Biomedical subjects

Sunil Kumar Singh

Publications and source records attributed to Sunil Kumar Singh.

11 recordsLinked to original sources

PubMed2006

Identification of 2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-pyrazol-1-yl]-N-propionylbenzenesulfonamide sodium as a potential COX-2 inhibitor for oral and parenteral administration.

Synthesis of prodrugs of orally active COX-2 inhibitor 3 involving sulfamoyl (SO(2)NH(2)) and hydroxymethyl (CH(2)OH) groups, and their biological evaluation are described. Of these prodrugs, the N-propionyl sulfonamide sodium 3k was found to be much superior to the parent compound 3 and other marketed COX-2 inhibitors in carrageenan induced rat paw edema model of inflammation due to highly elevated drug levels in systemic circulation. This prodrug has a potential both for oral as well as parenteral administration due to impressive analgesic activity, antipyretic potency, and extraordinary water solubility.

Administration, Oral↗

PubMed2006

N-acylated sulfonamide sodium salt: a prodrug of choice for the bifunctional 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamide class of COX-2 inhibitors.

Synthesis and biological evaluation of possible prodrugs of COX-2 inhibitors involving sulfonamide and hydroxymethyl groups of 2-hydroxymethyl-4-(5-phenyl-3-trifluoromethyl-pyrazol-1-yl) benzenesulfonamides are described. Out of many options, the sodium salt of N-propionyl sulfonamide demonstrated much improved pharmacological profiles and physicochemical properties suitable for oral as well as parenteral administration.

Acylation↗

PubMed2006

Bioavailability enhancement of poorly water soluble and weakly acidic new chemical entity with 2-hydroxy propyl-beta-cyclodextrin: selection of meglumine, a polyhydroxy base, as a novel ternary component.

The purpose of the present study was to investigate the influence of a polyhydroxy base, N-acetyl glucamine (also know as Meglumine), as a ternary component on the complexation of DRF-4367, a poorly water-soluble and weakly acidic anti-inflammatory molecule, with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD). The molecular inclusion of DRF-4367 with HPbetaCD alone and in combination with ternary component was aimed at improvement in solubility and, subsequently, dissolution rate-limited oral bioavailability. The solid complexes of DRF-4367 and HPbetaCD with or without meglumine (binary and ternary systems, respectively) were prepared as coevaporated product in different stoichiometric ratios and compared against physical mixture. The formation of inclusion complexes was confirmed by using classical instrumental techniques. Phase solubility studies suggested that meglumine was responsible for solubility improvement via multiple factors rather than just providing a favorable pH. Mechanisms and factors governing solubility enhancement were investigated by using phase solubility and thermodynamic parameters. The complexation of DRF-4367 with HPbetaCD is thermodynamically favored because the Gibbs free energies of transfer of the drug to the cyclodextrin cavity are negative. The solubilization efficiency and stability were further improved while retaining the favorable Gibbs free energies of transfer with the addition of meglumine. Inclusion ternary complex of DRF-4367 with HPbetaCD and meglumine showed significant improvement in dissolution compared with uncomplexed drug and binary system. Moreover, the phenomena of reprecipitation observed with binary system during dissolution could be avoided with meglumine as an enabling ternary component. This improved physicochemical behavior of ternary complex with the novel inclusion of a polyhydroxy base translated into an enhanced oral bioavailability of DRF-4367 compared with either uncomplexed drug or nanosuspension.

2-Hydroxypropyl-beta-cyclodextrin↗

PubMed2005

Molluscicidal evaluation of three common plants from India.

Mortality caused by the aqueous extract of latex of Thevetia peruviana, Alstonia scholaris and Euphorbia pulcherrima against two harmful freshwater snails, Lymnaea acuminata and Indoplanorbis exustus, is reported. Latices of all the plants at high doses were also lethal to freshwater fish Channa punctatus, which shares the habitat with these snails, but within 24 h, LC90 of snail L. acuminata did not cause any mortality to fishes in a mixed population of snail and fish. Therefore, these plant extracts may eventually be of great value for the control of harmful aquatic snails and other molluscan pests.

