WO2002080917A1 - Nouvelle utilisation d'inhibiteurs de la pompe a protons - Google Patents

Nouvelle utilisation d'inhibiteurs de la pompe a protons Download PDF

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Publication number
WO2002080917A1
WO2002080917A1 PCT/SE2002/000678 SE0200678W WO02080917A1 WO 2002080917 A1 WO2002080917 A1 WO 2002080917A1 SE 0200678 W SE0200678 W SE 0200678W WO 02080917 A1 WO02080917 A1 WO 02080917A1
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use according
drug
mdr
resistance
ppi
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PCT/SE2002/000678
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English (en)
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Lars Engstrand
Martin Holmberg
Rolf Larsson
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Forskarpatent I Uppsala Ab
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Priority claimed from SE0101229A external-priority patent/SE0101229D0/xx
Application filed by Forskarpatent I Uppsala Ab filed Critical Forskarpatent I Uppsala Ab
Publication of WO2002080917A1 publication Critical patent/WO2002080917A1/fr

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    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a novel use of proton pump inhibitors, such as omeprazole, esomeprazole, lansoprazole, rabeprazole and pantoprazole. More closely, the invention relates to use of proton pump inhibitors (PPIs) for production of a drug for treatment or prevention of a MDR (multidrug resistance) condition. In other words, the invention relates to use of proton pump inhibitors in combination with a drug for treatment of and in eucaryotic cells in the purpose of decreasing development of resistance against said drug.
  • PPIs proton pump inhibitors
  • MDR multidrug resistance
  • Pgp membrane bound 170 kD P-glycoprotein
  • MRP Multidrug Resistance Protein
  • BCRP Breast Cancer Related Protein
  • MXR Mitoxantrone resistance-associated transporter
  • the malaria parasite's development of resistance to the drug chloroquine is a major threat to world health. Malaria is among the most significant sources of global disease burden, causing approximately two million deaths every year, primarily in young children and pregnant women. The drug chloroquine, since its availability in the late 1940s, has been the mainstay of efforts to treat and control the disease.
  • chloroquine-resistance- reversal agent verapamil is capable of specifically enhancing the activity of chloroquine against chloroquine-resistant strains. Its mechanism of action is not clear though it appears to work by enhancing chloroquine uptake of the parasite.
  • the mechanism of chloroquine uptake has recently been suggested to be related to a Na+/H+ exchanger [10].
  • Multidrug resistance pumps were first discovered in eucaryotic cells, and they confer drug resistance on cells ranging from human tumor cells, to a variety of pathogens.
  • ABC transporters are also found in every parasite tested, so far, including Plasmodiumfalciparum.
  • the present inventors have found that proton pump inhibitors (PPIs) have MDR reversing ability. Thus, the inventors have discovered a completely new principle of MDR reversal. By using PPIs in combination with the desired drug the activity thereof can be greatly improved.
  • the present invention relates to the use of PPIs in combination with a said drug in the purpose increasing the effect of the said drug in vivo.
  • PPI is/are used in combination with a drug for treatment of and in eucaryotic cells in the purpose increasing the effect of a said drug.
  • the use of PPI(s) is not restricted to any particular drug but is expected to be generally applicable for increasing the effect of treatment or prevention of any drug resistance.
  • PPIs can potentiate the effect of vinca alcaloids, such as vincristine (vcr) in several human tumor cell lines and increase the activity of chloroquine inside the parasite in case of malaria.
  • vinca alcaloids such as vincristine (vcr)
  • vcr vincristine
  • the MDR reversing ability achieved with PPIs according to the invention may be due to the fact that PPIs interfere with the plasma membrane efflux system that extrudes drugs from the cells to be treated.
  • Alternative mechanisms may involve interference with subcellular drug distribution of cytotoxic drugs due to PPI effects on lysosomal drug trapping.
  • the invention relates to use of, or a method of using, proton pump inhibitors) for the production of a drug for treatment or prevention of a MDR (multidrug resistance) condition.
  • the PPI is omeprazole, esomeprazole, lansoprazole, rabeprazole or pantoprazole, or a combination thereof.
  • the drug may comprise PPI(s) alone or in combination with the cytotoxic drug.
