PHARMACODYNAMICS OF CALCIUM BLOCKERS IN ASTHMA

细胞内钙调节的改变可能是最终的共同之处 哮喘发病机制的途径。然而，钙的作用 这种疾病中的通道阻滞剂还没有定义。这项研究提出 以合乎逻辑和系统的方式调查潜在的疗效 这组药物控制慢性阻塞性肺疾病症状的安全性 哮喘，并评价乙酰甲胆碱诱导的有效性 用于选择临床有效成员的支气管收缩 给药类别、给药途径、给药剂量和给药频率。在第一阶段， 三组10名慢性哮喘患者将于7日接受治疗 分别服用安慰剂和分级剂量的吸入维拉帕米， 吸入地尔硫卓或口服地尔硫卓；每组一药。A支气管炎 在每次试验前后都要进行乙酰甲胆碱的激发试验 剂量。心电图、血压和存在主观主诉的情况 将每隔一段时间监测副作用，以确定每种药物的安全性 剂量。将每隔一段时间采集血样以检测维拉帕米， 地尔硫卓和代谢物血药浓度。每种药物的剂量 产生最大的封闭效果，没有毒性，将用于相 在这一阶段，吸入维拉帕米、口服和雾化吸入的效果 地尔硫卓和安慰剂在阻断支气管收缩反应中的作用 乙酰甲胆碱将在双盲随机交叉试验中测定 方法对40例慢性哮喘患者进行治疗。在四个不同的日子系列 将进行乙酰甲胆碱挑战，测量血清浓度， 并在12小时内每隔2小时进行一次毒性评估 剂量。响应时间曲线下的面积将用于确定 每种方案的相对强度和持续时间。在第三阶段，40 患者将接受为期三个月的安慰剂和 第二阶段的两种有效药物方案，分别被认为效果最差和 最有效的，以随机双盲交叉方式进行。剂量 并且给药频率将与在阶段使用的相同 哮喘症状出现的频率、不良反应、呼气峰 流速，以及吸入β-受体激动剂和额外药物的必要性 对于急性症状，患者将在日记中记录两次 每天。此外，患者将每隔两周就诊一次，以便 评估、肺活量测定、标准化运动负荷试验、血清水平 测量和合规性检查。

Altered regulation of intracellular calcium is probably the final common pathway for the pathogenesis of asthma. However, the role of calcium channel blockers in this disease has not been defined. This study proposes to investigate, in a logical and systematic manner, the potential efficacy and safety of this group of drugs in controlling the symptoms of chronic asthma, and to evaluate the usefulness of methacholine-induced bronchoconstriction for selecting a clinically effective member of this class, route, dose and frequency of administration. In the first phase, three groups of ten patients with chronic asthma will receive, on seven separate days, placebo and graded doses of either inhaled verapamil, inhaled diltiazem or oral diltiazem;one drug per group. A bronchial provocation test with methacholine will be performed before and after each dose. ECG, blood pressure and the presence of subjective complaints of side effects will be monitored at intervals to determine the safety of each dose. Blood samples will be obtained at intervals to measure verapamil, diltiazem and metabolite serum concentrations. The dose of each drug that produces maximum blocking effect without toxicity will be used for Phase II. In this phase, the effect of inhaled verapamil, oral and inhaled diltiazem and placebo in blocking the bronchoconstrictor response to methacholine will be determined in a double-blind randomized cross-over manner in 40 patients with chronic asthma. On four separate days serial methacholine challenges will be performed, serum concentrations measured, and toxicity assessed at 2 hour intervals for a 12 hour period after the dose. The area under the response-time curve will be used to determine the relative intensity and durationof each regimen. In the third phase, 40 patients will be treated for three one month periods with placebo and the two active drug regimens in Phase II that were judged least effective and most effective, in a randomized double-blind cross-over manner. The dose and frequency of administration will be the same as those used in Phase II. The frequency of asthmatic symptoms, adverse effects, peak expiratory flow rate, and the need for inhaled beta agonists and additional medicatons for acute symptoms will be recorded by the patinets in a diary twice daily. In addition, patients will be seen at two week intervals for evaluation, spirometry, a standardized exercise stress test, serum level measurements, and compliance check.