(12) Patent Application Publication (10) Pub. No.: US 2006/0100263 A1 Basile Et Al
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US 200601 00263A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2006/0100263 A1 Basile et al. (43) Pub. Date: May 11, 2006 (54) ANTIPYRETC COMPOSITIONS AND (52) U.S. Cl. .............................................................. 514/412 METHODS (57) ABSTRACT (76) Inventors: Anthony Basile, Hoboken, NJ (US); Warren Stern, Plymouth, MA (US) Methods and compositions containing bicifadine are pro vided for the treatment and prevention of hyperthermia in Correspondence Address: mammalian Subjects. The methods and compositions may be Jeffrey J. King used to prevent or treat fever, pyresis, menopausal hot GRAYBEAL UACKSON HALEY LLP flashes; peri menopausal hot flashes, postmenopausal hot Suite 350 flashes, hot flashes caused by anti-estrogen therapy, hot 155 - 108th Avenue NE flashes secondary to Surgical removal of estrogen producing Bellevue, WA 98004-5901 (US) tissue, hot flashes caused by radiation therapy, malignant hyperthermia, Serotonin syndrome, heat stroke, febrile sei (21) Appl. No.: 11/263,045 Zures, and neuroleptic malignant syndrome, among other conditions. Additional compositions and methods are pro (22) Filed: Oct. 31, 2005 vided employing bici fadine to treat pyresis and simulta neously elicit an analgesic response in mammalian Subjects. Related U.S. Application Data Yet additional compositions and methods are provided Provisional application No. 60/625.207, filed on Nov. which employ bici fadine in combination with a second (60) antipyretic agent, a second analgesic agent, or a different 5, 2004. therapeutic agent to yield more effective antipyretic treat Publication Classification ment tools, and/or dual activity therapeutic methods and formulations useful to prevent or reduce hyperthermia and (51) Int. C. one or more additional symptoms (e.g., pain, or depression) A6 IK 3/403 (2006.01) in mammalian Subjects. Patent Application Publication May 11, 2006 US 2006/01 00263 A1 1 O 2 -H Vehicle 1 O 1 -o-Aspirin 200 mg/kg -A-Bicifadine 50 mg/kg 100 -o-Bicifadine 100 mg/kg 9 9 9 8 9 7 O 1 2 3 4. Time After Oral Administration, (hrs) Figure l US 2006/01 00263 A1 May 11, 2006 ANTIPYRETC COMPOSITIONS AND METHODS tumor necrosis factor, the interferons, prostaglandains and the gp 130 receptor-activating family (interleukin-6, inter RELATED APPLICATIONS leukin-11, leukemia inhibitory factor, ciliary neurotropic 0001. This application claims priority to U.S. Provisional factor, and oncostatin M) which initiate metabolic changes patent application Ser. No. 60/625.207, filed Nov. 5, 2004. in the hypothalamic thermoregulatory center. 0008. Non-infectious causes of hyperthermia may TECHNICAL FIELD include thermoregulatory disorders, for example: Serotonin syndrome; neuroleptic malignant syndrome; malignant 0002 The present invention relates to methods and com hyperthermia; central nervous system thermoregulation dis positions for controlling body temperature changes in mam orders; impairment of heat loss, and/or thermal challenge (as malian Subjects. More specifically, the invention relates to typically observed in heat stroke); endocrine disorders such methods and compositions for preventing and/or treating as hyperthyroidism, pheochromocytoma and menopause hyperthermia and related conditions in mammals. (including peri menopausal and post menopausal thermal BACKGROUND disorders); and severe illnesses, such as stroke and cancer. 0009 Hyperthermia may also be induced by drugs such 0003. Thermal homeostasis in mammals is maintained as serotonergics (e.g., MDMA intoxication; Nisijima et al., through a complex interplay between regulatory neurons in 2001, Sprague et al., 2003, Birmes, 2003), antipsychotics the central and autonomic nervous systems. In humans, (e.g., haloperidol, which may trigger neuroleptic malignant normal body temperature is tightly controlled between 97.6° F. and 98.5° F. (Mackowiak, 1997), primarily by neurons in syndrome; Fricchione et al., 2000, Bhanushali and Tuite, the preoptic nucleus of the anterior hypothalamus (POAH) 2004), anticholinesterases, sympathomimetics, (Halloran and the septal nuclei. Neurons of the POAH process thermal and Bernard, 2004), and halothane in subjects with muta signals generated in the body core and periphery (skin) to tions of the ryanodine receptor. maintain normal body temperature by evoking physiological 0010) If uncontrolled, all types of hyperthermia can lead and/or behavioral responses that regulate heat production or to systemic damage, including central nervous system dissipation, including physical activity, Sweating, shivering, (CNS) damage, organ failure, and even death. vasodilation or vasoconstriction, mobilization of energy 0011. In most cases, hyperthermia is considered