WO2019240706A2 - Composé de dichloro-acétate de césium destiné à être utilisé dans le traitement du cancer - Google Patents

Composé de dichloro-acétate de césium destiné à être utilisé dans le traitement du cancer Download PDF

Info

Publication number
WO2019240706A2
WO2019240706A2 PCT/TR2019/050042 TR2019050042W WO2019240706A2 WO 2019240706 A2 WO2019240706 A2 WO 2019240706A2 TR 2019050042 W TR2019050042 W TR 2019050042W WO 2019240706 A2 WO2019240706 A2 WO 2019240706A2
Authority
WO
WIPO (PCT)
Prior art keywords
cesium
dichloroacetate
compound
cells
solution
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/TR2019/050042
Other languages
English (en)
Other versions
WO2019240706A3 (fr
Inventor
Caner DEMIR
Aybüke ÜRETMEN
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of WO2019240706A2 publication Critical patent/WO2019240706A2/fr
Publication of WO2019240706A3 publication Critical patent/WO2019240706A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0014—Skin, i.e. galenical aspects of topical compositions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration

Definitions

  • the invention is about a compound and its synthesis method, which is to be used in chemical and pharmaceutical industries.
  • the invention is especially about cesium dichloroacetate compound and its synthesis method, to be used in cancer treatment.
  • Cancer is a large disease group with more than 200 types, effecting any part of the body. Cancer, one of the leading causes of death globally, caused 8,8 million people to lose their lives in 2015 according to World Health Organization (WHO).
  • WHO World Health Organization
  • Cesium chloride (CsCI) and cesium bicarbonate (CsHC03) salts of the cesium element (Cs) are used in cancer studies that are done in in vivo and in vitro levels. Cesium is observed to have different reactions in different types of cancer. Known and used salts of cesium in cancer treatment do not have the ability to kill the cancerous cells or tumorous tissue with high effectivity. Cesium initiates programmed cell death in cancerous cells, named as apoptosis. However, most of the cancerous cells are resistant to apoptosis and would not easily undergo apoptosis. Another factor decreasing the effectiveness of the cesium is that entry of cesium inside a cell cannot be done with high effectivity. In addition to these, compounds such as chlorine in cesium salts and bicarbonate are not pestilent on cancerous cells. They only make cesium solutions to have a neutral pH value.
  • dichloroacidic acid 2,2 - dichloroacidic acid
  • sodium dichloroacetate and potassium dichloroacetate are utilized for their anti-cancer properties in in vivo and in vitro cancer studies.
  • a molecular structure aimed for the production of a metabolic inhibitor that is loaded with cancerous cell activity and anti-tumour immunity is explained.
  • Said structure aims for the mitochondria of the cancerous cell.
  • the structure consists of a piece like trifenylphosphonium cation and metabolic inhibitors aiming for the mitochondria like dichloroacetic acid, put together with a biologically degradable connecter.
  • Dichloroacetate is known to change the energy metabolic pathway in cancerous cells.
  • energy production out of glucose is provided by oxidative phosphorylation occurs in the mitochondria, by using oxygen.
  • energy production out of glucose is mainly provided by lactic acid fermentation, which does not use oxygen.
  • Dichloroacetate salts lead the increasing lactic acid fermentation pathways in cancerous cells towards oxidative phosphorylation as well. As a result of this, it opens the ways for apoptosis mechanism of the cancer cells.
  • dichloroacetate does not poses the power of high fatality in all cancer types.
  • Cs cesium
  • DCA dichloroacetate
  • Subject compound of the invention has high cytotoxic effect on cancerous cells.
  • the cause of this effect is due to the cesium elements and dichloroacetate molecules found together in the compound.
  • cesium’s and dichloroacetate’s effect on cancerous cells are brought together and a cytotoxically more effective compound, compared to their salts, are made.
