Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with chronic renal failure.

Six patients with chronic renal failure (CRF group) and four healthy subjects (HS group) were given 5 mg oral and intravenous doses of bumetanide in a random, crossover design. The CRF group had significantly lower plasma and renal clearances, resulting in a five-to sixfold reduction in the fractional urinary excretion of the drug. The percent free drug in plasma for the CRF group was more than double that for the HS group, and significant correlations were observed for volume of distribution at steady state vs. percent free (r = 0.661; P less than 0.05), nonrenal clearance vs. percent free (r = 0.796; P less than 0.01), and renal clearance vs. creatinine clearance (r = 0.995; P less than 0.001). Although bioavailability was relatively consistent among the HS (0.664 +/- 0.112) and CRF (0.689 +/- 0.149) groups, the absorption-time profiles were more irregular for both groups. Cumulative sodium excretion and overall efficiency of response to bumetanide did not differ significantly between the two routes of administration in either group.

Disposition and irreversible plasma protein binding of tolmetin in humans.

The pharmacokinetics and irreversible plasma protein binding of tolmetin were studied in six healthy subjects after the administration of a single, 400 mg dose of tolmetin. With HPLC analysis, tolmetin, tolmetin glucuronide, and the isomers of tolmetin glucuronide, which result from intramolecular acyl migration in vivo, were detected in the plasma up to 4 hours after administration, whereas these conjugates were present in the urine up to 24 hours. Irreversible binding of tolmetin to plasma proteins occurred in all subjects. Irreversible binding exhibited a better correlation with exposure to tolmetin glucuronide (r = 0.5618) and the isomers of tolmetin glucuronide (r = 0.8200) than with exposure to tolmetin (-0.3635). This is consistent with the hypothesis that covalent binding occurs via the acyl glucuronide.

Kinetics, dynamics, and bioavailability of bumetanide in healthy subjects and patients with congestive heart failure.

Four healthy subjects and six patients with congestive heart failure (CHF) were given 3 mg oral and intravenous doses of bumetanide in a random crossover fashion. Bumetanide was analyzed by HPLC, and sodium and potassium was analyzed by flame photometry. Aside from a modest reduction in renal clearance, the kinetics of bumetanide in CHF were similar to those in healthy subjects. The extent of bioavailability was 81%, with a variability of 20% to 25% about the mean for both groups. The cumulative dynamic responses to bumetanide, whether administered orally or intravenously, were essentially the same in each group. Pharmacodynamic modeling showed that there were no significant differences between healthy subjects and patients with CHF in either ER50 (bumetanide urinary excretion rate producing 50% of maximum drug effect) or S (slope), although the baseline effect was 15 times lower in CHF. The maximum effect attributable to bumetanide was twofold higher in healthy subjects and there was a significant correlation between this parameter and creatinine clearance (r = 0.964; p less than 0.001). Overall, these results indicate that a predictable transition from 3 mg intravenous to oral doses of bumetanide is possible in CHF.

Urinary protein binding, kinetics, and dynamics of furosemide in nephrotic patients.

The urinary protein binding, kinetics, and dynamics of furosemide were studied in five nephrotic patients after intravenous dosing. Serial plasma and urine samples containing furosemide were analyzed by HPLC, and drug binding to plasma and urinary proteins was determined using equilibrium dialysis techniques. In comparison to data reported previously in healthy subjects, the steady-state volumes of distribution and nonrenal plasma clearances were significantly increased in nephrotic patients, reflecting the reduced binding of furosemide to plasma proteins. Although there was no significant difference in renal clearance between these two groups, the unbound renal clearance of furosemide was significantly reduced in nephrotic patients even when compensated for by the number of functioning nephrons. Furosemide was extensively bound to urinary protein (19.6-78.4%), and the binding was dependent on the degree of proteinuria. Nevertheless, dose-response analyses, in which the response was represented by sodium excretion rate and the dose by urinary excretion rate of unbound drug, demonstrated that nephrotic patients were less responsive to equivalent amounts of unbound diuretic as compared to healthy subjects.

An overview of the clinical pharmacokinetics of nabumetone.

Nabumetone is a new, nonacidic, nonsteroidal antiinflammatory drug. At least 80% of nabumetone is absorbed, and food, milk, and aluminum antacids increase the rate, but not the extent, of absorption. It is rapidly metabolized in the liver to 6-methoxy-2-naphthylacetic acid (6MNA), the major circulating active metabolite. At steady state, the time to maximum plasma concentration for 6MNA is 1 to 4 h. 6MNA has a very low clearance rate and long half-life (about 24 h). In general, steady state plasma concentrations of 6MNA increase in proportion with increases in the dose of nabumetone administered. Steady state plasma concentrations of 6MNA in the elderly are slightly higher than in healthy volunteers; however, this does not appear to be clinically significant. Preliminary studies in patients with impaired renal function indicate that the pharmacokinetics are not altered in patients with mild to moderate disease.

