WO2009110862A1 - Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons - Google Patents

Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons Download PDF

Info

Publication number
WO2009110862A1
WO2009110862A1 PCT/US2008/002918 US2008002918W WO2009110862A1 WO 2009110862 A1 WO2009110862 A1 WO 2009110862A1 US 2008002918 W US2008002918 W US 2008002918W WO 2009110862 A1 WO2009110862 A1 WO 2009110862A1
Authority
WO
WIPO (PCT)
Prior art keywords
cancer
tumor
lansoprazole
pharmaceutically acceptable
proton pump
Prior art date
Application number
PCT/US2008/002918
Other languages
English (en)
Inventor
Bassam Damaj
Original Assignee
Bio-Quant, 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 Bio-Quant, Inc. filed Critical Bio-Quant, Inc.
Priority to AU2008352018A priority Critical patent/AU2008352018A1/en
Priority to MX2010009795A priority patent/MX2010009795A/es
Priority to CA2717481A priority patent/CA2717481A1/fr
Priority to KR1020107022003A priority patent/KR20100123750A/ko
Priority to JP2010549619A priority patent/JP2011513396A/ja
Priority to PCT/US2008/002918 priority patent/WO2009110862A1/fr
Priority to NZ587941A priority patent/NZ587941A/xx
Priority to EP08726452A priority patent/EP2254557A4/fr
Publication of WO2009110862A1 publication Critical patent/WO2009110862A1/fr
Priority to IL207749A priority patent/IL207749A0/en

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
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents

