Efficacy of Lacosamide and Rufinamide as Adjuncts to Midazolam-Ketamine Treatment Against Cholinergic-Induced Status Epilepticus in Rats.

Benzodiazepine pharmacoresistance develops when treatment of status epilepticus (SE) is delayed. This response may result from gamma-aminobutyric acid A receptors (GABAAR) internalization that follows prolonged SE; this receptor trafficking results in fewer GABAAR in the synapse to restore inhibition. Increase in synaptic N-methyl-D-aspartate receptors (NMDAR) also occurs in rodent models of SE. Lacosamide, a third-generation antiseizure medication (ASM), acts on the slow inactivation of voltage-gated sodium channels. Another ASM, rufinamide, similarly acts on sodium channels by extending the duration of time spent in the inactivation stage. Combination therapy of the benzodiazepine midazolam, NMDAR antagonist ketamine, and ASMs lacosamide (or rufinamide) was investigated for efficacy against soman (GD)-induced SE and neuropathology. Adult male rats implanted with telemetry transmitters for monitoring electroencephalographic (EEG) activity were exposed to a seizure-inducing dose of GD and treated with an admix of atropine sulfate and HI-6 1 minute later and with midazolam monotherapy or combination therapy 40 minutes after EEG seizure onset. Rats were monitored continuously for seizure activity for two weeks, after which brains were processed for assessment of neurodegeneration, neuronal loss, and neuroinflammatory responses. Simultaneous administration of midazolam, ketamine, and lacosamide (or rufinamide) was more protective against GD-induced SE compared with midazolam monotherapy. In general, lacosamide triple therapy had more positive outcomes on measures of epileptogenesis, EEG power integral, and the number of brain regions protected from neuropathology compared with rats treated with rufinamide triple therapy. Overall, both drugs were well tolerated in these combination models. SIGNIFICANCE STATEMENT: We currently report on improved efficacy of antiseizure medications lacosamide and rufinamide, each administered in combination with ketamine (NMDAR antagonist) and midazolam (benzodiazepine), in combatting soman (GD)-induced seizure, epileptogenesis, and brain pathology over that provided by midazolam monotherapy, or dual therapy of midazolam and lacosamide (or rufinamide) in rats. Administration of lacosamide as adjunct to midazolam and ketamine was particularly effective against GD-induced toxicity. However, protection was incomplete, suggesting the need for further study.

Evaluation of Midazolam-Ketamine-Allopregnanolone Combination Therapy against Cholinergic-Induced Status Epilepticus in Rats.

Status epilepticus (SE) is a life-threatening development of self-sustaining seizures that becomes resistant to benzodiazepines when treatment is delayed. Benzodiazepine pharmacoresistance is thought in part to result from internalization of synaptic GABAA receptors, which are the main target of the drug. The naturally occurring neurosteroid allopregnanolone is a therapy of interest against SE for its ability to modulate all isoforms of GABAA receptors. Ketamine, an N-methyl-D-aspartate (NMDA) receptor antagonist, has been partially effective in combination with benzodiazepines in mitigating SE-associated neurotoxicity. In this study, allopregnanolone as an adjunct to midazolam or midazolam-ketamine combination therapy was evaluated for efficacy against cholinergic-induced SE. Adult male rats implanted with electroencephalographic (EEG) telemetry devices were exposed to the organophosphorus chemical (OP) soman (GD) and treated with an admix of atropine sulfate and HI-6 at 1 minute after exposure followed by midazolam, midazolam-allopregnanolone, or midazolam-ketamine-allopregnanolone 40 minutes after seizure onset. Neurodegeneration, neuronal loss, and neuroinflammation were assessed 2 weeks after GD exposure. Seizure activity, EEG power integral, and epileptogenesis were also compared among groups. Overall, midazolam-ketamine-allopregnanolone combination therapy was effective in reducing cholinergic-induced toxic signs and neuropathology, particularly in the thalamus and hippocampus. Higher dosage of allopregnanolone administered in combination with midazolam and ketamine was also effective in reducing EEG power integral and epileptogenesis. The current study reports that there is a promising potential of neurosteroids in combination with benzodiazepine and ketamine treatments in a GD model of SE. SIGNIFICANCE STATEMENT: Allopregnanolone, a naturally occurring neurosteroid, reduced pathologies associated with soman (GD) exposure such as epileptogenesis, neurodegeneration, and neuroinflammation, and suppressed GD-induced toxic signs when used as an adjunct to midazolam and ketamine in a delayed treatment model of soman-induced status epilepticus (SE) in rats. However, protection was incomplete, suggesting that further studies are needed to identify optimal combinations of antiseizure medications and routes of administration for maximal efficacy against cholinergic-induced SE.

