Agents and Actions

, Volume 28, Issue 1–2, pp 53–61 | Cite as

Rocastine (AHR-11325), a rapid acting, nonsedating antihistamine

  • J. C. Nolan
  • D. J. Stephens
  • A. G. Proakis
  • C. A. Leonard
  • D. N. Johnson
  • B. F. Kilpatrick
  • M. H. Foxwell
  • J. M. Yanni
Allergy, Histamine and Kinins

Abstract

Rocastine [AHR-11325, 2-[2-(dimethylamino)ethyl]-2,3-dihydro-4-methylpyrido-[3,2-f]-1,4-oxazepine-5(4H)-thione (E)-2-butenedioate)] is a rapid-acting, potent, nonsedating antihistamine. In guinea pigs challenged with a lethal dose of histamine, rocastine is as effective [based on 1 hr. oral, protective dose (PD50s)] as brompheniramine, chlorpheniramine, pyrilamine, and promethazine and superior to astemizole, diphenhydramine, terfenadine, and oxaomide. Rocastine has a faster onset of action than does terfenadine; rocastine being as effective with a 15 min pretreatment time (PD50=0.13 mg/kg) as it is with a 1 hr pretreatment time (PD50=0.12 mg/kg), while the 15 min PD50 of terfenadine (PD50=44.0 mg/kg) is 22 times greater than the 1 hr PD50 (PD50=1.93 mg/kg). Against aerosolized histamine, rocastine was 7.12×, 2.63×, and equipotent to pyrilamine in preventing histamine-induced prostration at pretreatment times of 1, 3, and 6 hr, respectively. Rocastine protected guinea pigs from collapse induced by aerosolized antigen; rocastine was ∼36 × more potent (based on 1 hr PD50) than diphenhydramine and as potent as oxatomide and terfenadine. Rocastine did not alter the EEG of cats at doses in vast excess (150×) of its antihistaminic dose nor did it potentiate yohimbine toxicity in mice. Further, rocastine possesses no anticholinergic, antiadrenergic, or antiserotonergic propertiesin vitro. Rocastine is a selective, nonsedating, H1-antagonist with a rapid onset of action.

