WO2009071095A2

WO2009071095A2 - Prevention of hyperthermia subsequent to hypothermia treatment of ischemia

Info

Publication number: WO2009071095A2
Application number: PCT/DK2008/050293
Authority: WO
Inventors: Jacob Gotfredsen; Uno Jakob Weber
Original assignee: Neurokey A/S
Priority date: 2007-12-05
Filing date: 2008-12-05
Publication date: 2009-06-11
Also published as: WO2009071095A3

Abstract

The present invention relates to the prevention of hyperthermia or overshooting of normothermia during re-warming, subsequent to induction of hypothermia in humans, by the administration of at least one anti-pyretic compound of the present invention including but not limited to NSAIDS and acetaminophens, and/or administering at least one hypothermia inducing compound, wherein said hypothermia inducing compound is administered in decreasing dosages of said hypothermia inducing compound for a predetermined period, thereby reducing or preventing hyperthermia during re-warming, subsequent to medical or physical /mechanical hypothermia therapy.

Description

Prevention of hyperthermia subsequent to hypothermia treatment of ischemia

Field of invention

The present invention relates to prophylaxis or treatment of hyperthermia subsequent to induction of hypothermia.

Background of invention

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 will result in unconsciousness, brain damage or death.

The neuroprotective efficacy of induced hypothermia following or during ischemia of the brain is evident in experimental animal models of stroke [1 -1 1]. In humans, two trials conducted in cardiac arrest patients have shown improved neurological outcome of inducing hypothermia [12;13]. The therapeutic hypothermia did not increase the complication rate in these two trials and the use of induced hypothermia in comatose survivors of cardiac arrest is now recommended internationally [14].

Hypothermia counteracts ischemic brain damage by several mechanisms:

1 . Ischemia induces opening of the blood-brain barrier, a process that seems to be very sensitive to brain temperature [15]. This is evident from studies of tracers and their migration across the blood-brain barrier, in which hypothermia attenuates extravasation several hours after ischemia [16] and prevents vasogenic oedema [17].

2. Reperfusion after brain ischemia results in the production of free radicals, which causes peroxidation and destruction of membrane lipids [18]. Hypothermia prevents the production of free radicals such as hydroxyl and nitric oxide during reperfusion after brain ischemia [19;20;24].

3. Amino acids, such as glutamate, aspartate, and glycine, act as excitotoxic neurotransmitters by over stimulation of neurons in the vicinity of ischemic damage, which causes further injury. Hypothermia lowers the release and may even cause a more rapid reuptake of these transmitters [21 -23]. Release of excitotoxic neurotransmitters might also cause progressive neuronal death in the penumbra in stroke patients [22], and hypothermia after cerebral ischemia could attenuate this process.

4. During ischemia, cellular metabolism in the penumbra undergoes significant changes. As the neurons continue to fire, potassium ions flood into the extracellular space, calcium ions flow into the neurons leading to cytoskeletal degradation, and ATP concentrations fall as energy depletion continues [25].

Hypothermia reduces calcium influx and the subsequent breakdown of intracellular structures [26], improves potassium ion homoeostasis [27], and helps metabolic functions such as calcium or calmodulin-dependent protein kinase activity to recover [28;29].

5. By lowering of neutrophil and microglial activation after ischemia, hypothermia also has an anti-inflammatory effect [30;31].

6. Apoptosis and DNA changes are crucial stages in delayed neuronal death after transient cerebral ischemia [32]. Hypothermia directly inhibits apoptosis

[33] and may also increase endogenous production of the anti-apoptotic protein Bcl-2 [34]. Hypothermia may even have effects at the DNA level: A slight lowering of brain temperature results in less DNA fragmentation [35] and less apoptosis [36].

Induction of hypothermia by lowering of the core temperature of the body has been attempted by mechanical cooling devices such as surface cooling and cooling using catheters placed in a large vessel. However, these mechanical inducers of hypothermia have been shown to have considerable unwanted side effects. These side effects include shivering, serious infections and lung puncture. Shivering causes an increased exertion of the heart of the patient, and this will in some cases result in ischemia of the heart and thereby increased morbidity and mortality.

The regulation of the core temperature of the body by a pharmaceutical composition comprising a combination of compounds capable of inducing hypothermia not only solves the problem of reducing or preventing the effects of ischemia, such as tissue damaging effects, but may also be relevant as a safer and less expensive alternative to the currently employed mechanical methods.

Subsequent to physical (mechanical) or chemical hypothermia treatment the patient is brought back to normothermia, i.e. 37°C body temperature. However, the response of the body to hypothermia treatment is to increase the temperature rapidly which often results in the temperature over-shooting 37⁹C upon return to normothermia thus counteracting the effect of the performed hypothermia treatment. The inventors of the present invention have discovered that the over-shooting effect or hyperthermia, may be controlled by the administration of one or more compounds according to the present invention, upon returning the patient to 37°C subsequent to hypothermia therapy.

Summary of invention

The induction of hypothermia in humans with intact temperature regulating mechanisms is followed by the body's counter regulation when the cooling agent is eliminated. Unfortunately, from the perspective of the medical community, the heat generation in humans transitioning from hypothermia towards normothermia is frequently over-compensatory resulting in a period of hyperthermia, especially if the temperature change from hypothermia towards normothermia is rapid. This phenomenon is known as post-hypothermia therapy overshooting and may result in a periodic temperature elevation of up to two degrees Celsius above normothermia.

Post-hypothermia therapy overshooting is believed, especially if within the first hours after sudden cardiac arrest or any other indication mentioned in this invention, to result in an undesired outcome. This invention aims at minimizing/eliminating the potential for post-hypothermia therapy overshooting by slowing down the transition from (mild) hypothermia to normotemperature.

Accordingly, the present invention relates to the prevention of hyperthermia upon returning a patient to normothermia subsequent to mechanically or chemically induced hypothermia in humans. The invention comprises administration of a compound capable of inhibiting or reducing hyperthermia or administration of decreasing dosages of the hypothermia inducing compound for a predetermined period or a combination of both.

In the present context, a compound capable of inhibiting or reducing hyperthermia is an anti-pyretic compound.

Thus, in one embodiment of the invention prevention or reduction of hyperthermia is performed in a predictable and dose responsive fashion by use of a pharmaceutical composition comprising at least one compound capable of reducing or preventing hyperthermia, i.e. an anti-pyretic compound.

In another embodiment of the invention prevention or reduction of hyperthermia is performed in a predictable and dose responsive fashion by use of decreasing dosages of the hypothermia inducing compound for a predetermined period.

In one embodiment the chemically induced hypothermia is induced as a result of administration of at least one compound from class (1 ) below. The compound capable of reducing or preventing hyperthermia may be at least one compound selected from class (2) below:

1 . Hypothermia inducing compounds a. Cannabinoid receptor agonists; cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors, b. Vanilloid receptor agonists; capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors. c. Adenosine receptor agonists; adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors. d. Neurotensin receptor agonists; neurotensin analogs and compounds reaching and binding neurotensin receptors. e. Thyroxine derivatives, thyroid hormone receptor agonists and trace amine-associated receptor agonists. f. Cytochrome c oxidase inhibitors. g. Oxygen tension reducers.

2. Anti-pyretic compounds a. Paracetamol/acetaminophen b. NSAID

In one embodiment, the present invention discloses the use of a combination of compounds, wherein at least one is selected among hypothermia inducing compounds selected from the group of: a) vanilloid receptor agonists, b) cannabinoids and cannabimimetic compounds, c) adenosine or adenosine analogs, d) neurotensin or neurotensin analogs or a compound having at least 50% sequence identity to human neurotensin, e) and thyroxine derivatives, f) cytochrome c oxidase inhibitors and g) oxygen tension reducers; and at least one is selected among anti-pyretic compounds, selected from the group of: a) paracetamol/ acetaminophen and b) NSAID, for the preparation of a composition or medicament for the induction of hypothermia, such as for the treatment of ischemia in an individual, and for returning said individual to normothermia in a controlled and predicted manner subsequent to said hypothermia treatment.

In another embodiment, the present invention relates to the prevention of hyperthermia upon returning a patient to normothermia subsequent to chemically induced hypothermia in humans. This is performed in a predictable and dose responsive fashion after having administered one or more hypothermia inducing compounds, such as compounds selected from the group consisting of: a. Cannabinoid receptor agonists; cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors, and b. Vanilloid receptor agonists; capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors, and c. Adenosine receptor agonists; adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors, and d. Neurotensin receptor agonists; neurotensin analogs and compounds reaching and binding neurotensin receptors, and e. Thyroxine derivatives, thyroid hormone receptor agonists and trace amine-associated receptor agonists, and f. Cytochrome c oxidase inhibitors, and g. Oxygen tension reducers, by administering, for a predetermined period, gradually decreasing dosages of said hypothermia inducing compound until normothermia is reached for said patient.

Thereby the hyperthermia (overshooting) often present when not gradually decreasing the dosage of said one or more hypothermia inducing compounds. is prevented or reduced.

Examples of hypothermia inducing compounds are found in co-pending patent applications:

PCT/DK2007/000279 (WO 2007/140786), PCT/DK2007/050137 (WO 2008/040360), and PCT/DK2007/050138 (WO 2008/040361 ), as well as the patent applications having the title Combination treatment of ischemic effects, claiming priority from Danish patent applications PA 2007 01742 and PA 2008 01 105, having the title Combination of medical and physical cooling for the treatment of ischemic effects, claiming the priority from Danish patent application PA 2007 01744 and PA 2008 01 104, and having the title Neurotensin treatment of ischemia, claiming priority from PA 2007 01745 and PA 2008 00498.

It is also an aspect of the present invention to provide a medicament comprising a compound or a combination of compounds capable of reducing hyperthermia in an individual. Furthermore, the use of a combination of compounds according to the present invention for the preparation of a medicament for obviating the induction of hypothermia in an individual is an aspect of the present invention.

In conclusion, the present invention comprises use of at least one compound capable of preventing hyperthermia in an individual during re-warming subsequent to induced hypothermia, and the present invention further relates to the use of decreasing dosages of one or more hypothermia inducing compounds to prevent hyperthermia.

Description of drawings

Figure 1 : Controlled normalization of temperature. A total of 4 calves receives ongoing IV infusions of Dihydrocapsaicin (0.6 mg/kg body weight) for 5 hours and experience a reduction in body temperature of between approx. 3.5 to 4.5 degrees Celsius. At the end of the hypothermia period, the infusion is brought to a sudden stop in 2 of the calves (Temp 2198' and 'Temp 1718'), or the infusion is gradually slowed down in 2 of the calves (Temp 2254' and Temp 2389'). The first group (sudden infusion stop) reaches normothermia in about 60 minutes after infusion stop, whereas the second group (gradual slowing down of infusion) reaches normothermia in about 210 minutes.

Detailed description of the invention

The present invention comprises two principles for preventing or reducing overshooting, either by use of at least one compound capable of preventing overshooting of normothermia in an individual during re-warming subsequent to induced hypothermia, or by use of decreasing dosages of a hypothermia inducing compound or by use of both in combination.

A compound capable of reducing or preventing hyperthermia and a hyperthermia inhibiting or reducing compound are used interchangeably herein. In the present context, a compound capable of reducing or preventing hyperthermia or a hyperthermia inhibiting or reducing compound is synonymous with an antipyretic compound.

Definitions

Adenosine:

Adenosine is a nucleoside composed of adenine attached to a ribose (ribofuranose) moiety via a β-N9-glycosidic bond as described by the formula below.

Adenosine analog: An adenosine analog is any compound with a structure based on an adenosine and thus includes but is not limited to 5'-AMP, ADP, ATP and the like.

Agonist: A vanilloid receptor agonist is a vanilloid compound. A cannabinoid receptor agonist is a cannabinoid or a cannabimimetic compound. An adenosine receptor agonist is an adenosine, adenosine analog or adenosine-like compound. A neurotensin receptor agonist is a neurotensin or a neurotensin analog or a synthetic neurotensin or an artificial neurotensin or a neurotensin mimetic compound. A thyroxine receptor agonist is a thyroxine derivative or a thyronine. In the context of the present invention, an agonist is a compound capable of inducing hypothermia by binding to a receptor.

Alcohol: A class of organic compounds containing one or more hydroxyl groups (OH). In this context a saturated or unsaturated, branched or unbranched hydrocarbon group sitting as a substituent on a larger molecule.

