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Standard schizophrenia treatment involves antipsychotic medications that target D2 dopamine receptors. However, these drugs have limitations in addressing all symptoms and can lead to adverse effects such as motor impairments, metabolic effects, sedation, sexual dysfunction, cognitive impairment, and tardive dyskinesia. Recently, KarXT has emerged as a novel drug for schizophrenia. KarXT combines xanomeline, a muscarinic receptor M1 and M4 agonist, with trospium, a nonselective antimuscarinic agent. Of note, xanomeline can readily cross blood-brain barrier (BBB) and, thus, enter into the brain, thereby stimulating muscarinic receptors (M1 and M4). By doing so, xanomeline has been shown to target negative symptoms and potentially improve positive symptoms. Trospium, on the other hand, is not able to cross BBB, thereby not affecting M1 and M4 receptors; instead, it acts as an antimuscarinic agent and, hence, diminishes peripheral activity of muscarinic receptors to minimize side effects probably stemming from xanomeline in other organs. Accordingly, ongoing clinical trials investigating KarXT's efficacy in schizophrenia have demonstrated positive outcomes, including significant improvements in the Positive and Negative Syndrome Scale (PANSS) total score and cognitive function compared with placebo. These findings emphasize the potential of KarXT as a promising treatment for schizophrenia, providing symptom relief while minimizing side effects associated with xanomeline monotherapy. Despite such promising evidence, further research is needed to confirm the efficacy, safety, and tolerability of KarXT in managing schizophrenia. This review article explores the current findings and potential mechanisms of KarXT in the treatment of schizophrenia., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The dopamine content in cerebral structures has been related to neuronal excitability and several approaches have been used to study this phenomenon during seizure vulnerability period. In the present work, we describe the effects of dopamine depletion after the administration of 6-hidroxidopamine (6-OHDA) into the substantia nigra pars compacta of male rats submitted to the pilocarpine model of epilepsy. Susceptibility to pilocarpine-induced status epilepticus (SE), as well as spontaneous and recurrent seizures (SRSs) frequency during the chronic period of the model were determined. Since the hippocampus is one of main structures in the development of this experimental model of epilepsy, the dopamine levels in this region were also determined after drug administration. In the first experiment, 62% (15/24) of 6-OHDA pre-treated rats and 45% (11/24) of those receiving ascorbic acid as control solution progressed to motor limbic seizures evolving to SE, after the administration of pilocarpine. Severeness of seizures during the model´s the acute period, was significantly higher in epileptic experimental rats (56.52%), than in controls (4.16%). In the second experiment, the frequency of seizures in the model's chronic phase did not significantly change between groups. Our data show that dopamine may play an important role on seizure severity in the pilo's model acute period, which seems to be due to dopamine inhibitory action on motor expression of seizure.

Background: The muscarinic receptor agonist xanomeline has antipsychotic properties and is devoid of dopamine receptor-blocking activity but causes cholinergic adverse events. Trospium is a peripherally restricted muscarinic receptor antagonist that reduces peripheral cholinergic effects of xanomeline. The efficacy and safety of combined xanomeline and trospium in patients with schizophrenia are unknown., Methods: In this double-blind, phase 2 trial, we randomly assigned patients with schizophrenia in a 1:1 ratio to receive twice-daily xanomeline-trospium (increased to a maximum of 125 mg of xanomeline and 30 mg of trospium per dose) or placebo for 5 weeks. The primary end point was the change from baseline to week 5 in the total score on the Positive and Negative Syndrome Scale (PANSS; range, 30 to 210, with higher scores indicating more severe symptoms of schizophrenia). Secondary end points were the change in the PANSS positive symptom subscore, the score on the Clinical Global Impression-Severity (CGI-S) scale (range, 1 to 7, with higher scores indicating greater severity of illness), the change in the PANSS negative symptom subscore, the change in the PANSS Marder negative symptom subscore, and the percentage of patients with a response according to a CGI-S score of 1 or 2., Results: A total of 182 patients were enrolled, with 90 assigned to receive xanomeline-trospium and 92 to receive placebo. The PANSS total score at baseline was 97.7 in the xanomeline-trospium group and 96.6 in the placebo group. The change from baseline to week 5 was -17.4 points with xanomeline-trospium and -5.9 points with placebo (least-squares mean difference, -11.6 points; 95% confidence interval, -16.1 to -7.1; P<0.001). The results for the secondary end points were significantly better in the xanomeline-trospium group than in the placebo group, with the exception of the percentage of patients with a CGI-S response. The most common adverse events in the xanomeline-trospium group were constipation, nausea, dry mouth, dyspepsia, and vomiting. The incidences of somnolence, weight gain, restlessness, and extrapyramidal symptoms were similar in the two groups., Conclusions: In a 5-week trial, xanomeline-trospium resulted in a greater decrease in the PANSS total score than placebo but was associated with cholinergic and anticholinergic adverse events. Larger and longer trials are required to determine the efficacy and safety of xanomeline-trospium in patients with schizophrenia. (Funded by Karuna Therapeutics and the Wellcome Trust; ClinicalTrials.gov number, NCT03697252.)., (Copyright © 2021 Massachusetts Medical Society.)

Cognitive impairment is one of the most common comorbidities in temporal lobe epilepsy. To recapitulate epilepsy-associated cognitive decline in an animal model of epilepsy, we generated pilocarpine-treated chronic epileptic mice. We present a protocol for three different behavioral tests using these epileptic mice: novel object location (NL), novel object recognition (NO), and pattern separation (PS) tests to evaluate learning and memory for places, objects, and contexts, respectively. We explain how to set the behavioral apparatus and provide experimental procedures for the NL, NO, and PS tests following an open field test that measures the animals' basal locomotor activities. We also describe the technical advantages of the NL, NO, and PS tests with respect to other behavioral tests for assessing memory function in epileptic mice. Finally, we discuss possible causes and solutions for epileptic mice failing to make 30 s of good contact with the objects during the familiarization sessions, which is a critical step for successful memory tests. Thus, this protocol provides detailed information about how to assess epilepsy-associated memory impairments using mice. The NL, NO, and PS tests are simple, efficient assays that are appropriate for the evaluation of different kinds of memory in epileptic mice.

A 63-year-old man with pharyngeal cancer had been prescribed pilocarpine hydrochloride for xerostomia after concomitant chemoradiotherapy. After 6 months of taking pilocarpine hydrochloride, he was referred to our hospital due to gradually developing renal insufficiency. The patient underwent detailed urinalysis, blood chemistry analysis, immune-serology testing. A renal biopsy was also performed. He was diagnosed with chronic tubulointerstitial nephritis (TIN) caused by lymphocytic infiltration of the interstitium, tubular atrophy, and interstitial fibrotic changes. Infections, autoimmune diseases, and genetic factors were ruled out as causes of TIN; a drug-induced lymphocyte stimulation test confirmed that he had high stimulation index scores for pilocarpine hydrochloride and a normal range stimulation score for other supplements. These results indicated that the TIN could have been induced by pilocarpine hydrochloride. Drug discontinuation partly improved his renal function and tubule marker levels. To our knowledge, this is the first report of TIN following administration of pilocarpine hydrochloride. This finding could contribute to future treatment decisions for patients with TIN and those using pilocarpine hydrochloride.

