ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03692.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.tb03693.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The new drug approvals of 1987, 1988, and 1989 were analyzed to determine whether there are any emerging trends in the US drug development and review processes. Sixty‐four new drugs were approved by the FDA during this period, of which 55 met the Center for the Study of Drug Development's definition of a new chemical entity (NEC). For the 55 NCEs, the mean length of the investigational new drug application (IND) phase (IND filing to NDA submission) was 5.2 years, the new drug application (NDA) phase (NDA submission to approval) was 2.9 years, and the total phase (IND filing to NDA approval) was 8.1 years. Nine of the 55 NCEs were classified by the FDA as 1A (important therapeutic gain), 15 were classified as 1B (modest gain), 29 were classified as 1C (little or no gain), and 2 were classified as 1AA (drugs to treat AIDS and AIDS‐related conditions); 10 drugs were granted orphan status. The mean NDA phase for 1A drugs was 2.4 years; 1B drugs, 2.9 years; 1C drugs, 3.1 years; 1AA drugs, 1.4 years; and orphan drugs, 2.5 years. Forty‐four of the 55 NCEs (80%) were available in foreign markets before US approval was given, with a mean of 6.5 years of prior marketing. These data are consistent with figures for previous years and suggest little change in the rate of new drug development and review in the United S

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03694.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The Cardiac Antiarrhythmic Suppression Trial (CAST) showed flecainide and encainide induced excess mortality compared with placebo. Labeling drugs as Class 1C is based on clinical observations, comprising measurements of the electrocardiographic parameters QRS, H‐V and J‐T intervals and of effective refractory period (ERP) as follows: 1—(QRS) wide, 2—(HV) long, 3—(ERP) unchanged, 4—(JT) unchanged. In vitro electrophysiology helped to explain the clinical findings. Flecainide and encainide rendered Na channels as nonconducting, but F and E were only slowly released from the channels after repolarization. At any given drug concentration, a proportion of total channels were eliminated, and the steady‐state proportion increased at rising heart rate. It is not proven that the properties that lead to classification of a drug as 1C were those that caused excess deaths in the CAST. The proarrhythmic tendency of 1C drugs can be reduced by beta‐blockade, and the mechanisms of adrenergic arrhythmogenicity are discussed. Propafenone is both a 1C drug and a beta‐blocker, and its pharmacologic profile is reviewed to illustrate how it resembles and differs from flecainide and encainide. Some features of the CAST are assessed with particular reference to the extent to which conclusions drawn from the results may be justifiably extrapolated to other drugs

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03695.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The current study evaluated the effect of two beta adrenergic—blocking agents, propranolol (PRP) and atenolol (ATN), versus placebo on cerebral blood flow (CBF) of three homogeneous groups of cirrhotic patients with portal hypertension. CBF was measured by the noninvasive 133‐Xenon inhalation method at rest and 1 hour after a single oral dose of PRP (40 mg), or ATN (100 mg), or placebo. Blood pressure and heart rate (HR) were measured at the beginning of each examination, and end‐tidal pCO2(PeCO2) was monitored. The HR decreased significantly in both the PRP and ATN groups (P<.01), whereas no changes were recorded for both PeCO2and mean arterial blood pressure (MABP). The comparisons of the CBF differences among groups (ANOVA with the significance levels adjusted by the Bonferroni's correction) showed a significant increase in CBF after ATN as compared with both placebo (P<.02) and PRP (P<.01), whereas no significant differences were seen after PRP as compared with placebo. Our results confirm that PRP does not significantly affect CBF, whereas ATN induces an increase in CBF, although the underlying mechanism is difficult to ex

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03696.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The effect of treatment with enalapril (10 days at 10 mg/d followed by 4 weeks at 20 mg/d) on forearm hemodynamics was assessed in eight normotensive patients and eight patients with hypertension affected by Type II diabetes as well as in eight patients with essential hypertension and normal glucose tolerance. The ACE inhibitor decreased regional vascular resistances and increased the maximum arteriolar‐vasodilating capacity and venous distensibility in the three groups of patients. Thus, this study shows that ACE inhibition by enalapril improves regional hemodynamics in patients with Type II diabete