Efficacy of a combined anti-seizure treatment against cholinergic established status epilepticus following a sarin nerve agent insult in rats.

The development of refractory status epilepticus (SE) following sarin intoxication presents a therapeutic challenge. Here, we evaluated the efficacy of delayed combined double or triple treatment in reducing abnormal epileptiform seizure activity (ESA) and the ensuing long-term neuronal insult. SE was induced in rats by exposure to 1.2 LD50 sarin followed by treatment with atropine and TMB4 (TA) 1 min later. Double treatment with ketamine and midazolam or triple treatment with ketamine, midazolam and levetiracetam was administered 30 min post-exposure, and the results were compared to those of single treatment with midazolam alone or triple treatment with ketamine, midazolam, and valproate, which was previously shown to ameliorate this neurological insult. Toxicity and electrocorticogram activity were monitored during the first week, and behavioral evaluations were performed 2 weeks post-exposure, followed by biochemical and immunohistopathological analyses. Both double and triple treatment reduced mortality and enhanced weight recovery compared to TA-only treatment. Triple treatment and, to a lesser extent, double treatment significantly ameliorated the ESA duration. Compared to the TA-only or the TA+ midazolam treatment, both double and triple treatment reduced the sarin-induced increase in the neuroinflammatory marker PGE2 and the brain damage marker TSPO and decreased gliosis, astrocytosis and neuronal damage. Finally, both double and triple treatment prevented a change in behavior, as measured in the open field test. No significant difference was observed between the efficacies of the two triple treatments, and both triple combinations completely prevented brain injury (no differences from the naïve rats). Delayed double and, to a greater extent, triple treatment may serve as an efficacious delayed therapy, preventing brain insult propagation following sarin-induced refractory SE.

Morus Alba Fruit Extract and its Fractions Ameliorate Streptozotocin Induced Cognitive Deficit in Mice via Modulating Oxidative and Cholinergic Systems.

Increased oxidative stress and acetylcholinesterase (AChE) activity are key pathological characters contributing to the memory disorders. Thus, drugs targeting both oxidative stress and AChE are being explored for the management of cognitive dysfunction. Morus alba fruits (commonly consumed for its high nutritious value) are known to have antioxidant and AChE inhibitory effects. However, the role of Morus alba fruits in the management of memory disorders has not reported yet. This investigation was conducted to assess the antioxidant and AChE inhibitory potential of Morus alba fruit extracts in-vitro and to identify the components responsible for such effects. Further, the obtained bioactive component was studied for possible memory improvement effects against streptozotocin (STZ) induced dementia. To isolate the bioactive component in-vitro DPPH and AChE assays guided fractionation was performed. Memory functions in mice were determined using Morris Water Maze test while brain biochemical parameters were measured to understand the mechanism of action. In-vitro assays revealed strong AChE and DPPH inhibitory potential of methanol extract (ME), therefore, it was further fractionated. Among various fractions obtained, ethyl-acetate fraction (EAF) was found to possess marked AChE and DPPH inhibitory activities. On subsequent fractionation of EAF, bioactivity of obtained sub-fractions was found to be inferior to EAF. Further, both ME and EAF improved STZ (intracerebroventricular) induced cognitive dysfunction in animals by restoring endogenous antioxidant status (superoxide dismutase and reduced glutathione) and reducing thiobarbituric acid reactive species and nitric oxide levels along with brain AChE and myeloperoxidase activity. TLC densitometric studies showed appreciable levels of phenolic acids and quercetin in both EAF and ME. It can be concluded that Morus alba fruit extract has the ability to modulate cholinergic and oxidative system due to presence of phenolic and flavonoid compounds and hence, could aid in the management of memory disorders.

Activation of the High-Affinity Choline Transporter 1 in the Spinal Cord Relieves Stress-Induced Hyperalgesia.