a serious stores through thyroid hormone and glucagon release, and condition by medical practitioners and aggressive efforts are metabolic thermogenesis from white and brown fat. undertaken to reduce pyresis if it extends significantly 0004 These homeostatic mechanisms are typically beyond the normal temperature range and/or for an extended invoked through activation of the sympathetic (peripheral period of time. Attempts to reduce hyperthermia are under noradrenergic) nervous system. Released norepinephrine taken with the objectives of increasing the comfort of can then activate Cadrenergic receptors in the vasculature patients and, more importantly, to avoid morbidity, includ to mediate vasoconstriction and heat retention (Frank et al., ing systemic damage such as organ injury or failure, result 1997), while B receptor activation invokes thermogenesis ing from chronic elevations of body temperature (Aronoff (i.e., production of heat from white and brown fat stores) and Neilson, 2001, Greisman and Mackowiak, 2002). Com (Granneman et al., 2003, Cannon and Nedergaard, 2004). mon sequelae to hyperthermia which are secondary or Thermogenesis and heat retention can also be activated by attendant clinical targets for intervention can include febrile cholinergic mechanisms (e.g., to elicit shivering), and/or seizures, myocardial infarction, rhabdomyolysis, pancreati serotonergic mechanisms (e.g., activation of vascular tis, hepatic failure, respiratory distress, ataxia, cognitive 5-HT2A receptors to cause vasoconstriction) (Blessing and impairment, myoglobinuria, renal failure, liver damage and Seaman, 2003). disseminated intravascular coagulopathy, among other 0005 Failure of the body to maintain normal thermal adverse, hyperthermia-associated conditions (see, e.g., Gre homeostasis results in either hypothermia (lowering of body isman and Mackowiak, 2002, Lazarus et al., 1989). temperature below normal), or hyperthermia (elevation of 0012 Current therapies for hyperthermia include the use body temperature above normal), either of which can lead to of conventional antipyretic drugs such as acetaminophen, a wide range of adverse sequelae, including organ failure non-steroidal anti-inflammatories (NSAIDS), anti-inflam and even death. matories Such as glucocorticoids, and hormone replacement therapy in the treatment of endocrine disorders. However, 0006 The most common manifestation of hyperthermia these therapies all have side effects and are not necessarily is pyresis, or fever. Fever may be intermittent, characterized effective for all types of hyperthermia. For example, by daily spikes followed by a return to normal temperature, NSAIDS are associated with a significant risk of gastrointes or remittent, in which the temperature does not return to tinal and renal toxicities, as well as a potential for causing normal. Fever may be caused by infection (e.g., viral, Reye's syndrome. Glucocorticoids are also powerful immu bacterial or fungal infection) or mediated by various non nosuppressants, which may leave patients susceptible to infectious conditions (e.g., inflammatory, neoplastic, or infection. PraZosin and other alpha-adrenergic antagonists immunological disorders), and may result from elevated may cause hypotension, which can lead to tachycardia and heat production and/or increased heat conservation (e.g., Syncope. Hormone replacement therapy, such as estrogen reduced heat dissipation capacity). replacement therapy, is contraindicated in many patients, 0007 Fevers caused by infection typically result from a particularly those with a history of cancer or venous throm release of exogenous pyrogens by infectious agents, for boembolism. Hormone replacement therapy has also been example bacterial lipopolysaccharides. These exogenous linked to increased risks of cancer, coronary artery disease, pyrogens trigger endogenous pyrogens Such as IL-13, IL-6, and stroke. US 2006/01 00263 A1 May 11, 2006 0013 In view of the foregoing, there remains an impor additional active agent(s) that is/are combinatorially formu tant, unmet need in the art for alternative compositions and lated or coordinately administered with bici fadine to yield methods to prevent and/or reduce hyperthermia and associ an antipyretic composition or coordinate treatment response. ated conditions in mammalian Subjects. A related need exists Exemplary combinatorial formulations and coordinate treat for improved tools and methods for prophylaxis and treat ment methods in this context employ bicifadine in combi ment of specific forms of hyperthermia, for example to treat nation with one or more additional antipyretic agents, and/or peri- and post menopausal hot flashes, and to ameliorate in combination with one or more additional analgesic other forms of intermittent, recurring hyperthermia. agents. SUMMARY OF