Use of drug combinations for treating insulin resistance
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Publication Number
US-8673964-B2
Publication Date
2014-03-18
Expiration Date
Abstract
The present invention provides pharmaceutical compositions comprising: (a) a modulator of hepatic parasympathetic tone, (b) at least one diabetes drug, and (c) a pharmaceutically acceptable carrier. The present invention includes methods for the treatment and/or prevention of insulin resistance, type 2 diabetes, impaired glucose intolerance, and other associated disorders with pharmaceutical compositions described herein. The invention also provides for a kit comprising a pharmaceutical composition and instructions for its use.
Core Innovation
The invention relates to combination therapies for HISS-dependent insulin resistance (HDIR) and associated type 2 diabetes by modulating feeding-driven hepatic parasympathetic tone. The described concept links acetylcholine signaling through muscarinic receptors to nitric oxide (NO) generation, then to cGMP, which is associated with HISS release. Hepatic parasympathetic signaling interruption leads to insulin resistance.
The invention also relates to increasing hepatic glutathione (GSH) as part of the insulin-sensitizing approach for HDIR. Hepatic GSH elevations contribute to the maintenance of the hepatic insulin sensitizing pathway in connection with HISS release. Accordingly, the disclosed compositions include bethanechol and N-acetylcysteine together with a pharmaceutically acceptable carrier.
The patent further describes complementary NO-related and parasympathetic tone-related combination approaches using NO donors and cholinergic interventions. Reported composition examples include pairing bethanechol with N-acetylcysteine and pairing bethanechol with a NO donor such as SIN-1, with synergy described for improved insulin sensitivity. The patent additionally describes hepatic denervation reversal experiments in which combining a parasympathetic tone-modulating agent with a NO donor shows synergistic reversal.
Claims Coverage
The independent claim provides coverage for a pharmaceutical composition with two named active components and a pharmaceutically acceptable carrier, subject to the limitation that the composition does not comprise a growth factor. The relevant dependent claims add further component limitations such as specific chemical forms, liver-targeting substances, and enumerated ingredient sets.
Bethanechol plus N-acetylcysteine pharmaceutical composition without growth factor
A pharmaceutical composition comprising bethanechol, N-acetylcysteine, and a pharmaceutically acceptable carrier, where the composition does not comprise a growth factor.
Nitrosylated bethanechol composition
A pharmaceutical composition in which bethanechol is nitrosylated.
Liver-targeting substance selection for the composition
A pharmaceutical composition further including a pharmaceutically acceptable liver-targeting substance selected from albumin, a liposome, or a bile salt.
Therapeutic use for type II diabetes and related glycemic disorders
A method for treating or inhibiting type II diabetes, insulin resistance, or impaired glucose intolerance by administering a therapeutically effective amount of the pharmaceutical composition.
Antioxidant selection for the composition
A pharmaceutical composition in which its antioxidant is chosen from vitamin E, vitamin C, an isoflavone, zinc, selenium, ebselen, or a carotenoid.
Across the relevant independent and dependent claim set, coverage centers on a bethanechol and N-acetylcysteine pharmaceutical composition without growth factors, with additional optional limitations including nitrosylated bethanechol, liver-targeting substances, therapeutic-use administration for type II diabetes, insulin resistance, or impaired glucose intolerance, and predefined antioxidant selections.
Stated Advantages
Improved insulin sensitivity is described, including synergistic improvements when combining bethanechol with N-acetylcysteine relative to either alone.
Synergistic reversal of hepatic denervation-associated effects is described when combining bethanechol and SIN-1.
Combination therapy is described as improving measures of glycemic control in reported models and a described human meal-test study design.
Documented Applications
Sucrose-fed rat model evaluations of insulin sensitivity are described using the rapid insulin sensitivity test (RIST) index for combinations including bethanechol plus N-acetylcysteine and related examples.
Hepatic denervation reversal experiments are described, including synergy when combining bethanechol with SIN-1.
An open-label human meal-test study design is described for bethanechol plus N-acetylcysteine in pre/diabetic males with endpoints including postprandial hyperglycemia.
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