Pre-clinical pharmacokinetics and acute toxicological evaluation of a monastrol derivative anticancer candidate LaSOM 65 in rats.

1. The present work investigated the pharmacokinetic and tissue distribution as well as acute toxicity of a new chemical entity (NCE), the anticancer candidate LaSOM 65 in Wistar rats. 2. LaSOM 65 pharmacokinetics was investigated after intravenous (i.v., 1 mg/kg) and oral (p.o., 10 and 30 mg/kg) dosing. Tissue distribution was assessed after i.v. bolus dose. Acute toxicity was evaluated after i.v. (1, 2.5 and 5 mg/kg) and p.o. (50, 100 and 150 mg/kg) administration. 3. Short half-life (1.75 ± 0.71 h), a clearance of 0.85 ± 0.18 L/h/kg and a volume of distribution of 1.76 ± 0.24 L/kg were observed after i.v. dosing. The compound showed good bioavailability and linear pharmacokinetics after oral doses. The NCE distributes consistently in lung and fatty tissues, with penetration ratios of 2.7 and 1.4, respectively. The other tissues investigated presented smaller penetration ratios. Adverse clinical symptoms were observed only after i.v. administration, and regressed 3 h after dosing. Compared with controls, no statistical differences were found for serum analysis, body weight and relative organ weight, indicating no acute toxicological effects. 4. Overall, LaSOM 65 showed good pharmacokinetic characteristics and no signs of acute toxicity, indicating that it is a promising anticancer candidate.

The efficacy of microemulsion-based delivery to improve vitamin E properties: evaluation of the antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice.

OBJECTIVES: A microemulsion-based delivery system was designed to improve vitamin E (VE) properties, and its antinociceptive, antioxidant, antidepressant- and anxiolytic-like activities in mice were evaluated. METHODS: Male Swiss mice received, by intragastric route, canola oil (20 ml/kg), blank microemulsion (B-ME) (20 ml/kg), VE free (VE-F) (200 mg/kg) or VE microemulsion (VE-ME) (200 mg/kg). In acute treatment, a single dose of treatments was administrated and 30 min after behavioural tests were performed. In the subchronic treatment, mice received such treatments, once a day, for 8 days. On the eighth day, behavioural tests were performed. KEY FINDINGS: In the subchronic treatment, VE-ME increased entries and spent time in the open arms in the elevated plus-maze test and decreased the immobility time in the tail suspension test, but no change was found after acute treatment. Acute and subchronic treatments with VE-ME increased response latency to thermal stimulus in the hot-plate test. VE-ME decreased the thiobarbituric acid reactive species levels in the acute and subchronic protocols. Additionally, in subchronic treatment, VE-ME increased renal catalase activity, but VE-F reduced its activity. CONCLUSIONS: Vitamin E-microemulsions showed antioxidant, antinociceptive, antidepressant- and anxiolytic-like actions; thus, ME-based delivery improved pharmacological properties of VE.

A surface modification of clozapine-loaded nanocapsules improves their efficacy: A study of formulation development and biological assessment.

This work aimed to develop nanocapsules (NC) coated with polysorbate 80 (P80), cationic chitosan (CS) or polyethylene glycol (PEG) using clozapine (CZP) as the drug model. The zeta potential, pH and encapsulation efficiency were directly affected by the CS coating. Using the bag dialysis method, the in vitro CZP release from CS-coated nanocapsules was similar to the PEG-coated at pH 7.4. Nanocapsules coated with PEG and CS exhibited an increased action duration compared to the P80-coated nanocapsules in pseudo-psychosis induced by d,l-amphetamine in rats. When comparing both groups, the group administered CS-coated nanocapsules showed better activity than the PEG-coated nanocapsules at 6, 10 and 12h after d,l-amphetamine administration. The pharmacokinetic assessment in rats demonstrated that the observed half-lives were free CZP