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Effect of antihistamines on argon laser-induced cutaneous sensory and pain thresholds and on histamine-induced wheal and flare.

A double-blind, randomized, placebo-controlled comparison of the analgesic and antihistaminic effects of four commonly used antihistamines (terfenadine, antazoline, diphenhydramine and cimetidine) was performed. Wheal and flare areas after histamine skin prick and sensory and pain thresholds induced by cutaneous argon laser irradiation were determined. Terfenadine, antazoline and diphenhydramine significantly reduced wheal and flare after histamine skin pricks. Only diphenhydramine increased the pain threshold to noxious cutaneous laser stimulations (22%) with a concomitant reduction of histamine wheal (61.5%) and flare (52.8%). The sensory threshold was not affected significantly. The antihistaminic and analgesic effects were not related.

Adult↗

HERG, a primary human ventricular target of the nonsedating antihistamine terfenadine.

BACKGROUND: Administration of the antihistamine terfenadine (Seldane) to patients may result in acquired long QT syndrome and ventricular arrhythmias. One human cardiac target is Kv1.5, which expresses the ultrarapid outward K+ current (Ikur) in atrium but may play only a minor role in ventricle. Another possible target is HERG, the human ether-a-go-go-related gene that expresses a delayed rectifier current (IKr) in human ventricle and produces hereditary long QT syndrome when defective. METHODS AND RESULTS: We therefore heterologously expressed Kv1.5 and HERG in Xenopus oocytes to compare the sensitivity of each to terfenadine. We found that HERG was 10 times more sensitive than Kv1.5 to terfenadine block. The apparent Kd values for HERG and Kv1.5 currents were 350 nmol/L and 2.7 mumol/L, respectively. These Kd values compare well with values reported for terfenadine block of IKr and IKur currents in human atrial myocytes. The Kd value for HERG block is relevant to the toxicity of the antihistamine, since the clinical terfenadine concentrations in human plasma may reach the 100 nmol/L range. CONCLUSIONS: Terfenadine carboxylate, the major metabolite of terfenadine, does not block either HERG or Kv1.5, which agrees with the hypothesis that the buildup of parent terfenadine is the likely explanation for its cardiotoxicity. We propose that the blocking of HERG by terfenadine explains the acquired long QT syndrome. HERG is likely to be the primary target for the known cardiotoxic effects of other, related antihistamines.

Animals↗

A double-blind, placebo-controlled trial of decongestant-antihistamine for the treatment of sinusitis in children.

We studied the effectiveness of nasal decongestant-antihistamine in treating acute sinusitis in children. All subjects received oral amoxicillin for 14 days. Subjects randomized to the decongestant-antihistamine group received nasal oxymetazolone and oral syrup containing brompheniramine and phenylpropanolamine. Controls received placebo nasal saline and oral syrup. In both groups symptoms resolved quickly, and radiographs improved significantly. Responses to treatment were similar between the two groups. Water's radiographs of the maxillary sinuses proved reliable in the assessment of the degree of sinus involvement. We conclude that decongestant-antihistamine need not be given to the child with acute maxillary sinusitis.

Acute Disease↗

Astemizole: a long-acting, nonsedating antihistamine.

Astemizole is a long-acting, highly selective histamine1-receptor antagonist with minimal central and anticholinergic effects. Comparison studies have shown astemizole to be equal or superior to currently available antihistamines, beclomethasone nasal spray, and cromolyn sodium in relieving allergic symptoms of seasonal and perennial allergic rhinitis. Other uses include treatment of allergic conjunctivitis and chronic urticaria. Astemizole is not as effective for treatment of acute allergic symptoms because of its delayed onset of action. Astemizole and its active metabolite, desmethylastemizole, have long elimination half-lives permitting once-daily dosing. The incidence of sedation is lower than with conventional antihistamines, but increased appetite and weight gain do occur. Astemizole should be useful for both maintenance and prophylactic therapy in patients with chronic allergic conditions who cannot tolerate the sedative or anticholinergic effects of conventional antihistamines.

Animals↗

Cetirizine from topical phosphatidylcholine-hydrogenated liposomes: evaluation of peripheral antihistaminic activity and systemic absorption in a rabbit model.

