Curcumin and enalapril ameliorate renal failure by antagonizing inflammation in 5/6 nephrectomized rats: role of phospholipase and cyclooxygenase.

Previously, we showed that curcumin prevents chronic kidney disease (CKD) development in ⅚ nephrectomized (Nx) rats when given within 1 wk after Nx (Ghosh SS, Massey HD, Krieg R, Fazelbhoy ZA, Ghosh S, Sica DA, Fakhry I, Gehr TW. Am J Physiol Renal Physiol 296: F1146-F1157, 2009). To better mimic the scenario for renal disease in humans, we began curcumin and enalapril therapy when proteinuria was already established. We hypothesized that curcumin, by blocking the inflammatory mediators TNF-α and IL-1ß, could also reduce cyclooxygenase (COX) and phospholipase expression in the kidney. Nx animals were divided into untreated Nx, curcumin-treated, and enalapril-treated groups. Curcumin (75 mg/kg) and enalapril (10 mg/kg) were administered for 10 wk. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was comparably reduced by curcumin and enalapril, with only enalapril significantly lowering blood pressure. Compared with controls, Nx animals had higher plasma/kidney TNF-α and IL-1ß, which were reduced by curcumin and enalapril treatment. Nx animals had significantly elevated kidney levels of cytosolic PLA(2), calcium-independent intracellular PLA(2), COX 1, and COX 2, which were comparably reduced by curcumin and enalapril. Studies in mesangial cells and macrophages were carried out to establish that the in vivo increase in PLA(2) and COX were mediated by TNF-α and IL-1ß and that curcumin, by antagonizing the cytokines, could significantly reduce both PLA(2) and COX. We conclude that curcumin ameliorates CKD by blocking inflammatory signals even if it is given at a later stage of the disease.

MicroRNA profiles in allograft tissues and paired urines associate with chronic allograft dysfunction with IF/TA.

Despite the advances in immunosuppression, renal allograft attrition over time remains unabated due to chronic allograft dysfunction (CAD) with interstitial fibrosis (IF) and tubular atrophy (TA). We aimed to evaluate microRNA (miRNA) signatures in CAD with IF/TA and appraise correlation with paired urine samples and potential utility in prospective evaluation of graft function. MiRNA signatures were established between CAD with IF/TA versus normal allografts by microarray. Validation of the microarray results and prospective evaluation of urine samples was performed using real-time quantitative-PCR (RT-qPCR). Fifty-six miRNAs were identified in samples with CAD-IF/TA. Five miRNAs were selected for further validation based on array fold change, p-value and in silico predicted mRNA targets. We confirmed the differential expression of these five miRNAs by RT-qPCR using an independent set of samples. Differential expression was detected for miR-142-3p, miR-204, miR-107 and miR-211 (p < 0.001) and miR-32 (p < 0.05). Furthermore, differential expression of miR-142-3p (p < 0.01), miR-204 (p < 0.01) and miR-211 (p < 0.05) was also observed between patient groups in urine samples. A characteristic miRNA signature for IF/TA that correlates with paired urine samples was identified. These results support the potential use of miRNAs as noninvasive markers of IF/TA and for monitoring graft function.

Thrombin generation time is a novel parameter for monitoring enoxaparin therapy in patients with end-stage renal disease.

BACKGROUND: Patients with end-stage renal disease (ESRD) who receive enoxaparin are at increased risk for adverse bleeding episodes. This phenomenon appears to occur despite judicious monitoring of antifactor Xa (aFXa) activity. Better monitoring parameters are needed to quantify the anticoagulant effects of enoxaparin in the ESRD population. OBJECTIVES: The objective of this study was to determine the utility of using thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM) to monitor the degree of anticoagulation in ESRD subjects, and to compare these results to aFXa activity, the current gold-standard monitoring parameter. METHODS: Eight healthy volunteers without renal dysfunction and eight ESRD subjects were enrolled into this study. Subjects received a single dose of enoxaparin 1 mg kg(-1) subcutaneously, and blood samples were obtained for the determination of aFXa activity, TGT, PCF and CEM at baseline, 4, 8, and 12 h postdose. RESULTS: Baseline, 4, 8, and 12-h aFXa activity concentrations were not different between groups. However, the corresponding TGT at 8 and 12 h was significantly prolonged in the ESRD group (P = 0.04, and P = 0.008, respectively). The 4-h peak TGT trended toward significance (P = 0.06). There were no differences in PCF or CEM across time. CONCLUSIONS: These data suggest that the parameter aFXa activity is a poor predictor of the anticoagulant effect of enoxaparin in patients with ESRD. Thrombin generation time appears to be more sensitive to the antithrombotic effects of enoxaparin in this population. Further large-scale trials are needed to corroborate these data.

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.

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.

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.

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.

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.

Antifactor Xa activity correlates to thrombin generation time, platelet contractile force and clot elastic modulus following ex vivo enoxaparin exposure in patients with and without renal dysfunction.

