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PubMed2002

Clinical pharmacology of H1-antihistamines in the skin.

BACKGROUND: The extent of the distribution of H(1)- antihistamines into the skin and H(1)-antihistamine activity in the skin are clinically relevant in the treatment of allergic skin disorders. METHODS: In a prospective, randomized, double-blind, parallel-group, multiple-dose study, we gave fexofenadine 180 mg, loratadine 10 mg, or chlorpheniramine 8 mg to 21 men (7 in each group). Before dosing and at 1, 3, 6, 9, and 24 hours after the first antihistamine dose as well as at 168, 192, and 216 hours after the first dose (ie, 12, 36, and 60 hours after the seventh and last consecutive daily H(1)-antihistamine dose), we measured fexofenadine, loratadine, or chlorpheniramine concentrations in plasma and in skin tissue samples obtained through use of punch biopsies, along with suppression of histamine-induced skin wheals and flares. Loratadine metabolites, including desloratadine and its metabolites, were not measured, and chlorpheniramine metabolites were not measured. RESULTS: All 21 participants completed the study. Skin/plasma fexofenadine ratios ranged from 1.2 +/- 0.5 at 1 hour to 110 +/- 74 at 24 hours, and skin fexofenadine concentrations exceeded loratadine and chlorpheniramine skin concentrations at each test time. This was reflected in significant wheal and flare suppression by fexofenadine in comparison with loratadine at 3 hours and in comparison with chlorpheniramine at 6 and 9 hours (wheal) and from 3 to 24 hours and at 192 hours (flare). Compared with fexofenadine, loratadine significantly suppressed the wheal at 192 hours, and compared with chlorpheniramine, it significantly suppressed the wheal at 9 hours and the flare at 24 and 192 hours. At no time did chlorpheniramine suppress the wheal or flare significantly more than fexofenadine or loratadine. CONCLUSIONS: In skin disorders for which H(1)-antihistamines are recommended, these results support the use of fexofenadine or loratadine, and they indicate the need for reexamination of the use of chlorpheniramine.

Adult↗
PubMed2001

Terfenadine-beta-Cyclodextrin inclusion complex with antihistaminic activity enhancement.

Terfenadine, an antihistaminic drug, has relatively low bioavailability after oral administration due to its limited solubility in water. To enhance the antihistaminic activity of terfenadine, the terfenadine-beta-cyclodextrin (1:2) inclusion complex was prepared by the neutralization method. The solubility and dissolution of the inclusion complex were carried out, and its antihistaminic activity was then evaluated and compared with terfenadine powder by the passive subcutaneous anaphylaxis method in rats. The formation constant of the inclusion complex was higher at lower pH, while its formation ratio was 1:2 irrespective of pH. For terfenadine, it improved the solubility 200 times and the dissolution rate 5 times. It gave a low histamine level at 30 min, followed by a sustained low level until 60 min, while terfenadine powder gave a low histamine level at 60 min, suggesting that it had faster and more effective antihistaminic activity than terfenadine powder in rats due to fast dissolution and absorption of terfenadine. It is concluded that this inclusion complex enhanced the antihistaminic activity of terfenadine following the enhanced solubility and dissolution of terfenadine.

Algorithms↗
PubMed2004

Continuous infusion interleukin-2 and antihistamines in melanoma: a retrospective review showing activity of this combination.

A recent randomized trial suggests that there may be an advantage in terms of survival with the combination of histamine and subcutaneous interleukin-2 (IL-2), compared to IL-2 alone. It has been postulated, then, that antihistamines may actually be antagonistic to IL-2 and, therefore, interfere with its antitumor activity. Because antihistamines such as cimetidine and ranitidine are commonly used as prophylaxis against gastrointestinal toxicity commonly seen with IL-2, and, because antihistamines may increase natural killer cell activity, it is reasonable to examine the response rate for this combination. An OVID Medline literature search between 1985 and 2003 was done. Continuous infusion (CIV) interleukin- 2 was used as the reference therapy because of the relatively constant IL-2 levels generated by this approach. Included studies were those in which either cimetidine, ranitidine, or famotidine were regularly scheduled and administered concurrently with IL-2, typically for gastrointestinal ulcer prophylaxis. Six (6) studies were identified. A total of 21 patients responded to therapy. Total response rate was 11%, with a 95% Confidence Interval: 7-17%. Four (4) complete responses were noted. Complete response rate was 2%, with a 95% Confidence Interval: 1-6%. These response rates are consistent with previously noted IL-2 response rates. In this retrospective review of CIV IL-2 and antihistamines, this combination appears to be active in melanoma. There appears to be no deleterious effect of routine antihistamine on the CIV IL-2 response rate.