Immune system dysregulation in 1991 Gulf War Veterans was caused in part by the nerve gas prophylactic drug pyridostigmine bromide (PB) by direct agonist activation of muscarinic receptors on anergic B and T lymphocytes, leading to multiple types of autoimmune illnesses, and this effect may have been potentiated by combat stress., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Extending the delivery of drugs into the eyes while reducing systemic bioavailability is of utmost importance in the management of chronic ocular diseases. Topical application onto the lower eyelid skin, as an alternative to eye drops, is seen to be a valuable strategy in the treatment of chronic eye diseases. To elucidate the critical value of delivering drugs in solution onto the eyeball through the eyelid skin, pharmacokinetic studies of pilocarpine were conducted, and the results were verified using a direct pharmacodynamic study in rats. The mean residence time of pilocarpine after topical eyelid application to the eyelid skin, conjunctiva, eyeball, and plasma were 14.9, 8.50, 6.29, and 8.11 h, respectively. Conjunctiva and eyeball concentrations of pilocarpine at 8 h were 80-fold and 8-fold higher after topical eyelid application, respectively, than those for eye drops. Pupillary constriction was sustained over 8 h after topical eyelid application. Topical eyelid skin application exhibited a localized drug absorption and specific drug accumulation in the ocular tissues. Hence, it is rational to prepare topical formulations directed onto the eyelid skin, which is suitable for drugs required for long-term treatment., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Purpose: We evaluated the efficacy and safety of a combination of 2 mg tolterodine and 9 mg pilocarpine, vs tolterodine monotherapy in patients with overactive bladder., Materials and Methods: We enrolled patients with overactive bladder symptoms in a multicenter, randomized, double-blind, parallel, active control study. Patients were randomized to the combination or 2 mg tolterodine twice daily for 12 weeks. After the double-blind period finished all patients were started on the combination for 12 weeks. Study co-primary end points were the change from baseline in the mean number of daily micturitions and cumulative incidence of dry mouth at the end of 12 weeks. Secondary end points were other overactive bladder symptoms, the total xerostomia inventory score and results of a visual analogue scale for dry mouth at the end of 12 and 24 weeks., Results: The mean change in the number of daily micturitions from baseline to 12 weeks was -1.49 and -1.74 in the combination and tolterodine monotherapy groups, respectively. The mean difference was -0.26 (95% CI -0.79-0.27), confirming noninferiority. At 12 weeks the incidence of dry mouth was lower in the combination group than in the tolterodine monotherapy group (30.0% vs 42.9%, p = 0.009). All secondary and other efficacy outcomes related to overactive bladder symptoms improved in each group with no significant differences between the groups at 12 weeks. Changes from baseline in the total xerostomia inventory score and the visual analogue scale for dry mouth were significantly lower in the combination group than in the tolterodine monotherapy group., Conclusions: Tolterodine and pilocarpine alleviated dry mouth in patients with overactive bladder while maintaining anticholinergic efficacy similar to that of tolterodine.

To determine the incidence and risk of Parkinson disease (PD) in patients with Sjögren syndrome (SS) according to a nationwide population-based database.In total, 12,640 patients in the SS cohort and 50,560 in the non-SS cohort were enrolled from Taiwan's National Health Insurance Research Database from 2000 to 2010. We used the Cox multivariable proportional hazards model to determine the risk factors for PD in the SS cohort.We observed an increased incidence of PD in patients with SS, with a crude hazard ratio (HR) of 1.40 and an adjusted HR (aHR) of 1.23. The cumulative incidence of PD was 1.95% higher in the SS cohort than in the non-SS cohort. The SS cohort had an elevated HR under medication use, namely cevimeline and pilocarpine (crude HR, 1.28), hydroxychloroquine (crude HR, 1.43; aHR, 1.46), and methylprednisolone (crude HR, 2.21; aHR, 1.49). Patients receiving other non-hydroxychloroquine immunosuppressant therapies had a lower risk (aHR, 0.86) of PD. Furthermore, patients with SS aged 20 to 49 years had a 1.93-fold higher risk of PD than did those without SS (aHR, 1.93). The risk of PD was higher (aHR, 2.20) in patients with SS without comorbidities than in those with comorbidities. The aHR of PD significantly increased when the follow-up period exceeded 9 years (aHR, 1.93).We determined an increased risk of PD in patients with SS. Further investigation is warranted to determine the possible underlying mechanisms and the potential role of non-hydroxychloroquine immunosuppressants in ameliorating PD.

This quiz will discuss two patients with end-stage kidney disease (ESKD) on dialysis presenting with diaphoresis and hypernatremia.

Drug discovery strives for selective ligands to achieve targeted modulation of tissue function. Here we introduce engineered context-sensitive agonism as a postreceptor mechanism for tissue-selective drug action through a G protein-coupled receptor. Acetylcholine M 2 -receptor activation is known to mediate, among other actions, potentially dangerous slowing of the heart rate. This unwanted side effect is one of the main reasons that limit clinical application of muscarinic agonists. Herein we show that dualsteric (orthosteric/allosteric) agonists induce less cardiac depression ex vivo and in vivo than conventional full agonists. Exploration of the underlying mechanism in living cells employing cellular dynamic mass redistribution identified context-sensitive agonism of these dualsteric agonists. They translate elevation of intracellular cAMP into a switch from full to partial agonism. Designed context-sensitive agonism opens an avenue toward postreceptor pharmacologic selectivity, which even works in target tissues operated by the same subtype of pharmacologic receptor., (Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.)

Allergic contact dermatitis is an important cause of periorbital dermatitis. Topical ophthalmic agents are relevant sensitizers. Contact dermatitis to ophthalmic medications can be challenging to diagnose and manage given the numerous possible offending agents, including both active and inactive ingredients. Furthermore, a substantial body of literature reports false-negative patch test results to ophthalmic agents. Subsequently, numerous alternative testing methods have been described. This review outlines the periorbital manifestations, causative agents, and alternative testing methods of allergic contact dermatitis to ophthalmic medications.

