Drugs online research references
Ann Allergy. 1987 Dec;59(6 Pt 2):4-8.
Receptor effects of cetirizine.
Snyder SH, Snowman AM.
Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland.
First-generation H1-antagonist antihistamines such as hydroxyzine have a significant ability to cross the blood-brain barrier and cause sedation, which limits their usefulness in the treatment of allergic disorders. Cetirizine, a carboxylated metabolite of hydroxyzine, possesses the parent compound's antihistaminic activity but does not cause sedation. This lack of CNS effects may be due to cetirizine's greater selectivity or potency at H1 receptors in the brain, compared with its effects at the receptors involved in sedation, or it may result from the agent's relative exclusion from the CNS compartment. We compared cetirizine's activity at central H1 sites with the activity of hydroxyzine and terfenadine. We also compared the abilities of cetirizine and three other antihistamines to cross the blood-brain barrier. We found the drugs' potency at H1 receptors in the CNS to be similar to their activities in other tissues. However, their selectivity varied widely. Cetirizine, in fact, failed to bind at any of the receptors investigated except H1 sites, even at concentrations as high as 10 micron. Both hydroxyzine and D-chlorpheniramine crossed the blood-brain barrier in significant amounts. Terfenadine did so to a much lesser extent, and cetirizine passed into the CNS only half as readily as terfenadine. We suggest that cetirizine's reduced incidence of sedative side effects may stem partly from its selectivity for H1 receptors over sites involved in sedation, and partly from its relative exclusion from the CNS.
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892448&dopt=Abstract
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Ann Allergy. 1987 Dec;59(6 Pt 2):43-8.
Clinical pharmacodynamics of antihistamines.
Maddox DE, Reed CE.
Department of Allergic Diseases, Mayo Clinic and Foundation, Rochester, Minnesota.
Antihistamines act by competing with histamine for H1 or H2 histamine receptors on cell membranes. In addition, most of the common antihistamines bind other receptors and thus exert other pharmacologic actions. For all practical purposes, mast cells and basophils are the main physiologic sources of histamine, and the primary usefulness of antihistamines is in diseases characterized by excessive production and release of histamine by these two cell types. Experimental models have proven useful for evaluating antihistamine compounds in humans. In these model systems, a test drug may be employed to block one or more of the known effects of exogenously administered histamine or a histamine agonist. Or the release of endogenous histamine may be brought about in a controlled fashion by agents such as allergens, opiates, or compound 48/80, and the drug's effects on this process may then be measured. In the case of the central nervous system, unfortunately, such models are not available and other means of evaluation must be devised. The dose response and duration of action of orally administered antihistamines can be determined in a simple skin model by their blocking of the wheal and erythema (flare) resulting from an intradermal challenge with histamine, an allergen, or compound 48/80. Antihistamines can also be evaluated in urticaria induced by scratching or cold. Itching that commonly follows injection of histamine or an allergen into the skin is also inhibited by this class of drugs. Most of the commonly used antihistamines are effective in these models, which form the basis for evaluating antihistamines in the treatment of skin diseases. In the nose and conjunctiva, other model strategies are used.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892449&dopt=Abstract
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Ann Allergy. 1987 Dec;59(6 Pt 2):9-12.
A primate model for the evaluation of antihistamines.
Fireman P, Skoner D, Tanner E, Doyle W.
Children's Hospital, Pittsburgh, Pennsylvania.
Studies of the efficacy of antihistamines in treating human upper airway pathology are difficult to design and conduct. In part, this is the result of a lack of objective measures of the nasal response. The purpose of this study was to develop a monkey model for the objective evaluation of antihistamine effectiveness and, using this model, to study the efficacy of cetirizine. Computer-assisted active anterior rhinomanometry was used to assess nasal airway resistance (NAR) before and after a nasal histamine provocation in conscious rhesus monkeys (Macaca mulatta). To establish dose-response relationships for oral antihistamines in monkeys, we measured the suppression of wheal-and-flare reactions by two such agents, oral cetirizine (CET) 0.1 to 1 mg/kg and chlorpheniramine (CHL) 0.07 to 0.2 mg/kg. The decreases in wheal sizes were maximal 60 to 120 minutes after CET 1.0 mg/kg (90%), and after CHL 0.2 mg/kg (70%). The four monkeys were challenged intranasally with increasing histamine doses (0.5, 1, 5, and 10 mg). The NAR was measured 15 minutes after each dose. At least three days later and 90 minutes after oral pretreatment with either CET 1 mg/kg or CHL 0.2 mg/kg, the intranasal challenges were repeated. Postchallenge NAR data are given as the percent increase from the baseline NAR values. The four monkeys studied had coefficients of variation of 13%, 15%, 16%, and 26% respectively for baseline studies. Mean percent increases in NAR +/- standard deviation were 14% +/- 0.4%, 47% +/- 10.0%, 45% +/- 3.0%, and 72% +/- 6.0% after intranasal challenge with 0.5, 1, 5, and 10 mg of histamine, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
online pharmacy ref source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=2892453&dopt=Abstract
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