Astemizole

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Astemizole
Astemizole.png
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 YesY
ATC code R06AX11
PubChem CID 2247
IUPHAR ligand 2603
DrugBank DB00637
ChemSpider 2160 YesY
UNII 7HU6337315 YesY
KEGG D00234 YesY
ChEBI CHEBI:2896 YesY
ChEMBL CHEMBL296419 YesY
Chemical data
Formula C28H31FN4O 
Mol. mass 458.571 g/mol
 YesY (what is this?)  (verify)

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 It has been withdrawn from the market in most countries because of rare but potentially fatal side effects (QTc interval prolongation and related arrhythmias due to hERG channel blockade).[1]

Metabolism[edit]

It is metabolized by CYP3A4.[2]

Pharmacology[edit]

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).

Despite some earlier reports that Astemizole does not cross the blood–brain barrier, several studies[3][4] have shown high permeability and high binding to protein folds associated with Alzheimer's.

Astemizole may also act on histamine H3 receptors, thereby producing adverse effects.[citation needed]

Astemizole does also act as FIASMA (functional inhibitor of acid sphingomyelinase).[5]

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

Astemizole may cause life-threatening arrhythmia.

Toxicity[edit]

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

Research[edit]

It has been reported that this drug might prevent much of the muscle wasting (atrophy) that occurs in immobile, bedridden patients.[6] 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.[7] 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.[8]

Astemizole has been found to have anti prion activity, and might be a treatment for AIDs.[9]

References[edit]

  1. ^ Zhou Z, Vorperian VR, Gong Q, Zhang S, January CT (June 1999). "Block of HERG potassium channels by the antihistamine astemizole and its metabolites desmethylastemizole and norastemizole". J. Cardiovasc. Electrophysiol. 10 (6): 836–43. doi:10.1111/j.1540-8167.1999.tb00264.x. PMID 10376921. 
  2. ^ 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. doi:10.1046/j.1365-2125.2001.01292.x. PMC 2014443. PMID 11259984. 
  3. ^ Rojo, Leonel E.; Alzate-Morales, Jans; Saavedra, Iván N.; Davies, Peter; Maccioni, Ricardo B. (2010). "Selective Interaction of Lansoprazole and Astemizole with Tau Polymers: Potential New Clinical Use in Diagnosis of Alzheimer's Disease". Journal of Alzheimer's Disease (IOS Press) 19 (2): 573–589. doi:10.3233/JAD-2010-1262. ISSN 1875-8908. PMC 2951486. Retrieved April 26, 2013. 
  4. ^ Di, Li; Kerns, Edward H; Fan, Kristi; McConnell, Oliver J; Carter, Guy T (7 March 2003). "High throughput artificial membrane permeability assay for blood–brain barrier". European Journal of Medicinal Chemistry 38 (3): 223–232. doi:10.1016/S0223-5234(03)00012-6. 
  5. ^ 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. PMC 3166082. PMID 21909365. 
  6. ^ "Purdue researchers find 'switch' for skeletal-muscle atrophy". Purdue University. 2006-05-24. Retrieved 2009-06-22. 
  7. ^ Wang X, Hockerman GH, Green Iii HW, Babbs CF, Mohammad SI, Gerrard D, Latour MA, London B, Hannon KM, Pond AL (May 24, 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. 
  8. ^ 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. 
  9. ^ http://www.scripps.edu/news/press/2013/20130403lasmezas.html

External links[edit]