Correlation and prediction of phenytoin protein binding using standard laboratory parameters in patients after renal transplantation.

Renal transplant recipients provide a unique model for protein-binding studies in that patients experience hypoalbuminemia and renal dysfunction, both of which alter protein binding. The purposes of this investigation were to model the relationship between serum creatinine, blood urea nitrogen (BUN), albumin, and the unbound fraction of phenytoin (FU, as a percentage) in patients who had undergone renal transplant, and to determine the value of these measurements in predicting FU. Blood from 29 patients was collected at various time points after establishment of graft function. Sera were spiked with phenytoin to a concentration of 15 mg/L, and total/unbound phenytoin concentrations were determined. Correlations between FU and the biochemical indices of serum creatinine, BUN, and albumin were determined using multiple regression. The algorithm with the highest correlation at all times after the transplant became the method to predict future FU. This algorithm was applied prospectively in 23 samples from 14 other patients with variable renal function after transplant. Samples were analyzed as above and the corresponding biochemical indices of serum creatinine, BUN, and albumin were used to calculate FU values. Accuracy of the predictions was evaluated using prediction-error analysis. The best relationship between FU and the measured biochemical indices incorporated serum creatinine and albumin [y = 24.3 + 0.6(serum creatinine) - 3.9(albumin)] and served as the method for FU prediction. Prediction-error analysis resulted in a bias of -5.1% and a precision of 5.7%. This method failed to estimate FU with sufficient accuracy to permit clinical utility. The predicted value underestimated the measured value, and some other variable(s) must be affecting the binding even though serum creatinine and albumin are within or approaching the reference range. Consequently, estimating FU in patients with a history of uremia and hypoalbuminemia, based on measures of serum creatinine and albumin alone, should not be used.

Cefazolin dialytic clearance by high-efficiency and high-flux hemodialyzers.

Cefazolin dialytic clearance has not been determined in patients undergoing hemodialysis with high-efficiency or high-flux dialyzers. The objective of this study is to determine the pharmacokinetics and dialytic clearance of cefazolin and develop dosing strategies in these patients. Twenty-five uninfected subjects undergoing chronic thrice-weekly hemodialysis were administered a single dose of intravenous cefazolin (15 mg/kg) after their standard hemodialysis session. Fifteen subjects underwent hemodialysis with high-efficiency hemodialyzers, and 10 subjects underwent hemodialysis with high-flux hemodialyzers. Blood and urine samples were collected serially over the interdialytic period, during the next intradialytic period, and immediately after the next hemodialysis session. Serum and urine concentrations of cefazolin were determined by high-performance liquid chromatography. Differential equations describing a two-compartment model were fit to the cefazolin serum concentration-time data over the study period, and pharmacokinetic parameters were determined. Mean dialytic clearance values for cefazolin were significantly greater in the high-flux group compared with the high-efficiency group (30.9 +/- 6.52 versus 18.0 +/- 6.26 mL/min, respectively; P: < 0.05). Cefazolin reduction ratios were significantly greater (0.62 +/- 0.08 versus 0.50 +/- 0.07; P: < 0.005) in the high-flux group compared with the high-efficiency group and correlated well with equilibrated urea reduction. The pharmacokinetic model developed from patient data was used to simulate cefazolin serum concentration data for high-efficiency and high-flux dialyzers. Cefazolin doses of 15 or 20 mg/kg after each hemodialysis session maintained adequate serum concentrations throughout a 2- or 3-day interdialytic period regardless of hemodialyzer type.

Trends in crime and the introduction of a needle exchange program.

OBJECTIVES: This study sought to determine whether introduction of a needle exchange program would be associated with increased crime rates. METHODS: Trends in arrests were compared in program and nonprogram areas before and after introduction of a needle exchange program in Baltimore. Trends were modeled and compared via Poisson regression. RESULTS: No significant differences in arrest trends emerged. Over the study period, increases in category-specific arrests in program and nonprogram areas, respectively, were as follows: drug possession, 17.7% and 13.4%; economically motivated offenses, 0.0% and 20.7%; resistance to police authority, 0.0% and 5.3%; and violent offenses, 7.2% and 8.0%. CONCLUSIONS: The lack of association of overall and type-specific arrest data with program implementation argues against the role of needle exchange programs in increasing crime rates.

Comparing new participants of a mobile versus a pharmacy-based needle exchange program.

