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PubMed1985

Analgesic effects of antihistaminics.

The literature provides considerable evidence indicating that several, but not all antihistaminics, are indeed analgesic agents and some are analgesic adjuvants as well. Those for which effectiveness is reported includes diphenhydramine, hydroxyzine, orphenadrine, pyrilamine, phenyltoloxamine, promethazine, methdilazine, and tripelennamine. The proposed mechanisms of analgesic action of antihistaminics are reviewed and discussed. The literature suggests that more than one mechanism of action exists for them. There is considerable evidence suggesting that histaminergic and serotoninergic central pathways are involved in nociception and that antihistaminic drugs can modulate their responses (1). The evidence for a role for norepinephrine and dopamine and the effects of antihistaminics on them are less well established. Still other pathways have been proposed. A greater understanding of pain mechanisms will aid in elucidating the role of antihistaminics in analgesia.

Analgesia↗
PubMed1993

The comparative actions and adverse effect profile of single doses of H1-receptor antihistamines in the airways and skin of subjects with asthma.

BACKGROUND: The development of potent H1-receptor antagonists that are free of adverse effects has renewed interest in their use in the treatment of asthma. METHODS: We performed a study of the action of chlorpheniramine, terfenadine, brompheniramine, cetirizine, cyproheptadine, clemastine, and astemizole compared with placebo on histamine-induced skin wheals and bronchoconstriction in a single group of patients with asthma. Another group underwent methacholine bronchoprovocation. RESULTS: Antihistamine pretreatment increased mean baseline measurements of forced expiratory volume in 1 second (FEV1) between 2.58% and 9.28% compared with placebo, which was significant for all drugs except brompheniramine and clemastine. Compared with placebo, all antihistamines provided significant protection against histamine-induced bronchoconstriction when measured as the provocation concentration required to cause a 20% fall in FEV1; terfenadine and cetirizine provided significantly greater protection than other antihistamines. Protection against histamine-induced skin wheals, measured as the slope of the log concentration-response curve, was only significant for the new drugs, terfenadine and cetirizine. There was a good correlation between the protective effect of the drugs in the skin and airways (r = 0.85; p < 0.01). No significant difference in methacholine provocation concentration required to cause a 20% fall in FEV1 values between treatments was found. CONCLUSIONS: The new H1-receptor antagonists terfenadine and cetirizine provided significantly better protection than the older antihistamines against the action of histamine in the skin and airways. None of the antihistamines showed evidence of anticholinergic activity in the asthmatic airways at the doses studied.

Adult↗
PubMed1991

Treatment of urticaria and angioedema: low-sedating H1-type antihistamines.

H1-type antihistamines are considered the therapeutic agents of choice for treating urticaria and angioedema. The use of traditional H1 antihistamines is limited by their side effects. In recent years low-sedating H1 antihistamines with reduced sedative and anticholinergic side effects have become popular choices for the treatment of urticaria and angioedema. Terfenadine and astemizole are currently available in the United States, and cetirizine and loratadine, currently under review at the Food and Drug Administration, are available in other countries. Terfenadine, cetirizine, and loratadine achieve rapid peak plasma concentrations in 1 to 2 hours, whereas astemizole has a slow onset of action. In double-blind, placebo-controlled studies of chronic idiopathic urticaria, low-sedating H1 antihistamines were more effective than placebo. The choice of a particular low-sedating H1 antihistamine depends on pharmacokinetic considerations and frequency of administration.

Angioedema↗
PubMed1995

Drugs with antihistaminic properties as a cause of atypical cutaneous lymphoid hyperplasia.

