Effects of intratympanic injection of latanoprost in Meniere's disease: a randomized, placebo-controlled, double-blind, pilot study.

OBJECTIVE: To determine the short-term effects of latanoprost, a selective FP prostanoid receptor agonist, in Meniere's disease. STUDY DESIGN AND METHODS: Latanoprost was administered by intratympanic injection once daily for 3 days. Before the first injection (day 1) and on days 5 and 15, hearing and tinnitus were determined. The patients assessed vertigo on a visual analogue scale on days 1-15. The study was randomized, double-blind, and placebo-controlled. RESULTS: Latanoprost reduced vertigo/dysequilibrium around 30% (P < 0.05), and improved speech discrimination around 15% (P < 0.05). Tinnitus loudness deteriorated after injection of placebo (P < 0.01) but not after latanoprost. Side effects were few. CONCLUSION AND SIGNIFICANCE: Latanoprost alleviated vertigo/dysequilibrium and improved hearing. The results indicate that the drug potentially could be useful for treatment of Meniere's disease.

Detection of the free acid of bimatoprost in aqueous humor samples from human eyes treated with bimatoprost before cataract surgery.

PURPOSE: To determine whether bimatoprost is hydrolyzed to its free acid after topical application in humans in vivo. DESIGN: Prospective, masked, and vehicle controlled. PARTICIPANTS: Thirty-one eyes of 31 patients with cataracts. METHODS: Beginning 7 days before scheduled cataract surgery, one eye of each patient was treated with bimatoprost 0.03% or vehicle once daily, with the last drop administered 2 to 12 hours before anterior chamber paracentesis before cataract surgery. In a masked fashion, aqueous humor specimens were assayed for bimatoprost and its free acid by high-pressure liquid chromatography and mass spectrometry. MAIN OUTCOME MEASURE: Detection of the free acid of bimatoprost in aqueous humor. RESULTS: Aqueous humor concentrations of the free acid of bimatoprost were 22.0+/-7.0 nmol/l (mean +/- standard error of the mean, n = 12) and 7.0+/-4.6 nmol/l (n = 8) at 2 and 12 hours, respectively, and below the limit of detection after vehicle (n = 10). Concentrations of bimatoprost (amide) were 5.7+/-1.4 and 1.1+/-0.4 nmol/l at 2 and 12 hours, respectively, and undetectable after vehicle. CONCLUSION: After topical application of bimatoprost in humans, a sufficient concentration of its free acid, a potent FPprostanoid receptor agonist, is found in the aqueous humor to account for its ability to reduce intraocular pressure.

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.

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.

Localization of prostanoid receptors and cyclo-oxygenase enzymes in guinea pig and human cochlea.

Endogenous production of prostaglandins has been demonstrated in the cochlea, but no information is available on the distribution of the cyclo-oxygenase (COX) enzymes, or prostanoid receptors in the cochlea. The purpose of the present study was to investigate the localization of the FP, EP(1) and EP(3) prostanoid receptors as well as the COX-1 and COX-2 enzymes in the cochlea of guinea pig and man. Cochleas were processed for immunohistochemistry using routine techniques. Appropriate controls comprised incubation with specific blocking peptides, or incubation without primary antibodies. Both in guinea pig and man the FP prostanoid receptor was abundantly distributed in the cochlea, e.g., in stria vascularis, the spiral ligament, spiral ganglion, and organ of Corti. The immunohistochemical staining of the EP(1) and EP(3) receptors in the same structures was significantly weaker and sometimes lacking altogether (e.g., EP(3) receptor in human cochlea). Weak, but mostly consistent immunostaining of the COX-1 enzyme was found in the cochlear structures. The COX-2 enzyme appeared to be lacking. The abundant distribution of the FP receptor in several important cochlear structures both in guinea pig and man suggests a physiological function for PGF(2alpha) in the cochlea. The COX-1 enzyme seems to be constitutively expressed in the cochlea in contrast to COX-2.

Production of prostaglandin e(2) by iridial melanocytes exposed to latanoprost acid, a prostaglandin F(2 alpha) analogue.

