The transcorneal penetration of commercial ophthalmic formulations containing timolol maleate in rabbit eyes.

PURPOSE: We investigated the transcorneal penetration of commercial ophthalmic formulations containing timolol maleate in rabbit eyes. METHODS: One drop (30 µL) of each ophthalmic solution (Xalacom(®), DuoTrav(®), Cosopt(®), and Timoptol(®)) was administered to the conjunctival sac of the rabbits' eyes and the timolol maleate aqueous humor concentration was measured by high-performance liquid chromatography 15, 60, 120, and 240 min after the completion of administration. The effect of timolol ophthalmic solution pH (5.7-6.8) on ocular penetration was also examined. RESULTS: The concentration [Cmax (µg/mL)] of timolol maleate, found in each of the 4 ophthalmic solutions, penetrated to the aqueous humor was as follows: DuoTrav>Cosopt>Timoptol>Xalacom. The concentration of timolol maleate penetrated to the aqueous humor was highest with solutions in the vicinity of pH 6.8. CONCLUSIONS: The concentration of timolol maleate penetrated to the aqueous humor was highest in DuoTrav followed by Cosopt, Timoptol, and Xalacom, and the pH and Benzalkonium chloride (BAK) concentration of the ophthalmic solution were believed to be factors that influenced this phenomena.

Bimatoprost-loaded ocular inserts as sustained release drug delivery systems for glaucoma treatment: in vitro and in vivo evaluation.

The purpose of the present study was to develop and assess a novel sustained-release drug delivery system of Bimatoprost (BIM). Chitosan polymeric inserts were prepared using the solvent casting method and characterized by swelling studies, infrared spectroscopy, differential scanning calorimetry, drug content, scanning electron microscopy and in vitro drug release. Biodistribution of 99mTc-BIM eye drops and 99mTc-BIM-loaded inserts, after ocular administration in Wistar rats, was accessed by ex vivo radiation counting. The inserts were evaluated for their therapeutic efficacy in glaucomatous Wistar rats. Glaucoma was induced by weekly intracameral injection of hyaluronic acid. BIM-loaded inserts (equivalent to 9.0 µg BIM) were administered once into conjunctival sac, after ocular hypertension confirmation. BIM eye drop was topically instilled in a second group of glaucomatous rats for 15 days days, while placebo inserts were administered once in a third group. An untreated glaucomatous group was used as control. Intraocular pressure (IOP) was monitored for four consecutive weeks after treatment began. At the end of the experiment, retinal ganglion cells and optic nerve head cupping were evaluated in the histological eye sections. Characterization results revealed that the drug physically interacted, but did not chemically react with the polymeric matrix. Inserts sustainedly released BIM in vitro during 8 hours. Biodistribution studies showed that the amount of 99mTc-BIM that remained in the eye was significantly lower after eye drop instillation than after chitosan insert implantation. BIM-loaded inserts lowered IOP for 4 weeks, after one application, while IOP values remained significantly high for the placebo and untreated groups. Eye drops were only effective during the daily treatment period. IOP results were reflected in RGC counting and optic nerve head cupping damage. BIM-loaded inserts provided sustained release of BIM and seem to be a promising system for glaucoma management.

Bimatoprost 0.03%/timolol 0.5% preservative-free ophthalmic solution versus bimatoprost 0.03%/timolol 0.5% ophthalmic solution (Ganfort) for glaucoma or ocular hypertension: a 12-week randomised controlled trial.

AIM: To compare the efficacy and safety of single-dose bimatoprost 0.03%/timolol 0.5% preservative-free (PF) ophthalmic solution with bimatoprost 0.03%/timolol 0.5% ophthalmic solution in patients with open-angle glaucoma or ocular hypertension. METHODS: In this multicentre, randomised, parallel-group study, patients were randomised to bimatoprost/timolol PF or bimatoprost/timolol once daily in the morning for 12 weeks. Primary efficacy endpoints, reflecting differing regional regulatory requirements, included change from baseline in worse eye intraocular pressure (IOP) in the per-protocol population at week 12, and the average eye IOP at weeks 2, 6 and 12 in the intent-to-treat population. RESULTS: 561 patients were randomised (278 to bimatoprost/timolol PF; 283 to bimatoprost/timolol); 96.3% completed the study. Both treatment groups showed statistically and clinically significant mean decreases from baseline in worse eye IOP and in average eye IOP at all follow-up time points (p<0.001). Bimatoprost/timolol PF met all pre-established criteria for non-inferiority and equivalence to bimatoprost/timolol. Ocular adverse events were similar between treatment groups, with conjunctival hyperaemia being the most frequent. Most were mild or moderate in severity. CONCLUSIONS: Bimatoprost/timolol PF demonstrated non-inferiority and equivalence in IOP lowering compared with bimatoprost/timolol, with no significant differences in safety and tolerability. TRIAL REGISTRATION NUMBER: NCT01177098.

