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Adenosine Deaminase Inhibitor

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Jana Sawynok – One of the best experts on this subject based on the ideXlab platform.

Isao Nakanishi – One of the best experts on this subject based on the ideXlab platform.

Virgilio Mattoli – One of the best experts on this subject based on the ideXlab platform.

Anthony Poon – One of the best experts on this subject based on the ideXlab platform.

  • antinociceptive and anti inflammatory properties of an Adenosine kinase Inhibitor and an Adenosine Deaminase Inhibitor
    European Journal of Pharmacology, 1999
    Co-Authors: Anthony Poon, Jana Sawynok

    Spinal administration of an Adenosine kinase Inhibitor, alone or in combination with an Adenosine Deaminase Inhibitor, produces antinociception in inflammatory pain tests. In the present study, we examined the antinociceptive and anti-inflammatory effects produced by the peripheral (intraplantar) administration of 5′-amino-5′-deoxyAdenosine (an Adenosine kinase Inhibitor), 2′-deoxycoformycin (an Adenosine Deaminase Inhibitor), and combinations of both agents in the carrageenan-induced thermal hyperalgesia and paw oedema model in the rat. When injected in the ipsilateral paw immediately prior to carrageenan injection, both agents produced antinociception only at the highest dose (1 micromol), whereas a reduction in paw swelling was evident at a lower dose (300 nmol). Significant augmentation in both the antinociceptive and anti-inflammatory effects was seen when 5′-amino-5′-deoxyAdenosine and 2′-deoxycoformycin were co-administered in equimolar doses at all dose levels. Both effects were mediated via activation of Adenosine receptors, as indicated by blockade by an Adenosine receptor antagonist. When administered into the contralateral paw, 1 micromol 5′-amino-5′-deoxyAdenosine+1 micromol 2′-deoxycoformycin produced prominent antinociception, indicating a systemic drug activity. There was only a modest reduction in paw oedema in the carrageenan-injected (ipsilateral) paw, suggesting that much of this activity was locally mediated. Reversal of systemic effects on thermal thresholds by an intrathecal Adenosine receptor antagonist implicates a spinal site of action in this instance. An ipsilateral administration of 1 micromol 5′-amino-5′-deoxyAdenosine, but not 1 micromol 2′-deoxycoformycin, reduced carrageenan-induced c-Fos expression in the spinal dorsal horn, and this was further reduced by the peripheral co-injection of the two agents. These results provide evidence for a predominantly spinal antinociceptive effect and a predominantly peripheral anti-inflammatory effect produced by Inhibitors of Adenosine kinase and Adenosine Deaminase.

  • peripheral antinociceptive effect of an Adenosine kinase Inhibitor with augmentation by an Adenosine Deaminase Inhibitor in the rat formalin test
    Pain, 1998
    Co-Authors: Jana Sawynok, Allison Reid, Anthony Poon

    Abstract This study examined the ability of an Adenosine kinase Inhibitor (5′-amino-5′-deoxyAdenosine; NH2dAD), an Adenosine Deaminase Inhibitor (2′-deoxycoformycin), and combinations of these agents to produce a peripheral modulation of the pain signal in the low concentration formalin model. Drugs were administered in combination with 0.5% formalin, or into the contralateral hindpaw to test for systemic effects, and episodes of flinching behaviors determined. Coadministration of NH2dAD 0.1–100 nmol with formalin produced antinociception as revealed by an inhibition of flinching behaviors. This action was peripherally mediated as it was not seen following contralateral administration of the NH2dAD, and was due to accumulation of Adenosine and activation of cell surface Adenosine receptors as it was blocked by the Adenosine receptor antagonist caffeine. Antinociception was intensity-dependent, as it was not seen when higher concentrations of formalin (0.75%, 1.5%) were used. The coadministration of the selective Adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine revealed the presence of an Inhibitory tone of Adenosine when the intrinsic antinociceptive effect of NH2dAD was obscured by the solvent or the stimulus intensity. 2′-Deoxycoformycin 0.1–100 nmol did not produce any intrinsic effect, but 100 nmol coadministered with low concentrations of NH2dAD, which lacked an intrinsic effect, augmented antinociception by NH2dAD. Again, this was a peripheral rather than a systemic response. The combined action of the Adenosine kinase and Deaminase Inhibitors was completely reversed by coadministration of caffeine. Antinociception with NH2dAD is observed at higher concentrations of formalin in second trial experiments. This study demonstrates a peripheral antinociceptive action mediated by endogenous Adenosine which accumulates following the peripheral inhibition of Adenosine kinase; this action is due to activation of an Adenosine A1 receptor.

  • antinociception by Adenosine analogs and Inhibitors of Adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat
    Pain, 1998
    Co-Authors: Anthony Poon, Jana Sawynok

    Abstract The present study examined the spinal antinociceptive effects of Adenosine analogs and Inhibitors of Adenosine kinase and Adenosine Deaminase in the carrageenan-induced thermal hypehyperalgesia model in the rat. The possible enhancement of the antinociceptive effects of Adenosine kinase Inhibitors by an Adenosine Deaminase Inhibitor also was investigated. Unilateral hindpaw inflammation was induced by an intraplantar injection of lambda carrageenan (2 mg/100 μ l), which consistently produced significant paw swelling and thermal hypehyperalgesia. Drugs were administered intrathecally, either by acute percutaneous lumbar puncture (individual agents and combinations) or via an intrathecal catheter surgically implanted 7–10 days prior to drug testing (antagonist experiments). N 6 -cyclohexylAdenosine (CHA; Adenosine A 1 receptor agonist; 0.01–1 nmol), 2-[ p -(2-carboxyethyl)phenylethylamino]-5′- N -ethylcarboxamidoAdenosine (CGS21680; Adenosine A 2A receptor agonist; 0.1–10 nmol), 5′-amino-5′-deoxyAdenosine (NH 2 dAdo; Adenosine kinase Inhibitor; 10–300 nmol), and 5-iodotubercidin (ITU; Adenosine kinase Inhibitor; 0.1–100 nmol) produced, to varying extents, dose-dependent antinociception. No analgesia was seen following injection of 2′-deoxycoformycin (dCF; an Adenosine Deaminase Inhibitor; 100–300 nmol). Reversal of drug effects by caffeine (non-selective Adenosine A 1 /A 2 receptor antagonist; 515 nmol) confirmed the involvement of the Adenosine receptor, while antagonism by 8-cyclopentyl-1,3-dimethylxanthine (CPT; Adenosine A 1 receptor antagonist; 242 nmol), but not 3,7-dimethyl-1-propargylxanthine (DMPX; Adenosine A 2A receptor antagonist; 242 nmol), evidenced an Adenosine A 1 receptor mediated spinal antinociception by NH 2 dAdo. dCF (100 nmol), which was inactive by itself, enhanced the effects of 10 nmol and 30 nmol NH 2 dAdo. Enhancement of the antinociceptive effect of ITU by dCF was less pronounced. None of the antinociceptive drug regimens had any effect on paw swelling. These results demonstrate that both directly and indirectly acting Adenosine agents, when administered spinally, produce antinociception through activation of spinal Adenosine A 1 receptors in an inflammatory model of thermal hypehyperalgesia. The spinal antinociceptive effects of selected Adenosine kinase Inhibitors can be significantly augmented when administered simultaneously with an Adenosine Deaminase Inhibitor.

John W. Phillis – One of the best experts on this subject based on the ideXlab platform.