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Effect of an inhaled antihistamine (clemastine) as a bronchodilator and as a maintenance treatment in asthma.

Although intravenous chlorpheniramine can cause bronchodilatation, oral and parenteral antihistamines have not proved useful in treating asthma. Inhaled antihistamines may cause throat irritation, but a recent study of the antihistamine, clemastine, showed it to be an effective bronchodilator without irritant effects. We have extended these studies to determine the site of action of inhaled clemastine and to assess its potential usefulness both as a bronchodilator and as a maintenance treatment. Eleven stable asthmatic patients received inhaled clemastine and placebo and the effect was assessed by serial maximum expiratory flow volume (MEFV) curves breathing air and a helium/oxygen (He/O2) mixture. There was no significant improvement in peak flow rates during air breathing after clemastine and no significant difference between the responses to drug and placebo. Minor but significant changes were seen in some flow measurements on the downslope of the MEFV curve during air and He/O2 breathing, and these are tentatively ascribed to a dilating effect of clemastine on peripheral airways where flow is laminar. Subsequent administration of inhaled isoprenaline showed the patients to be still capable of significant bronchodilatation. The addition of clemastine, from a pressurised aerosol, to the patients' therapeutic regimen for two weeks was no more effective than placebo in controlling airflow obstruction, and did not reduce the need for standard bronchodilators. In our patients clemastine was not a clinically useful bronchodilator either acutely or as a maintenance treatment for asthma.

Adult

Double-blind, controlled study of clemastine fumarate, chlorpheniramine and placebo in patients with seasonal allergic rhinitis.

A whole body plethysmograph (body box) equipped with a flow meter (see Figure 1) was used for objective quantification of the effects of single doses of clemastine fumarate 2.68 mg, chlorpheniramine 4 mg and placebo in a double-blind study of 48 patients with seasonal allergic rhinitis. This technique offers an objective means of assessing drug effects on nasal congestion and obstruction. Before the development of whole body plethysmography, only subjective assessments of antihistamines' effects on nasal blockage or congestion were available. These subjective reports usually noted that nasal blockage or congestion was refractory to antihistamines or minimally relieved by them. However, in this study, nasal and oral airway resistances, each measured by whole body plethysmography, were lowered by clemastine fumarate and chlorpheniramine. These results were corroborated by the patients' and physician's assessments of changes in symptom severity and the physician's evaluation of intranasal photographs taken for each patient. Oral airway resistance of patients treated with clemastine fumarate was improved to a significantly greater extent than in patients receiving placebo. At two hours post-drug, patients receiving clemastine fumarate usually showed a greater response in most assessments than those receiving chlorpheniramine, and the trend of most comparisons was clearly in favor of clemastine fumarate. Patients in all three treatment groups experienced drowsiness but both incidence and severity were lower with clemastine fumarate.

Airway Resistance

Bronchodilatation after inhalation of the antihistamine clemastine.

H1 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%), salbutamol (0.5%), and placebo. Bronchodilatation was assessed by changes in the forced expiratory volume in one second (FEV1) and peak expiratory flow rate (PEFR) over four hours. Both clemastine and salbutamol caused significant bronchodilatation. The mean maximum percentage increases in FEV1 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.

Adult

Double-blind, controlled study of clemastine fumarate, chlorpheniramine and placebo in the symptomatic treatment of seasonal allergic rhinitis in desensitized and nondesensitized patients.

In double-blind trials clemastine fumarate 2.68 mg. chlorpheniramine 4 mg and placebo were randomly assigned to two groups of patients with seasonal allergic rhinitis. Thirty-nine desensitized patients were given one of the three test drugs in a parallel design; 67 nondesensitized patients each received two of the three drugs in a crossover design. Assessment of drug activity in each study was by whole body plethysmography and intranasal color photography as well as by subjective methods. Objective measurements showed clemastine fumarate was significantly superior to placebo and often better than chlorpheniramine in decreasing true nasal resistance and relieving nasal congestion. High placebo responses characterized the subjective evaluations, although the active drugs were clearly better. Responses varied somewhat between desensitized and nondesensitized patients. The number of reports of sedative effect, high in all groups, seemed to be more closely related to these antihistamine conditioned patients than to activity of the drugs themselves, based on previous reports of low sedation with clemastine fumarate. The techniques described proved very useful in distinguishing relative activity of antihistamines. Clemastine fumarate, the new antihistamine studied, appears to offer certain advantages over the older drug, chlorpheniramine.

Airway Resistance

Evaluation of in vivo parameters of drug metabolizing enzyme activity in man after administration of clemastine, phenobarbital or placebo.

