Does preservative content affect drug permeability? The permeability analysis in vitro of 3 ophthalmic Latanoprost formulations in a human epithelial cell culture model. / Czy przenikalnosc leku jest uwarunkowana zawartoscia srodka konserwujacego? Analiza in vitro na modelu komórkowym nablonka ludzkiej rogówki przenikalnosci trzech preparatów okulistycznych zawierajacych latanoprost.

Aim: Comparative permeability analysis of the 3 following Latanoprost formulations intended for ophthalmic use: Xaloptic (Pol­pharma S.A.), Xalatan (Pfizer Europe MA EEIG) and Monoprost (Thea Pharma S.A.) across human corneal epithelium (HCE-T culture model) in vitro. Material and methods: Permeability analysis was performed under conditions suitable for latanoprost API (active pharmaceutical ingredient). Statistical analysis of permeability and drug quantity after passing across a cellular membrane was performed using ANOVA test and Tukey's multiple comparison test (GraphPad Prism 6.00 for Windows, GraphPad Software, La Jolla California, USA Results: The following differences in permeability were noted between the analyzed drugs: The permeability rates for Xaloptic and Xalatan were 5.49 ± 1.64 x 10-6 cm/s and 4.66 ± 1.13 x 10-6 cm/s, respectively. Xaloptic showed the highest permeability through human corneal epithelium (23.70 ± 1.71 x 10-6 cm/s) and the highest conversion rate (28.13 ± 5.85%). As compared to Xaloptic, Xalatan slight, yet statistically significant differences with the permeability rate of 21.21 ± 1.29 x 10-6 cm/s and a conversion rate of 18.41 ± 2.96%). Monoprost demonstrated the lowest permeability (0.39 ± 0.07 x 10-6 cm/s) and the lowest conversion rate (0.34 ± 0.16%). Conclusion: The differences in permeability and bioavailability between the 3 ophthalmic latanoprost formulations are attributable to the differences in their composition. They are also related to the content of preservative in each preparation.

Mechanism - based translational pharmacokinetic - pharmacodynamic model to predict intraocular pressure lowering effect of drugs in patients with glaucoma or ocular hypertension.

PURPOSE: To develop a mechanism based translational pharmacokinetic-pharmacodynamic (PKPD) model in preclinical species and to predict the intraocular pressure (IOP) following drug treatment in patients with glaucoma or ocular hypertension (OHT). METHODS: Baseline diurnal IOP of normotensive albino rabbits, beagle dogs and patients with glaucoma or OHT was collected from literature. In addition, diurnal IOP of patients treated with brimonidine or Xalatan® were also obtained from literature. Healthy normotensive New Zealand rabbits were topically treated with a single drop of 0.15% brimonidine tartrate and normotensive beagle dogs were treated with a single drop of Xalatan®. At pre-determined time intervals, IOP was measured and aqueous humor samples were obtained from a satellite group of animals. Population based PKPD modeling was performed to describe the IOP data and the chosen model was extended to predict the IOP in patients. RESULTS: Baseline IOP clearly depicts a distinctive circadian rhythm in rabbits versus human. An aqueous humor dynamics based physiological model was developed to describe the baseline diurnal IOP across species. Model was extended to incorporate the effect of drug administration on baseline IOP in rabbits and dogs. The translational model with substituted human aqueous humor dynamic parameters predicted IOP in patients following drug treatment. CONCLUSIONS: A physiology based mechanistic PKPD model was developed to describe the baseline and post-treatment IOP in animals. The preclinical PKPD model was successfully translated to predict IOP in patients with glaucoma or OHT and can be applied in assisting dose and treatment selection and predicting outcome of glaucoma clinical trials.

Biodegradable nanoparticles for controlled subconjunctival delivery of latanoprost acid: in vitro and in vivo evaluation. Preliminary results.