BACKGROUND: Although an association between antihistaminic drugs and atypical cutaneous lymphoid infiltrates has not been reported previously, in vitro evidence suggests that these agents perturb certain lymphoid functions through binding to histamine receptors, including a novel growth-promoting intracellular histamine receptor, designated HIC. OBJECTIVE: We studied the clinical findings and histopathologic findings in 14 patients taking antihistaminic drugs in whom atypical cutaneous lymphoid infiltrates developed. METHODS: We retrospectively reviewed the clinical and histologic features of these patients' skin lesions. RESULTS: The clinical presentations included solitary or multiple nodules and plaques, and multiple papules. In some patients a temporal association between drug therapy and clinical course was observed, as the lesions improved or resolved after a decrease or discontinuation of the drug. Eleven patients were taking two or more medications that in vitro are associated with alterations in lymphocyte function, including agents without antihistaminic properties. A diagnosis of pseudolymphoma seemed clinically apposite in seven of the 14 patients on the basis of either resolution of the eruption or presentation of a solitary nodule that did not recur after excision. Histologic analysis showed four distinct morphologies: mycosis fungoides-like, nodular dermal infiltrates consistent with either lymphocytoma cutis or lymphoma cutis, lymphomatoid vascular reaction, and follicular mucinosis. Common to cases showing the first pattern were histologic features suggesting a delayed-type hypersensitivity reaction, thus enabling their distinction from mycosis fungoides. The infiltrates were predominantly of T-cell phenotype. CONCLUSION: Antihistamines are associated with atypical lymphoid hyperplasia in some patients. The antihistaminic drug may not be the provocative agent per se; rather, a drug-induced immunodysregulatory state may render an abnormal immune response to some other exogenous antigen. Multidrug therapy with these and other agents known to exert immunomodulatory effects may increase susceptibility to the development of atypical lymphoid hyperplasia and malignant lymphoma.

Adult↗
PubMed2004

Drug interaction between methamphetamine and antihistamines: behavioral changes and tissue concentrations of methamphetamine in rats.

Methamphetamine is a psychomotor stimulant, whereas first generation antihistamines cause sedation. Several studies have demonstrated that first generation antihistamines potentiate methamphetamine-induced psychomotor activation and two possible mechanisms have been postulated. One is blockage of the central histaminergic neuron system and the other is inhibition of dopamine reuptake. However, the exact mechanism is still controversial. In this study, we examined in behavioral tests the effects of selected antihistamines on methamphetamine-induced psychomotor activation in rats, and measured plasma and brain tissue concentrations of methamphetamine. We found that some antihistamines significantly potentiate methamphetamine-induced psychomotor activation in rats and that plasma and brain tissue concentrations of methamphetamine in rats treated with methamphetamine in combination with D-chlorpheniramine were markedly higher than those in rats treated with methamphetamine alone. These results suggest that the potentiating effects of antihistamines are due to not only central effects but also the alteration of the pharmacokinetics of methamphetamine.

Animals↗
PubMed2002

Comparative pharmacology of H1 antihistamines: clinical relevance.

H1 antihistamines have similar efficacy in the treatment of allergic disorders; however, they differ in terms of their chemical structure, clinical pharmacology, and safety. This review focuses on the clinical pharmacology (pharmacokinetics and pharmacodynamics) of the newer oral H1 antihistamines (acrivastine, cetirizine, desloratadine, ebastine, fexofenadine, levocetirizine, loratadine, and mizolastine). Understanding the pharmacokinetics and pharmacodynamics of these H1 antihistamines provides an objective basis for selection of appropriate dosages and dose intervals. Pharmacokinetic and pharmacodynamic studies provide a rationale for the modified dosage regimens that may be required in special populations, such as the very young, the elderly, those with hepatic or renal dysfunction, or those taking other medications concurrently. Many H1 antihistamines are currently available for use. Clinical pharmacology studies help physicians to select the best H1 antihistamines for their patients.

Administration, Oral↗
PubMed1998

Cancer recurrences and secondary primary cancers after use of antihistamines or antidepressants.