The biodisposition and hypertrichotic effects of bimatoprost in mouse skin.

Studies on bimatoprost were performed with two objectives: (i) to determine whether bimatoprost possesses hair growth-stimulating properties beyond eyelash hypertrichosis and (ii) to investigate the biodisposition of bimatoprost in skin for the first time. Bimatoprost, at the dose used clinically for eyelash growth (0.03%) and given once daily for 14 days, increased pelage hair growth in C57/black 6 mice. This occurred as a much earlier onset of new hair growth in shaved mice and the time taken to achieve complete hair regrowth, according to photographic documentation and visual assessment. Bimatoprost biodisposition in the skin was determined at three concentrations: 0.01%, 0.03% and 0.06%. Dose-dependent C(max) values were obtained (3.41, 6.74, 12.3 µg/g tissue), and cutaneous bimatoprost was well maintained for 24 h following a single dose. Bimatoprost was recovered from the skin only as the intact molecule, with no detectable levels of metabolites. Thus, bimatoprost produces hypertrichosis as the intact molecule.

Effects of corneal thickness on the intraocular penetration of travoprost 0.004%.

PURPOSE: To determine whether the intraocular penetration of travoprost 0.004% is affected by central corneal thickness. METHODS: Sixty-four patients who were scheduled for cataract surgery without any other ophthalmologic pathology of significance were enrolled in this study. At 120 min before surgery, one drop of travoprost 0.004% was instilled in the eye to be operated on. At the start of surgery, a sample of aqueous humour was extracted to subsequently determine its AL-5848 concentration. These concentrations were compared among three groups of patients established according to central corneal thickness measurements obtained by ultrasound pachymetry. RESULTS: Mean AL-5848 concentrations were 3.27±2.03 ng/ml in Group I (CCT<511 microns), 3.27±2.44 ng/ml in Group II (CCT≥511 and ≤574 microns), and 2.73±2.15 ng/ml in Group III (CCT>574 microns), indicating no significant differences among the groups. CONCLUSIONS: We were unable to demonstrate the greater or lesser penetration of travoprost depending on corneal thickness, which could explain differences in patient responses to this drug.

Comparison of human ocular distribution of bimatoprost and latanoprost.

PURPOSE: This study investigated the ocular distribution of bimatoprost, latanoprost, and their acid hydrolysis products in the aqueous humor, cornea, sclera, iris, and ciliary body of patients treated with a single topical dose of 0.03% bimatoprost or 0.005% latanoprost for understanding concentration-activity relationships. METHODS: Thirty-one patients undergoing enucleation for an intraocular tumor not affecting the anterior part of the globe were randomized to treatment with bimatoprost or latanoprost at 1, 3, 6 or 12 h prior to surgery. Concentrations of bimatoprost, bimatoprost acid, latanoprost, and latanoprost acid in the human aqueous and ocular tissues were measured using liquid chromatography tandem mass spectrometry. RESULTS: Following topical administration, intact bimatoprost was distributed in human eyes with a rank order of cornea/sclera >iris/ciliary body >aqueous humor. Bimatoprost acid was also detected in these tissues, where its low levels in the cornea relative to that of latanoprost acid indicated that bimatoprost hydrolysis was limited. Latanoprost behaved as a prodrug that entered eyes predominantly via the corneal route. Levels of latanoprost acid were distributed as cornea >>aqueous humor>iris>sclera>ciliary body. CONCLUSIONS: Our study provided experimental evidence that levels of bimatoprost in relevant ocular tissues, and not only aqueous humor, are needed to understand the mechanisms by which bimatoprost lowers intraocular pressure (IOP) in human subjects. The data suggest that bimatoprost reached the target tissues favoring the conjunctival/scleral absorption route. Findings of intact bimatoprost in the target ciliary body indicated its direct involvement in reducing IOP. However, bimatoprost acid may have only a limited contribution on the basis that bimatoprost has greater/similar IOP-lowering efficacy than latanoprost, yet bimatoprost acid levels were a fraction of latanoprost acid levels in the aqueous humor and cornea and only sporadically detectable in the ciliary body. In this report, human ocular tissues were examined concurrently with aqueous humor for the in vivo distribution of bimatoprost, bimatoprost acid, latanoprost, and latanoprost acid.

