The effect of hemodialysis on cycloserine, ethionamide, para-aminosalicylate, and clofazimine.

STUDY OBJECTIVES: Determine hemodialysis clearances of the second-line antitubercular drugs cycloserine (CS), ethionamide (ETA), para-aminosalicylate (PAS), and clofazimine (CFZ). DESIGN: Open-label, pharmacokinetic study SETTING: Outpatient long-term hemodialysis unit PARTICIPANTS: Eight long-term hemodialysis patients Interventions: Single oral doses of CS, 500 mg, ETA, 500 mg, PAS, 4,000 mg, and CFZ, 200 mg, were given 2 h (4 h for PAS) prior to hemodialysis (median blood flow rate, 400 mL/min; median dialysate flow rate, 600 mL/min; median hemodialysis time, 3.5 h). MEASUREMENTS AND RESULTS: Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate fluid was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using validated high-performance liquid chromatography (for ETA and PAS), capillary electrophoresis (for CS), and colorimetry (for CFZ). Dialysate samples were analyzed for acetyl-PAS. Median recoveries of drug in dialysate were 56% (CS), 2.1% (ETA), 6.3% (PAS parent compound), and 0% (CFZ) of the doses administered. Acetyl-PAS was dialyzed to a greater extent than its parent compound. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during dialysis were 189 (CS), 58 (ETA), 206 (PAS), and 0 (CFZ) mL/min. CONCLUSIONS: ETA, CFZ, and PAS were not significantly dialyzed. CS is significantly removed by hemodialysis and should be dosed after hemodialysis.

Pharmacokinetics of cycloserine under fasting conditions and with high-fat meal, orange juice, and antacids.

STUDY OBJECTIVES: To determine the effect of a high-fat meal, orange juice, and antacids on absorption of a single oral dose of cycloserine and to estimate its population pharmacokinetic parameters. DESIGN: Randomized, four-period, crossover study. SETTING: Clinical research center. PATIENTS: Twelve healthy volunteers. INTERVENTIONS: Subjects received single doses of cycloserine 500 mg after a 12-hour fast (reference), with a high-fat meal, with orange juice, and with antacids. They also received clofazimine 200 mg, ethionamide 500 mg, and p-aminosalicylic acid granules 6000 mg. MEASUREMENTS AND MAIN RESULTS: Plasma samples were collected for 48 hours and assayed by validated high-performance capillary electrophoresis assay. Concentration-time data were analyzed with noncompartmental, one-compartment, and population methods. The maximum concentration (Cmax) of cycloserine was decreased (p=0.02) by the high-fat meal. No other statistically significant differences were observed for Cmax and area under the curve from time zero to infinity across the four treatments. The high-fat meal significantly (p<0.0001) delayed time to maximum concentration by 4.7 times compared with that of the reference (1.1 hr). CONCLUSION: The pharmacokinetics of cycloserine were minimally affected by orange juice and antacids, whereas the high-fat meal delayed absorption. Administering cycloserine without a high-fat meal avoids potential alterations in the pattern of absorption.

Flight-skill decay and recurrent training.

This article addresses the problem of flight-skill decay. The complexity of the problem is outlined with regard to identifying the nature and extent of decayed skills. It is suggested that cognitive/procedural skills are more prone than control-oriented skills to decay over periods of disuse. Effective recurrent training methods offer the most promise in forestalling loss of proficiency. Several such methods are described, and the importance of cognitive training is emphasized. Finally, criteria are noted for evaluating the utility of recurrent training media. The theories and practical measures discussed apply to many skills other than those of flying.

Clarithromycin pharmacokinetics in the desert tortoise (Gopherus agassizii).

Clarithromycin is a new, safe orally administered macrolide antibiotic active against Mycoplasma sp. in humans. Single-dose and multidose pharmacokinetic parameters were determined for clarithromycin in wild-caught desert tortoises (Gopherus agassizii) seropositive for M. agassizii. Clarithromycin blood levels were measured in three tortoises for up to 72 hr after a single oral dose of 7.5 mg/kg. In a second group of six tortoises, levels were measured after a dose of 15 mg/kg. Noncompartmental iterative two-stage Bayesian and nonparametric expectation maximization pharmacokinetic parameters were determined for each animal assuming first order rate constants. At 15 mg/kg, the maximum concentration was 1.37 microg/ml, the time to maximum concentration was 8.0 hr, and a plasma half-life of 11.69 hr was derived from the latter method. The absorption constant was 0.08/hr, the absorption half-life was 8.47 hr, and the weight-normalized volume of distribution was 5.30 L/kg. Predictions derived by the latter method suggested a dosage of 15 mg/kg p.o. every 24 hr to achieve maximal blood levels of > or =1 microg/ml for multiple dosing. However, results from a preliminary multidose study with three tortoises indicate that the drug is accumulated; therefore, the predicted dose may be closer to 15 mg/kg p.o. every 2-3 days to maintain blood levels of 2-7.5 microg/ml. (For n = 3, 2-point linear regression median estimates for the apparent elimination rate constant (K) and half-life are 0.0227/hr and 30.52 hr, respectively.) This multidose accumulation reflects a slower apparent elimination than that predicted in the eight single-dose tortoises (i.e., K = 0.0593/hr, t1/2 = 11.69 hr). This study highlights a potential pitfall of depending solely on single-dose studies and the potential value of oral administration in reptiles.

