MERCURY-3: a randomized comparison of netarsudil/latanoprost and bimatoprost/timolol in open-angle glaucoma and ocular hypertension.

PURPOSE   : To compare the efficacy and safety of the fixed-dose combination (FDC) of netarsudil 0.02%/latanoprost 0.005% ophthalmic solution (NET/LAT; Roclanda®) with bimatoprost 0.03%/timolol maleate 0.5% (BIM/TIM; Ganfort®) ophthalmic solution in the treatment of open-angle glaucoma (OAG) and ocular hypertension (OHT). METHODS: MERCURY-3 was a 6-month prospective, double-masked, randomized, multicenter, active-controlled, parallel-group, non-inferiority study. Patients (≥ 18 years) with a diagnosis of OAG or OHT in both eyes that was insufficiently controlled with topical medication (IOP ≥ 17 mmHg in ≥ 1 eye and < 28 mmHg in both eyes) were included. Following washout, patients were randomized to once-daily NET/LAT or BIM/TIM for up to 6 months; efficacy was assessed at Week 2, Week 4, and Month 3; safety was evaluated for 6 months. Comparison of NET/LAT relative to BIM/TIM for mean IOP at 08:00, 10:00, and 16:00 h was assessed at Week 2, Week 6, and Month 3. Non-inferiority of NET/LAT to BIM/TIM was defined as a difference of ≤ 1.5 mmHg at all nine time points through Month 3 and ≤ 1.0 mmHg at five or more of nine time points through Month 3. RESULTS: Overall, 430 patients were randomized (NET/LAT, n = 218; BIM/TIM, n = 212), and all received at least one dose of study medication. Efficacy analyses were performed at Month 3 on 388 patients (NET/LAT, n = 184; BIM/TIM, n = 204). NET/LAT demonstrated non-inferiority to BIM/TIM, with a between-treatment difference in IOP of ≤ 1.5 mmHg achieved at all time points and ≤ 1.0 mmHg at the majority of time points (six of nine) through Month 3. Mean diurnal IOP during the study ranged from 15.4 to 15.6 mmHg and 15.2 to 15.6 mmHg in the NET/LAT and BIM/TIM groups respectively, with no between-group statistically significant difference. No significant differences were observed in key secondary endpoints. No serious, treatment-related adverse events (AEs) were observed, and AEs were typically mild/moderate in severity. The most common treatment-related AEs were conjunctival hyperemia (NET/LAT, 30.7%; BIM/TIM, 9.0%) and cornea verticillata (NET/LAT, 11.0%; BIM/TIM, 0%). CONCLUSIONS: Once-daily NET/LAT was non-inferior to BIM/TIM in IOP reduction in OAG and OHT, with AEs consistent with previous findings. NET/LAT offers a compelling alternative FDC treatment option for OAG and OHT.

Screening, characterization, and determination of suspected additives bimatoprost and latanoprost in cosmetics using NMR and LC-MS methods.

Recently, many new types of cosmetic illegal additives have been screened in the market. Most of the new additives were new drugs or analogues with very similar structures to other prohibited additives, which were difficult to be identified by liquid chromatography-mass spectrometry (LC-MS) only. Therefore, a new strategy is proposed, which is chromatographic separation combined with nuclear magnetic resonance spectroscopy (NMR) structural identification. The suspected samples were screened by ultra-high-performance liquid chromatography tandem high-resolution mass spectrometry (UPLC-Q-TOF-MS), followed by purification and extraction through silica-gel column chromatography and preparative high-performance liquid chromatography (HPLC). Finally, the extracts were identified unambiguously by NMR as bimatoprost and latanoprost, which were identified to be new cosmetic illegal additives in eyelash serums in China. Meanwhile, bimatoprost and latanoprost were quantified by high-performance liquid chromatography tandem triple quadrupole mass spectrum (HPLC-QQQ-MS/MS). The quantitative method demonstrated good linearity in the range of approximately 0.25-50 ng/mL (R2 > 0.9992), with limit of detection (LOD) and limit of quantification (LOQ) values of 0.01 and 0.03 mg/kg, respectively. The accuracy, precision, and reproducibility were confirmed to be acceptable.

Periocular invasive melanoma manifestation in a patient using bimatoprost: case report and literature review.

