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Biomedical subjects

F J Frey

Publications and source records attributed to F J Frey.

At least 145 records · Page 8Linked to original sources
PubMed1985

Pharmacokinetic and pharmacodynamic interaction between furosemide and metolazone in man.

In various clinical situations a poor diuretic response to furosemide may be improved by the addition of metolazone. The mechanism of this additive effect is unclear. The purpose of the present investigation was to establish whether metolazone changes the pharmacokinetics of furosemide and by this mechanism enhances the diuretic effect. Eight volunteers were given an intravenous infusion of 4 mg h-1 of furosemide for 12 h. After 6 h 2.5 mg metolazone were administered orally. The addition of metolazone increased diuresis, urinary excretion of sodium and chloride (P less than 0.01), but decreased urinary excretion of calcium (P less than 0.01), while furosemide excretion remained unchanged. Total body clearance and renal clearance values of furosemide were similar before and after administration of metolazone. Our data confirm the additive diuretic effect of the combination treatment metolazone-furosemide and show for the first time a distinct hypocalciuric action of metolazone, similar to thiazides. Moreover metolazone does not affect the pharmacokinetics of furosemide.

Calcium↗
PubMed1985

Thigh muscle mass and function in patients treated with glucocorticoids.

Treatment with glucocorticoids causes wasting of proximal skeletal muscles. There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is unknown. The present investigation was designed to establish in what respect moderate physical training may alter muscle mass and function as assessed quantitatively by computed tomography (CT) and with an isokinetic dynamometer (Cybex II). Compared with matched controls, both female (n = 17) and male (n = 22) patients treated with prednisone (15.4 +/- 6.6 mg die-1) had a lower mid-thigh muscle area of 20 and 45% and an increased mid-thigh fat/muscle ratio of 25 and 100%, respectively. The mean peak torque and the total work output of the thigh muscle were lower by 20-30% (n = 14). Fifty days of isokinetic training in six patients increased the thigh muscle area, decreased the thigh fat area and normalized the mean peak torque and total work output. Thus, glucocorticoid-induced muscle wasting can be reversed by increasing physical activity.

Adult↗
PubMed1985

The effect of altered prednisolone kinetics in patients with the nephrotic syndrome and in women taking oral contraceptive steroids on human mixed lymphocyte cultures.

The purpose of this study was to examine the influence of altered prednisolone kinetics in patients with the nephrotic syndrome and women taking oral contraceptive steroids on mixed lymphocyte cultures (MLC). After oral and iv prednisolone treatment, blood samples were collected over 24 h. The area under the plasma concentration vs. time curve (AUC) of unbound, transcortin- bound, and albumin-bound prednisolone was determined. All plasma samples were incubated with MLCs, and the area under the inhibition vs. time curve of the MLC (AUIC), a measure of the effect over time, was calculated. The steroid concentrations required to produce half-maximal inhibition (EC50) were calculated. The 10 women taking oral contraceptives had higher AUCs of unbound and transcortin-bound prednisolone than the 10 normal subjects. The mean biological effect (AUIC value) was more pronounced in women taking contraceptive steroids. An analysis of the concentration-response curves revealed that the EC50 values of total, but not unbound, prednisolone were higher in women taking contraceptives. Compared with the normal subjects, the 9 nephrotic patients had lower total and comparable unbound AUCs of prednisolone. The AUIC values were higher whereas the EC50 values of unbound and total prednisolone were lower in the nephrotic patients. These findings indicate that the increased steroid effect in women taking oral contraceptives is explained by higher concentrations of prednisolone, while the increased effect in nephrotic patients is not attributable to the abnormal kinetics or protein binding of prednisolone.

Adult↗
PubMed1985

Evidence that prednisone-induced myopathy is reversed by physical training.

