Multiple-dose pharmacokinetics of pentoxifylline and its metabolites during renal insufficiency.

OBJECTIVE: To characterize pentoxifylline (PTF) and metabolite disposition after multiple oral doses given two and three times a day to patients with renal dysfunction. DESIGN: An open-label, randomized, crossover, parallel group design. SETTING: Community-based clinical research center. PATIENT POPULATIONS: Subjects with renal function stratified based on 24-hour urinary creatine clearance (Clcr): group I = Clcr > 80 mL/min (n = 9); group II = Clcr 30-80 mL/min (n = 6); and group III = Clcr < 30 mL/min (n = 10). METHODS: PTF 400 mg bid or tid was administered on days 1-7 and 400 mg bid or tid was given on days 14-20 with a 1-week washout. Timed blood samples were taken on days 1, 7, and 20. Blood samples were analyzed for PTF and its metabolites (M-I, M-IV, M-V) by gas-liquid chromatography. MAIN OUTCOME MEASURES: Maximum plasma concentrations (Cmax), time to maximum concentration (tmax), average steady-state plasma concentration (CavgSS), and area under the plasma concentration-time curve at steady-state (AUCSS) were determined by visual and model independent methods. ANOVA, paired t-test, and linear regression were used with significance level set at p < 0.05. RESULTS: The ratio of PTF AUCSS (tid):AUCSS (bid) and M-I AUCSS (bid and tid) were not significantly different between the groups. Significant differences were found in M-IV and M-V Cmax, AUCSS, CavgSS, and AUCSS ratios (M-IV:PTF and M-V:PTF) between renal function groups (p < 0.05 for all). A change in dosage regimen from tid to bid resulted in significant changes in M-IV and M-V CavgSS for subjects with normal renal function and in those with moderate dysfunction, although not in subjects with severe renal dysfunction. CONCLUSIONS: Renal dysfunction did not cause significant accumulations of PTF or M-I after multiple bid and tid dosing, however, M-IV and M-V had significant accumulation in patients with renal impairment. Dosage reduction to 400 mg bid for patients with moderate renal impairment and 200-400 mg/d for severe renal impairment, as well as close clinical monitoring, seem prudent until the complex pharmacologic interactions of PTF and its metabolites can be further delineated.

Purified factor IX using monoclonal immunoaffinity technique: clinical trials in hemophilia B and comparison to prothrombin complex concentrates.

Replacement therapy for hemophilia B (factor IX deficiency) using prothrombin complex concentrate (PCC) has been associated with serious complications of thromboembolic events and transmission of viral infections. Monoclonal antibody-purified factor IX (Mononine) provides a highly purified factor IX concentrate, while eliminating other vitamin K-dependent factors (II, VII, and X). Mononine was evaluated for in vivo recovery, half-life, and for its safety and efficacy in 10 patients with hemophilia B. The in vivo recovery of factor IX with Mononine was a 0.67 +/- 0.14 U/dL (mean +/- SD) increase per 1U/kg of infused factor IX, and the biologic half-life (t1/2), determined using the terminal phase of elimination, was 22.6 +/- 8.1 hours. Comparison of in vivo recovery of other vitamin K-dependent factors following a single infusion of either Mononine or PCC showed that, whereas Mononine infusion caused no changes in other vitamin K-dependent factors or in prothrombin activation fragment (F1+2), PCC infusion was associated with significant increases of factors II (2.7 U/dL per 1 U/dL of IX increase) and X (2.2 U/dL for 1 U/dL for 1 U/dL of IX). Patients who used Mononine as their sole therapeutic material during the 12-month period showed an excellent response in hemostasis for their bleeding episodes. Their experience with long-term use of Mononine was at least equivalent to their previous experience with PCC in the frequency and amount of factor usage. No patients developed antibody against mouse IgG or an increase in IX inhibitor during the 12-month period. These results indicate that monoclonal antibody-purified factor IX concentrate provides hemostatically effective factor IX replacement while avoiding extraneous thrombogenic substances.

