WO2017148945A1 - Hexafluoro-2-propanol utilisé comme inhibiteur d'invasion de cellules tumorales - Google Patents

Hexafluoro-2-propanol utilisé comme inhibiteur d'invasion de cellules tumorales Download PDF

Info

Publication number
WO2017148945A1
WO2017148945A1 PCT/EP2017/054640 EP2017054640W WO2017148945A1 WO 2017148945 A1 WO2017148945 A1 WO 2017148945A1 EP 2017054640 W EP2017054640 W EP 2017054640W WO 2017148945 A1 WO2017148945 A1 WO 2017148945A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
propanol
hexafluoro
treatment
prevention
Prior art date
Application number
PCT/EP2017/054640
Other languages
English (en)
Inventor
Beatrice BECK SCHIMMER
Martin Andreas URNER
Wendelin Stark
Original Assignee
Universität Zürich
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 Universität Zürich filed Critical Universität Zürich
Publication of WO2017148945A1 publication Critical patent/WO2017148945A1/fr

Links

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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • the present invention relates to the use of compounds of general formula (R 1 ) n -R 2 -(CF 3 ) m , particularly to hexafluoroisopropanol, for the prevention and treatment of malignant tumors, particularly the inhibition of tumor cell invasion and metastasis.
  • Malignant cancers belong to the top 10 leading causes of death in the upper-middle and high income countries. Malignant tumors overcome multiple barriers, including the extracellular matrix, before invading blood or lymph vessels on their way to spread throughout the body. Therefore tissue invasion, metastasis and migrating represent critical steps in the development of a disseminated neoplastic disease.
  • volatile anesthetics have been shown to reduce invasion of malignant tumor cells through a down-regulation of Matrix Metalloproteinase-9 (Muller-Edenborn et al.; Anesthesiology, 2012; 1 17(2):293).
  • Matrix Metalloproteinase-9 Matrix Metalloproteinase-9
  • the use of volatile anesthetics is associated with several disadvantages. Due to the anesthetic side-effect patients have to be monitored and ventilated in a controlled environment such as an operating room or an intensive care unit during administration. Dosing especially in sub-anesthetic concentrations is very difficult. These limitations severely limit the use of volatile anesthetics. Therefore substances with the tumor invasion suppressing effects but without the volatile and anesthetic effects of known substances are warranted.
  • the problem underlying the present invention is to provide the means for inhibition of tumor cell invasion and/or migration. This problem is solved by the subject-matter of the independent claims.
  • parenteral administration refers to administration by injection, infusion, or implantation.
  • epithelial tumor in its meaning known in the art of medicine; it refers to tumors that develop from epithelial cells.
  • Epithelial cells line the cavities and surfaces of organs and blood vessels. They can be derived from ectoderm, mesoderm or endoderm.
  • mesenchymal tumor is used in its meaning known in the art of medicine; it refers to tumors that develop from mesenchymal cells.
  • the mesenchyme is the embryonic connective tissue, which is the origin of adult connective tissue, bones, cartilage, heart, smooth muscle tissue, kidneys, adrenal gland, blood vessels etc.
  • Non-limiting examples of mesenchymal tumors are fibrosarcoma, osteosarcoma, chondrosarcoma, leukemia and rhabdomyosarcoma.
  • alkyl is used in its meaning known in the art of chemistry; it refers to a linear or a branched form of a saturated hydrocarbon of the general formula C n H 2 n+i , wherein n is a number equal to or larger than 1.
  • alkyls are methyl (CH 3 ), ethyl (C 2 H 5 ) or propyl (C 3 H 7 ).
  • alkenyl is used in its meaning known in the art of chemistry; it refers to a linear or branched form of an unsaturated hydrocarbon of the general formula C n H 2 n-i , wherein n is a number equal to or larger than 2.
  • alkenyls are ethenyl (C 2 H 3 ) or propenyl (C 3 H 5 ).
  • cycloalkyl is used in its meaning known in the art of chemistry; it refers to a cyclic form of a saturated hydrocarbon of the general formula ⁇ ⁇ ⁇ 2( ⁇ +1-9)-1 , wherein n is the number of carbon atoms and n is a number equal to or larger than 3 and g is the number of rings in the molecule.