Alicvclic group: the term "alicyclic group" means a cyclic hydrocarbon group having properties resembling those of aliphatic groups. Aliphatic group: in the context of the present invention, the term "aliphatic group" means a saturated or unsaturated linear or branched hydrocarbon group. This term is used to encompass alkyl, alkenyl, and alkynyl groups, for example.

Alkoxyl group: the term alkoxyl group or alkoxy covers an alkyl linked to a larger moiety by oxygen.

Alkyl group: the term "alkyl group" means a saturated linear or branched hydrocarbon group including, for example, methyl, ethyl, isopropyl, t-butyl, heptyl, dodecyl, octadecyl, amyl, 2-ethylhexyl, and the like.

Alkenyl group: the term "alkenyl group" means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon double bonds, such as a vinyl group.

Alkvnyl group: the term "alkynyl group" means an unsaturated, linear or branched hydrocarbon group with one or more carbon-carbon triple bonds.

Amphiphil: substance containing both polar, water-soluble and nonpolar, water- insoluble groups.

Anti-pyretic compound: a compound capable of reducing or preventing hyperthermia or a hyperthermia inhibiting or reducing compound.

Aromatic group: the term "aromatic group" or "aryl group" means a mono- or polycyclic aromatic hydrocarbon group.

Apoptosis: Apoptosis is a process of suicide by a cell in a multi-cellular organism. It is one of the main types of programmed cell death (PCD), and involves an orchestrated series of biochemical events leading to a characteristic cell morphology and death.

Aromatic group: the term "aromatic group" or "aryl group" means a mono- or polycyclic aromatic hydrocarbon group. Asystole: Cessation of electrical activity in the ventricles of the heart. Without electrical activity the heart ceases to contract and the result is cardiac arrest.

Cerebral ischemia: Global cerebral ischemia is an ischemic condition where the brain does not receive enough blood flow to maintain normal neurological function. Cerebral ischemia can be the result of various diseases/conditions such as cardiac arrest, or the result of arterial obstruction such as strangulation.

Coma: A prolonged period of unconsciousness following brain injury or metabolic disorders. The person in coma may have a simple reflex in response to touch or pain, but essentially there is no meaningful response to external stimuli.

Cannabinoid: Compound capable of binding to a cannabinoid receptor and isolated from or identical to a compound isolated from an organism such a plant or animal. In the present context any compound capable of binding a cannabinoid receptor. Also, the term cannabinoid is used as a general term covering both cannabinoid and cannabimimetic compounds.

Cannabimimetic: Compound capable of binding to a cannabinoid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a cannabinoid receptor.

Capsaicinoid: Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and isolated from or identical to a compound isolated from an organism such as a plant or animal. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor. A capsaicinoid may also be referred to as a vanilloid receptor agonist.

Capsaicinoid-like: Compound capable of binding to a capsaicinoid receptor / vanilloid receptor and produced or synthesized chemically by standard techniques known in the art. In the present context any compound capable of binding a capsaicinoid receptor / vanilloid receptor. A capsaicinoid-like compound may also be referred to as a vanilloid receptor agonist. Combination of compounds: Herein the term generally covers a combination of at least two compounds selected from the group consisting of vanilloid receptor agonist, capsaicinoid, capsaicinoid-like, cannabinoid and cannabimimetic compound, adenosine, adenosine analogs and derivatives, neurotensin, neurotensin analogs, thyroxine derivatives, thyronamine, cytochrome c oxidase inhibitors and oxygen tension reducers. The term may also include combinations of other compounds or drugs or the like.

Compound: A chemical substance formed from two or more elements, held together by chemical bonds, with a fixed ratio determining the composition. The elements lose their individual chemical properties and the compound has new properties.

Herein a term covering all of the following: vanilloid receptor agonist, capsaicinoid, capsaicinoid-like, cannabinoid and cannabimimetic compound, adenosine, adenosine analogs and derivatives, neurotensin, neurotensin analogs and peptides having at leat 50% sequence identity to human neurotensin (NT or NT1 -13) of SEQ

ID NO: 1 , thyroxine derivative, thyronamine, cytochrome c oxidase inhibitor and oxygen tension reducers.

Cyclic group: the term "cyclic group" means a closed ring hydrocarbon group that is classified as an alicyclic group, aromatic group, or heterocyclic group.

Cvcloalkenyl: means a monovalent unsaturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkenyl, lower alkoxy, lower haloalkoxy, alkenylthio, halo, haloalkenyl, hydroxyalkenyl, nitro, alkoxycarbonenyl, amino, alkenylamino, alkenylsulfonyl, arylsulfonyl, alkenylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkenylaminocarbonyl, arylaminocarbonyl, alkenylcarbonylamino and arylcarbonylamino.

Cvcloalkyl: means a monovalent saturated carbocyclic radical consisting of one, two or three rings, of three to eight carbons per ring, which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylamino- sulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, arylaminocarbonyl, alkylcarbonylamino and arylcarbonylamino.

Cationic group: A chemical group capable of functioning as a proton donor when a compound comprising the chemical group is dissolved in a solvent, preferably when dissolved in water.

Cytochrome c oxidase inhibitor: means a compound that binds to and interferes with the function of cytochrome c oxidase; a mitochondrial transmembrane complex involved in metabolism. These include but are not limited to H₂S (hydrogen sulfide); cyanide (CN) or its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na₂[Fe(CN)₅NO]^H₂O); Azide and its derivates; Carbon monoxide (CO); and/or Sodium sulfide (Na₂S).

Decreasing dosages of said hypothermia inducing compound until normothermia is reached for said patient means that for two or more consecutive dosages, the dosage administered next is smaller than the dosage administered immediately before, such as being from 5 % to 50 % smaller than the former dosage. In case of a continuous administration, such as through an automatic infusion pump the dosage may either be decreased continuously for a predetermined amount of time or decreased stepwise as discussed above for bolusadministrations.

Form a ring: means that the atoms mentioned are connected through a bond when the ring structure is formed.

Global ischemia: Anoxia resultant from ceased blood supply to the entire body resulting in tissue damage through a variety of mechanisms including apoptosis.

Global cerebral ischemia: Anoxia resultant from ceased blood supply to the entire brain resulting in tissue damage through a variety of mechanisms including apoptosis.

Group: (Moiety / substitution) as is well understood in this technical area, a large degree of substitution is not only tolerated, but is often advisable. Substitution is anticipated on the materials of the present invention. As a means of simplifying the discussion and recitation of certain terminology used throughout this application, the terms "group" and "moiety" are used to differentiate between chemical species that allow for substitution or that may be substituted and those that do not allow or may not be so substituted. Thus, when the term "group" is used to describe a chemical substituent, the described chemical material includes the unsubstituted group and that group with O, N, or S atoms, for example, in the chain as well as carbonyl groups or other conventional substitution. Where the term "moiety" is used to describe a chemical compound or substituent, only an unsubstituted chemical material is intended to be included. For example, the phrase "alkyl group" is intended to include not only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like, but also alkyl substituents bearing further substituents known in the art, such as hydroxy, alkoxy, alkylsulfonyl, halogen atoms, cyano, nitro, amino, carboxyl, etc. Thus, "alkyl group" includes ether groups, haloalkyls, nitroalkyls, carboxyalkyls, hydroxyalkyls, sulfoalkyls, etc. On the other hand, the phrase "alkyl moiety" is limited to the inclusion of only pure open chain saturated hydrocarbon alkyl substituents, such as methyl, ethyl, propyl, t-butyl, and the like. The same definitions apply to "alkenyl group" and "alkenyl moiety"; to "alkynyl group" and "alkynyl moiety"; to "cyclic group" and "cyclic moiety; to "alicyclic group" and "alicyclic moiety"; to "aromatic group" or "aryl group" and to "aromatic moiety" or "aryl moiety"; as well as to "heterocyclic group" and "heterocyclic moiety".

Heterocyclic group: the term "heterocyclic group" means a closed ring hydrocarbon in which one or more of the atoms in the ring is an element other than carbon (e.g., nitrogen, oxygen, sulphur, etc.).

Heterocyclyl means a monovalent saturated cyclic radical, consisting of one to two rings, of three to eight atoms per ring, incorporating one or two ring heteroatoms (chosen from N, O or S(O)₀-₂, and which can optionally be substituted with one or two substituents selected from the group consisting of hydroxyl, oxo, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminofarbonyl, aryl- aminocarbonyl, alkylcarbonylamino, or arylcarbonylamino. Heteroaryl means a monovalent aromatic cyclic radical having one to three rings, of four to eight atoms per ring, incorporating one or two heteroatoms (chosen from nitrogen, oxygen, or sulphur) within the ring which can optionally be substituted with one or two substituents selected from the group consisting of hydroxy, cyano, lower alkyl, lower alkoxy, lower haloalkoxy, alkylthio, halo, haloalkyl, hydroxyalkyl, nitro, alkoxycarbonyl, amino, alkylamino, alkylsulfonyl, arylsulfonyl, alkylaminosulfonyl, arylaminosulfonyl, alkylsulfonylamino, arylsulfonylamino, alkylaminocarbonyl, aryl- aminocarbonyl, alkylcarbonlamino and arylcarbonylamino.

Hyperthermia inhibiting compound: an anti-pyretic compound

Hyperthermia: A body temperature above normothermia.

Hypothermia: Lowering of the body temperature below normal level.

Ischemia: Restriction in blood supply with resultant dysfunction or damage of tissue. Ischemia includes ischaemia and ischaemia.

Ischemic tissue damage: Tissue damage due to ischemia.

Lactic acidosis: Lactic acidosis is a condition caused by the buildup of lactic acid in the body. An important cause of lactic acidosis is inadequate oxygen supply to tissues. Lactic acidosis leads to acidification of the blood (acidosis), and is considered a distinct form of metabolic acidosis.

Moieties of a particular compound cover group(s) or part(s) of said particular compound.

Neurotensin: Neurotensin is the 13 amino acid peptide of SEQ ID NO. 1.

Neurotensin analog: A neurotensin analog is any sequence having at least 50% sequence identity to mature neurotensin of SEQ ID NO. 1 .

Neurotensin receptor: The neurotensin receptors are transmembrane receptors which bind neurotensin. Two of the receptors encoded by the NTSR1 and NTSR2 genes contain 7 transmembrane helices and are G protein-coupled. The third receptor has a single transmembrane domain and is encoded by the SORT1 gene.

Neurotensin receptor agonist: is a compound capable of imposing an agonizing effect of a neurotensin receptor and include but is not limited to neurotensin, neuromedin, NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contulakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, [¹²⁵l]neurotensin, Thr10contulakin-G, D-Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.

Normothermia: Normal temperature of an organism, i.e. 37°C in Homo sapiens.

Oxygen tension reducers: reduces the concentration of oxygen around or within the body. These include but are not limited to: Carbon monoxide (CO), Sodium sulfide (Na₂S) and hydrogen sulfide (H₂S).

Overshooting: Overshooting is equivalent to hyperthermia, when occurring in an individual having been subjected to hypothermia.

Pharmaceutical composition: or drug, medicament or agent refers to any chemical or biological material, compound, composition or combinations of any of these especially combinations of compounds, capable of inducing a desired therapeutic effect when properly administered to a patient. Some drugs are sold in an inactive form that is converted in vivo into a metabolite with pharmaceutical activity. For purposes of the present invention, the terms "pharmaceutical composition" and "medicament" encompass both the inactive drug and the active metabolite.

Predetermined period: the period for which the hyperthermia inhibiting compound is administered or for which gradually decreasing dosages of said hypothermia inducing compound is administered, normally until normothermia is reached.

Pulseless electrical activity: The electrical activity of the heart continues in a normal or abnormal pattern, but one that is consistent with contractions of the heart. But either due to damage to the heart muscle, blockage of the main arteries leading from the heart or lack of blood flowing to the heart there is no effective blood flow. The result is cardiac arrest.

Rewarminq: is the process of returning the body-temperature of an individual in a state of hypothermia to normothermia.

Substituted lower alkyl: means a lower alkyl having one to three substituents selected from the group consisting of hydroxyl, alkoxy, amino, amido, carboxyl, acyl, halogen, cyano, nitro and thiol.

Thyroxine derivatives: the term as used herein is meant to cover all forms and processed derivatives of the thyroid hormones, including thyroxine (T₄), triiodothyronine (T₃), thyronamine, 3-lodothyronamine, 3,5-Diiodothyronamine, and 3,5,3'-triiodothyronamine. The term is also used to encompass thyroid hormone receptor agonists and trace amine-associated receptor agonists, and these terms may be used interchangably herein.

Vanilloid receptor agonist: A capsaicinoid or capsaicinoid-like compound capable of binding a vanilloid receptor / capsaicinoid receptor.