Aqueous humor concentrations of bimatoprost free acid, bimatoprost and travoprost free acid in cataract surgical patients administered multiple topical ocular doses of LUMIGAN or TRAVATAN.

PURPOSE: To quantify the aqueous humor (AH) concentrations of bimatoprost (amide), travoprost (isopropyl ester), and their hydrolysis products, bimatoprost free acid (BFA) and travoprost free acid (TFA), after multiple topical ocular doses of LUMIGAN and TRAVATAN, respectively, in patients awaiting cataract surgery. METHODS: In 2 separate open-label, sparse-sampling trials, glaucoma patients with cataracts received LUMIGAN (bimatoprost ophthalmic solution, 0.03%) or TRAVATAN (travoprost ophthalmic solution, 0.004%) bilaterally once daily for at least 21 days prior to cataract surgery. Anterior chamber paracentesis was performed at selected times up to 5 h after the last dose and an AH sample was collected. AH samples were assayed by an independent bioanalytical laboratory using a sensitive and validated tandem LC-MS/MS method. The assay lower limits of quantitation were 0.59 nM for bimatoprost, 0.29 nM for BFA, and 0.44 nM for TFA. RESULTS: AH concentrations of BFA (17-phenyl-trinor PGF(2alpha)) were quantifiable in all but one sample at 0.5 h. The maximum concentration achieved (C(max)) of BFA was 30.9 + or - 16.41 nM (n =5), observed at 2 h postdose. AH concentrations of bimatoprost amide were lower than BFA at all time points, with a C(max) of 6.81 + or - 1.36 nM (n = 7) at 1 h postdose. For TFA, measurable AH concentrations were obtained at all time points with a TFA C(max) of 3.91 + or - 2.27 nM (n = 5), which was observed at 3 h after the dose (all data are mean + or - SEM). CONCLUSIONS: Once daily topical ocular administration of LUMIGAN or TRAVATAN for 3 weeks resulted in significant concentrations of BFA and TFA in the AH. Quantifiable levels of bimatoprost amide were also measured. Maximum concentrations of BFA (30.9 nM) and TFA (3.91 nM) in the anterior chamber are sufficient to fully activate the FP prostanoid receptors in the target cells of the ciliary muscle and trabecular meshwork. Both bimatoprost in LUMIGAN and travoprost in TRAVATAN are essentially prodrugs that are rapidly hydrolyzed to their respective free acids that induce the IOP-lowering effect observed with both drugs in vivo.

Interaction of ocular hypotensive agents (PGF2 alpha analogs-bimatoprost, latanoprost, and travoprost) with MDR efflux pumps on the rabbit cornea.

PURPOSE: The objectives of this work were (i) to screen ocular hypotensive prostaglandin (PGF2 alpha) analogs--bimatoprost, latanoprost, and travoprost as well as their free acid forms--for interaction with efflux pumps on the cornea and (ii) to assess the modulation of efflux upon co-administration of these prostaglandin analogs. METHODS: Cultured rabbit primary corneal epithelial cells (rPCEC) were employed as an in vitro model for rabbit cornea. Transporter-specific interaction studies were carried out using Madin-Darby canine kidney (MDCK) cells overexpressing MDR1, MRP1, MRP2, MRP5, and BCRP. Freshly excised rabbit cornea was used as an ex vivo model to determine transcorneal permeability. RESULTS: Cellular accumulation studies clearly showed that all prostaglandin analogs and their free acid forms are substrates of MRP1, MRP2, and MRP5. Bimatoprost was the only prostaglandin analog in this study to interact with P-gp. In addition, none of these molecules showed any affinity for BCRP. K (i) values of these prostaglandin analogs obtained from dose-dependent inhibition of erythromycin efflux in rPCEC showed bimatoprost (82.54 microM) and travoprost (94.77 microM) to have similar but higher affinity to efflux pumps than latanoprost (163.20 microM). Ex vivo studies showed that the permeation of these molecules across cornea was significantly elevated in the presence of specific efflux modulators. Finally, both in vitro and ex vivo experiments demonstrated that the efflux of these prostaglandin analogs could be modulated by co-administering them together. CONCLUSION: Bimatoprost, latanoprost, travoprost, and their free acid forms are substrates of multiple drug efflux pumps on the cornea. Co-administration of these molecules together is a viable strategy to overcome efflux, which could simultaneously elicit a synergistic pharmacological effect, since these molecules have been shown to activate different receptor population for the reduction of intraocular pressure (IOP).