  • the main purpose of the invention is to break the apoptosis resistance of cancerous cells and make them undergo apoptosis.
  • cesium and dichloroacetate works together to break apoptosis resistance of cancerous cells and make them undergo apoptosis.
  • cesium dichloroacetate is made up of basic cesium hydroxide (CsOH) or cesium bicarbonate (CsHCOs) reacting with acidic dichloroacetic acid (CHChCOOH).
  • Cesium compounds with basic pH values in aqueous solutions may also be used in the reaction.
  • the invention is a drug containing cesium dichloroacetate which is aimed to use for cancer treatment in human and animals, shrinking and terminating in vivo tumors, terminating cell proliferation and division.
  • Figure 1 FTIR analysis of the synthesized cesium dichloroacetate compound.
  • FIG. 1 FTIR analysis of the cesium hydroxide compound.
  • Figure 3 FTIR analysis of the dichloroacetic acid compound.
  • FIG. 4 Representation of synthesized cesium dichloroacetate (CsDCA), cesium chloride (CsCI) and sodium dichloroacetate (NaDCA) compounds application over PC3 prostate cancer cell line, measurement times and measurement criteria.
  • CsDCA cesium dichloroacetate
  • CsCI cesium chloride
  • NaDCA sodium dichloroacetate
  • Figure 5-a The amount of cells, normalized according to the control, after 24 hours, which were treated with cesium chloride (CsCI).
  • Figure 5-b The amount of cells, normalized according to the control, after 24 hours, which were treated with sodium dichloroacetate (NaDCA).
  • Figure 5-c The amount of cells, normalized according to the control, after 24 hours, which were treated with cesium dichloroacetate (CsDCA).
  • CsDCA cesium dichloroacetate
  • Figure 6-a The amount of cells, normalized according to the control, after 48 hours, which were treated with cesium chloride (CsCI).
  • CsCI cesium chloride
  • Figure 6-b The amount of cells, normalized according to the control, after 48 hours, which were treated with sodium dichloroacetate (NaDCA).
  • NaDCA sodium dichloroacetate
  • Figure 6-c The amount of cells, normalized according to the control, after 48 hours, which were treated with cesium dichloroacetate (CsDCA).
  • CsDCA cesium dichloroacetate
  • Figure 7-a The amount of cells, normalized according to the control, after 72 hours, which were treated with cesium chloride (CsCI).
  • CsCI cesium chloride
  • Figure 7-b The amount of cells, normalized according to the control, after 72 hours, which were treated with sodium dichloroacetate (NaDCA).
  • NaDCA sodium dichloroacetate
  • Figure 7-c The amount of cells, normalized according to the control, after 72 hours, which were treated with cesium dichloroacetate (CsDCA).
  • CsDCA cesium dichloroacetate
  • FIG. 8 CI-Caspase-3 amounts of cells that were applied drugs containing synthesized cesium dichloroacetate (CsDCA) compound, cesium chloride (CsCI) and sodium dichloroacetate (NaDCA) compounds at hour 48.
  • CsDCA cesium dichloroacetate
  • CsCI cesium chloride
  • NaDCA sodium dichloroacetate
  • Figure 9 Images of ezrin protein marked by immunohistochemistry method.
  • the invention s subject compound, cesium dichloroacetate (CsDCA) compound, has high cytotoxic effect on cancerous cells.
  • the reason for this effect is that the compound contains both cesium (Cs) element and dichloroacetate (DCA) molecule.
  • basic cesium hydroxide (CsOH) or cesium bicarbonate (CsHC0 3 ) molecule and acidic dichloroacetic acid (CHCI2COOH) molecule are put into reaction and the cesium dichloroacetate (CsDCA) compound is synthesized. In this way, both cesium’s and dichloroacetate’s effect upon cancerous cells are combined.
  • cesium dichloroacetate compound when compared to its component’s salts, surprisingly showcases a more effective cytotoxic property.
  • cesium dichloroacetate compound is shown to portray a different bond structure than cesium hydroxide and dichloroacetic acid given in Figure 2 and Figure 3, respectively, and other molecules used in the synthesis.
  • subject compound cesium dichloroacetate, cesium element and dichloroacetate molecule shows a synergic effect.