Ventricular fibrillation: Very fast irregular electrical activity in the ventricles of the heart. Individual beats cannot be distinguished and the heart is in stand-still or vibrating slightly. The result is cardiac arrest.

Ventricular tachycardia: Very fast electrical activity in the ventricles of the heart. The electrical activity maintains a pattern where individual contractions can be distinguished. Ventricular tachycardia may be associated with normal cardiac function, reduced cardiac function or functional cardiac arrest. This depends on the rate of the tachycardia and the state of the heart muscle.

Hypothermia

Induction of hypothermia is used for a variety of diseases and disorders. In particular induction of hypothermia is used for reducing tissue damages due to ischemia. Ischemia is the reduction or abolition of blood supply to a tissue. The associated deficiency of oxygen and nutrients may lead to cell death (necrosis) in areas of the affected tissue. The damage induced by the lack of oxygenated blood in the brain occurs in two stages. First cellular metabolism is arrested due to lack of oxygen and some cells and tissue will die within minutes as a consequence hereof. Secondly a cascade of processes such as apoptosis is initiated and continues up to 12 hours after the event that initially induced the ischemic state has been abolished. The tissue damaged by the second cascade can be crucial and cause greater harm to the individual than the primary damage happening within the first minutes of ischemia.

The induced hypothermic effect is presumed to counteract ischemic damage by several mechanisms in the brain: Prevention of the blood-brain-barrier disruption that happens soon after ischemic onset that allows oedema formation from extravasation; Diminishing of the oxygen-based free-radical production; Reduction of the excitotoxic-neurotransmitter release that overstimulates neighboring neurons; Lowering of the metabolic rate and subsequent energy depletion; and antiinflammatory action. Induction of hypothermia has a neuroprotective effect.

Ischemia may occur under various circumstances; of special relevance to the present invention are the circumstances relating to cardiovascular diseases, asphyxia and traumatic brain injuries.

Traumatic brain injury (TBI) is a common cause of death and of physical as well as mental impairment throughout the world. TBI may result from accidents, be due to violence or be self-inflicted. Traumatic brain injury, also called intracranial injury, or simply head injury, occurs when a sudden trauma causes brain damage. TBI can result from a closed head injury or a penetrating head injury. Parts of the brain that can be damaged include the cerebral hemispheres, cerebellum, and brain stem. Symptoms of a TBI can be mild, moderate, or severe, depending on the extent of the damage to the brain. Outcome can be anything from complete recovery to permanent disability or death. Ischemia is a significant factor contributing to the neurological damage frequently seen in patients suffering from TBI. o

Individuals suffering from elevated body temperatures due to an infection, ischemic damage, heat- or sunstroke or the like will also benefit from induction of hypothermia.

Fever (also known as pyrexia, or a febrile response) is a frequent medical symptom that describes an increase in especially internal body temperature to levels above normal. Fever is most accurately characterized as a temporary elevation in the body's thermoregulatory set-point, meaning that the temperature is raised by the body in a controlled manner. Fever is a symptom of many different diseases such as infectious diseases, immunological diseases, cancers metabolic disorders and more.

Hyperpyrexia is an extreme degree of fever, where the set body temperature is elevated greater than or equal to 41 degree Celsius. Such a high temperature is considered a medical emergency and requires immediate medical attention.

Fever and hyperpyrexia differ from hyperthermia. Hyperthermia is an increase in body temperature over the body's thermoregulatory set-point, due to excessive heat production or insufficient thermoregulation, or both. Hyperthermia may be caused by heat- or sunstroke, exposure, dehydration and more. A special variant of hyperthermia is malignant hyperthermia which may arise due to administration of general anesthesia.

The outcome of several types of surgery is improved if the individual undergoing the surgery is placed under hyperthermia prior to or during the surgery. Examples of such operations are neurosurgeries, thorax surgeries and especially cardiac surgeries. The lowering of the body temperature slows down the metabolic rate and thus reduces the need for e.g. oxygen during the surgery giving more time to the surgeon to perform complicated procedures.

See also the following co-pending applications, which are hereby incorporated by reference, for details regaring the diseases and disorders for which induction of hypothermia may be used: PCT/DK2007/000279 (WO 2007/140786), PCT/DK2007/050137 (WO 2008/040360), and PCT/DK2007/050138 (WO 2008/040361 ), as well as the patent applications having the title Combination treatment of ischemic effects, claiming priority from Danish patent applications PA 2007 01742 and PA 2008 01 105, having the title Combination of medical and physical cooling for the treatment of ischemic effects, claiming the priority from Danish patent application PA 2007 01744 and PA 2008 01 104, and having the title Neurotensin treatment of ischemia, claiming priority from PA 2007 01745 and PA 2008 00498.

Hyperthermia

Hyperthermia is the increase of the core temperature of the body above normal level. Normal body temperature in an adult human measured rectally over 24 hours is 37 degree Celsius +/- 0.6 degree Celsius and is thus variable between individuals, and over time within the individual. Hyperthermia as a medical condition is usually defined as the effects seen on the body once the core temperature increase above 38 degree Celsius. It may become critical, if the body temperature increases above 40 °C. In the present application hyperthermia is defined as the increase of the core body temperature above normal levels. This implies that any temperature above the normal core body temperature of the specific individual with its natural variations at the given point in time of the day, or period, herein is defined as being hyperthermic. In particular, hyperthermia is a temperature above 38.5 °C, such as above 39 °C, such as above 39.5 °C, such as above 40.0 °C, such as above 40.5°C, such as above 41 .0°C, such as above 41.5⁹C, such as above 42.0 °C.

Body temperature may be measured by a variety of means by mercury, electronic or plastic strip thermometers on different areas of the body such as the forehead, mouth, armpit, ear or rectum. It is presently understood, that the temperature referred to in the present application is the core body temperature, and that some of the above methods of measurement will indicate a different temperature than the core temperature.

As discussed above the induction of hypothermia in humans with intact temperature regulating mechanisms may be followed by the body's counter regulation when the cooling agent is eliminated that may overshoot normothermia. Post-hypothermia therapy overshooting is believed, especially if within the first days hours after sudden cardiac arrest or any other indication mentioned herein, to result in an undesired outcome.

It is thus an object of the present invention to provide at least one compound for the production of a medicament for the prevention or reduction of hyperthermia in an individual suffering from ischemia, wherein the at least one compound is capable of reducing or inhibiting hyperthermia or overshooting of normothermia. Said hyperthermia inhibiting compound is an anti-pyretic compound.

In particular this invention reduces hyperthermia or overshooting of normothermia to a specific temperature such as about 37 degree Celsius to about 37.5 degree Celsius, or most preferably, the present invention is capable of reducing and/or preventing hyperthermia or overshooting of normothermia to any of the above specific temperatures within a range of +/- 0.5 degree Celsius, such as the range being between +/- 0.4 degree Celsius, such as between +/-0.3 degree Celsius, such as between +/- 0.2 degree Celsius, or such as between +/- 0.1 degree Celsius of the desired temperature. The temperature range or specific temperature also referred to as the target temperature of the one or more compounds and/or the medicament comprising the one or more compounds.

Target temperature and peak effect

The target temperature of the hyperthermia inhibiting compound or anti-pyretic compound is the core body temperature that can be reached upon administering the compound according to the present invention as prescribed according to potency, dosage and so on.

This invention will often show a peak in hyperthermia reducing effect 30 minutes to 180 minutes after administration, but may potentially peak sooner or later than described by this interval. The hyperthermia reducing effect will frequently last from 1 hour to 12 hours, but may potentially last shorter or longer than described by this interval.

It is an object of the present invention to provide compounds suitable for a quick reduction of hyperthermia which may be of long or short duration and compounds suitable for a slow reduction in core body temperature which may be of long or short duration.

It is also an object of the present invention to provide an administration scheme suitable for a quick reduction of hyperthermia which may be of long or short duration and an administration scheme suitable for a slow reduction in core body temperature which may be of long or short duration.

It is an aspect of the present invention that the compounds / treatments herein may be given while the individual receiving the treatment is surrounded by any given temperature. In other words, the temperature of the surroundings, especially the room in which the individual resides, is not of relevance to the treatment. The treatment will reduce the temperature of the individual and/or induce hypothermia whether the room temperature is ambient, high or low such as at any temperature between 5 and 45 degree Celsius.

Compounds capable of inhibiting hyperthermia

In one embodiment the invention relates to use of compounds capable of inhibiting hyperthermia, wherein said compound is an anti-pyretic compound.

Antipyretic drugs are drugs that lower your body temperature from a raised state without affecting the normal body temperature if the patient does not have fever. Antipyretics cause the hypothalamus to override an interleukin-induced increase in temperature. The body will then work to lower the temperature and the result is a reduction in fever. Most are also used for other purposes. The largest group of antipyretics is the non-steroidal anti-inflammatory drugs (NSAIDs).

The antipyretic drugs may be used singularly or in combination for treating or preventing overshooting of normothermia during re-warming subsequent to medically or mechanically induced hypothermia used with the aim of treating or preventing tissue damaging effects of ischemia or anoxia.

Thus, in one embodiment the hyperthermia inhibiting compound is selected from the group consisting of NSAIDs and acetaminophens, such as the following: In one embodiment at least one NSAID selected from the group consisting of Salicylates such as but not limited to Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate and Salicyl salicylate is administered.

In another embodiment at least one NSAID selected from the group consisting of Arylalkanoic acids such as but not limited to Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac and Tolmetin is administered.

In another embodiment at least one NSAID selected from the group consisting of 2- Arylpropionic acids such as but not limited to Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid and Suprofen is administered.

In another embodiment at least one NSAID selected from the group consisting of N- Arylanthranilic acids such as but not limited to Mefenamic acid and Meclofenamic acid is administered.

In another embodiment at least one NSAID selected from the group consisting of Oxicams such as but not limited to Piroxicam, Lornoxicam, Meloxicam and Tenoxicam is administered.

In another embodiment at least one NSAID selected from the group consisting of COX-2 inhibitors such as but not limited to Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib and Valdecoxib is administered.

In another embodiment at least one NSAID selected from the group consisting of Sulphonanilides such as but not limited to Nimesulide is administered.

In another embodiment at least one NSAID selected from the group consisting of Pyrazolidine derivatives such as but not limited to Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone is administered. In another embodiment at least one compound selected from Licofelone and Omega-3 fatty acids is administered.

The invention also includes combinations of the above mentioned compounds, either as an integrated drug, administered simultaneously, or administered consecutively. Such a combination may occasionally be superior to any treatment based on the solitary use of any single NSAID or acetaminophen.

Therefore, an an embodiment of the present invention the at least one compound is one compound, such as two compounds, such as three compounds, such as four compounds, such as five compounds, for example six compounds, such as seven compounds, for example eight compounds, such as nine compounds, for example ten compounds.

In one embodiment the combination of compounds comprises at least one NSAID selected from the group consisting of but not limited to Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In an embodiment of the present invention the two or more compounds are two compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In another embodiment of the present invention the two or more compounds are three compounds selected from the group consisting of Aspirin, Amoxiprin,

Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In a further embodiment of the present invention the two or more compounds are four compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen,

Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In a further embodiment of the present invention the two or more compounds are five compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In a further embodiment of the present invention the two or more compounds are six compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In a further embodiment of the present invention the two or more compounds are seven compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone,

Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

In a further embodiment of the present invention the two or more compounds are eight compounds selected from the group consisting of Aspirin, Amoxiprin,

In a further embodiment of the present invention the two or more compounds are nine compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen,

In a further embodiment of the present invention the two or more compounds are ten or more compounds selected from the group consisting of Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, Mefenamic acid, Meclofenamic acid, Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, Nimesulide, Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone, Licofelone and Omega-3 fatty acids.

Dosage

The dosage of the compounds or combinations of compounds according to the invention depends on the compounds or combination of compound in question; however, the amount of is also closely related to the pharmaceutical composition of the medicament, any second, third or more compound of the medicament or any second active ingredient of the medicament. It will be recognized by one of skill in the art that the optimal quantity and spacing of individual dosages of a compound or a pharmaceutically acceptable salt thereof will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimums can be determined by conventional techniques. It will also be appreciated by one of skill in the art that the optimal course of treatment, i.e., the number of doses of a compound or a pharmaceutically acceptable salt thereof given per day for a defined number of days, can be ascertained by those skilled in the art using conventional course of treatment determination tests.

