cloprostenol and Disease-Models--Animal

Prostaglandin F2α analogs, commonly prescribed for glaucoma treatment, have been shown to induce side effects such as cutaneous hypertrichosis and hyperpigmentation. Therefore, these medications have theoretic applications in the treatment of alopecia and disorders of hypopigmentation. We reviewed the literature to find original studies assessing the use of prostaglandin F2α analogs in these settings. Studies and reports were analyzed in regards to androgenic alopecia, alopecia areata, chemotherapy-induced alopecia, vitiligo, and hypopigmented scarring. Based on the results of these studies, and consideration of pathophysiologic mechanism, the most promising applications for prostaglandin F2α analogs include androgenic alopecia, chemotherapy-induced alopecia, and alopecia areata concurrently treated with corticosteroids.

Topics: Adrenal Cortex Hormones; Alopecia; Amides; Animals; Bimatoprost; Cloprostenol; Dinoprost; Disease Models, Animal; Double-Blind Method; Drug Evaluation, Preclinical; Eyelashes; Glaucoma; Hair Follicle; Humans; Hyperpigmentation; Hypertrichosis; Hypopigmentation; Melanins; Mice; Prostaglandins F, Synthetic; Randomized Controlled Trials as Topic; Retrospective Studies; Single-Blind Method

When Zika virus emerged as a public health emergency there were no drugs or vaccines approved for its prevention or treatment. We used a high-throughput screen for Zika virus protease inhibitors to identify several inhibitors of Zika virus infection. We expressed the NS2B-NS3 Zika virus protease and conducted a biochemical screen for small-molecule inhibitors. A quantitative structure-activity relationship model was employed to virtually screen ∼138,000 compounds, which increased the identification of active compounds, while decreasing screening time and resources. Candidate inhibitors were validated in several viral infection assays. Small molecules with favorable clinical profiles, especially the five-lipoxygenase-activating protein inhibitor, MK-591, inhibited the Zika virus protease and infection in neural stem cells. Members of the tetracycline family of antibiotics were more potent inhibitors of Zika virus infection than the protease, suggesting they may have multiple mechanisms of action. The most potent tetracycline, methacycline, reduced the amount of Zika virus present in the brain and the severity of Zika virus-induced motor deficits in an immunocompetent mouse model. As Food and Drug Administration-approved drugs, the tetracyclines could be quickly translated to the clinic. The compounds identified through our screening paradigm have the potential to be used as prophylactics for patients traveling to endemic regions or for the treatment of the neurological complications of Zika virus infection.

Topics: Animals; Antiviral Agents; Artificial Intelligence; Chlorocebus aethiops; Disease Models, Animal; Drug Evaluation, Preclinical; High-Throughput Screening Assays; Immunocompetence; Inhibitory Concentration 50; Methacycline; Mice, Inbred C57BL; Protease Inhibitors; Quantitative Structure-Activity Relationship; Small Molecule Libraries; Vero Cells; Zika Virus; Zika Virus Infection

To investigate the toxic-inflammatory effects of prostaglandin analogs on the ocular surface.. Twenty-three rats were divided into four groups. Bimatoprost 0.03% (I), latanoprost 0.005% (II), and travoprost 0.004% (III) were applied during 6 months; a control group (IV) received no treatment. Dysplasia and keratinization were evaluated on the ocular surface. In the subepithelial area, the number of lymphocytes and mast cells were counted morphologically, and collagen staining densities were compared subjectively in groups.. The ratio of keratinization was 3/12 and 1/10, in groups I and II. The lymphocyte cell counts were 1.4 ± 0.19, 2.2 ± 0.39, 2.27 ± 0.33, and 1.87 ± 0.35 (p > .05). The mast cell counts were 2.58 ± 0.5, 5.4 ± 1.1, 5.7 ± 0.58, and 3.0 ± 0.59. They were significantly higher in groups II and III than in group I (p < .05). Mean collagen density scores were 1.00 ± 0.85, 2.00 ± 0.00, and 1,73 ± 0.70. Group II and III scores were higher than group I scores (p < .05).. Latanoprost and travoprost seem to have more toxic-inflammatory effects on the ocular surface than bimatoprost.

