WO2019140429A1 - Traitement d'une déficience cognitive associée à une chimiothérapie - Google Patents

Traitement d'une déficience cognitive associée à une chimiothérapie Download PDF

Info

Publication number
WO2019140429A1
WO2019140429A1 PCT/US2019/013602 US2019013602W WO2019140429A1 WO 2019140429 A1 WO2019140429 A1 WO 2019140429A1 US 2019013602 W US2019013602 W US 2019013602W WO 2019140429 A1 WO2019140429 A1 WO 2019140429A1
Authority
WO
WIPO (PCT)
Prior art keywords
liver extract
liver
extract
acetone
water
Prior art date
Application number
PCT/US2019/013602
Other languages
English (en)
Inventor
William J. Hermann, Jr.
Sanjeev P. SAHNI
Roger SAHNI
Original Assignee
Nexco Group Of Companies, Inc.
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 Nexco Group Of Companies, Inc. filed Critical Nexco Group Of Companies, Inc.
Publication of WO2019140429A1 publication Critical patent/WO2019140429A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/37—Digestive system
    • A61K35/407—Liver; Hepatocytes

Definitions

  • the present disclosure is directed to a method of treating Chemotherapy Associated Cognitive Impairment using a mammalian liver extract that is efficacious in treating this condition.
  • liver extract has been used for the treatment of a wide range of infectious and noninfectious dermatologic conditions, including ache vulgaris, Journal Invest Dermatology, 2:205-218 (1939); first and second degree burns, Mississippi Valley Medical Journey, 76: 199 (1954); sunburn, Clinical Medicine, 3 :245 (1956); poison ivy dermatitis, Clin. Med., 3 :425 (1956) and Herpes zoster, Southern Medical Journal, 50: 1524 (1957). The active principle and mechanism have not been described. Although some medical practitioners have used liver extract for the treatment of dermatologic conditions, it is not regarded as an antiviral or immune modulator agent even for skin therapy.
  • liver extract has been reported to have bradykinin potentiating activity. Tewksbury et al., Arch. Blochem. Biophys. (U.S.), 112, 453 (1965); Tewksbury, Archives Int'l. de Pharmacodynamie et de Therapie, 173, 426 (1968); Tewksbury, Dissertation Abstracts International-Part II, Vol. 25/04, p. 2214 (1964). Further, one commercially-available liver extract (sold under the trademark KUTAPRESSIN by Kremers-Urban Co., Milwaukee, Wisconsin) exerts its action, according to product literature, only with respect to tissues that have been injured and when inflammation and edema are present.
  • U.S. Pat. No. 5,055,296, filed by certain inventors common to the present application further discloses use of a particular heat stable, acetone-insoluble, water-soluble mammalian liver extract, designated as "KU 10,001" that was shown to be effective in the treatment of mammals infected with a non-dermatological virus and, in particular, chronic fatigue syndrome.
  • KU 10,001 acetone-insoluble, water-soluble mammalian liver extract
  • U.S. Pat. No. 5,284,664 filed by certain inventors common to the present application, disclose a heat stable, acetone-insoluble, water-soluble mammalian liver extract, that is said to be effective in the treatment of symptoms of Alzheimer's Disease.
  • the liver extract was also partially sequenced, and that sequence listing is incorporated herein by reference.
  • U.S. Pat. No. 5,316,775, filed by certain inventors common to the present application discloses the same mammalian liver extract and demonstrates it to be effective in the treatment of Hepatitis B infections.
  • U.S. Pat. No. 5,334,395, filed by certain inventors common to the present application discloses use of the same mammalian liver extract and demonstrates it to be effective in the treatment of Epstein-Barr viral infections.
  • U.S. Pat. No. 4,254,103 discloses a method of extracting Hepatoprotector Factor (HF) from bovine liver to be used in the treatment of cirrhosis of the liver and viral hepatitis.
  • HF Hepatoprotector Factor
  • U.S. Pat. No. 4,883,660 discloses gel bases for use in pharmaceutical compositions comprising a glycol solvent, and ethoxylated fatty alcohols or ethoxylated behenyl alcohol.
  • the composition is suitable for topical, systemic and oral administration of pharmaceutical agents.
  • U.S. Pat. No. 5,492,937 discloses a composition which is a liquid at or below room temperature, and forms a highly viscous gel at body temperature.