Simple acid-base disorders.

This article reviews normal acid-base regulation, related laboratory tests, and the potential disorders if the body's ability to compensate is disrupted. Acid derived from the oxidation of proteins and through tissue metabolism must be excreted or neutralized daily by the kidneys and lungs to maintain a proper acid-base balance. Acid-base homeostasis is normally maintained by chemical buffering, changes in renal hydrogen-ion excretion, and alterations in the rate and volume of alveolar ventilation. Metabolic disorders are characterized by disturbances in bicarbonate (HCO3-) concentration, and respiratory disorders develop with primary alterations in the partial pressure of carbon dioxide (Pco2). Metabolic acidosis is characterized by low pH, low serum HCO3- concentrations, and a compensatory decrease in Pco2 with hyperventilation. Bicarbonate administration can correct this disorder, and equations for calculating the necessary amount of HCO3- are presented. Metabolic alkalosis is characterized by a primary increase in HCO3-, compensatory hypoventilation, and an increase in Pco2 (hypercapnia). The drug therapy for this disorder is directed at either saline-responsive alkalosis or saline-resistant alkalosis. Formulas for estimating the volume requirements of patients and appropriate doses of acidifying agents are presented. Respiratory acidosis and alkalosis are also discussed. The initial therapy for the hypercapnia associated with respiratory acidosis requires reversing the underlying pulmonary disease with steroids, bronchodilators, or antibiotics. The increased Pco2 in this conditions must be lowered slowly to avoid precipitating cardiac arrhythmias and seizures. The correction of respiratory alkalosis requires elevating the Pco2 and again treating the underlying disease. Pharmacists should be knowledgeable about acid-base regulation and the disorders that frequently occur with disease because drugs are capable of inducing or exacerbating these disorders and are often key elements in therapy.

Current concepts in clinical therapeutics: drug therapy in acute renal failure.

The etiology and classification, pathophysiology, diagnosis, clinical course, and drug therapy of acute renal failure (ARF) are reviewed. ARF, a rapid reduction in kidney function that results in decreased glomerular filtration rate and tubular function, is caused by many different factors and can cause multiple organ dysfunction. The major causes of ARF are classically divided into three broad categories: (1) prerenal, or hypoperfusion states, (2) intrarenal, or intrinsic renal parenchymal disease, and (3) post-renal, or urinary obstructive disorders. The underlying pathogenic abnormality is renal tubular cell damage in patients with prerenal azotemia; vascular and glomerular damage is often secondary to immunologic mechanisms. Interstitial nephritis, often drug-induced, results from an immunologically mediated inflammatory renal response. Obstructive nephropathy results from partial or complete blockade of urine flow. Diagnosis relies heavily on patient history and physical examination; laboratory data, renal imaging, and sometimes renal biopsy results can yield important clues. The clinical course of ARF consists of four phases: insult and onset, maintenance, diuresis, and recovery. Morbidity and mortality are high. Drug therapy is directed at preventing or reversing the renal lesion before ARF becomes established and supporting the patient to allow the body to correct the lesion once it occurs. Prevention of prerenal azotemia and intrarenal disease is directed at identifying patients at risk, minimizing nephrotoxicity, and maintaining adequate urine output. In patients with established renal failure, an appropriate intravascular volume and pressure must be re-established and underlying problems must be corrected. Fluid, electrolyte, and acid-base balance are critical, and other serious effects on the gastrointestinal and neurologic systems must be addressed. Even though morbidity and mortality remain unacceptably high in patients with acute renal failure, promising progress has been made during the last 20-30 years.

Documented effectiveness of clinical pharmacy services.

