WO2004054497A2 - Verwendung einer trpm8 aktivierenden substanz zur tumorbehandlung - Google Patents
Verwendung einer trpm8 aktivierenden substanz zur tumorbehandlung Download PDFInfo
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- WO2004054497A2 WO2004054497A2 PCT/DE2003/004233 DE0304233W WO2004054497A2 WO 2004054497 A2 WO2004054497 A2 WO 2004054497A2 DE 0304233 W DE0304233 W DE 0304233W WO 2004054497 A2 WO2004054497 A2 WO 2004054497A2
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- trpm8
- icilin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- 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
- A61K31/05—Phenols
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/337—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having four-membered rings, e.g. taxol
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/4965—Non-condensed pyrazines
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Definitions
- TRPM8 activating substance for tumor treatment.
- the invention relates to the use of TRPM8 modulating substances for producing a pharmaceutical composition for the treatment of tumor diseases.
- the invention further relates to such compositions and to a treatment plan.
- Trpp8 and TRPM8 are used synonymously below.
- Trpp ⁇ is described in Tsavaler et al. , Cancer Res, 61: 3760-3769 (2001) as a prostate-specific gene which is predominantly expressed in human prostate tumors. Trpp8 is significantly upregulated. According to this reference, Trpp ⁇ is found in androgen-dependent prostate cell lines, but not in androgen-independent cell lines, which also do not express PAP (prostate acid phosphatase) and PSA (prostate specific antigen). Trpp ⁇ is believed to function as a calcium channel protein.
- Trp proteins are said to belong to the so-called sturgeon operated calcium channels (SOC) and capacitive calcium entry channels (CCE). Involvement in apoptosis was shown in LNCaP cells (ertz et al., J Biol Chem, 275: 11470-11477 (2000)).
- the 5694 bp Trpp ⁇ cDNA has a 3312 bp open reading frame which codes for a 1104 amino acid protein with allegedly seven transmembrane domains with a molecular weight of approx. 127,500 Da.
- Trpp8 sequences are described in references US-6,194,152, US-6,183,968, O-99/46374, O-99/09166, O-01/25273, WO-01/25272, WO-01/34802, O-01/46258, O-01/42467 and O-01/1633.
- References US Pat. No. 6,194,152 and WO-01/51633 disclose the use of the sequences mentioned therein for the detection of tumor cells and various substance classes in a general manner for the treatment of prostate cancer.
- Menthol is a secondary plant substance that occurs naturally as a monoterpene in peppermint and is the main component of peppermint oil. Menthol induces a sensation of cold on the skin as well as in the mouth and nose by stimulating certain nerve cells. Another substance that triggers a sensation of cold is Icilin. Both substances activate peripheral nerve cells, whereby the ion channel TRPM8 is selectively activated and ions such as Ca2 + and Na + in the cell. From the references McKemy et al., Nature 416 (6876): 52-52 (2002) and Peier et al. , Cell 108 (5): 705-715 (2002) it is known that the human orthologic TRPM8 functions as a menthol sensor in mice and rats. The same is known for icilin. TRPM8 also acts as a cold receptor in a temperature range from 8 ° C to 25 ° C.
- TRPM8 A physiological function of TRPM8 in tumor tissues is unknown.
- Prostate cancer in particular is a disease that occurs with increasing incidence with increasing age. So far, prostate cancer has essentially been diagnosed pathologically and mostly treated by removing the prostate. Removal of the prostate has several adverse effects on a patient. Improved diagnosis and treatment of this type of cancer, particularly without the need for prostate removal, is therefore highly desirable.
- the invention is based on the technical problem of specifying pharmaceutical compositions for the treatment of tumor diseases, in particular prostate cancer diseases. Fundamentals of the invention and preferred exemplary embodiments.
- the invention teaches the use of a TRPM8 activating substance for producing a pharmaceutical composition for the treatment of tumor diseases, in particular prostate cancer, in which TRPM8 is overexpressed.
- the finding is based on the surprising finding that in tumors which have an increased expression of the ion channel TRPM8, the activation of the TRPM8 inhibits or slows down the tumor growth.
- permanent activation specifically destabilizes the ion balance of the tumor cells, which are thereby driven into apoptosis.
- a substance is preferably used which is selected from the group consisting of "menthol, menthyl derivatives, pyrrolidinyl derivatives of furanone, icilin, icilin derivatives and mixtures of these substances".
