Evidence is presented for the specific in vivo and in vitro inhibition of isovaleryl CoA dehydrogenation by hypoglycin A and its derivative, a-ketomethylenecyclopropylpropionic acid. a-MethylbutyrylCoA dehydrogenation was also impaired, but the degree of inhibition was much lower. Isobutyryl CoA dehydrogenation was not inhibited. 4-Pentenoic acid inhibited none of these reactions. It is concluded that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase, contrary to previous assumptions that it is dehydrogenated by green acyl CoA dehydrogenase. The present concept agrees with our previous findings in isovaleric acidemia, a genetic disorder in which a specific defect of isovaleryl CoA dehydrogenase was observed. It was also demonstrated that isovaleric acidemia can be induced in experimental animals by the administration of hypoglycin A. Furthermore, some symptoms of "the vomiting sickness of Jamaica" appear to be due to isovaleric acid accumulation secondary to the ingestion of hypoglycin A.Isovaleric acidemia is a genetic defect of leucine metabolism (1-4) in which isovaleric acid accumulates in blood in large amounts. Based on the biochemical findings in this hereditary disorder, we proposed that isovaleryl CoA is dehydrogenated by a specific enzyme, isovaleryl CoA dehydrogenase (1,3) and that this enzyme is deficient in patients with isovaleric acidemia ( Fig. 1). It was previously believed that isovaleryl CoA, butyryl CoA, and hexanoyl CoA were dehydrogenated by a single enzyme, acyl CoA dehydrogenase (5,6).It has subsequently been shown that oxidation of leucine is inhibited by hypoglycin A (7,8). In contrast, oxidation of valine and isoleucine are not significantly inhibited by this compound (8). However, the specific step in the pathway of leucine metabolism that is inhibited by hypoglycin A has not been precisely identified.Hypoglycin A is an unusual amino acid having the structure of a-aminomethylenecyclopropylpropionic acid (9). It has been extracted from unripe fruits of ackee grown in Jamaica and has been identified as the cause of the "vomiting sickness of Jamaica" (10). Extreme hypoglycemia (11) In vivo experimentsAmino acids were given by stomach tube 30 min after intramuscular injection of the inhibitor. The blood samples were drawn by heart puncture 150 min after injection of the inhibitor. Short chain fatty acid analyses were performed by gasliquid chromatography (GLC) (1).In vitro experiments Incubations were for 3 hr at 37°C. The tissues and the incubation medium were homogenized after acidification with 0.5 ml of 2 N H2SO4 and extracted with 20 vol of chloroform-methanol 2:1. The filtered extract was separated into two phases by mixing with 0.2 N NaOH (0.2 vol of the extract). Unlabeled carrier was added to the homogenate before extraction.Only the upper alkaline layer, which contains most of the water soluble salts of carboxylic acids and acidic conjugates, was analyzed. The steam-distillable fractions after acid hydrolysis were designated as total fr...

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Sinemet-controlled release (CR4) consisting of 50 mg carbidopa/200 mg levodopa was compared with Sinemet 25/100 in 24 Parkinson’s disease (PD) patients during a 16-week double-blind cross-over study. The mean age of the patients was 66.2 years, their mean duration of PD was 9.3 years. All of the patients had response fluctuations consisting mainly of the ‘wearing-off’ phenomenon. Some of the patients also experienced the ‘on-off’ phenomenon. All patients were evaluated using the unified Parkinson disease rating scale. The following significant differences were noted on Sinemet CR4. More patients noted a decrease in dyskinesias and response fluctuations; more patients experienced a decrease in stage when ‘on’; more patients were ‘on’ longer during the day, and more patients were globally improved. The mean number of doses per day were significantly less on Sinemet CR4 (mean 5.0, range 3–8) than on Sinemet 25/100 (mean 6.2, range 4–11 doses/day). The mean dose of levodopa in Sinemet CR4 was 1,186 ± 458 mg and the mean dose of carbidopa was 797 ± 115 mg. The mean dose of levodopa in Sinemet 25/100 was 873 ± 304 mg and the mean dose of carbidopa was 218 ± 76 mg. This study indicates that Sinemet CR4 is a useful addition for patients with response fluctuations.

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