Latanoprost Solution Research Articles

Comparison of In Vitro Corneal Permeation and In Vivo Ocular Bioavailability in Rabbits of Three Marketed Latanoprost Formulations.

All latanoprost formulations currently available for the treatment of glaucoma or ocular hypertension contain the same concentration of latanoprost (0.005%) but differ in excipients, which may affect corneal drug permeability or stability. This study aimed at comparing corneal penetration of three marketed latanoprost solutions with different excipient formulations in invitro and invivo drug permeability studies. Three latanoprost formulations were tested under good laboratory practice conditions: a formulation containing benzalkonium chloride (BAK) but no surfactant (Preserved latanoprost); the same formulation except preservative-free (PF) without BAK or surfactant (SF) (PF SF latanoprost); and a different formulation without BAK but containing a non-ionic surfactant (MGHS 40 at 5%) combined with thickening agents (Carbomer 974P, Macrogol 4000) (PF latanoprost). Corneal permeation of latanoprost acid (LAT) was first determined invitro using a reconstructed human corneal epithelium tissue. Then, invivo pharmacokinetic studies were performed on pigmented rabbits, for which LAT concentration was measured in the aqueous humour (AH) and iris-ciliary body (ICB). Invitro, the cumulative transport of LAT was linear between 1h and 4h for preserved latanoprost and PF SF latanoprost, and LAT concentrations matched exactly at each timepoint. By contrast, the permeation of PF latanoprost was linear between 2h and 12h and was significantly lower than that of preserved latanoprost and PF SF latanoprost at 4 and 8h (p<0.001). In rabbits, the concentrations of LAT in AH and ICB were not statistically different between preserved latanoprost and PF SF latanoprost at each timepoint, except at 1h in ICB (p=0.005). By comparison, the LAT concentration of PF latanoprost was statistically (p<0.05) lower than that of preserved latanoprost and PF SF latanoprost in AH and ICB from 0.5 to 3h. BAK did not influence the corneal penetration of latanoprost in invitro and invivo studies. The formulation containing a non-ionic surfactant resulted in lower and slower ocular penetration compared with preserved or PF SF formulations. This raises questions about the relevance of BAK and some surfactants in enhancing corneal penetration of ocular formulations.

A novel ophthalmic latanoprost 0.005% nanoemulsion: a cytotoxicity study.

Benzalkonium chloride (BAK), the most commonly used preservative in anti-glaucoma eye drops, inflicts damage to the ocular surface. A novel anti-glaucoma formulation that avoids the use of BAK has been developed. The aim of this study was to evaluate the cytotoxicity of this formulation and to compare it with an ophthalmic solution containing BAK. Two different latanoprost eye drops were used: one ophthalmic solution (LSc) containing BAK 0.02% and one ophthalmic nanoemulsion (LNe) with a soft preservative (potassium sorbate 0.18%). Human epithelial conjunctival cells were incubated for 15, 30, and 60min with either LSc or LNe. The cytotoxicity was determined by MTT assay. Cell death was measured by flow cytometry using annexin V-FITC and propidium iodide. The values of cell viability and proliferation obtained from cells exposed to LNe were between 80 and 90% relative to the control group, whereas values obtained from cells exposed to LSc were around 30% at all study times (p < 0.05 at 15 and 30min; p < 0.01 at 60min). The percentage of viable cells decreased significantly when cells were incubated with LSc compared with cells incubated with LNe at all the study times, while the percentage of cells in late apoptosis/necrosis increased significantly in cells exposed to LSc compared to LNe. The new latanoprost nanoemulsion is significantly less cytotoxic on human conjunctival cells than LSc. These results suggest that the new formulation might be gentler on the eye surface than currently available BAK-preserved latanoprost solutions.