Definitions

  • Embodiments of the invention relate, in part, to methods of treating tumor cells by administration of a proton pump inhibitor.
  • Cytotoxic agents remain the mainstay of cancer treatment due to high unmet needs in the disease. Because the oral and gastrointestinal mucosa is often significantly damaged by cancer therapy, management of these problems is an important challenge for oncologists. Such treatment complications are generally not severe or life threatening, but they can result in both treatment delays and dose reductions in potentially curative regimens. Numerous therapeutic approaches have been evaluated as prophylaxis or treatment for mucosal damage in patients undergoing cancer therapy. The results of large-scale, placebo-controlled, comparative trials demonstrate that administration of a proton pump inhibitor can provide both significant symptom relief and prophylaxis against upper gastrointestinal ulceration in patients receiving cancer chemotherapy.
  • proton pump inhibitors have been used to lower a tumor cell's resistance to cytotoxic agents.
  • the mechanisms underlying this phenomenon appear to take advantage of functions involved in the control of cell homeostasis.
  • One mechanism of resistance may be alteration of the tumor microenvironment via changes in the pH gradient between the extracellular environment and the cell cytoplasm and/or in the pH gradient between the cell cytoplasm and lysosomal compartments.
  • the extracellular (i.e., interstitial) pH of solid tumors is substantially more acidic than that of normal tissues, and the acidic pH of the tumor microenvironment may impair the uptake of weakly basic chemotherapeutic drugs.
  • the proton pump inhibitor or a pharmaceutically acceptable salt thereof may be administered as a pharmaceutically acceptable composition and may decrease tumor cell volume.
  • the pharmaceutically acceptable composition may include a buffering agent.
  • the pharmaceutically acceptable composition may include about 20 mg to about 400 mg of lansoprazole. After administration, the pharmaceutically acceptable composition may interact with tumor cells outside of the gastric lumen.
  • the proton pump inhibitor may induce apoptosis in the tumor cells and/or may lower the pH of the tumor cells. In an embodiment, the proton pump inhibitor may induce apoptosis in the cancer cells by modifying the K + level of the tumor cells.
  • the proton pump inhibitor may be a substituted benzimidazole compound having H + ZK + ATPase inhibiting activity.
  • the proton pump inhibitor is selected from the group consisting of lansoprazole, omeprazole, rabeprazole, esomeprazole, pantoprazole, pariprazole, leminoprazole, SCH 28080, and enantiomers, isomers, free bases, salts, and mixtures thereof.
  • a composition may be administered in a dosage of about 180 mg/day of lansoprazole.
  • the proton pump inhibitor may be administered in an amount of about 10 mg/kg to about 100 mg/kg.
  • Tumor cells may be selected from a group consisting of: RPMI8226, NC37, MC/CAR, SUDHL4, RPMI6666, GDM-I, MOLT3, J45-01, MCF7, HL60 clone 15, Pl 16, SW620, MV-4-11, SKMEL5, DAUDI, DOHH2, HUT102, CCRF-CEM, HUT78, A3, MDA-MB-435, MDA-MB-231, and RS4.11.
  • the tumor cells are selected from a group consisting of: ES-2, IGROV 1, OVCAR5, OVCAR8, J-gamma-1, KU812, NK92MI, 786-0, A498, H522, SNB 19, OVCAR4, H9, HH, EKVX, OVCAR5, UACC257, H226, UO-31, NAMALWA, SKMEL28, SKMEL2, M14, H322M, HCC2998, HL60, HT29, A549, RXF393, PC3, H460, MCl 16, MOLT4, JMI, HOP-62, HCT-15, SF-539, SF295, ST486, U251, and UACC-62.
  • the tumor cells may be associated with a disease selected from the group consisting of: carcinoma, lymphoma, blastoma, myeloma, sarcoma, leukemia, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, and hepatic carcinoma.
  • a disease selected from the group consisting of: carcinoma, lymphoma, blastoma, myeloma, sarcoma, leukemia, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinom
  • a second chemotherapeutic agent may be administered with a proton pump inhibitor.
  • a proton pump inhibitor such as lansoprazole
  • a second chemotherapeutic agent are administered together in the same or separate dosage form.
  • the proton pump inhibitor, such as lansoprazole, and a second chemotherapeutic agent may be administered before, after or simultaneously.
  • the pharmaceutical composition may include lanzoprazole, for example, in a dose of about 120 mg to about 400 mg or more per day.
  • the lanzoprazole is administered in a dose of about 120 mg to about 300 mg, wherein upon administration to the subject the composition interacts with a mass of growth deregulated cells outside of the subject's gastric lumen.
  • the lansoprazole may induce apoptosis in the growth deregulated cells and the mass of growth deregulated cells may be reduced in size after about three weeks from the administration.
  • Also described are methods of treating lymphoma including administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.
  • the method may include administering to a patient in need thereof lansoprazole or pharmaceutically acceptable salts thereof in an amount effective to inhibit the growth of the tumor.
  • the inhibition of growth may be measured as a delay in tumor doubling time.
  • the tumor doubling time may be extended by a factor of at least two.
  • the volume of the tumor may be reduced by at least 10%.
  • the methods may include administering to a patient in need thereof a pharmaceutically effective amount of -A- lansoprazole or a pharmaceutically acceptable salt thereof.
  • the cancer may be selected from the group consisting of: carcinoma, lymphoma, blastoma, sarcoma, leukemia, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, and hepatic carcinoma.
  • the methods may include administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.
  • kidney cancer Also described are methods of treating kidney cancer.
  • the methods may include administering to a patient in need thereof a pharmaceutically effective amount of lansoprazole or a pharmaceutically acceptable salt thereof.
  • lansoprazole may be administered at a dosage of about 120 mg/day to about 300 mg/day. Lansoprazole may be administered at a dosage of about 10 mg/kg/day to about 150 mg/kg/day.
  • the survival rate of a subject receiving a pharmaceutical composition of the invention may be greater than about 15% as compared to a patient administered a placebo.
  • FIGS. IA- IAU depict experimental results of tumor cells from the following cell lines treated with lansoprazole: 786-O (HG. IA), ACHN (PIG. IB), A498 (FlG. 1C), H226 (HG. ID), H522 (HG. IE), HOP92 (HG. IF), SNB 19 (HG. IG), SUDHL4 (HG. IH), OVCAR4 (HG. II), IGROVl (HG. IJ), H9 (HG. IK), UO-31 (HG. IL), HH (HG. IM), DAUDI (HG. IN), LOXIMVI (HG. 1O), NAMALWA (HG. IP), EKVX (HG.
  • IQ DOHH2 (HG. IR), SNB75 (HG. IS), SKMEL28 (HG. IT), SKMEL5 (HG. IU), SKMEL2 (HG. IV), OVC AR5 (HG. IW), M14 (HG. IX), UACC257 (HG. IY), H322M (HG. IZ), KM12 (HG. IAA), H332M (HG. IAB), HUT102 (HG. IAC), HL60 (HG. IAD), CCRF-CEM (HG. IAE), HUT78 (HG. IAF), HT29 (HG. IAG), HCTl 16 (HG. IAH), CAKI-I (HG. IAI), DU-145 (HG. IAJ), A549 (HG.
  • FIGS. 2A-2O depict experimental results of tumor cells from the following cell lines treated with lansoprazole: Du-145 (FIG. 2A), J45-01 (FIG. 2B), MOLT3 (FlG. 2C), HUT78 (FIG. 2D), J-gamma-1 (FlG. 2E), MCF7 (FIG. 2F), Colo205 (FIG. 2G), HL60 clone 15 (FlG. 2H), T47D (FlG. 21), Pl 16 (FlG. 2J), Ku812 (FIG. 2K), SW620 (FlG. 2L), NK92MI (HG. 2M), MV-4-11 (HG. 2N), and HS578T (FlG. 20).
