Methods and compositions for the treatment of ischemic injury to tissue using therapeutic hypothermia

#Ischemia is the lack of oxygenated blood flow to various body parts and organs. Cerebral ischemia is an ischemic condition where the brain or parts of the brain do not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various serious diseases such as stroke and cardiac arrest or the result of arterial obstruction such as strangulation. Severe or prolonged cerebral ischemia results in unconsciousness, brain damage, or death.

#Therapeutic hypothermia has been shown to minimize brain injury and improve prognosis after cardiac arrest (CA). Mild therapeutic hypothermia, which involves decreasing core body temperature (Tb) to between 32-34° C. within 2 hr of restoration of spontaneous circulation (ROSC) and maintaining reduced Tb for 12-24 hr, is currently the only clinical intervention available for global cerebral ischemia (Hypothermia-after-Cardiac-Arrest-Study-Group, 2002; Seupaul and Wilbur, 2011). The clinical benefit of mild therapeutic hypothermia following focal cerebral ischemia is less clear (Bi et al., 2011; Faridar et al., 2011), but cooling shows obvious benefits in animal models of ischemic stroke (Busto et al., 1987). The fact that therapeutic hypothermia has not so far shown benefits in stroke trials may stem from failure to achieve Tb's between 32-34° C. (Faridar et al., 2011; Jordan and Carhuapoma, 2007). Shivering is the most problematic issue in achieving and maintaining hypothermia using conventional technology that relies on external or internal cooling mechanisms such as ice packs or i.v. infusion of cold saline. Shivering counteracts efforts to lower Tb and can be exceedingly uncomfortable for awake patients, such as those with a typical ischemic stroke (Sessler, 2009). Using standard pharmacotherapies to suppress shivering, current cooling techniques achieve core body temperature of only 35° C. in patients with acute ischemic stroke (Kollmar et al., 2009) or conscious healthy volunteers (Testori et al., 2011). What is needed are methods and compositions for inducing therapeutic hypothermia to facilitate treating or preventing ischemic brain damage.

#Disclosed herein are methods and compositions related to the induction of hypothermia in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising at least one compound capable of inducing hypothermia, thereby benefiting patients suffering from illnesses characterized by ischemic tissue damage.

#The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate several embodiments and together with the description illustrate the disclosed compositions and methods.

#FIG. 1 shows a torpid arctic ground squirrel (AGS).

#FIG. 2A-FIG. 2B show that AGS housed at ambient temperature (Ta) of 18° C., 12:12 L:D demonstrate a circannual rhythm in euthermic (nonhibernating) body temperature.

#Before the present compounds, compositions, and/or methods are disclosed and described, it is to be understood that they are not limited to specific synthetic methods or specific recombinant biotechnology methods unless otherwise specified, or to particular reagents unless otherwise specified, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting.

#As used in the specification and the appended claims, the singular forms “a,” “an” and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “a pharmaceutical carrier” includes mixtures of two or more such carriers, and the like.

#Ranges can be expressed herein as from “about” one particular value, and/or to “about” another particular value. When such a range is expressed, another embodiment includes from the one particular value and/or to the other particular value. Similarly, when values are expressed as approximations, by use of the antecedent “about,” it will be understood that the particular value forms another embodiment. It will be further understood that the endpoints of each of the ranges are significant both in relation to the other endpoint, and independently of the other endpoint. It is also understood that there are a number of values disclosed herein, and that each value is also herein disclosed as “about” that particular value in addition to the value itself. For example, if the value “10” is disclosed, then “about 10” is also disclosed. It is also understood that when a value is disclosed that “less than or equal to” the value, “greater than or equal to the value” and possible ranges between values are also disclosed, as appropriately understood by the skilled artisan. For example, if the value “10” is disclosed the “less than or equal to 10” as well as “greater than or equal to 10” is also disclosed. It is also understood that the throughout the application, data is provided in a number of different formats, and that this data, represents endpoints and starting points, and ranges for any combination of the data points. For example, if a particular data point “10” and a particular data point 15 are disclosed, it is understood that greater than, greater than or equal to, less than, less than or equal to, and equal to 10 and 15 are considered disclosed as well as between 10 and 15. It is also understood that each unit between two particular units are also disclosed. For example, if 10 and 15 are disclosed, then 11, 12, 13, and 14 are also disclosed.