Treatment with glucocorticoids causes wasting of proximal skeletal muscles. There is evidence that physical training improves muscle mass and strength in glucocorticoid-treated rats. Whether this is also true in humans is not known. The present investigation was designed to establish in what respect moderate physical training may alter muscle mass and function as assessed quantitatively by computed tomography (CT) and an isokinetic dynamometer (Cybex II). Compared with matched normal subjects (n = 12), patients (n = 12) treated with prednisone [12.6 +/- 3.3 (+/- SD) mg/day] had a 20% lower midthigh muscle area and a 36% increase in midthigh fat to muscle ratio. The mean peak torque and the total work output of the thigh muscle were lower by more than 20%. Baseline measurements of total work output or peak torque at all tested velocities increased with midthigh muscle area (r = 0.73; n = 24; P less than 0.001). Fifty days of isokinetic training in 12 patients increased the thigh muscle area, decreased the thigh fat area, and normalized the mean peak torque and total work output. The increase in peak torque was inversely correlated with the daily dose of prednisone (r = 0.60; n = 12; P less than 0.05). Thus, glucocorticoid-induced muscle wasting can be reversed by increasing physical activity in patients taking a low to moderate dose of prednisone.

Adult↗
PubMed1985

Pharmacokinetics of 3 prednisolone prodrugs. Evidence of therapeutic inequivalence in renal transplant patients with rejection.

Renal allograft rejections are often treated with high doses of prednisone or prednisolone. The solubility of the biologically active prednisolone is poor. Therefore prednisolone is given i.v. as prednisolone disodium phosphate (prednisolone phosphate) or as prednisolone sodium tetrahydrophthalate (prednisolone phthalate). The time course of hydrolysis of high doses of these prodrugs and the reduction of high doses of oral prednisone into prednisolone has not been investigated. Therefore 10 patients treated for acute rejection were given, on 3 occasions, oral prednisone, i.v. prednisolone phosphate, or i.v. prednisolone phthalate in equimolar doses corresponding to 7 mg/kg of prednisolone. Blood samples were collected over a 24-hr period. Measurements were performed by high-performance liquid chromatography and equilibrium dialysis. The time to peak, the peak concentrations, and the area under the plasma-concentration-vs.-time curve (AUC) of prednisone and of unbound prednisolone were calculated. In all patients the hydrolysis of the prednisolone phosphate ester was faster than that of the prednisolone phthalate ester. The mean (+/- SD) peak concentrations of unbound prednisolone were higher after i.v. prednisolone phosphate (18.5 +/- 3.4 micrograms/ml) than after i.v. prednisolone phthalate (2.9 +/- 0.5 micrograms/ml) or after oral prednisone (3.1 +/- 0.8 micrograms/ml), (P less than 0.001). The mean AUCs of unbound prednisolone were 2324 +/- 683 micrograms/ml/min from prednisolone phosphate, 1209 +/- 324 micrograms/ml/min from prednisolone phthalate, and 1584 +/- 556 micrograms/ml/min from oral prednisone. The AUCs of prednisolone from i.v. prednisolone phosphate (P less than 0.001) or from oral prednisone (P less than 0.005) were higher than from i.v. prednisolone phthalate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1984

[Transcortin concentrations in the plasma of normal persons and patients with kidney and liver diseases].

The purpose of the study was to assess the influence of chronic kidney and liver diseases on the transcortin concentrations in plasma. The mean (+/- SD) plasma concentration of transcortin was 45.0 +/- 6.7 mg/l in women not taking oral contraceptive steroids and 41.2 +/- 6.7 mg/l in healthy male volunteers. Patients with the nephrotic syndrome had low transcortin concentrations (females: 20.9 +/- 8.5 mg/l; males: 26.0 +/- 6.0 mg/l). Abnormally low concentrations were measured in females treated for endstage renal disease with chronic ambulant peritoneal dialysis (CAPD) (30.8 +/- 7.5 mg/l). Patients on hemodialysis or with a functioning renal allograft had normal transcortin concentrations in plasma. Females suffering from a primary biliary cirrhosis had normal transcortin concentrations and male patients with an alcoholic cirrhosis had abnormally low mean transcortin concentrations in plasma (32.6 +/- 7.4 mg/l). The transcortin concentrations in patients with a Gilbert syndrome were normal. Among patients with a kidney or liver disease, the large variability of the transcortin concentration in plasma indicates that the knowledge of the transcortin concentration or the unbound steroid concentration in plasma is mandatory for the interpretation of total glucocorticoid concentrations in plasma.

