Animals with experimental renal disease maintained on diets restricted in protein develop less severe renal lesions and less proteinuria than do animals maintained on a normal or high protein diet. To determine whether restriction of dietary protein will reduce urinary albumin excretion in patients with established nephrosis and whether such dietary restriction will result in decreased albumin pools, we performed paired studies on nine nephrotic patients. They were fed sequential diets with a protein content of 1.6 and then 0.8 g/kg body wt, each for 2 weeks. Caloric intake remained constant at 35 Kcal/kg. In six patients the high protein diet was fed first; in three the order of dietary administration was reversed. Urinary albumin excretion was reduced on the low protein diet in all patients regardless of dietary order. Both the renal clearance of albumin and the fractional renal albumin clearance were reduced significantly on the low protein diet. The rate of albumin synthesis was greater on the high protein diet, but so was the rate of albuminuria. Despite the higher rate of albumin synthesis during the period of high protein intake, serum albumin concentration and plasma albumin mass were both less than during the period of low protein intake. Thus, dietary protein restriction in patients with established nephrosis results in decreased urinary albumin excretion in excess of any reduction in creatinine clearance. Total albumin mass is preserved and plasma albumin mass is actually increased during the period of dietary protein restriction. Protein restriction may be feasible in nephrotic patients.(ABSTRACT TRUNCATED AT 250 WORDS)

The absolute oral bioavailability and pharmacokinetics of clindamycin administered to 16 healthy volunteers and 16 patients with AIDS were compared. Clindamycin was given intravenously (i.v.) (Cleocin phosphate) at a dose of 600 mg as a 25-min infusion and orally (Cleocin hydrochloride) by use of a crossover design in both study groups. Plasma samples were analyzed by gas-liquid chromatography. Plasma drug clearance and volume of distribution at the steady state following the i.v. dose differed between study groups. The clearances were 0.27 0.06 liter/h/kg in healthy volunteers and 0.21 0.06 liter/h/kg in AIDS patients (P = 0.014; Mann-Whitney U test); the volumes of distribution at the steady state were 0.79 + 0.13 and 0.66 0.12 liter/kg in healthy volunteers and AIDS patients, respectively (P = 0.005). The elimination half-life did not differ between the two groups. The bioavailability of clindamycin capsules in AIDS patients was approximately 1.5 times that in healthy volunteers (0.53 + 0.14 versus 0.75 + 0.20; P = 0.002). Peak concentrations following the oral dose were higher in AIDS patients as well (7.7 2.5 versus 5.3 1.0 mg/liter, P = 0.0008). Three AIDS patients experienced severe diarrhea following the oral dose; four patients had mild diarrhea following the i.v. dose. No adverse effects were reported by the healthy volunteers. The pharmacokinetic parameters observed in this study for AIDS patients may be useful for the consideration of clindamycin dosage regimens in patients treated for toxoplasmic encephalitis. These findings suggest that the effect of AIDS on drug disposition deserves further investigation, particulariy for orally administered drugs.Toxoplasmic encephalitis (TE) is considered the most common cause of intracerebral mass lesions in patients with AIDS, occurring in 3 to 40% of AIDS patients (16). Standard therapy for TE includes the synergistic combination of pyrimethamine and sulfadiazine, which provides a sequential blockade of folic acid metabolism. However, many patients with AIDS are unable to complete a course of therapy because of adverse reactions (18).Clindamycin has been used either alone or more frequently in combination with pyrimethamine to treat TE in patients with AIDS who develop untoward side effects to the sulfonamide component of the standard pyrimethaminesulfadiazine therapy (4,10,15,21,23,24). Recently, the results of an international prospective study comparing the combinations pyrimethamine-sulfadiazine and pyrimethamine-clindamycin suggest that the relative efficacies of the two combination treatments are approximately equal (3).The activity of clindamycin against Toxoplasma gondii is controversial: clindamycin was effective in a murine model of TE (11) but was ineffective in a model based on Taxoplasma-infected rat monocytes (9). Clindamycin does not penetrate adequately into cerebrospinal fluid, even in the presence of bacterial meningitis (7); however, it has been suggested that damage of the blood-brain barrier in AIDS patients, involving marked tissue de...

Ribavirin is an antiviral agent used in the treatment of chronic hepatitis C virus infection. One of the limitations associated with the use of ribavirin is a reversible anemia caused by its accumulation in erythrocytes. Therefore, it is of interest to determine ribavirin levels in erythrocytes, as well as in plasma, as these measurements may be predictive of hematotoxicity. In the present study, we describe a high-performance liquid chromatographic (HPLC) assay for ribavirin in whole blood to estimate concentrations of free ribavirin and phosphorylated anabolites in erythrocytes. Since ribavirin exists primarily as phosphorylated anabolites (mono-, di-, and triphosphates) in erythrocytes, whole-blood extracts were initially dephosphorylated with acid phosphatase. The enzyme-treated samples were subjected to phenyl boronic acid column extraction for cleanup. The purified fraction was analyzed by reversed-phase HPLC, which was optimized for determination of ribavirin levels in whole blood. The recoveries of ribavirin from whole blood ranged from 63.1 to 90.7% at concentrations ranging from 1.67 to 40.0 μM. Intra- and interassay variations estimated at these concentrations were 3.2 to 10.4 and 4.7 to 11.7%, respectively. This method was used to quantitate ribavirin in samples both treated and untreated with acid phosphatase to estimate the extent of intracellular phosphorylation in erythrocytes. The method was also used to evaluate the effects of dipyridamole, a nucleoside transporter inhibitor, on ribavirin disposition in erythrocytes in in vitro experiments.

