piperidines and Ocular-Hypertension

To assess the clinical safety, tolerability, and efficacy of topically administered MGV354, a soluble guanylate cyclase (sGC) activator, in patients with ocular hypertension (OH) or glaucoma.. Double-masked, randomized, and vehicle-controlled study.. Parts 1 and 2 evaluated safety and tolerability to identify the maximum tolerated dose (MTD) of once-daily MGV354 in 32 healthy volunteers (Part 1) and 16 patients with OH or glaucoma (Part 2) at a single clinical site. Part 3 was a multisite trial that evaluated intraocular pressure (IOP)-lowering efficacy of the MTD administered nightly for 1 week in 50 patients with minimum IOP of 24 mm Hg at 8 AM, with a main outcome measure of mean diurnal IOP at day 8 compared to baseline (ClinicalTrials.govNCT02743780).. There was no difference in favor of MGV354 for IOP lowering; change from baseline to day 8 in mean diurnal IOP was -0.6 mm Hg for MGV354-treated patients and -1.1 mm Hg for vehicle-treated patients in Part 3, with a confidence interval of -0.7 to 1.7. The most common adverse events reported after MGV354 administration were conjunctival and ocular hyperemia.. Overall, MGV354 0.1% demonstrated no statistically significant effect compared to vehicle in lowering IOP based on the study's main outcome measure. MGV354 produced ocular hyperemia consistent with its pharmacology.

Topics: Administration, Ophthalmic; Adolescent; Adult; Aged; Double-Blind Method; Enzyme Activators; Female; Glaucoma, Open-Angle; Guanylate Cyclase; Humans; Intraocular Pressure; Male; Maximum Tolerated Dose; Middle Aged; No-Observed-Adverse-Effect Level; Ocular Hypertension; Ophthalmic Solutions; Piperidines; Pyrazoles; Pyridines; Tonometry, Ocular; Treatment Outcome; Visual Acuity; Young Adult

Rapid sequence induction using succinylcholine is associated with an increase in intraocular pressure (IOP). This may lead to loss of ocular contents in open globe injuries. No method has previously been shown to prevent this increase in IOP. We investigated whether remifentanil, an ultra-short-acting opioid, could attenuate this increase in IOP during rapid sequence induction of anaesthesia. Forty-five patients were randomized blindly to receive remifentanil 1 microgram kg-1, fentanyl 2 micrograms kg-1 or placebo 1 min before thiopental, succinylcholine and tracheal intubation. IOP and haemodynamic variables were measured before, 1 min after the test solution, 30 s after thiopental, 30 s after succinylcholine, immediately after intubation and then every 3 min for 9 min. Remifentanil obtunded the increase in IOP after succinylcholine and intubation, so it could be suitable for use in open globe injuries.

Topics: Adult; Analgesics, Opioid; Double-Blind Method; Female; Fentanyl; Hemodynamics; Humans; Intubation, Intratracheal; Male; Middle Aged; Neuromuscular Depolarizing Agents; Ocular Hypertension; Piperidines; Remifentanil; Succinylcholine

We have studied changes in intraocular pressure (IOP) in 30 patients after succinylcholine (suxamethonium) and tracheal intubation following administration of propofol 2 mg kg-1 and either remifentanil 1 microgram kg-1 (group R) or saline (group S). IOP was measured before induction, before administration of succinylcholine and the study drug, before intubation and for every 1 min after intubation for 5 min. There was a significant decrease in IOP in group R compared with group S from the time of administration of the study drugs to the end of the study (P < 0.006).

Topics: Adult; Aged; Analgesics, Opioid; Anesthetics, Intravenous; Blood Pressure; Double-Blind Method; Female; Heart Rate; Humans; Intubation, Intratracheal; Male; Middle Aged; Neuromuscular Depolarizing Agents; Ocular Hypertension; Ophthalmologic Surgical Procedures; Piperidines; Propofol; Remifentanil; Succinylcholine

Topics: Animals; Antihypertensive Agents; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Ocular Hypertension; Piperidines; Pyrazoles; Pyridines; Rabbits

Glaucoma is a neurodegenerative disease of the eye with an estimated prevalence of more than 111.8 million patients worldwide by 2040, with at least 6 to 8 million projected to become bilaterally blind. Clinically, the current method of slowing glaucomatous vision loss is to reduce intraocular pressure (IOP). In this manuscript, we describe the in vitro cytoprotective and in vivo long lasting IOP-lowering activity of the poly D, L-lactic-co-glycolic acid (PLGA) nanoparticle-encapsulated hybrid compound SA-2, possessing nitric oxide (NO) donating and superoxide radical scavenging functionalities.. Hybrid compound SA-2 upregulated cGMP in hTM cells, increased outflow facility and decreased IOP in rodent models of OHT. Compound SA-2 possessing an antioxidant moiety provided additive cytoprotective activity to oxidatively stressed hTM cells by scavenging reactive oxygen species (ROS) and increasing SOD enzyme activity. Additionally, the PLGA nanosuspension formulation (SA-2 NPs) provided longer duration of IOP-lowering activity (up to 3 days) in comparison with the free non-encapsulated SA-2 drug. The data have implications for developing novel, non-prostaglandin therapeutics for IOP-lowering and cytoprotective effects with the possibility of an eye drop dosing regimen of once every 3 days for patients with glaucoma.