Purpose of the study was to develop and assess a novel controlled drug delivery system of latanoprost acid (LA). Poly(lactide)/Monomethoxy-poly(ethyleneglycol) (PLA-PEG) nanoparticles (NPs) were prepared using an emulsification-solvent evaporation technique. NPs were characterized in vitro according to their size, ζ-potential, drug entrapment efficiency and LA release. LA-loaded NPs (equivalent to 8.5 µg LA) were administered into the subconjunctival space of normotensive rabbits (group A). A free LA solution of the same drug content was subconjunctivally injected in a second rabbit group (group B), while blank NPs were administered in a third group (group C). A group of untreated animals (group D) served as the control. Intraocular pressure (IOP) was monitored for 8 consecutive days, using the Tono-pen XL. Aqueous humor (AH) levels of LA were evaluated for 6 days post-administration, by means of HPLC. Mean nanoparticle size was 80 nm. The drug entrapment efficiency was 18.3%. NPs sustained the release of LA over several days in vitro. Non-significant differences in baseline IOP were found between groups (p = 0.22). LA-loaded NPs exerted a significant hypotensive effect on group A, while IOP values remained significantly lower compared to the rest groups, throughout the study (p = 0.04). LA AH concentrations in group B continuously decreased with time, while LA levels in group A steadily increased. On day 6, LA levels were higher in group A compared to group B (344 ± 73.5 ng/ml and 228 ± 41.01 ng/ml, respectively). No adverse effects were observed. In conclusion, after subconjunctival administration, the LA-loaded NPs provided sustained LA delivery in vivo. They appear to be a promising system for the controlled subconjunctival delivery of LA.

Latanoprost systemic exposure in pediatric and adult patients with glaucoma: a phase 1, open-label study.

OBJECTIVE: To evaluate short-term safety and steady-state systemic pharmacokinetics (PK) of latanoprost acid in pediatric subjects with glaucoma or ocular hypertension who received the adult latanoprost dose. DESIGN: Phase 1, open-label, multicenter study. PARTICIPANTS: Pediatric patients of 3 age groups (<3, 3-<12, and 12-<18 years) and adults (≥18 years) receiving latanoprost ophthalmic solution 0.005% once daily in 1 or both eyes for ≥2 weeks. INTERVENTION: Latanoprost was administered in both eyes each morning post-screening. Subjects returned 3 to 28 days later for evaluation of plasma concentrations, withholding morning latanoprost. At the clinic, a single drop of latanoprost ophthalmic solution was instilled into both eyes. Plasma latanoprost acid concentrations were collected predose and 5, 15, 30, and 60 minutes after administration. MAIN OUTCOME MEASURES: Latanoprost acid plasma exposure. RESULTS: The evaluable PK analysis set included data from 39 of 47 enrolled subjects. The median peak plasma concentration value was higher in the <3-year age group (166 pg/ml) versus other groups (49, 16, and 26 pg/ml for the 3-<12-year, 12-<18-year, and ≥18-year age groups, respectively). The median area under the concentration-time curve from zero to last measurable concentration value was also higher in the <3-year age group (2716 pg/min/ml) versus other groups (588, 106, and 380 pg/min/ml for the 3-<12-year, 12-<18-year, and ≥18-year age groups, respectively). Latanoprost acid was rapidly eliminated from the blood, with plasma concentrations undetectable within 10 to 30 minutes postdose in all but the <3-year age group. There were no discontinuations or dose reductions due to adverse events or treatment-emergent adverse events. CONCLUSIONS: Latanoprost acid systemic exposure was higher in younger children versus adolescents and adults, attributed primarily to lower body weight and smaller blood volume. Latanoprost acid was eliminated rapidly in all age groups and resulted in only a brief period of systemic exposure after once-daily dosing. Higher systemic exposure was not accompanied by adverse events, and on the basis of extrapolation of safety data from adults, this pilot study suggests an adequate safety margin for systemic adverse effects with use of the adult topical dose of latanoprost in pediatric patients. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosures may be found after the references.

Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating prostaglandin F2α agonist, in preclinical models.