The term "unit dosage form" as used herein refers to physically discrete units suitable as unitary dosages for human and animal individuals, each unit containing a predetermined quantity of a combination of compounds, alone or in together with other agents, calculated in an amount sufficient to produce the desired effect in association with a pharmaceutically acceptable diluent, carrier, or vehicle. The specifications for the unit dosage forms of the present invention depend on the particular combination employed and the effect to be achieved, as well as the pharmaco-dynamics associated with each of the compounds of the combination in the host. The dose administered should be an "effective amount" or an amount necessary to achieve an "effective level" in the individual patient.

Since the "effective level" is used as the preferred endpoint for dosing, the actual dose and schedule can vary, depending on inter-individual differences in pharma- cokinetics, drug distribution, and metabolism. The "effective level" can be defined, for example, as the blood or tissue level desired in the individual that corresponds to a concentration of one or more combinations according to the invention. The effective level can also be defined as the amount needed pr kg body weight, in other words the concentration, required to reach the peak effect for a specific combination of compounds. Also, the effective level depends on the magnitude of the hyperthermia or overshooting of normothermia.

For all methods of use disclosed herein for the combinations of compounds, the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.001 to about 80 mg/kg of total body weight.

For all hyperthermia inhibiting compounds disclosed herein, the daily oral dosage regimen will preferably be from about 0.01 to about 80 mg/kg of total body weight. The daily parenteral dosage regimen will be from about 0.01 to about 2,400 mg/kg of total body weight, preferably, the dosage of the medicament according to the present invention is between 10 μg to 10 mg pr kg total body weight, such as between 100 μg to 1 mg pr kg total body weight, depending on the compound of choice.

Preferably, the dosage of the medicament according to the present invention is between 1 μg to 100 mg pr kg total body weight, such as between 10 μg to 50 mg pr kg total body weight, for example between 20 μg to 20 mg pr kg total body weight, such as 100 μg to 10 mg, for example 500 μg to 1 mg depending on the compound of choice. It follows, that the preferred dosage may be between 1 μg and 1 mg pr kg total body weight, such as between 10 μg and 100 μg pr kg total body weight, such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg, 100 μg, 200 μg, 300 μg, 400 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1 mg, 2 mg, 3 mg, 4 mg, 5 mg, 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 50 mg or 100 mg pr kg total body weight, again depending on the compound chosen.

Also, the preferred dosage range may be between 100 μg and 100 mg pr kg total body weight, such as between 200 μg and 90 mg, between 300 μg and 80 mg, such as between 400 μg and 70 mg, such as between 500 μg and 60 mg, such as between 600 μg and 50 mg, such as between 700 μg and 40 mg, such as between 800 μg and 30 mg, such as between 900 μg and 20 mg, such as between 1 mg and 10 mg pr kg total body weight. Alternatively, the dosage may be found in the range of from 100 μg to 2000 μg, such as 200 μg to 1800 μg, or 300 μg to 1600 μg, 400 μg to 1400 μg, 500 μg to 1200 μg, 600 μg to 1000 μg or 500 μg to 2000 μg.

For any anti-pyretic compound such as any NSAID or acetaminophen according to the invention the dosage range may be calculated based on the calf study model described in Example 14. Medicament

The reduction or prevention of hyperthermia and/or controlled return to normothermia of a patient having been treated by mechanical or chemical/medical hypothermia therapy by any combination of the herein described compounds is performed by preparing, producing and thus providing a medicament or pharmaceutical composition comprising a combination of at least one compound of the group consisting of NSAIDs and acetaminophens. The medicament of the present invention may thus also comprise a combination of compounds for the reduction or prevention of hyperthermia and/or controlled return to normothermia in an individual being or having been treated by mechanical or chemical/medical hypothermia therapy.

It is an object of the present invention to provide a medicament comprising one or more compound or compounds capable of reverting body temperature to between 36 and 38 °C in an individual, subsequent to induction of hypothermia, in particular to about a body temperature of 37°C, in an individual, subsequent to induction of hypothermia.

It is also an object of the present invention to provide a medicament that reverts induced hypothermia of between 32 and 36 degree Celsius.

It is also an object of the present invention to provide a medicament capable of reducing hyperthermia rapidly.

It is also an object of the present invention to provide a medicament capable of reducing hyperthermia slowly.

It is also an object of the present invention to provide a medicament wherein one compound reduces hyperthermia rapidly.

It is also an object of the present invention to provide a medicament wherein one compound reduces hyperthermia slowly. Decreasing dosage of hypothermia inducing compound(s)

As discussed above, another embodiment of the present invention for preventing or reducing hyperthermia or overshooting after administration of a hypothermia inducing compound relates to administration of decreasing dosages of said hypothermia inducing compound(s) for a predetermined period at the end of the treatment, thereby returning the individual to normothermia in a controlled manner.

Depending on the administration form, the manner of decreasing may be a stepwise decrease or a continuous decrease, the latter being particularly relevant when using continuous administration, such as continuous infusion.

The gradual reduction of the dosage of the hypothermia inducing compound(s) may occur following a special scheme. Said scheme may comprise instructions on how to gradually reduce the dosage of the compound(s). Said scheme may thus comprise instruction on when to reduce the dosage of the compound(s) (such as between 15 minutes and 24 hours before completion of administration), how much to reduce the dosage of the compound(s), and the manner in which this is done.

In this embodiment, when decided to terminate the hypothermia treatment the dosage given may be decreased stepwise, such as decreasing each dose to about 5-50 percent of the previous dose. In another embodiment each dosage administered during the decrease is reduced by a fixed predefined percentage of the treatment dosage, such as reduced by 5-25 percent of the treatment dosage at every decrease. In this context the treatment dosage refers to the dosage used for initiating and/or maintaining the hypothermia.

Pharmacological hypothermia therapy, especially when administered by infusion, is characterised by the ability to adjust the infusion rate of the post-hypothermia therapy period to prolong or shorten the time-span from hypothermia to normothermia. A sudden infusion stop will cause a higher temperature gradient towards normothermia/post-hypothermia therapy overshooting than an infusion that is slowly brought to a close. When the hypothermia inducing compound is administered continuously, the decrease may follow a fixed decreasing rate. The optimal predetermined period depends on the magnitude of potential or actual hyperthermia and the means of induction of hypothermia prior to rewarming. Normally the predetermined time period for administering the hypothermia inducing compound(s) in gradually decreasing dosages is from 5 min up to several hours, for example up to 24 hours, such as from Vz hour up to 12 hours, more preferably from Vz hour to 2 hours, even more preferably from Vz hour to 1 hour. The predetermined time period is typically determined to end when the individual is brought to normothermia.

Alternatively, instead of a fixed time period the predetermined period may be the period until the individual is brought to normothermia as defined above.

Hypothermia-inducing compounds

Examples of hypothermia inducing compounds are as discussed above as selected from the group consisting of: a. Cannabinoid receptor agonists; cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors, and b. Vanilloid receptor agonists; capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors, and c. Adenosine receptor agonists; adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors, and d. Neurotensin receptor agonists; neurotensin analogs and compounds reaching and binding neurotensin receptors, and e. Thyroxine derivatives, thyroid hormone receptor agonists and trace amine-associated receptor agonists, and f. Cytochrome c oxidase inhibitors, and g. Oxygen tension reducers.

The hypothermia inducing compounds according to the present invention may be administered as a single agent (one compound), or they may be administered as a combination of two or more compounds, such as two compounds in combination, three compounds in combination, four compounds in combination, five compounds in combination, six compounds in combination or seven compounds in combination. The term 'one or more' or 'at least one' includes both of the above embodiments. The use of a combination of hypothermia inducing compounds is disclosed in co- pending PCT-applications from the same inventors, one having number WO 2008/040361 (PCT/DK2007/050138) and another bearing the title 'Combination treatment of ischemic effects' claiming priority from Danish patent applications PA 2007 01742 and PA 2008 01 105.

In one embodiment, the hypothermia-inducing compound is a cannabinoid selected from the group consisting of delta-9-THC (Tetrahydrocanna-binol), delta-8-THC, delta-8-THC phosphate, Cannabinol (CBN), Cannabidiol (CBD), Cannabidiol-type CBD, Cannabidivarin (CBDV), Cannabichromene-type CBG, Cannabigerol-type CBG, Tetrahydrocanna-bivarin (THCV, THV), Tetrahydrocanna-binol- and cannabinol-type THC or CBN, Iso-Tetrahydro-cannabinol-type iso-THC, Cannabielsion-type CBE, Cannabicyclo l-type CBL, Cannabicitran-type CBT, HU- 308, JWH-133, JWH-139, JWH-051 , L-759633, L-759656, HU-210 ((-)-1 1 -OH-delta- 8-tetrahydrocannabinol-dimethylheptyl), HU-21 1 (Dexanabinol, 7-hydroxy-D6- tetrahydrocannabinol 1 ,1 -dimethylheptyl), Desacetyl-L-nandrolol, Nabilone, Levonantradol; non-classic cannabinoids such as: CP-55940, CP55244 and CP47497; aminoalkylindoles such as: R(+)WIN55212, S(-)WIN-55213, JWH-015 and L-768242; eicosanoids / endogenous cannabinoids such as: Anandamide (arachidonyl ethanolamine), 2-Arachidonyl-glycerol (2-AG, Noladin ether),

Palmitoylethanol-amine, Virodhamine (O-arachidonoyl-ethanolamine), Palmitoyl ethanolamide, Oleamide; other cannabinoid compounds such as: Arvanil, Metanandamide, ACEA, ACPA, BAY 38-7271 and 0-1812 and phosphate derivatives of any of the above.

In another embodiment, the hypothermia-inducing compound is a vanilloid receptor agonist selected from the group consisting of Capsaicin (C; 8-methyl-N-vallilyl-6- nonenamide), Dihydrocapsaicin (DHC), Nordihydro-capsaicin (NDHC), Homodihydro-capsaicin (HDHC), Homocapsaicin (HC), Olvanil (N-9-Z- octadecenoyl-vanillamide), Rinvanil (vanillamide of ricinoleic acid), Arvanil (N- vanillylarachidonamide), PhAR (phenylacetylrinvanil), Nuvanil, Farvanil (vanillamide of farnesic acid), Ac-Rinvanil, Retvanil (vanillamide of retinoic acid), Nonivamide, Ervanil (vanillamide of erucic acid), Resiniferatoxin (RTX), Anandamide (arachidonyl ethanolamine), N-arachidonoyldopamine (NADA), N-arachidonoyl-L-serine (ARA-S), Arachidonyl-2-chloroethylamide, 2-aminoethoxydiphenyl borate (2-APB), Evodiamine, Propofol, Isovelleral, Scutigeral, 12-hydroperoxyeicosatetraenoic acid, Alpha-sanshool, Beta-sanshool, Gamma-sanshool, Delta-sanshool, Alpha-hydroxy- sanshool, Beta-hydroxy-sanshool, Piperine, Zingerone, and Bv8.

In yet another embodiment, the hypothermia-inducing compound is an adenosine receptor agonist or an adenosine analog selected from the group consisting of adenosine, 5'-AMP, ATP, ADP, adenine nucleotides, as well as other substituted adenosine compounds, 5'-(N-ethyl-carboxamido)-adenosine (NECA), (R)-PIA, (S)- PIA, AB-NECA, CCPA, CGS 21680, CGS 21680, CGS 24012, 2-chloroadenosine, 2-hexynyl-NECA, IB-MECA, N(6)-cyclopentyladenosine, (R,S)-PHPNECA, IAB- MECA, IB-MECA, CI-IB-MECA, cyclopentyladenosine, I-ABA, IAB-MECA, MCP- NECA, MPC-MECA, PENECA, AB-MECA, APNEA, CV-1674, CV-1808, cyclopentyladenosine, 2-hexynyl-NECA, metrifudil, N(6)-cyclohexyladenosine, LUF5831 and Tecadenoson (CV-510), or an adenosine uptake inhibitor such as dipyridamole or theofyllin.

In yet another embodiment, the hypothermia-inducing compound is a neurotensin receptor agonist or a neurotensin analog selected from the group consisting of NT64D, NT64L, NT65L, NT66D, NT66L, NT67L, NT69L, NT71 , NT72, NT73, NT74, NT75, NT76, NT77, Trp1 1 NT, contulakin-G, EISAI-1 , EISAI-2, JMV2004, JMV2012, JMV431 , JMV449, JMV457, JMV458, large neuromedin, large neurotensin, neuromedin, neurotensin, neurotensin, [¹²⁵l]neurotensin, Thr10contulakin-G, D- Trp1 1 -neurotensin, levocabastine, SR48692, xenin, PD-149163 and CGX-1 160.

