WO1994028883A1 - Compositions therapeutiques et procedes d'utilisation - Google Patents

Compositions therapeutiques et procedes d'utilisation Download PDF

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Publication number
WO1994028883A1
WO1994028883A1 PCT/US1994/006653 US9406653W WO9428883A1 WO 1994028883 A1 WO1994028883 A1 WO 1994028883A1 US 9406653 W US9406653 W US 9406653W WO 9428883 A1 WO9428883 A1 WO 9428883A1
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WO
WIPO (PCT)
Prior art keywords
weight
parts
acid
component
mammal
Prior art date
Application number
PCT/US1994/006653
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English (en)
Inventor
Raymond K. Brown
Original Assignee
Brown Raymond K
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 Brown Raymond K filed Critical Brown Raymond K
Priority to DE4494231T priority Critical patent/DE4494231T1/de
Priority to GB9525254A priority patent/GB2294637B/en
Priority to US08/564,088 priority patent/US6066670A/en
Priority to AU70603/94A priority patent/AU7060394A/en
Publication of WO1994028883A1 publication Critical patent/WO1994028883A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid

Definitions

  • the invention relates to admixture compositions of short chain organic fatty acids which have biological effects. For example, they are useful in the treatment of numerous pathologies that affect mammals.
  • the invention also relates to methods of treatment of such pathologies, wherein appropriate therapeutically effective amounts of the compositions are adminis ered.
  • carboxylic acid containing compositions are biologically active, and several short chain organic acids which are naturally occurring acids have previously been implicated in the treatment of various pathological conditions.
  • Nordman U.S. Patent No. 3,291,689, discloses the treatment of hepatic ammonia intoxication with a mixture of L-arginine and malic acid.
  • U.S. Patent No. 3,718,664 discloses the use of thioctic acid derivatives in the treatment of acidosis.
  • Rubenstein U.S. Patent No. 4,971,760, discloses the sterilization of blood, blood constituents, and transplant tissues with a disinfectant that includes lactic acid and sodium chlorite.
  • Naphtholic acid derivatives were discovered to be useful in enhancing oxygen availability to mammalian tissue by Suh et al., U.S. Patent No. 5,015,663.
  • Hoffler et al . U.S. Patent No. 5,043,357, disclose a virucidal agent that is predominantly comprised of ethanol and/or alcohol but which includes a minor amount of a short chain organic acid.
  • U.S. Patent No. 5,093,140 discloses an aqueous bactericide that contains organic acids.
  • composition which comprises an admixture of sorbic acid, aconitic acid, malic acid, fumaric acid, crotonic acid, and optionally aconitic acid.
  • Organic acids are a large group of compounds, many of which can be derived from proteins, carbohydrates, and fats. Although many occur naturally, many can be synthetically produced without great difficulty.
  • Sorbic acid is a crystalline diolefinic acid having the formula C 6 H 8 0. Typically, it is used as mold and yeast inhibitor; a fungistatic agent for foods, especially cheeses; or to improve the characteristics of drying oils, the gloss of alkyd type coatings, or the milling properties of cold rubber.
  • Aconitic acid is a white crystalline acid having the formula C-jHgO ⁇ . Typically, it is used in manufacturing itaconic acid or as a plasticizer for buna rubber and plastics.
  • Malic acid is a crystalline dicarboxylic acid having the formula C 4 H 4 0 3 and is typically found in three isomeric crystalline forms.
  • Fumaric acid is a crystalline unsaturated dicarboxylic acid having the formula C 4 H 4 O 4 . Fumaric acid is typically usec as a substitute for tartaric acid in beverages and baking powders, as a replacement or partial replacement of citric acid in soft drinks, and as an antioxidant.
  • Crotonic acid is an unsaturated aliphatic acid having the formula It exists in the crystalline form, and is typically used in the manufacture of copolymers with vinylacetate that are used in lacquers and paper sizing, and in the manufacture of softening agents for synthetic rubber.
  • each of the four required individual acids will independently comprise from about 1 to about 50 parts by weight and, optionally, aconitic acid will comprise from 0 to about 50 parts by weight, based upon 100 parts by weight of the five acids combined.
  • sorbic acid comprises from about 5 to about 40 parts by weight
  • aconitic acid comprises from 0 to about 50 parts by weight
  • malic acid comprises from about 1 to about 30 parts by weight
  • fumaric acid comprises from about 1 to about 30 parts by weight
  • crotonic acid comprises from about 1 to about 30 parts by weight, based upon 100 parts by weight of the five acids combined.
  • sorbic acid comprises from about 20 to about 30 parts by weight
  • aconitic acid comprises from about 35 to about 45 parts by weight
  • malic acid comprises from about 10 to about 20 parts by weight
  • fumaric acid comprises from about 10 to about 20 parts by weight
  • crotonic acid comprises from about 1 to about 20 parts by weight, based upon 100 parts by weight of the five acids combined.
  • Suitable pharmaceutically active carriers may be combined with the admixture.
  • Such carriers include those known to those skilled in the art and can be added at any point in the mixing process. If a pharmaceutically active carrier is used, the carrier will comprise from about 1 to about 99 parts by weight and the acid admixture will comprise from about 99 to about 1 part by weight, based upon 100 parts by weight of acid admixture and carrier combined.
  • the acid admixture with or without the carrier can be formulated into dosage unit forma including, but not limited to, capsules and tablets.
  • dosage unit forma including, but not limited to, capsules and tablets.
  • Methods of preparation of dosage unit forms would be known to those skilled in the art.
  • Agents which facilitate the manufacture and/or use of such dosage unit forms may be added such as plasticizers, lubricants, excipients, diluents and the like.
  • Methods of treatment of various pathologies contemplated by the present invention involve the administration of therapeutically effective amounts of the admixture to mammals in need of such treatment. Administration is by means known to those skilled in the art. Preferably, administration is systemic and most preferably, it is oral.