  • FIGS. 3A-3K depict experimental results of tumor cells from the following cell lines were treated with lansoprazole, omeprazole, and SCH 28080: IGROVl OFIG. 3A), OVCAR8 (HG. 3B), ES-2 (FlG. 3C), CAOV3 (HG. 3D), OVCAR5 (HG. 3E), SUGHL4 (HG. 3F), RPMI8226 (FlG. 3G), RPMI6666 (FlG. 3H), NC37 (FlG. 31), GDM-I (FIG. 3J), and MC/CAR (HG. 3K).
  • FIGS. 4A-4C depict mean tumor volume over time in a nude mouse model treated with lansoprazole.
  • the nude mice were exposed to tumor cell lines G401 (FlG. 4A), HEPG2 (HG. 4B), and JR (HG. 4C).
  • FIGS. 5A-5C depict mean tumor volume over time in a nude mouse model treated with lansoprazole.
  • the nude mice were exposed to tumor cell lines G401 OFIG. 5A), RS 1184 B (HG. 5B), and SR (FlG. 5C).)
  • FIGS. 6A-6M show depicts results of contacting various tumor cells with lansoprazole: MCl 16 (HG. 6A), HOP-62 (FlG. 6B), JMI (HG. 6C), RPMI6666 (FlG. 6D), MOLT4 (HG. 6E), HCT-15 (RG. 6F), RSl 184 (HG. 6G), ST486 OFIG. 6H), U251 (FlG. 61), SF-539 (HG. 6J), SF295 (FlG. 6K), UACC-62 (HG. 6L), and SR (FlG. 6M).
  • the present disclosure relates to methods of treating a tumor by administering a pharmaceutical composition including a proton pump inhibitor. Additionally, the present disclosure relates to methods of treating a tumor by contacting or administering a pharmaceutical composition including a proton pump inhibitor in the presence or absence of a cytotoxic drug or chemotherapeutic agent with or to a tumor cell. While the present disclosure may be embodied in many different forms, several specific embodiments are discussed herein with the understanding that the present disclosure is to be considered only as an exemplification of the principles of the invention, and it is not intended to limit the invention to the embodiments illustrated.
  • 'Treating or “treatment” as used herein does not require a complete cure. It means that the symptoms of the underlying disease or condition are at least reduced, and/or that one or more of the underlying cellular, physiological, or biochemical causes or mechanisms causing the symptoms are reduced and/or eliminated. It is understood that reduced, as used in this context, means relative to the state of the disease or condition, including the molecular state of the disease or condition, not just the physiological state of the disease or condition.
  • growth deregulated cell represents a single or multiple cancerous cells characterized by unregulated cell growth.
  • a growth deregulated cell may form a mass of tissue that results from excessive cell growth or proliferation, either benign (noncancerous) or malignant (cancerous) including pre-cancerous lesions.
  • cancer and “cancerous” refer to or describe the physiological condition in mammals in which a population of cells are characterized by unregulated cell growth. Examples of such may include, but are not limited to, carcinoma, lymphoma, blastoma, sarcoma, and leukemia.
  • cancers include, but are not limited to, squamous cell cancer, small-cell lung cancer, non-small cell lung cancer, adenocarcinoma of the lung, squamous carcinoma of the lung, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, liver cancer, bladder cancer, hepatoma, breast cancer, colon cancer, colorectal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma and various types of head and neck cancers.
  • PPI proto pump inhibitor
  • omeprazole lansoprazole
  • pantoprazole pantoprazole
  • rabeprazole dontoprazole
  • perprazole s-omeprazole magnesium
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omeprazole magnesium)
  • dontoprazole perprazole (s-omepra
  • Proton pump inhibitors are also functionally defined as compounds that act by irreversibly blocking the hydrogen/potassium adenosine triphosphatase enzyme system (the H + ZK + ATPase, or more commonly just gastric proton pump) of the gastric parietal cell.
  • the proton pump is the terminal stage in gastric acid secretion, being directly responsible for secreting H + ions into the gastric lumen, making it an ideal target for inhibiting acid secretion.
  • Proton pump inhibitors also include the compound SCH 28080.
  • “Pharmaceutically acceptable salts of lansoprazole” refers to those salts of lansoprazole derivatives that retain the biological effectiveness and properties of the free acids or free bases and that are not otherwise unacceptable for pharmaceutical use.
  • Pharmaceutically acceptable salts of lansoprazole derivatives include salts of acidic or basic groups which may be present in the lansoprazole derivatives. Derivatives of lansoprazole that are basic in nature are capable of forming a wide variety of salts with various inorganic and organic acids.
  • the acids that may be used to prepare pharmaceutically acceptable acid addition salts of such basic compounds are those that form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as chloride, bromide, iodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, acid citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate (i.e., l,l'-methylene-bis-(2- hydroxy-3-naphthoate)) salts
  • Derivatives of lansoprazole that include an amino moiety can also form pharmaceutically acceptable salts with various amino acids, in addition to the acids mentioned above.
  • Derivatives of lansoprazole that are acidic in nature are capable of forming a wide variety of salts with various inorganic and organic bases. Suitable base salts are formed from bases that donate cations to form non-toxic salts, suitable cations include, but are not limited to, sodium, aluminum, calcium, lithium, magnesium, potassium, zinc and diethanolamine salts.
  • suitable cations include, but are not limited to, sodium, aluminum, calcium, lithium, magnesium, potassium, zinc and diethanolamine salts.
  • terapéuticaally effective refers to the ability of an active ingredient, for example, lansoprazole, to elicit the biological or medical response that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • active ingredient for example, lansoprazole
  • Non-limiting examples include, but are not limited to, reduction of tumor size in a patient, extended survival time, and the like.
  • terapéuticaally effective amount includes the amount of an active ingredient, for example, lansoprazole, that will elicit the biological or medical response that is being sought by the researcher, veterinarian, medical doctor or other clinician.
  • the compounds of the invention may be administered in amounts effective at reducing tumor size and/or extending survival time.
  • a therapeutically effective amount of an active ingredient is the quantity of the compound required to achieve a desired therapeutic and/or prophylactic effect, such as the amount of the active ingredient that results in the prevention of or a decrease in the symptoms associated with the condition (for example, to meet an end-point).
  • An effective amount may include an amount with or without undue adverse side effects, including but not limited to, raising of gastric pH, reduced gastrointestinal bleeding, reduction in the need for blood transfusion, improved survival rate, more rapid recovery, parietal cell activation and H + , K + -ATPase inhibition or improvement or elimination of symptoms, and other indicators as are selected as appropriate measures by those skilled in the art.
  • pharmaceutically acceptable refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, or to a human, as appropriate.
  • pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. Supplementary active ingredients can also be incorporated into the compositions.