Prostaglandin F2a analogs (PGAs) are considered efficacious in the first-line treatment of glaucoma. They have however been associated with a number of periocular side effects. We present a case of periocular hyperpigmentation and progression to lentigo maligna melanoma (LMM) in a patient using bimatoprost eye drops. We conducted a literature review regarding the etiology and pathophysiology of periocular pigmentation in this setting.A 71-year-old female Caucasian patient with open-angle glaucoma using bimatoprost exclusively in her right eye noticed an ipsilateral lower eyelid/upper cheek area dark lesion after commencing treatment. Examination demonstrated a heterogeneously pigmented lesion. Excisional biopsy demonstrated extensive lentigo maligna (melanoma in situ) with superficially invasive malignant melanoma in the lesion center. The patient underwent successful staged excision and reconstruction. Literature review has demonstrated case reports supporting periocular hyperpigmentation; however, there has been no description of progression to periocular lentigo maligna and melanoma in a patient using bimatoprost.

Effect of retrobulbar prostaglandin analog injection on orbital fat in rats.

PURPOSE: Periorbital fat atrophy is a known side effect of topical prostaglandin analogs (PA). This side effect may have implications in the treatment of diseases like thyroid orbitopathy. In this in vivo study we aimed to evaluate the effects of retrobulbar injection of three different PAs on orbital fat. METHODS: Eighteen adult male Wistar-albino rats were divided into three groups of six animals. 0.1 ml of 0.03% bimatoprost, 0.005% latanoprost, or 0.005% travoprost was injected into the right orbits and saline was injected into the left orbits, as controls. Both orbits were exenterated after 3 weeks. Histological cross-sections were analyzed using ImageJ image analysis software. Intraconal adipocyte density was calculated. RESULTS: There was no significant difference in the adipocyte density between the PA injected orbits and the control side in each of the three groups. When calculations from all three groups were analyzed together, again the difference in the adipocyte density between the PA injected orbits and the control side was not significant. CONCLUSION: No significant fat atrophy was noted in this rat model three weeks after retrobulbar injection of PAs. To evaluate retrobulbar injection of PA as a potential therapy for orbital diseases with fat proliferation, in vivo studies in different animal models, higher concentrations of PA, or longer follow-up duration are required.

Effects of topical prostaglandin therapy on corneal layers thickness in primary open-angle glaucoma patients using anterior segment optical coherence tomography.

PURPOSE: To evaluate the effects of latanoprost, bimatoprost, and travoprost eye drops and their preservatives on each corneal layer thickness in patients with primary open-angle glaucoma (POAG). METHODS: We retrospectively analyzed 79 eyes of 79 patients with POAG who were receiving prostaglandin therapy. Patients were divided into three subgroups according to monotherapy with latanoprost, bimatoprost, and travoprost during a mean of 43.14 ± 19.12 months follow-up period. In addition, the central corneal epithelial thickness (CET), central corneal stromal thickness (CST), and total central corneal thickness (CCT) were measured by anterior segment optical coherence tomography (AS-OCT) at baseline and every six months after treatment initiation at each visit between 9 and 12 o'clock in the morning. Furthermore, intraocular pressure (IOP) was measured with Goldmann applanation tonometry (GAT) after AS-OCT measurements at each visit. RESULTS: All three groups were not significantly different in age, gender, follow-up period, and mean intraocular pressure values (p > 0.05 for all). The reduction of CCT in the latanoprost, bimatoprost, and travoprost groups was 6.53 ± 3.17, 18.59 ± 8.42, and 10.1 ± 1.13 µm, respectively. The decrease in CST values was 4.65 ± 1.54, 15.84 ± 7.47, 9.69 ± 1.45 µm, and CET values were 1.88 ± 1.66, 2.75 ± 0.73, 0.41 ± 0.54 µm in all groups, respectively. A statistically significant thinning was observed in all corneal layers (p < 0.05) except the CST values in the latanoprost group and CET values in the travoprost group. However, no significant difference was found in the average reduction of CET, CST, and CCT values among the three groups (p > 0.05). CONCLUSION: Topical treatment with latanoprost, bimatoprost, and travoprost affects each layer of the cornea separately according to the active and protective substances contained in these eye drops. On the other hand, the thinning effect on the corneal layers was similar in these three drugs because there was no significant difference between the three groups in the total amount of thinning of the corneal layers during the follow-up period.