  • This composition is comprised of a cellulose ether, a surfactant, and other optional additives. It may be used for oral or local administration of a pharmaceutical to the skin, mucous membrane, eye, or body cavity.
  • U.S. Pat. No. 5,589, 192 discloses a gel formulation for use with local anesthetics.
  • a support of non-woven fabric with an impervious backing sheet is coated with a copolymer containing a local anesthetic.
  • a polymer/drug matrix is formed, and an aqueous fluid is used to coat the surface of the matrix, converting the matrix into a gel with good percutaneous absorption.
  • U.S. Pat. No. 5,595,760 discloses a composition which includes a soluble, gelable salt of a peptide, and a pharmaceutical carrier. The composition forms a gel upon interacting with body fluids after injection, and the peptides are released continuously over a period of at least three days.
  • U.S. Pat. No. 6, 156,349 filed by certain inventors common to the present application, discloses use of the same mammalian liver extract and demonstrates it to be effective in the treatment of Human Immunodeficiency Virus (HIV) when administered in suppository form.
  • HIV Human Immunodeficiency Virus
  • CACI Chemotherapy Associated Cognitive Impairment
  • chemotherapy drugs An illness referred to as Chemotherapy Associated Cognitive Impairment (CACI) has been associated with a range of drugs used in the treatment of cancer referred to as chemotherapy drugs.
  • CACI may be caused by the chemotherapy drugs or other conditions related to cancer and its treatment.
  • CACI symptoms often start during or just after treatment, though they may persist or even get worse after treatment is over.
  • Patients suffering from CACI demonstrate numerous symptoms including fatigue, short term memory problems, and cognitive problem.
  • the cognitive problems may include being unusually disorganized, confusion, difficulty concentrating, difficulty finding the right word, difficulty learning new skills, difficulty multitasking, a feeling of mental fogginess, shortened attention span, and taking longer than usual to complete routine tasks. To date, there is no known effective treatment for CACI.
  • the present disclosure is related to methods for treatment of CACI in human patients, specifically using a mammalian liver extract.
  • One embodiment according to the present disclosure includes a method of treating Chemotherapy Associated Cognitive Impairment (CACI) which comprises administering to a person suffering from CACI a therapeutically-effective amount of a mammalian liver extract, the extract being characterized by being heat stable, insoluble in acetone and soluble in water.
  • CACI Chemotherapy Associated Cognitive Impairment
  • the liver extract may be contained in a pharmaceutically-acceptable carrier at a concentration of about 2.5% by weight solids.
  • the liver extract may be contained in a pharmaceutically-acceptable carrier at a concentration of about 2.5% by weight solids.
  • the liver extract is contained in water.
  • the present disclosure is related to a method for treating CACI in humans. Specifically, the present disclosure is related to administering a mammalian liver extract to a human patient.
  • the present invention is susceptible to embodiments of different forms. There are shown in the drawings, and herein will be described in detail, specific embodiments with the understanding that the present invention is to be considered an exemplification of the principles and is not intended to limit the present invention to that illustrated and described herein.
  • compositions and methods are described in terms of “comprising” various components or steps (interpreted as meaning “including, but not limited to”), the compositions and methods can also “consist essentially of or “consist of the various components and steps, such terminology should be interpreted as defining essentially closed-member groups.
  • the portion of mammalian liver extract that has been discovered to be effective in treating CACI is the fraction which is heat stable, insoluble in acetone and soluble in water.
  • the liver extract prepared according to the disclosure herein is free from fatty acids, and vitamins, and specifically is free from vitamin B-12, a vitamin naturally occurring in liver. Work in progress suggests polysaccharides may be present in KUTAPRESSIN (Kremers-Urban Co.) in the form of proteoglycans and/or glycoproteins.
