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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2012/11/12 19:45:35」(JST)

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Astemizole (R43512, marketed under the brand name Hismanal) was a second-generation antihistamine drug that has a long duration of action. Astemizole was discovered by Janssen Pharmaceutica in 1977. It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias).

Metabolism

It is metabolized by CYP3A4.^[1]

It has been withdrawn from the market in most countries because of rare but potentially fatal interactions with CYP3A4 enzyme inhibitors (e.g. erythromycin, grapefruit juice).

Pharmacology

Astemizole is a histamine H1-receptor antagonist. It is structurally similar to terfenadine and haloperidol (a butyrophenone antipsychotic). It has anticholinergic and antipruritic effects.

Astemizole competitively binds to histamine H1-receptor sites in the gastrointestinal tract, uterus, blood vessels, and bronchial muscle. This suppresses the formation of edema and pruritus (caused by histamine).

Astemizole does not cross the blood–brain barrier, and H1 receptor binding is mostly in the peripheral rather than central nervous system (CNS depression is thus minimal). Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.

Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase).^[2]

Astemizole is rapidly absorbed from the gastrointestinal tract; protein binding is around 96 percent.

Astemizole may cause life-threatening arrhythmia.

Toxicity

Astemizole has an oral LD₅₀ of approximately 2052 mg/kg (in mice).

Research

It has been reported that this drug might prevent much of the muscle wasting (atrophy) that occurs in immobile, bedridden patients.^[3] An experiment on a small number of mice showed that astemizole blocked the activity of a protein present in muscle that is involved in muscle atrophy.^[4] However, the concerns for the drug's long-term effects on the heart preclude its routine use in humans for this indication.

Astemizole has recently been found to be a potent treatment for malaria. It has a mechanism of action similar to chloroquine but has activity even in chloroquine-resistant parasites.^[5]

External links

Statement on Astemizole from Health Canada

References

^ Matsumoto S, Yamazoe Y (February 2001). "Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine". British Journal of Clinical Pharmacology 51 (2): 133–42. PMC 2014443. PMID 11259984. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0306-5251&date=2001&volume=51&issue=2&spage=133.
^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852.
^ "Purdue researchers find 'switch' for skeletal-muscle atrophy". Purdue University. 2006-05-24. http://news.uns.purdue.edu/html4ever/2006/060524.Pond.atrophy.html. Retrieved 2009-06-22.
^ Wang X, Hockerman GH, Green Iii HW, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL (May24 2006). "Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway". FASEB J 20 (9): 1531–3. doi:10.1096/fj.05-5350fje. PMID 16723379.
^ Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ (2006). "A clinical drug library screen identifies astemizole as an antimalarial agent". Nat Chem Biol 2 (8): 415–16. doi:10.1038/nchembio806. PMID 16816845.

UpToDate Contents

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English Journal

Human ether à-gogo K(+) channel 1 (hEag1) regulates MDA-MB-231 breast cancer cell migration through Orai1-dependent calcium entry.

Hammadi M, Chopin V, Matifat F, Dhennin-Duthille I, Chasseraud M, Sevestre H, Ouadid-Ahidouch H.SourceLaboratoire de Physiologie Cellulaire, JE 2530, UFR Sciences, 33 rue Saint-Leu, Université de Picardie Jules Verne, Amiens, France.
Journal of cellular physiology.J Cell Physiol.2012 Dec;227(12):3837-46. doi: 10.1002/jcp.24095.
Breast cancer (BC) has a poor prognosis due to its strong metastatic ability. Accumulating data present ether à go-go (hEag1) K(+) channels as relevant player in controlling cell cycle and proliferation of non-invasive BC cells. However, the role of hEag1 in invasive BC cells migration is still un
PMID 22495877

Tuning of EAG K+ channel inactivation: Molecular determinants of amplification by mutations and a small molecule.

Garg V, Sachse FB, Sanguinetti MC.SourceDepartment of Physiology, 2 Department of Bioengineering, and 3 Nora Eccles Harrison Cardiovascular Research and Training Institute, University of Utah, Salt Lake City, UT 84112.
The Journal of general physiology.J Gen Physiol.2012 Sep;140(3):307-24.
Ether-à-go-go (EAG) and EAG-related gene (ERG) K(+) channels are close homologues but differ markedly in their gating properties. ERG1 channels are characterized by rapid and extensive C-type inactivation, whereas mammalian EAG1 channels were previously considered noninactivating. Here, we show tha
PMID 22930803

Japanese Journal

Genetic deficiency of carnitine/organic cation transporter 2 (slc22a5) is associated with altered tissue distribution of its substrate pyrilamine in mice

