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Nebbioso A.,The Second University of Naples | Pereira R.,University of Vigo | Khanwalkar H.,Institute Of Genetique Et Of Biologie Moleculaire Et Cellulaire | Khanwalkar H.,Lupin Ltd Research Park | And 12 more authors.
Molecular Cancer Therapeutics | Year: 2011

Deregulation of the epigenome is recognized as cause of cancer and epigenetic factors are receiving major attention as therapeutic targets; yet, the molecular mode of action of existing epi-drugs is largely elusive. Here, we report on the decryption of the mechanism of action of UVI5008, a novel epigenetic modifier, that inhibits histone deacetylases, sirtuins, and DNA methyltransferases. UVI5008 highly efficiently induces cancer cell-selective death in a variety of models and exerts its activities in several human tumor xenografts and genetic mouse models of human breast cancer in vivo. Its anticancer activity involves independent activation of death receptors and reactive oxygen species production. Importantly, UVI5008 action is not critically dependent on p53, Bcl-2 modifying factor, and/or TNF-related apoptosis-inducing ligand as cell death is efficiently induced in cells mutated or deficient for these factors limiting the risk of drug resistance development and maximizing its application spectrum. The simultaneous modulation of multiple (epigenetic) targets promises to open new avenues with unanticipated potential against cancer. ©2011 AACR.

Dadhania P.,Lupin Ltd Research Park | Vuddanda P.R.,Lulea University of Technology | Jain A.,Lupin Ltd Research Park | Velaga S.,Lulea University of Technology | Singh S.,Banaras Hindu University
RSC Advances | Year: 2016

The aim of the present research work was to develop asenapine (ASM) loaded nanostructured lipid carriers (ANLC) for the delivery of drugs in the brain by an intranasal route to enhance therapeutic efficacy. A quality by design approach was used for development and optimization of ANLC. A total of five independent variables were selected, in which three were compositions and two were process variables, while particle size and entrapment efficiency were selected as response variables. The final optimized batch was evaluated by various in vitro characterizations as well as in vivo brain and plasma pharmacokinetic studies. Finally, the ANLC was assessed for efficacy and safety profiling for upto three weeks by a behavior model viz. catalepsy, induced locomotor and paw test in Charles Foster rats. The observed particle size, entrapment efficiency and zeta potential of ANLC was found to be 167.30 ± 7.52 nm, 83.50 ± 2.48% and -4.33 ± 1.27 mV, respectively. Surface characterization studies demonstrated a spherical shape with a smooth surface of ANLC which follows the Korsmeyer-Peppas in vitro release kinetic model (r2 = 0.9911, n = 0.53). A brain pharmacokinetic study indicated a significantly higher (p < 0.05) peak drug concentration (Cmax: 74.13 ± 6.73 ng mL-1), area under the drug concentration-time curve (AUC0-24 h: 560.93 ± 27.85 h ng mL-1) and mean residence time (MRT: 7.1 ± 0.13 h) of ANLC compared to ASM in the brain via an intranasal route. The results of behaviour studies of ANLC showed a significant decrease in extra-pyramidal side effects with increasing antipsychotic effect after 1-2 week(s) of treatment. These findings demonstrate that nanostructured lipid carriers could be a new promising drug delivery system for intranasal delivery of asenapine in the treatment of schizophrenia. © 2015 The Royal Society of Chemistry.

Ahuja V.,Lupin Ltd Research Park | Sharma S.,Lupin Ltd Research Park
Journal of Applied Toxicology | Year: 2014

Early assessment of the toxicity potential of new molecules in pharmaceutical industry is a multi-dimensional task involving predictive systems and screening approaches to aid in the optimization of lead compounds prior to their entry into development phase. Due to the high attrition rate in the pharma industry in last few years, it has become imperative for the nonclinical toxicologist to focus on novel approaches which could be helpful for early screening of drug candidates. The need is that the toxicologists should change their classical approach to a more investigative approach. This review discusses the developments that allow toxicologists to anticipate safety problems and plan ways to address them earlier than ever before. This includes progress in the field of in vitro models, surrogate models, molecular toxicology, 'omics' technologies, translational safety biomarkers, stem-cell based assays and preclinical imaging. The traditional boundaries between teams focusing on efficacy/ safety and preclinical/ clinical aspects in the pharma industry are disappearing, and translational research-centric organizations with a focused vision of bringing drugs forward safely and rapidly are emerging. Today's toxicologist should collaborate with medicinal chemists, pharmacologists, and clinicians and these value-adding contributions will change traditional toxicologists from side-effect identifiers to drug development enablers. © 2013 John Wiley & Sons, Ltd.

Singh M.,Lupin Ltd Research Park | Pandya R.,Lupin Ltd Research Park | Chandra S.,Lupin Ltd Research Park | Sharma S.K.,Lupin Ltd Research Park
Scandinavian Journal of Laboratory Animal Science | Year: 2015

Blood samples obtained from experimental animals often need preservation due to several technical constraints. The present study was aimed to determine the effect of storage temperature and time on the stability of analytes in whole blood and plasma samples obtained from Wistar rats. Aspartate amino transferase, alkaline phosphatase, cholesterol, triglycerides, creati-nine, urea, glucose, total protein, total bilirubin, phosphorous, sodium, potassium and chloride did not show statistically significant changes in plasma preserved at -20 °C up to 4 weeks. However, alanine aminotransferase decreased by 4th week and gamma glutamyl transferase showed variance at different time points, while a statistically significant decrease was noted in albumin and calcium levels from the first week. A marked increase in LDH activity was noted after storage for 2 and 4 weeks. No substantial changes in complete blood count were noted. However, an increase was recorded in mean corpuscular volume at 72 hr and mean corpuscular hemoglobin at 48 hr and 72 hr in blood stored at 4 ±1°C. To conclude, the preservation temperatures of -20 ± 2 °C for plasma up to 4 weeks and 4 ±1°C up to 96 hr for whole blood in Wistar rats did not remarkably affect the stability of analytes except for LDH and may be considered for laboratory investigations if warranted. © 2015 Swedish Research Council. All Rights Reserved.

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