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Biomedical subjects

T W Gehr

Publications and source records attributed to T W Gehr.

At least 19 recordsLinked to original sources
PubMed1996

Pharmacokinetics of sematilide in renal failure.

A randomized, two-period, two-treatment study was conducted to investigate the effect of renal impairment on the pharmacokinetics of the Class III antiarrhythmic sematilide HCl. The pharmacokinetic-pharmacologic effect relationship and tolerability of sematilide HCl were also studied. The study included 22 subjects: 6 healthy volunteers and 16 patients with various degrees of renal impairment, including functionally anephric patients on intermittent hemodialysis. Separated by a 14-day washout period, the subjects received a constant rate intravenous infusion of 40 mg sematilide HCl over 30 minutes and a tablet containing 100 mg of the drug. The functionally anephric patients were studied during and off dialysis after intravenous and oral administration of the drug, respectively. Blood and urine samples were collected at defined times up to 48 hours and 72 hours, respectively, after administration. Sematilide concentrations in plasma, urine, and dialysate were measured by a validated high-performance liquid chromatography (HPLC) method with ultraviolet detection. The pharmacokinetic data analysis used a compartment model independent approach. The heart rate-corrected Lead II QT interval was recorded as a pharmacologic endpoint. Subjective symptoms, cardiovascular parameters, routine serum chemistry, and hematology and urinalysis parameters were measured to assess tolerability. Mean renal clearance after intravenous and oral administration was reduced in patients with severe renal impairment. Statistically significant linear correlations existed between total clearance of sematilide and creatinine clearance for all subjects who could be evaluated after both intravenous and oral administration. Steady-state volume of distribution, absolute bioavailability, and nonrenal clearance of sematilide were independent of renal function. The mean dialysis clearance was 98 mL/min, indicating effective removal of the drug by hemodialysis. In accord with the drug's Class III pharmacologic activity, the heart rate corrected Lead II QT intervals were prolonged in all subjects after intravenous and oral administration of the drug. The pharmacologic effect to plasma concentration relationship in renal patients and in healthy subjects was comparable. Based on the experimentally determined linear relationship between total clearance of sematilide and creatinine clearance, modified dose regimens for sematilide HCl in patients with renal impairment and functionally anephric patients off hemodialysis were developed.

Adult↗
PubMed1996

Colloid infusions reduce glomerular filtration in resuscitated burn victims.

OBJECTIVE: Colloids are used clinically to minimize edema yet may have detrimental consequences on glomerular filtration. The purpose of this study is to assess the renal and hormonal effects of colloid supplementation in the fluid resuscitation of burn victims. DESIGN: Analytic cohort study. MATERIAL AND METHODS: Immediately following their 24 hour post-burn fluid resuscitation with Ringer's lactate, six burn patients (% total body surface area burn 30-57%) were given primed, continuous infusions of inulin and p-aminohippuric acid for 6 hours. Albumin (25% solution, 3 mL/kg/h) was given for the final 4 hours of study. MEASUREMENTS AND MAIN RESULTS: Albumin infusion increased plasma volume by 37%; however, glomerular filtration rate decreased by 32% (p < 0.05). There was no significant change in urine output, sodium excretion, or effective renal plasma flow. Plasma volume expansion with albumin normalized elevated basal levels of aldosterone and plasma renin activity. CONCLUSIONS: These findings illustrate that despite substantially increasing plasma volume, colloid infusions reduce glomerular filtration and may limit any associated diuresis. Furthermore, this study demonstrates that hormonal regulation of blood volume remains intact after moderate burn injury.

Adult↗
PubMed1996

Diuretic combinations in refractory oedema states: pharmacokinetic-pharmacodynamic relationships.