OBJECTIVE: To compare characteristics of first-time needle exchange participants who enrolled at a mobile van-based exchange site versus a fixed pharmacy-based exchange site, in an area where both types of needle exchange programs were available. METHODS: Demographic and drug use data were collected on needle exchange program participants on enrollment. Participants were included if they were first-time participants at the Baltimore needle exchange program between December 1997 and March 1999, and if their first visit was at either one van-based site or at one of two pharmacy-based sites. Descriptive statistics and inferences were based on the type of needle exchange into which participants enrolled. RESULTS: Among 286 first-time participants, 92% were African American, 28% were women, 11% were currently employed, 55% completed high school, and the median age was 40 years. In multivariate analyses, van-based enrollment was more common among frequent injectors (odds ratio [OR] = 2.0), but less common among African American participants (OR = 0.21). CONCLUSIONS: Our data suggest that different venues for needle exchange program settings attract different types of drug injecting participants. This suggests that offering different venue types to reach participants with differing drug use patterns will be important to optimize risk reduction strategies.

The poor accuracy of indirect measurements of cadaveric donor kidney weights.

Reports that examined the issue of whether transplantation of inadequate nephron mass may be a risk factor for long-term allograft failure yielded conflicting results. One of the more accurate methods of estimating glomerular mass is kidney weight. Most of the clinical studies used body surface area (BSA) or kidney length as estimates of kidney weight. To test the hypothesis that indirect measures of kidney weight are accurate estimates of kidney weight, we compared the kidney weight of 41 consecutive cadaveric kidneys to donor BSA, dimensions measured with calipers at the time of transplantation, and dimensions supplied by the Organ Procurement Agency (OPA). Linear regression analysis was used with kidney weight as the dependent variable and BSA, kidney length, or kidney volume as the independent variable. Kidney length measured with calipers was also compared to kidney length supplied by the OPA. Kidney weight had the best correlation with kidney volume and kidney length determined by caliper measurements (r = 0.640 and 0.646, respectively). The regression analysis showed that the correlation of kidney weight with BSA was 0.487. The correlation of OPA-provided kidney length with kidney weights was poor (r = 0.410). The linear regression of caliper-measured kidney length versus OPA length yielded a slope of 0.360, instead of an ideal slope of 1. The assumption has been made that kidney weight or a surrogate of kidney weight has an excellent correlation with nephron mass. Some of the variability in studies that attempted to examine the effect of transplanted nephron mass on allograft outcome may be due to inaccurate estimates used for kidney weight. Our data suggest that surrogate measurements of kidney weight may not be accurate. We recommend that measured kidney weight should be used in studies examining the effect of donor renal mass on allograft outcomes.

Plasma iohexol clearance in automated peritoneal dialysis--its role in adequacy determination.

OBJECTIVE: To compare the relationship of plasma iohexol clearance to standard adequacy measures in an automated peritoneal dialysis (APD) population. DESIGN: Prospective, nonrandomized, open label, simultaneous clearance studies of novel (iohexol) and traditional (urea and creatinine) markers of dialysis quantitation. SETTING: Outpatient peritoneal dialysis units associated with tertiary care university hospitals. PATIENTS: Eighteen stable patients, 13 undergoing continuous cycling peritoneal dialysis (CCPD) and 5 receiving intermittent dialysis, who underwent 24-hour clearance studies were enrolled in and completed the study. INTERVENTIONS: Each subject received 15 mL of iohexol intravenously the morning of a scheduled dialysis night. Blood was obtained for determination of serum concentrations of urea nitrogen and creatinine, and plasma iohexol concentration. Dialysate and urine were collected over 24 hours. MAIN OUTCOME MEASURES: Urea and creatinine data from the total pooled dialysate and from the 24-hour urine collection were used to calculate daily Kt/Vurea and normalized total daily creatinine clearance (CrCl). Total plasma iohexol clearance was calculated using a one-compartment model with the Brochner-Mortensen correction. RESULTS: Normalized [to 1.73 m2 body surface area (BSA)] iohexol clearance correlated very well with normalized CrCl (r2 = 0.777; p < 0.001). A weaker correlation was observed between Kt/Vurea and normalized iohexol clearance (r2 = 0.213; 0.05 < p < 0.1). When data are not normalized using BSA or urea distribution volume, the regressions are improved for both creatinine (r2 = 0.820) and urea (r2 = 0.533). These results were comparable between those on CCPD and those on intermittent therapy. CONCLUSION: Total plasma iohexol clearance provides a simple assessment for APD adequacy by eliminating collection problems inherent to the methodologies currently employed. Such simplicity allows for more frequent assessments of delivered dialysis dose and efficacy of prescription changes.

Cefazolin as empiric therapy in hemodialysis-related infections: efficacy and blood concentrations.

