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Antihistamine drug
Astemizole (marketed under the brand name Hismanal , developmental code R43512) was a second-generation
antihistamine drug that has a long duration of action. Astemizole was discovered by
Janssen Pharmaceutica in 1977. It was withdrawn from the market globally in 1999 because of rare but potentially fatal side effects (
QTc interval prolongation and related
arrhythmias due to
hERG channel blockade).
[2]
[3]
Pharmacology
Astemizole is a histamine
H1-receptor antagonist . It has
anticholinergic and
antipruritic effects.
Astemizole is rapidly absorbed from the gastrointestinal tract and 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
[4]
[5] 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 ).
[6]
Astemizole has been researched as a treatment for
Creutzfeldt-Jakob Disease (CJD).
[7]
Toxicity
Astemizole has an oral
LD50 of approximately 2052 mg/kg (in mice).
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): 133–142.
doi :
10.1046/j.1365-2125.2001.01292.x .
PMC
2014443 .
PMID
11259984 .
^ 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". Journal of Cardiovascular Electrophysiology . 10 (6): 836–843.
doi :
10.1111/j.1540-8167.1999.tb00264.x .
PMID
10376921 .
S2CID
25655101 .
^ Charles O, Onakpoya I, Benipal S, Woods H, Bali A, Aronson JK, et al. (2019).
"Withdrawn medicines included in the essential medicines lists of 136 countries" . PLOS ONE . 14 (12): e0225429.
Bibcode :
2019PLoSO..1425429C .
doi :
10.1371/journal.pone.0225429 .
PMC
6887519 .
PMID
31791048 .
^ Rojo LE, Alzate-Morales J, Saavedra IN, Davies P, Maccioni RB (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 . 19 (2). IOS Press: 573–589.
doi :
10.3233/JAD-2010-1262 .
PMC
2951486 .
PMID
20110603 .
^ Di L, Kerns EH, Fan K, McConnell OJ, Carter GT (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 .
PMID
12667689 .
^ Kornhuber J, Muehlbacher M, Trapp S, Pechmann S, Friedl A, Reichel M, et al. (2011).
"Identification of novel functional inhibitors of acid sphingomyelinase" . PLOS ONE . 6 (8): e23852.
Bibcode :
2011PLoSO...623852K .
doi :
10.1371/journal.pone.0023852 .
PMC
3166082 .
PMID
21909365 .
^ Karapetyan YE, Sferrazza GF, Zhou M, Ottenberg G, Spicer T, Chase P, et al. (April 2013).
"Unique drug screening approach for prion diseases identifies tacrolimus and astemizole as antiprion agents" . Proceedings of the National Academy of Sciences of the United States of America . 110 (17): 7044–7049.
Bibcode :
2013PNAS..110.7044K .
doi :
10.1073/pnas.1303510110 .
PMC
3637718 .
PMID
23576755 .
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