Suspected cholinergic toxicity due to cevimeline hydrochloride and Bacopa monnieri interaction: a case report.

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.

Cevimeline co-treatment attenuates olanzapine-induced metabolic disorders via modulating hepatic M3 muscarinic receptor: AMPKα signalling pathway in female rats.

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-GSK3ß 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.

Neuropharmacology of Cevimeline and Muscarinic Drugs-Focus on Cognition and Neurodegeneration.

At present, Alzheimer's disease (AD) and related dementias cannot be cured. Therefore, scientists all over the world are trying to find a new approach to prolong an active life of patients with initial dementia. Both pharmacological and non-pharmacological pathways are investigated to improve the key symptom of the disease, memory loss. In this respect, influencing the neuromodulator acetylcholine via muscarinic receptors, such as cevimeline, might be one of the therapeutic alternatives. The purpose of this study is to explore the potential of cevimeline on the cognitive functions of AD patients. The methodology is based on a systematic literature review of available studies found in Web of Science, PubMed, Springer, and Scopus on the research topic. The findings indicate that cevimeline has shown an improvement in experimentally induced cognitive deficits in animal models. Furthermore, it has demonstrated to positively influence tau pathology and reduce the levels of amyloid-ß (Aß) peptide in the cerebral spinal fluid of Alzheimer's patients. Although this drug has not been approved by the FDA for its use among AD patients and there is a lack of clinical studies confirming and extending this finding, cevimeline might represent a breakthrough in the treatment of AD.

Use of Prescription Sialagogues for Management of Xerostomia in Chronic Graft-versus-Host-Disease.

The aim of this study is to analyze utilization patterns of prescription sialagogues for management of xerostomia in patients with chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (alloHSCT). There have been several small reports describing the clinical use of sialagogue therapy in the management of patients with cGVHD. While these reports suggest that sialagogue therapy is safe and effective in this unique patient population, the numbers of patients reported, and overall evidence base, remain limited. The objective of this study was to characterize medication utilization and treatment outcomes in a cohort of patients with cGVHD and xerostomia who were prescribed sialagogue therapy. A retrospective chart review was conducted of patients who were diagnosed with cGVHD and prescribed sialagogue therapy for xerostomia from 2005 to 2019. Data collected included patient demographics, date of alloHSCT, date of oral cGVHD diagnosis, concurrent immunosuppressive medications, sialagogue regimen, worst xerostomia score (on a 1 to 10 scale), and patient-reported outcomes. The study included 70 patients managed with pilocarpine (n = 57) and cevimeline (n = 13), with a median age of 62 years (range: 24 to 82). Overall median duration of therapy was 7 months (range: 1 to 154). The baseline median self-reported worst xerostomia score was 6 of 10. Median percent reported improvement was 10%, 40%, and 50% for FU1 (<6 months), FU2 (6 to 12 months), and FU3 (>12 months) accordingly. Most patients who reported lower percentage improvement utilized the medication for less than 6 months, and those with moderate response were compliant for longer than 6 months. When all patients were considered, there was a significant reduction (median of 1.5 points; range: 0 to 7) in the xerostomia score from pre (median: 6.5; range: 1 to 10) to post (median: 5; range: 0 to 10) (P< .001). Most common side effects were nausea (2.9%) and diarrhea (1.4%). Patients with cGVHD and xerostomia reported improvement in symptoms with sialagogue therapy and remained on medication for a median of 7 months with infrequent side effects. The sustained duration of therapy suggests perceived benefits, though prospective, blinded, and randomized studies are needed.

Cevimeline-induced anti-inflammatory effect through upregulations of mucins in the ocular surface of a dry eye mouse model.

This study aimed to investigate the effects of various concentrations of cevimelines (CVMs) and compare them with commercial drugs in a murine model of dry eye. The experimental mouse model used male and female NOD.B10.H2b mice over 12 weeks of age. Desiccation stress was performed at 30-40% ambient humidity, and subcutaneous injection of 0.5 mg/0.2 mL scopolamine hydrobromide was performed four times a day for 10 days. The efficacy of various concentrations of CVMs (seven experimental groups) was first evaluated, and then 2% CVM was compared with commercial drugs, such as cyclosporine A (CsA), diquafosol (DQS), and rebamipide (REB) (seven experimental groups). The clinical changes, including tear production, corneal irregularity, and fluorescein staining, were measured after the instillation of various concentrations of CVMs and commercial drugs for 0, 3, 5, 7, and 10 days. Histological changes, such as corneal detachment, conjunctival goblet cell and mucin density staining, were assessed by staining the cornea or conjunctiva with hematoxylin-eosin, periodic acid-Schiff, and alcian blue. The expression of inflammatory markers and mucin factors was detected by immunohistochemistry and immunofluorescence in the lacrimal gland, cornea, and conjunctiva. Tear production was significantly increased in the 2% CVM group and was similar to that in the DQS and REB groups (P < 0.05). The corneal smoothness and fluorescein staining score were significantly improved in the 2% CVM group and were similar to those in the REB group (P < 0.05). Corneal epithelial cells were significantly decreased in the 2% CVM group, with similar observations made in the DQS and REB groups (P < 0.05). The conjunctival goblet cells and mucin density recovered in the 2% CVM group were similar to those in the CsA and REB groups (P < 0.05). The 2% CVM group showed suppressed expression of inflammatory factors in the lacrimal gland and was comparable to that seen in the CsA and REB groups. The expression of mucin factors was upregulated in the cornea and conjunctiva of the 2% CVM group and was similar to that of the CsA and REB groups. In conclusion, administration of CVM resulted in recovery or clinical and histological improvement of the murine dry eye model, and all the observed parameters were comparable to those with commercial drugs.