Adult↗
PubMed1984

[Practical aspects of glucocorticosteroid therapy].

Alternate-day corticosteroid regimens have been advocated for maintenance therapy of several disorders. The objectives of this dose-spacing regimen are to decrease the undesired side effects of corticosteroids and at the same time to preserve their therapeutic effect. An analysis of the literature reveals that both the desired and the undesired effects of corticosteroids are decreased in alternate-day regimens as compared to daily regimens; whether dose-spacing improves the ratio of desired to undesired effects has not yet been established. Since for pharmacokinetic reasons the total exposure to prednisolone is lower in alternate-day regimens than in daily regimens, there is no reason to convert the daily prednisone regimen into an alternate-day schedule, instead of simply reducing the daily dose, in a patient with a good response to daily prednisone. Chronic maintenance of supraphysiologic levels of glucocorticoids is associated with the development of osteopenia. One mechanism responsible for osteopenia is an increase in bone resorption rates attributable to increased parathyroid hormone secretion secondary to inhibition of intestinal calcium absorption. There is evidence that administration of 25-hydroxyvitamin D and calcium may abrogate glucocorticosteroid-induced inhibition of intestinal calcium absorption and improve glucocorticoid-induced osteopenia. This evidence is discussed.

Calcium↗
PubMed1984

Pharmacokinetic interaction of contraceptive steroids with prednisone and prednisolone.

The oestrogenic component of oral contraceptives affects the activity of liver enzymes and the concentrations of plasma proteins implicated in steroid metabolism and transport. The present study was designed to determine these effects on the kinetics of prednisone and prednisolone. After an oral dose of prednisone, women on oral contraceptive steroids (n = 10) had higher mean (+/- SD) area under the plasma concentration versus time curves of total (428 +/- 67 micrograms/ml/min vs 188 +/- 28 micrograms/ml/min, p less than 0.001) and unbound prednisolone (64 +/- 10 micrograms/ml/min vs 41 +/- 10 micrograms/ml/min, p less than 0.001) than women not taking oral contraceptive steroids (n = 10). The differences were attributable to a lower non-renal clearance of prednisolone and to a higher apparent systemic availability of the drug in contraceptive users than in the controls. The affinity of albumin and transcortin for prednisolone was lower in women on oral contraceptives than in controls (p less than 0.001). Thus, altered kinetics and protein binding may account for the known increase in glucocorticoid efficacy by oestrogens.

Adult↗
PubMed1984

Altered plasma protein-binding of prednisolone in patients with the nephrotic syndrome.

Prednisolone binds in plasma to both albumin and transcortin. Since altered concentrations of plasma proteins change capacity and association constants of the drug-protein complex and thus influence the disposition of the drug, the kinetics of prednisolone following oral prednisone and intravenous (IV) prednisolone were studied in ten nephrotic patients and in 12 healthy volunteers. Compared to normal volunteers, nephrotic patients had significantly higher mean (+/- SD) association constants for the albumin-prednisolone complex (4.20 +/- 2.10 X 10(3) M-1 v 2.26 +/- 0.46 X 10(3) M-1, P less than 0.005) and tended to have higher association constants for the transcortin-prednisolone complex. Following the IV administration of prednisolone and the oral administration of prednisone, nephrotic patients exhibited lower total plasma concentrations of prednisolone than did normal volunteers. The difference was attributable to lower albumin-bound and/or transcortin-bound, but not unbound, concentrations of prednisolone in plasma. The mean prednisolone bioavailability from oral prednisone was not different between nephrotic patients and controls. When calculated with reference to total prednisolone concentrations in plasma, the mean nonrenal clearance rate, but not the mean renal clearance rate, was higher in the nephrotic patients than in the controls (2.63 +/- 0.61 mL/min/kg v 1.85 +/- 0.33 mL/min/kg, P less than 0.005). Compared to normal volunteers, patients with the nephrotic syndrome had lower renal clearance rates of unbound prednisolone when prednisolone was given intravenously (1.58 +/- 0.88 mL/min/kg v 2.89 +/- 0.89 mL/min/kg, P less than 0.005) or when prednisone was given orally (1.18 +/- 0.86 mL/min/kg v 2.80 +/- 1.13 mL/min/kg, P less than 0.005). Nephrotic patients had lower ratios of unbound prednisolone clearance/creatinine clearance (fractional excretion) after IV prednisolone (1.50 +/- 0.81 v 2.27 +/- 0.49, P less than 0.025) or after oral prednisone (1.07 +/- 0.60 v 2.12 +/- 0.77, P less than 0.005) than the controls. Since these fractional excretion values of unbound prednisolone exceeded one, there must be glomerular filtration of prednisolone bound to plasma proteins and/or tubular secretion of prednisolone. This study indicates that the nephrotic dysproteinemia changes the binding of prednisolone to plasma proteins not only in point of quantity, but also in point of quality, and alters the disposition of prednisolone.