Diuretic resistance is encountered in a number of disease states, such as chronic renal failure, nephrotic syndrome, congestive heart failure (CHF) and cirrhosis. Diuretic stratagems which produce sequential nephron segment blockade, and thus a synergistic diuretic response, are frequently necessary and are regularly employed in these conditions. Pharmacokinetic determinants of diuretic response, including dose administered, absolute bioavailability, and tubular transport capacity and transport rate, are reviewed here. Pharmacodynamic factors are perhaps more important to overall response, and often result in modification of the dose-response relationship; these are also reviewed here. Stratagems used to maximise the diuretic response to loop diuretics include correcting abnormal haemodynamic parameters, utilising larger doses or constant intravenous infusions, and using albumin as a vehicle to deliver the loop diuretic to the site of tubular secretion. If these measures fail, then diuretic combinations are useful. Perhaps the most effective is the combination of metolazone (a thiazide-type diuretic) and a loop diuretic. The rationale for and use of various diuretic combinations, with particular emphasis on the metolazone-loop diuretic combination, is reviewed here and applied to the major disease states associated with diuretic resistance.

Diuretics↗
PubMed1994

Novel high-performance liquid chromatographic method using solid-phase on-line elution for determination of metolazone in plasma and whole blood.

A novel solid-phase on-line elution HPLC method employing fluorescence detection to measure metolazone in plasma and whole blood has been developed. The method is sensitive and selective for metolazone and linear over a dynamic range of 1-50 ng/ml with a sample requirement of 250 microliters. The limit of quantitation for the method is 1 ng/ml and combined intra- and inter-day accuracy and precision had an error and coefficient of variation of 2.9 and 5.5%, respectively.

Chromatography, High Pressure Liquid↗
PubMed1994

The pharmacokinetics of intravenous and oral torsemide in patients with chronic renal insufficiency.

Torsemide is a diuretic that acts in the thick ascending limb of the loop of Henle. Unlike furosemide, it undergoes substantial hepatic elimination and should not accumulate in patients with renal insufficiency. Therefore the pharmacokinetics of intravenous and oral torsemide and its metabolites were investigated in patients with chronic renal insufficiency. Two groups of 24 patients stratified by creatinine clearance (30 to 60 ml/min and < 30 ml/min) were studied in two separate randomized dose escalating crossover studies, one using intravenous torsemide and the other using oral torsemide. The pharmacokinetics of both intravenous and oral torsemide were linear over the dosage range studied. Absolute bioavailability was essentially 100%. Renal clearance was greatly diminished and correlated with renal function. Total plasma clearance and half-life were not related to renal function and were found to be similar to those of healthy subjects. The substantial nonrenal clearance of torsemide prevents accumulation in patients with chronic renal insufficiency.

Administration, Oral↗
PubMed1994

The pharmacodynamics of intravenous and oral torsemide in patients with chronic renal insufficiency.

The pharmacodynamics of intravenous and oral torsemide were determined in two randomized cross-over clinical trials in patients with chronic renal insufficiency. There was no significant difference in the rate or magnitude of the diuretic response between oral and intravenous administration. As has been shown with other loop diuretics, patients with chronic renal insufficiency have a reduced diuretic response compared with healthy subjects. This diuretic resistance is primarily related to a diminished delivery of drug to the urinary site of action. The response of torsemide at the tubular level is not different from that seen in subjects with normal renal function. Metabolites of torsemide do not appear to contribute to the diuretic response. A dose of 50 to 100 mg dependent on renal function is required to obtain a maximal response. A ceiling dose of approximately 100 mg in patients with chronic renal insufficiency is therefore recommended.

Administration, Oral↗
PubMed1994

Hormonal, blood pressure, and peritoneal transport response to short-term ACE inhibition.