  • linear or branched, substituted or non-substituted alkyl, alkenyl or cycloalkyl encompasses linear or branched, substituted or non-substituted alkyl; linear or branched, substituted or non-substituted alkenyl and linear or branched, substituted or non-substituted cycloalkyls.
  • the inventors surprisingly found in transmigration experiments that the primary metabolite of the volatile anesthetic sevoflurane, 1 , 1 , 1 ,3,3,3-hexafluoro-2-propanol (HFIP; CAS No. 920- 66-1 ), significantly reduced invasion and migration of colorectal cancer cells.
  • HFIP volatile anesthetic sevoflurane
  • Volatile anaesthetics such as sevoflurane are hydrophobic and marginally soluble in water or other biological fluids such as blood. Therefore, their intravenous administration is only feasible by addition of emulsifiers and stabilization agents. These attempts fail in a clinical setting due to a lot of difficulties such as the anaesthetic side-effect of the anaesthetics, dosing problems or pain during injection caused by the emulsifier.
  • HFIP is intravenously administrable and lacks the anesthetizing ether basic structure of volatile anesthetics. Being the primary metabolite of sevoflurane, extensive pharmacokinetic and toxicological data for HFIP is already available.
  • HFIP seems to have an inhibiting effect on critical steps in the evolvement of neoplastic diseases, overcomes limitations of volatile anesthetics, and therefore potentially enables the future treatment of a broad patient population suffering from malignant diseases by preventing tumor cell spread and metastasis.
  • hexafluoro-2-propanol (1 , 1 , 1 ,3,3,3- hexafluoropropan-2-ol) for use in a method for prevention or treatment of malignant tumors is provided.
  • a pharmaceutical composition comprising hexafluoro-2-propanol for use in prevention or treatment of malignant tumors.
  • a pharmaceutical carrier or excipient may be present.
  • Volatile anesthetics such as sevoflurane are hydrophobic and marginally soluble in water or other biological fluids such as blood. Therefore, their intravenous administration is only feasible by addition of emulsifiers and stabilization agents. These attempts fail in a clinical setting due to a lot of difficulties such as the anesthetic side effect of the anesthetics, dosing problems or pain during injection caused by the emulsifier.
  • derivatives of volatile anesthetics such as specified by formula I above, are intravenously administrable and lack the anesthetizing ether basic structure of volatile anesthetics.
  • a compound of formula (I) for use in a method for prevention or treatment of malignant tumors is provided.
  • a pharmaceutical composition comprising at least one compound according to the first aspect of the invention for use in prevention or treatment of malignant tumors.
  • a pharmaceutical carrier or excipient may be present.
  • the compound of formula (I) is 1 , 1 , 1 ,3,3,3-Hexafluoropropan-2-ol (CAS: 920-66-1 ). Specific description of the invention
  • hexafluoro-2-propanol (1 , 1 , 1 ,3,3,3- hexafluoropropan-2-ol) for use in a method for prevention or treatment of malignant tumors is provided.
  • tumor cell invasion and/or migration is inhibited by hexafluoro-2- propanol.
  • the malignant tumor is selected from epithelial tumor, mesenchymal tumor, adenocarcinoma and colon carcinoma.
  • hexafluoro-2-propanol is for parenteral administration. This overcomes the limitations of volatile anesthetics such as the requirement of mechanical ventilation.
  • a pharmaceutical composition comprising hexafluoro-2-propanol (1 , 1 , 1 ,3,3,3-hexafluoropropan-2-ol) for use in prevention or treatment of malignant tumors is provided.
  • a pharmaceutical carrier or excipient may be present.
  • the pharmaceutical composition is for parenteral administration, such as intravenous, intramuscular or subcutaneous administration.
  • parenteral administration such as intravenous, intramuscular or subcutaneous administration.
  • the active ingredient, optionally together with excipients can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • hexafluoro-2-propanol may be administered in any conventional dosage form in any conventional manner.
  • Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermal ⁇ , orally, inhalative or topically.
  • the preferred modes of administration are intravenous, intrathecal, intraperitoneal, peri- or epidural, subcutaneous, intramuscular or topical.
  • hexafluoro-2-propanol may be administered alone or in combination with adjuvants that enhance the stability or facilitate administration of pharmaceutical compositions containing hexafluoro-2-propanol.