Topics: Amides; Animals; Antihypertensive Agents; Bimatoprost; Cloprostenol; Conjunctiva; Conjunctival Diseases; Cornea; Corneal Diseases; Disease Models, Animal; Follow-Up Studies; Glaucoma; Intraocular Pressure; Latanoprost; Male; Ophthalmic Solutions; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rats; Rats, Wistar; Travoprost

Examination of the response of the retinal proteome to elevated intraocular pressure (IOP) and to the pharmacological normalization of IOP is crucial, in order to develop drugs with neuroptorective potential. We used a hereditary rat model of ocular hypertension to lower IOP with travaprost and dorzolamide applied topically on the eye surface, and examine changes of the retinal proteome. Our data demonstrate that elevated IOP causes alterations in the retinal protein profile, in particular in high-mobility-group-protein B1 (HMGB1), calmodulin, heat-shock-protein (HSP) 70 and carbonic anhydrase II expression. The changes of the retinal proteome by dorzolamide or travoprost are different and independent of the IOP lowering effect. This fact suggests that the eye drops exert a direct IOP-independent effect on retinal metabolism. Further investigations are required to elucidate the potential neuroprotective mechanisms signaled through changes of HMGB1, calmodulin, HSP70 and carbonic anhydrase II expression in glaucoma. The data may facilitate development of eye drops that exert neuroprotection through direct pharmacological effect.

Topics: Animals; Calmodulin; Carbonic Anhydrase II; Cloprostenol; Disease Models, Animal; Glaucoma; HMGB1 Protein; HSP70 Heat-Shock Proteins; Intraocular Pressure; Ophthalmic Solutions; Peptide Mapping; Proteome; Proteomics; Rats; Retina; Sulfonamides; Thiophenes; Travoprost

The IOP lowering effects of NCX 139, a new chemical entity comprising latanoprost amide and a NO-donating moiety, were compared to those of the respective des-nitro analog in in vitro assays and in rabbit and dog models of ocular hypertension. The NO donor, molsidomine as well as the prostamide bimatoprost (Lumigan(®)) and the prostaglandin agonist, latanoprost (Xalatan(®)) were also investigated for comparison. NCX 139 but not its des-nitro analog resulted in NO-mediated vascular relaxant effect in pre-contracted rabbit aortic rings (EC(50)=0.70±0.06 μM; E(max)=80.6±2.9%). Like bimatoprost (IC(50)=3.07±1.3 μM) or latanoprost (IC(50)=0.48±0.15 μM), NCX 139 displaced (3)H-PGF2α binding on recombinant human prostaglandin-F (FP) receptors with an estimated potency of 0.77±0.13 μM. In transient ocular hypertensive rabbits, bimatoprost and latanoprost were not effective while molsidomine elicited a dose-dependent reduction of IOP confirming the responsiveness of rabbits to NO but not to FP receptor agonists. NCX 139 tested at a therapeutically relevant dose, significantly lowered IOP while the des-nitro analog was not effective (0.03% NCX 139, Δ(max)=-12.8±2.0 mmHg). In glaucomatous dogs, 0.03% NCX 139 decreased IOP to a greater extent compared to an equimolar dose of the respective des-nitro derivative (Δ(max)=-4.6±1.0 and -2.7±1.3 mmHg, respectively for NCX 139 and its des-nitro analog). Albeit with low potency, NCX 139 also resulted effective in normotensive dogs while it did not reduce IOP in normotensive rabbits. NCX 139, a compound targeting two different and important mechanisms, is endowed with ocular hypotensive effects more evident in hypertensive conditions which may be of interest in the search of more effective treatments for hypertensive glaucoma.

