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Biomedical subjects

S Venkatraman

Publications and source records attributed to S Venkatraman.

At least 19 recordsLinked to original sources
PubMed2006

SCH 503034, a mechanism-based inhibitor of hepatitis C virus NS3 protease, suppresses polyprotein maturation and enhances the antiviral activity of alpha interferon in replicon cells.

Cleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases functional viral proteins essential for viral replication. Recent studies by Foy and coworkers strongly suggest that NS3-mediated cleavage of host factors may abrogate cellular response to alpha interferon (IFN-alpha) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L. Johnson, C. Wang, P. M. Fish, M. Yoneyama, T. Fujita, S. M. Lemon, and M. Gale, Jr., Proc. Natl. Acad. Sci. USA 102:2986-2991, 2005, and E. Foy, K. Li, C. Wang, R. Sumpter, Jr., M. Ikeda, S. M. Lemon, and M. Gale, Jr., Science 300:1145-1148, 2003). Blockage of NS3 protease activity therefore is expected to inhibit HCV replication by both direct suppression of viral protein production as well as by restoring host responsiveness to IFN. Using structure-assisted design, a ketoamide inhibitor, SCH 503034, was generated which demonstrated potent (overall inhibition constant, 14 nM) time-dependent inhibition of the NS3 protease in cell-free enzyme assays as well as robust in vitro activity in the HCV replicon system, as monitored by immunofluorescence and real-time PCR analysis. Continuous exposure of replicon-bearing cell lines to six times the 90% effective concentration of SCH 503034 for 15 days resulted in a greater than 4-log reduction in replicon RNA. The combination of SCH 503034 with IFN was more effective in suppressing replicon synthesis than either compound alone, supporting the suggestion of Foy and coworkers that combinations of IFN with protease inhibitors would lead to enhanced therapeutic efficacy.

Antiviral Agents↗
PubMed2004

A validated chiral HPLC method for the enantiomeric separation of tolterodine tartarate.

An isocratic chiral HPLC method was developed for the separation of tolterodine tartarate enantiomers. The mobile phase consists of n-hexane and isopropyl alcohol in the ratio of 980:20 (v/v) with 1 ml diethylamine and 0.6 ml trifluoroacetic acid. Chiralcel OD-H (250 mm x 4.6mm) column was used at constant room temperature. Flow rate was kept at 0.5 ml/min. This method is capable of detecting the S-isomer up to 0.1 microg/ml. The method was validated in terms of linearity, precision, limit of detection (LOD) and limit of quantification (LOQ).

Benzhydryl Compounds↗
PubMed2004

Randomized, placebo-controlled trial of rofecoxib in the acute treatment of migraine.

OBJECTIVE: To investigate the clinical profile of rofecoxib, a long-acting (approximately 17-hour half-life) selective cyclo-oxygenase-2 inhibitor, for the acute treatment of migraine. METHODS: A randomized, double-blind, placebo-controlled, parallel-group study was conducted. Patients age > or =18 treated a moderate or severe migraine headache with placebo (n = 182), rofecoxib 25 mg (n = 183), or rofecoxib 50 mg (n = 192). The primary efficacy measure was headache relief (mild or no pain) 2 hours after dose. RESULTS: The proportions of patients with migraine headache relief at 2 hours after dose were 34.3% for placebo, 54.0% for rofecoxib 25 mg (p < 0.001 vs placebo), and 56.7% for rofecoxib 50 mg (p < 0.001 vs placebo). Rofecoxib 25 and 50 mg were superior to placebo in providing pain freedom at 2 hours, 24-hour sustained headache relief, and 24-hour sustained pain freedom; in reducing photophobia, phonophobia, nausea (50 mg only), and functional disability at 2 hours after dose; and in improving some quality-of-life scores over 24 hours. More patients on rofecoxib 50 mg reported adverse events (39.6%) than patients on rofecoxib 25 mg (26.8%) or placebo (23.6%) regardless of drug relatedness; however, the incidences of drug-related adverse events were similar between treatment groups. These adverse events were generally mild or moderate in severity. The most commonly reported adverse events were dry mouth, dizziness, somnolence, nausea, dyspepsia, paresthesia, and asthenia, with similar incidences between treatment groups. CONCLUSION: Rofecoxib 25 and 50 mg were effective and generally well tolerated for the acute treatment of migraine attacks.

