Effect of hypocholesterolemic agents on central nervous system cholesterol biosynthesis III. Zuclomiphene in combination with AY9944 and triparanol.

Treatment of developing rats with a combination of hypocholesterolemic agents, zuclomiphene in combination with AY9944 and Triparanol, resulted in the accumulation of Δ⁷ sterols in the brain. Abnormal levels of desmosterol and zymosterol were also present in the brain tissue of the treated animals. Pre-treatment of the animals with the combination of drugs followed by intracerebral injection of [2-¹⁴C]mevalonic acid yielded comparable labeling of free sterols in treated and control animals. There was a significant increase in the labeled squalene oxidc-steryl ester fraction derived from the brains of animals receiving drug treatment, but a significant decrease in labeled cholesterol. Examination of the labeled free sterol fraction by means of silver nitrate-impregnated thin-layer chromatography and radioactivity-monitored gas-liquid chromatography indicated that sterol biosynthesis was impeded in the brains of the treated animals when compared to control animals. There was an increase in labeled sterols having a C-4 methyl group in test animals' brain in comparison to controls. [¹⁴C]zymosterol was also elevated in brain of drug treated animals.     

Fate of silvex following oral administration to humans

The fate of silvex [2-(2,4,5-trichlorophenoxy)propionic acid] was defined in seven men and in one woman following oral administration of 1 mg/kg. No adverse effects were observed. Samples of blood plasma, urine, and feces were collected at designated time intervals through 168 hr. Plasma samples were analyzed for silvex only, while samples of urine and feces were analyzed for silvex, silvex conjugate(s), 2,4,5-trichlorophenol, and 2,4,5-trichlorophenol conjugate(s). Apparent first-order kinetics described the biphasic clearance of silvex from plasma and excretion in urine. The half-life values for clearance of silvex from plasma were 4.0 +/- 1.9 and 16.5 +/- 7.3 hr for the initial and terminal phases, respectively. Peak plasma levels of silvex occurred within 2-4 hr after dosage. Within 24 hr after administration, 65% of the administered dose had been excreted in urine. Silvex was excreted in urine as silvex and silvex conjugate(s). The half-life values for excretion of silvex per se in urine were 5.0 +/- 1.8 and 25.9 +/- 6.3 hr for the two phases, respectively. Small amounts (3.2% or less) of silvex and/or silvex conjugate(s) were eliminated in feces. Recovery of silvex and its conjugate(s) in urine and feces through 168 hr ranged from 66.6 to 95.1% of the administered dose, with a mean value and standard deviation of 80.3 +/- 10.5%. In humans, silvex is readily absorbed after ingestion and subsequently readily excreted, predominantly via the urine.     

Fatty acid composition of myelin isolated from the brain of a patient with cellular deficiency of co-enzyme forms of vitamin B12

Myelin fractionation and subsequent lipid isolation have been carried out on a brain from a patient who suffered from a cellular deficiency of the adenosylcobalamin and methylcobalamin co-enzyme forms of vitamin B₁₂. Examination of the fatty acid composition of choline and ethanolamine glycerophospholipids indicated a relative enrichment of odd-chain fatty acids which were identified by gas-liquid chromatography-mass spectroscopy as C₁₅, C_15:1, C₁₇ and C_17:1. A mixture of methyl branched C₁₇ fatty acids was also identified. Odd-chain fatty acids accounted for 9.8% of the total fatty acid in the myelin choline phospholipid compared to control values of 1.2%. The affected brain myelin phospholipids had a lower unsaturated fatty acid content. Examination of the myelin sphingolipids, sphingomyelin, cerebroside and sulfatide, yielded abnormal fatty acid profiles. The sphingomyelin contained only small amounts of C_24:1 fatty acid. Both normal and hydroxy fatty acid containing cerebroside and sulfatide had reduced levels of C₂₄ fatty acid. Determination of the relative hydroxy and normal fatty acid content of the galactolipids indicated an abnormally high hydroxy fatty acid level. Abnormal fatty acid profiles of brain cerebral sphingolipids have not been previously described in cases of vitamin B₁₂ deficiency. Whether or not these alteration are characteristic will only be established by estimating sphingolipids in other such cases.