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Title:
METHODS FOR USING (-)-PERHEXILINE
Document Type and Number:
WIPO Patent Application WO/2015/131231
Kind Code:
A1
Abstract:
A method for preventing, treating and/or reversing a disease, condition or state in a subject in need thereof by administering to the subject an effective amount of the (-)-perhexiline or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of (+)- perhexiline, or a pharmaceutical composition containing same. The diseases, components, features, conditions or states are associated with, caused by, manifesting, or resulting in, a reduced cellular redox state, hypoxia, an undesired lactic acid production or lactate utilization, and/or lactic acidosis.

Inventors:
DRUZGALA PASCAL-JEAN (US)
MILNER PETER (US)
SALLUSTIO BENEDETTA (AU)
LICARI JOHN (AU)
Application Number:
AU2015/000121
Publication Date:
September 11, 2015
Filing Date:
March 03, 2015
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
ADELAIDE RES & INNOVATION PTY (AU)
HEART METABOLICS LTD (IE)
CENTRAL ADELAIDE LOCAL HEALTH NETWORK INC (AU)
DRUZGALA PASCAL-JEAN (US)
MILNER PETER (US)
SALLUSTIO BENEDETTA (AU)
LICARI JOHN (AU)
International Classes:
A61K31/4458; A61P3/00; A61P9/00; A61P31/00; A61P33/00
Domestic Patent References:
WO2006099244A12006-09-21
WO2003037323A22003-05-08
WO2005097121A12005-10-20
WO2007096251A12007-08-30
WO2014036603A12014-03-13
Foreign References:
US20110275649A12011-11-10
Other References:
GOULD B.J. ET AL.: "Stereoselective Pharmacokinetics of Perhexiline", XENOBIOTICA, vol. 16, no. 5, 1986, pages 491 - 502
ABOZGUIA K. ET AL.: "Metabolic Modulator Perhexiline Corrects Energy Deficiency and Improves Exercise Capacity in Symptomatic Hypertrophic Cardiomyopathy", CIRCULATION, vol. 122, no. 16, 2010, pages 1562 - 1569
Attorney, Agent or Firm:
PHILLIPS ORMONDE FITZPATRICK (22 & 23367 Collins Stree, Melbourne Victoria 3000, AU)
Download PDF:
Claims:
CLAIMS

1. A method of preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization in a subject in need thereof, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

2. The method according to claim 1 , wherein the disease, condition or state is associated with undesired lactic acid production or undesired lactate utilization.

3. The method according to claims 1 or 2, wherein the disease, condition or state is a cancer.

4. The method according to claim 3, wherein the administration of the (-)-perhexiline inhibits proliferation of cancer cells, increases apoptosis of cancer cells, improves mitochondrial function, increases cytosolic lactate utilisation and/or increases the oxidation of pyruvate under hypoxia.

5. The method according to claims 1 or 2, wherein the disease, condition or state is associated with lactic acidosis.

6. The method according to any one of claims 1 , 2 or 5, wherein the disease, condition or state comprises chronic hypoxic pulmonary hypertension.

7. The method according to any one of claims 1 , 2 or 5, wherein the disease, condition or state is selected from one or more of the group comprising of type I diabetes, type II diabetes, gestational diabetes, MELAS syndrome, and lactic acidosis in severe cases of malaria infections.

8. The method according to any one of claims 1 , 2 or 5, wherein the disease, condition or state is selected from one or more of the group comprisingof leukemia, lymphoma, thiamine deficiency, infection, pancreatitis, short bowel syndrome, hepatic, renal, or diabetic dysfunction, drug and/or toxin exposure, renal failure, or an inborn error of metabolism.

9. The method according to any one of claims 1 , 2 or 5, wherein the disease, condition or state is selected from one or more of the group comprising of 3-hydroxyacyl-CoA dehydrogenase II deficiency, 3-methylglutaconic aciduria type 4 (MGA4), acetaminophen administration, anoxia, cardiomyopathy, chronic kidney disease, coenzyme Q cytochrome c reductase deficiency, copperhead snake poisoning, crotalidae snake poisoning, diabetic nephropathy, ethanol abuse, Finnish lethal neonatal metabolic syndrome, hereditary fructose-1 ,6-bisphosphatase deficiency, fructosuria, glycogen storage disease type I, glycogen storage disease type 1 C, glycogen storage disease type 1 D, glycogen storage diseases, lactic acidosis arising from a heart condition, lactic acidosis arising from hemorrhage, hydroxyacyl-coA dehydrogenase type 2 deficiency, lactic acidosis arising from a kidney condition, lipoamide dehydrogenase deficiency, lactic acidosis arising from liver failure, lactic acidosis arising from a lung condition, MELAS syndrome, malignant hyperthermia, Malonic aciduria, medium and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, lactic acidosis arising from a metabolic disorder, metfonmin administration, mitochondrial DNA depletion syndrome, mitochondrial encephalomyopathy aminoacidopathy, lactic acidosis arising from mitochondrial myopathy , mitochondrial neurogastrointestinal encephalopathy syndrome, myoclonus with epilepsy with ragged red fibers, myopathy with lactic acidosis and sideroblastic anemia polyneuropathy, ophthalmoplegia, leukoencehalopathy, intestinal pseudo-obstruction, posthemorrhagic anemia, pyruvate carboxylase deficiency pyruvate decarboxylase deficiency, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase phosphatase deficiency, respiratory failure, SCHAD deficiency, septicemia, shock, short bowel syndrome, small non-cleaved cell lymphoma, succinic acidemia, type 10 17 -hydroxysteroid dehydrogenase deficiency, type I glycogen storage disease, or von Gierke Disease.

10. The method according to any one of claims 1 , 2 or 5, wherein the disease, condition or state is associated with administration of a drug.

1 1 . The method according to claim 10, wherein the drug comprises a biguanide drug.

12. The method according to claim 10, wherein the drug comprises a drug selected from one or more of metformin, phenformin, isoniazid, fialuridine, and a nucleoside reverse transcriptase inhibitor.

13. The method according to any one of claims 1 to 12, wherein the administration of the (-)-perhexiline increasescellular redox state, reduces cellular lactic acid production, increases cellular oxidative glycolysis and/or increases cellular glycogenesis.

14. A method of preventing and/or treating a disease, condition or state associated with impaired cellular respiration and anaerobic metabolism of glucose in a subject in need thereof, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

15. A method of improving sensitivity to insulin in a subject in need thereof, the method comprising exposing to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

16. A method of preventing and/or treating diabetes in a subject in need thereof, the method comprising administering to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer, and metformin and/or a pharmaceutically acceptable salt, prodrug or derivative thereof.

17. The method according to claim 16, wherein the diabetes comprises type II diabetes, gestational diabetes or pre-diabetes.

18. A method of reducing or reversing lactic acidosis or its effects in a subject associated with administration of a drug, the method comprising exposing to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

19. The method according to claim 18, wherein the drug comprises a biguanide drug.

20. The method according to claim 19, wherein the drug comprises metformin, phenformin, isoniazid, fialuridine, a nucleoside reverse transcriptase inhibitor and/or a pharmaceutically acceptable salt, prodrug or derivative thereof.

21 . A method of reducing or reversing lactic acidosis and/or undesired lactic acid production in a subject treated with metformin, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

22. A method of improving the redox state of a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

23. A method of reducing lactic acid production, increasing oxidative glycolysis and/or increasing glycogenesis in a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

24. The method according to claims 22 or 23, wherein the cell is a cancer cell.

25. Use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a disease, condition or state associated with reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

26. The use according to claim 25, wherein the (-)-enantiomer comprises 95% or greater of the total perhexiline in the medicament.

27. The use according to claims 25 or 26, wherein the medicament comprises 25 to 250 mg (-)-perhexiline.

28. The use according to any one of claims 25 to 27, wherein the medicament comprises an amount of (-)-perhexiline that when administered to a subject in need thereof once daily produces a plasma concentration in one of the following ranges: 0.05-0.30 mg/L, 0.05-0.60 mg/L, 0.05-0.90 mg/L, 0.05-01.20 mg/L, 0.15-0.30 mg/L, 0.15-0.60 mg/L, 0.15- 0.90 mg/L, 0.15-1.20 mg/L and all subranges therebetween.

29. A method of preventing and/or treating a cancer, diabetes or chronic hypoxic pulmonary hypertension in a subject in need thereof, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

30. Use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a cancer, diabetes or chronic hypoxic pulmonary hypertension.

31 . A combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) one or more of a Ca2+ channel blocker, a prostacyclin analogue, an endothelin receptor antagonist, and a PDE5 inhibitor;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat chronic hypoxic pulmonary hypertension in a subject.

32. A combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) an anti-cancer agent;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat cancer in a subject.

33. A combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) an anti-diabetic agent;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat diabetes in a subject.

34. A combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) a biguanide drug;

wherein the components are provided in a form for separate or co-administration to a subject.

35. A combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) metformin;

wherein the components are provided in a form for separate or co-administration to a subject.

36. A pharmaceutical composition comprising an effective amount of a biguanide drug and substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof.

37. A method for screening for an agent for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization, the method comprising:

selecting a modified form of (-)-perhexiline; and

identifying the modified form of (-)-perhexiline as an agent for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

38. The method according to claim 37, wherein the method comprises determining the ability of the modified form of (-)-perhexiline to activate pyruvate dehydrogenase and/or inhibit pyruvate dehydrogenase kinase.

39. A method of reducing lactic acidosis and/or undesired lactic acid production in a subject treated with a biguanide drug, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

40. A method of increasing the redox state of a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

41 . The method according to any of claims 1 to 40, further comprising administering to the subject an effective amount of (-)-perhexiline in an amount of from about 1 mg to about 25 mg per day, and all subranges therebetween, wherein the subject is a poor metabolizer of (-)-perhexiline.

42. The method according to any one of claims 1 to 40, further comprising administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween, wherein the subject is an extensive metabolizer of (-)-perhexiline.

43. A method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof, and

administering to the subject an effective amount of (-)-perhexiline in an amount of from about 1 mg to about 25 mg per day, and all sub-ranges therebetween, wherein the subject is a poor metabolizer of (-)-perhexiline.

44. The method according to claim 43, further comprising administering to the subject an effective amount of a biguanide drug.

45. A method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof; and

administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween,

wherein the subject is an extensive metabolizer of (-)-perhexiline.

46. The method according to claim 45, further comprising administering to the subject a therapeutically-effective amount of a biguanide drug, such as metformin.

47 A method for reducing the secretion of glucagon from a pancreatic a-cell, comprising contacting the a-cell with an effective amount of (-)-perhexiline to suppress the conduction of sodium ions through sodium channels.

48. A method for treating diabetes in a subject in need thereof, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof, and chronic renal failure; and administering to said subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween.

49. The method according to claim 48, further comprising administering to the subject an effective amount of a biguanide drug, such as metformin.

50. A method for treating diabetes in a subject in need thereof, comprising

providing the subject having diabetes or at least one component, feature, condition or state thereof and serum creatinine > 1 .4 mg/dL; and

administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween.

51 . The method according to claim 50, further comprising administering to the subject an effective amount of a biguanide drug, such as metformin.

52. A method for preventing and/or treating diseases, components, features, conditions or states associated with, caused by, manifesting, or resulting in, hypoxia and/or lactic acidosis, as substantially described in the specification, figures, tables, and/or claims.

53. A method for treating a subject with VHL disease and/or tumors associated with VHL disease, comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

54. A method for treating a subject with clear cell renal cell carcinoma, comprising administering to the subject an effective amount of (-)-perhexiline and at least one of a VEGF inhibitor (such as bevacizumab (Avastin®), Ranibizumab and the like) or a carbonic anhydrase IX inhibitor, or combinations thereof.

55. A method for treating cancer comprising:

(a) selecting a subject having a cancer that may be responsive to at least one EGFR inhibitor;

(b) administering to the patient a therapeutically effective regimen comprising (i) at least one EGFR inhibitor and (ii) (-)-perhexiline; wherein the EGFR inhibitor and (-)-perhexiline are administered together or sequentially.

Description:
METHODS FOR USING (-)-PERHEXILINE

PRIORITY CLAIM

[0001 ] This application claims priority to United States provisional patent application number 61/946,891 filed on 3 March 2014, United States provisional patent application number 61/947,427 filed on 4 March 2014, United States provisional patent application number 61/948,513 filed on 5 March 2014, and United States provisional patent application number 61/985,395 filed on 28 April 2014, the contents of which are hereby incorporated by reference.

FIELD

[0002] The present disclosure generally relates to the use of the (-)-enantiomer of perhexiline (2-(2,2-dicyclohexylethyl)piperidine) for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

BACKGROUND

[0003] It has become increasingly apparent that many diseases, conditions and states are associated with a perturbed cellular redox state and/or undesired lactic acid production or lactate utilization.

[0004] Among cancer patients, spontaneous lactic acidosis can occur with hematologic and lymphoid malignancies, as well as solid tumors. Lactic acidosis has been observed in patients with breast, colon, ovarian, and small cell lung cancers, among others. Hematologic malignancies, including acute leukemias and high-grade lymphomas (e.g., Burkitt's, Diffuse Histiocytic, Diffuse Large B-cell, Follicular, Histiocytic, Hodgkin's, Large B-cell, Mantle Cell, Natural Killer/T-cell, Non-Hodgkin's, and T-cell) are the most common neoplastic disorders believed to be associated with lactic acidosis. When lactic acidosis is encountered in such malignancies, it is believed to portend an extremely poor prognosis.

[0005] Most cancer cells produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells. This phenomenon is known as the Warburg effect, which is a cellular adaptation to the hypoxic environment existing in solid tumors and the resulting glycolytic phenotype inhibits apoptosis and promotes cell proliferation. Agents that target this phenomenon have considerable therapeutic potential for preventing and/or treating cancer.

[0006] Chronic hypoxic pulmonary hypertension is an example of a condition associated with suppressed expression and function of voltage-gated K + channels (Kv) in pulmonary artery smooth muscle cells and a shift in cellular redox balance toward a reduced state. Early lactic acidosis can arise from reduced blood perfusion to tissues. Reducing or reversing lactic acidosis or its effects in patients susceptible to, or suffering from, chronic hypoxic pulmonary hypertension would be beneficial.

[0007] The administration of many drugs can also lead to a perturbed cellular redox state and/or undesired lactic acid production or lactate utilization, which often provides limitations or drawbacks to the use of the drugs. For example, one of the serious potential adverse effects of the use of biguanide drugs, such as the use of metformin to treat diabetes, is lactic acidosis. Such situations demonstrate the therapeutic advantages of using such drugs in combination with agents that act to reduce or reverse lactic acidosis

[0008] Accordingly, there are a variety of situations where it would be advantageous to improve cellular redox, reduce levels of lactic acid, increase glucose uptake and/or increase glucose utilization.

SUMMARY

[0009] To the extent necessary to provide descriptive support, the entire subject matter and/or text of the appended claims is incorporated herein by reference.

[0010] The present disclosure is based on the discovery that (-)-perhexiline possesses heretofore unrecognized therapeutic advantages for the treatment and/or prevention of diseases, conditions or states associated with a reduced or diminished cellular redox state, hypoxia and/or undesired lactic acid production or utilization, as well as associated with decreased glucose uptake and/or decreased glucose utilization.

[001 1 ] Certain example embodiments of the present disclosure provide a method for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization in a subject in need thereof, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0012] Other exemplary embodiments of the present disclosure provide use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[0013] Certain further embodiments of the present disclosure provide a method of preventing and/or treating a disease, condition or state associated with impaired cellular respiration and anaerobic metabolism of glucose in a subject in need thereof, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0014] Certain embodiments of the present disclosure provide a method of improving sensitivity to insulin in a subject susceptible to, or suffering from, type 2 diabetes, the method comprising administering to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0015] Certain embodiments of the present disclosure provide a method of preventing and/or treating diabetes in a subject, the method comprising administering to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer, and metformin and/or a pharmaceutically acceptable salt, prodrug or derivative thereof.

[0016] Certain embodiments of the present disclosure provide a method of reducing or reversing lactic acidosis or its effects in a subject associated with administration of a drug (e.g., an anti-diabetic drug, such as metformin), the method comprising administering to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0017] Certain embodiments of the present disclosure provide a method of reducing or reversing lactic acidosis and/or undesired lactic acid production in a subject treated with metformin, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0018] Certain embodiments of the present disclosure provide a method of improving the redox state of a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0019] Certain embodiments of the present disclosure provide a method of reducing lactic acid production, increasing oxidative glycolysis and/or increasing glycogenesis in a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0020] Certain embodiments of the present disclosure provide a method of preventing and/or treating a cancer, diabetes or chronic hypoxic pulmonary hypertension in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0021 ] Certain embodiments of the present disclosure provide use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[0022] Certain embodiments of the present disclosure provide use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a cancer, diabetes or chronic hypoxic pulmonary hypertension.

[0023] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and (ii) one or more of a Ca2 + channel blocker, a prostacyclin analogue, an endothelin receptor antagonist, and a PDE5 inhibitor;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat chronic hypoxic pulmonary hypertension in a subject.

[0024] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) an anti-cancer agent;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat a cancer in a subject.

[0025] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) an anti-diabetic agent;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat diabetes in a subject.

[0026] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) metformin;

wherein the components are provided in a form for separate or co-administration to a subject.

[0027] Certain embodiments of the present disclosure provide a pharmaceutical composition comprising an effective amount of a biguanide drug and substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof. [0028] Certain embodiments of the present disclosure provide a method of screening for an agent for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization, the method comprising:

selecting a modified form of (-)-perhexiline; and

identifying the modified form of (-)-perhexiline as an agent for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[0029] Certain embodiments of the present disclosure provide a method of reducing lactic acidosis and/or undesired lactic acid production in a subject treated with a biguanide drug, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0030] Certain embodiments of the present disclosure provide a method of increasing the redox state of a cell, the method comprising exposing the cell to an effective amount of (-)- perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0031 ] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof, and

administering to the subject an effective amount of (-)-perhexiline in an amount of from about 1 mg to about 25 mg per day, and all sub-ranges therebetween, wherein the subject is a poor metabolizer of (-)-perhexiline.

[0032] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof; and

administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween, wherein the subject is an extensive metabolizer of (-)-perhexiline. [0033] Certain embodiments of the present disclosure provide a method for reducing the secretion of glucagon from a pancreatic a-cell, comprising contacting the a-cell with an effective amount of (-)-perhexiline to suppress the conduction of sodium ions through sodium channels.

