Clinical pharmacology of bruceantin by radioimmunoassay

During the phase I clinical trial of a new antitumor agent, bruceantin, the pharmacology was studied in 18 cancer patients. The drug was infused intravenously (IV) for 3 h at doses ranging from 1 to 3.6 mg/m2 per day for 5 days. The plasma drug disappearance curves were biphasic, with a fast initial half-life of less than 15 min. The second half-life (t1/2 beta) varied from 0.7 to 38 h among different patients and was not dose-related. The difference between the t1/2 beta on day 1 and that on day 5 was not significant. In patients with normal liver function, the mean plasma concentration at the end of infusion was 22 ng/ml, and the value of the area under the concentration X time curve (AUC) was 111 (ng/ml)h. In contrast, in patients with abnormal liver function the corresponding values were 115 ng/ml and 830 (ng/ml)h, respectively. In addition, these patients had a slower elimination half-life of 10.9 h and a decreased total clearance of 157 ml/min/m2, as compared with 2.6 h and 671 ml/min/m2, respectively, for the normal group. All these differences were statistically significant. Patients with abnormal liver function developed more severe toxicity, including fever, severe nausea, vomiting, and hypotension. Two patients with severe hepatic dysfunction received a reduced dose and developed no toxicity. These results demonstrated the importance of the effects of liver dysfunction on drug disposition and showed that the dosage should be reduced in patients with hepatic dysfunction.     

Preparation of N-cyclohexylbenzothiazole-2-sulphenamide by oxidative condensation

It has been shown that in the preparation of N-cyclohexylbenzothiazole-2-sulphenamide by the reaction of 2-mercaptobenzothiazole with cyclohexylamine in the presence of sodium hypochlorite, N-cyclohexyl-benzothiazole-2-sulphonamide, sodium benzothiazole-2-sulphonate, benzothiazole-2-sulphonyl chloride, 2,2′-dithiobisbenzothiazole, and probably sodium benzothiazole-2-sulphinate can be formed as by-products, in amounts depending on pH, temperature and amount of amine used. Mechanisms are suggested for the reactions involved.     

Biochemical activity of centipedegrass against fall armyworm larvae

Centipedegrass,Eremochloa ophiuroides (Munro) Hack, severely inhibits growth of the fall armyworm larva,Spodoptera frugiperda (J.E. Smith). Fresh centipedegrass extracts and extract fractions were deposited on Celufil, incorporated into meridic-based diets and bioassayed against neonate larvae of the fall armyworm in the laboratory. The methanol extract (F₁) caused the greatest reduction in larval weight. When F₁, was partitioned between méthylene chloride and water, the activity was transferred to the water-soluble fraction (F₅), which, when further fractionated using preparative C-18 reverse-phase chromatography, yielded active F₇ and F₈ fractions. Gas chromatograph-mass spectrometry and high-pressure liquid chromatography (HPLC) showed F₇ to be 95% caffeoylquinic acids with chlorogenic acid as the major constituent. HPLC analysis of F₈ revealed maysin [2-O- -L-rhamnosyl-6-C-(6-deoxy-Xylo-hexos-4-ulosyl)luteolin] and other luteolin derivatives. Chlorogenic acid and other caffeoylquinic acids, maysin, and other luteolin derivatives are the major factors responsible for the antibiotic resistance of centipedegrass to larvae of the fall armyworm.     

Native state kinetic stabilization as a strategy to ameliorate protein misfolding diseases: a focus on the transthyretin amyloidoses

Small molecule-mediated protein stabilization inside or outside of the cell is a promising strategy to treat protein misfolding/misassembly diseases. Herein we focus on the transthyretin (TTR) amyloidoses and demonstrate that preferential ligand binding to and stabilization of the native state over the dissociative transition state raises the kinetic barrier of dissociation (rate-limiting for amyloidogenesis), slowing and in many cases preventing TTR amyloid fibril formation. Since T119M-TTR subunit incorporation into tetramers otherwise composed of disease-associated subunits also imparts kinetic stability on the tetramer and ameliorates amyloidosis in humans, it is likely that small molecule-mediated native state kinetic stabilization will also alleviate TTR amyloidoses.     

Cerivastatin

Cerivastatin is a synthetic HMG-CoA reductase inhibitor with high liver selectivity, which lowers plasma cholesterol levels by inhibiting endogenous cholesterol synthesis. In vitro, the affinity of cerivastatin for HMG-CoA reductase was higher than that of lovastatin, simvastatin and pravastatin. This higher enzyme affinity was reflected in vivo, with a lower ED50 (dose causing 50% inhibition) for cerivastatin in rats and beagle dogs compared with lovastatin. Cerivastatin 0.2 mg/day significantly reduced low density lipoprotein (LDL)-cholesterol, total cholesterol and triglyceride levels, and increased high density lipoprotein (HDL)-cholesterol levels, in patients with type IIa hypercholesterolaemia. Available data indicate that cerivastatin has a tolerability profile similar to that of other HMG-CoA reductase inhibitors. No drug interactions were observed when cerivastatin was coadministered with digoxin, warfarin, cimetidine or the antacid magnesium/aluminium hydroxide.     

A Liquid Silazane Precursor To Silicon Nitride

The reaction of dichlorosilane, H₂SiCl₂, with gaseous NH₃ in dichloromethane or diethyl ether solution results in the formation of a silazane oil containing silicon, hydrogen, and nitrogen in good yield. This ammonolysis product can be pyrolyzed in an N₂ atmosphere (temperature to 1150°C) to give α-Si₃N₄ in ∼70% yield. The ceramic product formed has a relatively porous, fine-grained microstructure with some cracks and blisters.