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Biomedical subjects

J G Gambertoglio

Publications and source records attributed to J G Gambertoglio.

At least 73 records · Page 4Linked to original sources
PubMed1983

Amdinocillin pharmacokinetics. Simultaneous administration with cephalothin and cerebrospinal fluid penetration.

In the treatment of serious infections, combinations of beta-lactam antibiotics are being utilized in order to avoid aminoglycoside toxicity and to achieve antibacterial synergy. The pharmacokinetic disposition of amdinocillin and cephalothin was determined, when administered alone or in combination to healthy volunteers, as well as the penetration of amdinocillin into human cerebrospinal fluid. Six subjects received, on separate occasions, single intravenous doses of amdinocillin 10 mg/kg, cephalothin 15 mg/kg, or a combination of the two in the same doses. The elimination half-lives of amdinocillin and cephalothin are increased when these drugs are given simultaneously, compared with when they are administered alone. However, no significant differences were observed. When they were given in combination, no significant changes in plasma clearance, renal clearance, or steady-state volume of distribution were found. Eight patients undergoing lumbar puncture for various neurologic disorders without inflamed meninges received a single dose of 10 mg/kg amdinocillin intravenously. One to two hours later, simultaneous plasma and cerebrospinal fluid samples were obtained. The concentration of amdinocillin in the cerebrospinal fluid ranged from approximately 1 to 10 percent of concomitant plasma concentrations. Thus, amdinocillin penetrates in the cerebrospinal fluid in marginal amounts in the absence of meningeal inflammation.

Adult↗
PubMed1983

Volume shifts and protein binding estimates using equilibrium dialysis: application to prednisolone binding in humans.

Sizable volume shifts can occur during equilibrium dialysis. This net movement of water, presumably caused by the osmotic effect of plasma proteins, reduces the concentration of binding proteins. In this paper the theory of protein binding estimation is extended, equations are developed for calculating the unbound and bound drug concentrations at dialysis equilibrium by correcting for the dilution of the proteins, and the equations are applied to a study of prednisolone. To demonstrate the importance of correcting for the volume shift, the parameters of a model in which prednisolone binds to corticosteroid-binding globulin, a protein with a limited capacity, and albumin were estimated. Unbound and bound concentrations were determined by correcting for both volume shifts (average 31%) and loss of drug to the buffer side, by correcting only for loss of drug to buffer side, and by making no correction at all (the usual method of treating equilibrium dialysis data). The error introduced by neglecting volume shifts was analyzed by comparing the parameter values obtained using the three methods. The results confirm the need to adjust for volume shifts and imply that reported binding constants obtained by equilibrium dialysis may be in error for many substances.

Blood Proteins↗
PubMed1983

Furosemide assays and disposition in healthy volunteers and renal transplant patients.

A variety of furosemide assays and their application to biological samples have been described over the past 2 decades. We describe development of a specific, sensitive assay appropriate for efficient measurement of large numbers of biological samples. With development of this methodology we have demonstrated that the putative 2-amino-4-chloro-5-sulfamoylanthranilic acid metabolite is an artifact of sample preparation. In addition, some preparative techniques overestimate furosemide because they hydrolyze the glucuronide conjugate back to the parent compound. Applications of this assay to studies of normal subjects and patients who have received kidney transplants demonstrate a relatively constant amount of glucuronide formation and evidence that this conjugation occurs in the kidney. We also show that patients with renal transplants who are resistant to the effects of furosemide appear to have decreased secretion of the drug into the urinary site of action, the mechanism of which is unknown.

Furosemide↗
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↗
PubMed1982

Comparison of the disposition of total and unbound sulfisoxazole after single and multiple dosing.

Plasma concentrations of total and unbound sulfisoxazole were followed after single intravenous and oral doses of 1 g sulfisoxazole and during a 500-mg, four-time-a-day dosing regimen in six healthy males, using a specific high pressure liquid chromatographic assay method. Saturable plasma protein binding was observed at total concentrations above 80-100 mg/liter. The clearance of sulfisoxazole was 18.7 +/- 3.9 ml/min for total drug and 232 +/- 64 ml/min for unbound drug. Renal elimination, on the average, accounted for 49% of the clearance of sulfisoxazole. The apparent volume of distribution for total drug was 10.9 +/- 2.0 liters and 136 +/- 36 liters for unbound drug, indicating that sulfisoxazole is primarily distributed extracellularly. Accumulation of N4-acetyl-sulfisoxazole during multiple dosing did not affect the disposition of sulfisoxazole. Adjusting for variable renal clearances between oral and intravenous administration and using the unbound plasma concentrations, the bioavailability for an oral dose of sulfisoxazole was found to be 0.95 +/- 0.04.

Administration, Oral↗
PubMed1982

Prednisone and prednisolone bioavailability in renal transplant patients.