Effect of travoprost, latanoprost and bimatoprost PGF2α treatments on the biomechanical properties of in-vivo rabbit cornea.

Prostaglandin F2α analogues (PGF2α), one of the most commonly prescribed classes of hypotensive agents, could decrease collagen fibril density and remodel the extracellular matrix in cornea. We hypothesized that PGF2α's would induce corneal softening, reduce the accuracy of intraocular pressure (IOP) measurement and lead to uncertainty in the effectiveness of the therapy. We determined the stress-strain behavior of rabbit cornea after PGF2α usage and evaluated the effect of biomechanical changes associated with PGF2α treatment on IOP measurements by Goldmann Applanation Tonometry (GAT). The tangent modulus decreased after PGF2α treatment, while the stromal interfibrillar spacing increased. PGF2α was shown to also affect the lateral eye with lower effect, which did not undergo direct eyedrop treatment. Significant decreases in the numerical predictions of GAT-IOP were predicted in all treated groups relative to control groups. Different PGF2α's (travoprost, latanoprost and bimatoprost) were associated with different extents of reduction in tissue stiffness and changes in corneal microstructure. PGF2α-induced changes in corneal mechanical properties could reduce the accuracy of IOP measurement and may cause an overestimation of the effect of PGF2α in lowering IOP, possibly leading to uncertainties in glaucoma management.

Topical bimatoprost in the treatment of eyelash loss in alopecia totalis and universalis: A prospective, open-label study.

Bimatoprost is a synthetic prostaglandin structural analogue used among other indications to increase eyelash growth. The aim of this prospective, open-label study was to evaluate the safety and efficacy of topical bimatoprost in the treatment of eyelash loss in alopecia areata totalis (AT) and universalis (AU). Study subjects applied ophthalmic bimatoprost (0.3 mg/ml) solution to the eyelid margins once nightly for at least 12 weeks (mean treatment period was 30.6 weeks). A total of 16 out of 17 subjects completed the study. Only the subjects with eyelashes present at baseline experienced an increase in eyelash length and thickness. No new eyelash regrowth was induced. In patients with AT and AU topical bimatoprost affected existing eyelashes, but failed to induce regrowth of new eyelashes.

Triple combination therapy of narrowband ultraviolet B, fractional carbon dioxide laser and topical bimatoprost 0.01% for non-segmental vitiligo on non-facial areas: A randomized half-body, double-blind, placebo-controlled, comparative study.

Combination therapy shows superior outcomes over monotherapy in treating vitiligo. Topical bimatoprost is a melanogenic agent effectively used to induce repigmentation. However, topical bimatoprost 0.01% has never been explored in non-facial vitiligo, and triple therapy of phototherapy, fractional laser and topical bimatoprost has never been examined. This study aims to investigate the efficacy and safety of triple-modality treatment, combining narrowband ultraviolet B (NB-UVB), fractional carbon dioxide (CO2 ) laser and topical bimatoprost 0.01% for stable non-segmental vitiligo on non-facial areas. Fifteen vitiligo patients with at least two symmetrical, comparable-sized lesions on non-facial regions were included. The paired lesions were randomized to receive a treatment regimen of twice-daily application of either bimatoprost 0.01% solution or placebo in combination with once-monthly fractional CO2 laser and twice-weekly NB-UVB therapy for 12 weeks. There were no statistically significant differences in the vitiligo surface area (VSA) and melanin concentration (MC) at baseline between treatment sides. After 12 weeks of treatment, the percentage change from baseline of MC on the triple-therapy side was significantly higher than that on the dual-therapy side, 27.17 ± 13.62% versus 22.82 ± 10.10% (p = 0.028). The change from baseline of VSA was also greater on the triple-therapy side; however, a statistically significant difference was not reached. Improvement grades of repigmentation and adverse events were similar on both sides. Triple therapy with NB-UVB, fractional CO2 laser and topical bimatoprost 0.01% tends to be safe and more effective as compared to dual therapy of NB-UVB and fractional CO2 laser in non-facial vitiligo.

Peripheral anterior synechiae after selective laser trabeculoplasty among Chinese patients.

