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Methods and compositions for mitigating pain

a technology of nitrate and esters, which is applied in the direction of drug compositions, phosphorous compound active ingredients, nitro compound active ingredients, etc., can solve the problem that no attempt has been made to develop organic nitrates themselves as analgesic agents, and achieve the effect of raising cgmp levels

Inactive Publication Date: 2007-03-22
QUEENS UNIV OF KINGSTON
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, no attempt has been made to develop organic nitrates themselves as analgesic agents, that is, organic nitrates that do not rely on an ASA or NSAID moiety, nor an opiate, for analgesic properties.

Method used

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  • Methods and compositions for mitigating pain
  • Methods and compositions for mitigating pain
  • Methods and compositions for mitigating pain

Examples

Experimental program
Comparison scheme
Effect test

example 1

Characterization of Guanylyl Cyclase Activation

[0136] Activation of soluble guanylyl cyclase (GCase) by nitrates IIIm, IVa, IVb, WVd, IVe, WVf, Ig, WVj, Va, Vb, and GTN was assayed employing partially purified enzyme freshly prepared from the 105,000 g supernatant fraction of rat aorta homogenates, using the radioimmunoassay method described by Bennett et al. (1992). Dose-response curves were obtained for GCase activation by nitrates IVa, IVb, IVd, IVe, IVf, IVg, IVj, and GTN in the presence and absence of cysteine and dithiothreitol (DTT; both 2mM). In all cases, data were normalized to the maximal GTN response carried out in identical GCase preparations. Experimental incubations were performed at 37° C for 10 min. The data for WVd is summarized in FIG. 1. The GCase assay data show that WVd activates GCase, with a submiulimolar EC-50 (effective concentration for 50% of the subjects) in the absence of any added thiol, in contrast to GTN, which requires added cysteine. Compounds WV...

example 2

Characterization of Cyclic GMP Accumulation

[0140] In order to extend the GCase data further, the effects of nitrates Va, IlIm, Vb, Vc, and WVk on cyclic GMP accumulation in intact isolated rat aorta were examined (FIGS. 4, 5). Thoracic aortic strips were prepared from male Sprague-Dawley rats (Charles-River, Canada) as described in McGuire et al. (1994) and Stewart et al. (1989). Tissues were contracted submaximally with phenylephrine (0.1CtM) and exposed to various concentrations of drug for 1 min. Cyclic GMP accumulation was determined using the radioitnmunoassay method described by Bennett et al. (1992). At concentrations of 1 liM and 10 AM, GTN and WVk significantly increased cGMP accumulation (FIGS. 5). At a concentration of 1 AM, Va, IIlm, Vb, and Vc did not significantly increase cyclic GMP accumulation (FIGS. 4a, 5a). At a concentration of 10 [tM, Va, Vb, and WVk significantly increased cyclic GMP accumulation whereas IIIm and Vc did not (FIGS. 4b, 5b).

[0141] Sections of ...

example 3

Characterization of Relaxation of Isolated Blood Vessels

[0142] In order to extend the GCase data, the relaxing effects of nitrates Illm, WVc, WVd, WVf, WVg, WVh, Wk, Va, Vb, and Vc on rat aortic tissue were examined. Thoracic aortic strips were prepared from male Sprague-Dawley rats (Charles-River, Canada) as described in McGuire et al. (1994), and Stewart et al. (1989). Tissues were contracted submaximally with phenylephrine (0.1 pM) and exposed to various concentrations of nitrovasodilator to obtain concentration-response curves. In this intact tissue assay, all of the nitrates were observed to cause relaxation of the tissue with a maximal relaxant response equal to that obtained with GTN. However, the compounds differed in potency, with EC-50 values of 7.87 nM, 94.3 nM, 6.59 ,M, 25.2 tM, 11.0 μM, and 0.203 μM, for GTN and compounds Va, IVd, IVg, WVf, and IVc, respectively (FIG. 7,8). In another series of experiments, the EC-50 values for relaxation were 0.61 nM, 3.19 nM, 8.40 n...

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Abstract

Methods and therapeutic compounds for treating pain, mitigating inflammation, effecting analgesia and / or effecting sedation in a subject are described. A subject is administered an effective amount of a therapeutic compound which is a nitrate ester. Novel pharmaceutical compositions are also described.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] The application is a continuation of U.S. Ser. No. 09 / 473,713, filed Dec. 29, 1999, which is incorporated herein by reference.FIELD OF THE INVENTION [0002] This invention relates to nitrate esters and use thereof in mitigating pain and effecting analgesia. More particularly this invention relates to organic nitrates which have therapeutic utility as analgesics, anti-inflammatory agents and sedatives. BACKGROUND OF THE INVENTION [0003] The nitrate ester, glyceryl trinitrate (GTN), or nitroglycerin, has been used as a vasodilator in the treatment of angina pectoris for over a hundred years, and the dominant, contemporary belief is that GTN exerts its therapeutic effect through in tivo release of nitric oxide (NO). Other organic nitrates (nitrate esters), such as isosorbide dinitrate, have also been identified as effective and clinically important vasodilators. NO itself has been identified as Endothelium Derived Relaxing Factor (EDRF) and...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/66A61K31/54A61K31/426A61K31/21A61K31/00C07D295/12A61K31/04A61K31/216A61K31/223A61K31/235A61K31/24A61K31/255A61K31/26A61K31/265A61K31/275A61K31/36A61K31/37A61K31/38A61K31/381A61K31/385A61K31/39A61K31/40A61K31/401A61K31/404A61K31/407A61K31/415A61K31/416A61K31/425A61K31/47A61K31/495A61K31/506A61K31/522A61K31/5375A61K31/575A61K31/662A61K38/00A61P23/00A61P25/04A61P25/20A61P25/22A61P29/00C07C203/04C07C203/06C07C205/40C07C309/12C07C317/18C07C323/12C07C323/20C07C323/58C07C323/62C07C327/28C07C331/10C07D207/16C07D207/32C07D207/337C07D209/26C07D215/36C07D231/12C07D277/24C07D277/28C07D295/088C07D307/33C07D311/16C07D311/18C07D317/60C07D327/04C07D331/02C07D333/42C07D333/44C07D333/48C07D339/08C07D409/04C07D411/04C07D473/04C07D473/08C07D487/04C07D491/04C07D491/052C07F9/38C07F9/40C07J9/00C07J41/00
CPCA61K31/00C07J41/0061A61K31/21A61K31/275A61K31/381A61K31/385A61K31/39A61K31/426A61K31/5375C07C203/04C07C203/06C07C205/40C07C309/12C07C317/18C07C323/12C07C323/20C07C323/58C07C323/62C07C327/28C07C331/10C07D207/16C07D207/337C07D277/24C07D295/088C07D307/33C07D311/16C07D317/60C07D327/04C07D333/44C07D333/48C07D339/08C07D409/04C07D487/04C07D491/04C07F9/3808C07F9/4006C07J41/0055A61K31/04A61P23/00A61P25/04A61P25/20A61P25/22A61P29/00
Inventor THATCHER, GREGORY R.J.BENNETT, BRIAN M.REYNOLDS, JAMES N.JHAMANDAS, KHEM
Owner QUEENS UNIV OF KINGSTON
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