Advertisement

Clinical Pharmacokinetics

, Volume 36, Issue 5, pp 329–352 | Cite as

Clinical Pharmacology of New Histamine H1 Receptor Antagonists

  • F. Estelle R. SimonsEmail author
  • Keith J. Simons
Review Article Pharmacokinetic-Pharmacodynamic Relationships

Abstract

The recently introduced H1 receptor antagonists ebastine, fexofenadine and mizolastine, and the relatively new H1 antagonists acrivastine, astemizole, azelastine, cetirizine, levocabastine and loratadine, are diverse in terms of chemical structure and clinical pharmacology, although they have similar efficacy in the treatment of patients with allergic disorders.

Acrivastine is characterised by a short terminal elimination half-life (t1/2,β) [1.7 hours] and an 8-hour duration of action. Astemizole and its metabolites, in contrast, have relatively long terminal t1/2,β values; astemizole has a duration of action of at least 24 hours and is characterised by a long-lasting residual action after a short course of treatment. Azelastine, which has a half-life of approximately 22 hours, is primarily administered intranasally although an oral dosage formulation is used in some countries.

Cetirizine is eliminated largely unchanged in the urine, has a terminal t1/2,β of ∼7 hours and a duration of action of at least 24 hours. Ebastine is extensively and rapidly metabolised to its active metabolite; carebastine, has a half-life of ∼15 hours and duration of action of at least 24 hours. Fexofenadine, eliminated largely unchanged in the faeces and urine, has a terminal t1/2,β of ∼14 hours and duration of action of 24 hours, making it suitable for once or twice daily administration.

Levocabastine has a terminal t1/2,β of 35 to 40 hours regardless of the route of administration, but is only available as a topical application administered intranasally or ophthalmically in patients with allergic rhinoconjunctivitis. Loratadine is rapidly metabolised to an active metabolite descarboethoxyloratadine and has a 24-hour duration of action. Mizolastine has a terminal t1/2,β of ∼13 hours and duration of action of at least 24 hours.

Most orally administered new H1 receptor antagonists are well absorbed and appear to be extensively distributed into body tissues; many are highly protein-bound. Most of the new H1 antagonists do not accumulate in tissues during repeated administration and have a residual action of less than 3 days after a short course has been completed. Tachyphylaxis, or loss of peripheral H1 receptor blocking activity during regular daily use, has not been found for any new H1 antagonist.

Understanding the pharmacokinetics and pharmacodynamics of these new H1 antagonists provides the objective basis for selection of an appropriate dose and dosage interval and the rationale for modification in the dosage regimen that may be needed in special populations, including elderly patients, and those with hepatic dysfunction or renal dysfunction. The studies cited in this review provide the scientific foundation for using the new H1 antagonists with optimal effectiveness and safety.