  • the MDR condition is associated with cancer treatment with cytostatics, such as vincaalcaloids, such as vincristine and vinorelbine, taxanes, such as taxol and taxotere, tubuline inhibitors and tubuline stimulators.
  • cytostatics such as vincaalcaloids, such as vincristine and vinorelbine
  • taxanes such as taxol and taxotere
  • tubuline inhibitors and tubuline stimulators are especially advantageous when the MDR condition is associated with treatment of tumors with lymphatic origin.
  • the use of PPI is when the MDR condition is associated with treatment of a parasitic infection such as an infection by Plasmodium falciparum causing malaria.
  • the MDR condition is caused by an antiparasitic agent, such as chloroquine.
  • the present invention also provides use of proton pump inhibitor(s) for the production of a drug for treatment or prevention of a resistance condition associated with treatment of a bacterial infection with antibacterial agent(s), such as antibiotic(s).
  • the resistance condition may be a MDR (multidrug resistance) condition.
  • the drug may comprise PPI(s) alone or in combination with antibiotic(s).
  • the PPI is omeprazole, esomeprazole, lansoprazole, rabeprazole or pantoprazole, or a combination thereof.
  • a preferred example of an antibiotic is a macrolide, such as azitromycin.
  • the bacterial infection may be an intracellular or facultative intracellular infection and may be caused by, for example, Legionella spp, Helicobacter pylori, Streptococcus pneumoniae, Staphylococcus spp, Streptococcus pyogenes, Chlamydia spp, Listeria monocytogenes.
  • PPI(s) All the mentioned uses of PPI(s) according to the invention have the effect of increasing the effect of an in vivo administered drug.
  • the use of PPI(s) of the invention gives a synergistic effect of a drug in vivo. This synergistic effect is for example seen in cancer patients treated with cytostatics.
  • the invention relates to a method of treating or preventing a MDR (multidrug resistance) condition, comprising administration of a pharmaceutical composition comprising proton pump inhibitor(s), PPI(s), to an individual.
  • a pharmaceutical composition comprising proton pump inhibitor(s), PPI(s)
  • the administration of PPI(s) is also useful for increasing the effect of an in vivo administered drug.
  • the pharmaceutical composition may comprise the drug and be administered simultaneously with the PPI(s).
  • the pharmaceutical composition does not comprise the drug and in this case the drug is administered in association with the PPI(s) or at an interval before of after the PPI administration.
  • the invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising proton pump inhibitor(s) and a drug selected from cytostatics/anti-neoplastic agent(s); anti- parastic agents; and anti-bacterial agents. These agents may be selected from those mentioned above or other suitable agents.
  • Fig. 1-3 show the concentration-response curves of the three cell-line pairs.
  • la-g are U-937 GTB and U-937-vcr; 2a-g are 8226/S and dox40; 3a-g are H69 and H69-AR.
  • the graphs are presented as mean of 5-7 experiments ⁇ SE. Incubation with only vcr or dox are presented as mean of 13-20 experiments ⁇ SE.
  • Fig. 4a-b show the survival index % and the concentration-response curves of the cell-lines U937-GTB and U937-ver when incubated with taxotere or vinorelbine and lanzoprazole ( 2 and lO ⁇ g/ml).
  • Fig. 5a-c show the cytotoxicity of the PPIs and PSC alone on the cell-lines.
  • Fig 6 shows inhibitory effect of Lanzo in combination with chloroquine against Plasmodium falsciparum.
  • the lymphoma cell line U-937 GTB and its subline U-937-vcr, the small cell lung cancer cell line NCI-H69 (H69) and its subline H69-AR were obtained from American Type Culture Collection (ATCC, Rockville, MD, USA).
  • U-937-vcr was selected for vincristine resistance, proposed to be tubulin associated [11].
  • H69-AR selected for dox resistance expresses the multidrug resistance protein, MRP [12], [3] while dox40, also selected for doxo resistance, expresses the P- glycoprotein 170 (Pgp).
  • Adriamycin® (doxorubicine), Oncovin® (vincristine,) Taxotere® (docetaxel) and Navelbine® (vinorelbine) all purchased from commercial sources were obtained from the local hospital pharmacy.