Articles documenting the effectiveness of clinical pharmacy services were reviewed and categorized. A list of articles describing clinical pharmacy services published in the primary pharmacy literature or presented at ASHP Midyear Clinical Meetings was prepared. Selected articles were evaluated further for documented evidence of the impact of these services on patient care. Impact was defined as any one of the following outcomes: decreased morbidity (side effects, toxicity, or adverse drug reactions), decreased mortality, improved prescribing or monitoring practices, improved therapeutic outcome, and increased compliance. Ongoing clinical pharmacy services were described in 144 meeting abstracts and 117 published papers. Of the 33 papers suitable for further review, 16 provided documentation of probable or definite impact on patient care as a result of clinical pharmacy services. Three types of clinical services were provided: patient education and counseling, pharmacokinetic monitoring, and clinical drug monitoring and information. Nine studies involved ambulatory patients; eight of these involved adult patients, while one used pediatric patients. Seven of the nine studies demonstrated increased compliance through patient education and counseling. Seven studies involved adult hospitalized patients. More well-designed studies documenting the effects of clinical pharmacy services on patient outcome are needed.

Cimetidine clearance during intermittent and chronic peritoneal dialysis.

A case report evaluating the clearance of cimetidine during intermittent peritoneal dialysis and chronic ambulatory peritoneal dialysis is presented. A 50-year-old white man with end-stage renal disease using chronic ambulatory peritoneal dialysis was hospitalized with uremic pericarditis. He was treated with indomethacin and aggressive intermittent peritoneal dialysis. Cimetidine 300 mg every 12 hours was prescribed for ulcer prophylaxis. After taking cimetidine for seven days, the clearance of cimetidine during intermittent peritoneal dialysis was evaluated by collecting blood and dialysate samples during a four-hour dialysis period. The patient was discharged using chronic ambulatory peritoneal dialysis. Cimetidine 300 mg every 12 hours was continued. One week after discharge, the clearance of cimetidine during a four-hour dwell period of chronic ambulatory peritoneal dialysis was measured. Cimetidine clearance was approximately 4 ml/min for both intermittent and chronic ambulatory peritoneal dialysis. Clinically unimportant quantities of cimetidine were removed by intermittent and chronic ambulatory peritoneal dialysis. The need for supplemental doses of cimetidine during peritoneal dialysis is not supported.

Interference of cephalosporins and cefoxitin with serum creatinine determination.

The interference of cephalosporins and cefoxitin with serum creatinine (Crs) determinations was studied. Various concentrations of cephapirin, cefazolin, cefamandole, cephalothin, and cefoxitin were added to serum samples. Apparent creatinine concentrations were measured with the Beckman ASTRA, Technicon SMAC, and DuPont ACA analyzers. Pharmacokinetic models were used to predict serum drug concentrations as a function of time and renal function and to estimate the magnitude of interference in varying situations. The magnitude of the interference was proportional to the concentration of the drug in the sample and additive with baseline concentrations of creatinine in the serum. Negligible interferences occurred with cephapirin, cefazolin, and cefamandole. False elevations (i.e., Crs greater than or equal to 0.2 mg/dl over baseline) were detected with clinically achievable serum concentrations of cephalothin and cefoxitin. For patients with normal renal function (creatinine clearance greater than 50 ml/min), this drug interaction would be negligible from 20 minutes to two hours after drug administration, depending on the assay used. For patients with renal failure, measurable interferences could persist for up to 16 hours after dose administration. The critical concentrations were different for the three procedures and both antibiotics. The degree of interference varies with the assay procedure used, the serum concentration of the drug, and the patient's renal function. To minimize drug interference, blood samples for serum creatinine determinations should be drawn at the time of minimum drug concentration.

Pharmacokinetics and irreversible binding of tolmetin and its glucuronic acid esters in the elderly.

In a previous study, the disposition and irreversible plasma protein binding of tolmetin have been described in young volunteers. Significant levels of tolmetin glucuronide and its isomer(s) were found in plasma, and irreversible binding was shown to occur in all subjects. In the present study, the pharmacokinetics and irreversible binding in 5 elderly volunteers are investigated after a single dose (400 mg) of tolmetin. No difference of physiological importance has been found, unless weight correction is employed, when compared with the young subjects. Very strong correlations were present between the level of binding and exposure to the glucuronide or its isomer. An elderly patient currently treated with tolmetin (400 mg b.i.d.) also participated in the study. The results show an accumulation of the irreversible binding to levels 4-17 times higher than after a single dose. Nevertheless, neither toxic nor allergic reactions have been observed in this patient.

Accuracy of four methods of home blood glucose monitoring in hemodialysis patients.