In another embodiment, the hypothermia-inducing compound is a thyroxine derivative selected from the group consisting of thyroxine, 3,5,3'-triiodothyronine, thyronamine; 3-lodothyronamine; 3,5-diiodothyronamine; and 3,5,3'- triiodothyronamine.

In yet another embodiment, the hypothermia-inducing compound is a cytochrome C oxidase inhibitor selected from the group consisting of H₂S (hydrogen sulfide); cyanide (CN) or its derivates such as hydrogen cyanide (HCN) or sodium nitroprusside (Na₂[Fe(CN)₅NO]^H₂O); Azide and its derivates; Carbon monoxide (CO); and Sodium sulfide (Na₂S). In another embodiment, the hypothermia-inducing compound is an oxygen tension reducer selected from the group consisting of Carbon monoxide (CO), Sodium sulfide (Na₂S) and hydrogen sulfide (H₂S).

Treatment dosages of hypothermia inducing compounds

The treatment dosages of hypothermia inducing compounds may be found in one or more of co-pending patent applications, ie the dosages used for initiating and/or maintaining hypothermia:

PCT/DK2007/000279 (WO 2007/140786), PCT/DK2007/050137 (WO

2008/040360), and PCT/DK2007/050138 (WO 2008/040361 ), as well as the patent applications having the title Combination treatment of ischemic effects, claiming priority from Danish patent applications PA 2007 01742 and PA 2008 01 105, having the title Combination of medical and physical cooling for the treatment of ischemic effects, claiming the priority from Danish patent application PA 2007 01744 and PA 2008 01 104, and having the title Neurotensin treatment of ischemia, claiming priority from PA 2007 01745 and PA 2008 00498.

Based hereon, the preferred dosages of a cannabinoid compound such as, but not limited to HU-210 and KN38-7271 (BAY38-7271 ), is between 1 μg and 1 mg pr kg total body weight, such as between 10 μg and 100 μg pr kg total body weight, such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg pr kg total body weight. The dosage may depend on the administration form. For example, it is preferable to administer HU-210 in the range of from 10 μg and 100 μg pr kg total body weight intravenously.

For one of the compounds in this invention, HU-210, the dosage regime will be between 2 and 1000 microgram/kg of total body weight, such as between 4 and 900 microgram/kg of total body weight, such as between 6 and 800 microgram/kg of total body weight, such as between 8 and 700 microgram/kg of total body weight, such as between 10 and 600 microgram/kg of total body weight. Preferably, the dosage regime will be between 15 and 500 microgram/kg of total body weight, more preferably between 20 and 400 microgram/kg of total body weight. More preferably at least 40 microgram/kg of total body weight, such as at least 50 microgram/kg of total body weight, such as at least 60 microgram/kg of total body weight, such as at least 70 microgram/kg of total body weight, such as at least 80 microgram/kg of total body weight, such as at least 100 microgram/kg of total body weight. The dosages mentioned are the dosages for inducing hypothermia as defined herein. The dosage may be administered as one single bolus or divided into two or more dosages given over a period of time; alternatively it may be administered by continuous IV.

Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additional dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.

For another compound in this invention, delta-8-THC phosphate, the dosage regime will be between 0.25 and 600 mg/kg of total body weight, such as between 0.5 and 500 mg/kg of total body weight, 1 and 400 mg/kg of total body weight, 2 and 300 mg/kg of total body weight, 3 and 200 mg/kg of total body weight. Preferably, the dosage regime will be between 4 and 150 mg/kg of total body weight, more preferably between 5 and 100 mg/kg of total body weight. More preferably at least 10 mg/kg of total body weight, such as at least 20 mg/kg of total body weight, such as at least 30 mg/kg of total body weight, such as at least 40 mg/kg of total body weight, such as at least 50 mg/kg of total body weight, such as at least 60 mg/kg of total body weight, such as at least 100 mg/kg of total body weight. The dosages mentioned are the dosages for inducing hypothermia as defined herein. The dosage may be administered as one single bolus or divided into two or more dosages given over a period of time; alternatively it may be administered by continuous IV. Additionally the hypothermic effect may be maintained by administering one or more dosages some hours after the first dosage, such as at least 6 hours later, or such as at least 12 hours later. Such additional dosages may be of the same amount as the first dosage or an amount being at the most one-half or one-quarter of the first dosage.

Likewise, the preferred dosages of a vanilloid compound such as, but not limited to dihydrocapsaicin, is between 10 μg and 2000 μg pr kg total body weight, such as between 100 μg and 1000 μg such as or about 10 μg, 20 μg, 30 μg, 40 μg, 50 μg, 60 μg, 70 μg, 80 μg, 90 μg or 100 μg pr kg total body weight, or 150 μg, 200 μg, 250 μg, 300 μg, 350 μg, 400 μg, 450 μg, 500 μg, 600 μg, 700 μg, 800 μg, 900 μg, 1000, 1500 μg or 2000 μg pr kg total body weight when injected in the individual intravenously. Alternatively, dihydrocapsaicin and other vanilloids may be injected intramuscularly at dosages between 100 μg and 100 mg pr kg total body weight, such as between 200 μg and 90 mg, between 300 μg and 80 mg, such as between 400 μg and 70 mg, such as between 500 μg and 60 mg, such as between 600 μg and 50 mg, such as between 700 μg and 40 mg, such as between 800 μg and 30 mg, such as between 900 μg and 20 mg, such as between 1 mg and 10 mg pr kg total body weight. Alternatively, the dosage may be found in the range of from 100 μg to 2000 μg, such as 200 μg to 1800 μg, or 300 μg to 1600 μg, 400 μg to 1400 μg, 500 μg to 1200 μg, 600 μg to 1000 μg, or 500 μg to 2000 μg pr kg total body weight.

When gradually decreasing the dosages, the starting point is the treatment dosage, and the end point will either be a dosage close to zero or the dosage at which the individual is returned to normothermia.

By gradually decreasing the dosage of the hypothermia inducing compound(s) it is also an object of the present invention to provide a medicament comprising one or more compound or compounds capable of reverting body temperature to between 36 and 38 °C, in an individual, subsequent to induction of hypothermia, in particular to a body temperature of about 37°C, in an individual, subsequent to induction of hypothermia.

The hypothermia inducing compound administed in decreasing dosages may be coadministered with hyperthermia inhibiting compounds if appropriate.

Pharmaceutical composition Whilst it is possible for the compounds or salts of the present invention to be administered as the raw chemical, it is preferred to present them in the form of a pharmaceutical formulation. Accordingly, the present invention further provides a pharmaceutical formulation, for medicinal application, which comprises a combination of compounds of the present invention or pharmaceutically acceptable salts thereof, as herein defined, and a pharmaceutically acceptable carrier there for. O

The compounds and combinations of compounds of the present invention may be formulated in a wide variety of oral administration dosage forms. The pharmaceutical compositions and dosage forms may comprise the combinations of compounds of the invention or their pharmaceutically acceptable salts or a crystal forms thereof as the active components. The pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules. A solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, wetting agents, tablet disintegrating agents, or an encapsulating material.

The compounds and combinations of compounds of the present invention may be formulated for parenteral administration (e.g., by injection, for example bolus injection or continuous infusion) and may be presented in unit dose form in ampoules, pre-filled syringes, small volume infusion or in multi-dose containers with an added preservative. The compositions may take such forms as suspensions, solutions, or emulsions in oily or aqueous vehicles, for example solutions in aqueous polyethylene glycol. Examples of oily or non-aqueous carriers, diluents, solvents or vehicles include propylene glycol, polyethylene glycol, vegetable oils (e.g., olive oil), and injectable organic esters (e.g., ethyl oleate), and may contain formulatory agents such as preserving, wetting, emulsifying or suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form, obtained by aseptic isolation of sterile solid or by lyophilisation from solution for constitution before use with a suitable vehicle, e.g., sterile, pyrogen-free water.

Oils useful in parenteral formulations include petroleum, animal, vegetable, or synthetic oils. Specific examples of oils useful in such formulations include peanut, soybean, sesame, cottonseed, corn, olive, petrolatum, and mineral. Suitable fatty acids for use in parenteral formulations include oleic acid, stearic acid, and isostearic acid. Ethyl oleate and isopropyl myristate are examples of suitable fatty acid esters.

Suitable soaps for use in parenteral formulations include fatty alkali metal, ammonium, and triethanolamine salts, and suitable detergents include (a) cationic o

detergents such as, for example, dimethyl dialkyl ammonium halides, and alkyl pyridinium halides; (b) anionic detergents such as, for example, alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether, and monoglyceride sulphates, and sulfosuccinates, (c) non-ionic detergents such as, for example, fatty amine oxides, fatty acid alkanolamides, and polyoxyethylenepolypropylene copolymers, (d) amphoteric detergents such as, for example, alkyl-. beta.-aminopropionates, and 2-alkyl- imidazoline quaternary ammonium salts, and (e) mixtures thereof.

The parenteral formulations typically will contain from about 0.5 to about 25% by weight of the active ingredient in solution. Preservatives and buffers may be used. In order to minimize or eliminate irritation at the site of injection, such compositions may contain one or more non-ionic surfactants having a hydrophile - lipophile balance (HLB) of from about 12 to about 17. The quantity of surfactant in such formulations will typically range from about 5 to about 15% by weight. Suitable surfactants include polyethylene sorbitan fatty acid esters, such as sorbitan monooleate and the high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by the condensation of propylene oxide with propylene glycol. The parenteral formulations can be presented in unit-dose or multi-dose sealed containers, such as ampoules and vials, and can be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid excipient, for example, water, for injections, immediately prior to use. Extemporaneous injection solutions and suspensions can be prepared from sterile powders, granules, and tablets of the kind previously described.

Thus, in one embodiment the medicament of the present invention, comprises a pharmaceutically acceptable carrier.

Pharmaceutically acceptable salts

Pharmaceutically acceptable salts of the instant compounds, where they can be prepared, are also intended to be covered by this invention. These salts will be ones which are acceptable in their application to a pharmaceutical use. By that it is meant that the salt will retain the biological activity of the parent compound and the salt will not have untoward or deleterious effects in its application and use in treating diseases. Pharmaceutically acceptable salts are prepared in a standard manner. If the parent compound is a base it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.

The compound or combination of compounds of the invention may be administered in the form of an alkali metal or earth alkali metal salt thereof, concurrently, simultaneously, or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of a pharmaceutical composition thereof, whether by oral, rectal, or parenteral (including subcutaneous) route, in an effective amount.

A pharmaceutically acceptable salt means any salt of the compounds mentioned. In particular, it means a pharmaceutically acceptable acid addition salt. Pharmaceutically acceptable acid addition salts of the compounds include salts derived from non-toxic inorganic acids such as hydrochloric, nitric, phosphoric, sulphuric, hydrobromic, hydriodic, hydrofluoric, phosphorous and the like, as well as the salts derived from non-toxic organic acids, such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, alkanedioic acids, aromatic acids, aliphatic and aromatic sulfonic acids, etc. Such salts thus include sulphate, pyrosulphate, bisulphate, sulphite, bisulphite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate, propionate, caprylate, isobutyrate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, mandelate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate, benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate, maleate, tartrate, methanesulfonate, and the like.

eh An aspect of the present invention regards the pH of the medicament. The pH of the medicament depends on the administration form, as the pH of the medicament preferably is suitable for the route of administration chosen. An embodiment of the present invention comprises a medicament wherein the pH of the composition is between pH 5 and pH 9, such as between pH 5.5 and 8.5 such as between pH 6 and 8, such as between pH 6.5 and 7.5. Most preferably the pH of the medicament is in accordance with the route of administration and the tissue to which the medicament is administered.

It is also an object of the present invention to provide a medicament the pH of the composition is between pH 5 and pH 9.

Administration

The main routes of drug delivery, in the treatment method are intravenous, oral, and topical, as will be described below. Other drug-administration methods, such as subcutaneous injection or via inhalation, which are effective to deliver the drug to a target site or to introduce the drug into the bloodstream, are also contemplated. In particular for the hypothermia inducing compound(s) it is preferred to use the same route of administration for the decreasing dosages as is used for the treatment dosages.

The mucosal membrane to which the pharmaceutical preparation of the invention is administered may be any mucosal membrane of the individual to which the biologically active substance is to be given, e.g. in the nose, vagina, eye, mouth, genital tract, lungs, gastrointestinal tract, or rectum, preferably the mucosa of the nose, mouth or rectum.