  • PSC 833 PSC 833 (PSC), kind gift fromNovartis (Basel, Switzerland), were dissolved in ethanol at lmg/ml and stored in -70° C. Fluoresceindiacetate (FDA; Sigma). Genistein (Sigma) was dissolved in DMSO to lOmg/ml and stored in -70° until use.
  • Lansoprazole and omeprazole, powder (AstraZeneca and Takeda Chemical Company, LTD) were stored in +4° C protected from light. New stock solutions, lmg/ml dissolved in ethanol, were freshly prepared made for each plate batch. All other reagents were of analytical grade and obtained from commercial sources.
  • TMCA Fluorometric Microculture Cytotoxicity Assay
  • the medium in the V- shaped plates were removed by aspiration using a microplate washer, Multiwash, (Dynatech Laboratories, Chantilly, VA) and 200 ⁇ l PBS was added using the same washer.
  • the flatbottomed plates were flicked by hand and 200 ⁇ l PBS were added with the above mentioned plate washer.
  • lOO ⁇ l HEPES buffer containing FDA to a final concentration of lO ⁇ g/ml were added to each well.
  • the plates were incubated for 45 minutes at 37° C and then the generated fluorescence in each well were detected with a microtiterplate spectrofluorometer, Fluoroscan ⁇ , (Labsystems OY., Helsinki, Finland) excitation and emission filters set to 480 and 530 nm, respectively.
  • the results are presented as survival index (SI), defined as fluorescence in test wells in percent of control wells with blank values subtracted. All calculations were made with custom made software, Microsoft Excel, (Microsoft, Redmond, WA) using a Macintosh computer (Apple Computer, Cupertino, CA).
  • vcr-lansoprazole 2 and lO ⁇ g/ml Five plate configurations were used; vcr-lansoprazole 2 and lO ⁇ g/ml, vcr-omeprazole 2 and lO ⁇ g/ml, vcr-PSC 1 and 3 ⁇ g/ml, dox-lansoprazole 2 and lO ⁇ g/ml and dox-omeprazole 2 and lO ⁇ g/ml.
  • Figures 1-3 shows the concentration-response curves of the three cell-line pairs, la-g are U- 937 GTB and U-937-vcr. 2a-g are 8226/S and dox40, 3a-g are H69 and H69-AR.
  • the graphs are presented as mean of 5-7 experiments ⁇ SE. Incubation with only vcr or dox are presented as mean of 13-20 experiments ⁇ SE.
  • Table 1 shows IC50 values for the six cell lines. IC50 is defined as the drug concentration giving a SI of 50% compared to untreated control cells.
  • Figures 4b shows the concentration-response curves of cell-lines incubated with taxotere and vinorelbine, respectively, and lanzoprazole 2 and lO ⁇ g/ml
  • Figures 5a-c shows the cytotoxicity of the PPIs and PSC alone on the cell-lines.
  • Figure 1 a-g show concentration response curves for U-937 GTB and U-937- vcr.
  • both lanzo and omeprazole decreased the IC50 values 4,5 and 6.5 fold, respectively in both cell lines.
  • lanzo a slight decrease in IC50 value was observed in U-937-vcr and for omeprazole there was a slight increase in IC50 values for vcr in both cell lines, (not significant)
  • Figure 2 a-g shows concentration response curves for 8226/S and dox40.
  • IC50 was halved in 8226/S when vcr was co-incubated with lanzo or omeprazole at 10 ⁇ g/ml. At 2 ⁇ g/ml no significant change in IC50 was observed in 8226/S. Dox40 produced no IC50 value for vcr and vcr+omeprazole 2, IC74 and IC58 were 0.5 ⁇ g/ml. IC50 values for vcr+lanzo 2 and 10 and vcr+omeprazole 10 were 0.3 and 0.2 ⁇ g/ml. When lanzo and omeprazole were incubated with dox no significant change in IC50 values were observed compared to dox alone. PSC was included as a reference compound for a potent PGP and a weak MRP inhibitor. At 1 and 3 ⁇ g/ml a 3-250 fold decrease of IC50 in the cell lines were observed.
  • Figure 3 a-g shows concentration response curves for H69 and H69-AR.