Keywords

Adis International Limited Allergy Clin Immunol Terfenadine Cetirizine Loratadine 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Simons FER, Simons KJ. The pharmacology and use of H1 receptor antagonist drugs. N Engl J Med. 1994; 330: 1663–70.PubMedCrossRefGoogle Scholar
  2. 2.
    Simons FER. Antihistamines. In: Middleton Jr E, Reed CE, Ellis EF, et al., editors. Allergy principles and practice. St Louis: Mosby-Year Book, Inc., 1998: 612–37.Google Scholar
  3. 3.
    Chauhan AJ, Holgate ST. Histamine receptors and antihistamines. In: Townley RG, Agrawal DK, editors. Immuno-pharmacology of allergic diseases. New York: Marcel Dekker, Inc., 1996: 605–38.Google Scholar
  4. 4.
    Simons FER. H1-receptor antagonists: comparative tolerability and safety. Drug Saf. 1994; 10: 350–80.PubMedCrossRefGoogle Scholar
  5. 5.
    Simons FER. The eternal triangle: benefit, risk, and cost of therapeutic agents. Ann Allergy Asthma Immunol. 1996; 77: 337–40.PubMedCrossRefGoogle Scholar
  6. 6.
    Simons KJ, Simons FER. H1-receptor antagonists: pharmacokinetics and clinical pharmacology. In: Simons FER, editor. Histamine and H1-receptor antagonists in allergic disease. New York: Marcel Dekker Inc., 1996: 175–213.Google Scholar
  7. 7.
    Desager J-P, Horsmans Y. Pharmacokinetic-pharmacodynamic relationships of H1-antihistamines. Clin Pharmacokinet. 1995; 28: 419–32.PubMedCrossRefGoogle Scholar
  8. 8.
    Woosley RL. Cardiac actions of antihistamines. Annu Rev Pharmacol Toxicol. 1996; 36: 233–52.PubMedCrossRefGoogle Scholar
  9. 9.
    Woosley RL, Chen Y, Freiman JP, et al. Mechanism of the cardiotoxic actions of terfenadine. JAMA. 1993; 269: 1532–6.PubMedCrossRefGoogle Scholar
  10. 10.
    Brogden RN, McTavish D. Acrivastine: a review of its pharmacological properties and therapeutic efficacy in allergic rhinitis, urticaria and related disorders. Drugs. 1991; 41: 927–40.PubMedCrossRefGoogle Scholar
  11. 11.
    Chang SY, Nelson FR, Findlay JWA, et al. Quantitative gas chromatographic-mass spectrometric analysis of acrivastine and a metabolite in human plasma. J Chromatogr. 1989; 497: 288–95.PubMedCrossRefGoogle Scholar
  12. 12.
    Cohen AF, Hamilton MJ, Liao SHT, et al. Pharmacodynamics and pharmacokinetics of BW 825C: a new antihistamine. Eur J Clin Pharmacol. 1985; 28: 197–204.PubMedCrossRefGoogle Scholar
  13. 13.
    Jallad NS, Garg DC, Fleck RJ, et al. Pharmacokinetics of acrivastine, a new H1-antagonist, following ascending doses. J Clin Pharmacol. 1985; 25: 629–37.Google Scholar
  14. 14.
    Balasubramanian R, Klein KB, Pittman AW, et al. Pharmacokinetics of acrivastine after oral and colonic administration. J Clin Pharmacol. 1989; 29: 444–7.PubMedGoogle Scholar
  15. 15.
    Liao SHT, Fleck RJ, Blum MR, et al. Clinical pharmacokinetics and safety of acrivastine with pseudoephedrine in geriatric volunteers [abstract]. J Pharm Sci. 1987; 76: S113.Google Scholar
  16. 16.
    Hamilton MJ, Ashby L, Cohen AF, et al. A comparative study of acrivastine and terfenadine on histamine (Hi-receptor) antagonism in skin and central actions in man. Br J Clin Pharmacol. 1985; 20: 283P–4P.Google Scholar
  17. 17.
    Petersen LJ, Bindslev-Jensen C, Poulsen LK, et al. Time of onset of action of acrivastine in the skin of pollen-allergic subjects: a double-blind, randomized, placebo-controlled comparative study. Allergy. 1994; 49: 27–30.PubMedCrossRefGoogle Scholar
  18. 18.
    Lahti A, Haapaniemi T. Initiation of the effects of acrivastine and cetirizine on histamine-induced wheals and itch in human skin. Acta Derm Venereol (Stockh). 1993; 73: 350–1.Google Scholar
  19. 19.
    Rolan PE, Adams J, Posner J. Comparison of the onset of H1-antagonism with acrivastine and terfenadine by histamine bronchial challenge in volunteers. J Int Med Res. 1989; 17 Suppl. 2: 35B–9B.PubMedGoogle Scholar
  20. 20.
    Janssens MM-L. Astemizole: a nonsedating antihistamine with fast and sustained activity. Clin Rev Allergy. 1993; 11: 35–63.PubMedGoogle Scholar
  21. 21.
    Al-Deeb OA, Abdel-Moety EM, Bayomi SM, et al. Spectrophotometric quantification of astemizole and its demethylated metabolite in urine after TLC separation. Eur J Drug Metab Pharmacokinet. 1992; 17: 251–5.PubMedCrossRefGoogle Scholar
  22. 22.
    Mangalan S, Patel RB, Gandhi TP, et al. Detection and determination of free and plasma protein-bound astemizole by thinlayer chromatography: a useful technique for bioavailability studies. J Chromatogr. 1991; 567: 498–503.PubMedCrossRefGoogle Scholar
  23. 23.
    Meuldermans W, Hendrickx J, Lauwers W, et al. Excretion and biotransformation of astemizole in rats, guinea-pigs, dogs and man. Drug Develop Res. 1986; 8: 37–51.CrossRefGoogle Scholar
  24. 24.
    Heykants J, Van Peer A, Woestenborghs R, et al. Dose-proportionality, bioavailability, and steady-state kinetics of astemizole in man. Drug Dev Res. 1986; 8: 71–8.CrossRefGoogle Scholar
  25. 25.
    Laine K, Kivistö KT, Neuvonen PJ. The effect of activated charcoal on the absorption and elimination of astemizole. Human Exp Toxicol. 1994; 13: 502–5.CrossRefGoogle Scholar