  • the same liver extract has been used heretofore in treating skin conditions and Epstein-Barr virus infections.
  • the liver extract employed in the present disclosure is prepared by separating a fraction from mammalian livers, preferably porcine liver.
  • the starting material may be a liver preparation as described in Pharmacopeia of the United States, Vol. 15, p. 379 (which describes a boiled liver extract suitable for parenteral use), in National Formulary, Vol. XII, p. 222 (which describes an aqueous solution of the thermostable fraction of mammalian liver) or in National Formulary, Vol. XI, p. 192-94 (which describes several thermostable liver preparations).
  • the starting material may be fresh liver, frozen liver or a commercially-available liver preparation.
  • An acetone-insoluble fraction is separated from the starting material. This may be accomplished by admixing a large excess of acetone with the starting material which results in an acetone-insoluble fraction that is separated from the acetone. The treatment with acetone may be repeated. The acetone-insoluble fraction, after being separated from the acetone, is dissolved in water. Any remaining acetone is removed by, for example, distillation. The material effective in treating Epstein-Bart virus infection is contained in the water solution.
  • the starting material is dissolved in water with phenol.
  • the solution is incubated at room temperature and after incubation, the solution is clarified by filtration, and the solution is passed over a cation exchange resin.
  • the resulting resin-treated solution is then concentrated by evaporation, diluted with water, and centrifuged.
  • the acetone-insoluble fraction is then separated from the supernatant by adding a large excess of acetone and further processed as described above.
  • the acetone-insoluble fraction may be further purified to remove the color pigments by treatment with activated charcoal.
  • the acetone-insoluble fraction may be dissolved in water and contacted with ammonia-activated charcoal.
  • a pharmaceutically-acceptable preservative usually is added to the water solution.
  • phenol at from about 0.05 to about 1%, preferably about 0.5% may be added.
  • liver extract useful in the present disclosure may be prepared according to, but is not limited to, the following examples.
  • Liver Fraction I described in National Formulary XI, page 193, was dissolved in water to a concentration of 16% by weight. Phenol was added to a final concentration of 1%. The solution was mixed and incubated for seven days at room temperature. It was then clarified by filtration, and diluted to 8% solids by weight in water.
  • This aqueous solution was then passed three times through a cation exchange resin (sulfonated polystyrene).
  • the resin-treated solution was clarified by filtration and concentrated to 40% total solids by weight by evaporation under vacuum at 65-70 degrees C.
  • Cold water (5-10 degrees C) was added (five volumes of water to seven volumes of liver solution) with mixing.
  • the resultant solution was then centrifuged and the supernatant collected (Sharples-type centrifuge at 1 liter per minute). Phenol was added to a final concentration 0.5-1%.
  • the solution was adjusted to pH 6.0-7.0, with HC1 or NaOH as necessary, clarified by filtration, and heated to 40 degrees C.
  • acetone was added (20-30 liters acetone per liter liver solution). The acetone-precipitable material was allowed to settle and most of the acetone was decanted off. The remaining suspension was incubated overnight at room temperature, after which the suspension was diluted to 10 liters with water, and the acetone was removed by distillation. Phenol and water were then added to give a final preparation containing 0.5% phenol and greater than 25 mg total solids per ml (herein designated "KU 10,000").
  • KU 10,000 was adjusted to pH 6.0-7.0 with HC1 or NaOH, as necessary and diluted to 25 mg total solids per ml. with water (i.e., 2.5% by weight solids). The solution was then sterile filtered in suitable vials for use. This final solution is referred to herein as "KU 10,001 ".