Several prostaglandin analogues used for glaucoma treatment cause increased pigmentation of the iris. The purpose of the present study was investigate whether latanoprost, a PGF(2 alpha) analogue, has any effect on the production of endogenous prostaglandins in iridial melanocytes, which could be important in the mechanism leading to increased pigmentation. Bovine and human iridial melanocytes in culture were used for the experiments. Production of endogenous prostaglandins was measured by enzyme immunoassay, and the melanin content was measured spectrophotometrically. In bovine iridial melanocytes, latanoprost acid caused a significant increase of the PGE(2) production, which could be blocked by indomethacin and NS398, indicating an involvement of cyclo-oxygenase 2. In order to study the selectivity of the phenomenon other endogenous substances/drugs were tested, e.g., acetylcholine, carbachol, noradrenaline, neuropeptide Y, substance P and alpha-MSH, but none was found to have any significant effect. Human iridial melanocytes also responded to latanoprost acid with increased production of PGE(2) and in 1 out of 5 individuals increased melanogenesis coincided with increased PGE(2) production. In bovine iridial melanocytes, latanoprost acid did not stimulate melanogenesis. These results indicate that latanoprost acid cause enhanced formation of endogenous prostaglandins that may have auto- and/or paracrine effects in the melanocytes, possibly associated with melanogenesis.

Studies on ocular inflammation and development of a prostaglandin analogue for glaucoma treatment.

This review summarizes the Ernst H. Bárány Prize Lecture given at the meeting of the International Society of Eye Research in Geneva 2002. In the paper the path from the author's early studies on neurogenic inflammation in the eye to the search for a suitable prostaglandin analogue for glaucoma treatment, and the development of latanoprost are described. In particular the solution to the nociceptive and hyperemic side-effects of naturally occurring prostaglandins in the eye, the mechanism of action of FP prostanoid receptor agonists as well as the selection of dose for glaucoma treatment are discussed. In addition, pharmacokinetical aspects of latanoprost, and the melanogenic side-effect of prostaglandins in the iris are addressed. The paper is primarily focused on studies performed by the author and complete reference to other previous, or contemporary studies is therefore not always given as the purpose is not to present a comprehensive review article.

Effect of latanoprost on hair growth in the bald scalp of the stump-tailed macacque: a pilot study.

Latanoprost, a selective FP prostanoid receptor agonist used in the treatment of glaucoma, has a hypertrichotic side effect. Using the macaque model of androgenetic alopecia, we examined the effect of latanoprost on hair growth. Eight monkeys were divided into 2 groups; one group received a daily topical application of 50 microg/ml of latanoprost for 5 months; a control group had a daily application of vehicle. For an additional 3 months, 2 monkeys from each group were given 500 microg/ml latanoprost, while the remaining monkeys continued with the previous treatment. Hair growth was evaluated by monthly photographs and phototricho-graphic analysis. Fifty microg/ml of latanoprost caused minimal hair growth. Latanoprost at 500 microg/ml induced moderate to marked hair regrowth with 5-10% conversion of vellus hairs to intermediary or terminal hairs. The vehicle group showed no effect. Further evaluation of latanoprost as an agent for treatment of human androgenetic alopecia is indicated.

Transcription of prostanoid receptor genes and cyclooxygenase enzyme genes in cultivated human iridial melanocytes from eyes of different colours.

Several prostaglandin analogues used for glaucoma treatment have been shown to cause increased iridial pigmentation as side-effect. In the present study we identified the types of prostanoid receptors and cyclooxygenase (COX) enzymes that are expressed in human iridial melanocytes isolated from eyes of different colours. Iris specimens were obtained during trabeculectomy surgery, or from enucleated eyes, and the iridial melanocytes were isolated and cultivated. The transcription of the DP, EP1, EP2, EP3, EP4, FP, IP and TP prostanoid receptor genes as well as the COX-1 and COX-2 enzyme genes was investigated using reverse transcriptase-polymerase chain reaction (RT-PCR). Of the prostanoid receptors the FP receptor gene was found to be most consistently transcribed in the melanocytes isolated from both blue- and hazel-coloured eyes. No RNA of the DP, EP2 and TP receptor genes could be detected, whereas the EP1, EP3, EP4 and IP receptor genes were found to be transcribed in melanocytes from some eyes. The COX-2 gene was found to be transcribed, but the COX-1 gene less consistently. There was no difference in gene transcription pattern between melanocytes originating from eyes treated with latanoprost, and eyes not previously treated with the prostaglandin. These results indicate that the FP prostanoid receptor gene is transcribed in cultivated human iridial melanocytes of both blue and hazel eyes, whereas the other prostanoid receptor genes seem to be transcribed much less frequently, or not at all. Surprisingly, the COX-2 rather than the COX-1 gene, was found to be transcribed in the melanocytes.