  • Cesium dichloroacetate compound synthesized to kill cancer cells or tumorous tissue, functions by disrupting the metabolism of cancerous cells. It deranges the intracellular potassium balance by blocking potassium channels from inside or outside of the cell. As a result of this, cell membrane potential is disturbed. Secondary effects develop in accordance with this. Changes occur about the entrance of materials that are carbon sources, like glucose, inside the cell. Flow of ions, between the inside and the outside of the cell, changes.
  • Intracellular ion flow is also affected due to structural deformation of the cell skeleton (cytoskeleton) inside the cell.
  • cytoskeleton cytoskeleton
  • the intracellular electrical balance changes too. Connection between intracellular skeletal proteins and extracellular matrix is corrupted. Consequently, the migration ability of the cancerous cell is eliminated.
  • synthesized compound annihilates cancerous cell’s ability to metastasize.
  • it increases intracellular reactive oxygen amount by shifting the metabolism of the cell towards aerobic respiration. Hereby, it decreases the apoptosis resistance of cancerous cell by increasing intracellular stress.
  • the amount of lactate and proton produced in the cell decreases due to the shift of metabolism in the cancerous cell.
  • cancerous cells undergo controlled cell death (apoptosis). Necrosis can be observed in a small amount of cells.
  • controlled cell death by apoptosis in most of the cells in tumorous tissue is requested, in some, death by necrosis is preferred. While the cells die by necrosis, they release molecules that may stimulate immune system, such as protein, fat and glycoprotein. In this way, it is enabled for the immune system to migrate to this area by recognizing the tumorous tissue and the tumorous tissue to be exterminated faster.
  • CsDCA cesium dichloroacetate
  • synthesized cesium dichloroacetate (CsDCA) compound, cesium chloride (CsCI) and sodium dichloroacetate (NaDCA) compounds are applied on to the cell line of PC3 prostate cancer and the results are evaluated by taking measurements at specific time intervals, according to the control group cells.
  • the purpose of cesium chloride (CsCI) and sodium dichloroacetate (NaDCA) application is to separately specify the effectivity of cesium and dichloroacetate.
  • CsCI cesium chloride
  • NaDCA sodium dichloroacetate
  • CsCI cesium chloride
  • NaDCA sodium dichloroacetate
  • CsDCA cesium dichloroacetate
  • FIG 6-a the amount of cells, after the cesium chloride (CsCI) application, normalized numbers of cells at 48 th hour according to control, is shown. In application results, a 50% decrease is observed in cesium chloride (CsCI) applied cells, compared to the cells in control group.
  • Figure 6-b the amount of cells, after the sodium dichloroacetate (NaDCA) application, normalized numbers of cells at 48 th hour according to control, is shown. In application results, 25% increase is observed in sodium dichloroacetate (NaDCA) applied cells, compared to the cells in control group.
  • CaDCA sodium dichloroacetate
  • CI-Kaspaz-3 Active caspase-3 (CI-Kaspaz-3) amount is checked to determine if cells die by apoptosis to be determined.
  • CI-Caspase-3 amounts of cells, in 48 th hour, which are applied with drugs containing synthesized cesium dichloroacetate (CsDCA) compound, cesium chloride (CsCI) and sodium dichloroacetate (NaDCA) compounds, is determined by immunohistochemistry method. When the results are evaluated, cesium dichloroacetate (CsDCA) gives the highest apoptotic index value.
  • CsDCA cesium dichloroacetate
  • ezrin protein amounts marked with immunohistochemistry method, is shown.
  • CsDCA cesium dichloroacetate
  • Cesium hydroxide is produced through the reaction of pollucite, lime and calcium chloride. Also, it can be synthesized with barium hydroxide and cesium sulphide. Cesium hydroxide used in synthesis reaction is mostly used in parted cesium titanosilicates production, electrical battery production, production of ion exchange materials used in radioactive waste cleaning, as a catalyser in methyl propionate and formaldehyde reaction, as a catalyser in organic synthesis reactions and as additional material in some zeolite types. Cesium hydroxide on its own cannot be used in cancer treatment. Since cesium hydroxide is a strong base, it cannot be administrated to a human being orally or via blood.