  • Taxotere and PPI Taxotere and PPI; and vinorelbine and PPI
  • Figure 4a shows the effect of lanzoprazole on vinorelbine and taxotere induced cytotoxicity. As appears in the figure, SI% (survival index) is markedly reduced by the addition of PPI.
  • Figure 4b shows the effect of lanzoprazole on vinorelbine and taxotere induced cytotoxicity in U-937 GTB and U-937- vcr cells. As appears in the figure, PPI's have a significant effect on taxotere and vinorelbine induced cytotoxicity in U-937-vcr-cells.
  • Figures 5a-c shows the cytotoxicity of the PPIs and PSC alone on the cell-lines.
  • SI of 8226/S and dox40 varied between 90-113% when incubated with the PPIs alone. At 3 (g/ml of PSC, SI was 76 % compared to untreated dox40.
  • SI in H69 and H69-AR varied between 73-110% when incubated with the PPIs alone.
  • a SI of 76 % was observed in H69-AR when incubated with PSC.
  • a SI above 100 % such as for U-937 GTB for example is probably due to assay variability but may also indicate an unspecif ⁇ c growth stimulation or a stimulation of the intracellular esterases responsible for the hydrolysis of FDA to fluorescein.
  • the chloroquine resistant P. falciparum strain FCR 3 S 1 was kept in continuos culture in RPMI-hepes medium supplemented with 10% AB serum.
  • a 3 H-hypoxanthine incorporation assay for screening of inhibitory effect of different drug compounds was used [14, 15].
  • the parasite was diluted in the medium to a parasitemia of 0.2% and a hematocrite of 2%.
  • Lanzoprazole (Takeda chemical industries LTD, Osaka, Japan) were dissolved in DMSO and diluted in RPMI to final concentrations of 2, 5, 10 and 20 ⁇ g/ml. Chloroquine was used in concentrations from 10 ⁇ g/ml down to 2 ng/ml (fig 7). The effect of lanzoprazole was tested with and without the addition of chloroquine. DMSO alone was used as control. The microtiter plates were incubated in a candle jar at 37 °C for 24 hours to allow inhibition of the proliferation. 3 H-hypoxanthine at a concentration of 0.5 ⁇ Ci diluted in RPMI medium was added to each well and the culture was continued for another 18 hours. Finally, the parasite cultures were harvested on filter papers using an automatic cell harvester. The incorporated radioactivity was measured in a microbeta counter after addition of scintillation fluid. Results are shown as mean inhibition of five polymerisation assays.
  • Lanzoprazole alone had an mean inhibitory effect at the highest concentration (20 ⁇ g/ml) comparable to inhibition of the P. falciparum proloferation in combination with chloroquine at 2 ng/ml.
  • Lanzoprazole alone or in combination with chloroquine had an inhibitory effect on the resistant strain FCR3 SI and the synergistic effect was clearly dose dependent (Fig 6).
  • the cut-off level for the synergistic effect was shown when the chloroquine concentration reached 32 ng/ml.
  • a dose dependent effect was also shown for concentration of lanzoprazole (Fig 6).
  • DMSO alone had no inhibitory effect.
  • the wild-type pfindrl gene product Pghl is located in the vacuole, which is the site of action of chloroquine. Pghl contributes to the acidification of the vacuole by pumping either directly or indirectly a pronated compound within the valuole. Being a weak base, chloroquine may accumulate into vacuoles in which the pH is decreased. Mutations in pfindrl would prevent such a decrease in pH, hence less chloroquine would accumulate at the site of action.
  • Lanzoprazole may maintain low pH-levels by a so far unknown mechanism to concentrate chloroquine into the vacuoles and by this revert resistance. Another possible mechanism could be that lanzoprazole interferes with a plasma membrane efflux system. By acting at this level, a synergistic effect between chloroquine and lanzoprazole will appear and thus, the proton pump inhibitor may act as a resistance modulator. Researcher are seeking additional, non-pfmdrl chloroquine resistance genes, and one such candidate gene segregates with active efflux of the drug.
  • the invention also describes intracellular killing of bacteria by azitromycin - a macrolide with a high degree of intracellular accumulation - in cells expressing resistance to cytotoxic drugs.