The 24 h urinary excretion of 6beta-hydroxycortisol and D-glucaric acid, the plasma half lives and total clearances of aminopyrine, and serum gamma-glutamyl-transpeptidase activity have been measured in nineteen healthy male volunteers. The study was done double blind and was conducted as a test of induction of microsomal drug metabolizing enzymes during and after daily doses of 6 mg clemastine, 300 mg phenobarbital or a placebo. The urinary excretion of 6beta-hydroxycortisol and D-glucaric acid was significantly increased in the phenobarbital group, the standard for induction. No changes were observed after treatment with clemastine or placebo. Phenobarbital also reduced the half life of aminopyrine, but it was not affected by clemastine or placebo. Gamma-glutamyl-transpeptidase activity increased only in the phenobarbital group. The elimination constant k2 of aminopyrine and the excretion of glucaric acid in the pre-medication period were correlated (p less than 0.05) The results indicate that the tests were of diagnostic value in determination of microsomal enzyme induction by phenobarbital. Failure to observe similar changes after treatment with clemastine imply failure of induction of this activity under the experimental conditions.

17-Hydroxycorticosteroids

Double-blind trials of clemastine ('Tavegil') in allergic rhinitis.

Two double-blind randomised trials are reported comparing the effectiveness of the antihistamines, clemastine and chlorpheniramine in comparable doses, in relieving the symptoms of allergic rhinitis. In the first trial, treating 58 adults seen in a general practice, both drugs were prescribed in tablet form; l mg. clemastine b.d. and 4 mg. chlorpheniramine b.d. The second trial was carried out in 42 patients attending a children's E.N.T. out-patient department and the drugs were prescribed as clemastine elixir (0.5 mg. b.d.) or as chlorpheniramine syrup (2 mg. b.d.). Both drugs were effective in providing symptomatic relief in a significant number of patients, and the overall efficacy of clemastine was marginally better than that of chlorpheniramine, especially in the second trial in children. Side-effects were minimal and drowsiness was not a problem.

Adolescent

Inhibition of idiosyncratic reactions to aspirin in asthmatic patients by clemastine.

An H1-receptor blocking antihistamine, clemastine, taken before aspirin gave complete or partial protection against flushing, rhinorrhea, cough, and headache in ten asthmatic patients with idiosyncrasy to aspirin. In five of the ten patients aspirin-precipitated bronchoconstriction was also reduced or prevented after pretreatment with clemastine. Thus histamine appears to play a part in the production of most non-respiratory symptoms occurring after aspirin ingestion in intolerant patients with asthma. Bronchial reactions might depend partly on histamine and partly on the action of other spasmogens. It is suggested that inhibition of prostaglandins of the E series by aspirin-like drugs plays a crucial part in the release of histamine from tissue stores in aspirin-sensitive asthmatic patients. Clemastine might be of use in the treatment of acute reactions to aspirin.

Adult

The interaction between ethanol and antihistamines: 2. Clemastine.

Eighty paid student volunteers (35 male, 45 female) were used in an experiment to investigate the effects of a therapeutic dose of clemastine (1 mg) alone and in combination with a social dose of ethanol (0.54 g/kg) on perceptual, cognitive and motor functions. Both drugs were given orally. Clemastine did not significantly modify performance when given alone, and the performance decrements induced by ethanol were not enhanced by clemastine premedication.

Adult

Gaschromatography of clemastine. A study of plasma kinetics and biological effect.

A method for estimation of clemastine in human plasma has been developed. By chronic acid oxidation the drug is degradated to chlorobenzophenone, which can then be analysed by gas-liquid-chromatography using electron-capture detection. The plasma levels of clemastine after oral and i.v. administration have been studied. Using different methods for extraction of the drug from plasma a metabolic degradation of the pyrrolidine part of clemastine is demonstrated. The metabolite proposed may be biologically active. The plasma level of the drug was found to be directly related to its biologic effect, measured as inhibition of the histamine-induced flare in human skin.

Administration, Oral

A comparative study of clemastine ('Tavegil') and chlorpheniramine maleate in the treatment of hay fever.

A double-blind randomised parallel group study was carried out in 46 patinets to compare the effectiveness of clemastine with that of chlorpheniramine maleate in the treatment of hay fever. The results showed that both drugs were equally effective in controlling the symptoms of hay fever without side-efects or other untoward reactions. It is suggested that clemastine is a logical first choice antihistamine as well as being an effective alternative where tolerance to other antihistamines develops.