The aim of the study was to investigate the ocular hypotensive activity of a nitric oxide (NO)-donating latanoprost, BOL-303259-X, following topical administration. The effect of BOL-303259-X (also known as NCX 116 and PF-3187207) on intraocular pressure (IOP) was investigated in monkeys with laser-induced ocular hypertension, dogs with naturally-occurring glaucoma and rabbits with saline-induced ocular hypertension. Latanoprost was used as reference drug. NO, downstream effector cGMP, and latanoprost acid were determined in ocular tissues following BOL-303259-X administration as an index of prostaglandin and NO-mediated activities. In primates, a maximum decrease in IOP of 31% and 35% relative to baseline was achieved with BOL-303259-X at doses of 0.036% (9 µg) and 0.12% (36 µg), respectively. In comparison, latanoprost elicited a greater response than vehicle only at 0.1% (30 µg) with a peak effect of 26%. In glaucomatous dogs, IOP decreased from baseline by 44% and 10% following BOL-303259-X (0.036%) and vehicle, respectively. Latanoprost (0.030%) lowered IOP by 27% and vehicle by 9%. Intravitreal injection of hypertonic saline in rabbits increased IOP transiently. Latanoprost did not modulate this response, whereas BOL-303259-X (0.036%) significantly blunted the hypertensive phase. Following BOL-303259-X treatment, latanoprost acid was significantly elevated in rabbit and primate cornea, iris/ciliary body and aqueous humor as was cGMP in aqueous humor. BOL-303259-X lowered IOP more effectively than latanoprost presumably as a consequence of a contribution by NO in addition to its prostaglandin activity. The compound is now in clinical development for the treatment of glaucoma and ocular hypertension.

Role of expression of prostaglandin synthases 1 and 2 and leukotriene C4 synthase in aspirin-intolerant asthma: a theoretical study.

Altered expressions of the key enzymes in arachidonic acid (AA) metabolism, prostaglandin synthase 1 and 2 and cysteinyl leukotriene C(4) synthase, are of importance in understanding aspirin-induced asthma. We propose a mathematical model of AA metabolism and its interaction with non-steroidal anti-inflammatory drugs (NSAIDs). Model simulations depict the impact of modified expressions of the above enzymes on the time dependent synthesis of cysteinyl leukotrienes and anti-inflammatory prostaglandins before and during NSAID exposure in different model states describing healthy humans as well as aspirin-tolerant and -intolerant asthmatics. The results are compared and evaluated with experimental data taken from the literature. Our results identify the decreased expression of prostaglandin H synthase 1 and increased expression of leukotriene C(4) synthase as the key elements in AA metabolism that contribute to increased leukotriene C(4) and decreased anti-inflammatory prostaglandins after NSAID dosing in aspirin-intolerant patients. On the other hand, the decreased expression of prostaglandin H synthase 2 implies permanently increased leukotriene C(4) and lowers the sensitivity to increased drug doses. The model is used for identification of susceptible patient populations for aspirin and ibuprofen, and for identification of critical aspirin doses that might induce bronchoconstriction.

The effect of a single dose of topical 0.005% latanoprost and 2% dorzolamide/0.5% timolol combination on the blood-aqueous barrier in dogs: a pilot study.

OBJECTIVE: To determine the effects of 0.005% latanoprost and 2% dorzolamide/0.5% timolol on the blood-aqueous barrier (BAB) in normal dogs. ANIMALS STUDIED: Eight mixed-breed and pure-breed dogs. PROCEDURES: Baseline anterior chamber fluorophotometry was performed on eight normal dogs. Sodium fluorescein was injected and the dogs were scanned 60-90 min post-injection. Seventy-two hours following the baseline scan, one eye received one drop of latanoprost. Fluorophotometry was repeated 4 h after drug administration. Following a washout period, the identical procedure was performed 4 h after the administration of dorzolamide/timolol. The degree of BAB breakdown was determined by comparing the concentrations of fluorescein within the anterior chamber before and after drug administration. BAB breakdown was expressed as a percentage increase in the post-treatment fluorescein concentration over the baseline concentration: %INC [Fl] = {([Fl](post)-[Fl](baseline))/[Fl](baseline)} x 100. The percentage increase in fluorescein concentration in the treated eye was compared to that in the nontreated eye using a paired t-test with significance set at P < or = 0.05. RESULTS: Following administration of latanoprost, the fluorescein in the treated eyes increased 49% (+/- 58%) from baseline compared to 10% (+/- 31%) in the untreated eyes (P = 0.016). Following administration of dorzolamide/timolol, the fluorescein concentration increased 38% (+/- 54%) compared to baseline vs. 24% (+/- 38%) in the untreated eyes (P = 0.22). CONCLUSIONS: The results of this study show that topical latanoprost may cause BAB disruption in normal dogs while topical dorzolamide/timolol may have no effect on the BAB in normal dogs.