Topics: Amides; Animals; Antihypertensive Agents; Aorta; Bimatoprost; Chromatography, High Pressure Liquid; Cloprostenol; Dinoprost; Disease Models, Animal; Dogs; Glaucoma; Intraocular Pressure; Latanoprost; Male; Molsidomine; Nitrates; Nitric Oxide; Nitric Oxide Donors; Ocular Hypertension; Prostaglandins F, Synthetic; Rabbits; Tandem Mass Spectrometry; Tonometry, Ocular; Vasodilation; Vasodilator Agents

The aim of this study was to use a validated acute rabbit model to test the toxicity of a novel formulation of fixed-combination travoprost 0.004%/timolol 0.5% ophthalmic solution, which contains the antimicrobial preservative polyquaternium-1 (PQ), compared with the commercial formulation of fixed combinations travoprost 0.004%/timolol 0.5% ophthalmic solution and latanoprost 0.005%/timolol 0.5% ophthalmic solution, which both contain the preservative benzalkonium chloride (BAK).. Adult male New Zealand albino rabbits (n=24) were randomly divided into four groups. Phosphate-buffered saline (PBS), travoprost/timolol PQ, travoprost/timolol BAK, or latanoprost/timolol BAK were instilled onto rabbit eyes one drop, 15 times at 5 minute intervals. The ocular surface reactions were investigated at hour 4 and day 1 using slit lamp examination; in-vivo confocal microscopy (IVCM) for cornea, limbus, and conjunctiva-associated lymphoid tissue (CALT); conjunctival impression cytology; and standard immunohistology in cryosections for detecting CD45+ infiltrating cells and MUC-5AC-labeled cells.. Travoprost/timolol PQ was better tolerated than travoprost/timolol BAK or latanoprost/timolol BAK. This improved tolerance was evident via clinical observation under slit lamp, IVCM in different layers of the cornea and conjunctiva, conjunctival impression cytology of superficial epithelium aspects, and immunohistochemistry for inflammatory infiltration of CD45+ cells in the cornea and goblet cell distribution. Travoprost/timolol PQ was similar to PBS in regards to in-vivo findings, the Draize test for ocular irritation, and epithelial and limbal aspects as evaluated with IVCM. Treatment with either travoprost/timolol PQ or PBS produced no obvious inflammatory infiltration inside and outside the CALT follicles, yielded similar IVCM toxicity scores and CD45+ cell counts, and eyes treated with either solution had normal goblet cells.. The fixed combination of travoprost/timolol with 0.001% PQ had decreased ocular surface toxicity relative to the BAK-containing solutions. The potential benefit to the human ocular surface with oncedaily dosing needs to be evaluated clinically.

Topics: Animals; Anti-Bacterial Agents; Antihypertensive Agents; Benzalkonium Compounds; Cell Survival; Cloprostenol; Conjunctiva; Disease Models, Animal; Drug Combinations; Epithelium, Corneal; Latanoprost; Male; Ocular Hypertension; Ophthalmic Solutions; Polymers; Preservatives, Pharmaceutical; Prostaglandins F, Synthetic; Rabbits; Timolol; Travoprost; Treatment Outcome

To evaluate "in vivo" the effect of topical travoprost on the central corneal thickness (CCT) of rabbit eyes, and the changes in the CCT after acute increases of intraocular pressure (IOP) in these eyes.. This is an interventional, prospective, case-control, masked study. Topical travoprost was applied once daily for one month to the right eye of six New Zealand male rabbits, the left eye of each animal served as control. The baseline CCT and IOP were measured under general anesthesia. After the IOP was stabilized at 15 and 30 mmHg, as registered by direct cannulation of the anterior chamber, CCT measurements were measured again at both pressure levels.. The baseline CCT was thicker in eyes previously treated with travoprost (study group) than in control eyes (p < 0.01). The CCT decreased in both groups when IOP was raised to 15 and 30 mmHg, and there were no statistically significant difference in absolute CCT values between study and control eyes at any of the IOP levels (p = 0.5). However, the amount of CCT decrease from baseline values was greater in eyes previously treated with travoprost (study group) than in control ones, at both 15 and 30 mmHg IOP levels (p = 0.01 and 0.02, respectively).. Rabbit corneas treated with topical travoprost show a different strain response to acute increases in IOP than control eyes.

