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WO2007059039A1 - Derives de thyroxine pour preconditionnement contre accident cerebrovasculaire - Google Patents

Derives de thyroxine pour preconditionnement contre accident cerebrovasculaire Download PDF

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WO2007059039A1
WO2007059039A1 PCT/US2006/044001 US2006044001W WO2007059039A1 WO 2007059039 A1 WO2007059039 A1 WO 2007059039A1 US 2006044001 W US2006044001 W US 2006044001W WO 2007059039 A1 WO2007059039 A1 WO 2007059039A1
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thyronamine
lower alkyl
preconditioning
injury
subject
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Mary Stenzel-Poore
Kristian Doyle
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Oregon Health and Science University
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Oregon Health and Science University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • This disclosure relates to the field of neuroprotection. More specifically, the present disclosure relates to administration of a thyroxine derivative to inhibit cellular and organ damage due to excitotoxic injury, ischemia and/or hypoxia.
  • Thyroxine is the principal secreted form of thyroid hormone and makes up 95% of all thyroid hormone found in the circulation (Mortoglou et ah, Hormones, 3: 120-126, 2004). T4 is deiodinated in target tissue to 3,5,3'-triiodothyronamine (T3), the more active form of thyroid hormone, which has a higher affinity for thyroid hormone receptors found on the nuclear membrane (Hiroi et ah, Proceeding of the National Academy of Science, 103 : 14104- 14109, 2006). Both T4 and T3 regulate metabolism and tissue thermogenesis by gene transcription, a process that takes hours to come into effect (Scanlan et ah, Nat.
  • thyroid hormone Physiological effects of thyroid hormone include the induction of hyperthermia and increased cardiac output. Thyroid hormone can be further deiodinated and decarboxylated into 3-iodothyronamine (TlAM) and thyronamine (TOAM) (Scanlan et ah, Nat. Med., 10:638- 642, 2004). These newly characterized thyronamines have been found in rodent brain, peripheral organs and blood. TlAM and TOAM have the opposite effect to T4 and T3, rapidly inducing hypothermia in a mechanism independent of gene transcription.
  • TlAM 3-iodothyronamine
  • TOAM thyronamine
  • TlAM and TOAM are not ligands for traditional thyroid hormone receptors but are agonists for trace amine associated receptor 1 (TAARl), a G-protein coupled receptor found on the plasma membrane (Scanlan et ah, Nat. Med., 10:638-642, 2004).
  • TARl trace amine associated receptor 1
  • ip Intraperitoneal injection of TlAM and TOAM induces hypothermia within 30 minutes, with no long-term adverse effects. This hypothermic response occurs in the absence of shivering and piloerection, indicating that the hypothermic effect of TlAM and TOAM is not opposed by the body's natural homeothermic response.
  • hypothermia is a profoundly neuroprotective treatment for stroke (Kammersgaard et al, Stroke, 31:2251-2256, 2000; Schwab et al, Acta. Neurochir. Suppl, 71 : 131-134, 1998; Schwab et al., Nervenstoff., 70:539-546, 1999; Schwab et al, Stroke, 29:2461-2466, 1998; Colbourne and Corbett, J. Neuroscl, 15:7250-7260, 1995; Colbourne et al., J. Cereb. Blood Flow Metab., 20: 1702-1708, 2000; Colbourne et al., MoI.
  • the protective effect is dependent on the duration and depth of hypothermia and its timing relative to the onset of stroke. It has not been possible to identify a single action of hypothermia that is responsible for its marked neuroprotective actions. It may work so well simply because it works through a multitude of protective mechanisms simultaneously, something that distinguishes it from most neuroprotective drugs.
  • hypothermia confers benefit
  • Mechanisms by which hypothermia confers benefit include improving the ratio between metabolic demand and substrate supply by reducing metabolic rate, reducing free radical formation, blunting reperfusion injury, and reducing the release of glutamate (Krieg AM., Annu. Rev. Immunol, 20:709-760, 2002).
  • Hypothermia also has negative side effects, for example it can cause an inhibition of coagulation, cardiac arrythmia, pulmonary edema and an increased risk of infection due to immunosuppression. However these side effects can be effectively managed with primary care without causing long term adverse effects (Polderman KH, Intensive Care Med., 30:757-769, 2004).
  • hypothermia Studies that have looked at the effect of administering hypothermia show that the sooner hypothermia is initiated after ischemia the greater the level of protection conferred (Maier et ah, J. Neurosurg., 94:90-96, 2001).
  • the cannabinoid HU- 120 has been used to induce hypothermia and protect against ischemia in rats (Leker et ah, Stroke, 34:2000-2006, 2003).
  • HU-120 has toxic side effects that limit its application for humans. Additional studies with hypothermia inducing cannabinoids have been more encouraging.
  • the cannabinoid WIN 55,212-2 can induce therapeutic hypothermia with fewer side effects than HU-120, however WIN 55,212-2 has the limitation of requiring continuous intravenous infusion for the hypothermic effect to be maintained (Bonfils et ah, Neurochem. Int., 49(5):508-518, 2006). Another recent study demonstrates that hydrogen sulfide can be used to reduce temperature in rodents (Blackstone et ah, Science, 308:518, 2005).
  • hydrogen sulfide is also a mediator of cerebral ischemic damage which could counterbalance the beneficial effects of hypothermia if hydrogen sulfide were to be used as a treatment for stroke (Qu et ah, Stroke, 37:889-893, 2006).
  • Thyroxine derivatives such as TlAM and TOAM
  • TlAM and TOAM have also been proposed as cryogens for the treatment of an already evolving stroke (U.S. Patent No. 6,979,750; Scanlan et ah, Nature Med., 10:638-642, 2004).
  • These metabolites are naturally found in blood, brain and peripheral organs.
  • TlAM and TOAM can be used as acute neuroprotective agents following the onset of the stroke.
  • TlAM and TOAM induce an equivalent level of hypothermia following stroke, and when this effect is blocked neuroprotection is lost. This implies that the protective effect of acute administration of TlAM and TOAM is due to hypothennia.
  • thyronamine derivatives are useful as cytoprotective agents, for example in the prophylaxis of cellular damage induced by a variety of cellular insults.
  • This disclosure concerns preconditioning agents that mediate cellular protection (such as neuroprotection during hypoxia), and provides methods for reducing and/or ameliorating damage due to excitotoxic, ischemic and/or hypoxic events, such as stroke and traumatic brain injury.
  • Certain thyroxine derivatives, designated herein as thyronamine preconditioning agents are administered prior to a potential incident of cellular injury, such as an excitotoxic, hypoxic and/or ischemic event.
  • mice Following injection of the agent, mice show a pronounced drop in temperature (from 37°C to 31°C) that persists for several hours.
  • Animals treated with thyronamine preconditioning agents exhibit reduced cellular damage due to ischemia as compared to control mice, or mice treated with other thyroxine derivatives. This finding allows these agents to be used in situations in which a likelihood of cellular injury (such as that caused by a hypoxic event such as ischemia) is increased, for example by administration to subjects who are at risk for neurological injury such as a stroke or who are about to undergo a surgical procedure or other activity in which such injury may occur.
  • the preconditioning agent is administered at least 10 to 12 hours before the anticipated cellular injury (such as an ischemic event), or at least 24 to 48 hours prior to the event.
  • the agent is administered on a regular regimen to a subject at risk of cellular (such as neurological) injury, for example by administration of an effective protective amount to a subject at least once a week.
  • the agent is chronically administered to a subject who has a neurodegenerative disease (such as Alzheimer's disease) that benefits from the cytoprotective effect of the agent.
  • the agent is used to protect the brain against injury induced by repeated seizures (as in epilepsy).
  • the disclosed method is believed to provide the advantage of substantially avoiding neurological damage induced by injuries such as excititoxic injury or hypoxia (including ischemia), instead of merely attempting to limit the damage after it has already occurred.
  • FIG. IA is a schematic illustration of TOAM and TlAM.
  • FIG. IB is an illustration of 3-Methylthyronamine.