Reactivity of human labial glands in response to cevimeline treatment.

Among the pathologies affecting the salivary glands, the Sjögren's syndrome (SS), an autoimmune disease, causes progressive destruction of the glandular tissue. The effect of SS is particularly evident on the labial glands and the morphological analysis of these minor glands is considered useful for diagnosis. Cevimeline hydrochloride (SNI), a selective muscarinic agonist drug, is one of the elective treatments for the hyposalivation due to SS, acting not only on major salivary glands, but also on labial glands since their secretion is primarily under parasympathetic control. Aim of this study is to describe the morphology of human labial glands treated with SNI by light, transmission, and high-resolution scanning electron microscopy. Moreover, a morphometric analysis was applied to the light and transmission electron microscopy micrographs to obtain data that were then compared with analogous data collected on control and carbachol-treated labial glands. Following SNI administration, the mucous tubules exhibited enlarged lumina, which were filled with a dense mucous secretion. Occasionally, small broken debris of the cells were retrieved into the lumen. In the mucous secretory cells, some mucous droplets fused to form a large vacuole-like structure. Similarly, the seromucous acini showed both dilated lumina and canaliculi. These above reported signs of secretion were confirmed through morphometric analysis and a milder action of SNI than carbachol on labial parenchyma was observed. This study confirmed that SNI also evoked secretion on labial glands and that its effect is more physiologic than that of the pan-muscarinic agonists.

Comparing the effectiveness and adverse effects of pilocarpine and cevimeline in patients with hyposalivation.

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.

Meta-analysis on pharmacological therapies in the management of xerostomia in patients with Sjogren's syndrome.

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.

Terapia farmacológica y avances terapéuticos en xerostomía e hiposalivación / Pharmacological therapy and therapeutic advancesin xerostomy and hyposalivation

La saliva juega un rol determinante en el mantenimiento y función de los tejidos orales, donde un decremento en los niveles del flujo salival conllevan a una hiposalivación o hiposialia, trayendo consigo una serie de características que propician un ambiente ideal para la instalaciónde microorganismos oportunistas y condiciones nocivas para la saludoral y sistémica de los pacientes. Hoy en día existen múltiples causas que conllevan a una hiposialia, entre ellas el síndrome de Sjõgren, la radioterapia de haz externo, entre otras, los cuales se han puesto a prueba mediante sialogogos farmacológicos como pilocarpina, cevimelina, betanecoly carbacolina, además de alternativas terapéuticas para revertir los signos obtenidos por la hiposalivación y mitigar los síntomas de xerostomía. El objetivo del presente es realizar una revisión de literatura sobre el tratamiento farmacológico en hiposalivación y xerostomía ensíndrome de Sjõgren y radioterapia de haz externo.

Saliva plays a determinant role in the maintenance and function of oral tissues, where a decrease in salivary flow levels leads to hyposalivation or hyposialia, bringing with it a series of characteristics that provide anideal environment for the installation of opportunistic microorganisms and conditions harmful to the oral and systemic health of patients.Today there are many causes that lead to hyposialia, including Sjögren’ssyndrome, external beam radiotherapy, among others, which have beentested by pharmacological sialogogs such as pilocarpine, cevimelin, betanecol and carbacoline, in addition to therapeutic alternativesto reverse the signs obtained by hyposalivation and to mitigate the symptoms of xerostomia. The objective of the present is to make a reviewof the literature on the pharmacological treatment in hyposalivation and xerostomia in Sjögren’s syndrome and external beam radiotherapy.

Effects of cevimeline on excitability of parasympathetic preganglionic neurons in the superior salivatory nucleus of rats.

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.

Structural characterization of cevimeline and its trans-impurity by single crystal XRD.

Cevimeline is muscarinic receptor agonist which increases secretion of exocrine glands. Cevimeline base is a liquid (m.p. 20-25 °C) at ambient conditions, therefore its pharmaceutical formulation as a solid hydrochloride hemihydrate has been developed. The synthesis of cevimeline yields its cis- and trans-isomers and only the cis-isomer is recognized as the API and used in the finished formulation. In this study structural and physicochemical investigations of hydrochloride hemihydrates of cis- and trans-cevimelines have been performed. Single crystal X-ray analyses of both cis- and trans-isomers of cevimeline are reported here for the first time. It was found that the cis-isomer, the API, has less dense crystal packing, lower melting point and higher solubility in comparison to the trans-isomer.