Administration, Oral↗
PubMed1984

Phenytoin modulates the pharmacokinetics of prednisolone and the pharmacodynamics of prednisolone as assessed by the inhibition of the mixed lymphocyte reaction in humans.

Following induction of the microsomal liver enzymes, lower total prednisolone concentrations in plasma and an altered pattern of the prednisolone metabolites generated were observed. The purpose of the present study was to establish whether--as a consequence of an enhanced clearance--lower unbound concentrations of prednisolone in plasma are detectable after enzyme induction and to determine if the altered prednisolone metabolism modulates the biological effect. Before and during phenytoin dosage in ten volunteers, the mean (+/-SD) total body clearance (ml min-1 kg-1) of both total and unbound prednisolone increased from 2.74 +/- 0.47 to 3.94 +/- 0.66 (P less than 0.001) and from 10.76 +/- 2.68 to 16.00 +/- 3.17 (P less than 0.001), respectively. These increments were due to increased non-renal clearances. The immunosuppressive activity as a function of time in plasma determined as the percent inhibition of the mixed lymphocyte reaction decreased by one third after phenytoin dosing, while the EC50 values of unbound prednisolone were unaffected. Thus enzyme induction decreases both the unbound prednisolone concentration and the steroid efficacy.

Adult↗
PubMed1984

Pharmacokinetics and pharmacodynamics of three different prednisolone prodrugs: effect on circulating lymphocyte subsets and function.

To be pharmacologically active, i.v. prednisolone disodium phosphate (prednisolone phosphate), prednisolone sodium tetrahydrophthalate (prednisolone phthalate), and oral prednisone have to be converted in vivo into prednisolone. The purpose of the present study was to establish whether these agents are functionally equivalent when given in equimolar doses. The peak concentrations of total and unbound prednisolone assessed by HPLC and equilibrium dialysis in five normal volunteers were five to 12 times higher after i.v. prednisolone phosphate than after i.v. prednisolone phthalate or oral prednisone (p less than 0.001). The area under the plasma concentration vs time curves (AUC) of total and unbound prednisolone was higher after i.v. prednisolone phosphate than after oral prednisone or i.v. prednisolone phthalate (p less than 0.001). The immunosuppressive activity of the plasma samples was determined as the percentage inhibition of the mixed lymphocyte reaction, and the area under the inhibition vs time curve of the MLR (AUIC), a measure of immunosuppressive capacity over time, was calculated. After i.v. prednisolone phthalate or oral prednisone, the mean AUC of unbound prednisolone were 45 and 61% of that obtained after i.v. prednisolone phosphate, and the corresponding AUIC were 76 and 68%, respectively, indicating lower systemic availability of prednisolone and less of an immunosuppressive effect in plasma after i.v. prednisolone phthalate or oral prednisone than after i.v. prednisolone phosphate. These differences in biologic activity of the plasma were corroborated by determining ex vivo the cell cycle progression within the G1 phase, and the interleukin 2 (IL 2) release after the activation of peripheral lymphocytes obtained at various time points after administration of the three steroids. After steroid doses corresponding to 1 mg/kg of prednisolone, a transient inhibition of 80% of IL 2 production was observed with all three glucocorticoids given, whereas the maximal inhibition of the IL 2 production was 60, 30, and 22% after a low dose (0.1 mg/kg) of prednisolone phosphate, prednisone, or prednisolone phthalate, respectively. After the low dose, only minimal changes in the percentages of the OKT4+ and OKT8+ cells were detectable, whereas after the high dose of all three steroids the ratio of OKT4+ to the OKT8+ cells dropped, the decline being more pronounced after prednisolone phosphate than after prednisolone phthalate or prednisone.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1983