BACKGROUND: The mechanism underlying irritable bowel syndrome (IBS), a common disease with hyperalgesia, remains elusive. The spinal cholinergic system is involved in pain modulation, but its role in IBS is unknown. AIMS: To determine whether high-affinity choline transporter 1 (CHT1, a major determinant of the cholinergic signaling capacity), is implicated in spinal modulation of stress-induced hyperalgesia. METHODS: A rat IBS model was established by water avoidance stress (WAS). Visceral sensations were detected by abdominal withdrawal reflex (AWR) and visceromotor response (VMR) to colorectal distension (CRD). Abdominal mechanical sensitivity was determined by von Frey filaments (VFFs) test. RT-PCR, Western blot, and immunostaining were performed for spinal CHT1 expression. Spinal acetylcholine (ACh) was measured by ELISA; the influence of spinal CHT1 on hyperalgesia were evaluated by intrathecal administration of MKC-231 (a choline uptake enhancer) and hemicholinium-3 (HC-3, a specific inhibitor of CHT1). Minocycline treatment was used to explore the role of spinal microglia in hyperalgesia. RESULTS: After 10 days of WAS, AWR scores and VMR magnitude to CRD, and the number of withdrawal events in VFF test were increased. Double-labeling showed that CHT1 in the dorsal horn was expressed in most of the neurons and almost all the microglia. The CHT1 expression and ACh levels in the spinal cord and the density of CHT1-positive cell in the spinal dorsal horn were enhanced in WAS-exposed rats. HC-3 enhanced pain responses in WAS rats; MKC-231 alleviated pain in WAS rats by upregulating CHT1 expression and increasing ACh production in the spinal cord. Furthermore, microglial activation in the spinal dorsal horn promoted the stress-induced hyperalgesia, and MKC-231 achieved analgesic effects by inhibiting the spinal microglial activation. CONCLUSIONS: CHT1 exerts antinociceptive effects in spinal modulation of chronic stress-induced hyperalgesia by increasing ACh synthesis and suppressing microglial activation. MKC-231 has potential for treating disorders accompanied by hyperalgesia.

Protective Effects of Inosine on Memory Consolidation in a Rat Model of Scopolamine-Induced Cognitive Impairment: Involvement of Cholinergic Signaling, Redox Status, and Ion Pump Activities.

This study investigated the effects of inosine on memory acquisition and consolidation, cholinesterases activities, redox status and Na+, K+-ATPase activity in a rat model of scopolamine-induced cognitive impairment. Adult male rats were divided into four groups: control (saline), scopolamine (1 mg/kg), scopolamine plus inosine (50 mg/kg), and scopolamine plus inosine (100 mg/kg). Inosine was pre-administered for 7 days, intraperitoneally. On day 8, scopolamine was administered pre (memory acquisition protocol) or post training (memory consolidation protocol) on inhibitory avoidance tasks. The animals were subjected to the step-down inhibitory avoidance task 24 hours after the training. Scopolamine induced impairment in the acquisition and consolidation phases; however, inosine was able to prevent only the impairment in memory consolidation. Also, scopolamine increased the activity of acetylcholinesterase and reduced the activity of Na+, K+-ATPase and the treatment with inosine protected against these alterations in consolidation protocol. In the animals treated with scopolamine, inosine improved the redox status by reducing the levels of reactive oxygen species and thiobarbituric acid reactive substances and restoring the activity of the antioxidant enzymes, superoxide dismutase and catalase. Our findings suggest that inosine may offer protection against scopolamine-induced memory consolidation impairment by modulating brain redox status, cholinergic signaling and ion pump activity. This compound may provide an interesting approach in pharmacotherapy and as a prophylactic against neurodegenerative mechanisms involved in Alzheimer's disease.

In Vivo Sex-Dependent Effects of Perinatal Pb2+ Exposure on Pilocarpine-Induced Seizure Susceptibility and Taurine Neuropharmacology.

Lead (Pb2+) is a developmental neurotoxicant that disrupts the GABA-shift and subsequently causes alterations in the brain's excitation-to-inhibition (E/I) balance. This finding suggests that neurodevelopmental Pb2+ exposures may increase the risk of brain excitability and/or seizure susceptibility. Prior studies have suggested that neurodevelopmental Pb2+ exposures may cause excitotoxicity of cholinergic neurons, but little to no research has further investigated these potential relationships. The present study sought to evaluate the potential for perinatal neurodevelopmental Pb2+ exposures of 150 ppm and 1000 ppm on pilocarpine-induced seizures through the M1 receptor. The study also evaluated the potential for sex- and treatment-dependent differences in brain excitability. The study revealed that Control females have elevated cholinergic brain excitability and decreased GABAergic inhibition in response to pilocarpine-induced seizures. At low Pb2+ exposures, males exhibited more cholinergic brain excitability, whereas at higher Pb2+ exposures, females exhibited more cholinergic brain excitability. Further, taurine was able to provide neuroprotection against pilocarpine-induced seizures in males, whereas females did not reveal such observations. Thus, the present study adds new insights into the potential for cholinergic seizure susceptibility as a function of sex and the dosage ofneurodevelopmental Pb2+ exposure and how taurine may provide selective pharmacodynamics to treat or recover cholinergic system aberrations induced by neurotoxicants.