Topics: Animals; Antihypertensive Agents; Cloprostenol; Cornea; Disease Models, Animal; Dose-Response Relationship, Drug; Follow-Up Studies; Glaucoma; Intraocular Pressure; Male; Ophthalmic Solutions; Prospective Studies; Rabbits; Tonometry, Ocular; Travoprost; Ultrasonography

Hypertrichosis or alopecia of the eyelashes is associated with various diseases or may be drug induced. Although neither increase nor loss of eyelashes is life threatening, eyelash disorders can be psychologically disturbing. However, as control of eyelash growth and the underlying mechanisms of eyelash hypo- or hypertrichosis are largely obscure, available therapy is limited.. To improve this situation, we sought to establish a pragmatic, well-defined mouse model for the study and pharmacological investigation of eyelash follicle biology..   We took a morphometric approach to establish an eyelash model using female C57BL/6J mice by comparing with pelage hairs and highlighting the differences. We next applied a hypertrichosis-triggering agent and investigated its effect using the model.. In eyelashes, a synchronized growth cycle was observed after morphogenesis but was completed earlier than pelage hairs. Exogen was strictly regulated and occurred in every cycle in the eyelash. Otherwise, general morphological features of mouse eyelashes (shafts, follicles, morphogenesis and growth cycle) were comparable with those of pelage hairs. The eyelash growth-stimulatory agent in humans, bimatoprost, significantly extended the duration of anagen, resulting in more and longer eyelashes, but there was no evidence of follicle neogenesis.. This study shows that mouse eyelashes offer an excellent in vivo model for the quantitative and qualitative analysis of eyelash morphology, development, growth cycle, exogen and pharmacological modulation. This model will help to elucidate the unknown molecular controls of eyelash growth, and to develop novel drugs to treat eyelash disorders.

Topics: Amides; Animals; Antihypertensive Agents; Bimatoprost; Cell Cycle; Cloprostenol; Disease Models, Animal; Eyelashes; Female; Hair Follicle; Hypertrichosis; Mice; Mice, Inbred BALB C

This study was planned to investigate the neuroprotective potentials of three commercially available prostaglandin analogues (PGA), in the ischemia and reperfusion model (I/R). Thirty New Zealand rabbits were divided into 5 groups and except for the control group (non-ischemic, non-treated), 0.9% NaCl, bimatoprost, latanoprost, or travoprost were applied to both eyes of animals of the respective groups for 1 week. At the end of treatment, ischemia was induced in both eyes of the 4 treatment groups by anterior chamber irrigation of the animals for 60 min. Following 24 h reperfusion, the animals were sacrificed. Enucleated eyes and retinal tissues were investigated by light microscopy, electron microscopy, immunohistochemicstry for retinal histopathology, intracellular and apoptotic cells and by retinal morphometry. Vitreous samples were biochemically investigated for probable role of reactive oxygen species, by measuring xanthine oxidase (XO) activity. Analysis of morphometric measurements and vitreous XO activity revealed significant differences between the PGA-treated groups and the NaCl-treated group (P<0.05). Similarly, apoptotic cell counts in different retinal layers showed that PGA-treated groups had fewer apoptotic cells in all retinal layers than the NaCl-treated ischemic group (P<0.05). PGA may have high protective potential for different retinal layers and cells. Biochemical analysis of vitreous showed that all PGAs decreased vitreous XO activity significantly compared to the NaCl-treated group (P<0.05). However we could not find any statistically significant differences among the analogues. PGAs may reduce the injury induced by I/R, through the inhibition of XO activity, and it seems that their effects are elicited through numerous pathways.

Topics: Amides; Animals; Antihypertensive Agents; Apoptosis; Bimatoprost; Cloprostenol; Disease Models, Animal; Latanoprost; Male; Neuroprotective Agents; Prostaglandins F, Synthetic; Prostaglandins, Synthetic; Rabbits; Reactive Oxygen Species; Reperfusion Injury; Retina; Retinal Diseases; Travoprost; Vitreous Body; Xanthine Oxidase