  • KU 10,172 prepared according to Example II was fractionated on reverse phase C. sub.18 prep column, eluted with buffer A: 20 mM ammonium acetate pH 7.0, B: 80% acetonitrite in buffer A, gradient run at 214 nm, programmed zero to 80% B in 80 min. at 8.4 ml/min. Fractions collected 8.4 ml/test tube. All tubes were analyzed by analytical C 18 reverse phase column and size exclusion high pressure liquid chromatography column Tsk 125 and pooled to twelve fractions based on its retention times. Eight fractions KU 10,201 to KU 10,208 were tested for anti-viral activity and showed a significant cell protection activity.
  • KU 10,203 and KU 10,207 prepared according to Example III were further purified on reverse phase Ci 8 prep column, eluted with buffer A: 20 mM ammonium actuate pH 7.0, B: 80% acetonitrile in buffer A, gradient run at 214 nm, programmed: Zero to 80% B in 80 min, at 8.4 ml/min. Fractions collected 8.4 ml test tube. All tubes were analyzed by analytical Ci 8 reverse phase column and size exclusion high pressure liquid chromatography column (Tsk 125) and pooled according to its retention times to produce KU 10,214 and KU 10,215.
  • the cDNA from rat liver for the KU 10,214 and KU 10,215 fractions that were active in the bioassay was isolated and cloned using the polymerase chain reaction technique.
  • the desired sequence to be amplified was that of the gene in pig liver cells that encodes the peptides in the KU 10,214 and KU 10,215 fractions.
  • KU 10,214 has the amino acid sequence: (Ala or Val or Ile) - (Glu or Gln) - (His or Pro or Arg) - Gly - Thr - His - X - Pro - His - Gly
  • KU 10,215 has the amino acid sequence: (Ala or Val or Ile) - (Glu or Gln) - (His or Pro) - Gly - (Tyr or Met) - His - Gly - X - His - Gly - X - X - Gly - X - Gln
  • the oligonucleotide primer 5'CATGGICCICATGGI3' [the letter“I” indicates Inosine] was designed based on the five amino acid sequence (HGPHG) region sequence that was common to both the KU 10,214 and KU 10,215 fractions active in the bioassay. This primer corresponds to the indicated amino acids regardless of codon usage except for His. Codon bias analysis for all pig gene sequences found in the databank Genbank 66 showed His codon at CAT to be used about 2.5 times as often as His codon CAC. This and the rarity of CG dinucleotides in peptide coding regions of mammalian genomes (Sambrook, I, Fritsch, E. F. and Maniatis, T.
  • RNA Isolation [0046] Total RNA (2.5 mg) was isolated from 1.5 grams of fresh liver tissue from a female pig by rapid homogenation in guanidine thiocyanate followed by extraction with phenol (Chomczynski, P. and Sacchi, N. (1987) Anal. Biochem 162, 156-159). After two successive precipitations with isopropanol, the purified RNA was dissolved in water. The RNA was then subjected to poly(U) Sepharose chromatography, (Jacobson, A. (1987) Meth. Enzymology 152, 254-261), which yielded 21 pg of Poly(A)+RNA from 1 mg of total RNA. cDNA Synthesis and Intermediate Polymerase Chain Reaction Amplification
  • Double stranded cDNA was prepared from the Poly(A)+RNA by a modification of the method of Gubler and Hoffman (Gene 25, 283 (1983)). Five pg of Poly(A)+RNA was used with an oligo(dT)-Hind III primer and AMV reverse transcriptase to synthesize the first strand, and second strand conversion was accomplished using RNase H and E. Coli DNA polymerase I. The yield was 30% first strand conversion and 100% second strand conversion. The double stranded cDNA was extracted with phenol and precipitated with ethanol by conventional methods. After treatment with T4 DNA polymerase to flush the ends, the cDNA was ligated with UNIAMP adaptors (Clontech Labs Inc.
  • the amplified cDNA was precipitated with ethanol, collected by centrifugation and dissolved in 20 pi water.
  • a 1 m ⁇ sample was used for polymerase chain reaction amplification with the specific primer described above in combination with oligo (dT)-Hind III primer.
  • Conditions for polymerase chain reaction were 30 cycles at 94 degrees C for 1 minute, and 72 degrees C for 2 minutes per cycle, with a final extension at 72 degrees C for 5 minutes.
  • a fraction of the reaction products were analyzed by agarose gel electrophoresis in the presence of ethidium bromide. The results showed 3 major DNA species in the range of 200 bp (base pairs), 400 bp and 500 bp. Control reactions in which the primers were omitted produced no detectable products.
  • the remainder of the polymerase chain reaction products was treated with T4 DNA polymerase to flush the ends, and then purified by phenol extraction and ethanol precipitation.