Antineoplastic Agents↗
PubMed2002

Are antihistamines useful in managing asthma?

There continues to be a great deal of interest in the anti-asthmatic role of antihistamines. Antihistamines have recently been shown to have anti-inflammatory properties that are more extensive than simply the blocking of histamine receptors. For example, new evidence suggests that the suppression of cell adhesion molecule expression occurs with these drugs. The anti-inflammatory and anti-asthmatic effects of antihistamines have been evaluated in patients with both allergic asthma and rhinitis, given the established association between allergic inflammation of the upper and lower airways, with evidence to suggest that antihistamines have clinically relevant anti-asthmatic properties. As well as conferring benefits in asthma symptom control and the measurement of lung function, studies assessing the effect of histamine receptor antagonists on bronchial hyperresponsiveness suggest that there is bronchoprotection during both methacholine and mannitol challenges. Recently, there has also been considerable interest in the effect of combining an antihistamine with a leukotriene receptor antagonist. This combination has an anti-asthmatic effect that is greater than that of either drug given alone and may be comparable to inhaled corticosteroid therapy.

Acetates↗
PubMed2006

Chronic unremitting urticaria: is the use of antihistamines above the licensed dose effective? A preliminary study of cetirizine at licensed and above-licensed doses.

Recently, several authors have suggested an off-label increase of antihistamine dosage should be given to patients with chronic urticaria (CU) not responding to the usual, recommended doses, in order to gain better control of the disease. However, this recommendation is not evidence-based. The objective of this study was to assess the effectiveness of increased doses of antihistamines in patients with CU showing poor control at recommended doses. In total, 22 adult patients with moderate/severe CU not controlled with the usual antihistamine doses were studied. These subjects recorded urticaria severity on a visual analogue scale (range 0-10) for 2 weeks. During the first week, they were treated with cetirizine at the licensed dose (10 mg/day), and with a three-fold increased dose (10 mg x 3/day) during week 2. Only 1 patient (5%) responded satisfactorily to the increased dosage of antihistamine; in the remaining 21 subjects, urticaria scores did not change, and these patients had to be treated with steroids, ciclosporin, and in 1 case with cyclophosphamide. Disease control was eventually gained in all cases. This study suggests that the proportion of patients with severe CU that may gain a better control of their disease with high, off-label doses of antihistamines is probably small, and that most patients will eventually have to undergo more aggressive treatments.

Adult↗
PubMed2006

Treatment of severe chronic idiopathic urticaria with oral mycophenolate mofetil in patients not responding to antihistamines and/or corticosteroids.

BACKGROUND: Urticarial patients are usually treated with oral antihistamines and 50% respond well to this treatment; however, the other 50% do not respond to antihistamines and need a more aggressive approach, such as short or prolonged courses of oral corticosteroids or cyclosporine. Potential adverse effects, however, limit this regimen. OBJECTIVE: To determine the efficacy of mycophenolate mofetil, an immunomodulatory drug, in the treatment of patients with severe chronic urticaria. METHODS: In an open-label, uncontrolled trial, nine patients with documented chronic urticaria who had been treated previously with antihistamines and/or corticosteroids with poor response were enrolled in the trial. After 2 weeks of baseline assessment, patients received 1000 mg twice daily of mycophenolate mofetil for 12 weeks. Improvement was monitored using the urticarial activity score, which is the sum of the wheal number score and itch severity score. Patients also recorded their daily need for other medications to control allergic symptoms. RESULTS: There was a significant decrease in the urticarial activity score relative to the baseline assessment at the end of the study period (P < 0.001). All patients were able to stop prednisone on completion of the study. There was also a decrease in antihistamine dose, but this did not reach statistical significance. Treatment with mycophenolate mofetil was not associated with significant adverse effects. CONCLUSIONS: Mycophenolate mofetil may be a valuable and safe treatment for patients with chronic urticaria who do not respond to antihistamines and/or corticosteroids, and who require aggressive treatment to control their disease symptoms. Further controlled clinical studies are needed to determine its value.