The accuracy of four techniques of home blood glucose monitoring in hemodialysis patients was compared. Arterial-venous blood samples were collected from 23 patients undergoing hemodialysis and analyzed for serum glucose concentrations using an automated laboratory method. Capillary-blood glucose concentrations were also determined in each patient by visual readings of the Chemstrip bG and Dextrostix reagent strips and by reflectometer readings of the StatTek Glucose and Dextrostix reagent strips. Readings of glucose concentration obtained by each of the four techniques were compared with laboratory-determined values, and the true and absolute deviations in these values for each technique were recorded. The effect of patient hematocrit on deviations in glucose concentration readings was evaluated by analysis of variance. The mean glucose concentration readings obtained using the visual and reflectometer (Dextrometer) readings of Dextrostix were substantially less accurate than the other two techniques when compared with serum glucose concentrations determined by the laboratory. The StatTek technique gave the smallest mean absolute deviation from laboratory-determined values. No correlation was found between the patient's hematocrit and either the true or absolute deviations in glucose concentrations. The Chemstrip bG and StatTek techniques are reasonably accurate methods for home monitoring of blood glucose concentrations in diabetic patients undergoing hemodialysis.

Comparison of methods for estimating digoxin dosing regimens.

Five methods of predicting serum digoxin concentrations (SDCs), used in conjunction with three equations for estimating creatinine clearance, were compared. Radioimmunoassay was used to determine the nadir SDCs in 79 patients (38 men, 41 women) meeting predetermined study criteria. All patients, whose ages ranged from 33 to 94 years, had steady-state digoxin levels, were on oral digoxin, and were free from thyroid dysfunction, malabsorption syndromes, dehydration, and renal failure. Three equations, involving combinations of age, lean body weight, and serum creatinine, were used to estimate creatinine clearance (Clcr). These Clcr values were then used in each of five equations to estimate SDCs. The estimated SDCs were compared to actual SDCs in the 79 patients, and the effects of changing the fraction of dose absorbed and the method of determining Clcr were analyzed. No substantial difference in predictive reliability was evident among the methods studied. Poor correlations existed between observed and calculated SDCs (r less than 0.70), and these correlations were not significantly affected by gender, fraction of dose absorbed, or method of Clcr estimation. Higher correlations were found for the oldest and youngest age groups. Severe limitations are associated with the use of the formulas studied.

A comparative study on the genetic effects of hycanthone and oxamniquine.

Oxamniquine (UK-4271; 6-hydroxymethyl-2-isopropylaminomethyl-7-nitro-1,2,3,4-tetrahydroquinoline) is a new schistosomicidal agent currently undergoing clinical investigation in South America. Essentially a complete cure rate against Brazilian Schistosoma mansoni has been seen in adults with a single im dose of 7.5 mg/kg or a single oral dose of 15 mg/kg. These regimens were tolerated without significant toxicity. To assess its mutagenic potential, oxamniquine was examined in a battery of genetic tests designed to detect mutations at the gene and chromosome levels. For comparative purposes, hycanthone, a schistosomicide with extensively studied mutagenic properties, was evaluated in a similar series of tests. Point mutations were measured in a series of histidineless auxotrophs of Salmonella typhimurium in direct plate and host-mediated assays. Gross chromosomal aberrations were assessed in human leucocyte cultures and in bone marrow preparations from drug-treated mice. Effects on germ cells were tested in the dominant-lethal assay. Hycanthone showed significant mutagenic activity in the direct bacterial tests and the in vivo and in vitro cytogenetic assays. No response was detected in the host-mediated or dominant-lethal assays. On the other hand, oxamniquine produced no drug-related mutagenic effects in the cytogenetic, host-mediated, or dominant-lethal tests at doses up to 150 mg/kg administered parenterally. Oxamniquine produced a weak response in the frameshift mutant, TA1538, of Salmonella typhimurium in direct plate tests with and without liver microsomal enzymes. However, this response was achieved only by using a concentration of compound which was several orders of magnitude higher than that required to produce a similar response to hycanthone.

Effect of pH on the stability of heparin in 5% dextrose solutions.

The effect of pH and time on the stability of heparin sodium in dextrose 5% in water (D5W) injection and in dextrose 5% in 0.45% sodium chloride injection was studied. Admixtures of heparin sodium 5,000 units/250 ml were tested after 0, 10, 20 and 30 minutes and 1, 2, 6, 12 and 24 hours of storage at room temperature. The pH of the carrier solutions was adjusted to 2, 4 or 9 prior to adding the heparin sodium. Heparin activity was measured using a thrombin clotting time assay. Samples were tested for pH changes at the same times. No substantial changes in heparin activity over the 24-hour period occurred with any of the pH-adjusted solutions. The pH of the heparin-D5W admixtures remained constant over time. The two carrier solutions, over a pH range of 2 to 9, appear to be suitable vehicles for heparin sodium.

