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This study investigated features of the value function for voice using subjects from four countries: Great Britain, Mexico, The Netherlands, and the United States. Across these four groups of subjects the shape of the value function was found to be similar, though differences in the estimated reference points were detected. Consistent with predictions derived from prospect theory (Kahneman & Tversky, 1979) the relationship between the value of voice and the magnitude of voice was found to be direct, monotonic, and nonlinear. The largest increment in value occurred when the magnitude of voice shifted from mute to some voice. Thereafter, increments in value tended to decline in magnitude suggesting diminishing marginal returns on the response measure of procedural fairness. An unexpected finding was that the final segment of the value function was convex indicating increasing marginal returns as the magnitude of voice shifted from its penultimate level to its maximum possible level. The study also investigated whether subjects' reported expectations of voice correspond to the value function reference point as theorized in the literature. Findings suggest that self-reported expectations of voice are higher than the estimated value function reference point.

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Relying on concepts found in prospect theory (D. Kahneman & A. Tversky, 1979), the value function of voice-based participation (i.e., the relationship between the amount of voice received and the value attached to that quantity) was examined. In keeping with tenets of prospect theory, the value function of voice exhibited a nonlinear pattern. Points were identified in which voice displayed significant improvements and diminishing marginal returns on response measures of process fairness, decision control, and outcome satisfaction. Task meaningfulness, a moderator of voice-based participation, did not change the general shape of the value function but did influence the intensity of participant reactions at low and high levels of voice. Voice influence, a second moderator of voice-based participation, had minimal impact on participant responses.

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A sensitive method was developed to determine permethrin extracted from phosphate buffer and cattle plasma by potassium cyanide catalyzed transesterification of this insecticide with refluxing ethanol and detection of the resulting ethyl esters by capillary gas chromatography with an electron capture detector. With a reflux time of 2 h and with 3-phenoxybenzyl 2-chlorobenzoate as an internal standard, linear calibration curves from buffer (5-250 ng) and plasma (5-100 ng) were obtained. Precision and accuracy of the method were < or = 15%. The limit of detection was approximately 2.5 ng/ml (cis) and 1 ng/ml (trans) from buffer. In cattle sprayed along the back at 2 mg/kg, the concentration of cis- and trans-permethrin in plasma was below the detection limit (5 ng/ml).

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In rats treated ip with N-ethylbenzamide (EB) at doses of 250-500 mg/kg, this amide was metabolized by hydrolysis to ethylamine and benzoic acid, the latter detected in the urine as hippuric acid. Proposed metabolic pathways were investigated by treatment of male Wistar rats with EB and N-ethyl-alpha-13C-benzamide followed by examination of urine samples by high-resolution NMR spectroscopy. Ethylamine was detected by 1H and 13C NMR techniques. Estimation of metabolite levels in 24-hr posttreatment urine by 1H NMR spectroscopy with an internal standard of 3-(trimethylsilyl)-1-propanesulfonic acid and correction for background levels of hippuric acid in control urine showed that the percentage of the dose excreted as hippuric acid was 52-76%. The corresponding range for the excretion of ethylamine (detected as an ethylammonium cation) was 27-41%. Signals for EB, benzamide, and benzoic acid were not above the background in urine of treated animals. A similar NMR study with unlabeled p-chloro-N-ethylbenzamide (p-Cl EB) resulted in the detection of p-chlorohippuric acid and ethylamine. Treatment of rats with N,N-diethylbenzamide and p-chloro-N,N-diethylbenzamide gave the same detectable metabolites in the urine as those found in experiments with EB and p-Cl EB. These observations could be rationalized with a metabolic pathway involving an initial oxidative mono-N-deethylation reaction followed by enzymatic hydrolysis of the secondary amides to ethylamine and benzoic acids and conjugation of the latter with glycine. N-Methylbenzamide was also found to be eliminated in the urine as hippuric acid.