  • Any suitable route of administration may be employed for providing a subject with an effective amount of lansoprazole.
  • Rectal, parenteral non-limiting examples include subcutaneous, intramuscular, intravenous), transdermal, topical, oral administration, ocular, otic, nasal administration and like forms of administration are possible.
  • Oral dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, and the like.
  • composition may comprise dry formulations, solutions and/or suspensions of the proton pump inhibitors.
  • the terms "suspension” and “solution” are interchangeable with each other and mean solutions and/or suspensions of the substituted benzimidazoles.
  • the drug after administration of the PPI, the drug is absorbed through the gastric lumen and delivered via the bloodstream to various tissues and cells of a subject including various tumor cells.
  • the PPI comes in contact with tumor cells and prevents the tumor cell from expunging H + by inhibiting the H/K ATPase proton pump. Inhibition of the proton pump may raise the intracellular pH of the tumor cells, eventually leading to cell apoptosis.
  • a pharmaceutical composition including a proton pump inhibitor such as lansoprazole, omeprazole, or other proton pump inhibitor and derivatives thereof may be used for the treatment or prevention of cancer.
  • a pharmaceutical composition comprising a proton pump inhibitor such as lansoprazole may be used for the treatment or prevention of ovarian cancer, lymphoma, B lymphocyte myeloma, Hodgkins lymphoma, breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervical cancer. Treatment of these conditions may be accomplished by administering to a subject an effective amount of the pharmaceutical composition according to embodiments of the present invention.
  • the dosage range of lansoprazole or other proton pump inhibitors such as substituted benzimidazoles and derivatives thereof may range from approximately ⁇ 20 mg/day to approximately 400 mg/day or more.
  • the approximate daily oral dosage may be about 20 mg of esomeprazole, about 360 mg omeprazole, about 240 mg pantoprazole, about 120 mg rabeprazole, and the pharmacologically equivalent doses of other PPIs including, but not limited to donprazole, pariprazole, dontoprazole, ransoprazole, perprazole (s-omeprazole magnesium), and leminoprazole.
  • the dosage range of lansoprazole or other proton pump inhibitors such as substituted benzimidazoles and derivatives thereof may range from approximately ⁇ 10 mg/kg to approximately 100 mg/kg or more.
  • a pharmaceutical composition of the proton pump inhibitors utilized in embodiments of the present invention may be administered in any form to a subject. This may be accomplished, for example, by administering the solution via a nasogastric (ng) tube or other indwelling tubes placed in the GI tract.
  • ng nasogastric
  • the terms, "individual,” “patient,” or “subject” are used interchangeably herein and include any mammal, including animals, for example, primates, for example, humans, and other animals, for example, dogs, cats, swine, cattle, sheep, and horses.
  • the compounds of the invention can be administered to a mammal, such as a human, but can also be other mammals, for example, an animal in need of veterinary treatment, for example, domestic animals (for example, dogs, cats, and the like), farm animals (for example, cows, sheep, pigs, horses, and the like) and laboratory animals (for example, rats, mice, guinea pigs, and the like).
  • the term "subject” includes cells in a culture or tumor tissue cells.
  • a liquid oral pharmaceutical composition may be prepared by mixing lansoprazole (PREV ACID®) and/or other proton pump inhibitor or derivatives thereof with a solution including a buffering agent.
  • lansoprazole and/or another proton pump inhibitor(s) may be mixed with a sodium bicarbonate solution to achieve a desired final lansoprazole (or other PPI) concentration.
  • concentration of lansoprazole in the solution may range from approximately ⁇ 180 mg/ml to approximately 300.0 mg/ml or more.
  • a liquid oral pharmaceutical composition may be prepared by mixing lansoprazole (PREV ACED®) and/or other proton pump inhibitor or derivatives thereof with a solution including a buffering agent.
  • lansoprazole and/or another proton pump inhibitor(s) may be mixed with a sodium bicarbonate solution to achieve a desired final lansoprazole (or other PPI) concentration.
  • concentration of lansoprazole in the solution may range from approximately ⁇ 180 mg/ml to approximately 300.0 mg/ml or more.
  • buffering agent shall mean any pharmaceutically appropriate weak base or strong base (and mixtures thereof) that, when formulated or delivered with (e.g., before, during and/or after) the PPI, functions to substantially prevent or inhibit the acid degradation of the PPI by gastric acid sufficient to preserve the bioavailability of the PPI administered.
  • the buffering agent if used, may be administered in an amount sufficient to substantially achieve the above functionality.
  • the buffering agent of the present invention when in the presence of gastric acid, need only elevate the pH of the stomach sufficiently to achieve adequate bioavailability of the drug to effect therapeutic action.
  • buffering agents include, but are not limited to, sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium glucomate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate coprecipitate, a mixture of an amino acid and a buffer, a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer.
  • Additional buffering agents include sodium citrate, sodium tartarate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts.
  • a pharmaceutically acceptable buffering agent may comprise a bicarbonate salt of Group IA metal as buffering agent, and may be prepared by mixing the bicarbonate salt of the Group IA metal, preferably sodium bicarbonate, with water.
  • the concentration of the bicarbonate salt of the Group IA metal in the composition may be any concentration.
  • the bicarbonate concentration may range from approximately 5.0 percent to approximately 60.0 percent.
  • the concentration of the bicarbonate salt of the Group IA metal may range from approximately 7.5 percent to approximately 10.0 percent.
  • sodium bicarbonate is the salt and is present in a concentration of approximately 8.4 percent.
  • the amount of sodium bicarbonate 8.4% used in the solution of the present invention is approximately 1 mEq (or mmole) sodium bicarbonate per 2 mg lansoprazole, with a range of approximately 0.2 mEq (mmole) to 5 mEq (mmole) per 2 mg of lansoprazole.
  • enterically-coated lansoprazole particles may be used.
  • lansoprazole powder may be used.
  • the enterically coated lansoprazole particles may be mixed with a sodium bicarbonate (NaHCO 3 ) solution (8.4%), which dissolves the enteric coating and forms a lansoprazole solution.
  • NaHCO 3 sodium bicarbonate
  • the lansoprazole solution may have pharmacokinetic advantages over standard time-released lansoprazole capsules, including: (a) more rapid drug absorbance time (about 10 to 60 minutes) following administration for the lansoprazole solution versus about 1 to 3 hours following administration for the enteric-coated pellets; (b) the NaHCO 3 solution protects the lansoprazole from acid degradation prior to absorption; (c) the NaHCO 3 acts as an antacid while the lansoprazole is being absorbed; and (d) the solution may be administered through an existing indwelling tube without clogging, for example, nasogastric or other feeding tubes (J e J una l or duodenal), including small bore needle catheter feeding tubes.