Cetirizine, an effective, minimally sedating, second-generation H1-antihistamine is widely used orally to treat allergic skin disorders. This study was performed to assess the peripheral H1-antihistaminic activity and extent of systemic absorption of cetirizine from liposomes applied to the skin. Cetirizine was incorporated into small unilamellar vesicles (SUV) and multilamellar vesicles (MLV) prepared using L-alpha-phosphatidylcholine hydrogenated (HPC), and into Glaxal Base (GB) as the control. In a randomized, crossover study, each formulation, containing 10 mg of cetirizine, was applied to the depilated backs of 6 rabbits (3.08 +/- 0.05 kg). Histamine-induced wheal tests and blood sampling were performed before cetirizine application and at designated times for up to 24 hours afterwards. Compared with baseline, histamine-induced wheal formation was suppressed by cetirizine in SUV only at 24 hours, in MLV from 0.5 to 24 hours, and in GB from 0.5 to 8 hours (P < or = .05). Wheal suppression by cetirizine in SUV at 24 hours (91.7% +/- 5.2%) and in MLV from 1 to 24 hours (93.8% +/- 2.2% to 76.2% +/- 6.5%) was greater than in GB (36.5% +/- 7.4% to 60.6% +/- 14.2%) from 1 to 24 hours (P < or = .05). Faster onset, as well as greater and more persistent suppression was obtained from cetirizine in MLV. Plasma cetirizine concentrations from MLV (area under the curve [AUC] of 221.2 +/- 42.3 ng x hr/mL) were lower than from GB (AUC of 248.3 +/- 34.6 ng.hr/mL). In this model, cetirizine from MLV had excellent topical H(1)-antihistamine activity, while systemic exposure was reduced, compared with cetirizine from GB.

Absorption↗

Bioisosteric transformation of H1-antihistaminic benzimidazole derivatives.

With the aim of obtaining new H1-antihistaminic agents, transformations of previously reported antihistaminic benzimidazoles were performed on the basis of the concept of bioisosterism. Among the compounds prepared, imidazo[4,5-b]pyridine (8) and 4(3H)-quinazolinone (11) exhibited significant H1-antihistaminic activity.

Animals↗

Antimuscarinic effects of antihistamines: quantitative evaluation by receptor-binding assay.

Quantitative evaluation of antimuscarinic effects of antihistamines (H1- and H2-receptor antagonists) was carried out using a receptor-binding assay. The -inhibition constants (Ki values) of twenty seven H1-receptor antagonists, one related antidepressant and three H2-receptor antagonists at H1-receptors and muscarinic receptors in the bovine cerebral cortex were determined. All the H2-receptor antagonists examined showed very low affinity for the muscarinic receptors. On the other hand, some H1-receptor antagonists (mequitazine, cyproheptazine, clemastine, diphenylpyraline, promethazine, homochlorcyclizine and alimemazine) had high affinity for the muscarinic receptors (Ki = 5.0-38 nM). Another group of H1-receptor antagonists (mepyramine, terfenadine, metapyrilen, azelastine, hydroxyzine and meclizine) had low affinity for the muscarinic receptors (Ki = 3,600-30,000 nM). Thus, a broad range of antimuscarinic potencies among the antihistamines was demonstrated. These results should provide helpful information with regard to the clinical and experimental use of antihistamines.

Animals↗

A review of the second-generation antihistamine ebastine for the treatment of allergic disorders.

Ebastine is a once-daily, non-sedating, selective, long-acting, second-generation antihistamine. The use of ebastine is indicated in patients suffering from intermittent and persistent allergic rhinitis and chronic idiopathic urticaria. Ebastine 10 mg/day, appears as effective as other second-generation antihistamines, such as cetirizine and loratadine. Ebastine 20 mg/day is indicated in patients with moderate and severe allergic symptoms. No cardiovascular effects of ebastine are described, although there is a pharmacokinetic interaction when ketoconazole or macrolides are co-administered. Ebastine has no relevant effects on the psychomotor performance. Even with ebastine 20 mg/day skilled performance does not appear to be impaired. Furthermore, ebastine 5-10 and 2.5 mg, appears to be efficient and can be used safely in children 6-11 and 2-5 years of age, respectively. Ebastine appears to be a safe, effective and well-tolerated second-generation antihistamine in the treatment of allergic rhinitis and chronic idiopathic urticaria.

Anti-Allergic Agents↗

Blockade of cardiac potassium and other channels by antihistamines.