PURPOSE: Peripheral anterior synechiae (PAS) have been reported as a complication after argon laser trabeculoplasty, but rarely reported after selective laser trabeculoplasty (SLT). This study aims to determine the incidence and predictors of this potential complication in phakic eyes of Chinese patients. METHODS: A retrospective review of consecutive Chinese phakic patients who underwent SLT for primary open-angle glaucoma or ocular hypertension from 2011 to 2015 was analyzed for post-operative outcomes, including the development of PAS. RESULTS: There was a total of 292 patients (509 eyes) that were of Chinese ethnicity and eligible in our analysis. The 4-year incidence of PAS was 13.57% for the 221 eyes with documented gonioscopy after SLT, and the time, since first SLT, to PAS diagnosis was 5.62 years (2052 ± 75.2 days). After accounting for the inter-eye correlation by the mixed effect Cox regression model (AUC = 0.885), the predictors of earlier PAS diagnosis were baseline intraocular pressure (≥ 18 versus < 18) (HR = 4.6, p = 0.031), baseline use of bimatoprost (HR = 14.97, p = 0.006), and pre-existing hypertension (HR = 11.78, p = 0.016). There was no significant association of earlier PAS diagnosis with age (p = 0.434), baseline number of medications used (p = 0.693), and baseline use of brinzolamide (p = 0.326). CONCLUSION: PAS development after SLT appears to be more common in Chinese patients, with a presumed 4-year incidence of 13.6%, based on retrospective review of eyes with subsequent documented gonioscopy findings. TRIAL REGISTRATION: Hong Kong University Clinical Trials Registry (HKUCTR-2350).

Enhanced Uptake and Retention of 0.03% Bimatoprost, 0.5% 5-Fluorouracil, and 5% Minoxidil After 1,550-nm or 1,927-nm Nonablative Laser Pretreatment.

BACKGROUND: Laser pretreatment with cosmeceutical topicals is growing in popularity. However, lasers may also enhance the uptake of medical topicals that treat dermatologic conditions, such as vitiligo, alopecia, and cancerous and precancerous lesions. Permeation of these topicals must be quantified to optimize treatment protocols. OBJECTIVE: To analyze transdermal uptake of 3 topicals after nonablative fractional 1,550-nm erbium-doped glass or 1,927-nm thulium fiber laser pretreatment. METHODS AND MATERIALS: Human donor tissue was pretreated with a nonablative fractional 1,550-nm erbium-doped glass or 1,927-nm thulium fiber laser followed by application of 0.03% bimatoprost, 0.5% 5-fluorouracil, or 5% minoxidil. Permeation and retention were measured over 24 hours (bimatoprost and 5-fluorouracil) or 90 minutes (minoxidil), and uptake was calculated. RESULTS: Pretreatment with 1,927-nm thulium laser (500 MTZ/cm2; 5 mJ; 5 W) enhanced uptake and retention of bimatoprost versus untreated control at 24 hours post-treatment. Pretreatment with 1,550-nm erbium-doped glass laser (2,000 MTZ/cm2; 10 mJ; 30 W) enhanced permeation, uptake, and retention of 5-fluorouracil at 24 hours post-treatment and enhanced permeation and uptake of minoxidil at 90 minutes post-treatment. CONCLUSION: Nonablative laser pretreatment may enhance topical treatment of dermatologic conditions. Device settings must be optimized to maximize topical permeation while minimizing laser-associated thermal side effects.

Cytotoxicity, Mitochondrial Functionality, and Redox Status of Human Conjunctival Cells after Short and Chronic Exposure to Preservative-Free Bimatoprost 0.03% and 0.01%: An In Vitro Comparative Study.

Prostaglandin analogues (PGAs), including bimatoprost (BIM), are generally the first-line therapy for glaucoma due to their greater efficacy, safety, and convenience of use. Commercial solutions of preservative-free BIM (BIM 0.03% and 0.01%) are already available, although their topical application may result in ocular discomfort. This study aimed to evaluate the in vitro effects of preservative-free BIM 0.03% vs. 0.01% in the human conjunctival epithelial (HCE) cell line. Our results showed that long-term exposure to BIM 0.03% ensues a significant decrease in cell proliferation and viability. Furthermore, these events were associated with cell cycle arrest, apoptosis, and alterations of ΔΨm. BIM 0.01% does not exhibit cytotoxicity, and no negative influence on conjunctival cell growth and viability or mitochondrial activity has been observed. Short-time exposure also demonstrates the ability of BIM 0.03% to trigger reactive oxygen species (ROS) production and mitochondrial hyperpolarisation. An in silico drug network interaction was also performed to explore known and predicted interactions of BIM with proteins potentially involved in mitochondrial membrane potential dissipation. Our findings overall strongly reveal better cellular tolerability of BIM 0.01% vs. BIM 0.03% in HCE cells.

