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Taneja I.,Academy of Scientific and Industrial Research | Taneja I.,CSIR - Central Electrochemical Research Institute | Erukala M.,National Institute of Pharmaceutical Education and Research, Rae Bareli | Raju K.S.R.,Academy of Scientific and Industrial Research | And 5 more authors.
Bioanalysis | Year: 2013

Malaria is the leading parasitic disease in emerging countries. Therapeutic drug monitoring of antimalarial drugs is becoming increasingly important due to their spreading resistance. Measuring systemic antimalarial drug concentrations is also vital for safety and PK evaluations during clinical development. The dried blood spot (DBS) technique is a convenient alternative sample-collection method to venipuncture, especially in resource-limited areas where the clinical studies of antimalarials are usually carried out. Various bioanalytical methods for antimalarial drug estimation utilizing DBS sampling have been reported. This review discusses the applicability and relevance of DBS in quantitative assessment of antimalarial drugs, the advantages and drawbacks of DBS, and the difficulties encountered during its implementation. © 2013 Future Science Ltd.


Koley D.,CSIR - Central Electrochemical Research Institute | Koley D.,Academy of Scientific and Innovative Research | Srinivas K.,CSIR - Central Electrochemical Research Institute | Krishna Y.,CSIR - Central Electrochemical Research Institute | Gupta A.,National Institute of Pharmaceutical Education and Research, Rae Bareli
RSC Advances | Year: 2014

A direct Mannich type diastereoselective biomimetic cyclization using acetal as a pro-nucleophile leading to the hydroxymethyl substituted bicyclic framework of various bicyclic alkaloids is presented. Following this protocol, total synthesis of (±)-epilupinine and formal syntheses of (±)-laburnine, (±)-isoretronecanol and (±)-tashiromine are described. © 2013 The Royal Society of Chemistry.


Wahajuddin,CSIR - Central Electrochemical Research Institute | Wahajuddin,National Institute of Pharmaceutical Education and Research, Rae Bareli | Arora S.,National Institute of Pharmaceutical Education and Research, Rae Bareli
International Journal of Nanomedicine | Year: 2012

A targeted drug delivery system is the need of the hour. Guiding magnetic iron oxide nanoparticles with the help of an external magnetic field to its target is the principle behind the development of superparamagnetic iron oxide nanoparticles (SPIONs) as novel drug delivery vehicles. SPIONs are small synthetic γ-Fe2O3 (maghemite) or Fe3O4 (magnetite) particles with a core ranging between 10 nm and 100 nm in diameter. These magnetic particles are coated with certain biocompatible polymers, such as dextran or polyethylene glycol, which provide chemical handles for the conjugation of therapeutic agents and also improve their blood distribution profile. The current research on SPIONs is opening up wide horizons for their use as diagnostic agents in magnetic resonance imaging as well as for drug delivery vehicles. Delivery of anticancer drugs by coupling with functionalized SPIONs to their targeted site is one of the most pursued areas of research in the development of cancer treatment strategies. SPIONs have also demonstrated their efficiency as nonviral gene vectors that facilitate the introduction of plasmids into the nucleus at rates multifold those of routinely available standard technologies. SPION-induced hyperthermia has also been utilized for localized killing of cancerous cells. Despite their potential biomedical application, alteration in gene expression profiles, disturbance in iron homeostasis, oxidative stress, and altered cellular responses are some SPION-related toxicological aspects which require due consideration. This review provides a comprehensive understanding of SPIONs with regard to their method of preparation, their utility as drug delivery vehicles, and some concerns which need to be resolved before they can be moved from bench top to bedside. © 2012 Wahajuddin and Arora, publisher and licensee Dove Medical Press Ltd.


Wahajuddin,CSIR - Central Electrochemical Research Institute | Wahajuddin,National Institute of Pharmaceutical Education and Research, Rae Bareli | Singh S.P.,CSIR - Central Electrochemical Research Institute | Raju K.S.R.,CSIR - Central Electrochemical Research Institute | And 2 more authors.
Journal of Pharmaceutical and Biomedical Analysis | Year: 2012

