Biomedical subjects

T W Gehr

Publications and source records attributed to T W Gehr.

At least 19 recordsLinked to original sources

PubMed2001

The pharmacokinetics of subcutaneous enoxaparin in end-stage renal disease.

STUDY OBJECTIVE: To evaluate the pharmacokinetics of enoxaparin in end-stage renal disease (ESRD), and determine if dosage reduction is necessary to maintain antifactor Xa activity concentrations within the therapeutic range. DESIGN: Prospective, single-dose pharmacokinetic study. SETTING: University-affiliated general clinical research center. PATIENTS: Eight nonthrombosed patients with ESRD requiring hemodialysis. INTERVENTION: All subjects received a single dose of enoxaparin sodium 1 mg/kg subcutaneously and had serial plasma antifactor Xa activity concentrations measured over 24 hours. MEASUREMENTS AND MAIN RESULTS: The pharmacokinetics of enoxaparin were determined from plasma antifactor Xa activity concentrations, and various multiple-dose regimens were simulated. After administration of the drug, total body clearance was 14.6 ml/minute and there was a 2-fold prolongation in antifactor Xa activity half-life compared with values reported in healthy subjects. All other pharmacokinetic parameters were similar to those in healthy subjects and patients with chronic renal insufficiency. An accumulation ratio of 1.6 was estimated for a dosing interval of every 12 hours based on single-dose pharmacokinetics. When various therapeutic regimens were simulated to predict average steady-state antifactor Xa activity, standard enoxaparin dosages of 1 mg/kg subcutaneously every 12 hours and 1.5 mg/kg every 24 hours resulted in average steady-state concentrations within the therapeutic range. CONCLUSIONS: Based on antifactor Xa activity, ESRD has little effect on the pharmacokinetics of enoxaparin, and dosing adjustments are unnecessary.

Adult↗

PubMed2000

Chronically increased intra-abdominal pressure produces systemic hypertension in dogs.

OBJECTIVE: Determine if increased intra-abdominal pressure (IAP) alone can cause systemic hypertension in a chronic canine model. DESIGN: Evaluate effects of increase in IAP with progressive inflation and deflation of an intra-abdominal balloon on systemic blood pressure in experimental and control animals. SUBJECTS: Male dogs weighing 15-25 kg underwent placement of an intra-abdominal balloon which was progressively inflated on a weekly basis in the experimental animals (5) over 4 weeks to 25 mmHg above baseline and kept there for an additional 2 weeks before gradual deflation over 2 weeks. Control animals (5) had the balloon placed but not inflated. Pain was controlled with osmotic analgesic pumps. MEASUREMENTS: The animals were anesthetized, blood pressure (BP) measured and blood drawn for plasma renin activity (PRA), aldosterone, atrial naturetic peptide (ANP), catecholamines, and serum sodium (Na). A right heart catheter was inserted for measuring cardiac output (CO) and pulmonary artery occlusion pressure (PAOP) at baseline, week 5 (maximal IAP) and week 7 (after balloon deflation). The animals were weighed and urinary bladder pressures recorded weekly before and after abdominal balloon inflation. RESULTS: Systolic (122+/-3 to 155+/-5 mmHg, P<0.05) and diastolic (82+/-4 mmHg to 107+/-7 mmHg, P<0.05) BP rose at 5 weeks at 25 mmHg IAP>baseline and returned to control with balloon deflation. Both systolic and diastolic BP rose (P<0.05) above control animals BP at 15 mmHg IAP at 2 weeks and remained elevated until abdominal decompression, at week 7. There were no significant changes in net animal weight, PRA, aldosterone, ANF, catecholamines, Na, CO or PAOP. CONCLUSION: Increased IAP from progressively inflating an intra-abdominal balloon in dogs was associated with significant increases in systolic and diastolic BP that resolved with balloon deflation. Increased IAP may be a cause for systemic hypertension in central obesity and pre-eclampsia.

Abdomen↗

PubMed2000

Disposition and safety of omapatrilat in subjects with renal impairment.

