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WO1996011679A1 - Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires - Google Patents

Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires Download PDF

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Publication number
WO1996011679A1
WO1996011679A1 PCT/US1994/011434 US9411434W WO9611679A1 WO 1996011679 A1 WO1996011679 A1 WO 1996011679A1 US 9411434 W US9411434 W US 9411434W WO 9611679 A1 WO9611679 A1 WO 9611679A1
Authority
WO
WIPO (PCT)
Prior art keywords
carbonate
dichloroacetic acid
range
salt
mixture
Prior art date
Application number
PCT/US1994/011434
Other languages
English (en)
Inventor
Peter W. Stacpoole
Robert M. Bersin
Original Assignee
Stacpoole Peter W
Bersin Robert M
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Stacpoole Peter W, Bersin Robert M filed Critical Stacpoole Peter W
Priority to PCT/US1994/011434 priority Critical patent/WO1996011679A1/fr
Priority to JP8513169A priority patent/JPH11511725A/ja
Priority to DK94930669T priority patent/DK0786993T3/da
Priority to AU79719/94A priority patent/AU703842B2/en
Priority to AT94930669T priority patent/ATE218333T1/de
Priority to CA002202397A priority patent/CA2202397C/fr
Priority to EP94930669A priority patent/EP0786993B1/fr
Priority to DE69430760T priority patent/DE69430760T2/de
Priority claimed from CA002202397A external-priority patent/CA2202397C/fr
Priority to US08/465,608 priority patent/US5643951A/en
Publication of WO1996011679A1 publication Critical patent/WO1996011679A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients

Definitions

  • the present invention relates to pharmaceutical compositions and methods for the treatment of metabolic and cardiovascular disorders and to certain dichloroacetate derivatives as the active ingredients therein.
  • DCA also stimulates lactate oxidation in animal tissue and significantly decreases lactic acid levels and overall morbidity in patients with lactic acidosis [Stacpoole et al, N. En ⁇ . J. Med.. Vol. 309:390 (1983); Blackshear et al, Diabetes Care. Vol. 5:391 (1982)].
  • DCA reduces circulating triglyceride and cholesterol concentrations in obese [Felts et al, Dia ⁇ betes. Vol. 25 (suppl.):363 (1976)] and diabetic [Hayet et al, Metabolism. Vol. 29:120 (1980); Riles et al, Diabetes. Vol.
  • DCA also markedly decreases blood cholesterol levels in patients with various forms of hyper- lipidemia [Stacpoole et al, N. En ⁇ . J. Med.. Vol. 298:526 (1978); Moore et al, Atherosclerosis. Vol. 33:285 (1979)].
  • DCA is toxic to lower animals and humans, particularly upon chronic administration. It has been reported that a human patient who received DCA for about four months developed a mild poly- neuropathy that resolved when treatment stopped [Moore et al, ibid] . Chronic administration of DCA to lower animals in doses exceeding those used clinically also induces a revers ⁇ ible peripheral neuropathy, changes in testicular morphology and lenticular opacities [Stacpoole, N. En ⁇ . J. Med.. Vol. 300:372 (1979)].
  • DCA is known to oxidize in vivo to glyoxalate and subsequently to oxalate [Demangre et al, Biochem. Biophvs. Res. Comm.. Vol. 85:1180 (1978); Harris et al, Arch. Biochem. Biophys.. Vol. 189:364 (1978) and Currey et al, Clin. Phar ⁇ macol. Ther.. Vol. 37:894 (1985)].
  • Oxalate is a known neuro- toxin [Bilbao et al, Can. J. Neurol. Sci.. Vol. 3:63 (1976)] and cataract inducing chemical [Fielder et al, Br. J. Op thal.. Vol. 64:782 (1980)], and may be at least partly responsible for the neuropathic changes associated with the chronic administration of DCA.
  • the drug also improves cardiac output and left ven ⁇ tricular mechanical efficiency under conditions of myocardial ischemia or failure, probably by facilitating myocardial metabolism of carbohydrate and lactate as opposed to fat.
  • DCA may also enhance regional lactate removal and restoration of brain function in experimental stages of cerebral ischemia [Stacpoole, Metabolism, ibid] .
  • DCA appears to inhibit its own metabolism, which may influence the duration of its pharmacologic actions and lead to toxicity.
  • DCA can cause a reversible peripheral neuropathy that may be related to thiamine deficiency and may be amelio ⁇ rated or prevented with thiamine supplementation [Stacpoole, Metabolism, ibidl .
  • CarbicarbTM is a substantially equimolar mixture of sodium carbonate (Na 2 C0 3 ) and sodium bicarbonate (NaHC0 3 ) which buffers solutions thereof to bicarbonate ions without a net generation of C0 2 .
  • the mixture has been employed in humans and animals to restore normal systemic (blood) and/or intra- cellular pH and acid-base status which results in an improve ⁇ ment in the metabolism and function of cells, tissues and organisms [Filley et al. Trans. Am. Clin. Clinatol Assoc.. Vol. 96, page 141 (1934); Whalen et al, Clin. Res.. Vol. 36, page 374A (1988); and Bersin et al, Circulation. Vol. 77, page 227 (1988)].
  • compositions in unit dosage form adapted for admin ⁇ istration to a human for the treatment of metabolic and/or cardiovascular disorders comprising a therapeutically effec ⁇ tive amount of a composition comprising dichloroacetic acid or a pharmaceutically acceptable salt or derivative thereof and a pharmaceutically acceptable, substantially equimolar mixture of carbonate ions and bicarbonate ions, the weight ratio of dichloroacetic acid, derivative or salt thereof to said mix ⁇ ture of carbonate and bicarbonate ions being in the range of from about 100:1 to about .01:lj and a pharmaceutically acceptable carrier therefor.
  • the present invention is predicated on the discovery that combinations of DCA and mixtures of carbonates and bicar- bonates in certain ratios synergistically enhance the thera ⁇ cookeric activities of each agent when administered in thera ⁇ cookerically effective dosages to humans in need of treatment for metabolic and/or cardiovascular disorders.
  • DCA would promote aerobic oxidation of lactate and generate by this means increased bicarbonate ions (as a buffer for cells) and increase levels of high energy metabolites, such as ATP and creatine phosphate.
  • the improvement in acid- base and energy status caused by DCA and the carbonate/bicar ⁇ bonate mixture would, in turn, increase the functional capacity of tissues such as the heart, leading to improved mechanical function and efficiency and better perfusion of tissues by the blood.
  • carbonate/bicarbonate and “mixture of carbonate and bicarbonate ions” are intended to include a mixture of carbonate and bicarbonate salt, e.g., sodium carbonate and sodium bicarbonate, which is therapeutically effective for the treatment of metabolic and/or cardiovascular disorders such as, for example, CarbicarbTM, an agent well known in the art as evidenced by the references to Filley et al, Shapiro et al and Bersin et al, supra. and which comprises a mixture containing an equimolar ratio of sodium carbonate to sodium bicarbonate.
  • carbonate/bicarbonate and “mixture of carbonate and bicarbonate ions” are intended to include a mixture of carbonate and bicarbonate salt, e.g., sodium carbonate and sodium bicarbonate, which is therapeutically effective for the treatment of metabolic and/or cardiovascular disorders such as, for example, CarbicarbTM, an agent well known in the art as evidenced by the references to Filley et al, Shapiro et al and Ber
  • DCA dichloro ⁇ acetic acid
  • salts thereof with pharmaceutically acceptable cations e.g., sodium, potassium, diisopropylam onium
  • derivatives thereof which possess the therapeutic properties and activities of dichloroacetic acid such as the compounds described in U.S. Patent Nos. 4,801,497 and 4,558,050, the entire disclosures of which are incorporated herein by refer ⁇ ence.
  • composition of the invention by admixing DCA with a suitable carbonate, e.g., sodium carbonate in solution.
  • a suitable carbonate e.g., sodium carbonate
  • Free hydrogen ion liberated in solution by the DCA is buffered by the carbonate ions to form free bicarbonate ions.