A simple, sensitive and specific reversed phase high performance liquid chromatographic (RP-HPLC) method for simultaneous determination of atenolol, paracetamol, hydrochlorothiazide, caffeine, cephalexin, metoprolol, propranolol, ketoprofen along with phenol red (a non-absorbable compound) in samples obtained from intestinal in situ single-pass perfusion studies, was developed and validated. Chromatography was carried out on RP18 column with mobile phase comprising of 10mM phosphate buffer (pH 2.5) and methanol in gradient mode. The calibration curves were linear for all nine permeability model compounds (r 2>0.999) across the concentration range of 1.25-40μg/ml. The coefficient of variation for intra and inter-day assay precision was between 0.04 and 3.08% and the accuracy was between 98.39 and 109.45%. Stability studies were carried out at different storage conditions and all the analytes were found to be stable. The method was successfully applied for analysing the permeability samples obtained from in situ single pass perfusion studies. The effective permeability (P eff) values obtained upon cassette administration were in close proximity to the permeability values obtained upon single administration of model compounds. In conclusion, the developed RP-HPLC method can be used for high throughput cassette validation of rat in situ perfusion model for intestinal permeability assessment. © 2012 Elsevier B.V.


Kaur G.,CSIR - Central Electrochemical Research Institute | Kaur G.,Integral University | Singh N.,CSIR - Central Electrochemical Research Institute | Lingeshwar P.,National Institute of Pharmaceutical Education and Research, Rae Bareli | And 4 more authors.
Pulmonary Pharmacology and Therapeutics | Year: 2015

Recently, inhibition of poly (ADP-ribose) polymerase-1 (PARP1) was shown to be protective in experimental pulmonary hypertension (PH) and prevented right ventricular hypertrophy (RVH) associated with it. However, molecular mechanism behind cardioprotection by PARP1 inhibition in PH still needs detailed exploration. Therefore, effect of inhibition of PARP1 on the right ventricle (RV) dysfunction was studied in monocrotaline (MCT) induced PH model. Following a single dose administration of MCT (60mg/kg, s.c.), male Sprague-Dawley rats were treated with PARP1 inhibitor 1,5-Isoquinolinediol (ISO, 3mg/kg, i.p.) for 35 days for preventive study and from day 21-35 for curative study. RV pressure (RVP) and RVH were measured after 35 days. Histophathological studies, PARP1 activity, mRNA and protein expression were studied in isolated RV. Oxidative and nitosative stress, inflammation and Matrix metalloproteinases (MMPs)/Tissue inhibitor of metalloproteinase 2 (TIMP2) were also assessed. Mitochondrial dysfunction was studied by mitochondrial membrane permeability and estimation of Nicotinamide adenine dinucleotide (NAD) and Adenosine triphosphate (ATP). Apoptosis in RV was assessed by Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), caspase 3 activity and cleaved PARP1 expression. PARP1 inhibition significantly reversed the increase in RVP and RVH in both preventive and curative treatment in the MCT-injected rats. ISO lowered oxidative and nitrosative stress and inflammation and restored the balance of MMPs/TIMP2 expression. PARP1 inhibition prevented mitochondrial dysfunction and the release of cell death factors from mitochondria. ISO also decreased apoptosis by decreasing number of TUNEL positive cells, caspase 3 activity and PARP1 cleavage in RV. Thus, PARP1 inhibition ameliorated PH induced RV hypertrophy and may emerge as a new therapeutic target for PH. © 2014 Elsevier Ltd.


Kamble B.,University of Mysore | Kamble B.,National Institute of Pharmaceutical Education and Research, Rae Bareli | Gupta A.,University of Mysore | Moothedath I.,University of Mysore | And 4 more authors.
Chemico-Biological Interactions | Year: 2016

Abstarct Gymnema sylvestre, important Indian traditional herbal medicine has been used for diabetes from several years and marketed as single or multi-herb formulations globally. People are consuming G. sylvestre along with conventional hypoglycemic drugs. Therefore, there is need of evidence based assessment of risk versus benefits when G. sylvestre co-administered with conventional oral hypoglycemic drugs. In present investigation, pharmacodynamics and pharmacokinetic interactions with oral hypoglycemic drug, glimepiride (GLM) was studied in streptozotocin (STZ) induced diabetic rats. A specific and rapid HPLC-ESI-MS/MS method was established for simultaneous quantification of GLM and gymnemagenin (GMG) in rat plasma. Pharmacokinetic and pharmacodynamic interaction studies were carried out in STZ induced diabetic rats after concomitant administration of 400 mg/kg of G. sylvestre extract and 0.8 mg/kg of GLM for 28 days. The developed HPLC-ESI-MS/MS method was rapid, specific, and precise. Con-comitant oral administration of G. sylvestre extract (400 mg/kg) and GLM (0.8 mg/kg) in diabetic rats for 28 days showed beneficial pharmacodynamic interactions whereas no major alterations in the pharmacokinetics parameters of GLM and GMG were observed. This interaction demonstrated in animal model implies that significant clinical outcome might occur during concomitant administration of G. sylvestre extract and GLM especially in diabetic patients and warrants further studies in the same set up. © 2015 Elsevier Ireland Ltd. All rights reserved.