Administration, Oral↗
PubMed1987

Antiallergic activity of loratadine, a non-sedating antihistamine.

Loratadine is a new non-sedating antihistamine. The present studies compared loratadine and terfenadine, another non-sedating antihistamine, for their ability to inhibit the bronchial response to histamine and other autacoids which have been implicated as contributing to the symptoms of an allergic reaction. In addition, the two antihistamines were evaluated in models of immunologically mediated allergic reactions. Loratadine is a more potent inhibitor of histamine-induced bronchospasm in guinea pigs than is terfenadine. Both antihistamines exhibit marked antiserotonin activity at doses 10 times their antihistamine ED50 values. In contrast, loratadine and terfenadine produce little or no inhibition of the bronchial responses to methacholine, leukotriene C4 or platelet-activating factor. An allergic bronchospasm in guinea pigs is inhibited by loratadine (ED50 = 0.40 mg/kg, p.o.) and terfenadine (ED50 = 1.7 mg/kg, p.o.). The bronchospasm associated with allergic anaphylaxis in rats is significantly inhibited by 10 mg/kg, p.o. loratadine and 30 mg/kg, p.o. terfenadine. Loratadine exhibits antiallergy activity in vitro. At micromolar concentrations, loratadine inhibits the release of histamine from Con A and A23187-stimulated rat peritoneal mast cells and the release of histamine and leukotriene C4 from a Con A-stimulated cloned murine mast cell line.

Animals↗
PubMed1995

A clinical study to evaluate the efficacy of the antihistamine doxylamine succinate in the relief of runny nose and sneezing associated with upper respiratory tract infection.

Antihistamines are widely used in common cold medications, although the role of histamine in the development of common cold symptoms is unclear and the use of antihistamines for the treatment of common cold is controversial. It is clear that antihistamines do not offer a cure for common cold but they may alleviate symptoms of sneezing and runny nose. The present study was designed to investigate the efficacy of an antihistamine, doxylamine, on the symptoms of runny nose and sneezing associated with common cold. We conducted a randomized double-blind study in cold sufferers. One thousand and one volunteers with cold symptoms were screened in four centres (UK, Denmark, Belgium, Germany) and 688 satisfied the entry criteria of the study. The main reasons for excluding subjects were a low nasal secretion weight (secretion weight < 0.2g, 72%) and a low subjective rhinorrhoea score (24%). Volunteers were randomized to receive either doxylamine succinate 7.5 mg by mouth four times a day up to nine doses (n = 345) or placebo (n = 343). The principal measurements were prospectively defined as runny nose and sneezing symptom scores. Data were analysed on an intention-to-treat basis, using Cochran-Mantel-Haenszel statistics controlling for baseline symptom scores. A between-group comparison showed that doxylamine-treated volunteers benefited from a significantly greater reduction in runny nose scores (P < 0.01) and sneezing scores (P < 0.001), than those volunteers in the placebo group. Doxylamine therapy was well tolerated; the incidence of unexpected side-effects was comparable with placebo. Of the expected side-effects, 13.3% of doxylamine-treated patients reported drowsiness. The incidence of sedative effects was lower than has been reported for other commonly used first-generation antihistamines.

Common Cold↗
PubMedDate not supplied

Efficacy measurement of topical antihistamines: a review.

More and more antihistamines are used in gels or ointments for local antipruritic therapy. Among other factors, the efficacy is dependent on the penetration properties of the respective agents and the optimal choice of vehicle substances. To avoid expensive treatment with unsatisfying success, a reliable efficacy measurement would be desirable prior to the admission of new topical antihistamine preparations. Therefore we reviewed the literature for common methods to assess the efficacy of local antihistamines in healthy volunteers. The principle is to apply the test substance to marked test areas and to challenge the skin after a certain time with a standardised amount of histamine, allergens or mast-cell-degranulating substances. For the test evaluation, the areas of wheal, flare and itch are measured and compared between antihistamine-treated and control fields. Challenge models and most of the described evaluation methods are suited for the preliminary efficacy measurement of antihistamines. However, to be able to compare the results, a standardised procedure used by all investigators would be desirable.

Administration, Oral↗
PubMed1995

Regulation of potassium channels by nonsedating antihistamines.