- menthol encompasses all enantiomers and mixtures of the enantiomers.
- substances which differ structurally from the above substances can also be used, the activation of TRPM8 being regarded as an essential selection criterion.
- An example of such a different substance is 2-isopropyl-N-2,3-trimethylbutyramide.
- Examples are: 5-methyl-4- (1-pyrrolidinyl) -3- [2H] -furanone, 4,5-dimethyl-3- (1-pyrrolidinyl) -2- [5H] -furanone, 4-methyl-3 - (1-pyrrolidinyl) -2- [5H] furanone.
- Icilin is shown in Formula III. Also included are cilin derivatives which activate TRPM8. According to the exemplary embodiments, this can be easily tested.
- a pharmaceutical composition according to the invention can be prepared galenically with customary auxiliaries and carriers, preferably for injection, i. ., ip or im, or infusion.
- the dose is preferably in the range from 0.1 to 5000 mg / kg body weight, preferably 1 to 100 mg / kg body weight to one day, can be divided into 1 to 10 dose units. It is expedient to prepare the composition for continuous or discounted periodic administration over a period of at least 2 weeks, preferably at least 8 weeks, most preferably at least 20 weeks. This is linked to a treatment plan that provides for continued administration during these periods.
- a discontinuous periodic dose is given by the single dose being given in defined time periods. The time periods can range, for example, from 1 hour to 7 days.
- a continuous administration takes place with suitable systems, which bring about a continuous release of the substance.
- suitable systems which bring about a continuous release of the substance.
- therapeutic substances adsorbed on or in polymeric microparticles are possible, the substances being slowly released from the injected microparticles.
- Such systems are known to the person skilled in the art in extensive variants.
- Systems that continuously deliver active substances also include transdermal systems, which the average person skilled in the art is also familiar with in a wide variety.
- the invention also teaches a method for the treatment of tumor diseases, in particular prostate cancer, wherein a diseased patient is given a physiologically effective dose of a substance that inhibits TRPM8.
- hypothermia can be continuous or discontinuous. In the case of discontinuous hypothermia, this can take place before, during and / or after the administration of the pharmaceutical composition according to the invention.
- TRPM8 is used for all human isoforms, known or new, based on amino acids.
- TRPM8 is also called Trpp8.
- the proteins and peptides encoded by the nucleic acids disclosed in the sequence listings and the proteins or peptides disclosed in the sequence listing are included, as are the TRPM8 sequences disclosed in the literature references indicated or the proteins or peptides encoded thereby.
- This term also includes the short sequences disclosed in the context of this description, which come from the isoforms, for example immunization sequences.
- homologs are included which only represent partial sequences of the explicitly disclosed sequences, for example one or more exons, or complementary sequences thereto, with the proviso that these have at least the same affinity for a protein- or peptide-specific target molecule, in particular the substances used according to the invention, tie.
- the terms of the proteins or peptides also include partial sequences in addition to the full lengths of the disclosed sequences (see also the preceding paragraph), specifically with a minimum length of 4 amino acids, preferably 10 to 30 amino acids.
- treatment also includes prophylaxis.
- a tumor cell overexpresses TRPM8 if the amount of TRPM8 RNA or TRPM8 protein formed in a tumor cell is higher than in normal cells of the same tissue type, preferably originating from the same patient. It is understood that the same measurement methods are used for the tumor / normal comparison. Various measurement methods for determining nucleic acids and / or proteins or peptides in cells are known to the person skilled in the art, all of which can be used.
- An activator is a compound or substance which either promotes the formation of TRPM8 or increases the activity of TRPM8 formed, based on the TRPM8 activity in the absence of the activator.
- an activator can be a substance that intervenes in the cascade of TRPM8.
- an activator can be a substance which binds with the TRPM8 formed, in such a way that further physiological interactions with endogenous substances are increased compared to the same interactions, but without binding of the activator.
- An activator preferably increases the transport of cells upon contact with cells expressing TRPM8 Ions in or out of a cell compared to a cell with the same TRPM8 expression level, but without contacting the activator. Ion transport can be determined, for example, according to Peier et al., Cell 108 (5): 705-715 (2002).
- Counter ions for ionic compounds are, for example, Na + , K + , Li + or cyclohexylammonium.