  • Pathologies which are effectively treated with the organic acid admixture described herein include but are not limited to acidosis; viral infections including, but not limited to, cytomaglovirus and hepatitis infections; tumors; and bacterial and fungal infections, including but not limited to i _ aureus. E. coli, and C. albicans.
  • the amount of the admixture necessary to treat acidosis is an anti-acidosis effective amount.
  • the amounts of the admixture necessary to treat a viral infection, and particularly hepatitis and cy omegalovirus infections are an anti-viral effective amount, and particularly anti-hepatitis and an anti-cytomegalovirus effective amounts.
  • the amount required to treat tumors, and bacterial and fungal infections are anti- tumor, anti-bacterial, and anti-fungal effective amounts, respectively.
  • the actual amounts of the admixture to be administered will depend independently upon the age, weight, sex, sensitivity, medical condition, including but not limited to stage of a particular infection or disease, or the like, of an individual.
  • the amount will be a safe non-toxic amount.
  • amounts can be determined by experimentation well-known in the art such as by establishing a matrix of dosages and frequencies and assigning a group of experimental subjects to each point in the matrix. Typically, that amount will range from about 1000 to about 2000 milligrams per day for a 150 pound man and preferably about 1500 milligrams per day for a 150 pound man.
  • a daily dosage identifies the average amount of the mixture administered to an individual. Although the daily dosage may actually be administered daily, it need not be administered daily. The daily dosage is merely an average dosage that an individual receives when the mixture is administered over a period of time. The daily dosage can be administered in divided portions so that the total amount administered is the daily dosage.
  • Example 2 A patient had a temperature of 101°F and symptoms of acute urinary and prostate infection. The patient was treated with 1500 mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 parts by weight of fumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of total admixture for ten days. Symptoms and temperature subsided by the 4th or 5th day. Antimicrobial and alkalizing activity and therapeutic effects of the admixture are illustrated in Table 2. Cultures which were positive for streptococci were negative by the third week.
  • a patient with urine culture positive for cytomegalovirus infection was treated with 1500 mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw of fumaric acid, and 4 pbw of crotonic acid, based upon 100 pbw of total admixture for six weeks. After six weeks, a cytomegalovirus urine culture was negative.
  • Example 5 A patient having cancer of the prostate with a PSA of
  • PSA was lowered to 2.4. Seven months after Zolodex treatment was discontinued, PSA rose to 13.
  • the patient then received 1500 mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw of fumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of total admixture, and PSA was lowered to 1.65. Nightly urination decreased from 5-6 times/night to two times/night and the patient's general energy increased 80%.
  • a patient was diagnosed with a pancreatic mass. The patient also had nausea, pain, an inability to eat, weight loss, and weakness.
  • the patient who weighed about less than eighty pounds, was given 50 mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw of fumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of total admixture for two months.
  • the epigastric mass was no longer palpable.
  • a repeat cystoscopy two months later showed only several small papillary lesions in the urinary bladder and a small lesion in the prostatic urethra. Rectal examination was unremarkable.
  • CAT SCAN confirmed the improvement observed by cystoscopy.
  • a patient was diagnosed with long standing Hepatitis C.
  • the patient was treated with 1500 mg/day of an admixture of 24 pbw of sorbic acid, 40 pbw of aconitic acid, 16 pbw of malic acid, 16 pbw of fumaric acid, and 4 pbw of crotonic acid based upon 100 pbw of total admixture.
  • the challenge organism was Cytomegalovirus, (CMV) and the host cell line was MRC-5, ATCC CCL-171.
  • Reagents and media were EMEM with Earle's salts supplemented with heat inactivated fetal bovine serum (FBS) , glutamine, and penicillin streptomycin
  • MEM complete sterile phosphate buffered saline
  • NBCS newborn calf serum
  • the virus stock culture was titered and adjusted to contain approximately 10 7 CCID 30 /ml (50% cell-culture infectious doses per milliliter) and stored in liquid nitrogen until use.
  • the virus stock was thawed and was diluted 10-fold in MEM through
  • MRC-5 monolayers 5 confluent MRC-5 monolayers.
  • the cells were incubated at 37 + 1°C, in 5% C0 2 , for 2 hours to allow the virus to adsorb to the cells. After adsorption, the medium was withdrawn from the monolayers, the cells were washed once with PBS, and refed with MEM. The monolayers were incubated for 14 days at 37 ⁇ 1°C, in 5% C0 2 , and subsequently were observed for virus-specific cytopathogenic effects (CPE) . The test solution was tested by combining the virus with the admixture at a 1:10 dilution.
  • CPE virus-specific cytopathogenic effects
  • This suspension was agitated continuously at a constant temperature of 25°C and samples were withdrawn at 3 and 6 minutes to determine a survivor curve and to calculate a D-value.
  • the sampled suspensions were neutralized with a 1:1 dilution in new-born calf serum and were diluted ten-fold in MEM.
  • One ml aliquots of the neutralized mixture were plated onto MRC-5 monolayers (four wells per dilution) and were incubated at 37 + 1°C in a 5% C0 2 in air atmosphere for 2 hours. Following the incubation period, the fluids were removed.
  • the monolayers were washed with PBS, refed MEM and were incubated at 37 ⁇ 1°C in a 5% C0 2 in air atmosphere for thirteen days.
  • Control virus stock was titered at the time of the test as described, to confirm that the titer was in an acceptable range.
  • the maintenance of the virus titer was evaluated using PBS instead of the test solution. Samples were taken less than 15 seconds after the initiation of the test (zero time control) and after 6 minutes (final time control) .
  • the average CCID 30 /ml for each titer was determined by the Reed and Muench method.
  • AX CCID 50 /ml at Tx