  26. 26.
    Möller C, Andlin-Sobocki P, Blychert L-O. Pharmacokinetics of astemizole in children. Rhinology. 1992; 13: 21–5.Google Scholar
  27. 27.
    Zazgornik J, Scholz N, Heykants J, et al. Plasma concentrations of astemizole in patients with terminal renal insufficiency, before, during and after hemodialysis. Int J Clin Pharmacol Ther Toxicol. 1986; 24: 246–8.PubMedGoogle Scholar
  28. 28.
    Lavrijsen K, Van Houdt J, Meuldermans W, et al. The interaction of ketoconazole, itraconazole and erythromycin with the in vitro metabolism of antihistamines in human liver microsomes [abstract]. Allergy. 1993; 48: 34.Google Scholar
  29. 29.
    Holmes GB, Adams MA, Hunt TL, et al. Eighteen-week, steady-state astemizole/pseudoephedrine bioequivalency study [abstract]. Pharmacotherapy. 1991; 11: 109.Google Scholar
  30. 30.
    Lefebvre RA, Van Peer A, Woestenborghs R. Influence of itraconazole on the pharmacokinetics and electrocardiographic effects of astemizole. Br J Clin Pharmacol. 1997; 43: 319–22.PubMedCrossRefGoogle Scholar
  31. 31.
    Gendreau-Reid L, Simons KJ, Simons FER. Comparison of the suppressive effect of astemizole, terfenadine, and hydroxyzine on histamine-induced wheals and flares in humans. J Allergy Clin Immunol. 1986; 77: 335–40.PubMedCrossRefGoogle Scholar
  32. 32.
    Janssens MM-L, Caers LI. Onset of action of astemizole. Int J Clin Pharm Res. 1991; 11: 219–29.Google Scholar
  33. 33.
    Humphreys F, Hunter JAA. The effects of astemizole, cetirizine and loratadine on the time course of weal and flare reactions to histamine, codeine and antigen. Br JDermatol. 1991; 125: 364–7.CrossRefGoogle Scholar
  34. 34.
    Simons FER, McMillan JL, Simons KJ. A double-blind, single-dose, crossover comparison of cetirizine, terfenadine, loratadine, astemizole, and chlorpheniramine versus placebo: suppressive effects on histamine-induced wheals and flares during 24 hours in normal subjects. J Allergy Clin Immunol. 1990; 86: 540–7.PubMedCrossRefGoogle Scholar
  35. 35.
    Berkowitz RB, Dockhorn R, Lockey R, et al. Comparison of efficacy, safety, and skin test inhibition of cetirizine and astemizole. Ann Allergy Asthma Immunol. 1996; 76: 363–8.PubMedCrossRefGoogle Scholar
  36. 36.
    Simons FER, Watson WTA, Becker AB, et al. Histamine blockade after astemizole in children: a single-dose, placebo-controlled study. Pediatr Allergy Immunol. 1994; 5: 214–7.PubMedCrossRefGoogle Scholar
  37. 37.
    Lantin JP, Huguenot CH, Pécoud A. Effect of the H1-antagonist astemizole on the skin reactions induced by histamine, codeine and allergens. Curr Ther Res. 1990; 47: 683–92.Google Scholar
  38. 38.
    Day JH, Briscoe MP, Clark RH, et al. Onset of action and efficacy of terfenadine, astemizole, cetirizine, and loratadine for the relief of symptoms of allergic rhinitis. Ann Allergy Asthma Immunol. 1997; 79: 163–72.PubMedCrossRefGoogle Scholar
  39. 39.
    Howarth PH, Emanuel MB, Holgate ST. Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine-induced skin weal responses and relationship to serum levels. Br J Clin Pharmacol. 1984; 18: 1–8.PubMedCrossRefGoogle Scholar
  40. 40.
    Howarth PH, Holgate ST. Comparative trial of two non-sedative H1-antihistamines, terfenadine and astemizole, for hay fever. Thorax. 1984; 39: 668–72.PubMedCrossRefGoogle Scholar
  41. 41.
    Malo J-L, Fu CL, L’Archevêque J, et al. Duration of the effect of astemizole on histamine-inhalation tests. J Allergy Clin Immunol. 1990; 85: 729–36.PubMedCrossRefGoogle Scholar
  42. 42.
    Benoît C, Malo J-L, Ghezzo H, et al. Single-dose effect of astemizole on bronchoconstriction induced by histamine in asthmatic subjects. chest. 1992; 101: 1318–25.PubMedCrossRefGoogle Scholar
  43. 43.
    McNeely W, Wiseman LR. Intranasal azelastine: a review of its efficacy in the management of allergic rhinitis. Drugs. 1998; 56: 91–114.PubMedCrossRefGoogle Scholar
  44. 44.
    McTavish D, Sorkin EM. Azelastine: a review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential. Drugs. 1989; 38: 778–800.PubMedCrossRefGoogle Scholar
  45. 45.
    Pivonka J, Segelman FH, Hartman CA, et al. Determination of azelastine and desmethylazelastine in human plasma by high-performance liquid chromatography. J Chromatogr. 1987; 420: 89–98.PubMedCrossRefGoogle Scholar
  46. 46.
    Tatsumi K, Ou T, Yamada H, et al. Studies on metabolic fate of a new antiallergic agent, azelastine (4-(p-chlorobenzyl)-2-[N-methylperhydroazepinyl-(4)]-1-(2H)-phthalazinone hydrochloride). Jpn J Pharmacol. 1980; 30: 37–48.PubMedCrossRefGoogle Scholar
  47. 47.
    Weliky I, Howard JR, Wichmann JK. Absolute bioavailability and pharmacokinetics of azelastine [abstract]. Pharm Res. 1990; 7: S247.CrossRefGoogle Scholar
  48. 48.
    Riethmüller-Winzen H, Peter G, Büker KM, et al. Tolerability, pharmacokinetics and dose linearity of azelastine hydrochloride in healthy subjects. Arzneimittel Forschung Drug Res. 1994; 44: 1136–40.Google Scholar
  49. 49.
    Peter G, Romeis P, Borbe HO, et al. Tolerability and pharmacokinetics of single and multiple doses of azelastine hydrochloride in elderly volunteers. Arzneimittel Forschung Drug Res. 1995; 45: 576–81.Google Scholar