A randomized trial evaluating the safety profile of sugammadex in high surgical risk ASA physical class 3 or 4 participants.

BACKGROUND: The aim of this randomized, double-blind trial was to evaluate the safety and tolerability profile, including cardiac safety, of sugammadex-mediated recovery from neuromuscular block in participants undergoing surgery who met the American Society of Anesthesiologists (ASA) Physical Class 3 or 4 criteria. Specifically, this study assessed the impact of sugammadex on cardiac adverse events (AEs) and other prespecified AEs of clinical interest. METHODS: Participants meeting ASA Class 3 and 4 criteria were stratified by ASA Class and NMBA (rocuronium or vecuronium) then randomized to one of the following: 1) Moderate neuromuscular block, sugammadex 2 mg/kg; 2) Moderate neuromuscular block, neostigmine and glycopyrrolate (neostigmine/glycopyrrolate); 3) Deep neuromuscular block, sugammadex 4 mg/kg; 4) Deep neuromuscular block, sugammadex 16 mg/kg (rocuronium only). Primary endpoints included incidences of treatment-emergent (TE) sinus bradycardia, TE sinus tachycardia and other TE cardiac arrhythmias. RESULTS: Of 344 participants randomized, 331 received treatment (61% male, BMI 28.5 ± 5.3 kg/m2, age 69 ± 11 years). Incidence of TE sinus bradycardia was significantly lower in the sugammadex 2 mg/kg group vs neostigmine/glycopyrrolate. The incidence of TE sinus tachycardia was significantly lower in the sugammadex 2 and 4 mg/kg groups vs neostigmine/glycopyrrolate. No significant differences in other TE cardiac arrythmias were seen between sugammadex groups and neostigmine/glycopyrrolate. There were no cases of adjudicated anaphylaxis or hypersensitivity reactions in this study. CONCLUSIONS: Compared with neostigmine/glycopyrrolate, incidence of TE sinus bradycardia was significantly lower with sugammadex 2 mg/kg and incidence of TE sinus tachycardia was significantly lower with sugammadex 2 mg/kg and 4 mg/kg. These results support the safety of sugammadex for reversing rocuronium- or vecuronium-induced moderate and deep neuromuscular block in ASA Class 3 or 4 participants. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03346057 .

A case report of cholinergic rebound syndrome following abrupt low-dose clozapine discontinuation in a patient with type I bipolar affective disorder.

BACKGROUND: Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature; however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder. CASE PRESENTATION: A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal range. While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient's psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200 mg daily. A cholinergic rebound syndrome was then evoked. The patient's ability to speak recovered dramatically and fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of biperiden daily. CONCLUSIONS: This case report underscores that cholinergic rebound syndrome may occur in patients suffering from bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.

A Pilot Study of a Standardized Smoking Cessation Intervention for Patients with Vascular Disease.

BACKGROUND: The goal of this study is to evaluate the efficacy of a smoking cessation intervention performed by a vascular surgery provider compared with current smoking cessation practices. METHODS: Patients with peripheral arterial and aneurysmal disease who presented to the vascular surgery service at a tertiary care center over a 9-month period were randomized to either control or intervention group. Both control and intervention groups received 2 weeks of free nicotine patches and referral to an outpatient smoking-cessation program. The intervention group additionally received a brief presentation by a vascular surgeon regarding the benefits of smoking cessation, with a focus on vascular complications. At enrollment and at follow-up, patients underwent carbon monoxide breath testing and completed a survey. The primary outcome was smoking cessation or reduction among control and intervention groups in patients who underwent medical management, endovascular procedures, or open surgical procedures. Fisher's exact test was used to assess the primary outcome among groups. RESULTS: Fifty-nine patients were enrolled in the trial initially, but 55 had 1-month follow-up (control n = 28, intervention n = 27) and 52 had long-term follow-up (control n = 28, intervention n = 24). By long-term follow-up, 40 patients (77%) had reduced smoking by at least 50% and 16 patients (31%) had quit completely. At long-term follow-up, 88% of patients in the intervention group and 68% of patients in the control group reduced smoking (P = 0.1). CONCLUSIONS: A large proportion of vascular patients who received 2 weeks of nicotine replacement with or without the addition of brief smoking cessation counseling delivered by a vascular surgery provider were able to reduce smoking and maintain reduction after 6 months. Delivery of a brief standardized smoking cessation counseling session by a vascular surgery provider is safe and feasible. Additional randomized controlled trials with large enrollment periods and long follow-up are needed to determine the efficacy of this intervention in comparison to standard care.

