Saeed A. Jortani

Thioridazine enantiomers in human tissues

Enantiomers of thioridazine (TRZ) were determined in postmortem tissues obtained from a patient on chronic TRZ therapy by sequential achiral and chiral high pressure liquid chromatography. Tissue concentrations of (+)-TRZ found in liver, brain, bile and blood were: 6.46, 0.40, 0.48 and 0.07 mg/l or mg/kg, respectively. Concentrations of (-)-TRZ in liver, brain, bile and blood were: 12.2, 0.81, 1.07 and 0.20 mg/l or mg/kg, respectively. These data demonstrate the stereoselective disposition of TRZ in human tissues.

NMDA antagonists: Lack of antipunishment effect in squirrel monkeys☆

Effects of the noncompetitive N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP) and competitive antagonists 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP) and 2-amino-4,5-(1,2-cyclohexyl)-7-phosphonoheptanoic acid (NPC 12626) were studied in 6 squirrel monkeys trained under a multiple schedule of unpunished and punished lever pressing. PCP (0.03-0.3 mg/kg, IM) failed to produce increases in punished responding, even at doses that produced extreme response-rate decreases in nonpunishment components. Similarly, CPP (1-17 mg/kg) and NPC 12626 (3-30 mg/kg) did not produce increases in punished responding at any dose tested. Repeated administration of NPC 12626 (17 mg/kg) for 4 consecutive days did not result in increased rates of punished responding. The benzodiazepine anxiolytic midazolam (0.3 mg/kg) and, to a lesser extent, the barbiturate pentobarbital (5.6 mg/kg), produced increases in punished responding in the same subjects at doses that did not markedly affect unpunished responding. Coadministration of PCP (0.03 mg/kg) with doses of midazolam ranging from 0.03-3 mg/kg did not produce changes in the midazolam dose-response curve for either unpunished or punished responding. These results fail to support findings in rats that NMDA antagonists produce antipunishment effects similar to those of benzodiazepine anxiolytics.

Discriminative stimulus effects of esteratic local anesthetics in squirrel monkeys

A number of esteratic local anesthetics serve as positive reinforcers and produce cocaine-like discriminative stimulus effects in animals. It has been suggested that the affinity of these compounds for a site on the dopamine transporter, and not their local anesthetic actions, is responsible for these abuse-related behavioral effects. In the present study, three local anesthetics previously shown to be self-administered in animals were examined in squirrel monkeys trained to discriminate cocaine (0.3 mg/kg) from saline in a two-lever, food-reinforced procedure. Dimethocaine (0.1-3.0 mg/kg) fully and dose-dependently substituted for cocaine. Doses of dimethocaine (1.7 mg/kg) and cocaine (0.3 mg/kg) which produced full (> 80%) substitution for cocaine were administered in combination with the dopamine D1 receptor antagonist SCH 39166 ((-)-trans-6,7,7a,8,9,13b-hexahydro-3-chloro-2-hydroxy-N-methyl-5H -benzo [d]naphtho-(2,1-b)azepine) and the dopamine D2 receptor antagonist raclopride (both at 0.003-0.03 mg/kg). SCH 39166 fully blocked the cocaine-like discriminative stimulus effects of dimethocaine and cocaine, but raclopride produced only partial antagonism of cocaine-lever selection. In addition, there was some evidence that raclopride blocked cocaine-lever responding produced by a lower dose of dimethocaine. In substitution studies, neither procaine (1-10 mg/kg) nor chloroprocaine (1-30 mg/kg) produced cocaine-like effects. These results support a role for dopamine in the behavioral effects of some local anesthetics.

Determination of serum acetaminophen in emergency toxicology : evaluation of newer methods : Abbott TDx and second derivative ultraviolet spectrophotometry

Newer methods for the determination of serum acetaminophen in emergency toxicology, the Abbott TDx immunoassay and second derivative ultraviolet spectrophotometry, were evaluated and compared to a high pressure liquid chromatographic procedure. The Abbott TDx immunoassay within-run and day to day precision yielded coefficients of variance below 2.7% and 7.2% respectively: Abbott TDx immunoassay results correlated well with those of high pressure liquid chromatographic in patient serums 15.0 to 333 mg/L acetaminophen; r2 = 0.954, n = 40. The Abbott TDx immunoassay assay was rapid, easy to perform, free of interferences from other drugs and exhibited no carryover from previous samples. The within run precision of the second derivative ultraviolet spectrophotometry method yielded coefficients of variance of less than 7.0%. Second derivative ultraviolet spectrophotometry results demonstrated good correlation with high pressure liquid chromatographic results in patient sera; r2 = 0.923, n = 40; however, performance deteriorated below 50.0 mg/L acetaminophen. Spectral interferences were noted at high concentrations of some drugs.

Systemic magnesium chloride administration fails to produce phencyclidine-like discriminative stimulus effects in rats

Systemic administration of magnesium chloride was evaluated for phencyclidine (PCP)-like discriminative stimulus effects. Six rats were trained to discriminate PCP (1.25 mg/kg, i.p.) from saline under a two-lever fixed-ratio 32 schedule of food reinforcement. Magnesium chloride (10-80 mg/kg, i.p.) failed to substitute for PCP, with no dose producing greater than an average of 21% PCP-lever responding. At doses greater than 40 mg/kg, magnesium chloride decreased rates of responding, providing evidence that it was evaluated over a behaviorally-relevant dose range. The results provide further evidence for differences in the behavioral effects of drugs which antagonize N-methyl-D-aspartate receptor-mediated neurotransmission by different mechanisms.