Environmental temperature and choline requirements in rats. II. Choline and methionine requirements for lipotropic activity

Young rats were fed choline-deficient diets and maintained at different environmental temperatures. The hepatic lipid level remained normal in rats at 2 degrees when 25 mg of choline per 100 g of food was fed; 50 mg of choline per 100 g food was required at 21 degrees and 100 mg of choline per 100 g food at 33 degrees to prevent excessive lipid accumulation. These values were equivalent to a mean daily intake per rat of 3 mg of choline at 2 degrees, 5.5 mg at 21 degrees, and 7 mg at 33 degrees respectively. When the growth rate was slower owing to a slight inadequacy of histidine in the basal choline-deficient diet, normal hepatic lipid was maintained by supplements of 50 mg of choline per 100 g food at 21 degrees and 33 degrees. Increasing the methionine content of the diet two- or three-fold from a basal value of 340 mg per 100 g food was as effective as 200 mg of choline per 100 g of food in lowering hepatic lipids at 2 degrees, 21 degrees, and 33 degrees.     

Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency

A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC₅₀ values 0.28, 0.28, 0.25, 0.33, 0.76 µM and 8.26, 4.4, 1.78, 3.95, and 4.06 µM, respectively. Further toxicological analysis established the Median lethal dose (LD₅₀), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.     

Improved potency and reduced toxicity of the antifungal peptoid AEC5 through submonomer modification

As proteolytically stable peptidomimetics, peptoids could serve as antifungal agents to supplement a therapeutic field wrought with toxicity issues. We report the improvement of an antifungal peptoid, AEC5, through an iterative structure-activity relationship study. A sarcosine scan was used to first identify the most pharmacophorically important peptoid building blocks of AEC5, followed by sequential optimization of each building block. The optimized antifungal peptoid from this study, β-5, has improved potency towards Cryptococcus neoformans and decreased toxicity towards mammalian cells. For example, the selectivity ratio for C. neoformans over mammalian fibroblasts was improved from 8 for AEC5 to 37 for β-5.     

The effects of different inactivating agents on the potency, toxicity and stability of pertussis vaccine

The effect of heat (56 degrees C for 10 min), formaldehyde (0.1% at 37 degrees for 24h), glutaraldehyde (0.05% at room temperature for 10 min), thimerosal (0.02% at 37 degrees C for 24h), acetone-I (three treatments at room temperature) and acetone-II (three treatments at room temperature and fourth treatment at 37 degrees C), when used as inactivating agents in the preparation of pertussis suspension, was studied with regard to potency, toxicity and stability. Five batches each of Bordetella pertussis strains 134 and 509 were used for the study. The thimerosal inactivated pertussis (TIP) preparation was 1.5-2 times more potent than the heat inactivated pertussis (HIP) preparation. The potency values of the formaldehyde inactivated pertussis (TIP) and glutaraldehyde inactivated pertussis (GIP) preparations were similar to those of the HIP preparation, while the potencies of the acetone-I treated pertussis (A(I)TP) and acetone-II treated pertussis (A(II)TP) preparations were about half those of the HIP preparation. The FIP preparation was the least toxic showing maximum weight gain in the mouse weight-gain test (MGWT), while the TIP preparation did not pass the MWGT. The weight gains shown the GIP, A(I)TP and A(II)TP preparations were greater than those shown by the HIP preparation. The potency of pertussis component in the adsorbed diphtheria-pertussis-tetanus (DPT) vaccine was stable at 4-8 degrees C and 25 degrees C for three months for all types of pertussis vaccine. There was about 54-65% loss in the potency of the samples after three months at 35 degrees C. The inactivating agents used in the manufacture of pertussis preparations had no effect on the stability of the vaccine.     

Oral toxicity of Photorhabdus toxins against thrips species

The oral toxicity of excretion products of several Photorhabdus and Xenorhabdus strains was tested on two thrips species: Frankliniella occidentalis and Thrips tabaci. Out of 46 Photorhabdus isolates and six Xenorhabdus isolates only six North American P. temperata isolates were toxic to the thrips species. After 7 days of drinking from P. temperata supernatant a mortality of 90% could be reached. Thrips were also killed after sucking from leaves covered with the toxins. Toxins have a negative effect on thrips fecundity. Possibilities of using P. temperata in the control of thrips will be discussed.     

Mutagenicity and toxicity of carcinogenic and other hydrazine derivatives: correlation between toxic potency in animals and toxic potency in Salmonella typhimurium TA1538.

Eleven hydrazine derivatives and an aromatic amine were examined for mutagenicity and toxicity to Salmonella typhimurium. Phenylhydrazine, 2-nitrophenylhydrazine, 4-nitrophenylhydrazine, 2,4-dinitrophenylhydrazine, p-tolylhydrazine, and 4-nitroaniline were found to be frameshift mutagens (strain TA1538). Benzylhydrazine, m-hydroxybenzylhydrazine, p-hydrazinobenzoic acid, L-tyrosine hydrazide, p-aminobenzoyl hydrazide, and isoniazid were not mutagenic. All chemicals were toxic to strain TA1538. A qualitative correlation was found between the pK of the compounds and their mutagenicity. Relative toxicities of hydrazines to bacteria were found to be closely correlated with the relative toxicities of the same compounds in animals. Described herein is a methodology for the rapid prescreening of chemicals which may be used as drugs for those with a high benefit/risk ratio.