  • FIG. 1C is an illustration of N-Methyl-O-(p-trifluoromethyl)benzyl-tyramine Hydrochloride, wherein X is H, Ri is CF 3 , and R 2 is methyl.
  • FIG. ID is an illustration of 3-iodotyramine hydrochloride.
  • OPhenyl-3-iodotyramine hydrochloride: R] is H, R 2 is H; (9-(p-Fluoro)phenyl-3-iodotyramine hydrochloride: Ri is F, R 2 is methyl.
  • FIGS. 2A and B are graphs demonstrating that acute administration of TlAM and TOAM causes hypothermia and protection against ischemic injury.
  • FIGS. 3A and B are graphs demonstrating preconditioning with TlAM and TOAM. Preconditioning with TlAM but not TOAM induces delayed tolerance to ischemic injury.
  • the methods and compositions are therefore useful in the treatment of neurological conditions, such as those caused by hypoxia (including ischemia) and certain types of neurological disease (such as those in which hypoxia or excitotoxic injury are pathophysiological features).
  • Hypothermia can also be used as a preconditioning stimulus to prevent or reduce the extent of damage resulting from excitotoxic, ischemic and/or hypoxic events.
  • Hypothermia induced tolerance commences within 6 hours, peaks at approximately 1 or 2 days and returns to baseline by about 7 days after preconditioning stimulation (Nishio et al., Ann N Y Acad. ScL, 890:26-41, 1999).
  • Hypothermia induced tolerance is dependent on de novo protein synthesis and may be dependent on modification of proteins by SUMOylation (Nishio et al., Ann. NY Acad.
  • hypothermia is inconvenient to induce as a preconditioning stimulus.
  • compositions that include a cryogen which can be administered as a preconditioning agent to protect a subject against excitotoxic, ischemic and/or hypoxic injury.
  • Certain embodiments of the disclosed methods involve methods of preventing cellular damage due to excitotoxic, ischemic and/or hypoxic events by administering a class of thyroxine derivatives, designated herein as thyronamine preconditioning agents, prior to the onset of an event that produces an excitotoxic, ischemic and/or hypoxic condition or state.
  • a state is a neurological injury, such as a neurological injury induced by trauma or disease in which hypoxia (including ischemia) or exicitoxic injury induces cellular damage.
  • a first aspect of the disclosure relates to a method of protecting a cell in a subject (such as a human subject) against such injury.
  • the method involves administering to the subject a therapeutically effective amount of a composition that includes the thyronamine preconditioning agent.
  • the composition is administered prior to an event that produces or is likely to produce the neurological injury.
  • Administration of the thyronamine preconditioning agent elicits a response by the subject that protects against cellular damage.
  • the composition is administered to a subject selected on the basis of an increased risk for the neurological insult.
  • the subject is selected prior to undergoing a surgical procedure that increases the risk of the adverse event, such as a vascular surgical procedure, for example, endarterectomy (such as carotid endarterectomy), pulmonary bypass or coronary artery bypass graft surgery.
  • a surgical procedure that increases the risk of the adverse event, such as a vascular surgical procedure, for example, endarterectomy (such as carotid endarterectomy), pulmonary bypass or coronary artery bypass graft surgery.
  • the subject is selected on the basis of participation in a contact sport or in combat, or in other activities that increase the risk of traumatic brain injury, which is associated with increased risk of excitotoxic, ischemic and/or hypoxic injury.
  • the thyronamine preconditioning agent is administered at least about 6 or 10 hours prior to the exctitoxic, ischemic and/or hypoxic event, for example 6-12 or 10-12 hours before the event. In other examples, the agent is administered 24-48 hours prior to the event. For some applications, especially in subjects with a chronically increased risk of such a deleterious event (such as prolonged exposure to potential head trauma or a chronic neurological disease such as a degenerative neurological disease, such as Alzheimer's disease), multiple doses of the preconditioning agent are administered in sufficient proximity to one another to provide sustained neuroprotection.
  • a chronically increased risk of such a deleterious event such as prolonged exposure to potential head trauma or a chronic neurological disease such as a degenerative neurological disease, such as Alzheimer's disease
  • the thyronamine preconditioning agent is administered on a schedule calculated to maintain the preconditioning effect, such as at intervals of less than about 1 week, such as a biweekly interval, or a daily interval.
  • the repeated doses can be maintained, such that the ultimate dose is delivered within 1 week prior to an anticipated episode of potential neurological injury (such as an excitotoxic, ischemic and/or hypoxic event).
  • a subject at increased risk of stroke can be administered a weekly or more often than weekly dose of the thyronamine preconditioning agent to induce and maintain a protected state.
  • subjects with chronic conditions that can result in neurological injury such as excitotoxic injury (for example subjects with epilepsy or Alzheimer's disease) can be administered repeated doses of a thyronamine preconditioning agent to protect against excitotoxic injury.
  • the cytoprotective method disclosed herein is suitable for preconditioning to protect neural cells, as well as muscle cells, liver cells, kidney cells, endothelial cells and immune system cells.
  • a thyronamine preconditioning agent can be administered to a subject prior to an excitotoxic, ischemic and/or hypoxic event (such as a stroke) to protect brain cells, such as hippocampal, cortical and/or other neurons.
  • a thyronamine preconditioning agent can be administered to a subject to protect muscle cells, such as cardiac muscle cells.
  • the thyronamine preconditioning agent is administered to a subject that engages in activities with an increased likelihood of traumatic brain injury.
  • the thyronamine preconditioning agent is administered to a pregnant woman to protect her fetus against hypoxia in utero.
  • fetal protection can be of particular importance in events that can lead to fetal injury, such as perinatal hypoxia, placental insufficiency or a pregnancy associated hypertension (for example preeclampsia or eclampsia).
  • Administration of the thyronamine preconditioning agent can be performed by any of a variety of routes, including oral, nasal and rectal routes as well as parenteral routes, such as intraperitoneal, intravenous, intramuscular, subcutaneous, subdermal and transdermal routes.
  • the composition can be administered by an intrathecal, intraventricular, and/or epidural route.
  • Any thyronamine derivative and/or analogs thereof that induces a sufficient level and duration of hypothermia, and exhibits desirable toxicology characteristics can be administered as a thyronamine preconditioning agent.
  • thyronamine preconditioning agents include 3-iodothyronamine (TlAM), 3- methylthyronamine, N-methyl-O-(p-trifluoromethyl)benzyl-tyramine hydrochloride, O- phenyl-3-iodotyramine hydrochloride or O-(p-Fluoro)phenyl-3-iodotyramine hydrochloride.
  • the agent is TlAM.
  • the thyronamine preconditioning agent is administered in one or more doses sufficient to elicit preconditioning, such as at least about 0.005 mg/kg.
  • the agent is administered at a dose of at least about 0.02 mg/kg.
  • no more than about 5 mg/kg of the agent is administered, such as about 0.2 mg/kg.
  • the dosage range is 0.005-5 mg/kg, or 0.02-5 mg/kg, or 0.2-5 mg/kg.
  • Another feature of this disclosure is the use of a thyronamine preconditioning agent in the preparation of a medicament for the induction of hypothermia to provide a prophylactic treatment of cellular injury, such as injury resulting from an excitotoxic, ischemic and/or hypoxic event.
  • the preconditioning agent can be combined with other active agents (either in the composition or in methods of treatment).
  • the preconditioning agent can be administered in advance of a potential ischemic event, and another protective agent (such as osteopontin) can be administered at the time the actual injury occurs.
  • the preconditioning agent can be combined with a second agent designed to help treat the condition (such as vascular occlusion or hypertension) leading to the cellular injury.
  • the second agent could be an anti-hypertensive (such as enalapril), a treatment for hypercholesterolemia (for example a lipid lowering drug such as Lipitor/atorvastin calcium), or an anticoagulant drug (such as a drug that inhibits platelet aggregation for example ticlopodine or aspirin).
  • an anti-hypertensive such as enalapril
  • a treatment for hypercholesterolemia for example a lipid lowering drug such as Lipitor/atorvastin calcium
  • an anticoagulant drug such as a drug that inhibits platelet aggregation for example ticlopodine or aspirin.
