dihydropyridines and Asthma

Candesartan, an AT(1) receptor antagonist, has been reported to have no association with persistent cough in subjects with hypertension, but there has been no study on the safety of its administration to hypertensive patients with symptomatic asthma. The aim of this study was to compare the adverse effects of candesartan and calcium antagonists on cough, pulmonary function, and bronchial hyperresponsiveness in these patients.. Sixty mildly to moderately hypertensive patients with bronchial asthma received either candesartan (n=30) or the calcium antagonists nifedipine or manidipine (n=30) for 6 months. The candesartan group included 5 subjects with a history of ACE inhibitor-induced cough. There were no differences between the 2 groups in patient characteristics, ACE gene polymorphism, pulmonary function, or bronchial hyperresponsiveness to methacholine. Control of hypertension was the primary end point; new cough detected by self-administrated questionnaire and an increase in cough frequency by visual analog scale were the second end point. No patient complained of persistent cough. Neither mean visual analog scale score nor pulmonary functions changed during this study. Bronchial hyperresponsiveness had a tendency to improve in the candesartan group, but there was no difference between the 2 groups.. Incidence, frequency, and severity of persistent cough, pulmonary functions, and bronchial hyperresponsiveness did not change in either the candesartan or calcium antagonist group. It is suggested that candesartan is as effective and safe as calcium antagonists in the treatment of hypertension associated with symptomatic asthma.

Topics: Adult; Aged; Antihypertensive Agents; Asthma; Benzimidazoles; Biphenyl Compounds; Blood Pressure; Bronchial Hyperreactivity; Calcium Channel Blockers; Cough; Dihydropyridines; Female; Genetic Testing; Humans; Hypertension; Incidence; Male; Methacholine Chloride; Middle Aged; Nifedipine; Nitrobenzenes; Pain Measurement; Peptidyl-Dipeptidase A; Piperazines; Polymorphism, Genetic; Respiratory Function Tests; Tetrazoles; Treatment Outcome

Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.

Topics: Adult; Aged; Asthma; Dihydropyridines; Double-Blind Method; Female; Forced Expiratory Volume; Humans; Imidazoles; Male; Middle Aged; Peak Expiratory Flow Rate; Platelet Activating Factor; Quality of Life; Single-Blind Method

The aim of this study was to assess the bronchodilator effect and short-term safety of cumulative single doses of inhaled bimakalim (E Merck, Darmstadt), a potassium channel opener, compared to placebo in 12 adult patients with chronic, mild to moderate, non-allergic bronchial asthma. The study was a randomized, placebo-controlled, cross-over study and the only efficacy variable measured was the forced expiratory volume in one second (FEV1). The patients had an FEV-1 > 50% of predicted normal value and a reversibility of more than 15% at entrance to the study. Inhaled bimakalim and placebo were delivered by a Pariboy nebulizer. The doses tested in a cumulative manner were 10, 25, 40 and 100 micrograms (total cumulative dose 175 micrograms), each individual dose given at 60-min intervals. Plasma bimakalim concentrations were measured at time 0 and 60 min after each dose. No bronchodilator effect was shown, with inhaled bimakalim at the doses tested. Reasons for the lack of efficacy of inhaled bimakalim in this study may be due to low doses of administered drug or to a true lack of bronchodilatation effect in the study patients. Inhaled bimakalim was well tolerated. No headache or cardiovascular events were seen with the cumulative dose of 175 micrograms bimakalim.

Topics: Administration, Inhalation; Adolescent; Adult; Aged; Antihypertensive Agents; Asthma; Benzopyrans; Bronchi; Bronchodilator Agents; Dihydropyridines; Double-Blind Method; Female; Humans; Kinetics; Male; Middle Aged; Potassium Channels

The effect of UK-74,505, a specific platelet-activating factor (PAF) antagonist, on the early (EAR) and late asthmatic response (LAR) to inhaled allergen was studied in a randomized, double-blind, placebo-controlled crossover study. A total of eight adult male atopic asthmatic subjects completed the protocol (one withdrew after screening), all having demonstrated a dual response to inhaled allergen (EAR, > 20% fall in FEV1 between 0 and 1 h; LAR, > 15% fall in FEV1 between 4 and 8 h after challenge). Subjects were studied on 2 days at least 10 days apart. After measurement of baseline FEV1, subjects ingested a single oral dose of 100 mg UK-74,505 or matched placebo (P). Allergen challenge was performed 3 h later and the FEV1 was then measured for 8 h. There was no difference between UK-74,505 and placebo in the maximum percentage change from baseline (+/- SEM) for either EAR or LAR (EAR, UK-74,505 -25.6 +/- 4.8%, P -24.0 +/- 3.3%; LAR, UK-74,505 -20.8 +/- 4.4%, P -25.7 +/- 3.8%). There was no significant difference in the area under the percentage change from baseline FEV1-time curve. Ex vivo platelet aggregation to PAF was measured at 0, 2, 6, 8, and 10 h after the dose. There was marked inhibition of platelet aggregation to PAF for 10 h following UK-74,505 but not placebo (% maximum aggregation to PAF, UK-74,505, -69.9%; P, 0.13%; p = 0.0001). Histamine challenge was performed in five patients the day before and after each study day. There was no significant difference between UK-74,505 and placebo in PD20 to histamine (mean PD20 before and after UK-74,505, 1.31 and 0.96 mumol; P, 1.32 and 1.17 mumol). UK-74,505 did not affect either the EAR or the LAR to inhaled allergen or bronchial responsiveness, despite its potency and long duration of action. This suggests that PAF does not have a major role in the acute response to inhaled allergen.

Topics: Adolescent; Adult; Allergens; Asthma; Bronchial Provocation Tests; Dihydropyridines; Double-Blind Method; Forced Expiratory Volume; Humans; Imidazoles; Male; Middle Aged; Platelet Activating Factor; Platelet Aggregation

The role of Ca2+ as a mediator of many cellular responses, including stimulus-secretion and excitation-contraction coupling, is reviewed. Pathways of Ca2+ mobilization are discussed in terms of both intracellular and plasmalemmal processes. The extent to which specific antagonists exist, active at these several sites, is noted, with particular emphasis on the clinically available Ca2+ channel antagonists, including verapamil, nifedipine, and diltiazem.

Topics: Allosteric Regulation; Asthma; Binding Sites; Calcium; Calcium Channel Blockers; Cell Membrane; Chemical Phenomena; Chemistry; Dihydropyridines; Humans; Ion Channels; Muscle, Smooth; Phospholipids; Pyridines