ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04961.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04962.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

A survey of the U.S. pharmaceutical industry was conducted to obtain data on the length of the review process for supplemental indications of already‐approved new chemical entities (NCEs). Responses were received from 51 firms and covered supplemental indications of 348 NCEs that were approved during 1963 to 1988. Since extensive toxicity and safety evaluation would generally not be required for supplemental indication reviews, one would expect supplemental indications, on average, to be reviewed more quickly than applications for the associated original indications. The mean ± standard deviation review time for the 172 supplemental indications in the sample is 21.5 ± 18 months; the average review time for the associated 94 original indications is 23.5 ± 18 months. The difference in average review times is not statistically significant. Analysis of review times for indications grouped by Food and Drug Administration (FDA) reviewing division showed a statistically significant difference between supplemental and associated original indication review times only in the cardio‐renal division. In that division, average review times were longer for supplemental indications (25.6 vs. 19.3 mo; P<.05). Analysis of time trends showed a significant increase in average supplemental indication review time for 1985 to 1988 approvals relative to the average associated original indication review time (P<.01) and to average supplemental indication review time for earlier time periods (P<.01). These results suggest the need for a close examination of the supplemental indication review policy of t

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04963.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The subdivision of class 1 antiarrhythmic agents into groups a, b, and c was originally based on clinical electrophysiologic findings. Class 1b compounds did not alter QRS or HV interval in sinus rhythm, but the compounds did lengthen ERP in spite of shortening JT. Class 1c agents widened QRS and prolonged HV at low concentrations in sinus rhythm, but had little effect on ERP or JT. Cellular electrophysiologic studies provided an explanation for these clinical effects by frequency‐dependent onset/offset kinetics. Class 1b drugs became rapidly attached to sodium channels after depolarization, which rendered them nonconducting, but the drugs also dissociated rapidly after repolarization so that by the end of a normal diastole nearly all channels were back to their conducting state. In contrast, class 1c drugs became more slowly attached, and more slowly detached, so that a proportion of sodium channels was permanently eliminated as long as the drug was present. This caused slow conduction in the His—Purkinje system and ventricle. Both clinical and cellular electrophysiologic studies show that moricizine HCl is a class 1c ag

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04964.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The efficacy of mexiletine and quinidine in controlling ventricular couplets (VC) and ventricular tachycardia (VT) was compared in 156 trials (78 for each drug) in 114 consecutive patients. Forty‐two patients received both drugs, whereas 36 patients were given mexiletine, and 36 patients received quinidine only. During acute drug testing, mexiletine was more effective than quinidine in controlling VC and VT (54 vs. 32 patients, respectively, P<.001) and resulted in fewer proarrhythmic events (4 vs. 13, respectively, P<.05). Mean duration of follow‐up for mexiletine (27 ± 14 mo) and quinidine (21 ± 14 mo) did not differ. Long‐term success was more frequent with mexiletine administration than quinidine administration (33/47 vs. 10/30 patients, respectively, P<.01). The incidence of sudden death during follow‐up with the two drugs did not differ overall, but more patients with ejection fraction ≥ 40% died suddenly while taking quinidine than while receiving mexiletine (4/17 vs. 0/24, P<.02). Mexiletine is as effective as quinidine for treating VC and VT and appears to be less proarrhythmic. It should be considered as an initial choice in the management o

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04965.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

This study was designed to determine the dose linearity and proportionality of moricizine after multiple‐dose administrations of 450 to 900 mg/day. The study design was an open‐label, four‐treatment, four‐period sequentials escalating dose. Twelve subjects each received multiple doses of 150, 200, 250, and 300 mg of moricizine every 8 hours during 7 days of treatment. Blood samples for pharmacokinetic determinations were obtained on day 7 of each treatment period during an 8‐hour time interval. Cmindeterminations were also made on specific days of each treatment period. The AUCτ(area under the curve from time 0 to 8 hours), Cmax, and Cminparameters were all normalized to the 250‐mg (750 mg/day) dose. No statistically significant differences were seen in these parameters at the four treatment levels. It was concluded that moricizine follows first‐order or linear pharmacokinetics after multiple dosing and exhibits dose proportional pharmacokinetics in the dosage‐range studies. This range corresponds to the clinically use

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04966.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