BACKGROUND: Terfenadine and astemizole are widely prescribed nonsedating antihistamines that have been associated with QT-interval prolongation and ventricular arrhythmias. Since potassium channels are intrinsically involved in repolarization, this study was designed to evaluate the effect of the nonsedating antihistamines on potassium channel modulation. METHODS AND RESULTS: The whole-cell patch-clamp technique was used to study K+ currents in enzymatically isolated rat and guinea pig ventricular myocytes. Three distinct K+ channels were examined: the inward rectifier (IK1), the delayed rectifier (IK), and the transient outward (I(to)) currents. The dialyzing pipette solution was buffered with EGTA, and ionic channels other than potassium were pharmacologically inhibited or electrically inactivated. Both astemizole and terfenadine suppressed the IK1 channel by 17% to 50% in a voltage-dependent manner in rat and guinea pig myocytes. Ito was evaluated in rat ventricular myocytes. Both drugs also inhibited the maintained component of I(to) to a lesser extent, by 23%, in a dose-dependent, reversible manner. IK was examined mainly in guinea pig myocytes. Terfenadine but not astemizole slightly inhibited IK, by 9%, and only at higher drug concentrations. The medications had dose-dependent inhibitory actions, with specific K+ channel suppression evident only beginning at concentrations > 0.1 mumol/L. CONCLUSIONS: These findings suggest that the mechanism of action of the rare proarrhythmic effects of the nonsedating antihistamines appears to be secondary to potassium channel blockade. A significant voltage-dependent blockade of the IK1 channel was demonstrated, as well as additional inhibitory effects on I(to) and IK channels. These actions lead to delayed repolarization, QT interval prolongation, and enhanced susceptibility to the development of premature ventricular depolarizations. Caution is advised in the prescription of nonsedating antihistamines, particularly in patients at risk of elevated serum levels of the antihistamine or patients with existing repolarization abnormalities.

Animals↗
PubMed2005

Effects of first and second generation antihistamines on muscarinic induced mucus gland cell ion transport.

BACKGROUND: The first generation antihistamines, such as diphenhydramine, are fairly potent muscarinic antagonists in addition to being H1 selective antihistamines. The antimuscarinic action is often not desirable since it is in part responsible for the drying of secretions in the airways and the sedative effect. We therefore examined a number of antihistamines for antimuscarinic effects on ion transport by mucus gland cells isolated from the airways of swine. Enzymatically isolated airway mucus gland cells were purified utilizing density gradients and grown in culture on porous inserts (Millicell HA) at an air interface. Cells grown in this manner maintain phenotype and polarity. Transport of ions, as short-circuit current measured under voltage-clamp, was measured in response to acetylcholine (ACh) or histamine applied to the serosal side of the gland cell layers. Concentration-response relationships for ACh or histamine were generated in the presence and absence of various drugs. The potencies against muscarinic receptor activation were estimated using the dose-ratio method of Schild. RESULTS: Three known muscarinic antagonists were used to validate the system. Atropine had a pA2 of 9.4 +/- 0.1 (n = 9). 4-DAMP and methoctramine had pA2 values of 8.6 +/- 0.1 and 5.6 +/- 0.1, respectively (n = 12, 11) all consistent with inhibition of an M3 subtype muscarinic receptor. The rank order of potency of the antihistamines against the inhibition of M3 receptors was desloratadine = diphenhydramine > hydroxyzine (pA2; 6.4, 6.2, 4.8, respectively). pA2 values for fexofenadine, loratadine and cetirizine were not determined since they had no effect on the cholinergic response at the highest drug concentrations tested (10, 10 and 100 microM, respectively). The pA2 values for the antihistamines against the histamine response could not be calculated, but the estimates of the rank order of potency were estimated to be desloratadine > cetirizine approximate to hydroxyzine > fexofenadine > loratadine > diphenhydramine. CONCLUSION: The rank order of selectivity for histamine receptors over muscarinic receptors was estimated to be cetirizine approximate to fexofenadine > loratadine > desloratadine > or = hydroxyzine > or = diphenhydramine.

Animals↗
PubMed2003

Synthesis of eosinophil infiltration inhibitors with antihistaminic activity.