  50. 50.
    Morganroth J, Lyness WH, Perhach JL, et al. Lack of effect of azelastine and ketoconazole coadministration on electrocardiographic parameters in healthy volunteers. J Clin Pharmacol. 1997; 37: 1065–72.PubMedGoogle Scholar
  51. 51.
    Atkins P, Merton H, Karpink P, et al. Azelastine inhibition of skin test reactivity in humans [abstract]. J Allergy Clin Immunol. 1985; 75: 167.CrossRefGoogle Scholar
  52. 52.
    Greiff L, Andersson M, Svensson C, et al. Topical azelastine has a 12-hour duration of action as assessed by histamine challenge-induced exudation of α2-macroglobulin into human nasal airways. Clin Exp Allergy. 1997; 27: 438–44.PubMedCrossRefGoogle Scholar
  53. 53.
    Meltzer EO, Storms WW, Pierson WE, et al. Efficacy of azelastine in perennial allergic rhinitis: Clinical and rhinomanometric evaluation. J Allergy Clin Immunol. 1988; 82: 447–55.PubMedCrossRefGoogle Scholar
  54. 54.
    Rafferty P, Harrison PJ, Aurich R, et al. The in vivo potency and selectivity of azelastine as an H1 histamine-receptor antagonist in human airways and skin. J Allergy Clin Immunol. 1988; 82: 1113–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Wood-Baker R, Holgate ST. The comparative actions and adverse effect profile of single doses of H1-receptor antihistamines in the airways and skin of subjects with asthma. J Allergy Clin Immunol. 1993; 91: 1005–14.PubMedCrossRefGoogle Scholar
  56. 56.
    Albazzaz MK, Patel KR. Effect of azelastine on bronchoconstriction induced by histamine and leukotriene C4 in patients with extrinsic asthma. Thorax. 1988; 43: 306–11.PubMedCrossRefGoogle Scholar
  57. 57.
    Rafferty P, Ng WH, Phillips G, et al. The inhibitory actions of azelastine hydrochloride on the early and late bronchocon-strictor responses to inhaled allergen in atopic asthma. J Allergy Clin Immunol. 1989; 84: 649–57.PubMedCrossRefGoogle Scholar
  58. 58.
    Spencer CM, Faulds D, Peters DH. Cetirizine: a reappraisal of its pharmacological properties and therapeutic use in selected allergic disorders. Drugs. 1993; 46: 1055–80.PubMedCrossRefGoogle Scholar
  59. 59.
    Baltes E, Coupez R, Brouwers L, et al. Gas chromatographic method for the determination of cetirizine in plasma. J Chromatogr. 1988; 430: 149–55.PubMedCrossRefGoogle Scholar
  60. 60.
    Pandya KK, Bangaru RA, Gandhi TP, et al. High-performance thin-layer chromatography for the determination of cetirizine in human plasma and its use in pharmacokinetic studies. J Pharm Pharmacol. 1996; 48: 510–3.PubMedCrossRefGoogle Scholar
  61. 61.
    Wood SG, John BA, Chasseaud LF, et al. The metabolism and pharmacokinetics of 14C-cetirizine in humans. Ann Allergy. 1987; 59: 31–4.PubMedGoogle Scholar
  62. 62.
    Muscara MN, De Nucci G. Comparative bioavailability of single doses of tablet formulations of cetirizine dihydrochloride in healthy male volunteers. Int J Clin Pharmacol Ther. 1995; 33: 27–31.PubMedGoogle Scholar
  63. 63.
    Pagliara A, Testa B, Carrupt P-A, et al. Molecular properties and pharmacokinetic behaviour of cetirizine, a zwitterionic H1-receptor antagonist. J Med Chem. 1998; 41: 853–63.PubMedCrossRefGoogle Scholar
  64. 64.
    Watson WTA, Simons KJ, Chen XY, et al. Cetirizine: a pharmacokinetic and pharmacodynamic evaluation in children with seasonal allergic rhinitis. J Allergy Clin Immunol. 1989; 84: 457–64.PubMedCrossRefGoogle Scholar
  65. 65.
    Desager JP, Dab I, Horsmans Y, et al. A pharmacokinetic evaluation of the second-generation H1-receptor antagonist cetirizine in very young children. Clin Pharmacol Ther. 1993; 53: 431–5.PubMedCrossRefGoogle Scholar
  66. 66.
    Pariente-Khayat A, Rey E, Dubois MC, et al. Pharmacokinetics of cetirizine in 2- to 6-year-old children. Int J Clin Pharmacol Ther. 1995; 33: 340–4.PubMedGoogle Scholar
  67. 67.
    Spicak V, Dab I, Hulhoven R, et al. Pharmacokinetics and pharmacodynamics of cetirizine in infants and toddlers. Clin Pharmacol Ther. 1997; 61: 325–30.PubMedCrossRefGoogle Scholar
  68. 68.
    Lefebvre RA, Rosseel MT, Bernheim J. Single dose pharmacokinetics of cetirizine in young and elderly volunteers. Int J Clin Pharm Res. 1988; 8: 463–70.Google Scholar
  69. 69.
    Matzke GR, Yeh J, Awni WM, et al. Pharmacokinetics of cetirizine in the elderly and patients with renal insufficiency. Ann Allergy. 1987; 59: 25–30.PubMedGoogle Scholar
  70. 70.
    Simons FER, Watson WTA, Minuk GY, et al. Cetirizine pharmacokinetics and pharmacodynamics in primary biliary cirrhosis. J Clin Pharmacol. 1993; 33: 949–54.PubMedGoogle Scholar
  71. 71.
    Horsmans Y, Desager JP, Hulhoven R, et al. Single-dose pharmacokinetics of cetirizine in patients with chronic liver disease. J Clin Pharmacol. 1993; 33: 929–32.PubMedGoogle Scholar
  72. 72.
    Awni WM, Yeh J, Halstenson CE, et al. Effect of haemodialysis on the pharmacokinetics of cetirizine. Eur J Clin Pharmacol. 1990; 38: 67–9.PubMedCrossRefGoogle Scholar
  73. 73.