Once-daily and twice-daily dosing of p-aminosalicylic acid granules.

The study objective was to determine the minimum frequency of dosing for standard 4-g doses of p-aminosalicylic acid (PAS) granules. Two sequential six-patient pharmacokinetic studies are described, followed by clinical data from 40 subsequent patients. All patients had multidrug-resistant tuberculosis (MDR-TB). Serum was collected at two to three time points after dosing, and assayed by a validated high performance liquid chromatography (HPLC) assay. Data were analyzed using noncompartmental methods. In six patients, twice-daily dosing produced median serum concentrations at 4, 8, and 12 h post-dose of 25.8, 23.2, and 16.4 microgram/ml. In six patients, once-daily dosing produced median serum concentrations at 6, 12, and 24 h post-dose of 23.4, 3.7, and 0 microgram/ml. In 40 patients, twice-daily dosing produced median serum concentrations at 4 to 8 and 9 to 12 h post-dose of 24.8 and 20.6 microgram/ml. Unlike once-daily dosing, twice-daily PAS maintained serum concentrations in excess of 1 microgram/ml, the typical minimal inhibitory concentration against Mycobacterium tuberculosis, for the entire dosing interval. We now use twice-daily PAS granules for our patients with MDR-TB.

Pharmacokinetics of ethambutol under fasting conditions, with food, and with antacids.

Ethambutol (EMB) is the most frequent "fourth drug" used for the empiric treatment of Mycobacterium tuberculosis and a frequently used drug for infections caused by Mycobacterium avium complex. The pharmacokinetics of EMB in serum were studied with 14 healthy males and females in a randomized, four-period crossover study. Subjects ingested single doses of EMB of 25 mg/kg of body weight under fasting conditions twice, with a high-fat meal, and with aluminum-magnesium antacid. Serum was collected for 48 h and assayed by gas chromatography-mass spectrometry. Data were analyzed by noncompartmental methods and by a two-compartment pharmacokinetic model with zero-order absorption and first-order elimination. Both fasting conditions produced similar results: a mean (+/- standard deviation) EMB maximum concentration of drug in serum (Cmax) of 4.5 +/- 1.0 micrograms/ml, time to maximum concentration of drug in serum (Tmax) of 2.5 +/- 0.9 h, and area under the concentration-time curve from 0 h to infinity (AUC0-infinity) of 28.9 +/- 4.7 micrograms.h/ml. In the presence of antacids, subjects had a mean Cmax of 3.3 +/- 0.5 micrograms/ml, Tmax of 2.9 +/- 1.2 h, and AUC0-infinity of 27.5 +/- 5.9 micrograms.h/ml. In the presence of the Food and Drug Administration high-fat meal, subjects had a mean Cmax of 3.8 +/- 0.8 micrograms/ml, Tmax of 3.2 +/- 1.3 h, and AUC0-infinity of 29.6 +/- 4.7 micrograms.h/ml. These reductions in Cmax, delays in Tmax, and modest reductions in AUC0-infinity can be avoided by giving EMB on an empty stomach whenever possible.

The effect of hemodialysis on isoniazid, rifampin, pyrazinamide, and ethambutol.

This study examines hemodialysis clearances of isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB). Seven chronic hemodialysis patients were studied. Six were given single oral doses (INH 300 mg, RIF 600 mg, PZA 1000 mg, and EMB 25 mg/kg) 2 h before hemodialysis (Cobe Centrysystem 3 hemodialysis machine; Fresenius F80B dialyzer; median blood flow rate 400 ml/min; dialysate flow rate 600 ml/min; median hemodialysis time 3.5 h). The seventh subject, being treated for tuberculosis (TB), was studied with his usual regimen. Arterial and venous serum samples were collected at the beginning and end of hemodialysis, and hourly during hemodialysis. Dialysate was collected for the duration of hemodialysis. All samples were assayed for drug concentrations using high-performance liquid chromatography (HPLC) (INH, RIF) and gas chromatography/mass spectrometry (GC/MS) (PZA, EMB) methods. Median recoveries of drug in dialysate were 9% (INH), 4% (RIF), 45% (PZA), and 2% (EMB) of the doses administered. Median hemodialysis clearances calculated by dividing the amount recovered in dialysate by the serum area under the curve during hemodialysis were 124 (INH), 40 (RIF), 270 (PZA), and 46 (EMB) ml/min. INH, RIF, and EMB were not significantly removed by hemodialysis. PZA is significantly dialyzed and should be dosed after hemodialysis.