Kato Sayaka,Kato Yukio,Nakamura Tadakatsu,Sugiura Tomoko,Kubo Yoshiyuki,Deguchi Yoshiharu,Tsuji Akira
Biopharmaceutics and Drug Disposition 30(9), 495-507, 2009-10
… The renal uptake of pyrilamine was saturable (K m∼236 μM) and was strongly inhibited by cyproheptadine, astemizole, ebastine and terfenadine. …
NAID 120001856982

Prediction of drug-induced QT interval prolongation in telemetered common marmosets

Tabo Mitsuyasu,Hara Toshiko,Sone Sachiko,Shishido Nobuyuki,Kuramoto Shino,Nakano Kounosuke,Onodera Hideko,Kimura Kazuya,Kobayashi Kazuko
Journal of toxicological sciences 33(3), 315-325, 2008-08-01
… With the individual correction method, the QT-prolonging drugs (astemizole, dl-sotalol) showed QTc interval prolongations and the non-QT-prolonging drugs (dl-propranolol, nifedipine) did not show QTc interval prolongations. … The plasma concentrations of astemizole and dl-sotalol associated with QTc interval prolongations in common marmosets were similar to those in humans, suggesting that the sensitivity of common marmosets would be appropriate for evaluating risk of drug-induced QT interval prolongation. …
NAID 110006862208

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Astemizole
Systematic (IUPAC) name
	1-[(4-fluorophenyl)methyl]- N-[1-[2-(4-methoxyphenyl)ethyl]- 4-piperidyl]benzoimidazol-2-amine
Clinical data
AHFS/Drugs.com	Multum Consumer Information
MedlinePlus	a600034
Pregnancy cat.	C (USA)
Legal status	Unscheduled
Routes	Oral
Pharmacokinetic data
Bioavailability	?
Metabolism	Hepatic
Half-life	24 hours
Excretion	Fecal
Identifiers
CAS number	68844-77-9
ATC code	R06AX11
PubChem	CID 2247
IUPHAR ligand	2603
DrugBank	DB00637
ChemSpider	2160
UNII	7HU6337315
KEGG	D00234
ChEBI	CHEBI:2896
ChEMBL	CHEMBL296419
Chemical data
Formula	C28H31FN4O
Mol. mass	458.571
	SMILES Fc1ccc(cc1)Cn2c5ccccc5nc2NC4CCN(CCc3ccc(OC)cc3)CC4;
	InChI InChI=1S/C28H31FN4O/c1-34-25-12-8-21(9-13-25)14-17-32-18-15-24(16-19-32)30-28-31-26-4-2-3-5-27(26)33(28)20-22-6-10-23(29)11-7-22/h2-13,24H,14-20H2,1H3,(H,30,31) ; Key:GXDALQBWZGODGZ-UHFFFAOYSA-N ;
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英: astemizole
商: Hismanal

[pmid11259984-1] Matsumoto S, Yamazoe Y (February 2001). "Involvement of multiple human cytochromes P450 in the liver microsomal metabolism of astemizole and a comparison with terfenadine". British Journal of Clinical Pharmacology 51 (2): 133–42. PMC 2014443. PMID 11259984. http://www.blackwell-synergy.com/openurl?genre=article&sid=nlm:pubmed&issn=0306-5251&date=2001&volume=51&issue=2&spage=133.

[pmid18504571-2] Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, Mühle C, Terfloth L, Groemer T, Spitzer G, Liedl K, Gulbins E, Tripal P (2011). "Identification of novel functional inhibitors of acid sphingomyelinase". PLoS ONE 6 (8): e23852. doi:10.1371/journal.pone.0023852.

[PU2006-3] "Purdue researchers find 'switch' for skeletal-muscle atrophy". Purdue University. 2006-05-24. http://news.uns.purdue.edu/html4ever/2006/060524.Pond.atrophy.html. Retrieved 2009-06-22.

[FASEBJ2006-Wang-4] Wang X, Hockerman GH, Green Iii HW, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL (May24 2006). "Merg1a K+ channel induces skeletal muscle atrophy by activating the ubiquitin proteasome pathway". FASEB J 20 (9): 1531–3. doi:10.1096/fj.05-5350fje. PMID 16723379.

[5] Chong CR, Chen X, Shi L, Liu JO, Sullivan DJ (2006). "A clinical drug library screen identifies astemizole as an antimalarial agent". Nat Chem Biol 2 (8): 415–16. doi:10.1038/nchembio806. PMID 16816845.

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astemizole