[0034] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof, and chronic renal failure; and

administering to said subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween.

[0035] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject in need thereof, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof and serum creatinine > 1.4 mg/dL; and

administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween.

[0036] Certain embodiments of the present disclosure provide a method for treating a subject with VHL disease and/or tumors associated with VHL disease, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+) enantiomer.

[0037] Certain embodiments of the present disclosure provide a method for treating a subject with clear cell renal cell carcinoma, the method comprising administering to the subject an effective amount of (-)-perhexiline and at least one of a VEGF inhibitor (such as bevacizumab (Avastin®), Ranibizumab and the like) or a carbonic anhydrase IX inhibitor, or combinations thereof.

[0038] Certain embodiments of the present disclosure provide a method for treating a cancer comprising:

(a) selecting a subject having a cancer that may be responsive to at least one EGFR inhibitor; (b) administering to the patient a therapeutically effective regimen comprising (i) at least one EGFR inhibitor and (ii) (-)-perhexiline;

wherein the EGFR inhibitor and (-)-perhexiline are administered together or sequentially.

BRIEF DESCRIPTION OF THE FIGURES

[0039] Exemplary embodiments will be better understood and appreciated in conjunction with the following detailed description of example embodiments taken together with the accompanying figures. It is to be understood that the following description of the figures is for the purpose of describing example embodiments only and is not intended to be limiting with respect to this disclosure.

[0040] Figure 1 shows histological assessment of mean (sd) hepatic lipid and glycogen content (% field area) in Dark Agouti rats (n=4) treated with vehicle (Cont), racemic (Rac), (+)- or (-)-perhexiline for 8 weeks ( * p<0.05 vs Cont).

[0041 ] Figure 2 shows in panel A total pyruvate dehydrogenase proteins content and in panel B phosphorylated pyruvate dehydrogenase content in control (CONT) Dark Agouti rats and those injected with isoprenaline (50 mg/kg) alone (ISO) or following 2 weeks pre- treatment with 200 mg/kg/day of (+)-, (-)- or racemic-perhexiline. * p<0.05, ** p<0.01 , *** p<0.001 c.f. ISO

[0042] Figure 3 shows lactate production over 24 hours in cells exposed to 0 or 1 μΜ (-)-perhexiline under normoxic or hypoxic conditions.

[0043] Figure 4 shows the extent of glucose oxidation to C0 2 assessed using 13 C-glucose under normoxic culture conditions.

[0044] Figure 5 shows that (-)- perhexiline decreases the relative flux of glucose to lactate production versus oxidation to C0 2 .

[0045] Figure 6 shows the effect of the enantiomers of perhexiline on the viability of fibroblasts, and osteosarcoma cell lines grown in FCS.

[0046] Figure 7 shows the effect of the enantiomers of perhexiline on the viability of fibroblasts, and osteosarcoma cell lines grown in the absence of FCS. [0047] Figure 8 shows the effects of enantiomers of perhexhiline on lactate production in BTK-143 and MSK cells.

[0048] Figure 9 shows the effects of enantiomers of perhexhiline on ATP production in osteosarcoma cells and fibroblasts.

[0049] Figure 10 shows the effects of enantiomers of perhexhiline on cancer cell invasion and metastasis in human and rat osteosarcoma cell lines.

DETAILED DESCRIPTION

[0050] It will be understood by all readers of this written description that the exemplary embodiments described and claimed herein may be suitably practiced in the absence of any recited feature, element or step that is, or is not, specifically disclosed herein. All publications and references cited herein, including those in the background section, are expressly incorporated herein by reference in their entirety. However, with respect to any similar or identical terms found in both the incorporated publications or references and those explicitly put forth or defined in this document, then those terms definitions or meanings explicitly put forth in this document shall control in all respects. Further, any reference to prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

[0051 ] The example embodiments disclosed herein relate, in part, to the use of the substantially pure (-)-enantiomer of perhexiline for preventing and/or treating a disease condition or state associated with associated with a reduced cellular redox state and/or undesired lactic acid production or undesired lactate utilization, and to the use of the substantially pure (-)-enantiomer of perhexiline in combination with other drugs that when used reduce cellular redox state and/or result in undesired lactic acid production or lactate utilization.

[0052] Certain disclosed embodiments may have one or more combinations of advantages. For example, some of the advantages of the embodiments disclosed herein include, but are not limited to, one or more of the following: improved methods for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization; improved methods for reducing the undesired side effects associated with the use of some drugs; the use of combination therapy with some drugs to reduce side effects associated with those drugs; treatments with improved efficacy and/or reduced side effects; new methods for identifying metabolic agents for use in the prevention and/or treatment of disease, condition or state associated with associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization; to provide one or more advantages in the art; or to provide a useful commercial choice. Other advantages of certain embodiments are disclosed herein or may be appreciated in practicing one or more example embodiments described herein.

[0053] Included within the scope of the embodiments described herein are therapeutic compositions, and uses of such compositions, containing between 0% and 100% of the (-)-enantiomer of perhexiline. In one exemplary embodiment, the present disclosure relates to the use of substantially enantiomerically pure ("enantiopure") negative isomer of perhexiline, and in particular, to the use of substantially enantiopure (-)-perhexiline for preventing and/or treating a disease, condition or state associated with reduced cellular redox state and/or undesired lactic acid production or lactate utilization. The present disclosure also relates to pharmaceutical compositions comprising substantially enantiopure (-)-perhexiline, alone and in combination with other agents, and to the identification of agents for preventing and/or treating a disease, condition or state associated with reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[0054] Any techniques for the preparation/isolation/separation of individual perhexiline compound enantiomers may be used including chiral synthesis from a suitable optically pure precursor or resolution of the racemate using, for example, chiral chromatography, recrystallization, resolution, diastereomeric salt formation, or derivatization into diastereomeric adducts followed by separation. Other methods may also be employed to separate enantiomers such as the classic technique of chiral acid precipitation, which is described in applications EP 828,702 and WO 00/32554 and U.S. Pat. No. 4,571 ,424, which are hereby incorporated by reference in their entirety. Still other methods known to one of skill in the art and routine modifications thereof, and/or following procedures similar to those described herein and routine modifications thereof, and/or procedures found in, for example, Davies et al., J Chrom B, 832 (2006) 1 14-120; Jaques et al., Tetrahedron Letters, 48 (1971 ) 4617-4620; Pollnitz et al., Journal of Agricultural and Food Chemistry 2004, 52, 3244-3252, Gayen, Internet Electronic Journal of Molecular Design 2005, 4, 556-578, Shirley et al., J Amer. Chem. Soc. 1957, 3481 -3485, Morimoto J Med. Chem. 2001 , 44, 3355-3368, Esaki Tetrahedron 2006, 62, 10954-10961 , Kogon, Organic Syntheses 1963, Collective Volume 4, 182, US 5,883,254, Caton, J. Chem. Soc. C 1967, 13, 1204, US 5,025,031 , Harada, Bioorganic & Medicinal Chemistry 2001 , 9, 2955-2968, U.S. Pat. No. 5,292,740, and Hopfgartner et al, J. Mass. Spectrom. 1996, 37, 69-76, and references cited therein and routine modifications thereof.

[0055] One of skill in the art will appreciate that although the present disclosure exemplifies embodiments of compositions, and use of such compositions, containing a substantially enantiomerically pure (-)-isomer of the perhexiline compound, the present disclosure contemplates other example embodiments comprising the use of stereoisomeric mixtures of perhexiline but that still achieve advantageous therapeutic effects, depending on one or more of the various factors described herein.

[0056] One way to characterize a chemical composition containing a compound having at least one chiral center is by the effect of the composition on a beam of polarized light. When a beam of plane polarized light is passed through a solution of a chiral compound, the plane of polarization of the light that emerges is rotated relative to the original plane. This phenomenon is known as optical activity, and compounds that rotate the plane of polarized light are said to be optically active. One enantiomer of a compound will rotate the beam of polarized light in one direction, and the other enantiomer will rotate the beam of light in the opposite direction. The enantiomer that rotates the polarized light in the clockwise direction is the (+)-enantiomer and the enantiomer that rotates the polarized light in the counterclockwise direction is the (-)-enantiomer.

[0057] The present disclosure is based on the recognition that (-)-perhexiline has therapeutic advantages to treat and/or to prevent diseases associated with hypoxia and/or lactic acid production.

[0058] To facilitate understanding of this disclosure set forth herein, a number of terms are defined below. Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are generally well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein generally have the same meaning as commonly understood in the art to which this disclosure belongs. In the event that there is a plurality of definitions for a term used herein, those in this section prevail unless stated otherwise.

[0059] As used herein, the singular forms "a," "an," and "the" may refer to plural articles (i.e., "one or more," "at least one," etc.) unless specifically stated otherwise. [0060] Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. Where a specific range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is included therein. All smaller sub ranges are also included. The upper and lower limits of these smaller ranges are also included therein, subject to any specifically excluded limit in the stated range.

[0061 ] The term "about" or "approximately" means an acceptable error for a particular value, which depends in part on how the value is measured or determined. In certain embodiments, "about" can mean one or more standard deviations. When the antecedent term "about" is applied to a recited range or value it denotes an approximation within the deviation in the range or value known or expected in the art from the measurements method. For removal of doubt, it shall be understood that any range stated herein that does not specifically recite the term "about" before the range or before any value within the stated range inherently includes such term to encompass the approximation within the deviation noted above.

[0062] The term "preventing", and related terms such as "prevention" and "prevent", refer to obtaining a desired pharmacologic and/or physiologic effect in terms of delaying, precluding, arresting or suppressing the appearance of one or more symptoms in a subject and/or reducing the risk of the subject from acquiring a disorder.

[0063] The term "treatment", and related terms such as "treating" and "treat", refer to obtaining a pharmacologic and/or physiologic effect in terms of improving the condition of a subject, abrogating, alleviating, ameliorating, arresting, suppressing, relieving and/or slowing the progression or cause of one or more symptoms in the subject, a partial or complete stabilization of the subject, a regression of the one or more symptoms, or a cure of a disease, condition or state in the subject.

[0064] The term "subject" refers to an animal, including, but not limited to, a primate (e.g., human, monkey, chimpanzee, gorilla, and the like), rodents (e.g., rats, mice, gerbils, hamsters, ferrets, and the like), lagomorphs, swine (e.g., pig, miniature pig), equine, canine, feline, and the like. The terms "subject", and "patient" are used interchangeably herein in reference, for example, to a mammalian subject, such as a human patient in need of treatment. The subject may be susceptible to, or suffering from, a disease, condition or state as described herein.

[0065] In certain embodiments, the subject is suffering from, or susceptible to, a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production and/or lactate utilization.

[0066] Certain embodiments of the present disclosure provide a method for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or an undesired lactic acid production and/or undesired lactate utilization in a subject in need thereof. The diseases, components, features, conditions or states are associated with, caused by, manifesting, or resulting in, a reduced cellular redox state, hypoxia, an undesired lactic acid production or lactate utilization, and/or lactic acidosis.

[0067] Certain embodiments of the present disclosure provide a method of preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization in a subject in need thereof, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0068] In certain embodiments, the disease, condition or state is associated with undesired lactic acid production or undesired lactate utilization.

[0069] In certain embodiments, the disease, condition or state is a cancer. Suitable examples of cancers treatable by the use of (-)-perhexiline include but are not limited to breast, colon, ovarian, small cell lung cancer, bone cancers including osteosarcoma, hematologic malignancies, including acute leukemias and high-grade lymphomas (e.g., Burkitt's, Diffuse Histiocytic, Diffuse Large B-cell, Follicular, Histiocytic, Hodgkin's, Large B- cell, Mantle Cell, Natural Killer/T-cell, Non-Hodgkin's, T-cell, etc.) and/or other neoplastic disorders.

[0070] Certain embodiments of the present disclosure provide a method for preventing and/or treating a cancer in a subject in need thereof.

[0071 ] Certain embodiments of the present disclosure provide a method of preventing and/or treating a cancer in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer. [0072] In certain embodiments, the administration of the (-)-perhexiline inhibits proliferation of cancer cells, increases apoptosis of cancer cells, improves mitochondrial function, increases cytosolic lactate utilisation and/or increases the oxidation of pyruvate under hypoxia.

[0073] In certain embodiments, the disease, condition or state is associated with increased lactic acid production and/or increased lactate utilization. In certain embodiments, the disease, condition or state is associated with lactic acidosis.

[0074] In certain embodiments, the disease, condition or state comprises chronic hypoxic pulmonary hypertension.

[0075] Certain embodiments of the present disclosure provide a method of preventing and/or treating chronic hypoxic pulmonary hypertension in a subject in need thereof.

[0076] Certain embodiments of the present disclosure provide a method of preventing and/or treating chronic hypoxic pulmonary hypertension in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0077] In certain embodiments, the disease, condition or state is selected from one or more of the group consisting of type I diabetes, type II diabetes, gestational diabetes, prediabetes, mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS syndrome), and lactic acidosis in severe cases of malaria infections. In certain embodiments, the disease, condition or state comprises type II diabetes.

[0078] Certain embodiments of the present disclosure provide a method of preventing and/or treating diabetes in a subject in need thereof.

[0079] Certain embodiments of the present disclosure provide a method of preventing and/or treating diabetes in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0080] In certain embodiments, the disease, condition or state is selected from one or more of the group consisting of leukemia, lymphoma, thiamine deficiency, infection, pancreatitis, short bowel syndrome, hepatic, renal, or diabetic dysfunction, renal failure, drug and/or toxin exposure, and an inborn error of metabolism. [0081 ] In certain embodiments, the disease, condition or state is selected from one or more of the group consisting of 3-hydroxyacyl-CoA dehydrogenase II deficiency, 3- methylglutaconic aciduria type 4 (MGA4), acetaminophen administration, anoxia, cardiomyopathy, chronic kidney disease, coenzyme Q cytochrome c reductase deficiency, copperhead snake poisoning, crotalidae snake poisoning, diabetic nephropathy, ethanol abuse, Finnish lethal neonatal metabolic syndrome, hereditary fructose-1 ,6-bisphosphatase deficiency, fructosuria, glycogen storage disease type I, glycogen storage disease type 1 C, glycogen storage disease type 1 D, glycogen storage diseases, lactic acidosis arising from a heart condition, lactic acidosis arising from hemorrhage, hydroxyacyl-coA dehydrogenase type 2 deficiency, lactic acidosis arising from a kidney condition, lipoamide dehydrogenase deficiency, lactic acidosis arising from liver failure, lactic acidosis arising from a lung condition, MELAS syndrome, malignant hyperthermia, Malonic aciduria, medium and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, metabolic syndrome lactic acidosis arising from a metabolic disorder, metformin administration, mitochondrial DNA depletion syndrome, mitochondrial encephalomyopathy aminoacidopathy, lactic acidosis arising from mitochondrial myopathy, mitochondrial neurogastrointestinal encephalopathy syndrome, myoclonus with epilepsy with ragged red fibers, myopathy with lactic acidosis and sideroblastic anemia polyneuropathy, ophthalmoplegia, leukoencehalopathy, intestinal pseudo-obstruction, posthemorrhagic anemia, pyruvate carboxylase deficiency pyruvate decarboxylase deficiency, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase phosphatase deficiency, respiratory failure, SCHAD deficiency, septicemia, shock, short bowel syndrome, small non-cleaved cell lymphoma, succinic acidemia, type 10 17β- hydroxysteroid dehydrogenase deficiency, type I glycogen storage disease, and von Gierke Disease.

[0082] In certain embodiments, the administration of the (-)-perhexiline is used for the treatment of cancer, including cancers affected by EGFR, treatment ofmetasteses, treatment of chronic hypoxic pulmonary hypertension, the treatment of diabetic patients receiving metformin, the improvement of cardiac function following septic shock, improved exercise endurance, sensitization of metformin-cytotoxicity on cancer cells by synergism with metformin, reduction of cortical lactate levels and consequent reduction in damage to brain cells following cerebral ischemia, treatment of pulmonary hypertension and compensatory right ventricular hypertrophy, improvement on heart function following ischemic event, use as a sodium channel blocker, treatment for hyperglycemia or lowering the plasma level of glycosylated haemoglobin (HbAlc) or glucose, anti-proliferative properties against cancers, pro-apoptotic properties against cancers, anti-metastatic properties, and treatment of Von Hippel Lindau disease and/or tumors associated with VHL disease, reducing lactic acidosis and/or undesired lactic acid production in a subject treated with a biguanide drug, increasing the redox state of a cell, reducing the secretion of glucagon from a pancreatic alpha cell, and treating a subject with clear cell renal cell carcinoma.

[0083] Certain embodiments of the present disclosure provide a method of improving sensitivity to insulin in a subject in need thereof.

[0084] Certain embodiments of the present disclosure provide a method of improving sensitivity to insulin in a subject susceptible to, or suffering from, diabetes, the method comprising exposing to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[0085] In certain embodiments, the diabetes comprises type I diabetes, type II diabetes, gestational diabetes or pre-diabetes.

[0086] Certain embodiments of the present disclosure provide a method of preventing and/or treating diabetes in a subject in need thereof.

[0087] Certain embodiments of the present disclosure provide a method of preventing and/or treating diabetes in a subject, the method comprising administering to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer, and metformin and/or a pharmaceutically acceptable salt, prodrug or derivative thereof.

[0088] In certain embodiments, the diabetes comprises type I diabetes, type II diabetes, gestational diabetes or pre-diabetes.

[0089] In certain embodiments, the subject is suffering from, or susceptible to, a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production and/or lactate utilization.

[0090] In certain embodiments, the subject is suffering from, or susceptible to, a cancer.

[0091 ] In certain embodiments, the subject is suffering from, or susceptible to, a disease, condition or state associated with lactic acidosis. [0092] In certain embodiments, the subject is suffering from, or susceptible to, chronic hypoxic pulmonary hypertension or heart failure.

[0093] In certain embodiments, the subject is suffering from, or susceptible to, type I diabetes, type II diabetes, gestational diabetes, MELAS syndrome, and lactic acidosis in severe cases of malaria infection.

[0094] In certain embodiments, the subject is suffering from, or susceptible to, leukemia, lymphoma, thiamine deficiency, infection, pancreatitis, short bowel syndrome, hepatic, renal, or diabetic dysfunction, renal failure, drug and/or toxin exposure, and an inborn error of metabolism.