OBJECTIVES: Reports in the scientific literature have described accelerated tumor growth in association with antidepressant and antihistamine exposure in experimental rodent cancer models. This study was designed to determine whether exposure to prescription antidepressants or antihistamines is associated with tumor growth in humans. METHODS: Two nested case-control studies were conducted with a cohort of 1467 patients with breast cancer, colon cancer, or melanoma diagnosed between 1988 and 1994. Eligible patients included 95 with a cancer recurrence and 78 with a second primary lesion diagnosed during the follow-up period. Five control subjects were matched to each case patient according to cancer site, stage, and follow-up time. Conditional logistic regression was used to compare risk for tumor recurrence or occurrence of a second primary tumor among patients using antidepressants or antihistamines with risk among unexposed patients. RESULTS: For a cohort of patients who were predominantly female (78%), with breast cancer (57%) and with a tumor in situ or with localized disease (79%), the average age was 62 years at cancer diagnosis and average duration of follow-up period was 2.2 years. Use of antidepressants or antihistamines was unrelated to risk for tumor recurrence (odds ratio, 0.97; 95% confidence interval, 0.52 to 1.78) or second primary tumors (odds ratio, 0.94; 95% confidence interval, 0.50 to 1.77). CONCLUSION: Typical use of antidepressant or antihistamine drugs did not increase risk for recurrent or second primary tumors among patients with cancer.

Adult↗
PubMed1990

Allergen-induced increase in nonspecific nasal reactivity is blocked by antihistamines without a clear-cut relationship to eosinophil influx.

Antihistaminic compounds have been suggested to possess other properties besides H1-receptor antagonism. To evaluate whether two different antihistamines could inhibit local eosinophil infiltration and allergen-induced nonspecific nasal hyperreactivity, 15 subjects with seasonal allergic rhinitis participated in a double-blind, randomized, placebo-controlled study outside the pollen season. At steady-state levels of either 60 mg of terfenadine, twice daily, cetirizine, 10 mg once daily, or placebo, a nasal methacholine challenge was performed before and 24 hours after a nasal allergen challenge. The volume of the methacholine-induced nasal secretions was measured. The response to allergen was determined with a scoring technique. Cells from the nasal mucosal surface were harvested with the aid of a rhinobrush. Both antihistamines induced a similar (p less than 0.01) reduction in nasal symptoms after the allergen challenge compared with placebo. Both antihistamines inhibited the increased nonspecific nasal reactivity induced by methacholine 24 hours later (p less than 0.05). The allergen challenge induced an increase in surface eosinophils, which, however, appeared unaffected by any of the active treatments. Since histamine per se does not induce changes in nonspecific reactivity, we suggest that the antihistamines possess other properties besides being H1-receptor antagonists.

Allergens↗
PubMed1990

The role of antihistamines in the treatment of chronic urticaria.

For many years, H1 antihistamines have been the primary management option for urticaria. However, undesirable side effects, particularly daytime sedation, have limited the usefulness of these classic antihistamines. A new class of peripherally acting, nonsedating antihistamines (e.g., terfenadine, astemizole, loratadine, and cetirizine) has proved to have clinical efficacy comparable with the classic antihistamines. In comparative trials between the various nonsedating agents, no significant difference in efficacy has been noted. All these agents have good safety profiles, although astemizole use has been correlated with increased appetite and weight gain in some patients, and cetirizine has caused slightly increased sedative effects compared with placebo. Although H1/H2 antihistamine combinations have been proposed as possible treatments for urticaria, studies have produced mixed results.

Chronic Disease↗
PubMed2002

The effect on social welfare of a switch of second-generation antihistamines from prescription to over-the-counter status: a microeconomic analysis.

