H1-Antihistamines
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《新英格兰医药杂志》
To the Editor: Simons (Nov. 18 issue)1 provides a comprehensive review of the advances in drug therapy with histamine H1-receptor antagonists. However, the author states that there is no current evidence supporting the use of such therapy for asthma — a statement possibly biased by selective referencing. There are recent data in the literature that suggest that modern H1-receptor antagonists such as desloratadine, fexofenadine, and levocetirizine have antiinflammatory effects in patients with atopic asthma.2,3,4 Indeed, fexofenadine improves airway hyperresponsiveness and reduces exhaled nitric oxide, improves peak expiratory flow, and reduces albuterol use, to a degree similar to that with montelukast, when given as add-on therapy with inhaled corticosteroids.4 Moreover, the combination of cetirizine and montelukast is as effective with regard to peak expiratory flow, symptoms of asthma, and albuterol use as therapy with inhaled plus intranasal budesonide in patients with asthma and allergic rhinitis.5 Further long-term studies are indicated to evaluate the effects of histamine H1-receptor antagonists on exacerbations of atopic asthma.
Daniel K.C. Lee, M.D.
Ipswich Hospital
Ipswich IP4 5PD, United Kingdom
dkclee@doctors.org.uk
Graeme P. Currie, M.D.
Aberdeen Royal Infirmary
Aberdeen AB25 2ZN, United Kingdom
Brian J. Lipworth, M.D.
Ninewells Hospital and Medical School
Dundee DD1 9SY, United Kingdom
References
Simons FER. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-2217.
Lee DK, Bates CE, Currie GP, Lipworth BJ. Comparative in vivo bioactivity of modern H1-antihistamines on AMP challenge in atopic asthma. J Allergy Clin Immunol 2003;111:337-341.
Lee DK, Gray RD, Wilson AM, Robb FM, Soutar PC, Lipworth BJ. Single and short-term dosing effects of levocetirizine on adenosine monophosphate bronchoprovocation in atopic asthma. Br J Clin Pharmacol 2004;58:34-39.
Lee DK, Jackson CM, Haggart K, Lipworth BJ. Repeated dosing effects of mediator antagonists in inhaled corticosteroid-treated atopic asthmatic patients. Chest 2004;125:1372-1377.
Wilson AM, Orr LC, Sims EJ, Dempsey OJ, Lipworth BJ. Antiasthmatic effects of mediator blockade versus topical corticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med 2000;162:1297-1301.
To the Editor: Simons mentions six classes of medicines with important H1-antihistamine properties but omits another important class — atypical antipsychotic drugs. Indeed, olanzapine and quetiapine are potent H1-antihistamines1; olanzapine is among the most potent histamine H1-receptor blockers of any commonly used medication approved by the Food and Drug Administration. These medicines can have H1-related side effects, such as sedation.
Simons notes recent work on potential antiinflammatory properties of H1-antagonists (beyond their effects on histamine itself), such as their ability to decrease levels of interleukin-6.2 This antiinflammatory property may imply that H1-antihistamines should be considered and studied as potential therapeutic agents for diseases related to high levels of interleukin-6. In particular, interleukin-6 is an important positive trophic factor for myeloma cells, and H1-antihistamines should be studied for use in myeloma.3
Eric L. Altschuler, M.D., Ph.D.
Mt. Sinai School of Medicine
New York, NY 10029
eric.altschuler@mssm.edu
Richard E. Kast, M.D.
University of Vermont
Burlington, VT 05401
References
Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29-39.
Triggiani M, Gentile M, Secondo A, et al. Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol 2001;166:4083-4091.
Kast RE, Altschuler EL. Combination of bupropion, paroxetine and quetiapine as adjuvant treatment for multiple myeloma. Med Hypotheses 2004;62:817-818.
