(1978). Thorax, 33, 479482 Bronchodilatation after inhalation of the antihistamine clemastine. H, receptor blocking antihistamines administered by mouth have not found a clear place in the management of bronchial asthma. We investigated the possibility that higher concentrations of these drugs, administered directly to the bronchial tree, might produce bronchodilatation.Twelve asthmatic patients inhaled aerosols generated from solutions of clemastine (0 05%0), salbutamol (0 5%), and placebo. Bronchodilatation was assessed by changes in the forced expiratory volume in one second (FEVY) and peak expiratory flow rate (PEFR) over four hours.Both clemastine and salbutamol caused significant bronchodilatation. The mean maximum percentage increases in FEV, for clemastine and salbutamol were 21 1 % and 29 2% respectively. The mean maximum percentage increases in PEFR were 31-2% and 35-2% respectively. There was no significant difference in the maximum bronchodilatation produced by the two drugs.Clemastine, when administered by aerosol inhalation, appears to be an effective bronchodilator.The role of histamine in the production of acute asthma is controversial. There is evidence that histamine is released in allergic reactions in the lung (Schild et al, 1951), and challenge studies have shown that the bronchi of asthmatics are more sensitive to histamine than those of nonasthmatics (Curry, 1947;Tiffenau, 1958;Townley et al, 1965). Oral antihistamine drugs have not found a place in treating asthma, however, and are widely thought to be ineffective (Lancet, 1955).Assuming that histamine plays a role in asthma, the therapeutic failure of antihistamines could be due either to the failure to block the H2 receptor sites or to incomplete H, receptor blockade caused by inadequate local concentrations of drugs. Indeed, higher doses of antihistamines, given by mouth or parenterally, have caused bronchodilatation (Popa, 1977), but central nervous system depression limits their use by this route.We have attempted to assess whether the administration of an H, receptor blocking antihistamine, clemastine, given directly to the bronchi as an aerosol, could cause therapeutically useful bronchodilatation. PatientsTwelve patients (age range 29-70, mean 46) gave informed consent. All were in hospital having recovered from a severe exacerbation of bronchial asthma and were in a relatively stable clinical state. All had previously shown reversibility of airways obstruction by a greater than 15% increase in peak expiratory flow rate (PEFR) after inhaling salbutamol aerosol 200 ,ug. Six of the twelve patients were atopic by prick skin testing. On three consecutive mornings each patient had baseline measurements of PEFR (the best of three recordings) using a Wright peak flow meter and forced expiratory volume in one second (FEV1) using a dry wedge spirometer (Vitalograph). Each subject then inhaled from a Wright's nebuliser 1 ml each of either clemastine 0-05% in saline, salbutamol 0 5%, or physiological saline as 479 on 10 May 2018 by guest....

ABsrRACT The bronchodilation produced by increasing intravenous doses of aminophylline, salbutamol, and a combination of aminophylline and salbutamol given in random order was determined in 10 stable asthmatics on three consecutive days. On a fourth day, response to placebo injections was determined. Forced expiratory volume in one second (FEV1) was measured at twominute intervals after each dose until FEV, returned to a new baseline. At no dosage level was there synergy between the two agents in terms of either mean percentage increase in FEV, or the integrated response. The failure to demonstrate synergy has implications both with respect to the clinical use and the underlying mechanism of action of these drugs.B2 adrenergic stimulants and methyl xanthine derivatives are commonly prescribed together in the management of asthma. B2 adrenergic stimulants increase production of cyclic (3,5) adenosine monophosphate (cyclic AMP) from ATP by stimulation of adenyl cyclase.1 Methyl xanthine derivatives reduce the rate of degradation of cyclic AMP by inhibition of phosphodiesterase.2 Since B2 adrenergic stimulants and methyl xanthine derivatives produce increases in cyclic AMP concentration by different mechanisms, the question arises whether the interaction between these two classes of drug is synergistic3-synergy being defined as an interaction between two agents when given in combination which produces a response greater than the sum of their individual responses.Synergy has been demonstrated experimentally using guinea pig tracheal muscle, human leucocytes, and human lung fragments4-6 but has not been demonstrated conclusively in vivo.7-9 In an attempt to demonstrate synergy we have constructed doseresponse curves to intravenous salbutamol and aminophylline when given separately and in combination. MethodsTen well-controlled asthmatics requiring regular inhaled salbutamol and who showed greater than 15 % improvement in forced expiratory volume (FEV1) Address for reprint requests: Dr PDJ Handslip, Medical Unit, St Thomas' Hospital, London SEI 7EH.after inhalation of 200 ,tg salbutamol gave informed consent. Subjects recorded peak expiratory flow rate (PEFR) and an asthma score for two weeks before investigation to establish stability. The subjects were fasting and had received no bronchodilator therapy for at least eight hours before study.On three consecutive mornings an intravenous cannula was inserted and FEV1 values were recorded until consecutive values were identical. On three separate mornings salbutamol, aminophylline, or a combination of the two were given intravenously in random order, in increasing doses. The doses used were salbutamol 25, 50, 75, 100, 150, 200 ,-g; aminophylline 25, 50, 75, 100, 150, 200 mg; aminophylline + salbutamol 25, 25: 50, 50: 75, 75: 100, 100: 150, 150: 200, 200 mg/,ug.After each bolus, FEV1 values were recorded every two minutes taking the best of two values until FEV1 had returned to a stable baseline. The next bolus was then given. The maximum dose which could be given on ...

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