The use of terfenadine and astemizole, two long-acting nonsedating histamine H1 receptor antagonists, has been associated with prolongation of the QT interval, development of ventricular arrhythmias, particularly torsade de pointes, and sudden cardiac death. Both drugs block the rapidly activating component of the delayed rectifier channel, I(Kr). At much higher concentrations, they also block several other cardiac channels (Na+, Ca2+, K+). Since many other antihistamines can also block one or other of the cardiac ion currents (e.g. loratadine blocks the human cardiac K+ channel, hKv1.5, with the same potency as terfenadine), these results are also reviewed and their clinical relevance discussed. Because of the proarrhythmic risk, some antihistamines should be taken only at the recommended doses and avoided in patients with liver disease or in those taking medications that inhibit oxidative cytochrome P-450 enzymes. These drugs should also be avoided in those with the congenital long QT syndrome or with secondary forms of delayed repolarisation (hypokalaemia, bradycardia, drug-induced QT prolongation). Identification of predisposing factors could enable physicians to anticipate, and thereby avoid, this potentially lethal complication of antihistamine therapy.

Animals↗

Safety and tolerability profiles of intranasal antihistamines and intranasal corticosteroids in the treatment of allergic rhinitis.

Intranasal corticosteroids and intranasal antihistamines are efficacious topical therapies in the treatment of allergic rhinitis. This review addresses their relative roles in the management of this disease, focusing on their safety and tolerability profiles. The intranasal route of administration delivers drug directly to the target organ, thereby minimising the potential for the systemic adverse effects that may be evident with oral therapy. Furthermore, the topical route of delivery enables the use of lower doses of medication. Such therapies, predominantly available as aqueous formulations following the ban of chlorofluorocarbon propellants, have minimal local adverse effects. Intranasal application of therapy can induce sneezing in the hyper-reactive nose, and transient local irritation has been described with certain formulations. Intranasal administration of corticosteroids is associated with minor nose bleeding in a small proportion of recipients. This effect has been attributed to the vasoconstrictor activity of the corticosteroid molecules, and is considered to account for the very rare occurrence of nasal septal perforation. Nasal biopsy studies do not show any detrimental structural effects within the nasal mucosa with long-term administration of intranasal corticosteroids. Much attention has focused on the systemic safety of intranasal application. When administered at standard recommended therapeutic dosage, the intranasal antihistamines do not cause significant sedation or impairment of psychomotor function, effects that would be evident when these agents are administered orally at a therapeutically relevant dosage. The systemic bioavailability of intranasal corticosteroids varies from <1% to up to 40-50% and influences the risk of systemic adverse effects. Because the dose delivered topically is small, this is not a major consideration, and extensive studies have not identified significant effects on the hypothalamic-pituitary-adrenal axis with continued treatment. A small effect on growth has been reported in one study in children receiving a standard dosage over 1 year, however. This has not been found in prospective studies with the intranasal corticosteroids that have low systemic bioavailability and therefore the judicious choice of intranasal formulation, particularly if there is concurrent corticosteroid inhalation for asthma, is prudent. There is no evidence that such considerations are relevant to shorter-term use, such as in intermittent or seasonal disease. Intranasal therapy, which represents a major mode of drug delivery in allergic rhinitis, thus has a very favourable benefit/risk ratio and is the preferred route of administration for corticosteroids in the treatment of this disease, as well as an important option for antihistaminic therapy, particularly if rapid symptom relief is required.

Administration, Intranasal↗

Pharmacokinetic-pharmacodynamic relationships of H1-antihistamines.

Histamine H1-receptor antagonists are reversible, competitive inhibitors of the actions of histamine, a critical mediator in the pathophysiology of the allergic response. This review is mainly devoted to second generation antihistamines that possess a low sedation potential compared with first generation compounds. The pharmacokinetic and pharmacodynamic data of 10 compounds have been updated. Some values are lacking for drugs under development, but also for older antihistamines. Thereafter, pharmacokinetic-pharmacodynamic relationships are reported from published or original documents. A linear pharmacokinetic-pharmacodynamic relationship has been found for acrivastine, astemizole, cetirizine, ebastine and terfenadine, whereas nonlinear relationships have been calculated for ebastine (in the dog), levocabastine, mizolastine, noberastine and terfenadine. It must be concluded that this type of approach for therapeutic optimisation is very fruitful and may enable large numbers of clinical studies to be avoided. Trends for the future include: (i) in vitro binding studies with the human H1-receptor obtained by molecular biology; (ii) the characterisation of the cytochromes P450 responsible for the biotransformation of antihistamine; (iii) the calculation of the pharmacokinetic-pharmacodynamic relationship in healthy individuals; and (iv) prospective effect-controlled clinical studies.

Histamine H1 Antagonists↗

Selecting the optimal oral antihistamine for patients with allergic rhinitis.

