Delving into the Latest Updates on Cevimeline Hydrochloride with Synapse

Background and PurposeCurrent pharmacotherapies for Tourette syndrome (TS) are often unsatisfactory and poorly tolerated, underscoring the need for novel treatments. Insufficient striatal acetylcholine has been suggested to contribute to tic ontogeny. Thus, we tested whether activating M1 and/or M4 receptors—the two most abundant muscarinic receptors in the striatum—reduced tic‐related behaviours in mouse models of TS.Experimental ApproachStudies were conducted using CIN‐d and D1CT‐7 mice, two TS models characterized by early‐life depletion of striatal cholinergic interneurons and cortical neuropotentiation, respectively. First, we tested the effects of systemic and intrastriatal xanomeline, a selective M1/M4 receptor agonist, on tic‐like and other TS‐related responses. Then, we examined whether xanomeline effects were reduced by either M1 or M4 antagonists or mimicked by the M1/M3 agonist cevimeline or the M4 positive allosteric modulator (PAM) VU0467154. Finally, we measured striatal levels of M1 and M4 receptors and assessed the impact of VU0461754 on the striatal expression of the neural marker activity c‐Fos.Key ResultsSystemic and intrastriatal xanomeline reduced TS‐related behaviours in CIN‐d and D1CT‐7 mice. Most effects were blocked by M4, but not M1, receptor antagonists. VU0467154, but not cevimeline, elicited xanomeline‐like ameliorative effects in both models. M4, but not M1, receptors were down‐regulated in the striatum of CIN‐d mice. Additionally, VU0467154 reduced striatal c‐Fos levels in these animals.Conclusion and ImplicationsActivation of striatal M4, but not M1, receptors reduced tic‐like manifestations in mouse models, pointing to xanomeline and M4 PAMs as novel putative therapeutic strategies for TS.

01 Jul 2024·FASEB BioAdvances

Bile acids differentially regulate longitudinal smooth muscle contractility in everted mouse ileum

Article

Author: Dike, Peace N ; Chang, Diana S ; Preidis, Geoffrey A ; Soni, Krishnakant G

AbstractBile acids regulate gastrointestinal motility by mechanisms that are poorly understood. Standard isolated tissue bath assays might not recapitulate in vivo physiology if contractile responses to certain bile acids require direct application to the intestinal mucosa. We sought to determine the feasibility of quantifying longitudinal smooth muscle contractile responses to bile acids from intact segments of everted mouse ileum. Ileum from adult female C57BL/6J mice was isolated, gently everted over a notched metal rod, and mounted in tissue baths. Individual bile acids and agonists of bile acid receptors were added to the baths, and longitudinal smooth muscle contractile responses were quantified by isometric force transduction. Ursodeoxycholic acid robustly increased contractile responses in a dose‐dependent manner. Deoxycholic acid stimulated contractility at low doses but inhibited contractility at high doses. Chenodeoxycholic acid, glycocholic acid, and lithocholic acid did not alter contractility. The dose‐dependent increase in contractility resulting from the application of ursodeoxycholic acid was recapitulated by INT‐777, an agonist of the Takeda G protein‐coupled receptor 5 (TGR5), and by cevimeline, a muscarinic acetylcholine receptor agonist. Agonists to the nuclear receptors farnesoid X receptor, glucocorticoid receptor, pregnane X receptor, vitamin D receptor, and to the plasma membrane epidermal growth factor receptor did not modify baseline contractile patterns. These results demonstrate that gentle eversion of intact mouse ileum facilitates the quantification of longitudinal smooth muscle contractile responses to individual bile acids. Prokinetic effects of ursodeoxycholic acid and low‐dose deoxycholic acid are replicated by agonists to TGR5 and muscarinic acetylcholine receptors.

23 Dec 2022·Science Advances

Long-term functional regeneration of radiation-damaged salivary glands through delivery of a neurogenic hydrogel

Article

Author: Sinada, Hanan ; Cruz Pacheco, Noel ; Gaylord, Eliza A. ; Alsberg, Eben ; Li, Jianlong ; Bahney, Chelsea S. ; Berthoin, Lionel ; Jeon, Oju ; Knox, Sarah M. ; May, Alison J. ; Chang, Jiun Chiun ; Mohabbat, Seayar ; Sudiwala, Sonia ; Lombaert, Isabelle M.A.