Expression of multidrug resistance associated protein 5 (MRP5) on cornea and its role in drug efflux.

PURPOSE: The purpose of this manuscript is to investigate the presence of nucleoside/nucleotide efflux transporter in cornea and to evaluate the role in ocular drug efflux. METHODS: RT-PCR, immunoprecipitation followed by Western blot analysis and immunostaining were employed to establish molecular presence of multidrug resistance associated protein 5 (MRP5) on cornea. Corneal efflux by MRP5 was studied with bis(POM)-PMEA and acyclovir using rabbit and human corneal epithelial cells along with MRP5 over expressing cells (MDCKII-MRP5). Ex vivo studies using excised rabbit cornea and in vivo ocular microdialysis in male New Zealand white rabbits were used to further evaluate the role of MRP5 in conferring ocular drug resistance. RESULTS: RT-PCR confirms the expression of MRP5 in both rabbit and human corneal epithelial cells along with MDCKII-MRP5 cells. Immunoprecipitation followed by Western blot analysis using a rat (M511-54) monoclonal antibody that reacts with human epitope confirms the expression of MRP5 protein in human corneal epithelial cells and MDCKII-MRP5 cells. Immunostaining performed on human cornea indicates the localization of this efflux pump on both epithelium and endothelium. Efflux studies reveal that depletion of ATP decreased PMEA efflux significantly. MRP5 inhibitors also diminished PMEA and acyclovir efflux. However, depletion of glutathione did not alter efflux. MDR1 and MRP2 did not contribute to PMEA efflux. However, MRP2 is involved in acyclovir efflux while MDR1 do not participate in this process. TLC/autoradiography suggested the conversion of bis(POM)-PMEA to PMEA in rabbit and human corneal epithelial cells. Two well known antiglaucoma drugs, bimatoprost and latanoprost were rapidly effluxed by MRP5. Ex vivo study on intact rabbit corneas demonstrated accumulation of PMEA in cornea in the presence of ATP-depleting medium. In vivo ocular pharmacokinetics also revealed a significant increase in maximum aqueous humor concentration (C(max)) and area under the aqueous humor time curve (AUC) of acyclovir in the presence of MK-571, a specific MRP inhibitor. CONCLUSIONS: Taken together immunolocalization on human cornea, in vitro efflux in human, rabbit corneal and MRP5 over expressing cells, ex vivo and in vivo studies in intact rabbit cornea suggest that MRP5 on cornea can significantly lower the permeability of antiviral and glaucoma drugs. These findings may be valuable in developing formulation strategies to optimize ocular bioavailability of topically administered ocular agents.

Bimatoprost/timolol: a review of its use in glaucoma and ocular hypertension.

Topically administered bimatoprost 0.03%/timolol 0.5% ophthalmic solution (bimatoprost/timolol: Ganfort) comprises the synthetic prostamide bimatoprost (structurally related to prostaglandin F2 alpha) and the beta-adrenergic receptor antagonist timolol. Bimatoprost/timolol (one drop administered in the affected eye[s] once daily in the morning or evening) is an effective and well tolerated fixed combination for lowering intra-ocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension (OHT), including individuals uncontrolled on monotherapy with a beta-adrenergic receptor antagonist or prostaglandin analogue/prostamide.

Travoprost/timolol fixed combination.

BACKGROUND: Travoprost and timolol are topical ocular hypotensive medications that have been used in the treatment of glaucoma. The fixed combination eye drop, Duotrav (travoprost 0.004% and timolol maleate 0.5%), has recently been introduced into the market. OBJECTIVE: In this paper, the results of clinical trials and existing data on the performance of travoprost/timolol are discussed and analyzed. METHODS: Appopriate studies for review were identified using PubMed. Studies selected for review compared efficacy and side-effect profile of fixed combination travoprost/timolol with travoprost and timolol used concomitantly, latanoprost and timolol used concomitantly, fixed combination latanoprost/timolol, travoprost alone and timolol alone. RESULTS/CONCLUSION: Fixed combination eye drops such as travoprost/timolol offer the potential benefits of increased patient adherence, reduced exposure to preservatives, and reduced cost.

Efficacy and safety of bimatoprost/timolol fixed combination in the treatment of glaucoma or ocular hypertension.