BACKGROUND: Omapatrilat, a vasopeptidase inhibitor, preserves natriuretic peptides and inhibits the renin angiotensin aldosterone system by simultaneously inhibiting neutral endopeptidase and angiotensin-converting enzyme. METHODS: Oral omapatrilat, 10 mg/d, was administered for 8 to 9 days to three groups of eight subjects with varying degrees of renal function (CLCR values, normal > or = 80; mild to moderate impairment < 80 to > or = 30; severe impairment < 30 mL/min/1.73 mL2) and to six subjects undergoing maintenance hemodialysis. Omapatrilat and its metabolites (phenylmercaptopropionic acid, S-methylomapatrilat, S-methylphenylmercaptopropionic acid, and cyclic S-oxide-omapatrilat) were quantified in plasma by a validated liquid chromatography/mass spectrometry method. The model, Cmax or AUC(0-T) = intercept + slope x CLCR, was tested for a possible linear correlation between Cmax (peak plasma concentrations) or AUC(0-T) (area under plasma concentration versus time curve) and CLCR. RESULTS: For omapatrilat and its inactive metabolites, phenylmercaptopropionic acid, S-methylomapatrilat, and S-methylphenylmercaptopropionic acid, the median times to peak plasma concentrations (tmax) were 1.5 to 2, 2 to 3, 2.5 to 3.5, and 7 to 10 hours, respectively, and were independent of renal function. After Cmax attainment, plasma concentrations declined rapidly to about 10% of Cmax values. Cyclic S-oxide-omapatrilat, a potentially active metabolite, was undetectable at all sampling time points. Hemodialysis did not decrease circulating levels of omapatrilat. There was minimal accumulation of omapatrilat and phenylmercaptopropionic acid and moderate accumulation of the S-methylated metabolites. For omapatrilat and S-methylphenylmercaptopropionic acid, neither Cmax nor AUC(0-T) was CLCR dependent. However, AUC(0-T) for phenylmercaptopropionic acid and both the Cmax and AUC(0-T) for S-methylomapatrilat were CLCR dependent. CONCLUSIONS: The pharmacokinetics of omapatrilat, the only clinically relevant active compound studied, was independent of CLCR. For patients with reduced renal function, adjusting initial omapatrilat dose is not suggested. Hemodialysis did not significantly contribute to the clearance of omapatrilat. The long-term pharmacodynamic response to omapatrilat will dictate dose-adjustment needs.

Administration, Oral↗

PubMed2000

The pharmacokinetics and pharmacodynamics of losartan in continuous ambulatory peritoneal dialysis.

The pharmacokinetics and pharmacodynamics of losartan and its active metabolite, E-3174, were studied in 8 stable, hypertensive continuous ambulatory peritoneal dialysis (CAPD) patients. Following a 1-week washout period, subjects received 100 mg of losartan orally for 7 days. On Days 1 and 7, hemodynamic and hormonal responses were determined, as were PK parameters on Day 7. Peritoneal equilibration testing was performed pre-Day 1 and on Day 7. AUC0-24 and t1/2 for losartan and E-3174 were 95 +/- 49.9 micrograms.min/mL and 176 +/- 82.1 micrograms.min/mL and 172.5 +/- 86.7 minutes and 628 +/- 575 minutes, respectively. These values are similar to those of normal subjects and subjects on hemodialysis. Peritoneal clearance of losartan and E-3174 was negligible. All subjects demonstrated a substantial reduction in blood pressure with at least a 10 mmHg drop in diastolic BP. Plasma renin activity (PRA) values increased, but aldosterone, endothelin, norepinephrine, and epinephrine values did not change following 7 days of losartan. Losartan was well tolerated in all study subjects.

Adult↗

PubMed2000

Cost-effectiveness of sevelamer versus calcium carbonate plus atorvastatin to reduce LDL in patients with chronic renal insufficiency with dyslipidemia and hyperphosphatemia.

We conducted a cost-effectiveness analysis to compare costs and clinical outcomes of sevelamer versus calcium carbonate plus atorvastatin for treatment of dyslipidemia in patients with chronic renal insufficiency. The model was from the third-party payer perspective. Efficacy and adverse event rates for each regimen were obtained from published clinical trials. Drug costs were based on average wholesale prices; monitoring costs were based on Medicare reimbursement rates. Our model suggests that the combination of calcium carbonate plus atorvastatin is substantially more cost-effective than sevelamer in reducing low-density lipoprotein (LDL) in these patients. One-way sensitivity analyses were performed to assess if 25% and 50% price reductions in sevelamer affected overall cost-effectiveness results. A 50% sevelamer price reduction was less expensive than combination therapy but remained less cost-effective. A two-way sensitivity analysis on the probability that a patient achieves the goal of a 35% LDL reduction resulted in calcium carbonate plus atorvastatin remaining more cost-effective. Further cost-effectiveness studies are necessary to corroborate our data.