  • additives may be incorporated into the inventive solution to enhance its stability, sterility and isotonicity.
  • antimicrobial preservatives, antioxidants, chelating agents, and additional buffers may be added, such as AMBICIN®.
  • AMBICIN® antimicrobial preservatives
  • antioxidants antioxidants
  • chelating agents such as EDTA
  • additional buffers such as AMBICIN®.
  • microbiological evidence shows that this formulation inherently possesses antimicrobial and antifungal activity.
  • antibacterial and antifungal agents such as, for example, parabens, chlorobutanol, phenol, sorbic acid, and the like may enhance prevention of the action of microorganisms.
  • isotonic agents for example, sugars, sodium chloride, and the like may be included in the composition.
  • thickening agents such as methylcellulose may be desirable to use in order to reduce the settling of the lansoprazole or other PPI or derivatives thereof from the suspension.
  • a solution may further comprise flavoring agents (e.g., chocolate, root beer or watermelon) or other flavorings stable at pH 7 to 9, and anti-foaming agents (e.g., simethicone 80 mg, MyliconTM).
  • flavoring agents e.g., chocolate, root beer or watermelon
  • anti-foaming agents e.g., simethicone 80 mg, MyliconTM
  • Embodiments of the invention further includes a pharmaceutical composition including lansoprazole or other proton pump inhibitor and derivatives thereof and one or more buffering agents in a form convenient for storage, whereby when the composition may be placed into an aqueous solution, the composition dissolves yielding a suspension suitable for enteral administration to a subject.
  • the pharmaceutical composition may be in a solid form prior to dissolution or suspension in an aqueous solution.
  • the lansoprazole or other PPIs and buffering agent may be formed into a tablet, capsule, pellets or granules, by methods well known to those skilled in the art.
  • the resultant lansoprazole solution may be stable at room temperature for several weeks and inhibit the growth of bacteria or fungi.
  • the solution may maintain greater than 90% of its potency for 12 months.
  • a pharmaceutical composition including lansoprazole or other PPI with buffer in a solid form which may be later dissolved or suspended in a prescribed amount of aqueous solution to yield the desired concentration of lansoprazole and buffer, the cost of production, shipping, and storage may be greatly reduced as no liquids are shipped (reducing weight and cost), and there is no need to refrigerate the solid form of the composition or the solution.
  • the resultant solution may then be used to provide dosages for a single patient over a course of time, or for several patients.
  • the formulations of the present invention may also be manufactured in concentrated forms, such as tablets, suspension tablets and effervescent tablets or powders, such that upon reaction with water or other diluent, an aqueous form of the present invention is produced for oral, enteral, or parenteral administration.
  • the solid formulation of the present disclosure may be in the form of a powder, a tablet, a capsule, or other suitable solid dosage form (e.g., a pelleted form or an effervescing tablet, troche or powder), which creates a solution according to the invention in the presence of diluent or upon ingestion.
  • suitable solid dosage form e.g., a pelleted form or an effervescing tablet, troche or powder
  • the water in the stomach secretions or water which is used to swallow the solid dosage form may serve as an aqueous diluent.
  • compositions of the present disclosure include a PPI, for example lansoprazole, as the active ingredient, or a pharmaceutically acceptable salt thereof, and may also include a pharmaceutically acceptable carrier, and optionally, other therapeutic ingredients.
  • PPI for example lansoprazole
  • a sodium salt, a lithium salt, a potassium salt, a magnesium salt, a calcium salt, or a barium salt of lansoprazole may be used.
  • the salt may be a crystal.
  • the salt of the present invention may be a sodium salt (in particular a crystal) of (R)-2-[[[3-methyl-4-(2,2,2 -trifluoroethoxy)-2-pyridinyl]methyl]sulfinyl]— lH-benzimidazole, a potassium salt (in particular a crystal) of (R)-2-[[[3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinyl] methyl] sulf ⁇ nyl]-- lH-benzimidazole, and the like.
  • the salt may be solvated.
  • the PPI may be administered in combination with PEG 300.
  • the active ingredient for example lansoprazole, may be mixed with PEG 300 and administered to a subject.
  • the PPI may be administered to a subject together with another chemotherapeutic agent.
  • chemotherapeutic agents include, but are. not limited to, alkylating agents, such as carboplatin and cisplatin; nitrogen mustard alkylating agents; nitrosourea alkylating agents, such as carmustine (BCNU); antimetabolites, such as methotrexate; purine analog antimetabolites; pyrimidine analog antimetabolites, such as fluorouracil (5-FU) and gemcitabine; hormonal antineoplastics, such as goserelin, leuprolide, and tamoxifen; natural antineoplastics, such as aldesleukin, interleukin-2, docetaxel, etoposide (VP-16), interferon, paclitaxel, and tretinoin (ATRA); antibiotic natural antineoplastics, such as bleomycin, dactin
  • additional drugs may also be used in combination with the PPI and/or another chemotherapeutic agent, even if not considered antineoplastic agents themselves: dactinomycin; daunorubicin HCl; docetaxel; doxorubicin HCl; epoetin alfa; etoposide (VP-16); ganciclovir sodium; gentamicin sulfate; interferon leuprolide acetate; meperidine HCl; methadone HCl; ranitidine HCl; vinblastin sulfate; and zidovudine (AZT).
  • combination therapy refers to co-administering a PPI inhibitor, for example, lansoprazole, and another chemotherapeutic agent, as part of a specific treatment regimen intended to provide the beneficial effect from the co-action of these therapeutic agents.
  • the beneficial effect of the combination includes, but is not limited to, pharmacokinetic or pharmacodynamic co-action resulting from the combination of therapeutic agents.
  • Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually weeks, months or years depending upon the combination selected).
  • Combination therapy is intended to embrace administration of multiple therapeutic agents in a sequential manner, that is, wherein each therapeutic agent is administered at a different time, as well as administration of these therapeutic agents, or at least two of the therapeutic agents, in a substantially simultaneous manner.
  • Substantially simultaneous administration can be accomplished, for example, by administering to the subject a single tablet or capsule having a fixed ratio of each therapeutic agent or in multiple, single capsules for each of the therapeutic agents.
  • Sequential or substantially simultaneous administration of each therapeutic agent can be effected by any appropriate route including, but not limited to, oral routes, intravenous routes, intramuscular routes, and direct absorption through mucous membrane tissues.
  • the therapeutic agents can be administered by the same route or by different routes.
  • a first therapeutic agent of the combination selected may be administered by intravenous injection while the other therapeutic agents of the combination may be administered orally.
  • all therapeutic agents may be administered orally or all therapeutic agents may be administered by intravenous injection.