A series of [1, 2, 4]triazolo[1, 5-b]pyridazines (5) and imidazo[1, 2-b]pyridazines (6) having cyclic amines was synthesized and evaluated for antihistaminic activity and inhibitory effect on eosinophil infiltration. When a piperidine or a piperazine containing a benzhydryl group and a suitable spacer was incorporated at the 6-position, the fused pyridazines were found to exhibit both antihistaminic activity and an inhibitory effect on eosinophil chemotaxis. Above all, 6a showed potent antihistaminic activity, but little blockade of central H(1) receptors in contrast with its complete blockade of peripheral H(1) receptors as determined by an ex vivo binding assay. Furthermore, 6a inhibited eosinophil infiltration of the skin caused by a topical antigen challenge in sensitized guinea pigs, while an antihistamine terfenadine was not effective. After the pharmacokinetic study, 6a was found to be rapidly hydrolyzed to 6o, which was also orally active. Compound 6o, 2-[6-[[3-[4-(diphenylmethoxy)piperidino]propyl]amino]imidazo[1, 2-b]pyridazin-2-yl]-2-methylpropionic acid dihydrate (TAK-427), having both antihistaminic and antiinflammatory activity, is currently undergoing clinical trials as a therapeutic agent for atopic dermatitis and allergic rhinitis.

Animals↗
PubMed2005

Treatment for allergic rhinitis and chronic idiopathic urticaria: focus on oral antihistamines.

OBJECTIVE: To review the efficacy and safety of first- and newer-generation antihistamines for the management of allergic rhinitis and chronic idiopathic urticaria (CIU), with a focus on management in the pharmacy. DATA SOURCES: A literature review was performed using MEDLINE (1966-October 2005), with no time or language restrictions. Key words or phrases used were histamine, antihistamine(s), first- and second-generation, allergic rhinitis, chronic idiopathic urticaria, quality of life, impairment, sedation, cost-effectiveness, astemizole, cetirizine, desloratadine, diphenhydramine, fexofenadine, loratadine, hydroxyzine, ketotifen, and mizolastine. Additional references were found in the bibliographies of the articles cited. STUDY SELECTION AND DATA EXTRACTION: Clinical trials and other experimental studies of the use of antihistamines for the management of allergic rhinitis and CIU were selected. Review papers and guidelines were also included. DATA SYNTHESIS: First-generation antihistamines are effective at ameliorating the symptoms of allergic rhinitis and CIU; however, they are associated with adverse effects due to a lack of selectivity for the histamine H(1)-receptor and an ability to bind to cerebral H(1)-receptors. Newer-generation agents, in general, possess high H(1)-receptor selectivity and a low tendency to cross the blood-brain barrier, while maintaining efficacy. In general, safety at elevated doses has been demonstrated for the newer antihistamines, although higher rates of sedation and impairment have been reported with increasing doses for some agents. CONCLUSIONS: Pharmacists can play an important role in the management of allergic rhinitis and CIU by considering the relative advantages of newer-generation agents when reviewing treatment options.

Chronic Disease↗
PubMed2002

Next generation antihistamines: therapeutic rationale, accomplishments and advances.

Antihistamines, among the most commonly prescribed drugs in the world, have evolved considerably since the first generation was introduced >50 years ago. The first generation antihistamines (e.g., chlorpheniramine, diphenhydramine, promethazine and hydroxyzine) are still widely available and in use today. These drugs have considerable sedative effects caused by their ability to cross the blood-brain barrier. The next generation of antihistamines to emerge in the market were devoid of these sedative effects; however, two (terfenadine and astemizole) have shown rare but lethal cardiotoxic side effects. The third generation antihistamines, metabolites of the earlier drugs, have demonstrated no cardiac effects of the parent drugs and are at least as potent. Many have exhibited superior pharmacokinetic and pharmacological profiles, including an improved onset of action and duration of effect. The clinical benefit of these newer oral antihistamines will clearly help improve the quality of life of patients with chronic allergies.

Animals↗
PubMed1976

Antihistamines: pharmacology and clinical use.