[0095] In certain embodiments, the subject is suffering from, or susceptible to, 3- hydroxyacyl-CoA dehydrogenase II deficiency, 3-methylglutaconic aciduria type 4 (MGA4), acetaminophen administration, anoxia, cardiomyopathy, chronic kidney disease, coenzyme Q cytochrome c reductase deficiency, copperhead snake poisoning, crotalidae snake poisoning, diabetic nephropathy, ethanol abuse, Finnish lethal neonatal metabolic syndrome, hereditary fructose-1 ,6-bisphosphatase deficiency, fructosuria, glycogen storage disease type I, glycogen storage disease type 1 C, glycogen storage disease type 1 D, glycogen storage diseases, lactic acidosis arising from a heart condition, lactic acidosis arising from hemorrhage, hydroxyacyl-coA dehydrogenase type 2 deficiency, lactic acidosis arising from a kidney condition, lipoamide dehydrogenase deficiency, lactic acidosis arising from liver failure, lactic acidosis arising from a lung condition, MELAS syndrome, malignant hyperthermia, Malonic aciduria, medium and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency, metabolic syndrome lactic acidosis arising from a metabolic disorder, metformin administration, mitochondrial DNA depletion syndrome, mitochondrial encephalomyopathy aminoacidopathy, lactic acidosis arising from mitochondrial myopathy, mitochondrial neurogastrointestinal encephalopathy syndrome, myoclonus with epilepsy with ragged red fibers, myopathy with lactic acidosis and sideroblastic anemia polyneuropathy, ophthalmoplegia, leukoencehalopathy, intestinal pseudo-obstruction, posthemorrhagic anemia, pyruvate carboxylase deficiency pyruvate decarboxylase deficiency, pyruvate dehydrogenase deficiency, pyruvate dehydrogenase phosphatase deficiency, respiratory failure, SCHAD deficiency, septicemia, shock, short bowel syndrome, small non-cleaved cell lymphoma, succinic acidemia, type 10 17B-hydroxysteroid dehydrogenase deficiency, type I glycogen storage disease, and von Gierke Disease. [0096] In certain embodiments, the subject has an increased risk or likelihood of suffering from a disease, condition or state as described herein.

[0097] In certain embodiments, the subject has an increased risk or likelihood of suffering from a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production and/or lactate utilization.

[0098] In certain embodiments, the subject is suffering from, or susceptible to, one or more adverse effects associated with the administration of a drug. In certain embodiments, the subject is suffering from, or susceptible to, lactic acidosis associated with the administration of a drug.

[0099] In certain embodiments, the subject is suffering from, or susceptible to, one or more adverse effects associated with the administration of a biguanide drug, such as metformin or phenformin. In certain embodiments, the subject is suffering from, or susceptible to, one or more adverse effects associated with the administration of a drug selected from one or more of metformin, phenformin, isoniazid, fialuridine, and a nucleoside reverse transcriptase inhibitor.

[00100] In certain embodiments, the one or more adverse effects associated with administration of a drug comprise lactic acidosis. In certain embodiments, the one or more adverse effects associated with administration of a drug comprise one or more complications associated with lactic acidosis.

[00101] For example, some subjects receiving metformin also suffer from heart failure. Metformin is known to induce lactic acidosis and in subjects with heart failure, metformin's lactic acidosis inducing properties can undesirably synergize with the lactic acidosis originating from heart failure. Subjects with heart failure also often have coexisting renal dysfunction, which is another aggravating factor for lactic acidosis. Administration of (-)-perhexiline counteracts the negative effects of metformin.

[00102] Certain embodiments of the present disclosure provide a method of reducing or reversing lactic acidosis or its effects in a subject associated with administration of a drug.

[00103] Certain embodiments of the present disclosure provide a method of reducing or reversing lactic acidosis or its effects in a subject associated with administration of a drug, the method comprising exposing to the subject an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00104] In certain embodiments, the drug comprises a biguanide drug. In certain embodiments, the drug comprises metformin and/or a pharmaceutically acceptable salt, prodrug or derivative thereof. Other drugs are as described herein.

[00105] Certain embodiments of the present disclosure provide a method of reducing or reversing lactic acidosis and/or undesired lactic acid production in a subject treated with metformin, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00106] In certain embodiments the administration of the (-)-perhexiline to the subject improves cellular redox state, reduces cellular lactic acid production, increases cellular oxidative glycolysis and/or increases cellular glycogenesis.

[00107] Certain embodiments of the present disclosure provide a method of preventing and/or treating a disease, condition or state associated with impaired cellular respiration and anaerobic metabolism of glucose in a subject in need thereof.

[00108] Certain embodiments of the present disclosure provide a method of preventing and/or treating a disease, condition or state associated with impaired cellular respiration and anaerobic metabolism of glucose in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00109] Certain embodiments of the present disclosure provide a method of improving the redox state of a cell.

[001 10] Certain embodiments of the present disclosure provide a method of improving the redox state of a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer. [001 1 1] Methods for exposing cells to agents are known in the art. In certain embodiments, the cell is exposed to (-)-perhexiline in vitro. In certain embodiments, the cell is exposed to (-)-perhexiline ex vivo. In certain embodiments, the cell is exposed to (-)-perhexiline in vivo. In certain embodiments, the cell is exposed to (-)-perhexiline in vitro and in vivo.

[001 12] Examples of in vivo exposure comprise various methods for the administration of (-)-perhexiline to a subject, such as a human or animal subject, and are as described herein.

[001 13] Examples of ex vivo exposure include exposure of cells taken from a subject to (-)-perhexiline in a liquid medium and/or exposure to a pre-drug that is metabolised to (-)-perhexiline in the cells and then re-introduced into the subject. Methods for exposing cells to agents are known in the art.

[001 14] Examples of in vitro exposure include exposure of the cell to (-)-perhexiline in a liquid medium and/or exposure to a pre-drug that is metabolised (-)-perhexiline in the cell. Methods for exposing cells to agents are known in the art.

[001 15] In certain embodiments, the cell is a cancer cell, including a primary cancer cell or a metastatic cancer cell. In certain embodiments, the cell is an endothelial cell, including a cardiac endothelial cell. In certain embodiments, the cell is a liver cell. In certain embodiments, the cell is a muscle cell, including a cardiac myocyte.

[001 16] Methods for determining the redox state of a cell in vitro, ex vivo or in vivo are known in the art.

[001 17] Certain embodiments of the present disclosure provide a method of reducing lactic acid production, increasing oxidative glycolysis and/or increasing glycogenesis in a cell.

[001 18] Certain embodiments of the present disclosure provide a method of reducing lactic acid production, increasing oxidative glycolysis and/or increasing glycogenesis in a cell, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer. [001 19] Methods for exposing cells to agents are as described herein. In certain embodiments, the cell is exposed to (-)-perhexiline in vitro. In certain embodiments, the cell is exposed to (-)-perhexiline ex vivo. In certain embodiments, the cell is exposed to (-)-perhexiline in vivo. In certain embodiments, the cell is exposed to (-)-perhexiline in vitro and in vivo.

[00120] Examples of in vivo exposure comprise various methods for the administration of (-)-perhexiline to a subject, such as a human or animal subject, and are as described herein.

[00121] Examples of ex vivo exposure include exposure of cells taken from a subject to (-)-perhexiline in a liquid medium and/or exposure to a pre-drug that is metabolised to (-)-perhexiline in the cells and then re-introduced into the subject. Methods for exposing cells to agents are known in the art.

[00122] Examples of in vitro exposure include exposure of the cell to (-)-in a liquid medium and exposure to a pre-drug that is metabolised (-)-perhexiline in the cell, and are as described herein.

[00123] In certain embodiments, the cell is a cancer cell, including a primary cancer cell or a metastatic cancer cell. In certain embodiments, the cell is an endothelial cell, including a cardiac endothelial cell. In certain embodiments, the cell is a liver cell. In certain embodiments, the cell is a muscle cell, including a cardiac myocyte.

[00124] Methods for determining the extent of lactic acid production, oxidative glycolysis and glycogenesis of a cell in vitro or in vivo are known in the art.

[00125] The term "perhexiline" refers to the chemical compound 2-(2,2-dicyclohexylethyl) piperidine and which has the following chemical structure:

[00126] Perhexiline exists in two enantiomeric forms about the chiral carbon atom ( * ), the (+)-enantiomer and the (-)-enantiomer. The enantiomer that rotates the polarized light in the clockwise direction is the (+)-enantiomer and the enantiomer that rotates the polarized light in the counterclockwise direction is the (-)-enantiomer.

[00127] The term "pharmaceutically acceptable salt" means a salt of (-)-perhexiline, which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals and generally without undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit/risk ratio, and generally water or oil-soluble or dispersible, and effective for its intended use.

[00128] The term "prodrug" denotes a compound that is a modification of the therapeutic agent, compound of interest (e.g., active pharmaceutical ingredient) and that is converted to the therapeutic agent or compound at the target site (for example, through enzymatic conversion). A prodrug is administered into a patient to provide, for example, enhanced bioavailability for, or reduced toxicity of, the therapeutic agent or compound itself.

[00129] Each of the terms "perhexiline," "(-)-perhexiline," and "(+)-perhexiline" may include a pharmaceutically acceptable salt thereof (for example, without limitation, the maleate salt, the hydrochloride salt or the lactate salt), a prodrug thereof, a chemical derivative, and/or a stereoisomeric derivative thereof.

[00130] The term "modified form of perhexiline" as used in reference to screening methods refers to a chemical, structural, isomeric or stereoisomeric derivative of perhexiline.

[00131] In certain embodiments, the perhexiline is substantially enantiopure, being in a form that comprises a single enantiomer substantially free of the other enantiomer.

[00132] In certain embodiments, the perhexiline comprises a single enantiomer that comprises greater than about 95% of the enantiomer. In certain embodiments, the perhexiline comprises a single enantiomer that comprises greater than about 96%, 97%, 98% or 99% of the enantiomer.

[00133] In certain embodiments, the perhexiline comprises a single enantiomer that comprises less than about 5% of the other enantiomer. In certain embodiments, the perhexiline comprises a single enantiomer that comprises less than about 4%, 3%, 2% or 1 % of the other enantiomer. [00134] The term "effective amount" as used herein refers to that amount of an agent (e.g., a perhexiline enantiomer) that is sufficient to produce the desired effect, such as prevention and/or treatment of a disorder. When administered to a subject in need thereof this is typically referred to as a "therapeutically effective amount". The effective amount will vary depending upon a number of factors, including for example the specific activity of the agent being used, the severity of the disease, condition or state in the subject, the age, physical condition, existence of other disease states, and nutritional status of the subject. The term "effective amount" also refers to the amount of a compound that is sufficient to elicit the biological or medical response of a cell, tissue, system, animal, or human that is being sought by a researcher, veterinarian, medical doctor, or clinician.

[00135] The concentration of (-)-perhexiline in a treated subject can be determined using a suitable method, for example, plasma or red blood cells using high pressure liquid chromatography or other measuring means. The effective amount can be determined by one of skill in the art for treating the disease, condition or state as described herein.

[00136] In certain embodiments, (-)-perhexiline is administered to the subject in an amount ranging from one of the following non-limiting ranges: 1 μg kg to 100 mg/kg; 1 μg kg to 10 mg/kg; 1 μg kg to 1 mg/kg; 1 μg/kg to 100 μg/kg; 1 μg/kg to ^g/kg; 10 μg/kg to 100 mg/kg; 10 μg/kg to 10 mg/kg; 10 μg/kg to 1 mg/kg; 10 μg/kg to 100 μg/kg; 100 μg/kg to 100 mg/kg; 100 μg/kg to 10 mg/kg; 100 μg/kg to 1 mg/kg; 1 mg/kg to 10 mg/kg; and 10 mg/kg to 100 mg/kg body weight, and all subranges therebetween.

[00137] In certain embodiments, (-)-perhexiline is administered to the subject in an amount to produce a plasma concentration of 2.4 mg/ml or less, 2.2 mg/ml or less, 2.0 mg/ml or less, 1.8 mg/ml or less, 1 .6 mg/ml or less, 1.4 mg/ml or less, 1.2 mg/ml or less, 1.0 mg/ml or less, 0.8 mg/ml or less, 0.6 mg/ml or less, 0.4 mg/ml or less, 0.2 mg/ml or less, 0.1 mg/ml or less, or 0.05 mg/ml or less. In certain embodiments, the (-)-enantiomer of perhexiline is administered to the subject in an amount to produce a plasma concentration of 2.4 mg/ml or greater, 2.2 mg/ml or greater, 2.0 mg/ml or greater, 1.8 mg/ml or greater, 1 .6 mg/ml or greater, 1.4 mg/ml or greater, 1 .2 mg/ml or greater, 1 .0 mg/ml or greater, 0.8 mg/ml or greater, 0.6 mg/ml or greater, 0.4 mg/ml or greater, 0.2 mg/ml or greater, 0.1 mg/ml or greater, or 0.05 mg/ml or greater.

[00138] In certain embodiments, (-)-perhexiline is administered to the subject in an amount to produce a plasma concentration from one of the following non-limiting ranges: 0.01-0.6 mg/L; 0.02-0.6 mg/L, 0.05-0.6 mg/L, 0.075-0.6 mg/L, 0.1 -0.6 mg/L, 0.125-0.6 mg/L, 0.15-0.6 mg/L, 0.2-0.6 mg/L, 0.3-0.6 mg/L, 0.4-0.6 mg/L, 0.5-0.6 mg/L, .01 -0.5 mg/L; 0.025- 0.5 mg/L, 0.05-0.5 mg/L, 0.075-0.5 mg/L, 0.1-0.5 mg/L, 0.125-0.5 mg/L, 0.15-0.5 mg/L, 0.2- 0.5 mg/L, 0.3-0.5 mg/L, 0.4-0.5 mg/L, 0.01 -0.4 mg/L; 0.025-0.4 mg/L, 0.05-0.4 mg/L, 0.075- 0.4 mg/L, 0.1 -0.4 mg/L, 0.125-0.4 mg/L, 0.15-0.4 mg/L, 0.2-0.4 mg/L, 0.3-0.4 mg/L, 0.01 -0.3 mg/L; 0.025-0.3 mg/L, 0.05-0.3 mg/L, 0.075-0.3 mg/L, 0.1 -0.3 mg/L, 0.125-0.3 mg/L, 0.15- 0.3 mg/L, 0.2-0.3 mg/L, 0.01 -0.2 mg/L; 0.025-0.2 mg/L, 0.05-0.2 mg/L, 0.075-0.2 mg/L, 0.1 - 0.2 mg/L, 0.125-0.2 mg/L, 0.15-0.2 mg/L, 0.01-0.1 mg/L; 0.025-0.1 mg/L, 0.05-0.1 mg/L, 0.075-0.1 mg/L, 0.01 -0.075 mg/L; 0.025-0.075 mg/L, 0.05-0.075 mg/L, 0.01-0.05 mg/L; 0.025-0.05 mg/L, or 0.01 -0.025 mg/L, and all subranges therebetween.

[00139] In certain embodiments, the amount of (-)-perhexiline administered to the subject produces a plasma concentration of less than 0.6 mg/L. In certain embodiments, the amount of (-)-perhexiline administered to the subject produces a plasma concentration in one of the following ranges: 0.05-0.30 mg/L, 0.05-0.60 mg/L, 0.05-0.90 mg/L, 0.15-1.20 mg/L, 0.15- 0.60 mg/L, 0.15-0.90 mg/L, and 0.15-1.20 mg/L and all subranges therebetween.

[00140] In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a loading dose of about 50 mg, about 100 mg, about 150 mg or about 200 mg. In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a loading dose of 50 mg or less, 100 mg or less, 150 mg or less, or 200 mg or less. In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a loading dose of 50 mg or greater, 100 mg or greater, 150 mg or greater, or 200 mg or greater.

[00141] In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a maintenance dose of about 50 mg, about 100 mg, about 150 mg or about 200 mg. In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a maintenance dose of 50 mg or less, 100 mg or less, 150 mg or less, or 200 mg or less. In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a maintenance dose of 50 mg or greater, 100 mg or greater, 150 mg or greater, or 200 mg or greater. The maintenance dose may for example be administered daily, every second day, twice a week, once a week or once a fortnight.

[00142] In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises a loading dose as described herein in conjunction with a maintenance dose as described herein. It will be appreciated that the loading dose may be provided over a suitable time period, for example 5-7 days, and the maintenance dose may also be provided over a suitable time period. In certain embodiments, the maintenance dose may be provided over a period of 1 month, 2 months, 3 months, 6 months, 1 year or indefinitely.

[00143] In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises 100-150 mg once daily for 5-7 days and 50 mg daily thereafter, or 50-100 mg once daily for 5-7 days and 50 mg daily thereafter. In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises 50-75 mg once a week or 25-50 mg once a week. In certain embodiments, the amount of (-)-perhexiline administered to the subject comprises 50 mg daily on a continuous basis, with no loading dose. 100-150 mg once daily for 5-7 days and 50 mg daily thereafter, or 50-100 mg once daily for 5-7 days and 50-100 mg or greater daily thereafter.

[00144] (-)-Perhexiline may be exposed to a cell, or administered to the subject, in a suitable form.

[00145] In this regard, the terms "administering" or "providing" includes administering an enantiomer of perhexiline, and/or administering a salt, prodrug or derivative of perhexiline, that will form an effective amount of the active agent within the body of the subject. The terms include routes of administration that are systemic (e.g., via injection such as intravenous injection, orally in a tablet, pill, capsule, or other dosage form useful for systemic administration of pharmaceuticals), and topical (e.g., creams, solutions, suppositories, sublingual and the like, including solutions such as mouthwashes, for topical oral administration). Methods of drug administration are generally known in the art.

[00146] (-)-Perhexiline may be administered alone or may be delivered in a mixture with other therapeutic agents and/or agents that enhance, stabilise or maintain the activity of the enantiomer of perhexiline.

[00147] In certain embodiments, the methods further comprise administering to the subject another active agent, such as one or more of a Ca 2+ channel blocker, a prostacyclin analogue, an endothelin receptor antagonist, and a PDE5 inhibitor, an anti-cancer agent, an anti-diabetic agent, and a biguanide drug.