Do Prostaglandin Analogue Lash Lengtheners Cause Eyelid Fat and Volume Loss?

BACKGROUND: Prostaglandin analogues (PGAs; a first-line antiglaucoma treatment) have been remarketed as popular eyelash-lengthening serums due to their lash-lengthening and lash-thickening side effects. Periorbital volume loss is now a well-established side effect of topical PGAs used to treat glaucoma (prostaglandin-associated periorbitopathy) but has not, to date, been listed as a potential side effect of lash-lengthening serums containing PGAs. OBJECTIVES: The aim of this study was to identify whether periorbital fat/volume loss is seen in users of PGA lash lengtheners. METHODS: This investigation comprised a case report and an informal randomized controlled study comparing "before-and-after" color photographs displayed on the websites of manufacturers of PGA-containing lash lengtheners (PGALLs) (ie, containing bimatoprost, norbimatoprost, isopropyl cloprostenate, dechloro-dihydroxy-difluoro-ethylcloprostenolamide, or methylamido-dihydro-noralfaprostal) vs 2 control groups: non-PGALLs (NPGALL) and false eyelashes (FLs). Expert and layperson blinded graders used a purpose-designed grading system to identify subtle signs of periorbital fat/volume loss over time. RESULTS: A 35-year-old female developed thin, wrinkled, darker skin, and periorbital hollowing after 10 months of treatment with Lash Boost (Rodan & Fields, San Francisco, CA), containing isopropyl cloprostenate, which reversed 6 months after discontinuation. Fifteen "before-and-after" pairs of photographs (PGALL, n = 10; NPGALL, n = 3; FL, n = 2) were graded by 5 graders (3 expert, 2 layperson). Mean grading score was 8.2 (of 19) in the PGALL group, 2.3 in the NPGALL group, and 3.2 in the FL group. PGALL scores were significantly higher than scores in the NPGALL (P < 0.001) and FL (P = 0.017) groups. CONCLUSIONS: Review of commercial "before-and-after" photographs suggests that PGALL users develop changes compatible with prostaglandin-associated periorbitopathy. Consumers must be aware of the possibility of periorbital volume loss prior to commencing treatment with PGALLs. Often the customer-facing product ingredient list contains no mention of PGAs.

The effect of topical bimatoprost on corneal clarity in primary open-angle glaucoma: a longitudinal prospective assessment.

PURPOSE: To study the effect of topical bimatoprost on the corneal optical density values using a dual Scheimpflug Placido analysis system. METHODS: This longitudinal case-control study included 18 patients with newly diagnosed primary open-angle glaucoma who received topical bimatoprost as a first-line treatment and 20 healthy individuals (age and sex-matched controls). Corneal densitometry data were obtained using the dual Scheimpflug analyzer at pre-treatment and 1st, 6th, 12th, 18th months of post-treatment. Repeated measures of ANOVA and Pearson correlation tests were used for statistical analysis. RESULTS: There were statistically significant differences between pre-treatment and post-treatment 1st and 6th months corneal densitometry values (p < 0.001, p = 0.007, respectively). However, there was no statistically significant difference between the post-treatment 12th and 18th months (p > 0.05). Corneal densitometry values decreased during the 1st month. Intraocular pressure (IOP) differences were statistically significant between baseline and 1 month after treatment (P < 0.001), however not statistically significant between the 1st and 6th, 6th and 12th, 12th and 18th months after treatment (p > 0.05, for all). Corneal densitometry was not correlated with IOP (r = - 0.037, p = 0.44). In the control group, there was no statistically significant difference between baseline and post-baseline 18th-month corneal densitometry measurements (p > 0.05). CONCLUSIONS: Topical bimatoprost administration might result in a decrease in corneal densitometry measurement. It is of clinical importance that topical bimatoprost administration can affect corneal transparency and cause a possible alteration in corneal properties.

Prostaglandin F2α and EP2 agonists, and a ROCK inhibitor modulate the formation of 3D organoids of Grave's orbitopathy related human orbital fibroblasts.