Concern about the increasing incidence of vancomycin-resistant organisms has tempered the enthusiasm for indiscriminate vancomycin use. Cefazolin has an antibacterial activity profile similar to vancomycin against most pathogens encountered in the hemodialysis (HD) population. We evaluated the clinical efficacy and serum concentrations that were achieved during empiric cefazolin use. Fifteen consecutive HD patients (five, conventional HD; five, high-efficiency HD; and five, high-flux HD) with suspected or documented infections warranting antibiotic intervention, including access-related, respiratory tract, urinary tract, or wound infections, were enrolled. Each patient received intravenous cefazolin (20 mg/kg actual body weight rounded to the nearest 500-mg increment [range, 1 to 2 g]) after each dialysis treatment for at least three doses. Cefazolin concentrations were obtained before and immediately after the next three consecutive dialysis treatments. Thirteen patients were evaluated for efficacy and all 15 were evaluated for toxicity and cefazolin blood concentrations. All patients showed at least a short-term (3-week) clinical resolution of infection with cefazolin treatment. No central nervous system toxicities were noted and no other adverse events were expressed by the patients during the course of cefazolin treatment. Predialysis cefazolin concentrations, as determined by high-performance liquid chromatography, were 70.2 +/- 42.7 (conventional HD), 45.6 +/- 18.9 (high-efficiency HD), and 41.6 +/- 23.9 mg/L (high-flux HD) over the three dialysis sessions. Cefazolin at doses of approximately 20 mg/kg administered post-HD appears to be a safe and effective empiric therapy and yields predialysis cefazolin concentrations of 2.5 times or greater than those considered to be the minimum inhibitory concentration breakpoint (16 mg/L) for susceptible organisms. These data support the broader use of cefazolin for empiric treatment in the HD population, allowing vancomycin to be reserved for confirmed resistant organisms.

Seleçäo simultânea para produçäo de leite e porcentagem de gordura com diferentes pesos econômicos e estratégias de núcleos MOET - simulaçäo estocástica / Simultaneously selection for milk yield and fat percentage with different economic weights and nucleus strategy - stochastic simulation

Um programa contínuo de seleçäo em núcleos MOET, adulto, foi simulado para duas características com modelo estocástico. Os animais foram selecionados pela produçäo de leite e porcentagem de gordura. Foram calculdados três pesos econômicos com base no lucro obtido com a característica em questäo, sendo a seleçäo baseada nestes pesos econômicos. Os fatores estudados foram: número de vacas, estratégia de acasalamento e número de progênies nascidas. A estratégia fatorial de acasalamento tendeu a produzir maiores taxas de ganhos que a hierárquica. Os ganhos genéticos tenderam a aumentar com o aumento no número de doadoras e no número de progênies por doadora. Nos três índices, as maiores taxas de ganhos genéticos foram obtidas nos núcleos com acasalamento fatorial, 36 doadoras no núcleo e 20 progênies por doadora. No ganho genético individual das duas características, os ganhos foram maiores para a característica que possibilitasse maior lucro, de acordo com seu peso econômico calculado. As menores taxas de endogamia foram obidas, nos três índices, com aumento no númerio de doadoras, reduçäo no número de progênies por doadora e acasalamento hierárquico

Drug dosing in acute renal failure: the role of renal replacement therapy in altering drug pharmacokinetics.

The combination of multiple medical problems requiring complex drug therapy with rapidly changing organ functions that lead to pharmacokinetic alterations makes drug regimen design in the intensive care unit challenging. Acute renal failure leads to even greater physiologic disturbances requiring additional pharmacologic, nutritional, and dialytic support. A variety of renal replacement modalities, both intermittent and continuous, are used to manage the solute, volume, and acid-base derangements of patients with acute renal failure. Renal replacement therapies differ in their impact on drug dosing. The clinician must consider the impact of both disease and treatment if drug prescribing is to be optimal. Principles of solute removal are reviewed and concepts of drug regimen design are discussed. A practical approach to drug prescribing in this setting is described. Examples of dose adjustments for intermittent and continuous renal replacement therapies are provided.

A primer on continuous renal replacement therapy for critically ill patients.