  • adjuvants may provide increased dissolution or dispersion, provide adjunct therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side-effects incurred when used as monotherapies.
  • dosage forms of hexafluoro-2-propanol include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
  • a compound for use in a method for prevention or treatment of malignant tumors according to formula (I)
  • - n is 1 , 2, 3, 4 or 5
  • - m is 1 , 2, 3 or 4,
  • each R 1 is independently selected from the group consisting of OH, NH 2 , COOH, - COOR 4 , -CHO, -C(0)-R 4 , -CONH 2 , and -CONHR 4 ; wherein R 4 is in each instance independently selected from linear or branched, substituted or non-substituted C-r, C 2 -, or C 3 -alkyl, alkenyl or cycloalkyl and each R 1 is bound to R 2 ,
  • R 2 denotes a linear, substituted or non-substituted alkyl
  • the compound of formula (I) has less than seven carbon atoms, for use in a method for prevention or treatment of malignant tumors.
  • R 2 is a Ci -4 alkyl.
  • R 2 is substituted with 1 to 3 substituents, each substituent being selected independently from one another from the group consisting of -F, -CI, -Br, -I, -OH, -NH 2 , -COOH, -COOR 4 , -CHO, -C(0)-R 4 , -CONH 2 , and -CONHR 4 ; wherein R 4 is a linear or branched, substituted or unsubstituted Ci -3 or CMO alkyl, alkenyl, or cycloalkyl.
  • R 2 is substituted with 1 to 3 fluorine (F) substituents.
  • n 1 and m is 2.
  • n is 1 and m is 1.
  • R 4 is substituted with 1 to 3 substituents, each substituent being selected independently from one another from the group consisting of -F, -CI, -Br, -I, -OH, -NH 2 , -COOH, and -CONH 2 . In certain embodiments, R 4 is substituted with 1 to 3 fluorine (F) substituents.
  • the compound of formula (I) has less than six carbon atoms. In certain embodiments, the compound of formula (I) has less than five carbon atoms. In certain embodiments, the compound of formula (I) has three carbon atoms.
  • the compound for use in a method for prevention or treatment of malignant tumors is selected from the group consisting of:
  • the compound for use in a method for prevention or treatment of malignant tumors is selected from the group consisting of:
  • the compound has an octanol-water partition coefficient of less than 20.
  • tumor cell invasion and/or migration is inhibited.
  • the malignant tumor is selected from epithelial tumor, mesenchymal tumor, adenocarcinoma and colon carcinoma.
  • the compound is for parenteral administration. This overcomes the limitations of volatile anesthetics such as the requirement of anesthesia care.
  • the compound of formula (I) is provided for use in a method of prevention or treatment of a malignant tumour disease, wherein the tumour is derived from an epithelial cell.
  • the compound of formula (I) is provided for use in a method of prevention or treatment of a malignant tumour disease, wherein the tumour is derived from a colon cell.
  • a pharmaceutical composition comprising at least one compound according to the first aspect of the invention for use in prevention or treatment of malignant tumors is provided.
  • a pharmaceutical carrier or excipient may be present.
  • the pharmaceutical composition is for parenteral administration, such as intravenous, intramuscular or subcutaneous administration.
  • parenteral administration such as intravenous, intramuscular or subcutaneous administration.
  • the active ingredient, optionally together with excipients can be made into a solution before parenteral administration by the addition of suitable solvents. Solutions such as are used, for example, for parenteral administration can also be employed as infusion solutions.
  • the compound may be administered in any conventional dosage form in any conventional manner.
  • Routes of administration include, but are not limited to, intravenously, intramuscularly, subcutaneously, intrasynovially, by infusion, sublingually, transdermal ⁇ , orally, inhalative or topically.
  • the preferred modes of administration are intravenous, intrathecal, intraperitoneal, peri- or epidural, subcutaneous, intramuscular or topical.
  • the compound may be administered alone or in combination with adjuvants that enhance the stability or facilitate administration of pharmaceutical compositions.
  • adjuvants may provide increased dissolution or dispersion, provide adjunct therapy, and the like, including other active ingredients.