Background: Pilocarpine has been used widely in the treatment of dry mouth and glaucoma. In this review, the authors assessed the efficacy and safety of pilocarpine for patients with head and neck cancer who have radiation-induced xerostomia., Types of Studies Reviewed: The authors conducted a systematic search including meta-analyses and randomized controlled trials in the following databases: MEDLINE, Embase, Cochrane Library, and Science Citation Index Expanded. The primary outcome was the severity of xerostomia (measured using visual analog scale [VAS] scores). Adverse events were other outcomes of interest. The authors performed meta-analyses where appropriate. The authors used the Cochrane Collaboration's tool for assessing risk of bias to assess the quality of the study., Results: The authors identified 6 studies (including 752 patients in total). The results of a meta-analysis of 3 articles showed that pilocarpine was associated with a 12-point increase in VAS score (mean difference, 12.00; 95% confidence interval [CI], 1.93-22.08; P = .02) and higher rates of adverse events compared with placebo in terms of sweating (odds ratio [OR], 3.71; 95% CI, 2.34-5.86; P < .00001). There were no differences in rhinitis (OR, 1.21; 95% CI, 0.68-2.16; P = .52) and nausea (OR, 1.44; 95% CI, 0.83-2.49; P = .19)., Conclusions and Practical Implications: On the basis of the best available evidence, the results of this meta-analysis provide evidence that pilocarpine offers statistically significant clinical benefits for the symptomatic treatment of radiation-induced xerostomia in patients with head and neck cancer. However, the authors of this systematic review found the best available evidence in the meta-analysis in 3 studies, 1 of which showed no effect. The authors of this systematic review suggest that these patients take 5 milligrams of pilocarpine 3 times daily, and that there is need for further study., (Copyright © 2016 American Dental Association. Published by Elsevier Inc. All rights reserved.)

Overactive bladder is one of the most common bladder problems, but an estimated 20 million Americans have underactive bladder (UAB), which makes going to the bathroom difficult, increases the risk of urinary tract infections, and even leads to institutionalization. This article provides an overview of UAB in older adults, and discusses the prevalence, predisposing factors, cause, clinical investigations, and treatments. At present, there is no effective therapy for UAB. A great deal of work still needs to be done on understanding the pathogenesis and the development of effective therapies., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: This is an updated version of the original Cochrane review on parasympathomimetic drugs for the treatment of salivary gland dysfunction due to radiotherapy (published in Issue 3, 2007). Salivary gland dysfunction is a predictable side effect of radiotherapy to the head and neck region. Pilocarpine hydrochloride (a choline ester) is licensed in many countries for the treatment of radiation-induced salivary gland dysfunction. Other parasympathomimetics have also been used 'off licence' in the treatment of this condition., Objectives: To determine the efficacy and tolerability of parasympathomimetic drugs in the treatment of radiation-induced salivary gland dysfunction (specifically radiation-induced xerostomia)., Search Methods: For this update, we ran searches of the Cochrane Oral Health Group Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL 2015, Issue 6), MEDLINE, EMBASE, and CINAHL in July 2015. We checked the reference lists of retrieved articles for additional studies, contacted experts in the field for unpublished and ongoing trials, and contacted relevant pharmaceutical companies for unpublished and ongoing trials., Selection Criteria: The selection criteria for the review were: 1) randomised controlled trials; 2) people suffering from radiation-induced salivary gland dysfunction; 3) people treated with parasympathomimetic drugs; and 4) assessable data available on primary outcome measure., Data Collection and Analysis: The two review authors independently collected data from the full-text version of relevant papers including: 1) citation details; 2) participants; 3) interventions; 4) assessments; 5) outcomes (that is efficacy, tolerability); and 6) quality issues.Due to a lack of appropriate data, we were unable to perform a meta-analysis., Main Results: In the original review, three studies, including a total of 298 participants, fulfilled the inclusion criteria. All three studies involved the use of pilocarpine hydrochloride. We have included no additional studies in the update of the review; we have excluded eight additional studies.The data suggest that pilocarpine hydrochloride is more effective than placebo and at least as effective as artificial saliva. The response rate was 42% to 51%. The time to response was up to 12 weeks. The overall side effect rate was high, and side effects were the main reason for withdrawal (6% to 15% of participants taking 5 mg three times a day had to withdraw). The side effects were usually the result of generalised parasympathomimetic stimulation (for example sweating, headaches, urinary frequency, vasodilatation). Response rates were not dose dependent, but side effect rates were dose dependent., Authors' Conclusions: There is limited evidence to support the use of pilocarpine hydrochloride in the treatment of radiation-induced xerostomia. Currently, there is little evidence to support the use of other parasympathomimetic drugs in the treatment of radiation-induced xerostomia. Available studies suggest that approximately half of patients will respond, but side effects can be problematic. The conclusions of the update are the same as the conclusions of the original review, since no new relevant studies have been published in the interim.

Purpose: To evaluate the relationship between glaucoma medication usage and dry eye using a Taiwan nationally representative sample., Methods: We identified patients with glaucoma diagnoses (ICD-9-CM [International Classification of Diseases, Ninth Revision, Clinical Modification] codes 365) from Taiwan claims data. The study group included 2065 glaucoma patients with newly diagnosed dry eye (ICD-9-CM code 375.15) identified during 2000 and 2011. The control subjects were 8260 glaucoma patients without dry eye who were frequency matched for age, sex, and the year of the index date. The following variables were considered: sex (male/female) and age (12 to 34 years, 35 to 49 years, 50 to 64 years, and ≥ 65 years). Six available glaucoma drugs in Taiwan were analyzed, namely, prostaglandin analog, β-blocker, carbonic anhydrase inhibitor, α-agonists, pilocarpine, and combination drugs. Univariate and multivariate unconditional logistic regressions were used to estimate the effects of glaucoma treatment and comorbidities on the risk of dry eye as indicated by odds ratios (ORs) with 95% confidence intervals (CIs). Further analysis was performed to assess the dose-response effect on the risk of dry eye according to the cumulative number of different types of glaucoma medications used., Results: Among the 2065 dry eye case patients, 63.3% were female and 48.9% were aged 65 years and older. After adjusting for potential confounding factors, an increased risk of dry eye was observed for all glaucoma medications (prostaglandin analog: adjusted OR, 1.48; 95% CI, 1.30 to 1.69; β-blocker: adjusted OR, 1.57; 95% CI, 1.35 to 1.83; carbonic anhydrase inhibitor: adjusted OR, 1.38; 95% CI, 1.20 to 1.59; pilocarpine: adjusted OR, 1.19; 95% CI, 1.07 to 1.32; combination drugs: adjusted OR, 1.32; 95% CI, 1.09 to 1.58) with the exception of α-agonists. The adjusted OR of having dry eye increased with the number of glaucoma medications used. Similar trends were observed for both female and male subjects., Conclusions: An increased number of glaucoma medications used may increase dry eye risk, particularly in subjects who use more than two types of glaucoma medications and in female subjects. Clinicians should be cautious when prescribing medications for glaucoma patients.

Muscarinic agonists are the most commonly used agents for treating the underactive bladder (UAB). However, because of the absence of pharmacologic specificity for bladder-only effects and possibly as a result of degenerative and other post-synaptic changes involving detrusor smooth muscle cells, they are simply not effective and side effects are common. If safe and effective therapy for UAB is made available, then most experts agree that the potential market would exceed industry expectations, just as antimuscarinic agents for overactive bladder did in the late 1990 s. The pharmaceutical and biotechnology industries that have a pipeline to urology and women's health should consider UAB as a potential target condition. A rational approach to treating the pathology of UAB is presented with a discussion of potential targets that may allow the development of safe and effective agents for the treatment of UAB.

