Johan Stjernschantz

A Six-month, Randomized, Double-masked Study Comparing Latanoprost with Timolol in Open-angle Glaucoma and Ocular Hypertension

PURPOSE To compare the intraocular pressure (IOP)-reducing effect and side effects of 0.005% latanoprost administered once daily with 0.5% timolol administered twice daily in patients with open-angle glaucoma or ocular hypertension. METHODS This was a randomized, double-masked study with two parallel groups and a treatment period of 6 months. The primary objective of the study is to compare the IOP-reducing effect of lantanoprost with that of timolol at the end of the 6-month treatment period. A total of 294 patients were included: 149 were in the latanoprost group and 145 were in timolol group. Latanoprost was administered in the evening. RESULTS Diurnal IOP (9:00 am, 1:00 pm, 5:00 pm) was reduced from 25.2 to 16.7 mmHg (33.7%) with lantanoprost and from 25.4 to 17.1 mmHg (32.7%) with timolol as determined at the end of the 6-month treatment period. No upward drift in IOP occurred with either drug during the treatment period. Latanoprost caused a somewhat more conjunctival hyperemia than timolol and more corneal punctuate epithelial erosions. However, both drugs were generally well tolerated. The most significant side effect of latanoprost was increased pigmentation of the iris which was observed in 15 patients (10.1%). Timolol caused more systemic side effects than latanoprost. CONCLUSIONS Latanoprost 0.005% administered once daily in the evening reduced IOP at least as well as timolol 0.5% administered twice daily. Latanoprost was generally well tolerated systemically and in the eye. However, the drug has an unusual side effect of increasing the pigmentation of the iris, particularly in individuals with green-brown or blue-brown eyes.

Effects on Intraocular Pressure and Side Effects of 0.005% Latanoprost Applied Once Daily, Evening or Morning: A Comparison with Timolol

PURPOSE To compare the effect on intraocular pressure (IOP) and side effects of 0.005% latanoprost applied once daily, morning or evening, with 0.5% timolol applied twice daily. METHODS A 6-month randomized, double-masked, multicenter study with three parallel groups was undertaken. Two hundred sixty-seven patients were randomized, 84 to timolol, 89 to latanoprost in the morning for 3 months and then in the evening for another 3 months, and 94 to latanoprost with the treatment schedule reversed. RESULTS After 6 months, timolol reduced diurnal IOP from 24.6 to 17.9 mmHg (27%); latanoprost applied in the morning, from 25.5 to 17.7 mmHg (31%); and latanoprost applied in the evening, from 24.8 to 16.2 mmHg (35%). The efficacy of latanoprost applied in the evening was statistically superior to latanoprost applied in the morning and to timolol (P < 0.001). Latanoprost induced a slight increase in conjunctival hyperemia in 31.4% of treated patients, compared with 15.9% for timolol. Sporadic episodes of mild punctate corneal epithelial erosions were three times as frequent in latanoprost-treated eyes as in timolol-treated eyes. The most significant ocular side effect was increased pigmentation of the iris observed in five and suspected in seven more latanoprost-treated eyes. All these eyes had a mixed green-brown or blue/gray-brown iris color. Timolol reduced heart rate by 3 beats/minute (P < 0.005). CONCLUSIONS The effect on diurnal IOP of latanoprost applied once daily in the evening is superior to that of timolol. The main difference in side effects is increased pigmentation of the iris induced by latanoprost, most likely due to stimulation of melanogenesis in iris stromal melanocytes.

Increased uveoscleral outflow as a possible mechanism of ocular hypotension caused by prostaglandin F2α-1-isopropylester in the cynomolgus monkey

The effects of topical application of a single dose of prostaglandin F2 alpha, administered as the isopropylester, on the intraocular pressure (IOP), aqueous humor flow (AHF), conventional, and uveoscleral outflow were studied in cynomolgus monkeys under pentobarbital anesthesia. 1 microgram PGF2 alpha decreased the IOP by 2.9 +/- 0.6 mmHg (3 hr after the application) as compared with the vehicle-treated control eye. The mean AHF during the whole experiment was slightly higher in the experimental than in the control eye, 1.34 +/- 0.11 microliters min-1 compared with 1.16 +/- 0.09 microliters min-1. The uveoscleral outflow was significantly increased in the PGF2 alpha-treated eye, 0.98 +/- 0.12 microliters min-1 compared with 0.61 +/- 0.10 microliters min-1 for the control eye. The conventional outflow was lower in the experimental eye throughout the experiment. Topical application of 10 micrograms pilocarpine at the time when the fall in IOP was expected prevented the drop in the IOP. Simultaneously the increase in the uveoscleral outflow was abolished. After systemic pretreatment with atropine, 1 mg (kg body weight)-1 i.v., there was no significant difference in IOP, AHF, conventional or uveoscleral outflow between the PGF2 alpha-treated, and the control eye. The results of the present investigation suggest that PGF2 alpha decreases the intraocular pressure by increasing the uveoscleral outflow. The mechanism behind the increase in the uveoscleral outflow remains to be established. Relaxation of the ciliary muscle as well as enlarged intramuscular spaces and loss of extracellular material may contribute to the effect.

