Ocular hypotensive effect of fixed-combination brinzolamide/brimonidine adjunctive to a prostaglandin analog: a randomized clinical trial.

PurposeTo determine whether intraocular pressure (IOP) lowering with fixed-combination brinzolamide/brimonidine (BBFC) adjunctive to a prostaglandin analog (PGA) was superior to that of vehicle+PGA in patients with open-angle glaucoma or ocular hypertension who were inadequately controlled with PGA monotherapyMethodsThis 6-week, multicenter, randomized, double-masked, parallel-group trial was conducted at 30 clinical sites in the United States between October 2013 and May 2014. Eligible patients were adults with open-angle glaucoma or ocular hypertension and with mean IOP ≥21 and <32 mm Hg, whereas receiving an open-label PGA (latanoprost, bimatoprost, or travoprost). Patients instilled a PGA once-daily in a run-in phase before randomization to masked BBFC or vehicle adjunctive treatment. Masked treatments were instilled 3 times daily for 6 weeks, and patients continued once-daily use of their PGA. The primary efficacy end point was the between-group difference in mean diurnal IOP (average of 0800, 1000, 1500, and 1700 hours time points) at week 6.ResultsAt week 6, mean diurnal IOP with BBFC+PGA was lower than with vehicle+PGA (17.1±0.4 mm Hg vs 20.5±0.4 mm Hg; between-group difference, -3.4±0.5 mm Hg; P<0.0001; 95% confidence interval, -4.5 to -2.4 mm Hg). BBFC+PGA reduced mean diurnal IOP by 5.7 mm Hg (25%) from the baseline IOP achieved with PGA monotherapy.ConclusionsTherapy with BBFC produced an additive IOP-lowering effect compared with a PGA alone or in conjunction with vehicle. BBFC may provide an effective treatment option for patients receiving PGA monotherapy who require additional IOP reduction.

The receptor for the orexigenic peptide melanin-concentrating hormone is a G-protein-coupled receptor.

Gene-knockout studies of melanin-concentrating hormone (MCH) and its effect on feeding and energy balance have firmly established MCH as an orexigenic (appetite-stimulating) peptide hormone. Here we identify MCH as the ligand for the orphan receptor SLC-1. The rat SLC-1 is activated by nanomolar concentrations of MCH and is coupled to the G protein G alpha i/o. The pattern of SLC-1 messenger RNA expression coincides with the distribution of MCH-containing nerve terminals and is consistent with the known central effects of MCH. Our identification of an MCH receptor could have implications for the development of new anti-obesity therapies.

Effects of K+ channel blockers on the anoxic response of CNS myelinated axons.

Compound action potentials (CAPs) from adult rat optic nerves were recorded in vitro. The area under the CAP was compared before and after 1 h anoxia/reoxygenation. Resting compound membrane potential was measured using the cold grease-gap technique. The acute reduction of CAP magnitude by anoxia was unaffected by TEA (20 mM), 4-AP (300 microM), or the KATP blockers glibenclamide (300 microM) and tolbutamide (2 mM). Neither these K+ channel blockers, nor glipizide (100 microM) or the KATP activator diazoxide (500 microM) altered post-anoxic CAP area recovery. In contrast, although Cs+ (5 mM) accelerated anoxic CAP failure and membrane depolarization, this cation significantly increased CAP area recovery post-anoxia from 22+/-10% (s.d.) to 60+/-22% (p < 0.0001). The unique effects of Cs+ suggest that inward rectifier channels may play an important role in the induction of anoxic injury in optic nerve axons.

Fast and slow skeletal muscles express a common basic profile of acetylcholinesterase molecular forms.

Recent evidence suggests that the high content of acetylcholinesterase (AChE) globular form G4, characteristic of fast muscles, is controlled by phasic high-frequency activity performed by these muscles. This indicates that inactive, though still innervated, fast muscles should be devoid of their characteristic G4 pool. Accordingly, in the absence of phasic activity, both fast and slow muscles should exhibit a common basic profile of AChE molecular forms of the slow type. We first tested this hypothesis by examining the AChE content in cultures of myotubes obtained from the fusion of satellite cells originating from fast and slow muscles. These two cell populations produced AChE molecular-form profiles of the slow type characterized by modest levels of G4 together with an increased proportion of the asymmetric forms A8 relative to A12. Second, we determined the impact of muscle paralysis on the specific content of AChE molecular forms of adult rat fast and slow muscles. Complete paralysis of hindlimb muscles was achieved by chronic superfusion of tetrodotoxin (TTX) onto the sciatic nerve. Ten days after TTX inactivation, the distributions of AChE molecular forms of both fast extensor digitorum longus (EDL) and plantaris muscles were transformed into ones resembling the slow soleus, the latter showing no significant modifications in its AChE profile. Finally, we investigated the impact of nerve-mediated phasic high-frequency stimulation of TTX-inactivated fast and slow muscles on the content of AChE molecular forms. This stimulation produced a profile of AChE molecular forms similar to that observed in control EDL muscles, indicating that phasic activation counteracted the TTX-induced transformation in the distribution of AChE molecular forms in fast EDL muscles. Together, these results are consistent with the proposal that adult fast muscles constitutively express a basic profile of AChE molecular forms of the type displayed by slow muscles, onto which varying levels of G4 are added according to the amount of phasic activity performed by the muscles.

Mechanical stimulation increases expression of acetylcholinesterase in cultured myotubes.

We tested the hypothesis that acetylcholinesterase (AChE) expression in skeletal muscle cells is increased by passive mechanical stimulation. To this end, primary cultures of myotubes were subjected to repeated cycles of stretch-relaxation for 5 min, 30 min, 3 h, and 24 h, using the Flexercell FX-2000 strain unit. Although mechanical stimulation did not affect AChE expression at early time points, it led to a significant increase (42%; P < 0.05) in total AChE activity at 24 h. This increase reflected a general elevation in the activity of all AChE molecular forms as opposed to a preferential increase in a specific form. Tetrodotoxin (TTX) treatment did not prevent the increase in AChE expression, whereas nifedipine partially blocked it. These changes in enzyme expression were accompanied by increases in the levels of AChE mRNA, suggesting the involvement of pretranslational regulatory mechanisms. Together, these results illustrate that, in addition to neural activation and trophic factors, passive mechanical forces modulate expression of AChE in skeletal muscle cells. Because TTX did not prevent the increase in AChE expression, it appears that the effects of mechanical stimulation are independent of electrical activity, which further indicates the use of an alternate signaling pathway.