3D organoid cultures were used to elucidate the periocular effects of several anti-glaucoma drugs including a prostaglandin F2α analogue (bimatoprost acid; BIM-A), EP2 agonist (omidenepag; OMD) or a Rho-associated coiled-coil containing protein kinase (ROCK) inhibitor (ripasudil; Rip) on Grave's orbitopathy (GO) related orbital fatty tissue. 3D organoids were prepared from GO related human orbital fibroblasts (GHOFs) obtained from patients with GO. The effects of either 100 nM BIM-A, 100 nM OMD or 10 µM Rip on the 3D GHOFs organoids were examined with respect to organoid size, physical properties by a micro-squeezer, and the mRNA expression of extracellular matrix (ECM) proteins including collagen (COL) 1, COL 4, COL 6, and fibronectin (FN), ECM regulatory genes including lysyl oxidase (LOX), Connective Tissue Growth Factor (CTGF) and inflammatory cytokines including interleukin-1ß (IL1ß) and interleukin-6 (IL6). The size of the 3D GHOFs organoids decreased substantially in the presence of BIM-A, but also increased substantially in the presence of the others (OMD or Rip). The physical stiffness of the 3D GHOFs organoids was significantly decreased by Rip. BIM-A caused significantly the down-regulation of three ECM genes, Col 1, Col 6 and Fn, and two ECM regulatory genes and the up-regulation of IL6. In the presence of OMD, two ECM genes, Col 1 and Fn, and LOX were significantly down-regulated but IL1ß and IL6 were significantly up-regulated. In the case of Rip, Col 1, FN and CTGF were significant down-regulated. Our present findings indicate that anti-glaucoma drugs modulate the structures and physical properties 3D GHOFs organoids in different manners by modifying the gene expressions of ECM, ECM regulatory factors and inflammatory cytokines. The results indicate that the benefits and demerits of anti-glaucoma medications need to be scrutinized carefully, in cases of patients with GO.

Phosphodiesterase inhibitors and prostaglandin analogues in dermatology: A comprehensive review.

Due to immune-mediated nature, medicines with immunomodulatory and anti-inflammatory effects can used to treat many dermatologic diseases. Phosphodiesterase and prostaglandins are involved in many inflammatory pathways that cause cutaneous disorders. Phosphodiesterase inhibitors (PDEIs) and prostaglandin analogues are currently employed to treat several dermatologic disorders. Given the few comprehensive reviews in this context, focusing on the dermatologic applications and efficacy of these medicines appears valuable. The present comprehensive review was, therefore, performed on the applications of PDEIs and prostaglandin analogues in different cutaneous disorders. All the relevant articles were selected to perform this review by searching databases such as Medline, Google Scholar, Scopus, and Web of Science. Oral PDEIs, especially apremilast, is an effective medicine in psoriasis and a number of other cutaneous disorders such as vitiligo. Topical PDEIs, including crisaborole ointment 2%, is a safe and effective treatment in atopic dermatitis. Prostaglandin analogues, especially their topical forms such as latanoprost and bimatoprost, have different applications in cutaneous disorders, including pigmentary disorders, especially vitiligo and hair repigmentation; for instance, bimatoprost is used for eyelash repigmentation. Prostaglandin analogues are also used in alopecia, including androgenetic alopecia and alopecia areata. Oral (apremilast) and topical (crisaborole) PDEIs and topical prostaglandin analogues, including latanoprost and bimatoprost, were found safe and effective in different skin diseases. In terms of efficiency and safety, these medicines compete with other medications of similar use even with higher efficacy and fewer side effects that necessitate further studies.

Revisiting the Safety of Prostaglandin Analog Eyelash Growth Products.

BACKGROUND: The FDA approved bimatoprost ophthalmic solution 0.03% for treatment of eyelash hypotrichosis in 2008. Consumer concern persists regarding potential side effects of this product. OBJECTIVE: To identify gaps in the safety information associated with the use of prostaglandin eyelash growth products. MATERIALS AND METHODS: Literature searches were performed using PubMed, Embase, and Nexis Uni databases without restriction to publication date, language, or study setting. RESULTS: The literature pertaining to bimatoprost for treatment of eyelash hypotrichosis is dominated by industry-sponsored clinical trials. Study design choices create gaps in our understanding of the clinical safety of these products. CONCLUSION: Because of study design choice, clinical trials of bimatoprost for eyelash growth may have systematically underreported the incidence of drug application discomfort and prostaglandin-associated periorbitopathy. The risk of increased iris pigmentation remains inadequately investigated. Consequently, there is an ongoing need to educate and monitor patients who choose to use these products.