  • combination therapies utilize lower dosages of the conventional therapeutics, thus avoiding possible toxicity and adverse side-effects incurred when used as monotherapies.
  • dosage forms of the compound include pharmaceutically acceptable carriers and adjuvants known to those of ordinary skill in the art.
  • the invention is further defined by the following items:
  • n 1 , 2, 3, 4 or 5
  • n 1 , 2, 3 or 4,
  • each R 1 is independently selected from the group consisting of:
  • R 4 is in each instance independently selected from linear or branched, substituted or non-substituted C , C 2 -, or C 3 -alkyl, alkenyl or cycloalkyl and each R 1 is bound to R 2 ,
  • R 2 denotes a linear, substituted or non-substituted alkyl
  • Item 2 The compound for use in a method for prevention or treatment of malignant tumors according to claim 1 , wherein R 2 is a Ci -4 alkyl.
  • Item 3 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein R 2 is substituted with 1 to 3 substituents, each substituent being selected independently from one another from the group consisting of -F, -CI, -Br, -I, -OH, -NH 2 , -COOH, -COOR 4 , -CHO, -C(0)-R 4 , -CONH 2 , and -CONHR 4 ; wherein R 4 is a linear or branched, substituted or unsubstituted Ci -3 alkyl or CMO alkyl, alkenyl, or cycloalkyl.
  • Item 4 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein n is 1 and m is 1 or 2.
  • Items 5 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein n is 1 , m is 1 or 2 and R 2 is a Ci-3 alkyl.
  • Item 6 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein the compound has an octanol- water partition coefficient of less than 20.
  • Item 7 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, selected from the group consisting of:
  • Item 8 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein tumor cell invasion and/or migration is inhibited.
  • Item 9 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein the malignant tumor is selected from epithelial tumor, mesenchymal tumor, adenocarcinoma and colon carcinoma.
  • Item 10 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein the tumour is derived from a colon cell.
  • Item 1 1 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein the tumour is a tumour derived from an epithelial cell.
  • Item 12 The compound for use in a method for prevention or treatment of malignant tumors according to any one of the preceding items, wherein the compound is for parenteral administration.
  • Item 13 A pharmaceutical composition comprising at least one compound as specified any one of items 1 to 7 for use in prevention or treatment of malignant tumors.
  • Item 14 The pharmaceutical composition according to item 13, wherein the pharmaceutical composition is for parenteral administration.
  • the invention is further illustrated by the following examples and figures, from which further embodiments and advantages can be drawn. These examples are meant to illustrate the invention but not to limit its scope.
  • Fig. 1 shows transmigration of mouse colon carcinoma (MC38/GFP) cells in
  • MC38/GFP cells were exposed for 15 min to Sevoflurane (2.2 Vol%), to hexafluoroisopropanol (4 mM) or to culture medium (control group).
  • Fetal calf serum (10%) served as unspecific chemoattractant and was added to the lower compartments of the migration chambers.
  • the number of transmigrated carcinoma cells exposed to culture medium solely has been defined as the control group.
  • HFIP hexafluoro-2- propanol.
  • Fig. 2 shows the amount of DNA and NADPH oxidase-related metabolic activity
  • MMTT tetrazolium bromide assay
  • Fig. 3 shows a schematic illustration of experimental setting to measure transmigration of mouse colon carcinoma (MC38/GFP) cells in Matrigel-coated 24-well migration plates.
  • MC38/GFP cells were exposed for 15 min to sevoflurane (2.2Vol%), to various trifluorinated molecules (final concentration of 4 mM), or to culture medium (control group).
  • Fetal calf serum (10%) served as unspecific chemoattractant and was added to the lower compartments of the migration chambers (positive control).
  • Fig. 4 shows the set of molecules that was chosen to be tested in the present experiments in order to represent the effects of small, water-soluble molecules (molecular weight of below 250) of different chemical nature (alcohols, amino acids, and amides) carrying at least one trifluorinated carbon group (CF 3 ).