High-performance liquid chromatographic determination of tolmetin, tolmetin glucuronide and its isomeric conjugates in plasma and urine.

A rapid and sensitive analytical procedure is described for the simultaneous measurement of tolmetin (T), tolmetin glucuronide (1 beta-TG) and the isomers of tolmetin glucuronide in plasma and urine. A reversed-phase liquid chromatographic system is used with an ion-pairing mobile phase of methanol-tetrabutylammonium hydrogensulfate buffered to pH 4.5 and kept at a constant temperature of 50 degrees C. Detection is by UV at 313 nm. Plasma (0.5 ml) and urine (0.1 ml) are collected in pre-cooled containers and immediately adjusted to pH 3.0 to minimize TG isomerization and hydrolysis. Samples are then deproteinated with acetonitrile, the supernatant is evaporated to dryness and reconstituted in an acetate buffer (pH 4.5), and 50 microliters are injected onto the system. Using zomepirac as the internal standard, the measurable, linear concentration ranges are 0.05-50 micrograms/ml for T in plasma and 0.025-50 micrograms/ml for T in urine. Chromatographic peaks representing T,1 beta-TG and three isomers of TG were identified, all with retention times less than 10 min. The need for special handling of biological samples is discussed.

Factors affecting diazepam infusion: solubility, administration-set composition, and flow rate.

The sorption of diazepam in large-volume i.v. admixtures to administration-set components and in i.v. containers was analyzed quantitatively. Solubility of diazepam in phosphate buffer at various pH levels and in i.v. fluids was measured. Partition coefficients of diazepam into components of i.v. administration sets and i.v. containers were studied by shaking a solution of diazepam in 0.9% sodium chloride, with finely cut components and measuring the change in diazepam in the aqueous phase. Flow studies through an administration set of a 0.04-mg/ml diazepam solution in 5% dextrose injection were done, varying both the flow rate and the length of tubing. The maximum free-base solubility of diazepam in phosphate buffer was 0.048 mg/ml; its solubility was 0.058, 0.050, and 0.064 mg/ml in lactated Ringer's, 0.9% sodium chloride, and 5% dextrose injections, respectively. Equilibrium partition coefficients were highest for polyvinyl chloride tubing and flexible bags. Volume-control sets made of cellulose propionate had lower but sufficiently large partition coefficients to cause diazepam loss. Polyolefin semi-rigid and glass containers had low partition coefficients. In the flow studies, the amount of solution-contact time correlated with the extent of absorption. As flow rate decreased or tubing length increased, the amount of diazepam absorbed increased proportionately. A nomogram and a predictive dosing chart are presented for calculation of actual diazepam doses delivered at various flow rates and tubing lengths. Diazepam can be administered safely and effectively by i.v. infusion. The use of volume-control sets and flexible polyvinyl chloride bags should be avoided with diazepam solutions. Polyolefin semi-rigid containers are acceptable alternatives to glass. The concentration of diazepam infusions should not exceed 0.04 mg/ml.

Cimetidine-theophylline interaction: effects of age and cimetidine dose.

Influences of cimetidine dose and age on the cimetidine-theophylline interaction were evaluated. Group Y consisted of nine young adults, aged 22-35 years, and Group O of nine elderly adults, aged 60-74 years. Each subject completed three study phases in this randomized crossover study. During Phase A, oral dosing of 5 mg/kg theophylline was followed by 14 serial blood samples drawn over 36 h. Phases B and C involved the same procedures, but with oral cimetidine treatment of either 200 or 300 mg every 6 h, respectively. Theophylline pharmacokinetic parameters for Group Y, Group O, and Groups Y + O were calculated. Analyses of variance (ANOVA) for crossover design were performed for each variable. Intragroup interphase ANOVA results were interpreted using multiple range tests (Tukey's Q). Comparisons between groups were performed using two-sided Student's t tests (alpha = 0.05). Within each phase, the area under the concentration-time curve (AUC), elimination half-life (t1/2 el), clearance (Clp), and volume of distribution (Vd) of theophylline for the elderly subjects were not significantly different from those of the younger adults. Mean changes in AUC, t1/2 el, and Clp between Phases A and B for both Groups Y and O were highly significant (29.2 vs. 40.4, 36.7 vs. 44.8, and 25.9 vs. 29.8%, respectively). Further significant changes in those parameters were associated with 1.2 g/day of cimetidine (Phase C). Alterations of theophylline pharmacokinetics by cimetidine appear to be dose-related and are of similar magnitude in elderly and young healthy adults.