[00148] In certain embodiments, an administration vehicle (e.g., pill, tablet, implant, injectable solution, etc.) contains both (-)-perhexiline and additional agent(s).

[00149] The methods of administration may also include combination therapy. In this regard, the subject is treated or given another drug or treatment modality in conjunction with (-)-perhexiline as described herein. This combination therapy can be sequential therapy where the subject is treated first with one agent and then the other agent, or the two or more treatment modalities are given simultaneously.

[00150] "Co-administering" or "co-administration" refers to the administration of two or more therapeutic or active agents together at one time. The two or more therapeutic or active agents can be co-formulated into a single dosage form or "combined dosage unit", or formulated separately and subsequently combined into a combined dosage unit, typically for intravenous administration or oral administration. Dosage units for other administration routes are contemplated.

[00151] When administered to a subject in need thereof, the effective dosage may vary depending upon the mode of administration, the condition, and severity thereof, as well as the various physical factors related to the subject being treated. As discussed herein, suitable daily doses range from about 1 μg kg to about 20 mg/kg. The daily dosages are expected to vary with route of administration, and the nature of the (-)-perhexiline administered.

[00152] In certain embodiments the methods comprise administering to the subject escalating doses of (-)-perhexiline and/or repeated doses.

[00153] In certain embodiments, (-)-perhexiline is administered orally. In certain embodiments, (-)-perhexiline is administered via injection, such as intravenous injection. In certain embodiments, (-)-perhexiline is administered parenterally. In certain embodiments, (-)-perhexiline is administered by direct introduction to the lungs, such as by aerosol administration, by nebulized administration, and by being instilled into the lung. In certain embodiments, (-)-perhexiline is administered by implant. In certain embodiments, (-)-perhexiline is administered by subcutaneous injection, intraarticularly, rectally, intranasally, intraocularly, vaginally, or transdermally. Other administration routes are contemplated.

[00154] Pharmaceutical compositions containing (-)-perhexiline described herein may be administered at once, or multiple times at intervals of time. It is understood that the precise dosage and duration of treatment may vary with the age, weight, and condition of the patient being treated, and may be determined empirically using known testing protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, specific dosage regimens should be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the formulations. [00155] In the case wherein a patient's condition does not improve, upon the physician's discretion the administration of the compounds may be administered chronically, that is, for an extended period of time, including throughout the duration of the patient's life in order to ameliorate or otherwise control or limit the symptoms of the patient's disorder. In the case wherein the patient's status does improve, upon the doctor's discretion the administration of the compounds may be given continuously or temporarily suspended for a certain length of time (i.e., a "drug holiday").

[00156] Once improvement of the patient's condition has occurred, a maintenance dose is administered if necessary. Subsequently, the dosage or the frequency of administration, or both, can be reduced, as a function of the symptoms, to a level at which the improved disease, disorder or condition is retained. Patients can, however, require intermittent treatment on a long-term basis upon any recurrence of symptoms.

[00157] "Intravenous administration" is the administration of substances directly into a vein. "Oral administration" is a route of administration where a substance is taken through the mouth, and includes buccal, sublabial and sublingual administration, as well as enteral administration and that through the respiratory tract, unless made through e.g. tubing so the medication is not in direct contact with any of the oral mucosa. Typical forms for the oral administration of therapeutic agents include the use of tablets or capsules.

[00158] The term "release controlling excipient" refers to an excipient whose primary function is to modify the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

[00159] The term "nonrelease controlling excipient" refers to an excipient whose primary function do not include modifying the duration or place of release of the active substance from a dosage form as compared with a conventional immediate release dosage form.

[00160] In certain embodiments, (-)-perhexiline is administered as an immediate release formulation. The term "immediate release formulation" is a formulation which is designed to quickly release a therapeutic or active agent in the body over a shortened period of time.

[00161] In certain embodiments, (-)-perhexiline is administered as a controlled release formulation, a modified release formulation, a sustained release formulation or an extended release formulation. [00162] In certain embodiments, (-)-perhexiline is administered as a sustained release formulation. The term "sustained release formulation" is a formulation which is designed to slowly release a therapeutic or active agent in the body over an extended period of time.

[00163] In certain embodiments, (-)-perhexiline is administered as an extended release formulation.

[00164] (-)-Perhexiline may be formulated into a controlled release formulation, a modified release formulation, a sustained release formulation or an extended release formulation by a suitable method. For example, modified release formulations and extended release formulations are as described generally in US Patent 8,173,708, US Patent 4,606,909 and US 4,769,027 (each of which are hereby incorporated by reference).

[00165] For example, the formulation may comprise a multiplicity of individually coated or microencapsulated units that are made available upon disintegration of the formulation (for example a pill or tablet) in the stomach of the subject. Each of the individually coated or microencapsulated units may contain cross-sectionally substantially homogenous cores containing particles of a sparingly soluble active substance, the cores being coated with a coating that is substantially resistant to gastric conditions but which is erodable under the conditions prevailing in the gastrointestinal tract.

[00166] Extended release formulations may also involve pills of pharmaceutically acceptable material (e.g., sugar/starch, salts, and waxes) coated with a water permeable polymeric matrix containing the enantiomer of perhexiline and next overcoated with a water- permeable film containing dispersed within it a water soluble particulate pore forming material.

[00167] Alternatively, (-)-perhexiline may be prepared in a formulation using a multilayered controlled release pharmaceutical dosage form. The dosage form contains a plurality of coated particles wherein each has multiple layers about a core containing (-)-perhexiline and whereby the core and at least one other layer of active is overcoated with a controlled release barrier layer, therefore providing at least two controlled releasing layers from the multilayered coated particle.

[00168] In certain embodiments, substantially enantiomerically pure (i.e., enantiopure) (-)-perhexiline (and/or a pharmaceutically acceptable salt, prodrug or derivative thereof) is used in a pharmaceutical composition or in the manufacture of a medicament. In certain embodiments, substantially enantiopure (-)-perhexiline (and/or a pharmaceutically acceptable salt, prodrug or derivative thereof) is used in a pharmaceutical composition and/or the preparation of a medicament for preventing and/or treating a disease, condition or state as described herein. In certain embodiments, substantially enantiopure (-)-perhexiline (and/or a pharmaceutically acceptable salt, prodrug or derivative thereof) is used in a pharmaceutical composition and/or the preparation of a medicament for preventing and/or treating a disease, condition or state associated with associated with reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[00169] Certain embodiments of the present disclosure provide use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a disease, condition or state associated with reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[00170] Certain embodiments of the present disclosure provide use of substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof in the manufacture of a medicament for preventing and/or treating a cancer, diabetes or chronic hypoxic pulmonary hypertension.

[00171] In certain embodiments, the (-)-perhexiline comprises about 95% or greater of the total perhexiline in the medicament or composition. In certain embodiments, the (-)-perhexiline comprises greater than about 96% or greater, about 97% or greater, about 98% or greater, or about 99% or greater of the total perhexiline in the medicament or composition, and all subranges therebetween.

[00172] In certain embodiments, the medicament or composition comprises less than about 5% of the other enantiomer. In certain embodiments, the medicament or composition comprises less than about 4%, 3%, 2% or 1 % of the other enantiomer, and all subranges therebetween.

[00173] In certain embodiments, the composition or medicament comprises 25 to 250 mg (-)-perhexiline, and all subranges therebetween. In certain embodiments, the composition or medicament comprises 25 mg (-)-perhexiline, 50 mg (-)-perhexiline, 75 mg (-)-perhexiline, 100 mg (-)-perhexiline, 125 mg (-)-perhexiline, 150 mg (-)-perhexiline, 175 mg (-)-perhexiline, 200 mg (-)-perhexiline, 225 mg (-)-perhexiline or 250 mg (-)-perhexiline, or an amount of (-)-perhexiline about the aforementioned amounts. In certain embodiments, the composition or medicament comprises 25 mg or less (-)-perhexiline, 50 mg or less (-)-perhexiline, 75 mg or less (-)-perhexiline, 100 mg or less (-)-perhexiline, 125 mg or less (-)-perhexiline, 150 mg or less (-)-perhexiline, 175 mg or less (-)-perhexiline, 200 mg or less (-)-perhexiline or , 225 mg or less (-)-perhexiline or 250 mg or less (-)-perhexiline.

[00174] In certain embodiments, the medicament or composition comprises an amount of (-)-perhexiline that when administered to a subject in need thereof once daily produces a plasma concentration in one of the following ranges: 0.05-0.30 mg/L, 0.05-0.60 mg/L, 0.05- 0.90 mg/L, 0.05-01.20 mg/L, 0.15-0.30 mg/L, 0.15-0.60 mg/L, 0.15-0.90 mg/L, 0.15-1.20 mg/L and all subranges therebetween. Other ranges are contemplated and are as described herein.

[00175] In certain embodiments, the (-)-perhexiline is provided with a pharmaceutically acceptable carrier suitable for administering a pharmaceutical composition to a subject in need thereof.

[00176] Carriers may be chosen based on the route of administration as described herein, the location of the target issue, the form of (-)-perhexiline being delivered, the time course of delivery of the drug, etc. The term "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," or "physiologically acceptable excipient" refers to a pharmaceutically-acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, excipient, solvent, or encapsulating material. Non-limiting examples include a solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type that is substantially inert pharmacologically. An example of a pharmaceutically acceptable carrier is physiological saline. Other physiologically acceptable carriers and their formulations are known in the art. Some examples of materials which can serve as pharmaceutically acceptable carriers include, sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; detergents such as TWEEN 80; buffering agents such as magnesium hydroxide and aluminium hydroxide; alginic acid; pyrogen-free water; isotonic saline; Ringer's solution; ethyl alcohol; and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulfate and magnesium stearate, as well as colouring agents, releasing agents, coating agents, sweetening, flavouring and perfuming agents, preservatives and antioxidants can also be present. Each a "pharmaceutically acceptable" material should be compatible with the other ingredients of a pharmaceutical formulation. It must also be suitable for use in contact with the tissue or organ of humans and animals without excessive toxicity, irritation, allergic response, immunogenecity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See, Remington: The Science and Practice of Pharmacy, 21 st Edition; Lippincott Williams & Wilkins: Philadelphia, PA, 2005; Handbook of Pharmaceutical Excipients, 5th Edition; Rowe et al, Eds., The Pharmaceutical Press and the American Pharmaceutical Association: 2005; and Handbook of Pharmaceutical Additives, 3rd Edition; Ash and Ash Eds., Gower Publishing Company: 2007; Pharmaceutical Preformulation and Formulation, Gibson Ed., CRC Press LLC: Boca Raton, FL, 2004), each of which are incorporated by reference in their entirety.

[00177] In certain embodiments, (-)-perhexiline may be administered or present in a pharmaceutical composition as a pharmaceutically acceptable salt, solvate or prodrug thereof. The term "pharmaceutically acceptable salt" refers to acid addition salts or metal complexes which are commonly used in the pharmaceutical industry. Metal complexes include zinc, iron, and the like. Suitable acids for use in the preparation of pharmaceutically acceptable salts include, but are not limited to, acetic acid, 2,2-dichloroacetic acid, acylated amino acids, adipic acid, alginic acid, ascorbic acid, L-aspartic acid, benzenesulfonic acid, benzoic acid, A- acetamidobenzoic acid, boric acid, (+)-camphoric acid, camphorsulfonic acid, (+)-(IS)- camphor-10-sulfonic acid, capric acid, caproic acid, caprylic acid, cinnamic acid, citric acid, cyclamic acid, cyclohexanesulfamic acid, dodecylsulfuric acid, ethane- 1 ,2- disulfonic acid, ethanesulfonic acid, 2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronic acid, L- glutamic acid, a-oxo-glutaric acid, glycolic acid, hippuric acid, hydrobromic acid, hydrochloric acid, hydroiodic acid, (+)-L-lactic acid, (±)-DL-lactic acid, lactobionic acid, lauric acid, maleic acid, (-)-L-malic acid, malonic acid, (±)-DL-mandelic acid, methanesulfonic acid, naphthalene-2 -sulfonic acid, naphthalene- 1 , 5 -disulfonic acid, 1 -hydroxy -2 -naphthoic acid, nicotinic acid, nitric acid, oleic acid, orotic acid, oxalic acid, palmitic acid, pamoic acid, perchloric acid, phosphoric acid, L-pyroglutamic acid, saccharic acid, salicylic acid, ^aminosalicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid, tannic acid, (+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid, trifluoroacetic acid, undecylenic acid, suberic acid, valeric acid and the like.

[00178] Suitable bases for use in the preparation of pharmaceutically acceptable salts, including, but not limited to, inorganic bases, such as magnesium hydroxide, calcium hydroxide, potassium hydroxide, zinc hydroxide, or sodium hydroxide; and organic bases, such as primary, secondary, tertiary, and quaternary, aliphatic and aromatic amines, including L-arginine, benethamine, benzathine, choline, deanol, diethanolamine, diethylamine, dimethylamine, dipropylamine, diisopropylamine, 2-(diethylamino)-ethanol, ethanolamine, ethylamine, ethylenediamine, isopropylamine, N-methyl-glucamine, hydrabamine, IH- imidazole, L-lysine, morpholine, 4-(2-hydroxyethyl)-morpholine, methylamine, piperidine, piperazine, propylamine, pyrrolidine, l-(2-hydroxyethyl)-pyrrolidine, pyridine, quinuclidine, quinoline, isoquinoline, secondary amines, triethanolamine, trimethylamine, triethylamine, N-methyl-D-glucamine, 2-amino-2-(hydroxymethyl)- 1 ,3 - propanediol, tromethamine, and the like.

[00179] (-)-Perhexiline may also be designed as a prodrug, which is a functional derivative of the compound as disclosed herein and is readily convertible into the parent compound in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent compound. They may, for instance, be bioavailable by oral administration whereas the parent compound is not. The prodrug may also have enhanced solubility in pharmaceutical compositions over the parent compound. A prodrug may be converted into the parent drug by various mechanisms, including enzymatic processes and metabolic hydrolysis. See Harper, Progress in Drug Research 1962, 4, 221 - 294; Morozowich et al. in "Design of Biopharmaceutical Properties through Prodrugs and Analogs," Roche Ed., APHA Acad. Pharm. Sci. 1977; "Bioreversible Carriers in Drug in Drug Design, Theory and Application," Roche Ed., APHA Acad. Pharm. Sci. 1987; "Design of Prodrugs," Bundgaard, Elsevier, 1985; Wang et al., Curr. Pharm. Design 1999, 5, 265- 287; Pauletti et al., Adv. Drug. Delivery Rev. 1997, 27, 235-256; Mizen et al., Pharm. Biotech. 1998, 1 1 , 345-365; Gaignault et al., Pract. Med. Chem. 1996, 671 -696; Asgharnejad in "Transport Processes in Pharmaceutical Systems," Amidon et al., Ed., Marcell Dekker, 185- 218, 2000; Balant et al., Eur. J. Drug Metab. Pharmacokinet. 1990, 15, 143-53; Balimane and Sinko, Adv. Drug Delivery Rev. 1999, 39, 183-209; Browne, Clin. Neuropharmacol. 1997, 20, 1 -12; Bundgaard, Arch. Pharm. Chem. 1979, 86, 1 -39; Bundgaard, Controlled Drug Delivery 1987, 17, 179-96; Bundgaard, Adv. Drug Delivery Rev.1992, 8, 1 -38; Fleisher et al, Adv. Drug Delivery Rev. 1996, 19, 1 15-130; Fleisher et al., Methods Enzymol. 1985, 1 12, 360-381 ; Farquhar et al., J. Pharm. Sci. 1983, 72, 324-325; Freeman et al., J. Chem. Soc, Chem. Commun. 1991 , 875-877; Friis and Bundgaard, Eur. J. Pharm. Sci. 1996, 4, 49- 59; Gangwar et al., Des. Biopharm. Prop. Prodrugs Analogs , 1977, 409-421 ; Nathwani and Wood, Drugs 1993, 45, 866-94; Sinhababu and Thakker, Adv. Drug Delivery Rev. 1996, 19, 241-273; Stella et al., Drugs 1985, 29, 455-73; Tan et al., Adv. Drug Delivery Rev. 1999, 39, 1 17-151 ; Taylor, A v. Drug Delivery Rev. 1996, 19, 131-148; Valentino and Borchardt, Drug Discovery Today 1997, 2, 148-155; Wiebe and Knaus, Adv. Drug Delivery Rev. 1999, 39, 63-80; Waller et al., Br. J. Clin. Pharmac. 1989, 28, 497-507.

[00180] In certain embodiments, the pharmaceutical compositions or medicament comprises other therapeutic agents and/or agents that enhance, stabilise or maintain the activity of the active. Examples of other agents are as described herein.

[00181] Oral formulations containing (-)-perhexiline as described herein may comprise any conventionally used oral forms, including tablets, capsules, buccal forms, troches, lozenges and oral liquids, suspensions or solutions. Capsules may contain mixtures of the active compound(s) with inert fillers and/or diluents such as the pharmaceutically acceptable starches (e.g. corn, potato or tapioca starch), sugars, artificial sweetening agents, powdered celluloses, such as crystalline and microcrystalline celluloses, flours, gelatins, gums, etc. Useful tablet formulations may be made by conventional compression, wet granulation or dry granulation methods and utilize pharmaceutically acceptable diluents, binding agents, lubricants, disintegrants, surface modifying agents (including surfactants), suspending or stabilizing agents, including magnesium stearate, stearic acid, talc, sodium lauryl sulfate, microcrystalline cellulose, carboxymethylcellulose calcium, polyvinylpyrrolidone, gelatin, alginic acid, acacia gum, xanthan gum, sodium citrate, complex silicates, calcium carbonate, glycine, dextrin, sucrose, sorbitol, dicalcium phosphate, calcium sulfate, lactose, kaolin, mannitol, sodium chloride, talc, dry starches and powdered sugar. Surface modifying agents include nonionic and anionic surface modifying agents. Representative examples of surface modifying agents include, but are not limited to, poloxamer 188, benzalkonium chloride, calcium stearate, cetostearl alcohol, cetomacrogol emulsifying wax, sorbitan esters, colloidol silicon dioxide, phosphates, sodium dodecylsulfate, magnesium aluminium silicate, and triethanolamine. Oral formulations may utilize standard delay or time-release formulations to alter the absorption of the enantiomer of perhexiline. The oral formulation may also consist of administering the active ingredient in water or a fruit juice, containing appropriate solubilizers or emulsifiers as needed.

