Search Results - (Author, Cooperation:L. Z. Benet)

2014-02-28

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Animals ; Cell Differentiation ; Cell Proliferation ; Cellular Reprogramming ; Disease Models, Animal ; Endoderm/cytology ; Female ; Fibroblasts/*cytology ; Hepatocytes/*cytology/*transplantation ; Humans ; Liver/*cytology ; Liver Failure/pathology/therapy ; Male ; Mice ; Multipotent Stem Cells/cytology

1437-160X

Etodolac ; Pharmacokinetics ; Pharmacodynamics ; Sustained release ; Food effects

Springer Online Journal Archives 1860-2000

Medicine

Summary Etodolac exhibits linear pharmacokinetics, good oral bioavailability, greater than 99% protein binding, a low oral clearance (almost exclusively non-renal), a relatively small volume of distribution and a half-life that averages 7.3±4.0 h. No significant pharmacokinetic differences have been noted in patients with mild to moderate renal impairment, in patients with cirrhosis, in the elderly or in patients with arthritis. The pharmacodynamics of the drug are well characterized in terms of pain intensity differences (PID) yielding an EC50 of 13 μg/ml. The extensive kinetic/dynamica characterization of etodolac, together with its short half-life, makes the drug an ideal candidate for a sustained-release (SR), once-a-day formulation. Etodolac SR formulations exhibit the same pharmacokinetic characteristics as the conventional-release (CR) formulation, except for a longer time to peak concentration and a lower peak concentration. Fluctuation ratios upon multiple dosing are comparable for equal total daily doses of etodolac SR and twice-daily doses of the CR formulation. Administration with food (high-fat meal) did not affect areas under the curve for either the CR or the SR product. Simulation analyses for etodolac SR suggest that PID responses are maintained over 24 h.

Electronic Resource

1432-1041

haemodialysis ; protein binding ; prednisolone ; clearance ; renal transplant ; free clearance ; dialysate loss

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Summary The impact of nonlinear plasma protein binding of a drug on its removal by haemodialysis has been quantified. Prednisolone 10–100 mg was given i.v. to 10 renal transplant patients on haemodialysis for acute tubular necrosis. Dialysate and afferent and efferent blood samples were collected simultaneously in 67 instances. Total and unbound prednisolone in plasma and its total concentration in blood and dialysate were assessed by high performance liquid chromatography and equilibrium dialysis. The amount of prednisolone lost, as measured directly in the dialysate (21.8±4.4 µg/min, $${{\bar x}}$$ ± SE), was predictable from the afferent-efferent blood concentration differences (20.1±4.8 µg/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1±3.0 µg/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r 2=0.96) and hyperbolically with the total prednisolone concentration in plasma. The latter hyperbolic relationship is adequately described by the equation for nonlinear plasma protein binding, using the affinity and capacity constants of albumin and transcortin for prednisolone (r 2=0.98). Thus, the haemodialysis clearance of total prednisolone is concentration-dependent, while the clearance of unbound prednisolone is constant (76 ml/min). Free clearance values or measurements of afferent-efferent blood concentrations are mandatory for a drug showing nonlinear plasma protein binding in order to predict the amount lost in the dialysate.

Electronic Resource

1432-1041

furosemide ; kidney transplant patients ; metabolism ; renal function ; furosemide glucuronide ; biliary excretion

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Summary The metabolic fate of furosemide was studied in kidney transplant patients after oral and intravenous administration of the diuretic at therapeutic doses. Serial urine samples were collected over a 24 h period and furosemide was analyzed by a specific high performance liquid chromatographic method using fluorescence detection. We found no evidence of the putative furosemide metabolite, 2-amino-4-chloro-5-sulfamoylanthranilic acid (CSA), in any of the samples analyzed. The amount of furosemide excreted as the glucuronide metabolite accounted for 8% of the available dose, whether administered orally or by intravenous infusion. In addition, the significant positive correlation observed between the percent of the available dose excreted as furosemide glucuronide and the renal clearance of furosemide (r=0.581,p〈0.02) suggests that the glucuronidation process for furosemide may be occurring in the kidney. Furosemide and its glucuronide metabolite accounted for only 45% of the intravenous dose recovered in the urine. Biliary excretion of unchanged furosemide and/or furosemide glucuronide into the feces probably accounts for the remainder of the dose not recovered.