OBJECTIVES: To characterize the multiple continuous renal replacement therapy (CRRT) techniques available for the management of critically ill adults, and to review the indications for and complications of use, principles of drug removal during CRRT, drug dosage individualization guidelines, and the influence of CRRT on patient outcomes. DATA SOURCES: MEDLINE (January 1981-December 1996) was searched for appropriate publications by using terms such as hemofiltration, ultrafiltration, hemodialysis, hemodiafiltration, medications, and pharmacokinetics; selected articles were cross-referenced. STUDY SELECTION: References selected were those considered to enhance the reader's knowledge of the principles of CRRT, and to provide adequate therapies on drug disposition. DATA SYNTHESIS: CRRTs use filtration/convection and in some cases diffusion to treat hemodynamically unstable patients with fluid overload and/or acute renal failure. Recent data suggest that positive outcomes may also be attained in patients with other medical conditions such as septic shock, multiple organ dysfunction syndrome, and hepatic failure. Age, ventilator support, inotropic support, reduced urine volume, and elevated serum bilirubin concentrations have been associated with poor outcomes. Complications associated with CRRT include bleeding due to excessive anticoagulation and line disconnections, fluid and electrolyte imbalance, and filter and venous clotting. CRRT can complicate the medication regimens of patients for whom it is important to maintain drug plasma concentrations within a narrow therapeutic range. Since the physicochemical characteristics of a drug and procedure-specific factors can alter drug removal, a thorough assessment of all factors needs to be considered before dosage regimens are revised. In addition, an algorithm for drug dosing considerations based on drug and CRRT characteristics, as well as standard pharmacokinetic equations, is proposed. CONCLUSIONS: The use of CRRT has expanded to encompass the treatment of disease states other than just acute renal failure. Since there is great variability among treatment centers, it is premature to conclude that there is enhanced survival in CRRT-treated patients compared with those who received conventional hemodialysis. This primer may help clinicians understand the need to individualize these therapies and to prospectively optimize the pharmacotherapy of their patients receiving CRRT.

Combination of low-dose niacin and pravastatin improves the lipid profile in diabetic patients without compromising glycemic control.

OBJECTIVE: To determine the efficacy and tolerability of the addition of low-dose niacin (1.5 g/d) in a diabetic hypercholesterolemic population who were unable to attain desired lipid control with low-dose (20 mg) pravastatin monotherapy. RESEARCH DESIGN AND METHODS: This was a prospective, open-label study conducted over a 14-week period. Twenty-three diabetic patients with low-density lipoprotein (LDL) cholesterol concentrations of at least 150 mg/dL after dietary therapy were recruited from the outpatient diabetes clinic of a university teaching hospital. After 4 weeks of dietary stabilization and baseline determination of the lipid profile and glycemic control, patients received pravastatin 20 mg once daily for 4 weeks. Laboratory parameters were reassessed and niacin was added to the regimen in qualifying patients. Over 2 weeks, patients' regimens were titrated to a maximal dosage of 500 mg tid. Patients continued to receive the combination regimen for 4 weeks and were reassessed. MEASUREMENTS AND MAIN RESULTS: Sixteen patients (14 non-insulin-dependent diabetes mellitus, 2 insulin-dependent diabetes mellitus) completed the study. Mean fasting blood sugar and fructosamine concentrations were unchanged throughout the study. Five patients required minor alterations (3 increased, 2 decreased) in their hypoglycemic regimens during the study. The addition of low-dose niacin to pravastatin therapy resulted in a significant lowering of LDL cholesterol compared with pravastatin monotherapy. CONCLUSIONS: Low-dose niacin is a promising addition to hydroxymethylglutaryl-coenzyme A reductase inhibitor therapy in the treatment of hypercholesterolemia in patients with diabetes mellitus.

Pharmacokinetics and cardiovascular effects of ma-huang (Ephedra sinica) in normotensive adults.

The purpose of this study was to evaluate heart rate and blood pressure responses to a commercially available source of ma-haung, a natural source of the sympathomimetic substance, ephedrine, and to evaluate the pharmacokinetic properties of the product in normotensive, healthy adults. On day 1, twelve study participants were monitored with an ambulatory blood pressure device between hours 7 and 20. On day 2, they ingested four capsules of powdered ma-huang at hours 8 and 17 while again wearing the monitor between hours 7 and 20. Serial plasma samples were obtained and concentrations of ephedrine were analyzed by high-performance liquid chromatography. Pharmacokinetic parameters of ephedrine were determined from plasma concentration-time profiles. The ephedrine alkaloid content of each capsule was also determined by high-performance liquid chromatography. Six participants experienced a statistically significant increase in heart rate, but the effects on blood pressure were variable. The half-life, volume of distribution, clearance, and maximum concentration in plasma of ephedrine in the ma-huang product were similar to values previously reported for a 20 mg, immediate-release ephedrine tablet. Values for the absorption rate were considerably lower and time to reach maximum concentration was longer for the capsules, compared with the standard tablet. Variability in alkaloid content of ephedrine was low and yielded a mean dose of ephedrine at 19.4 mg; pseudoephedrine at 4.9 mg; and methylephedrine at 1.2 mg for a four-capsule dose. In summary, ma-haung had variable effects on blood pressure and increased heart rate in healthy, normotensive adults. Pharmacokinetic parameters for ephedrine were in agreement with those previously reported; however, the absorption rate was much slower after ingestion of ma-huang.