Estimation of theophylline clearance during continuous arteriovenous hemofiltration.

Pharmacologic agents and other non-protein-bound compounds smaller than 5,000 daltons have the potential to be removed by continuous arteriovenous hemofiltration (CAVH). A proposed method for estimating drug clearance by CAVH (ClCAVH) equates ultrafiltrate clearance to the product of the sieving coefficient and the average ultrafiltration rate. This simplified approach for estimating ClCAVH would be a clinically useful method for calculating replacement doses, as it economizes on the sampling and analytical requirements associated with the conventional method. Presented are some theoretical considerations and a brief evaluation of the accuracy of this proposed method. The evaluation was conducted using an animal model whereby CAVH was performed in four male beagles. During the hemofiltration period, an i.v. bolus of theophylline, 6 mg/kg, was administered over 15 s. Samples for analysis of theophylline were collected from the arterial, venous, and ultrafiltrate ports at 0, 5, 15, 30, 45, 60, 90, 120, 180, 240, 360, and 480 min following dosage administration. The volume of ultrafiltrate produced during each collection interval was measured. Theophylline serum concentrations were determined by a high performance liquid chromatography assay. Statistically, the simplified method was found to result in significantly (p less than 0.05) larger estimates of ultrafiltrate clearance when compared to the conventional method. However, the average magnitude of difference was only 9% and does not constitute a clinically significant margin between the two methods.

Effect of predialysis verapamil on intradialytic blood pressure in chronic hemodialysis patients.

Decreased left ventricular compliance because of hypertrophy or fibrosis may contribute to hypotension during hemodialysis. While calcium channel blockade may reduce intradialytic hypotension in patients with left ventricular hypertrophy and refractory pulmonary congestion, it is unknown whether such an effect might be seen in unselected hemodialysis patients. Verapamil (40 mg) or a placebo was given 1 hour before hemodialysis to 10 patients in a double-blind crossover study. Two 2 week verapamil periods alternated with two 2 week placebo periods. Patients received bicarbonate for either 3 hours (7 patients, high-flux, Filtral, Gambro-Hospal Inc., Williamsburg, VA) or for 4 hours (3 patients, Travenol 15.11 or CA 110, Baxter Healthcare, Deerfield, IL). Left ventricular hypertrophy was present by ultrasound in 7 of 8 patients tested and by electrocardiogram in 1 of the remaining 2. Intradialytic blood pressures were similar during the drug and placebo trials. The number of episodes of symptomatic hypotension per hemodialysis was 0.99 with verapamil and 0.93 during the placebo periods (p less than 0.05). Thus, a single predialysis dosage of verapamil has no effect on intradialytic blood pressure in an unselected hemodialysis population.

Treatment of peritonitis in patients undergoing continuous ambulatory peritoneal dialysis.

The epidemiology, etiology, pathogenesis, diagnosis, and pharmacotherapy of peritonitis in patients with end-stage renal disease treated with continuous ambulatory peritoneal dialysis (CAPD) are reviewed. CAPD-associated peritonitis is a localized infection of the peritoneal cavity. Approximately 70% of the cases are caused by a single gram-positive microorganism indigenous to the patient's skin or upper respiratory tract that infects the peritoneal cavity. Gram-negative microorganisms cause 25% of the cases; fungi, anaerobes, and mycobacteria cause approximately 5%. Clinical manifestations include a cloudy, turbid peritoneal dialysate effluent and abdominal pain or tenderness. Diagnosis is confirmed by the detection and isolation of microorganisms in the peritoneal dialysate effluent. Of patients with CAPD-associated peritonitis, 70-80% can be successfully treated on an outpatient basis with intraperitoneal (i.p.) instillation of antimicrobials. Vancomycin, cephalosporins, and aminoglycosides are the agents most commonly used to treat CAPD-associated peritonitis. Most recently, alternative dosing regimens using intermittent i.p. administration of vancomycin have been used. In certain types of CAPD-associated peritonitis (those caused by Pseudomonas aeruginosa or fungi), removal of the peritoneal catheter may be required to achieve a cure. Approximately two thirds of the patients transferring to another form of dialysis from CAPD do so because of peritonitis. Currently available data indicate that the most effective therapy for CAPD-associated peritonitis is i.p. administration of antimicrobial agents with activity against the suspected microorganism.