Topics: Administration, Ophthalmic; Adult; Aged, 80 and over; Animals; Antihypertensive Agents; Aqueous Humor; Biological Availability; Cells, Cultured; Cyclic GMP; Disease Models, Animal; Drug Carriers; Female; Free Radical Scavengers; Glycolates; Humans; Intraocular Pressure; Male; Mice, Inbred C57BL; Nitric Oxide Donors; Ocular Hypertension; Ophthalmic Solutions; Piperidines; Rats; Rats, Inbred BN; Rats, Sprague-Dawley; Reactive Oxygen Species; Sclera; Superoxide Dismutase; Tissue Distribution; Trabecular Meshwork; Venous Pressure

Hypertension is an independent risk factor for diabetic retinopathy, yet anti-hypertensive medications such as blockade of angiotensin II do not completely protect against vision-threatening vascular disease. We hypothesized that the potent vasoactive factor, endothelin (ET), is up-regulated in diabetic retinopathy and antagonism of the ET type A receptor (ETRA) or ET type B receptor (ETRB) ameliorates retinal vascular leakage independently of any blood pressure lowering effects. Spontaneously hypertensive rats (SHR) and their normotensive and genetic controls, Wistar Kyoto rats, were randomized to become diabetic or non-diabetic and studied for 8 weeks. Rats were further randomized to receive by intravitreal injection the ETRA antagonist, BQ123, the ETRB antagonist, BQ788, or vehicle, 5 days after the induction of streptozotocin diabetes and 4 weeks later. The treatments had no effect on systolic blood pressure which remained elevated in SHR. ET-1, ET-2, ETRA and ETRB were expressed in retina and retinal pigment epithelium (RPE)/choroid and increased by hypertension or diabetes. BQ123 reduced ET-1 and ET-2 expression in retina and RPE/choroid, while BQ788 had a similar effect but did not influence the mRNA levels of ET-1 in retina. Retinal vascular leakage and Müller cell stress as well as vascular endothelial growth factor (VEGF) expression in retina and RPE/choroid, were increased by hypertension or diabetes and there was an additive effect of these conditions. Treatment with BQ123 or BQ788 effectively reduced these events as well as the elevated levels of inflammatory factors in the retina. Our findings indicate that local ET systems exist in the retina and RPE/choroid that are up-regulated by hypertension and diabetes. The ability of locally delivered ET receptor antagonists to supress these overactive ET systems and reduce retinal vascular leakage and VEGF in the presence of hypertension indicate the potential of these approaches for the treatment of diabetic retinopathy.

Topics: Animals; Antihypertensive Agents; Blood Pressure; Blood-Retinal Barrier; Choroid; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin-1; Endothelin-2; Enzyme-Linked Immunosorbent Assay; Fluorescent Antibody Technique, Indirect; Intravitreal Injections; Ocular Hypertension; Oligopeptides; Peptides, Cyclic; Piperidines; Rats; Rats, Inbred SHR; Rats, Inbred WKY; Real-Time Polymerase Chain Reaction; Retina; Retinal Pigment Epithelium; Streptozocin

Neuroprotection in retinal experimental work consists primarily of preventing retinal ganglion cell (RGC) loss after exposure to a hostile event. We have studied the neuroprotective effect on RGCs in an ischemia-reperfusion model by activation of the cannabinoid receptor CB1 using topical application of WIN 55212-2. Intraocular pressure (IOP) was increased by continuous infusion of phosphate buffer saline (PBS) into the anterior chamber of the eye. Mean intraocular pressure was increased up to 88.5 ± 0.29 mm Hg (control normal IOP 15.1 ± 0.25 mm Hg), for 35 min. Animals were distributed in 3 groups. Left eyes underwent acute rise in intraocular pressure. First group was treated with topical Tocrisolve™ 100 in both eyes. Second group was treated with 1% solution of CB1 agonist WIN 55212-2 in both eyes. Third group was treated with WIN 55212-2 1% and CB1 antagonist AM 251 1% solutions in both eyes. Subsequently, RGCs were immunolabeled with Brn3a and automated quantification of retinal mosaics of RGCs were performed. The ischemic damage led to a mean loss in RGC density of 12.33%. After topic administration of WIN 55212-2, mean loss of RGCs was of 2.45%. Co-treatment with CB1 antagonist AM 251 abolished almost completely the neuroprotective effect of WIN 55212-2. Topic 1% WIN 55212-2 showed a neuroprotective effect on RGC degeneration after ischemia-reperfusion without pre-activation of CB1 receptors.