Singh S.P.,CSIR - Central Electrochemical Research Institute | Wahajuddin,CSIR - Central Electrochemical Research Institute | Tewari D.,CSIR - Central Electrochemical Research Institute | Patel K.,National Institute of Pharmaceutical Education and Research, Rae Bareli | Jain G.K.,CSIR - Central Electrochemical Research Institute
Fitoterapia | Year: 2011

In the present study, we are reporting permeability and pharmacokinetics of nobiletin in rat plasma and brain, using a validated reverse phase high performance liquid chromatographic method. Protein precipitation method was used for the extraction of nobiletin and coumarin (IS) from rat plasma and brain tissue. The system was run in isocratic mode with mobile phase consisting of potassium dihydrogen ortho-phosphate (pH 4.5; 0.04 mM) and acetonitrile in ratio of 50:50, v/v. The total chromatographic run time was 9.0 min. The method was proved to be accurate and precise at linearity range of 0.05-10 μg/mL with a correlation coefficient (r) of ≥ 0.994 in rat plasma and ≥ 0.995 in rat brain. The intra- and inter-day precision and accuracy values are found to be within the assay variability limits as per the FDA guidelines. Nobiletin was found stable in the battery of stability studies viz., bench-top, auto-sampler, freeze/thaw cycles and long term storage in a freezer at - 70 ± 10 °C. Maximum concentrations of nobiletin in both plasma and brain were observed at 1 h after single oral dosing (50 mg/kg). The maximum concentration in plasma and brain were 1.78 and 4.20 μg/mL, respectively. The AUC 0-t in plasma and brain were 7.49 and 20.66 μg•h/mL, respectively. The mean elimination half life (t 1/2) in plasma and brain were 1.80 and 11.42 h, respectively. The Parallel Artificial Membrane Permeability Assay (PAMPA) permeability of nobiletin was found to be high at both pH 4.0 and 7.0. © 2011 Elsevier B.V. All rights reserved.


Wahajuddin,CSIR - Central Electrochemical Research Institute | Wahajuddin,National Institute of Pharmaceutical Education and Research, Rae Bareli | Singh S.P.,CSIR - Central Electrochemical Research Institute | Raju K.S.R.,National Institute of Pharmaceutical Education and Research, Rae Bareli | And 3 more authors.
Malaria Journal | Year: 2011

Background: Despite the wide spread use of lumefantrine, there is no study reporting the detailed preclinical pharmacokinetics of lumefantrine. For the development of newer anti-malarial combination(s) and selection of better partner drugs, it is long felt need to understand the detailed preclinical pharmacokinetics of lumefantrine in preclinical experimental animal species. The focus of present study is to report bioavailability, pharmacokinetics, dose linearity and permeability of lumefantrine in rats. Methods. A single dose of 10, 20 or 40 mg/kg of lumefantrine was given orally to male rats (N = 5 per dose level) to evaluate dose proportionality. In another study, a single intravenous bolus dose of lumefantrine was given to rats (N = 4) at 0.5 mg/kg dose following administration through the lateral tail vein in order to obtain the absolute oral bioavailability and clearance parameters. Blood samples were drawn at predetermined intervals and the concentration of lumefantrine and its metabolite desbutyl-lumefantrine in plasma were determined by partially validated LC-MS/MS method. In-situ permeability study was carried in anaesthetized rats. The concentration of lumefantrine in permeability samples was determined using RP-HPLC. Results: For nominal doses increasing in a 1:2:4 proportion, the Cmaxand AUC0-values increased in the proportions of 1:0.6:1.5 and 1:0.8:1.8, respectively. For lumefantrine nominal doses increasing in a 1:2:4 proportion, the Cmaxand the AUC 0-tvalues for desbutyl-lumefantrine increased in the proportions of 1:1.45:2.57 and 1:1.08:1.87, respectively. After intravenous administration the clearance (Cl) and volume of distribution (Vd) of lumefantrine in rats were 0.03 ( 0.02) L/h/kg and 2.40 ( 0.67) L/kg, respectively. Absolute oral bioavailability of lumefantrine across the tested doses ranged between 4.97% and 11.98%. Lumefantrine showed high permeability (4.37 × 10-5 cm/s) in permeability study. Conclusions: The pharmacokinetic parameters of lumefantrine and its metabolite desbutyl-lumefantrine were successfully determined in rats for the first time. Lumefantrine displayed similar pharmacokinetics in the rat as in humans, with multiphasic disposition, low clearance, and a large volume of distribution resulting in a long terminal elimination half-life. The absolute oral bioavailability of lumefantrine was found to be dose dependent. Lumefantrine displayed high permeability in the in-situ permeability study. © 2011 Wahajuddin et al; licensee BioMed Central Ltd.


