Methods and compositions for the treatment of ischemic injury to tissue using therapeutic hypothermia
Inventors
Drew, Kelly • Jinka, Tulasi • Bogren, Lori • Bailey, Isaac • Carlson, Zachary • Olson, Jasmine
Assignees
University of Alaska Fairbanks
Publication Number
US-10092591-B2
Publication Date
2018-10-09
Expiration Date
2034-02-27
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Abstract
Disclosed are compositions and methods for inducing therapeutic hypothermia in a subject.
Core Innovation
The invention discloses compositions and methods for inducing therapeutic hypothermia in a subject through the administration of at least one A1 adenosine receptor (A1AR) agonist and at least one A1AR antagonist. The invention specifically details the use of A1AR agonists that cross the blood-brain barrier, such as capadenoson or a combination of capadenoson with N6-cyclohexyladenosine (CHA), along with the A1AR antagonist 8-p-sulfophenyltheophylline (8-SPT), which does not cross the blood-brain barrier.
The invention is aimed at solving the problem of effective induction and maintenance of therapeutic hypothermia for treating ischemic brain injury, particularly following cardiac arrest, by pharmacologically modulating body temperature. Conventional cooling techniques are limited by issues such as shivering, making them less effective and uncomfortable, especially in conscious patients. The disclosed methods overcome these limitations by pharmacologically suppressing shivering and allowing dose-responsive, predictable induction of hypothermia.
Additional aspects include maintenance of hypothermia by repeated or continuous administration of the agonist/antagonist combination, titration of the antagonist to minimize side effects, and the possibility of enhancing hypothermia induction under dietary restrictions. The compositions and methods may also be used in conscious subjects and involve a variety of administration routes, including intraperitoneal, intravenous, subcutaneous, intramuscular, by cutaneous patch, and oral.
Claims Coverage
There are two main independent inventive features defined by the claims in this patent.
Treating ischemic brain injury with specific A1AR agonist-antagonist combination
A method of treating ischemic brain injury caused by cardiac arrest in a subject by administering a therapeutically effective amount of an A1 adenosine receptor (A1AR) agonist and an A1AR antagonist, where the A1AR agonist is capadenoson or a combination of capadenoson with N6-cyclohexyladenosine (CHA), and the A1AR antagonist is 8-p-sulfophenyltheophylline (8-SPT). The A1AR agonist must cross the blood-brain barrier and the A1AR antagonist must not cross the blood-brain barrier. Treating ischemic brain injury involves alleviating shivering in the subject.
Controlling core body temperature using A1AR agonist and antagonist
A method of controlling core body temperature in a subject by administering a therapeutically effective amount of an A1AR agonist and an A1AR antagonist, where the A1AR agonist is capadenoson or a combination of capadenoson with CHA, and the A1AR antagonist is 8-SPT. The method requires the A1AR agonist to cross the blood brain barrier, the antagonist to not cross the blood-brain barrier, and the A1AR agonist to alleviate shivering.
The inventive features provide methods for treating ischemic brain injury and controlling core body temperature by defined use of specific A1AR agonists and antagonists, with selectivity for blood-brain barrier permeability and mitigation of shivering.
Stated Advantages
Enables predictable, dose-responsive induction of hypothermia using pharmaceutical compositions.
Allows induction and maintenance of therapeutic hypothermia without reliance on mechanical cooling devices, thus reducing unwanted side effects such as shivering.
Suppresses shivering and nonshivering thermogenesis, enabling effective hypothermia even in conscious subjects.
Provides a safer and less expensive alternative compared to mechanical cooling methods.
Mitigates peripheral side effects of A1AR agonists by co-administration with a peripherally acting antagonist.
Improves survival and decreases brain injury following ischemic insults such as cardiac arrest.
Documented Applications
Treatment of ischemic brain injury caused by cardiac arrest in a subject.
Induction and maintenance of therapeutic hypothermia in patients suffering from illnesses characterized by ischemic tissue damage.
Controlling core body temperature in a subject.
Facilitation of therapeutic hypothermia to treat or prevent ischemic brain damage.
Managing shivering during induction of hypothermia.
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