Antifactor Xa activity is the gold standard monitoring parameter for low molecular weight heparin (LMWH) derivatives. It is frequently measured in high-risk populations, such as patients with renal dysfunction. Despite antifactor Xa monitoring, however, bleeding in renal dysfunction patients receiving LMWH remains a problem. This study determined the relationship between antifactor Xa activity and three novel coagulation monitoring parameters: thrombin generation time (TGT), platelet contractile force (PCF) and clot elastic modulus (CEM). This study also assessed the effect of renal dysfunction on these relationships. This was an ex vivo pharmacodynamic study of the relationship between antifactor Xa activity and TGT, PCF and CEM in subjects both with and without renal dysfunction. Thirty subjects completed this study (10 controls, 10 chronic kidney disease subjects, and 10 end-stage renal disease subjects receiving hemodialysis). Blood samples obtained from participants were spiked with increasing enoxaparin concentrations (0.25, 0.5, 1.0 and 3.0 IU mL(-1)). Samples were analyzed for TGT, PCF and CEM. The relationship between antifactor Xa activity and TGT, PCF and CEM was determined by Pearson's correlation. The effect of renal dysfunction on the relationship between antifactor Xa activity and TGT, PCF and CEM was determined by analysis of covariance. There is strong correlation between antifactor Xa activity and TGT, CEM and PCF. The presence of renal dysfunction significantly prolongs the TGT, and decreases the CEM relative to controls. These results suggest that patients with renal dysfunction have a greater pharmacodynamic response to LMWH, independent of the pharmacokinetics of LMWH.

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.

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.

A prospective study of vascular access infections at seven outpatient hemodialysis centers.

Vascular access infections are a major cause of morbidity and mortality in hemodialysis patients, and the use of antimicrobials to treat such infections contributes to the emergence and spread of antimicrobial-resistant bacteria. To determine the incidence of and risk factors for vascular access infections, we studied hemodialysis patients at 7 outpatient dialysis centers (4 in Richmond, VA, and 3 in Baltimore, MD) during December 1997 to July 1998. Vascular access infections were defined as local signs (pus or redness) at the vascular access site or a positive blood culture with no known source other than the vascular access; and hospitalization or receipt of an intravenous (IV) antimicrobial. A total of 796 patients were followed for 4,134 patient-months. The vascular access infection rate was 3.5/100 patient-months, ie, patients had a 3.5% risk of infection each month. Independent risk factors were the specific dialysis unit where the patient was treated (relative hazard varying from 1.0 to 4.1 among the 7 centers), catheter access (relative hazard, 2.1 v implanted access), albumin level (relative hazard, 2.4 for lowest v highest quartile), urea reduction ratio (relative hazard, 2.2 for lowest v highest quartile), and hospitalizations during the previous 90 days (relative hazard, 4.9 for >/=6 v zero hospitalizations). These data confirm that vascular access infections are common in hemodialysis patients and that infection rates differ substantially among different centers. Catheter use should be minimized to reduce these infections. Additionally, the possibility that improved serum albumin and urea reduction ratio could reduce vascular access infections should be evaluated.

Treatment of malnutrition with 1.1% amino acid peritoneal dialysis solution: results of a multicenter outpatient study.

A peritoneal dialysis (PD) solution containing 1.1% amino acids as the osmotic agent was evaluated in a 3-month randomized, prospective, open-label study in malnourished PD patients. Patients in the treatment group (DAA) received one or two exchanges daily with the amino acid solution, depending on tolerance, in place of glucose solutions. Controls (DD) received their usual therapy with glucose dialysate. Fifty-four DAA and 51 DD patients completed the study. In DAA, but not in DD patients, there was a significant increase at month 3 in serum insulin-like growth factor-1 (IGF-1) levels and significant decreases in serum potassium (all 3 months) and inorganic phosphorus levels (months 1 and 3), indicating a general anabolic response. Prealbumin and transferrin levels were significantly increased in DAA but not in DD patients at month 1, but the groups did not differ at months 2 and 3. In patients with baseline albumin levels less than 3.5 g/dL (bromcresol green [BCG] method), DAA patients showed increases in albumin, transferrin (months 1 and 2), and prealbumin levels (all 3 months) relative to baseline values, whereas these serum protein levels were unchanged in DD patients, although the changes from baseline did not differ between groups. In this subgroup, midarm muscle circumference (MAMC) did not change in DD or DAA patients. In patients with baseline albumin levels of 3.5 g/dL or greater, DD patients had decreases in albumin and total protein levels at all 3 months and in prealbumin levels at months 1 and 2, relative to baseline. In DAA patients, there were fewer changes in serum proteins. MAMC increased significantly from baseline in DAA but not in DD patients, although changes from baseline did not differ between DAA and DD groups. DAA patients showed no changes in peritoneal membrane transport characteristics. The results indicate that treatment with one or two exchanges daily of this amino acid-based PD solution is safe and provides nutritional benefit for malnourished PD patients.

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.

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.

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.

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.

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.

Diuretics in congestive heart failure.

Congestive heart failure (CHF) is a condition characterized by a number of hormonal and renal adaptations which together conspire to salt and water retention. Diuretic therapy has been, and continues to be, a cornerstone to therapy for CHF. The rational use of diuretics, or diuretic combination such as metolazone-furosemide, can both effectively administer to the congestive symptoms seen in heart failure as well as temper many of the complications of this therapeutic modality.

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.