ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03262.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Whereas the latest data suggest that the number of new chemical entities (NCE) launches worldwide may be on the increase, both recent and longer term data show a decline in the rate of NCE introductions into Israel. In terms of percentage availability, only 30% of NCEs available worldwide during 1978–1987 were introduced in Israel during the same period, compared with 42% for the U.S.A. In both countries there has been a decreasing percentage availability since 1983/84. The percentage availability of commercially significant NCEs was greater (47%) compared to all NCEs introduced in Israel. Whereas in the U.S.A. the lower the therapeutic rating the higher the proportion of NCEs, in Israel the B‐ and C‐rated drugs were equally represented. NCEs with an A‐rating had a similar share of all NCEs (ca 15%) in both countries. The average time lag for NCEs launched worldwide to reach Israel during 1978–1987 was 4 to 5 years, but in recent years there has been a considerable decline. Commercially significant NCEs introduced in Israel had on average a shorter time lag of 0.5 years than the average for all NCEs introduced. In spite of a preponderance of NCEs first launched in the U.S.A. there was on average a slight relative lag into the U.S.A. compared to Israel. This was probably due to there being a number of NCEs first introduced in Israel with a long delay before they were subsequently approved in the U.S.A. There was an average delay for A‐rated new drugs into the U.S.A. of 7 years compared to their Israeli introduction dates, with half of these top‐rated drugs being available in Israel before they had received NDA approval. The results are discussed in terms of the regulatory process and the influence of prior registration in the U.S.A., U.K. and in other countries. Most NCEs introduced in Israel are marketed or registered beforehand in either the U.S.A. or U.K. or both. In Israel the overseas application lag is usually considerable in relation to the registration lag, which is the opposite to the U.S.A. situation. Nevertheless, in cases where there is a clear therapeutic need for a drug in Israel then it appears that the assumed influence of prior U.S.A. and U.K. registration is less of a factor. Furthermore, for NCEs with commercial potential in Israel one can assume a reduced overseas ap

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03263.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03264.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

This is the first reported large clinical trial of the antianginal and acute ischemic effectiveness and safety of dilevalol (the R, R‐isomer of labetalol) in patients with chronic stable angina pectoris. This was a multicenter double blind fixed‐dose parallel group placebo controlled trial. Patients with chronic stable angina and positive and reproducible exercise tests (±20%) were included. If randomized, patients entered one of four fixed dose groups (twice a day placebo, 100 mgm, 200 mgm and 400 mgm bid for 2 weeks). Exercise testing was performed at 2 hours (peak) and 12 hours (trough) postdosing. This was followed by a 2‐week once‐a‐day dosing regimen in which patients received the same total daily dose as the prior 2 weeks, with the full dose in the morning and a matched placebo in the evening. Exercise testing was performed at 2 hours (peak) and 24 hours (trough) postdosing. Anginal frequency and NTG consumption were significantly reduced, and equally so, by qd and bid regimens. The time of exercise to the onset of angina increased and the proportion of patients terminating exercise because of moderate angina decreased in a dose response fashion for both peak and trough tests and for both qd and bid regimens. There was also a dose related decrease in exercise induced ST segment depression and an increase in time to 1 mm ST depression. In 15 patients, 24‐hour ambulatory monitoring also revealed a decrease in episodes of silent ischemia. No significant side effects related to the study drug occurred. Thus, dilevalol was effective in the treatment of angina pectoris since it was well tolerated, favorably improved exercise induced ischemia (both painful and silent ischemia), and reduced anginal frequency and NTG

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03265.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

As part of a multiple dose bioavailability study, 80‐mg verapamil hydrochloride tablets were administered to healthy subjects every 8 hours for 15 doses. Statistically significant successive decreases in verapamil maximum plasma concentrations (Cmax) and area under the concentration‐time curve (AUC) values were observed corresponding to dosing at 8 AM, 4 PM, and 12 AM. Mean Cmaxand AUC values from the 12 AM dose were decreased 36% and 30%, respectively, relative to those from the 8 AM dose. Similar effects on norverapamil pharmacokinetics were observed. Decreased Cmaxand AUC values show that verapamil absorption is influenced by the time of day when doses are administered. Pharmacokinetic simulation results suggest that the rate of absorption is reduced approximately by one half and two thirds during the 4 PM and 12 AM dosing intervals, respectively, relative to the 8 AM dosing interval. The reductions in verapamil absorption as a function of time of administration observed in this study may in part explain previous reports of reduced antihypertensive effect during evening and night hours as compared to daytime ho

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03266.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

