Intermediate Administration Research Articles

Kynurenine formamidase inhibition as a possible mechanism for certain teratogenic effects of organophosphorus and methylcarbamate insecticides in chicken embryos

At least two types of developmental anomalies are induced in chicken embryos by certain organophosphorus (OP) and methylcarbamate (MC) insecticides. One of them (Type I) leads to micromelia and abnormal feathering and another (Type II) involves arthrogryposis, wry neck and rumplessness. Type I but not type II teratogenesis is associated with a lowered embryo NAD level and is alleviated on restoring the NAD level by administration of intermediates in the tryptophan to NAD biosynthetic pathway. These and other observations with chicken embryos suggest but do not in themselves establish that impairment in the conversion of tryptophan to NAD, possibly by inhibition of kynurenine formamidase, leads to type I teratogenesis. This hypothesis is supported by finding that mouse liver kynurenine formamidase is extremely sensitive to in vivo inhibition by those OP and MC compounds which are the most potent NAD lowering agents and teratogens in the chicken embryo, i.e. crotonamide phosphates and pyrimidyl phosphorothionates such as dicrotophos and diazinon and MC compounds such as carbaryl. Teratological or other toxicological manifestations of kynurenine formamidase inhibition are probably restricted to species and developmental stages where reduced enzyme activity significantly impairs maintenance of normal levels of NAD or other essential biochemicals derived from kynurenine.

Effectiveness of intermediate‐term use of secobarbital

Secobarbital, 100 mg, was evaluated in two separate sleep laboratory drug evaluation studies, each with 4 insomniac patients. In both studies, the effect of secobarbital in inducing and maintaining sleep was evaluated, as well as the effects of the drug on sleep stages. Statistical analysis demonstrated that the results of the two studies could be combined. With short-term drug administration of secobarbital (up to 3 nights), there was an improvement in both sleep induction and sleep maintenance. Total wake time was decreased 43% below baseline and was consistently decreased in each third of the night. With intermediate-term drug administration (2 wk), total wake time was decreased only 14% (not statistically significant). Following drug withdrawal, the degree of sleep difficulty returned to baseline levels. The results indicate that secobarbital 100 mg is effective for short-term use but loses much of its effectiveness with intermediate use and suggest that the drug is of limited value for insomniac patients who require nightly medication beyond a period of 1 wk. With short-term administration, secobarbital induced a slight decrease in rapid eye movement (REM) and slow-wave sleep and a significant increase in stage 2 sleep. With intermediate administration, sleep stage values were similar to baseline levels. Following withdrawal, there was only a minimal increase in REM sleep above baseline levels, a significant increase in stage 3 sleep, and a significant decrease in stage 2 sleep. The rebound increase in stage 3 sleep is similar to that reported following withdrawal of pentobarbital.

Metabolism of sinapic acid and related compounds in the rat.

1. Administration of sinapic acid to the rat results in the excretion of 3-hydroxy-5-methoxyphenylpropionic acid, dihydrosinapic acid, 3-hydroxy-5-methoxycinnamic acid and unchanged sinapic acid in the urine. The sinapic acid conjugate sinalbin is also catabolized to free sinapic acid and 3-hydroxy-5-methoxyphenylpropionic acid in the rat. 2. 3,4,5-Trimethoxycinnamic acid is metabolized in part to sinapic acid and 3-hydroxy-5-methoxyphenylpropionic acid. 3. 3,5-Dimethoxycinnamic acid is metabolized to 3-hydroxy-5-methoxycinnamic acid and 3-hydroxy-5-methoxyphenylpropionic acid. 4. The metabolic interrelationships of these compounds were studied by the administration of intermediates and a metabolic pathway is proposed. 5. The metabolism of the corresponding benzoic acids was studied, but these compounds and their metabolites were shown not to be intermediates or products of the metabolism of the related cinnamic acids.