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Abstract Objective This study assessed the effect of cevimeline and different concentrations of gum arabic on the parotid gland of rats being given xerostomia-inducing methotrexate. Methods One hundred twenty-five rats were divided into five equal groups of twenty-five each. The rats in Group I received basic diets, while those in Groups II, III, IV, and V received 20 mg/kg MTX as a single intraperitoneal dose on day one. Group III received 10 mg/kg CVM dissolved in saline orally and daily, and the other two groups received a 10% W/V aqueous suspension of GA. Therefore, Group IV received 2 ml/kg suspension orally and daily, while Group V received 3 ml/kg suspension orally and daily. After 9 days, the parotid glands were dissected carefully and prepared for hematoxylin and eosin (H&E) staining as a routine histological stain and caspase-3 and Ki67 immunohistochemical staining. Quantitative data from α-Caspase-3 staining and Ki67 staining were statistically analysed using one-way ANOVA followed by Tukey’s multiple comparisons post hoc test. Results Regarding caspase-3 and Ki67 immunohistochemical staining, one-way ANOVA revealed a significant difference among the five groups. For Caspase-3, the highest mean value was for group II (54.21 ± 6.90), and the lowest mean value was for group I (15.75 ± 3.67). The other three groups had mean values of 31.09 ± 5.90, 30.76 ± 5.82, and 20.65 ± 3.47 for groups III, IV, and V, respectively. For Ki67, the highest mean value was for group I (61.70 ± 6.58), and the lowest value was for group II (18.14a ± 5.16). The other three groups had mean values of 34.4 ± 9.27, 48.03 ± 8.40, and 50.63 ± 8.27 for groups III, IV, and V, respectively. Conclusion GA, rather than the normally used drug CVM, had a desirable effect on the salivary glands of patients with xerostomia.

Olanzapine is an atypical antipsychotic drug and a potent muscarinic M3 receptor (M3R) antagonist. Olanzapine has been reported to cause metabolic disorders, including dyslipidemia. Anaplastic lymphoma kinase (Alk), a tyrosine kinase receptor well known in the pathogenesis of cancer, has been recently identified as a key gene in the regulation of thinness via the regulation of adipose tissue lipolysis. This project aimed to investigate whether Olanzapine could modulate the hepatic Alk pathway and lipid metabolism via M3R. Female rats were treated with Olanzapine and/or Cevimeline (an M3R agonist) for 9 weeks. Lipid metabolism and hepatic Alk signaling were analyzed. Nine weeks' treatment of Olanzapine caused metabolic disturbance including increased body mass index (BMI), fat mass accumulation, and abnormal lipid metabolism. Olanzapine treatment also led to an upregulation of Chrm3, Alk, and its regulator Ptprz1, and a downregulation of Lmo4, a transcriptional repressor of Alk in the liver. Moreover, there were positive correlations between Alk and Chrm3, Alk and Ptprz1, and a negative correlation between Alk and Lmo4. However, cotreatment with Cevimeline significantly reversed the lipid metabolic disturbance and adipose tissue accumulation, as well as the upregulation of the hepatic Alk signaling caused by Olanzapine. This study demonstrates evidence that Olanzapine may cause metabolic disturbance by modulating hepatic Alk signaling via M3R, which provides novel insight for modulating the hepatic Alk signaling and potential interventions for targeting metabolic disorders. [ABSTRACT FROM AUTHOR]