Objectives: There are currently no head-to-head comparisons of sialagogues for Primary Sjögren's syndrome (pSS). We compared the tolerability and side effect profile of pilocarpine and cevimeline in patients with pSS and determined clinical, laboratory and pathological variables associated with therapeutic failure., Methods: We retrospectively reviewed the use of pilocarpine and cevimeline in 118 patients with pSS who fulfilled the 2002 American European Consensus Group criteria in a University-based setting. Clinical, laboratory and pathological baseline variables were collected. Failure of therapy was defined as the clinician or patient's decision to stop treatment either due to lack of efficacy or side effects., Results: Cevimeline was associated with lower failure rates compared to pilocarpine among first-time users: 27% vs. 47% (p=0.02), and all users: 32% vs. 61% (p<0.001). Severe sweating was the most frequent side effect leading to cessation of therapy and occurred more frequently in pilocarpine (25%) than cevimeline (11%) users (p=0.02). Patients who previously failed one secretagogue were less likely to discontinue treatment with the other agent, 52% of first-time users vs. 27% of second-time users (p=0.004). Only ANA positivity was associated with failure: [59% vs. 38%] (p=0.03)., Conclusions: pSS patients were more likely to continue cevimeline than pilocarpine long-term due to fewer reported side effects with cevimeline. Therapeutic failure of one secretagogue did not predict similar results with the other since second time users were more likely to continue long-term treatment.

Introduction: Metabotropic glutamate receptor 5 (mGluR5) that regulates glutamatergic neurotransmission contributes to pathophysiology of epilepsy. In this study, we monitored the changes of mGluR5 in vivo using [11C]ABP688 PET during the epileptogenesis in a pilocarpine-induced epilepsy rat model., Methods: In vivo mGluR5 images were acquired using [11C]ABP688 microPET/CT in pilocarpine-induced chronic epilepsy rat models and controls. We also acquired microPET/CT at acute, subacute as well as chronic periods after status epilepticus. Non-displaceable binding potential (BPND) of [11C]ABP688 was calculated using simplified reference tissue model in a voxel-based manner. mGluR5 BPND of the rat brains of epilepsy models and controls were compared., Results: Status epilepticus developed after pilocarpine administration and was followed by recurrent spontaneous seizures for more than 3 weeks. In chronic epilepsy rat model, BPND in hippocampus and amygdala was reduced on a voxel-based analysis. Temporal changes of mGluR5 BPND was also found. In acute period after status epilepticus, mGluR5 BPND was reduced in the whole brain. BPND of caudate-putamen was restored in subacute period, while BPND of the rest of the brain was still lower. In chronic period, global BPND was normalized except in hippocampus and amygdala., Conclusions: In vivo imaging of mGluR5 using [11C]ABP688 microPET/CT could successfully reveal the regional changes of mGluR5 binding potential of the rat brain in a pilocarpine-induced epilepsy model. The temporal and spatial changes in mGluR5 availability suggest [11C]ABP688 PET imaging in epilepsy provide abnormal glutamatergic network during epileptogenesis.

In models of status epilepticus ghrelin displays neuroprotective effects mediated by the growth hormone secretagogue-receptor 1a (GHS-R1a). This activity may be explained by anticonvulsant properties that, however, are controversial. We further investigated neuroprotection and the effects on seizures by comparing ghrelin with a more effective GHS-R1a agonist, JMV-1843. Rats were treated either with ghrelin, JMV-1843 or saline 10 min before pilocarpine, which was used to induce status epilepticus. Status epilepticus, developed in all rats, was attenuated by diazepam. No differences were observed among the various groups in the characteristics of pilocarpine-induced seizures. In saline group the area of lesion, characterized by lack of glial fibrillary acidic protein immunoreactivity, was of 0.45 ± 0.07 mm(2) in the hippocampal stratum lacunosum-moleculare, and was accompanied by upregulation of laminin immunostaining, and by increased endothelin-1 expression. Both ghrelin (P<0.05) and JMV-1843 (P<0.01) were able to reduce the area of loss in glial fibrillary acidic protein immunostaining. In addition, JMV-1843 counteracted (P<0.05) the changes in laminin and endothelin-1 expression, both increased in ghrelin-treated rats. JMV-1843 was able to ameliorate neuronal survival in the hilus of dentate gyrus and medial entorhinal cortex layer III (P<0.05 vs saline and ghrelin groups). These results demonstrate diverse protective effects of growth hormone secretagogues in rats exposed to status epilepticus.

Objectives: To determine the efficacy and compare the side-effects of cevimeline and pilocarpine in the secretion of saliva in patients with xerostomia., Methods: A randomized, cross-over, double blind study was designed. Fifteen patients with diagnosis of xerostomia were assigned to take either 5 mg of pilocarpine or 30 mg of cevimeline three times a day for four weeks. Salivary flow rates were measured during the initial baseline, first and second month appointments. Statistical analysis was carried out with ANOVA and post hoc t-tests., Results: Twelve patients completed both medication treatments. Although both medications proved to increase salivary secretion, there was no significant difference between pilocarpine and cevimeline. Also, the perceived side-effects between the two medications were similar., Conclusion: Both medications increased the secretion of saliva at the end of four weeks. However, there was a slightly higher increment in saliva with pilocarpine. However, the difference was not statistically significant., (©2013 Special Care Dentistry Association and Wiley Periodicals, Inc.)

Safinamide is an α-aminoamide derivative that is currently in Phase III clinical trial development as an add-on therapy to levodopa or dopamine agonists for patients with Parkinson's disease. Safinamide is a monoamine oxidase B inhibitor with additional non-dopaminergic actions. The present experiments were performed to evaluate the ability of safinamide to attenuate parkinsonian motor impairments using the tremulous jaw movement model, an animal model of parkinsonian tremor. In rats, tremulous jaw movements can be induced with dopamine (DA) antagonists, DA depletion, and cholinomimetics, and can be reversed by various antiparkinsonian drugs, including L-DOPA, DA agonists, anticholinergics and adenosine A2A antagonists. In these present experiments, tremulous jaw movements were induced with the anticholinesterase galantamine (3.0mg/kg IP), the muscarinic agonist pilocarpine (0.5mg/kg IP), and the dopamine D2 antagonist pimozide (1.0mg/kg IP). Safinamide significantly reduced the number of tremulous jaw movements induced by galantamine, pilocarpine, and pimozide, with consistent effects across all three drugs at a dose range of 5.0-10.0mg/kg. The results of this study support the use of safinamide as a treatment for parkinsonian tremor., (Copyright © 2013 Elsevier Inc. All rights reserved.)