  • excitotoxic injury or "excitotoxic brain injury” refers to injury (including death), of neural cells, particularly neural cells of the brain, due to excessive stimulation of cell-surface receptors. Most commonly, excitotoxic injury is mediated through glutamate receptors, for example, by overactivation of N-methyl-d-aspartate (NMDA)-type glutamate receptors, resulting in excessive Ca 2+ influx through the receptor's associated ion channel.
  • NMDA N-methyl-d-aspartate
  • Excitotoxic injury is believed to play a role in diverse conditions, including epilepsy, traumatic injury, and Alzheimer's disease.
  • An excitotoxic event is an event that results in excessive and deleterious stimulation of cell surface receptors.
  • hypoxia refers to a lack of oxygen.
  • hypoxia refers to an insufficiency of oxygen at a cellular, tissue or organismal level.
  • Hypoxia can be caused by, for example, the reduction in partial pressure of oxygen (in the blood or in a tissue), inadequate oxygen transport (for example, due to a failure of oxygenated blood to reach a target tissue or cell), or the inability of the tissues to use oxygen.
  • Hypoxia can result from an increased oxygen demand in tissue that is unable to provide a commensurate increased oxygen supply, for example because of vascular disease.
  • infarct refers to cell or tissue death due to a localized lack of oxygen (hypoxia).
  • a hypoxic event is an event that results in insufficiency of oxygen at a cellular, tissue or organismal level.
  • hypoxia is the result of "ischemia," the reduction in oxygenated blood flow to a target tissue or organ.
  • An "ischemic event” is an event or occurrence that results in decreased blood flow to a cell, collection or group of cells, tissue, or organ. Ischemic events include vasoconstriction, thrombosis and embolism, resulting in reduced blood flow to a tissue or organ.
  • stroke refers to an interruption of the blood supply to any part of the brain.
  • a stroke can be due to an ischemic event (for example, occlusion of a blood vessel due to a thrombus or an embolism) or hemorrhage (for example, of a cerebral blood vessel).
  • ischemic event for example, occlusion of a blood vessel due to a thrombus or an embolism
  • hemorrhage for example, of a cerebral blood vessel.
  • a subject is "at risk for" an ischemic or hypoxic event if there is an increased probability that the subject will undergo an ischemic or hypoxic event relative to the general population. Accordingly, risk is a statistical concept based on empirical and/or actuarial data. Commonly, risk can be correlated with one or more indicators, such as symptoms, signs, characteristics, properties, occurrences, events or undertakings, of a subject. For example, with respect to risk of stroke, indicators include but are not limited to high blood pressure (hypertension), atrial fibrillation, transient ischemic events, prior stroke, diabetes, high cholesterol, angina pectoris, and heart disease.
  • risk indicators for hypoxic events include surgery, especially cardiovascular surgeries, such as endarterectomy, pulmonary bypass surgery or coronary artery bypass surgery. Additional risk factors or indicators include non-medical activities, such as motorcycle riding, contact sports and combat. Other risk factors are discussed herein, and yet more can be recognized by those of ordinary skill.
  • the term "protect" with respect to an excitotoxic, ischemic or hypoxic event refers to the ability of composition or treatment regimen to prevent, reduce in severity, or otherwise lessen the effects of an excitotoxic, ischemic or hypoxic event at a cellular, tissue or organismal level.
  • Methods for measuring severity of effects of an excitotoxic, ischemic or hypoxic event include neurological, including behavioral, indicia (e.g., ascertainable via neurological examination of a subject) as well as by evaluation of cellular and metabolic parameters.
  • Certain examples of techniques for evaluating tissue damage include Computed Axial Tomography (CT scan, CAT scan); Magnetic Resonance Imaging (MRI scan, MR scan); Carotid Ultrasound, including Transcranial Doppler (TCD); Cerebral Angiography: (Cerebral arteriogram, Digital subtraction angiography [DSA]); Computed Tomographic Angiography: (CT-angiography, CT-A, CTA); Magnetic Resonance Angiography (MRA) and/or other diagnostic procedures known to those of ordinary skill in the art.
  • CT scan Computed Axial Tomography
  • MRI scan Magnetic Resonance Imaging
  • MR scan Magnetic Resonance Imaging
  • Carotid Ultrasound including Transcranial Doppler (TCD)
  • Cerebral Angiography Cerebral arteriogram, Digital subtraction angiography [DSA]
  • Computed Tomographic Angiography (CT-angiography, CT-A, CTA); Magnetic Resonance Angiography (
  • Cytoprotection refers to cellular protection, such as the protection provided by hypothermia against cellular injury induced by hypoxia (such as that caused by ischemia) or excitotoxic injury (such as that seen in stroke and many neurological diseases).
  • a "subject” is a living multi-cellular vertebrate organism, a category that includes both human and veterinary subjects, including human and non-human mammals. In a clinical setting with respect to preconditioning against excitotoxic injury and/or hypoxia, a subject is usually a human subject, although veterinary subjects are also contemplated.
  • neural cell is any cell in a lineage that originates with a neural stem cell and includes a mature neuron.
  • the term neural cell includes neurons (nerve cells) as well as their progenitors regardless of their stage of differentiation. In the context of an adult brain, neural cells are predominantly differentiated neurons.
  • a "non-neural cell” is a cell of a lineage other than a neural cell lineage, that is a lineage that does not culminate in the differentiation of a mature neuron.
  • the non-neural cell may reside in the central nervous system (CNS), for example, in the brain (such as glial cells and immune system cells, such as B cells, dendritic cells, macrophages and microglia), or may exist in an organ outside the CNS, such as cardiac, skeletal or smooth muscle (a muscle cell), liver (a hepatic cell) or kidney (a renal cell) and so forth.
  • CNS central nervous system
  • Non-neural cells include cells of the immune system, regardless of whether they reside in the CNS or elsewhere in the body of the organism.
  • Neurological injury refers to damage to neural tissue (such as the brain, spinal cord, or peripheral nerves) that impairs the function of the neural tissue.
  • Examples of neurological injury include brain injury that leads to cognitive impairment or motor or sensory deficits.
  • a "cytoprotective cytokine” is a soluble protein (or glycoprotein) involved in the regulation of cellular proliferation and function that acts to preserve cellular function and prevent (or reduce) death of a cell in response to a stressful or otherwise aversive stimulus.
  • Cytoprotective cytokines include transforming growth factor ⁇ (TGF- ⁇ ), tumor necrosis factor ⁇ (TNF ⁇ ), and type I interferons, such as interferon ⁇ (IFN ⁇ ).
  • TGF- ⁇ transforming growth factor ⁇
  • TNF ⁇ tumor necrosis factor ⁇
  • IFN ⁇ type I interferons
  • a “neuroprotective cytokine” is a cytoprotective cytokine that acts to preserve cellular function and reduce cell death in neural cells.
  • compositions are formulated for administration to human and/or animal (veterinary) subjects, and typically include one or more active component (such as one or more of the thyronamine preconditioning agents disclosed herein) as well as one or more additional components to facilitate administration to a subject, for the therapeutic or prophylactic treatment (prevention or reduction) of a condition or disease.
  • additional components can include pharmaceutically acceptable carriers, buffers or excipients. Pharmaceutically acceptable carriers, buffers and so forth, are well known in the art, and are described, e.g., in Remingtons Pharmaceutical Sciences, 19 th Ed., Mack Publishing Company, Easton, Pennsylvania, 1995.
  • prophylactic treatment refers to the treatment of a subject prior to the full manifestation of an event, condition or disease for the purpose of preventing or reducing the symptoms, signs or consequences of the event, condition or disease.
  • prophylactic treatment of ischemia or hypoxia refers to the treatment of a subject prior to the occurrence of an ischemic or hypoxic event (that is, prior to a first ischemic or hypoxic event, or prior to a subsequent ischemic or hypoxic event, or prior to the completion or culmination of an ongoing or recurrent ischemic or hypoxic event) and prior to the completion of the natural consequences and/or sequelae of the event.