Cholinergic medication for antipsychotic-induced tardive dyskinesia.

BACKGROUND: Tardive dyskinesia (TD) remains a troublesome adverse effect of conventional antipsychotic (neuroleptic) medication. It has been proposed that TD could have a component of central cholinergic deficiency. Cholinergic drugs have been used to treat TD. OBJECTIVES: To determine the effects of cholinergic drugs (arecoline, choline, deanol, lecithin, meclofenoxate, physostigmine, RS 86, tacrine, metoxytacrine, galantamine, ipidacrine, donepezil, rivastigmine, eptastigmine, metrifonate, xanomeline, cevimeline) for treating antipsychotic-induced TD in people with schizophrenia or other chronic mental illness. SEARCH METHODS: An electronic search of the Cochrane Schizophrenia Group's Study-Based Register of Trials (16 July 2015 and April 2017) was undertaken. This register is assembled by extensive searches for randomised controlled trials in many electronic databases, registers of trials, conference proceedings and dissertations. References of all identified studies were searched for further trial citations. SELECTION CRITERIA: We included reports identified by the search if they were of controlled trials involving people with antipsychotic-induced TD and chronic mental illness, who had been randomly allocated to either a cholinergic agent or to a placebo or no intervention. Two review authors independently assessed the methodological quality of the trials. DATA COLLECTION AND ANALYSIS: Two review authors extracted data and, where possible, estimated risk ratios (RR) or mean differences (MD), with 95% confidence intervals (CI). We analysed data on an intention-to-treat basis, with the assumption that people who left early had no improvement. We assessed risk of bias and created a 'Summary of findings' table using GRADE. MAIN RESULTS: We included 14 studies investigating the use of cholinergic drugs compared with placebo published between 1976 and 2014. All studies involved small numbers of participants (five to 60 people). Three studies that investigated the new cholinergic Alzheimer drugs for the treatment of TD are new to this update. Overall, the risk of bias in the included studies was unclear, mainly due to poor reporting; allocation concealment was not described, generation of the sequence was not explicit, studies were not clearly blinded, we are unsure if data are incomplete, and data were often poorly or selectively reported.We are uncertain about the effect of new or old cholinergic drugs on no clinically important improvement in TD symptoms when compared with placebo; the quality of evidence was very low (RR 0.89, 95% CI 0.65 to 1.23; 27 people, 4 RCTs). Eight trials found that cholinergic drugs may make little or no difference to deterioration of TD symptoms (low-quality evidence, RR 1.11, 95% CI 0.55 to 2.24; 147 people). Again, due to very low-quality evidence, we are uncertain about the effects on mental state (RR 0.50, 95% CI 0.10 to 2.61; 77 people, 5 RCTs), adverse events (RR 0.56, 95% CI 0.15 to 2.14; 106 people, 4 RCTs), and leaving the study early (RR 1.09,95% CI 0.56 to 2.10; 288 people 12 RCTs). No study reported on social confidence, social inclusion, social networks, or personalised quality of life. AUTHORS' CONCLUSIONS: TD remains a major public health problem. The clinical effects of both older cholinergic drugs and new cholinergic agents, now used for treating Alzheimer's disease, are unclear, as too few, too small studies leave many questions unanswered. Cholinergic drugs should remain of interest to researchers and currently have little place in routine clinical work. However, with the advent of new cholinergic agents now used for treating Alzheimer's disease, scope exists for more informative trials. If these new cholinergic agents are to be investigated for treating people with TD, their effects should be demonstrated in large well-designed, conducted and reported randomised trials.

[Factors Affecting Development of Cholinergic Symptoms after Irinotecan Administration].

