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ABSTRACT: This study aimed to develop an LC-MS/MS assay for the quantitation of S002-857 in plasma, urine and feces to evaluate the
pharmacokinetic parameters and elimination pathway for further development of S002-857. A sensitive and selective LC-MS/MS
method was developed and validated for estimating a novel antidiabetic flavone derivative, S002-857, synthesized by Central
Drug Research Institute, CSIR, Lucknow, India. Plasma and urine samples were prepared by two-step liquid-liquid extraction
with diethyl ether and feces by protein precipitation using acetonitrile. The analyte was chromatographed on a cyano column
with methanol-ammonium acetate buffer (pH 4.6, 10mM; 90:10, v/v). The calibration curves were linear over a range of 0.78–400ngmL−1 for plasma and 1.56–400ngmL−1 for urine and feces samples. The accuracy and precision were <15% for plasma, urine and feces samples. The recoveries from
spiked plasma, urine and feces samples were >85%. S002-857 was stable in plasma for 8h at ambient temperature, 30days at
−60°C and after three freeze-thaw cycles. The assay was successfully applied to determine the pharmacokinetic parameters
and excretion profile in male rats.
KeywordsLC-MS/MS–Excretion–Pharmacokinetics–Antidiabetic–S002-857
Chromatographia 04/2012; 73(9):905-912. · 1.20 Impact Factor
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Alok K Verma,
Himanshu Singh,
Mavurapu Satyanarayana,
Swayam P Srivastava,
Priti Tiwari,
Amar B Singh,
Anil K Dwivedi,
Shio K Singh,
Mukesh Srivastava,
Chandishwar Nath,
Ram Raghubir,
Arvind K Srivastava, Ram Pratap
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ABSTRACT: The hybrid congeners 62-90 of 6- and 7-hydroxyflavones with aminopropanol have been synthesized and evaluated for their antidiabetic activity in sucrose-challenged low-dosed streptozotocin (STZ)-induced diabetic rats and db/db mice. The optical enantiomers 70a, 70b, 90a, and 90b of two congeners 70 and 90 exhibiting consistent antidiabetic and antidyslipidemic activities were also prepared, and their antidiabetic activity results indicate its association mainly with S isomers. These compounds also lower cholesterol and TG profiles while improving high-density lipoprotein cholesterol to CHOL ratio in db/db mice. The bioavailability of compound 70 and its isomer varies between 27 and 29% whereas that of the more polar compound 90a is poor as determined in rat by oral and intraperitoneal administrations.
Journal of Medicinal Chemistry 04/2012; 55(10):4551-67. · 4.80 Impact Factor
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Alok K. Verma,
Himanshu Singh,
M. Satyanarayana,
Swayam P. Srivastava,
Priti Tiwari,
Amar B. Singh,
Anil K. Dwivedi,
Shio K. Singh,
Mukesh Srivastava,
Arvind K. Srivastava,
C. Nath,
R. Raghubir, Ram Pratap
Journal of Medicinal Chemistry 01/2012; 55(55):4551. · 4.80 Impact Factor
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Tetrahedron 01/2012; · 3.03 Impact Factor
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ABSTRACT: A series of chalcone based PPAR-α agonists were synthesized and evaluated for their antidyslipidemic activity in high fructose high fat fed dyslipidemic Syrian golden hamsters. Most of the compounds exhibited antidyslipidemic activity. The compounds 4c and 4f have been identified as most potent antidyslipidemics. A definite structure-activity relationship was observed while varying the nature as well as the position of the substituent.
Bioorganic & medicinal chemistry letters 06/2011; 21(11):3475-8. · 2.65 Impact Factor
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Natural Product Reports 09/2010; 27(11):1571-93. · 9.79 Impact Factor
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ABSTRACT: The aim of the study was to investigate the in-situ absorption kinetics, plasma protein binding and pharmacokinetic characteristics of a novel synthetic flavone derivative, S002-853, which shows pronounced antidiabetic and antidyslipidaemic activity.
Quantification of S002-853 in plasma was performed by the LC-MS/MS method and in-situ sample analysis was carried out by the HPLC-UV method.