Atorvastatin↗

PubMed2000

Risk-benefit ratio of angiotensin antagonists versus ACE inhibitors in end-stage renal disease.

The effective treatment of hypertension is an extremely important consideration in patients with end-stage renal disease (ESRD). Virtually any drug class--with the possible exception of diuretics--can be used to treat hypertension in the patient with ESRD. Despite there being such a wide range of treatment options, drugs which interrupt the renin-angiotensin axis are generally suggested as agents of choice in this population, even though the evidence in support of their preferential use is quite scanty. ACE inhibitors, and more recently angiotensin antagonists, are the 2 drug classes most commonly employed to alter renin-angiotensin axis activity and therefore produce blood pressure control. ACE inhibitor use in patients with ESRD can sometimes prove an exacting proposition. ACE inhibitors are variably dialysed, with compounds such as catopril, enalapril, lisinopril and perindopril undergoing substantial cross-dialyser clearance during a standard dialysis session. This phenomenon makes the selection of a dose and the timing of administration for an ACE inhibitor a complex issue in patients with ESRD. Furthermore, ACE inhibitors are recognised as having a range of nonpressor effects that are pertinent to patients with ESRD. Such effects include their ability to decrease thirst drive and to decrease erythropoiesis. In addition, ACE inhibitors have a unique adverse effect profile. As is the case with their use in patients without renal failure, use of ACE inhibitors in patients with ESRD can be accompanied by cough and less frequently by angioneurotic oedema. In the ESRD population, ACE inhibitor use is also accompanied by so-called anaphylactoid dialyser reactions. Angiotensin antagonists are similar to ACE inhibitors in their mechanism of blood pressure lowering. Angiotensin antagonists are not dialysable and therefore can be distinguished from a number of the ACE inhibitors. In addition, the adverse effect profile for angiotensin antagonists is remarkably bland, with cough and angioneurotic oedema rarely, if ever, occurring. In patients with ESRD, angiotensin antagonists are also not associated with the anaphylactoid dialyser reactions which occur with ACE inhibitors. The nonpressor effects of angiotensin antagonists--such as an influence on thirst drive and erythropoiesis--have not been explored in nearly the depth, as they have been with ACE inhibitors. Although ACE inhibitors have not been compared directly to angiotensin antagonists in patients with ESRD, angiotensin antagonists possess a number of pharmacokinetic and adverse effect characteristics, which would favour their use in this population.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2000

Pharmacokinetics and blood pressure response of losartan in end-stage renal disease.

BACKGROUND: Losartan is a selective angiotensin AT1 receptor antagonist currently employed in the management of essential hypertension. This compound is in common use in populations with renal failure and end-stage renal disease (ESRD). OBJECTIVE: To investigate the pharmacokinetics and pharmacodynamics of losartan in patients with ESRD in order to establish administration guidelines. METHODS: Patients were administered losartan 100 mg/day for 7 days, and after the seventh and final dose pharmacokinetic parameters were determined for both losartan and its active metabolite E-3174. During the study, the haemodialytic clearances of losartan and E-3174 were measured during a standard 4-hour dialysis session. Neurohumoral and biochemical changes were assessed during losartan administration. RESULTS: The pharmacokinetics of losartan and E-3174 in haemodialysis patients did not alter to a clinically significant level. Losartan administration was accompanied by a decline in plasma aldosterone level as well as by an increase in plasma renin activity. Losartan administration resulted in a decline in plasma uric acid level, despite the fact that the study participants had no residual renal function. Losartan and E-3174 were not dialysable. CONCLUSIONS: The pharmacokinetics of losartan and E-3174 are minimally altered in ESRD; thus, dosage adjustment is not required in the presence of advanced dialysis-dependent renal failure. In addition, postdialysis supplementation is not required for losartan because of the negligible dialysability of losartan and E-3174.

