New antihistaminic theophylline or theobromine derivatives.

A series of 3,4-dihydro-1,3-dimethyl-7-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones and 3,7-dihydro-3,7-dimethyl-1-[3-(4-substituted-piperazin-1-yl)- substituted-alkyl]-1H-purine-2,6-diones was synthesized and evaluated for antihistaminic activity. Some of them displayed good inhibition of both histamine-induced bronchospasm in the anesthetized guinea pig at 10 micrograms/kg by the intravenous route and of passive cutaneous anaphylaxis in the rat at 10 mg/kg by the oral route. Comparison of the two most active compounds revealed a higher antihistaminic activity with the compounds containing a (phenylthio)propyl group (1 and 2) as compared with that containing a phenoxy group. Compound 2 [RS-49014, 3,4-dihydro-1,3-dimethyl-7-[3-[4-[3-(phenylthio)propyl]piperazin-1 -yl]- 2-hydroxypropyl]-1H-purine-2,6-dione] was selected for clinical trials on the basis of a comparative pharmacological study with chlorpheniramine, ketotifen, promethazine, and theophylline.

Concentration-dependent behavioral changes in mice following short-term inhalation exposure to various industrial solvents.

Mice were exposed during a 4-hr period to various concentrations of 13 aliphatic or aromatic solvents which affect primarily the central nervous system (CNS). The test compounds were benzyl chloride, butyl alcohol, chlorobenzene, cyclohexanone, 1,2-dichloroethylene, diisobutyl ketone, isopropyl acetate, methyl ethyl ketone, styrene, tetrachloroethylene, 1,1,1-trichloroethane, toluene, and ortho-xylene. After exposure, measurements were made to see whether these neurotoxicants would decrease the immobility developed in a "behavioral despair" swimming test. Each chemical was shown to reduce the total duration of immobility measured over a 3-min period in a concentration-related manner. The systematic determination of the atmospheric concentrations responsible for a 50% decrease in immobility (ID50) permitted classification of the solvents in terms of their relative potencies. The possibility of using such experimental data as tentative guidelines for setting safe levels of work exposure to the neurotoxicants was suggested, considering the existence of quantitative relationships between the ID50 values and the current occupational standards.