  • Combination therapy may also embrace the administration of the therapeutic agents as described above in further combination with other biologically active ingredients and non-drug therapies.
  • the combination therapy further includes a non-drug treatment
  • the non-drug treatment may be conducted at any suitable time so long as a beneficial effect from the co-action of the combination of the therapeutic agents and non-drug treatment is achieved.
  • the beneficial effect is still achieved when the non-drug treatment is temporally removed from the administration of the therapeutic agents, perhaps by days or even weeks.
  • the components of the combination may be administered to a patient simultaneously or sequentially. It will be appreciated that the components may be present in the same pharmaceutically acceptable carrier and, therefore, are administered simultaneously. Alternatively, the active ingredients may be present in separate pharmaceutical carriers, such as, conventional oral dosage forms, that can be administered either simultaneously or sequentially.
  • a PPI may be used in the manufacture of a medicament for the treatment of a tumor.
  • use of lansoprazole in the manufacture of a medicament for the treatment of a tumor represents one embodiment of the invention.
  • adherent cells were plated approximately 16-24 hours before the day of the experiment in 180 ⁇ l growth media. On the day of the experiment, the plated adherent cells were analyzed and counted and suspension cells were plated in 180 ⁇ l growth media.
  • 10x lansoprazole compounds and vehicle was prepared.
  • the 10x lansoprazole compounds were prepared by diluting lansoprazole to final concentrations of 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, and 1 ⁇ M.
  • a vehicle was prepared by preparing a solution of PBS, equivalent to the volume used for 10 ⁇ M lansoprazole wherein the Ix solution constitutes -0.06% PBS.
  • the cells were incubated at 37°C, 5% CO 2 for 5 minutes and the absorbance was obtained at 560 nm using a Dynex Opsys MR plate reader.
  • the cells used for this procedure were the following cell lines: IGROVl (ovarian cancer); OVCAR 8 (ovarian cancer); ES-2 (ovarian cancer); CA0V3 (ovarian cancer); OVCAR5 (ovarian cancer); SUDHL4 (lymphoma); RPMI8226 (myeloma); RPMI6666 (Hodgkin's lymphoma); NC37 (lymphoma); GDM-I (leukemia); MC/CAR (prostate cancer); DU-145 (prostate cancer), J45-01 (leukemia), M0LT3 (leukemia), HUT78, J-gamma-1 (leukemia), MCF7 (leukemia), COLO205 (colon cancer), HL60 CLONE 15 (leukemia), T47D (breast cancer), Pl 16 (intestinal cancer),
  • ES-2 IGROV 1, OVCAR5, OVCAR8, J-gamma-1, KU812, NK92MI, 786-O, A498, H522, SNB 19, OVC AR4, H9, HH, EKVX, OVCAR5, UACC257, H226, UO-31, NAMALWA, SKMEL28, SKMEL2, M14, H322M, HCC2998, HL60, HT29, A549, RXF393, PC3, H460, RPMI8226, NC37, MC/CAR, SUDHL4, RPMI6666, GDM-I, MOLT3, J45-01, MCF7, HLoO clone 15, Pl 16, SW620, MV-4-11, SKMEL5 (melanoma), DAUDI, DOHH2, HUT102, CCRF-CEM, HUT78, A3, MDA-
  • Adherent cells are plated approximately 16-24 hours before the day of the experiment in 180 ⁇ l growth media. On the day of the experiment, the plated adherent cells are analyzed and counted and suspension cells are plated in 180 ⁇ l growth media.
  • the 1Ox lansoprazole compound, vehicle and chemotherapeutic cocktail are prepared.
  • 1Ox lansoprazole compounds are prepared by diluting lansoprazole to final concentrations of 100 ⁇ M, 30 ⁇ M, 10 ⁇ M, 3 ⁇ M, and 1 ⁇ M.
  • a vehicle is prepared by preparing a solution of PBS, equivalent to the volume used for 10 ⁇ M lansoprazole wherein the Ix solution constitutes -0.06% PBS.
  • the chemotherapeutic cocktail is prepared by obtaining a 1Ox solution by diluting a Velcade solution to 10 ⁇ M, 100 ⁇ M, a Etoposide solution to 1 mM and 20 ⁇ M, and a Taxol solution to 200 ⁇ M.
  • 10 ⁇ l of the various 10x lansoprazole solutions, the chemotherapeutic cocktail and the vehicle are added to the cells.
  • the cells are incubated at 37°C, 5% CO 2 for 48 hours.
  • the media is then aspirated.
  • the plate containing the cell suspension is then spun at 1500 RPM for 10 minutes.
  • the media is slowly removed using a multichannel pipettor.
  • Cells used for this procedure may include the following cell lines: IGROVl, OVCAR 8, ES-2, CAO V3, OVCAR5 SUDHL4, RPMI8226, RPMI6666, NC37, GDM-I, MC/CAR, DU-145, J45-01, M0LT3, HUT78, J-GAMMAl, MCF7, COLO205, HL60 CLONE 15, T47D, Pl 16, KU812, SW620, MK92-M1, MV-4-11, HS578T, HT29, HCT 116, CAKI-I, A549, H460, A3, MDA-MB231, MALME 3M, RXF393, RS4.11, PC3, OVCAR3, MDA-MB435, HUT102, HL60, CCRF-CEM, HUT78, 786-O, ACHN, A498, H226, H522, HO P92, SNB 19, OVCAR4, H9, UO-31, HH, DAUDI, LOX
  • JR rhabdomyosarcoma
  • HepG2 liver carcinoma
  • SR Liquid Leukemia leukemia
  • RS 1184 B Lymphoma lymphoma
  • G401 rhabdoid (kidney) cancer cells for use in a xenograft mouse model were collected from JR, HepG2, SR Liquid Leukemia, RS 1184 B Lymphoma, and G401 rhabdoid tumor cell lines and injected at 5xlO 6 cells per nude mouse in a volume of 100 ⁇ l subcutaneously. The animals were examined three times weekly to determine the progression of the tumors and determine body weight. Dosing started when tumors reached the -75-150 mm 3 size.
  • mice were randomized and distributed in groups in such a way that mean tumor weights in all groups were within 15% of the mean tumor weight in Group 1 (Control - vehicle group).
  • an effective amount of lansoprazole was administered to the mice in a suspension of PEG300 at a concentration of 100 mg/kg.
  • lansoprazole effectively reduced tumor growth in mice and extended life span of the population.
  • Lansoprazole was especially effective in treating tumor cells derived from the HepG2, G401, and SR Liquid Leukemia tumor cell lines.
  • ATPase inhibitors such as omeprazole, lansoprazole, pantoprazole, rabeprazole, dontoprazole, perprazole (s-omeprazole magnesium), donprazole, ransoprazole, pariprazole, and leminoprazole.
  • FIGS. 3A-3K show the experimental results when tumor cells from the following cell lines were treated with lansoprazole, omeprazole, and SCH 28080: IGROVl (FlG. 3A), OVCAR8 (HG. 3B), ES-2 (HG. 3C), CAOV3 (HG. 3D), OVCAR5 (HG. 3E), SUDHL4 (FIG. 3F), RPMI8226 (FlG. 3G), RPMI6666 (FlG. 3H), NC37 (FlG.
  • FIGS. 3E-I and 3K 100 ⁇ M of lansoprazole was effective in reducing tumor cell growth (Omeprazole was effective for reducing tumor cell growth for the MC/CAR cell line as depicted in FIG. 3K). Additionally, a 10 ⁇ M concentration of lansoprazole, omeprazole, and SCH28080 was effective in reducing tumor cell growth of the GDM-I cell line as depicted in FIG. 3J.
  • the subject is first examined and diagnosed with a tumor.
  • the diagnosis of a tumor is accomplished by means known to those of skill in the art.
  • a pharmaceutically acceptable composition is administered to the subject.
  • the pharmaceutically acceptable composition contains lansoprazole, an excipient, and instructions for administering the pharmaceutically acceptable composition to the subject suffering from the tumor. It is determined that the subject is not suffering from elevated gastric acid production.
  • the pharmaceutically acceptable composition is administered according to the instructions provided.
  • the instructions indicate how much of the pharmaceutically acceptable composition is administered to the subject in order to reduce the size of the diagnosed tumor.
  • the volume of the diagnosed tumor is reduced, further growth of the tumor is inhibited via cellstatic activity, and tumor cells are killed by the pharmaceutically acceptable composition via cellcidal activity.