Allergic rhinitis (AR) is now recognised as a global health problem that affects 10-30% of adults and up to 40% of children. Each year, millions of patients seek treatment from their healthcare provider. However, the prevalence of AR maybe significantly underestimated because of misdiagnosis, under diagnosis and failure of patients to seek medical attention. In addition to the classical symptoms such as sneezing, nasal pruritus, congestion and rhinorrhoea, it is now recognised that AR has a significant impact on quality of life (QOL). This condition can lead to sleep disturbance as a result of nasal congestion, which leads to significant impairment in daily activities such as work and school. Traditionally, AR has been subdivided into seasonal AR (SAR) or perennial AR (PAR). SAR symptoms usually appear during a specific season in which aeroallergens are present in the outdoor air such as tree and grass pollen in the spring and summer and weed pollens in the autumn (fall); and PAR symptoms are present year-round and are triggered by dust mite, animal dander, indoor molds and cockroaches. Oral histamine H(1)-receptor antagonists (H(1) antihistamines) are one of the most commonly prescribed medications for the treatment of AR. There are several oral H(1) antihistamines available and it is important to know the pharmacology, such as administration interval, onset of action, metabolism and conditions that require administration adjustments. When prescribing oral H(1) antihistamines, the healthcare provider must take into account the clinical efficacy and weigh this against the risk of adverse effects from the agent. In addition to the clinical efficacy, potential for improvement in QOL with a particular treatment should also be considered.

Administration, Oral↗

Treatment of allergic rhinitis: H1-antihistamines and intranasal steroids.

Allergic rhinitis is charterized as an inflammatory disease of the nasal mucosa. In clinical practice, H(1)-antihistamines and topical corticosteroids are most commonly used pharmacological agents for the treatment of allergic rhinitis. The beneficial effects of steroids depend upon their long-term anti-inflammatory effect rather than upon direct receptor antagonism. This is different to H(1)-antihistamines, which block both neural and vascular H(1) receptors and have a clinical effect on symptoms such as nasal itching, sneezing, and rhinorrhea. H(1)-antihistamines are rapidly absorbed and most of them are metabolized by the hepatic cytochrome P system and begin to reduce nasal symptoms (itching and sneezing) within one hour. Understanding of both the efficacy and the pharmacological properties of these commonly used drugs in the treatment of nasal allergic inflammation and its related nasal symptoms is very important. From a clinical viewpoint, it will provide a useful guideline for an appropriate use of these drugs.

Administration, Intranasal↗

Effect of antihistamine eye drops on the conjunctival provocation test with Japanese cedar pollen allergen.

BACKGROUND: Approximately 16.2% of the Japanese population suffer from cedar pollinosis, with various manifestations such as ophthalmic, laryngo-pharyngeal and skin symptoms in addition to nasal symptoms. Thus, the annual pollen season is an agonizing period for patients. No study has reported symptoms and their clinical courses after conjunctival provocation with purified cedar pollen allergen Cry j1 as well as suppression of these allergen-induced ocular symptoms by antihistamine eye drops. METHODS: Nine patients with Japanese cedar pollinosis who had no nasal or ocular symptoms were included in the present study, after obtaining informed consent in writing. 1) Purified cedar pollen allergen Cry j1 was instilled in the left eye and phosphate-buffered saline (PBS) in the right eye as a control. 2) Levocabastine hydrochloride ophthalmic suspension and ketotifen fumarate ophthalmic solution were respectively instilled in the left and right eyes, which were then challenged with the allergen. Ocular symptoms after provocation with the allergen were recorded through the clinical course. RESULTS: Pollen allergen-induced ocular symptoms were itching and hyperemia of the palpebral conjunctiva, and itching lasted for more than 5 hours. Moreover, preadministration of antihistamine eye drops suppressed the increases in the ocular symptom scores, eliminating itching within 1 hour. Allergen provoked not only ocular symptoms but also nasal symptoms in 77.8% of patients. CONCLUSIONS: Preadministration of antihistamine eye drops suppressed the symptoms induced by the allergen, which suggests that this is an effective early therapy for Japanese cedar pollinosis, if it is started before the pollen season. However, self-protection by patients using a mask may not be effective enough to suppress nasal symptoms during the pollen season, requiring them to additionally wear glasses to avoid exposure to the allergen.

Adult↗

Effect of systemic corticoid and antihistamine alone or in combination on elements of the response to a two dose nasal allergen challenge.

