An improved method for toxicological profiling of chemical substances.

Toxicity profiling is an integral part of the drug discovery pipeline. The 3Rs principle-Replacement, Reduction, and Refinement, is considered a golden rule in determining the most appropriate approach for toxicity studies. The acute toxicity study with proper estimate of median lethal dose (LD50) is usually an initial procedure for the determination of most suitable test doses for preclinical toxicological and pharmacological profiling. Several methods, which have been devised to determine the LD50, are faced with the challenge of using a large number of animals and time constraints. Despite the inherent advantage of the newer OECD Test Guidelines, the increasing concerns among toxicologists, the regulatory authorities and the general public, on the need to adhere to 3Rs principle, necessitated the need for an improved approach. Such an approach should not only minimize the time and number of animals required, but also take into cognizance animal welfare, and give accurate, comparable, and reproducible results across laboratories. While taking advantage of the inherent merits of the existing methods, here is presented the mathematical basis and evaluation of an improved method for toxicity profiling of test substances and estimation of LD50. The method makes use of the generated Table of values for the selection of appropriate test doses. Our proposed method has capacities to optimize the time and number of animal use, ensure more reliable and reproducible results across laboratories, allow for easy selection of doses for subsequent toxicity profiling, and be adaptable to other biological screening beyond toxicity studies.

ANTIMALARIAL activities and alkaloids from Crinum jagus (Thomps) DANDY.

ETHNOPHARMACOLOGICAL RELEVANCE: Locally, among the Yoruba speaking people of South Western, Nigeria, the bulb of Crinum jagus (CJ), known as "ogede odo" is used to treat malaria and as an anthelmintic among other uses. AIMS OF THIS STUDY: Study aimed at identifying the purified active fractions and constituents of this fraction in an antiplasmodial activity-guided process. MATERIALS AND METHODS: Antiplasmodial activity-guided fractionation of the bulb and leaf extracts of CJ was investigated against chloroquine-sensitive (NK 65) Plasmodium berghei using 4-day suppressive and prophylactic methods. Molluscicidal activity of the extracts was assayed on adult Biomphalaria glabrata molluscs following WHO test protocols. Fractionation and purification of the active bulb extract was achieved using various chromatographic and spectroscopic techniques to isolate its constituents. Isolated compounds were identified using different spectroscopic methods. RESULTS AND DISCUSSION: Both extracts had oral median lethal dose (LD50) greater than 5000 mg/kg body weight (b.wt.). The leaf extract had 40% lethality on molluscs while the bulb extract was inactive. The chemosuppressive and prophylactic antimalarial effects of the bulb extract were 76.55 ± 2.76% and 90.49 ± 2.70% (p<0.05) respectively at 1000 mg/kg b. wt. while the reference drugs; chloroquine and pyrimethamine, had 80.26 ± 3.09% and 50.39 ± 6.80% chemosuppressive effects, respectively. Lycorine (1) and crinamine (2) were isolated from the alkaloidal fraction with 71.36 ± 12.54% antiplasmodial activity. CONCLUSION: The leaf and bulb extracts of Crinum jagus displayed low molluscicidal and moderate antimalarial activities. Lycorine and crinamine were identified from the antiplasmodial alkaloidal active fraction of the bulb.