Topics: Administration, Topical; Animals; Benzoxazines; Cell Count; Disease Models, Animal; Female; Intraocular Pressure; Morpholines; Naphthalenes; Neuroprotective Agents; Ocular Hypertension; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reperfusion Injury; Retinal Diseases; Retinal Ganglion Cells; Tonometry, Ocular

Topics: Analgesics, Opioid; Humans; Neuromuscular Depolarizing Agents; Ocular Hypertension; Piperidines; Remifentanil; Succinylcholine

Systemically administered cannabinoids can reduce intraocular pressure (IOP), but produce undesirable cardiovascular and central nervous system effects. In a chronic model of ocular hypertension, we examined the efficacy of acute topical administration of WIN55212-2 (WIN) in a novel commercially available vehicle and in combination with timolol.. IOP was chronically elevated by the surgical ligature of vortex veins in Sprague Dawley rats. IOP was measured by using Goldmann applanation tonometry. IOP, blood pressure (BP), and heart rate (HR) were measured at baseline and 30, 60, 90, and 120 min after the topical administration of WIN 1.0%, 0.25%, 0.06%, or 0.015%, the commercially available vehicle, timolol 0.5%, or a combination of WIN and timolol. SR141716 (CB1 antagonist) or SR144528 (CB2 antagonist) was administered topically 30 min before WIN to determine receptor specificity. To determine ocular and systemic penetration, 3H WIN 55212-2 was administered topically and tissues were collected at 60 and 120 min. Ocular irritation was evaluated by slit-lamp examination (SLE) at baseline and 120 min.. WIN significantly decreased IOP in the hypertensive eye, with no BP or HR effects. SR141716 pretreatment significantly inhibited the IOP effects of WIN 1.0% in a dose-dependent manner, while SR 144528 was not as effective. No significant additive effects were observed by combining WIN (0.5% or 1.0%) with timolol 0.5%. WIN was retained in ocular tissue with a t1/2 of 80-100 min. SLE at 120 min revealed no solvent or drug-related toxic effects.. In a chronic ocular hypertensive rat model, topically applied WIN is an effective, nontoxic ocular hypotensive agent with no hemodynamic side-effects. This effect was predominantly CB1 receptor mediated, but some CB2 contribution could not be ruled out.

Topics: Administration, Topical; Adrenergic beta-Antagonists; Animals; Benzoxazines; Blood Pressure; Calcium Channel Blockers; Camphanes; Heart Rate; Intraocular Pressure; Irritants; Male; Morpholines; Naphthalenes; Ocular Hypertension; Piperidines; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Rimonabant; Timolol

To evaluate whether high intraocular pressure (IOP)-induced ischemia is associated with modifications in the retinal endocannabinoid metabolism and to ascertain whether drugs that interfere with the endocannabinoid system may prevent retinal damage due to ischemic insult.. Anandamide (AEA) synthesis, transport, hydrolysis, and AEA endogenous levels were assessed by means of high-performance liquid chromatography in the retinas of rats undergoing 45 minutes of ischemia followed by 12 hours of reperfusion. Under these experimental conditions, binding to cannabinoid (CB1R) and vanilloid (TRPV1) receptor was assessed with rapid-filtration assays. AEA-hydrolase (FAAH, fatty acid amide hydrolase), CB1R and TRPV1 protein content was determined by enzyme-linked immunosorbent assay. Finally, to characterize the neuroprotective profile of drugs that interfere with the endocannabinoid system, cell counting in the retinal ganglion cell (RGC) layer and real-time polymerase chain reactions for Thy-1 mRNA expression were used.. In rat retina, ischemic insult followed by reperfusion resulted in enhanced FAAH activity and protein expression paralleled by a significant decrease in the endogenous AEA tone, whereas the AEA-membrane transporter or the AEA-synthase NAPE-PLD (N-acyl-phosphatidylethanolamine-hydrolyzing-phospholipase-d) were not affected. Retinal ischemia-reperfusion decreased the expression of cannabinoid (CB1) and vanilloid (TRPV1) receptors. Systemic administration of a specific FAAH inhibitor (e.g., URB597) reduced enzyme activity and minimized the retinal damage observed in ischemic-reperfused samples. Similarly, intravitreal injection of the AEA stable analogue, R(+)-methanandamide, reduced cell loss in the RGC layer, and this was prevented by systemic administration of a CB1 or TRPV1 selective antagonist (e.g., SR141716 and capsazepine, respectively).. The original observation that retinal ischemia-reperfusion reduces endogenous AEA via enhanced expression of FAAH supports the deduction that this is implicated in retinal cell loss caused by high IOP in the RGC layer.