The compounds and combinations of compounds of the invention may be administered parenterally, that is by intravenous, intramuscular, intraspinal, subcutaneous, intraarterial, intracardiac, intraosseous, intradermal, intrathecal, transdermal, transmucosal, inhalational, epidural, sublingual, intravitreal, intranasal, intrarectal, intravaginal or intraperitoneal administration, in particularly intravenous. Appropriate dosage forms for such administration may be prepared by conventional techniques. The combinations of compounds may also be administered by inhalation that is by intranasal and oral inhalation administration. Appropriate dosage forms for such administration, such as an aerosol formulation or a metered dose inhaler, may be prepared by conventional techniques.

The combinations of compounds according to the invention may be administered with at least one other compound. The compounds may be administered simultaneously, either as separate formulations or combined in a unit dosage form, or administered sequentially.

A preferred embodiment of the present invention is a medicament for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation. More preferably the administration form is by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.

In one embodiment, the at least one compound of the present invention is administered by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.

In another embodiment, the at least one compound of the present invention is administered by injection, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.

In one particular embodiment of the present invention, the compound or compounds of the present invention are administered by intravenous infusion, a bolus or a continuous infusion.

Individual

The individual that may benefit from the administration of a medicament as described herein may be an individual being returned to normothermia subsequent to medical or mechanical hypothermia therapy said patient suffering or having suffered from ischemia. Being in need of treatment thus indicates that the health of the individual is benefitted by the administration of the at least one compound of the present invention.

Examples

Example 1 - Cardiac arrest

A 57-year-old woman is taken care of by the ambulance staff that finds her in ventricular fibrillation approximately 5 minutes after having collapsed without warning. The patient is immediately defibrillated and spontaneous circulation and ventilations occurred. On arrival to the hospital, 21 minutes after having collapsed, the patient has a palpable pulse. Staff at the emergency room has been alerted in advance. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

Hypothermia therapy is conducted as described in this invention. Two or more compounds are administered: One (see 1.) that induces hypothermia and one or more (see 2.) that minimizes the hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia: 1. Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 (intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers 2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid, Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6) Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication (1.) 1 -8 additional bolus injections of the hypothermia inducing compound(s) may be required. In a similar fashion, one or several doses, whether orally, rectally, intravenously, or otherwise administered may be required in order to prevent overshooting.

At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.

Example 2 - Cardiac arrest A 22-year-old male athlete collapses when doing sports. Medical staff finds ventricular fibrillation/ventricular tachycardia approximately 6 minutes after collapse. He is successfully defibrillated and the patient is rushed to the hospital. In the ambulance, the physician present in the ambulance team decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

Hypothermia therapy is conducted as described in this invention. Two or more compounds are administered: One (see 1.) that induces hypothermia and one or more (see 2.) that minimizes the hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia: 1. Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 (intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers

2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac,

Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid, Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone,

Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6) Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication (1.) 1 -8 additional bolus injections of the hypothermia inducing compound(s) may be required. In a similar fashion, one or several doses, whether orally, rectally, intravenously, or otherwise administered may be required in order to prevent overshooting. At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted.

Example 3 - Cardiac arrest

A 66-year-old man is undergoing elective heart surgery. He suffers from irregular cardiac rhythm during the procedure and goes into cardiac arrest with much impaired circulation for 6 minutes after which the surgical team manages to restore circulation. Subsequent to restoration of circulation, the surgeon in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

Hypothermia therapy is conducted as described in this invention. Two or more compounds are administered: One (see 1.) that induces hypothermia and one or more (see 2.) that minimizes the hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia: 1. Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210

(intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g.

40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers 2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid,

Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6) Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

Example 4 - Cardiac arrest An electrician accidentally receives a high-voltage jolt and immediately slips into a coma. The company physician manages to resuscitate the cardiac arrest patient after just 7 minutes. The patient is rushed to hospital where the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid, Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6)

Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

Example 5 - Perinatal asphyxia

A newborn baby suffers cerebral ischemia during delivery as the umbilical cord gets wrapped around his neck. The APGAR score 10 minutes after delivery is 6. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

Hypothermia therapy is conducted as described in this invention. Two or more compounds are administered: One (see 1.) that induces hypothermia and one or more (see 2.) that minimizes the hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia:

1 . Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210

(intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of

0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers

Example 6 - Asphyxia

A 9-year-old boy is in a coma when he is rescued out of a burning house. CRP is commenced on the spot but he is not awake when the ambulance arrives at hospital after a 15 minutes drive. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.

1. Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 (intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers

2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid, Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6) Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib,

Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

Example 7 - Stroke

A 78-year-old woman is admitted to hospital 50 minutes after experiencing sudden onset lack of mobility of the left arm and leg and as well and difficulties speaking. The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

Example 8 - Stroke

A 29-year-old man suffers continuous pains in the back of his head for two weeks after which he suddenly collapses and slips into a coma. The patient is diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain. Hypothermia therapy is conducted as described in this invention. Two or more compounds are administered: One (see 1.) that induces hypothermia and one or more (see 2.) that minimizes the hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia: 1. Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 (intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers

Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone) The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication (1.) 1 -8 additional bolus injections of the hypothermia inducing compound(s) may be required. In a similar fashion, one or several doses, whether orally, rectally, intravenously, or otherwise administered may be required in order to prevent overshooting.

Example 9 - Myocardial infarction

A 55-year-old man is admitted to hospital 18 minutes after experiencing nausea, shortness of breath, and severe chest pains. The patient who is suffering myocardial infarction is evaluated by the physician in charge who decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the heart and other tissues.

2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin,

Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen,

Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid, Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6) Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

The purpose of hypothermia therapy is to lower the patient's core body temperature to 32-34 degrees Celsius for 12-24 hours (current American Heart Association recommendation). Depending on the individual's response to the medication (1.) 1 -8 additional bolus injections of the hypothermia inducing compound(s) may be required. In a similar fashion, one or several doses, whether orally, rectally, intravenously, or otherwise administered may be required in order to prevent over- shooting.

Example 10 - Traumatic brain injury

A 41 -year-old man receives a severe blow to the head from a falling brick on a construction site. The patient is still unconscious when he 24 minutes after the trauma is brought to the Emergency Room. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

1 . Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 (intravenous bolus injection of e.g. 10O microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers

2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid, Meclofenamic acid, 5) Pyrazolidine derivatives: Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone, Sulfinpyrazone, 6) Oxicams: Piroxicam, Lornoxicam, Meloxicam, Tenoxicam, 7) COX-2 inhibitors: Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib, Valdecoxib, 8) Sulphonanilides: Nimesulide, 9) Others: Licofelone)

Example 11 - Pulmonary embolism

A 60-year-old woman is feeling rather well two days after major surgery when she suddenly slips into a coma. Following acute surgery, brought on by a pulmonary embolism, she is stabilized. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain and other tissues.

Hypothermia therapy is conducted as described in this invention. Two or more compounds are administered: One (see 1.) that induces hypothermia and one or more (see 2.) that minimizes the hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia: 1 . Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin (subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers 2. Anti-hyperthermia (anti-overshooting) compounds of this invention include antipyretics such as: a. Paracetamol/acetaminophen (such as, but not limited to, Tylenol) b. NSAID (such as, but not limited to, 1 ) Salicylates: Aspirin, Amoxiprin, Benorilate, Choline magnesium salicylate, Diflunisal, Methyl salicylate, Magnesium salicylate, Salicyl salicylate, 2) Arylalkanoic acids: Diclofenac, Aceclofenac, Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac, Tolmetin, 3) 2-Arylpropionic acids: Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen, Naproxen, Oxaprozin, Tiaprofenic acid, Suprofen, 4) N-Arylanthranilic acids: Mefenamic acid,

At the hospital, concurrent treatments and examinations are not influenced by the administration of the hypothermia-inducing drug. Such other treatments and examinations proceed uninterrupted. Example 12 - Modified pyrogenicity test on rabbits

Each combination of compounds in a low, medium and high dose will be screened initially on 3 rabbits. Temperature, blood pressure, pulse will be measured for 72 hours following administration of active substances. These parameters will be reco rd ed as f o 11 ows :

Continuous recording (time=0-3h), every 30 minutes (time=3-6h), every 1 hour (time=6-12h), every 2 hours (time=12-24h), every 6 hours (time=24-48h), every 12 hours (time=48-72h)

These are the specifics of the initial screening:

Type of rabbits: New Zealand White, Charles River Weight: >1.5 kg

Gender: Female

Room temperature: 21⁰C (+/- 1⁰C)

Relative humidity: 55% (+/- 5%)

Type of temperature probe: PC Based pyrogen testing system, Ellab APT 91 Cage type: Pro Plast Noryl, 2475 cm2

Number of rabbits in a cage: 1

Water and food access: Ad lib in cage.

12-hour light period: Yes

Example 13 - Porcine study model

In order to evaluate an effective hypothermic dose of a receptor agonist compound according to the invention, the compound may be tested in the porcine study model. The porcine model is used because the body weight of the pigs is comparable to the body weight of humans. The efficacy of a compound tested in the porcine model may be correlated with the efficacy of the cannabinoid or vanilloid compound tested in the same porcine study model. Study subjects

The evaluation is carried out on "dansk landrace" pigs with a body weight of 70-90 kilo. The pigs will not be sedated; they will be fed twice a day; and they will be subjected to a day cycle consisting of 12 hours of light followed by 12 hours of dark.

Drug administration

The compound investigated are administered i.v. as bolus injections and may consist of 1 solitary injection, alternatively 2-4 repeated injections within a timeframe of 24 hours from the initial injection.

Generally 4 different doses plus vehicle are tested producing varying degrees of hypothermic responses.

Hypothermic effect The primary effect evaluated is hypothermia. Temperature is measured using a temperature probe that is surgically positioned in a femoral artery two weeks prior to commencement of the study. The probe is connected to telemetry equipment (e.g. implanted telemetry from Data Sciences International) ensuring the required readouts.

Temperature is measured every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Temperature measurement will be conducted via a permanent femoral artery temperature probe (telemetry).

The minimum temperature as well as a graph of the temperature at each point of measurement is recorded for each dose of compound or compound mixture.

Other effects Blood pressure, heart rate and ECG will be registered every 15 minutes from 1 hour prior to drug administration to 12 hours after drug administration, and every 30 minutes subsequently until 24 hours after drug administration. Example 14 - Calf study model

In order to evaluate the effectiveness of one or several compounds capable of preventing hyperthermia during rewarming subsequent to induction of hypothermia for the prophylaxis and treatment of tissue damaging effects of ischemia, according to the invention, such treatment may be tested in the calf study model. The calf model is used because the body weight of the calves is comparable to the body weight of humans.

Study subjects The evaluation is carried out on male "sortbroget malkeko/Holstein" calves with a body weight of 75-85 kilo or 70-90 kilo. The calves are positioned in individual booths; they are not sedated; they are fed twice a day (milk at 8:00 A.M. and hay/food pills at an unspecified hour, depending on the effects of the compounds examined); and they are subjected to a day cycle consisting of 16 hours of light followed by 8 hours of dark. The ambient temperature is 20°C+/-2°C.

Drug administration

The compounds investigated are administered i.v. (in the jugular vein) as bolus injections and/or p.o. or topically and may consist of 1 solitary administration, alternatively 2-8 repeated administrations within a timeframe of 12-24 hours from the initial administration.

A treatment consists of a solitary compound or a combination of compounds comprising one or more of the groups listed here: NSAIDs, acetaminophens.

Generally 4 different doses plus vehicle are tested producing varying degrees of anti-hyperthermic responses.

Hypothermic effect The primary effect evaluated is avoidance of hyperthermia (over-shooting) following hypothermia therapy, whether it is medically or mechanically induced. Temperature is measured using a temperature probe (ADInstruments) that is surgically positioned in vena cava cranialis one week prior to commencement of the study. The probe is connected to a Powerlab ensuring the required read-outs. O--

Temperature is measured 100 times/second and compounded every 15 minutes from 1 hour prior to drug administration to 24 hours after administration.

Other effects Blood pressure and heart rate are measured 100 times/second and compounded every 15 minutes from 1 hour prior to drug administration to 24 hours subsequent to administration. Data is collected using a Powerlab.