[00182] In certain embodiments, an oral formulation of (-)-perhexiline may contain one or more of lactose, maize starch, sucrose and purified talc.

[00183] In certain embodiments, it may be desirable to administer (-)-perhexiline directly to the airways in the form of an aerosol. Formulations for the administration of aerosol forms are known in the art. [00184] In certain embodiments, (-)-perhexiline may also be administered parenterally (such as directly into the joint space) or intraperitoneally. For example, solutions or suspensions of these compounds in a non-ionised form or as a pharmacologically acceptable salt can be prepared in water suitably mixed with a surfactant such as hydroxy- propylcellulose. Dispersions can also be prepared in glycerol, liquid polyethylene glycols and mixtures thereof in oils.

[00185] In certain embodiments, (-)-perhexiline may also be administered by injection. Pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils.

[00186] In certain embodiments, (-)-perhexiline may also be administered intravenously. Compositions containing (-)-perhexiline described herein suitable for intravenous administration may be formulated by a skilled person.

[00187] In certain embodiments, (-)-perhexiline may also be administered transdermally. Transdermal administrations are understood to include all administrations across the surface of the body and the inner linings of bodily passages including epithelial and mucosal tissues. Such administrations may be carried out using the modulator as described herein, or pharmaceutically acceptable salts thereof, in lotions, creams, foams, patches, suspensions, solutions, and suppositories (rectal and vaginal).

[00188] Transdermal administration may also be accomplished through the use of a transdermal patch containing the active compound and a carrier that is inert to the active compound, is non-toxic to the skin, and allows delivery of the agent for systemic absorption into the blood stream via the skin. The carrier may take any number of forms such as creams and ointments, pastes, gels, and occlusive devices. The creams and ointments may be viscous liquid or semisolid emulsions of either the oil-in-water or water-in-oil type. Pastes comprised of absorptive powders dispersed in paraffin containing the active ingredient may also be suitable. A variety of occlusive devices may be used to release the active ingredient into the blood stream such as a semi-permeable membrane covering a reservoir containing the active ingredient with or without a carrier, or a matrix containing the active ingredient.

[00189] In certain embodiments, (-)-perhexiline may also be administered by way of a suppository. Suppository formulations may be made from traditional materials, including cocoa butter, with or without the addition of waxes to alter the suppository's melting point, and glycerin. Water soluble suppository bases, such as polyethylene glycols of various molecular weights, may also be used.

[00190] Additional numerous various excipients, dosage forms, dispersing agents and the like that are suitable for use in connection with the administration of the enantiomer of perhexiline and/or the formulation into medicaments or pharmaceutical compositions. See Remington's Pharmaceutical Sciences, supra.

[00191] Certain embodiments of the present disclosure provide a combination product comprising (-)-perhexiline, and/or one or more active agents and/or instructions for administering the enantiomer of perhexiline to a subject in need thereof to prevent and/or treat one or more of the diseases, conditions or states as described herein.

[00192] Certain embodiments of the present disclosure provide a kit or article of manufacture for performing the methods as described herein is provided. The kit may comprise one or more modulators, agents, reagents, components, compositions, formulations, products and instructions as described herein. The kit or article of manufacture can include a container (such as a bottle) with a desired amount of (-)-perhexiline (or pharmaceutical composition thereof) as disclosed herein. Further, such a kit or article of manufacture can further include instructions for use. The instructions can be attached to the container, or can be included in a package (such as a box or a plastic or foil bag) holding the container.

[00193] Certain embodiments of the present disclosure provide a kit for preventing and/or treating a disease, condition or state associated with associated with reduced cellular redox state and/or undesired lactic acid production or lactate utilization, the kit comprising (-)-perhexiline and optionally comprising one or more of instructions for administering (-)-perhexiline to a subject in need thereof.

[00194] Certain embodiments of the present disclosure provide a combination product comprising substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof and another active agent.

[00195] Certain embodiments of the present disclosure provide a combination product comprising the following components: (i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) one or more of a Ca 2+ channel blocker, a prostacyclin analogue, an endothelin receptor antagonist, and a PDE5 inhibitor;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat chronic hypoxic pulmonary hypertension in a subject.

[00196] Certain embodiments of the present disclosure comprise a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) an anti-cancer agent;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat cancer in a subject.

[00197] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) an anti-diabetic agent;

wherein the components are provided in a form for separate or co-administration to prevent and/or treat diabetes in a subject.

[00198] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) a biguanide drug;

wherein the components are provided in a form for separate or co-administration to a subject.

[00199] Certain embodiments of the present disclosure provide a combination product comprising the following components:

(i) substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof; and

(ii) metformin; wherein the components are provided in a form for separate or co-administration to a subject.

[00200] Certain embodiments of the present disclosure provide a pharmaceutical composition and one or more active agents as described herein. In certain embodiments, the active agent comprises one or more of a Ca 2+ channel blocker, a prostacyclin analogue, an endothelin receptor antagonist, and a PDE5 inhibitor, an anti-cancer agent, an anti-diabetic agent, and a biguanide drug.

[00201] Certain embodiments of the present disclosure provide for therapies combined with the use of (-)-perhexiline. For example, suitable anti-cancer agents that may be used with (-)-perhexiline, as described herein, (i.e., for preventing or treating diseases, components, features, conditions or states are associated with, caused by, manifesting, or resulting in, a reduced cellular redox state, hypoxia, an undesired lactic acid production or lactate utilization, and/or lactic acidosis), include, but are not limited to, chemotherapeutic agents and radiation. Suitable chemotherapeutic agents may include, but are not limited to, members selected from the group consisting of methotrexate, vincristine, adriamycin, cisplatin, taxol, paclitaxel, non-sugar containing chloroethylnitrosoureas, 5-fluorouracil, mitomycin C, bleomycin, doxorubicin, dacarbazine, taxol, fragyline, Meglamine GLA, valrubicin, carmustaine and poliferposan, MMI270, BAY 12-9566, RAS famesyl transferase inhibitor, famesyl transferase inhibitor, MMP, dacarbazine, LY294002, PX866, MTA LY231514, LY264618/Lometexol, Glamolec, CI-994, TNP-470, Hycamtin/Topotecan, PKC412, Valspodar/PSC833, Novantrone/Mitroxantrone, Metaret/Suramin, Batimastat, E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3433, lncelNX-710, VX-853, ZD0101 , IS1641 , ODN 698, TA 2516/Marmistat, BB2516/Marmistat, CDP 845, D2163, PD183805, DX8951f, Lemonal DP 2202, FK 317, Picibanil/OK-432, AD 32/Valrubicin, Metastron/strontium derivative, Temodal/Temozolomide, Evacet/liposomal doxorubicin, Yewtaxan/Paclitaxel, Taxol/Paclitaxel, Xeload/Capecitabine, Furtulon/Doxifluridine, Cyclopax/oral paclitaxel, Oral Taxoid, SPU-077/Cisplatin, HMR 1275/Flavopiridol, CP-358 (774)/EGFR, CP-609 (754)/RAS oncogene inhibitor, BMS-182751/oral platinum, UFT(Tegafur/Uracil), Ergamisol/Levamisole, Eniluracil/776C85/5FU enhancer, Campto/Levamisole, Camptosar/lrinotecan, Tumodex/Ralitrexed, Leustatin/Cladribine, Paxex/Paclitaxel, Doxil/liposomal doxorubicin, Caelyx liposomal doxorubicin, Fludara/Fludarabine, Pharmarubicin/Epirubicin, DepoCyt, ZD1839, LU 79553/Bis- Naphtalimide, LU 103793/Dolastain, Caetyx liposomal doxorubicin, Gemzar/Gemcitabine, ZD 0473/Anormed, YM 1 16, Iodine seeds, CDK4 and CDK2 inhibitors, PARD inhibitors, D4809/Dexifosamide, Ifes/Mesnex/lfosamide, Vumon/Teniposide, Paraplatin/Carboplatin, Plantinol/cisplatin, Vepeside/Etoposide, ZD 9331 , Taxotere/Docetaxel, prodrug of guanine arabinoside, Taxane Analog, nitrosoureas, alkylating agents such as melphelan and cyclophosphamide, Aminoglutethimide, Asparaginase, Busulfan, Carboplatin, Chlorombucil, Cytarabine HCI, Dactinomycin, Daunorubicin HCI, Estramustine phosphate sodium, Etoposide (VP16-213), Floxuridine, Fluorouracil (5-FU), Flutamide, Hydroxyurea (hydroxycarbamide), Ifosfamide, Interferon Alfa-2a, Alfa-2b, Leuprolide acetate (LHRH- releasing factor analogue), Lomustine (CCNU), Mechlorethamine HCI (nitrogen mustard), Mercaptopurine, Mesna, Mitotane), Mitoxantrone HCI, Octreotide, Plicamycin, Procarbazine HCI, Streptozocin, Tamoxifen citrate, Thioguanine, Thiotepa, Vinblastine sulfate, Amsacrine (m-AMSA), Azacitidine, Erthropoietin, Hexamethylmelamine (HMM), Interleukin 2, Mitoguazone (methyl-GAG; methyl glyoxal bis-guanylhydrazone; MGBG), Pentostatin (2'deoxycoformycin), Semustine (methyl-CCNU), Teniposide (VM-26), Vindesine sulfate, and the like, and combinations or mixtures thereof.

[00202] Certain embodiments of the present disclosure provide the co-administration of anti-diabetic agents with (-)-perhexiline. Suitable anti-diabetic agents that may be used with the (-)-perhexiline, as described herein, include, without limitation, biguanides (e.g., metformin or phenformin), glucosidase inhibitors (e.g., acarbose or miglitol), insulins (including insulin secretagogues or insulin sensitizers, regular-acting insulin, short-acting insulin, intermediate-acting insulin, long-acting insulin, inhaled insulin, insulin analogues, and the like), meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, gliclazide, chlorpropamide and glipizide), biguanide/glyburide combinations (e.g., Glucovance®), thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone), PPAR- alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dual agonists, glycogen phosphorylase inhibitors, inhibitors of fatty acid binding protein (aP2), glucagon-like peptide- 1 (GLP-1 ) or other agonists of the GLP-1 receptor, SGLT2 inhibitors and other dipeptidyl peptidase IV (DPP4) inhibitors, tolazamide, tolbutamide, isaglitazone (known as MCC-555), 2-[2-[(2R)-4-hexyl-3,4-dihydro-3-oxo-2H-1 ,4-benzoxazin-2-yl]ethoxy]-benzene acetic acid, GW2570, targretin, 9-cis-retinoic acid, ascarbose, miglitol, L-783281 , TE-1741 1 , T-1095, BAY-279955, pramlintide, phlorizen, acetohexamide, buformin, glibornuride, glyhexamide, glymidine, linogliride, palmoxirate, zopolrestat, etoformin, gliclazide, glypinamide, and the like, and combinations or mixtures thereof. [00203] Certain embodiments of the present disclosure provide a pharmaceutical composition comprising an effective amount of a biguanide drug and substantially enantiopure (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof.

[00204] Certain embodiments of the present disclosure provide methods for screening for new therapeutic agents.

[00205] In certain embodiments, the new therapeutic agents are candidate agents for preventing and/or treating a disease, condition or state as described herein.

[00206] Certain embodiments of the present disclosure provide a method for screening for an agent for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization, the method comprising:

selecting a modified form of (-)-perhexiline; and

identifying the modified form of (-)-perhexiline as an agent for preventing and/or treating a disease, condition or state associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization.

[00207] In certain embodiments, the method of screening comprises determining the ability of the modified form of (-)-perhexiline to activate pyruvate dehydrogenase and/or inhibit pyruvate dehydrogenase kinase. Methods for determining the ability of an agent to activate pyruvate dehydrogenase and inhibit pyruvate dehydrogenase kinase are known in the art.

[00208] In certain embodiments, the methods for screening comprise administering the candidate agent to an animal or human subject and testing the effect of the candidate agent. In certain embodiments, the methods for screening comprise administering the candidate agent to an animal or human subject and testing the effect of the candidate agent as an agent for one or more of the following: improves cellular redox state, reduces cellular lactic acid production, increases cellular oxidative glycolysis and increases cellular glycogenesis.

[00209] In certain embodiments of the methods as described herein, the (-)-perhexiline provides an improved safety profile in all subjects, such as for example in subjects with reduced CYP2D6 activity and/or with proficient CYP2D6 activity. In certain embodiments, the (-)-perhexiline provides an improved safety profile in subjects with reduced CYP2D6 activity and/or in subjects with proficient CYP2D6 activity. The accession number for human CYP2D6 Protein is Genbank CAG30316.

[00210] In certain embodiments, of the methods as described herein, the subject "in need thereof" has a reduced ability to metabolise perhexiline. In certain embodiments, the subject has reduced CYP2D6 activity. In certain embodiments, the use of (-)-perhexiline provides an improved safety profile in subjects with reduced CYP2D6 activity.

[0021 1] In certain embodiments the method for treating diabetes comprises a subject diagnosed as having diabetes and chronic renal failure is given a therapeutically-effective amount of (-)-perhexiline in an amount of from about 25 mg to 500 mg per day, including all sub-ranges therebetween.

[00212] In certain embodiments of the disclosure provides for a method for treating diabetes that comprises co-administering perhexiline and a biguanide drug such as metformin to a subject with diabetes and renal failure.

[00213] In certain embodiments, the method for treating diabetes in a subject comprises providing the subject the having diabetes or at least one component, feature, condition or state thereof and serum creatinine > 1.4 mg/dL, and administering to the subject a therapeutically-effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and including all sub-ranges therebetween.

[00214] In certain embodiments the method for treating diabetes in a subject having symptoms of diabetes and having serum creatinine >1.4 mg/dL, comprises co-administering to a subject a therapeutically-effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, including all subranges therebetween, and a biguanide drug such as metformin.

[00215] In certain embodiments, the disclosure provides a method for preventing and/or treating diseases, components, features, conditions or states associated with, caused by, manifesting, or resulting in, hypoxia and/or lactic acidosis.

[00216] In certain embodiments, a method is provided for treating a patient with VHL disease and/or tumors associated with VHL disease comprising administering (-)-perhexiline to a patient in need thereof. [00217] In certain embodiments of the disclosure, a method for treating a patient with clear cell renal cell carcinoma is provided, comprising administering to a patient in need thereof an effective amount of (-)-perhexiline and at least one of a VEGF inhibitor (such as bevacizumab (Avastin®), Ranibizumab and the like) or a carbonic anhydrase IX inhibitor, or combinations thereof.

[00218] In certain embodiments of the disclosure, a method for treating cancer is provided that comprises, (a) selecting a patient having a cancer that may be responsive to at least one EGFR inhibitor; and (b) administering to the patient a therapeutically effective regimen comprising (i) at least one EGFR inhibitor and (ii) (-)-perhexiline; wherein the EGFR inhibitor and (-)-perhexiline are administered together or sequentially.

[00219] Diseases, conditions or states associated with a reduced cellular redox state and/or undesired lactic acid production or lactate utilization are as described herein.

[00220] Treatment with (-)-perhexiline may be for a defined intervention period (for example 8 weeks) or be maintained indefinitely. Serum and/or plasma (-)-perhexiline levels may be determined at various intervals and any adverse effects monitored. The onset of hepatoxicity, peripheral neuropathy may be monitored. Dose or frequency adjustments can be made based on the serum concentrations, clinical symptoms and any adverse effects.

[00221] Certain embodiments of the present disclosure provide a method of reducing lactic acidosis and/or undesired lactic acid production in a subject treated with a biguanide drug, the method comprising administering to the subject an effective amount of the (-)- enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00222] Certain embodiments of the present disclosure provide a method of increasing the redox state of a cell, the method comprising exposing the cell to an effective amount of (- )-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00223] In certain embodiments, the methods as described herein further comprise administering to the subject an effective amount of (-)-perhexiline in an amount of from about 1 mg to about 25 mg per day, and all subranges therebetween. In certain embodiments, the methods as described herein further comprise administering to the subject an effective amount of (-)-perhexiline in an amount of from about 1 mg to about 25 mg per day, and all subranges therebetween, wherein the subject is a poor metabolizer of (-)-perhexiline.

[00224] In certain embodiments, the methods as described herein further comprise administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween. In certain embodiments, the methods as described herein further comprise administering to the subject an effective amount of (-)-perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween, wherein the subject is an extensive metabolizer of (-)-perhexiline.

[00225] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof, and

administering to the subject an effective amount of (-) perhexiline in an amount of from about 1 mg to about 25 mg per day, and all sub-ranges therebetween, wherein the subject is a poor metabolizer of (-)-perhexiline.

[00226] In certain embodiments, the method further comprises administering to the subject an effective amount of a biguanide drug.

[00227] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof; and

administering to the subject an effective amount of (-) perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween, wherein the subject is an extensive metabolizer of (-)-perhexiline.

[00228] In certain embodiments, the method further comprises administering to the subject a therapeutically-effective amount of a biguanide drug, such as metformin.

[00229] Certain embodiments of the present disclosure provide a method for reducing the secretion of glucagon from a pancreatic a-cell, comprising contacting the a-cell with an effective amount of (-)-perhexiline to suppress the conduction of sodium ions through sodium channels.

[00230] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject in need thereof, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof, and chronic renal failure; and

administering to said subject an effective amount of (-) perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween.

[00231] In certain embodiments, the method further comprises administering to the subject an effective amount of a biguanide drug, such as metformin.

[00232] Certain embodiments of the present disclosure provide a method for treating diabetes in a subject in need thereof, comprising:

providing the subject having diabetes or at least one component, feature, condition or state thereof and serum creatinine > 1.4 mg/dL; and

administering to the subject an effective amount of (-) perhexiline in an amount of from about 25 mg per to about 500 mg per day, and all subranges therebetween.

[00233] In certain embodiments, the method further comprised administering to the subject an effective amount of a biguanide drug, such as metformin.

[00234] Certain embodiments of the present disclosure provide a method for treating a subject with VHL disease and/or tumors associated with VHL disease, comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+) enantiomer.

