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Methods and compositions comprising nitric oxide donors and opioid analgesics

An opioid and nitric oxide technology, applied in the field of μ-opioid receptor agonists and compounds of opioid receptors, can solve problems such as confusion and difficulty in explaining the cause of PDN.

Inactive Publication Date: 2005-11-30
THE UNIV OF QUEENSLAND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This confusion of observations, combined with differences in animal and human models of diabetes, complicates the interpretation of the causes of PDN

Method used

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  • Methods and compositions comprising nitric oxide donors and opioid analgesics
  • Methods and compositions comprising nitric oxide donors and opioid analgesics
  • Methods and compositions comprising nitric oxide donors and opioid analgesics

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0100] Evaluation of transient allodynia of μ-opioid receptor agonists in STZ diabetic rats ability

[0101] Materials and methods

[0102] Jugular cannulation and diabetes induction

[0103] Deep and stable anesthesia was induced using a mixture of ketamine (100 mg / kg, intraperitoneal) and xylazine (16 mg / kg, intraperitoneal) in order to insert a polyethylene tube (previously filled with 0.1 ml sterile saline) into the right cervical cavity. vein. Test that the jugular vein is placed correctly by drawing a small amount of blood. Diabetes was induced by rapid intravenous injection of streptozotocin (STZ) (85 mg / kg) in 0.1 M citrate buffer into the jugular vein.

[0104] Diabetes was confirmed by monitoring water intake and blood glucose concentrations in individual rats. For rapid research use, use Glucostix TM or Precision QID TM Test kit to monitor blood sugar.

[0105] Consistent with standard procedures accepted in the art, rats that drank more than 100 ml of ...

Embodiment 2

[0139] L-arginine restores the analgesic ability of opioid receptor agonists in PDN

[0140] Materials and methods

[0141] Study Design, L-Arginine Administration and Opioid Dosage Regimen

[0142] This study included 3 groups of STZ-diabetic DA rats: Group 1 STZ-diabetic DA rats (n=25, 256±3.6g, mean±SEM) were studied continuously over a period of 6 months, individual rats Received: (i) one of 3 bolus doses of subcutaneous morphine or oxycodone to generate dose-response curves at 9, 12 and 24 weeks after STZ administration, or (ii) morphine and / or 16 and 20 weeks after STZ administration Oxycodone ED 50 dose. In some instances of the crossover experiments, rats in each experimental group had two or three opportunities to receive a single subcutaneous dose of morphine or oxycodone, with a full 4-day washout between doses. At week 9 after STZ administration, STZ-diabetic rats of Group 1 were subjected to dietary intervention with L-arginine supplementation (1 g per day...

Embodiment 3

[0203] Preparation of morphine-nitric oxide conjugate 1

[0204] Morphine 1

[0205] Morphine hydrochloride trihydrate (1.5 g) was dissolved in a minimum amount of water (RO form) (-20 mL) and sufficient saturated sodium bicarbonate was added to precipitate the morphine. Morphine 1 was collected by vacuum filtration and washed first with distilled water (20 mL) and then with a small amount of cold diethyl ether (5 mL). The white solid was protected from light with aluminum foil and placed under high vacuum (0.01 mmHg) for 3 hours.

[0206] 5-Nitrovaleric acid 2

[0207] The title compound was prepared according to the method of EP 0 984 012 A2 (K.M. Lundy, M.T. Clark). Briefly, silver nitrate (23.48 g, 0.153 mol) was pre-dried under high vacuum (0.01 mmHg) and then dissolved in anhydrous acetonitrile (70 mL) under argon atmosphere. The solution was heated to 50°C, and 5-bromovaleric acid (5 g, 0.028 mol) (dissolved in anhydrous acetonitrile (3 mL)) was added rapidly by s...

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Abstract

Compositions and methods that induce, promote or otherwise facilitate pain relief are disclosed. These compositions and methods comprise a nitric oxide donor which either directly or indirectly prevents, attenuates or reverses the development of reduced opioid sensitivity, together with a compound which activates the opioid receptor that is the subject of the reduced opioid sensitivity. The compositions and methods prevent or alleviate pain, especially in neuropathic conditions and even more especially in peripheral neuropathic conditions such as painful diabetic neuropathy (PDN). The preferred nitric oxide donor is L-arginine whilst the preferred compounds which activate the opioid receptor are morphine and oxycodone. Conjugate compounds comprising the nitric oxide donor and an opioid analgesic are also disclosed.

Description

field of invention [0001] The present invention generally relates to compositions and methods for inducing, promoting or facilitating pain relief. More particularly, the invention relates to the use of compounds that directly or indirectly prevent, reduce or reverse the development of reduced opioid sensitivity, as well as opioids that activate the subject of reduced opioid sensitivity, in methods or compositions for preventing or alleviating pain Compounds that resemble substance receptors. Even more particularly, the present invention is contemplated in vertebrate (particularly human) subjects in pain-related conditions, especially in neuropathic conditions, more particularly in conditions such as painful diabetic neuropathy In peripheral neuropathy disorders such as (PDN), the use of two or more compounds reduces the symptoms of pain. These compounds may be provided alone or in combination with other compounds such as compounds useful for the management of neuropathic con...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K31/00A61P25/04C07D489/04C07D489/08
CPCA61K31/00A61K47/481A61K31/137C07D489/08C07D489/04A61K47/55A61P25/04
Inventor M·T·史密斯L·布朗M·B·P·哈维C·M·威廉斯
Owner THE UNIV OF QUEENSLAND