  • the prophylactic treatment occurs prior to the onset of hypoxia that can lead to neurological damage.
  • thyronamine preconditioning agent refers to a thyroxine derivative compound that produces a cytoprotective (for example, neuroprotective) effect when administered to a subject prior to the onset of an excitotoxic, ischemic and/or hypoxic event.
  • Thyronamine preconditioning agents are potent agonists of the TAARl receptor, and are characterized by the ability to induce hypothermia in vivo.
  • thyronamine preconditioning agents include 3-iodothyronamine, 3-methylthyronamine, N-methyl-(9-(p- trifluoromethyl)benzyl-tyramine hydrochloride, O-phenyl-3-iodotyramine hydrochloride or O- (p-Fluoro)phenyl-3-iodotyramine hydrochloride. Structures of exemplary thyronamine preconditioning agents are illustrated in FIGS. IA-D and in Tables 1 and 2.
  • analog or “functional analog” refers to a modified form of the respective thyronamine derivative in which one or more functional side or linking groups has been modified such that the analog retains substantially the same biological activity or improved biological activity as the unmodified thyronamine derivative in vivo and/or in vitro.
  • Ant or thyronamine agonist refers to an endogenous or exogenous compound, substance or entity that has affinity for and stimulates physiologic activity at cell receptors normally stimulated by naturally-occurring substances, thus triggering a biochemical response characteristic of those receptors.
  • the term refers to a thyronamine derivative or analog, a suitable homolog, or a portion thereof, capable of promoting at least one of the biological responses normally associated with thyronamine.
  • treatment with a thyronamine agonist can result in lowered body temperature of a mammalian subject.
  • Receptor refers to a molecule, a polymeric structure, or polypeptide in or on a cell that specifically recognizes and binds a compound acting as a molecular messenger, for example, neurotransmitter, hormone, lymphokine, lectin, or drug.
  • a ligand is said to "activate” a receptor if the ligand binds to the receptor, and such binding results in the initiation of one or more signaling events, such as translocation or phosphorylation of the receptor and/or other signaling molecules.
  • a "TAARl" receptor is trace-amine-associated receptor 1, for which the thyronamine preconditioning agents are ligands.
  • Exemplary TAARl receptors are catalogued in GenBank, for example, the sequence of the mouse TAARl receptor can be found under GenBank reference numbers NP444435, AAI25371, AAI25369; the sequence of the rat TAARl receptor can be found under accession number NP599155; and the human TAARl receptor can be found under accession number AAIO 1826 (all as of the filing date of this disclosure).
  • acyl refers group of the formula RC(O)- wherein R is an organic group.
  • “Lower alkyl” refers to an optionally substituted, saturated straight or hydrocarbon having from about 1 to about 12 carbon atoms (and all combinations and subcombinations of ranges and specific numbers of carbon atoms therein), with from about 1 to about 8 carbon atoms, being preferred.
  • Alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclopenlyl, isopentyl, neopentyl, n-hexyl, isohexyl, 3-methylpentyl, 2,2-dimethylbutyl, and 2,3-dimethylbutyl.
  • lower alkyl are those aliphatic hydrocarbon chains that are optionally substituted.
  • cycloalkyl refers to a non-aromatic carbon-based ring composed of at least three carbon atoms.
  • examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.
  • "Optional” or “optionally” means that the subsequently described event or circumstance may or may not occur, and that the description includes instances in which it does not.
  • Effective amount refers to an amount of a compound that can be therapeutically (including prophylactically) effective to inhibit, prevent or treat the symptoms of particular disease, disorder or side effect.
  • “Pharmaceutically acceptable” refers to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem complications commensurate with a reasonable benefit/risk ratio.
  • Pharmaceutically acceptable carriers, excipients and diluents are known to those of ordinary skill in the art and are described, for example, in Remington 's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), which describes compositions and formulations suitable for pharmaceutical delivery of the compounds herein disclosed.
  • “In combination with,” “combination therapy” and “combination products” refer, in certain embodiments, to the concurrent administration to a patient of the thyronamine preconditioning agents and at least one additional pharmaceutical (for example, therapeutic) agent.
  • each component can be administered at the same time or sequentially in any order at different points in time. Thus, each component can be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect.
  • the thyronamine preconditioning agent is administered in combination with a therapeutic agent that reduces injury when administered during or following an excitotoxic, ischemic and/or hypoxic event.
  • Dosage unit refers to physically discrete units suited as unitary dosages for the particular individual to be treated. Each unit can contain a predetermined quantity of active compound(s) calculated to produce the desired therapeutic effect(s) in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms can be dictated by (a) the unique characteristics of the active compound(s) and the particular therapeutic effect(s) to be achieved, and (b) the limitations inherent in the art of compounding such active compound(s).
  • a "preconditioning dose” is a dose of an effective compound, or composition containing such a compound, that protects a cell against injury or death, for example injury or death due to an ischemic or hypoxic event.
  • the preconditioning dose is an amount that is effective to induce hypothermia sufficient to provide a cytoprotective effect.
  • the dosage of the effective compound or composition varies from compound to compound and between species.
  • a suitable preconditioning dose for any compound can be determined empirically.
  • Exposure of cells to subthreshold levels (that is, at a level below that which causes injury) of a stressful (e.g., cytotoxic) stimulus can induce tolerance to subsequent events that would otherwise result in injury.
  • This effect has been termed preconditioning, and is relevant to preventing or reducing injury due to cytotoxic insult such as hypoxia (e.g., due to ischemic events) in a variety of cell and tissue types, including neural cells, muscle cell (e.g., skeletal as well as cardiac muscle cells), kidney cells and liver cells.
  • Preconditioning sometimes involves a fundamental change in the genomic program or response (that is, the pattern of gene expression produced in response) to excitotoxic, ischemic and/or hypoxic injury that shifts the outcome from cell death to cell survival (Stenzel-Poore et al, The Lancet, 362:1028-1037, 2003).
  • This change in gene expression, or genomic reprogramming, in response to cytotoxic insults, such as excitotoxic, ischemic and/or hypoxic events involves a pronounced suppression of gene expression (for example, of inflammatory cytokines, and certain ion channels and channel regulators, e.g., K + and Ca ++ channels, such as glutamate receptors), which is ordinarily injurious.
  • Such suppression contrasts sharply with the upregulation of mRNA by ischemic and/or hypoxic events without preconditioning.
  • This change is not simply the lack of a response, but rather a reprogramming of the genomic response that involves the downregulation of genes that control metabolism, cell-cycle regulation, and, in neural cells, ion-channel activity. Additionally, in certain cells of the immune system, preconditioning elicits a shift from pro-inflammatory to anti-inflammatory cytokines.
  • Preconditioning in the brain that is, of neural cells
  • hypothermia that is, to a reduction in core body temperature. This effect is dependent on de novo protein synthesis, and involves changes in genomic programming associated with inflammation.
  • Thyroxine preconditioning agents such as the thyronamine derivatives 3-iodothyronamine (TlAM), 3-methylthyronamine, N-methyl-C>-(p- trifluoromethyl)benzyl-tyramine hydrochloride, O-phenyl-3-iodotyramine hydrochloride or O- (p-Fluoro)phenyl-3-iodotyramine hydrochloride, can favorably be used as preconditioning agents.
  • TlAM 3-iodothyronamine
  • N-methyl-C>-(p- trifluoromethyl)benzyl-tyramine hydrochloride O-phenyl-3-iodotyramine hydrochloride or O- (p-Fluoro)phenyl-3-iodotyramine hydrochloride
  • hypothermic preconditioning protects the brain is different than the mechanism by which acute administration of hypothermia protects the brain.
  • Acute induction of hypothermia can directly protect neurons post-ischemia by reducing reaction rate by the QlO effect.
  • the QlO effect refers to the factor by which biochemical reaction rate is increased for each 10°C increase in temperature. For each 1 0 C decrease in temperature there will be a 10% reduction in tissue metabolic requirements and free radical production.
