Physicochemical, pharmacokinetic, efficacy and toxicity profiling of a potential nitrofuranyl methyl piperazine derivative IIIM-MCD-211 for oral tuberculosis therapy via in-silico-in-vitro-in-vivo approach.

Recent tuberculosis (TB) drug discovery programme involve continuous pursuit for new chemical entity (NCE) which can be not only effective against both susceptible and resistant strains of Mycobacterium tuberculosis (Mtb) but also safe and faster acting with the target, thereby shortening the prolonged TB treatments. We have identified a potential nitrofuranyl methyl piperazine derivative, IIIM-MCD-211 as new antitubercular agent with minimum inhibitory concentration (MIC) value of 0.0072 µM against H37Rv strain. Objective of the present study is to investigate physicochemical, pharmacokinetic, efficacy and toxicity profile using in-silico, in-vitro and in-vivo model in comprehensive manner to assess the likelihood of developing IIIM-MCD-211 as a clinical candidate. Results of computational prediction reveal that compound does not violate Lipinski's, Veber's and Jorgensen's rule linked with drug like properties and oral bioavailability. Experimentally, IIIM-MCD-211 exhibits excellent lipophilicity that is optimal for oral administration. IIIM-MCD-211 displays evidence of P-glycoprotein (P-gp) induction but no inhibition ability in rhodamine cell exclusion assay. IIIM-MCD-211 shows high permeability and plasma protein binding based on parallel artificial membrane permeability assay (PAMPA) and rapid equilibrium dialysis (RED) assay model, respectively. IIIM-MCD-211 has adequate metabolic stability in rat liver microsomes (RLM) and favourable pharmacokinetics with admirable correlation during dose escalation study in Swiss mice. IIIM-MCD-211 has capability to appear into highly perfusable tissues. IIIM-MCD-211 is able to actively prevent progression of TB infection in chronic infection mice model. IIIM-MCD-211 shows no substantial cytotoxicity in HepG2 cell line. In acute toxicity study, significant increase of total white blood cell (WBC) count in treatment group as compared to control group is observed. Overall, amenable preclinical data make IIIM-MCD-211 ideal candidate for further development of oral anti-TB agent.

An investigation into the potential use of nanoparticles as adjuvants for the production of polyclonal antibodies to low molecular weight compounds.

Two nanoparticle based adjuvants were assessed for their ability to produce polyclonal antibodies in rabbits to low molecular weight target analytes, i.e. veterinary drugs banned from use in food producing animals. The nanoparticles, Montanide IMS 251 and amphiphilic poly (γ-glutamic acid) were compared against a mineral oil adjuvant, Montanide ISA 50, which had previously been shown to be successful in producing antibodies to haptens whilst being safe to use with respect to the welfare of the host animals. The adjuvants were assessed for their tendency to cause adverse effects to the host animals and by the quality of the antibodies generated in terms of assay sensitivity. None of the three adjuvants employed in the trial generated any measurable adverse effects in the host animals. While the mineral oil adjuvant produced higher titres of antibodies the nanoparticle adjuvants were found to produce antibodies of statistically comparable sensitivity. Based on IC(50) values, six antisera displayed potential to detect the required level of the target compounds; five of these were produced by rabbits immunised with the two different nanoparticle adjuvants. As antibody sensitivity is the main performance criteria of an analytical immunoassay, it can be concluded that the nanoparticle adjuvants under evaluation are fit for the purpose described in this study.

[Medico-biological evaluation of sodium salt of nitrofurylacrylic acid as a food additive]. / Mediko-biologicheskaia otsenka natrievoi soli 5-nitrofurilakrilovoi kisloty kak pishchevoi dobavki.

Nitrofurylacrylic acid sodium salt is a substance of moderate toxicity. Its LD50 for male rats after oral administration comprises 1220 mg/kg, for female rats--1400 mg/kg. The minimal toxic dose, in case of long-term administration comprises 14 mg/kg. At the level of doses from 0.04 to 4.0 mg/kg no mutagenic effect was detected. Oral and subcutaneous administration of minimal tolerance doses of the agent induced formation of malignant neoplasms developing, predominantly, from the epithelial tissue, with localization depending on the route of the agent administration. A conclusion has been made on impossibility of using this substance as a food additive.