Advantages of Efficacy and Safety of Fixed-Dose Tafluprost/Timolol Combination Over Fixed-Dose Latanoprost/Timolol Combination.

PURPOSE: To compare the safety and efficacy of fixed-dose tafluprost/timolol combination (Taf/T-FDC) with those of fixed-dose latanoprost/timolol combination (Lat/T-FDC) by measuring the intraocular pressure (IOP)-lowering effect, ocular pharmacokinetics, and ocular surface toxicity. METHODS: The IOP-lowering effect of Taf/T-FDC and Lat/T-FDC in ocular normotensive monkeys was evaluated at 4 and 8 h after instillation in study A, at 12, 14, 16, and 18 h after instillation in study B, and at 24, 26, 28, and 30 h after instillation in study C. Drug penetration into the eye was evaluated by measuring the concentrations of timolol, tafluprost acid (active metabolic form of tafluprost), and latanoprost acid (active metabolic form of latanoprost) using liquid chromatography coupled with tandem mass spectrometry after single instillation of Taf/T-FDC or Lat/T-FDC to Sprague Dawley rats. Cytotoxicity following 1-30 min exposure of SV40-transformed human corneal epithelial cells to Taf/T-FDC or Lat/T-FDC was analyzed using 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium assays. Undiluted and 10-fold diluted solutions of each FDC were evaluated. RESULTS: The IOP-lowering effect of Taf/T-FDC was almost equivalent to that of Lat/T-FDC at 4-8 h after instillation. The peak IOP reduction of Taf/T-FDC and Lat/T-FDC was observed at 8 h after instillation, and there is no difference between the two. The difference between them was observed at 24-30 h after instillation, and Taf/T-FDC demonstrated a significantly greater IOP-lowering effect than Lat/T-FDC at 24-30 h after instillation. The IOP-lowering effect of Taf/T-FDC was sustained up to 30 h after instillation, while that of Lat/T-FDC had almost disappeared at 28 h after instillation. Timolol concentrations in aqueous humor after Taf/T-FDC instillation were higher than those after Lat/T-FDC instillation (Cmax, 3870 ng/mL vs 1330 ng/mL; AUCinf, 3970 ng·h/mL vs 1250 ng·h/mL). The concentrations of tafluprost acid and latanoprost acid in aqueous humor after instillation of Taf/T-FDC and Lat/T-FDC, respectively, were similar to those after instillation of mono-preparations of tafluprost and latanoprost, respectively. The cytotoxic effect of Taf/T-FDC to the human corneal epithelial cells was significantly lower than that of Lat/T-FDC at all evaluated time points in both undiluted and 10-fold diluted FDCs. CONCLUSION: Taf/T-FDC provides increased IOP-lowering effect duration and lower potential ocular surface toxicity than Lat/T-FDC.

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.

PhXA34, a new potent ocular hypotensive drug. A study on dose-response relationship and on aqueous humor dynamics in healthy volunteers.

The prostaglandin analogue PhXA34 was tested in two studies in normal human eyes; 1, 3, and 10 micrograms of PhXA34 reduced the intraocular pressure by about 2, 3, and 4 mm Hg, respectively, 6 to 10 hours after a single topical dose. The only side effect observed was a slight conjunctival hyperemia after 10 micrograms of PhXA34. In a second study we determined the effect of 10 micrograms of PhXA34 once daily for 7 days on intraocular pressure, outflow facility, aqueous flow, blood-aqueous barrier permeability, ocular discomfort, and hyperemia. The mean intraocular pressure was below 9 mm Hg 12 hours post dose. About one third of the intraocular pressure reduction could be explained by increased outflow facility. Aqueous flow was unaffected. Treatment caused a 21% increase in aqueous fluorescence 1 hour after an oral dose of fluorescein. Mild ocular discomfort and some hyperemia were initially observed in half of the subjects, but frequency and magnitude of these side effects declined during the study.

The effects on aqueous dynamics of PhXA41, a new prostaglandin F2 alpha analogue, after topical application in normal and ocular hypertensive human eyes.