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne un mélange d'acide sorbique, d'acide malique, d'acide fumarique, d'acide crotonique et, éventuellement, d'acide aconitique. La présente invention concerne également des procédés pour le traitement de divers états pathologiques, tels que les infections virales, l'acidose, les tumeurs et les infections bactériennes et fongiques par administration de quantités thérapeutiquement efficaces d'un mélange décrit ci-dessus.
PCT/US1994/006653 1993-06-08 1994-06-08 Compositions therapeutiques et procedes d'utilisation WO1994028883A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
DE4494231T DE4494231T1 (de) 1993-06-08 1994-06-08 Therapeutische Zusammensetzung und ihre Anwendung
GB9525254A GB2294637B (en) 1993-06-08 1994-06-08 Therapeutic compositions and methods of use
US08/564,088 US6066670A (en) 1994-06-08 1994-06-08 Therapeutic compositions and methods of use
AU70603/94A AU7060394A (en) 1993-06-08 1994-06-08 Therapeutic compositions and methods of use

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US7393493A 1993-06-08 1993-06-08
US073,934 1993-06-08

Publications (1)

Publication Number Publication Date
WO1994028883A1 true WO1994028883A1 (fr) 1994-12-22

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ID=22116689

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Application Number Title Priority Date Filing Date
PCT/US1994/006653 WO1994028883A1 (fr) 1993-06-08 1994-06-08 Compositions therapeutiques et procedes d'utilisation

Country Status (5)

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AU (1) AU7060394A (fr)
CA (1) CA2164837A1 (fr)
DE (1) DE4494231T1 (fr)
GB (1) GB2294637B (fr)
WO (1) WO1994028883A1 (fr)