Topics: Amidohydrolases; Animals; Arachidonic Acids; Benzamides; Cannabinoid Receptor Modulators; Capsaicin; Carbamates; Cell Count; Chromatography, High Pressure Liquid; Endocannabinoids; Enzyme Inhibitors; Enzyme-Linked Immunosorbent Assay; Hydrolysis; Intraocular Pressure; Male; Ocular Hypertension; Piperidines; Polyunsaturated Alkamides; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Reperfusion Injury; Retinal Diseases; Retinal Ganglion Cells; Retinal Vessels; Reverse Transcriptase Polymerase Chain Reaction; Rimonabant; RNA, Messenger; Thy-1 Antigens; TRPV Cation Channels

To assess the neuroprotective effects of different glutamate modulation strategies, with a nonselective (MK801) and a selective (ifenprodil) NMDA receptor antagonist and a metabotropic glutamate receptor agonist (mGluR Group II, LY354740), in glaucoma-related in vivo rat models of retinal ganglion cell (RGC) apoptosis.. RGC apoptosis was induced in Dark Agouti (DA) rats by staurosporine (SSP) treatment. Single agents MK801, ifenprodil, or LY354740, or MK801 and LY354740 combined, were administrated intravitreally at different doses. Eyes were imaged in vivo using a recently established technique and the results confirmed histologically. The most effective combined therapy regimen of MK801 and LY354740 was then assessed in a chronic ocular hypertension (OHT) rat model with application at 0, 1, and 2 weeks after OHT surgery and the effects assessed as described before.. All strategies of glutamate modulation reduced SSP-induced-RGC apoptosis compared with the control, in a dose-dependent manner: MK801 (R2= 0.8863), ifenprodil (R2= 0.4587), and LY354740 (R2= 0.9094), with EC50s of 0.074, 0.0138, and 19 nanomoles, respectively. The most effective combination dose of MK801 and LY354740 was 0.06 and 20 nanomoles (P < 0.05), respectively, and the optimal timing of the therapy was 0 weeks after OHT surgery (P < 0.05).. This novel SSP model was validated as a useful tool for screening neuroprotective strategies in vivo. Group II mGluR modulation may be a useful treatment for RGC death. Combination therapy optimized to limit neurotoxic effects of MK801 may be an effective neuroprotective approach in retinal degenerative disease. Furthermore, treatments that minimize secondary RGC degeneration may be most useful in glaucoma.

Topics: Animals; Apoptosis; Bridged Bicyclo Compounds; Disease Models, Animal; Dizocilpine Maleate; Dose-Response Relationship, Drug; Drug Therapy, Combination; Excitatory Amino Acid Agonists; Excitatory Amino Acid Antagonists; Glaucoma; Glutamic Acid; Intraocular Pressure; Male; Neuroprotective Agents; Ocular Hypertension; Piperidines; Rats; Receptors, Metabotropic Glutamate; Receptors, N-Methyl-D-Aspartate; Retinal Ganglion Cells; Staurosporine

1. This work was conducted to provide new data concerning the possible dose-dependent activity of dopamine (DA) after ocular instillation. Experiments were done in rabbits with normal intraocular pressure (IOP), or after transitory induced ocular hypertension in water-loaded animals. 2. In ocular normotensive animals, a biphasic dose-dependent activity is observed, with no significant effect for 0.001% and 0.003% DA, a decrease in IOP after 0.005% and 0.01% DA instillation, then an important increase in IOP at concentrations from 0.05% onwards. 3. During transitory ocular hypertension, this phenomenon was confirmed, with a marked ocular hypotensive activity for 0.01% DA, no effect after 0.005% DA, then an important ocular hypertension with 0.05% and 0.5% DA as compared to the control group (0.9% NaCl). 4. An immediate and similar ocular hypertensive effect with DA could be reproduced by a subsequent instillation at high concentration (1%), while the hypotensive activity induced at low concentration (0.01%) is followed by a long-lasting refractory period (about 18 h). 5. Such a dose-dependent biphasic effect was also observed with N-methyl-dopamine (NMDA) after ocular instillation. The effects of instilled dopaminergic compounds were tested and ocular hypotensive activities of the S(-)enantiomer of the DA analogues 3-(3-hydroxyphenyl)-N-propylpiperidine (3-PPP), and of thiothixene (TIX) were also demonstrated. 6. The possible relationships to DA1 and DA2 receptors of the dual effect is discussed.

Topics: Animals; Dopamine; Dopamine Agents; Dose-Response Relationship, Drug; Intraocular Pressure; Male; N-Methylaspartate; Ocular Hypertension; Piperidines; Rabbits; Receptors, Dopamine; Thiothixene