  • the DNA was ligated with ECOR I linkers under standard conditions.
  • the prepared DNA was ligated with ECO RI/Hind III EXLOX vector arms, packaged in vitro, and plated on E. Coli by standard methods.
  • the resulting library contained 3xl0 5 independent clones and was amplified to a titer of 3xl0 10 pfp/ml.
  • the library was plated at a density corresponding to approximately 1,000 plaques per 82 mm plate. Plaque lifts were prepared and hybridized with random-primer labeled DNA probes by conventional methods. Using a probe from DNA amplified with the specific primer described above, virtually every plaque produced a positive hybridization signal. This indicated the library contained the desired inserts of polymerase chain reaction products.
  • Sequencing experiments determined 96 base pairs at the 5' end and 110 pairs at the 3' of the cDNA insert, which appeared to be identical in the clones sequenced.
  • the 5' 96 base pairs encoded a 32 amino acid polypeptide (Sequence Id. No. 1) whose first four amino acids GPHG corresponded to those of the primer HPGHG. (Sequence Id. No. 2)
  • the 110 pairs at the 3' end (Sequence Id. No. 3) had a TAA or ATG stop codon in all three reading frames, so the C-terminal of the polypeptide is L (encoded by 5'CTA3'), (Sequence Id. No.
  • the physiologically-active polypeptide may be characterized by its physical and chemical properties.
  • the active polypeptide is insoluble in acetone, and soluble in water. It has a molecular weight as determined by molecular sieve chromatography experiments to be about 5,000-40,000.
  • polypeptides useful in the present disclosure may administered via injection, for example, intramuscular injection.
  • forms of administration which may include orally, such as pill or liquid form, transdermally, such as a cream or patch applied to the skin, and in suppository form.
  • the polypeptides may be employed in the form of pharmaceutically-acceptable salts of the components, such as the alkali metal salts.
  • the pharmaceutically-acceptable amides, lower alkyl esters, protected derivatives, other derivatives and analogues of the components of the polypeptides are also contemplated.
  • the polypeptides may be used as a water solution, it may also be utilized in association with other pharmaceutical carriers, for example, in saline solution.
  • the polypeptide since the polypeptide is preferably administered by injection, it is contemplated that the extract will be contained in a water base carrier.
  • a preferred product is a polypeptide water solution containing about 2.5% by weight of polypeptide. More generally, the polypeptide ranges from 5 pg to 500 pg per ml of carrier.
  • the acetone-insoluble liver extract useful in the present disclosure may be administered by injection, for example, intramuscular injection. However, other forms of administration are contemplated.
  • the liver extract may be employed in the form of pharmaceutically-acceptable salts of the components, such as the alkali metal salts.
  • pharmaceutically-acceptable amides, lower alkyl esters, protected derivatives, other derivatives and analogues of the components of the liver extract are also contemplated.
  • the liver extract may be used as a water solution, it may also be utilized in association with other pharmaceutical carriers, for example, in saline solution.
  • the liver extract since the liver extract is preferably administered by injection, it is contemplated that the extract will be contained in a water base carrier.
  • a preferred product is a water solution containing about 2.5% by weight of liver extract solids.
  • the acetone-insoluble liver extract useful in the present disclosure may be administered by transdermally.
  • a transdermal delivery system has been discovered to be a particularly effective method of delivering a mammalian liver extract, such as KUTAPRESSIN, when further concentrated according to the present disclosure. Such a transdermal delivery system allows the concentrated liver extract to be absorbed into the blood in concentrations apparently adequate for the treatment of CACI.
  • the transdermal colloidal dispersion employed in the present disclosure is one of the preferred methods for administering the liver extract.
  • a soy lecithin gel is prepared from 10 grams of soy lecithin, to which 11.7 ml of isopropyl palmitate and 0.2 g of sorbic acid are added. The gel is then allowed to meld for 24 hours.