BACKGROUND: The US Food and Drug Administration (FDA) recently held a meeting to determine whether the status of second-generation antihistamines (SGAs) should be switched from prescription (Rx) to over-the-counter (OTC) status. OBJECTIVE: This article provides a conceptual microeconomic framework for addressing issues regarding the impact of such a switch on social welfare. METHODS: A review of the economic literature on Rx-to-OTC switches was conducted. Relevant articles published in English between 1990 and 2001 were identified through searches of ABI Info, EconLit, PsychInfo, MEDLINE, CANCERLIT, AIDSLINE, and HealthStar, as well as a general Internet search for statements in the press or on the FDA Web site. The search terms used were Rx, prescription, OTC, over-the-counter, second-generation antihistamines, nonsedating antihistamines, first-generation antihistamines, and sedating antihistamines. Microeconomic models focusing on consumer surplus were employed to determine the potential price response and social-welfare implications of a switch of SGAs to OTC status. RESULTS: Unlike the agents involved in previous Rx-to-OTC switches, SGAs are still under patent protection. Economic theory suggests that a firm that is protected by a patent will price aggressively. The market for OTC SGAs is likely to be more elastic due to a lack of insurance coverage for OTC products; hence, drug manufacturers would be likely to charge a lower price if SGAs were sold OTC. However, a lower price does not necessarily guarantee an improvement in social welfare; the net impact is determined by whether the increase in consumer surplus outweighs the deadweight loss (losses of consumer and producer surplus not transferred to other parties). Additionally, the assumption of a price reduction would be called into question if there were inequalities in marginal costs between the Rx and OTC markets. In this situation, the postswitch price might increase or not be reduced significantly. CONCLUSIONS: It is uncertain whether granting OTC status to SGAs would be cost saving to society, particularly as these drugs are patent protected. The social-welfare implications of such a switch would depend heavily on pricing strategies and consumer behavior. Further analyses are needed to determine how both factors influence social welfare; only then can the costs and benefits of a switch be understood completely.

Drug Industry↗
PubMed2001

The ACVD task force on canine atopic dermatitis (XXI): antihistamine pharmacotherapy.

Antihistamines frequently are recommended by veterinary dermatologists for symptomatic treatment of pruritus associated with canine atopic dermatitis (AD), perhaps because of their moderate success in some human patients with AD. A critical review of the literature describing antihistamine use in canine AD reveals that the majority of published, peer-reviewed studies are open, uncontrolled or partially-controlled trials. Such studies vary widely in reported efficacy, from perhaps 0 to 75% of patients, even using the same drug. The few blinded placebo-controlled trials available have failed to confirm efficacy of these drugs to relieve the pruritus of canine AD. Some studies indicate that synergistic effects could occur with concurrent use of essential fatty acid supplements. Consequently, at the time of this writing, there is insufficient evidence to conclude for or against the efficacy of antihistamines for treatment of canine AD. Additional blinded, randomized and controlled trials with larger numbers of patients are necessary to establish which of the antihistamine drugs currently available, if any, are truly efficacious for canine AD. Nevertheless, present clinician consensus suggests that several different antihistamine drugs should be evaluated in sequence, for 7-14 days each, in canine patients with AD.

Animals↗
PubMed1998

A review and investigation into the mechanistic basis of the genotoxicity of antihistamines.

The genotoxicity of twenty one clinically used (or discontinued) antihistamines is reviewed. New results are also presented from an evaluation of selected antihistamines in the V79 in vitro micronucleus assay. For two antihistamines, no genotoxicity data is available. Of the remaining nineteen, nine have been reported as positive and one equivocal in at least one genotoxicity assay despite the fact that none possess structural alerts for genotoxicity. Ethidium displacement and bleomycin amplification studies in V79 cells indicate that nine of these ten antihistamines are capable of intercalative DNA binding. Further, nine of the ten positive compounds, but none of the tested compounds which also intercalate but are reported to be negative in gene-tox assays (e.g. triprolidine, chlorcyclizine, clemastine), possess a dimethylamino substituent suggesting the requirement for this cationic function in the genotoxicity. It is proposed that the apparent genotoxicity of antihistamines and possibly many other pharmaceuticals derives from a hitherto unappreciated propensity of these drugs for stabilized intercalative DNA binding. It is further proposed that the bleomycin amplification assay may provide a widely applicable means for assessing functional intercalative drug/DNA interaction in intact mammalian cells.

Animals↗
PubMed1986

Synthesis of 2-(4-substituted-1-piperazinyl)benzimidazoles as H1-antihistaminic agents.