Electronic Resource

1432-1041

prazosin ; congestive heart failure ; pharmacokinetics ; oral dose ; comparison with healthy volunteers

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Summary The pharmacokinetics of prazosin (Minipress®) were studied in nine patients with NYHA Class 3 or 4 congestive heart failure and in five healthy controls. After a single 5 mg oral dose, plasma concentrations of prazosin, as reflected in the area under the plasma concentration-time curve (AUC) and prazosin plasma half-life, were approximately double in the patients in comparison to the control group. Reduction in hepatic blood flow, altered gastrointestinal absorption of the drug or diminished intrinsic hepatic metabolic activity in the patient group may have contributed to the observed changes in prazosin disposition. The finding of higher prazosin plasma concentrations in patients with refractory heart failure demonstrates the need for close monitoring of these individuals following administration of the drug in the treatment of chronic congestive heart failure.

Electronic Resource

1432-1041

prednisolone ; hydrocortisone ; cushingoid syndrome ; pharmacokinetics ; renal transplant ; oral disease

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Summary To establish if the appearance of cushingoid side effects in patients taking exogenous glucocorticoids is related to the disposition and metabolism of these steroids and endogenous hydrocortisone, 15 stable renal transplant patients and 12 patients treated with prednisone for oral mucocutaneous vesiculo-erosive diseases were investigated. All 27 patients were given their usual prednisone dose orally on one occasion, and 24 were given the same amount of prednisolone intravenously on another occasion. Following dosing, plasma samples were obtained for determination of the areas under the plasma concentration time curves of total prednisolone, prednisone and hydrocortisone by high performance liquid chromatography, and of unbound prednisolone by equilibrium dialysis. The bioavailability of prednisone, the interconversion of prednisone into prednisolone, the clearance of total and unbound prednisolone, the prednisolone binding capacity of albumin and transcortin, and the affinity of albumin for prednisolone did not differ between the 14 patients without cushingoid side effects and the 13 cushingoid patients. Compared to those who had cushingoid features, patients who developed no side effects had a higher affinity constant for prednisolone binding to transcortin − 2.04±0.27 × 107 L/M vs. 1.34±0.16×107 (X±SE;P〈0.05), more frequently exhibited peak hydrocortisone levels within the normal range (6/14 vs 1/13), more often had measurable (〉10ng/ml) hydrocortisone in the plasma samples collected during the kinetic studies (123/291 vs 74/325;P〈0.001) and had higher areas under the plasma concentration time curve of hydrocortisone (median, range), i.e. 8081 ng/ml · min (0–21 637 ng/ml · min) vs 386 ng/ml · min (0–16 329 ng/ml · min;P〈0.005). The data suggest that endogenous hydrocortisone production is not as suppressed in patients with visible cushingoid signs as in noncushingoid patients, and that there is no significant difference in the pharmacokinetics of exogenous glucocorticoids between patients with and without cushingoid side effects.

Electronic Resource

1432-1041

prednisolone ; protein binding ; prednisone ; hydrocortisone ; transcortin

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Medicine

Summary The protein binding of prednisolone was studied in plasma obtained from healthy volunteers in the presence of added amounts of prednisone and hydrocortisone. The plasma protein binding was determined using in vitro equilibrium dialysis for 16 h at 37°C against isotonic Krebs-Ringer buffer using radioactive prednisolone. Prednisone appeared to have no effect on prednisolone binding. This surprising result was observed even when prednisone concentrations were more than 35 fold greater than prednisolone concentrations. In contrast, a marked competition between hydrocortisone and prednisolone was observed. These binding data were fit using a nonlinear least squares regression computer program and the capacity and affinity constants for the binding of prednisolone to transcortin and albumin were estimated including the competition for binding sites between prednisolone and hydrocortisone. The results from these studies compare favorably with recent parameter calculations, and our previous work where differences in binding were noted between cushingoid and noncushingoid patients.

Electronic Resource

1618-2650

Springer Online Journal Archives 1860-2000

Chemistry and Pharmacology

Electronic Resource