  • Fig. 5 shows transmigration of mouse colon carcinoma (MC38/GFP) cells in
  • HFIP hexaflouro-2-propanol
  • B, C trifluorinated molecules carrying a hydroxyl group
  • D trifluorinated aminoacid
  • Fetal calf serum (10%) served as unspecific chemoattractant and was added to the lower compartments of the migration chambers (positive control). At least three samples per group were evaluated. Examples
  • the inventors compared the transmigration of mouse colon carcinoma cells treated either with sevoflurane or with its primary metabolite, hexafluoro-2-propanol (HFIP) or with different water-soluble molecules carrying trifluorinated carbon groups (CF 3 ).
  • HFIP hexafluoro-2-propanol
  • CF 3 water-soluble molecules carrying trifluorinated carbon groups
  • Matrigel-coated filter membranes Extensively used in vitro models to study tumor cell transmigration across artificial anatomic barriers are Matrigel-coated filter membranes. In these models, Matrigel mimics the extracellular matrix in vitro, while the use of filter chambers allows for a quantitative assessment of tumor cell migration.
  • mice colon carcinoma cell line MC-38GFP was assessed using filter plates (Millipore, Billerica, MA) coated with 10 ⁇ _ pure Matrigel (BD, Biosciences), as described elsewhere (Muller-Edenborn et al.; Anesthesiology, 2012; 1 17(2):293). Briefly, MC-38GFP cells were exposed for 15 minutes to 2.2 vol % sevoflurane (Sevorane, Abbott, Switzerland), to hexafluoro-2-propanol (at a final concentration of 4 mM) (Sigma-Aldrich, Buchs, Switzerland) or to culture medium solely (control group).
  • the cells (2* 10 4 /100 ⁇ ) were seeded on Matrigel-coated 24-well migration plates with 8 pm inserts. 10% fetal calf serum served as unspecific chemoattractant and was added to the lower compartment (400 ⁇ ). Cells were allowed to migrate for 6 h at 37°C. Non migrated cells were removed from the upper chamber with a cotton swab. Filters were cut, fixed with paraformaldehyde and stained with diamidinophenylindole. The filters were put on glass slides and covered with mounting medium and cover slips. Sixteen automatically randomized pictures of each sample were taken on a Leica LX microscope (Leica, Buffalo Grove, IL) and GFP/diamidinophenylindole cells were counted.
  • Table 1 shows B coefficients and corresponding 95% confidence intervals.
  • the number of transmigrated carcinoma cells (MC-38GFP cells) without sevoflurane or HFIP-treatment has been defined as the control group in the regression model.
  • Dependent variable percentage of transmigrated MC-38GFP cells.
  • Table 2 shows B coefficients and corresponding 95% confidence intervals.
  • HFIP hexafluoro-2-propanol.
  • This set of molecules was chosen to be tested in order to represent the effects of small, water-soluble molecules (molecular weight of below 250) of different chemical nature (alcohols, amino acids, and amides) carrying at least one trifluorinated carbon group (CF 3 ).
  • a final concentration of 4 mM in the culture medium was targeted. Either 10% fetal calf serum in medium serving as unspecific chemoattractant (positive control), or DMEM as negative control was added to the lower compartment of the Matrigel-coated migration plate (400ul). The starved cells were then allowed to migrate for 6 h at 37°C in an incubator. Non migrated cells were removed from the upper chamber with a cotton swab. Filters were directly measured at 395/475 nm (Tecan infinite M200pro). Mixed model analysis was used to analyze the results. A p-value ⁇ 0.05 was considered statistically significant. Results:
  • Table 3 shows the B coefficient and corresponding 95% confidence interval.
  • the number of trifluorinated carbon groups in the respective molecule has been entered as independent variable in the regression model.
  • Fetal calf serum (10%) served as unspecific chemoattractant and was added to the lower compartments of the migration chambers (reference category in the model).
  • Sevoflurane, HFIP, as well as other molecules carrying a CF 3 group significantly reduce invasion and migration of malignant tumor cells. This effect has been shown for a broad range of chemically different, fluorinated molecules (alcohols, amino acids, and amides), assuming that the effect is related to a functional group (CF 3 ) rather than being a molecule- related property.
  • the administration of trifluorinated molecules might therefore represent a promising future treatment opportunity to prevent tumor cell spread.