There is growing experimental evidence that tracing the elements involved in brain hyperexcitability, excitotoxicity, and/or subsequent neurodegeneration could be a valuable source of data on the molecular mechanisms triggering or promoting further development of epilepsy. The most frequently used experimental model of the temporal lobe epilepsy observed in clinical practice is the one based on pilocarpine-induced seizures. In the frame of this study, the elemental anomalies occurring for the rat hippocampal tissue in acute and silent periods after injection of pilocarpine in rats were compared. X-ray fluorescence microscopy was applied for the topographic and quantitative elemental analysis. The differences in the levels of elements such as P, S, K, Ca, Fe, Cu, and Zn between the rats 3 days (SE72) and 6 h (SE6) after pilocarpine injection as well as naive controls were examined. Comparison of SE72 and control groups showed, for specific areas of the hippocampal formation, lower levels of P, K, Cu, and Zn, and an increase in Ca accumulation. These results as well as further analysis of the differences between the SE72 and SE6 groups confirmed that seizure-induced excitotoxicity as well as mossy fiber sprouting are the mechanisms involved in the neurodegenerative processes which may finally lead to spontaneous seizures in the chronic period of the pilocarpine model. Moreover, in the light of the results obtained, Cu seems to play a very important role in the pathogenesis of epilepsy in this animal model. For all areas analyzed, the levels of this element recorded in the latent period were not only lower than those for controls but were even lower than the levels found in the acute period. The decreased hippocampal accumulation of Cu in the phase of behavior and EEG stabilization, a possible inhibitory effect of this element on excitatory amino acid receptors, and enhanced seizure susceptibility in Menkes disease (an inherited Cu transport disorder leading to Cu deficiency in the brain) suggest a neuroprotective role rather than neurodegenerative and proconvulsive roles of Cu in pilocarpine-induced epilepsy.

A 34-year-old Caucasian female with advanced primary angle closure glaucoma developed acute angle closure following administration of g.pilocarpine 2% given as preparation for laser peripheral iridotomies. Subsequent investigations supported an underlying diagnosis of spherophakia with no systemic associations. She required peripheral iridotomies, bilateral clear lens extractions and left cyclodiode laser to control her intraocular pressures. This case highlights the situations when pilocarpine should be given with caution and also the increasing role of phacoemulsification as an alternative to filtration surgery in primary angle closure glaucoma management.

Despite a large therapeutic arsenal of old and new antiepileptic drugs (AEDs), there remains a substantial unmet need for the patients with refractory (AED-resistant) epilepsy. Animal models of refractory epilepsy are needed for at least two goals; (1) better understanding of the mechanisms underlying resistance to AEDs, and (2) development of more efficacious AEDs for patients with refractory seizures. It is only incompletely understood why two patients with seemingly identical types of epilepsy and seizures may respond differently to the same AED. Prompted by this well-known clinical phenomenon, we tested whether epileptic rats from the same epilepsy model respond differently to AEDs and previously discovered phenobarbital (PB) responsive and resistant animals in groups of rats in which epilepsy had been induced by sustained electrical stimulation of the basolateral amygdala (BLA). In the present study, we used the same approach for the widely used pilocarpine model of temporal lobe epilepsy. Epileptic rats from this model were continuously video/EEG monitored over seven consecutive weeks, starting with a predrug control period of two weeks, then two weeks of daily treatment with PB at maximum tolerated doses, and finally a postdrug control period of three weeks. In those rats that were included in response selection, 50% did not adequately respond to PB, whereas PB significantly decreased seizure frequency and severity in another 50% of the animals. Responders and nonresponders did not differ in predrug seizure frequency, PB plasma levels or hippocampal neurodegeneration, but behavioral differences were observed in anxiety models. These findings demonstrate that in the pilocarpine model, similar to epilepsy patients, epileptic rats differ in their response to an AED, which is most likely due to as yet unknown genetic factors., (Copyright © 2011. Published by Elsevier Inc.)

Existing therapies for schizophrenia have limited efficacy, and significant residual positive, negative, and cognitive symptoms remain in many individuals with the disorder even after treatment with the current arsenal of antipsychotic drugs. Preclinical and clinical data suggest that selective activation of the muscarinic cholinergic system may represent novel therapeutic mechanisms for the treatment of schizophrenia. The therapeutic relevance of earlier muscarinic agonists was limited by their lack of receptor selectivity and adverse event profile arising from activation of nontarget muscarinic receptors. Recent advances in developing compounds that are selective to muscarinic receptor subtypes or activate allosteric receptor sites offer tremendous promise for therapeutic targeting of specific muscarinic receptor subtypes in schizophrenia.

Previous studies in rat models of neurodegenerative disorders have shown disregulation of striatal synaptotagmin7 mRNA. Here we explored the expression of synaptotagmin7 mRNA in the brains of rats with seizures triggered by the glutamatergic agonist kainate (10 mg/kg) or by the muscarinic agonist pilocarpine (30 mg/kg) in LiCl (3 mEq/kg) pre-treated (24 h) rats, in a time-course experiment (30 min-1 day). After kainate-induced seizures, synaptotagmin7 mRNA levels were transiently and uniformly increased throughout the dorsal and ventral striatum (accumbens) at 8 and 12 h, but not at 24 h, followed at 24 h by somewhat variable upregulation within different parts of the cerebral cortex, amigdala and thalamic nuclei, the hippocampus and the lateral septum. By contrast, after LiCl/pilocarpine-induced seizures, there was a more prolonged increase of striatal Synaptotagmin7 mRNA levels (at 8, 12 and 24 h), but only in the ventromedial striatum, while in some other of the aforementioned brain regions there was a decline to below the basal levels. After systemic post-treatment with muscarinic antagonist scopolamine in a dose of 2 mg/kg the seizures were either extinguished or attenuated. In scopolamine post-treated animals with extinguished seizures the striatal synaptotagmin7 mRNA levels (at 12 h after the onset of seizures) were not different from the levels in control animals without seizures, while in rats with attenuated seizures, the upregulation closely resembled kainate seizures-like pattern of striatal upregulation. In the dose of 1 mg/kg, scopolamine did not significantly affect the progression of pilocarpine-induced seizures or pilocarpine seizures-like pattern of striatal upregulation of synaptotagmin7 mRNA. In control experiments, equivalent doses of scopolamine per se did not affect the expression of synaptotagmin7 mRNA. We conclude that here described differential time course and pattern of synaptotagmin7 mRNA expression imply regional differences of pathophysiological brain activation and plasticity in these two models of seizures.

Vaginal dryness is a common problem for which effective and safe nonestrogenic treatments are needed. Based on preliminary promising data that pilocarpine attenuated vaginal dryness, the current trial was conducted. A double-blind, placebo-controlled, randomized trial design was used to compare pilocarpine, at target doses of 5 mg twice daily and 5 mg four times daily, with a placebo. Vaginal dryness was recorded by patient-completed questionnaires at baseline and weekly for 6 weeks after study initiation. The primary endpoint for this study was the area under the curve summary statistic composed of the longitudinal responses obtained at baseline and through the 6 weeks of treatment to a numerical analogue scale asking patients to rate their perceived amount of vaginal dryness. The primary analysis was carried out by a single t test using a two-side alternative to compare the collective pilocarpine treatment arms with the collective placebo arms. A total of 201 patients enrolled in this trial. The primary analysis, comparing vaginal dryness symptoms in the collective pilocarpine arms against the placebo arm, did not reveal any benefit for the pilocarpine treatment. This finding was confirmed by other secondary analyses. Toxicity evaluation revealed more nausea, sweating, rigors, and urinary frequency with the pilocarpine arms compared with the placebo arm.