Adult↗

PubMed1999

The pharmacokinetics of carvedilol and its metabolites after single and multiple dose oral administration in patients with hypertension and renal insufficiency.

INTRODUCTION: Carvedilol, a chiral compound possessing nonselective beta- and alpha1-blocking activity, is used for the treatment of hypertension and congestive heart failure (CHF). The enantiomers of carvedilol exhibit similar alpha1-blocking activity; only S-carvedilol possesses beta-blocking activity. Carvedilol is primarily hepatically metabolized, with less than 2% of the dose excreted renally as unchanged drug. METHODS: The pharmacokinetics of carvedilol, R-carvedilol, and S-carvedilol were studied in hypertensive patients (control; n = 13) versus patients with hypertension and advanced renal insufficiency not yet on dialysis [GFR < or = 30 ml x min(-1) (CRI, chronic renal insufficiency), n = 12] following single (12.5 mg, Day 1) and multiple (25 mg once daily, Days 2 9) dosing. RESULTS: Mean with (SD) AUC(0-24h) (ng x h x ml(-1)) for carvedilol was 220 (120) and 618 (335) in CRI compared with 165 (83.5) and 413 (247) in controls on Days 1 and 9, respectively, primarily due to higher R-carvedilol concentrations. Mean with (SD) Cmax (ng x ml(-1)) for carvedilol were 53.4 (31.4) and 128 (63.3) in CRI compared with 46.7 (23.3) and 104 (58.9) in controls on Days 1 and 9, respectively. The difference in group mean values was characterized by considerable overlap in individual AUC(0-24h) and Cmax values between groups. There was no apparent difference in mean terminal elimination half-life for carvedilol between groups on each study day. Less than 1% of the dose was excreted in urine as unchanged carvedilol in both groups. Blood pressure and heart rate declined in both groups to a similar degree. CONCLUSION: Compared with controls, average AUC(0-24 h) values for carvedilol were approximately 40% and 50% higher on study Days 1 and 9 in patients with renal insufficiency, primarily due to higher R-carvedilol concentrations with only a small change (<20%) in S-carvedilol concentrations, the isomer possessing beta-blocking activity. These changes in pharmacokinetics are modest in view of the large interindividual variability. Carvedilol was well tolerated in both groups. Although the present study cannot provide a final conclusion, based on the results of the present study, no changes in dosing recommendations for carvedilol are warranted in patients with moderate/severe renal insufficiency.

Adrenergic alpha-Antagonists↗

PubMed1999

Effect of increased renal venous pressure on renal function.

OBJECTIVE: Acute renal failure is seen with the acute abdominal compartment syndrome (AACS). Although the cause of acute renal failure in AACS may be multifactorial, renal vein compression alone has not been investigated. This study evaluated the effects of elevated renal vein pressure (RVP) on renal function. METHODS: Two groups of swine (18-22 kg) were studied after left nephrectomy and placement of a renal artery flow probe to measure renal artery blood flow, renal vein catheter, and ureteral cannula. Two hours were allowed for equilibration and an inulin infusion was begun to calculate inulin clearance for measurement of glomerular filtration rate. Group 1 animals (n = 4) had RVP elevated by 30 mm Hg for 2 hours with renal vein constriction. RVP was then returned to baseline for 1 hour. In group 2 (n = 4), the RVP was not elevated. The cardiac index (2.9 +/- 0.5 L/min/m2) and mean arterial pressure (101 +/- 9 mm Hg) remained stable. Plasma renin activity and serum aldosterone were measured every 60 minutes. RESULTS: Elevation of RVP (0-30 mm Hg above baseline) in the experimental group showed a significant decrease in renal artery blood flow index (2.7 to 1.5 mL/min per g) and glomerular filtration rate (26 to 8 mL/min) compared with control. In addition, there was significant elevation of plasma serum aldosterone (14 to 25 microng/dL) and plasma renin activity (2.6 to 9.5 microng/mL per h) as well as urinary protein leak in the experimental animals compared with control. These changes were partially or completely reversible as RVP returned toward baseline. CONCLUSION: Elevated RVP alone leads to decreased renal artery blood flow and glomerular filtration rate and increased plasma renin activity, serum aldosterone, and urinary protein leak. These changes are consistent with the renal pathophysiology seen in AACS, morbid obesity, and preeclampsia. The changes are partially or completely reversed by decreasing renal venous pressure as occurs with abdominal decompression for AACS.

