Paclitaxel in self-micro emulsifying formulations: oral bioavailability study in mice

The anticancer drug paclitaxel is formulated for i.v. administration in a mixture of Cremophor EL and ethanol. Its oral bioavailability is very low due to the action of P-glycoprotein in the gut wall and CYP450 in gut wall and liver. However, proof-of-concept studies using the i.v. formulation diluted in drinking water have demonstrated the feasibility of the oral route as an alternative when given in combination with inhibitors of P-glycoprotein and CYP450. Because of the unacceptable pharmaceutical properties of the drinking solution, a better formulation for oral application is needed. We have evaluated the suitability of various self-micro emulsifying oily formulations (SMEOF’s) of paclitaxel for oral application using wild-type and P-glycoprotein knockout mice and cyclosporin A (CsA) as P-glycoprotein and CYP450 inhibitor. The oral bioavailability of paclitaxel in all SMEOF’s without concomitant CsA was low in wild-type mice, showing that this vehicle does not enhance intestinal uptake by itself. Paclitaxel (10 mg/kg) in SMEOF#3 given with CsA resulted in plasma levels that were comparable to the Cremophor EL-ethanol containing drinking solution plus CsA. Whereas the AUC increased linearly with the oral paclitaxel dose in P-glycoprotein knockout mice, it increased less than proportional in wild-type mice given with CsA. In both strains more unchanged paclitaxel was recovered in the feces at higher doses. This observation most likely reflects more profound precipitation of paclitaxel within the gastro-intestinal tract at higher doses. The resulting absolute reduction in absorption of paclitaxel from the gut was possibly concealed by partial saturation of first-pass metabolism when P-glycoprotein was absent. In conclusion, SMEOF’s maybe a useful vehicle for oral delivery of paclitaxel in combination with CsA, although the physical stability within the gastro-intestinal tract remains a critical issue, especially when applied at higher dose levels

Improving the biopharmaceutical attributes of mangiferin using vitamin E-TPGS co-loaded self-assembled phosholipidic nano-mixed micellar systems

The current research work encompasses the development, characterization, and evaluation of self-assembled phospholipidic nano-mixed miceller system (SPNMS) of a poorly soluble BCS Class IV xanthone bioactive, mangiferin (Mgf) functionalized with co-delivery of vitamin E TPGS. Systematic optimization using I-optimal design yielded self-assembled phospholipidic nano-micelles with a particle size of  80% of drug release in 15 min. The cytotoxicity and cellular uptake studies performed using MCF-7 and MDA-MB-231 cell lines demonstrated greater kill and faster cellular uptake. The ex vivo intestinal permeability revealed higher lymphatic uptake, while in situ perfusion and in vivo pharmacokinetic studies indicated nearly 6.6- and 3.0-folds augmentation in permeability and bioavailability of Mgf. In a nutshell, vitamin E functionalized SPNMS of Mgf improved the biopharmaceutical performance of Mgf in rats for enhanced anticancer potency

The relationship between executive functions and fluid intelligence in Parkinson's disease.

BACKGROUND: We recently demonstrated that decline in fluid intelligence is a substantial contributor to frontal deficits. For some classical 'executive' tasks, such as the Wisconsin Card Sorting Test (WCST) and Verbal Fluency, frontal deficits were entirely explained by fluid intelligence. However, on a second set of frontal tasks, deficits remained even after statistically controlling for this factor. These tasks included tests of theory of mind and multitasking. As frontal dysfunction is the most frequent cognitive deficit observed in early Parkinson's disease (PD), the present study aimed to determine the role of fluid intelligence in such deficits. METHOD: We assessed patients with PD (n=32) and control subjects (n=22) with the aforementioned frontal tests and with a test of fluid intelligence. Group performance was compared and fluid intelligence was introduced as a covariate to determine its role in frontal deficits shown by PD patients. RESULTS: In line with our previous results, scores on the WCST and Verbal Fluency were closely linked to fluid intelligence. Significant patient-control differences were eliminated or at least substantially reduced once fluid intelligence was introduced as a covariate. However, for tasks of theory of mind and multitasking, deficits remained even after fluid intelligence was statistically controlled. CONCLUSIONS: The present results suggest that clinical assessment of neuropsychological deficits in PD should include tests of fluid intelligence, together with one or more specific tasks that allow for the assessment of residual frontal deficits associated with theory of mind and multitasking