Cytotoxicity evaluation of a novel latanoporst 0.005% nanoemulsion

AbstractPurposeTo evaluate the cytotoxicity of a new Latanoprost Benzalkonium chloride (BAK)‐free nanoemulsion and to compare it with a Latanoprost solution containing BAK.MethodsNormal Human Conjunctival epithelial cells (IOBA‐NHC) were incubated for 15, 30, and 60 minutes with 1:6 dilutions of either latanoprost solution containing BAK (LSc), (latanoprost 0.005%, BAK 0.02%, Xalatan, Pfizer) or latanoprost nanoemulsion (LNe), (latanoprost 0.005%, potassium sorbate 0.18%; Louten Emulsion, POEN). Cytotoxicity was determined by MTT assay. Cell death was measured by flow cytometry using annexin V‐FITC and propidium iodide.ResultsCytotoxicity evaluation: the values of cell viability and proliferation obtained from cells exposed to LNe were between 80 and 90% relative to control group, whereas values obtained from cells exposed to LSc were around 30% relative to control group at all study times (p &lt; 0.05 at 15 and 30 minutes; p &lt; 0.01 at 60 minutes).Cell death evaluation: the percentage of viability was significantly lower in cells exposed to LSc compared with those incubated with LNe at all study times (p &lt; 0.05 at 15 and 30 minutes; p &lt; 0.01 at 60 minutes). Viability of cells exposed to LNe was higher than 90% at all study times, whereas there was a time‐dependent decrease in cells exposed to Lsc. The percentage of viable cells in the LNe group was comparable to the viability of control group (93.1%) at all study times. No statistical differences between groups reached in early apoptotic cells. A significant increase of late apoptosis and necrosis cells were observed at all study times for those incubated with Lsc (p &lt; 0.05; p &lt; 0.01 at 30 and 60 minutes).ConclusionsThe new latanoprost nanoemulsion is significantly less cytotoxic on human conjunctival cells than LSc. It suggests that the new formulation could be gentler on the eye surface than currently available BAK preserved latanoprost solutions, with levels of cytotoxicity equivalent to control.

Peripheral Latanoprost Administration Lowers Intraocular Pressure in the Wistar Rat.

PurposeInstillation of latanoprost eye drops into the conjunctival sac to lower intraocular pressure (IOP) is the most frequently used treatment for primary open-angle glaucoma. The aim of this study was to evaluate the influence of latanoprost on IOP in the rat when applied peripherally.MethodsA rodent-dedicated tonometer was used to measure IOP in conscious adult male normotensive Wistar rats habituated to the measurement procedure. Commercially available 0.005% latanoprost solutions were continuously delivered to the periphery of the eye over 7 days using mini-pumps inserted subcutaneously in the animal’s back, and IOP was measured daily. For comparison, a solution containing an equimolar concentration of latanoprost acid, an active compound of latanoprost, was similarly infused into the eyes of different Wistar rats.ResultsContinuous subcutaneous infusion of latanoprost gradually decreased the IOP; the stable nadir of IOP, which was 20% lower than that prior to the start of infusion, was reached on day 3. The effect was statistically significant and fully reversed 2 days after cessation of drug delivery. Continuous subcutaneous application of the solution containing an equimolar amount of latanoprost acid did not appreciably influence the IOP.ConclusionSubcutaneous continuous delivery of latanoprost decreased the IOP in the conscious normotensive Wistar rats in this study. If this effect is confirmed in humans, it may open the possibility of using peripheral systems of drug delivery, which could significantly improve patient compliance.

Effects of 2% Dorzolamide Hydrochloride and 0.005% Latanoprost Solutions on the Eye Surface of Rabbits