  • dichloroacetic acid can be chemically produced through methods such as dichlroacetyl chloride hydrolysis, pentachloroethane and sulphuric acid hydrolysis or 1,1- dichloroacetone and nitric acid oxidation.
  • Dichloroacetic acid can be used; in organic synthesis reactions, production of glyoxylic acid, production of sulphonamide, speeding up of iron chelators, fiber production such as polyethylene terephthalate, as medical disinfectant and as chemical burner in living tissues.
  • Cesium compounds with basic pH value in aqueous solution can be used in he synthesis method.
  • cesium compound used in synthesis method is either cesium hydroxide (CsOH) or cesium bicarbonate (CsHC0 3 ).
  • cesium hydroxide (CsOH) and dichloroacetic acid (CHCI2COOH) chemicals are used.
  • Synthesis reaction is an acid base reaction. As a result of the synthesis, cesium dichloroacetate and water are released.
  • Cesium hydroxide is in powder form and it is a hygroscopic substance that absorbs moisture. For this reason, it is in cesium hydroxide hydrate (Cs0H.xH20) form when in powder form. Powder cesium hydroxide may contain water up to 20%, by weight. It can dissolve in water and ethanol. Powder cesium hydroxide should be stored in a dry place. Cesium hydroxide compound can be dried in a vacuumed drying oven, in a temperature range of 30-100°C, before preparation. In the preferred application of the invention, cesium hydroxide hydrate should be dried in a vacuumed drying oven, at 60°C, before preparing the cesium hydroxide compound.
  • aqueous solution containing (w/w) 5-80% of cesium hydroxide can be used directly.
  • the synthesis solution of cesium dichloroacetate contains 50-60% cesium hydroxide and 40-50% dichloroacetic acid respectively by weight.
  • the synthesis solution of cesium dichloroacetate contains 53,76% cesium hydroxide and 46,24% dichloroacetic acid.
  • the synthesis method of the invention contains the following steps:
  • Cesium hydroxide hydrate powder containing 1 mole (149,91 gr) of cesium hydroxide, is placed into a vessel. By extracting the weight of the hydrate in added cesium hydroxide hydrate powder, pure deionized water, as much as the weight obtained, is added. Cesium hydroxide powder can also be added into the water.
  • a mixer is used for the cesium hydroxide to homogeneously dissolve. Cesium hydroxide solution is mixed in the range of 100 - 1500 rpm, in the said mixer. In a preferred application of the invention, the rotation speed of the mixer is 400 rpm.
  • Dichloroacetic acid to be added on top of cesium hydroxide solution is measured to be 1 mole (128,94 gr).
  • the prepared dichloroacetic acid is added to the cesium hydroxide solution, which is mixed with the use of a dropping funnel or another container.
  • cesium hydroxide solution can also be added on top of dichloroacetic acid. pH and temperature are measured along the mixing procedure. The pH and temperature of the synthesis solution are expected to become fixated. If the pH value of the synthesis solution is above 7, dichloroacetic acid is added and if the pH value is below 7, 50% cesium hydroxide solution is added.
  • the pH value, regulated while mixing the synthesis solution is fixed to be in the rage of 6,8 and 7,2. In a preferred application of the invention, pH value is fixed at 7. Change of colour in the synthesis solution can be observed when dichloroacetic acid and cesium hydroxide are mixed. This change is related to pH value. The solution becomes transparent again when pH value comes close to 7.
  • the liquid phase of the formed synthesis solution is removed in the rotary evaporator under vacuum, in the drying oven and in spray dryer and cesium dichloroacetate is transformed into powder form.
  • Synthesis solution is preferably put in to rotary vacuum evaporator.