Acute Disease↗
PubMed2002

30pi aromatic meso-substituted heptaphyrin isomers: syntheses, characterization, and spectroscopic studies.

The syntheses of new aromatic 30pi heptaphyrins either through a [5 + 2] or a [4 + 3] acid-catalyzed condensation and oxidative coupling reactions of easily available and air-stable precursors are reported. The methodology followed is not only simple and efficient but also allows synthesis of a range of heptaphyrins with different heteroatoms in the core. The oxidative coupling reactions of modified tripyrranes 11 and tetrapyrranes 12 were found to be dependent on the acid concentration used and as well as the substituents present on the meso position. The change of meso aryl substituents in 11 and 12 to meso mesityl substituents gave a new heptaphyrin 18. The structural characterization has been done with extensive 1H and 2D NMR studies. The heptaphyrins reported here show rich structural diversity when the connections of the heterocyclic rings are altered, and accordingly, one ring and two ring inversions have been observed. By a judicious choice of the precursors it has been possible to control the site of ring inversion either in the bithiophene unit or in the tripyrrane unit. Theoretical calculations performed on three different heptaphyrins, 4, 5, and 17, also reveal that the inverted structures are approximately 35-40 kJ lower in energy relative to the corresponding noninverted structures. Furthermore, one of the heptaphyrins 10c shows the presence of two conformers in solution in the ratio 1:2 and no interconversion between the conformers have been observed in the temperature range of 343-228 K. On protonation, the aromaticity and the ring inversions are retained and the deltadelta values vary in the range 10.07-20.59 ppm. The energies of the Soret maxima and the HOMO-LUMO gap vary linearly with the increase in pi electrons further justifying the aromatic nature of the heptaphyrins.

Journal Article↗
PubMed2002

Porphyrins in photodynamic therapy - a search for ideal photosensitizers.

The utility of light as a therapeutic agent can be traced back over thousands of years when it was used in Ancient Egypt, India and China to treat a variety of skin diseases like psoriasis, vitiligo, rickets, cancer and psychosis. The isolation of porphyrins and their inherent tumor localizing properties coupled with its ability to generate reactive singlet oxygen when activated by light of particular wavelength which in turn results in cytotoxicity led to the emergence of a new modality namely, photodynamic therapy (PDT) as a therapeutic tool. The higher degree of selectivity offered by this modality and fewer side effects when compared to chemotherapy and radiotherapy has prompted the researchers around the globe to generate new photosensitizers. Porphyrins and expanded porphyrins are one class of molecules under intense investigation due to their photosensitizing ability for PDT application. Expanded porphyrins result from the expansion of the phi electron conjugation by increasing the number of heterocyclic rings or bridging carbons of the existing porphyrin framework. These chromophores show strong absorptions in the red region (650-800 nm) compared to that of normal 18phi porphyrins. The strong absorption of light by a water soluble nontoxic photosensitizing molecule in the therapeutic window resulting in maximum penetration of light into the tissues coupled with high singlet oxygen production will conceptualize an ideal photosensitizer. This review highlights various porphyrinoid sensitizers reported till date and their photosensitizing ability both in vitro and in vivo studies. Furthermore, the urgent need for developing ideal photosensitizer for PDT will also be highlighted.

Animals↗
PubMed2001

Peptidyl diazomethyl ketones inhibit the human rhinovirus 3C protease: effect on virus yield by partial block of P3 polyprotein processing.