  • the QlO effect can benefit neurons when hypothermia is applied during or post ischemia but not when hypothermia is applied before ischemia because it is remote to the injury process.
  • hypothermic preconditioning appears to be reliant on cellular reprogramming and direct biochemical changes in the intracellular and extracellular milieu.
  • Administration of thyronamine preconditioning agents as disclosed herein elicits effective multipathway reprogramming associated with hypothermic preconditioning.
  • cytoprotection against cellular injury typically begins within about 10-12 hours and lasts for up to several weeks, or more. In addition, protection can be extended by repeated administration of the agent.
  • neural cells including, e.g., hippocampal neurons and cortical neurons
  • muscle cells including cardiac and striated muscle cells
  • hepatic cells and renal cells can be protected against injury and death by administering a thyronamine preconditioning agent prior to the occurrence of an event capable of inducing the cellular injury, such as an excitotoxic, ischemic or hypoxic event.
  • a thyronamine preconditioning agent such as, 3-iodothyronamine, 3- methylthyronamine, N-methyl-(9-(p-trifluoromethyl)benzyl-tyramine hydrochloride, O-phenyl- 3-iodotyramine hydrochloride or 0-(p-Fluoro)phenyl-3 ⁇ iodotyramine hydrochloride
  • a subject that has been identified as having (e.g., diagnosed with) one or more risk factors indicative of an increased likelihood, relative to the general population or to a subject without the risk factor, of having an excitotoxic, ischemic and/or hypoxic event.
  • Preconditioning with thyronamine derivatives is useful for inhibiting (including preventing) cellular injury due to excitotoxic, ischemic and/or hypoxic events associated with a wide variety of conditions with disparate etiologies and symptoms, including stroke, traumatic brain injury and Alzheimer's disease.
  • excitotoxic, ischemic and/or hypoxic events associated with a wide variety of conditions with disparate etiologies and symptoms, including stroke, traumatic brain injury and Alzheimer's disease.
  • non-medical indicators of risk pertaining to behaviors or activities that are statistically associated with an increased likelihood of injuries that can include a hypoxic component.
  • such conditions can also include an excitotoxic component.
  • traumatic brain injury frequently involves an excitotoxic and/or a hypoxic component.
  • participation in activities that increase the risk of traumatic brain injury is an indicator that can be used to select a subject for administration of a preconditioning agent (such as a thyronamine derivative).
  • a preconditioning agent such as a thyronamine derivative
  • activities include, for example, motorcycle riding, motor vehicle racing, skiing, contact sports (such as, football, hockey, rugby, soccer, lacrosse, martial arts, boxing and wrestling), and the like.
  • impacts or wounds resulting from gunshot or explosives frequently cause traumatic brain injury.
  • activities that are associated with an increased risk of gunshot wounds or injury caused by explosive devices are an indicator of risk that can be used to select a subject for treatment with a thyronamine preconditioning agent according to the methods disclosed herein.
  • Hypoxia is typically associated with ischemic events in the CNS or elsewhere in the cardiovasculature, (such as cerebrovascular ischemia, or stroke, myocardial ischemia due to narrowing or blockage of the vessels of the heart, iatrogenic ischemia, due to surgical procedures, and the like).
  • ischemic events in the CNS or elsewhere in the cardiovasculature, (such as cerebrovascular ischemia, or stroke, myocardial ischemia due to narrowing or blockage of the vessels of the heart, iatrogenic ischemia, due to surgical procedures, and the like).
  • CABG coronary artery bypass graft
  • Such individuals are at high risk for neurological injury, such as that caused by an excitotoxic, ischemic and/or hypoxic event, and thus are subjects who can benefit from prophylactic administration of a thyronamine preconditioning agent prior (for example, between 24 hours and 1 week prior) to undergoing CABG surgery.
  • hypoxia can occur in utero due to conditions such as inadequate placental function (for example, due to abruptio placentae), preeclamptic toxicity, prolapse of the umbilical cord, or complications from anesthetic administration. Additionally, injury by some hypoxic events (such as strokes) involves an excitotoxic component as well as a hypoxic component.
  • a thyroxine derivative such as the thyronamine preconditioning agents (such as, 3-iodothyronamine, 3- methylthyronamine, N-methyl-C>-(p-trifluoromethyl)benzyl-tyramine hydrochloride, O-phenyl- 3-iodotyramine hydrochloride or 0-(p-Fluoro)phenyl-3-iodotyramine Hydrochloride, for example, TlAM) disclosed herein.
  • the thyronamine preconditioning agents such as, 3-iodothyronamine, 3- methylthyronamine, N-methyl-C>-(p-trifluoromethyl)benzyl-tyramine hydrochloride, O-phenyl- 3-iodotyramine hydrochloride or 0-(p-Fluoro)phenyl-3-iodotyramine Hydrochloride, for example, TlAM
  • Atheromatous plaques in a carotid artery are also risk factors associated with a potential ischemic event that can be caused by rupture and/or dislodgement of a portion of the plaque that can cause thromboembolic occlusion of the neurovasculature.
  • Thyronamines are analogs of the thyroid hormone thyroxine (T 4 ). Disclosed herein are thyronamines and thyronamine analogs for use as preconditioning agents. In certain embodiments such preconditioning agents exert a hypothermic effect, such as by activating TAAR. Certain preconditioning agents have the formula
  • X represents -CR 2 -, -C(O)CH 2 -, -(CH 2 ) H1 -;
  • each R independently is selected from H and lower alkyl
  • m is from 0 to 4.
  • Y is -NR 1 R 2 , or OR 3 ;
  • R 1 and R 2 independently are H, lower alkyl, ben:zyl, or together form a cycloalkyl group
  • R 3 is H, lower alkyl or acyl
  • R 4 and R 5 independently are H, cyano, halo, lower alkyl, fluoroalkyl, or -OR 11 ;
  • R 11 is H, acyl or lower alkyl
  • R 6 , R 7 , R 8 , R 9 and R 10 independently are selected from H, halogen, lower alkyl, haloalkyl nitro, or -OR 12 ;
  • R 12 is H, acyl or lower alkyl.
  • preconditioning agents are provided of the formula:
  • variable groups X, R , R and R >4- rR> 10 are selected from those groups set forth above.
  • at least one of R 4 , R 5 , R 6 and R 10 is an iodo group, for example, R 4 and/or R 5 may be iodo.
  • at least one of R 4 -R 10 is acyloxy (-OC(O)R), alkoxy, or hydroxy.
  • preconditioning agents are represented by the formulas or
  • variable groups X, R 1 , R 2 and R 4 , R 5 and R !2 are selected from the groups set forth above.
  • the preconditioning agents used have the formula
  • variable groups X, Y and R 4 -R 10 are as set forth above.
  • Particular examples of preconditioning agents according to this formula were evaluated for hypothermic potential in vitro and the results are recorded in Table 2:
  • thyronamine derivatives can be prepared from tyramine using copper mediated coupling of a boronic acid or analog and the appropriate protected phenol. Variations in the side chains (e.g., at Re) can be made by utilizing the appropriately protected boronic acid, or by other methods known to those of skill in the art.
  • U.S. Patent No. 6,979,750 and in Hart et al, J. Med. Chem., 49: 1101-1112, 2006, the disclosures of which are incorporated herein by reference to the extent that they are not inconsistent with the present disclosure.
  • thyronamine derivatives can be prepared from tyramine using copper mediated coupling of a boronic acid or analog and the appropriate protected phenol. Variations in the side chains (e.g., at Re) can be made by utilizing the appropriately protected boronic acid, or by other methods known to those of skill in the art.
  • 6,979,750 provides several alternative methods for preparing thyronamine derivatives, including thyronamine preconditioning agents with one or more R group substitutions.
  • R groups include amine groups, and salts thereof, halyl (e.g., I, F), lower alkyl groups, e.g., methyl groups, as well as substituted alkyls, including haloalkyl groups.
  • the thyronamine preconditioning agents can be synthesized and purified to a substantially pure form that is substantially devoid of organic impurities, such as unreacted starting reagents, unreacted intermediate compounds, and other compounds other than the desired thyronamine derivative(s).
