Cevimeline (0.1-100 μM) 会提高已消化的腮腺细胞中的细胞内 Ca2+ 含量 [1]。

给予西维美林（0.008-0.016mg/kg腹腔注射）的雄性Wistar大鼠表现出升压反应增强、唾液分泌增加以及腮腺血流量逐渐持续增加。在穹窿下器官中，0.016 mg/kg 的西维美林可减少血管紧张素 II 诱导的水摄入量和神经元活动 [1]。

Animal/Disease Models: Male Wistar rats (8 weeks old) were injected with angiotensin-II[1].
Doses: 0.008 mg/kg, 0.016 mg/kg.
Route of Administration: intraperitoneal (ip) injection.
Experimental Results: Salivation increased slowly and persistently, and blood flow increased. Increased in parotid and pressor responses.

Absorption, Distribution and Excretion
Rapidly absorbed with peak concentration after 1.5 to 2 hours
After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine.
6 L/kg
Elimination: Urine: 97%. Feces: 0.5%.
It is not known whether this drug is secreted in human milk.
After administration of a single 30 mg capsule, cevimeline was rapidly absorbed with a mean time to peak concentration of 1.5 to 2 hours. No accumulation of active drug or its metabolites was observed following multiple dose administration. When administered with food, there is a decrease in the rate of absorption, with a fasting T MAX of 1.53 hours and a T MAX of 2.86 hours after a meal; the peak concentration is reduced by 17.3%. Single oral doses across the clinical dose range are dose proportional. Cevimeline has a volume of distribution of approximately 6L/kg and is <20% bound to human plasma proteins. This suggests that cevimeline is extensively bound to tissues; however, the specific binding sites are unknown.
After 24 hours, 84% of a 30 mg dose of cevimeline was excreted in urine. After seven days, 97% of the dose was recovered in the urine and 0.5% was recovered in the feces.

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Metabolism / Metabolites
Primarily hepatic, isozymes CYP2D6 and CYP3A4 are responsible for the metabolism of cevimeline. Approximately 44.5% of the drug is converted to cis and trans-sulfoxide, 22.3% to glucuronic acid conjugate, and 4% to N-oxide of cevimeline. Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate.
The pharmacokinetics and metabolism cevimeline were investigated in six healthy volunteers after a single oral administration of 14(C)-cevimeline. ... The mean recoveries of the metabolites in urine at 24 hr after administration were 16.0% for cevimeline, 35.8% for cevimeline trans-sulfoxide, 8.7% for cevimeline cis-sulfoxide, 4.1% for cevimeline N-oxide, furthermore, two unknown metabolites, UK-1 and UK-2, were detected 14.6% and 7.7%, respectively. LC/MS analysis and hydrolysis studies revealed that UK-1 and UK-2 were glucuronic acid conjugates of cevimeline and cevimeline trans-sulfoxide, respectively.
Isozymes CYP2D6 and CYP3A3/4 are responsible for the metabolism of cevimeline. After 24 hours, 86.7% of the dose was recovered (16.0% unchanged, 44.5% as cis and trans-sulfoxide, 22.3% of the dose as glucuronic acid conjugate and 4% of the dose as N-oxide of cevimeline). Approximately 8% of the trans-sulfoxide metabolite is then converted into the corresponding glucuronic acid conjugate and eliminated. Cevimeline did not inhibit cytochrome P450 isozymes 1A2, 2A6, 2C9, 2C19, 2D6, 2E1, and 3A4.

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Biological Half-Life
5 ± 1 hours
Elimination: Approximately 5 hours.
The mean half-life of cevimeline is 5+/-1 hours.

Hepatotoxicity
In prelicensure trials of cevimeline, serum enzyme elevations were no more frequent than with placebo and there were no reports of acute liver injury. Since licensure and more wide scale use, cevimeline has remained free of association with instances of clinically apparent liver injury.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

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Protein Binding
< 20%

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Interactions
Cevimeline should be administered with caution to patients taking beta adrenergic antagonists, because of the possibility of conduction disturbances. Drugs with parasympathomimetic effects administered concurrently with cevimeline can be expected to have additive effects. Cevimeline might interfere with desirable antimuscarinic effects of drugs used concomitantly. Drugs which inhibit CYP2D6 and CYP3A3/4 also inhibit the metabolism of cevimeline. Cevimeline should be used with caution in individuals known or suspected to be deficient in CYP2D6 activity, based on previous experience, as they may be at a higher risk of adverse events.

[1]. Distinct effects of cevimeline and pilocarpine on salivary mechanisms, cardiovascular response and thirst sensation in rats.Arch Oral Biol. 2012 Apr;57(4):421-8. Epub 2011 Nov 17.

[2]. Effectiveness of cevimeline to improve oral health in patients with postradiation xerostomia.Head Neck. 2012 Aug;34(8):1136-42. doi: 10.1002/hed.21894. Epub 2012 Jan 9.

[3]. Cevimeline-induced monophasic salivation from the mouse submandibular gland: decreased Na+ content in saliva results from specific and early activation of Na+/H+ exchange.J Pharmacol Exp Ther. 2011 Apr;337(1):267-74. Epub 2011 Jan 14.