Dr. Simons replies: My statement that "current evidence does not support the use of H1-antihistamines in persistent asthma"1 holds true and differs from the paraphrase by Lee and colleagues — "there is no current evidence supporting the use of such therapy for asthma." At issue is the nature and the quality of the evidence.2,3,4,5
Under controlled conditions in the clinical laboratory, single-dose or short-term treatment with H1-antihistamines before challenge may protect against induced bronchospasm. The amount of protection varies with the H1-antihistamine, the dose, and the stimulus to bronchoconstriction. H1-antihistamines provide good protection against histamine-induced bronchospasm and AMP-induced bronchospasm (the model used in the recent studies cited by Lee and colleagues); partial protection against exercise-induced bronchospasm and allergen-induced bronchospasm; and little or no protection against methacholine-, leukotriene D4–, or neurokinin A–induced bronchospasm. Concomitant administration of an antileukotriene drug along with an H1-antihistamine may or may not enhance the bronchoprotective effect.2,3,4
With respect to the treatment of asthma in the community, many of the published clinical trials of H1-antihistamines are of suboptimal methodologic quality.1,5 First-generation H1-antihistamines may reduce symptoms but frequently cause sedation and other side effects.2,3,4,5 Second-generation H1-antihistamines in conventional doses reduce symptoms significantly in mild seasonal asthma1,2,3,4; however, in studies of persistent asthma, whether the medication is administered in conventional or higher doses, the beneficial effects as assessed according to reduction of symptoms and improved pulmonary function are modest and not always statistically significant.2,3,4 Moreover, the risk of sedation increases with the use of doubled or higher off-label doses of most second-generation H1-antihistamines, with the exception of fexofenadine.1 Outcomes of future, well-designed clinical trials of these medications, with exacerbations of asthma as the primary outcome, will be of interest, as will additional studies involving concomitant intervention with an H1-antihistamine and an antileukotriene agent.
In response to the comments by Drs. Altschuler and Kast: a seventh H1-antihistamine class entitled "others" was included in Table 2 of my article.1 Although only one medication, doxepin, was listed as an example, many other drugs, including atypical antipsychotics such as olanzapine and quetiapine, could certainly have been added. The hypothesis that H1-antihistamines may have a potential therapeutic role in "interleukin-6 diseases" is intriguing.
F. Estelle R. Simons, M.D.
University of Manitoba
Winnipeg, MB R3A IR9, Canada
lmcniven@hsc.mb.ca
References
Simons FER. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-2217.
Simons FER. Is antihistamine (H1-receptor antagonist) therapy useful in clinical asthma? Clin Exp Allergy 1999;29:Suppl 3:98-104.
Lordan JL, Holgate ST. H1-antihistamines in asthma. In: Simons FER, ed. Histamine and H1-antihistamines in allergic disease. 2nd ed. New York: Marcel Dekker, 2002:221-48.
Nelson HS. Prospects for antihistamines in the treatment of asthma. J Allergy Clin Immunol 2003;112:Suppl 4:S96-S100.
Schwarzer G, Bassler D, Mitra A, Ducharme FM, Forster J. Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children. Cochrane Database Syst Rev 2004;1:CD001384-CD001384.
Daniel K.C. Lee, M.D.
Ipswich Hospital
Ipswich IP4 5PD, United Kingdom
dkclee@doctors.org.uk
Graeme P. Currie, M.D.
Aberdeen Royal Infirmary
Aberdeen AB25 2ZN, United Kingdom
Brian J. Lipworth, M.D.
Ninewells Hospital and Medical School
Dundee DD1 9SY, United Kingdom
References
Simons FER. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-2217.
Lee DK, Bates CE, Currie GP, Lipworth BJ. Comparative in vivo bioactivity of modern H1-antihistamines on AMP challenge in atopic asthma. J Allergy Clin Immunol 2003;111:337-341.
Lee DK, Gray RD, Wilson AM, Robb FM, Soutar PC, Lipworth BJ. Single and short-term dosing effects of levocetirizine on adenosine monophosphate bronchoprovocation in atopic asthma. Br J Clin Pharmacol 2004;58:34-39.
Lee DK, Jackson CM, Haggart K, Lipworth BJ. Repeated dosing effects of mediator antagonists in inhaled corticosteroid-treated atopic asthmatic patients. Chest 2004;125:1372-1377.
Wilson AM, Orr LC, Sims EJ, Dempsey OJ, Lipworth BJ. Antiasthmatic effects of mediator blockade versus topical corticosteroids in allergic rhinitis and asthma. Am J Respir Crit Care Med 2000;162:1297-1301.
To the Editor: Simons mentions six classes of medicines with important H1-antihistamine properties but omits another important class — atypical antipsychotic drugs. Indeed, olanzapine and quetiapine are potent H1-antihistamines1; olanzapine is among the most potent histamine H1-receptor blockers of any commonly used medication approved by the Food and Drug Administration. These medicines can have H1-related side effects, such as sedation.