This study examined the effects of low dose systemic corticoid (methylprednisolone, MP), standard dose antihistamine (terfenadine, TF) or the combination on response to out-of-season acute allergen challenge. We feel that a single dose challenge delivered to the nose may represent real disease imperfectly and in this study used two doses given 1 hour apart, hoping to approximate better the circumstances of natural allergen stimulation. The study used clinical endpoints only: measured nasal airway resistance (NAR), sneeze count, and weight of blown nasal secretions. Subjects showed similar NAR, sneezing, and secretion response to both challenges. With placebo treatment, NAR rose after the first allergen provocation and returned to baseline about 30 minutes later. Antihistamine pretreatment appeared to delay but did not prevent this rise; low dose corticoid partially inhibited it, and the combination totally ablated the response. All active treatments suppressed sneezing and secretion better than placebo. Combination corticoid/antihistamine treatment showed no greater effect on sneeze/ secretion than did antihistamine alone; this differs from our findings in separate studies comparing analogous drug combinations in naturally-acquired ragweed hayfever.

Airway Resistance↗

Molecular pharmacology of second-generation antihistamines.

Histamine was the first allergic mediator identified in the early part of this century. It has three defined receptors, but most effects of histamine in allergic reactions are through the H1 receptor. The first H1 antagonists were introduced into clinical use in the late 1940s, and drugs of this class are still the preferred initial choice for management of allergic rhinitis and urticaria. The first-generation drugs were characterized by nonspecific binding to many receptors and penetration of the blood-brain barrier, resulting in multiple side effects. Within the central nervous system (CNS), interference with normal histamine binding to the H1 receptor is associated with drowsiness and psychomotor impairment. The second-generation drugs have a much improved benefit/adverse effect profile, largely based on greater potency, receptor specificity, and lower CNS penetration. The potency of antihistamines for blocking H1 receptors can be compared by their inhibition of the cutaneous wheal and flare response to histamine. These drugs seem to have additional antiallergic properties related to blockade of mediator release and interference with cellular recruitment and activation. Clinical trials comparing the efficacy of antihistamines in rhinitis and asthma are reviewed. Recent studies have explored the potential of antihistamines to prevent the progression of allergy and their enhanced efficacy when combined with leukotriene antagonists.

Asthma↗

Fungal transformations of antihistamines: metabolism of methapyrilene, thenyldiamine and tripelennamine to N-oxide and N-demethylated derivatives.

1. Strains of the fungus Cunninghamella elegans ATCC 9245 and 36112 were tested for their ability to transform the antihistamines methapyrilene (I), thenyldiamine (II) and tripelennamine (III). 2. Antihistamine metabolites were isolated by h.p.l.c., and identified by their 1H-n.m.r. and mass spectral properties. 3. All three drugs were transformed by both C. elegans strains to N-oxidized and N-demethylated derivatives. Metabolism during 96 h of incubation amounted to 85% for (I), 64% for (II), and 83% for (III). Metabolites soluble in organic solvents amounted to 62% to 86% of the total metabolism; approximately 88% to 95% of the organic-soluble metabolites were N-oxide derivatives of each antihistamine.

Aminopyridines↗

Fungal transformations of antihistamines: metabolism of brompheniramine, chlorpheniramine, and pheniramine to N-oxide and N-demethylated metabolites by the fungus Cunninghamella elegans.

1. Two strains of the filamentous fungus Cunninghamella elegans (ATCC 9245 and ATCC 36112) were screened for their ability to metabolize three alkylamine-type antihistamines; brompheniramine, chlorpheniramine and pheniramine. 2. Based on the amount of parent drug recovered after 168 h of incubation, C. elegans ATCC 9245 metabolized 60, 45 and 29% of brompheniramine, chlorpheniramine and pheniramine added respectively. The results from strain ATCC 36112 were essentially identical to those of strain ATCC 9245. 3. The metabolic products of N-oxidation and N-demethylation were isolated by reversed-phase hplc and identified by analysing their mass and proton nmr spectra. For all three antihistamines, the mono-N-demethylated metabolite was produced in the greatest amounts. The chloro- and bromo-substituents appeared not to affect the route of metabolism but did influence the relative amounts of metabolites produced. 4. Circular dichroism spectra of the metabolites and the unmetabolized parent antihistamines showed each to be a racemic mixture of the (+) and (-) optical isomers. In addition, comparison of the metabolism of racemic chlorpheniramine to that of optically pure (+) chlorpheniramine showed no significant differences in the ratios of metabolites produced. There was therefore no metabolic stereoselectivity observed by the fungal enzymes.

Biotransformation↗