  • the amount of free hydrogen ion liberated is an amount sufficient to result in buffering of half of the carbonate to bicarbonate, the result will be a mixture of DCA and an equimolar mixture of sodium carbonate and sodium bicarbonate, i.e., a mixture of DCA and CarbicarbTM.
  • compositions of the invention are suitable for the treatment of a wide variety of metabolic disorders, e.g., lactic acidosis, diabetes mellitus, hyperlipidemia, catabolic states and neurologic disorders associated with abnormal carbohydrate, lactic acid or lipid metabolism.
  • metabolic disorders e.g., lactic acidosis, diabetes mellitus, hyperlipidemia, catabolic states and neurologic disorders associated with abnormal carbohydrate, lactic acid or lipid metabolism.
  • Cardiovascular disorders for which the compositions and methods of the invention are useful for treating include heart failure, myocardial ischemia, myocardial infarction, cardiac arrythmia, cerebrovascular insufficiency or stroke.
  • compositions and methods of the invention are applicable for the treatment of any metabolic and/or cardio ⁇ vascular disorder or disease against which DCA or carbon ⁇ ate/bicarbonate alone is effective.
  • compositions and methods of the invention are particularly adapted for the treatment of lactic acidosis and myocardial dysfunction.
  • the above dichloroacetate derivatives may be formu ⁇ lated with pharmaceutically acceptable carriers adapted for oral administration (i.e., tablet, capsule or pill) and admin ⁇ istered orally.
  • the active agent may also be compounded for parenteral or transdermal administration.
  • the active ingredi ⁇ ent may be admixed or compounded with any conventional pharma ⁇ ceutically acceptable carrier.
  • any mode of administration, vehicle or carrier heretofore employed for the administration of DCA alone may be utilized for preparation and administration of the pharmaceutical compositions of the present invention.
  • Illustrative of such methods, vehicles and carriers are those described by Stacpoole et al [N. En ⁇ . J. Med.. Vol.
  • the formulations both for veterinary and for human use, of the present invention comprise a derivative together with one or more acceptable carriers therefor and optionally other therapeutic ingredients.
  • the carrier(s) must be "acceptable” in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
  • the formulations should not include oxidizing agents and other substances with which the derivatives are known to be incompatible.
  • the formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.
  • All methods include the step of bringing into association the derivative with the carrier which constitutes one or more accessory ingredients.
  • the formula ⁇ tions are prepared by uniformly and intimately bringing into association the derivative with the carrier(s) and then, if necessary, dividing the product into unit dosages thereof.
  • Formulations suitable for parenteral administration conveniently comprise sterile aqueous preparations of the derivatives which are preferably isotonic with the blood of the recipient.
  • Such formulations may be conveniently prepared by admixing solid derivatives with water to produce a solution or suspension which is filled into a sterile container and sealed against bacterial contamination.
  • sterile materials are used under aseptic manufacturing conditions to avoid the need for terminal sterilization.
  • Such formulations may optionally contain one or more additional ingredients among which may be mentioned preserva ⁇ tives, such as methyl hydroxybenzoate, chlorocresol, meta- cresol, phenol and benzalkonium chloride.
  • preserva ⁇ tives such as methyl hydroxybenzoate, chlorocresol, meta- cresol, phenol and benzalkonium chloride.
  • Such materials are of special value when the formulations are presented in multi- dose containers.
  • Buffers may also be included to provide a suitable pH value for the formulation.
  • Acceptable materials for such buffers include sodium phosphate and acetate.
  • Sodium chloride or glycerin may be used to render a formulation isotonic with the blood.
  • the formulations may be filled into the containers under an inert atmosphere such as nitrogen or may contain an antioxidant, and are conveniently presented in unit dose or multi-dose form, e.g., in a sealed ampoule.
  • the therapeutically effective amount of DCA and carbonate/bicarbonate to be included in the pharmaceutical composition of the invention depends, in each case, upon several factors, e.g., the type, size and condition of the animal, the disorder to be treated, the intended mode of administration, the capacity of the animal to incorporate the intended dosage form, etc.
  • amounts of DCA and carbonate/bicarbonate are included in each dosage form to provide amounts of DCA and carbonate/bicarbonate employed in conventional pharmaceutical compositions containing the agents alone.
  • compositions of the invention are formu ⁇ lated such that the dose of DCA is in the range of from about 1 to about 100 mg/kg, body weight, and preferably from about 5 to about 50 mg/kg, and the dose of carbonate/bicarbonate is in the range of from about 0.2 to about 10 mEq kg, body weight, and preferably from about 1 to about 5 mEq kg, body weight.
  • the composition of the invention is formulated such that the dose of DCA is in the range of from about 1 to about 200 mg/kg, body weight, and preferably from about 10 to about 100 mg/kg, and the dose of carbonate/bicarbonate is in the range of from about 0.2 to about 10 mEq/kg, body weight, and preferably from about 1 to about 5 mEq/kg, body weight.
  • compositions of the invention are formulated such that the dose of DCA is in the range of from about 1 to about 100 mg/kg, body weight, and preferably from about 5 to about 50 mg/kg, and the dose of carbonate/bicar ⁇ bonate is in the range of from about 0.2 to about 10 mEq/kg, body weight, and preferably from about 1 to about 5 mEq/kg, body weight.
  • the composition of the invention is formulated such that the dose of DCA is in the range of from about 1 to about 200 mg/kg, body weight, and preferably from about 10 to about 100 mg/kg, and the dose of carbonate/bicar ⁇ bonate is in the range of from about 0.2 to about 10 mEq/kg, body weight, and preferably from about 1 to about 5 mEq/kg, body weight.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