The incidence and time-course of latanoprost-induced iridial pigmentation as a function of eye color

Latanoprost, a phenyl-substituted analogue of prostaglandin F2 alpha administered as eye drops, induces increased melanogenesis in the iridial melanocytes of monkeys. Similar effects were seen in 12, 23 and 11% of patients in the USA, United Kingdom (UK) and Scandinavia, respectively, during one year of treatment. The highest incidence of induced pigmentation was seen in green-brown, yellow-brown and blue/grey-brown eyes, in that order. The relatively high proportion of patients with green-brown eyes in the UK explains the larger number of affected patients in this country. Typically, a concentric increase of the iris pigmentation appeared after six months (range: 3-17) and was judged to be noticeable by the patient in about 2/3 of the cases. After cessation of latanoprost, no change of the induced pigmentation has been seen in patients followed for two years, and there have been no signs of dispersion of pigment into the anterior chamber. Irides, homogeneously blue, grey, green or brown, were seldom affected. Naevi or freckles on iris, conjunctiva, or eye lids were not affected. It is intriguing that many patients with mixed eye color, particularly the blue-brown eyes, have not developed increased pigmentation even during two years of treatment. This could be due to a relatively slow melanogenesis or to refractory melanocytes in these individuals.

Calcitonin gene-related peptide in the eye: release by sensory nerve stimulation and effects associated with neurogenic inflammation

Calcitonin gene-related peptide (CGRP) in the anterior uvea coexists with tachykinins (substance P and neurokinin A) in sensory nerve fibers deriving from the trigeminal ganglion. Mechanical or electrical stimulation of the intracranial part of the trigeminal nerve/ganglion in rabbits produced a marked hyperemia in the anterior segment of the eye, increased intraocular pressure, breakdown of the blood-aqueous barrier and miosis. Simultaneously, CGRP-like immunoreactivity was released into the aqueous humor. This suggests that the highly vasoactive CGRP can be released from sensory nerve fibers to participate in vascular responses. Unlike the tachykinins, CGRP per se was without effect on the pupillary diameter while disrupting the blood-aqueous barrier (resulting in aqueous flare) upon intravitreal injection. In addition, CGRP enhanced the aqueous flare evoked by a minimal eye trauma (infrared irradiation of the iris). The miosis evoked by the intravitreal injection of substance P was more pronounced when CGRP was injected simultaneously, and finally, substance P induced aqueous flare much more effectively when given together with a threshold dose of CGRP.

Ocular and systemic pharmacokinetics of latanoprost in humans

The ocular pharmacokinetics of latanoprost (13,14-dihydro-17-phenyl-18, 19,20-trinor-PGF(2alpha)-isopropyl ester; Xalatan [Pharmacia-Upjohn, Peapack, NJ]) was studied in patients undergoing cataract surgery using radio-immunoassay, and the systemic pharmacokinetics of latanoprost was studied in healthy human volunteers with 3H-latanoprost as well as radioimmunoassay. After topical application, latanoprost was rapidly hydrolysed in the cornea and blood. The maximum concentration of the active drug, latanoprost acid, was detected in the aqueous humor 1-2 hours after topical administration of the clinical dose and amounted to 15-30 ng/ml. The half-life of latanoprost acid in the aqueous humor was 2-3 hours. In the systemic circulation the peak concentration of latanoprost acid appeared 5 minutes after topical application and reached a level of 53 pg/ml with an elimination half-life of 17 minutes. In patients that had been on the drug continuously for more than 1 year, 5 out of 10 had plasma levels of latanoprost acid below the limit of detection (<30 pg/ml). The mean plasma clearance was 0.40 +/- 0.04 l/h. kg, and the volume of distribution was 0.16 +/- 0.02 l/kg after intravenous administration. The corresponding figures after ocular administration were 0.88 l/h. kg, and 0.36 l/kg. The majority of the radioactivity was recovered in urine (88%) and the rest was found in feces. In the eye the main metabolism of latanoprost was the ester hydrolysis. The only prominent chromatographic peak in plasma corresponded to latanoprost acid. In urine no latanoprost or latanoprost acid was detected. Before excretion latanoprost acid was beta oxidized to 1,2-dinor and 1,2,3,4-tetranor latanoprost acid. These metabolites accounted for approximately 66% of the radioactivity in urine. In conclusion, latanoprost is rapidly hydrolyzed in the eye and blood to latanoprost acid. Minimal further metabolism occurs in the eye, but latanoprost acid undergoes beta oxidation and other metabolism outside the eye. After topical application the peak concentration in aqueous humor was approximately 10(-7) M, whereas that in plasma was about 10(-10) M or less.