The effect of diltiazem pretreatment on the pharmacokinetics of nifedipine were determined in six healthy male volunteers. Placebo or diltiazem (30 mg and 90 mg) was given orally three times daily for 3 days in a double‐blind, Latin square method. On the fourth day, a 20‐mg nifedipine was given orally 1 hour after the last dose of placebo or diltiazem. The mean elimination half‐life of nifedipine prolonged significantly following diltiazem (2.54 hours on placebo vs 3.40 hours on 30 mg diltiazem and 3.47 on 90 mg diltiazem, both P<.01). The mean AUC of nifedipine increased during diltiazem (1726.6 nmol × hr/ml on placebo vs 3838.0 on 30 mg diltiazem, and 5370.0 on 90 mg diltiazem, both P<.05, 30 mg vs 90 mg, 0.1

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03267.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

There are limited data on the effects of Class IB and IC antiarrhythmic drug combination for the treatment of ventricular tachycardia. The present study evaluated this combination in 12 patients who had sustained ventricular tachycardia (SuVT) during programmed electrical stimulation (PES) and failed IC antiarrhythmic therapy. Following combination of lidocaine and a IC agent (7 with encainide and 5 with flecainide), two had no inducible ventricular tachycardia (VT) and one had nonsustained VT (NSVT). In seven of nine patients who still had SuVT, the mean VT cycle length increased 40 ± 25 msec post combination compared to IC antiarrhythmic therapy. Seven patients who had a favorable response to the initial combination (100 msec increase in cycle length compared to baseline and no hemodynamic compromise) were then placed on IC + oral IB agent (5 with mexiletine, 2 with tocainide). Similar effects on VT inducibility and cycle length were observed following the oral combination. In conclusion, the addition of lidocaine to IC therapy produced favorable effects on induced ventricular tachycardia in 58% of patients compared to IC agent alone. Also, a positive PES response to lidocaine and IC therapy corresponded to a similar positive response when either mexiletine or tocainide was substituted for lidocai

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03268.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

The dose‐response relationship of verapamil‐SR was studied in 221 hypertensive patients. This double‐blind, parallel‐group, placebo‐controlled study compared placebo to 60 mg, 120 mg, 240 mg and 480 mg doily of verapamil‐SR. After 6 weeks of therapy, peak diastolic blood pressure was similar in the placebo group and the verapamil‐SR 60 mg group, 93.0 and 92.0 mmHg, respectively. The 120 mg, 240 mg and 480 mg verapamil‐SR groups produced significantly lower diastolic blood pressure, 89.8, 85.3 and 83.7 mmHg (P<0.01), respectively. At trough, placebo and verapamil‐SR 60 mg groups and 120 mg groups had diastolic blood pressures of 96.6, 97.0 and 97.1 mmHg, respectively. Diastolic blood pressure with the 240 mg dose (92.4 mmHg) was significantly lower than with the 120 mg dose (P<0.01). The 480 mg dose resulted in a diastolic blood pressure of 88.6 mmHg, which was significantly lower than the 240 mg dose (P0.8; P0.4; P<0.01). Headache and constipation, although not significantly different from placebo, were the most commonly reported adverse reactions in the verapamil‐SR groups, 6.3% (placebo—6.7%) and 5.1% (placebo—4.4%), respectively. Graded doses of verapamil‐SR produced a dose‐response curve in hypertensive patients with a greater than 80% responder rate at the 240 mg dose. Therefore, 240 mg of verapamil‐SR is effective monotherap

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03269.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

Dilevalol (100 mg) was given once daily for 8 days in eight elderly subjects with essential hypertension. Blood samples for plasma dilevalol concentrations were taken during an 8‐hour post‐drug period following the first and eighth dosages, and the time to maximum concentration (tmax), maximum plasma concentration (Cmax), distribution half‐life (t1/2α), elimination half‐life (t1/2β) and area under the plasma concentration‐time curve (AUC) were determined.A wide intra‐subject variability was observed in tmaxduring the repeated administration. A high inter‐subject variability was also demonstrated in tmax, Cmax, t1/2βand AUC during both observation periods. No significant difference was observed, however, in these pharmacokinetic parameters between the first and eighth dosages.These data indicate that the pharmacokinetic profiles of dilevalol are not altered during 8 days of therapy in elderly subjects with essential hypertension. Since elderly subjects are potentially heterogenous in capacities for handling the drug, the observed variability in pharmacokinetic parameters may reflect the heterogeneity in the sample chosen for examination in t

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03270.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

We have assessed the efficacy and tolerance of Nifedipine twice daily and Nisoldipine once daily, both alone and in combination with a beta‐blocker in 171 essential hypertensives in a randomized parallel comparison fashion. Both drugs were equally effective in lowering blood pressure: 72.6% of the subjects on Nisoldipine and 80.5% of those on Nifedipine reached a supine diastolic blood pressure ≤ 90 mmHg. Spontaneously reported side effects were frequent but no biochemical, hematological or electrocardiographic abnormalities were detec

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1989.tb03271.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY