Abstract
SK&F 93944 (temelastine), a novel histamine H1-receptor antagonist, has been studied in a variety of in vitro and in vivo test systems. SK&F 93944 was a competitive antagonist of histamine-induced contractions of guinea-pig ileum with a pA2 of 9.55 and a weak, non-competitive, inhibitor of the effects of histamine on guinea-pig atrium. In anaesthetized guinea-pigs SK&F 93944 displaced histamine bronchoconstriction dose-response curves at doses which had negligible effects on histamine tachycardia. In anaesthetized cats SK&F 93944 antagonized depressor responses to the histamine H1-receptor agonists, 2-(2-aminoethyl)pyridine and betahistine, at doses which had no effects on responses to the histamine H2-receptor agonist, dimaprit. Oral pretreatment with SK&F 93944 in conscious rats and guinea-pigs afforded protection versus the response to intradermal histamine injection. Comparative studies in each of the test systems showed that SK&F 93944 was of comparable or significantly greater potency than the standard compound, mepyramine. SK&F 93944 was found to be a weak, non-competitive antagonist of carbachol on the guinea-pig ileum but was devoid of measurable anticholinergic activity in vivo. Studies on the penetration of [14C]-SK&F 93944, labelled either in the isocytosine ring or in the butyl chain, showed that brain concentrations were very low when compared with the steady-state blood concentrations. In contrast, brain concentrations of [3H]-mepyramine exceeded blood concentrations by a factor of approximately 3. SK&F 93944 may have an advantage over classical histamine H1-receptor antagonists in that it is likely to be devoid of untoward effects on the central nervous system.
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- EBAUGH F. G., Jr, EMERSON C. P., ROSS J. F. The use of radioactive chromium 51 as an erythrocyte tagging agent for the determination or red cell survival in vivo. J Clin Invest. 1953 Dec;32(12):1260–1276. doi: 10.1172/JCI102855. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Harvey C. A., Owen D. A. Cardiovascular studies with SK&F 93319, an antagonist of histamine at both H1- and H2-receptors. Br J Pharmacol. 1984 Oct;83(2):427–432. doi: 10.1111/j.1476-5381.1984.tb16503.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Le Fur G., Malgouris C., Uzan A. Effect of mequitazine a non sedative antihistamine on brain H1 receptors. Life Sci. 1981 Aug 10;29(6):547–552. doi: 10.1016/0024-3205(81)90432-x. [DOI] [PubMed] [Google Scholar]
- Owen D. A., Pipkin M. A. A simple technique to simultaneously assess activity at histamine H1- and H2-receptors in vivo. J Pharmacol Methods. 1985 Jul;13(4):309–315. doi: 10.1016/0160-5402(85)90012-9. [DOI] [PubMed] [Google Scholar]
- Owen D. A., Pipkin M. A., Woodward D. F. Studies on cutaneous vascular permeability in the rat: increases caused by histamine and histamine-like agents. Agents Actions. 1984 Jan;14(1):39–42. doi: 10.1007/BF01966830. [DOI] [PubMed] [Google Scholar]
- Owen D. A. The effects of histamine and some histamine-like agonists on blood pressure in the cat. Br J Pharmacol. 1975 Oct;55(2):173–179. doi: 10.1111/j.1476-5381.1975.tb07626.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Tozzi S., Roth F. E., Tabachnick I. I. The pharmacology of azatadine, a potential antiallergy drug. Agents Actions. 1974 Oct;4(4):264–270. doi: 10.1007/BF01965229. [DOI] [PubMed] [Google Scholar]
- Van Wauwe J., Awouters F., Neimegeers C. J., Janssens F., Van Nueten J. M., Janssen P. A. In vivo pharmacology of astemizole, a new type of H1-antihistaminic compound. Arch Int Pharmacodyn Ther. 1981 May;251(1):39–51. [PubMed] [Google Scholar]