Objective: This study assessed the effect of cevimeline and different concentrations of gum arabic on the parotid gland of rats being given xerostomia-inducing methotrexate. Methods: One hundred twenty-five rats were divided into five equal groups of twenty-five each. The rats in Group I received basic diets, while those in Groups II, III, IV, and V received 20 mg/kg MTX as a single intraperitoneal dose on day one. Group III received 10 mg/kg CVM dissolved in saline orally and daily, and the other two groups received a 10% W/V aqueous suspension of GA. Therefore, Group IV received 2 ml/kg suspension orally and daily, while Group V received 3 ml/kg suspension orally and daily. After 9 days, the parotid glands were dissected carefully and prepared for hematoxylin and eosin (H&E) staining as a routine histological stain and caspase-3 and Ki67 immunohistochemical staining. Quantitative data from α-Caspase-3 staining and Ki67 staining were statistically analysed using one-way ANOVA followed by Tukey's multiple comparisons post hoc test. Results: Regarding caspase-3 and Ki67 immunohistochemical staining, one-way ANOVA revealed a significant difference among the five groups. For Caspase-3, the highest mean value was for group II (54.21 ± 6.90), and the lowest mean value was for group I (15.75 ± 3.67). The other three groups had mean values of 31.09 ± 5.90, 30.76 ± 5.82, and 20.65 ± 3.47 for groups III, IV, and V, respectively. For Ki67, the highest mean value was for group I (61.70 ± 6.58), and the lowest value was for group II (18.14a ± 5.16). The other three groups had mean values of 34.4 ± 9.27, 48.03 ± 8.40, and 50.63 ± 8.27 for groups III, IV, and V, respectively. Conclusion: GA, rather than the normally used drug CVM, had a desirable effect on the salivary glands of patients with xerostomia. [ABSTRACT FROM AUTHOR]

Olanzapine is an atypical antipsychotic drug and a potent muscarinic M3 receptor (M3R) antagonist. Olanzapine has been reported to cause metabolic disorders, including dyslipidemia. Anaplastic lymphoma kinase (Alk), a tyrosine kinase receptor well known in the pathogenesis of cancer, has been recently identified as a key gene in the regulation of thinness via the regulation of adipose tissue lipolysis. This project aimed to investigate whether Olanzapine could modulate the hepatic Alk pathway and lipid metabolism via M3R. Female rats were treated with Olanzapine and/or Cevimeline (an M3R agonist) for 9 weeks. Lipid metabolism and hepatic Alk signaling were analyzed. Nine weeks’ treatment of Olanzapine caused metabolic disturbance including increased body mass index (BMI), fat mass accumulation, and abnormal lipid metabolism. Olanzapine treatment also led to an upregulation of Chrm3, Alk, and its regulator Ptprz1, and a downregulation of Lmo4, a transcriptional repressor of Alk in the liver. Moreover, there were positive correlations between Alk and Chrm3, Alk and Ptprz1, and a negative correlation between Alk and Lmo4. However, cotreatment with Cevimeline significantly reversed the lipid metabolic disturbance and adipose tissue accumulation, as well as the upregulation of the hepatic Alk signaling caused by Olanzapine. This study demonstrates evidence that Olanzapine may cause metabolic disturbance by modulating hepatic Alk signaling via M3R, which provides novel insight for modulating the hepatic Alk signaling and potential interventions for targeting metabolic disorders.

Abstract Background Muscarinic agonists are indicated for the treatment of many conditions including ileus, urinary retention, glaucoma, and Sjögren’s syndrome. Due to their lack of tissue specificity, these drugs can lead to undesirable side effects at off-target sites and may be potentiated by supplements that impact the half-life of these drugs. Case presentation A 58-year-old Caucasian female with history of Sjögren’s syndrome, who was being managed with cevimeline, presented to the primary care office with reported hyperhidrosis, malaise, nausea, and tachycardia. She reported taking an herbal supplement containing B. monnieri and phosphatidylserine the previous night. It has been previously demonstrated that B. monnieri alters cytochrome P450 enzymes. Electrocardiogram showed no acute ST–T changes. Clinical improvement occurred with hydration and discontinuation of the supplement. Conclusions To our knowledge, there has only been one other documented cevimeline overdose, and it was not associated with an herbal supplementation interaction. Physicians should actively elicit herbal supplement information from patients to anticipate possible drug–herb interactions. An additional consideration of clinical relevance is the known genetic variability that may affect drug responsiveness due to differences in metabolism and half-life of drugs that arise from common genetic variants of cytochrome P450 genes.