The efficacy of a series of diazomethyl ketones (DMKs) was measured in rhinovirus-infected cultures and against the HRV14 3C protease. Their specificity and potency were confirmed against purified recombinant enzyme expressed in a yeast secretion system. An internally quenched fluorescent peptide substrate was used to assess the potency against the enzyme, obtaining a 50% inhibitory concentration (IC50) of 1 microM for both Z-L-F-Q-CHN2 and Z-V-L-F-Q-CHN2, while a lower affinity was observed for Z-F-Q-CHN2. The tripeptide Z-L-F-Q-CHN2 blocked viral replication with an IC50 value of 30 microM as judged by the reduction in viral induced cytopathy of HeLa-H1 cells, as well as a marked reduction in viral plaque formation (50% effective concentration=20 microM). Western blot analysis of viral proteins from infected cells indicates that this inhibitor works specifically by blocking viral polyprotein maturation, displaying a reduction of detectable 3C protease and an accumulation of the 3CD polypeptide. These results indicate that DMK inhibitors of the 3C protease have antiviral potency. Furthermore, the pattern of viral protein processing observed suggests that reducing the concentration of mature HRV 3C protease even in the presence of increased 3CD protein is sufficient to block proper viral processing and significantly reduce virus yield.

3C Viral Proteases↗
PubMed1999

Cyclobutane quisqualic acid analogues as selective mGluR5a metabotropic glutamic acid receptor ligands.

The conformationally constrained cyclobutane analogues of quisqualic acid (Z)- and (E)-1-amino-3-[2'-(3',5'-dioxo-1',2', 4'-oxadiazolidinyl)]cyclobutane-1-carboxylic acid, compounds 2 and 3, respectively, were synthesized. Both 2 and 3 stimulated phosphoinositide (PI) hydrolysis in the hippocampus with EC50 values of 18 +/- 6 and 53 +/- 19 microM, respectively. Neither analogue stimulated PI hydrolysis in the cerebellum. The effects of 2 and 3 were also examined in BHK cells which expressed either mGluR1a or mGluR5a receptors. Compounds 2 and 3 stimulated PI hydrolysis in cells expressing mGluR5a but not in those cells expressing mGluR1a. The EC50 value for 2 was 11 +/- 4 microM, while that for 3 was 49 +/- 25 microM. Both 2 and 3 did not show any significant effect on cells expressing the mGluR2 and mGluR4a receptors. In addition, neither compound blocked [3H]glutamic acid uptake into synaptosomal membranes, and neither compound was able to produce the QUIS effect as does quisqualic acid. This pharmacological profile indicates that 2 and 3 are selective ligands for the mGluR5a metabotropic glutamic acid receptor.

Animals↗
PubMed1999

Synthesis and dopamine receptor modulating activity of novel peptidomimetics of L-prolyl-L-leucyl-glycinamide featuring alpha,alpha-disubstituted amino acids.

In the present study, L-prolyl-L-leucyl-glycinamide (1) peptidomimetics 3a-3d and 4a-4d were synthesized utilizing alpha, alpha-disubstituted amino acids. These analogues were designed to explore the conformational effects of constraints at the phi3 and psi3 torsion angles. Constrained conformations were verified by the use of X-ray crystallography and circular dichroism. The effects of Pro-Leu-Gly-NH2 analogues 3a-3d and 4a-4d on enhancing rotational behavior induced by apomorphine in the 6-hydroxydopamine-lesioned animal models of Parkinson's disease were studied. The ability of these peptidomimetics to increase the binding of agonist N-propylnorapomorphine (NPA) to the dopamine D2 receptor was also examined. Extended analogue Pro-Leu-Deg-NH2 was the most active compound of this series. It was 10 times more potent and almost 2 times more effective than 1 in increasing apomorphine-induced rotations (56 +/- 15% at 1.0 mg/kg ip) and in enhancing [3H]NPA specific binding (40%).

Animals↗
PubMed1998

Synthesis and evaluation of peptidyl Michael acceptors that inactivate human rhinovirus 3C protease and inhibit virus replication.

