Histamine and the antiallergic antihistamines: a history of their discoveries.

The paper provides a historical overview of the discovery of both histamine and the H1 antihistamines. The context of these discoveries is provided in relation to the development of medicinal chemistry during the 19th century. Background is provided on the history of discovery of mechanisms of anaphylaxis and allergy and the immunology of hypersensitivity at the end of the 19th and early 20th century. The discovery of histamine and the antihistamines is then discussed in relation to the development of pharmacological receptor theory culminating in the discovery of the first antihistamines in the 1930s and their widespread clinical introduction in the 1940s.

How to do it. Get patients' consent to enter clinical trials.

Gaining patients' consent to enter clinical trials is essential, but not easy. Giving careful thought to the design of the study itself, information which patients receive, and the use of a signed consent form may all help. To be properly informed, patients need to know something about their condition, the proposed study, and alternative options. The type and amount of information will vary and investigators need to judge the level appropriate for each person. Patients should understand that taking part in a clinical trial is voluntary and that their decision will not affect the quality of care they receive. The process of obtaining consent requires time and good communication. Working with young, elderly, or mentally impaired patients, or those particularly vulnerable to coercion, requires special sensitivity to the potential dangers.

The time course of action of three differing doses of noberastine, a novel H1-receptor antagonist, on histamine-induced skin wheals and the relationship to plasma drug concentrations in normal human volunteers.

1. The time course and magnitude of effect of the novel H1-receptor antagonist noberastine, structurally modified from astemizole to achieve a more rapid onset while retaining a good duration of action, has been investigated using histamine-induced skin wheals in healthy volunteers. 2. The pharmacokinetics and pharmacodynamics of three doses (10, 20 and 30 mg) have been studied in a double-blind, placebo controlled, randomised cross-over trial involving 12 healthy male volunteers. 3. All doses of noberastine caused inhibition of histamine-induced skin wheals, which were significantly different from placebo (P < 0.0001) when assessed as the area under the percent inhibition of the response vs time curves. 4. Following single dose administration of 10, 20 and 30 mg noberastine significant inhibition of histamine-induced skin wheals occurred and this effect persisted beyond 24 h. 5. At the higher (20 and 30 mg) doses studied significant inhibition of the histamine-induced skin wheal occurred by 1 h of dosing, whereas this did not occur until 2 h following the 10 mg dose. 6. An increase in plasma concentrations of noberastine was seen after administration of all doses, with mean (s.d.) concentrations of 4.14 (3.70), 8.38 (7.81) and 12.66 (11.82) ng ml-1 1 h following administration of 10, 20, and 30 mg respectively. 7. Visual analogue scale measurements of drowsiness identified no sedative effects above those of placebo at any of the dose levels. 8. We conclude that noberastine is an effective H1-receptor antagonist in the human as assessed by its effect on histamine-induced skin wheals.

Absence of withdrawal effects of ritanserin following chronic dosing in healthy volunteers.

The possible development of withdrawal symptoms following abrupt discontinuation of ritanserin after chronic administration of 10 mg daily for 8 weeks was investigated in a placebo controlled trial in 40 healthy subjects. The study consisted of two phases. In the first phase, under single blind conditions, all subjects received placebo for 2 weeks followed by a single daily dose of ritanserin (10 mg) for 8 weeks. In the second phase, under double blind conditions, subjects were randomised to receive either placebo or to continue on ritanserin (10 mg) for a further 4 weeks. Psychological assessments were performed at the start of and at intervals throughout the study. Levels of anxiety, concentration, quality of sleep and morning vigilance were measured throughout by daily visual analogue scales. No significant changes were detected in any of the measures in the group of subjects who received ritanserin compared to the group who received placebo during the second phase of the study. Ritanserin discontinuation following chronic dosing in healthy volunteers does not appear to be associated with withdrawal symptoms.

Effect of H1-receptor blockade on late cutaneous reactions to antigen: a double-blind, controlled study.

This study is of the effect of the blockade of histamine H1 receptors by a long-acting antihistamine on the immediate and late clinical response to antigen (Ag) and on the recruitment of eosinophils in the late-phase cutaneous reaction. Ten adult volunteers with late-phase reactions to the intradermal injection of either Dermatophagoides pteronyssinus or Phleum pratense (timothy) pollen performed a double-blind, crossover study. Each volunteer took astemizole, 10 mg, or identical placebo, daily for 2 weeks. Ag in the concentration that induced a late reaction in the screening visit was injected intradermally at the end of each drug period. The early reaction was measured serially for 30 minutes and the late reaction at 4 and 6 hours. Biopsies of the Ag and control sites were also performed at 6 hours. After a 6-week washout period, subjects then took the opposite medication for 2 weeks and returned for skin testing and biopsy. Skin testing demonstrated that astemizole inhibited the immediate response to both histamine and allergen but had no effect on the late response at 4 hours and at 6 hours. Biopsy specimens revealed no significant effect on eosinophil recruitment at 6 hours. We conclude that histamine H1-receptor blockade has no effect on the late cutaneous reaction to Ag.

Hay fever, a post industrial revolution epidemic: a history of its growth during the 19th century.

Although other forms of allergic disease were described in antiquity, hay fever is surprisingly modern. Very rare descriptions can be traced back to Islamic texts of the 9th century and European texts of the 16th century. It was only in the early 19th century that the disease was carefully described and at that time was regarded as most unusual. By the end of the 19th century it had become commonplace in both Europe and North America. This paper attempts to chart the growth of hay fever through the medical literature of the 19th century. It is hoped that an understanding of the increase in prevalence between 1820 and 1900 may provide an insight for modern researchers and give some clues into possible reasons for the epidemic nature of the disease today.

