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C.A. Rasmussen, B.T. Gabelt, K.R. Russell, B. Tian, P.L. Kaufman; Blood Pressure Effects on Bremazocine IOP Response; Outflow Facility in Cynomolgus Monkeys . Invest. Ophthalmol. Vis. Sci. 2003;44(13):3436.
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Purpose: To further characterize the ocular hypotensive mechanism of bremazocine HCl (BRE), a kappa opioid receptor agonist, shown to lower intraocular pressure (IOP), and decrease aqueous humor formation (AHF) in monkeys and rabbits. Methods: Mean arterial pressure (MAP), calculated as 2/3 diastolic + 1/3 systolic blood pressure, was recorded, via cuff or arterial line, at 15 min intervals, and IOP (Goldmann tonometer) was recorded at 30 min intervals for 4-6 hours, in 5 ketamine-anesthetized normotensive cynomolgus monkeys after topical administration of a single dose of 10µg or 100µg BRE in 2 x 5 µl drops to one eye, vehicle to opposite eyes. In separate experiments, angiotensin II (ATII), in a 0.303µg/ml solution, was infused at a rate between 200µl-600µl min to maintain MAP after 100µg BRE administration. Outflow facility (OF) was determined by two-level constant pressure perfusion of the anterior chamber (AC) with Bárány’s solution, followed by AC exchanges with 2 or 3 doses of BRE, ranging from 0.01µg/ml to 100µg/ml in 8 monkeys under pentobarbital anesthesia. Results: BRE caused a dose-related decrease in MAP. The 10µg dose significantly decreased MAP compared to same-day pretreatment baseline (BL) at hrs 0.5,1.0 and 2.0 (p<0.05; n=5), with a maximum decrease of 23% at 0.5 hrs. MAP returned to BL at 3 hrs. The 100µg dose significantly reduced MAP from hrs 0.5 –2 after treatment (p<0.05; n=5) with a maximum decrease of 39% at 1 hr. MAP returned to BL at 6 hrs. Maintaining MAP at near BL levels with ATII after topical administration of 100µg BRE eliminated the decrease in IOP. ATII alone, infused at 200µl-600µl min, caused an 18-29% (mean 24±0.02 n=5) increase in MAP over 4 hours, and a 6-11% (mean 9±0.01 n=5) increase in IOP. OF measurements to date showed that BRE insignificantly decreased OF. No toxicity was observed at any dose by slit lamp biomicroscopy. Conclusions: The IOP lowering effect of topical BRE, in monkeys, is likely due to the significant drop in MAP which is probably also responsible for the decrease in AHF reported previously. BRE does not appear to alter OF in monkeys.
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