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03697.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Supine office blood pressures (SOBP) and 24‐hour automated ambulatory blood pressure monitorings (AABPM) showed blood pressure reductions from a stable baseline to active treatment with 120‐, 240‐, and 480‐mg doses of a new verapamil QD capsule (solid—spheroidal—oral once‐daily drug‐absorption system; (SODAS) in patients with mild‐to‐moderately severe (diastolic blood pressures 95–119 mm Hg) essential hypertension. Reductions were documented at 24 hours, hourly, and by the 24 hour average, using SOBP and AABPM, after the once‐daily verapamil administration. Both SOBP and the 24‐hour average by AABPM were significantly reduced from baseline by active verapamil treatment of 120‐, 240‐, and 480‐mg doses. In comparison to verapamil QD (0 mg), blood pressure reductions from baseline to active treatment were significant at the 240‐ and 480‐mg doses but not at the 120‐mg dose. There was a significant linear dose response. This verapamil formulation (SODAS) was effective throughout the 2

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03698.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

Cerebral blood flow (CBF), glucose (FDG), and oxygen metabolism (OM) were evaluated by positron emission tomography (PET) in 18 healthy volunteers who were randomized to a 72‐hour course of either 600 mg/d of fleroxacin or placebo. Such studies attempted to assess potentially serious, yet unexplained, central nervous system adverse effects of the fluorinated quinolone class. Baseline and postplacebo values for CBF (mL/min/100 g) and FDG (mg/min/100 g) were: 53 ± 6 and 5.7 ± 1.8; and 49.6 ± 4.4 and 5.2 ± 1.2, respectively. Identical values for fleroxacin were: 53.9 ± 4.8 and 6.3 ± 1.1; and 54.4 ± 2.2 and 6.8 ± 1.5, respectively. The differences between fleroxacin and placebo were not significant. There was also no effect seen in OM between placebo and the active drug. The authors conclude that short‐term administration of fleroxacin does not alter CBF, FDG, or OM in healthy

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03699.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The disposition of amikacin was studied in 98 patients receiving treatment for severe gram‐negative sepsis. Several factors were identified which were significantly related to the drug's elimination rate. These included renal function (r = .67), age (r = –.55), distribution volume (r = .34), and weight (r = –.31). These variables explain 62% of the variance (R2) in elimination rate constant when combined in a multiple regression model. The drug's half‐life demonstrated considerable interpatient variation in patients with a normal serum creatinine (.68–14.4 hrs) or with a normal creatinine clearance (.68–7.2 hrs). The drug's distribution volume ranged from .08 to .48 L/Kg. The drug's clearance varied from 6.5 to 200 mL/hr/kg for patients with a normal serum creatinine and 17.8 to 200 mL/hr/kg for patients with a normal creatinine clearance. The interpatient variation in the drug's kinetic parameters is a concerning clinical problem. Measuring serum amikacin concentrations and adjusting dosage regimens are necessary to achieve desired peak and trough serum con

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03700.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY

摘要:

The effects of an antacid and of cimetidine on the serum concentrations of azithromycin were examined in volunteers. Ten subjects were given 500 mg azithromycin alone and immediately after being given 30 mL Maalox (Rorer, Fort Washington, PA) in a crossover design. There were no statistically significant differences in Tmaxor AUC0–48after administration of azithromycin alone or with antacid, but mean values of Cmaxwere reduced by 24% (P= .015). Thus, although Cmaxwas decreased, the extent of absorption of azithromycin was not affected by coadministration with an antacid. Two groups of six volunteers were given 500 mg azithromycin on day 1. On day 8, one group was given 800 mg cimetidine 2 hours before a dose of azithromycin; the remaining group received placebo before azithromycin. There were no differences in the pharmacokinetic parameters produced by administration with cimetidine or placebo, relative to those on day 1. Thus, cimetidine administered 2 hours before a dose of azithromycin had no apparent effect on the serum concentrations of azithromyci

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1991.tb03701.x

出版商:Blackwell Publishing Ltd    

年代:1991

数据来源: WILEY