Clinical profile of astemizole. A survey of 50 double-blind trials.

From clinical-pharmacologic and clinical data involving over 2,800 patients, astemizole appears to be a very effective and well-tolerated antihistamine. It is superior to placebo and commonly used antihistamines for the relief of rhinitis, particularly rhinorrhea and sneezing. It has a pronounced effect on ocular itching and lacrimation in conjunctivitis and on pruritus and wheals in urticaria. This superiority is due to a very specific, almost complete and sustained histamine H1-blockade. The clinical data confirm the experimental data in relation to its lack of sedative effects.

Astemizole and other H1-antihistaminic drug treatment of asthma.

The disparity between the activation of mast cells in the airways of patients with allergic asthma and the lack of efficacy of H1-antihistamines in asthma therapy has been difficult to reconcile. Histamine causes bronchoconstriction when inhaled by subjects with asthma and is released in detectable amounts into the circulation after bronchial provocation with an antigen. However, it is only weakly antagonized at bronchial H1-receptors by conventional antihistamines such as chlorpheniramine and clemastine, achieving dose ratios of 2 to 4 at maximally tolerated doses. Astemizole and terfenadine are two new H1-histamine antagonists with greatly increased potency and no sedative and anticholinergic side effects. Astemizole has a delayed onset of maximal activity but induces prolonged H1-blockade that extends 15 to 30 days after the end of treatment, whereas terfenadine has a rapid onset of action with a much shorter duration of effect. With therapeutic doses (10 mg/day), astemizole is at least four times more potent in antagonizing histamine-induced bronchoconstriction than the previously available H1-antihistamines and also effectively antagonizes antigen-induced bronchoconstriction in asthma. Astemizole has been shown to be highly effective in the symptomatic treatment of seasonal allergic rhinoconjunctivitis, with the exception of nasal obstruction. With continued treatment, astemizole also offers useful protection from the symptoms of seasonal asthma. Thus the role of histamine in the pathogenesis of asthma should be reappraised. Potent H1-histamine antagonists such as astemizole and terfenadine may offer some benefit in asthma therapy, but the precise clinical indications for their use will require critical evaluation.

Astemizole, a potent histamine H1-receptor antagonist: effect in allergic rhinoconjunctivitis, on antigen and histamine induced skin weal responses and relationship to serum levels.

The efficacy of astemizole, a new, long acting, oral histamine H1-receptor antagonist was compared to placebo for the treatment of allergic rhinitis and conjunctivitis during the grass pollen season of 1982. Sixty-three patients with a positive skin prick test to grass pollen and current symptoms participated in an 8 week, double-blind, randomized study. Astemizole, 10 mg, was significantly better than placebo in alleviating both nose (P less than 0.05) and eye (P less than 0.01) symptoms despite significantly greater use of the reserve medication, clemastine, by the placebo group (P less than 0.003). There was a lag period of 5 days after initiation of therapy before treatment benefit became manifest. Subdivision of nasal symptoms indicated significant improvement compared to placebo over the 8 weeks for sneezing (P less than 0.05) and runny nose (P less than 0.05) but not blocked nose. The absence of effect on nasal blockage was confirmed by parallel measurement of nasal calibre by body plethysmography. The antihistaminic potency of astemizole was indicated by an 80% inhibition of the histamine induced skin weal response after 8 weeks therapy. A positive correlation was found between serum drug levels and % inhibition of histamine skin weal (r = 0.64, P less than 0.001). Astemizole was free from adverse sedative or anticholinergic effects but did cause a mean increase in weight of 1.3 kg (P less than 0.01) after 8 weeks therapy, not found with placebo.

A method for evaluating therapy for hay fever. A comparison of four treatments.

This study was undertaken in order to develop a method for comparing the value of different forms of treatment for hay fever. A cross-over trial was carried out in sixty-one patients, comparing four treatments: topical corticosteroids, topical cromoglycates, placebo tablets and oxatomide (a new oral treatment with antihistamine and cromoglycate-like properties). Three methods were used to compare these treatments: (1) post-treatment symptom questionnaires; (2) daily analogue line scores of symptoms; and (3) nasal FEV1. Of these, daily analogue line diary scores, with an analysis which took into account variation in pollen count, proved to be the most sensitive. By employing this diary method, it was shown that all three active treatments were significantly better than placebo and that topical corticosteroids were significantly better than topical cromoglycates. The activity of oxatomide was found to be not significantly different from that of steroids or cromoglycate, but it was associated with more frequent side-effects. It is suggested that daily diaries, combining symptom relief and freedom from side effects into a single score of 'usefulness' adjusted for pollen count, are suitable means for comparing treatments for hay fever.

Cinnarizine in the treatment of chronic asthma.

1 Cinnarizine, an inhibitor of calcium ion transport across smooth muscle cell membrane, has been shown to exert an anti-asthmatic effect in patients with chronic asthma. 2 It is postulated that antagonism to calcium ion transport across the mast cell membrane may cause the compound to have a pharmacological effect similar to sodium cromoglycate. 3 Cinnarizine is orally active and its therapeutic effect is demonstrated in a double-blind, cross-over, placebo controlled study. 4 Patient benefit was shown by a significant improvement in peak flow rate. A non-significant trend towards a reduction in symptomatic bronchodilator usage and a decrease in asthma symptom score was also shown. 5 It is concluded that cinnarizine could well prove to be the first of a new family of anti-asthmatic drugs offering a protective effect when taken systemically.