The absorption rate constant was 0.274/h in a mild alkaline environment, which S002-853 experiences in the intestine following oral dose administration. Plasma protein binding was found to be 26.37 +/- 2.58% at a concentration of 1 microg/ml. The pharmacokinetic parameters were determined in male rats after administration of a single 40 mg/kg oral dose and 10 mg/kg intravenous dose. The peak plasma concentration (C(max)) was found to be 60.93 ng/ml at 8 h after oral administration. Irregular concentration-time profiles with secondary peaks were observed after oral dose administration. The elimination half-life of the compound was 19.56 h and 16.30 h after oral and intravenous doses, respectively. Comparison of the AUC after oral and intravenous dosing of S002-853 indicates that only about 29.48% (bioavailability) of the oral dose reaches the systemic circulation.
In-situ study of S002-853 shows slow absorption from the gastrointestinal tract. S002-853 also shows low plasma protein binding. The pharmacokinetic parameters after oral and intravenous dose reveal low oral bioavailability and high mean residence time.
The Journal of pharmacy and pharmacology. 05/2010; 62(5):604-9.
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Drugs & Pharmaceutical, Current Highlights. 01/2009; 43:39-49.
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ABSTRACT: Gugulipid, an ethyl acetate extract of the resin of plant Commiphora whighitii is an established hypolipidemic agent in clinical practice. The major constituent of gugulipid is guggulsterone [4, 17 (20)-pregnadiene-3, 16-dione]. It has been observed recently that patients receiving lipid-lowering drugs like statins have a reduced risk of dementia. Therefore, the present study was planned to explore the potential of gugulipid as cognitive enhancer. Gugulipid (12.5, 25 and 50 mg/kg, p.o.) showed dose dependent improvement in scopolamine-induced deficits in passive avoidance test. The maximal effective dose of gugulipid i.e. 50 mg/kg, p.o. was used for further studies on streptozotocin (STZ) model of dementia in mice. Gugulipid was investigated for its effect on learning and memory, parameters of oxidative stress (GSH and MDA) and acetylcholinesterase (AChE) activity in the STZ (ic)-treated mice. Intracerebral (ic) injections of STZ (0.5 mg/kg) on 1st and 3rd day caused significant deficit in memory in passive avoidance and Morris water maze test after the 14th day of first dose. In passive avoidance, transfer latency time (TLT) was not increased on retention trials in STZ (ic) group while gugulipid treatment resulted in significant increase in TLT on retention trials in STZ (ic)-treated mice. In Morris water maze test the latency time to reach platform in STZ (ic)-treated mice was significantly higher than control and vehicle (artificial CSF). Pre-treatment of gugulipid (50 mg/kg, p.o.) daily for 14 days started with the first dose of STZ (ic), significantly prevented STZ (ic)-induced memory deficit. Post-treatment i.e. after 14 days of first dose of STZ (ic) of gugulipid (50 mg/kg, p.o.) significantly decreased the latency time indicating anti-dementia activity. Effect of gugulipid and STZ in visible platform test was similar to those seen with hidden platform. Gugulipid and STZ-treated mice did not cause significant change in locomotor activity. Furthermore, STZ (ic) resulted into increase in AChE activity, low level of GSH and high concentration of MDA in brain on 21st day as compared to control. Gugulipid treatment caused significant decrease in AChE activity, low level of MDA and high concentration of GSH in brain following STZ (ic) as compared to vehicle administration in STZ (ic)-treated mice. The study demonstrated that gugulipid has significant protective affect against streptozotocin-induced memory deficits model of dementia that can be attributed to anti-oxidant and anti-AChE activity of gugulipid. These observations suggest gugulipid as a potential anti-dementia drug (CDRI, Lucknow has obtained US patent No. 6896901 for use of gugulipid as cognitive enhancer).
Pharmacology Biochemistry and Behavior 05/2007; 86(4):797-805. · 2.53 Impact Factor
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ABSTRACT: A series of chalcone based aryloxypropanolamines were synthesized and evaluated for their antihyperglycemic activity in SLM and STZ rat models. Most of the compounds exhibited moderate to good activity ranging from 6.5% to 31.1% in SLM and 8.3% to 22.6% in STZ models, respectively. The most potent compound 5 g exhibited glucose lowering of 26.7% in SLM and 22.6% in STZ models. A definite structure-activity relationship was observed while varying the nature as well as the position of the amine in ring B.