To determine the mechanism by which travoprost, a prodrug of a prostaglandin F2alpha analog, reduces intraocular pressure (IOP) in cynomolgus monkey eyes.. One eye each of 12 monkeys was treated with laser burns to the trabecular meshwork to elevate IOP. At least 4 months later (Baseline Day), IOP was measured by pneumatonometry (9:00 AM and 11:45 AM), and aqueous flow and outflow facility were determined by a fluorophotometric method. Uveoscleral outflow was calculated. Both eyes were treated with travoprost 0.004% at 9:00 AM and 5:00 PM for two days and at 9:30 AM on the third day (Treatment Day), when measurements were repeated as on Baseline Day. Statistical analyses were performed using two-tailed, paired t tests.. On Treatment Day compared with Baseline Day, IOP in hypertensive eyes was reduced at 2.25 hours (25.8 +/- 11.2 vs 33.7 +/- 13.2 mm Hg; mean +/- standard error of the mean [SEM]; P = 0.02) and 16 hours (26.3 +/- 10.2 vs 35.1 +/- 13.6 mm Hg; P = 0.02) after treatment. The increase in uveoscleral outflow was not significant. In normotensive eyes, IOP was reduced at 2.25 hours (19.0 +/- 3.7 vs 23.0 +/- 4.0 mm Hg; P = 0.03) and 16 hours (20.7 +/- 5.4 vs 23.4 +/- 5.3 mm Hg; P = 0.01) after treatment, and uveoscleral outflow was significantly (P = 0.02) increased (1.02 +/- 0.43 vs 0.35 +/- 0.72 microL/min).. Travoprost reduces IOP in normotensive monkey eyes by increasing uveoscleral outflow. The IOP reduction in hypertensive eyes is probably via the same mechanism, although the increased uveoscleral drainage did not reach statistical significance. Travoprost had no effect on aqueous flow or outflow facility.

Topics: Animals; Antihypertensive Agents; Aqueous Humor; Cloprostenol; Disease Models, Animal; Female; Fluorophotometry; Intraocular Pressure; Laser Coagulation; Macaca fascicularis; Ocular Hypertension; Prodrugs; Tonometry, Ocular; Trabecular Meshwork; Travoprost

To establish a mouse model for the pharmacological analysis of antiglaucoma drugs, considering the effect of variations in IOP during 24 hours on the drugs' effects, and to evaluate the effect of a newly developed FP agonist, tafluprost, on mouse IOP, in comparison with three clinically available prostaglandin (PG) analogues.. Inbred adult ddY mice were bred and acclimatized under a 12-hour light-dark cycle. With mice under general anesthesia, a microneedle method was used to measure IOP. A single drop of 3 muL of either drug or vehicle solution was topically applied once into one eye in each mouse, in a blinded manner, with the contralateral, untreated eye serving as the control. IOP reduction was evaluated by the difference in IOP between the treated and untreated eyes in the same mouse. First, to determine the period feasible for demonstrating a larger magnitude of ocular hypotensive effect, the 24-hour diurnal variation in mouse IOP was measured, and 0.005% latanoprost was applied at the peak or trough time of variation in 24-hour IOP. The time point of the most hypotensive effect was selected for further studies, to evaluate the effects of PG analogues. Second, mice received tafluprost (0.0003%, 0.0015%, 0.005%, or 0.015%), latanoprost (0.001%, 0.0025%, or 0.005%), travoprost (0.001%, 0.002%, or 0.004%), or isopropyl unoprostone (0.03%, 0.06%, or 0.12%), and each corresponding vehicle solution. IOP was then measured at 1, 2, 3, 6, 9, and 12 hours after drug administration. The ocular hypotensive effects of the other three PG analogues were compared with that of tafluprost. All experiments were conducted in a masked study design.. The IOP in the untreated mouse eye was higher at night than during the day. Latanoprost significantly lowered IOP at night (21.4%), compared with the IOP in the untreated contralateral eye 2 hours after administration. The maximum IOP reduction was 20.2% +/- 2.0%, 18.7% +/- 2.5%, and 11.2% +/- 1.8% of that in the untreated eye 2 hours after administration of 0.005% tafluprost, 0.005% latanoprost, and 0.12% isopropyl unoprostone, respectively, whereas it was 20.8% +/- 4.6% at 6 hours with 0.004% travoprost (n = 7 approximately 17). The order of ocular hypotensive effects of three clinically used PG analogues in mice was comparable to that in humans. Area under the curve (AUC) analysis revealed dose-dependent IOP reductions for each PG analogue. Tafluprost 0.005% decreased IOP more than 0.005% latanoprost at 3, 6, and 9 hours (P = 0.001-0.027) or 0.12% unoprostone at 2, 3, and 6 hours (P = 0.0004-0.01).. The 24-hour variation in mouse eyes should be taken into consideration when evaluating the reduction of IOP. The mouse model was found to be useful in evaluating the pharmacological response to PG analogues. A newly developed FP agonist, 0.005% tafluprost, lowered normal mouse IOP more effectively than did 0.005% latanoprost.