Background: The glaucoma is a progressive optical neuropathy generally associated to the increase of the intraocular pressure (IOP). It is a disease of difficult therapeutic conduct and potential cause of blindness. The dorzolamide at 2% and the latanoprost at 0.005% are topical antiglaucoma drugs that cause significant reduction of the IOP. We decided to evaluate the local adverse effects of the dorzolamide at 2% and of the latanoprost at 0.005% in rabbits treated during 120 days.Materials, Methods &amp; Results: Eighteen adult male rabbits were used in this study. They were randomly distributed into 3 groups (G) [n = 6]. Each animal received topical treatment in both eyes: GI (latanoprost at 0.005%, SID); GII (dorzolamide at 2%, TID) and GIII (ultra-pure water, TID) during 120 days. Ophthalmological evaluation was carried out through daily clinical examination, and at the end of the 120 days of treatment, it was verified clinical-ophthalmological alterations in the eyelids. The measurement of ECC was performed in triplicate, obtaining the lowest value among them as a result. They were carried out at the same time, in the morning between 9 and 10 am in order to avoid the effects of daytime ECC variation related to corneal hydration. In animals from group I, changes were observed in two eyes. Conjunctival hyperemia and ocular secretion, both in mild degree, were evidenced, respectively, in 13.75% and 9.1% of the observations. Conjunctival hyperemia was characterized from the 16th day and lasted until the final time (120 days). The animals from GII, treated with dorzolamide at 2%, presented the highest number of ophthalmological alterations. At the end of the experiment, conjunctival and eyelid changes and presence of ocular secretion, both ranging from mild to moderate, were observed in 60% and 16.32% of eyes, respectively. The animals from control group, GIII, did not present ophthalmological alterations.Discussion: Clinical signs observed in eyes treated with 0.005% latanoprost and 2% dorzolamide hydrochloride demonstrated manifestations of toxicity and / or ocular allergy. The adverse effects described may be related to the preservative of eye drops, benzalkonium chloride, a quaternary ammonia, which demonstrated ocular tissue toxicity, in vivo and in vitro. Benzalkonium chloride present in antiglacomatous drugs can cause conjunctival inflammation affecting the normal immunological functions of the eye. The presence of the preservative mainly justifies the changes found in the group of animals treated with 0.005% latanoprost, considering that the concentration of benzalkonium chloride in this drug is 0.02%, that is, two and a half times greater than of 2% dorzolamide, which is 0.008%. It should be noted that deleterious effects were associated. The other hypothesis associated with the adverse effects observed in the 2% dorzolamide treated group is related to the pH of the drug. This eye drop has a pH of 5.6, while that of 0.005% latanoprost is 6.7. This indicates that 2% dorzolamide may have secondarily induced ocular changes by virtue of its acidic pH. The association of low pH and the presence of benzalkonium chloride in concentration above 0.005% as a preservative of eye drops explains the high percentage of changes observed in this group. When facing the results, one can conclude that the treatment with the latanoprost at 0.005% and dorzolamide at 2% promoted clinical alterations to the eyelids and the conjunctive of rabbits.

Topical latanoprost solution in combination with microneedling in treatment of segmental vitiligo

Background Vitiligo is a depigmenting disorder of the skin and mucous membranes. Latanoprost (LT) is a prostaglandin F2α analog used in the treatment of glaucoma and was found to induce skin pigmentation. Aim This comparative study aims to assess efficiency of topical 0.005% LT solution in combination with microneedling for treatment of segmental vitiligo. Patients and methods The authors addressed 50 patients with segmental vitiligo stable for at least one year divided into two groups in this study: group A included 25 patients treated with topical 0.005% LT solution in combination with microneedling sessions by using dermapen, and group B included 25 patients who were treated with topical 0.005% LT solution alone without microneedling. The response to treatment was evaluated by serial photographs, degree of pigmentation, and vitiligo area scoring index (VASI). All patients were evaluated before the start of the treatment and each month after the end of the treatment. Results The group A, which was treated by combination of topical 0.005% LT ophthalmic solution and microneedling, showed significant improvement in VASI score, whereas group B, which was treated by topical 0.005% LT ophthalmic solution alone without microneedling, showed minimal improvement in VASI score. Conclusion The use of microneedling in combination with using topical LT improves the results of treatment of segmental vitiligo.

An Innovative Therapeutic Protocol for Vitiligo: Experience with the Use of Fraxel Herbium Laser, Topical Latanoprost and Successive Irradiation with UVA - 1 Laser.

Despite the continuous introduction of innovative therapies for vitiligo, today none of them provide constant and excellent results in term of repigmentation. The authors report their experience in treating a localised form of vitiligo with a new protocol consisting in the use of a Fraxel Herbium laser, and in the following application of topical Latanoprost solution and, one day after, in lesional irradiation with UVA1 laser.