A total of 203 patients with hypertension (supine diastolic blood pressure of 100–119 mm Hg) from six centers entered into a 3‐week placebo baseline followed by 5 weeks of active treatment (either placebo or isradipine 2.5, 5, 7.5, or 10 mg BID) to determine the effectiveness of isradipine on blood pressure control. Electrocardiographic criteria for left‐ventricular ischemia were coded blindly using the Minnesota Codes 4‐1 to 4‐4 and 5‐1 to 5‐3 at the end of baseline and active treatment periods. One hundred seventy patients with hypertension and matching and complete electrocardiograms completed the study for analysis: 63 (37%) were white and 117 (69%) were men. They were 52.1 ± 10.3 years old mean ± SD; range: 22–77 years). No myocardial infarction occurred during the active phase. Fifty‐eight of 170 (34%) at baseline and 54 of 116 (32%) at week 5 had left atrial enlargement. Romhilt‐Estes left‐ventricular hypertrophy was not significantly different at baseline versus active treatment: 14 of 170 (8.2%) versus 15 of 170 (8.8%). At baseline, the rate of active ischemia was 28.2% (48/170); 27.8% (10/36) were randomized to receive placebo during active treatment and 28.4% (38/134) were given isradipine (P = NS). For those without ischemia at baseline, the rate of change to electrocardiographic ischemia during active treatment was 0% (0/26) for those receiving placebo and 3.1% (3/96) for those taking isradipine (P = NS). For those with ischemia at baseline, the rate of change to no ischemia during active treatment was 20% (2/10) for those receiving placebo and 10.5% (4/38) for those taking isradipine (P = NS). Overall, ischemia at baseline versus active treatment was: placebo (P = NS)‐27.8% (10/36) to 22.2% (8/36); and isradipine (P = NS)‐28.4% (38/134) to 27.6% (37/134). However, 3 of 96 patients without ischemia at baseline changed to ischemia while receiving isradipine. Such individuals should be investigated for epicardial coronary artery disease. In contrast, 4 of 38 patients with ischemia at baseline reverted to no ischemia while taking isradipine. The group that received isradipine and had good diastolic blood pressure control did not have more el

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04967.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The short‐term effects of atenonol and nifedipine on plasma levels of atrial natriuretic peptide (ANP), plasma renin activity (PRA), and plasma aldosterone (PA) were studied in two groups of patients with uncomplicated essential hypertension. Urinary catecholamines, and sodium and potassium excretion were also studied. A group of 20 patients with hypertension, after a wash‐out period of at least 10 days, was randomly subdivided into two protocol therapy subgroups. One group (six men and four women) received atenolol (100 mg/d), and the other group (six men and four women) received nifedipine (30 mg/d). Circulating plasma levels of ANP, PRA, and PA were determined by radioimmunoassay, and other variables were determined by routine laboratory techniques before therapy and at day 3 and day 7 after the treatment began. Arterial blood pressure and heart rate were monitored during the study. Both drugs reduced arterial blood pressure (P<.001) significantly. The atenonol therapy decreased heart rate (P<.001), increased plasma ANP levels and urinary catecholamine excretion, and decreased PRA and circulating PA levels. Nifedipine treatment did not modify plasma ANP values, whereas it increased PRA and PA circulating levels and urinary catecholamine excretion. No differences were shown for urinary volume, urinary sodium, and potassium excretions during the two different treatments. These findings suggest that the increased plasma ANP levels could contribute to the antihypertensive effects of the β‐adrenoreceptor blockers, by a reduction in PRA and PA levels and a vasodilatative effect. On the other hand, short‐term treatment with nifedipine increased PRA and PA circulating levels without modifying ANP values, which suggests that its hypotensive effects are not mediate

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04968.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Inhaled and oral over‐the‐counter bronchodilators are used for self‐therapy by asthmatic patients. To evaluate their safety and efficacy, we compared epinephrine and theophylline combined with ephedrine with inhaled metaproterenol and the placebo. Twelve asthmatic patients were studied in a randomized, double‐blind, placebo‐controlled, crossover trial comparing forced expiratory volume in 1 second (FEV1) after two inhalations of epinephrine (0.2 mg/inh), 1 minute apart, followed in 15 minutes by theophylline (130 mg) with ephedrine (24 mg) versus two inhalations of metaproterenol (0.65 mg/inh), 1 minute apart, versus placebo inhaler and tablets. Onset of FEV1>15% above baseline values occurred within 15 seconds after inhalations for 100% of epinephrine‐treated patients, 92% of metaproterenol‐treated patients, and 33% of placebo‐treated patients. FEV1responses were significantly greater (P<.05) for epinephrine at 0.66 to 1.66 minutes compared with the responses of metaproterenol, and epinephrine and theophylline that was combined with ephedrine compared with metaproterenol beginning at 2 hours. Mean duration of activity was 5.7 hours for the epinephrine‐ and theophylline with ephedrine‐treated patients, 4.9 hours for metaproterenol‐treated patients, and 2 hours for the placebo group. There were statistically significant differences for patients receiving epinephrine and theophylline with ephedrine versus the placebo group (P<.001), metaproterenol patients versus the placebo group (P = .02), and patients receiving epinephrine and theophylline with ephedrine versus metaproterenol‐treated patients (P<.05). Compared with inhaled metaproterenol, inhaled epinephrine followed in 15 minutes by a theophylline—ephedrine tablet had a significantly earlier onset, longer duration of action, numerically greater peak effect, and patient preference. This combination of oral and inhaled bronchodilator medication is as safe and effective

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04969.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The pharmacokinetics of intravenously administered theophylline were studied in five healthy nonsmokers. Each subject received 5 mg/kg of theophylline as aminophylline after an overnight fast and again after a standard high‐fat meal. Although there was wide between‐day variation in the elimination rate constant in three of the five subjects, no statistically significant differences were observed in area under the time‐versus‐concentration curve, maximum serum theophylline concentration, elimination rate constant, or apparent volume of distribution between the two treatments. A statistical power analysis indicated that if differences in volume of distribution and maximum serum theophylline concentration occur in the general population, the mean differences are less than 15% and 20%, respectively. This suggests that alterations in intravascular drug distribution resulting from eating a high‐fat meal do not contribute importantly to previously reported effects of food on serum theophylline concentrations after or

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb04970.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY