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Pentoxyverine (rINN) or carbetapentane is an antitussive (cough suppressant) commonly used for cough associated with illnesses like common cold. It is sold over-the-counter in the United States as Solotuss,^[1] or in combination with other medications, especially decongestants. One such product is Certuss, a combination of guaifenesin and pentoxyverine.^[2]

The drug is available in the form of drops, suspensions and suppositories.^[1]^[3]

Uses

The drug is used for the treatment of dry cough associated with conditions such as common cold, bronchitis or sinusitis. Like codeine and other antitussives, it relieves the symptom, but does not heal the illness.^[1] No controlled clinical trials regarding the efficiency of pentoyxverine are available.^[4]

Pharmacologists use the substance as a selective agonist at the sigma-1 receptor in animal^[5] and in vitro experiments.^[6]^[7]

Contraindications

Pentoxyverine is contraindicated in persons with bronchial asthma^[4] or other kinds of respiratory insufficiency (breathing difficulties), as well as angle-closure glaucoma. No data are available for the use of pentoxyverine during pregnancy, lactation, or children under two years of age, wherefore the drug must not be used under these circumstances.^[3]

Antitussive drugs are not useful in patients with extensive phlegm production because they prevent coughing up the phlem.^[4]

Adverse effects

The most common side effects (seen in more than 1% of patients) are upper abdominal (belly) pain, diarrhoea, dry mouth, and nausea or vomiting. Allergic reactions of the skin like itching, rashes, hives and angiooedema are rare. The same is true for anaphylactic shock and convulsions.^[3]^[8]

Overdose

Overdosage leads to drowsiness, agitation, nausea and anticholinergic effects like tachycardia (high heart rate), dry mouth, blurred vision, glaucoma, or urinary retention.^[1]^[3] Especially in children, pentoxyverine can cause hypoventilation,^[4] but much more seldom than codeine and other opioid antitussives.

The treatment of overdosage aims at the symptoms; there are no specific antidotes available.^[3]

Interactions

No interactions have been described at usual doses. It is possible that pentoxyverine can increase the potency of sedative drugs like benzodiazepines, some anticonvulsants and antidepressants, and alcohol. Likewise, some consumer informations warn patients from taking the drug in combination with or up to two weeks after monoamine oxidase inhibitors, which are known to cause potentially fatal reactions in combination with the (chemically only distantly related) antitussive dextromethorphan.^[1]^[3]^[4]

Mechanism of action

Pentoxyverine suppresses the cough reflex in the central nervous system,^[1] but the exact mechanism of action is not known with certainty. The drug acts as an antagonist at muscarinic receptors^[3] (subtype M₁) and as an agonist at sigma receptors (subtype σ₁).^[5] Its anticholinergic properties can theoretically relax the pulmonary alveoli and reduce phlegm production. Spasmolytic and local anaesthetic properties have also been described.^[4] The clinical relevance of these mechanisms is uncertain.

Pharmacokinetics

The substance is absorbed quickly from the gut and reaches its maximum plasma concentration (C_max) after about two hours. If applied rectally, C_max is reached after four hours. The bioavailability of the suppositories, measured as area under the curve (AUC), is about twofold that of oral formulations, due to a first pass effect of over 50%. By far the most important metabolisation reaction is ester hydrolysis, which accounts for 26.3% of the total clearance through the kidneys. Only 0.37% are cleared in form of the original substance.^[3] The plasma half life is 2.3 hours for oral formulations and three to 3.5 hours for suppositories.^[9] Pentoxyverine is also excreted into the breast milk.^[3]

Chemical properties

Pentoxyverine dihydrogen citrate, the salt that is commonly used for oral preparations, is a white to off-white, crystalline powder. It dissolves easily in water or chloroform, but not in benzene, diethyl ether, or petroleum ether, and melts at 90–95 °C.^[4] Other orally available salts are the hydrochloride and the tannate;^[10] suppositories contain the free base.^[3]

References

^ ^a ^b ^c ^d ^e ^f "Carbetapentane". Drugs.com. http://www.drugs.com/mtm/carbetapentane.html.
^ "Certuss". Drugs.com. http://www.drugs.com/mtm/certuss.html.
^ ^a ^b ^c ^d ^e ^f ^g ^h ⁱ ^j Jasek, W., ed. (2008) (in German). Austria-Codex (63 ed.). Vienna: Österreichischer Apothekerverlag. ISBN 978-3-85200-188-3.
^ ^a ^b ^c ^d ^e ^f ^g Dinnendahl, V.; Fricke, U., eds. (2010) (in German). Arzneistoff-Profile. 4 (23 ed.). Eschborn, Germany: Govi Pharmazeutischer Verlag. ISBN 978-3-7741-9846-3.
^ ^a ^b Brown, C.; Fezoui, M.; Selig, W. M.; Schwartz, C. E.; Ellis, J. L. (2004). "Antitussive activity of sigma-1 receptor agonists in the guinea-pig". British Journal of Pharmacology 141 (2): 233–240. doi:10.1038/sj.bjp.0705605. PMC 1574192. PMID 14691051. //www.ncbi.nlm.nih.gov/pmc/articles/PMC1574192/. edit
^ Kume, T.; Nishikawa, H.; Taguchi, R.; Hashino, A.; Katsuki, H.; Kaneko, S.; Minami, M.; Satoh, M. et al. (2002). "Antagonism of NMDA receptors by sigma receptor ligands attenuates chemical ischemia-induced neuronal death in vitro". European Journal of Pharmacology 455 (2–3): 91–100. doi:10.1016/S0014-2999(02)02582-7. PMID 12445574. edit
^ "Carbetapentane Citrate CAS#: 23142-01-0". Chemicalbook. http://www.chemicalbook.cn/ProductChemicalPropertiesCB2476609_EN.htm.
^ Dootz, H.; Kuhlmann, A.; Hoffmann, K., eds (in German). Rote Liste (2005 ed.). Aulendorf: Editio Cantor. 24 037. ISBN 3-87193-306-6.
^ Steinhilber, D.; Schubert-Zsilavecz, M.; Roth, H. J. (2005) (in German). Medizinische Chemie [Medical Chemistry]. Stuttgart: Deutscher Apothekerverlag. p. 190. ISBN 3-7692-3483-9.
^ "Pentoxyverine Full Prescribing Information". MIMS. http://www.mims.com/USA/drug/info/pentoxyverine?type=full&h=pentoxyverine.

English Journal

The use of carbetapentane for spinal anesthesia and use-dependent block of sodium currents.

Leung YM1, Tzeng JI, Kuo CS, Chen YW, Chu CC, Wang JJ.
European journal of pharmacology.Eur J Pharmacol.2013 Aug 15;714(1-3):366-72. doi: 10.1016/j.ejphar.2013.07.013. Epub 2013 Jul 16.
Although carbetapentane produces skin (peripheral) infiltrative analgesia, the underlying mechanism of carbetapentane in local anesthesia is not well understood. The purpose of the study was to examine the effect of carbetapentane on voltage-gated Na(+) channels and its efficacy on spinal (central)
PMID 23872380

Examining protection from anoxic depolarization by the drugs dibucaine and carbetapentane using whole cell recording from CA1 neurons.

White SH1, Brisson CD, Andrew RD.
Journal of neurophysiology.J Neurophysiol.2012 Apr;107(8):2083-95. doi: 10.1152/jn.00701.2011. Epub 2012 Jan 25.
As an immediate consequence of stroke onset, failure of the Na(+)-K(+)-ATPase pump evokes a propagating anoxic depolarization (AD) across gray matter. Acute neuronal swelling and dendritic beading arise within seconds in the future ischemic core, imaged as changes in light transmittance (ΔLT). AD i
PMID 22279188

Characterization of pentoxyverine metabolites in urine using GC/MS after intoxication with Silomat cough drops.