  • the thyronamine preconditioning agent can be at least 75% pure, such as at least about 80% pure, or at least about 85% pure.
  • the thyronamine derivative is at least about 90% pure, or even about 95% or 98% pure.
  • the thyronamine derivative can be greater than 99% pure, such as 100% pure.
  • thyronamine preconditioning agent includes in addition to the bioactive thyroxine derivatives expressly described, stereoisomers, prodrugs, pharmaceutically acceptable salts, hydrates, solvates, acid salt hydrates, N-oxide or isomorphic crystalline forms, etc. These thyronamine derivatives include compounds in which the parent compound is modified by making acid or base salts thereof.
  • stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
  • the stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non-toxic inorganic or organic acids.
  • such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
  • inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like
  • organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic,
  • physiologically acceptable salts are prepared by methods known in the art, e.g., by dissolving the free amine bases with an excess of the acid in aqueous alcohol, or neutralizing a free carboxylic acid with an alkali metal base such as a hydroxide, or with an amine.
  • Certain acidic or basic compounds can exist as zwitterions. All forms of the compounds, including free acid, free base and zwitterions, are contemplated to be within the scope of the present compositions and methods. It is well known in the art that compounds containing both amino and carboxyl groups often exist in equilibrium with their zwitterionic forms. Thus, any of the compounds described herein throughout that contain, for example, both amino and carboxyl groups, also include reference to their corresponding zwitterions.
  • thyronamine derivatives that are prodrugs.
  • a prodrug is a compound specifically designed to maximize the amount of the thyronamine active species that reaches the desired site of reaction, which is inactive or minimally active for the activity desired, but through biotransformation is converted into the biologically active thyronamine derivative.
  • thyronamine preconditioning agents are selected to induce profound hypothermia in a subject.
  • TlAM is shown herein to induce a lowering of a subject's temperature (e.g., as measured using a rectal or infrared thermometer) by at least 6 0 C, or more.
  • TlAM induces a reduction of temperature (as measured in a mouse model) from 37°C to 31°C, which is sustained for a prolonged period of up to six or more hours.
  • a preconditioning agent can be selected that reduces a subject's body temperature by at least 6 0 C, to at least 31°C, and/or to an equal or greater extent (that is, to a lower temperature) than TlAM.
  • TlAM is the thyronamine preconditioning agent.
  • thyronamine derivatives suitable as preconditioning agents that reduce a subject's temperature by at least 6 0 C (that is, to an extent equal to or greater than TlAM) include 3- methylthyronamine, N-methyl-O-(p-trifluoromethyl)benzyl-tyramine hydrochloride, O-phenyl- 3-iodotyramine hydrochloride and ⁇ 9-(p-Fluoro)phenyl-3-iodotyramine Hydrochloride.
  • Additional thyronamine derivatives that are suitable as thyronamine preconditioning agents can easily be identified (and novel agents can be synthesized) that induce hypothermia to an equivalent level and for an equivalent duration as TlAM.
  • Thyronamine preconditioning agents can be administered to a subject, such as a human subject, as disclosed herein or in the form of a stereoisomer, prodrug, pharmaceutically acceptable salt, hydrate, solvate, acid salt hydrate, N-oxide or isomorphic crystalline form thereof, or in the form of a pharmaceutical composition where the compound is mixed with suitable carriers or excipient(s) in a therapeutically effective amount, for example, a preconditioning dose to protect against excitotoxic, ischemic and/or hypoxic injury.
  • thyronamine derivatives and analogs and pharmaceutical compositions described herein can be administered by a variety of routes.
  • routes of administration can, for example, include oral, nasal, transmucosal (e.g., rectal), or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intravenous, intrathecal, intraventricular, spinal, epidural, or intraperitoneal injections.
  • parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intravenous, intrathecal, intraventricular, spinal, epidural, or intraperitoneal injections.
  • one can administer the compound in a local rather than systemic manner for example via injection of the compound directly into the subject at a specific site, often in a depot or sustained release formulation.
  • a targeted drug delivery system for example, in a liposome coated vesicle.
  • the liposomes can be targeted to and taken up selectively by the tissue of choice.
  • the thyronamine preconditioning agents described herein are administered orally or nasally.
  • compositions (medicaments) described herein can be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes.
  • Pharmaceutical compositions for use as described herein can be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically.
  • the agents can be formulated in aqueous solutions, e.g., in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiological saline buffer.
  • penetrants appropriate to the barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the compounds can be formulated readily by combining with pharmaceutically acceptable carriers that are well known in the art. Such carriers enable the compounds to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated.
  • Pharmaceutical preparations for oral use can be obtained by mixing the compounds with a solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example, maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl- cellulose, sodium carboxymethylcellulose, and/or polyvinylpyrrolidone (PVP).
  • disintegrating agents can be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings.
  • concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments can be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.
  • compositions which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds can be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols.
  • stabilizers can be added. All formulations for oral administration should be in dosages suitable for such administration.
  • the compositions can take the form of tablets or lozenges formulated in conventional manner.
  • the compounds for use are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebuliser, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant e.g., dichlorodifluoromethane, trichlorofluoromethane,
  • the compounds can be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection can be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative.
  • the compositions can take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Pharmaceutical formulations for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds can be prepared as appropriate oily injection suspensions.
  • Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes.
  • Aqueous injection suspensions can contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran.
  • the suspension can also contain suitable stabilizers or agents which increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • the active ingredient can be in powder form for constitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
  • the compounds can also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
  • the compounds can also be formulated as a depot preparation.
  • Such long acting formulations can be administered by implantation (for example subcutaneously or intramuscularly) or by intramuscular injection.
  • the compounds can be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.
  • a suitable pharmaceutical carrier for hydrophobic compounds is a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase.
  • the cosolvent system can be the VPD co-solvent system.
  • VPD is a solution of 3% (w/v) benzyl alcohol, 8% (w/v) of the nonpolar surfactant polysorbate 80, and 65% (w/v) polyethylene glycol 300, made up to volume in absolute ethanol.
  • the VPD co-solvent system (VPD: 5W) consists of VPD diluted 1: 1 with a 5% (w/v) dextrose in water solution.
  • This cosolvent system dissolves hydrophobic compounds well, and itself produces low toxicity upon systemic administration.
  • the proportions of a co-solvent system can be varied considerably without destroying its solubility and toxicity characteristics.
  • identity of the co-solvent components can be varied: for example, other low-toxicity nonpolar surfactants can be used instead of polysorbate 80; the fraction size of polyethylene glycol can be varied; other biocompatible polymers can replace polyethylene glycol, e.g. polyvinyl pyrrolidone; and other sugars or polysaccharides can substitute for dextrose.
  • hydrophobic pharmaceutical compounds can be employed.
  • Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs.
  • Certain organic solvents such as dimethylsulfoxide also can be employed, although usually at the cost of greater toxicity.
  • the compounds can be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent.
  • sustained-release materials have been established and are well known by those skilled in the art.
  • Sustained-release capsules can, depending on their chemical nature, release the compounds for a few weeks up to over 100 days.
  • the pharmaceutical compositions also can comprise suitable solid or gel phase carriers or excipients. Examples of such carriers or excipients include but are not limited to calcium carbonate, calcium phosphate, various sugars, starches, cellulose derivatives, gelatin, and polymers such as polyethylene glycols.
  • compositions for administering the iodo-thyronamine (see, e.g., Remington 's Pharmaceutical Sciences, by E. W. Martin, Mack Publishing Co., Easton, PA, 19th Edition (1995), incorporated herein by reference).
  • the pharmaceutical compositions generally comprise a differentially expressed protein, agonist or antagonist in a fo ⁇ n suitable for administration to a subject.
  • the pharmaceutical compositions are generally fo ⁇ nulated as sterile, substantially isotonic and in full compliance with all Good Manufacturing Practice (GMP) regulations of the U.S. Food and Drug Administration.