Landscapes

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

Abstract

L'invention concerne l'utilisation d'hexafluoro-2-propanol dans le cadre d'un procédé pour prévenir ou traiter des tumeurs malignes, notamment une invasion et/ou une migration de cellules tumorales.
PCT/EP2017/054640 2016-02-29 2017-02-28 Hexafluoro-2-propanol utilisé comme inhibiteur d'invasion de cellules tumorales WO2017148945A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP16157849.7 2016-02-29
EP16157848 2016-02-29
EP16157848.9 2016-02-29
EP16157849 2016-02-29

Publications (1)

Publication Number Publication Date
WO2017148945A1 true WO2017148945A1 (fr) 2017-09-08

Family

ID=58162628

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2017/054640 WO2017148945A1 (fr) 2016-02-29 2017-02-28 Hexafluoro-2-propanol utilisé comme inhibiteur d'invasion de cellules tumorales

Country Status (1)

Country Link
WO (1) WO2017148945A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4056175A4 (fr) * 2019-11-08 2023-12-06 Central Glass Company, Limited Procédé permettant de tuer sélectivement des cellules contenant des agrégats de protéines, kit associé, médicament thérapeutique pour des maladies de mauvais repliement de protéines et produit médicamenteux permettant d'éliminer des agrégats de protéines de produit sanguin

Non-Patent Citations (9)

* Cited by examiner, † Cited by third party
Title
ALBINI ET AL., CANCER RES, vol. 47, no. 12, 1987, pages 3239 - 3245
BJÖRN MÜLLER-EDENBORN ET AL: "Volatile Anesthetics Reduce Invasion of Colorectal Cancer Cells through Down-regulation of Matrix Metalloproteinase-9", ANESTHESIOLOGY., vol. 117, no. 2, 1 August 2012 (2012-08-01), PHILADELPHIA, PA, US, pages 293 - 301, XP055264451, ISSN: 0003-3022, DOI: 10.1097/ALN.0b013e3182605df1 *
BORSIG ET AL., PROC NATL ACAD SCI USA, vol. 99, no. 4, 2002, pages 2193 - 2198
BROWN ET AL: "1 Sevoflurane: an update", BAILLIERE'S CLINICAL ANAESTHESIOLOGY, BAILLIERE TINDALL, PHILADELPHIA, US, vol. 9, no. 1, 1 March 1995 (1995-03-01), pages 1 - 14, XP005119195, ISSN: 0950-3501 *
EVAN KHARASCH: "Downloaded From: http", 1 June 1995 (1995-06-01), pages 1369 - 1378, XP055264577, Retrieved from the Internet <URL:http://anesthesiology.pubs.asahq.org/article.aspx?articleid=1950370> [retrieved on 20160412] *
MULLER-EDENBORN ET AL., ANESTHESIOLOGY, vol. 117, no. 2, 2012, pages 293
SERGEY SHITYAKOV ET AL: "Sevoflurane-Sulfobutylether-[beta]-Cyclodextrin Complex: Preparation, Characterization, Cellular Toxicity, Molecular Modeling and Blood-Brain Barrier Transport Studies", MOLECULES, vol. 20, no. 6, 3 June 2015 (2015-06-03), pages 10264 - 10279, XP055361090, DOI: 10.3390/molecules200610264 *
TERRANOVA ET AL., PROC NATL ACAD SCI USA, vol. 83, no. 2, 1986, pages 465 - 469
URNER ET AL., ENVIRONMENTAL SCIENCE & TECHNOLOGY, vol. 48, no. 23, 2014, pages 13960 - 8