Effects of perioperative topical dorzolamide hydrochloride-timolol maleate administration on incidence and severity of postoperative ocular hypertension in dogs undergoing cataract extraction by phacoemulsification.

OBJECTIVE To assess the effects of topically applied 2% dorzolamide hydrochloride-0.5% timolol maleate ophthalmic solution (DHTM) on incidence and severity of postoperative ocular hypertension (POH; ie, intraocular pressure [IOP] > 25 mm Hg) in dogs undergoing cataract extraction by phacoemulsification. DESIGN Randomized, masked, controlled study. ANIMALS 103 dogs (180 eyes). PROCEDURES Pertinent history, signalment, and ophthalmic examination findings were recorded. Dogs received 1 drop of DHTM or sham treatment solution (sterile, buffered, isotonic eye drops) in both eyes 14 hours and 2 hours before anesthetic induction and at the time of corneal incision closure (ie, end of surgery); IOPs were assessed by rebound tonometry 2, 4, 6, and 8 hours after surgery and between 7:30 and 8:00 am on the following day. Dogs with IOPs of 26 to 45 mm Hg received 1 drop of 0.005% latanoprost solution topically; the surgeon's treatment of choice was used for dogs with IOPs > 45 mm Hg. Incidence of POH and postoperative IOPs were compared between treatment groups. RESULTS DHTM treatment resulted in significantly lower incidence of POH than did sham treatment at the level of the dog (18/53 [34%] vs 31/50 [62%]) and the eye (24/94 [26%] vs 42/86 [48%]). Mean IOP did not differ between groups at the time of POH detection. The DHTM-treated eyes that developed POH were significantly more likely to have a 1-hour follow-up IOP < 25 mm Hg after latanoprost administration than were sham-treated eyes (19/25 [76%] vs 18/35 [51%]; OR, 3.87). CONCLUSIONS AND CLINICAL RELEVANCE Multidose perioperative administration of DHTM in dogs undergoing phacoemulsification reduced the incidence of POH and improved responsiveness of POH to latanoprost treatment.

Comparison of two- and three-times-daily topical ophthalmic application of 0.005% latanoprost solution in clinically normal dogs.

To determine whether 2- or 3-times-daily application of topical ophthalmic 0.005% latanoprost solution is more effective at lowering intraocular pressure (IOP) in clinically normal dogs. 9 clinically normal dogs. For each dog, I drop of latanoprost 0.005% solution was applied to 1 eye every 8 or 12 hours each day for 5 days; the contralateral eye received topical ophthalmic treatment with 1 drop of saline (0.9% NaCl) solution at the times of latanoprost application. Ocular examinations of both eyes were performed every 6 hours starting 48 hours prior to and ending 42 hours after the treatment period. Following a 5-week washout interval, the procedures were repeated but the previously latanoprost-treated eye of each dog received latanoprost application at the alternate frequency. Mean ± SD IOP reduction in the latanoprost-treated eyes was 31 ± 6.9% with 2-times-daily application and 33 ± 8.2% with 3-times-daily application. A 2-way repeated-measures ANOVA revealed significant differences in IOP with contributions by treatment (2 or 3 times daily), time of day (diurnal variation), and individual dog. The maximum mean daily IOP reduction in latanoprost-treated eyes was detected on day 3 of latanoprost treatment in each group. Eyes treated 3 times daily had significantly smaller pupil diameter and greater conjunctival hyperemia than eyes treated 2 times daily. The clinical importance of the ocular hypotensive effects of 3-times-daily topical ophthalmic application of 0.005% latanoprost solution in dogs with glaucoma warrants investigation.