Example 15 - Receptor studies Modulation of CB and TRPV1 activities will be assessed in vitro by measuring cannabinoid and/or cannabimimetic compound and vanilloid receptor agonist induced Ca2+ flux, respectively. This will be done using FLIPR and HEK293 cells stably expressing recombinant human (h) and rat (r) TRPV1 (hTRPV1 -HEK293 and rTRPV1 -HEK293, respectively) and recombinant human (h) and rat (r) CB receptors (hCB1 -HEK293, hCB2-H293, rCB1 -HEK293 and rCB2-H293) and especially in cells co-expressing human or rat TRPVI and CB receptors (hTRPV1 -hCB1 -HEK293 and hTRPV1 -hCB2-HEK293). Intracellular Ca2+ levels will be measured in CB, TRPV1 and coCB/TRPVI -expressing cells during exposure to compounds and combinations of compounds. A concentration dependent increase in Ca2+ influx will be observed. The efficacy of vanilloid agonists will be estimated by comparing these to the maximum response induced by capsaicin, likewise the efficacy of cannabinoids will be estimated by comparing these to the maximum response induced by cannabidiol. A combination of capsaicin and cannabidiol will be used as reference for measuring combinations of drugs.

Example 16 - gradual reduction of Dihydrocapsaicin by infusion A total of 4 calves receives ongoing IV infusions of Dihydrocapsaicin (0.6 mg/kg body weight) for 5 hours and experience a reduction in body temperature of between approx. 3.5 to 4.5 degrees Celsius. At the end of the hypothermia period two scenarios is tested (as shown in figure 1 ):

• the infusion is brought to a sudden stop in 2 of the calves (Temp 2198' and 'Temp 1718'), or

• the infusion is gradually slowed down in 2 of the calves (Temp 2254' and Temp 2389') The difference in temperature outcome is dramatically different between the two groups. The first group (sudden infusion stop) reaches normothermia in about 60 minutes after infusion stop, whereas the second group (gradual slowing down of infusion) reaches normothermia more slowly; in about 210 minutes. This is shown in figure 1.

The principle of slowing down the infusion rate to reach exactly the optimal temperature gradient in order to avoid/minimize post-hypothermia therapy overshooting applies to Dihydrocapsaicin as well as all other compounds of this invention.

Example 17 - gradual reduction of hypothermia-inducing compound

A patient is admitted in a hospital and diagnosed with a stroke. The patient is evaluated and the physician in charge decides that the patient shall receive hypothermia therapy immediately to minimize the risk of damage to the brain.

In another example, the patient may be diagnosed with for example cardiac arrest, perinatal asphyxia, myocardial infarction, traumatic brain injury or pulmonary embolism.

Hypothermia therapy is conducted as described in this invention. One or more compounds are administered that induces hypothermia. These are known to cause hyperthermia (over-shooting) frequently associated with hypothermia therapy as the patient approaches post-therapeutic normothermia: 1. Hypothermia inducing compounds of this invention include: a. Cannabinoid receptor agonists. Including, but not limited to HU-210 (intravenous bolus injection of e.g. 100 microgram/kg body weight) and/or delta-8-THC phosphate (intravenous bolus injection of e.g. 40 mg/kg body weight) b. Vanilloid receptor agonists. Including, but not limited to dihydrocapsaicin

(subcutaneous or intravenous bolus injection of 0.01 mg/kg to 80 mg/kg) c. Adenosine receptor agonists (including, but not limited to 5'-AMP) d. Neurotensin receptor agonists e. Thyroxine derivatives f. Cytochrome C oxidase inhibitor g. Oxygen tension reducers

In order to prevent over-shooting, the dosis of the hypothermia-inducing compound(s) given is reduced towards the end of treatment. If for example dihydrocapcaisin is administered to the patient by an intravenous infusion of 0.6 microgram/kg body weight per hour, said infusion may be administered by a gradual decrease in dosage of dihydrocapcaisin, such that the majority of the dosage is given within the first hour, and lower amounts of the dosage is given in the subsequent hours.

References

(1 ) Busto R, Dietrich WD, Globus MY, Valdes I, Scheinberg P, Ginsberg MD: Small differences in intraischemic brain temperature critically determine the extent of ischemic neuronal injury. J Cereb Blood Flow Metab 1987; 7(6):729-738.

(2) Barone FC, Feuerstein GZ, White RF: Brain cooling during transient focal ischemia provides complete neuroprotection. Neurosci Biobehav Rev 1997; 21 (1 ):31 -44.

(3) Onesti ST, Baker CJ, Sun PP, Solomon RA: Transient hypothermia reduces focal ischemic brain injury in the rat. Neurosurgery 1991 ; 29(3):369-373.

(4) Coimbra C, Wieloch T: Moderate hypothermia mitigates neuronal damage in the rat brain when initiated several hours following transient cerebral ischemia. Acta Neuropathol (Berl) 1994; 87(4):325-331.

(5) Zhang Y, Wong KC, Zhang Z: The effect of intraischemic mild hypothermia on focal cerebral ischemia/reperfusion injury. Acta Anaesthesiol Sin 2001 ; 39(2):65-69. (6) Yamashita K, Eguchi Y, Kajiwara K, lto H: Mild hypothermia ameliorates ubiquitin synthesis and prevents delayed neuronal death in the gerbil hippocampus. Stroke 1991 ; 22(12):1574-1581.

(7) Ooboshi H, lbayashi S, Takano K, Sadoshima S, Kondo A, Uchimura H, Fujishima M: Hypothermia inhibits ischemia-induced efflux of amino acids and neuronal damage in the hippocampus of aged rats. Brain Res 2000; 884(1 ~2):23- 30.

(8) Colbourne F, Corbett D, Zhao Z, Yang J, Buchan AM: Prolonged but delayed postischemic hypothermia: a long-term outcome study in the rat middle cerebral artery occlusion model. J Cereb Blood Flow Metab 2000; 20(12):1702-1708.

(9) Kawai N, Okauchi M, Morisaki K, Nagao S: Effects of delayed intraischemic and postischemic hypothermia on a focal model of transient cerebral ischemia in rats.

Stroke 2000; 31 (8):1982-1989.

(10) Maier CM, Sun GH, Kunis D, Yenari MA, Steinberg GK: Delayed induction and long-term effects of mild hypothermia in a focal model of transient cerebral ischemia: neurological outcome and infarct size. J Neurosurg 2001 ; 94(1 ):90-96.

(1 1 ) Maier CM, Ahern K, Cheng ML, Lee JE, Yenari MA, Steinberg GK: Optimal depth and duration of mild hypothermia in a focal model of transient cerebral ischemia: effects on neurologic outcome, infarct size, apoptosis, and inflammation. Stroke 1998; 29(10):2171 -2180.

(12) Mild therapeutic hypothermia to improve the neurologic outcome after cardiac arrest: N Engl J Med 2002; 346(8) :549-556.

(13) Bernard SA, Gray TW, Buist MD, Jones BM, Silvester W, Gutteridge G, Smith K: Treatment of comatose survivors of out-of-hospital cardiac arrest with induced hypothermia. N Engl J Med 2002; 346(8) :557-563.

(14) Bernard S: Therapeutic hypothermia after cardiac arrest: now a standard of care. Crit Care Med 2006; 34(3):923-924. (15) Dietrich WD, Halley M, Valdes I, Busto R: Interrelationships between increased vascular permeability and acute neuronal damage following temperature-controlled brain ischemia in rats. Acta Neuropathol (Berl) 1991 ; 81 (6):615-625.

(16) Karibe H, Zarow GJ, Graham SH, Weinstein PR: Mild intraischemic hypothermia reduces postischemic hyperperfusion, delayed postischemic hypoperfusion, blood-brain barrier disruption, brain edema, and neuronal damage volume after temporary focal cerebral ischemia in rats. J Cereb Blood Flow Metab 1994; 14(4):620-627.

(17) Huang ZG, Xue D, Preston E, Karbalai H, Buchan AM: Biphasic opening of the blood-brain barrier following transient focal ischemia: effects of hypothermia. Can J Neurol Sci 1999; 26(4):298-304.

(18) Bagenholm R, Nilsson UA, Kjellmer I: Formation of free radicals in hypoxic ischemic brain damage in the neonatal rat, assessed by an endogenous spin trap and lipid peroxidation. Brain Res 1997; 773(1 -2):132-138.

(19) KiI HY, Zhang J, Piantadosi CA: Brain temperature alters hydroxyl radical production during cerebral ischemia/reperfusion in rats. J Cereb Blood Flow Metab 1996; 16(1 ):100-106.

(20) Kumura E, Yoshimine T, Takaoka M, Hayakawa T, Shiga T, Kosaka H: Hypothermia suppresses nitric oxide elevation during reperfusion after focal cerebral ischemia in rats. Neurosci Lett 1996; 220(1 ):45-48.

(21 ) Baker AJ, Zornow MH, Grafe MR, Scheller MS, Skilling SR, Smullin DH, Larson AA: Hypothermia prevents ischemia-induced increases in hippocampal glycine concentrations in rabbits. Stroke 1991 ; 22(5):666-673.

(22) Takagi K, Ginsberg MD, Globus MY, Dietrich WD, Martinez E, Kraydieh S, Busto R: Changes in amino acid neurotransmitters and cerebral blood flow in the ischemic penumbral region following middle cerebral artery occlusion in the rat: correlation with histopathology. J Cereb Blood Flow Metab 1993; 13(4):575-585. (23) Nakashima K, Todd MM: Effects of hypothermia on the rate of excitatory amino acid release after ischemic depolarization. Stroke 1996; 27(5):913-918.

(24) Maier CM, Sun GH, Cheng D, Yenari MA, Chan PH, Steinberg GK: Effects of mild hypothermia on superoxide anion production, superoxide dismutase expression, and activity following transient focal cerebral ischemia. Neurobiol Dis 2002; 1 1 (1 ):28-42.

(25) Pulsinelli W: Pathophysiology of acute ischaemic stroke. Lancet 1992; 339(8792):533-536.

(26) Eguchi Y, Yamashita K, Iwamoto T, lto H: Effects of brain temperature on calmodulin and microtubule-associated protein 2 immunoreactivity in the gerbil hippocampus following transient forebrain ischemia. J Neurotrauma 1997; 14(2):109-1 18.

(27) Sick TJ, Tang R, Perez-Pinzon MA: Cerebral blood flow does not mediate the effect of brain temperature on recovery of extracellular potassium ion activity after transient focal ischemia in the rat. Brain Res 1999; 821 (2):400-406.

(28) Hu BR, Kamme F, Wieloch T: Alterations of Ca2+/calmodulin-dependent protein kinase Il and its messenger RNA in the rat hippocampus following normo- and hypothermic ischemia. Neuroscience 1995; 68(4):1003-1016.

(29) Busto R, Globus MY, Neary JT, Ginsberg MD: Regional alterations of protein kinase C activity following transient cerebral ischemia: effects of intraischemic brain temperature modulation. J Neurochem 1994; 63(3):1095-1 103.

(30) Ishikawa M, Sekizuka E, Sato S, Yamaguchi N, lnamasu J, Bertalanffy H,

Kawase T, ladecola C: Effects of moderate hypothermia on leukocyte- endothelium interaction in the rat pial microvasculature after transient middle cerebral artery occlusion. Stroke 1999; 30(8):1679-1686. o

(31 ) lnamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Post- ischemic hypothermia delayed neutrophil accumulation and microglial activation following transient focal ischemia in rats. J Neuroimmunol 2000; 109(2):66-74.

(32) Hara A, Niwa M, Iwai T, Yano H, Bunai Y, Uematsu T, Yoshimi N, Mori H:

Increase of fragmented DNA transport in apical dendrites of gerbil CA1 pyramidal neurons following transient forebrain ischemia by mild hypothermia. Neurosci Lett 2000; 280(1 )73-77.

(33) Xu L, Yenari MA, Steinberg GK, Giffard RG: Mild hypothermia reduces apoptosis of mouse neurons in vitro early in the cascade. J Cereb Blood Flow Metab 2002; 22(1 ):21 -28.

(34) Zhang Z, Sobel RA, Cheng D, Steinberg GK, Yenari MA: Mild hypothermia increases Bcl-2 protein expression following global cerebral ischemia. Brain Res MoI Brain Res 2001 ; 95(1 -2)75-85.

(35) Niwa M, Hara A, Iwai T, Nakashima M, Yano H, Yoshimi N, Mori H, Uematsu T: Relationship between magnitude of hypothermia during ischemia and preventive effect against post-ischemic DNA fragmentation in the gerbil hippocampus. Brain Res 1998; 794(2) :338-342.

(36) lnamasu J, Suga S, Sato S, Horiguchi T, Akaji K, Mayanagi K, Kawase T: Postischemic hypothermia attenuates apoptotic cell death in transient focal ischemia in rats. Acta Neurochir Suppl 2000; 76:525-527.