Hyperlipemia is a common manifestation of the nephrotic syndrome. Serum lipid concentrations have been observed by others to be negatively correlated with serum protein concentration. Hyperlipemia has been postulated to result from a coordinate increase in the synthesis of both albumin and lipoproteins, as well as from their decreased catabolism. Simultaneous measurements of serum lipid concentration and the rate of albumin synthesis have not been previously reported. We measured the rate of albumin synthesis, urinary albumin loss, serum albumin, protein, cholesterol and triglyceride concentration in 13 nephrotic patients. Changes in the rate of albumin synthesis and in urinary albumin excretion were induced in eight patients by alteration in dietary protein intake. The resultant changes in serum triglyceride and cholesterol were analyzed by multiple regression analysis. The rate of albumin synthesis measured while patients were eating a low protein diet was 12.61 +/- 1.20 g/1.73 m2/day, well within normal limits, yet both serum triglyceride and cholesterol concentrations were markedly elevated (265 +/- 65 mg/dl and 325 +/- 44 mg/dl, respectively). Albumin synthetic rate increased to 17.60 +/- 1.25 g/1.73 m2/day when dietary protein intake was increased, while serum triglyceride and cholesterol concentrations changed little; triglyceride concentration was 306 +/- 75 mg/dl and cholesterol 376 +/- 55 mg/dl. Serum cholesterol concentration, by multiple regression analysis, was dependent only upon the renal clearance of albumin P less than 0.0001, and changes in serum cholesterol concentration was dependent only upon changes in the renal clearance of albumin, P less than 0.001. Serum cholesterol concentration was completely independent of the rate of albumin synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Six normal adult volunteers were administered 15 mg/kg of ethambutol (EMB) by a constant-rate 1-hr infusion. Plasma and urine samples were collected up to 24 and 72 hr, respectively. Peak plasma levels following the 1-hr infusion ranged from 11.6 to 15.4 microgram/ml. Subsequent postinfusion EMB levels exhibited multiphasic decay. In the 12-hr period following infusion, EMB levels showed biexponential decay. However, 24-hr plasma levels in all subjects were observed to be higher than those predicted using a two-compartment body model. The alpha phase in these subjects had a mean half-life of 8.6 min while the half-life of the beta phase ranged from 2.5 to 3.6 hr (mean 3.1). The half-life of the gamma phase estimated from plasma data points between 12 and 24 hr averaged 1.2 +/- 3.6 hr. A terminal gamma t1/2 of 15.4 +/- 1.7 hr was calculated from 12-72 hr urine data. The mean value for the steady-state volume of distribution using a noncompartmental method was 3.89 liters/kg. Plasma EMB clearance ranged from 7.47 to 8.87 ml/min/kg (mean 8.57). The fraction of the dose eliminated unchanged varied from 0.75 to 0.84 (mean 0.79). Renal clearance ranged from 5.93 to 8.45 ml/min/kg (mean 6.81), indicating active tubular secretion.

Foscarnet (trisodium phosphonoformate), an investigational pyrophosphate analog increasingly used to treat refractory cytomegalovirus retinitis and mucocutaneous herpes simplex virus infections in immunocompromised patients, has been reported to cause abnormalities in serum calcium and phosphate, including cases of fatal hypocalcemia. To further elucidate the magnitude and mechanism of these abnormalities in humans treated with foscarnet for opportunistic herpes virus infections, we analyzed anaerobic serum specimens and 24-h urine samples before and after single and multiple doses of iv foscarnet and performed a series of in vitro experiments with normal human serum and plasma. Plasma ionized calcium concentrations acutely decreased by a mean 0.17 mmol/L in the 6 individuals who received a 90 mg/kg dose of foscarnet and by a mean 0.28 mmol/L in the 11 individuals who received a 120 mg/kg dose (P = 0.016, 90 vs. 120 mg/kg dose). Results of in vitro experiments showed a highly significant inverse linear relationship between foscarnet and ionized calcium concentrations, but no correlation between foscarnet and total calcium or phosphate concentration. Dialysis experiments suggested that the complexing of foscarnet with ionized calcium could be a cause of this ionized hypocalcemia. Physicians must be aware of this phenomenon and should measure serum ionized calcium during foscarnet therapy (preferably at the end of a foscarnet infusion) whenever neurological or cardiological abnormalities occur.

Limited information is available on the pharmacokinetics and bioavailability of prednisone and prednisolone in patients with different disease states. This is partly due to difficulty in measuring these drugs in biological fluids at the usual dosages prescribed to patients. This article attempts to comprehensively review these studies categorized under the following four sections: (1) bioavailability--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of antacids, effect of food, effect of other drugs (aminophylline, cholestyramine); (2) pharmacokinetics--healthy volunteers, patients with respiratory disease, patients with liver disease, patients with kidney disease, pediatric patients with various diseases, effect of other drugs, enzyme induction of steroids and the effect on the kinetics of steroids and other drugs; (3) protein binding; and (4) analytical methods. The literature is reviewed through August 1979.

Six normal adult volunteers received