Efficacy and safety of carteolol long-acting solution 2% compared with timolol gel-forming solution 0.5% in patients with primary open-angle glaucoma and ocular hypertension: A randomized, parallel-group, open-label phase IV study in Taiwan

Purpose: The purpose of this study is to compare the efficacy and safety of 2% long-acting carteolol solution with 0.5% timolol gel-forming solution added to primary treatment of 0.005% latanoprost solution in patients with primary open-angle glaucoma and ocular hypertension. Materials and Methods: After at least 4 weeks primary treatment with latanoprost, all patients received the combination therapy with either 2% long-acting carteolol or 0.5% timolol gel in addition to latanoprost for 8 weeks. We measured intraocular pressure (IOP) and evaluated systemic and local adverse events between Day 1 and Day 56. Results: Carteolol significantly reduced the IOP from baseline (latanoprost monotherapy) by 11.0% at Day 28 and 11.2% at Day 56. Timolol also reduced IOP by 11.5% at Day 28 and 11.0% at Day 56. There was no statistically significant difference in the IOP reduction between the two groups. There was no adverse event related to the administration of these anti-glaucoma medications during the study period. Conclusions: Both once daily carteolol and timolol medications are safe and effective treatments combined with latanoprost single therapy.

In vivo performance of a drug-eluting contact lens to treat glaucoma for a month

For nearly half a century, contact lenses have been proposed as a means of ocular drug delivery, but achieving controlled drug release has been a significant challenge. We have developed a drug-eluting contact lens designed for prolonged delivery of latanoprost for the treatment of glaucoma, the leading cause of irreversible blindness worldwide. Latanoprost-eluting contact lenses were created by encapsulating latanoprost–poly(lactic-co-glycolic acid) films in methafilcon by ultraviolet light polymerization. In vitro and in vivo studies showed an early burst of drug release followed by sustained release for one month. Contact lenses containing thicker drug–polymer films demonstrated released a greater amount of drug after the initial burst. In vivo, single contact lenses were able to achieve, for at least one month, latanoprost concentrations in the aqueous humor that were comparable to those achieved with topical latanoprost solution, the current first-line treatment for glaucoma. The lenses appeared safe in cell culture and animal studies. This contact lens design can potentially be used as a treatment for glaucoma and as a platform for other ocular drug delivery applications.

A Comparative Study of a Preservative-Free Latanoprost Cationic Emulsion (Catioprost) and a BAK-Preserved Latanoprost Solution in Animal Models

Benzalkonium chloride (BAK), a common preservative in eye drops, can induce ocular surface toxicity that may decrease glaucoma therapy compliance. The ocular hypotensive effect, pharmacokinetic (PK) profiles, and local tolerance of a preservative-free latanoprost 0.005% cationic emulsion (Catioprost(®)), and a BAK-preserved latanoprost 0.005% solution (Xalatan(®)), were compared. The ocular hypotensive effect was evaluated in monkeys with elevated intraocular pressure (IOP) induced by laser photocoagulation of the trabecular meshwork. Each monkey (n=8) received both latanoprost formulations once daily for 5 consecutive treatment days in a crossover design with at least a 2-week washout period between treatments. IOP was measured at baseline (on day 1, no instillation), on vehicle treatment day (day 0), and on treatment days 1, 3, and 5 before drug instillation and then hourly for 6 h. In rabbits, the ocular and systemic concentrations of latanoprost free acid were determined following a single instillation and the local tolerance of twice daily instillations over 28 days was assessed. Both the preservative-free and BAK-preserved latanoprost formulations shared the same efficacy profile with the maximum IOP reduction occurring 2 h after each morning dose (-15%, -20%, and -26%; -15%, -23%, and -23% on days 1, 3, and 5, respectively) and lasting through 24 h. The equivalence in efficacy was confirmed by the PK data demonstrating similar area under the curves (AUCs). While both formulations were well tolerated, the incidence of conjunctival hyperemia was reduced by 42% with the BAK-free latanoprost cationic emulsion. In animal models, a preservative-free latanoprost cationic emulsion was as effective as Xalatan(®) for lowering IOP with an improved ocular tolerance profile.