When a single medication does not adequately control intraocular pressure, additional intraocular hypotensive agents are often added to the therapeutic regime. However, regimen complexity has been associated with reduced patient compliance. Treatment with a fixed combination may, therefore, increase compliance as a result of simplifying the dosage regimen. Bimatoprost/timolol fixed combination (BTFC) combines two clinically effective agents that decrease elevated intraocular pressure by independent mechanisms. In two clinical studies, BTFC was more effective than its individual components. Furthermore, in a non-inferiority study BTFC has been shown to be as effective as the association of its individual components. BTFC was clinically effective and generally well tolerated, with no unexpected adverse reactions reported for the BTFC compared with those reported for bimatoprost or timolol monotherapies.

Travoprost/timolol.

Travoprost 0.004%/timolol 0.5% fixed combination (travoprost/timolol) is a once-daily eyedrops solution comprising the prostaglandin F(2alpha) analogue travoprost and the beta-adrenoceptor antagonist timolol. It is indicated for the treatment of patients with open-angle glaucoma or ocular hypertension who are insufficiently responsive to topical beta-adrenoceptor antagonists or prostaglandin analogues. Once-daily travoprost/timolol had generally similar efficacy to travoprost plus timolol and was more effective than travoprost or timolol monotherapy in reducing intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension in randomised, well designed studies. Both travoprost/timolol and latanoprost plus timolol maintained IOP control, and travoprost/timolol was shown to be noninferior to latanoprost/timolol in randomised, well designed studies. Travoprost/timolol was generally well tolerated, with a tolerability profile similar to those of travoprost plus timolol, travoprost or timolol monotherapy and latanoprost plus timolol. The majority of adverse events, such as ocular hyperaemia, were mild and resolved with or without treatment.

[Circadian rhythm variations of intraocular pressure and therapeutic decisions: interpretation of clinical trial results based on a statistical model]. / Variations nycthémérales de la pression intraoculaire et décisions thérapeutiques: Interprétation des résultats d'essais cliniques à partir d'un modèle statistique.

Therapeutic decisions (treatment initiation, continuation, change, combination, etc.) based on intraocular pressure (IOP) monitoring require knowledge of both circadian IOP fluctuations and the pharmacological circadian rhythm of the active ingredients. A simple model was applied to data from two clinical trials to estimate the consequences of circadian IOP fluctuations on (1) ocular hypertension diagnosis, (2) therapeutic adjustments, and (3) the daily cumulative effect of marginally low therapeutic differences. A grid for clinical interpretation of the average IOP differences is presented. The probability of an IOP that exceeds the target value for the diagnosis or therapy varied to a large extent throughout the day. IOP was higher in the morning than in the evening. The IOP variance (measured by standard deviation) was an important factor in decision-making, regardless of the IOP value itself. Regular IOP monitoring over the entire day allowed minimization of the time spent above a target value. IOP differences that seemed low when expressed in average values in therapeutic trials could have clinically significant consequences in the practitioner's decisions. The data presented suggest that ocular hypertension diagnosis and therapeutic decisions should be made early in the morning, at least for most patients. In any case, the time of the measurement should be considered in the therapeutic approach.

Travoprost: a potent ocular hypotensive agent.

Travoprost (isopropyl (Z)-7-[(1R,2R,3R,5S)-3,5-dihydroxy-2-[(1E,3R)-3-hydroxy-4-[alpha,alpha,alpha,trifluoro-m-tolyl)oxy]-1butenyl]cyclopentyl]-5-heptenoate) is an isopropyl ester prodrug and a high-affinity, selective FP prostaglandin- receptor full agonist. This prodrug is a synthetic prostaglandin analogue, which in appropriate cases is administered topically for the treatment of glaucoma and ocular hypertension. The isopropyl ester prodrug is rapidly hydrolyzed by esterases in the cornea to the biologically active, free acid. Travoprost has demonstrated preferential affinity and full agonist activity for the FP receptor in the nanomolar range, with no meaningful affinity or activity at other receptors. Like other compounds of this class, the reduction of intraocular pressure by travoprost is due at least in part to increased uveoscleral outflow. Results from phase II and phase III pivotal studies for FDA approval in the United States have demonstrated that travoprost is an effective topical agent for treatment of elevated intraocular pressure in patients with open-angle glaucoma and ocular hypertension. Travoprost is a safe drug, with local side effects including hyperemia, eyelash growth and iris color change. The dosing is once per day in the evening, and storage does not require refrigeration. Travoprost will be a helpful new drug in the medical management of glaucoma.

Travoprost.