Upon administration of irinotecan(CPT-11), cholinergic symptoms, such as perspiration and abdominal pain, may develop. These symptoms are reported to increase with higher doses of CPT-11. However, to date, in Japan, factors influencing cholinergic symptoms, such as dosage of CPT-11, regular medications, and laboratory values indicating liver function, have not been studied. Therefore, to assess such factors, we conducted a retrospective investigation. Cholinergic symptoms occurred in 74(40.4%)of 183 patients. Moreover, of these 74 patients, cholinergic symptoms occurred in 45 patients(60.8%)in the first course, and sweating was the most common symptom in these patients. According to binomial logistic regression analysis, the most significant factor affecting cholinergic symptom expression was a single dose(per body surface area)(odds ratio: 1.03, 95% confidence interval: 1.02-1.05, p<0.01), and the cut-off value in the receiver operating characteristic curve was 137mg/m2. By detecting cholinergic symptoms at an early stage after the administration of a single dose of CPT-11, the discontinuation of therapy administration can be avoided, and cholinergic symptoms can be alleviated.

[Centrally acting cholinomimetics in the complex therapy of progressive glaucomatous optic neuropathy].

UNLABELLED: Many factors exist that are associated with higher risk of glaucoma progression. Arterial hypotension, low perfusion pressure, vasospastic syndrome, diabetes mellitus, myopia, etc. increase the need for neuroprotective therapy, which is aimed at stabilizing the pathological process and creating favorable conditions for maintaining visual functions. The aim of this study was to assess the therapeutic efficacy of Gliatilin as part of the complex treatment of progressive glaucomatous optic neuropathy. MATERIAL AND METHODS: A total of 240 patients were randomly selected and divided into 2 groups, 120 patients each. Both groups were matched for age, somatic comorbidity, and the gravity of the glaucomatous process. Patient age averaged 71.3±1.6 years. Advanced glaucoma prevailed in both groups: 70.0 and 76.6% correspondingly. Neuroprotective therapy included drugs from different pharmacological classes so that different aspects of pathogenesis were addressed. Apart from that, patients from Group I first received intravenous Gliatilin (1000 mg/4ml, 12--15 doses) and then switched to oral (1 capsule b.i.d. for 4 months). All patients underwent standard ophthalmic examination and static perimetry. RESULTS: No adverse effects were observed over the first two weeks of Gliatilin course, during which the patients stayed in the hospital. IOP level was normal and stable. Although neuroprotective therapy does not directly affect IOP, stability of the latter describes the dynamics of the glaucomatous process. When assessing changes in visual functions, particular attention was paid to the central visual field, foveolar and total light sensitivity, peripheral visual field, and MD and PSD indices. All mean values showed a tendency toward improvement, more pronounced in the Gliatilin group. CONCLUSION: A complex therapy cannot be limited to a single drug only, and to make better decisions, one should consider not only ocular, but also general condition of the patient. Adjuvant Gliatilin in the complex therapy of progressive glaucoma is appropriate and efficient, especially in case of systemic atherosclerosis and cerebrovascular insufficiency. The frequency of stabilization therapy depends on the efficacy of the latest course and clinical manifestations of the glaucomatous process.

Efficacy of varenicline combined with nicotine replacement therapy vs varenicline alone for smoking cessation: a randomized clinical trial.

IMPORTANCE: Behavioral approaches and pharmacotherapy are of proven benefit in assisting smokers to quit, but it is unclear whether combining nicotine replacement therapy (NRT) with varenicline to improve abstinence is effective and safe. OBJECTIVE: To evaluate the efficacy and safety of combining varenicline and a nicotine patch vs varenicline alone in smoking cessation. DESIGN, SETTING, AND PARTICIPANTS: Randomized, blinded, placebo-controlled clinical trial with a 12-week treatment period and a further 12-week follow-up conducted in 7 centers in South Africa from April 2011 to October 2012. Four hundred forty-six generally healthy smokers were randomized (1:1); 435 were included in the efficacy and safety analyses. INTERVENTIONS: Nicotine or placebo patch treatment began 2 weeks before a target quit date (TQD) and continued for a further 12 weeks. Varenicline was begun 1 week prior to TQD, continued for a further 12 weeks, and tapered off during week 13. MAIN OUTCOMES AND MEASURES: Tobacco abstinence was established and confirmed by exhaled carbon monoxide measurements at TQD and at intervals thereafter up to 24 weeks. The primary end point was the 4-week exhaled carbon monoxide-confirmed continuous abstinence rate for weeks 9 through 12 of treatment, ie, the proportion of participants able to maintain complete abstinence from smoking for the last 4 weeks of treatment, as assessed using multiple imputation analysis. Secondary end points included point prevalence abstinence at 6 months, continuous abstinence rate from weeks 9 through 24, and adverse events. Multiple imputation also was used to address loss to follow-up. RESULTS: The combination treatment was associated with a higher continuous abstinence rate at 12 weeks (55.4% vs 40.9%; odds ratio [OR], 1.85; 95% CI, 1.19-2.89; P = .007) and 24 weeks (49.0% vs 32.6%; OR, 1.98; 95% CI, 1.25-3.14; P = .004) and point prevalence abstinence rate at 6 months (65.1% vs 46.7%; OR, 2.13; 95% CI, 1.32-3.43; P = .002). In the combination treatment group, there was a numerically greater incidence of nausea, sleep disturbance, skin reactions, constipation, and depression, with only skin reactions reaching statistical significance (14.4% vs 7.8%; P = .03); the varenicline-alone group experienced more abnormal dreams and headaches. CONCLUSIONS AND RELEVANCE: Varenicline in combination with NRT was more effective than varenicline alone at achieving tobacco abstinence at 12 weeks (end of treatment) and at 6 months. Further studies are needed to assess long-term efficacy and safety. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01444131.