    Simons FER, Sussman GL, Simons KJ. Effect of the H2-antagonist Cimetidine on the pharmacokinetics and pharmacodynamics of the H1-antagonists hydroxyzine and cetirizine in patients with chronic urticaria. J Allergy Clin Immunol. 1995; 95: 685–93.PubMedCrossRefGoogle Scholar
  74. 74.
    Simons FER, Murray HE, Simons KJ. Quantitation of H1-receptor antagonists in skin and serum. J Allergy Clin Immunol. 1995; 95: 759–64.PubMedCrossRefGoogle Scholar
  75. 75.
    Juhlin L, de Vos C, Rihoux J-P. Inhibiting effect of cetirizine on histamine-induced and 48/80-induced wheals and flares, experimental dermographism, and cold-induced urticaria. J Allergy Clin Immunol. 1987; 80: 599–602.PubMedCrossRefGoogle Scholar
  76. 76.
    Rivest J, Despontin K, Ghys L, et al. Pharmacological modulation by cetirizine and ebastine of the cutaneous reactivity to histamine. Dermatologica. 1991; 183: 208–11.PubMedCrossRefGoogle Scholar
  77. 77.
    Sannita WG, Crimi E, Riela S, et al. Cutaneous antihistaminic action of cetirizine and dose-related EEG concomitants of sedation in man. Eur J Pharmacol. 1996; 300: 33–41.PubMedCrossRefGoogle Scholar
  78. 78.
    Perzanowska M, Malhotra D, Skinner SP, et al. The effect of cetirizine and loratadine on codeine-induced histamine release in human skin in vivo assessed by cutaneous microdialysis. Inflamm Res. 1996; 45: 486–90.PubMedCrossRefGoogle Scholar
  79. 79.
    Tashkin DP, Brik A, Gong Jr H. Cetirizine inhibition of histamine-induced bronchospasm. Ann Allergy. 1987; 59: 49–52.PubMedGoogle Scholar
  80. 80.
    Brik A, Tashkin DP, Gong Jr H, et al. Effect of cetirizine, a new histamine H1-antagonist, on airway dynamics and responsiveness to inhaled histamine in mild asthma. J Allergy Clin Immunol. 1987; 80: 51–6.PubMedCrossRefGoogle Scholar
  81. 81.
    Wiseman LR, Faulds D. Ebastine: a review of its pharmacological properties and clinical efficacy in the treatment of allergic disorders. Drugs. 1996; 51: 260–77.PubMedCrossRefGoogle Scholar
  82. 82.
    Martinez-Tobab A, Tarrus E, Seguru J, et al. Pharmacokinetic studies in rats, dogs and man. Drugs Today 1992; 28 Suppl. B: 57–67.Google Scholar
  83. 83.
    Yamaguchi T, Hashizume T, Matsuda M, et al. Pharmacokinetics of the H1-receptor antagonist ebastine and its active metabolite carebastine in healthy subjects. Arzneimittel Forschung Drug Res. 1994; 44: 59–64.Google Scholar
  84. 84.
    Vincent J, Liminana R, Meredith PA, et al. The pharmacokinetics, antihistamine and concentration-effect relationship of ebastine in healthy subjects. Br J Clin Pharmacol. 1988; 26: 497–502.PubMedCrossRefGoogle Scholar
  85. 85.
    Marino EL, Jansat JM, March MA, et al. Parametrization by nonlinear regression analysis of the active acid metabolite of ebastine using different weighting methods. Int J Clin Pharmacol Ther. 1996; 34: 546–9.PubMedGoogle Scholar
  86. 86.
    Simons FER, Watson WTA, Simons KJ. Pharmacokinetics and pharmacodynamics of ebastine in children. J Pediatr. 1993; 122: 641–6.PubMedCrossRefGoogle Scholar
  87. 87.
    Huang M-Y, Argenti D, Wilson J, et al. Single dose and steady-state pharmacokinetics of carebastine following administration of 10 mg ebastine tablets once daily in healthy elderly and young adults [abstract]. Pharm Res. 1993; 10: S–391.CrossRefGoogle Scholar
  88. 88.
    Wilson J, Huang M-Y, Argenti D, et al. Comparative pharmacokinetics of carebastine/ebastine in moderately renally impaired and healthy volunteers following a single 10mg dose of ebastine [abstract]. Pharm Res. 1993; 10: S–391.Google Scholar
  89. 89.
    Huang M-Y, Wilson J, Argenti D, et al. Comparative pharmacokinetics of ebastine/carebastine in liver cirrhosis and healthy volunteers following administration of a 10mg ebastine tablet [abstract]. Pharm Res. 1993; 10: S–390.CrossRefGoogle Scholar
  90. 90.
    Hashizume T, Mise M, Terauchi Y, et al. N-dealkylation and hydroxylation of ebastine by human liver cytochrome P450. Drug Metab Dispos. 1998; 26: 566–71.PubMedGoogle Scholar
  91. 91.
    Van Rooij J, Schoemaker HC, Bruno R, et al. Cimetidine does not influence the metabolism of the H1-receptor antagonist ebastine to its active metabolite carebastine. Br J Clin Pharmacol. 1993; 35: 661–3.PubMedCrossRefGoogle Scholar
  92. 92.
    Mattila MJ, Kuitunen T, Plétan Y. Lack of pharmacodynamic and pharmacokinetic interactions of the antihistamine ebastine with ethanol in healthy subjects. Eur J Clin Pharmacol. 1992; 43: 179–84.PubMedCrossRefGoogle Scholar
  93. 93.
    Nelson HS, Bucher B, Buchmeier A, et al. Suppression of the skin reaction to histamine by ebastine. Ann Allergy Asthma Immunol. 1995; 74: 442–7.PubMedGoogle Scholar
  94. 94.
    Wood-Baker R, Holgate ST. Dose-response relationship of the H1-histamine antagonist, ebastine, against histamine and methacholine-induced bronchoconstriction in patients with asthma. Agents Actions. 1990; 30: 284–6.PubMedCrossRefGoogle Scholar
  95. 95.
    Markham A, Wagstaff AJ. Fexofenadine. Drugs. 1998; 55: 269–74.PubMedCrossRefGoogle Scholar
  96. 96.
    Hoechst Marion Roussel. Telfast Product Monograph. Oxford: The Medicine Group (Education) Ltd., 1997.Google Scholar