OBJECTIVE: To study the effects of a topically applied prostaglandin F2 alpha analogue, PhXA41 (Latanoprost; 13,14-dihydro-17-phenyl-18,19,20-trinor-prostaglandin F2 alpha-isopropyl ester), on aqueous dynamics in the human eye. DESIGN: A randomized, double-masked study was carried out on 20 normal and 20 ocular hypertensive humans. One eye of each subject was treated with 0.006% PhXA41, while the contralateral eye received placebo twice daily for 5 days. MAIN OUTCOME: Compared with placebo, PhXA41 reduced intraocular pressure in both groups by approximately 20%. RESULTS: Tonographic facility of outflow was increased 24% in the normal group and 30% in the ocular hypertensive group; no changes were observed in the rates of aqueous humor flow in either group. The changes in tonographic facility were insufficient to fully explain the ocular hypotensive effect of the drug, suggesting that PhXA41 enhances outflow via the uveoscleral pathway. The suitability of fluorophotometry as a measure of flow was confirmed by three methods of comparing blood-aqueous barrier permeability: polarization of cameral fluorescence, intensity of backscattered light from the anterior chamber (flare), and cameral fluorescence after oral administration of fluorescein sodium. All of these measured parameters were normal, suggesting that this compound has no clinically significant effects on the blood-aqueous barrier or on the accuracy of fluorophotometry. PhXA41 was well tolerated in both groups. Only four of 40 subjects reported a transient foreign-body sensation, and only one of 40 subjects was observed to have greater than moderate conjunctival hyperemia. Most subjects had no symptoms and no measurable hyperemia. CONCLUSIONS: These results suggest that PhXA41 is a potentially useful ocular hypotensive agent that enhances the egress of aqueous humor via both major outflow pathways. The relative lack of ocular side effects in this study further suggests that this agent has promise for the treatment of chronic glaucoma.

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.

Development of a radioimmunoassay for latanoprost and its application in a long-term study in monkeys.

13,14-Dihydro-17-phenyl-18,19,20-trinor-PGF2 alpha-isopropyl ester (latanoprost) is a new prostaglandin drug developed for the treatment of glaucoma. In clinical trials a daily dose of 1.5 micrograms is effective in reducing the intraocular pressure. In toxicological studies doses from 2 micrograms/eye to 100 micrograms/eye have been used in various species. This paper reports the development and validation of a radioimmunoassay of latanoprost acid (PhXA85) and its application to toxicokinetic studies performed in monkeys. An antiserum was raised in rabbits by immunization with PhXA85 coupled to BSA at the carboxylic acid by the mixed anhydride method. The antibody titre was found to be about 1:2000 to 1:3000. The cross-reactivity with 13,14-dihydro-15(R,S)-17-phenyl-trinor-PGF2 alpha, 13,14-dihydro-15(S)-17-phenyl-trinor-PGF2 alpha, dinor-PhXA85. 17-phenyl-trinor-PGF2 alpha, latanoprost and PGF2 alpha was 46.4, 4.2, 7.6, 2.2, 0.1 and 0.039%, respectively. The intra-assay precision was between +/-7.7 and 11.7% (CV) at the level of 320 pg/ml and +/-8.3 and 9.7% with 1280 pg/ml in plasma samples from man, monkey, rat and aqueous humour from human and rabbit. Similarly, the intra-assay accuracy varied between 95.9 and 102.5% and 89.0 and 109.0% for the low and high standards, respectively. The inter-assay precision and accuracy were between +/- 6.0 and 13.4% and 91.0 and 92.8% in the monkey plasma samples. The limit of detection was 3 pg/tube or 30 pg/ml. In a long-term study, the acid of latanoprost was rapidly cleared from plasma in monkeys treated with eye drops of latanoprost (2 x 3 micrograms/day) over a period of 1 year.

Action of prostanoids on the emetic reflex of Suncus murinus (the house musk shrew).

