ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04708.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

In congestive heart failure, down‐regulation of myocardial β‐adrenoceptors (β‐AR) due to an elevated sympathetic tone is well known. In infancy and childhood, heart failure is usually related to congenital heart disease (CHD). Therefore, 71 samples of right atrial tissue of infants and children with CHD undergoing cardiac surgery were studied for β‐adrenoceptor density and distribution of the β1‐/β2‐AR subtypes. In 49 cases, the coupling of the β‐AR to the adenylate cyclase (AC) was examined. In a further study of 19 myocardial samples, AC was selectively stimulated with β1‐ or β2‐AR whereas the other subtype was blocked by an antagonist. The following results were obtained: (1) Infants and children with severe acyanotic or cyanotic CHD had severely reduced β‐AR densities. (2) In most of the cases, the β‐AR down regulation is β1‐subtype selective, but in critically ill newborns with congenital aortic valve stenosis or transposition of the great arteries, there is additional significant β2‐AR down‐regulation. In Fallot patients treated with the β‐antagonist propranolol, a significant increased β‐AR number compared with untreated Fallot patients was found. (3) β‐Adrenoceptor reduction in CHD is correlated with elevated noradrenaline plasma levels, thus proving a sympathetic dysregulation. (4) In CHD with moderate hemodynamic load, β2‐AR coupling to AC was markedly more efficient than β1‐AR coupling. The small number of myocardial β2‐AR produced most of the cyclic adenosine monophosphate. (5) In severe acyanotic and cyanotic CHD, a partial decoupling of the β2‐AR to the AC occurred. This may be a first step before β2‐AR are reduced in number in severe cardiac failure. These results explain why catecholamine therapy in in/ants and children with CHD sometime fails. Because the contractile force can be increased by β2‐AR, partial β2‐agonists may improve cardiac performance in acute heart failure. The most appropriate drugs are those that modulate or bypass the neurohumoral pathomechanisms in chronic heart failure like angiotensin‐converting enzyme‐inhibitors, β‐AR antagonists, dopamine2‐agonists, and phosphodiesterase‐inhibitors. Further studies are neede

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04709.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04710.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The accuracy and precision of an intelligent dosing system (IDS) for FK506 in predicting doses to achieve target drug levels has been prospectively evaluated in transplant and autoimmune patients. For dose individualization, the knowledge base is updated with patient‐specific feedback including the current dose, drug level, and the new target level. The study population of 147 patients consisted of 97 transplant patients (liver and kidney) and 50 patients with autoimmune disorders. Patients in the transplant study group were entered sequentially and followed as a cohort. Patients in the autoimmune study group were randomly assigned to one of three predefined FK506 concentration windows (low, 0.1–.3; medium, 0.4–.7; and high, 0.8–1.3 ng/mL) as part of a concentration controlled clinical trial. Predictions of steady‐state plasma drug levels were made throughout the clinical course of autoimmune patients and during the first 6 weeks post‐transplant in liver and kidney recipients. FK506 concentration in plasma was measured by a monoclonal antibody based ELISA assay. Accuracy was computed as the mean prediction error (mpe). Precision was computed as the root mean squared prediction error (rmspe). The accuracy of the IDS in each study group was as follows: 0.016 ng/mL (liver), −0.034 ng/mL (kidney), and −0.022 ng/mL (autoimmune). Because the 95% confidence interval included zero in each case, the IDS showed no bias. The precision of the IDS in each study group was as follows: 0.133 ng mL (liver), 0.1903 ng/mL (kidney), and 0.1188 ng/mL (autoimmune). These results indicate that the FK506 IDS is both accurate and very precise (reproducible) in transplant and autoimmune patients. The performance of the FK506 compares favorably with previously reported pharmacokinetic dosing methods such as population nomograms and adaptive control feedback methods (least‐squares and Bayesian). Based on our findings, this IDS should have a number of important uses relevant to the drug development process, the prescribing physician and the individual patient. It provides an evident method for implementing concentration controlled clinical trials. It should accelerate the physician's learning curve while at the same time help to maximize therapeutic drug efficacy and minimize toxicity with drugs exhibiting nonlinear kinetics and narrow therapeutic indices. Preliminary studies suggest that these assets result in a significant cost‐benefit advantage by reducing the duration of hospitalization. Current studies are in progress to validate this and carefully measure its phar