Abdomen↗

PubMed1997

Simple high-performance liquid chromatographic method for determination of losartan and E-3174 metabolite in human plasma, urine and dialysate.

A simple high-performance liquid chromatographic (HPLC) method was developed for the determination of losartan and its E-3174 metabolite in human plasma, urine and dialysate. For plasma, a gradient mobile phase consisting of 25 mM potassium phosphate and acetonitrile pH 2.2 was used with a phenyl analytical column and fluorescence detection. For urine and dialysate, an isocratic mobile phase consisting of 25 mM potassium phosphate and acetonitrile (60:40, v/v) pH 2.2 was used. The method demonstrated linearity from 10 to 1000 ng/ml with a detection limit of 1 ng/ml for losartan and E-3174 using 10 microl of prepared plasma, urine or dialysate. The method was utilized in a study evaluating the pharmacokinetic and pharmacodynamic effects of losartan in patients with kidney failure undergoing continuous ambulatory peritoneal dialysis (CAPD).

Antihypertensive Agents↗

PubMed1997

The pharmacokinetics of pravastatin in patients on chronic hemodialysis.

OBJECTIVE: The single-dose and steady-state pharmacokinetics of the HMG CoA reductase inhibitor pravastatin and its two metabolites, SQ 31,906 and SQ 31,945, were evaluated in 12 hemodialysis patients. A single 20-mg i.v. dose was employed, followed by daily oral dosing of 20 mg over four hemodialysis intervals. RESULTS: No statistical differences in the pharmacokinetics of pravastatin or SQ 31,906 were evident when comparing the first and last days of oral dosing with pravastatin. The pharmacokinetic parameters of pravastatin and SQ 31,906 were similar to those of healthy volunteers. SQ 31,945, the inactive polar metabolite, did accumulate in dialysis patients, as evidenced by an accumulation index of 1.7 +/- 1.0. Although metabolic clearance is the predominant mode of elimination of pravastatin, hemodialysis clearances of pravastatin, SQ 31,906 and SQ 31,945 will contribute to total body clearance since dialytic clearance ranged from 40 to 80 ml.min-1. CONCLUSION: Pravastatin can be safely administered in the usual dosages to subjects with renal failure on hemodialysis and no change in dosing is necessary.

Administration, Oral↗

PubMed1997

The pharmacokinetics of irbesartan in renal failure and maintenance hemodialysis.

PURPOSE: An open-label, multiple-dose, parallel-group study was conducted to evaluate the pharmacokinetics of the angiotensin II receptor antagonist irbesartan in subjects with varying degrees of renal function. METHODS: Forty subjects were divided into four treatment groups on the basis of 24-hour creatinine clearance (CLCR): normal renal function (> 75 ml/min/1.73 m2), mild to moderate renal impairment (30 to 74 ml/min/1.73 m2), severe renal impairment (< 30 ml/min/1.73 m2), and maintenance hemodialysis. Subjects received 100 mg irbesartan daily for 8 days (or 300 mg daily for 9 days for the hemodialysis group). Serial blood and urine samples were collected for 24 hours after the first and last of eight successive daily doses. In addition, arterial and venous blood samples were collected during two hemodialysis sessions from subjects requiring maintenance hemodialysis. RESULTS: There was no statistically significant linear relationship between CLCR and maximum plasma concentrations, dose-adjusted area under the plasma concentration time curve values on days 1 or 8, or any other pharmacokinetic parameters among the renal function groups studied. There was no indication of drug accumulation with repetitive dosing. In the subjects receiving hemodialysis, arterial-venous concentration differences for irbesartan were negligible, suggesting that this compound is not cleared through hemodialysis. In addition, irbesartan was well tolerated. CONCLUSION: Based on pharmacokinetic parameters, no starting dose adjustment is necessary in subjects with mild to severe renal impairment, inclusive of hemodialysis. Subjects with volume depletion may have an exaggerated response to an initial dose of irbesartan and, under such circumstances, volume depletion should be corrected or a lower starting dose of irbesartan should be considered.

Adult↗

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↗