Several prostanoids were investigated for a potential to induce emesis in Suncus murinus. The TP receptor agonist 11alpha,9alpha-epoxymethano-15S-hydroxyprosta-5Z,13E-dienoic acid (U46619) induced emesis at doses as low as 3 microg/kg, i.p. but the DP receptor agonist 5-(6-Carboxyhexyl)-1-(3-cyclohexyl-3-hydroxypropyl) hydantoin (BW245C) was approximately 1000 times less potent. The emetic action of U46619 (300 microg/kg, i.p.) was antagonized significantly by the TP receptor antagonist, vapiprost (P<0.05). EP (prostaglandin E(2), 17-phenyl-omega-trinor prostaglandin E(2), misoprostol and sulprostone), FP (prostaglandin F(2alpha) and fluprostenol) and IP (iloprost and cicaprost) receptor agonists failed to induce consistent emesis at doses up to 300-1000 microg/kg, i.p. Fluprostenol reduced nicotine (5 mg/kg, s.c.)-but not copper sulphate (120 mg/kg, intragastric)-induced emesis; the other inconsistently emetic prostanoids were inactive to modify drug-induced emesis. The results indicate an involvement of TP and possibly DP and FP receptors in the emetic reflex of S. murinus.

Nocloprost, a unique prostaglandin E2 analog with local gastroprotective and ulcer-healing activity.

Nocloprost (9 beta-chloro-16,16-dimethyl prostaglandin E2 (PGE2)) was examined for gastroprotective and ulcer-healing activity and compared to 16,16-dimethyl PGE2 (dmPGE) in rats. Nocloprost given intragastrically (i.g.) at various doses (0.01-10 micrograms/kg) 30 min before 100% ethanol, acidified aspirin (ASA), acidified taurocholate, water immersion, or restraint stress dose dependently prevented the formation of gastric lesions, the ID50 values being 0.25, 0.58, 0.06 and 0.12 micrograms/kg, respectively. The gastroprotection provided by nocloprost given i.g. was somewhat enhanced by the presence of acid in the stomach and was reduced by inhibition of gastric acid secretion. Nocloprost given s.c. also showed protective activity against ethanol damage but was ineffective when applied intraduodenally. The protective effect of nocloprost lasted about 8 h whereas that induced by dmPGE lasted 6 h. Nocloprost (0.01-100 micrograms/kg) given i.g. failed to affect gastric acid secretion or intestinal secretion (enteropooling) but prevented the increased gastroduodenal alkaline secretion. Nocloprost alone caused only a transient increase in the mucosal blood flow but prevented the fall in blood flow caused by 100% ethanol. [3H]Nocloprost was absorbed from the small intestine but was then taken up and metabolized by the liver and excreted into the bile so that very little reached the systemic circulation in an unchanged form. Nocloprost, unlike dmPGE, accelerated the healing of chronic gastric ulcerations and enhanced mucosal growth. We conclude that nocloprost is a locally active PGE2 analog with high cytoprotective and ulcer-healing efficacy.

Latanoprost. A review of its pharmacological properties, clinical efficacy and tolerability in the management of primary open-angle glaucoma and ocular hypertension.

Latanoprost is an ester prodrug analogue of prostaglandin F2 alpha which effectively reduces intraocular pressure (IOP) by increasing uveoscleral outflow rather than altering conventional trabeculo-canalicular) aqueous outflow. The IOP-lowering effect of latanoprost lasts for 20 to 24 hours after a single dose, which allows a single daily dosage regimen. Data from 4 randomised double-masked multicentre studies indicate that a once daily dose of topical latanoprost 0.005% is as effective as timolol 0.5% twice daily in the treatment of patients with primary open-angle glaucoma or ocular hypertension. A number of studies also demonstrate that latanoprost enhances IOP-lowering effects when applied in combination with other antiglaucoma agents. Latanoprost is well tolerated with no, or barely detectable, conjunctival hyperaemia, and, unlike timolol, is not associated with systemic adverse effects. However, 3 to 10% of patients treated with latanoprost 0.005% have shown increased iris pigmentation after 3 to 4.5 months' treatment. In summary, the available data show that latanoprost is a potent IOP-lowering agent with a number of positive features including a single daily dosage regimen, a novel mechanism of action that enhances the IOP-lowering effect of contemporary agents, and a lack of systemic adverse effects. These properties suitably poise latanoprost for a prominent position in the management of patients with primary open-angle glaucoma and ocular hypertension.

Latanoprost : an update of its use in glaucoma and ocular hypertension.