  • a 20% poly(oxypropylene)-poly(oxy ethylene) copolymer gel, such as Pluronic 127 (BASF) is prepared by adding 0.2 g of potassium sorbate and 100 ml of distilled water to 20 g of Pluronic 127. This gel is also allowed to meld for 24 hours.
  • Dessicated liver extract is used to prepare the gel formulation.
  • One way in which this may be accomplished is described below by dessicating 3 vials (60 ml) of commercially available KUTAPRESSIN.
  • a Nalgene dessicating system is set up using calcium sulfate as the dessicating absorbant.
  • Two evaporating dishes containing the KUTAPRESSIN are placed in the apparatus and a vacuum is applied via a pump for 7 minutes.
  • the dessicating absorbant must be changed every 24 hours, and the vacuum pressure must be reapplied after each change of absorbant to restore the vacuum. After 72 hours, the liquid will be absorbed, leaving only active ingredient.
  • the Pluronic 127 is then transferred to the KUTAPRESSIN emulsion. This results in a colloidal dispersion.
  • the colloidal dispersion is then transferred between the syringes about 20 times to further emulsify the mixture.
  • This final colloidal dispersion volume is about 30 ml, and it contains KUTAPRESSIN at a concentration of about 50 mg/ml.
  • transdermal delivery system comprised of lecithin and other penetration enhancers; vehicles other than lecithin which alter the molecular environment of the epidermis; an adhesive patch containing a drug reservoir, with or without a rate controlling membrane, covered by an occlusive backing; iontophoresis; and phonophoresis may be used to deliver the liver extracts of the present disclosure.
  • An acetone-insoluble liver extract useful in the present disclosure preferably is administered percutaneously, for example, using a transdermal colloidal dispersion delivery system in the form of a patch applied to the skin, or by applying the colloidal dispersion directly to the skin.
  • a transdermal colloidal dispersion delivery system in the form of a patch applied to the skin, or by applying the colloidal dispersion directly to the skin.
  • other forms of administration are contemplated.
  • the liver extract may be employed in the form of pharmaceutically acceptable salts of the components, such as alkali metal salts.
  • pharmaceutically acceptable amides, lower alkyl esters, protected derivatives, other derivatives and analogs of the components of the liver extract are also contemplated.
  • transdermal colloidal dispersion formulation is preferred, other pharmaceutical carriers, for example, a saline solution, could be employed.
  • the liver extract preferably is administered percutaneously while contained in a colloidal dispersion.
  • a preferred product is a colloidal dispersion comprised of any of a variety of transdermal delivery vehicles and penetration enhancers containing KUTAPRESSIN which has been concentrated to a level of about 50 mg/ml. Iontophoretic and phonophoretic methods of introducing KUTAPRESSIN transdermally are also contemplated.
  • Dosages may vary depending upon the condition of the patient. Generally, however, it has been found that the administration of 400 mg of KUTAPRESSIN per day will produce beneficial results in as little as about 4 weeks.
  • a patient suffering from CACI may receive a periodic dose of KUTAPRESSIN percutaneously.
  • the dosage amount may vary based on the concentration of the drug, the characteristics of the patient, and the condition of the patient.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Zoology (AREA)
  • Engineering & Computer Science (AREA)
  • Biomedical Technology (AREA)
  • Biotechnology (AREA)
  • Cell Biology (AREA)
  • Developmental Biology & Embryology (AREA)
  • Immunology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne une méthode thérapeutique pour traiter une déficience cognitive associée à une chimiothérapie. La méthode consiste à administrer une quantité thérapeutiquement efficace d'un extrait de foie de mammifère, l'extrait étant caractérisé en ce qu'il consiste en un peptide ou un fragment peptidique stable à la chaleur, insoluble dans l'acétone et hydrosoluble.
PCT/US2019/013602 2018-01-15 2019-01-15 Traitement d'une déficience cognitive associée à une chimiothérapie WO2019140429A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US201862617333P 2018-01-15 2018-01-15
US62/617,333 2018-01-15