Alstonia↗

PubMed2005

Validated HPLC analytical method with programmed wavelength UV detection for simultaneous determination of DRF-4367 and Phenol red in rat in situ intestinal perfusion study.

A simple, precise and accurate isocratic reverse-phase liquid chromatography method with programmed wavelength detection has been validated to quantify DRF-4367 and Phenol red, simultaneously for application in rat in situ single pass intestinal perfusion study to assess intestinal permeability of DRF-4367, a novel cox-2 inhibitor. The method was validated on RP C-18 analytical column. Mobile phase consisted of sodium dihydrogen orthophosphate (pH 3.2, 0.01 M)-acetonitrile-methanol (30:50:20, v/v/v). The developed method has a short run time of 12 min with a flow rate of 1.0 ml/min. The injector volume was set to 20 microl and acquisition was carried out using a PDA detector while processing was done by timed wavelength extraction. The percentage R.S.D. and recovery in all studies indicated that the method was suitable for the intended purpose. The validated method was found to be linear and precise in the working range. Suitability of storage at cold temperature was ensured along with complete sample recovery.

Animals↗

PubMed2005

Cell adhesion in Arabidopsis thaliana is mediated by ECTOPICALLY PARTING CELLS 1--a glycosyltransferase (GT64) related to the animal exostosins.

Despite the fact that several hundred glycosyltransferases have been identified from sequencing of plant genomes, the biological functions of only a handful have been established to date. A Poplar glycosyltransferase 64 (GT64) family member that is differentially expressed during the cell division and elongation phases of cambial growth was identified from previously generated transcript profiling of cambium tissues. The predicted Poplar GT64 protein has a closely related Arabidopsis homolog ECTOPICALLY PARTING CELLS (EPC1). Mutation of the EPC1 gene, one of three Arabidopsis GT64 family members, results in plants with a dramatically reduced growth habit, defects in vascular formation and reduced cell-cell adhesion properties in hypocotyl and cotyledon tissues. Secondary growth is enhanced in epc1 hypocotyl tissues and it is proposed that this results from the abnormal cell-cell adhesion within the cortical parenchyma cell layers. Loss of cell-cell contacts within cotyledon and leaf tissues is also proposed to account for vascular patterning defects and the fragile nature of epc1 tissues. The EPC1 protein thus plays a critical role during plant development in maintaining the integrity of organs via cell-cell adhesion, thereby providing mechanical strength and facilitating the movement of metabolites throughout the plant.

Amino Acid Sequence↗

PubMed2004

Toxic effect of stem bark and leaf of Euphorbia hirta plant against freshwater vector snail Lymnaea acuminata.

The aqueous stem bark and leaf extracts of plant Euphorbia hirta (family-Euphorbiaceae) have potent molluscicidal activity. Sub-lethal doses (40% and 80% of LC50) of aqueous stem bark and leaf extracts of this plant also significantly (P<0.05) alter the levels of total protein, total free amino acid, nucleic acids (DNA and RNA) and the activity of enzyme protease and acid and alkaline phosphatase in various tissues of the vector snail Lymnaea acuminata in time and dose dependent manner. Euphorbia hirta (family-Euphorbiaceae) commonly known as Dudhi, is a common medicinal plant of India, which is used in variety of diseases i.e. cough, asthma, colic, dysentery, genito urinary diseases.

Amino Acids↗

PubMed2004

Non-endocytic penetration of core histones into petunia protoplasts and cultured cells: a novel mechanism for the introduction of macromolecules into plant cells.

The results of the present work demonstrate that core histones are able to penetrate the plasma membrane of plant cells. Confocal microscopy has revealed that incubation of petunia protoplasts with fluorescently labeled core histones resulted in cell penetration and nuclear import of the externally added histones. Intracellular accumulation was also confirmed by an ELISA-based quantitative method using biotin-labeled histones. Penetration into petunia protoplasts and cultured cells was found to be non-saturable, occurred at room temperature and at 4 degrees C and was not inhibited by Nocodazole. Furthermore, penetration of the biotinylated histone was neither blocked by the addition of an excess of free biotin molecules, nor by non-biotinylated histone molecules. All these results clearly indicate that the observed uptake is due to direct translocation through the cell plasma membrane and does not occur via endocytosis. Our results also show that the histones H2A and H4 were able to mediate penetration of covalently attached BSA molecules demonstrating the potential of the histones as carriers for the delivery of macromolecules into plant cells. To the best of our knowledge, the findings of the present paper demonstrate, for the first time, the activity of cell penetrating proteins (CPPs) in plant cells.