Latanoprost (Xalatan) is an ester analogue of prostaglandin F2alpha that reduces intraocular pressure (IOP) by increasing uveoscleral outflow. The IOP-lowering efficacy of latanoprost 0.005% lasts for up to 24 hours after a single topical dose, which allows for a once-daily dosage regimen. In patients with ocular hypertension or open-angle glaucoma, a single drop of latanoprost 0.005% solution (about 1.5 microg) administered topically once daily reduced diurnal IOP by 22 to 39% over 1 to 12 months' treatment in well-controlled trials; efficacy was maintained during treatment periods of up to 2 years. At this dosage, latanoprost was significantly more effective than timolol 0.5% twice daily in 3 of 4 large, double-blind, randomised studies, was generally as effective as bimatoprost or travoprost, and was significantly more effective than dorzolamide, brimonidine or unoprostone. Furthermore, in patients whose IOP was poorly controlled with timolol, switching to latanoprost monotherapy was at least as effective at lowering IOP as adding dorzolamide or pilocarpine to the regimen. Latanoprost has also shown significant additive effects when used in combination with one or more other glaucoma medications. The fixed combination of latanoprost plus timolol was significantly more effective than either of its individual components in two double-blind randomised studies and more effective than the fixed combination of dorzolamide and timolol in a 3-month, evaluator-masked study. Data in patients with angle-closure glaucoma are limited, but in patients with elevated IOP after undergoing iridotomy, latanoprost 0.005% once daily was significantly more effective than timolol 0.5% twice daily at reducing IOP over 12 weeks of treatment in a large double-blind, randomised study. Latanoprost is generally well tolerated and, unlike timolol, induces minimal systemic adverse events. In well-controlled, 6-month trials, the most commonly occurring drug-related ocular events in latanoprost recipients were mild to moderate conjunctival hyperaemia (3 to 15%) and iris colour change (2 to 9%); these seldom required patient withdrawal although the latter may be permanent. Latanoprost 0.005% as a single daily drop has shown good IOP-lowering efficacy in patients with open-angle glaucoma or ocular hypertension and does not produce the cardiopulmonary adverse effects associated with beta-blockers. Thus, latanoprost is a valuable addition to the first-line treatment options for patients with open-angle glaucoma or ocular hypertension. In addition, adjunctive treatment with latanoprost in patients who are refractory to beta-blocker therapy is a viable, second-line treatment option. Although preliminary findings are promising, wider clinical experience is required to define the place of latanoprost in the treatment of angle-closure glaucoma.

An evaluation of the fixed-combination of latanoprost and timolol for use in open-angle glaucoma and ocular hypertension.

Glaucoma is one of the leading causes of irreversible blindness worldwide. Although there is no cure for this chronic disease, medical treatment is aimed at reducing levels of intraocular pressure (IOP) using ocular hypotensive agents. Very often, patients require more than one IOP-reducing drug, resulting in complex medication regimens that may be difficult to maintain and that can lead to non-compliance. A fixed-combination (FC) ophthalmic solution consisting of the prostaglandin, latanoprost (0.005%), and the beta-blocker, timolol (0.5%), is now available. The primary mechanism of action of latanoprost is to increase uveoscleral outflow whereas timolol lowers IOP levels by decreasing the formation of aqueous humor in the ciliary epithelium. Due to the unique mechanism of action of latanoprost, once-daily dosing of one drop of FC latanoprost/timolol results in additional IOP reduction compared with either drug administered separately. FC latanoprost/timolol is well-tolerated and has a safety profile similar to that of its individual components. This combination drug provides a safe, effective and convenient alternative for the treatment of patients with elevated IOP levels uncontrolled with monotherapy.

Bioavailability in the human eye of a fixed combination of latanoprost and timolol compared to monotherapy.

The ocular pharmacokinetics of a single topical administration of a fixed combination (FC) of latanoprost 0.005% and timolol 0.5% was compared to the monotherapies of latanoprost and timolol in cataract surgery patients. The absorption rate of latanoprost and timolol into the aqueous humor was similar after administration of the FC compared to the two drugs given separately. The aqueous humor concentration of the acid of latanoprost tended to be higher 1-4 hours after administration of FC compared to latanoprost monotherapy. This resulted in an increased AUC. The Tmax and elimination half-life of both latanoprost and timolol were similar after administration of either FC or the two drugs given as monotherapy. Latanoprost did not have any influence on the ocular pharmacokinetics of timolol. The bioavailability of latanoprost and timolol into human aqueous humor, after FC, was at least as good as for the two drugs administered separately.