(37) Silva C, Silva J, Ribeiro MJ, Avelino A, Cruz F: Urodynamic effect of intravesical resiniferatoxin in patients with neurogenic detrusor overactivity of spinal origin: results of a double-blind randomized placebo-controlled trial. Eur Urol 2005; 48(4):650-655.

(38) Payne CK, Mosbaugh PG, Forrest JB, Evans RJ, Whitmore KE, Antoci JP, Perez-Marrero R, Jacoby K, Diokno AC, O'Reilly KJ, Griebling TL, Vasavada SP, Yu AS, Frumkin LR: Intravesical resiniferatoxin for the treatment of interstitial cystitis: a randomized, double-blind, placebo controlled trial. J Urol 2005; 173(5):1590-1594. (39) Kim JH, Rivas DA, Shenot PJ, Green B, Kennelly M, Erickson JR, O'Leary M, Yoshimura N, Chancellor MB: Intravesical resiniferatoxin for refractory detrusor hyperreflexia: a multicenter, blinded, randomized, placebo-controlled trial. J Spinal Cord Med 2003; 26(4):358-363.

(40) Hayes AG, Oxford A, Reynolds M, Shingler AH, Skingle M, Smith C, Tyers MB: The effects of a series of capsaicin analogues on nociception and body temperature in the rat. Life Sci 1984; 34(13):1241 -1248.

(41 ) Woods AJ, Stock MJ, Gupta AN, Wong TT, Andrews PL: Thermoregulatory effects of resiniferatoxin in the rat. Eur J Pharmacol 1994; 264(2):125-133.

(42) Miller MS, Brendel K, Buck SH, Burks TF: Dihydrocapsaicin-induced hypothermia and substance P depletion. Eur J Pharmacol 1982; 83(3-4):289-292.

(43) Ding Z, Cowan A, Rawls SM: Capsaicin evokes hypothermia independent of cannabinoid CB1 and CB2 receptors. Brain Res 2005; 1065(1 -2):147-151.

(44) Jakab B, Helyes Z, Varga A, Bolcskei K, Szabo A, Sandor K, Elekes K, Borzsei R, Keszthelyi D, Pinter E, Petho G, Nemeth J, Szolcsanyi J: Pharmacological characterization of the TRPV1 receptor antagonist JYL1421 (SC0030) in vitro and in vivo in the rat. Eur J Pharmacol 2005; 517(1 -2):35-44.

(45) Swanson DM, Dubin AE, Shah C, Nasser N, Chang L, Dax SL, Jetter M, Breitenbucher JG, Liu C, Mazur C, Lord B, Gonzales L, Hoey K, Rizzolio M, Bogenstaetter M, Codd EE, Lee DH, Zhang SP, Chaplan SR, Carruthers Nl: Identification and biological evaluation of 4-(3-trifluoromethylpyridin-2-yl)piperazine- 1 -carboxylic acid (5-trifluoromethylpyridin-2-yl)amide, a high affinity TRPV1 (VR1 ) vanilloid receptor antagonist. J Med Chem 2005; 48(6) :1857-1872.

(46) Leker RR, Gai N, Mechoulam R, Ovadia H: Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke 2003; 34(8):2000- 2006. (47) Ovadia H, Wohlman A, Mechoulam R, Weidenfeld J: Characterization of the hypothermic effect of the synthetic cannabinoid HU-210 in the rat. Relation to the adrenergic system and endogenous pyrogens. Neuropharmacology 1995; 34(2):175-180.

(48) Maas Al, Murray G, Henney H, III, Kassem N, Legrand V, Mangelus M, Muizelaar JP, Stocchetti N, Knoller N: Efficacy and safety of dexanabinol in severe traumatic brain injury: results of a phase III randomised, placebo-controlled, clinical trial. Lancet Neurol 2006; 5(1 ):38-45.

(49) Huestis MA, Gorelick DA, Heishman SJ, Preston KL, Nelson RA, Moolchan ET, Frank RA: Blockade of effects of smoked marijuana by the CB1 -selective cannabinoid receptor antagonist SR141716. Arch Gen Psychiatry 2001 ; 58(4):322- 328.

(50) Hosko MJ, Schmeling WT, Hardman HF: Evidence for a Caudal Brainstem Site of Action for Cannabinoid Induced Hypothermia. Brain Research Bulletin. 1981 , Vol. 6, p. 253.

Sequence listing

SEQ ID NO 1 : Neurotensin NT(M 3) QLYENKPRRP YIL

SEQ ID NO. 2: NT64D

L-Arg L-Arg L-Pro D-neo-Trp L-IIe L-Leu

SEQ ID NO. 3: NT64L L-Arg L-Arg L-Pro L-neo-Trp L-IIe L-Leu

SEQ ID NO. 4:NT65L

L-Arg L-Arg L-Pro L-neo-Trp tert-Leu L-Leu SEQ ID NO. 5: NT66D

D-Lys LArg L-Pro D-neo-Trp tert-Leu L-Leu

SEQ ID NO. 6: NT66L D-Lys L-Arg L-Pro L-neo-Trp tert-Leu L-Leu

SEQ ID NO. 7: NT67L

D-Lys L-Arg L-Pro L-neo-Trp L-IIe L-Leu SEQ ID NO.8: NT69L

N-methyl-Arg L-Lys L-Pro L-neo-Trp tert-Leu L-Leu

SEQ ID NO.9:NT69L" N-methyl-Arg L-Arg L-Pro L-neo-Trp tert-Leu L-Leu

SEQ ID NO.10: NT71

N-methyl-ARG Diaminobutyric acid L-Pro L-neo-Trp tert-Leu L-Leu SEQ ID NO.11: NT72

D-Lys L-Pro L-neo-Trp tert-Leu L-Leu

SEQ ID NO.12: NT73 D-Lys L-Pro L-neo-Trp L-IIe L-Leu

SEQ ID NO.13: NT74

Diaminobutyric acid L-Pro L-neo-Trp tert-Leu L-Leu

SEQ ID NO.14:NT75 Diaminobutyric acid L-Pro L-neo-Trp L-IIe L-Leu

SEQ ID NO.15: NT76

L-Arg D-ornithine L-Pro L-neo-Trp L-IIe L-Leu SEQ ID NO.16: NT77

L-Arg D-ornithine L-Pro L-neo-Trp tert-Leu L-Leu

SEQ ID NO 17: Neuromedin IPYIL

SEQ ID NO 18:JMV-449 H-Lys-psi-(CH2NH)-Lys-Pro-Tyr-lle-Leu-OH

SEQ ID NO 19:CGX-1160 MQTAYWVMVMMMVWIAAPLSEGGKLNDVIRGLVPDDITPQLILGSLISRRQSEEGGSNATK KPYILRASDQVASGP

Claims

1. Composition comprising at least one anti-pyretic compound for preventing or reducing hyperthermia in an individual during re-warming subsequent to induced hypothermia, and/or comprising at least one hypothermia inducing compound for preventing or reducing hyperthermia in an individual during re-warming subsequent to hypothermia induced by administration of said hypothermia inducing compound, wherein said hypothermia inducing compound is administered in decreasing dosages of said hypothermia inducing compound for a predetermined period.

2. The composition of claim 1 wherein the prevention of hyperthermia is prevention of over-shooting of normothermia.

3. The composition of any of claims 1 to 2 wherein reducing of hyperthermia is reducing over-shooting of normothermia.

4. The composition of any of claims 1 to 3 wherein the at least one compound capable of preventing hyperthermia is an acetaminophen or paracetamol.

5. The composition of any of claims 1 to 3 wherein the at least one compound capable of preventing hyperthermia is at least one NSAID.

6. The composition of claim 5 wherein the at least one NSAID is at least one compound selected from the group consisting of Salicylates, Arylalkanoic acids,

2-Arylpropionic acids, N-Arylanthranilic acids, Oxicams, COX-2 inhibitors, Sulphonanilides and Pyrazolidine derivatives

7. The composition of claim 6 wherein the at least one salicylate is at least one compound selected from the group consisting of Aspirin, Amoxiprin, Benorilate,

Choline magnesium salicylate, Diflunisal, Faislamine, Methyl salicylate, Magnesium salicylate and Salicyl salicylate.

8. The composition of claim 6 wherein the at least one Arylalkanoic acid is at least one compound selected from the group consisting of Diclofenac, Aceclofenac,

Acemetacin, Bromfenac, Etodolac, Indometacin, Nabumatone, Sulindac and Tolmetin.

9. The composition of claim 6 wherein the at least one 2-Arylpropionic acid is at least one compound selected from the group consisting of Ibuprofen, Carprofen, Fenbufen, Flurboprofen, Fenoprofen, Ketoprofen, Ketorolac, Loxoprofen,

Naproxen, Oxaprozin, Tiaprofenic acid and Suprofen.

10. The composition of claim 6 wherein the at least one N-Arylanthranilic acid is at least one compound selected from the group consisting of Mefenamic acid and Meclofenamic acid.

1 1 . The composition of claim 6 wherein the at least one Pyrazolidine derivative is at least one compound selected from the group consisting of Phenylbutazone, Azapropazone, Metamizole, Oxyphenbutazone and Sulfinpyrazone.

12. The composition of claim 6 wherein the at least one Oxicam is at least one compound selected from the group consisting of Piroxicam, Lornoxicam, Meloxicam and Tenoxicam.

13. The composition of claim 6 wherein the at least one COX-2 inhibitor is at least one compound selected from the group consisting of Celecoxib, Etoricoxib, Lumiracoxib, Paracoxib, Refecoxib and Valdecoxib.

14. The composition of claim 6 wherein the at least one Sulphonanilide is Nimesulide.

15. The composition of claim 5 wherein the compound capable of preventing hyperthermia is Licofelone or Omega-3 fatty acids.

16. The composition of claim 1 wherein the hypothermia was induced by administration of one or more compounds selected from the group consisting of: a) Vanilloid receptor agonists, capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors, and b) Cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors, and c) Adenosine receptor agonists, adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors, and d) Neurotensin receptor agonists, neurotensin analogs and compounds reaching and binding neurotensin receptors, and e) Thyroxine derivatives, thyroid hormone receptor agonists and trace amine-associated receptor agonists, and f) Cytochrome c oxidase inhibitors, and g) Oxygen tension reducers.

17. The composition of claim 1 wherein the hypothermia was induced by mechanical hypothermia therapy.

18. The composition of claim 1 wherein the at least one compound as defined in any of claims 3 to 15 is administered in combination with one or more second active ingredients.

19. The composition of claim 18 wherein the one or more second active ingredients are selected from the compounds defined in any of claims 18 to 22.

20. The composition according to any of preceding claims, for administration by injection, suppository, oral administration, sublingual tablet or spray, cutaneous administration, or inhalation.

21. The composition according to claim 20, wherein the injection is intravenous, intramuscular, intraspinal, intraperitoneal, subcutaneous, a bolus or a continuous administration.

22. The composition according to claim 1 , wherein hypothermia inducing compound is selected from the group consisting of: a) Vanilloid receptor agonists, capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors, and b) Cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors, and c) Adenosine receptor agonists, adenosine analogs or adenosine uptake inhibitors and agonist compounds reaching and binding to adenosine receptors, and d) Neurotensin receptor agonists, neurotensin analogs and compounds reaching and binding neurotensin receptors, and e) Thyroxine derivatives, thyroid hormone receptor agonists and trace amine-associated receptor agonists, and f) Cytochrome c oxidase inhibitors, and g) Oxygen tension reducers.

23. The composition according to claim 1 or 22, wherein the hypothermia inducing compound is selected from the group consisting of a) Vanilloid receptor agonists, capsaicinoids or capsaicinoid-like agonists reaching and binding to vanilloid receptors, and b) Cannabinoids or cannabimimetic agonists reaching and binding to cannabinoid receptors.

24. The composition according to any of the claims 1 , and 22-23, wherein the predetermined period is a fixed period of from 5 minutes to 24 hours.

25. The composition according to any of the claims 1 , and 22-23, wherein the predetermined period is the period until normothermia is reached.

26. The composition according to any of the claims 1 , and 22-25, wherein the dosage is decreased stepwise, such as decreasing each dosage to about 5-50 percent of the previous dosage.

27. The composition according to any of the claims 1 , and 22-25, wherein the dosage is decreased stepwise, such as reduced by a fixed predefined percentage of a treatment dosage, such as reduced by 5-25 percent of the treatment dosage at every decrease.

28. The composition according to any of the claims 1 , and 22-27, wherein the hypothermia inducing compound is administered continuously, such as by continuous infusion, and the decrease follows a fixed decreasing infusion rate.