Comparison of two fixed combinations of latanoprost and timolol in open-angle glaucoma.

OBJECTIVE: To compare the intraocular pressure (IOP)-reducing effect of the fixed combinations of timolol 0.5% and latanoprost 0.001% or 0.005% after 4 weeks' treatment. DESIGN: Following a 1-week run-in period on timolol 0.5% once daily, 139 patients were randomized to once-daily treatment with a fixed combination of timolol 0.5% and latanoprost 0.001% (comb. 10) or latanoprost 0.005% (comp. 50) or to the individual monotherapies. The IOP was measured at inclusion and at 8 a.m., noon and 4 p.m. on days 1, 7 and 28. RESULTS: Comb. 10, comb. 50, latanoprost and timolol reduced IOP by 3.7, 6.1, 4.9 and 2.1 mmHg, respectively, from a baseline mean diurnal IOP (+/- SEM) of 24.8 +/- 0.5, 24.1 +/- 0.4, 25.2 +/- 1.2 and 24.8 +/- 0.9 mmHg, respectively. The difference in IOP reduction was significant between comb. 50 and comb. 10 (P < 0.001), latanoprost (P = 0.046) and timolol (P < 0.001) in favor of comb. 50. There was also a significant difference between latanoprost and timolol (P = 0.007), in favor of latanoprost. All treatments were generally well tolerated. CONCLUSION: This study indicates that a fixed combination of latanoprost 0.005% and timolol 0.5% could be useful in the treatment of glaucoma.

CGRP(8-37) and CGRP(32-37) contract the iris sphincter in the rabbit eye: antagonism by spantide and GR82334.

The effects of intracameral injections of CGRP(8-37) and CGRP(32-37) on pupil diameter and blood-aqueous barrier have been investigated in rabbits. The rabbits, which were pretreated with indomethacin and a muscarinic antagonist (biperiden), responded with miosis to both CGRP fragments. CGRP(8-37) was much more potent than CGRP(32-37) but one order of magnitude less potent than substance P. Nerve blockade with tetrodotoxin did not affect the response, indicating a direct effect on the iris sphincter muscle. Pre-treatment with the unselective tachykinin receptor antagonist spantide or the NK1 receptor selective antagonist GR82334 caused a rightward shift of the dose-response curves for both fragments, while the CCK receptor antagonist loxiglumide had no inhibitory effect. Neither of the fragments induced any marked leakage of Evans blue into the aqueous humor indicating that there was no agonistic interaction with CGRP receptors in the eye. We conclude that CGRP(8-37) and CGRP(32-37) are miotic agents in the rabbit eye, possibly by acting as neurokinin receptor agonists.

C-terminal calcitonin gene-related peptide fragments and vasopressin but not somatostatin-28 induce miosis in monkeys.

The miotic effects of C-terminal calcitonin gene-related peptide (CGRP) fragments, somatostatin-28 and vasopressin have been evaluated with special attention being paid to possible interactions with cholecystokinin (CCK)A receptors. The peptides were injected intracamerally to anesthetized monkeys pretreated with indomethacin and atropine. CGRP-(32-37) induced a miosis with a potency 1000 times lower than that previously found with sulphated CCK-8. Two other fragments, CGRP-(30-37) and CGRP-(31-37), also had miotic properties. The CGRP-(32-37)-induced miosis was antagonized by the CCKA receptor antagonist loxiglumide. No contractile effect was elicited by 67 pmol-7.4 nmol somatostatin-28. Vasopressin (360 pmol) caused a small reduction in pupil size. Loxiglumide pretreatment did not affect the reduction in pupil size but a vasopressin receptor antagonist partly inhibited the response. The results indicate that CGRP-(32-37) is a miotic with low potency but high efficacy in the monkey eye, probably interacting with CCKA receptors, and that vasopressin is a mitotic with low potency and efficacy, probably acting via vasopressin receptors.

Vascular effects of calcitonin gene-related peptide (CGRP) and cholecystokinin (CCK) in the monkey eye.

The effects of cholecystokinin (CCK) and calcitonin gene-related peptide (CGRP) on ocular blood flow were studied in monkeys using the labelled microsphere method. Intracameral administration of 800 pmole CGRP increased the blood flow significantly in the conjunctiva, ciliary body and sclera. There was no significant change in the choroid and retina. CCK-33 (800 pmole) caused no significant effects on the blood flow in the tissues examined, when compared to the control eyes. A miotic response was however noted, consistent with previous results. Neither peptide caused significant changes in the intraocular pressure. These results suggest that CGRP has a vasodilatory effect in some parts of the monkey eye, whereas CCK-33 is a miotic with no marked effect on ocular blood flow.

Cholecystokinin contracts isolated human and monkey iris sphincters; a study with CCK receptor antagonists.

