Are you Vijay Dhawan?

Claim your profile

Publications (6)22.56 Total impact

  • Vijay Dhawan, David Janero, James Ellis
    [Show abstract] [Hide abstract]
    ABSTRACT: There are several methods utilized for detection of nitric oxide (NO) and its various metabolites in biological systems. These include spectrophotometric analysis, high performance liquid chromatography, mass spectrophotometry, electro-paramagnetic resonance (EPR), and gas-phase chemiluminscence. Of these, the gas-phase chemiluminescence technique is perhaps the most sensitive, with a limit of detection in the femtomole range. Furthermore, as there are a number of commercially available NO analyzers, it is possible to directly compare results from different laboratories using this technique. Described in this unit is a group-specific derivatization approach with gas-phase chemiluminscence detection to profile NO metabolites in vivo.
    Current protocols in pharmacology 12/2006; Chapter 12:Unit12.10.
  • [Show abstract] [Hide abstract]
    ABSTRACT: A series of glycolamide naproxen prodrugs containing a nitrate group as a nitric oxide (NO) donor moiety has been synthesized. These compounds were evaluated for their anti-inflammatory activity, naproxen release, and gastric tolerance. Compounds 4a, 4b, 5a, 5b, 7b, and 7c exhibited anti-inflammatory activity equivalent to that of the parent NSAID, naproxen-Na, in the rat carrageenan paw edema model. At equimolar doses relative to naproxen-Na, the NO-donor glycolamide derivatives 4a, 4b, 5a, 5b, 7b, and 7c were gastro-sparing in the rat. Naproxen formation from these NO-donor glycolamides varied among the structures examined, with the N-substituent on the amide group having a particular influence, and demonstrated their prodrug nature. Compound 7b was selected for exemplary demonstration that the glycolamide nitrates can be bioactivated to release NO. These data open the possibility that naproxen glycolamide nitrates may represent a safer alternative to naproxen as anti-inflammatory medicines.
    Bioorganic & Medicinal Chemistry 05/2006; 14(8):2589-99. · 2.90 Impact Factor
  • Nitric Oxide-biology and Chemistry - NITRIC OXIDE-BIOL CHEM. 01/2006; 14(4):41-41.
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Cyclooxygenase (COX, EC 1.14.99.1) inhibitor-nitric oxide (NO) donor (CINOD) hybrid compounds represent an attractive alternative to NSAID and coxib therapy. This report compares two CINODs, NMI-1182 (naproxen-glyceryl dinitrate) and AZD3582 (naproxen-n-butyl nitrate), for their ability to inhibit COX-1 and -2, deliver bioavailable nitric oxide, and release naproxen, using in vitro biochemical and pharmacological methods. In human whole blood, both CINODs showed inhibition, comparable to naproxen, of both COX isozymes and slowly released naproxen. Both CINODs donated bioavailable NO, as detected by cGMP induction in the pig kidney transformed cell line, LLC-PK1, but NMI-1182 was more potent by 30-100 times than AZD3582, GTN, GDN, and ISDN and considerably faster in inducing cGMP synthesis than AZD3582. The nitrate groups of GTN, NMI-1182, and AZD3582 appeared to be bioactivated via a common pathway, since each compound desensitized LLC-PK1 cells to subsequent challenge with the other compounds. Similar cGMP induction also occurred in normal, untransformed cells (human renal proximal tubule epithelial cells and hepatocytes from man, rat, and monkey); again, NMI-1182 was superior to AZD3582. NMI-1182 was also the more metabolically labile compound, releasing more absolute nitrate and nitrite (total NO(x)) in human stomach (in which NO is salutary) and liver S9 homogenates. Naproxen was also more rapidly freed from NMI-1182 than AZD3582 in human stomach, although liver S9 hydrolyzed both CINODs with similar rates. These in vitro tests revealed that NMI-1182 may be a better CINOD than AZD3582 because of its superior NO donating and naproxen liberating properties.
    Biochemical Pharmacology 12/2005; 70(9):1343-51. · 4.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO) enhances anti-inflammatory drug action. Through a metabonomics approach termed "NObonomics," the effects of a prototypic NO donor (organic nitrate)-cyclooxygenase-2 inhibitor hybrid (NO-coxib), NMI-1093, on the NO metabolite status of the circulation and major organs have been profiled in vivo in the rat. An oral anti-inflammatory NMI-1093 bolus elicited acute tissue-, time-, and dose-dependent changes in oxidative and nitroso/nitrosyl NO metabolites. Gastric N-nitrosation and hepatic S-nitrosation and heme nitrosylation emerged as sensitive indices of this NO-coxib's metabolism. Acute NMI-1093-induced nitros(yl)ation correlated positively as a function of nitrate plus nitrite formation across all organs examined, suggesting a unifying in vivo mechanism consequent to NMI-1093 biotransformation that links oxidative and nitros(yl)ative routes of NO chemical biology and thereby may support downstream NO signaling. NMI-1093 depressed erythrocyte nitros(yl)ation, likely by inhibiting cellular carbonic anhydrase and shifting the intracellular balance between nitrogen oxides and carbonates. Glutathione-S-transferase or cytochrome P450 inhibitors also attenuated NMI-1093's NO metabolism in a compartment-selective fashion. Although not itself a NO donor, the des-nitro coxib analog of NMI-1093 influenced basal NO metabolite profiles, implicating a cyclooxygenase-NO synthase interaction in physiological NO regulation. By detailing the global NO metrics of a unique coxib bearing a popular NO-donor pharmacophore (i.e., a nitrate moiety) and defining some critical mechanistic determinants, this study demonstrates how NObonomics can serve as valuable tool in helping elucidate NO systems biology and the effect of NO-donor and non-NO-donating therapeutics thereon.
    Free Radical Biology and Medicine 12/2005; 39(9):1191-207. · 5.27 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Nitric oxide (NO)-derived products may modify tissue constituents, forming S- and N-nitroso adducts and metal nitrosyls implicated in NO signaling. Nitrovasodilator drugs have been in widespread use for more than a century, yet their biotransformation pathways to NO and their effects as NO donors across tissues remain ill defined. By using a metabonomics approach (termed "NObonomics") for detailing the global NO-related metabolism of the cornerstone nitrovasodilator, glyceryl trinitrate (GTN; 0.1-100 mg/kg), in the rat in vivo, we find that GTN biotransformation elicits extensive tissue nitros(yl)ation throughout all major organ systems. The corresponding reaction products remained detectable hours after administration, and vascular tissue was not a major nitros(yl)ation site. Extensive heart and liver modifications involved both S- and N-nitrosation, and RBC S-nitrosothiol formation emerged as a sensitive indicator of organic nitrate metabolism. The dynamics of GTN-derived oxidative NO metabolites in blood did not reflect the nitros(yl)ation patterns in the circulation or in tissues, casting doubt on the usefulness of plasma nitrite/nitrate as an index of NO/NO-donor biodynamics. Target-tissue NO metabolites varied in amount and type with GTN dose, suggesting a dose-sensitive shift in the prevailing routes of GTN biotransformation ("metabolic shunting") from thiol nitrosation to heme nitrosylation. We further demonstrate that GTN-induced nitros(yl)ation is modulated by a complex, tissue-selective interplay of enzyme-catalyzed pathways. These findings provide insight into the global in vivo metabolism of GTN at pharmacologically relevant doses and offer an additional experimental paradigm for the NObonomic analysis of NO-donor metabolism and signaling.
    Proceedings of the National Academy of Sciences 12/2004; 101(48):16958-63. · 9.81 Impact Factor