The role of orexinergic system in the regulation of cataplexy.

Loss of orexin/hypocretin causes serious sleep disorder; narcolepsy. Cataplexy is the most striking symptom of narcolepsy, characterized by abrupt muscle paralysis induced by emotional stimuli, and has been considered pathological activation of REM sleep atonia system. Clinical treatments for cataplexy/narcolepsy and early pharmacological studies in narcoleptic dogs tell us about the involvement of monoaminergic and cholinergic systems in the control of cataplexy/narcolepsy. Muscle atonia may be induced by activation of REM sleep-atonia generating system in the brainstem. Emotional stimuli may be processed in the limbic systems including the amygdala, nucleus accumbens, and medial prefrontal cortex. It is now considered that orexin/hypocretin prevents cataplexy by modulating the activity of different points of cataplexy-inducing circuit, including monoaminergic/cholinergic systems, muscle atonia-generating systems, and emotion-related systems. This review will describe the recent advances in understanding the neural mechanisms controlling cataplexy, with a focus on the involvement of orexin/hypocretin system, and will discuss future experimental strategies that will lead to further understanding and treatment of this disease.

Treatment of cholinergic-induced status epilepticus with polytherapy targeting GABA and glutamate receptors.

Despite new antiseizure medications, the development of cholinergic-induced refractory status epilepticus (RSE) continues to be a therapeutic challenge as pharmacoresistance to benzodiazepines and other antiseizure medications quickly develops. Studies conducted by Epilepsia. 2005;46:142 demonstrated that the initiation and maintenance of cholinergic-induced RSE are associated with trafficking and inactivation of gamma-aminobutyric acid A receptors (GABAA R) thought to contribute to the development of benzodiazepine pharmacoresistance. In addition, Dr. Wasterlain's laboratory reported that increased N-methyl-d-aspartate receptors (NMDAR) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPAR) contribute to enhanced glutamatergic excitation (Neurobiol Dis. 2013;54:225; Epilepsia. 2013;54:78). Thus, Dr. Wasterlain postulated that targeting both maladaptive responses of reduced inhibition and increased excitation that is associated with cholinergic-induced RSE should improve therapeutic outcome. We currently review studies in several animal models of cholinergic-induced RSE that demonstrate that benzodiazepine monotherapy has reduced efficacy when treatment is delayed and that polytherapy with drugs that include a benzodiazepine (eg midazolam and diazepam) to counter loss of inhibition, concurrent with an NMDA antagonist (eg ketamine) to reduce excitation provide improved efficacy. Improved efficacy with polytherapy against cholinergic-induced seizure is demonstrated by reduction in (1) seizure severity, (2) epileptogenesis, and (3) neurodegeneration compared with monotherapy. Animal models reviewed include pilocarpine-induced seizure in rats, organophosphorus nerve agent (OPNA)-induced seizure in rats, and OPNA-induced seizure in two mouse models: (1) carboxylesterase knockout (Es1-/- ) mice which, similarly to humans, lack plasma carboxylesterase and (2) human acetylcholinesterase knock-in carboxylesterase knockout (KIKO) mice. We also review studies showing that supplementing midazolam and ketamine with a third antiseizure medication (valproate or phenobarbital) that targets a nonbenzodiazepine site rapidly terminates RSE and provides further protection against cholinergic-induced SE. Finally, we review studies on the benefits of simultaneous compared with sequential drug treatments and the clinical implications that lead us to predict improved efficacy of early combination drug therapies. The data generated from seminal rodent studies of efficacious treatment of cholinergic-induced RSE conducted under Dr. Wasterlain's guidance suggest that future clinical trials should treat the inadequate inhibition and temper the excess excitation that characterize RSE and that early combination therapies may provide improved outcome over benzodiazepine monotherapy.