A series of 2-(4-substituted-1-(homo)piperazinyl)benzimidazoles was prepared and tested for H1-antihistaminic activity in vitro and in vivo. Most of the compounds showed antihistaminic activity and some of the 1-[2-(substituted-oxy)ethyl] derivatives exhibited potent activity. In a structure-activity comparison it was found that the oxygen atom in the 2-(substituted-oxy)ethyl group at the 1-position of the benzimidazole nucleus played an important role for potent antihistaminic activity, especially in vivo. One of the most potent compounds, 1-(2-ethoxyethyl)-2-(4-methyl-1-homopiperazinyl)benzimidazole (69), was 39 times more potent than chlorpheniramine maleate in H1-antihistaminic activity in vivo and was selected for clinical evaluation. The structure of compound 69 is of interest because it provides only a single aromatic unit linked through a chain to a basic nitrogen, while most H1-antihistaminic agents have structures that comprise a double-aromatic unit linked through a chain to a basic tertiary amino group.

Animals↗
PubMed1992

Differential plasma duration of antiplatelet-activating factor and antihistamine activities of oral Sch 37370 in humans.

Preclinical studies have established that Sch 37370 (1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo[5,6]-cyclohepta [1,2-b]pyridin-11-ylidene)piperidine) is an orally active antagonist of platelet-activating factor (PAF) and histamine H1-receptors with potential therapeutic use in the treatment of asthma. To evaluate the efficacy and duration of anti-PAF and antihistamine actions of oral Sch 37370 in humans, a single dose (5 mg/kg) of Sch 37370 was given orally to each of 10 male subjects in a placebo-controlled, double-blind crossover study. Blood samples were drawn before and at various times (2 to 48 hours) after Sch 37370 or placebo. Plasma samples were analyzed for Sch 37370 by a gas chromatographic method, for the anti-PAF activity by measuring the aggregation of platelets stimulated with PAF, and for the antihistamine activity by measuring displacement of [3H]pyrilamine from rat brain membrane binding sites. The plasma anti-PAF activity declined from high levels at 2 hours to barely detectable levels at 24 hours; however, significant activity was still present at 12 hours. The plasma levels of Sch 37370 closely paralleled the anti-PAF profile. The plasma antihistamine activity reached a maximum within 2 to 8 hours and declined thereafter. However, 48 hours after Sch 37370, the antihistamine activity was still present at a significant level in most subjects. It is concluded that, in humans, oral Sch 37370 antagonizes both PAF and histamine with plasma antihistamine activity lasting longer than plasma anti-PAF activity.

Administration, Oral↗
PubMed1999

Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity.

Despite the enormous success of second generation antihistamines, in the mid-1980s, about 10 years after their introduction in the market, several reports appeared in the literature indicating the rare occurrence of a form of polymorphic ventricular dysrhythmia, the 'torsade de pointes', after the administration of astemizole or terfenadine. This cardiac side-effect has been interpreted as a consequence of the interference of these drugs with cardiac K+ channels involved in action potential repolarization, and in particular with the IKr component of the cardiac repolarizing current. As the K+ channels encoded by the human ether-a-gogo-related gene (HERG) seem to represent the molecular basis of IKr, this cardiac K+ channel was soon recognized as a primary target for second generation antihistamine-induced proarrhythmic effects. In fact, both terfenadine and astemizole have been shown to block HERG K+ channels in a concentration range similar to that found in the plasma of subjects with cardiotoxic manifestations. However, no correlation can be found between the ability to prolong the cardiac action potential duration and the H1-antagonistic activity by several antihistamines, suggesting that HERG blockade and cardiotoxic potential are not class properties of second generation antihistamines. In fact, other molecules such as cetirizine, loratadine, acrivastine, and fexofenadine seem to lack both cardiotoxic potential and HERG-blocking ability at therapeutically relevant concentrations. The marked heterogeneity displayed by second generation antihistamines in their ability to prolong the cardiac action potential duration and to block HERG K+ channels might be of considerable therapeutical significance for those patients at risk of developing cardiac dysrhythmias and in need of therapy with H1-receptor blockers; it also emphasizes the importance of an evaluation of the possible blockade of HERG K+ channels during the early developmental phases of novel compounds belonging to this therapeutical class.

Cation Transport Proteins↗
PubMed1999

Spontaneous reporting of suspected adverse reactions to antihistamines: a national and international perspective.

