Pharmacokinetics and anesthetic potency of a thiopental isomer.

In developing a high-performance liquid chromatographic assay for thiopental [5-ethyl-5-(1-methylbutyl)-2-thiobarbituric acid], a thiopental isomer [5-ethyl-5-(1-ethylpropyl)-2-thiobarbituric acid] was found. This isomer occurs (6-7%) in supposedly pure thiopental and in the commercially available thiopental sodium administered to patients for induction of anesthesia. A similar type of isomer also occurs in pentobarbital, the oxybarbiturate analogue of thiopental. Because the disposition and anesthetic potency of the isomer is unknown, its pharmacokinetic properties were determined in humans and its anesthetic potency in mice. In five surgical patients, the terminal elimination half-life, clearance, and volume of distribution at steady state of the isomer were not statistically different from those of thiopental. In mice, the isomer proved to be as effective as thiopental for induction of anesthesia. The LD50 and sleep time at one-half the LD50 did not statistically differ between the two compounds in mice. The close structural similarity of thiopental and the isomer results in similar pharmacokinetic and anesthetic properties. It does not appear critical that the isomer be separated from thiopental in subsequent pharmacological research.

The role of metabolism and protein binding in thiopental anesthesia.

The role of metabolism, relative to redistribution, in the termination of anesthesia was examined in patients receiving a single bolus iv injection of thiopental. Additionally, it was determined if nonlinear protein binding occurs immediately after the bolus iv injection of thiopental, possibly enhancing thiopental effect. Thiopental pharmacokinetics and protein binding were determined in 12 surgical patients with normal hepatic function. Using the pharmacokinetic equations listed in the appendix, plasma concentration over time data were used to quantitate the contribution of metabolism to the early decline of thiopental plasma concentrations after a single iv bolus administration. The fraction of thiopental loss from the central compartment due to metabolism was calculated to be 0.14 +/- 0.06 (mean +/- SD) at 1 min and 0.18 +/) 0.04 at 15 min. These data confirm that metabolism is far less important than distribution in the initial decline of blood and brain concentrations of thiopental, and, therefore, termination of thiopental anesthetic effect. The protein binding of thiopental from 0.5 to 15 min was found to be linear over a concentration range of 93 +/- 60 micrograms/ml to 6.9 +/- 0.62 micrograms/ml. Thus, concentration-dependent or nonlinear protein binding of thiopental after a single iv bolus administration could not be demonstrated and does not enhance thiopental anesthetic effect.

Ocular pathology, tear production, and tear lysozyme in rheumatoid arthritis.

Ninety-seven rheumatoid arthritis (RA) patients receiving investigational nonsteroidal antiinflammatory drugs were found to have a 31.9% prevalence and 24.5%/year incidence of ocular pathology. None of these ocular lesions were definitely related to their RA or drug therapy. Twenty-one of these patients were studied further for evidence of keratoconjunctivitis sicca. None of these patients had abnormal rose bengal staining, but over half had decreased tear production on both stimulated and unstimulated Schirmer's testing and many patients had high tear lysozyme levels. Increased tear lysozyme levels and decreased Schirmer's tests correlated with a modified rheumatoid activity index.

Decreased protein binding and thiopental kinetics.

Thiopental kinetics and protein binding were determined in seven surgical patients with chronic renal failure and a thiopental free fraction of 28.0 +/- 6.5% (SD) and in seven age- and weight-matched normal surgical patients with a thiopental free fraction of 15.7 +/- 2.4%. Thiopental clearance, based upon total plasma concentrations, rose from 3.2 +/- 0.6 ml/kg/min in the normal group to 4.5 +/- 1.1 ml/kg/min in the chronic renal failure group. Volume of distribution at steady state, also based on total drug concentrations, rose from 1.9 +/- 0.5 l/kg in the normal group to 3.0 +/- 1.0 l/kg in the chronic renal failure group. These changes in clearance and volume of distribution at steady state are secondary to changes in free drug distribution and elimination. When kinetics were calculated from free drug concentrations, the intrinsic clearance, unbound volume of distribution at steady state, and free fraction in tissues in the normal and renal failure groups did not differ substantially. These data suggest that the kinetic changes based on total drug concentrations are secondary to changes in free fraction in plasma. In chronic renal failure patients, the underlying rate and extent of thiopental distribution and elimination are much the same as in normal patients.

Transscleral ocular siderosis.

Intraocular migration of iron from iron foreign bodies in an extraocular or intrascleral location was studied in rabbits. Focal changes occurred in the choroid and retina beneath the foreign bodies. Significant amounts of iron diffused through the sclera into the globes. This iron was typically deposited in the epithelium of the ciliary processes and in the tissues at the choroid-scleral junction in the posterior pole.

Ultrasonic enhancement of nitrogen mustard cytotoxicity in mouse leukemia.

Mouse leukemia L1210 cells were exposed to continuous wave 2 MHz, 10 W/cm(2) ultrasound for 10 minutes while suspended in nitrogen mustard solution in vitro. Mice subsequently inoculated with these cells had longer survival times than control animals that received cells exposed to the drug but not ultrasound. Without the drug, ultrasound did not alter survival time. Tracer studies revealed increased cellular accumulation of drug under the influence of ultrasound.