  97. 97.
    Stoltz M, Arumugham T, Lippert C, et al. Effect of food on the bioavailability of fexofenadine hydrochloride (MDL 16455A). Biopharm Drug Dispos. 1997; 18: 645–8.PubMedCrossRefGoogle Scholar
  98. 98.
    Lippert C, Ling J, Brown P, et al. Mass balance and pharmacokinetics of MDL 16,455A in healthy, male volunteers [abstract]. Pharm Res. 1995; 12: S–390.Google Scholar
  99. 99.
    Russell T, Stoltz M, Weir S. Pharmacokinetics, pharmacodynamics, and tolerance of single- and multiple-dose fexofenadine hydrochloride in healthy male volunteers. Clin Pharmacol Ther. 1998; 64: 612–21.PubMedCrossRefGoogle Scholar
  100. 100.
    Robbins DK, Castles MA, Pack DJ, et al. Dose proportionality and comparison of single and multiple dose pharmacokinetics of fexofenadine (MDL 16455) and its enantiomers in healthy male volunteers. Biopharm Drug Dispos. 1998; 19: 455–63.PubMedCrossRefGoogle Scholar
  101. 101.
    Simons FER, Bergman JN, Watson WTA, et al. The clinical pharmacology of fexofenadine in children. J Allergy Clin Immunol. 1996; 98: 1062–4.PubMedCrossRefGoogle Scholar
  102. 102.
    Rao N, Weilert DR, Grace MGA, et al. Pharmacokinetics of terfenadine-acid-metabolite, MDL 16,455A, in healthy geriatric subjects [abstract]. Pharma Res 1995; 12 Suppl.: S386.Google Scholar
  103. 103.
    Simons FER, Simons KJ. Peripheral H1-blockade effect of fexofenadine. Ann Allergy Asthma Immunol. 1997; 79: 530–2.PubMedCrossRefGoogle Scholar
  104. 104.
    Harris Ag, Iezzoni DG, Hubbell JP, et al. Comparative pharmacokinetic and pharmacodynamic crossover study seldane tablets and allegra capsules [abstract]. J Allergy Clin Immunol. 1999; 103: S253.Google Scholar
  105. 105.
    Day JH, Briscoe MP, Welsh A, et al. Onset of action, efficacy, and safety of a single dose of fexofenadine hydrochloride for ragweed allergy using an environmental exposure unit. Ann Allergy Asthma Immunol. 1997; 79: 533–40.PubMedCrossRefGoogle Scholar
  106. 106.
    Bernstein DI, Schoenwetter WF, Nathan RA, et al. Efficacy and safety of fexofenadine hydrochloride for treatment of seasonal allergic rhinitis. Ann Allergy Asthma Immunol. 1997; 79: 443–8.PubMedCrossRefGoogle Scholar
  107. 107.
    Paul E, Berth-Jones J, Ortonne J-P, et al. Fexofenadine hydrochloride in the treatment of chronic idopathic urticaria: a placebo-controlled, parallel-group, dose-ranging study. J Dermatol Treat. 1998; 9: 143–9.CrossRefGoogle Scholar
  108. 108.
    Pratt CM, Mason J, Russell T, et al. Cardiovascular safety of fexofenadine HCl. Am J Cardiol 1999. In press.Google Scholar
  109. 109.
    Vermeeren A, O’Hanlon JF. Fexofenadine’s effects, alone and with alcohol, on actual driving and psychomotor performance. J Allergy Clin Immunol. 1998; 101: 306–11.PubMedCrossRefGoogle Scholar
  110. 110.
    Reilly MC, Tanner A, Meltzer EO. Work, classroom and activity impairment instruments: validation studies in allergic rhinitis. Clin Drug Invest. 1996; 11: 278–88.CrossRefGoogle Scholar
  111. 111.
    Heykants J, Van Peer A, Van de Velde V, et al. The pharmacokinetic properties of topical levocabastine: a review. Clin Pharmacokinet. 1995; 29: 221–30.PubMedCrossRefGoogle Scholar
  112. 112.
    Dechant KL, Goa KL. Levocabastine: a review of its pharmacological properties and therapeutic potential as a topical antihistamine in allergic rhinitis and conjunctivitis. Drugs. 1991; 41: 202–24.PubMedCrossRefGoogle Scholar
  113. 113.
    Heykants J, Van Peer A, Woestenborghs R, et al. Pharmacokinetics and bioavailability of levocabastine (R 50547) in man. Arch Int Pharmacodyn Ther. 1985; 274: 329–30.Google Scholar
  114. 114.
    Zazgornik J, Huang ML, Van Peer A, et al. Pharmacokinetics of orally administered levocabastine in patients with renal insufficiency. J Clin Pharmacol. 1993; 33: 1214–8.PubMedGoogle Scholar
  115. 115.
    Pesco-Koplowitz L, Hassall A, Lee P, et al. Lack of effect of erythromycin and ketoconazole on the pharmacokinetics and pharmacodynamics of stady-state intranasal levocabastine. J Clin Pharmacol. 1999; 39: 76–85.PubMedCrossRefGoogle Scholar
  116. 116.
    Haria M, Fitton A, Peters DH. Loratadine: a reappraisal of its pharmacological properties and therapeutic use in allergic disorders. Drugs. 1994; 48: 617–37.PubMedCrossRefGoogle Scholar
  117. 117.
    Martens J. Determination of loratadine and pheniramine from human serum by gas chromatography-mass spectrometry. J ChromatogrB. 1995; 673: 183–8.CrossRefGoogle Scholar
  118. 118.
    Johnson R, Christensen J, Lin C-C. Sensitive gas-liquid chromatographic method for the determination of loratadine and its major active metabolite, descarboethoxyloratadine, in human plasma using a nitrogen-phosphorus detector. J Chromatogr B. 1994; 657: 125–31.CrossRefGoogle Scholar
  119. 119.
    Katchen B, Cramer J, Chung M, et al. Disposition of 14C-SCH 29851 in humans [abstract]. Ann Allergy. 1985; 55: 393.Google Scholar
  120. 120.
    Hilbert J, Radwanski E, Weglein R, et al. Pharmacokinetics and dose proportionality of loratadine. J Clin Pharmacol. 1987; 27: 694–8.PubMedGoogle Scholar
  121. 121.