Cells, Cultured↗

PubMed2004

2-hydroxymethyl-4-[5-(4-methoxyphenyl)-3-trifluoromethyl-1H-1-pyrazolyl]-1-benzenesulfonamide (DRF-4367): an orally active COX-2 inhibitor identified through pharmacophoric modulation.

Analogs of 1,5-diarylpyrazoles with a novel pharmacophore at N1 were designed, synthesized and evaluated for the in-vitro cyclooxygenase (COX-1/COX-2) inhibitory activity. The variations at/around position-4 of the C-5 phenyl ring in conjunction with a CF3 and CHF2 groups at C-3 exhibited a high degree of potency and selectivity index (SI) for COX-2 inhibition. The in-vivo evaluation of these potent compounds with a few earlier ones indicated the 4-OMe-phenyl analog and the 4-NHMe-phenyl analog with a CF3, and the 4-OEt-phenyl analog with a CHF2 group at C-3 to possess superior potency than celecoxib. In addition to its impressive anti-inflammatory, antipyretic, analgesic and anti-arthritic properties, compound (DRF-4367) was found to possess an excellent pharmacokinetic profile, gastrointestinal (GI) safety in the long-term arthritis study and COX-2 potency in human whole blood assay. Thus, compound was selected as an orally active anti-inflammatory candidate for pre-clinical evaluation.

Animals↗

PubMed2004

Methanesulfonamide group at position-4 of the C-5-phenyl ring of 1,5-diarylpyrazole affords a potent class of cyclooxygenase-2 (COX-2) inhibitors.

The effect of methanesulfonamide (MeSO(2)NH) group on COX-2 inhibitory activity of 1,5-diarylpyrazole is described. While this group being at position-4 of the N(1)-phenyl ring was found to be ineffective, its installation at position-4 of the C-5 phenyl ring offered several potent and selective inhibitors of COX-2 with IC(50) as low as 30 nM.

Cyclooxygenase 2↗

PubMedDate not supplied

Oral bioavailability and pharmacokinetics of DRF-4367, a new COX-2 inhibitor in rats.

The pharmacokinetic characterization of DRF-4367 (a new diaryl pyrazole derivative), a potent selective COX-2 inhibitor was performed in Wistar rats. In the first study, a single dose of 2, 5, 10, 30 or 100 mg/kg DRF-4367 was given orally to rats for investigating the dose proportionality and/or linearity in the pharmacokinetics. In the second study, a single intravenous bolus dose of DRF-4367 was given at a dose of 10 mg/kg to calculate the absolute oral bioavailability, clearance and volume of distribution parameters. Blood samples were drawn at predetermined intervals up to 24 h post-dose. The concentrations of DRF-4367 in various plasma samples were determined by a validated HPLC method. Plasma concentration versus time data was generated following oral and i.v dosing and subjected to a noncompartmental pharmacokinetic analysis. Following oral administration, maximum concentrations of DRF-4367 were achieved at about 3 h and were unchanged with incremental doses. Both Cmax and AUC0-infinity appeared to increases less than proportional to the administered oral doses. While the doses increased in the ratio of 1.0 : 2.5 : 5.0 : 15.0 : 50.0, the mean AUC0-infinity and Cmax increased in the ratios of 1.0 : 2.8 : 4.5 : 8.6 : 14.5 and 1 : 2.4 : 4.1 : 6.2 : 8.3, respectively. Following i.v. administration, the concentration of DRF4367 declined in a monoexponential fashion with terminal elimination half-life of 5.7 h. The systemic clearance and volume of distribution of DRF-4367 in rats were 0.36 L/h/Kg and 2.2 L/Kg respectively after i.v administration. Elimination half-life was unchanged with route of administration and with increase in oral doses. Absolute oral bioavailability of DRF-4367 in the efficacy dose range was 70-80%.

Administration, Oral↗