  • GMP Good Manufacturing Practice
  • compositions suitable for use include compositions wherein the thyronamine preconditioning agents are contained in a therapeutically effective amount. Determination of an effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.
  • a therapeutically effective dose can be estimated initially from cell culture assays.
  • a dose can be formulated in animal models to achieve a circulating concentration range that includes the LD 50 as determined in cell culture (i.e., the concentration of test compound that is lethal to 50% of a cell culture) or the LDioo as determined in cell culture (i.e., the concentration of compound that is lethal to 100% of a cell culture). Such information can be used to more accurately determine useful doses in humans.
  • Initial dosages can also be estimated from in vivo data, such as in an animal model of stroke.
  • Dosage amount and interval can be adjusted individually to provide plasma levels of the active compound which are sufficient to maintain therapeutic effect.
  • Therapeutically effective serum levels can be achieved by administering multiple doses each day. In cases of local administration or selective uptake, the effective local concentration of the drug can not be related to plasma concentration.
  • One having skill in the art will be able to optimize therapeutically effective local dosages without undue experimentation.
  • the amount of composition administered will, of course, be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration and the judgment of the prescribing physician.
  • the therapy can be repeated intermittently, for example, in subjects at ongoing risk for an excitotoxic, ischemic and/or hypoxic event, or in subjects with a neurodegenerative disorder having an excitotoxic component, such as Alzheimer's disease.
  • the thyronamine preconditioning agent can be provided alone or in combination with other drugs, such as for example, antiinflammatories, antibiotics, corticosteroids, vitamins and the like.
  • the thyronamine preconditioning agent is administered prior to an excitotoxic, ischemic and/or hypoxic event as disclosed herein, and an additional pharmaceutical agent is administered during or following the event.
  • the additional agent can also be a thyronamine derivative (such as the same thyronamine derivative as the thyronamine preconditioning agent, or an analog thereof), or the additional agent can be another compound that has a neuroprotective effect with respect to excitotoxic, ischemic and/or hypoxic injury (for example, endotoxin, CpG oligonucleotides, osteopontin).
  • a thyronamine derivative such as the same thyronamine derivative as the thyronamine preconditioning agent, or an analog thereof
  • the additional agent can be another compound that has a neuroprotective effect with respect to excitotoxic, ischemic and/or hypoxic injury (for example, endotoxin, CpG oligonucleotides, osteopontin).
  • Synergism between the thyronamine derivatives described herein (or analogs) and other drugs can occur.
  • the typical daily dose of a pharmaceutical composition of thyronamine preconditioning agents varies according to individual needs, the condition to be treated and with the route of administration. Suitable doses are in the general range of from 0.001 to 10 mg/kg bodyweight of the recipient per day. The particular activity encountered at a particular dose will depend on the nature of the pharmaceutical composition of thyronamine derivatives and analogs used.
  • the pharmaceutical composition of thyronamine preconditioning agents can be in unit dosage form, for example, a tablet or a capsule so that the patient can self-administer a single dose, hi general, unit doses contain in the range of from 0.05—100 mg of a compound of the pharmaceutical composition of thyronamine derivatives and analogs. Unit doses contain from 0.05 to 10 mg of the pharmaceutical composition.
  • the active ingredient can be administered from 1 to 6 times a day.
  • daily doses are in general in the range of from 0.05 to 600 mg per day.
  • daily doses are in the range of from 0.05 to 100 mg per day or from 0.05 to 5 mg per day.
  • the dosage can vary within this range depending upon the dosage form employed and the route of administration utilized.
  • a thyronamine preconditioning agent is selected that has no or minimal toxicity at preconditioning dosage.
  • One of the advantages, among others, of using the thyronamine derivatives and analogs described herein as preconditioning agents is their lack of toxicity at doses sufficient to elicit a preconditioning effect. For example, it has been found that repeated intraperitoneal doses of 75 mg/kg or TlAM produced no ill effects in mice. Since the i.v.
  • serum half-life (tj ⁇ ) of TlAM is about 2-2.5 hours, repeated (e.g., daily, biweekly, or other interval of less than or up to about 1 week) dosages of the iodo-thyronamine derivatives described herein without ill effects is predictable.
  • HEK293 cells stably transfected with either rTAARl or mTAARl were harvested in Krebs-Ringer-HEPES buffer (KRH) and preincubated in KRH with 200 ⁇ M 3-isobutyl-l- methylxanthine (IBMX).
  • IBMX 3-isobutyl-l- methylxanthine
  • Cells were incubated in KRH with 100 ⁇ M IBMX with the test compound, forskolin (10 ⁇ M), or vehicle (DMSO) for 1 h at 37 0 C (400 ⁇ L total volume). The cells were then boiled for 20 min after adding an equal volume of 0.5 mM sodium acetate buffer and centrifuged to remove cellular debris.
  • Example 2 Acute administration of thyronamine derivates is neuroprotective
  • exemplary thyronamine derivatives were administered in a mouse model of ischemia.
  • TlAM and TOAM were administered 1 hour following experimentally induced ischemia.
  • TlAM and TOAM were obtained by chemical synthesis as described in U.S. Patent No. 6,979,750, and dissolved in 75% saline/25% DMSO.
  • C57BL/6 mice male, 8-10 wks were obtained from Jackson laboratories. All procedures met NIH guidelines with the approval of the Oregon Health & Science University Institutional Animal Care and Use Committee.
  • Cerebral focal ischemia was induced by middle cerebral artery occlusion (MCAO) as previously published (Clark et al., Neurol. Res., 19:641-648, 1997). Briefly, mice were anesthetized by halothane inhalation (4%/ 1 O2) and maintained with 1.5%/ 1 O2. The middle cerebral artery was blocked by threading silicone-coated 7-0 monofilament nylon surgical suture through the external carotid to the internal carotid, blocking its bifurcation into the MCA and anterior cerebral artery. The filament was maintained intraluminally for 60 min while the mice were maintained under anesthesia. The filament was then removed, thereby restoring blood flow. Cerebral blood flow (CBF) was monitored throughout the surgery by laser Doppler flowmetry (Periflow 5000; Perimed, Sweden). Body temperature was monitored throughout. Post surgery, mice had free access to soft food and were sacrificed after 24 hours.
  • MCAO middle cerebral artery occlusion
  • mice were i.p administered lOO ⁇ l of vehicle (75%saline/25%DMSO), TlAM (50mg/kg) or TOAM (50mg/kg) 1 hour after the end of ischemia and placed in a cage on an adjustable heating pad set to its lowest setting (Sunbeam Heating Pad). At this setting the temperature in the cage was 28 0 C, allowing the temperature of the drug treated animals to fall.
  • TlAM and TOAM "hypothermia blocked" group of animals mice were kept in a separate cage on an adjustable heating pad with the setting of the pad continually adjusted to keep the drug treated animals at the same temperature as the vehicle injected animals. Temperature was monitored by infrared thermometer.
  • mice were deeply anesthetized with isoflurane, then perfused via the ascending aorta with heparinized saline (2 U/ml), at a flow rate of 9 ml/ min. Brains were rapidly removed, placed on a tissue slicer (Stoelting, Wood Dale, IL, USA) and covered with soft agarose. The olfactory bulb and cerebellum were removed and discarded. The remaining brain was sectioned into 1 mm slices beginning from the rostral end.
  • Data are shown as means ⁇ SD of n determinations. Data from cell viability assays and in vivo stroke experiments were analyzed by one-way ANOVA followed by Bonferroni's multiple comparison test, using Graphpad Prism version 4.0 (Graphpad software, San Diego, CA, USA).
  • mice administered TlAM and TOAM had significantly reduced infarct volumes compared to control injected mice, showing a 35% and 32% reduction respectively (FIG. 2B).
  • TlAM and TOAM were dependent on the hypothermic effects of the drugs.
  • separate groups of animals were injected with TlAM or TOAM and maintained on an adjustable heating pad. The temperature of the mice was monitored hourly and the setting of the heating pad adjusted to maintain the mice at the same temperature as the vehicle injected animals. When the hypothermic effects of TlAM and TOAM were blocked the protective effects of these drugs was lost (FIG. 2B).