Effects of topical prostaglandin drops on angiogenesis in an in ovo chick chorioallantoic membrane model.

BACKGROUND: To investigate the effects of bimatoprost, latanoprost and travoprost on angiogenesis in the chick chorioallantoic membrane (CAM) model in ovo. MATERIALS AND METHODS: Fifty fertilized specific-pathogen-free chick eggs were used in this preclinical, prospective, experimental embryo study. Eggs were randomly distributed into 5 groups of ten eggs. Eggs were placed in the incubator after disinfection of their shells with alcohol and monitored appropriate temperature and humidity. On the 3rd day of incubation, a small window was opened on the eggshell. Bimatoprost in group 1, latanoprost in group 2, travoprost in group 3, bevacizumab in group 4, phosphate-buffered-saline (PBS) used in group 5 was applied by injection to CAM. The sterile film was glued onto the broken part of the shell and the eggs were placed in the incubator again. On the 8th day of incubation, eggs were opened and vascular structures on CAMs were examined. Digital photographs were taken, analysed in the ImageJ open source image processing software and differences between groups were evaluated. Thereafter, VEGF (Vascular endothelial growth factor) levels were measured appropriately in the embryo samples. RESULTS: All embryos in the prostaglandin groups and the PBS control group were observed to have life signs confirmed by heart rate. In 8 embryos in the bevacizumab group, no life signs were confirmed, while 2 embryos with life signs showed severe hypoplasia. Vascular density, number of vessels and VEGF levels in the bimatoprost, latanoprost and travoprost groups, there were statistically significantly higher than the PBS control group. CONCLUSION: This study demonstrates that topical prostaglandin drops increase angiogenesis in the chick CAM model in ovo.

Bimatoprost-Loaded Silica Shell-Coated Nanoparticles-Laden Soft Contact Lenses to Manage Glaucoma: In Vitro and In Vivo Studies.

Currently, glaucoma is managed by frequent instillation of bimatoprost eye drop therapy, which showed very poor ocular bioavailability. Contact lens is widely used as medical device to improve the drug retention on the ocular tissues. However, the traditional methods of drug loading in the contact lens matrix showed high burst release and changes the optophysical properties of the contact lens material. In this paper, a novel bimatoprost-loaded silica shell nanoparticles-laden soft contact lenses were developed to achieve sustain drug delivery without altering the optophysical properties of the contact lens. Silica-shell nanoparticles were prepared using octyltrimethoxysilane (OTMS) and microemulsion. Traditional soaking method (SM-BT), direct bimatoprost loading method (DL-BT), and microemulsion-laden contact lens (ME-BT) were developed for comparison. The silica shell-coated nanoparticles-laden soft contact lenses (SiS-BT) showed improved swelling, transmittance, oxygen permeability, and lysozyme adherence compared to SM-BT, DL-BT, and ME-BT lenses. The DL-BT and ME-BT batch showed high bimatoprost lost/leaching during extraction and sterilization steps, with low cumulative drug release. Also, SiS-BT lens showed sustain bimatoprost release for 96 h. In a rabbit tear fluid model, the SiS-BT lens showed high bimatoprost concentration for 72 h compared to ME-BT lens and eye drop therapy. Based on histopathological studies of cornea, the SiS-BT lens was found to be safe for human applications. The data demonstrated the novel application of silica shell nanoparticles to deliver bimatoprost from the contact lens for extended period of time without altering the optophysical properties of the contact lens.

[Bimatoprost promotes hair growth of reconstructed hair follicles in mice through activation of the Wnt/ß-catenin signaling pathway].