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The O2 and NADPH-dependent metabolism of N,N-diethylbenzamide (DEB), a topically applied insect repellent, has been investigated in liver microsomal suspensions from phenobarbital-pretreated male Wistar rats. Incubation conditions for the enzymatic production of N-ethylbenzamide (EB) from DEB (0.2 mM) were studied by use of HPLC with UV detection. With the microsomal enzymes suspended in 10 mM phosphate buffer (pH 7.4) and the substrate delivered in acetone (10 microliter), the yield of EB was 81.9 +/- 2.9% in five replicated experiments with NADPH (2 mM) and MgCl2 (4 mM). Conversion of DEB to EB was strongly inhibited by carbon monoxide, a cytochrome P-450 inhibitor. A sample of N,N-diethyl-alpha,alpha'-13C-benzamide was synthesized and was used, in conjunction with high-resolution 13C NMR spectroscopy, to identify the metabolites arising from oxidation of the ethyl group. Using the distortionless enhancement by polarization transfer pulse sequences and a substrate concentration of 0.4 mM, 13C-labeled acetaldehyde and glycolaldehyde, both detected as the hydrates, were found in the microsomal incubates. N-Ethyl-N-(alpha-hydroxyethyl)benzamide, the presumed metabolic progenitor of acetaldehyde, was not detected in these metabolic experiments. A pathway is proposed to account for the metabolic generation of glycolaldehyde by hydroxylation of both carbons of the N-ethyl group.

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A series of new 5-(1-hydroxy-2-haloethyl)-2'-deoxyuridines (3, 6, 8) were synthesized in 60-70% yields by addition of HOX (X = Br, Cl, I) to the vinyl substituent of the respective 5-vinyl-2'-deoxyuridines (2, 5, 7). Treatment of 3a,b with methanolic sulfuric acid afforded the corresponding 5-(1-methoxy-2-haloethyl)-2'-(deoxyuridines (4a,b). The 5-(1-hydroxy-2-chloroethyl) (3b), 5-(1-methoxy-2-bromoethyl) (4a), 5-(1-hydroxy-2-bromo-2-(ethoxycarbonyl)ethyl) (6a), and 5-(1-hydroxy-2-iodo-2-(ethoxycarbonyl)ethyl) (6b) derivatives exhibited in vitro antiviral activity (ID50 = 0.1-1 microgram/mL range) against herpes simplex virus type 1 (HSV-1). 5-(1-Hydroxy-2-bromo-2-(ethoxycarbonyl)-ethyl)-2'-deoxyuridine (6a) was the most active cytotoxic agent in the in vitro L1210 screen exhibiting an ED50 of 11 micrograms/mL relative to melphalan (ED50 = 0.15 micrograms/mL).

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Two experiments were conducted to test the antiepileptic properties of CL 218-872, a triazolopyridizine reported to have anxiolytic and anticonvulsant effects without accompanying sedative and ataxic effects. In Experiment 1 pretreatment with CL 218-872, a recently synthesized and potent triazolopyridizine, reduced kainic acid-induced convulsions and subsequent neuropathology in rats given ip doses of 25 mg/kg or greater. CL 218-872 at doses of 50 mg/kg or greater was more effective than a high dose of diazepam (20 mg/kg) in blocking status epilepticus-like convulsions and the associated widespread neuropathological sequelae. Moreover, diazepam pretreatment was associated with a higher mortality rate than CL 218-872. In Experiment 2 the efficacy of intervention with 20 mg/kg diazepam was compared with that of 50 mg/kg CL 218-872 in suppressing ongoing convulsions and reducing subsequent brain damage following a convulsant dose of kainic acid. Although CL 218-872 and diazepam were equally effective behaviorally (i.e., in suppressing kainic acid-induced convulsions), CL 218-872 was superior in its ability to reduce subsequent neuropathology, especially in the hippocampus and neocortex. Because kainic acid has been suggested as a model for human status epilepticus, CL 218-872 may be a potentially therapeutic treatment for this disorder.

