of the open arms of the elevated plus-maze without affecting locomotion and increased the plasma levels of corticosterone. In contrast, bicuculline in the dose range used (1.8-60 pmol/side) induced seizures, but had no effects on the exploration of the maze. CONCLUSIONS: It is suggested that GABA(A) ρ receptors may have a role in the amygdaloid modulation of fear and anxiety.

The conditioned eyeblink response: a role for the GABA-B receptor?

In well-trained animals, infusion of the GABA-B agonist baclofen into the cerebellar interpositus nucleus and overlying cortex abolished the conditioned response (CR) with no effect on the unconditioned response (UR) with doses at or above 5.0 mM. Infusion of the GABA-B antagonist CGP 5584-5A alone had no effect on the CR or UR. However, administration of 5 mM baclofen soon after infusion of CGP 5584-5A (15 min) resulted in no reduction of percent CR and only partial reduction of CR amplitude. Naive animals given interpositus infusions of baclofen during training showed no learning, yet learned normally in postinfusion training. The distribution of (radiolabelled) baclofen was localized and remained within the cerebellum. The results presented here are consistent with a growing body of literature supporting the hypothesis that the memory trace for eyeblink conditioning is formed and stored in the cerebellum and may involve GABAergic mechanisms.