Lupin Ltd Research Park

Pune, India

Lupin Ltd Research Park

Pune, India

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Bokare A.M.,Lupin Ltd Research Park | Praveenkumar A.K.,Lupin Ltd Research Park | Bhonde M.,Lupin Ltd Research Park | Nayak Y.,Manipal University India | And 2 more authors.
Neurochemical Research | Year: 2017

Beta-amyloid peptide (Aβ) induced neurotoxicity is considered as a hallmark of the pathogenesis of Alzheimer’s disease (AD). The present study demonstrated the neuroprotective role of 5-HT6 receptors against Aβ-induced neurotoxicity in PC-12 cells. The 5-HT6 receptor agonist EMD-386088 and antagonist SB-399885 were used as pharmacological tools. The NMDA receptor antagonist, memantine, was used as reference standard. The Aβ25−35 (50 µM) induced apoptosis, increased reactive oxygen species (ROS) generation and impaired neurite outgrowth in PC-12 cells. Pre-treatment with 10 µM EMD-386088 and SB-399885 had significantly protected neuronal cell death by maintaining higher cell viability through attenuation of intracellular ROS. Further, both compounds significantly prevented Aβ25−35-induced impairment in neurite outgrowth in PC-12 cells. Similarly, memantine prevented Aβ25−35-induced neurotoxicity in PC-12 cells. These findings suggest that 5-HT6 receptor ligands have protected neurons from Aβ25−35 induced toxicity by reducing ROS and through prevention of impairment in neurite outgrowth. Therefore, 5-HT6 receptor could be an important disease-modifying therapeutic target for AD. © 2017 Springer Science+Business Media New York


Kanode R.,Lupin Ltd Research Park | Chandra S.,Lupin Ltd Research Park | Sharma S.,Lupin Ltd Research Park
Toxicology Mechanisms and Methods | Year: 2017

Non-genotoxic carcinogens may play a significant role in development of cancer. Currently short-term assays for mutagenicity classify genotoxic carcinogens and lack the abilities to detect epigenetic carcinogens. The need to develop an endpoint always remains to recognize potentially carcinogenic agents employing rapid and practical bioassays. For this, the present study utilized TA98 and TA1537 tester strains of Salmonella typhimurium to evaluate four non-genotoxic carcinogenic agents (Coumarin, β-Myrcene, Bis(2-ethylhexyl) phthalate and trans-anethole). These chemicals were tested individually and in combination with promutagens 2-aminoanthracene (2AA) and benzo(a)pyrene (BP) in presence of metabolic activation system (S9) by plate incorporation method. Exposure to all four test chemicals revealed marked increase of revertant colonies in promutagen combined groups as compared to promutagens alone. However significantly greater fold responses were observed with 2AA combination groups (Coumarin +2AA, β-Myrcene +2AA, Bis(2-ethylhexyl) phthalate +2AA and trans-anethole +2AA) with TA98 strain as compared with TA1537, which seems to have enhanced the mutagenic response of 2AA in metabolically activated conditions. It is concluded that out of both tester strains TA98 strain of Salmonella typhimurium has the potential to detect non-genotoxic carcinogens when combined with potent promutgens either by inhibiting or modulating activities of liver microsomal enzymes biochemically which may indirectly contribute to neoplastic alterations. Further this simple, short-term alternative assay may provide rapid information during extrapolative toxicology for differentiating genotoxic and non-genotoxic carcinogens. © 2017 Informa UK Limited, trading as Taylor & Francis Group


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.


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.


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.


PubMed | Lupin Ltd Research Park
Type: Review | Journal: Drug discovery today | Year: 2016

The sensitivity of the various preclinical models used to predict toxicity in humans varies. In this review, we analyze the various models used to predict safety in drug discovery and development with a view to understanding their translational value in humans. Twenty recently approved anticancer drugs were studied and the available nonclinical and clinical adverse effects information available from the US Food and Drug Administration (FDA) was analyzed. We found that gastrointestinal and hematopoietic toxicities in humans were predicted to the maximum extent by nonclinical models, whereas respiratory, integumentary, renal, nervous, hepatic, and cardiovascular were moderately predicted. Ocular, endocrine, and musculoskeletal toxicities were poorly predicted while lymphatic and immune toxicities were difficult to predict.


PubMed | Lupin Ltd. Research Park
Type: Journal Article | Journal: AAPS PharmSciTech | Year: 2013

The purpose of the present study was to control in vitro burst effect of the highly water-soluble drug, ropinirole hydrochloride to reduce in vivo dose dumping and to establish in vitro-in vivo correlation. The pharmacokinetics of two entirely different tablet formulation technologies is also explored in this study. For pharmacokinetics study, FDA recommends at least 10% difference in drug release for formulations to be studied but here a different approach was adopted. The formulations F8A and F9A having similar dissolution profiles among themselves and with Requip XL (f 2 value 72, 77, 71 respectively) were evaluated. The C max of formulation F8A comprising hypromellose 100,000 cP was 1005.16 pg/ml as compared to 973.70 pg/ml of formulation F9A comprising hypromellose 4000 cP irrespective of T max of 5 and 5.75 h, respectively. The difference in release and extent of absorption in vivo was due to synergistic effect of complex RH release mechanism; however, AUC0-t and AUC0- values were comparable. The level A correlation using the Wagner-Nelson method supported the findings where R (2) was 0.7597 and 0.9675 respectively for formulation F8A and F9A. Thus, in vivo studies are required for proving the therapeutic equivalency of different formulation technologies even though f 2 50. The technology was demonstrated effectively at industrial manufacturing scale of 200,000 tablets.


PubMed | Lupin Ltd. Research Park
Type: Journal Article | Journal: Pharmaceutical development and technology | Year: 2015

Venlafaxine Hydrochloride (VH) is a highly soluble and highly permeable antidepressant compound. Thus controlling VH release from tablet dosage form over a prolonged period is a challenge.The objective of this work was to study the effect of various barrier layer formulation compositions, its orientations and manufacturing technology on release profile of highly soluble VH.Different barrier compositions and orientations were established on the same extended release formulations of VH using compression as well as film coating technologies. Barrier effectiveness in reducing the VH release was verified through in vitro dissolution studies.The belly band portion of the tablets was successfully oriented in different ways to develop bilayer as well as trilayer tablets. The compression technology had substantially reduced the VH release up to 16% in various compositions and orientation as compared to core tablet. The film coating technology had reduced the VH release up to 14% effectively; thereby shifting the dissolution curve to downside.The explored belly band portion of the tablets had reduced the VH release substantially. These innovatively created different barrier orientation technologies hold the great promise of commercialization in future.


PubMed | Lupin Ltd Research Park
Type: Journal Article | Journal: Journal of applied toxicology : JAT | 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. Todays 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.

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