| Size | Price | |
|---|---|---|
| 500mg | ||
| 1g | ||
| Other Sizes |
Cevimeline (FKS-508; SNI-2011; AF-102B; SNK-508; trade name Evoxac) is a potent parasympathomimetic and muscarinic agonist thas has been approved for use in the treatment of dry mouth and Sjögren's syndrome, as well as Xerostomia symptoms.
| ln Vitro |
Cevimeline (0.1-100 μM) raises the intracellular Ca2+ content in parotid gland cells that have been digested [1].
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|---|---|
| ln Vivo |
Male Wistar rats administered with cevimeline (0.008-0.016 mg/kg intraperitoneally) exhibited increased pressor response, increased salivation, and a gradual and sustained rise in parotid gland blood flow. In the subfornical organ, cevimeline, at 0.016 mg/kg, reduces angiotensin II-induced water intake and neuronal activity [1].
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| Animal Protocol |
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. |
| ADME/Pharmacokinetics |
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. 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. Biological Half-Life 5 ± 1 hours Elimination: Approximately 5 hours. The mean half-life of cevimeline is 5+/-1 hours. |
| Toxicity/Toxicokinetics |
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). Protein Binding < 20% 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. |
| References | |
| Additional Infomation |
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. Drug Indication For the treatment of symptoms of dry mouth in patients with Sjögren's Syndrome. FDA Label 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. Therapeutic Uses Cevimeline is indicated for the treatment of symptoms of dry mouth commonly associated with Sjogren's syndrome. /Included in US product labeling/ 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. 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. |
| Molecular Formula |
C10H17NOS
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|---|---|
| Molecular Weight |
199.31
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| Exact Mass |
199.1031
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| CAS # |
107233-08-9
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| Related CAS # |
Cevimeline hydrochloride;107220-28-0;Cevimeline hydrochloride hemihydrate;153504-70-2;(+)-Cevimeline hydrochloride hemihydrate
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| PubChem CID |
2684
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| Appearance |
Typically exists as solid at room temperature
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
308.5±42.0 °C at 760 mmHg
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| Melting Point |
195-197ºC
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| Flash Point |
140.4±27.9 °C
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| Vapour Pressure |
0.0±0.7 mmHg at 25°C
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| Index of Refraction |
1.586
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| LogP |
1.23
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| Hydrogen Bond Donor Count |
0
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| Hydrogen Bond Acceptor Count |
3
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| Rotatable Bond Count |
0
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| Heavy Atom Count |
13
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| Complexity |
215
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| Defined Atom Stereocenter Count |
0
|
| SMILES |
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]
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| InChi Key |
WUTYZMFRCNBCHQ-WPRPVWTQSA-N
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| InChi Code |
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
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| Chemical Name |
Spiro(1-azabicyclo(2.2.2)octane-3,5'-(1,3)-oxathiolane), 2'-methyl-, (2'R,3R)-rel-
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| Synonyms |
FKS508 SNI 2011AF-102BSNK 508FKS-508 SNI-2011AF 102BSNK-508AF102B SNI2011 SNK508 AF-102B, Cevimeline, FKS 508, HSDB 7286, SNI 2011
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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
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| Solubility (In Vivo) |
Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.
Injection Formulations
Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)(e.g. IP/IV/IM/SC) *Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution. Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline) Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil) Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals). View More
Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)] Oral Formulations
Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium) Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals). View More
Oral Formulation 3: Dissolved in PEG400 (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 5.0173 mL | 25.0865 mL | 50.1731 mL | |
| 5 mM | 1.0035 mL | 5.0173 mL | 10.0346 mL | |
| 10 mM | 0.5017 mL | 2.5087 mL | 5.0173 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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