Diurnal blood pressure variation in kidney-pancreas transplant recipients.

Blood pressure normally follows a characteristic pattern throughout the 24 h cycle with daytime pressures higher than nighttime pressures. Patients lacking a nocturnal decrease in pressure have a higher incidence of end organ damage. This investigation was designed to characterize the diurnal pattern of blood pressure and to evaluate blood pressure load in patients who have received a combined kidney-pancreas (KP) transplant. Ten patients (mean 10 months posttransplant) underwent 48 h of noninvasive ambulatory blood pressure monitoring using a commercially available device (SpaceLabs 90202 or 90207). Blood pressure was measured every 15 min from 6 AM to 9 PM and every 30 min from 9 PM to 6 AM. Ambulatory monitoring revealed a markedly increased nocturnal blood pressure (up to 25% greater than daytime pressures). These patients were found to have a higher nocturnal blood pressure load than during the day. No relationship was demonstrated between diurnal blood pressure variation and immunosuppression regimen, elapsed time after transplantation, or antihypertensive treatment. These results indicate that close attention must be given to the nocturnal blood pressure of KP recipients and suggest that standard antihypertensive medication regimens do not adequately treat the nocturnal hypertension in these patients. This may predispose these patients to further cardiovascular or cerebrovascular complications.

Phenytoin and plasmapheresis: importance of sampling times and impact of obesity.

The effect of plasmapheresis (PP) on total and free phenytoin clearance is reported. An obese patient with the diagnosis of thrombotic thrombocytopenic purpura (TTP) was treated with PP. Twelve episodes of PP, having exchange volumes of 1.5-2.25 times the plasma volume with a mean +/- SD 7.7 +/- 0.8 L of plasma removed, were studied. A significant (p < 0.05) difference was observed with a mean change in plasma phenytoin concentrations from pre- to end-PP of 7.32 +/- 2.5 mg/L compared to 1.98 +/- 0.7 mg/L observed pre-PP to 1 h post-PP. These values corresponded to 48.4 +/- 11.6 and 15.0 +/- 6.7% decreases in phenytoin concentrations at the two aforementioned time periods. To prevent misinterpretation of plasma phenytoin concentrations, samples should not be obtained for at least 2 h after PP.

Cefuroxime axetil.

Cefuroxime axetil is a orally active prodrug formulation of cefuroxime, which upon absorption undergoes immediate deesterification to free cefuroxime. Cefuroxime axetil offers an in vitro antibacterial spectrum against many gram-positive and some gram-negative organisms. Its beta-lactamase stability makes it useful in treating a variety of infections caused by beta-lactamase-producing strains of Haemophilus influenzae, Branhamella catarrhalis, and Staphylococcus aureus. Cefuroxime axetil has good activity against the Enterobacteriaceae and moderate activity against non-Bacteroides fragilis anaerobes. Clinical studies suggest it is at least as effective as ampicillin, amoxicillin, amoxicillin/clavulanic acid, penicillin V, or cefaclor in the treatment of uncomplicated urinary tract infections, acute otitis media, upper respiratory infections, skin and soft tissue infections, and uncomplicated gonorrhea.

Correlation of exposure to various respiratory pathogens with farmer's lung disease.

Complement-fixing antibodies (CFA) to a panel of microorganisms commonly associated with respiratory disease were measured in a number of agricultural populations. The panel included Mycoplasma pneumoniae, influenza viruses A and B, parainfluenza virus types 1, 2, and 3, adenovirus, and respiratory syncytial virus. The agricultural populations were grouped according to a clinical history of farmer's lung disease (FLD) and the presence of antibodies to the thermophilic actinomycetes (TA). Farmers with precipitating antibody activity to one or more of the TA (groups I and II) demonstrated a greater frequency of CFA to M. pneumoniae and parainfluenza virus types 1, 2, and 3 than those groups without antibody to the TA, but the level of CFA was not higher in the positive subjects. Immunoglobulin levels were also elevated in groups I and II when compared to the control groups. Unlike IgG and IgM, IgA was elevated only in the farmers who had a clinical history of FLD (group I) but not in farmers without a clinical history. The results suggest that farmers who develop FLD are exposed to a wider variety of pathogens than are other farmers, but do not respond in an accelerated manner.