Topics: Animals; Antihypertensive Agents; Circadian Rhythm; Cloprostenol; Dinoprost; Disease Models, Animal; Dose-Response Relationship, Drug; Intraocular Pressure; Latanoprost; Male; Mice; Mice, Inbred Strains; Ophthalmic Solutions; Prostaglandins F; Prostaglandins F, Synthetic; Time Factors; Travoprost

To compare the ocular hypotensive effect of the commercially available preparations of bimatoprost or travoprost added to latanoprost in monkey eyes with laser-induced unilateral glaucoma.. Four monkeys with unilateral laser-induced glaucoma were used in each treatment group and received drops in the glaucomatous eye only. Intraocular pressure (IOP) was measured hourly for 6 hours, beginning at 9:30 am on day 1 (untreated baseline), days 6 and 7 (single-agent therapy), and days 13 and 14 (2-drug combination therapy). On days 2 through 7, 1 drop of the scheduled single agent was given immediately after the 9:30 am IOP measurement, and on days 8 through 14, the second scheduled drug was given 5 minutes after the first. The following 5 different dosing protocols were studied: latanoprost with bimatoprost added, bimatoprost with latanoprost added, latanoprost with travoprost added, travoprost with latanoprost added, and latanoprost with a second dose of latanoprost added.. There were no statistically significant (P =.95) differences among the mean baseline IOPs in any of the 5 treatment groups. When applied as single agents, latanoprost, bimatoprost, and travoprost all produced significant (P<.05) and equivalent (P =.98) reductions in IOP. The mean +/-SEM maximum reduction (P<.05) from baseline IOP was 7.0 +/- 0.4 mm Hg (20% reduction) with travoprost alone, 6.5 +/- 1.6 mm Hg (18%) with bimatoprost alone, and 7.5 +/- 1.0 mm Hg (22%) with latanoprost alone. The mean +/-SEM maximum additive reductions in IOP were 3.0 +/- 0.6 mm Hg (P<.05) for travoprost added to latanoprost; 2.0 +/- 0.4 mm Hg (P<.05) for latanoprost added to travoprost; 4.8 +/- 1.3 mm Hg (P<.05) for bimatoprost added to latanoprost; 4.3 +/- 0.6 mm Hg (P<.05) for latanoprost added to bimatoprost; and 0.3 +/- 0.5 mm Hg (P>.60) for latanoprost added to itself. The combination of bimatoprost and latanoprost produced a greater (P<.05) lowering of IOP at trough and peak than the combination of travoprost and latanoprost.. Latanoprost, bimatoprost, and travoprost used as monotherapy produced significant and equivalent reductions in IOP in glaucomatous monkey eyes. The IOP effects of the commercial concentrations of bimatoprost or travoprost were additive to that of latanoprost, with bimatoprost showing a greater additive response than travoprost. Clinical Relevance Because treatment with multiple medications is common among patients with glaucoma, determining which glaucoma medications produce an additive ocular hypotensive response when used in combination has practical implications for clinicians.

Topics: Amides; Animals; Antihypertensive Agents; Bimatoprost; Cloprostenol; Disease Models, Animal; Drug Therapy, Combination; Female; Glaucoma; Intraocular Pressure; Latanoprost; Lipids; Macaca fascicularis; Prostaglandins F, Synthetic; Travoprost

We have tested the action of cloprostenol a relatively stable analogue of PGF2 alpha in experimentally induced gastric ulcer in rats by contention stress or indomethacin. Our results show that CIPG, administered at higher doses than those inducing an luteolytic effect, has a gastroprotective effect both in the contention stress-induced ulcer (2.30 + 0.26 in series III as compared to 3.80 +/- 0.73 in series III, p < 0.01) and in indomethacin-induced ulcer (2.69 +/- 0.38 in series V as compared to 3.61 +/- 0.34 in series IV, p < 0.01).

Topics: Animals; Cloprostenol; Disease Models, Animal; Drug Evaluation, Preclinical; Indomethacin; Male; Rats; Rats, Wistar; Stomach Ulcer; Stress, Psychological