Urinary 6 beta-hydroxyprednisolone excretion indicates enhanced prednisolone catabolism.

Patients with enhanced catabolism of prednisolone exhibit a reduction in steroid efficacy. Since prednisolone never reaches steady state at the usual dosage, the clearance rate can only be estimated by determining the area under the plasma concentration-time curve after an i.v. dose of prednisolone. To obviate that time-consuming procedure for screening of patients with enhanced prednisolone metabolism, we developed a quantitative assay for 6 beta-hydroxyprednisolone in urine to determine whether the urinary excretion of 6 beta-hydroxyprednisolone increases concomitantly with the clearance rate of total and of unbound prednisolone in subjects with an enhanced catabolism of prednisolone. The results are given separately for males and females because there is some debate as to whether females compared to males exhibit a higher capacity of the liver to hydroxylate steroids at the sixth position. Before and during the administration of phenytoin the total body clearance of total and of unbound prednisolone and the urinary excretion of prednisolone and of 6 beta-hydroxyprednisolone were determined in six female and eight male volunteers. The fraction of the i.v. dose of prednisolone excreted in urine as 6 beta-hydroxyprednisolone was higher in females than in males (p less than 0.001) and increased during phenytoin dosing from 6.4%-10.4% (range) to 15.6%-20.4% in females and from 2.4%-7.2% to 12.2%-18.3% in males. The ratio of 6 beta-hydroxyprednisolone to prednisolone in urine increased linearly with the nonrenal clearance of both total and unbound prednisolone. This is the first demonstration that the fractional excretion of 6 beta-hydroxyprednisolone increased after the induction of the microsomal liver enzymes. Thus measurements of urinary 6 beta-hydroxyprednisolone excretion may be of potential value to detect patients with enhanced catabolism of prednisolone.

Adult↗
PubMed1982

Simultaneous measurement of prednisone, prednisolone and 6 beta-hydroxyprednisolone in urine by high-performance liquid chromatography coupled with a radioactivity detector.

We describe the first method of routine measurement of prednisone, prednisolone and 6 beta-hydroxyprednisolone concomitantly in urine. Urine (3 ml) is extracted with ethyl acetate, washed with base and separated by high-performance liquid chromatography on a silica column with a solvent system of hexane--diethyl ether--ethanol--tetrahydrofuran--glacial acetic acid (59.9:31:2.3:6.5:0.3, v/v). The steroids are detected at 254 nm. Because no conventional internal standard was found, 6 beta-[3H]hydroxycortisol and [3H]prednisolone are added to urine prior to extraction; 3H is monitored by a radioactivity detector coupled with the chromatograph. The assay exhibits linearity from 200 to 7500 ng and an inter-day variability of less than 11.4% (C.V.).

Adult↗
PubMed1982

Nonlinear plasma protein binding and haemodialysis clearance of prednisolone.

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 micrograms/min, mean +/- SE), was predictable from the afferent-efferent blood concentration differences (20.1 +/- 4.8 micrograms/min), but not from measurements of total afferent-efferent prednisolone concentrations in plasma (13.1 +/- 3.0 micrograms/min). The amount of prednisolone lost in the dialysate increased linearly with unbound (r2 = 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 (r2 = 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.

Blood Proteins↗