Development and Characterizations of Pullulan and Maltodextrin-Based Oral Fast-Dissolving Films Employing a Box-Behnken Experimental Design.

Migraine is a neurological disorder characterized by severe headaches, visual aversions, auditory, and olfactory disorders, accompanied by nausea and vomiting. Zolmitriptan (ZMT®) is a potent 5HT1B/1D serotonin receptor agonist frequently used for the treatment of migraine. It has erratic absorption from the gastrointestinal tract (GIT), but its oral bioavailability is low (40-45%) due to the hepatic metabolism. This makes it an ideal candidate for oral fast dissolving formulations. Hence, the current study was undertaken to design and develop oral fast-dissolving films (OFDFs) containing ZMT for migraine treatment. The OFDFs were formulated by the solvent casting method (SCM) using Pullulan (PU) and maltodextrin (MDX) as film-forming agents and propylene glycol (PG) as a plasticizer. The strategy was designed using Box-Behnken experimental design considering the proportion of PU:MDX and percentage of PG as independent variables. The effectiveness of the OFDF's was measured based on the following responses: drug release at five min, disintegration time (D-time), and tensile strength (TS). The influence of formulation factors, including percent elongation (%E), thickness, water content, moisture absorption, and folding endurance on ZMT-OFDFs, were also studied. The results showed a successful fabrication of stable ZMT-OFDFs, with surface uniformity and amorphous shape of ZMT in fabricated films. The optimized formulation showed a remarkable rapid dissolution, over 90% within the first 5 min, a fast D-time of 18 s, and excellent mechanical characteristics. Improved maximum plasma concentration (C max) and area under the curve (AUC 0-t) in animals (rats) treated with ZMT-OFDFs compared to those treated with an intra-gastric (i-g) suspension of ZMT were also observed. Copolymer OFDFs with ZMT is an exciting proposition with great potential for the treatment of migraine headache. This study offers a promising strategy for developing ZMT-OFDFs using SCM. ZMT-OFDFs showed remarkable rapid dissolution and fast D-time, which might endeavor ZMT-OFDFs as an auspicious alternative approach to improve patient compliance and shorten the onset time of ZMT in migraine treatment.

Development of a new rapid, economical and eco-friendly HPLC method for in vitro and in vivo determination of zolmitriptan.

Multiple high-performance liquid chromatographic (HPLC) approaches have been briefly defined for the assessment of zolmitriptan (ZMT). These methods are either cumbersome or require a plentiful volume of organic solvents, thus offering extortionate procedures. The objective of this study was to establish and validate a new rapid, eco- friendly and cost-effective HPLC method for the analysis of ZMT. The calibration curve for ZMT was established using simulated salivary fluid (SSF) and rat plasma for in-vitro and in-vivo analysis, respectively. Chromatogram separation was performed using a CST column (250mm × 4.6mm, 5µm) as a stationary phase and maintained at a temperature of 40°C. The methods were authenticated for linearity, system suitability, accuracy, precision, reproducibility, limit of detection (LOD) and limit of quantification (LOQ). The results of the validation variables and stability studies indicated that the methods were established in accordance with the guidelines of ICH and the USFDA. The established technique was time-saving, precise, eco- friendly and economical compared with the reported technique. In addition, the developed method was sufficiently repeatable for in vitro and in vivo analysis of ZMT.

Comparative proteomics analysis of differential proteins in respond to doxorubicin resistance in myelogenous leukemia cell lines.

BACKGROUND: Chemoresistance remains a significant challenge in chronic myelogenous leukemia (CML) management, which is one of the most critical prognostic factors. Elucidation the molecular mechanisms underlying the resistance to chemoresistance may lead to better clinical outcomes. RESULTS: In order to identify potential protein targets involved in the drug-resistant phenotype of leukemia, especially the chronic myelogenous leukemia (CML), we used a high-resolution "ultra-zoom" 2DE-based proteomics approach to characterize global protein expression patterns in doxorubicin-resistant myelogenous leukemia cells compared with parental control cells. Ultra-high resolution of 2DE was achieved by using a series of slightly overlapping narrow-range IPG strips during isoelectric focusing (IEF) separation. A total number of 44 proteins with altered abundances were detected and identified by MALDI-TOF or LC-MS/MS. Among these proteins, enolase, aldolase, HSP70 and sorcin were up-regulated in doxorubicin-resistant myelogenous leukemia cell line, whereas HSP27 was down-regulated. Some of the results have been validated by Western blotting. Both enolase and aldolase were first reported to be involved in chemoresistance, suggesting that process of glycolysis in doxorubicin-resistant myelogenous leukemia cells was accelerated to some extent to provide more energy to survive chemical stress. Possible roles of most of the identified proteins in development of chemoresistance in myelogenous leukemia cells were fully discussed. The results presented here could provide clues to further study for elucidating the mechanisms underlying drug resistance in leukemia. CONCLUSIONS: As a whole, under the chemical stress, the doxorubicin-resistant myelogenous leukemia cells may employ various protective strategies to survive. These include: (i) pumping the cytotoxic drug out of the cells by P-glycoprotein, (ii) increased storage of fermentable fuel, (iii) sophisticated cellular protection by molecular chaperones, (iv) improved handling of intracellular calcium, (v) increased glucose utilization via increased rates of glycolysis. In the present study, proteomic analysis of leukemia cells and their drug resistant variants revealed multiple alterations in protein expression. Our results indicate that the development of drug resistance in doxorubicin-resistant myelogenous leukemia cells is a complex phenomenon undergoing several mechanisms.