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04711.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The first‐dose pharmacokinetics of FK506 was studied in nine orthotopic liver transplant patients receiving continuous intravenous infusion of 0.15 mg/kg/day. Multiple blood samples were obtained during the infusion and plasma FK506 concentrations were measured by enzyme‐linked immunosorbent assay. The plasma clearance ranged from 0.47 to 5.8 L/minute, and the half‐life ranged from 4.5 hours to 33.1 hours. These results indicate the pharmacokinetics of FK506 to be highly variable between patients. FK506 is extensively distributed outside the plasma compartment. FK506 is extensively metabolized in the body, with less than 1% of the administered dose being excreted in the urine as unchanged FK506. The large variability in FK506 kinetics during the immediate postoperative period is attributed to the variability in the functional status of the liver in the transplant patients. Because of the long half‐life of FK506, it takes more than 45 hours to reach steady‐state concentrations after continuous infusion. Based on the estimated kinetic parameters, it appears that a combination of a bolus or a rapid infusion of .02 mg/kg with a continuous infusion of 0.05 mg/kg/day will provide and maintain a concentration of more than 2 ng/mL from the beginning of the drug

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04712.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

Calcium‐channel blockers are a safe and effective treatment modality and have been used extensively in the treatment of angina and hypertension. Dilacor™ XR capsules, a new extended‐release formulation of diltiazem, has been developed for the treatment of hypertension. Dilacor XR (Rhône‐Poulenc Rorer Pharmaceuticals Inc., Collegeville, PA) uses a novel drug delivery system, the Geomatrix™ (JAGO Research AG, Zollikon, Switzerland) controlled‐release system, to deliver diltiazem at a constant rate for 24 hours. The rate of absorption is also slower. As doses of Dilacor XR were increased from 120 mg to 540 mg/day, there were disproportionate increases observed in area under the curve, maximum peak plasma concentration, minimum peak plasma concentration, and average peak plasma concentration. The efficacy data from two clinical trials have confirmed the established efficacy of diltiazem and the 24‐hour efficacy of Dilacor XR in the control of mild‐to‐moderate hypertension. The incidence of adverse effects with Dilacor XR in doses as high as 540 mg/day was generally comparable to that of placebo. This new extended‐release formulation of diltiazem should significantly facilitate blood pressure control because of better patient compliance with

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04713.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The efficacy of class 1C antiarrhythmic agents was determined in 36 patients with inducible sustained monomorphic ventricular tachycardia during baseline electrophysiology study (EPS), who continued to have inducible monomorphic ventricular tachycardia during EPS on class 1A antiarrhythmic therapy. Of 12 patients who partially responded to class 1A drugs, 11 (91.7%) continued to have a partial response during EPS on class 1C therapy, whereas one patient did not respond. Of 24 nonresponders to class 1A therapy, 2 (8.3%) responded during EPS on class 1C therapy, 7 (29.2%) partially responded, and 15 (62.5%) did not respond. In the 24 nonresponders to class 1A therapy, 9 of 17 patients (53%) with left ventricular ejection fraction (EF) 30% responded or partially responded to class 1C therapy, compared with none of 7 patients with EF<30% (P<.05). The EPS on class 1C agents in patients who fail to respond to class 1A therapy may be warranted oniy in those with EF ≥ 30

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04714.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