    Nomeir AA, Mojaverian P, Kosoglou T, et al. Influence of food on the oral bioavailability of loratadine and pseudoephedrine from extended-release tablets in healthy volunteers. J Clin Pharmacol. 1996; 36: 923–30.PubMedGoogle Scholar
  122. 122.
    Radwanski E, Hilbert J, Symchowicz S, et al. Loratadine: multiple-dose pharmacokinetics. J Clin Pharmacol. 1987; 27: 530–3.PubMedGoogle Scholar
  123. 123.
    Lin CC, Radwanski E, Affrime MB, et al. Pharmacokinetics of loratadine in pediatric subjects. Am J Ther. 1995; 2: 504–8.PubMedCrossRefGoogle Scholar
  124. 124.
    Hilbert J, Moritzen V, Parks A, et al. The pharmacokinetics of loratadine in normal geriatric volunteers. J Int Med Res. 1988; 16: 50–60.PubMedGoogle Scholar
  125. 125.
    Matzke GR, Halstenson CE, Opsahl JA, et al. Pharmacokinetics of loratadine in patients with renal insufficiency. J Clin Pharmacol. 1990; 30: 364–71.PubMedGoogle Scholar
  126. 126.
    Hilbert J, Radwanski E, Affrime MB, et al. Excretion of loratadine in human breast milk. J Clin Pharmacol. 1988; 28: 234–9.PubMedGoogle Scholar
  127. 127.
    Kosoglou T, Radwanski E, Batra VK, et al. Pharmacokinetics of loratadine and pseudoephedrine following single and multiple doses of onceversus twice-daily combination tablet formulations in healthy adult males. Clin Ther. 1997; 19: 1002–12.PubMedCrossRefGoogle Scholar
  128. 128.
    Parkinson A, Clement RP, Casciano CN, et al. Evaluation of loratadine as an inducer of liver microsomal cytochrome P450 in rats and mice. Biochem Pharmacol. 1992; 43: 2169–80.PubMedCrossRefGoogle Scholar
  129. 129.
    Yumibe N, Huie K, Chen K-J, et al. Identification of human liver cytochrome P450s involved in the microsomal metabolism of the antihistaminic drug loratadine. Int Arch Allergy Immunol. 1995; 107: 420.PubMedCrossRefGoogle Scholar
  130. 130.
    Yumibe N, Huie K, Chen K-J, et al. Identification of human liver cytochrome P450 enzymes that metabolize the nonsedating antihistamine loratadine. Formation of descarboethoxyloratadine by CYP3A4 and CYP2D6. Biochem Pharmacol. 1996; 51: 165–72.PubMedCrossRefGoogle Scholar
  131. 131.
    Brannan MD, Reidenberg P, Radwanski E, et al. Loratadine administered concomitantly with erythromycin: pharmacokinetic and electrocardiographic evaluations. Clin Pharmacol Ther. 1995; 58: 269–78.PubMedCrossRefGoogle Scholar
  132. 132.
    Carr RA, Edmonds A, Shi H, et al. Steady-state pharmacokinetics and electrocardiographic pharmacodynamics of clarithromycin and loratadine after individual or concomitant administration. Antimicrob Agents Chemother. 1998; 42: 1176–80.PubMedGoogle Scholar
  133. 133.
    Van Peer A, Crabbé R, Woestenborghs R, et al. Ketoconazole inhibits loratadine metabolism in man [abstract]. Allergy. 1993; 48: 34.Google Scholar
  134. 134.
    Brannan MD, Affrime MB, Reidenberg P, et al. Evaluation of the pharmacokinetics and electrocardiographic pharmacokinetics of loratadine with concomitant administration of Cimetidine [abstract]. Pharmacotherapy. 1994; 14: 347.Google Scholar
  135. 135.
    Kassem N, Roman I, Gural R, et al. Effects of loratadine (SCH 29851) in suppression of histamine-induced skin wheals. Ann Allergy. 1988; 60: 505–7.PubMedGoogle Scholar
  136. 136.
    Labrecque M, Ghezzo H, L’Archevêque J, et al. Duration of effect of loratadine and terfenadine administered once a day for one week on cutaneous and inhaled reactivity to histamine. Chest. 1993; 103: 777–81.PubMedCrossRefGoogle Scholar
  137. 137.
    Simons FER, Lukowski JL, Becker AB, et al. Comparison of the effects of single doses of the new H1-receptor antagonists loratadine and terfenadine versus placebo in children. J Pediatr. 1991; 118: 298–300.PubMedCrossRefGoogle Scholar
  138. 138.
    Roman IJ, Kassem N, Gural RP, et al. Suppression of histamine-induced wheal response by loratadine (SCH 29851) over 28 days in man. Ann Allergy. 1986; 57: 253–6.PubMedGoogle Scholar
  139. 139.
    Kontou-Fili K, Paleologos G, Herakleous M. Suppression of histamine-induced skin reactions by loratadine and cetirizine diHCl. Eur J Clin Pharmacol. 1989; 36: 617–9.PubMedCrossRefGoogle Scholar
  140. 140.
    Fadel R, Herpin-Richard N, Dufresne F, et al. Pharmacological modulation by cetirizine and loratadine of antigen and histamine-induced skin weals and flares, and late accumulation of eosinophils. J Int Med Res. 1990; 18: 366–71.PubMedGoogle Scholar
  141. 141.
    Town Gl, Holgate ST. Comparison of the effect of loratadine on the airway and skin responses to histamine, methacholine, and allergen in subjects with asthma. J Allergy Clin Immunol. 1990; 86: 886–93.PubMedCrossRefGoogle Scholar
  142. 142.
    Debelic M. Protection against histamine-induced bronchocon-striction by loratadine. Allergol Immunopathol (Madr). 1992; 20: 97–100.Google Scholar
  143. 143.
    Bousquet J, Chanal I, Skassa-Brociek W, et al. Lack of sub-sensitivity to loratadine during long-term dosing during 12 weeks. J Allergy Clin Immunol. 1990; 86: 248–53.PubMedCrossRefGoogle Scholar
  144. 144.