Publications (1)

Publication Number Publication Date
WO2019140429A1 true WO2019140429A1 (fr) 2019-07-18

Family

ID=67219286

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2019/013602 WO2019140429A1 (fr) 2018-01-15 2019-01-15 Traitement d'une déficience cognitive associée à une chimiothérapie

Country Status (1)

Country Link
WO (1) WO2019140429A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284664A (en) * 1988-08-04 1994-02-08 Kremers-Urban Company Method of treating the symptoms of Alzheimer's disease
US5840342A (en) * 1997-09-17 1998-11-24 Raithaus; Lawrence R. Shark liver extract for stimulating the immune system

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5284664A (en) * 1988-08-04 1994-02-08 Kremers-Urban Company Method of treating the symptoms of Alzheimer's disease
US5840342A (en) * 1997-09-17 1998-11-24 Raithaus; Lawrence R. Shark liver extract for stimulating the immune system

Similar Documents

Publication Publication Date Title
US5798102A (en) Treatment of cardiomyopathy
JPH01319422A (ja) 神経疾患治療剤
US20080268030A1 (en) Gene therapy for diabetic ischemic disease
US6165515A (en) Method for treatment of osteoporosis
US5482930A (en) Anti-inflammatory composition and method with des-Tyr dynorphin and analogues
JP3676362B2 (ja) ポリペプチドを含んだ改良された腹膜透析液
US5284664A (en) Method of treating the symptoms of Alzheimer's disease
EP0140998A1 (fr) Préparations ophtalmiques
JPH08225452A (ja) 知覚異常改善剤
JP4463885B2 (ja) 劇症肝炎疾患治療剤
WO2019140429A1 (fr) Traitement d'une déficience cognitive associée à une chimiothérapie
AU763224B2 (en) Novel bioactivating substance
US5316775A (en) Method of treating hepatitis B infection
US5334395A (en) Method of treating an epstein-barr viral infection
GB2092001A (en) Pharmaceutical preparations comprising sodium fructose-1, 6-diphosphate for treatment of burn patients
KR100466757B1 (ko) 생체에 펩티드성 약물을 유입시키기 위한 국소 제제
US6303127B1 (en) Treatment of disease states
AU2004283526A1 (en) Therapeutic applications for C-peptide
US4753942A (en) Method for the treatment of inflammatory conditions
US4024247A (en) Composition and method of using a protein mixture derived from liver
WO2005074892A1 (fr) Creme contenant des liposomes d'interferon
Novak et al. Partial purification of a toxin from tentacles of the sea anemone Anemonia sulcata
Iandoli et al. Treatment of subcorneal pustulosis by etretinate
JPS6231A (ja) 腎性貧血治療剤
US6350472B1 (en) Method of treating HIV infection with transdermal gel containing mammalian liver extract

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19738111

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19738111

Country of ref document: EP

Kind code of ref document: A1