Prednisone and prednisolone are drugs with the potential for therapeutic inequivalence due to bioavailability problems. The objective of our study was to compare the systemic bioavailability of prednisolone from oral prednisone and prednisolone. Nine kidney transplant patients receiving prednisone (12.5 to 22.5 mg per day) were administered, in a randomized fashion, the same dose of oral prednisone (Deltasone), oral prednisolone (Delta-cortef) and intravenous prednisolone (Hydeltrasol). Prednisolone and prednisone levels were measured using a specific high-pressure liquid chromatographic assay. Since prednisolone exhibits dose-dependent pharmacokinetics because of nonlinear plasma protein binding, bioavailability from oral prednisone and oral prednisolone, compared to the intravenous dose, was 84.5 +/- 17.8% and 95.5 +/- 17.6% using unbound drug concentrations. These differences were not statistically significant. Furthermore, no significant differences were observed between the two oral formulations in peak prednisolone levels, time of peak levels or half-life using either total or unbound drug concentrations. The results from our study indicate that both of the oral preparations tested provide similar bioavailability of active prednisolone and the conversion of prednisone to prednisolone occurs rapidly.

Administration, Oral↗
PubMed1982

Multiple-dose pharmacokinetics of amdinocillin in healthy volunteers.

The pharmacokinetics of amdinocillin (mecillinam) after multiple intravenous doses to healthy subjects are described. Assay of plasma and urine samples was carried out with a sensitive and specific high-pressure liquid chromatographic technique. A dose of 10 mg/kg of body weight was administered every 4 h for six doses. No accumulation was noted. Mean peak plasma concentrations were approximately 50 micrograms/ml, and the plasma half-life was approximately 53 min. Total plasma clearance was 4.6 ml/min per kg after the first dose, which declined slightly to 4.1 ml/min per kg after the last dose. Renal clearance remained fairly constant at approximately 2.9 ml/min per kg, or twice the creatinine clearance. The fraction excreted unchanged totaled 63% during the 4-h interval after the first dose and was nearly 70% overall. The steady-state volume of distribution was calculated to be 0.26 liter/kg. Urinary concentrations of amdinocillin were far in excess of the usual inhibitory concentrations for susceptible pathogens and were as high as 3,000 micrograms/ml. Dose of amdinocillin every 4 h provide plasma and urine concentrations which should be effective for the treatment of infections.

Adult↗
PubMed1982

Pharmacokinetics of cefonicid, a new broad-spectrum cephalosporin.

This study determined the pharmacokinetic disposition of cefonicid. A single dose of 7.5 mg/kg of body weight was administered to five healthy volunteers as a 5-min intravenous infusion. Multiple plasma and urine samples were collected for 48 h. Peak plasma concentrations ranged from 95 to 156 micrograms/ml and fell slowly (mean plasma half-life, 4.4 +/- 0.8 h), so that levels after 12 h were in the range of 6 to 12 micrograms/ml. Urinary concentrations were high but variable and ranged from 100 to 1,000 micrograms/ml for the first 12 h after the dose and averaged 84 micrograms/ml between 12 and 24 h. Plasma and renal clearances were 0.32 +/- 0.06 and 0.29 +/- 0.05 ml/min per kg, respectively. An average of 88 +/- 6% of the dose was excreted unchanged in the urine over 48 h. The mean steady-state volume of distribution was found to be 0.11 +/- 0.01 liters/kg.

Biological Assay↗
PubMed1982

Prescribing medication in long-term dialysis units.

Little information is available regarding the current patterns of medication use in long-term dialysis centers. Therefore, we surveyed the medication records of 1,023 patients undergoing long-term dialysis therapy in 27 dialysis centers. The mean number of medications prescribed per patient was 7.7 +/- 0.54, increasing patient age, increasing duration of dialysis, in-center dialysis, and the presence of underlying diabetic and hypertensive nephropathy were associated with increased frequency of medication use. The use of multiple pharmacologic agents was associated with a high frequency of drug duplication (12%), potential dosage error (9%), potential significant drug interaction (15%), and use of contraindicated drugs (2.5%). A lack of individualization of the use of several pharmacologic agents was apparent. An extreme degree of center variability in drug use was also apparent. Periodic review of medication use should be undertaken in the long-term dialysis setting.

Adult↗
PubMed1981

Furosemide kinetics and dynamics after kidney transplant.

We examined differences between responder (R) (40 to 80 mg/day) and nonresponder (NR) (greater than or equal to 120 mg/day) patients after kidney transplant with respect to furosemide kinetics and dynamics. Nonresponders had reduced plasma clearance (NR 64 +/- 21.4 and R 105 +/- 23 ml/min, two-sample t test; p less than 0.05), renal clearance (NR 18.4 +/- 8.1 and R 47.1 +/- 11.0 ml/min; p less than 0.005), and renal clearance to creatinine clearance ratio (NR 0.43 +/- 0.15 and R 0.80 +/- 0.07; p less than 0.005). Half-life rose in the nonresponders (NR 130 +/- 13 and R 87.6 +/- 16.3 min; p less than 0.005). There was no difference between groups with respect to nonrenal clearance, extent of availability, volume of distribution steady state, and the fraction of the dose excreted unchanged in the urine after intravenous administration. These results suggest that nonresponders have less ability to secrete furosemide into tubular fluid as well as less ability to respond to drug.