[00235] Certain embodiments of the present disclosure provide a method for treating a subject with clear cell renal cell carcinoma, comprising administering to the subject an effective amount of (-) perhexiline and at least one of a VEGF inhibitor (such as bevacizumab (Avastin®), Ranibizumab and the like) or a carbonic anhydrase IX inhibitor, or combinations thereof. [00236] Certain embodiments of the present disclosure provide a method for treating cancer comprising:

(a) selecting a subject having a cancer that may be responsive to at least one EGFR inhibitor;

(b) administering to the patient a therapeutically effective regimen comprising (i) at least one EGFR inhibitor and (ii) (-)-perhexiline;

wherein the EGFR inhibitor and (-)-perhexiline are administered together or sequentially.

[00237] Certain embodiments of the present disclosure provide a method of reducing cancer cell invasion and/or metastasis in a subject in need thereof.

[00238] Certain embodiments of the present disclosure provide a method of reducing cancer cell invasion and/or metastasis in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00239] Certain embodiments of the present disclosure provide a method of preventing and/or treating metastatic cancer in a subject in need thereof.

[00240] Certain embodiments of the present disclosure provide a method of preventing and/or treating metastatic cancer in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00241] Certain embodiments of the present disclosure provide a method for reducing metastasis of a cancer in a subject in need thereof.

[00242] Certain embodiments of the present disclosure provide a method for reducing metastasis of a cancer in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00243] Certain embodiments of the present disclosure provide a method for reducing growth of a metastatic cancer in a subject in need thereof. [00244] Certain embodiments of the present disclosure provide a method for reducing growth of a metastatic cancer in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00245] Certain embodiments of the present disclosure provide a method for reducing metastasis of a cancer in a subject in need thereof.

[00246] Certain embodiments of the present disclosure provide a method for reducing metastasis of a cancer in a subject, the method comprising administering to the subject an effective amount of the (-)-enantiomer of perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00247] Certain embodiments of the present disclosure provide a method of inhibiting cancer cell proliferation and/or promoting cancer cell apoptosis, the method comprising exposing the cell to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00248] Certain embodiments of the present disclosure provide a method of inhibiting cancer cell proliferation and/or promoting cancer cell apoptosis in a subject in need thereof.

[00249] Certain embodiments of the present disclosure provide a method of inhibiting cancer cell proliferation and/or promoting cancer cell apoptosis in a subject, the method comprising administering the subject to an effective amount of (-)-perhexiline and/or a pharmaceutically acceptable salt, prodrug or derivative thereof, substantially free of the (+)-enantiomer.

[00250] Certain embodiments of the present disclosure provide a method for preventing and/or treating diseases, components, features, conditions or states associated with, caused by, manifesting, or resulting in, hypoxia and/or lactic acidosis, as substantially described in the specification, figures, tables, and/or claims.

[00251] Certain exemplary embodiments are illustrated by some of the following examples. It is to be understood that the following description is for the purpose of describing particular embodiments only and is not intended to be limiting with respect to the above description or the claims. EXAMPLE 1 - Enantioselectivity of Perhexiline on Hepatic Glucose and Fatty Acid Utilization

[00252] We investigated the effects of the (+) and (-) enantiomers of perhexiline on hepatic glucose and fatty acid utilisation.

[00253] Adult female Dark Agouti (DA) rats (n=4 in each group) were administered 200 mg/kg daily of vehicle, racemic-, (+) or (-)-perhexiline maleate for a period of 2 months. The perhexiline maleate compound was administered mixed with peanut paste and coated onto standard rat chow. On day 56 of dosing, animals were anesthetised and blood was collected via a cardiac puncture in order to determine the concentrations of perhexiline enantiomers. Animals were then euthanized and hepatic, cardiac and neuronal tissues were harvested in order to determine perhexiline enantiomer and metabolite tissue concentrations and morphological changes. Tissues were cut in half and either immediately snap frozen in liquid nitrogen or placed into fixative solution for electron microscopy analysis.

[00254] Tissue was dissected into cubes of approximately 0.5 mm in each dimension and was fixed for one hour in electron microscopy (EM) fixative (4% formaldehyde and 1.5% glutaraldehyde in sodium cacodylate buffer, pH 7.2). The fixed tissue was post-fixed in 2% osmium tetroxide in sodium cacodylate buffer, en bloc stained with 2% uranyl acetate and dehydrated through 70%, 90% and 100% ethanol. Then, the tissue was processed through 1 ,2-epoxypropane, a 50/50 mixture of 1 ,2-epoxypropane and Procure 812 resin (Electron Microscopy Sciences, Fort Washington, USA) and two changes of 100% resin. Tissue and resin were transferred to Beem capsules and placed in an oven overnight at 90 °C. Survey sections of tissue blocks were cut with glass knives and stained with Toluidine Blue. Thin sections were cut at approximately 100 nm thickness on a Porter-Blum ultramicrotome (Sorvall, Newtown, USA) using a diamond knife (Micro Star Technologies, Huntsville, USA). Thin sections were stained with Reynolds' lead citrate and examined in a Hitachi H-600 transmission electron microscope (Tokyo, Japan 1983). Glycogen and lipids were identified and total content was measured as a percentage of the field of view.

[00255] Figure 1 shows histological assessment of mean (sd) hepatic lipid and glycogen content (% field area) in DA rats (n=4) treated with vehicle (Cont), racemic (Rac), (+)- or (-)-perhexiline for 8 weeks ( * p<0.05 vs Cont).

[00256] The data presented in Figure 1 shows that in Dark Agouti (DA) rats, (-)-perhexiline (at plasma concentrations of 0.22-0.39 mg/L) significantly increased hepatic glycogen but had no effect on lipids, whilst (+)-perhexiline (at plasma concentrations of 0.52- 0.80 mg/L) significantly increased hepatic lipids and also appeared to decrease glycogen (Fig. 1 ).

[00257] The data demonstrates significant enantioselectivity with respect to perhexiline's in vivo effects on hepatic glucose and fatty acid utilisation.

[00258] Based on these observations, it can be inferred that (-)-perhexiline has advantageous therapeutic properties to treat or to prevent pathological conditions where cellular redox balance is shifted toward the reduced state (i.e., the ratio of NAD+/NADH is low) and /or producing excess lactic acid. The increase in hepatic glycogen content indicates that (-)-perhexiline does not inhibit the glycogenesis part of the Cori cycle (unlike drugs such as metformin for example, which inhibits the Cori cycle and can produce toxic lactic acidosis), (-)-perhexiline promotes glycogenesis.

EXAMPLE 2 - Activation of Pyruvate Dehydrogenase (PDH)

[00259] DA rats were treated for 2 weeks with vehicle or 200 mg/kg/day of racemic, (+)- or (-)-perhexiline maleate, on day 15 myocardial necrosis was induced by i.p. injection of 50 mg/kg isoprenaline (HCI salt), with a second group of controls receiving an i.p. injection of saline (n=5-8). Total and phosphorylated pyruvate dehydrogenase in heart tissue was measured by Western blots.

[00260] The results are shown in Figure 2.

[00261] (-)-Perhexiline did not affect total PDH expression (Figure 2A), but was an extremely potent inhibitor of PDH deactivation (measured as phosphorylated PDH) in this model (Figure 1 B). Significantly, it appears to be more potent than (+)-perhexiline.

[00262] By activating PDH (-)-perhexiline decreases production of lactic acid and promotes oxidative glycolysis through the Krebs cycle. Accordingly, (-)-perhexiline decreases lactic acid through two different mechanisms: inhibits production by activating PDH and increases elimination through promoting glycogenesis. Accordingly, (-)-perhexiline prevents and/or treats diseases associated with hypoxia and/or lactic acid production (lactic acidosis). EXAMPLE 3 - Effect of (-)-Perhexiline on Lactate Production under Hypoxic Conditions

[00263] Materials & Methods. [00264] (i) Viability

[00265] Viability was measured using Alamai Blue reagent (Invitrogen, Cat# 156397SA). MCF-7 and fibroblast cells were incubated with vehicle or (+)- or (-)- perhexiline at a concentration range of 0.5 - 10 μιη over a 24 hour period. Following the incubation period, media was aspirated and discarded . The cells were then incubated with the Alamai Blue reagent (stock solution was diluted 1 in 10 with phosphate saline buffer) for 1 hour at 37°C. Absorbance was measured at 570 nm, using 600 nm as a reference wavelength.

[00266] (ii) Lactate

[00267] Lactate concentrations in the incubation medium were measured using a Lactate Colorimetric Assay Kit (Abeam, Cat# 65331 ) where lactate is oxidized by lactate dehydrogenase to generate a product which interacts with a probe to produce a color. MCF- 7 and fibroblast cells (seeded at 25,00 cells/well in a 96-well plate) were incubated with vehicle or (-)-perhexiline at a concentration of 1 μιη, over a period of 24 hours in normoxic conditions (95% oxygen and 5% carbon dioxide), or 20 hours normoxic conditions followed by 4 hours hypoxic (94% nitrogen, 1 % oxygen and 5% carbon dioxide) conditions, after which media was collected and stored at -80°C ready for lactate determination. In brief, a standard curve was generated by diluting a stock solution of L(+)-Lactate Standard, ranging from 20 μιη to 100 μιη Lactate with Lactate Assay buffer. Samples were prepared by diluting 1 μΙ of crude media to 49 μΙ of Lactate Assay buffer in a 96-well plate in duplicates. 50 μΙ of Reaction Mix, consisting of 46 μΙ Lactate Assay buffer, 2 μΙ Lactate Substrate Mix and 2 μΙ Lactate Enzyme Mix was added into each well containing the Lactate Standard or test samples and mixed well. The plate was then incubated for 30 minutes at room temperature and Absorbance is measured at 595 nm in a microplate reader (FLUOstar Optima, BMG Labtech). Background was corrected by subtracting the value derived from the zero lactate control from all standard readings and the value obtained from the correspondent cell culture media from the sample readings. Lactate concentration was then calculated for each sample by dividing the lactic acid amount (nmol) of the sample obtained from the standard curve by the sample volume (μΙ) added into each well. [00268] Results/Discussion [00269] (i) Viability

[00270] (+)- or (-)- perhexiline at concentrations up to 1 μΜ have practically no effect on the viability of either MCF-7 or fibroblast cultured under normoxic conditions for up to 24 hours.

[00271] Interestingly, MCF-7 cells were more sensitive to toxic effects of perhexiline (both enantiomers) than fibroblasts.

[00272] When the cells were cultured with perhexiline for 20 hours under normoxic conditions and then exposed to hypoxia for a further 4 hours there was no loss of viability in MCF-7 cells but a significant drop in fibroblast viability. Again (+)- or (-)- perhexiline concentrations up to 1 μΜ had no effect on cell viability and under hypoxic conditions both cell types appeared similarly sensitive to the toxic effects of perhexiline.

[00273] (ii) Lactate

[00274] Figure 3 shows measured lactate production over 24 hours in cells exposed to 0 or 1 μΜ (-)-perhexiline under normoxic or hypoxic conditions (as above).

[00275] In both cell types, hypoxia increases lactate production and incubation with (-)-perhexiline prevent the increase in lactate production, lowering lactate concentrations to levels similar to or lower than those of normoxic controls.

EXAMPLE 4 - Perhexiline enhances the utilisation (oxidation) of glucose

[00276] Materials and methods:

[00277] Cells were cultured with (-)-perhexiline (1 μΜ) for 24 h. Analysis of C0 2 gas production was carried out prior to and 24 hours after addition of perhexiline.

[00278] For each C0 2 analysis, cell culture flasks were fitted with an air tight gas sampling lid and gas content is allowed to equlibrate for 20 minutes prior to collection of the baseline gas sample. The cell media containing unlabelled glucose were then removed under sterile conditions and replaced with medium containing 2 mM of 13 C-glucose, flasks were then incubated as per normal culture conditions, and gas samples were then collected from flask headspace every 20-30 minutes for 1.5 hours. [00279] Gas samples were then analysed via isotope ratio mass spectrometry, which provides the ratio of 12 C0 2 : 13 C0 2 . Data were then represented as A 13 C0 2 , i.e., the change in 13 C0 2 signal from baseline.

[00280] Results / Conclusion

[00281] (i) C0 2

[00282] The 13 C0 2 area under the curve is shown in Figure 4. Glucose oxidation to C0 2 was assessed using 13 C-glucose under normoxic culture conditions. Compared to pre- perhexiline, incubations for 24 hours with 1 μΜ (-)-perhexiline increased glucose oxidation in both cell types by approximately 50%

[00283] (ii) Lactate/C0 2

[00284] As shown in Figure 5, when lactate production under similar incubation conditions was normalised for the respective 13 C0 2 production it is clear that, under normoxic conditions, (-)- perhexiline decreased the relative flux of glucose to lactate production versus oxidation to C0 2 in both cell types.

[00285] Conclusion

[00286] Consistent with the previously demonstrated activation of PDH, (-)-perhexiline at non-toxic concentrations enhances the utilisation (oxidation) of glucose (measured as C0 2 production).

[00287] The enhanced oxidative utilisation of glucose results in decreased lactate synthesis. This effect is clearly evident under hypoxic conditions where (-)-perhexiline attenuates anaerobic glycolysis and reduces lactate production. Thus (-)-perhexiline may (1 ) reduce the risk of lactic acidosis under hypoxic conditions or other circumstances resulting in decreased PDH activity and (2) may reduce aerobic lactate production, the primary energetic source in cancer cells, which may inhibit cancer cell growth and/or metastasis.

EXAMPLE 5 - Viability of normal and transformed cells in the presence of perhexiline

[00288] Fibroblasts, and osteosarcoma cell lines (BTK-143, human; KHOS, human; and MSK, rat) were all grown in DMEM supplemented with 2 mM (final concentration) of L- glutamine, 1 % penicillin and streptomycin and 10% fetal calf serum (FCS). BTK-143, MSK and KHOS cells were seeded at 10,000 cells per well and fibroblasts were seeded at 7,000 cells per well, in 96 well plates and incubated overnight at 37°C and 5% C0 2 , allowing cells to attach to the well. Once adhered cells were treated for 24 hours with increasing concentrations of (+)-, (-)- or Racemic perhexiline.

[00289] Cell viability was measured using trypan blue exclusion for fibroblasts and alamar blue fluorescent quantification for BTK-143, MSK and KHOS. Briefly, old media was aspirated and each well washed with warm PBS two times. A 10x concentrate of alamar blue was diluted with PBS to prepare a 1 x solution, and then 100uL was added to each well of the 96 well plate. Following 1 -2 hour incubation at 37°C and 5% C0 2 , fluorescence was measured at excitation wavelengths of 540-570nm and emission at 580-610 nm.

[00290] Data are shown in Figure 6 as median (range), n= 4 for each point.

[00291] Analysis by 2-way ANOVA indicates that for both enantiomers, concentrations less than 5 μΜ are not associated with significant loss of viability. Although (-)-perhexiline appears to always be associated with slightly lower cell viability than (+)-perhexiline, the differences are not large in magnitude.

[00292] We investigated the effect of FCS by determining the effects of (+)- and (-)- perhexiline on fibroblast viability following 24 hour exposure in culture. In addition, we also investigated the human breast cancer cell line (MCF-7) under the same conditions. The alamar blue assay was used for both cell lines.

[00293] The results are shown in Figure 7. The effects of the enantiomers on fibroblast cultures in the absence of FCS were similar to those with FCS. In the breast cancer cell line neither enantiomer caused significant loss of viability at concentrations less than 5 μΜ.

[00294] Summary:

[00295] In current clinical use, total plasma perhexiline concetrations are targeted not to exceed 2 μΜ. Given that perhexiline is highly protein bound in plasma, with an unbound fraction of approximately 0.02, the maximum unbound perhexiline concentrations targeted clinically do not exceed 0.04 μΜ. Thus, at current clinical doses neither enantiomer is likely to cause significant direct cell cytotoxicity in cancer cell lines. In addition, the cytotoxic potency of the perhexiline enantiomers appeard similar in both normal and transformed cells. EXAMPLE 6 - Effects of enantiomers of perhexhiline on Lactate Production

[00296] Despite the lack of significant differences in direct cytotoxicity, we also investigated the effects of each enantiomer on lactate production, on the basis that activation of pyruvate dehydrogenase results in decreased lactate production.

[00297] BTK-143 and MSK cells were grown in DMEM supplemented with 2 mM (final concentration) of L-glutamine, 1 % penicillin and streptomycin and 10% fetal calf serum. BTK-143 and MSK's were seeded at 10,000 cells per well in 96 well plates and incubated overnight at 37 °C and 5% C0 2 , allowing cells to attach to the well. Once adhered, cells were treated for 24 hours with increasing concentrations of (+)-, (-)- or Racemic perhexiline.

[00298] Lactate levels in media were analysed using the colorimetric L-Lactate Assay Kit (ab65331 , Abeam) according to the manufacturer's instructions. Briefly, using solution provided by the kit, 1 μί of media from each sample was diluted 1 :50 in a clear 96 well plate. Reaction mix (kit component) was then added to each sample and standard and then incubated for 30 minutes at room temperature. Absorbance was measured at 450 nm in a microplate reader.

[00299] The results are shown in Figure 8. Data are shown as median (range). BTK data is 4 replicates, MSK is duplicates.

[00300] Interestingly, there was a significant difference in lactate production between the human (BTK) and rat (MSK) osteosarcoma cells. Whilst the enantiomers had no effects of lactate production in the rat cell line, both significantly inhibited lactate production by the human osteosarcoma cell line, at low concentrations (by 12% and 33% at 0.1 μΜ, up to 23% and 36% at 5 μΜ) that were not associated with loss of viability.

EXAMPLE 7 - Effects of enantiomers of perhexhiline on ATP production

[00301] To follow the lactate experiments, we investigated whether the decreased lactic acid production in the human osteosarcoma cell line (and pyruvate dehydrogenase activation) was associated with altered cellular ATP. This was compared to the normal fibroblastcell line. [00302] Fibroblast and BTK-143 cells were grown in DMEM supplemented with 2 mM (final concentration) of L-glutamine, 1 % penicillin and streptomycin and 10% fetal calf serum. Fibroblast and BTK-143 were seeded at 20,000 cells per well in dark walled, clear bottom, 96 well plates and incubated overnight at 37°C and 5% C0 2 , allowing cells to attach to the well. Once adhered, cells were treated for 24 hours with increasing concentrations (+)-, (-)- or Racemic perhexiline for 24 hours.

[00303] Adenosine triphosphate (ATP) levels in cells were analysed using Luminescent ATP Detection Assay Kit (ab1 13849, Abeam) according to the manufacturer's instructions. Briefly, 100 μΙ_ of media was added to the 96 well plate. To this, 50 μΙ_ of detergent and substrate solution (kit components) were added to the sample and calibration wells. This was then incubated for 5 minutes in 37°C and 5% C0 2 and then dark adapted for a further 10 minutes and luminescence was measured.