A randomized two‐period crossover study was conducted in 20 healthy male volunteers to assess the effect of food on the pharmacokinetics of gepirone (BMY‐13805) and its metabolite, 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) after a single 20‐mg dose of gepirone either after fasting or after consumption of a standard high‐Fat breakfast. There was a 1‐week washout period between treatments. Plasma samples were obtained predose and at specified time points after dosing and analyzed for gepirone and 1‐PP content by a specific gas chromatographic‐mass spectrometric method. Food did not significantly affect gepirone maximum peak plasma concentration (Cmax) and half‐life (R 1/2). The mean gepirone Cmax was 16.98 ± 8.12 ng/mL (fed) and 18.73 ± 10.30 ng/mL (fasted), with mean t 1/2 of 3.32 ± 1.84 hours (fed) and 2.94 ± 0.90 hours (fasted). Food significantly increased the mean area under the curveinf(AUCinf) from 55.26 ± 35.74 ng.hour/mL (fasted) to 75.69 ± 42.79 ng.hour/mL (fed), and the mean residence timeinf(MRTinf) from 4.31 ± 0.78 hours (fasted) to 5.37 ± 1.21 hours (fed). The median time to maximum plasma concentration (tmax)for gepirone was also significantly increased in the presence of food, 2.0 hours, versus 0.75 hours in the absence of food. For 1‐PP, food had no affect on Cmax, t 1/2, or AUCinf. Mean t 1/2 for 1‐PP in the presence and absence of food was 6.06 ± 1.75 and 5.76 ± 1.75 hours, respectively. MRTinf, however, was increased significantly from 9.32 ± 2.68 hours (fasted) to 10.53 ± 2.89 hours (fed). Median tmax for 1‐PP was also significantly increased from 1.25 hours in the absence of food to 3.0 hours with food. The results of this study indicated that the onset and rate of absorption of gepirone were altered in the presence of food. The amount of gepirone reaching the systemic circulation was also increased in the presence of food. Food did not markedly affect peak blood levels of both parent and metabolit

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04715.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

The dose‐response relationship of oral famotidine at doses up to 10 mg was evaluated in 10 healthy male subjects to assess the extent and duration of inhibition of meal‐stimulated intragastric acid secretion. Each subject received single oral administrations of famotidine 0.5, 2.5, 5.0, and 10.0 mg and placebo in a double‐blind, randomized, crossover fashion. Intragastric pH was measured every 4 seconds for 24 hours and expressed as the mean pH for each 10‐minute interval. Standard high‐protein meals were provided 1 hour before each dose of study drug and at 3 and 9 hours postdose. The mean intragastric pH was significantly higher after famotidine doses 2.5, 5.0, and 10.0 mg than after placebo at times 2.5 to 3.0,1.8 to 3.2, and 1.7 to 4.2 hours postdose, respectively. There were no significant differences in mean pH seen between famotidine 0.5 mg versus placebo. The range of the pH means between 1.7 and 3.2 hours postdose was placebo (1.0 to 1.3), famotidine 0.5 mg (1.1 to 1.4), 2.5 mg (1.4 to 1.7), 5.0 mg (1.7 to 2.1), and 10.0 mg (2.0 to 2.3). There was a statistically significant linear dose‐response relationship between famotidine dose and intragastric pH between 1.7 and 3.8 hours and from 6.3 to 8.7 hours afte

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04716.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY

摘要:

It has been reported that the urinary excretions of chloride (CI), potassium (K), and magnesium (Mg), but not sodium (Na), after furosemide, a loop diuretic, were decreased by pretreatment with lisinopril, an ACE inhibitor in hypertensive subjects. The electrolytes disturbance induced by furosemide might be ameliorated by lisinopril. The present study re‐examines this potential drug interaction in healthy subjects. Lisinopril (20 mg) or its matching placebo was given orally using a double‐blind, crossover design. Four hours after lisinopril administration, furosemide (20 mg) was injected intravenously and urine was collected during the following intervals: 0–0.5, 0.5–1, 1–1.5, 1.5–2, 2–3, 3–4, and 4–6 hours. Blood samples for plasma furosemide concentration were obtained at 0.5,1,1.5,2, 3, 4, and 6 hours after the agent. There were no significant differences between the two trials in plasma concentrations of furosemide or urinary excretions of the agent. Urine volume and urinary excretions of electrolytes (Na, CJ, K, and Mg) after the furosemide with lisinopril administration were not significantly different from those of placebo at any observation period. These results suggest that the urinary excretions of electrolytes after furosemide administration are not influenced by pretreatmen

ISSN:0091-2700    

DOI:10.1002/j.1552-4604.1993.tb04717.x

出版商:Blackwell Publishing Ltd    

年代:1993

数据来源: WILEY