  • mice were administered 2 days prior to ischemia.
  • Mice were i.p injected with lOO ⁇ l vehicle, TlAM (50mg/kg) or TOAM (50mg/kg) 2 days prior to MCAO.
  • mice were maintained at ambient temperature (22 0 C) and temperature was recorded for 24 hours post injection as described in Example 1.
  • mice were kept in a separate cage on an adjustable heating pad with the setting of the pad continually adjusted to keep the temperature of the mice as close as possible to the vehicle treated mice. Temperature was monitored by infrared thermometer. Following surgery all preconditioned mice were kept on a heating pad set to low (the temperature in the cage was 28 0 C) and temperature was recorded every hour for at least 6 hours post surgery as well at 24 hours post surgery.
  • Example 4 Neuroprotection by TOAM and TlAM is a systemic effect
  • Oxygen and glucose deprivation was performed by washing cells with phosphate buffered saline (PBS) (0.5 mM CaCl 2 , 1.0 mM MgCl 2 ; pH 7.4) and placing them in an anaerobic chamber for 180 min (Coy Laboratories, 85 % N 2 , 5% H 2 , 10 % CO 2 ; 35 0 C). OGD was terminated by removing cells from the chamber, replenishing with media and replacing them back into the normoxic incubator. A peptide including amino acids 109-153 of the osteopontin protein (GENBANK accession no. CAA36132), which confers neuroprotection was used as a positive control (Invitrogen, Carlsbad, CA, USA, dose: 5nM).
  • PBS phosphate buffered saline
  • Cell viability assays were performed 24 hours post oxygen and glucose deprivation. 20 ⁇ l of MTT (5mg/ ml dissolved in PBS) were added to each well of 96 well plates and the plates incubated for 1 hour at 37 0 C. The media was then removed from each well and the cells permeabilized with lOO ⁇ l DMSO. Cell viability was determined by reading plates at a wavelength of 550nm and comparing plates that had undergone OGD to plates that had only had media replaced (sham wash plates).
  • TlAM and TOAM 5nM-500 ⁇ M
  • TlAM and TOAM are unable to induce hypothermia, thus any observed neuroprotection would be the result of a direct effect.
  • No protective dose of TlAM or TOAM was identified although higher doses of TlAM and TOAM were cytotoxic (FIG. 4A). This suggests that acute administration of TlAM and TOAM does not confer neuroprotection via a hypothermia independent mechanism. This experiment was repeated in primary rat neuronal cultures and the same result was obtained.
  • IH and 13C NMR spectra were taken on a Varian 400 (400 and 100 MHz, respectively). Data reported were calibrated to internal TMS (0.0 ppm) for all solvents unless otherwise noted and are reported as follows: chemical shift, multiplicity (app, apparent; par obsc, partially obscured; ovrlp, overlapping; br, broad; s, singlet; d, doublet; t, triplet; q, quartet; and m, multiplex), coupling constant, and integration. Inert atmosphere operations were conducted under argon passed through a Drierite drying tube in flame-dried or oven-dried glassware unless otherwise noted.
  • Anhydrous THF, DCM, diethyl ether, pyridine, and diisopropyl ethylamine were filtered through two columns of activated basic alumina and transferred under an atmosphere of argon gas in a solvent purification system designed and manufactured by J. C. Meyer (University of California, Irvine).
  • Anhydrous DMF was obtained by passing through two columns of activated molecular sieves. All other anhydrous solvents and reagents were purchased from Aldrich, Sigma-Aldrich, Fluka, or Acros and were used without any further purification unless otherwise stated. Final compounds were judged to be >95% pure by IH NMR analysis and confirmed by LC/MS and HPLC.
  • LC/MS was performed on a Waters AllianceHT LC/MS with a gradient of 0-100% methanol (0.05% TFA) over 7 min.
  • HPLC was performed on a Waters AllianceHT LC with a gradient of 0-100% acetonitrile (0.05% TFA) over 7 min.
  • Thyronamine Hydrochloride Refer to the general procedure for t-Boc deprotection described above. The crude reaction mixture was concentrated in vacuo and dried under high vacuum pressure to give 23 as a slightly tan solid (32.9 mg, 100% yield).
  • 3'-Iodothyronamine Hydrochloride (3'-TlAM). Refer to the general procedure for t-Boc deprotection described above. The crude reaction mixture was concentrated in vacuo and dried under high vacuum pressure to give 25 as a white solid (12.7 mg, 98% yield).
  • IH NMR 400 MHz, DMSO-c/6): ⁇ 10.24 (s, 1 H), 7.86 (s, 3 H), 7.30 (d, J) 2.4 Hz, 1 H), 7.23 (d, J) 8.4 Hz, 2 H), 6.96-6.86 (m, 4 H), 3.01 (br s, 2 H), 2.83 (app t, J) 7.6 Hz, 2 H).

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Abstract

L’invention a pour objet des procédés de préconditionnement contre les lésions dues à des accidents ischémiques et/ou hypoxiques par l’administration d’un dérivé de la thyronamine.
PCT/US2006/044001 2005-11-11 2006-11-10 Derives de thyroxine pour preconditionnement contre accident cerebrovasculaire Ceased WO2007059039A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130018026A1 (en) * 2011-07-14 2013-01-17 Latham Keith R Halogenated phenols for diagnostics, antioxidant protection and drug delivery

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB873206A (en) * 1957-07-31 1961-07-19 Glaxo Lab Ltd Improvements in or relating to pharmaceutical compositions
DE3231541A1 (de) * 1982-08-25 1984-03-01 Henning Berlin Gmbh Chemie- Und Pharmawerk, 1000 Berlin Arzneimittel, enthaltend 3,3',5-trijodthyronamin und verfahren zu seiner herstellung
WO1996040048A2 (fr) * 1995-06-07 1996-12-19 Karo Bio Ab Utilisations innovantes d'hormones thyroidiennes ou de composes ressemblant a des hormones thyroidiennes
WO2002005834A2 (fr) * 2000-07-14 2002-01-24 Karo Bio Ab Nouvelles utilisations d'hormones de la thyroide ou de composes agonistes semblables a l'hormone de la thyroide
WO2004093800A2 (fr) * 2003-04-18 2004-11-04 The Regents Of The University Of California Derives de thyronamine et analogues et des methodes d'utilisation de ces composes

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB873206A (en) * 1957-07-31 1961-07-19 Glaxo Lab Ltd Improvements in or relating to pharmaceutical compositions
DE3231541A1 (de) * 1982-08-25 1984-03-01 Henning Berlin Gmbh Chemie- Und Pharmawerk, 1000 Berlin Arzneimittel, enthaltend 3,3',5-trijodthyronamin und verfahren zu seiner herstellung
WO1996040048A2 (fr) * 1995-06-07 1996-12-19 Karo Bio Ab Utilisations innovantes d'hormones thyroidiennes ou de composes ressemblant a des hormones thyroidiennes
WO2002005834A2 (fr) * 2000-07-14 2002-01-24 Karo Bio Ab Nouvelles utilisations d'hormones de la thyroide ou de composes agonistes semblables a l'hormone de la thyroide
WO2004093800A2 (fr) * 2003-04-18 2004-11-04 The Regents Of The University Of California Derives de thyronamine et analogues et des methodes d'utilisation de ces composes

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
COTE P ET AL: "THYRONAMINE A NEW INOTROPIC AGENT ITS CARDIO VASCULAR EFFECTS AND MECHANISM OF ACTION", CARDIOVASCULAR RESEARCH, vol. 8, no. 6, 1974, pages 721 - 730, XP009081178, ISSN: 0008-6363 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130018026A1 (en) * 2011-07-14 2013-01-17 Latham Keith R Halogenated phenols for diagnostics, antioxidant protection and drug delivery
US8673269B2 (en) 2011-07-14 2014-03-18 Keith R. Latham Halogenated phenols for diagnostics, antioxidant protection and drug delivery

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