[00304] Experiments were performed in triplicate, and the data are shown as median (range) in Figure 9.

[00305] Statistical analysis by 2-way ANOVA suggests that total ATP concentrations in the osteosarcoma cells were unaffected by the enantiomers. However, (-)-perhexiline slightly increased total ATP concentrations in fibroblasts, whereas (+)-perhexiline had no effect.

EXAMPLE 8 - Effects of enantiomers of perhexhiline on cancer cell invasion and metastasis

[00306] Culture experiments examining the effects of the enantiomers on cell migration (i.e. invasion and metastasis) using human and rat osteosarcoma cell lines were also undertaken.

[00307] KHOS and MSK cells were grown in DMEM supplemented with 2 mM (final concentration) of L-glutamine, 1 % penicillin and streptomycin and 10% fetal calf serum. Cells were seeded at 1x10 6 cells in a T25 flask and incubated overnight at 37 °C and 5% C0 2 , allowing cells to attach to the well. Once adhered cells were treated for 24 hours with increasing concentrations of (+)-, (-)- or Racemic perhexiline.

[00308] Following the 24-hour incubation, cells were collected, counted and enough for 2x10 4 cells per well were labelled with calcein for 30 mins. Then 10 μί of Matrigel in serum free media (50:50) was layered onto the membrane of a modified Boyden chamber and incubated for 30 mins. 10% FBS in RPMI was used as a chemoattractant in the chamber wells, the membrane was then placed above the wells and the cells were added to the top of the gel. After 6 hours incubation, remaining cells above were removed, and the labelled invaded cells were measured using lumistar plate reader. Invasiveness is shown in Figure 10 as a percentage of the control cells, not treated with perhexiline.

[00309] As can be seen, (-)-perhexiline reducde invasiveness, at least for the human osteosarcoma cell line.

EXAMPLE 9 - Formulation of Tablet with (-)-Perhexiline

[00310] A 50 mg tablet of (-)-perhexiline may comprise the following constituents:

(-)-Perhexiline maleate: 50 mg as fine white crystalline powder

Lactose

Maize Starch

Sucrose

Talc

EXAMPLE 10 (Prophetic) - Treatment of Breast Cancer Using (-)-Perhexiline

[0031 1] Subjects suffering from breast cancer may be identified by known clinical and pathological tests.

[00312] Treatment of human patients with breast cancer may be undertaken by oral administration twice daily of a formulation of 50 mg (-)-perhexiline in tablet form further including lactose, maize starch, sucrose and purified talc or by oral administration once daily of a formulation of 100 mg (-)-perhexiline. The treatment with (-)-perhexiline may comprise combination therapy with one or more anti-cancer agents.

[00313] Treatment with (-)-perhexiline may be for a defined intervention period (for example 8-12 weeks) or be maintained indefinitely. Treatment may be contemporaneous with treatment with other anti-cancer agents, or occur before or after such treatments. Serum and/or plasma (-)-perhexiline levels may be determined at various intervals and any adverse effects monitored. Dose or frequency adjustments can be made based on the serum concentrations, clinical symptoms and any adverse effects. Patient's clinical progress will be monitored by standard techniques. [0001]

EXAMPLE 11 (Prophetic) - Treatment of Chronic Hypoxic Pulmonary Hypertension Using (-)-Perhexiline

[00314] Subjects suffering from chronic hypoxic pulmonary hypertension may be identified by known clinical tests and characteristics.

[00315] Treatment of human patients with chronic hypoxic pulmonary hypertension may be undertaken by oral administration twice daily of a formulation of 50 mg (-)-perhexiline in tablet form further including lactose, maize starch, sucrose and purified talc or by oral administration once daily of a formulation of 100 mg (-)-perhexiline. The treatment with (-)-perhexiline may comprise combination therapy with one or more agents.

[00316] Treatment with (-)-perhexiline may be for a defined intervention period (for example 8 weeks) or be maintained indefinitely. Treatment may be contemporaneous with treatment with other agents, or occur before or after such treatments. Serum and/or plasma (-)-perhexiline levels may be determined at various intervals and any adverse effects monitored. Dose or frequency adjustments can be made based on the serum concentrations, clinical symptoms and any adverse effects. Patient's clinical progress will be monitored by standard techniques.

EXAMPLE 12 (Prophetic) - Use of (-)-Perhexiline in Diabetic Patients Receiving Metformin

[00317] Subjects suffering from type II diabetes and on a treatment regime using metformin may be suitable for treatment with (-)-perhexiline.

[00318] In particular, subjects with type II diabetes and lactic acidosis associated with the use of metformin may be treated with (-)-perhexiline. In some instances, diabetics with kidney problems, liver problems, and heart problems which may exacerbate the appearance of lactic acidosis may also be treated with (-)-perhexiline.

[00319] Typically, for treating type 2 diabetes in adults, metformin (immediate release) is begun at a dose of 50 mg twice a day or 85 mg once daily. The dose is gradually increased by 50 mg weekly or 85 mg every two weeks as tolerated and based on the response of the levels of glucose in the blood. Maximum daily dose is 2550 mg given in three divided doses. If extended tablets are used, the starting dose is typically 50 mg or 100 mg daily (with the evening meal). The dose can be increased by 50 mg weekly up to a maximum dose of 250 mg once daily or in two divided doses.

[00320] For paediatric patients of 10-16 years of age, the starting dose is 50 mg twice a day. The dose can be increased by 50 mg weekly up to a maximum dose of 200 mg daily.

[00321] Treatment of human patients may be undertaken by oral administration twice daily of a formulation of 50 mg (-)-perhexiline in tablet form further including lactose, maize starch, sucrose and purified talc or by oral administration once daily of a formulation of 100 mg (-)-perhexiline. The treatment with (-)-perhexiline may comprise combination therapy with one or more agents.

[00322] Treatment with (-)-perhexiline may be for a defined intervention period (for example 8 weeks) or be maintained indefinitely. Treatment may be contemporaneous with treatment with other agents, or occur before or after such treatments. Serum and/or plasma (-)-perhexiline levels may be determined at various intervals and any adverse effects monitored. Dose or frequency adjustments can be made based on the serum concentrations, clinical symptoms, extent of lactic acidosis present and any adverse effects. Patient's clinical progress will be monitored by standard techniques.

EXAMPLE 13 (Prophetic) - Effect on cardiac function following septic shock

[00323] (-)-Perhexiline, a stimulator of pyruvate dehydrogenase activity, ameliorates lactic acidosis and enhances myocardial function in several clinical shock states. (-)- Perhexiline also improves survival in experimental lactic acidosis. Because of the key role played by the heart in the vascular collapse associated with fatal shock, the effects of (-)- perhexiline on myocardial performance in vitro are examined using the isolated working perfused heart preparation. Hearts are obtained from animals receiving a lethal dose for 50% of the group (LD 50 ) six hours of E. coli endotoxin or saline vehicle. The presence of (-)- perhexiline in the perfusate significantly elevates stroke work, cardiac output, and peak systolic pressure development in hearts from endotoxin-treated rats at filling pressures from 7.5 to 25 cm of water. (-)-Perhexiline has no significant effect on the mechanical performance of hearts obtained from vehicle injected controls. In both control and endotoxin treated rat hearts, (-)-perhexiline increases significantly the activity of pyruvic dehydrogenase. (-)-Perhexiline does not produce any alteration in ATP levels in the hearts from control animals; however, after endotoxin treatment (-)-perhexiline increased myocardial ATP content to control values, (-)-perhexiline is shown to augment myocardial performance in hearts from endotoxin-injected rats, and restore the depressed ATP concentration to normal levels.

EXAMPLE 14 (Prophetic) - Effect on exercise endurance

[00324] The effect of (-)-perhexiline on the performance and blood lactate levels of fed, untrained rats is evaluated while swimming for different durations. (-)-Perhexiline-treated rats are able to swim up to 40% longer than controls. This is associated with lower levels of blood and muscle lactate at rest and after 210 and 240 sec of swimming. At exhaustion, blood lactate is the same in the two groups even though the (-)-perhexiline rats have worked for a longer period of time. Pre-treatment with (-)-perhexiline does not alter the usual exercise- induced decreases in muscle ATP and creatine phosphate or liver glycogen. (-)-Perhexiline is shown to enhance the ability of rats to exercise at near maximal workloads. They are consistent with the notion that improved endurance is a consequence of a decreased rate of lactate production.

EXAMPLE 15 (Prophetic) - Effect on Cancer Cells Synergism with Metformin

[00325] Metformin may have a cytotoxic effect on cancer cells. To investigate sensitization of metformin-cytotoxicity, cancer cells are treated with (-)-perhexiline. Metformin-cytotoxicity is mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas (-)-perhexiline co-treatment enhances metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting pyruvate dehydrogenase kinase (PDK) and increasing mitochondrial respiration. (-)-Perhexiline co- treatment elicits cell death rather than cell survival despite high glucose and high GSH condition. In conclusion, (-)-perhexiline sensitizes metformin-cytotoxicity by reprogramming glucose metabolism in part from aerobic glycolysis to mitochondrial oxidation, which may be evidenced by measurements of glucose consumption, lactate release, and the ratio of oxygen consumption rate/extracellular acidification rate. EXAMPLE 16 (Prophetic) - Effect on Brain Cells Following Ischemic Event

[00326] Cerebral ischemic insult is one of the most clinically significant conditions leading to irreversible brain cell damage and death. Through animal studies, it appears that lowered intracellular pH due to the severe brain lactic acidosis following ischemia interferes with normal cell structure and function and leads to brain cell necrosis. Therefore, decreasing brain lactate is beneficial for preventing brain cell damage and death. It is possible to evaluate the effectiveness of post-insult treatment with (-)-perhexiline in controlling increases in brain lactate following partial global ischemia (PGI) in rats. PGI can be induced by bilateral carotid artery occlusion and induced hypotension. Animals that receive DCA immediately after a 30-minute ischemic insult (n=5) or 15 minutes after the end of an ischemic insult (n=5) have cortical lactate levels that are significantly lower (P < .005) than lactate levels in untreated insulted animals and that are not significantly different from those obtained with pre-insult (-)-perhexiline treatment in rats subjected to 30 minutes of PGI. Treatment of rats with (-)-perhexiline following PGI is effective in reducing cortical lactate levels and hence may limit irreversible damage to brain cells following cerebral ischemia.

EXAMPLE 17 (Prophetic) - Effect on Pulmonary Hypertension and Compensatory Right Ventricular Hypertrophy

[00327] The pulmonary arteries (PA) in pulmonary arterial hypertension (PAH) are constricted and remodeled: They have suppressed apoptosis, partly attributable to selective down-regulation of PA smooth muscle cell (PASMC) voltage-gated K + channels, including Kv1.5. The Kv downregulation-induced increase in [K + ]i, tonically inhibits caspases, further suppressing apoptosis. Mitochondria control apoptosis and produce activated oxygen species like H 2 0 2 , which regulate vascular tone by activating K + channels. (-)-Perhexiline prevents and reverses established monocrotaline-induced PAH (MCT-PAH), significantly improving mortality rate. Monocrotaline (MCT) is a toxic pyrrolizidine alkaloid of plant origin. Administration of small doses of MCT or its active metabolite, monocrotaline pyrrole (MCTP), to rats causes delayed and progressive lung injury characterized by pulmonary vascular remodeling, pulmonary hypertension, and compensatory right ventricular hypertrophy. Compared with MCT-PAH, (-)-perhexiline-treated rats (in drinking water on day 14 after MCT, studied on day 21 ) have decreased pulmonary, but not systemic, vascular resistance, PA medial thickness, and right ventricular hypertrophy. (-)-Perhexiline is similarly effective when given at day 1 or day 21 after MCT (studied day 28) but has no effect on normal rats. In summary, DCA reverses PA remodeling by increasing the mitochondria-dependent apoptosis/proliferation ratio and upregulating Kv1 .5 in the media.

EXAMPLE 18 (Prophetic) - Effect on heart function following ischemic event

[00328] Stimulation of glucose oxidation by (-)-perhexiline treatment is beneficial during recovery of ischemic hearts from non-diabetic rats. (-)-Perhexiline treatment of diabetic rat hearts (in which glucose use is extremely low) increases recovery of function of hearts reperfused following ischemia. Isolated working hearts from 6 week streptozotocin diabetic rats are perfused with 1 1 mM [2- 3 H,U- 14 C] glucose, 1 .2 mM palmitate, 20 μΙΙ/ιηΙ insulin, and subjected to 30 min of no-flow ischemia followed by 60 min reperfusion. Heart function (expressed as the product of heart rate and peak systolic pressure), prior to ischemia, is depressed in diabetic hearts compared to controls but recover to pre-ischemic levels following ischemia, whereas recovery of control is significantly decreased. This enhanced recovery of diabetic rat hearts occurs even though glucose oxidation during reperfusion is significantly reduced as compared to controls.

EXAMPLE 19 - Use of perhexiline as a sodium channel blocker

[00329] Both (-)-perhexiline and (+)-perhexiline are effective inhibitors/blockers of the late INa (sodium ion channel) and/or hCav1 .2 (calcium channel) currents. Perhexiline maintains ionic homeostasis and prevents diastolic Ca 2+ overload that leads to hypertrophy, arrhythmia (atrial fibrillation, atrial flutter, etc.). Table 1 shows perhexiline's effect on ion channels using cloned hNav1.5 sodium channels (SCN5A gene expressed in CHO cells). The effects on both peak and late INa will be evaluated. .

Table 1

[00330] Thus, perhexiline may be used in a method for treating or preventing arrhythmia in a subject in need thereof, said method comprising administering to the subject a therapeutically effective amount of perhexiline that inhibits an ion channel active during an arrhythmic event, wherein the ion channel is selected from the group consisting of a sodium channel and a calcium channel. In addition, pancreatic a-cells of diabetic subjects that have increased glucagon content, may express larger Na + current and have increased action potential duration, amplitude and firing frequency as compared to pancreatic a-cells of non- diabetic subjects. These conditions sensitize the cells for increased glucagon secretion. Thus, (-)-perhexiline's ability to inhibit sodium ion channels (suppresses the conduction of sodium ions through sodium channels) may be useful for decreasing abnormal glucagon secretion from a-cells, thereby being a viable and effective treatment option for hyperglycemia or lowering the plasma level of HbAlc or glucose in a subject in need thereof.

[00331] Based on these findings, (-)-perhexiline is believed to possess advantageous therapeutic properties that allow it to be used to prevent or treat pathological conditions where cellular redox balance is shifted toward the reduced state (i.e., the ratio of NAD7NADH is low) and/or producing excess lactic acid, as discussed further below, with the side effects caused by (+)-perhexiline.

EXAMPLE 16 (Prophetic) - Use of perhexiline to treat cancer

[00332] The glycolytic phenotype is a widespread phenomenon in solid cancer forms and commonly referred to as the Warburg effect. In particular, the Warburg effect is a cellular adaptation to the hypoxic environment existing in solid tumors. This glycolytic phenotype inhibits apoptosis and promotes cell proliferation. As such, (-)-perhexiline may be safely used (in a non-toxic way) to promote apoptosis in cancer cells by activating PDH in order to deactivate the glycolytic phenotype and shift the redox state back to normal. Conventional in vitro and in vivo protocols/experiments demonstrate that (-)-perhexiline reverses the Warburg effect and diminishes or ameliorates cell proliferation. In addition, (-)-perhexiline is tested in vivo, for example, with 13762 MAT cells, to show that (-)-perhexiline reduces the number of lung metastases observed macroscopically after injection of 13762 MAT cells into the tail vein of rats to demonstrate that (-)-perhexiline has anti-proliferative properties in addition to pro-apoptotic properties, and that it is effective against highly metastatic diseases in vivo.

EXAMPLE 17 (Prophetic) - Use of perhexiline to treat Von Hippel Lindau disease

[00333] Von Hippel-Lindau (VHL) disease is a rare, autosomal dominant genetic condition that predisposes individuals to benign and malignant tumors. Patients with VHL disease have a greatly increased risk of developing various types of tumors, including hemangioblastomas, clear cell renal cell carcinomas (ccRCC), and pheochromocytomas. VHL results from a mutation in the von Hippel-Lindau tumor suppressor gene on chromosome 3p25.3. The von Hippel-Lindau protein (pVHL) is involved in the regulation of a protein known as hypoxia inducible factor 1 a (HIF1 a). This is a subunit of a heterodimeric transcription factor that at normal cellular oxygen levels is highly regulated. In normal physiological conditions, pVHL recognizes and binds to HIF1 a only when oxygen is present due to the post translational hydroxylation of two proline residues within the HIF1 a protein. pVHL is an E3 ligase that ubiquitinates HIF1 a and causes its degradation by the proteasome. In low oxygen conditions or in cases of VHL disease where the VHL gene is mutated, pVHL does not bind to HIF1 a. This allows the subunit to dimerize with HIF1 β and activate the transcription of a number of genes, including vascular endothelial growth factor, platelet-derived growth factor B, erythropoietin and genes involved in glucose uptake and metabolism (e.g., GLUT1 and hexokinase). Pyruvate dehydrogenase kinase (PDK) is also a direct gene target of HIF-1 a. PDK inactivates the enzyme complex PDH, thus attenuating mitochondrial respiration and oxidative phosphorylation. The lack of PDH activity due to upregulation of PDK enhances ATP production via increased anaerobic glycolysis which is critical for the adaptation of cells to hypoxia. Therefore, by upregulating the expression of PDK, GLUT1 , and hexokinase, HIF1 a prepares the cell to operate in hypoxic conditions.

[00334] The lifetime risk of developing ccRCC in VHL disease patients is more than 70% by the age of 60 years. The kidneys of VHL disease patients display cystic changes or distortion of the tubular structure adjacent to cells. In addition to expressing HIF1 a, cells in these early lesions overexpress HIF1 a target genes, such as PDK, Glucose Transporter 1 (GLUT-1 ), VEGF, and carbonic anhydrase IX.

