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01.03.2008 | Original Research Article

Preclinical Efficacy and Safety Pharmacology of SUN-1334H, a Potent Orally Active Antihistamine Agent

verfasst von: Dr Sanjay N. Mandhane, Upendra B. Ayer, Ajay S. Midha, Chitturi Trinadha Rao, Thennati Rajamannar

Erschienen in: Drugs in R&D | Ausgabe 2/2008

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Abstract

Methods: In vitro antihistamine activity and selectivity of SUN-1334H was evaluated in a panel of receptor and enzyme assays and functional assays using isolated tissues. In vivo antihistamine and antiallergy efficacy were assessed following oral administration of SUN-1334H in histamine-induced bronchoconstriction in guinea pigs, skin wheal in beagle dogs and ovalbumin-induced rhinitis (sneezing, vascular permeability and intranasal pressure) in guinea pigs. Cardiovascular safety was assessed by CHO-K1/human ether-à-go-go related gene (hERG) K+ current assay, dog telemetry and guinea-pig ECG. CNS safety was assessed by functional observational battery in rats and pentobarbital-induced sedation and pentylenetetrazol-induced convulsions in mice. The effect on intestinal motility was assessed in rats.

Results: In vitro receptor binding assays showed that SUN-1334H had high histamine H₁ receptor binding affinity with an inhibition constant value of 9.7 nmol/L and either no or insignificant affinity with a panel of receptors and enzymes. In functional assays, SUN-1334H caused potent inhibition of histamineinduced contractions of isolated guinea-pig ileum with an IC₅₀ (half the maximal inhibitory concentration) of 0.198 μmol/L. In contrast, SUN-1334H had no significant effect on isolated tissue contractions induced by cholinergic, H₂-histaminergic, serotonergic, adrenergic receptor agonists or BaCl₂. In studies of animal models of histamine-mediated disorders, SUN-1334H potently inhibited histamine-induced bronchospasm over 24 hours following oral administration and completely suppressed histamine-induced skin wheal in beagle dogs and ovalbumin-induced rhinitis in guinea pigs. In CHO-K1/hERG cells, SUN-1334H did not modulate hERG K+-currents at concentrations as high as 100 μmol/L. Cardiovascular and CNS function and intestinal motility were not altered at doses several-fold greater than those required for efficacy, indicating a good safety profile of the drug.

Conclusions: SUN-1334H is a potent, orally active, highly selective H₁ receptor antagonist with a long duration of action in its preclinical profile. It has potential for the treatment of disorders involving histamine as a mediator.

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Titel: Preclinical Efficacy and Safety Pharmacology of SUN-1334H, a Potent Orally Active Antihistamine Agent
verfasst von: Dr Sanjay N. Mandhane
Upendra B. Ayer
Ajay S. Midha
Chitturi Trinadha Rao
Thennati Rajamannar
Publikationsdatum: 01.03.2008
Verlag: Springer International Publishing
Erschienen in: Drugs in R&D / Ausgabe 2/2008
Print ISSN: 1174-5886
Elektronische ISSN: 1179-6901
DOI: https://doi.org/10.2165/00126839-200809020-00004

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Preclinical Efficacy and Safety Pharmacology of SUN-1334H, a Potent Orally Active Antihistamine Agent

Abstract

Live-Webinar "Urologie und Sexualmedizin in der Praxis"

Springer Medizin

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