In vivo comparative study of ocular vasodilation, a relative indicator of hyperemia, in guinea pigs following treatment with bimatoprost ophthalmic solutions 0.01% and 0.03%

Abayomi B Ogundele, David Earnest, Marsha A McLaughlinAlcon Research, Limited, Fort Worth, TX, USAObjective: The objective of this in vivo study was to compare the incidence of vasodilation in guinea pigs following topical administration of bimatoprost ophthalmic solutions 0.01% and 0.03%.Methods: The study comprised 20 guinea pigs assigned to 2 treatment groups (10 per treatment group) to receive either bimatoprost 0.01% or bimatoprost 0.03%. Animals were hand-held under 2.75 × magnification to score ocular vasodilation (a measure of hyperemia), using a scoring system developed at Alcon Research, Ltd. Following baseline ocular scoring, each animal received a 30 μL dose to the left eye of either bimatoprost 0.01% (3 μg) or bimatoprost 0.03% (9 μg). Vasodilation was again scored at 1, 2, 3, 4, 5 and 6 hours after dosing. Incidence of vasodilation was calculated as the percent of total eyes in each 2-hour time interval with scores ≥2.Results: The incidence of vasodilation was higher in the bimatoprost 0.01% treatment group (range, 45.0% to 60.0%) than the bimatoprost 0.03% treatment group (range, 30.0% to 52.2%) at all post-dosing time points.Conclusion: The 2 bimatoprost formulations elicited ocular vasodilation of long duration (>6 hours) in the guinea pig model, with the bimatoprost 0.01% treatment group showing a higher incidence of ocular vasodilation than the bimatoprost 0.03% treatment group. Further clinical studies would be needed to determine whether the higher incidence of vasodilation may also be attributed to the increased BAK concentration in the bimatoprost 0.01% formulation.Keywords: bitamoprost, ocular vasodilation, hyperemi

Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Density, distribution, and status of the kit fox in Trans-Pecos, Texas

Vita.A survey was made in Trans-Pecos, Texas from August 1976 to August 1978 to determine the distribution and density of the kit fox (Vulpes macrotis neomexicana). Kit foxes are found in all counties west of the Pecos River. Their population numbers between 2,400 and 12,000 adults on 3.2 x 10⁶ ha of suitable habitat. Several methods for locating foxes were evaluated; night-lighting, predator calling, and grid ground-searching. None of these methods appears to be adequate in finding kit fox concentrations in the large, isolated regions of the Trans-Pecos. Between November 1977 and August 1978 a study was conducted on individual kit foxes on an area near Sanderson, Texas on the east side pf Brewster County. Eight kit foxes were trapped; 4 were tagged with radio collars. Each tagged fox lived in a different den. Kit foxes trapped during this study weighed an average of 1.75 kg. Total body length was 745mm, hindfoot length was 123 mm, and ear length from notch to tip was 75 mm. An average of 8 h was spent outside the den each day by a kit fox. Sixty percent of this time was spent foraging in the washes. At least 25% of a kit fox's day was spent hunting. Two vegetative types were used by a kit fox within its range. Desert scrubland was utilized for denning and vegetated washes were utilized for hunting. Vegetation on the denning areas was sparse and there were few small animals present. The washes were heavily vegetated and supported more small animals. Kit foxes are not in danger of extinction in Texas at this time. Their numbers should remain stable if trapping and predator control do not increase and suitable habitat does not decrease

Density, distribution, and status of the kit fox in Trans-Pecos, Texas

Vita.A survey was made in Trans-Pecos, Texas from August 1976 to August 1978 to determine the distribution and density of the kit fox (Vulpes macrotis neomexicana). Kit foxes are found in all counties west of the Pecos River. Their population numbers between 2,400 and 12,000 adults on 3.2 x 10⁶ ha of suitable habitat. Several methods for locating foxes were evaluated; night-lighting, predator calling, and grid ground-searching. None of these methods appears to be adequate in finding kit fox concentrations in the large, isolated regions of the Trans-Pecos. Between November 1977 and August 1978 a study was conducted on individual kit foxes on an area near Sanderson, Texas on the east side pf Brewster County. Eight kit foxes were trapped; 4 were tagged with radio collars. Each tagged fox lived in a different den. Kit foxes trapped during this study weighed an average of 1.75 kg. Total body length was 745mm, hindfoot length was 123 mm, and ear length from notch to tip was 75 mm. An average of 8 h was spent outside the den each day by a kit fox. Sixty percent of this time was spent foraging in the washes. At least 25% of a kit fox's day was spent hunting. Two vegetative types were used by a kit fox within its range. Desert scrubland was utilized for denning and vegetated washes were utilized for hunting. Vegetation on the denning areas was sparse and there were few small animals present. The washes were heavily vegetated and supported more small animals. Kit foxes are not in danger of extinction in Texas at this time. Their numbers should remain stable if trapping and predator control do not increase and suitable habitat does not decrease

Effects of rho kinase inhibitors on intraocular pressure and aqueous humor dynamics in nonhuman primates and rabbits

Purpose: This study examines the effects of 2 Rho kinase inhibitors on intraocular pressure (IOP) and aqueous humor dynamics. Methods: IOPs of New Zealand albino rabbits with ocular normotension and cynomolgus macaques (nonhuman primate, NHP) with chronic unilateral laser-induced glaucoma were measured at baseline and periodically after a 9 a.m. dose of H-1152, Y-27632, or vehicle. In a separate group of NHPs, aqueous flow, outflow facility, uveoscleral outflow, and IOP were determined after treatment with Y-27632 or vehicle control. Results: Decreases in IOP were found in rabbits (n = 5) at 6 h after one dose of 2% Y-27632 (29%, P = 0.0002) or 1% H-1152 (35%, P = 0.0001), and in hypertensive eyes of NHPs (n = 7-9) at 3 h after one dose of 2% Y-27632 (35%, P = 0.005) or 1% H-1152 (51%, P = 0.0003). With 2 doses of 1% Y-27632 or vehicle in NHP hypertensive eyes (n = 12), significant drug effects were IOP reduction of 28% (P = 0.05) at 2.5 h after the second dose and increases in aqueous flow (36%; P = 0.013), uveoscleral outflow (59%, P = 0.008), and outflow facility (40%; P = 0.01). In normotensive eyes of the same animals, aqueous flow increased by 21% (P = 0.03). No significant change was found in any of the other parameters. Conclusions: Y-27632 and H-1152 lower IOP in rabbits and hypertensive eyes of NHPs for at least 6 h after single doses. The Y-27632 effect on IOP in hypertensive NHP eyes is caused by increases in outflow facility and uveoscleral outflow. An increase in aqueous humor formation attenuates but does not prevent an IOP decrease