A Novel Selective Muscarinic Acetylcholine Receptor Subtype 1 Antagonist Reduces Seizures without Impairing Hippocampus-Dependent Learning

Previous studies suggest that selective antagonists of specific subtypes of muscarinic acetylcholine receptors (mAChRs) may provide a novel approach for the treatment of certain central nervous system (CNS) disorders, including epileptic disorders, Parkinson's disease, and dystonia. Unfortunately, previously reported antagonists are not highly selective for specific mAChR subtypes, making it difficult to definitively establish the functional roles and therapeutic potential for individual subtypes of this receptor subfamily. The M 1 mAChR is of particular interest as a potential target for treatment of CNS disorders. We now report the discovery of a novel selective antagonist of M-1 mAChRs, termed VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)benzo[c][1,2,5]thiadiazole-4-sulfonamide]. Equilibrium radioligand binding and functional studies demonstrate a greater than 75-fold selectivity of VU0255035 for M-1 mAChRs relative to M-2-M-5. Molecular pharmacology and mutagenesis studies indicate that VU0255035 is a competitive orthosteric antagonist of M-1 mAChRs, a surprising finding given the high level of M-1 mAChR selectivity relative to other orthosteric antagonists. Whole-cell patch-clamp recordings demonstrate that VU0255035 inhibits potentiation of N-methyl-D-aspartate receptor currents by the muscarinic agonist carbachol in hippocampal pyramidal cells. VU0255035 has excellent brain penetration in vivo and is efficacious in reducing pilocarpine-induced seizures in mice. We were surprised to find that doses of VU0255035 that reduce pilo-carpine-induced seizures do not induce deficits in contextual freezing, a measure of hippocampus-dependent learning that is disrupted by nonselective mAChR antagonists. Taken together, these data suggest that selective antagonists of M-1 mAChRs do not induce the severe cognitive deficits seen with nonselective mAChR antagonists and could provide a novel approach for the treatment certain of CNS disorders.

Medical versus surgical interventions for open angle glaucoma.

BACKGROUND: Open angle glaucoma (OAG) is a common cause of blindness.

OBJECTIVES: To assess the effects of medication compared with initial surgery in adults with OAG.

SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2012, Issue 7), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to August 2012), EMBASE (January 1980 to August 2012), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to August 2012), Biosciences Information Service (BIOSIS) (January 1969 to August 2012), Cumulative Index to Nursing and Allied Health Literature (CINAHL) (January 1937 to August 2012), OpenGrey (System for Information on Grey Literature in Europe) (www.opengrey.eu/), Zetoc, the metaRegister of Controlled Trials (mRCT) (www.controlled-trials.com) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 1 August 2012. The National Research Register (NRR) was last searched in 2007 after which the database was archived. We also checked the reference lists of articles and contacted researchers in the field.

SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing medications with surgery in adults with OAG.

DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted study authors for missing information.

MAIN RESULTS: Four trials involving 888 participants with previously untreated OAG were included. Surgery was Scheie's procedure in one trial and trabeculectomy in three trials. In three trials, primary medication was usually pilocarpine, in one trial it was a beta-blocker.The most recent trial included participants with on average mild OAG. At five years, the risk of progressive visual field loss, based on a three unit change of a composite visual field score, was not significantly different according to initial medication or initial trabeculectomy (odds ratio (OR) 0.74, 95% confidence interval (CI) 0.54 to 1.01). In an analysis based on mean difference (MD) as a single index of visual field loss, the between treatment group difference in MD was -0.20 decibel (dB) (95% CI -1.31 to 0.91). For a subgroup with more severe glaucoma (MD -10 dB), findings from an exploratory analysis suggest that initial trabeculectomy was associated with marginally less visual field loss at five years than initial medication, (mean difference 0.74 dB (95% CI -0.00 to 1.48). Initial trabeculectomy was associated with lower average intraocular pressure (IOP) (mean difference 2.20 mmHg (95% CI 1.63 to 2.77) but more eye symptoms than medication (P = 0.0053). Beyond five years, visual acuity did not differ according to initial treatment (OR 1.48, 95% CI 0.58 to 3.81).From three trials in more severe OAG, there is some evidence that medication was associated with more progressive visual field loss and 3 to 8 mmHg less IOP lowering than surgery. In the longer-term (two trials) the risk of failure of the randomised treatment was greater with medication than trabeculectomy (OR 3.90, 95% CI 1.60 to 9.53; hazard ratio (HR) 7.27, 95% CI 2.23 to 25.71). Medications and surgery have evolved since these trials were undertaken.In three trials the risk of developing cataract was higher with trabeculectomy (OR 2.69, 95% CI 1.64 to 4.42). Evidence from one trial suggests that, beyond five years, the risk of needing cataract surgery did not differ according to initial treatment policy (OR 0.63, 95% CI 0.15 to 2.62).Methodological weaknesses were identified in all the trials.