Westphal F1, Junge T, Radünz L, Stegk J, Rochholz G.
Forensic science international.Forensic Sci Int.2012 Feb 10;215(1-3):124-35. doi: 10.1016/j.forsciint.2011.03.002. Epub 2011 Mar 30.
A nearly two and a half year old boy was hospitalized after showing symptoms of disorientation and hallucination. The parents remembered the child playing with a bottle of Silomat cough drops, so that an intoxication was taken into consideration. After liquid/liquid extraction of a urine sample coll
PMID 21450423

Japanese Journal

Synthesis and in Vitro Evaluation of Iodinated Derivatives of Piperazine as a New Ligand for Sigma Receptor Imaging by Single Photon Emission Computed Tomography

Hirata Masahiko,Mori Tetsuya,Soga Seigo [他],UMEDA Takuya,OHMOMO Yoshiro
Chemical & pharmaceutical bulletin 54(4), 470-475, 2006-04-01
… The in vitro competition binding studies using [^3H] DTG (sigma-1, 2), [^3H] (+)-pentazocine (sigma-1), and [^3H] DTG in the presence of carbetapentane (sigma-2) as sigma receptor selective radioligands were revealed that iodinated analogues 4a-c possess high affinities to sigma receptors (IC_<50>: 4a=7.1, 4b=31.0, and 4c=77.3nM). …
NAID 110004820417

Effect of Carbetapentane or Melatonin on Cyanide-Induced Neurotoxicity in Mice

山本弘明,唐海旺
衛生化学 42(6), 487-491, 1996-12-31
… However, the incidence of seizures was significantly reduced by intracerebroventricular preinjection of carbetapentane (50 nmol/brain), an inhibitor of glutamate release, or by subcutaneous preinjection of melatonin (20 mg/kg), a potent free radical scavenger. … Furthermore, mortality elicited by potassium cyanide (8 or 9 mg/kg, s.c.) was also reduced by pretreatment with carbetapentane or melatonin. …
NAID 110003642247

DETERMINATION OF TERTIARY AMINO ANTITUSSIVES IN BODY FLUIDS BY GAS CHROMATOGRAPHY WITH SURFACE IONIZATION DETECTION

Ishii Akira,Seno Hiroshi,Kumazawa Takeshi,Suzuki Osamu
1993-12-20
… We could determine carbetapentane, clobutinol and oxeladin, tertiary amino antitussives, with extremely high sensitivity by gas chromatography with surface ionization detection (GC-SID). …
NAID 120005314004

Related Pictures

★リンクテーブル★

リンク元	「pentoxyverine」「カルベタペンタン」
拡張検索	「carbetapentane citrate」

「pentoxyverine」

Pentoxyverine
Systematic (IUPAC) name
	2-[2-(diethylamino)ethoxy]ethyl 1-phenylcyclopentanecarboxylate
Clinical data
AHFS/Drugs.com	International Drug Names
MedlinePlus	a606008
Pregnancy cat.	No studies; contraindicated
Legal status	OTC (US)
Routes	Oral, rectal
Pharmacokinetic data
Metabolism	Hepatic
Half-life	2.3 hours (oral), 3–3.5 hours (rectal)
Excretion	Renal
Identifiers
CAS number	77-23-6 ; 23142-01-0 (dihydrogen citrate); 1406-98-0 (tannate)
ATC code	R05DB05
PubChem	CID 2562
ChemSpider	2464
UNII	32C726X12W
KEGG	D08334
ChEMBL	CHEMBL73234
Chemical data
Formula	C20H31NO3
Mol. mass	333.465 g/mol
	SMILES O=C(OCCOCCN(CC)CC)C2(c1ccccc1)CCCC2;
	InChI InChI=1S/C20H31NO3/c1-3-21(4-2)14-15-23-16-17-24-19(22)20(12-8-9-13-20)18-10-6-5-7-11-18/h5-7,10-11H,3-4,8-9,12-17H2,1-2H3 ; Key:CFJMRBQWBDQYMK-UHFFFAOYSA-N ;
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