Objective: To investigate effect of Bimatoprost (BimP) on growth of reconstructed hair follicles in recipient nude mice. Methods: Primary epidermal and dermal cells were isolated from newborn C57BL/6J mice (1-day-old) skins, and the reconstructed hair follicles was implanted in the dorsal skin of Balb/c-nu nude mice using a silicon chamber protocol, then, the 18 nude mice were randomly divided into control group, BimP group and minoxidil group, with 6 mice in each group. After 2 weeks, topical treatment was applied to the grafted area of the nude mice by 2% minoxidil 100 µl, 0.03% BimP 100 µl and saline 100 µl, respectively, once daily for 2 weeks. At day 14 after treatment, the mice were euthanized to measure the length of dorsal hair, and the number and hair cycle of the reconstructed follicles was observed histologically. The total mRNA and proteins expression of Wnt3a, LEF1, ß-catenin and Frizzled7 were determined by qPCR and Western Blotting. The distribution and expression of ß-catenin in the reconstructed follicles was detected by immunofluorescence staining. Results: As compared to the control group, the BimP group had thicker and longer hair [(0.57±0.07) vs (0.36±0.05) cm, P<0.01], no significant difference was seen between the BimP and minoxidil group. The mRNA expression levels of Wnt3a (2.73±0.17 vs 1.00±0.14, P<0.01)、LEF1(1.71±0.12 vs 1.00±0.19, P<0.01)、ß-catenin (2.37±0.21vs 1.00±0.11, P<0.01) and Frizzled7 (2.62±0.15vs 1.00±0.18, P<0.01) were significantly increased in BimP group compared with the control group. Western Blotting showed the same results, the protein expression levels of Wnt3a (1.44±0.21vs 1.00±0.13, P<0.05)、LEF1 (1.36±0.15 vs 1.00±0.09, P<0.05)、ß-catenin (1.60±0.13 vs 1.00±0.16, P<0.01) and Frizzled7 (1.52±0.15 vs 1.00±0.21, P<0.05) in BimP group were higher than those in control group, and the difference was statistically significant. Immunofluorescence staining showed that ß-catenin was strongly expressed in hair bulb cells and sebaceous gland cells of reconstructed hair follicles in BimP group and minoxidil group, whereas barely seen in the control group. Conclusion: BimP directly promotes growth of reconstructed hair follicles in mice by activating canonical Wnt/ß-catenin signaling pathway.

Phase 3, Randomized, 20-Month Study of Bimatoprost Implant in Open-Angle Glaucoma and Ocular Hypertension (ARTEMIS 1).

PURPOSE: To evaluate the intraocular pressure (IOP)-lowering efficacy and safety of 10- and 15-µg bimatoprost implant in subjects with open-angle glaucoma (OAG) and ocular hypertension (OHT) after initial and repeated administrations. DESIGN: Randomized, 20-month, multicenter, subject- and efficacy evaluator-masked, parallel-group, phase 3 clinical study. PARTICIPANTS: Adults with OAG or OHT in each eye, open iridocorneal angle inferiorly in the study eye, and study eye baseline IOP (hour 0; 8 am) of 22-32 mmHg after washout. METHODS: Study eyes received bimatoprost implant 10 µg (n = 198) or 15 µg (n = 198) on day 1 with readministration at weeks 16 and 32, or twice-daily topical timolol maleate 0.5% (n = 198). Intraocular pressure was measured at hours 0 and 2 at each visit. MAIN OUTCOME MEASURES: Primary end points were IOP and change from baseline IOP through week 12. Safety measures included treatment-emergent adverse events (TEAEs) and corneal endothelial cell density (CECD). RESULTS: Both dose strengths of bimatoprost implant were noninferior to timolol in IOP lowering after each administration. Mean diurnal IOP was 24.0, 24.2, and 23.9 mmHg at baseline and from 16.5-17.2, 16.5-17.0, and 17.1-17.5 mmHg through week 12 in the 10-µg implant, 15-µg implant, and timolol groups, respectively. The incidence of corneal and inflammatory TEAEs of interest (e.g., corneal endothelial cell loss, iritis) was higher with bimatoprost implant than timolol and highest with the 15-µg dose strength. Incidence of corneal TEAEs increased after repeated treatment; with 3 administrations at fixed 16-week intervals, incidence of ≥20% CECD loss was 10.2% (10-µg implant) and 21.8% (15-µg implant). Mean best-corrected visual acuity (BCVA) was stable; 3 implant-treated subjects with corneal TEAEs had >2-line BCVA loss at their last visit. CONCLUSIONS: Both dose strengths of bimatoprost implant met the primary end point of noninferiority to timolol through week 12. One year after 3 administrations, IOP was controlled in most subjects without additional treatment. The risk-benefit assessment favored the 10-µg implant over the 15-µg implant. Ongoing studies are evaluating other administration regimens to reduce the potential for CECD loss. The bimatoprost implant has potential to improve adherence and reduce treatment burden in glaucoma.