  • Human derived cell-lines were used, with varying degree of multidrug resistance. Drugs that might interfere with antibiotic efflux and thus could act as resistance modulators were studied. Since proton-pump inhibitors (PPIs) such as omeprazole, lansoprazole and similar substances seem to have a synergistic effect in treatment of H. pylori infections with antibiotics, these drugs were tested in combination with azithromycin in order to study the efficacy of intracellular killing of H. pylori in cells with varying degrees of drug resistance.
  • PPIs proton-pump inhibitors
  • H. pylori clinical strain 88-23 (kindly provided by M. Blaser, Arlington, TN, USA), was grown on Colombia agar plates (Colombia II agar Base BBL®, Becton-Dickinson and Company, Cockeysville, MD, USA supplemented with 10% horse serum and 8.5% horse blood). Growth was performed at 37°C in a humid atmosphere under microaerophilic conditions (5% O 2 , 10% CO 2 and 85% N 2 ).
  • the bacteria Prior to infection, the bacteria were cultured for 36 h in Brucella Broth (10 g/1 Bacto® Peptone, (Difco Laboratories, Detroit, MI, USA), 5 g/1 Lab lemco Powder (Oxoid, Unipath LTD, Basingstoke, Hampshire, England), 10 g/1 Dextrose, 5 g/1 NaCl, 1 % Isovitalex BBL® (Becton-Dickinson and Company, Cockeysville, MD, USA)) with 10% fetal calf serum. The pH of the broth was adjusted to 6.0. The purity of the H. pylori cultures was verified by Gram staining and by biochemical characteristics i.e. positive in urease, catalase, and oxidase tests.
  • H. pylori broths were centrifuged for 15 min at 1000 x g.
  • the bacterial pellet was resuspended in RPMI-medium to a final concentration of about 1x10 bacteria/ml and 10 ⁇ l of the suspension was added to each well containing cells. Internalization was allowed for 12 h in 37° in an atmosphere with 5% CO 2 .
  • Extracellular H. pylori was eradicated by adding gentamicin (Gensumicin®, Roussel, Denham, Uxbridge, UK) to a final concentration of 50 mg/1 in the wells and incubating the exposed cells for 2 h.
  • Drug treatment Treatment
  • Azithromycin (Pfizer Inc., New York, USA) was added to the wells to a final concentration of 10 mg/1 with or without either omeprazole (Astra, Sweden) at a concentration of 20 mg/1, or lansoprazole (Takeda chemical industries LTD, Osaka, Japan) at 2 mg/1.
  • One control group was incubated with medium only. At 0, 4 and 24 h, cells from each group were transferred to Eppendorf tubes. The cells were washed twice with PBS, followed by 10 minutes lysis with distilled water. After centrifugation at 15800 x g for 5 minutes, the pellets, consisting of bacteria and cell debris, were dissolved in 1 ml of PBS.
  • One hundred microliters from each sample was plated on Colombia agar plates and incubated for 3 days before the colonies, i.e. the viable intracellular bacteria, were counted.
  • H. pylori Cell lines selected in different concentration of Vincristine, and exhibiting different MDR phenotypes were used in an intracellular infection assay. After incubation with H. pylori, the cells were treated with gentamicin to eradicate extracellular bacteria. Azitromycin (lOmg/l) was added to the medium, and surviving bacteria were counted at regular intervals. The intracellular survival of H. pylori was approximately a 100-fold higher in the resistant cells, with the bacteria totally protected at the azitromycin concentration used (lOmg/l). PPI alone had no effect on the intracellular bacteria (data not shown).
  • Adding lansoprazole or omeprazole made the bacteria susceptible to azitromycin to the same degree as those infecting the non-MDR U-937 GTB cell line. Furthermore, at 4 hours a potentiating effect of PPI on azitromycin was seen in the sensitive U-937 GTB cells.
  • Antibiotic resistance in intracellular organisms can be due not only to factors in the infecting microorganisms, but also to properties of the host cells.
  • Several known mechanisms of in vitro resistance to cytotoxic drugs could also be applicable for antibiotics.