[00335] Thus, in a further exemplary embodiment (-)-perhexiline may be used to treat patients with VHL disease and tumors associated with VHL disease. In addition, (-)- perhexiline may be used to treat ccRCC in combination with a VEGF inhibitor like bevacizumab (Avastin®) Ranibizumab and the like or in combination with a carbonic anhydrase IX inhibitor, or combinations and mixtures thereof. Examples of other VEGF inhibitors that may be useful in combination with (-)-perhexiline include Bevacizumab (hz mAb, target- hu VEGF, inhibition - VEGF binding to VEGFR1 , R2), 2C3 (ms mAb, target - hu VEGF, inhibition - VEGF binding to VEGFR2), r84 (hu mAb, target - hu, ms VEGF, inhibition - VEGF binding to VEGFR2), VEGF-Trap (hu Fc fp, target - hu, ms VEGF PIGF, inhibition - VEGF, PIGF binding to VEGFR1 , R2), MF1/IMC-18F1 (rt/hu MAb, target - ms/hu VEGFR1 , inhibition VEGFR1 activation by PIGF, VEGF, -B), DC101/IMC-1 C1 1 (rt/hz mAb, target - ms/hu VEGF, inhibition - VEGFR2 activation by VEGF, -C, -D) and IM-1 121 B (hu Mab, target - hu VEGFR2, inhibition - VEGFR2 activation by VEGF, -C, -D).

EXAMPLE 18 (prophetic) - Use of perhexiline to treat cancers affected by EGFR

[00336] The epidermal growth factor receptor (EGFR) is a trans-membrane glycoprotein which belongs to a family of structurally related receptor tyrosine kinases. EGFR feeds into the PI3K/AKT/mTOR pathway at the cell surface level. EGFR and its ligands are overexpressed or involved in autocrine growth loops in a number of tumor types. EGFR is believed to be important in multiple signal-transduction pathways and appears to play a critical role in both tumorigenesis and tumor growth. Activation of the proteins involved in these pathways ultimately leads to DNA synthesis and cell proliferation, and the EGFR pathway has been shown to be activated in a wide variety of cancers. Thus, EGFR is an attractive target for the treatment of treatment of proliferative disorders such as cancer and in the inhibition of angiogenesis in mammals. Several EGFR inhibitors have been developed for use in cancer treatment. "EGFR Inhibitor" means any compound, peptide or antibody which is an inhibitor of EGFR. These include monoclonal antibodies and small molecules. Generally, the polyclonal or monclonal antibodies bind to the extracellular ligand binding site of the EGFR, while small molecules bind to and inhibit the intracellular tyrosine kinase part of the EGFR.

[00337] It is believed that combination of a PDK inhibitor and an EGFR inhibitor would be an unexpected but powerful synergistic combination to block cell division. Without wishing to be bound by any theory of operation or mechanism of action, it is believed that PDH is phosphorylated (inactivated) in the mitochondria by PDK and then migrates to the nucleus where it is dephosphorylated by a phosphatase and reactivated. When phosphorylated, PDH upregulates the expression of epidermal growth factor (EGF), which then binds to the EGF receptor (EGFR) and promotes DNA synthesis and cell proliferation, as described above. In other words, the transmigration of PDH to the nucleus is blocked by EGFR inhibitors.

[00338] Thus, in a further example embodiment, (-)-perhexiline may be formulated or used in combination with (combination therapy) a pharmaceutical composition comprising at least one EGFR inhibitor for use in the treatment of cancer. In particular, disclosed is a method for treating cancer comprising:

(a) selecting a patient having a cancer that is believed to be responsive to at least one EGFR inhibitor;

(b) administering to the patient a therapeutically effective regimen comprising (i) at least one EGFR inhibitor and (ii) (-)-perhexiline;

wherein the EGFR inhibitor and (-)-perhexiline are administered together or sequentially.

[00339] Suitable EGFR inhibitors that may be used in conjunction with (-)-perhexline include, without limitation, erlotinib (N-(3-ethynylphenyl)-6,7-bis-(2-methoxyethoxy)-4- quinazolinamine), erlotinib hydrochloride (Tarceva®) (methods of preparation of erlotinib are disclosed in EP 0 817 775), imatinib, lapatinib, semazinib, cetuximab (Erbitux®, which is disclosed in EP 0 359 282), panitumumab (Vectibix®, which is disclosed in EP 0 359 282) and gefinitib (Iressa®, which is disclosed in EP 0 566 226), zalutumumab, nimotuzumab, and matuzumab, or combinations thereof. [00340] Without wishing to be bound by any theory of operation, (-)-perhexiline enhances the anti-cancer efficacy of the EGFR inhibitor. The term "combination therapy" refers to treatment comprising the administration of (-)-perhexiline, as described herein, or pharmaceutically acceptable salt thereof, and an EGFR inhibitor in combination. The therapeutic agents may be administered simultaneously, separately or sequentially.

[00341] Dosage regimens for each of the therapeutic agents used in the combination therapy embodiment may vary depending on, for example, the route of administration, the disease being treated and the EGFR inhibitor used. For example, the dose of EGFR inhibitor and/or (-)-perhexiline or a pharmaceutically acceptable salt thereof, may be in the range of about 10 mg to 2000 mg or more per day and all subranges therebetween. In particular, the dose of the EGFR inhibitor may be in the range 10 mg to 450 mg per day, and all subranges therebetween. The combination therapy may be administered one to four times daily, as needed. The combination therapy may be administered for a single fixed period of time, for example, 6 months. The combination therapy may be administered according to a cyclical schedule, where there are alternating treatment and non-treatment periods. Alternatively, the combination therapy may be administered continuously (until disease progression is ameliorated or unacceptable toxicity is observed).

[00342] For example, the cancers that may be treated by the above-described combination therapy include, without limitation, colorectal cancer, non-small cell lung carcinoma (NSCLC), adrenocortical carcinoma (ACC), gastrointestinal cancer, gall bladder cancer, bile duct cancer, liver cancer, pancreatic cancer, mesotheolioma cancer, peripheral T-cell lymphoma (PTCL), brain tumors, adenocarcinoma, osteosarcoma, pancreatic cancer, head and neck cancer, breast cancer, or neuroblastoma. The cancer may also be, for example: NSCL cancer, breast cancer, colon cancer, pancreatic cancer, lung cancer, bronchioloalveolar cell lung cancer, bone cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of the anal region, stomach cancer, gastric cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the vagina, carcinoma of the vulva, Hodgkin's Disease, cancer of the esophagus, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, prostate cancer, cancer of the bladder, cancer of the ureter, cancer of the kidney, renal cell carcinoma, carcinoma of the renal pelvis, mesothelioma, hepatocellular cancer, biliary cancer, chronic or acute leukemia, lymphocytic lymphomas, neoplasms of the central nervous system (CNS), spinal axis tumors, brain stem glioma, glioblastoma multiforme, astrocytomas, schwannomas, ependymomas, medulloblastomas, meningiomas, squamous cell carcinomas, pituitary adenomas, including refractory versions of any of the above cancers, or a combination of one or more of the above cancers. The precancerous condition or lesion includes, for example, the group consisting of oral leukoplakia, actinic keratosis (solar keratosis), precancerous polyps of the colon or rectum, gaslric epilheliai dysplasia, adenomatous dysplasia, hereditary nonpolyposis colon cancer syndrome (HNPCC), Barrett's esophagus, bladder dysplasia, and precancerous cervical conditions.

EXAMPLE 19 (Prophetic) - Use of perhexiline to treat lactic acidosis

[00343] Lactic acid (or lactate) is a product of anaerobic glycolysis resulting from pyruvate by the enzyme lactate dehydrogenase (LDH). The lactic acid can be found in blood and biological fluids of human beings and animals. A healthy adult male normally produces about 120 g of lactic acid a day. Among these, 40 g (33%) are produced by tissues characterized by an exclusively anaerobic metabolism (retina and blood red cells). The remaining 80 g (67%) are produced by other tissues (most of all muscle) on the basis of the actual oxygen availability. In the liver, lactic acid is reconverted into glucose (Cori cycle). Heart is able to metabolize lactic acid to produce energy. The increase of lactic acid (lactic acidosis) can occur in two conditions: (a) hypoxia, i.e. the oxygen deficiency (sometimes referred to as lactic acidosis of Type A, fast) or (b) high rate of anaerobic glycolysis (sometimes referred to as lactic acidosis of type B, slow).

[00344] In Type A lactic acidosis, the aerobic pathway (i.e. the oxidation metabolic pathway of pyruvate to carbon dioxide and water) is blocked for several reasons. This occurs, for example, in inborn errors of the mitochondrial respiratory chain, in cardiovascular diseases (ischemia, hypoxemia, anemia) and in other diseases. In particular, oxygen deficits (tissue hypoxia) are the common and often refractory causes of lactic acidosis, including pulmonary problems (low P0 2 ), circulatory problems (poor delivery of 0 2 ), and hemoglobin problems (low 0 2 -carrying capacity, for various reasons).

[00345] In Type B lactic acidosis, the anaerobic glycolitic pathway proceeds at a relatively high rate, thereby causing low ATP concentration levels. The pyruvic acid produced accumulates and is reduced to lactic acid by LDH. This occurs during intense exertion and in all conditions of decoupling of oxidative phosphorylation, resulting in the accumulation of lactate. For example, Type B lactic acidosis occurs in subjects having a deficiency of pyruvate dehydrogenase enzyme or in B1 vitamin deficiency, in which ATP is produced from fat metabolism, or when the conversion of lactate to glucose is slow because of liver or renal diseases or genetic or drug-induced defects in gluconeogenesis. Metabolic acidosis can also develop during pharmacological treatments, due to the exposition to chemical agents and in oncologic patients because cancer cells produce more lactate than normal cells even in aerobic conditions.

[00346] In certain example embodiments where the cause of lactic acidosis in a subject is hypoperfusion, (-)-perhexiline may be used to prevent, treat or ameliorate metabolic acidosis, regional or diffuse tissue hypoperfusion, hypoxia, shock, congestive heart failure, dehydration, acidosis in diabetes mellitus, patients with infections, inflammatory states, isoniazid induced metabolic acidosis, poisoning by ethanol, methanol, salicylate, or ethylene glycol, and the like.

[00347] In other example embodiments, (-)-perhexiline may be administered to a subject in need thereof to prevent or treat lactic acidosis, organic acidemias, hypertrophic cardiomyopathy, mitochondrial myopathy, increasing ATP production, altering the redox state, reversing the conversion of pyruvate to lactate, or enhancing endurance and muscle performance, or combinations thereof.

[00348] In certain exemplary embodiments, (-)-perhexiline may be used in a method for reducing elevated lactic acid and lactate concentrations in subjects suffering from an ischemic or hypoxic crisis that generate unwanted increases in blood or tissue lactate concentrations.

[00349] In still further example embodiments, (-)-perhexiline may be used to prevent, treat, or ameliorate lactic acidosis caused by one or more of the following: 3-Hydroxyacyl- CoA Dehydrogenase II Deficiency; 3-methylglutaconic aciduria, type 4; acetaminophen toxicity; anoxia; cardiomyopathy -hypotonia— lactic acidosis; cataract and cardiomyopathy; chronic Kidney Disease; coenzyme Q cytochrome c reductase deficiency; copperhead snake poisoning; crotalidae snake poisoning; cyanide; isoniazid; propylene glycol; phenformin; inborn errors of metabolism; poisoning by ethanol, methanol, salicylate, and ethylene glycol; dehydration; congestive heart failure; hypoxia; hypovolemic shock; diabetic nephropathy; finnish lethal neonatal metabolic syndrome; fructose-1 ,6-bisphosphatase deficiency; fructosuria; glycogen Storage Disease Type I; glycogen storage disease type 1 C; glycogen storage disease type 1 D; glycogen storage diseases; heart conditions; haemorrhage; herbal agent overdose, e.g., Germanium; Hydroxyacyl-COA dehydrogenase, type 2, deficiency; Kidney conditions; Lipoamide dehydrogenase deficiency; Liver failure; Lung conditions; MELAS (mitochondrial myopathy, encephalopathy, lactacidosis, stroke); MGA 4 (methylglutaconic aciduria); Malignant hyperthermia; Malonic aciduria; Medium and long chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency; Metabolic disorders; metformin; Mitochondrial DNA depletion syndrome; Mitochondrial encephalomyopathy - aminoacidopathy; Mitochondrial myopathy — lactic acidosis; Mitochondrial neurogastrointestinal encephalopathy syndrome; Myoclonus with epilepsy with ragged red fibers; Myopathy with lactic acidosis and sideroblastic anemia; Polyneuropathy — Ophthalmoplegia - Leukoencehalopathy— Intestinal Pseudo-Obstruction; Posthemorrhagic anemia; Pyruvate carboxylase deficiency; Pyruvate decarboxylase deficiency; Pyruvate dehydrogenase deficiency; pyruvate dehydrogenase phosphatase deficiency; respiratory failure; SCHAD deficiency; Septicemia; Shock; Short Bowel Syndrome; Small non-cleaved cell lymphoma; Succinic academia; succinic acidemia— lactic acidosis, congenital; Type 10 17 -hydroxysteroid dehydrogenase deficiency; Type I Glycogen Storage Disease; Von Gierke Disease; and the like.

[00350] In further example embodiments, (-)-perhexiline may be used in a method to prevent, treat, or ameliorate mitochondria-associated diseases or conditions by administering to a subject in need thereof (e.g., a warm-blooded mammal) an effective amount of (-)-perhexiline. The mitochondria-associated disease or condition may be one in which free radical mediated oxidative injury leads to tissue degeneration or in which cells inappropriately undergo apoptosis or fail to undergo apoptosis. Non-limiting examples of mitochondria-associated diseases or conditions that may be treated with (-)-perhexiline include cancer, stroke, diabetes mellitus (Type I or Type II), auto-immune disease, psoriasis, Alzheimer's Disease, Parkinson's Disease, Huntington's Disease, congenital muscular dystrophy, fatal infantile myopathy or later-onset myopathy, MELAS (Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke), MIDD (Mitochondrial Diabetes and Deafness), arthritis, NARP (Neuropathy, Ataxia, Retinitis Pigmentosa), MNGIE (Myopathy and external ophthalmoplegia, Neuropathy, Gastro-lntestinal, Encephalopathy), LHON (Leber's, Hereditary, Optic, Neuropathy), Kearns-Sayre disease, Pearson's Syndrome, PEO (Progressive External Ophthalmoplegia), Wolfram syndrome, DIDMOAD (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, Deafness), Leigh's Syndrome, dystonia, or schizophrenia.

[00351] Some patients who have heart failure experience complications when taking a biguanide, such as metformin, because metformin's lactic acidosis promoting properties can synergize with lactic acidosis originating from heart failure. To address this, (-)-perhexiline may be administered to counteract the negative effects of metformin. Reducing lactate efflux from hypoxic cells will help solve this problem. [00352] In renal failure patients, especially heart failure patients with renal failure, administering metformin leads to metabolic acidosis. As a result, metformin is used with caution in elderly patients who generally have poor renal function (chronic renal failure) or in patients with Serum Creatinine > 1.4 mg/dL. To address this problem, (-)-perhexiline may be effectively administered to diabetic patients with chronic renal failure or those with Serum Creatinine > 1 .4 mg/dL. (-)-Perhexiline may be administered alone (instead of metformin) or in combination with a biguanide, such as metformin, because (-)-perhexiline would prevent the metabolic acidosis associated with metformin use and metformin and (-)-perhexiline each lower blood sugar.

[00353] In a further exemplary embodiment, it is believed that (-)-perhexiline may be administered alone or in combination with a biguanide (e.g., metformin, phenformin, and the like) to treatment of diabetes. Without wishing to be bound by any theory of operation or mechanism of action, it is believed that (-)-perhexiline and a biguanide class drug (e.g., metformin or phenformin) each lowers blood sugar through different mechanisms (PDK and AMP-activated protein kinase, respectively). In addition, because administering biguanides can undesirably cause lactic acidosis in patients, administering (-)-perhexiline would also serve to reverse and/or prevent lactic acidosis, thereby making administration of biguanides safer. Further, with respect to dosing, the genetics of CYP2D6 have been extensively studied. Humans can be characterized "extensive metabolizers," "intermediate metabolizers" and "poor metabolizers". Each person has two alleles or genes for CYP2D6, which clears perhexiline and also both metabolites. There are a variety of different alleles in the population denoted as * 1 , * 2, * 3, and * 4, with * 1 being normal and the others being defective in terms of enzymatic activity levels, with the * 4 allele having almost no functional activity. Patients who have the * 4/ * 4 genotype have problems clearing perhexiline and are more susceptible to liver and nerve damage. Thus, prior to administration, genotyping each patient could be beneficial. For patients who have the * 4/ * 4 genotype, an amount of 1 mg to about 25 mg of (-)-perhexiline may be administered per day, e.g., about 5 mg/day or about 10 mg/day, without monitoring of plasma concentrations. For other non- * 4/ * 4 genotype patients, an amount of about 25 to about 500mg of (-)-perhexiline may be administered per day, e.g., about 100 mg/day or about 250 mg/day.

[00354] Included within the scope of the example embodiments described herein are therapeutic or pharmaceutical compositions, and uses of such compositions, containing between about 0% and 100% of the (-)-perhexiline of perhexiline and all subranges therebetween. In one exemplary embodiment, the present disclosure relates to the use of substantially enantiomerically pure ("enantiopure") negative isomer of perhexiline, and in particular, to the use of substantially enantiopure (-)-perhexiline for preventing and/or treating a disease, condition or state associated with hypoxia, and/or lactic acidosis or combinations thereof. The present disclosure also relates to pharmaceutical compositions comprising substantially enantiopure (-)-perhexiline and to the identification of agents for preventing and/or treating a disease, condition or state associated with hypoxia, and/or lactic acidosis or combinations thereof.

[00355] Although the present disclosure has been described with reference to particular examples, it will be appreciated by those skilled in the art that the disclosure may be embodied in many other forms.

[00356] Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in any country.

[00357] Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.

[00358] The subject headings used herein are included only for the ease of reference of the reader and should not be used to limit the subject matter found throughout the disclosure or the claims. The subject headings should not be used in construing the scope of the claims or the claim limitations.

[00359] Future patent applications may be filed on the basis of the present application, for example by claiming priority from the present application, by claiming a divisional status and/or by claiming a continuation status. It is to be understood that the following claims are provided by way of example only, and are not intended to limit the scope of what may be claimed in any such future application. Nor should the claims be considered to limit the understanding of (or exclude other understandings of) the present disclosure. Features may be added to or omitted from the example claims at a later date.