ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03851.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03852.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Challenged with the clearly demonstrated need for highly trained clinical pharmacologists for new drug development and review activities, the FDA Center for Drug Evaluation and Research (CDER) established an internal Staff College. This organizationally unique and innovative unit addressed the educational needs of both the new and the veteran CDER scientists. A multileveled strategy was conceptualized and implemented as described.

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03853.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03854.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03855.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Release rate constants and disappearance rate constants were determined for three atrial natriuretic peptides consisting of amino acids 1–98 (i.e., proANF 1–98), the midportion of the ANF prohormone consisting of amino acids 31–67 (i.e., proANF 31–67) and amino acids 99–126 (i.e., ANF) after right ventricular pacing at 100, 125, 150, and 180 bpm in six male mongrel dogs. Right atrial and femoral vein blood was obtained at baseline, and at 5, 12, 19, 26, 56, 86, 116, 146, and 206 minutes after right ventricular pacing. Resulting plasma concentration‐time data derived parameters were compared. The disappearance rate constants for atrial and femoral venous proANF 1–98 were 0.0144 ± 0.0087 (X ± SD) and 0.0175 ± 0.0075 min−1, respectively (t = 0.6158) and release rate constants were 0.1569 ± 0.1504 and 0.0670 ± 0.0393 min−1, respectively (t = 1.8269; P>.05). The proANF 31–67 disappearance rate constants were 0.0139 ± 0.0082 and 0.0148 ± 0.0132 min−1, respectively (t = 0.1192) and release rate constants were 0.0957 ± 0.0414 and 0.1984 ± 0.1762 min−1, respectively (t = 1.4812). The ANF elimination phase disappearance rate constants were 0.0663 ± 0.0273 and 0.1116 ± 0.0539 min−1(t = 2.0923, P>.05), respectively, and the release rate constants were 0.1335 ± 0.0532 and 0.1638 ± 0.0520 min−1(t = 0.7878, P>.05), respectively. These data indicate that proANF 1–98 and proANF 31–67 circulating β post‐distribution half‐lives are approximately 45 minutes whereas β half‐life of ANF is 10 minutes. Persisting concentrations of proANF 1–98 and proANF 31–67 in plasma may better explain the proported sustained pharmacologic effects that have been attributed to ANF, which has a mean a distribution phase

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03856.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

The occurrence of clinical and biochemical side effects of bezafibrate (400 mg daily) or simvastatin (20 mg daily) alone or combined was appraised in 13 healthy male normolipidemic subjects according to a single blind design. Each period of 2 weeks of treatment with bezafibrate or simvastatin or bezafibrate plus simvastatin was followed by a period of placebo (1 week). No subjects experienced myalgia or muscle weakness. Plasma creatine kinase (CK) elevations, particularly skeletal muscle CK (CK‐MM), were observed in 6 subjects: 11 times during different placebo periods, 5 times on bezafibrate, 4 times on simvastatin, and 4 times on combined bezafibrate‐simvastatin, but never reached 1,600 IU/L. Only a trend to an increase of CK mean values on combined bezafibrate‐simvastatin was shown. The hepatic transaminase and gamma‐glutamyltransferase activities remained unmodified throughout the trial, unlike alkaline phosphatase activity, which fell on bezafibrate and on bezafibrate plus simvastatin. The low‐density lipoprotein cholesterol level was more reduced with simvastatin than with bezafibrate. The addition of bezafibrate to simvastatin did not decrease it further. Lecithin: cholesterol acyltransferase activity expressed as fractional esterification rate was enhanced only on simvastatin and bezafibrate‐

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03857.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

The pharmacokinetic characteristics of a slow‐release formulation of clonidine (150 pg) were compared with those of a conventional formulation (75 μg) after acute and chronic (2 week) administration to 12 hypertensive subjects. The Tmaxof the slow‐release formulation was significantly later than for the conventional formulation after both acute (8.3 ± 6 hr vs. 2.1 ±2 hr) and chronic administration (4.0 ± 3 hr vs. 2.5 ± 2 hr). Although the Tmaxdid not change significantly with acute and chronic administration of the conventional preparation, it was significantly shorter after chronic administration of the slow‐release formulation when acute and chronic administration were compared. The Cmaxwas approximately 60% lower for the slow‐release formulation (1 × 150 μg; 0.42 ± 0.09 ng/mL) compared with the conventional formulation (2 × 75 pg; 0.70 ± 0.12 ng/mL) after acute administration, whereas in the steady state, in which the dose of the conventional preparation was halved (75 μg), the Cmaxvalues were comparable: 1 × 150 pg‐0.99 ± 0.27 ng/mL, 1 × 75 pg‐0.84 ± 0.20 ng/mL and the dose‐normalized interdose AUC were identical for the conventional (16.2 ± 4.3 ng/mL · hr) and slow release (16.6 ± 5.3 ng/mL · hr) products. T1/2values for the conventional formulation of clonidine exceeded 20 hours in all but one subject and were considerably longer than those in previous reports, including those of the authors, in which a less sensitive assay was used. T1/2was even longer for the slow‐release formulation after both acute and chronic dosing and was consistent with the continuing release of clonidine from the slow‐release product throughout the 48‐hour sampling time. The results confirm the slow‐release nature of the formulation and suggest that the elimination half‐life of clonidine does not correlate closely with the duration

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03858.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

Selected adverse events were evaluated from the combined randomized placebo‐controlled clinical trials (once‐a‐day or twice‐a‐day; monotherapy or combination therapy) of terazosin in hypertensive patients. The designs of these clinical trials were either titration to response or titration to a fixed dose. A grouped survival methodology using logistic regression, developed by Hosmane et al, was used to study the effects of age and dose on the incidence of adverse events. The analysis indicated that except for palpitations, nausea, headache, and dizziness the incidence of adverse events was not significantly related to either age or dose. Palpitations and headache decreased with increasing age and increasing dose and age, respectively. Dizziness and nausea increased at the maximum dose of 20 mg, but not at the 5‐ or

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03859.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY

摘要:

This four‐center, 20‐week, open‐label study evaluated transdermal clonidine as an adjunct to enalapril 10 mg daily and demonstrated patterns of compliance. Seventy‐four mildly to moderately hypertensive patients (mean seated blood pressure, 150/101 mm Hg) received enalapril 10 mg once daily as initial monotherapy. In 66 patients, the seated diastolic blood pressure remained 90 mm Hg at the trough blood levels of enalapril. Transdermal clonidine (3.5 cm2, 7.0 cm2, or 10.5 cm2, equivalent to 0.1 mg, 0.2 mg, and 0.3 mg clonidine/day, respectively) then was added as needed to achieve blood pressure control. Forty‐eight patients achieved diastolic blood pressures<90 mm Hg on concomitant therapy; 44 patients completed 8 weeks of maintenance dosing with a mean blood pressure of 134/85 mm Hg. Oral compliance, as measured by an electronic device that was actuated each time the medication vial was opened, varied from 48 to 140%. Compliance with the transdermal clonidine regimen was excellent; the patch was worn as directed during 96% of the patient‐weeks of therapy. The authors conclude that blood pressure can be controlled by a combination of transdermal clonidine and enalapril in patients that do not adequately respond to enalapril monotherapy. Patients poorly complying with oral regimens may be candidates for a trial of transdermal clonidine

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1992.tb03860.x

出版商:Blackwell Publishing Ltd    

年代:1992

数据来源: WILEY