Cajanus cajan (L) Millsp. seed extract ameliorates scopolamine-induced amnesia through increase in antioxidant defense mechanisms and cholinergic neurotransmission.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16.  The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action.  pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

Ciproxifan attenuates the memory impairment induced by lipopolysaccharide through modulation of cholinergic transmission in the mouse brain.

OBJECTIVE: We investigated the protective effect of ciproxifan on lipopolysaccharide (LPS)-induced memory impairment by altering the cholinergic system in a mouse model. MATERIALS AND METHODS: Groups of mice were given ciproxifan (1 or 3 mg/kg, p.o.) for 30 days. Neurotoxicity was induced with four doses of LPS (250 µg/kg, i.p.) from day-22 to day-25 of drug treatment in three groups. Then, mice were subjected to behavioral assessments using tests [elevated plus maze (EPM), novel object recognition (NOR), and Y-maze]. Also, brain tissues were collected for estimation of cholinergic transmission [acetylcholine (ACh) and acetylcholinesterase (AChE) levels]. RESULTS: Ciproxifan could rescue the memory impairment caused by LPS by shortening the transfer latency in the EPM test, increasing the time spent to explore a novel object and increasing the Discrimination Index in the NOR test and increasing the number of entries to the novel arm and duration of time spent in the novel arm in the Y-maze test. Ciproxifan increased the levels of ACh by decreasing AChE activity in LPS-treated mice. CONCLUSIONS: Ciproxifan treatment can improve memory impairment in mice by increasing ACh levels and decreasing AChE levels.

Composite biscuits from sandpaper and acha flour restore the altered activity of arginase, cholinergic, and purinergic enzymes in hypertensive-diabetic rats.

Hypertension is one of the common co-morbidities in diabetes. Thus, the present study sought to study the effects of composite biscuits from the mixture of acha (Digitaria exilis) and sandpaper (Fiscus exasperata) leaf flours (ASLF) on mean arterial blood pressure (MABP), arginase, cholinergic, purinergic enzymatic cascade, and nitric oxide (NO) levels as well as oxidative status in streptozotocin (STZ)/L-NG -nitro arginine methyl ester (L-NAME)-induced hypertensive/diabetic rats. Experimental rats were distributed randomly into 7 groups (n = 5). Group I-III rats were placed on the basal diet; IV-VII rats were placed on composite biscuits designated as A, B, C, and D respectively for 14 days. On the 13th day, the MABP of the experimental rats was monitored and recorded. Thereafter, the rats were sacrificed, tissues of interest were harvested, and homogenized. Subsequently, the activity of arginase cholinesterase and purinergic enzymes, as well as NO levels were evaluated in the experimental rats. However, hypertensive/diabetic rats placed on the formulated diet exhibited reduced MABP when compared with the untreated hypertensive/diabetic rats. Also, altered activity of arginase, cholinergic and purinergic were restored in diet-treated hypertensive/diabetic rats when compared with hypertensive/diabetic rats. Similarly, the NO level and antioxidant status of the treated hypertensive/diabetic rats were notably enhanced when compared with hypertensive/diabetic rats. It could be inferred that composite biscuits exhibited an ameliorative effect in hypertensive/diabetic states via their reductive effect on the MABP, arginase, cholinesterase, and purinergic enzymes and enhanced NO levels in hypertensive/diabetic rats. Meanwhile, the biscuit designated as D had seems better when their effects were compared holistically. PRACTICAL APPLICATIONS: Acha grains and sandpaper leaf have been used in the folklore for disease treatment. However, the production of composite biscuits from these naturally available recipes for the management of hypertensive diabetics proved therapeutic since their effect on hypertensive diabetic rats is positive. Therefore, the composite biscuit will offer nutraceutical benefits to both healthy and disease individuals.

Cholinergics, airway eosinophils and asthma exacerbation in the elderly.

Cholinomimetic agents have a number of potential indications in an ageing population. This case series emphasises the need to exercise caution while prescribing cholinergic drugs in elderly patients with asthma, particularly in patients with a history of virus-induced exacerbations and airway eosinophilia.