Adolescent

Comparisons among HC 20-211 (Ketotifen), clemastine, DSCG and beclomethasone dipropionate in nasal challenge.

Nasal challenge tests were used to compare the protective effect of pre-treatment with HC 20-511 (Ketotifen), a new antiallergic compound, clemastine, DSCG and beclomethasone dipropionate in 14 patients with hay fever. HC 20-511 and clemastine were tested in a double-blind fashion and DSCG and beclomethasone openly. Most of the patients experienced an intense nasal reaction when challenged with pollens without pre-treatment. The intensity of nasal reactions was determined by subjective symptoms, clinical findings and nasal peak expiratory flow values. All the drugs tested relieved the symptoms and signs induced by pollens in nasal challenge tests. This tendency was not, however, statistically significant for any of the drugs. When using the changes in nasal expiratory flow rate as a criterion of protectiveness, the differences among the compounds tested were also slight. HC 20-511 seems to be a promising antiallergic agent. However, long term clinical trials still are needed to establish its efficacy in various allergic disorders.

Adolescent

Effects of ketotifen and clemastine on passive transfer of reaginic reaction.

Passive transfer (PK) tests were performed with a reaginic serum on a recipient reacting with an immediate and a more prolonged reaction when specificity challenged. Both reactions are thought to be mediated by IgE immunology. Ketotifen, a cycloheptathiophene derivative, and clemastine, given to the recipient in maximal clinical doses for 3 days, inhibited the immediate reaction. Ketotifen had a very slight effect also on the prolonged reaction. The results indicate that the in vivo effects of ketotifen in the human system are due not so much to mast cell inhibitory mechanisms, but more to post-release antihistaminic and some anti-inflammatory properties.

Clemastine

Inhaled antihistamines--bronchodilatation and effects on histamine- and methacholine-induced bronchoconstriction.

To assess further the bronchodilator activity of inhaled antihistamines ten stable asthmatic subjects inhaled aerosols of clemastine, 1 mg/ml, and saline placebo administered double blind. Subjects underwent bronchial challenge with increasing concentrations of histamine and methacholine, and specific airways conductance was measured by whole body plethysmography at each concentration. There was a significant 21.9% increase in specific airways conductance after inhalation of clemastine. Subjects could tolerate significantly higher mean concentrations of histamine when treated with clemastine than with saline. The shift of the cumulative log histamine dose-reponse curve suggests that such protection is due to competitive antagonism to the inhaled clemastine. Clemastine did not protect subjects against methacholine-induced bronchoconstriction, which suggests that its bronchodilator properties are not related to any anticholinergic action.

Adult

[An experimental and clinical study of the effect of ketotifen in the treatment of extrinsic bronchial asthma (author's transl)].

The therapeutic value of ketotifen (Zaditen), a new anti-allergic drug, was studied in patients with extrinsic bronchial asthma. a) In 8 persons the protective effect on bronchial provocation tests with allergen was examined 3 and 14 days after treatment and compared with cromoglycate (Intal); b) 19 patients were treated for 6 months with 2 x 1 milligram ketotifen (n = 7), 2 x 2 mg ketotifen (n = 7), 2 x 1 mg clemastine (Tavegil) (n = 5). The results were as follows: a) The amount of inhaled allergen causing a fall of 20% in FEV1.0/VC was 9-12 times larger with both therapeutic regimens. b) Ketotifen definitely improved the asthmatic symptoms as compared with clemastine. The improvement was independent of the dosage. Side-effects occurred more frequently with clemastine. The study confirms the in vitro demonstrated anti-analphylactic properties of ketotifen; that it can be taken by mouth is of particular clinical interest.

Asthma

Clinical investigation of agents with prophylactic anti-allergic effects in bronchial asthma.

To determine the efficacy of ketotifen as an oral anti-asthmatic agent, experimental and therapeutic long-term trials were carried out. Four models were used in the expirmental therapeutic trials nad the antihistaminic agent clemastine and disodium cromoglycate were used as comparative substances. It was demonstrated that ketotifen provides protection against bronchopasm induced by allergens, histamine and exercise, but not against that induced by acetylcholine. In the therapeutic long-term trials, the efficacy and tolerance of ketotifen were compared with that of clemastine and disodium cromoglycate for a period of 6 months. In another study ketotifen was administered for 1 year. Ketotifen proved very effective in decreasing the frequency and duration of asthmatic attacks, concomitant medication could be reduced and the patients improved subjectively. From these trials it can be concluded that ketotifen is a safe and effective oral anti-anaphylactic agent for use in the long-term treatment of bronchial asthma.

Acetylcholine