[4]. Cevimeline (Evoxac) overdose.J Med Toxicol. 2011 Mar;7(1):57-9.

[5]. Effects of cevimeline on excitability of parasympathetic preganglionic neurons in the superior salivatory nucleus of rats. Auton Neurosci. 2017 Sep;206:1-7.

Cevimeline is a parasympathomimetic agent that act as an agonist at the muscarinic acetylcholine receptors M1 and M3. It is indicated by the Food and Drug Administration for the treatment of dry mouth associated with Sjögren's syndrome.
Cevimeline is an orally available cholinergic agonist that is used to treat symptoms of dry mouth in patients with keratoconjunctivitis sicca (Sjögren syndrome). Cevimeline has not been linked to serum enzyme elevations during therapy or to instances of clinically apparent liver injury.
Cevimeline is a cholinergic analogue with glandular secretion stimulatory activity. Cevimeline binds to and activates muscarinic receptors, thereby increasing the secretions in exocrine salivary and sweat glands. This cholinergic agonist also increases the tone of smooth muscle in the gastrointestinal and urinary tracts. Cevimeline is being studied as a treatment for dry mouth caused by radiation therapy to the head and neck.

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Drug Indication
For the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome.
FDA Label

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Mechanism of Action
Muscarinic agonists such as cevimeline bind and activate the muscarinic M1 and M3 receptors. The M1 receptors are common in secretory glands (exocrine glands such as salivary and sweat glands), and their activation results in an increase in secretion from the secretory glands. The M3 receptors are found on smooth muscles and in many glands which help to stimulate secretion in salivary glands, and their activation generally results in smooth muscle contraction and increased glandular secretions. Therefore, as saliva excretion is increased, the symptoms of dry mouth are relieved.
Cevimeline hydrochloride, a quinuclidine derivative of acetycholine, is a cholinergic agonist that bind to muscarinic receptors. In sufficient dosages, muscarinic agonists may cause increased exocrine (eg sweat, salivary) gland secretion and increased GI and urinary tract smooth muscle tone. Cevimeline exhibits a higher affinity for muscarinic receptors on lacrimal and salivary gland epithelium than for those on cardiac tissues. Cevimeline is structurally unrelated to other currently available drugs but is pharmacologically similar to pilocarpine, another oral cholinergic agonist that exerts predominantly muscarinic action. Both drug stimulate residual salivary gland tissues that are still functioning despite damage.

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Therapeutic Uses
Cevimeline is indicated for the treatment of symptoms of dry mouth commonly associated with Sjogren's syndrome. /Included in US product labeling/

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Drug Warnings
FDA Pregnancy Risk Category: C /RISK CANNOT BE RULED OUT. Adequate, well controlled human studies are lacking, and animal studies have shown risk to the fetus or are lacking as well. There is a chance of fetal harm if the drug is given during pregnancy; but the potential benefits may outweigh the potential risk./
The safety and efficacy of cevimeline for the treatment of dementia of Alzheimer's disease has not been established.
Excessive perspiration can occur when using cevimeline, and may cause dehydration. In the event that this occurs, patients should drink extra water and consult with their physician.
Risk of altered cardiac conduction and/or heart rate. Patients with clinically important cardiovascular disease may be unable to compensate for transient changes in hemodynamics or heart rhythm induced by cevimeline. Use with caution and under close medical supervision in patients with a history of cardiovascular disease (e.g., angina pectoris, myocardial infarction).
For more Drug Warnings (Complete) data for CEVIMELINE (14 total), please visit the HSDB record page.

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Pharmacodynamics
Cevimeline is a cholinergic agonist which binds to muscarinic receptors. Muscarinic agonists in sufficient dosage can increase secretion of exocrine glands, such as salivary and sweat glands and increase tone of the smooth muscle in the gastrointestinal and urinary tracts.

C10H17NOS

199.31

199.1031

107233-08-9

Cevimeline hydrochloride;107220-28-0;Cevimeline hydrochloride hemihydrate;153504-70-2;(+)-Cevimeline hydrochloride hemihydrate

2684

Typically exists as solid at room temperature

1.2±0.1 g/cm3

308.5±42.0 °C at 760 mmHg

195-197ºC

140.4±27.9 °C

0.0±0.7 mmHg at 25°C

1.586

1.23

37.77

0

3

0

13

215

0

S1[C@]([H])(C([H])([H])[H])O[C@@]2(C1([H])[H])C([H])([H])N1C([H])([H])C([H])([H])C2([H])C([H])([H])C1([H])[H]

WUTYZMFRCNBCHQ-WPRPVWTQSA-N

1S/C10H17NOS/c1-8-12-10(7-13-8)6-11-4-2-9(10)3-5-11/h8-9H,2-7H2,1H3/t8-,10-/m0/s1

Spiro(1-azabicyclo(2.2.2)octane-3,5'-(1,3)-oxathiolane), 2'-methyl-, (2'R,3R)-rel-

FKS508 SNI 2011AF-102BSNK 508FKS-508 SNI-2011AF 102BSNK-508AF102B SNI2011 SNK508 AF-102B, Cevimeline, FKS 508, HSDB 7286, SNI 2011

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。