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)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention porte sur des procédés de traitement d'une ou plusieurs cellules à croissance dérégulée. Une quantité efficace d'une composition pharmaceutique comprenant un inhibiteur de pompe à protons est administrée, permettant ainsi de traiter des cellules à croissance dérégulée à l'extérieur de la lumière gastrique d'un sujet.
PCT/US2008/002918 2008-03-04 2008-03-04 Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons WO2009110862A1 (fr)

Priority Applications (9)

Application Number Priority Date Filing Date Title
AU2008352018A AU2008352018A1 (en) 2008-03-04 2008-03-04 Methods to inhibit tumor cell growth by using proton pump inhibitors
MX2010009795A MX2010009795A (es) 2008-03-04 2008-03-04 Metodos para inhibir el crecimiento de celulas tumorales usando inhibidores de la bomba de protones.
CA2717481A CA2717481A1 (fr) 2008-03-04 2008-03-04 Procedes pour inhiber la croissance de cellules tumorales a l'aide d'inhibiteurs de la pompe a protons
KR1020107022003A KR20100123750A (ko) 2008-03-04 2008-03-04 양성자 펌프 억제제를 사용하여 종양 세포의 성장을 억제하는 방법
JP2010549619A JP2011513396A (ja) 2008-03-04 2008-03-04 プロトンポンプ阻害剤の使用により腫瘍細胞成長を阻害するための方法
PCT/US2008/002918 WO2009110862A1 (fr) 2008-03-04 2008-03-04 Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons
NZ587941A NZ587941A (en) 2008-03-04 2008-03-04 Methods to inhibit tumor cell growth by using lansoprazole
EP08726452A EP2254557A4 (fr) 2008-03-04 2008-03-04 Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons
IL207749A IL207749A0 (en) 2008-03-04 2010-08-23 Methods to inhibit tumor cell growth by using proton pump inhibitors

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2008/002918 WO2009110862A1 (fr) 2008-03-04 2008-03-04 Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons

Publications (1)

Publication Number Publication Date
WO2009110862A1 true WO2009110862A1 (fr) 2009-09-11

Family

ID=41056268

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US2008/002918 WO2009110862A1 (fr) 2008-03-04 2008-03-04 Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons

Country Status (9)