Background: Muscarinic agonists are indicated for the treatment of many conditions including ileus, urinary retention, glaucoma, and Sjögren's syndrome. Due to their lack of tissue specificity, these drugs can lead to undesirable side effects at off-target sites and may be potentiated by supplements that impact the half-life of these drugs.Case Presentation: A 58-year-old Caucasian female with history of Sjögren's syndrome, who was being managed with cevimeline, presented to the primary care office with reported hyperhidrosis, malaise, nausea, and tachycardia. She reported taking an herbal supplement containing B. monnieri and phosphatidylserine the previous night. It has been previously demonstrated that B. monnieri alters cytochrome P450 enzymes. Electrocardiogram showed no acute ST-T changes. Clinical improvement occurred with hydration and discontinuation of the supplement.Conclusions: To our knowledge, there has only been one other documented cevimeline overdose, and it was not associated with an herbal supplementation interaction. Physicians should actively elicit herbal supplement information from patients to anticipate possible drug-herb interactions. An additional consideration of clinical relevance is the known genetic variability that may affect drug responsiveness due to differences in metabolism and half-life of drugs that arise from common genetic variants of cytochrome P450 genes. [ABSTRACT FROM AUTHOR]

Background: Olanzapine is one of the most commonly used antipsychotic drugs; however, its metabolic disorders are the main obstacle in the clinic. Olanzapine is a potent antagonist of the M3 acetylcholine muscarinic receptor (M3R), while the downregulated hepatic M3R-AMPKα signalling pathway is involved in metabolic disorders. Aim: This study investigated the effects of chronic co-treatment with cevimeline (an agonist of M3Rs) in attenuating olanzapine-induced metabolic disorders and the underlying mechanisms. Methods: Forty-eight adult female Sprague-Dawley rats were treated orally with olanzapine (2 mg/kg, 3 times/day (t.i.d.)) and/or cevimeline (9 mg/kg, t.i.d.), or control (vehicle) for 9 weeks. Results: Cevimeline co-treatment significantly attenuated olanzapine-induced body weight gain and glucolipid metabolic disorders. Importantly, cevimeline co-treatment attenuated olanzapine-induced upregulation of M3Rs, while the co-treatment improved olanzapine-induced downregulation of AMPKα in the liver. Cevimeline co-treatment attenuated olanzapine-induced dyslipidaemia by modulating the hepatic M3R-AMPKα downstream pathways. Cevimeline co-treatment also improved lower activated AKT-GSK3β signalling to reverse impairment of glucose metabolism and insulin resistance caused by chronic olanzapine treatment. Conclusion: These results not only support the important role of M3R antagonism and its related AMPKα and downstream pathways in antipsychotic-induced metabolic disorders but also indicate that these pathways might be promising targets for pharmacological intervention to control these side effects caused by antipsychotic therapy. [ABSTRACT FROM AUTHOR]

Objective: To compare the safety and efficacy of pilocarpine and cevimeline in the secretion of saliva in patients with dry mouth. Methods: This is a randomized, crossover, double-blind trial. Half patients were administered pilocarpine 30mg, and the other half were administered cevimeline 5mg, three times a day in both cases, for a period of four weeks. After four weeks, one week washout period was provided, and then treatment was reversed in two groups for another four weeks. Patients were reevaluated at 4 and 9 weeks respectively. Results: 22 patients were divided into two groups of 11 patients each, and administered the medication. Although both medications proved to increase salivary secretion, there was no statistically significant difference observed between pilocarpine and cevimeline regarding their efficacy as well as side effects. Conclusion: No significant difference was observed between pilocarpine and cevimeline in salivary production or side effects. However, further studies with sufficient sample size are recommended to find out more effective and safe drug in xerostomia patients. [ABSTRACT FROM AUTHOR]

Objectives: Pilocarpine (PILO) and cevimeline (CEV) are muscarinic acetylcholine receptor agonists that stimulate salivary gland function. The aim of this investigation was to retrospectively run a head‐to‐head comparison for their effectiveness and frequency of adverse effects in patients with hyposalivation. Methods: A retrospective chart review was conducted for patients seen at the Oral Medicine Clinic at Tufts University School of Dental Medicine (TUSDM) and was prescribed PILO or CEV. Patients' demographics, medical history/medication, stimulated salivary (SS), and unstimulated salivary (US) flow recorded at the initial visit and at 3‐ and 6‐month follow‐ups were collected. Changes in dosage/frequency, side effects, and drug discontinuation were also reported. Results: A total of 110 patients' charts were reviewed. The majority of subjects (91%) were females with an average age of 61. At 3‐month follow‐up, the use of CEV showed significant improvement in SS compared to PILO (p =.033) but not in US (p =.10). At 6‐month follow‐up, there was no significant difference in SS or US between the two groups (SS: p =.09; US: p =.71). The use of PILO was associated with a higher proportion of adverse effects compared to CEV (p =.04). The overall adherence rate was significantly higher in the CEV group (p =.0056). Conclusions: The effectiveness of CEV and PILO is comparable. However, PILO seems to be associated with more reporting of side effects. [ABSTRACT FROM AUTHOR]