Twenty-one sedative and five non-sedating antihistamines are presently available on the UK market. Analysis of spontaneous reports of suspected adverse drug reactions was performed for those drugs with more than 90 reported reactions on the UK ADROIT database to the period ending 31 December 1997. Thus nine antihistamines, (four sedative antihistamines and five non-sedating antihistamines) were included. For each of the four sedative agents (azatidine, chlorpheniramine, diphenhydramine and trimeprazine), reactions associated with the cardiovascular, gastrointestinal, central nervous systems, the skin, general and psychiatric reactions made up more than 70% of total reported reactions. For all four agents, fatal reactions constituted less than 2.5% of total reactions. For each of the five non-sedating agents (acrivastine, astemizole, cetirizine, loratidine and terfenadine), reactions associated with the cardiovascular, gastrointestinal central nervous systems, the skin, general and psychiatric disorders together made up more than 75% of total reported reactions. For all five non-sedating agents, fatal reactions constituted less than 1% of total reactions. However, there were 21 reports of fatality in association with terfenadine, 11 (52%) of which were either sudden deaths or those associated with a cardiac rate of rhythm reaction. Analysis of the WHO database for non-sedating drugs showed a similar pattern, with terfenadine being associated with the highest frequency of reports of potentially serious arrhythmias and of sudden death and death related to disturbances of cardiac rate and rhythm combined. Despite the limitations of spontaneous reporting systems, comparison of the benefit-risk profiles of drugs using this data within a class of drugs can provide valuable information, and pharmacovigilance of antihistamines (and all other agents) using this and other means should continue for the lifetime of their use in humans.

Adverse Drug Reaction Reporting Systems↗
PubMed1997

Pregnancy outcome following first trimester exposure to antihistamines: meta-analysis.

To determine the relative risk for major malformations associated with antihistamine (H1 blockers) exposure in the first trimester of pregnancy, a literature search of all studies examining the association between antihistamines and major malformations for the period 1960 to 1991 was conducted, followed by meta-analysis. Odds ratio was calculated using the Mantel-Haenszel method. Twenty-four controlled studies met the inclusion criteria with more than 200,000 participating women. The summary odds ratio of major malformations associated with antihistamines taken during the first trimester was 0.76 (95% CI: 0.60-0.94). This analysis indicates that H1 blockers used mainly for morning sickness during the first trimester do not increase the teratogenic risk in humans and may, in fact, be associated with a protective effect. More study is needed to verify the possibility that by preventing vomiting, antihistamines may ensure better metabolic conditions to the fetus and thus may reduce some birth defects. Alternatively, it is possible that pregnancies characterized by vomiting are associated with better outcome due to other reasons, such as hormonal status or placental function. Women suffering from morning sickness which is not controlled by nonpharmacological methods can safely use antihistamines.

Abnormalities, Drug-Induced↗
PubMed2000

The effects of antihistamines on cognition and performance.

Allergic diseases are responsible for substantially more disability than is generally realized. Allergic rhinitis alone results in 3.5 million lost workdays and 2 million missed school days in the United States each year. Comorbid conditions such as asthma and sinusitis can be disabling as well, resulting each year in more than 10 million missed school days and more than 73 million days of restricted activity, respectively. Antihistamines continue to be the mainstay of treatment for allergic disorders. In the case of the first-generation antihistamines, however, the treatment may well be worse than the disease. Although these agents are effective H(1)-receptor antagonists, they are also highly lipophilic and readily cross the blood-brain barrier, causing considerable sedation. The second-generation agents are more lipophobic and possess different ionic charges than the first-generation antihistamines. As a result, they are far less likely to cross the blood-brain barrier and, for that reason, cause little if any sedation. In a recent comparative trial, subjects who were treated with the first-generation agent diphenhydramine were found to have significant performance deficits on tests of divided attention, working memory, vigilance, and speed. By contrast, subjects who were treated with the second-generation antihistamine loratadine performed as well as subjects who were treated with placebo. The sedative effects of the first-generation agents persist well into the next day and thus can potentially interfere with daytime performance and safety even when taken the night before. It is therefore recommended that patients whose occupations require vigilance, divided attention, or concentration receive only second-generation antihistamines.

Administration, Oral↗