Background: Bethanechol chloride is considered as a treatment in patients with high postvoid residual urine (PVR). It enhances detrusor muscle contraction, resulting in higher maximum flow rate, higher detrusor pressure at maximum flow, and lower PVR. The efficacy of this agent in patients after radical hysterectomy is unclear. We aim to evaluate the efficacy of bethanechol chloride compared with placebo for the prevention of bladder dysfunction after type III radical hysterectomy., Methods: Gynecologic cancer patients who underwent type III radical hysterectomy were randomized by computer-generated schedule to assign patients in a 1:1 ratio into 2 groups. The treatment group received bethanechol chloride (Ucholine 20 mg 3 times a day on the third to seventh postoperative day), and the control group received placebo. Patients and physicians were masked to treatment allocation. The primary end point was the rate of urethral catheter removal at 1 week postoperatively. If PVR was more than 30% of voided volume, the urethral catheter was reinserted, and medication would be continued but not for more than 1 month. This study was registered as ISRCTN92687416., Findings: There were 31 patients in each group without significant difference in baseline characteristics. Twenty-one patients (67.7%) in the treatment group and 12 patients (38.7%) in the control group had the urethral catheter removed at 1 week postoperatively (P = 0.04). Median duration of urethral catheterization was shorter in the treatment group (7 and 14 days, P = 0.03). However, the PVR and the incidence of urinary tract infection at 1 month postoperatively were not significantly different. Nine patients (29%) in the treatment group had adverse events such as nausea, abdominal distension, and abdominal cramping, which was higher than the control group (1 patient, 3.2%; P = 0.01). However, no patients required any medical treatments., Conclusions: Bethanechol chloride decreases the duration of urethral catheterization in patients who underwent type III radical hysterectomy with manageable adverse events.

Vagus nerve stimulation (VNS) is an effective adjunctive treatment for medically refractory epilepsy. In this study, we measured VNS-induced changes in hippocampal neurotransmitter levels and determined their potential involvement in the anticonvulsive action of VNS, to elucidate the mechanism of action responsible for the seizure suppressing effect of VNS in an animal model for limbic seizures. We used in vivo intracerebral microdialysis to measure VNS-induced changes in hippocampal extracellular concentrations of noradrenaline, dopamine, serotonin and GABA in freely moving, male Wistar rats. During the same experiment, the effect of VNS on pilocarpine-induced limbic seizures was assessed using video-EEG monitoring. The involvement of VNS-induced increases in hippocampal noradrenaline in the mechanims of action of VNS was evaluated by blocking hippocampal α(2)-receptors. VNS produced a significant increase in hippocampal noradrenaline concentration (69 ± 16% above baseline levels). VNS also increased the latency between pilocarpine infusion and the onset of epileptiform discharges, and reduced the duration and severity of pilocarpine-induced limbic seizures. A strong positive correlation was found between the noradrenergic and anticonvulsive effects of VNS. Blockade of hippocampal α(2 -receptors reversed the seizure-suppressing effect of VNS. VNS induces increases in extracellular hippocampal noradrenaline, which are at least partly responsible for its seizure-suppressing effect in a model for limbic seizures, and constitute a potential biomarker for the efficacy of VNS in temporal lobe epilepsy., (© 2011 The Authors. Journal of Neurochemistry © 2011 International Society for Neurochemistry.)

Recent evidence suggests that the sodium calcium exchanger (NCX) may contribute to the etiology of pentylenetetrazol-induced seizures. Here we further investigated the role of NCX in the etiology of seizures by quantifying the effects of KB-R7943 and SN-6, potent inhibitors of the reverse mode of NCX subtypes 3 (NCX3) and 1 (NCX1), respectively, on the occurrence of acute seizures and status epilepticus induced by intraperitoneal administration of pilocarpine, a muscarinic acetylcholine receptor agonist. Pretreatment with KB-R7943 significantly reduced the incidence of pilocarpine-induced seizures and status epilepticus in 22-56% of treated animals. In the remaining animals that exhibited seizures, KB-R7943 pretreatment delayed the onset of seizures and status epilepticus, and reduced seizure severity. Delayed onset of seizures and reduced seizure severity also were seen following pretreatment with SN-6. These findings suggest that altered NCX activity may contribute to the pathophysiology of pilocarpine-induced seizures and status epilepticus., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Small conductance calcium (Ca(2+)) activated SK channels are critical regulators of neuronal excitability in hippocampus. Accordingly, these channels are thought to play a key role in controlling neuronal activity in acute models of epilepsy. In this study, we investigate the expression and function of SK channels in the pilocarpine model of mesial temporal lobe epilepsy. For this purpose, protein expression was assessed using western blotting assays and gene expression was analyzed using TaqMan-based probes and the quantitative real-time polymerase chain reaction (qPCR) comparative method delta-delta cycle threshold ( big up tri, open big up tri, openCT) in samples extracted from control and epileptic rats. In addition, the effect of SK channel antagonist UCL1684 and agonist NS309 on CA1 evoked population spikes was studied in hippocampal slices. Western blotting analysis showed a significant reduction in the expression of SK1 and SK2 channels at 10days following status epilepticus (SE), but levels recovered at 1month and at more than 2months after SE. In contrast, a significant down-regulation of SK3 channels was detected after 10days of SE. Analysis of gene expression by qPCR revealed a significant reduction of transcripts for SK2 (Kcnn1) and SK3 (Kcnn3) channels as early as 10days following pilocarpine-induced SE and during the chronic phase of the pilocarpine model. Moreover, bath application of UCL1684 (100nM for 15min) induced a significant increase of the population spike amplitude and number of spikes in the hippocampal CA1 area of slices obtained control and chronic epileptic rats. This effect was obliterated by co-administration of UCL1684 with SK channel agonist NS309 (1microM). Application of NS309 failed to modify population spikes in the CA1 area of slices taken from control and epileptic rats. These data indicate an abnormal expression of SK channels and a possible dysfunction of these channels in experimental MTLE., (Published by Elsevier B.V.)

Persistent down-regulation in the expression of the hyperpolarization-activated HCN1 cation channel, a key determinant of intrinsic neuronal excitability, has been observed in febrile seizure, temporal lobe epilepsy, and generalized epilepsy animal models, as well as in patients with epilepsy. However, the role and importance of HCN1 down-regulation for seizure activity is unclear. To address this question we determined the susceptibility of mice with either a general or forebrain-restricted deletion of HCN1 to limbic seizure induction by amygdala kindling or pilocarpine administration. Loss of HCN1 expression in both mouse lines is associated with higher seizure severity and higher seizure-related mortality, independent of the seizure-induction method used. Therefore, down-regulation of HCN1 associated with human epilepsy and rodent models may be a contributing factor in seizure behavior.