OBJECTIVES: To evaluate the hormonal, blood pressure, and peritoneal transport effects of intraperitoneal enalaprilat and oral enalapril. DESIGN: A nonrandomized, nonblinded, prospective clinical trial was performed. SETTING: The study was conducted at the Clinical Research Unit at the Medical College of Virginia, a tertiary care center. PATIENTS: Six continuous ambulatory peritoneal dialysis (CAPD) patients with hypertension were enrolled in the study. All 6 patients received intraperitoneal enalaprilat. Five of the patients also received oral enalapril. INTERVENTIONS: Hormonal, clinical, and transport parameters were investigated in patients given intraperitoneal enalaprilat and oral enalapril. Standardized 2-L exchanges were performed during a control period, following 2.5 mg intraperitoneal enalaprilat and after a week of oral enalapril. Inulin, blood urea nitrogen (BUN) and creatinine clearances, and glucose absorption were determined during these exchanges. RESULTS: After intraperitoneal enalaprilat, both systolic and diastolic blood pressure significantly declined, reaching maximal decreases of -21.7 +/- 14.2% at 95 +/- 92 minutes, and of -23.3 +/- 15.4% at 105 +/- 105 minutes, respectively. Plasma angiotensin converting enzyme (ACE) activity was suppressed below detectable limits at four hours following intraperitoneal enalaprilat, and remained suppressed throughout all sampling time points following oral enalapril treatment. There was no significant change in drain volumes, glucose absorption, or BUN, creatinine, or inulin clearances, whether enalaprilat was administered intraperitoneally or enalapril orally. CONCLUSION: This study demonstrates that intraperitoneal administration of enalaprilat is a rapidly effective route of administration of this ACE inhibitor. There were no changes in peritoneal transport characteristics demonstrated.

Administration, Oral↗
PubMed1994

The effect of nonsteroidal agents (NSAIDs) on the pharmacokinetics and pharmacodynamics of metolazone.

NSAIDs attenuate the natriuretic response to loop diuretics. Their effect on the action of distal tubular diuretics is poorly explored. Accordingly, the pharmacokinetics and pharmacodynamics of metolazone [M], a distal tubular diuretic, with and without indomethacin [M+I] or sulindac [M+S] were examined in six healthy volunteers. Urine samples were obtained over 36 hours post-metolazone dosing for the determination of sodium, potassium and metolazone concentration. Though cumulative M excretion 750 +/- 247 [mucg/36 h] [M]; 749 +/- 239 [M+I]; 848 +/- 443 [M+S] was comparable between treatment groups, total sodium [Na+] excretion was significantly depressed in the presence of S or I, 685 +/- 114 [mEq/36 h] [M]; 454 +/- 90 [M+I] (p < or = 0.05); 553 +/- 123 [M+S] (p < or = 0.05). Peak Na+ excretion [muEq/min] was significantly decreased by I only and time to peak Na+ excretion did not differ amongst treatment groups. Total potassium [K+] excretion 160 +/- 39 [mEq/36 h] [M]; 111 +/- 53 [M+I] (p < or = 0.05); 135 +/- 31 [M+S] significantly decreased with I. This phenomenon was most evident between 12 and 36 hours. The administration of I or S with M significantly blunted sodium excretion on a purely pharmacodynamic basis while the decline in urinary potassium excretion upon addition of I to M related probably to an attenuation of braking phenomenon induced kaliuresis. These findings likely reflect NSAID-induced sodium reabsorption at loci prior to the site of action of metolazone.

Administration, Oral↗
PubMed1993

The pharmacokinetics and pharmacodynamics of fosinopril in haemodialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium (a new angiotensin-converting enzyme (ACE) inhibitor), were investigated in six haemodialysis patients. Intravenous 14C-fosinoprilat (7.5 mg), oral 14C-fosinopril sodium (10 mg) and oral fosinopril sodium (10 mg) were administered in an open-label, randomized study. Mean maximum concentration (Cmax), clearance (CL), volume of distribution at steady-state (Vss), mean residence time (MRTiv), and t1/2 values after IV administration of 14C-fosinoprilat were 2,042 micrograms.ml-1, 11.3 ml.min-1, 11.0 l, 16.3 h and 28.3 h, respectively. Following oral administration of 14C-fosinopril, mean Cmax, time to maximum plasma concentration (tmax), and fosinoprilat bioavailability values were 197 ng.ml-1, 5.2 h and 29.2%. Para-hydroxy fosinoprilat and fosinoprilat glucuronide comprised approximately 15% and 2% of radioactivity recovered in faeces. Four hours of haemodialysis only cleared approximately 1.5% of the administered dose. The maximum effect (Emax) model was fitted to the percentage inhibition of serum ACE activity vs. fosinoprilat concentration data in three patients. Emax ranged from 95.3 to 102.5%, and IC50 (the fosinoprilat concentration required to produce 50% of Emax) ranged from 2.6 to 4.2 ng.ml-1. Pharmacokinetic variables of the patients were similar to those in patients with moderate to severe renal dysfunction. Dosage modifications or supplemental dosing following dialysis are unnecessary.

