Bakula L. Trivedi
Vanderbilt University
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Featured researches published by Bakula L. Trivedi.
Pharmacology, Biochemistry and Behavior | 2001
Zhang-Jin Zhang; Dennis E. Schmidt; Tomas de Paulis; Bakula L. Trivedi; Emmanuel S. Onaivi; Michael H. Ebert; William A. Hewlett
Abstract Behavioral effects of desamino-3-iodozacopride (DAIZAC) [( S )-5-chloro-3-iodo-2-methoxy- N -(1-azabicyclo[2.2.2]oct-3-yl)benzamide], a selective high-affinity 5-HT 3 receptor antagonist ( K D 0.14 nM), were evaluated in the mouse elevated plus-maze using the anxiolytic benzodiazepine, diazepam, as a positive control. DAIZAC treatment produced a significant dose-related increase in the time spent in the open arm. The increased total time in the open arm resulted from a significant dose-dependent increase in the number of entries into that arm. The minimum dose of DAIZAC associated with a statistically significant increase in entries and time spent in the open arm was 0.05 mg/kg ip, consistent with its high affinity for the 5-HT 3 receptor. DAIZAC did not affect the amount of time spent in the open arm after each entry. Thus, DAIZAC reduced apparent avoidance of the open arm when the animal was in the central compartment, without affecting active avoidance of that arm when the animal was in the exposed condition. The increase in the open-arm entries was accompanied by a corresponding reduction in the number of entries into the closed arm with a consequent reduction in the time spent in the closed arm. The time spent in the closed arm after each entry was not altered by DAIZAC administration. As such, the sole apparent effect of DAIZAC was to alter the choice of arm to enter when the animal was in the central compartment. Diazepam also significantly increased total time in the open arm; however, the increase was not attributable to a single behavioral factor. The anxiolytic-like effects of DAIZAC reached maximum by 20–30 min and returned to baseline levels by 90 min. Ex vivo binding studies found that levels of DAIZAC-like activity assayed in brains of mice 25 min after DAIZAC injection were significantly correlated with the behavioral parameters associated with anxiolysis. These results indicate that DAIZAC produces dose-dependent anxiolytic-like behavioral changes in the mouse elevated plus-maze that are correlated with brain DAIZAC-like activity.
American Journal of Clinical Oncology | 2011
Emily Chan; Bonnie LaFleur; Mace L. Rothenberg; Nipun B. Merchant; Albert C. Lockhart; Bakula L. Trivedi; Christine H. Chung; Robert J. Coffey; Jordan Berlin
ObjectivesThe epidermal growth factor receptor (EGFR) and cyclooxygenase-2 (COX-2) pathways play key and often complementary roles in the pathogenesis of colorectal cancer (CRC). This study explores the clinical and biological effects of combined blockade of these pathways. MethodsCetuximab-naive patients with refractory CRC were treated with cetuximab (400 mg/m2 loading dose followed by weekly cetuximab at 250 mg/m2) and celecoxib (200 mg orally twice daily). Urinary PGE-M, a stable metabolite of PGE2 that correlates with in vivo COX-2 activity, and serum TGF-&agr;, a ligand that binds to EGFR, were measured serially to assess the biological effect of COX-2 and EGFR blockade. ResultsSeventeen patients accrued in this study. Of the 13 patients evaluable for response, 2 (15.4%) had confirmed partial responses, 4 (30.8%) had stable disease, and 7 (53.8%) had progressive disease. The median progression-free survival for all evaluable patients was 55 days (95% confidence interval, 45-112; range, 10-295 d). This study was terminated early owing to lack of sufficient clinical activity. There were no statistically significant differences in serum TGF-&agr; or urinary PGE-M between cycles in responders or nonresponders. ConclusionsThis regimen resulted in response rates similar to those published for cetuximab monotherapy in patients with recurrent CRC. Apart from a higher than expected rate of infusion reactions, no other unexpected toxicities were observed. No differences in serum TGF-&agr; or urinary PGE-M between cycles were seen, suggesting that the appropriate targets may not have been hit.