  • the liquid phase will be evaporated in pressures lower than 20 millibar, at a temperature range of 20 - 95 0 C and by rotating in the 20 - 300 rpm range. In a preferred application of the invention, the liquid phase is evaporated under a 8 millibar pressure, heated at 40 0 C and by rotating in 100 rpm.
  • the product concentrated in the rotating evaporator is poured into drying vessels and is let to dry in drying ovens with a temperature ranging from 40 to 100°C degrees or a vacuumed oven for 4 to 72 hours.
  • the product concentrated in the rotary evaporator is poured into drying vessels and is let to dry in the drying oven with a temperature ranging of 50°C degrees or a vacuumed oven for 24 hours.
  • a spray dryer, after rotary evaporator or on its own can be used to pulverize the solution.
  • the powder extracted after drying processes is dissolved with a needed amount of polar solvent (like water, dimethyl sulfoxide and ethanol) to be dissolved completely.
  • Extracted solution is purified with purification methods such as colon chromatography, precipitation and crystallization.
  • the liquid phase containing purified cesium dichloroacetate is evaporated, to extract pure cesium dichloroacetate, by lyophilisation between the temperature range of (-55°C) - (-85 °C) or drying by vacuumed below 20 millibar or non-vacuumed heating between the temperature range of 40 - 100°C.
  • the liquid phase containing purified cesium dichloroacetate is evaporated, to extract pure cesium dichloroacetate, by lyophilisation at a temperature of -55°C or drying by vacuumed under 8 millibar or non-vacuumed heating at the temperature of 50°C.
  • the synthesis solution is palced into a rotary evaporator under 8 millibar of pressure, heated at 40°C, at a rotating speed of 100 rpm. Concentrated product is put into drying vessels and is let to dry in vacuumed drying oven at 50°C, for 24 hours. Deionised water, enough to dissolve the powder completely, is added on top of the powder extracted from drying processes. The extracted solution is put into the appropriate chromatography colon and it enables to get rid of impurities such as dichloroacetic acid, cesium hydroxide and etc. The liquid phase containing purified cesium dichloroacetate, is powdered by lyophilisation, at -55°C degrees.
  • Cesium dichloroacetate compound can be administered to cancer patients via parenteral, orally or dermally. By administrating under the skin with subdermal carrier compounds, such as dimethyl sulfoxide, absorption can be increased.
  • subdermal carrier compounds such as dimethyl sulfoxide
  • Cesium dichloroacetate can be used with subdermal and in vivo biocompatible drug release materials and devices. Cesium dichloroacetate compound can be administrated with methods increasing the ability of a drug to reach to cells and to be received by cells such as nanoparticles, nanospheres, controlled drug release systems and targeted drug carrier systems.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Dermatology (AREA)
  • Engineering & Computer Science (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Inorganic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Oxygen Or Sulfur (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un composé de dichloro-acétate de césium destiné à être utilisé dans le traitement du cancer et son procédé de synthèse. Le césium et le dichloro-acétate agissent ensemble pour rompre la résistance à l'apoptose de cellules cancéreuses et faire en sorte qu'elles subissent une apoptose. Dans le composé de l'invention, le dichloro-acétate de césium, l'élément césium et la molécule d'acétate de dichloro-acétate présentent un effet synergique. En conséquence d'effets métaboliques, électrochimiques et potentiellement génétiques et épigénétiques, provoqués par le composé synthétisé mentionné ci-dessus, les cellules cancéreuses subissent une mort cellulaire contrôlée par apoptose et certaines d'entre elles subissent une nécrose.
PCT/TR2019/050042 2018-01-26 2019-01-21 Composé de dichloro-acétate de césium destiné à être utilisé dans le traitement du cancer Ceased WO2019240706A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR201801154 2018-01-26
TR2018/01154 2018-01-26