Keywords

Terfenadine Yohimbine Diphenhydramine Astemizole Promethazine 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. [1]
    A. Nicholson and B. Stone,Antihistamines: impaired performance and the tendency to sleep. Eur. J. Pharmacol.30, 27–32 (1986).Google Scholar
  2. [2]
    T. Roehrs, E. Tietz, F. Zorick and T. Roth,Daytime sleepiness and antihistamines. Sleep7(2), 137–141 (1984).PubMedGoogle Scholar
  3. [3]
    A. Nicholson,New antihistamines free of sedative side effects. Tips8, 247–249 (1987).Google Scholar
  4. [4]
    A. Barnett, L. Iorio, W. Kreutner, S. Tozzi, H. Ahn and A. Gulbenkian,Evaluation of the CNS properties of SCH 29851, a potential nonsedating antihistamine. Agents and Actions14(5/6), 590–597 (1984).PubMedGoogle Scholar
  5. [5]
    A. Ahn and A. Barnett,Selective displacement of [3H]mepyramine from peripheral vs. central nervous system receptors by loratadine. Eur. J. Pharmacol.127, 153–155 (1986).PubMedGoogle Scholar
  6. [6]
    N. Weich and J. Martin,Absence of an effect of terfenadine on guinea pig brain histamine H 1-receptors in vivo determined by receptor binding techniques. Arzneim.-Forsch./Drug Res.32(11) 1167–1170 (1982).Google Scholar
  7. [7]
    C. Calcutt, C. Ganellin, B. Jackson, B. Leigh, D. Owen and I. Smith,Evidence for low brain penetration by the H 1-receptor antagonist temelastine (SK & F 93944). Eur. J. Pharmacol.133, 67–74 (1987).Google Scholar
  8. [8]
    E. Brown, R. Griffiths, C. Harvey and D. Owen,Pharmacological studies with SK&F 93944 (temelastine), a novel histamine H 1-receptor antagonist with negligible ability to penetrate the central nervous system. Br. J. Pharmac.87, 569–578 (1986).Google Scholar
  9. [9]
    J. Van Wauwe, F. Awouters, C. Neimegeers, F. Janssens, J. Vannueten and P. Janssen,In vivo pharmacology of astemizole, a new type of H 1-antihistaminic compound. Arch. Int. Pharmacodyn.251, 39–51 (1981).PubMedGoogle Scholar
  10. [10]
    C. Faingold and C. Berry,Effects of antihistamine agents upon the electrographic activity of the cat brain: a power spectral density study. Neuropharmacology11, 491–498 (1972).PubMedGoogle Scholar
  11. [11]
    R. Ruckart and D. Johnson,Effects of antihistaminic agents on sleep patterns in cats: A new method for detecting sedative potential. Pharmacologist25 (Abstract) 180 (1983).Google Scholar
  12. [12]
    G. Bruce, R. Tabor, M. Haimes-Bartolf and W. Kinner,Effect of AHR-11325 on lung and brain histamine receptors. Pharmacologist26 (Abstract), 97 (1984).Google Scholar
  13. [13]
    R. Ruckart, B. Turley, S. Erdle and D. Johnson,CNS effects of AHR-11325, a new nonsedative antihistamine. Pharmacologist26 (Abstract), 222 (1984).Google Scholar
  14. [14]
    C. Leonard, C. Jackson, D. Stephens, A. Proakis, R. Alphin,AHR-11325, a new antihistamine agent. Pharmacologist26 (Abstract), 221 (1984).Google Scholar
  15. [15]
    P. Anderson and H. Bergstrand,Antigen-induced bronchial anaphylaxis in actively sensitized guinea pigs: effect of longterm treatment with sodium cromoglycate and aminophylline. Br. J. Pharmacol.74, 601–609 (1981).PubMedGoogle Scholar
  16. [16]
    R. Quinton,The increase in toxicity of yohimbine induced by imipramine and other drugs in mice. Br. J. Pharmacol.21, 51–66 (1963).PubMedGoogle Scholar
  17. [17]
    J. Malick,Yohimbine potentiation as a predictor of antidepressant action. In:Antidepressants: neurochemical, behavioral and clinical perspectives. Raven Press, New York (1981).Google Scholar
  18. [18]
    J. Van Rossum,Cummulative dose-response curves. II. Techniques for the making of dose-response curves in isolated organs and the evaluation of drug parameters. Arch. int. Pharmacodyn.143, 229–330 (1963).Google Scholar
  19. [19]
    O. Arunlakshana and H. SchildSome quantitative uses of drug antagonists. Br. J. Pharmacol.14, 48–58 (1959).PubMedGoogle Scholar
  20. [20]
    R. Chang, V. Tran and S. Snyder,Histamine H 1-receptors in brain labeled with 3-H-mepyramine. Eur. J. Pharmacol.48, 463–464 (1978).PubMedGoogle Scholar
  21. [21]
    W. Clarke, L. Jones and R. Lefkowitz,Hepatic alphadrenergic receptors. J. Biol. Chem.253(17), 5975–5979 (1978).PubMedGoogle Scholar
  22. [22]
    H. Yamamura and S. Snyder,Muscarinic cholinergic binding in rat brain. PNAS, USA,71, 1725–1729 (1974).Google Scholar
  23. [23]
    J. Leysen, J. Niemegeers, J. Van Hueten and P. Laduron, [3H]Ketanserin (R 41 468), a selective 3 H-ligand for serotonin 2 receptor binding sites. Mol. Pharmacol.21, 301–314 (1982).PubMedGoogle Scholar
  24. [24]
    J. Lundeen,Computer analysis of binding data. InReceptor binding in drug research. Ed. by R.A. O'Brien, Dekker NY, 31–49 (1986).Google Scholar
  25. [25]
    C. Perrier, M. Griessen,Action of H 1 and H2 inhibitors on the response of histamine sensitive adenylate cyclase from guineapig mucosa. Eur. J. Clin. Invest.6, 113–120 (1976).PubMedGoogle Scholar
  26. [26]
    A. Gilman,A protein binding assay for adenosine 3′, 5′-monophosphate. PNAS, USA,67, 305–312 (1970).Google Scholar
  27. [27]
    J. Litchfield and F. Wilcoxon,A simplified method for evaluating dose-effect experiments. J. Pharmac. Exp. Ther.96, 99–113 (1949).Google Scholar
  28. [28]
    H. Collier and G. James,Humoral factors affecting pulmonary inflation during acute anaphylaxis in the guinea pig in vivo. Br. J. Pharmacol. Chemother.30, 283–301 (1967).Google Scholar
  29. [29]
    S. Tozzi, F. Roth and I. Tabachnick,The pharmacology of azatadine, a potential antiallergy drug. Agents Actions4(4), 264–270 (1974).PubMedGoogle Scholar
  30. [30]
    D. Richards, R. Brogden, R. Heel, t. Speight and G. Avery,Astemizole a review of its pharmacodynamic properties and therapeutic efficacy. Drugs28, 38–61 (1984a).PubMedGoogle Scholar
  31. [31]
    W. Kreutner, R. Chapman, A. Gulbenkian, M. Siegel,Antiallergic activity of loratadine, a nonsedating antihistamine. Allergy42, 57–63 (1987).PubMedGoogle Scholar
  32. [32]
    J. Van Neuten, R. Xhonneux and P. Janssen,Preliminary data on antiseratonin effects of oxatomide, a novel antiallergic compound Arch. int. Pharmacodyn.232, 217–220 (1978).PubMedGoogle Scholar
  33. [33]
    H. Cheng and J. Woodward,Antihistaminc effect of terfenadine: a new piperidine-type antihistamine. Drug Dev. Res.2, 181–196 (1982).Google Scholar
  34. [34]
    D. Richards, R. Brogden, R. Heel, T. Speight and G. Avery,Oxatomide a review of its pharmacodynamic properties and therapeutic efficacy. Drugs27, 210–231 (1984b).PubMedGoogle Scholar
  35. [35]
    F. Awouters, C. Niemegeers, P. Janssen, M. Janssen, J. Van Denberk, L. Kennis, M. Van Der Aa and A. Van Heertum,Oxatomide: the prototype of a chemical series of compounds inhibiting both the release and the effects of allergic mediators. ACS Symposium Series118, 179–208 (1979).Google Scholar
  36. [36]
    C. Carter, N. Wojciechowski, J. Hayes, V. Skoutakis and L. Rickman,Terfenadine, a nonsedating antihistamine. Drug. Intell. Clin. Phar.19, 812–817 (1985).Google Scholar

Copyright information

© Birkhäuser Verlag 1989

Authors and Affiliations

  • J. C. Nolan
    • 1
  • D. J. Stephens
    • 1
  • A. G. Proakis
    • 1
  • C. A. Leonard
    • 1
  • D. N. Johnson
    • 1
  • B. F. Kilpatrick
    • 1
  • M. H. Foxwell
    • 1
  • J. M. Yanni
    • 1
  1. 1.Pharmacology DepartmentA.H. Robins Co.RichmondUSA

Personalised recommendations