European Journal of Medicinal Chemistry | 1997
T. de Paulis; William A. Hewlett; Dennis E. Schmidt; Ns Mason; Bakula L. Trivedi; Michael H. Ebert
Summary ( S )-5-Iodo-2,3-dimethoxy- N -(1-azabicyclo[2.2.2]oct-3-yl)benzamide (MIZAC) was prepared from 5-iodo-2,3-dimethoxybenzoyl chloride and ( S )-3-aminoquinuclidine. [ 125 I]Iodode-stannylation of its corresponding 5-tri- n -butyltin derivative gave [ 125 I]-MIZAC at 1800 Ci/mmol. Binding of [ 125 I]-MIZAC in rat entorhinal cortex revealed a K D of 1.37 ± 0.21 nM. A series of racemic 2- O -alkyl derivatives of MIZAC were prepared and 5-HT-3 receptor affinities were determined by inhibition of [ 125 I]-MIZAC binding. Optimal affinity for the receptor was obtained with small, electron-withdrawing substituents in the aromatic 5-position and with bulky substituents in the 3-position. [ 125 I]-MIZAC is a selective radioligand useful for in vitro identification of the 5-HT-3 receptor.
Bioorganic & Medicinal Chemistry Letters | 1996
Tomas de Paulis; Bakula L. Trivedi; Zhang-Jin Zhang; Dennis E. Schmidt; Michael H. Ebert; William A. Hewlett
Abstract TRIZAC is one of the most potent 5-HT-3 receptor antagonist reported to date, having 20-fold higher affinity than (S)-5-todozacopride. This high affinity (K1 0.05 ± 0.01 nM) and a moderate apparent lipophilicity (log Papp 2.12) makes TRIZAC a promising ligand for studying 5-HT-3 receptors.
Nuclear Medicine and Biology | 1998
William A. Hewlett; Dennis E. Schmidt; N. Scott Mason; Bakula L. Trivedi; Michael H. Ebert; Tomas de Paulis
In an effort to develop selective, high-affinity radioligands for the 5-HT-3 receptor, a series of homologues of 5-chloro-2,3-dimethoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide (2b) was prepared in which individual methoxy groups were replaced by ethoxyl, (2-fluoroethoxyl), allyloxyl, propargyloxyl, or (3-iodoallyl)oxyl groups. Affinities for the 5-HT-3 receptor were determined by displacement of the binding of [125I]MIZAC (2a), a selective 5-HT-3 receptor antagonist radioligand, in rat brain homogenates. The 3-substituted homologues were more potent than the lead compound, 2b. The homologue having the largest 3-substituent, i.e., E-(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-3-(3-iodo-2-propenyl)oxy- 2-methoxybenzamide (3b, THIZAC), had one of the highest affinities, Ki 0.08 nM. The 2-substituted homologues were equipotent with 2b, having Ki 0.2-0.3 nM, regardless of the size of the substituent. The corresponding iodoallyl derivative, E-(S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2-(3-iodo-2-propenyl)oxy- 3-methoxybenzamide (4, LIZAC), displayed a Ki of 0.29 nM. Saturation binding of [125I]-4 gave a KD of 0.31 +/- 0.04 nM and a Bmax of 2.36 +/- 0.10 fmol/mg of entorhinal cortex. In vivo biodistribution of [125I]-4 in the rat brain showed increased accumulation in hippocampus relative to that in cerebellum. Both the high-affinity ligands [125I]-3b and [125I]-4 are potentially useful radioligands for studying the 5-HT-3 receptor.
Surgery | 2005
Nipun B. Merchant; Christopher M. Rogers; Bakula L. Trivedi; Jason D. Morrow; Robert J. Coffey
Journal of Pharmacology and Experimental Therapeutics | 1999
William A. Hewlett; Bakula L. Trivedi; Zhang-Jin Zhang; Tomas de Paulis; Dennis E. Schmidt; David M. Lovinger; M. Sib Ansari; Michael H. Ebert
Biological Psychiatry | 1995
William A. Hewlett; T. de Paulis; Dennis E. Schmidt; Bakula L. Trivedi; Ns Mason; Michael H. Ebert
Journal of Surgical Research | 2008
Igor Voskresensky; Wooin Lee; Christopher M. Rogers; Bakula L. Trivedi; Robert J. Coffey; Nipun B. Merchant
Chemical & Pharmaceutical Bulletin | 1997
William A. Hewlett; Tomas de Paulis; N. Scott Mason; Dennis E. Schmidt; Bakula L. Trivedi; Zhang-Jin Zhang; Michael H. Ebert