The contractile effects of cholecystokinin (CCK) on iris sphincter and ciliary muscles from monkey and human eyes were studied using an isolated smooth muscle bath. The ability of the CCKA receptor antagonists, lorglumide and loxiglumide, to inhibit CCK-8s-induced contraction was also examined. Various neuropeptides reported to be present in capsaicin-sensitive sensory neurons were also screened for contractile effect. CCK contracted isolated human and monkey iris sphincters at nM concentrations. Both antagonists caused a rightward shift of the dose-response curve for CCK-8s on the monkey iris sphincter. The ciliary muscle from both species failed to contract in response to CCK-8s. Of the eight other neuropeptides screened on the monkey iris sphincter, only [Arg8]vasopressin elicited a weak contraction when used in microM concentrations. These results indicate that the primate iridial sphincter muscle exhibits a high sensitivity to CCK, and that CCKA receptor antagonists effectively block the CCK-induced contraction.

The capsaicin-induced inflammatory reaction in the cat eye: antagonism by ruthenium red.

The neurogenic ocular inflammatory response in the cat was investigated by means of intracameral injections of capsaicin. At a dose of 200 micrograms intracamerally the eye responded with a breakdown of the blood-aqueous barrier (BAB) and a transient ocular hypertension. A response of the same magnitude was observed when a dose of 1 microgram capsaicin was given. Most of the response to this lower dose was prevented by ruthenium red, an inorganic dye thought specifically to antagonize the effects of capsaicin on sensory nerve endings. Following injection of 200 micrograms capsaicin there was a transient increase in pupil size, but this response was not seen after 1 microgram. Repeated injections of 200 micrograms capsaicin when the effects of the first dose had vanished resulted in tachyphylaxis of the mydriatic response. A dose of 200 micrograms of capsaicin had no effect on resistance in the outflow routes for aqueous humour.

Outflow facility in the monkey eye: effects of calcitonin gene-related peptide, cholecystokinin, galanin, substance P and capsaicin.

A study in cats has shown that intracameral injection of calcitonin gene-related peptide (CGRP) increases the outflow facility by four- to fivefold concomitant with a decrease in intra-ocular pressure (IOP). Since there are great differences in the anatomy of the aqueous outflow routes between cats and primates, we have examined the effects of CGRP in the cynomolgus monkey. The possible influence of the sensory neuropeptides cholecystokinin (CCK), galanin and substance P on the outflow facility and IOP were also investigated. Determinations were performed using a two-level constant-pressure procedure. At 40-60 min after intracameral injection of 3 micrograms CGRP the outflow facility was increased from 0.68 +/- 0.11 to 1.03 +/- 0.15 microliters min-1 mmHg-1 in the CGRP-treated eyes, and from 0.71 +/- 0.12 to 0.79 +/- 0.10 microliter min-1 mmHg-1 in the control eyes. The mean difference in increase was 0.27 +/- 0.06 microliter min-1 mmHg-1 (P less than 0.01, n = 7). During the experiments there was a small rise in the IOP. CGRP at a dose of 3 micrograms caused a small rise in aqueous humor protein concentration. An attempt to release endogenous CGRP with capsaicin did not result in an increased outflow facility. Three micrograms each of CCK, galanin and substance P had no significant effect on either the outflow facility or the IOP. A miosis was observed in the experiments with CCK in agreement with previous findings. CCK seems thus to cause contraction of the pupillary sphincter but does not influence the ciliary muscle sufficiently to cause a facility effect in the monkey eye.(ABSTRACT TRUNCATED AT 250 WORDS)

Cholecystokinin causes contraction of the pupillary sphincter in monkeys but not in cats, rabbits, rats and guinea-pigs: antagonism by lorglumide.

The effects of intracameral injections of cholecystokinin (CCK) on the pupil size were determined in monkeys, cats, rabbits, rats and guinea-pigs. In animals under muscarinic cholinergic blockade, CCK caused miosis in monkeys but not in the other species investigated. In monkeys CCK-8 was more potent than CCK-33, which was, however, much more potent than non-sulphated CCK-8. These observations indicate that peripheral type A receptors mediated the miotic response. The effect of CCK-8 was not appreciably influenced by pretreatment with indomethacin, 3 mg kg-1 body wt, indicating that prostaglandins were not involved in the response. Nerve blockade with 0.9 micrograms tetrodotoxin intracamerally had no clear effect on the dose-response relationship for CCK-8. The effect of the peptide thus seems to be directly on receptors on the pupillary sphincter muscle. Pretreatment with lorglumide caused a dose-dependent rightward shift of the dose-response curve, indicating competitive antagonism. The results indicate that in monkeys, but not in rabbit, cats, rats and guinea-pigs, CCK is a potent miotic with a direct effect on the pupillary sphincter mediated by type A CCK receptors on the muscle.