    Simons FER. Mizolastine: antihistaminic activity from preclinical data to clinical evaluation. Clin Exp Allergy. 1999; 29: 1–8.Google Scholar
  145. 145.
    Arbilla S, Besserve A, Chaufour S, et al. Mizolastine: core scientific brochure. Paris: Synthélabo Groupe, Medical and Regulatory Affairs Direction, 1998.Google Scholar
  146. 146.
    Ascalone V, Guinebault P, Rouchouse A. Determination of mizolastine, a new antihistaminic drug, in human plasma by liquid-liquid extraction, solid-phase extraction, and column-switching techniques in combination with high-performance liquid chromatography. J Chromatogr. 1993; 619: 275–84.PubMedCrossRefGoogle Scholar
  147. 147.
    Rosenzweig P, Thebault JJ, Caplain H, et al. Pharmacodynamics and pharmacokinetics of mizolastine (SL 85.0324), a new nonsedative H1 antihistamine. Ann Allergy. 1992; 69: 135–9.PubMedGoogle Scholar
  148. 148.
    Mesnil F, Dubruc C, Mentre F, et al. Pharmacokinetic analysis of mizolastine in healthy young volunteers after single oral and intravenous doses: noncompartmental approach and compartmental modeling. J Pharmacokinet Biopharm. 1997; 25: 125–47.PubMedGoogle Scholar
  149. 149.
    Patat A, Gram LF, Dubruc C, et al. Effects of mizolastine, a new antihistamine, on psychomotor performance and memory in elderly subjects. Int Clin Psychopharmacol. 1994; 9: 101–8.PubMedCrossRefGoogle Scholar
  150. 150.
    Chaufour S, Holt B, Jensen R, et al. Interaction study between mizolastine, a new H1-antihistamine, and erythromycin [abstract]. Clin Pharmacol Ther. 1998; 63: 214.Google Scholar
  151. 151.
    Chaufour S, Le Coz F, Denolle T, et al. Lack of effect of mizolastine on the safety and pharmacokinetics of digoxin administered orally in repeated doses to healthy volunteers. Int J Clin Pharmacol Ther. 1998; 36: 286–91.PubMedGoogle Scholar
  152. 152.
    Mesnil F, Mentre F, Dubruc C, et al. Population pharmacokinetic analysis of mizolastine and validation from sparse data on patients using the nonparametric maximum likelihood method. J Pharmacokinet Biopharm. 1998; 26: 133–61.PubMedGoogle Scholar
  153. 153.
    Chosidow O, Dubruc C, Danjou P, et al. Plasma and skin suction-blister-fluid pharmacokinetics and time course of the effects of oral mizolastine. Eur J Clin Pharmacol. 1996; 50: 327–33.PubMedCrossRefGoogle Scholar
  154. 154.
    Pinquier J-L, Caplain H, Cabanis M—J, et al. Inhibition of histamine-induced skin wheal and flare after 5 days of mizolastine. J Clin Pharmacol. 1996; 36: 72–8.PubMedGoogle Scholar
  155. 155.
    Rosenzweig P, Caplain H, Chaufour S, et al. Comparative wheal and flare study of mizolastine vs terfenadine, cetirizine, loratadine and placebo in healthy volunteers. Br J Clin Pharmacol. 1995; 40: 459–65.PubMedGoogle Scholar
  156. 156.
    Prakash A, Lamb HM. Mizolastine: a review of its use in allergic rhinitis and chronic idiopathic urticaria. Biodrugs. 1998; 10: 41–63.PubMedCrossRefGoogle Scholar
  157. 157.
    Bousquet J, Chanal I, Murrieta M, et al. Lack of subsensitivity to mizolastine over 8-week treatment. Allergy. 1996; 51: 251–6.PubMedGoogle Scholar
  158. 158.
    Zhang M-Q, Walczynski K, Ter Laak AM, et al. Optically active analogues of ebastine: synthesis and effect of chirality on their antihistaminic and antimuscarinic activity. Chirality. 1994; 6: 631–41.PubMedCrossRefGoogle Scholar
  159. 159.
    Queralt M, Merlos M, Giral M, et al. Dual effect of a new compound, rupatadine, on edema induced by platelet-activating factor and histamine in dogs: comparison with antihistamines and PAF antagonists. Drug Dev Res. 1996; 39: 12–8.CrossRefGoogle Scholar
  160. 160.
    Wolf C, Schunack W. Synthesis and pharmacology of combined histamine H1-/H2-receptor antagonists containing diphenhydramine and cyproheptadine derivatives. Arch Pharm Pharm Med Chem. 1996; 329: 87–94.CrossRefGoogle Scholar
  161. 161.
    Zhang M-Q, Timmerman H. Leukotriene cysLT1 (LTD4) receptor antagonism of H1-antihistamines: an in vitro study. Inflamm Res. 1997; 46: S93–4.PubMedCrossRefGoogle Scholar
  162. 162.
    Tohda Y, Nakajima S, Shizawa T, et al. The inhibitory effect of TMK688, a novel anti-allergic drug having both 5-lipoxygenase inhibitory activity and anti-histamine activity, against bronchoconstriction, leukotriene production and inflammatory cell infiltration in sensitized guinea pigs. Clin Exp Allergy. 1997; 27: 110–8.PubMedCrossRefGoogle Scholar
  163. 163.
    Leurs R, Smit MJ, Timmerman H. Histamine receptors: specific ligands, receptor biochemistry, and signal transduction. In: Simons FER, editor. Histamine and H1-receptor antagonists in allergic disease. New York: Marcel Dekker, Inc., 1996: 1–32.Google Scholar
  164. 164.
    Dewar JC, Hall IP. A novel degenerate polymorphism in the human histamine H1-receptor gene [abstract]. Am J Respir Crit Care Med. 1998; 157: A773.Google Scholar

Copyright information

© Adis International Limited 1999

Authors and Affiliations

  1. 1.Faculty of MedicineThe University of Manitoba, and the Children’s Hospital of WinnipegWinnipegCanada
  2. 2.Faculties of Pharmacy and MedicineThe University of ManitobaWinnipegCanada

Personalised recommendations