AUTHORS' CONCLUSIONS: Primary surgery lowers IOP more than primary medication but is associated with more eye discomfort. One trial suggests that visual field restriction at five years is not significantly different whether initial treatment is medication or trabeculectomy. There is some evidence from two small trials in more severe OAG, that initial medication (pilocarpine, now rarely used as first line medication) is associated with more glaucoma progression than surgery. Beyond five years, there is no evidence of a difference in the need for cataract surgery according to initial treatment.The clinical and cost-effectiveness of contemporary medication (prostaglandin analogues, alpha2-agonists and topical carbonic anhydrase inhibitors) compared with primary surgery is not known.Further RCTs of current medical treatments compared with surgery are required, particularly for people with severe glaucoma and in black ethnic groups. Outcomes should include those reported by patients. Economic evaluations are required to inform treatment policy.

Medical versus surgical interventions for open angle glaucoma.

BACKGROUND: Open angle glaucoma (OAG) is the commonest cause of irreversible blindness worldwide. OBJECTIVES: To study the relative effects of medical and surgical treatment of OAG. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2005), MEDLINE (1966 to February 2005), EMBASE (1988 to February 2005), and reference lists of articles. We also contacted researchers in the field. SELECTION CRITERIA: Randomised controlled trials comparing medications to surgery in adults. DATA COLLECTION AND ANALYSIS: Two authors independently assessed trial quality and extracted data. We contacted trial investigators for missing information. MAIN RESULTS: Four trials involving 888 participants with previously untreated OAG were included. Surgery was Scheie's procedure in one trial and trabeculectomy in three trials. In three trials, primary medication was usually pilocarpine, in one trial a beta-blocker.In the most recent trial, participants with mild OAG, progressive visual field (VF) loss, after adjustment for cataract surgery, was not significantly different for medications compared to trabeculectomy (Odds ratio (OR) 0.74; 95% CI 0.54 to 1.01). Reduction of vision, with a higher risk of developing cataract (OR 2.69, 95%% CI 1.64 to 4.42), and more patient discomfort was more likely with trabeculectomy than medication.There is some evidence, from three trials, for people with moderately advanced glaucoma that medication is associated with more progressive VF loss and 6 to 8 mmHg less intraocular pressure (IOP) lowering than surgery, either by a Scheie's procedure or trabeculectomy. There was a trend towards an increased risk of failed IOP control over time for initial pilocarpine treatment compared to trabeculectomy. In the longer-term (two trials) the risk of failure was significantly greater with medication than trabeculectomy (OR 3.90, 95% CI 1.60 to 9.53; HR 7.27, 95% CI 2.23 to 25.71). Medicine and surgery have evolved since these trials were undertaken, and additionally the evidence is potentially subject to detection and attrition bias. AUTHORS' CONCLUSIONS: Evidence from one trial suggests, for mild OAG, that VF deterioration up to five-years is not significantly different whether treatment is initiated with medication or trabeculectomy. Reduced vision, cataract and eye discomfort are more likely with trabeculectomy. There is some evidence, for more severe OAG, that initial medication (pilocarpine, now rarely used as first line medication) is associated with greater VF deterioration than surgery. In general, surgery lowers IOP more than medication.There was no evidence to determine the effectiveness of contemporary medication (prostaglandin analogues, alpha2-agonists and topical carbonic anhydrase inhibitors) compared to surgery in severe OAG, and in people of black African ethnic origin who have a greater risk of more severe open angle glaucoma. More research is required.