- Suitable solid or liquid pharmaceutical preparation forms are, for example, granules, powders, dragees, tablets, (micro) capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions (i., Ip, im) as well as preparations with protracted release of active ingredient, in the production of which customary auxiliaries such as carriers, explosives, binders, coatings, swelling agents, lubricants or lubricants, flavorings, sweeteners and solubilizers are used.
- a pharmaceutical composition according to the invention can be produced by mixing at least one TRPM8 activator according to the invention in a defined dose with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries with a defined dose and preparing the desired dosage form.
- TRPM8 activator according to the invention in a defined dose with a pharmaceutically suitable and physiologically compatible carrier and, if appropriate, other suitable active ingredients, additives or auxiliaries with a defined dose and preparing the desired dosage form.
- Example 1 Reduction in colony formation rate.
- HEK293 cells were not transfected, transfected with TRPM8 or transfected with an empty vector.
- the cells were used in a soft agar assay (see reference Shappel et al., Cancer Research 61: 497-503 (2001)).
- the cells which are plated out and immobilized in the agar, grow three-dimensionally and independently of the substrate. The colony formation rate allows conclusions to be drawn about the tumorigenicity of the cells. 1000 cells each were plated out in the 6-well plate in 2 ml of medium containing soft agar and, after the agar had solidified, were overlaid with 1 ml of medium (DMEM with 10% FCS, 2 mM glutamine).
- Example 2 Tumor growth in nude mice.
- TRPM8 cDNA was subcloned into the expression vector pcDNA3.1 and then stably transfected into HEK293 cells. The expression of TRPM8 protein was detected in the Western blot with TRPM8-specific antibodies.
- 2 million HEK293-TRPM8 cells were injected subcutaneously into male nude mice or xenografted in the prostate.
- the test groups consisted of 10 animals each.
- the control groups were not treated or only treated with DMSO.
- the animals were treated by daily intraperitoneal application of 30 mg / kg body weight of cilin or menthol, dissolved in DMSO, over a period of three weeks.
- the growth of the subcutaneously injected cells was measured twice a week over the entire duration of the experiment. Immediately after the end of the tests, the xenon implants were resected, weighed and preserved. As a result, the treated animals showed a significantly lower tumor growth than the untreated control animals.
- TRPM8 sequences in particular splice variants, are given in the sequence listing.
- nucleic acid sequences these code for proteins, peptides or partial sequences of proteins or peptides which can be activated in the context of the invention.
- amino acid sequences is acti ⁇ in the invention.
- Further sequences for TRPM8 can be found in the literature mentioned at the beginning.
- NET Neuroendocrine tumors
- NET of the gastrointestinal tract are also known as Gaslio Entero-Pancreatic (GEP).
- GEP Gaslio Entero-Pancreatic
- organs of the respiratory tract e.g. The bronchi or lungs can develop NET. Little is known about the calcium homeostasis of these rare cancers, especially the role of TRP channels in NET.
- Nanosuspension (nanocrystals in aqueous solution smaller than l ⁇ m)
- Tiimor disease is neuroendocrine tumors, in particular of the gastrointestinal tract and the respiratory organs.
- Example 1 Reduction of the colony formation rate becomes Example 5
- Example 2 Tumor growth in Naoktmaes becomes Example 6
- Example 3 TRPM8 sequences becomes Example 10
- Example 1 Icilin induces cytotoxicity in TRPM8 transfectants
- HEK293 cells were stably transfected with TRPM8 (K52) or stably transfected with empty vector (M2). 5000 cells each were plated out in 96well plates in 100 ⁇ l medium and the next day Icilin, dissolved in DMSO in the final concentrations 30 ⁇ M, lO ⁇ M, 3 ⁇ M. As a control, completely untreated cells (Ko) and cells which were mixed with DMSO in a dilution corresponding to the highest Icilin concentration were also included. After 48 hours of incubation, the cells were photographed under the microscope. There was a clear concentration-dependent cytotoxic effect of Icilin on HEK293 TRPM8 transfectants, but not on Contxoll cells. The cytotoxicity correlates with a dramatic change in cell morphology. Cell morphology DMSO had no effect on cell growth or cell morphology.
- HEK293 cells were stably transfected with TRPM8 (52) or stably transfected with empty vector (M2). 5000 cells each were plated out in 96well plates as a batch in lOO ⁇ l medium and the next day Icilin, dissolved in DMSO in the final concentrations lO ⁇ M, 5 ⁇ M, l ⁇ M and lOOnM were added.