PubMed | National Institute of Pharmaceutical Education and Research, Rae Bareli and CSIR - Central Electrochemical Research Institute
Type: | Journal: Journal of chromatography. B, Analytical technologies in the biomedical and life sciences | Year: 2015

Recently, a fixed dose combination (FDC) of memantine (MM) and donepezil (DPZ) has been approved for the treatment of Alzheimers disease (AD). In the present work, a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the simultaneous determination of MM and DPZ was developed and validated in rat plasma over the linearity range of 0.2-400ng/mL using amantadine (AM) as an internal standard. Both the analytes and IS were extracted using one step liquid-liquid extraction procedure. The analytes were separated on C18 reversed phase column with mobile phase consisting of a mixture of methanol and 10mM ammonium acetate, pH 5 (92:8 v/v) at a flow rate of 0.7mL/min. The detection of the analytes was done on triple quadrupole mass spectrometer operated in positive electrospray ionization mode (ESI) and quantified using multiple reaction monitoring (MRM). The method was fully validated in terms of linearity, accuracy, precision, recovery, matrix effect, dilution integrity, carry-over effect and stability. The within- and between-run precisions were <10% and accuracy was all within 10%. The mean recovery of MM and DPZ was found to be greater than 80%. The % RSD value at higher as well as lower concentration was well within the acceptable range (15%) in all the stability experiments. The method was successfully applied to the oral pharmacokinetics and drug-drug interaction study of MM and DPZ in male Sprague Dawley (SD) rats.


PubMed | National Institute of Pharmaceutical Education and Research, National Institute of Pharmaceutical Education and Research, Rae Bareli, CSIR - Central Electrochemical Research Institute and Integral University
Type: | Journal: Pulmonary pharmacology & therapeutics | Year: 2016

Increased sympathetic nervous system (SNS) activity is associated with cardiovascular diseases but its role has not been completely explored in pulmonary hypertension (PH). Increased SNS activity is distinguished by elevated level of norepinephrine (NE) and activity of -Amino butyric acid Transminase (GABA-T) which degrades GABA, an inhibitory neurotransmitter within the central and peripheral nervous system. Therefore, we hypothesized that GABA-T may contribute in pathophysiology of PH by modulating level of GABA and NE. The effect of daily oral administration of GABA-T inhibitor, Vigabatrin (GVG, 50 and 75 mg/kg/day, 35 days) was studied following a single subcutaneous administration of monocrotaline (MCT, 60 mg/kg) in male SD rats. The pressure and hypertrophy of right ventricle (RV), oxidative stress, inflammation, pulmonary vascular remodelling were assessed after 35 days in MCT treated rats. The expression of GABA-T and HIF-1 was studied in lung tissue. The levels of plasma NE (by High performance liquid chromatography coupled with electrochemical detector; HPLC-ECD) and lung GABA (by liquid chromatography-mass spectrometry) were also estimated. GVG at both doses significantly attenuated increased in pressure (35.82 4.80 mm Hg, p < 0.001; 28.37 3.32 mm Hg, p < 0.001 respectively) and hypertrophy of RV, pulmonary vascular remodelling, oxidative stress and inflammation in lungs of MCT exposed rats. GVG also reduced the expression of GABA-T and HIF-1 in MCT treated rats. Increased NE level and decreased GABA level was also reversed by GVG in MCT exposed rats. GABA-T plays an important role in PH by modulating SNS activity and may be considered as a therapeutic target in PH.

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