Objective: To evaluate Japanese tolerability to pilocarpine of 5 mg t.i.d., Methods: From January 2006 to July 2006, 39 patients with xerostomia received 5 mg t.i.d. pilocarpine for at least for 12 weeks unless they had experienced unacceptable adverse effects. All patients received radiotherapy that included the parotid glands in the radiation field >50 Gy. The body weights of the patients ranged from 42 to 73 kg (median 60 kg)., Results: Thirty-six of the 39 patients were evaluable. The tolerated rate was only 47%. Of the 25 patients whose body weights were less than 65 kg, the tolerated rate was 36%, whereas the rate of the 11 patients whose body weights were 65 kg or above was 72% (p=0.050). The most common adverse effect was sweating with an incidence of 64%. Response rate, which was defined as the total number of patients with an increase of at least 25 mm from the baseline in the VAS score divided by the number of maintaining patients among those who started pilocarpine after more than 4 months from the start of radiotherapy, was 40% at 12 weeks (n=15)., Conclusion: For Japanese, 5mg t.i.d. pilocarpine caused a high incidence of unacceptable adverse effects. A lower dose of pilocarpine needs to be considered.

In functional assay assessments using the five muscarinic receptor subtypes, a second generation of muscarinic M(1)-preferring receptor agonists [AC-42 (1), AC-260584 (2), 77-LH-28-1 (3) and LY-593039 (4)] was shown to have higher selectivity for muscarinic M(1) over M(3) receptor as compared to historical agonists [talsaclidine (8), sabcomeline (10), xanomeline (11), WAY-132983 (12), cevimeline (9) and NGX-267 (6)]. Another striking difference of these more recent compounds is their affinities for the dopamine D(2) and 5-HT(2B) receptors. Taken together, these results suggest that the newer compounds may have a greater clinical safety profile, especially with regard to muscarinic M(3) receptor-mediated events, than the historical agonists, but their affinities for other receptors may still compromise their use to validate the therapeutic potential of muscarinic M(1) receptor agonists.

The primary objective of the dose-escalation trial for NGX267 was to estimate the maximally tolerated dose (MTD) and to gather detailed clinical and pharmacokinetic observations near the MTD. The MTD was defined based on the weighted average of moderate and severe adverse events. An adaptive design was employed to concentrate dosage assignments at or near the MTD. Favoring the acquisition of data near the MTD, at the expense of information at lower dosage levels, resulted in a shorter trial and no loss of the type of information required to inform subsequent studies where larger normal volunteer or patient samples are evaluated.

Background: Xerostomia is the feeling of dryness in the mouth, usually owing to hypofunctioning of the salivary glands. Causes of xerostomia include medications, the effects of radiation therapy on the salivary glands during the treatment of head and neck cancer or thyroid cancer, and autoimmune diseases such as Sjögren's syndrome. The primary treatment to reduce xerostomia is oral pilocarpine., Objective: This review discusses the randomized trials available on the efficacy and tolerability of oral pilocarpine for the treatment of xerostomia., Methods: The randomized trials of pilocarpine for xerostomia available in the medical literature are reviewed., Results/conclusion: Pilocarpine has some efficacy in the treatment of xerostomia from radiation therapy, graft-versus-host disease and Sjögren's syndrome. It has limited activity for the prevention of xerostomia during radiation therapy. It may have increased efficacy in combination with newer forms of radiation therapy.

Objective: To characterize the function of a new xanomeline-derived M1 agonist, 3-[3-(3-florophenyl-2-propyn-1-ylthio)-1,2,5-thiadiazol-4-yl]-1,2,5,6- tetrahydro-1-methylpyridine Oxalate (EUK1001), the acute toxicity and the effects on synaptic plasticity and cognition of EUK1001 were evaluated., Methods: To examine the median lethal dose (LD50) of EUK1001, a wide dose range of EUK1001 was administered by p.o. and i.p. in aged mice. Furthermore, novel object recognition task and in vitro electrophysiological technique were utilized to investigate the effects of EUK1001 on recognition memory and hippocampal synaptic plasticity in aged mice., Results: EUK1001 exhibited lower toxicity than xanomeline, and improved the performance of aged mice in the novel object recognition test. In addition, bath application of 1 micromol/L EUK1001 directly induced long-term potentiation in the hippocampus slices., Conclusion: We conclude that EUK1001 can improve the age-related cognitive deficits.

Objective: There are significant unmet needs in the treatment of schizophrenia, especially for the treatment of cognitive impairment, negative syndrome, and cognitive function. Preclinical data suggest that agonists with selective affinity for acetylcholine muscarinic receptors provide a potentially new mechanism to treat schizophrenia. The authors studied xanomeline, a relatively selective muscarinic type 1 and type 4 (M(1) and M(4)) receptor agonist, to determine if this agent is effective in the treatment of schizophrenia., Method: In this pilot study, the authors examined the efficacy of xanomeline on clinical outcomes in subjects with schizophrenia (N=20) utilizing a double-blind, placebo-controlled, 4-week treatment design. Outcome measures included the Positive and Negative Syndrome Scale (PANSS) for schizophrenia, the Brief Psychiatric Rating Scale (BPRS), the Clinical Global Impression (CGI) scale, and a test battery designed to measure cognitive function in patients with schizophrenia., Results: Subjects treated with xanomeline did significantly better than subjects in the placebo group on total BPRS scores and total PANSS scores. In the cognitive test battery, subjects in the xanomeline group showed improvements most robustly in measures of verbal learning and short-term memory function., Conclusions: These results support further investigation of xanomeline as a novel approach to treating schizophrenia.

Cevimeline hydrochloride, a specific agonist of the M3 muscarinic receptor, is beneficial in the treatment of symptoms of xerostomia and xerophthalmia associated with Sjögren's syndrome (SS). Cevimeline has not been evaluated in southern Chinese patients. Furthermore, the effects of cevimeline on health-related quality of life and oral health status are not known. In this randomised, double-blind, placebo-controlled crossover study, patients received cevimeline 30 mg or matched placebo three times per day over 10 weeks followed by a 4-week washout period before treatment crossover. Participants self-completed the following questionnaires: Xerostomia Inventory (XI), the General Oral Health Assessment Index (GOHAI), the Ocular Surface Disease Index (OSDI) and the Medical Outcomes Short Form (SF-36). Clinical assessments included sialometry, examination of the oral cavity for the degree of xerostomia and dental complications of xerostomia. Fifty patients (22 primary SS and 28 secondary SS) were enrolled in the trial. Forty-four patients completed the study. There was a significant improvement in the XI and GOHAI scores as well as the objective rating of xerostomic signs of the oral cavity after treatment with cevimeline. However, there was no improvement in salivary flow rates and dry eye symptoms. SS patients had lower SF-36 scores, but these did not improve after treatment with cevimeline.

