Looking for breakthrough ideas for innovation challenges? Try Patsnap Eureka!

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
View PDF4 Cites 3 Cited by
  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is based on the discovery that organic nitrates can have both beneficial and harmful effects on pain and inflammation. The invention provides methods and compositions for using organic nitrates to treat and mitigate pain, inflammation, and other related conditions. By regulating the balance between the nitrate's ability to release NO and its potency for GCase activation, the invention achieves the optimal therapeutic effect. The invention also takes advantage of the gastrointestinal toxicity of some analgesic drugs, using organic nitrates as a safer alternative. The therapeutic compounds used in the invention interact with guanylyl cyclase and modulate levels of cyclic nucleotides. The invention provides methods for treating pain, inflammation, and other related conditions using organic nitrates.

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
View more

Image

Smart Image Click on the blue labels to locate them in the text.
Viewing Examples
Smart Image
  • 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...

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

PUM

PropertyMeasurementUnit
RIaaaaaaaaaa
temperatureaaaaaaaaaa
temperatureaaaaaaaaaa
Login to View More

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

the structure of the environmentally friendly knitted fabric provided by the present invention; figure 2 Flow chart of the yarn wrapping machine for environmentally friendly knitted fabrics and storage devices; image 3 Is the parameter map of the yarn covering machine
Login to View More

Application Information

Patent Timeline
no application Login to View More
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
Who we serve
  • R&D Engineer
  • R&D Manager
  • IP Professional
Why Patsnap Eureka
  • Industry Leading Data Capabilities
  • Powerful AI technology
  • Patent DNA Extraction
Social media
Patsnap Eureka Blog
Learn More
PatSnap group products

Browse by: Latest US Patents, China's latest patents, Technical Efficacy Thesaurus, Application Domain, Technology Topic, Popular Technical Reports.

© 2024 PatSnap. All rights reserved.Legal|Privacy policy|Modern Slavery Act Transparency Statement|Sitemap|About US| Contact US: help@patsnap.com