Country Link
EP (1) EP2254557A4 (fr)
JP (1) JP2011513396A (fr)
KR (1) KR20100123750A (fr)
AU (1) AU2008352018A1 (fr)
CA (1) CA2717481A1 (fr)
IL (1) IL207749A0 (fr)
MX (1) MX2010009795A (fr)
NZ (1) NZ587941A (fr)
WO (1) WO2009110862A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2548555A1 (fr) * 2011-07-18 2013-01-23 Fondazione IRCCS Istituto Nazionale dei Tumori Inhibiteurs de pompe à protons en tant qu'immunomodulateurs
CN113667646A (zh) * 2021-08-27 2021-11-19 潘思源 一种肾癌索拉非尼耐药细胞株及其构建方法和应用
CN115475166A (zh) * 2022-09-13 2022-12-16 中南大学湘雅医院 瑞伐拉赞类化合物的应用、药物及制备方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023048508A1 (fr) * 2021-09-23 2023-03-30 국립암센터 Composition pharmaceutique destinée à la prévention ou au traitement du cancer, contenant une matière brunie d'oméprazole

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053690A1 (fr) * 2003-12-08 2005-06-16 Ki-Baik Hahm Utilisation de derives de benzimidazole pour la fabrication d'un medicament destine a traiter le cancer

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002080917A1 (fr) * 2001-04-06 2002-10-17 Forskarpatent I Uppsala Ab Nouvelle utilisation d'inhibiteurs de la pompe a protons
GB0403165D0 (en) * 2004-02-12 2004-03-17 Ct Novel uses for proton pump inhibitors

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2005053690A1 (fr) * 2003-12-08 2005-06-16 Ki-Baik Hahm Utilisation de derives de benzimidazole pour la fabrication d'un medicament destine a traiter le cancer

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2548555A1 (fr) * 2011-07-18 2013-01-23 Fondazione IRCCS Istituto Nazionale dei Tumori Inhibiteurs de pompe à protons en tant qu'immunomodulateurs
CN113667646A (zh) * 2021-08-27 2021-11-19 潘思源 一种肾癌索拉非尼耐药细胞株及其构建方法和应用
CN115475166A (zh) * 2022-09-13 2022-12-16 中南大学湘雅医院 瑞伐拉赞类化合物的应用、药物及制备方法
CN115475166B (zh) * 2022-09-13 2023-11-21 中南大学湘雅医院 瑞伐拉赞类化合物的应用、药物及制备方法

Also Published As

Publication number Publication date
NZ587941A (en) 2012-11-30
IL207749A0 (en) 2010-12-30
EP2254557A4 (fr) 2011-03-30
JP2011513396A (ja) 2011-04-28
MX2010009795A (es) 2010-12-21
KR20100123750A (ko) 2010-11-24
AU2008352018A1 (en) 2009-09-11
EP2254557A1 (fr) 2010-12-01
CA2717481A1 (fr) 2009-09-11

Similar Documents

Publication Publication Date Title
US20120322820A1 (en) Methods to inhibit tumor cell growth by using proton pump inhibitors
RU2586276C2 (ru) Антагонист кислотного насоса для лечения заболеваний, связанных с патологическим нарушением моторики желудочно-кишечного тракта
RU2743643C2 (ru) Комбинированная терапия противоопухолевым алкалоидом
WO2004043389B1 (fr) Procedes de traitement du cancer et procedes connexes
US20160324829A1 (en) Combination therapy with parp inhibitors
US20120190720A1 (en) Combination Therapy With Parp Inhibitors
US20090029966A1 (en) Combination therapy with parp inhibitors
WO2009110862A1 (fr) Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons
KR20130118981A (ko) 다형 교모세포종의 치료를 위한 마시텐탄 포함 조합물
US20120053559A1 (en) Treatment of Proliferative Diseases with Epothilone Derivatives and Radiation
TW201338772A (zh) 藥學組合物
KR100550839B1 (ko) 항균제
US20080207644A1 (en) Therapeutic materials and methods
KR20220169413A (ko) 타이람과 구리를 유효성분으로 하는 암 예방 또는 치료를 위한 병용 투여용 약학 조성물
ES2922752T3 (es) Composición combinada para prevenir o tratar el cáncer que comprende un derivado de benzofenona-tiazol como VDA y un inhibidor de topoisomerasa
IL141645A (en) Pharmaceutical preparations containing 3'-desamino-3 '- (2-methoxymorpolino) doxorubicin for the treatment of liver tumors
US20080280867A1 (en) Combination therapy with parp inhibitors
CN107137403B (zh) 一种pi3k/mtor抑制剂在制备治疗胰腺癌的药物中的用途
KR20100058662A (ko) 개에게서 림프종을 치료하기 위한 이다루비신
WO2003059355A1 (fr) Composes de quinazolinone dans des formes combinees pour un traitement de cancer ameliore
JP2000080031A (ja) 抗菌剤
ITMI20001984A1 (it) Uso dell'arginina nella preparazione di un medicamento per la preparazione e trattamento degli effetti collaterali associati alla somministr
WO2016021975A1 (fr) Procédé de préparation d'aérosol sublingual contenant un inhibiteur de pde-5 et composition pour pulvérisation sublinguale préparée par ce procédé
JP2018104292A (ja) マグネシウム化合物を有効成分とする医薬組成物

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: 08726452

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 207749

Country of ref document: IL

WWE Wipo information: entry into national phase

Ref document number: 2717481

Country of ref document: CA

WWE Wipo information: entry into national phase

Ref document number: MX/A/2010/009795

Country of ref document: MX

WWE Wipo information: entry into national phase

Ref document number: 2008352018

Country of ref document: AU

Ref document number: 2010549619

Country of ref document: JP

NENP Non-entry into the national phase

Ref country code: DE

WWE Wipo information: entry into national phase

Ref document number: 2008726452

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 587941

Country of ref document: NZ

ENP Entry into the national phase

Ref document number: 2008352018

Country of ref document: AU

Date of ref document: 20080304

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 20107022003

Country of ref document: KR

Kind code of ref document: A