Bioorganic & Medicinal Chemistry Letters 03/2007; 17(3):799-802. · 2.55 Impact Factor
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Ram Pratap,
Himanshu Singh,
Alok K. Verma,
Amar B. Singh,
Priti Tiwari,
M. Srivastava,
Arvind K. Srivastava,
Anil K. Dwivedi,
S. Singh,
Pratima Srivastava,
Shio K. Singh,
Chandeshwar Nath,
Ram Raghubir
Ref. No: US Patent App. 12/376,909, 2007, Year: 01/2007
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ABSTRACT: A new synthesis of 6-amino-1-hydroxyethoxymethyl-4 (5H)-oxopyrazolo[3, 4-d]pyrimidine (4) has been mentioned. Compound 4 exhibited inhibition of amastigotes of Leishmania donovani to the extent of 89 % at 30 microg/mL, whereas iso-guanine analogue 5 had the inhibition only to the extent of 52.8% at 100 microg/mL in vitro. In hamster model the maximum inhibitory response for compound 4 against amastigotes multiplication was observed to be 94% at 50 mg/kg single dose for 5 consecutive days.
Nucleosides Nucleotides & Nucleic Acids 02/2006; 25(1):55-60. · 0.90 Impact Factor
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ABSTRACT: A series of aryloxypropanolamines (5a-r) of different chalcones (3a-e) were synthesized and evaluated for antihyperglycemic activity in sucrose loaded (SLM) and streptozotocin (STZ) induced diabetic animal models. Among them compounds 5a, g, m, o, p and r showed significant reduction in blood glucose levels in both SLM and STZ animal models.
Bioorganic & Medicinal Chemistry 04/2004; 12(5):883-9. · 2.92 Impact Factor
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ABSTRACT: In recent years, the unique physical properties of synthetic hydrogels have been exploited in a number of interesting and novel applications. In particular polyampholytes have been the subject of many theoretical studies since they provide a model for studying the long-range interactions found in proteins and other forms of soft condensed matter. In balanced polyampholytes the net electrostatic forces are attractive so that in low ionic salt concentration, the chains have a tendency to collapse into compact globules. Addition of salt, which screens these interactions, induces a swelling of the chain. However the electrostatic interactions between polymeric and mobile charges that determine the hydrogel swelling equilibrium at high ionic strengths are still not very well understood. The purpose of this Master's thesis is to analyze the characteristics of balanced polyampholytes with different charge offsets produced by systematically varying the relative proportions of 2-sulfoethyl methacrylate -2-methacryloxyethyltrimethyl ammonium chloride (SEMA-MAETAC) in copolymers of 2-hydroxyethyl methacrylate (HEMA). Hydrogel equilibrium swelling measurements were made in different bath solutions such as DI (de-ionized) water, PBS (phosphate buffer solution) and different Nacl concentration. A slight swelling in DI water and collapse transitions at intermediate salt concentrations observed experimentally provides the equivalent results, compared with the earlier studies done on balanced polyampholytes. However the deswelling of the hydrogels in high ionic salt concentration found to be abnormal. Hydrogel membrane potential has been measured using a novel method considering the Donnan potential and the Diffusion potential at a charged membrane/salt solution interface. For the balanced polyampholyte hydrogel charges ranging from 0mM to 160mM we observe a negative iv slope in the steady state potential whereas we observe a positive slope in the steady state potential for the highest charged balanced polyampholyte hydrogel, which is 200mM in this case. Finally digital image processing techniques have been applied to examine the bacteria Pseudomonas fluorescens 5RL and hydrogel interactions. And the higher proliferation rates of the bacteria Pseudomonas fluorescens 5RL over neutral HEMA hydrogels compared to copolymer HEMA hydrogels with balanced charge densities in the range of 40 mM to 160 mM were analyzed using these techniques. Comparative change in the micro motion of the bacteria over balanced polyampholyte hydrogels and the unbalanced polyelectrolyte hydrogels were also presented. The cumulative result of this thesis is that the selection of the acidic and basic monomers used in the preparation of these hydrogels and their micro structural arrangements should be given importance and also the emphasis of digital image processing techniques in the application of molecular imaging. Mode of access: World Wide Web. Title from title page screen (viewed on June 29, 2005). Thesis advisor: A. E. English. Document formatted into pages (x, 108 p. : ill. (some col.)). Thesis (M.S.) -- University of Tennessee, Knoxville, 2005. Vita. Includes bibliographical references (p. 67-71).
