Effect of glycerol and hyperosmolality on intracranial pressure.

Glycerol has been used in cerebral edema for hyperosmolar dehydration of brain tissue, but only empirical relationships govern this use. Since the efficacy of treatment with glycerol would likely increase with data on the relationship between drug blood levels and intracranial pressure (ICP), we examined the clinical pharmacology of the drug. Plasma samples were assayed for glycerol by a new method using gas chromatography with a flame ionization detector. Data were collected from 12 children who were in Children's Hospital of Pittsburgh (CHP) and who had cerebral edema of differing etiology that was treated with glycerol; they were monitored by intraventricular catheter. Glycerol was infused according to CHP guidelines. ICP reduction correlated with glycerol concentration and plasma concentrations of 1 to 3 mg/ml (10 to 30 mOsm/ml) were necessary to maintain an ICP below 20 torr. The relationship between osmolality and plasma glycerol level was also examined; there was good correlation between the idiogenic osmolality and drug concentration. Our studies support the clinical observations that relatively high doses of glycerol (0.2 to 1.0 gm/kg/hr), leading to plasma concentrations of 10 to 30 mOsm/l, are necessary to control ICP in patients with cerebral edema. Glycerol blood levels may be estimated from serum osmolality.

Unique approach to calculation of first-order absorption rate constants from blood or urine data.

Several methods are employed to estimate an apparent first-order rate constant for absorption in a one-compartment model. A method for calculation of the absorption rate constant (Ka) has been derived based on the area under the concentration-time curve for blood data or the area under the excretion rate-time curve for urine data between the observed time of maximum concentration or rate (tmax) and the maximum concentration (Cmax) or maximum rate of excretion (Xu max). The method obviates the need for large numbers of samples in the absorptive phase. The method also avoids extensive calculation and is less influenced by errors in data points prior to Cmax or Xu max, where the rate of change is rapid and error is likely. The methods have been tested on theoretical data with and without error generated using a ragne of values for Ka and elimination rate constants (KE). Errors in the estimate Ka are proportional to error in the data. The method compares favorably with nonlinear regression analysis.

Rapid high-performance liquid chromatographic determination of bleomycin A2 in plasma.

A rapid and specific method for the determination of bleomycin A2 is described. A 50-microliter aliquot of 20% trichloroacetic acid was added to 200 microliter of plasma. The sample was vortexed and centrifuged, and 50 microliter of the clear supernate was injected into a liquid chromatograph equipped with a microparticulate reversed-phase column and a fixed wavelength detector. Elution was carried out using methanol-acetonitrile-0.0085 M heptanesulfonic acid-acetic acid. A linear calibration curve was found in the 0.05-5 microgram/ml range with an estimated precision of +/-6% (CV). Preliminary pharmacokinetic data in the rabbit also are reported.

Bioavailability of sulfonamide suspensions I: Dissolution profiles of sulfamethizole using paddle method.

A comparative bioavailability study was performed using two commercially available, chemically equivalent brands of sulfamethizole suspension. One gram of each suspension was administered to 12 different subjects following a completely randomized crossover design. Serum levels and derived pharmacokinetic parameters were compared statistically. There were no significant differences in the extent of sulfamethizole absorption from the two suspensions as evidenced by the area under the serum level--time curves. Significant differences (p less than 0.05) in the mean serum levels at 0.5 and 0.75 hr and differences in Cmax and tmax indicated that the absorption rate differed for the two products. In vitro tests including particle-size analysis and dissolution studies were performed. The size--frequency distribution of particles in the suspensions was studied using a resistance particle counter. The dissolution characteristics of the two products were studied using the Food and Drug Administration's paddle method and the spin-filter apparatus. Suspension A had a significantly greater amount of drug dissolved at 15 and 30 min using either method. It also had a greater percentage of particles at the smaller size range, indicating that the greater dissolution rate may be related directly to the decreased particle size. A comparison of the in vivo and in vitro results demonstrated a definite rank-order correlation between the dissolution performance of the two suspensions and the in vivo parameters reflecting the absorption rate. Suspension A had a greater amount of drug dissolved at 15 and 30 min and resulted in higher serum levels at 0.5 and 0.75 hr, a higher Cmax, and a shorter tmax.