Administration, Oral↗
PubMed1993

The peritoneal equilibration test in children.

Eight children, aged 15 months to 17 years 9 months, maintained by continuous ambulatory peritoneal dialysis (CAPD)/continuous cycling peritoneal dialysis and nine adults, aged 20-59 years, managed by CAPD were compared using a standardized peritoneal dialysis protocol, the peritoneal equilibration test (PET). The peritoneal glucose concentration tended to equilibrate with the serum glucose more rapidly in children, but the percentage of the glucose load absorbed was not different between the two age groups. There was an inverse trend between the percentage of glucose absorbed and age in children. Peritoneal creatinine clearance scaled to surface area in children was significantly less than that of the adults; however, the clearances became similar when adjusted for body weight. Peritoneal creatinine clearance scaled to surface area bore a positive and significant relationship to age which, when expressed per kilogram body weight, disappeared. Children had a significantly higher dialysate/plasma (D/P) creatinine ratio after the first 2 h of the PET, but this ratio approached unity by 4 h and was not different from adults. The fractional change in the creatinine D/P ratio during the PET was not different between the two age groups. Drain volume adjusted to surface area was significantly less in children than adults. This difference was reversed when drain volume was factored by weight. Similarly drain volume scaled to surface area demonstrated a significant and positive relationship to age, which disappeared when drain volume was expressed per kilogram body weight. Ultrafiltration, whether factored by weight or scaled to surface area, did not differ between the two groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1992

External-standard high-performance liquid chromatographic method for quantitative determination of furosemide in plasma by using solid-phase extraction and on-line elution.

A rapid and simple external-standard high-performance liquid chromatographic (HPLC) method has been developed for the determination of the concentration of furosemide in plasma. The analyte is extracted with a C-2 ethyl sorbent. On-line elution of the analyte into the HPLC system is accomplished with an advanced automated sample processor (Varian). Furosemide is quantified by fluorescence detection within a linear range of 25 to 1000 ng/mL (average correlation coefficient, 0.9998), with a limit of detection of 1.8 ng/mL. Both internal- and external-standard procedures were evaluated, and the external-standard procedure demonstrated superior characteristics. The external-standard procedure was precise to within a relative standard deviation of 8% and accurate with less than 3% error throughout the concentration range studied. The external-standard HPLC method was used to analyze the concentration of furosemide in greater than 1000 plasma samples obtained from patients with either normal kidney function or renal failure who had received furosemide either orally or intravenously in an experimental setting.

Aged↗
PubMed1991

Fosinopril pharmacokinetics and pharmacodynamics in chronic ambulatory peritoneal dialysis patients.

The pharmacokinetics and pharmacodynamics of fosinoprilat, the diacid of fosinopril sodium, a new angiotensin-converting enzyme (ACE) inhibitor, were investigated after the oral administration of 10 mg of fosinopril sodium to 6 chronic ambulatory peritoneal dialysis (CAPD) patients. The results from 1 patient are reported separately because of the presence of concomitant liver dysfunction. The mean t1/2, Cmax, tmax, and AUC values for 5 of the CAPD patients were 19.5 h, 202 ng.ml-1, 4.8 h, and 3.19 micrograms.h.ml-1, respectively. Values for 1 CAPD patient with liver dysfunction were t1/2 of 65.4 h, Cmax of 182 ng.ml-1, tmax of 9 h, and AUC of 18.1 micrograms.h.ml-1. Peritoneal clearance of fosinoprilat was negligible, ranging from 0.07 to 0.23 ml.min-1. Serum ACE activity remained significantly suppressed at 24 and 48 h after fosinopril sodium administration with mean decreases from baseline of 94.2% and 70.6%, respectively. ACE activity was suppressed to an even greater degree in the patient with liver dysfunction, remaining 97% inhibited 72 h after drug administration. Plasma renin activity (PRA) increased and plasma aldosterone concentrations decreased following drug administration. Mean arterial pressure did not change appreciably throughout the study. Dosage reductions may not be necessary in the majority of dialysis patients.