Simons notes recent work on potential antiinflammatory properties of H1-antagonists (beyond their effects on histamine itself), such as their ability to decrease levels of interleukin-6.2 This antiinflammatory property may imply that H1-antihistamines should be considered and studied as potential therapeutic agents for diseases related to high levels of interleukin-6. In particular, interleukin-6 is an important positive trophic factor for myeloma cells, and H1-antihistamines should be studied for use in myeloma.3
Eric L. Altschuler, M.D., Ph.D.
Mt. Sinai School of Medicine
New York, NY 10029
eric.altschuler@mssm.edu
Richard E. Kast, M.D.
University of Vermont
Burlington, VT 05401
References
Richelson E, Souder T. Binding of antipsychotic drugs to human brain receptors focus on newer generation compounds. Life Sci 2000;68:29-39.
Triggiani M, Gentile M, Secondo A, et al. Histamine induces exocytosis and IL-6 production from human lung macrophages through interaction with H1 receptors. J Immunol 2001;166:4083-4091.
Kast RE, Altschuler EL. Combination of bupropion, paroxetine and quetiapine as adjuvant treatment for multiple myeloma. Med Hypotheses 2004;62:817-818.
Dr. Simons replies: My statement that "current evidence does not support the use of H1-antihistamines in persistent asthma"1 holds true and differs from the paraphrase by Lee and colleagues — "there is no current evidence supporting the use of such therapy for asthma." At issue is the nature and the quality of the evidence.2,3,4,5
Under controlled conditions in the clinical laboratory, single-dose or short-term treatment with H1-antihistamines before challenge may protect against induced bronchospasm. The amount of protection varies with the H1-antihistamine, the dose, and the stimulus to bronchoconstriction. H1-antihistamines provide good protection against histamine-induced bronchospasm and AMP-induced bronchospasm (the model used in the recent studies cited by Lee and colleagues); partial protection against exercise-induced bronchospasm and allergen-induced bronchospasm; and little or no protection against methacholine-, leukotriene D4–, or neurokinin A–induced bronchospasm. Concomitant administration of an antileukotriene drug along with an H1-antihistamine may or may not enhance the bronchoprotective effect.2,3,4
With respect to the treatment of asthma in the community, many of the published clinical trials of H1-antihistamines are of suboptimal methodologic quality.1,5 First-generation H1-antihistamines may reduce symptoms but frequently cause sedation and other side effects.2,3,4,5 Second-generation H1-antihistamines in conventional doses reduce symptoms significantly in mild seasonal asthma1,2,3,4; however, in studies of persistent asthma, whether the medication is administered in conventional or higher doses, the beneficial effects as assessed according to reduction of symptoms and improved pulmonary function are modest and not always statistically significant.2,3,4 Moreover, the risk of sedation increases with the use of doubled or higher off-label doses of most second-generation H1-antihistamines, with the exception of fexofenadine.1 Outcomes of future, well-designed clinical trials of these medications, with exacerbations of asthma as the primary outcome, will be of interest, as will additional studies involving concomitant intervention with an H1-antihistamine and an antileukotriene agent.
In response to the comments by Drs. Altschuler and Kast: a seventh H1-antihistamine class entitled "others" was included in Table 2 of my article.1 Although only one medication, doxepin, was listed as an example, many other drugs, including atypical antipsychotics such as olanzapine and quetiapine, could certainly have been added. The hypothesis that H1-antihistamines may have a potential therapeutic role in "interleukin-6 diseases" is intriguing.
F. Estelle R. Simons, M.D.
University of Manitoba
Winnipeg, MB R3A IR9, Canada
lmcniven@hsc.mb.ca
References
Simons FER. Advances in H1-antihistamines. N Engl J Med 2004;351:2203-2217.
Simons FER. Is antihistamine (H1-receptor antagonist) therapy useful in clinical asthma? Clin Exp Allergy 1999;29:Suppl 3:98-104.
Lordan JL, Holgate ST. H1-antihistamines in asthma. In: Simons FER, ed. Histamine and H1-antihistamines in allergic disease. 2nd ed. New York: Marcel Dekker, 2002:221-48.
Nelson HS. Prospects for antihistamines in the treatment of asthma. J Allergy Clin Immunol 2003;112:Suppl 4:S96-S100.
Schwarzer G, Bassler D, Mitra A, Ducharme FM, Forster J. Ketotifen alone or as additional medication for long-term control of asthma and wheeze in children. Cochrane Database Syst Rev 2004;1:CD001384-CD001384.