Marked digoxin-like immunoreactive factor interference with an enzyme immunoassay.

A case in which digoxin-like immunoreactive factors (DLIF) interfered with an enzyme immunoassay in a patient with renal insufficiency is reported. A 79-year-old woman was found to have a serum digoxin concentration (SDC) determined by enzyme immunoassay of 5.0 ng/ml. Although all subsequent SDC determined by the enzyme immunoassay system were elevated, identical samples run on a fluorescence polarization immunoassay revealed SDC within the therapeutic range. Marked DLIF-related assay interference has been reported to occur with some digoxin assays; however, the enzyme immunoassay methods have never been reported to cross-react to the magnitude seen in this case.

Continuous arteriovenous hemofiltration: an alternative to hemodialysis.

An introduction to the procedure of continuous arteriovenous hemofiltration (CAVH) for management of acute renal failure, as well as a review of hemodialysis, is presented. Initially developed for the management of hemodynamically unstable patients with acute renal failure, CAVH now is also used for management of fluid overload and acid-base disturbances resulting from conditions such as acute pulmonary edema, congestive heart failure, septic shock, and oliguric states in which pharmacologic or parenteral nutrition therapy necessitates administration of large volumes of fluids. CAVH, in contrast to hemodialysis, does not typically involve use of blood pumps but uses the patient's own mean arterial pressure to generate a driving force across the hemofilter membrane. CAVH, like hemodialysis, can remove excess fluid and uremic toxins; however, fluid removal by CAVH is characterized by the slow, continuous process of ultrafiltration and thus avoids the risk of hypotension, muscle cramps, or disequilibrium syndrome. Furthermore, CAVH does not require fluid restriction, allowing for increased administration of parenteral nutrition and intravenous medications; neither does it require expensive equipment or highly trained personnel. Although CAVH membrane materials may differ, they all permit the removal of plasma water and non-protein-bound solutes with molecular weights less than 10,000. To prevent blood from clotting in the hemofilter, most patients will require administration of heparin, which in some patients may increase the possibility of hemorrhaging. CAVH also can remove pharmacologic agents from the blood; however, only the non-protein-bound fraction of the drug has the potential to be cleared from the bloodstream by CAVH.(ABSTRACT TRUNCATED AT 250 WORDS)

Accuracy of Bayesian, Sawchuk-Zaske, and nomogram dosing methods for vancomycin.

The predictive performance of a Bayesian method for vancomycin dosing was compared with that of two nomogram-based methods and the Sawchuk-Zaske method. Prospectively collected serum concentration data were evaluated retrospectively in patients who had at least two steady-state peak and trough serum vancomycin concentrations obtained during two different dosage regimens. The methods evaluated were a Bayesian program that uses a one-compartment weighted-sum-of-squares expression; the nomogram methods of Moellering and Matzke, which derive vancomycin clearance from urinary creatinine clearance; and the Sawchuk-Zaske method, which uses equations for one-compartment, first-order elimination. The ability of each method to predict the second set of serum concentrations when given the first set of concentrations was evaluated using mean prediction error (ME), mean absolute error (MAE), and root mean squared error (RMSE). To compare the predictions made by each of the four methods, the differences in mean error and the differences in the natural logarithm of mean absolute error and their 95% confidence intervals were compared. No significant difference in ME (bias) or MAE (precision) was found between the Moellering and Matzke methods. The Sawchuk-Zaske method was significantly more precise than the Matzke method in predicting peak serum concentrations and more precise than the Moellering or Matzke method in predicting trough concentrations. The Bayesian program was significantly more precise and less biased than the Moellering and Matzke methods and less biased than the Sawchuk-Zaske method in predicting both peak and trough concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)