Procédé de traitement de troubles métaboliques et/ou cardiovasculaires consistant à administrer à un être humain qui en a besoin une quantité thérapeutiquement efficace d'une composition comprenant de l'acide dichloroacétique ou un sel ou un dérivé pharmaceutiquement acceptable de cet acide, ainsi qu'un mélange pharmaceutiquement acceptable d'ions carbonate et bicarbonate, le rapport pondéral de l'acide dichloroacétique, du dérivé ou du sel de celui-ci et du mélange d'ions carbonate et bicarbonate se situant dans la plage entre 100:1 et 0,01:1 environ. L'invention concerne également des compositions pharmaceutiques sous forme de dosage unitaire adapté pour être administré à un être humain ayant besoin d'un traitement de troubles métaboliques et/ou cardiovasculaires et comprenant une quantité thérapeutiquement efficace d'une composition comprenant l'acide dichloroacétique ou un sel ou un dérivé de celui-ci pharmaceutiquement acceptable et un mélange pharmaceutiquement acceptable d'ions carbonate et bicarbonate, le rapport pondéral entre l'acide dichloroacétique, le sel ou dérivé de celui-ci et le mélange d'ions carbonate et bicarbonate se situant dans la plage comprise entre 100:1 environ et 0,01:1 environ; l'invention décrit également un excipient pharmaceutiquement acceptable.
PCT/US1994/011434 1992-09-16 1994-10-17 Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires WO1996011679A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
PCT/US1994/011434 WO1996011679A1 (fr) 1994-10-17 1994-10-17 Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires
JP8513169A JPH11511725A (ja) 1994-10-17 1994-10-17 炭酸塩／重炭酸塩で緩衝したジクロロ酢酸を含む組成物と、代謝異常および心血管障害の治療方法
DK94930669T DK0786993T3 (da) 1994-10-17 1994-10-17 Præparater omfattende carbonat/bicarbonatpufferjusteret dichloreddikesyre og deres anvendelse i behandlingen af stofskifte- og hjertekarsygdomme
AU79719/94A AU703842B2 (en) 1994-10-17 1994-10-17 Compositions comprising carbonate/bicarbonate buffered dichloroacetic acid and methods for treatment of metabolic and cardiovascular disorders
AT94930669T ATE218333T1 (de) 1994-10-17 1994-10-17 Carbonat/bicarbonat gepufferte dichloressigsäure enthaltende mittel und deren verwendung in der behandlung von metabolischen und kardiovaskulären erkrankungen
CA002202397A CA2202397C (fr) 1994-10-17 1994-10-17 Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires
EP94930669A EP0786993B1 (fr) 1994-10-17 1994-10-17 Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et leur utilisation dans le traitement de troubles metaboliques et cardiovasculaires
DE69430760T DE69430760T2 (de) 1994-10-17 1994-10-17 Carbonat/bicarbonat gepufferte dichloressigsäure enthaltende mittel und deren verwendung in der behandlung von metabolischen und kardiovaskulären erkrankungen
US08/465,608 US5643951A (en) 1992-09-16 1995-06-05 Compositions comprising carbonate/bicarbonate buffered dichloroacetic acid and methods for treatment of metabolic and cardiovascular disorders