There is increasing interest in the potential of transdermal drug delivery systems for the treatment of neurological disorders, especially in the elderly. In this population, the higher incidence of chronic diseases, such as diabetes mellitus, cardiovascular disease, neurological disease and chronic pain, has dramatically increased the need for long-term medications. Additionally, elderly patients often have a combination of several chronic diseases, meaning drug delivery, drug-drug interactions, absorption/blood concentrations, toxicity and compliance are of concern for patients as well as for their caregivers and physicians. Recent efforts have focused on developing pharmaceutical preparations that overcome these issues. For example, rate-controlled drug delivery systems have been under active development. Transdermal drug delivery systems have been developed to deliver phenserine, rivastigmine, nicotine and estradiol for the management of cognitive and behavioural dysfunctions in patients with Alzheimer's disease because this form of administration has several advantages, including maintenance of sustained therapeutic plasma concentrations of drugs, easy application and reduced systemic adverse effects. Thus, transdermal drug delivery for elderly patients offers promise as the ideal therapeutic approach to treating Alzheimer's disease.This article reviews the technical principles underlying the development of transdermal drug delivery systems, focusing on cholinesterase inhibitors, and the prospects for future development. The clinical performance of transdermal patches, again with emphasis on cholinesterase inhibitors, is also reviewed.

Cevimeline is an orally administered muscarinic receptor agonist that is indicated for the treatment of symptoms of dry mouth in patients with Sjogren's syndrome. Several well designed placebo-controlled trials demonstrated that 4-12 weeks' therapy with cevimeline 30 mg three times daily improved symptoms of dry mouth in patients with Sjogren's syndrome. Other symptoms, such as dry eye symptoms and overall dryness, also improved to a significantly greater extent with cevimeline than with placebo. Moreover, cevimeline significantly improved the salivary flow rate in patients with Sjogren's syndrome. Increased salivary flow was maintained in the longer term with cevimeline in patients with Sjogren's syndrome and symptoms of dry mouth, according to the results of an open-label 52-week study. From week 20 onwards, rates of patient and investigator satisfaction with the cevimeline dosage were > or =88%. Oral cevimeline 30 mg three times daily was generally well tolerated in patients with Sjogren's syndrome, with many of the most commonly reported adverse events reflecting the pharmacological action of the drug.

Purpose: To investigate the effect of concomitant administration of pilocarpine during radiotherapy for head-and-neck squamous cell carcinoma (HNSCC) on postradiotherapy xerostomia., Methods and Materials: A prospective, double blind, placebo-controlled randomized trial including 170 patients with HNSCC was executed to study the protective effect of pilocarpine on radiotherapy-induced parotid gland dysfunction. The primary objective endpoint was parotid flow rate complication probability (PFCP) scored 6 weeks, 6 months, and 12 months after radiotherapy. Secondary endpoints included Late Effects of Normal Tissue/Somatic Objective Management Analytic scale (LENT SOMA) and patient-rated xerostomia scores. For all parotid glands, dose-volume histograms were assessed because the dose distribution in the parotid glands is considered the most important prognostic factor with regard to radiation-induced salivary dysfunction., Results: Although no significant differences in PFCP were found for the two treatments arms, a significant (p = 0.03) reduced loss of parotid flow 1 year after radiotherapy was observed in those patients who received pilocarpine and a mean parotid dose above 40 Gy. The LENT SOMA and patient-rated xerostomia scores showed similar trends toward less dryness-related complaints for the pilocarpine group., Conclusions: Concomitant administration of pilocarpine during radiotherapy did not improve the PFCP or LENT SOMA and patient-rated xerostomia scores. In a subgroup of patients with a mean dose above 40 Gy, pilocarpine administration resulted in sparing of parotid gland function. Therefore, pilocarpine could be provided to patients in whom sufficient sparing of the parotid is not achievable.

Purpose: To assess the safety of long-term cevimeline treatment of radiation-induced xerostomia in patients with head-and-neck cancer; and to assess the efficacy of cevimeline in these patients., Methods and Materials: A total of 255 adults with head-and-neck cancer who had received more than 40 Gy of radiation 4 months or more before entry and had clinically significant salivary gland dysfunction received cevimeline hydrochloride 45 mg t.i.d. orally for 52 weeks. Adverse events (AEs), their severity, and their relationship to the study medication were assessed by each investigator. The efficacy assessment was based on subjects' global evaluation of oral dryness on a scale of 0 (none) to 3 (severe)., Results: Overall, 175 subjects (68.6%) experienced expected treatment-related AEs, most mild to moderate. The most frequent was increased sweating (47.5%), followed by dyspepsia (9.4%), nausea (8.2%), and diarrhea (6.3%). Fifteen subjects (5.9%) experienced Grade 3 treatment-related AEs, of which the most frequent was increased sweating. Eighteen subjects (7.1%) reported at least one serious AE, and 45 subjects (17.6%) discontinued study medication because of an AE. The global efficacy evaluation at the last study visit showed that cevimeline improved dry mouth in most subjects (59.2%). Significant improvement was seen at each study visit in the mean change from baseline of the numeric global evaluation score (p < 0.0001)., Conclusions: Cevimeline 45 mg t.i.d. was generally well tolerated over a period of 52 weeks in subjects with xerostomia secondary to radiotherapy for cancer in the head-and-neck region.

Objective: To compare the effect of a single 5-mg dose of pilocarpine hydrochloride on the salivary flow rate in three groups of xerostomic patients., Subjects and Methods: Forty-five patients were divided into three groups according to the etiology of their xerostomia: (i) radiotherapy; (ii) Sjögren's syndrome; and (iii) sialosis and xerogenic medications. Following the oral administration of a 5-mg pilocarpine hydrochloride tablet blood pressure, heart rate, body temperature and saliva secretion rates were monitored hourly for 3 h and adverse events were reported., Results: The most significant and persistent elevation of salivary flow rate was observed in the sialosis/drug-induced group followed by the Sjögren's syndrome group. The radiotherapy group presented a significant elevation of salivary secretion rate after 1 and 2 h, but returned to baseline at 3 h. No significant changes in vital signs were reported, except for low diastolic pressure measured at 1 h in the radiotherapy group. Several adverse events were recorded throughout the trial; however, only one patient withdrew from the study., Conclusion: Treatment with pilocarpine hydrochloride tablets may improve saliva secretion in patients taking xerogenic medications and/or suffering from metabolic sialosis expanding the beneficial potential of this sialogogue.

This study was conducted to assess the clinical efficacy and adverse effects of pilocarpine, bethanechol and cevimeline in patients with xerostomia. In this open-label crossover assessment in 20 patients with xerostomia, a one- to two-week course of each medication with a one-week washout period was prescribed. Side effects, symptoms, whole stimulated and unstimulated saliva were measured. Each sialogogue was found to increase saliva and decrease symptoms. A mixed-effects analysis showed a greater increase in stimulated saliva on bethanechol compared to pilocarpine (0.106, p = 0.0272). Increased sweating was the most common side effect, experienced more frequently with pilocarpine as compared to bethanechol (p = 0.0588) or cevimeline (p = 0.0143). A carryover effect beyond the washout period was seen. Effects on saliva and side effects vary between sialogogues, suggesting a benefit of trials with different sialogogues to determine individual patient preference. The observed carryover effect suggests that intermittent treatment may be an alternative to continuous treatment with sialogogues.