Introduction: Sjogren's syndrome is an immunologic disorder, characterized by symptoms of dry mouth and dry eyes. Management of xerostomia is more difficult and challenging, various pharmacologic agents have been tried and evaluated in the management of xerostomia in these patients, but the results were inconsistent and variable. Hence, the present study is aimed at evaluation and comparison of different pharmacological agents in the management of xerostomia in patients with Sjogren's syndrome. Materials and methods: A meta-analysis of case–control studies was conducted on pharmacological management of xerostomia in patients with Sjogren's Syndrome and the collected data are subjected to exclusion and inclusion criteria and standard mean difference (SMD), ODD's ratio and confidence intervals (95% CI) were calculated by Review Manager software using fixed and random effects model from the data of five studies. Results: Both objective response and subjective response evaluation favored experimental group suggesting an increase in unstimulated salivary flow rate using pharmacological agents. Interferon alpha 150 IU three times daily had a good effect in increasing the unstimulated whole saliva flow rate with SMD 2.72 at 95% CI [2.43, 3.00] p <.00001. Cevimeline vs placebo showed good response with ODDS ratio 2.74 at 95% CI [1.58, 4.76] p =.0003. Conclusion: Interferon – α 150 IU thrice daily was proven to be effective in increasing salivary flow rate and also has an advantage of disease modification in SS patients attributing to its immunomodulatory action. Cevimeline 30 mg thrice daily also had a considerable therapeutic effect in SS patients compared to Pilocarpine. [ABSTRACT FROM AUTHOR]

The superior salivatory nucleus (SSN) contains parasympathetic preganglionic neurons innervating the submandibular and sublingual salivary glands. Cevimeline, a muscarinic acetylcholine receptor (mAChR) agonist, is a sialogogue that possibly stimulates SSN neurons in addition to the salivary glands themselves because it can cross the blood-brain barrier (BBB). In the present study, we examined immunoreactivities for mAChR subtypes in SSN neurons retrogradely labeled with a fluorescent tracer in neonatal rats. Additionally, we examined the effects of cevimeline in labeled SSN neurons of brainstem slices using a whole-cell patch-clamp technique. Mainly M1 and M3 receptors were detected by immunohistochemical staining, with low-level detection of M4 and M5 receptors and absence of M2 receptors. Most (110 of 129) SSN neurons exhibited excitatory responses to application of cevimeline. In responding neurons, voltage-clamp recordings showed that 84% (101/120) of the neurons exhibited inward currents. In the neurons displaying inward currents, the effects of the mAChR antagonists were examined. A mixture of M1 and M3 receptor antagonists most effectively reduced the peak amplitude of inward currents, suggesting that the excitatory effects of cevimeline on SSN neurons were mainly mediated by M1 and M3 receptors. Current-clamp recordings showed that application of cevimeline induced membrane depolarization (9/9 neurons). These results suggest that most SSN neurons are excited by cevimeline via M1 and M3 muscarinic receptors. [ABSTRACT FROM AUTHOR]

The management of dry mouth is essential for patients with Sjögren's syndrome. The symptomatic treatment has included using air humidifiers, rinsing the mouth with water or mouthwash, the application of a salivary substitute and administration of secretagogues. There are three secretagogues suitable for the alleviation of dry mouth in Sjögren's syndrome patients in Japan; cevimeline hydrochloride hydrate (cevimeline), pilocarpine hydrochloride, and anetholtrithione. A relationship between the effect of cevimeline on saliva secretion and the degree of salivary gland destruction evaluated by sialography and histopathological findings in the labial minor salivary glands has been reported. These diagnostic approaches could provide useful prognostic information on the efficacy of cevimeline in Sjögren's syndrome patients. Concomitantly, a bite guard was suggested as an effective lubricating device because it maintains the lubricants in the proper location. In addition, the management of the complications of dry mouth, such as tooth caries, periodontitis and oral candidiasis, which all lead to a reduction in the QOL, is also important. Both the prevention and treatment of erythematous candidiasis is especially important in the management of Sjögren's syndrome.