Travoprost is a synthetic ester prodrug of a prostaglandin F(2alpha) analogue used in the treatment of open-angle glaucoma and ocular hypertension. Intraocular travoprost 0.004% once daily was significantly more effective at reducing intraocular pressure (IOP) in patients with open-angle glaucoma or ocular hypertension than placebo or timolol 0.5% twice daily and was at least as effective as latanoprost 0.005% once daily in randomised, double-blind studies. When used as adjunctive therapy with timolol 0.5% twice daily in patients with elevated IOP not adequately controlled by timolol alone, travoprost 0.004% showed significant additional IOP reduction in a randomised double-blind trial. Travoprost 0.004% was well tolerated in clinical trials. The majority of adverse events such as ocular hyperaemia and eyelash changes were mild and resolved without treatment.

Determination of travoprost and travoprost free acid in human plasma by electrospray HPLC/MS/MS.

A quantitative method for the analysis of AL-5848, the (+)-enantiomer of fluprostenol (FP), in human plasma is described. Plasma was spiked with a tetradeuterated analog of travoprost free acid (AL-5848X) as internal standard (IS) and acidified with 0.1 M formic acid. Sample clean up was performed using reversed phase solid-phase extraction. Following elution of the compounds of interest and evaporation to dryness, the residue was reconstituted in methanol:water (1:1) and chromatographed on an octadecylsilica (C18) column with negative ion electrospray ionization tandem mass spectrometry. The [M[bond]H](-) ions at m/z 457 and 461 for the analyte and IS, respectively, were subjected to collisional fragmentation with argon to yield the same intense 3-trifluoromethylphenolate (m/z 161) product ion. The validated concentration range was 0.010-3.00 ng/ml based on a 1.0 ml plasma aliquot. Fully adequate accuracy, precision, specificity, recovery and stability for routine use in clinical pharmacokinetic studies were demonstrated. Analysis of a second plasma aliquot following incubation with rabbit esterase allows the isopropyl ester pro-drug, travoprost (AL-6221), to be determined by difference.

Prostaglandin analog treatment of glaucoma and ocular hypertension.

OBJECTIVE: To review available data related to the use of prostaglandin analogs (bimatoprost, latanoprost, travoprost, unoprostone) in the management of ocular hypertension and open-angle glaucoma. DATA SOURCES: Primary and review articles were identified from a MEDLINE search (1966-May 2001) and requested information from product manufacturers. STUDY SELECTION AND DATA EXTRACTION: All available information, including that published in articles and abstracts, which was deemed relevant was included in this review. Limited data have been published to date. DATA SYNTHESIS: The prostaglandin analogs appear to be effective, well-tolerated agents for the reduction of intraocular pressure (IOP) in patients with primary open-angle glaucoma and ocular hypertension. This drug class offers an alternative for patients who do not achieve control with another topical antiglaucoma agent or for those with a contraindication to first-line therapy with beta-adrenergic antagonists. Based on preliminary clinical data, bimatoprost, latanoprost, and travoprost appear to be at least as effective as timolol, while the effectiveness of unoprostone is similar or slightly less. Prostaglandin analogs may be used in conjunction with other antiglaucoma medications, although further studies must establish the optimal combination. Whether clinical experience will yield outcomes in favor of one of the prostaglandin analogs remains to be determined. Patients should be educated on adverse events associated with prostaglandin analogs, particularly the potential for changes in the pigmentation of the iris and eyelashes. CONCLUSIONS: Bimatoprost, latanoprost, and travoprost appear to be equivalent to the current standard of therapy in the topical treatment of elevated IOP. Further clinical data published in article versus abstract format is required to better assess potential differences among these 3 agents.

Enantioselective behaviour of drugs used in domestic animals: a review.

The chirality of drugs, with particular reference to agents used in veterinary medicine, is reviewed. Basic concepts of chirality and aspects of the methodology for the separation of enantiomers are considered. Chiral compounds are in common use in animals and their pharmacological actions and side-effects (pharmacodynamics) and absorption into and fate within the body (pharmacokinetics) are of fundamental importance; pharmacodynamic and pharmacokinetic properties of enantiomeric pairs commonly differ and this has major implications for their effective and safe therapeutic use. As examples of the particular significance of chirality in veterinary medicine, the following drug classes are reviewed; benzimidazole anthelmintics, cloprostenol, verapamil, ketamine, halogenated hydrocarbon anaesthetics and 2-arylpropionic acid anti-inflammatory drugs. The implications of chirality for drug product development and approval by registration authorities are discussed.