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038519A1 (fr) * 1998-01-30 1999-08-05 Ivan Gorgiev Composition anticancereuse
WO2002055067A2 (fr) * 2001-01-12 2002-07-18 Fumapharm Ag Derives de l'acide fumarique utilises comme inhibiteurs nf-kappab
WO2003087174A2 (fr) * 2002-04-18 2003-10-23 Fumapharm Ag Oligomeres carbocycliques et oxycarbocycliques d'acide fumarique
US7087424B1 (en) 1999-01-29 2006-08-08 Australian National University Method of controlling fungal pathogens, and agents useful for same
US7157423B2 (en) 2001-01-12 2007-01-02 Fumapharm Ag Fumaric acid amides
US7320999B2 (en) 1998-11-19 2008-01-22 Fumapharm Ag Dimethyl fumarate for the treatment of multiple sclerosis
US8399514B2 (en) 2007-02-08 2013-03-19 Biogen Idec Ma Inc. Treatment for multiple sclerosis
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
WO2024126742A1 (fr) * 2022-12-16 2024-06-20 Universite De Tours Aconitate pour traitement d'une infection pulmonaire virale

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4828912A (en) * 1981-07-20 1989-05-09 Kimberly-Clark Corporation Virucidal product having virucidal and/or germicidal properties

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4828912A (en) * 1981-07-20 1989-05-09 Kimberly-Clark Corporation Virucidal product having virucidal and/or germicidal properties

Cited By (21)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999038519A1 (fr) * 1998-01-30 1999-08-05 Ivan Gorgiev Composition anticancereuse
US7915310B2 (en) 1998-11-19 2011-03-29 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7619001B2 (en) 1998-11-19 2009-11-17 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7612110B2 (en) 1998-11-19 2009-11-03 Biogen Idec International Ag Utilization of dialkylfumarates
US8524773B2 (en) 1998-11-19 2013-09-03 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7803840B2 (en) 1998-11-19 2010-09-28 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7320999B2 (en) 1998-11-19 2008-01-22 Fumapharm Ag Dimethyl fumarate for the treatment of multiple sclerosis
US8759393B2 (en) 1998-11-19 2014-06-24 Biogen Idec International Gmbh Utilization of dialkylfumarates
US7087424B1 (en) 1999-01-29 2006-08-08 Australian National University Method of controlling fungal pathogens, and agents useful for same
US7157423B2 (en) 2001-01-12 2007-01-02 Fumapharm Ag Fumaric acid amides
WO2002055066A1 (fr) * 2001-01-12 2002-07-18 Fumapharm Ag Derives d'acide fumarique en tant qu'inhibiteur du nf-kappab
WO2002055067A3 (fr) * 2001-01-12 2004-02-26 Fumapharm Ag Derives de l'acide fumarique utilises comme inhibiteurs nf-kappab
WO2002055067A2 (fr) * 2001-01-12 2002-07-18 Fumapharm Ag Derives de l'acide fumarique utilises comme inhibiteurs nf-kappab
US7432240B2 (en) 2001-01-12 2008-10-07 Biogen Idec International Gmbh Fumaric acid amides
US7790916B2 (en) 2002-04-18 2010-09-07 Biogen Idec International Gmbh Carbocyclic and oxacarbocyclic fumaric acid oligomers
US7906659B2 (en) 2002-04-18 2011-03-15 Biogen Idec International Gmbh Carbocyclic and oxacarbocyclic fumaric acid oligomers
WO2003087174A3 (fr) * 2002-04-18 2004-01-08 Fumapharm Ag Oligomeres carbocycliques et oxycarbocycliques d'acide fumarique
WO2003087174A2 (fr) * 2002-04-18 2003-10-23 Fumapharm Ag Oligomeres carbocycliques et oxycarbocycliques d'acide fumarique
US8980832B2 (en) 2003-09-09 2015-03-17 Biogen Idec International Gmbh Use of fumaric acid derivatives for treating cardiac insufficiency, and asthma
US8399514B2 (en) 2007-02-08 2013-03-19 Biogen Idec Ma Inc. Treatment for multiple sclerosis
WO2024126742A1 (fr) * 2022-12-16 2024-06-20 Universite De Tours Aconitate pour traitement d'une infection pulmonaire virale

Also Published As

Publication number Publication date
GB9525254D0 (en) 1996-02-21
DE4494231T1 (de) 1996-10-17
CA2164837A1 (fr) 1994-12-22
GB2294637A (en) 1996-05-08
AU7060394A (en) 1995-01-03
GB2294637B (en) 1997-11-12

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