Methods and compositions for treatment of peripheral neuropathies

A technology for peripheral neuropathy and drugs, which can be applied to nervous system diseases, drug combinations, active ingredients of heterocyclic compounds, etc., and can solve problems such as huge costs

Pending Publication Date: 2020-12-11
UNIVERSITY OF MANITOBA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

For health systems, the costs of providing relief from these symptoms are enormous

Method used

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  • Methods and compositions for treatment of peripheral neuropathies
  • Methods and compositions for treatment of peripheral neuropathies
  • Methods and compositions for treatment of peripheral neuropathies

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0144] In previous work, we showed that pirenzepine prevents and reverses small fiber neuropathy in diabetes. We now demonstrate that pirenzepine is also able to prevent large fiber motor nerve conduction velocity (MNVC) slowing in streptozotocin-induced (STZ-induced) diabetic rats ( figure 2 (A)) and sensory nerve conduction velocity (SNCV) slowed ( figure 2 (B)). The STZ rat is a model of type 1 diabetes. According to the method taught by Calcutt et al. (2003, Therapeutic efficacy of sonic hedgehog protein in experimental diabetic neuropathy, J.Clin.Invest.111:507-514), rats were treated with 5 mg / kg (s.c.) pirenzepine for 8 weeks. Nerve conduction velocity was measured according to the method taught by Mizisin et al. (NCV). The data showed that diabetes induced a time-dependent slowing of large fiber motor and sensory NCV (both p<0.01 vs control at 8 weeks of diabetes) and that pirenzepine treatment attenuated these conditions (both p<0.05 vs vehicle treatment (veh...

Embodiment 2

[0146] Cultured adult sensory neuronal subpopulations of age-matched control rats or 3-5 month STZ-induced diabetic rats were treated with a 1.0 μM pirenzepine-HCl dose. The first subpopulation was treated immediately, while the second, third and fourth subpopulations of neurons from control rats and diabetic rats were treated with pirenzepine 15 min, 30 min and 60 min later, respectively deal with. Cell cultures were lysed and used to prepare Western blots, which were probed with antibodies against phosphorylated AMPK (P-AMPK), total AMPK (T-AMPK) and total ERK (T-ERK). image 3 (A) shows gels produced by cultures of age-matched control rats, while image 3 (C) shows gels produced by cultures of diabetic rats. data displayed in image 3 In (B) and 3(D), wherein the Y-axis represents the protein levels quantified by blots in (A) and (C) and normalized to the control, it is shown that pirenzepine significantly activates normal rats ( image 3 (B)) and type 1 diabetic rats (...

Embodiment 3

[0148] Adult sensory neuron cultures from STZ-induced diabetic rats were treated with 1.0 μM pirenzepine following the procedure taught by Roy Chowdhury et al. (2012), with two adenoviruses overexpressing dominant-negative mutants of AMPK, the AMPK subunit The 1 and 2 mutants, termed "AdDN1" and "AdDN2" (the adenovirus overexpressing dominant negative mutants were a gift from Dr. Jason Dyck of the University of Alberta) were transduced two days after treatment. Figure 4 (A) and 4(B) are GFP fluorescence micrographs of adult rat sensory neuron cultures transduced with a control adenoviral vector expressing only GFP, where Figure 4 (A) Not receiving pirenzepine treatment while Figure 4 (B) Received pirenzepine treatment. Figure 4 (C) and 4(D) are GFP fluorescence micrographs of adult rat sensory neurons transduced with "AdDN" dominant-negative AMPK mutant, where Figure 4 (C) Not receiving pirenzepine treatment while Figure 4 (D) Received pirenzepine treatment. Figure ...

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Abstract

A composition for therapy of a peripheral neuropathy disorder in a subject in need thereof. The composition comprises an effective amount of an agent selected from a group consisting of pirenzepine, oxybutynin, muscarinic toxin 7, a muscarinic receptor antagonist, and combinations thereof, and a pharmacologically acceptable carrier and / or an excipient. The composition is useful for therapy of peripheral neuropathies exemplified by peripheral neuropathies induced by systemic diseases, peripheral neuropathies induced by metabolic diseases, chemotherapy-induced peripheral neuropathies, compression-induced peripheral neuropathies, peripheral neuropathies induced by exposure to dichloroacetate, immune- mediated peripheral neuropathies, peripheral neuropathies induced by infections, and genetically acquired peripheral neuropathies.

Description

[0001] field of invention [0002] The present invention relates to compositions for treating peripheral neuropathy, uses of such compositions, and methods of using such compositions. Background technique [0003] Peripheral neuropathy is a clinical problem in people afflicted with diabetes or treated with chemotherapeutic agents. Infections such as HIV and leprosy can also cause peripheral neuropathy. Clinical symptoms can include upper back and / or abdominal pain (ie, thoracoabdominal neuropathy), uncontrolled eye movements (ie, third nerve palsy), and progressive loss of neurological function including the peripheral nervous system (eg, polyneuropathy, mononeuropathy , mononeuritis simplex, autonomic neuropathy). Peripheral neuropathy includes: neuropathy associated with diabetes (diabetic neuropathy), neuropathy associated with HIV, neuropathy associated with nutritional deficiency, cranial nerve palsies, drug-induced neuropathy, industrial neuropathy, lymphomatous neurop...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61P25/02
CPCA61K9/0014A61K9/0019A61K9/0048A61K38/1767A61P25/02A61K31/352A61K31/216A61K31/496A61K31/46A61K45/06A61K31/5513A61K9/0053A61K2300/00
Inventor 保罗·弗尼豪奈吉尔·卡尔库特
Owner UNIVERSITY OF MANITOBA
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