Multiple dosing of prostaglandin F2 alpha or epinephrine on cynomolgus monkey eyes. I. Aqueous humor dynamics.

After obtaining baseline intraocular pressure (IOP) measurements for 1 week, prostaglandin (PG) F2 alpha (250 micrograms in 50 microliters saline) or epinephrine 2% solution (50 microliters) was topically applied twice daily for 2 weeks to one eye of six cynomolgus monkeys for each agent tested. Contralateral control eyes received their respective vehicles. PGF2 alpha significantly reduced IOP beginning 2 to 3 hr after the first dose, persisting thereafter. A significant (P less than 0.05) hypotensive effect remained for at least 10 hr after the first dose and at least 14 hr after the sixth dose. At 4 hr after the seventh dose, the mean reduction was 10.2 +/- 3.5 (+/- SD) mmHg below baseline (P less than 0.0025). At this time, there was also a significant (P less than 0.01) mean reduction of IOP in the contralateral vehicle-treated eyes of 6.0 +/- 3.3 (+/- SD) mmHg below baseline, which did not appear to be secondary to diurnal fluctuations, repeated tonometry, experimental manipulation, or inadvertent drug transfer. Epinephrine significantly (P less than 0.05) reduced IOP beginning 3 hr after the first dose, but this reduction was minimal and not consistent. Neither PGF2 alpha nor epinephrine altered aqueous flow as measured by fluorophotometry 2 to 6 hr after the fifth dose. Outflow facility could not be assessed by indentation tonography because IOP was often too low at the time of measurement. Whereas PGF2 alpha did not alter pupil size, epinephrine caused significant pupillary dilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Intraocular pressure effects of multiple doses of drugs applied to glaucomatous monkey eyes.

The effects of multiple dosing with 0.5% timolol maleate, 2% epinephrine hydrochloride, 4% pilocarpine hydrochloride, 1% vanadate, 1% forskolin (nonproprietary name, colforsin), or 0.5% prostaglandin F2 alpha on intraocular pressure (IOP) were each tested on eight cynomolgus monkey eyes in which glaucoma was induced by photocoagulating the trabecular meshwork with the argon laser. The week prior to drug therapy, baseline IOP measurements were carried out at hourly intervals from 9:30 am to 3:30 pm on three days. One to two days later, therapy was initiated. Each drug was applied topically to both eyes of each monkey twice daily for at least four days. The IOP was measured with a calibrated pneumatonometer at the same hourly intervals on treatment days as on the baseline days. The IOP at each time of day on treatment days was compared with the average baseline IOP measured at the corresponding time of day. Topical application of timolol, epinephrine, pilocarpine, vanadate, and prostaglandin F2 alpha significantly reduced IOP without evidence of tolerance or tachyphylaxis during the course of therapy. Forskolin did not significantly decrease IOP after the second day of treatment.

The effect of corynanthine on intraocular pressure in clinical trials.

A single drop, dose-response, double-masked study of the effect corynanthine, a selective alpha 1 adrenergic antagonist, on intraocular pressure (IOP) was carried out in 10 symmetrically ocular hypertensive patients. Corynanthine 1% had no significant pressure lowering effect. Topical application of a 2% solution significantly (P less than 0.05) reduced IOP for at least eight hours; at five hours, mean IOP (+/- SEM) was 20.6 +/- 2.0 mmHg and 26.0 +/- 4.9 mmHg, comparing treated and control eyes, respectively. The 5% solution caused a significant (P less than 0.05) bilateral reduction in IOP, comparing treated and control eyes to baseline IOP respectively. Two percent corynanthine applied topically two or three times daily for one, two, or three weeks to seven patients with symmetrical ocular hypertension did not reduce IOP. Alpha adrenergic antagonists may have a role in the treatment of glaucoma.

Pharmacological testing in the laser-induced monkey glaucoma model.

Glaucoma was induced in cynomolgus monkeys by photocoagulating the trabecular meshwork with the argon laser. Repeat treatments were often necessary and wide intraocular pressure fluctuations were characteristic. Baseline intraocular pressure was measured with a calibrated pneumatonometer hourly for six hours. On a succeeding day a baseline measurement was made, 50 microliter of the drug to be tested applied, and six hourly measurements of intraocular pressure repeated. The effects on intraocular pressure of timolol, epinephrine, pilocarpine, vanadate, prostaglandin F2 alpha (PGF2 alpha), forskolin, and corynanthine were tested in at least eight eyes. Significant (p less than 0.05) reductions of intraocular pressure were produced by 0.5% timolol, 2% epinephrine, 4% pilocarpine, 1% vanadate, 500 micrograms of PGF2 alpha and 1% forskolin. Five per cent corynanthine produced no significant lowering of intraocular pressure. Tonography revealed an increased outflow facility associated with the reduction of intraocular pressure 2 hours after the administration of 4% pilocarpine. This glaucoma animal model may be useful in investigating agents that lower intraocular pressure by a variety of mechanisms.

Corynanthine and aqueous humor dynamics in rabbits and monkeys.

The effects of corynanthine tartrate, a selective alpha 1-adrenergic receptor antagonist, were studied on intraocular pressure by pneumatonometry, outflow facility by tonography, and aqueous humor flow by fluorophotometry in laboratory animals. Unilateral topical administration of 5% corynanthine significantly lowered mean IOP (+/- SEM) in rabbits for at least six hours, in ten awake monkeys for six hours, and in ten monkeys anesthetized with ketamine for four hours. The maximum effect in awake monkeys occurred two hours after drug administration, from 15.8 +/- 0.5 mm Hg to 12.7 +/- 0.5 mm Hg, with no substantial change in control eyes. No change in outflow facility was demonstrated in 11 monkeys two hours after 5% corynanthine administration. Aqueous humor flow rates did not change in 12 monkeys up to three hours after drug administration. Corynanthine may act by increasing uveoscleral outflow.

Bile acid pool changes and regulation of cholate synthesis in experimental diabetes.

The effect of alloxan-diabetes and insulin treatment in bile acid pool size and composition, bile acid secretion and cholic acid synthesis was investigated in the rat. The size of the cholate pool was significantly increased 4 days after diabetes induction. It reached a constant size three times that of control animals after 2 weeks of diabetes. Changes in bile acid pool size and secretion were directly dependent of the insulin deficiency state since they were reversed by insulin treatment and were not influenced by the caloric intake of the animal nor the pharmacologic effect of alloxan. Biliary cholate secretion was also 3-fold increased in diabetic rats and it accounted for more than 80% of the total bile acids compared to 60% in the control group. The calculated daily rate of cholate synthesis was increased in diabetic rats and the circadian rhythm of cholate synthesis was abolished in this condition. Therefore, it was shown that the negative feedback mechanism that regulates bile acid snythesis was deleted in diabetes. This mechanism was partially restored after 2 weeks of insulin treatment. These studies demonstrated that bile acid metabolism was profoundly changed in alloxan-diabetic rats and suggested that insulin may play an important role in the regulation of bile acid snythesis and intestinal absorption.