Publications (2)

Publication Number Publication Date
WO2019240706A2 true WO2019240706A2 (fr) 2019-12-19
WO2019240706A3 WO2019240706A3 (fr) 2020-02-13

Family

ID=68842796

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/TR2019/050042 Ceased WO2019240706A2 (fr) 2018-01-26 2019-01-21 Composé de dichloro-acétate de césium destiné à être utilisé dans le traitement du cancer

Country Status (1)

Country Link
WO (1) WO2019240706A2 (fr)

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006108276A1 (fr) * 2005-04-11 2006-10-19 The Governors Of The University Of Alberta Procede de traitement anticancereux par dichloroacetate
EP2026657A4 (fr) * 2006-05-24 2009-12-09 Pharmaionix Inc Composition anticancéreuse et sa méthode d'utilisation
TW201722416A (zh) * 2015-12-31 2017-07-01 He Xuan Biotech Co Ltd Cd44及葉酸受體特異性結合之抗肝癌標靶藥物

Also Published As

Publication number Publication date
WO2019240706A3 (fr) 2020-02-13

Similar Documents

Publication Publication Date Title
Jacob et al. Humic substances as a potent biomaterials for therapeutic and drug delivery system—A review
AU4536999A (en) Use of a dipeptide for stimulating repair processes
Wu et al. Sulforaphane: expected to become a novel antitumor compound
CN108126206B (zh) 药物负载用掺钆单层水滑石及其制备方法和一种抗癌药物及其制备方法
Anvitha et al. Facile fabrication of titanium carbide (Ti3C2)-bismuth vanadate (BiVO4) nano-coupled oxides for anti-cancer activity
EP2026657A1 (fr) Composition anticancéreuse et sa méthode d'utilisation
US12138322B2 (en) Method of preventing the development of melanoma
Kanhouwa et al. Phenothiazines and breast cancer
US10076539B2 (en) Pharmaceutical use of potassium hydroxide
CN1582946B (zh) 积雪草酸衍生物在制备防治心、脑血管疾病的药物中的用途
CN102988422A (zh) 美洲大蠊纳米提取物及其制备方法
CN104277083B (zh) 一种木犀草素-7-o-β-D-葡萄糖醛酸苷制备方法及用途
CN109350620B (zh) 一种治疗卵巢癌的药物及其用途
AU2019475409B2 (en) Method of preventing the development of melanoma
RU2112530C1 (ru) Способ лечения опухолей
RU2146927C1 (ru) Препарат для лечения рака кожи и предраковых заболеваний кожи
CN115813949B (zh) 黄腐酸在制造防治放疗致皮肤灼伤的组合物的用途
CN103830273B (zh) 黄腐酸盐在制备促血管新生药物中的应用
WO2011119126A1 (fr) Utilisation de l'acide oxalique dans la fabrication d'une préparation médicinale qui possède une action antitumorale vis-à-vis des cellules malignes, préparation médicinale sur cette base et procédé de traitement
CN108210540A (zh) 红花水提取物在制备抗辐射药物中的应用
Xu et al. Corrigendum to “The application of proteomics and phosphoproteomics to reveal the molecular mechanism of salidroside in ameliorating myocardial hypoxia”[Heliyon 10 (9), May 2024, Article e30433]
RU2256443C2 (ru) Таблетка противоопухолевого действия, способ ее получения и способ лечения больных с онкологической патологией
RU2256444C2 (ru) Таблетка противоопухолевого действия, способ ее получения (варианты) и способ лечения больных с онкологической патологией
RU2222326C1 (ru) Способ лечения саркомы юинга
RU2555351C1 (ru) Способ лечения хронического описторхоза у больных с розацеа

Legal Events

Date Code Title Description
NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19819997

Country of ref document: EP

Kind code of ref document: A2