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Earlier studies indicated that the prevalence of congenital anomalies is greater in infants of epileptic mothers treated with anticonvulsants than in infants of mothers without epilepsy. We carried out a study of women in the General Practice Research Database who delivered liveborn infants between January 1988 and March 1993 and who were exposed to an anticonvulsant drug during the first trimester of pregnancy, and women with epilepsy not treated with anticonvulsants during pregnancy. We matched two nonexposed women without epilepsy to each exposed woman for age at delivery, date of baby's birth, and general practice. Two hundred ninety-seven women treated for epilepsy had 10 liveborn infants with major anomalies (3.4%) compared with 6 of the 594 nonexposed women (1.0%, RR = 3.3, 95% CI 1.2-9.2). We conclude that the infants of women with epilepsy who are treated with an anticonvulsant during the first trimester of pregnancy have an increased risk of major congenital anomalies.

Various basic esters of nitrogen (2) and carbocyclic (3 and 4) analogs of cannabinoids were synthesized using dicyclohexylcarbodiimide in methylene chloride. The compounds in the three series werw studied in selected pharmacological tests in mice, rats, dogs, and cats. It was shown that making the basic ester from the phenol retains biological activity and can lead to a greater selectivity of action, particularly the antinociceptive activity. The most interesting esters were 5, 6, 10, and 14 in the nitrogen analogs series and 19 and 20 in the carbocyclic series. Compound 5 was more potent than codeine in the writhing, hot-plate, and tail-flick tests and is at present undergoing clinical testing. Compound 20 was very potent in the mouse audiogenic seizure test and is of interest as an anticovulsant agent.

Sulfur analogs of cannabinoids corresponding to DMHP (1) were prepared utilizing the Pechmann condensation between the appropriate keto ester and (5-(1,2-dimethylheptyl)resorcinol, followed by Grignard reaction. Compounds of various structural types (2-6), which had different ring size and position of the sulfur atom substituted in the alicyclic ring, were found to be active CNS agents in pharmacological tests in mice, rats, and dogs. They showed profiles qualitatively similar to those of the nitrogen and carbocyclic analogs. Basic esters of the most interesting parent phenols 2 and 4 were also prepared and tested.

Aus den cyclischen β-Ketoestern (I), z.B. von S-haltigen Ringsystemen, und dem Resorcin (II) entstehen nach Pechmann die Kondensate (III), die uber eine Grignardreaktion zu den Diolen (IV) die Cyclen (V) sowie ihre Ester (VI) geben.