Salivary gland acinar cells are severely depleted after radiotherapy for head and neck cancer, leading to loss of saliva and extensive oro-digestive complications. With no regenerative therapies available, organ dysfunction is irreversible. Here, using the adult murine system, we demonstrate that radiation-damaged salivary glands can be functionally regenerated via sustained delivery of the neurogenic muscarinic receptor agonist cevimeline. We show that endogenous gland repair coincides with increased nerve activity and acinar cell division that is limited to the first week after radiation, with extensive acinar cell degeneration, dysfunction, and cholinergic denervation occurring thereafter. However, we found that mimicking cholinergic muscarinic input via sustained local delivery of a cevimeline–alginate hydrogel was sufficient to regenerate innervated acini and retain physiological saliva secretion at nonirradiated levels over the long term (>3 months). Thus, we reveal a previously unknown regenerative approach for restoring epithelial organ structure and function that has extensive implications for human patients.

100 Deals associated with Cevimeline Hydrochloride

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KEGG	Wiki	ATC	Drug Bank
D00661	Cevimeline Hydrochloride	N07AX03	DB00185

R&D Status

Approved

10 top approved records.

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Indication	Country/Location	Organization	Date
Sjogren's Syndrome	JP	Alfresa Pharma Corp.	20 Jun 2001
Sjogren's Syndrome	JP	Nippon Kayaku Co., Ltd.	20 Jun 2001
Sjogren's Syndrome	JP	Daiichi Sankyo Co., Ltd.	20 Jun 2001
Antisynthetase Syndrome	US	Cosette Pharmaceuticals, Inc.Startup	11 Jan 2000
Xerostomia	US	Cosette Pharmaceuticals, Inc.Startup	11 Jan 2000

Developing

10 top R&D records.

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Indication	Highest Phase	Country/Location	Organization	Date
Crouzon Syndrome With Acanthosis Nigricans	NDA/BLA	CA	KYE Pharmaceuticals, Inc.	12 Sep 2022
Dry Eye Syndromes	Phase 2	TW	Biotheravision, Inc.	15 Nov 2024
Dry Eye Syndromes	Phase 2	AU	Biotheravision, Inc.	15 Nov 2024
Alzheimer Disease	Phase 1	JP	Nippon Kayaku Co., Ltd.	-
Dementia	Phase 1	JP	Snow Brand Milk Products Co., Ltd.	-
Complication	Preclinical	US	Daiichi Sankyo, Inc.	01 Jun 2001
Head and Neck Neoplasms	Preclinical	US	Daiichi Sankyo, Inc.	01 Jun 2001
Toxicity	Preclinical	US	Daiichi Sankyo, Inc.	01 Jun 2001
Xerostomia	Preclinical	US	Daiichi Sankyo, Inc.	01 Jun 2001

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Clinical Result

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Phase

Evaluation

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Study	Phase	Population	Analyzed Enrollment	Group	Results	Evaluation	Publication Date


NCT01690052 (CTgov)	Not Applicable	Xerostomia	15	Cevimeline (Cevimeline)	ainlkckshk(bvktuvmxir) = fnmnovrobz xzsydyfidn (dnprapzcmd, wxhqofcsso - volobslzlt) View more	-	06 Aug 2014
				Pilocarpine (Pilocarpine)	ainlkckshk(bvktuvmxir) = qxbelmaovo xzsydyfidn (dnprapzcmd, qqqjlelrmb - lnysqipyfb) View more
Pubmed	Not Applicable	Primary Sjögren's syndrome	118	pilocarpine	vsgoykpfbj(zkvsuizgrt) = udkhdugyxi ymscvnjwij (msihnlxiwx ) View more	-	23 Jul 2014
				cevimeline	vsgoykpfbj(zkvsuizgrt) = gjcjwckjhc ymscvnjwij (msihnlxiwx ) View more