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP4056175A4 (fr) * 2019-11-08 2023-12-06 Central Glass Company, Limited Procédé permettant de tuer sélectivement des cellules contenant des agrégats de protéines, kit associé, médicament thérapeutique pour des maladies de mauvais repliement de protéines et produit médicamenteux permettant d'éliminer des agrégats de protéines de produit sanguin

Similar Documents

Publication Publication Date Title
KR102228055B1 (ko) 종양의 치료 또는 예방을 위한 병용 요법
Zhou et al. Non-cell-autonomous activation of IL-6/STAT3 signaling mediates FGF19-driven hepatocarcinogenesis
Robbins et al. The history and future of probenecid
Wu et al. Notch inhibitor PF-03084014 inhibits hepatocellular carcinoma growth and metastasis via suppression of cancer stemness due to reduced activation of Notch1–Stat3
Rubio et al. Mesenchymal stromal cells prevent bleomycin‐induced lung and skin fibrosis in aged mice and restore wound healing
US20220257767A1 (en) Ionic liquids for drug delivery
CA2751563A1 (fr) Procedes d&#39;inhibition de fibrogenese et de traitement de maladie fibrotique
JP2015508415A (ja) 麻酔化合物および関連する使用方法
Svensson Functional and biochemical effects of d-and l-amphetamine on central catecholamine neurons
CN108042514A (zh) 引起麻醉的方法
WO2017148945A1 (fr) Hexafluoro-2-propanol utilisé comme inhibiteur d&#39;invasion de cellules tumorales
EP3347001B1 (fr) Azophénols utilisés en tant qu&#39;inhibiteurs de l&#39;oncogène erg
TW202241438A (zh) 預防或治療ｅｇｆｒ功能異常相關的副作用的方法
Frei Tumour induction by low molecular weight alkylating agents
TW200539857A (en) Methods for treating multiple sclerosis and pharmaceutical compositions therefor
Dixon et al. Apparent Lack of Interaction Between Dimethyl Sulfoxide (DMSO) and a Variety of Drugs.
WO2012104788A2 (fr) Composes anti-angiogeniques, compositions pharmaceutiques les comprenant, et leur utilisation
US20050070565A1 (en) Chelerythrine, analogs thereof and their use in the treatment of bipolar disorder and other cognitive disorders
US9987301B2 (en) Heparin-based compositions and methods for the inhibition of metastasis
JP2016505054A (ja) 放射線損傷を防止し、放射線により損傷された組織の再生と修復を促進する薬剤の調製における、飽和アミン系化合物の応用
Dong et al. Inhibition of PTPRE suppresses tumor progression and improves sorafenib response in hepatocellular carcinoma
CN101883566B (zh) 用于治疗或预防涉及组胺h4受体的病症的美喹他嗪
Chen et al. Neuromuscular blocking agents and cancer: a narrative review
CN115227690B (zh) 土木香内酯在双表达型b细胞淋巴瘤中的应用
CN113679728B (zh) 一种磺胺类化合物及其在制备治疗糖尿病和并发症药物中的应用

Legal Events

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

Ref country code: DE

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

Ref document number: 17707342

Country of ref document: EP

Kind code of ref document: A1

122 Ep: pct application non-entry in european phase

Ref document number: 17707342

Country of ref document: EP

Kind code of ref document: A1