Human rhinovirus, the chief cause of the common cold, contains a positive-sense strand of RNA which is translated into a large polyprotein in infected cells. Cleavage of the latter to produce the mature viral proteins required for replication is catalyzed in large part by a virally encoded cysteine proteinase (3Cpro) which is highly selective for -Q approximately GP- cleavage sites. We synthesized peptidyl derivatives of vinylogous glutamine or methionine sulfone esters (e.g., Boc-Val-Leu-Phe-vGln-OR: R = Me, 1; R = Et, 2) and evaluated them as inhibitors of HRV-14 3C protease (3Cpro). Compounds 1 and 2 and several related tetra- and pentapeptide analogues rapidly inactivated 3Cpro with submicromolar IC50 values. Electrospray mass spectrometry confirmed the expected 1:1 stoichiometry of 3Cpro inactivation by 1, 2, and several other analogues. Compound 2 also proved to be useful for active site titration of 3Cpro, which has not been possible heretofore because of the lack of a suitable reagent. In contrast to 1, 2, and congeners, peptidyl Michael acceptors lacking a P4 residue have greatly reduced or negligible activity against 3Cpro, consistent with previously established structure-activity relationships for 3Cpro substrates. Hydrolysis of the P1 vinylogous glutamine ester to a carboxylic acid also decreased inhibitory activity considerably, consistent with the decreased reactivity of acrylic acids vs acrylic esters as Michael acceptors. Incorporating a vinylogous methionine sulfone ester in place of the corresponding glutamine derivative in 1 also reduced activity substantially. Compounds 1 and 2 and several of their analogues inhibited HRV replication in cell culture by 50% at low micromolar concentrations while showing little or no evidence of cytotoxicity at 10-fold higher concentrations. Peptidyl Michael acceptors and their analogues may prove useful as therapeutic agents for pathologies involving cysteine proteinase enzymes.

3C Viral Proteases↗
PubMed1998

Skin adhesives and skin adhesion. 1. Transdermal drug delivery systems.

The use of pressure-sensitive adhesives (PSAs) for skin-contact applications is discussed. The requirements of such adhesives in various applications are examined in detail. Commercially available classes of PSAs used for skin-contact applications are the acrylics, the polyisobutylenes, and the silicones. The main application examined in this review is transdermal drug delivery. The roles played by the PSA in two types of transdermal designs are described. Correlations between in vivo and ex vivo measurements of adhesion are discussed. Also, the reported human studies of various commercially available transdermals are examined critically, with a view to assessing the relative performance capabilities of each type of transdermal design. Finally, a comprehensive listing of currently commercialized transdermals is given.

Acrylates↗
PubMed1995

Experimental point spread function of fm pulse imaging scheme.

In this paper, we have examined the possibility of incorporating pulse compression techniques into a conventional medical B-scan imaging scheme. Linear frequency modulation fm, one form of pulse coding among many others, has been used in this study. With this approach, one can overcome current peak intensity limitations. A theoretical framework that includes medium propagation effects, transducer bandwidth and diffraction effects is presented, which could be used to examine the system point spread function under this imaging scheme. A prototype experimental set-up and signal processing are described and used for simple imaging tasks in attenuating and nonattenuating media. Analysis of the experimental point spread functions shows that resolution similar to conventional short pulse imaging can be achieved. However, the existence of large range side lobe levels usually associated with pulse compression processing can degrade contrast resolution in medical ultrasound. We have considered various different factors that can affect the range side lobe levels and examined their effect either experimentally or through simulations. The technique has the potential for improving signal-to-noise ratio (SNR), maximum penetration depth and resolution without exceeding peak intensity limitations. Some possible applications are discussed that merit further evaluation. Our work demonstrates the feasibility of this technique and presents a theoretical framework that can be used in future studies aimed at evaluating image quality, system performance, and possible artifacts under such an imaging scheme.

Computer Simulation↗