In Vivo Corneal Epithelial Permeability following Treatment with Prostaglandin Analoges with or without Benzalkonium Chloride

The effects of two intraocular pressure (IOP)-lowering agents, latanoprost with 0.02% benzylalkonium chloride (BAK) and travoprost Z without BAK, on corneal epithelial permeability, assessed by carboxyfluorescein uptake, were compared in a rabbit cornea model (n = 12). Loss of epithelial tight junctions was measured by ruthenium red uptake with transmission electron microscopy. There was a significant difference between corneal epithelium permeability of rabbits exposed to either travoprost Z or latanoprost preserved with 0.02% BAK (P < 0.0001). There was no difference between untreated controls and those receiving travoprost Z (P = 0.224). Epithelial permeability was significantly increased in the corneas of rabbits exposed to latanoprost in the 3-min drop test (2.16 ± 1.094 nm/sec) and the 3-min exposure (16.69 ± 3.15 nm/sec), compared with control or travoprost (P = 0.002), likely due to the presence of a 0.02% concentration of BAK in the latanoprost solutions. There was no detectable loss of epithelial tight junctions in corneas from the control or travoprost Z groups, compared with significant loss in the latanoprost group. Agents such as travoprost Z with an alternative preservative decreased the epithelial toxicity associated with the long-term use of IOP-lowering agents preserved with BAK.

Effects of topical administration of 0.005% latanoprost solution on eyes of clinically normal horses.

To determine the effect of 0.005% latanoprost solution on intraocular pressure (IOP) of eyes of clinically normal horses and establish the frequency of adverse effects of drug administration. 20 adult clinically normal horses. IOP was recorded (7, 9, and 11 AM; 3, 5, and 7 PM) on days 1 and 2 (baseline), days 3 to 7 (treatment), and days 8 to 9 (follow-up). Latanoprost was administered to 1 randomly assigned eye of each horse every 24 hours during the treatment period, following the 7 AM IOP recording. Pupil size and the presence or absence of conjunctival hyperemia, epiphora, blepharospasm, blepharedema, and aqueous flare were recorded prior to IOP measurement. IOP was reduced from baseline by a mean value of 1.03 mm Hg (5%) in males and 3.01 mm Hg (17%) in females during the treatment period. Miosis developed in all treated eyes and was moderate to marked in 77% of horses, with the peak effect observed 4 to 8 hours after drug administration. Conjunctival hyperemia, epiphora, blepharospasm, and blepharedema were present in 100, 57, 42, and 12% of treated eyes, respectively, 2 to 24 hours following drug administration. Aqueous flare was not observed at any time point. Although IOP was reduced with every 24-hour dosing of latanoprost, the frequency of prostaglandin-induced adverse events was high. Because recurrent uveitis appears to be a risk factor for glaucoma in horses, topical administration of latanoprost may potentiate prostaglandin-mediated inflammatory disease in affected horses.

Effects of 0.005% latanoprost solution on intraocular pressure in healthy dogs and cats.

To evaluate effects of daily topical ocular administration of latanoprost solution on intraocular pressure (IOP) in healthy cats and dogs. 9 domestic shorthair cats and 14 dogs. Latanoprost solution (0.005%) was administered topically to 1 eye (treated) and vehicle to the other eye (control) of all animals once daily in the morning for 8 days. Intraocular pressure was measured twice daily for the 5 days preceding treatment, and IOP, pupillary diameter, conjunctival hyperemia, and blepharospasm were measured 0, 1, 6, and 12 hours after the first 4 treatments and 0 and 12 hours after the final 4 treatments. Measurements continued twice a day for 5 days after treatment was discontinued. Aqueous flare was measured once daily during and for 5 days after the treatment period. Intraocular pressure and pupillary diameter were significantly decreased in the treated eye of dogs, compared with the control eye. Mild conjunctival hyperemia was also detected, but severity did not differ significantly between eyes. Blepharospasm and aqueous flare were not detected in either eye. Intraocular pressure in cats was not significantly affected by treatment with latanoprost. However, pupillary diameter was significantly decreased in the treated eye, compared with the control eye. Conjunctival hyperemia, aqueous flare, and blepharospasm were not detected in either eye. Once-daily topical ocular administration of latanoprost solution (0.005%) reduced IOP in healthy dogs without inducing adverse effects but did not affect IOP in healthy cats. Latanoprost may be useful for treating glaucoma in dogs.