Simple high-pressure liquid chromatographic determination of trisulfapyrimidines in human serum.

A simple and rapid high-pressure liquid chromatographic method was developed for the determination of sulfadiazine, sulfamerazine, and sulfamethazine in human serum. After the trichloroacetic acid precipitation of the serum proteins, an aliquot of the supernate is injected into a high-pressure liquid chromatograph equipped with a reversed-phase microparticulate column and a fixed wavelength UV detector. For each of the three components of trisulfapyrimidines, a linear calibration curve was observed in the 1-30-microgram/ml range, with the precision of the assay estimated to be +/- 2% (RSD). Preliminary pharmacokinetic data are also presented.

Unique approach for calculation of absorption rate constant.

Several methods are employed to estimate an apparent first-order rate constant for absorption in a one-compartment model (Ka). These include curve-stripping, nonlinear least squares regression, and the Wagner-Nelson approach. The Wagner-Nelson method in particular requires extensive calculation and may be subject to error. A method for calculation of the absorption rate constant has been derived based on the relationship between area under the concentration-time curve, between time of maximum concentration (tmax) and infinity, and maximum concentration (cmax). The method obviates the need for large numbers of samples in the absorptive phase. The method also avoids extensive calculations and is less influenced by errors in data points prior to Cmax where the rate of change of concentration is very rapid and error is likely. The value for Ka is corrected for by the error found in tmax (calculated using the estimated Ka) relative to the observed tmax. The method has been tested on theoretical data with and without error generated using a range of a and KE. Errors in the estimate of Ka are proportional to error in the data.

Rapid GLC determination of therapeutic plasma glycerin levels.

A new rapid and inexpensive method for the determination of therapeutic plasma glycerin concentrations is described. In this method, acetic anhydride and pyridine are added to 15 microliter of plasma. After brief incubation and centrifugation, an aliquot of the supernate is injected directly onto the 3% OV-1 column. A linear calibration curve was found in the 0.05--3-mg/ml range, with the precision of the assay estimated to be +/-5.5% (RSD). The method was used to determining preliminary pharmacokinetic data in the rabbit.

Time-dependent kinetics I: Exponential autoinduction of carbamazepine in monkeys.

The pharmacokinetics of carbamazepine were studied during a week-long infusion of the drug in 60% polyethylene glycol 400 solution in three rhesus monkeys. Serum concentrations approached steady state within 8-16 hr and then rapidly declined, within 72 hr, to a new asymptotic level approximately 46% of the maximum steady-state concentration. Serum concentrations remained at that level during the rest of the experimental period. The decline from the maximum value to the asymptotic steady state was exponential. It is postulated that the decline in the steady-state concentration is due to autoinduction by carbamazepine of its own metabolism.

Pharmacokinetics of carbamazepine in normal man.

The bioavailability of commercial carbamazepine talbets with and without meals was compared to a propylene glycol solution respect to extent of absorption in 6 normal humans after a dose of 6 MG/KG. The presence of dose-dependent kinetics within a clinically sigificant range was also investigated. Serum and urine samples were assayed by gal-liquid chromatography (GLC). Carbamazepine is rapidly absorbed from the propylene glycol solution. Eight per cent of the dose was absorbed from the commercial tablet, resulting in therapeutic serum concentrations(30 to 6 mcg/ni). The data were consitent with disolution rate-limited absorption. Mean half-lives ranged from 31 to 35 hr. No dose-dependent kinetics were observed following administration of does of 3. 6. or 9 mg/kg. The fraction of dose abosrbed, the fraction excredted unchanged in urine, the time of maxium serum concentration, and absorption and elimination half-lives appear to be independent of dose. The time course of side effects could not be correlated with serum carbamazepine levels, suggesting that metabolities contributed to side effects.