Administration, Oral↗
PubMed1980

Disposition kinetics of ethambutol in man.

Six normal adult volunteers were administered 15 mg/kg of ethambutol (EMB) by a constant-rate 1-hr infusion. Plasma and urine samples were collected up to 24 and 72 hr, respectively. Peak plasma levels following the 1-hr infusion ranged from 11.6 to 15.4 microgram/ml. Subsequent postinfusion EMB levels exhibited multiphasic decay. In the 12-hr period following infusion, EMB levels showed biexponential decay. However, 24-hr plasma levels in all subjects were observed to be higher than those predicted using a two-compartment body model. The alpha phase in these subjects had a mean half-life of 8.6 min while the half-life of the beta phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the gamma phase estimated from plasma data points between 12 and 24 hr averaged 1.2 +/- 3.6 hr. A terminal gamma t1/2 of 15.4 +/- 1.7 hr was calculated from 12-72 hr urine data. The mean value for the steady-state volume of distribution using a noncompartmental method was 3.89 liters/kg. Plasma EMB clearance ranged from 7.47 to 8.87 ml/min/kg (mean 8.57). The fraction of the dose eliminated unchanged varied from 0.75 to 0.84 (mean 0.79). Renal clearance ranged from 5.93 to 8.45 ml/min/kg (mean 6.81), indicating active tubular secretion.

Absorption↗
PubMed1980

Pharmacokinetics and bioavailability of prednisone and prednisolone in healthy volunteers and patients: a review.

Limited information is available on the pharmacokinetics and bioavailability of prednisone and prednisolone in patients with different disease states. This is partly due to difficulty in measuring these drugs in biological fluids at the usual dosages prescribed to patients. This article attempts to comprehensively review these studies categorized under the following four sections: (1) bioavailability--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of antacids, effect of food, effect of other drugs (aminophylline, cholestyramine); (2) pharmacokinetics--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of other drugs, enzyme induction of steroids and the effect on the kinetics of steroids and other drugs; (3) protein binding; and (4) analytical methods. The literature is reviewed through August 1979.

Adult↗
PubMed1980

Pharmacokinetics of mecillinam in health subjects.

Mecillinam is an amidino penicillinate derivative with a broad spectrum of activity against many gram-negative bacilli. Moreover, marked in vitro synergy against these organisms occurs when mecillinam is combined with other beta-lactam antibiotics. The purpose of this study was to determine the pharmacokinetic disposition of this antibiotic. A single dose of 10 mg/kg was administered to 12 healthy volunteers as a 15-min intravenous infusion. Multiple plasma and urine samples were collected at frequent intervals for 8 and 24 h, respectively. Plasma samples were assayed for mecillinam by using a specific high-pressure liquid chromatographic assay developed in our laboratory. Peak plasma levels ranged from 34 to 80 micrograms/ml, and after 4 h, plasma levels were 0.7 to 1.9 microgram/ml. The mean terminal plasma half-life was 51.1 +/- 8.6 min. The mean steady-state volume of distribution was calculated to be 0.23 +/- 0.04 liter/kg. The mean plasma and renal clearances were 3.5 +/- 0.4 and 2.5 +/- 0.4 ml/min per kg, respectively. The mean percentage of the dose excreted unchanged in the urine at 4 h was 67 +/- 5%; 71 +/- 6% was recovered in 24 h. Urine concentrations at 4 h were far above the minimum inhibitory concentration for susceptible gram-negative organisms.

Adult↗
PubMed1980

Prednisolone disposition in cushingoid and noncushingoid kidney transplant patients.

Little information is available on the disposition of prednisolone in kidney transplant patients and whether correlations exist between the pharmacokinetics and therapeutic or toxic effects of this drug. The present study was designed to determine the pharmacokinetics of prednisolone in six noncushingoid and six cushingoid transplant recipients. The elimination half-lives were not significantly different in the noncushingoid and cushingoid patients (2.3 vs. 3.3 h). However, other pharmacokinetic parameters were significantly lower in the cushingoid group: plasma clearance (147 vs. 82 ml/min) and volume of distribution (32 vs. 20 liters). In addition, the availability of prednisolone after oral prednisone administration was considerably variable (overall range, 27-108%) and was not significantly different between the two groups. Thus, in kidney transplant patients it appears that the plasma clearance and volume of distribution of prednisolone may distinguish between noncushingoid and cushingoid patients.

Adult↗
PubMed1979

Cefamandole kinetics in uremic patients undergoing hemodialysis.

A single intravenous 15 mg/kg dose of cefamandole was given to 6 patients in chronic renal failure before hemodialysis, and 3 were examined during an interdialysis period. Mean cefamandole clearance by hemodialysis was 24 +/- 12 ml/min; 35 +/- 15% of the dose was recovered in the dialysate. The cefamandole half-life (1 1/2) on dialysis was 4.0 +/- 0.29 hr; off dialysis it was 13.9 +/- 4.2 hr. High urine concentrations of cefamandole in these patients suggests usefulness in urinary tract infection.

Adult↗