Antihistamines are a diverse group of drugs which possess the ability to inhibit various histaminic actions. By and large, they bear a certain structural resemblance to histamine, and act principally to prevent histamine-receptor interaction through competition with histamine for histamine receptors. Consequently, they are helpful therapeutically in preventing, rather than reversing, histaminic actions. Individual antihistaminic drugs act to inhibit histaminic action at one or another histamine receptor (H1 or H2-receptor), but not at both receptors. The large number of antihistaminics which have been available for many years and employed chiefly as 'antiallergic' drugs are classified as H1-receptor inhibitors; they are most effective therapeutically in inhibiting manifestations of histamine-induced wheal and erythema formation and pruritus. H2-receptor inhibitors, agents which are able to inhibit histamine-induced gastric acid secretion, have been developed more recently. Antihistaminics in general and H1-receptor inhibitors in particular, exert a wide variety of pharmacological activities. Their use is frequently accompanied by undesirable side-effects, notably CNS depression, dryness of mucous membranes, and gastrointestinal effects. Used judiciously and in proper dosage, antihistaminic drugs are helpful in the control of allergic disorders, allergic rhinitis and urticaria in particular; newly developed H2-receptor inhibitors show therapeutic promise in the treatment of peptic ulceration.

Administration, Topical↗
PubMed2001

New insights into the second generation antihistamines.

Second generation antihistamines are recognised as being highly effective treatments for allergy-based disease and are among the most frequently prescribed and safest drugs in the world. However, consideration of the therapeutic index or the benefit/risk ratio of the H1 receptor antagonists is of paramount importance when prescribing this class of compounds as they are used to treat non-life threatening conditions. There are many second generation antihistamines available and at first examination these appear to be comparable in terms of safety and efficacy. However, the newer antihistamines in fact represent a heterogeneous group of compounds, having markedly differing chemical structures, adverse effects, half-life, tissue distribution and metabolism, spectrum of antihistaminic properties, and varying degrees of anti-inflammatory effects. With regard to the latter, there is growing awareness that some of these compounds might represent useful adjunct medications in asthma therapy. In terms of safety issues, the current second generation grouping includes compounds with proven cardiotoxic effects and others with the potential for adverse drug interactions. Moreover, some of the second generation H1 antagonists have given cause for concern regarding their potential to cause a degree of somnolence in some individuals. It can be argued, therefore, that the present second generation grouping is too large and indistinct since this was based primarily on the concept of separating the first generation sedating compounds from nonsedating H1 antagonists. Although it is too early to talk about a third generation grouping of antihistamines, future membership of such a classification could be based on a low volume of distribution coupled with a lack of sedating effects, drug interactions and cardiotoxicity.

Anti-Asthmatic Agents↗
PubMed2006

The role of antihistamines in asthma management.

Histamine is an important mediator in airway inflammation. It is elevated in the airways of asthmatic patients and is responsible for many of the pathophysiological features in asthma. Antihistamines block the actions of histamine and also have effects on inflammation which is independent of histamine-H(1)-receptor antagonism. Antihistamines have been shown to have bronchodilatory effects, effects on allergen-, exercise-, and adenosine-monophosphate-challenge testing, and also to prevent allergen-induced nonspecific airways hyperresponsiveness. Clinical studies have shown mixed results, and some studies have reported beneficial effects of azelastine, cetirizine, desloratadine, and fexofenadine on asthma symptoms or physiological measures in patients with asthma. The combination of an antihistamine and a leukotriene receptor antagonist has been shown to have additive effects in certain studies. Antihistamines have also been shown to delay or prevent the development of asthma in a subgroup of atopic children. These data suggest that antihistamines may have beneficial effects in the management of asthma.

Asthma↗
PubMed2006

In-silico pharmacodynamics: correlation of adverse effects of H2-antihistamines with histamine N-methyl transferase binding potential.

Adverse effects are exhibited by most drugs in current clinical practice, the causes for which are often not known. In this post genomic era, bioinformatics has the potential to address several issues in understanding the mechanism of drug action and in designing improved drugs. This study describes the analysis of the possible pharmacodynamic behaviour of antihistamines blocking the histamine H(2) receptor (H(2)-antihistamines), by adopting the basic tenets of a systems biology approach. The different components that could form an appropriate sub-system are identified, thus providing a system landscape. Docking and analysis of the chosen antihistamines into each of these components resulted in identifying histamine N-methyl transferase (HNMT) as a potential unintended target for H(2)-antihistamines. Correlation with experimental data available from the literature indicates the inhibition of HNMT to be a possible cause for the adverse effects exhibited by these drugs. Implications for design of safer H(2)-antihistamines are discussed. The method reported here has the potential for application as a general strategy in understanding drug effects.

Binding Sites↗