  • MDR cells may render intracellular bacteria inaccessible to certain antibiotics might have important implications for the persistence of these infections. If cells expressing MDR are infected in vivo, this could result in chronic, therapy-resistant infections. Whether this is the case in H. pylori infections is under debate, but we have shown that this is theoretically possible. Observations both in vitro and in vivo have shown that H. pylori is capable of invading epithelial cells. The sanctuary that provides a reservoire for H. pylori to reproduce the stomach after unsuccessful therapy is still unknown but one possibility is that H. pylori is also an intracellular organism with clinical consequences.
  • Germann, U. G., P-glycoprotein A mediator of multidrug resistance in tumour cells. European Journal of Cancer, 1996. 32A(6): p. 927-944.

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Abstract

La présente invention concerne une nouvelle utilisation d'inhibiteurs de la pompe à protons comme l'oméprazole, l'ésoméprazole, le lansoprazole, le rabéprazole et le pantoprazole. L'invention concerne également l'utilisation d'inhibiteurs de la pompe à protons (PPIs) pour produire un médicament de traitement ou de prévention d'un état de résistance multimédicament (MDR), tel qu'un état associé au traitement du cancer.
PCT/SE2002/000678 2001-04-06 2002-04-05 Nouvelle utilisation d'inhibiteurs de la pompe a protons WO2002080917A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
SE0101231-9 2001-04-06
SE0101229-3 2001-04-06
SE0101231A SE0101231D0 (sv) 2001-04-06 2001-04-06 Novel use of proton pump inhibitors
SE0101229A SE0101229D0 (sv) 2001-04-06 2001-04-06 Treatment or prevention of antibiotic resistance

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Cited By (7)

* 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
WO2005077365A2 (fr) * 2004-02-12 2005-08-25 Istituto Superiore di Sanità Utilisations d'inhibiteurs de pompe a protons
EP2254557A1 (fr) * 2008-03-04 2010-12-01 Bio-Quant, Inc. Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons
US20120322820A1 (en) * 2008-03-04 2012-12-20 Nexmed Holdings, Inc. Methods to inhibit tumor cell growth by using proton pump inhibitors
WO2015011282A2 (fr) * 2013-07-26 2015-01-29 ENERGEIA BIOSCIENCES B.V. GbR No. 321 Procédé d'identification de modulateurs de la libération de l'atp médiée par un transporteur abc et utilisation desdits modulateurs pour le traitement de maladies
CN104906099A (zh) * 2015-06-29 2015-09-16 杭州泛普生物科技有限公司 一种氯喹与长春新碱的药物组合
US9969780B1 (en) 2004-03-11 2018-05-15 Istituto Superiore Di Sanita Tat complexes, and vaccines comprising them

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
TRAUTMANN MATTHIAS ET AL.: "Combined activity of azithromycin and lansoprazole against helicobacter pyroli", HELICOBACTER, vol. 4, no. 2, 1999, pages 113 - 120, XP002954531 *

Cited By (14)

* 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
CN104161755A (zh) * 2004-02-12 2014-11-26 国家高等卫生院 质子泵抑制剂的新应用
WO2005077365A3 (fr) * 2004-02-12 2005-12-01 Inst Superiore Di Sanita Utilisations d'inhibiteurs de pompe a protons
CN1953750A (zh) * 2004-02-12 2007-04-25 国家高等卫生院 质子泵抑制剂的新应用
JP2007522182A (ja) * 2004-02-12 2007-08-09 イスティチュート スペリオーレ ディ サニータ プロトンポンプ阻害剤の新規使用
AU2005211938B2 (en) * 2004-02-12 2010-08-26 Istituto Superiore Di Sanita Novel uses for proton pump inhibitors
WO2005077365A2 (fr) * 2004-02-12 2005-08-25 Istituto Superiore di Sanità Utilisations d'inhibiteurs de pompe a protons
US9969780B1 (en) 2004-03-11 2018-05-15 Istituto Superiore Di Sanita Tat complexes, and vaccines comprising them
EP2254557A1 (fr) * 2008-03-04 2010-12-01 Bio-Quant, Inc. Procédés pour inhiber la croissance de cellules tumorales à l'aide d'inhibiteurs de la pompe à protons
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