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1. The 4-fluoro analogue of the monoamine oxidase-inhibiting antidepressant tranylcypromine was compared to the parent drug with regard to the following: inhibition of monoamine oxidases A and B in vitro and ex vivo; levels of both drugs in brain, liver, and blood after injection of equimolar doses; and effects on brain levels of the amines 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine. 2. 4-Fluorotranylcypromine was found to be 10 times more potent than tranylcypromine at inhibiting monoamine oxidases A and B in vitro in rat brain homogenates. 3. After administration (0.1 mmol/kg, ip), 4-fluorotranylcypromine attained higher brain and liver levels and provided greater availability than did tranylcypromine after the injection of an equimolar amount. 4. At the dose employed, the ex vivo monoamine oxidases A and B inhibitory profiles in brain and liver over a 24-hr period following tranylcypromine and 4-fluorotranylcypromine treatment were not different from each other. 5. Although the drugs had similar effects on inhibition of brain MAO ex vivo, they differed from one another at several time intervals in the increases in concentrations of 2-phenylethylamine, tryptamine, norepinephrine, dopamine, and 5-hydroxytryptamine produced in brain. 6. In conclusion, fluorination of tranylcypromine in the 4 position of the phenyl ring produced a drug which was more potent than the parent drug at inhibiting MAO in vitro and attained higher levels in brain than did tranylcypromine itself after intraperitoneal injection of equimolar amounts of the drugs. 4-Fluorotranylcypromine increased the concentrations of trace amines, catecholamines, and 5-hydroxytryptamine in brain at most time intervals following intraperitoneal injection, and at some time intervals there were differences from tranylcypromine with regard to the amine concentrations produced.

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Benzhydryl 2 beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam- 3 alpha-carboxylate 1,1-dioxide was prepared by heating benzhydryl 2 beta-(azidomethyl)-2 alpha-methylpenam-3 alpha-carboxylate 1,1-dioxide with (trimethylsilyl)acetylene. The ester group was removed by hydrogenolysis to give sodium 2 beta-[(1,2,3-triazol-1-yl)methyl]-2 alpha-methylpenam-3 alpha-carboxylate 1,1-dioxide (3i, YTR-830), which was found to be a potent inhibitor of various bacterial beta-lactamases. A series of related compounds was prepared in a similar way, and all of these compounds show excellent beta-lactamase inhibitory properties.

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The formation of p-hydroxytranylcypromine from intraperitoneally injected tranylcypromine was confirmed using two types of experiments. In the first, tranylcypromine levels were shown to be increased in brains of rats pretreated with agents known to be inhibitors of ring hydroxylation compared to rats pretreated with physiological saline. For the second set of experiments, p-hydroxytranylcypromine was identified in brain and urine (following intraperitoneal injection) by derivatizing with perfluoroacylating reagents and analyzing by electron-capture gas chromatography and by combined gas chromatography-mass spectrometry. In experiments in vitro, p-hydroxytranylcypromine was demonstrated to inhibit monoamine oxidase, although it was weaker than TCP in this regard and was a much stronger inhibitor of MAO-A than of MAO-B.

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Brain levels of 5-hydroxytryptamine (5-HT), tryptamine (T), 2-phenylethylamine (PEA) and monoamine oxidase activity at 5, 15, 30, 60, 120 and 240 min were determined in male Sprague-Dawley rats after intraperitoneal injection of the "pro-drug" N-2-cyanoethyltranylcypromine (CE-TCP, dose 0.1 mMole/kg). Analyses of 5-HT, T and PEA were performed on an electron-capture gas chromatograph with a capillary column. Activity of MAO-A and MAO-B was measured using a radiochemical method. Results indicate substantial inhibition of MAO in rat brain after intraperitoneal administration of CE-TCP, leading to elevated levels of 5-HT, T and PEA as early as 5 min after drug administration. Increases in brain levels of the trace amines T and PEA were much greater (approximately 40 and 100 times control levels, respectively) than with 5-HT (approximately 1.8 times control level) 240 min after administration of CE-TCP.

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