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
PCT/US1994/011434 WO1996011679A1 (fr) 1994-10-17 1994-10-17 Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires
CA002202397A CA2202397C (fr) 1994-10-17 1994-10-17 Compositions comprenant de l'acide dichloroacetique tamponne au carbonate/bicarbonate et procedes de traitement de troubles metaboliques et cardiovasculaires
US08/465,608 US5643951A (en) 1992-09-16 1995-06-05 Compositions comprising carbonate/bicarbonate buffered dichloroacetic acid and methods for treatment of metabolic and cardiovascular disorders

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WO1996011679A1 true WO1996011679A1 (fr) 1996-04-25

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011109874A1 (fr) * 2010-03-12 2011-09-15 The Australian National University Inhibition de la glutathione transférase zêta

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4631294A (en) * 1985-07-05 1986-12-23 University E.M., Inc. Treatment of cerebral ischemia with dichloroacetate

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4631294A (en) * 1985-07-05 1986-12-23 University E.M., Inc. Treatment of cerebral ischemia with dichloroacetate

Non-Patent Citations (10)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Volume 106, issued 1987, BARSAN, "Treatment of Cerebral Ischemia with Dichloroacetate", page 65, Abstract No. 131720q; & US,A,4 631 294. *
CHEMICAL ABSTRACTS, Volume 108, issued 1988, DIMLICH et al., "Comparison of Sodium Bicarbonate with Dichloroacetate Treatment of Hyperlactatemia and Lactic Acidosis in the Ischemic Rat", page 53, Abstract No. 143192y; & RESUSCITATION, 16(1), 13-30. *
CHEMICAL ABSTRACTS, Volume 108, issued 1988, SUN et al., "Carbicarb: An Effective Substitute for Sodium Bicarbonate for the Treatment of Acidosis", page 36, Abstract No. 106142m; & SURGERY, 102(5), 835-9. *
CHEMICAL ABSTRACTS, Volume 116, issued 1992, TOMSIG et al., "Inhibition of Lactate-Induced Swelling by Dichloroacetate in Human Astrocytoma Cells", page 36, Abstract No. 99064x; & BRAIN RES., 568(1-2), 92-100. *
CHEMICAL ABSTRACTS, Volume 117, issued 1992, UEDA, "Effect of Sodium Carbonate-Bicarbonate Mixture Upon Acid-Base Balance Dearrangements in Arterial Blood, Cerebrospinal Fluid and Brain Parenchyma Created by Circulatory Arrest in Dogs. Comparative Study with Sodium Bicarbonate", page 56, Abstract No. *
CHEMICAL ABSTRACTS, Volume 119, issued 1993, SONETT et al., "Sodium Bicarbonate Versus Carbicarb in Canine Myocardial Hypercarbic Acidosis", Abstract No. 40674; & J. CRIT. CARE, 8(1), 1-11. *
CHEMICAL ABSTRACTS, Volume 120, issued 1994, HUNTLEY et al., "Importance of Tonicity of Carbicarb on the Functional and Metabolic Responses of the Acidotic Isolated Heart", page 70, Abstract No. 260915v; & J. CRIT. CARE, 8(4), 222-7. *
CHEMICAL ABSTRACTS, Volume 121, issued 1994, IRITA et al., "The Limiting Effect of Dichloroacetate on Endotoxin-Induced Liver Damage in Starved Rats", Abstract No. 73781; & J. SURG. RES., 56(3), 216-20. *
CIRCULATION, Vol. 77, No. 1, issued 1988, BERSIN et al., "Improved Hemodynamic Function During Hypoxia with Carbicarb, A New Agent for the Management of Acidosis", pages 227-233. *
See also references of EP0786993A4 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2011109874A1 (fr) * 2010-03-12 2011-09-15 The Australian National University Inhibition de la glutathione transférase zêta

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