Adult↗
PubMed1991

Metolazone pharmacokinetics and pharmacodynamics in renal transplantation.

Metolazone pharmacokinetics and pharmacodynamics were investigated in five renal transplant patients and five creatinine clearance matched controls. Whereas the time to peak metolazone excretion was similar in both groups (with the exception of one renal transplant patient who subsequently was found to have chronic rejection), the percent of the administered dose excreted over 48 h was significantly less in renal transplant patients (8% in renal transplant patients vs 24% in controls). Diminished bioavailability of metolazone or tubular secretion likely accounted for this disparity in metolazone excretion. Both groups developed diuretic tolerance as indicated by hysteresis in the dose response relationship. Cumulative sodium excretion over three successive 12-h time intervals did not differ between groups. Despite this comparable natriuresis, potassium excretion was significantly less in the renal transplant patients during the first day of the study. Accordingly, metolazone administration may provide a means to "unmask" subclinical, tubular secretory dysfunction in the transplanted kidney, as exemplified by defects in metolazone secretion and potassium excretion.

Adult↗
PubMed1989

Triamterene and the kidney.

Triamterene (TA) is a mild 'potassium-sparing' diuretic usually employed in combination with other more potent diuretics in the treatment of hypertension. TA pharmacokinetics and pharmacodynamics in normal volunteers, elderly subjects and in patients with renal and hepatic dysfunction are reviewed. A variety of adverse renal effects, such as abnormalities in urinary sediment, nephrolithiasis, interstitial nephritis and acute renal failure, has been reported to occur and is also reviewed. Of particular concern with the increased availability of 'over-the-counter' nonsteroidal anti-inflammatory medications (NSAID) is the adverse interaction between TA and NSAID which may culminate in acute renal failure. Although a rare occurrence, the clinician should be aware of potential adverse reactions associated with the use of TA.

Humans↗
PubMed1988

Furosemide pharmacokinetics and pharmacodynamics in renal transplantation.

Furosemide was administered intravenously to four patients who had undergone renal transplantation in the past and four creatinine clearance--matched control subjects. Both patients who had undergone renal transplant and control subjects displayed similar pharmacokinetic and pharmacodynamic behavior, as assessed by drug delivery to the urine and sodium excretion, respectively. Despite similar degrees of natriuresis, patients who had undergone renal transplantation demonstrated a clear defect in urine potassium excretion. This defect in potassium excretion was not related to altered responsiveness of the renin-angiotensin-aldosterone axis because plasma renin activity increased in a normal fashion after furosemide in both control and transplant subjects. Although the plasma aldosterone response to increases in plasma renin activity was sluggish in patients undergoing renal transplantation, normal increases in plasma aldosterone levels were achieved in both groups, suggesting that there may be an intrinsic defect in distal tubular potassium secretion that can be unmasked by furosemide.

Adult↗
PubMed1987

Case report and review of the literature: ureteral endometriosis.

Endometriosis is a common disorder affecting women of all ages. Although urinary tract involvement is not uncommon, ureteral obstruction is an infrequent complication of endometriosis. A case is reported of acute renal failure caused by bilateral ureteral obstruction resulting from extensive pelvic endometriosis. All reported cases of ureteral endometriosis are reviewed with special emphasis on bilateral ureteral involvement. Physicians need to be aware of this reversible complication of endometriosis.

Acute Kidney Injury↗