Synergistic formulations of adenosine receptor modulating agents and anticholinergics
Inventors
LAUGHLIN, Bernard • Drew, Kelly
Assignees
University of Alaska Fairbanks
Publication Number
US-11911408-B2
Publication Date
2024-02-27
Expiration Date
2042-03-11
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Abstract
The present disclosure provides a pharmaceutical composition comprising i) an A1 adenosine receptor (A1AR) agonist, ii) an A1AR antagonist, and iii) an anticholinergic. Kits utilizing i) an A1 adenosine receptor (A1AR) agonist, ii) an A1AR antagonist, and iii) an anticholinergic are also provided, as well as methods utilizing the described pharmaceutical compositions and kits.
Core Innovation
The present disclosure provides pharmaceutical compositions comprising an A1 adenosine receptor (A1AR) agonist, an A1AR antagonist, and an anticholinergic. This formulation achieves synergistic effects, allowing for precise suppression of metabolism while preventing concomitant hypotension and bradycardia often associated with A1AR agonist therapy. Specifically, compositions may include 6N-cyclohexyladenosine (CHA) as the A1AR agonist, 8-(p-sulfophenyl)theophylline (8-SPT) as the A1AR antagonist, and atropine or glycopyrrolate as the anticholinergic agent.
The problem addressed relates to limitations of A1AR agonist therapy in clinical scenarios such as cardiac arrest, stroke, or cold-induced metabolic responses, where the desired metabolic depression is accompanied by severe, sometimes life-threatening side effects like hypotension and bradycardia. Monotherapies or simple combinations, such as using peripherally acting antagonists or anticholinergics alone, failed to fully resolve these unwanted effects, especially the initial centrally mediated hypotension following systemic administration of A1AR agonists.
The invention demonstrates that the use of all three agents, particularly the combination of a peripherally acting A1AR antagonist and an anticholinergic with the A1AR agonist, provides unexpected and synergistic mitigation of both central and peripheral hypotension while enabling robust metabolic suppression. The pharmaceutical compositions and methods described offer more precise control of metabolic rate and core body temperature, without the cardiovascular risks previously observed, representing a significant advancement over prior therapeutic approaches.
Claims Coverage
The patent's independent claims cover multiple inventive features involving a synergistic pharmaceutical composition, specific component ratios, functionally synergistic effects, and associated kits.
Pharmaceutical composition of CHA, 8-SPT, and atropine
A pharmaceutical composition comprising: - an A1 adenosine receptor (A1AR) agonist comprising 6N-cyclohexyladenosine (CHA), - an A1AR antagonist comprising 8-(p-sulfophenyl)theophylline (8-SPT), and - an anticholinergic, wherein the anticholinergic is atropine.
Pharmaceutical composition with specified agonist:antagonist ratios
A pharmaceutical composition wherein the ratio of A1AR agonist (CHA) to A1AR antagonist (8-SPT) is defined, the ratios being selected from a group including 25:1, 24:1, 23:1, 22:1, 21:1, 20:1, 19:1, 18:1, 17:1, 16:1, 15:1, 14:1, 13:1, 12:1, 11:1, 10:1, and 1:1 (mg/kg:mg/kg).
Pharmaceutical composition with defined triple-component ratios
A pharmaceutical composition comprising CHA, 8-SPT, and atropine with specified ratios of all three components (mg/kg:mg/kg:mg/kg), including but not limited to 25:1:1, 24:1:1, 23:1:1, 22:1:1, 21:1:1, 20:1:1, 19:1:1, 18:1:1, 17:1:1, 16:1:1, 15:1:1, 14:1:1, 13:1:1, 12:1:1, 11:1:1, 10:1:1, 10:10:1, and 10:15:1.
Pharmaceutical composition providing synergistic suppression of metabolism
A pharmaceutical composition as described above, wherein the combination provides synergistic suppression of metabolism. Furthermore, said suppression of metabolism occurs without concomitant hypotension.
Synergistic mitigation of CHA-induced effects
A pharmaceutical composition, as detailed, that provides synergistic mitigation of CHA-induced effects, including hypotension, centrally-mediated hypotension, peripherally-mediated hypotension, bradycardia, metabolic suppression, hypothermia, decreased rate of oxygen consumption, and decreased mean arterial pressure (MAP).
Kit containing the pharmaceutical components and carrier
A kit comprising: - CHA (A1AR agonist), - 8-SPT (A1AR antagonist), - an anticholinergic (atropine or glycopyrrolate), and - a pharmaceutically acceptable carrier, with the option for defined component ratios.
In summary, the patent claims inventive combinations and specific ratios of A1AR agonist, antagonist, and anticholinergic agents, with demonstrated functional synergy for suppressing metabolism while avoiding cardiovascular side effects, as well as kits containing these combinations.
Stated Advantages
Precise control of metabolic rate and core body temperature is achievable using the disclosed pharmaceutical compositions.
The compositions prevent hypotension and bradycardia that are otherwise associated with A1 adenosine receptor agonist therapy.
Unexpected synergistic effects allow for metabolic depression without concomitant hypotension, improving patient safety.
Use of the described composition increased survival rates in rats after cardiac arrest compared to the current standard of care.
The combinations permit the therapeutic benefits of A1AR agonists while mitigating undesirable side effects.
Documented Applications
Use during targeted temperature management in critical care following cardiac arrest.
Treatment to improve survival and neurological outcome after cardiac arrest and stroke.
Inhibition of cold-induced metabolic response during cold exposure.
Control of metabolism and core body temperature during therapeutic hypothermia.
Potential applications as an anticonvulsant, neuroprotectant, or for treating any condition addressed by activating CNS A1 adenosine receptors.
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