Intraocular Pressure-reducing Effect of PhXA41 in Ocular Hypertension: Comparison of Dose Regimens

PURPOSE To investigate the intraocular pressure (IOP)-reducing effect and side effects of PhXA41, a new prostaglandin F2 alpha (PGF2 alpha) analog, in ocular hypertension and to compare two different dose regimens of PhXA41. METHODS This was a 2-week randomized, placebo-controlled, double-masked study. PhXA41 eye drops at a concentration of 0.006% (60 micrograms/ml) were administered either once daily (evening) or twice daily (morning and evening) to patients with bilateral ocular hypertension. Each PhXA41 group consisted of 20 patients and the placebo group consisted of 10. RESULTS PhXA41, administered once or twice daily, reduced IOP by 8.9 and 7.1 mmHg, respectively, in the two treatment groups at the end of the 2-week treatment period. No clear-cut drift in the IOP reduction was observed during the treatment period, but the maximum response was obtained on day 2 in the group receiving PhXA41 twice daily. Both dose regimens of PhXA41 caused more conjunctival hyperemia than the placebo. At the end of the treatment period, 64% to 74% of the patients receiving PhXA41 exhibited no or barely detectable hyperemia. The corresponding figure in the placebo group was 90%. PhXA41 was well tolerated and only one patient dropped out of the study. CONCLUSIONS PhXA41 reduced IOP by 28% to 36% in patients with ocular hypertension with only mild side effects. Dosing once daily was at least as effective as twice daily. PhXA41 has the potential of becoming a useful new drug for glaucoma treatment.

Mechanism and clinical significance of prostaglandin-induced iris pigmentation.

The new glaucoma drugs latanoprost, isopropyl unoprostone, travoprost, and bimatoprost cause increased pigmentation of the iris in some patients. The purpose of the present article is to survey the available preclinical and clinical data on prostaglandin-induced iris pigmentation and to assess the phenomenon from a clinical perspective. Most of the data have been obtained with latanoprost, and it appears that there is a predisposition to latanoprost-induced iris pigmentation in individuals with hazel or heterochromic eye color. As latanoprost and travoprost are selective agonists for the prostaglandin F(2alpha) receptor, it is likely that the phenomenon is mediated by this receptor. Several studies indicate that latanoprost stimulates melanogenesis in iridial melanocytes, and transcription of the tyrosinase gene is upregulated. The safety aspects of latanoprost-induced iris pigmentation have been addressed in histopathologic studies, and no evidence of harmful consequences of the side effect has been found. Although a final assessment of the clinical significance of prostaglandin-induced iris pigmentation currently is impossible to make, it appears that the only clear-cut disadvantage is a potential heterochromia between the eyes in unilaterally treated patients because the heterochromia is likely to be permanent, or very slowly reversible.

Prostaglandin-induced iridial pigmentation in primates

Latanoprost, a new ocular hypotensive prostaglandin F2 alpha analogue prodrug, was found to induce increased pigmentation of monkey irides in chronic toxicity studies. This prompted us to investigate the effect of naturally occurring prostaglandins on the monkey iris to determine whether this pigmentary effect is unique for latanoprost or whether it is a class effect of prostaglandins. PGF2 alpha-isopropyl ester (IE), PGE2-IE and latanoprost were applied topically to cynomolgus monkey eyes for 18-44 weeks. One eye of each animal was treated, while the other served as control. In addition, latanoprost was applied to sympathectomized monkey eyes. PGF2 alpha-IE, PGE2-IE, as well as latanoprost, induced increased pigmentation in the monkey eye. The first signs of this effect were seen after about two months of treatment. Latanoprost also induced increased pigmentation in sympathectomized eyes. It is concluded that both naturally occurring prostaglandins and their synthetic analogues can induce increased iridial pigmentation in cynomolgus monkeys, and that the effect does not require the presence of sympathetic nerves.

Structure-activity relationships and receptor profiles of some ocular hypotensive prostanoids

A novel series of prostaglandin F (PGF) analogues have been prepared and evaluated in vivo and in vitro. Their intraocular pressure (IOP) lowering effects and potential side-effects, as prodrug eye drops, have been tested in cats, monkeys and rabbits. Furthermore, the PGF-analogues were tested as free acids for FP-receptor agonistic activity on cat iris sphincter. The results were compared to that of PGF2 alpha (C#1). Based on the structure-activity relationship investigations, inversion of the configuration, at carbon-9 (C#3) or carbon-11 (C#4), changes the potency and the receptor profile of PGF2 alpha. Replacement part of the omega-chain of PGF2 alpha with a benzene ring changes the potency and receptor profile of PGF2 alpha. The optimal position of the benzene ring is on carbon-17, 17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (C#8), and exhibited a much higher therapeutic index in the eye than PGF2 alpha or its ester. The biological activity of different substituents on the C#8 benzene ring have also been studied. Interestingly, introduction of a methyl group at positions 2 or 3 of the benzene ring (C#16 or C#17) affords compounds which are biologically more active than the methyl group at the 4-position (C#18). Furthermore, one of the analogues 13,14-dihydro-17-phenyl-18,19,20-trinor PGF2 alpha-isopropyl ester (latanoprost), has been found in clinical studies to be a highly potent and efficacious IOP-reducing agent for the treatment of glaucoma.