- Icilin dissolved in DMSO in the final concentrations lO ⁇ M, 5 ⁇ M, l ⁇ M and lOOnM were added.
- As a control completely untreated cells (Ko) as well as cells that were mixed with DMSO in a dilution corresponding to the highest Icilin concentration were included. After 48 hours of incubation, cell proliferation was determined by luminometric quantification of the intracellular ATP concentration. The relative light units (RLU) in relation to the treated control cells are shown.
- the presence of Icilin in TRPM8 positive cells causes a clear concentration-dependent inhibition of proliferation, while no effect
- Example 3 Icilin has a pro-apoptotic effect on TRPM8 transfectants
- HEK293 cells were stably transfected with TRPM8 (K52) or stably transfected with empty vector (M2). 5000 cells each were plated in 96-well plates as a 6-fold batch in 100 ⁇ l medium and the next day Icilin, dissolved in DMSO in the final concentrations 10 ⁇ M, 5 ⁇ m, 1 ⁇ m and 100 nm, was added. As a control, completely untreated cells (Ko) as well as cells that were mixed with DMSO in a dilution corresponding to the highest Icilin concentration were included. After 24 h of exercise, the induction of apoptosis was determined by fluorometric quantification of Caspase3 / 7 activity.
- RLU relative light units
- Example 4 Icilin has an anti-proliferative effect on LNCaP cells
- Each 8000 cells of the prostate tumor cell line LNCaP were plated in 96well plates as a ⁇ -fold approach in 100 ⁇ l medium and the next day Icilin, dissolved in DMSO in the final concentrations 30 ⁇ M and 3 ⁇ M was added.
- Paclitaxel (Pax) was also used in a concentration of 10nM and in combination with Icilin in the aforementioned concentrations.
- As a control cells to which DMSO was added in a dilution corresponding to the highest Icilin concentration were carried along. After 48 hours of incubation, cell proliferation was determined by luminometric quantification of the intracellular ATP concentration. The relative light units (RLU) are shown in relation to untreated control cells.
- cilin causes in LNCaP cells expressing TRPM8 endogenously showed a clear concentration-dependent inhibition of proliferation, while no effect on control cells was observed.
- Paclitaxel also inhibits proliferation.
- the combination of icilin with paclitaxel has a greater inhibition of proliferation than both substances alone (synergistic effect). Similar results were observed with other proliferation assays such as MTS, MTT, XTT.
- Example 5 Icilin causes a decrease in the rate of colony formation
- TRPM8 stably transfected HEK293 cells (K51, " K52) were immobilized in soft agar. The colony formation rate was determined as a measure of the substrate-independent growth. 1000 cells were plated out in 2 ml of medium in the 6-hole plate.
- TRPM8 stably transfected HEK293 cells were xenotransplanted intra-peritoneally (i.p.) in nude mice (MVlR -nu / nu, 9 weeks old, male, 2 million cells per animal). The animals were washed every 3 days over a period of 14 days with 20 ⁇ l of a lOOmM Icilin solution in DMSO i.p. treated. The control group was treated with DMSO only under the same conditions. Tumor growth was followed by daily body weight measurements. Icilin treatment resulted in significantly reduced tumor growth compared to the solvent-treated control group.
- TRPM8 is expressed in neuroendocrine tumors
- RNA was prepared from human neuroendocrine tumor cell lines, which originate from p-uikreaskarzinomen (BON-1, QGP-1) or colon carcinoma (LCC-18), and the TRPM8 expression was quantified by RT-PCR analysis. The relative expression of the mRNA is shown in comparison to TRPM8 positive LNCaP prostate tumor cells. All three tested neuroendocrine tumor cell lines express TRPM8 in significant amounts.
- Example 8 Iclin has a pro-apoptotic effect on neuroendocrine tumor cells
- Human neuroendocrine QGP-1 pancreatic tumor cells were plated in 96 well plates as a 6-fold batch in 100 ⁇ l medium (5000 cells / well) and the next day Icilin, dissolved in DMSO in the final concentrations 100 nm, 100 ⁇ m, 100 ⁇ m and 100 ⁇ m were added.
- As a control completely untreated cells (Ko) and cells to which DMSO was added in a dilution corresponding to the highest Icihn concentration were included. After 24 hours of incubation, the induction of apoptosis was determined by fluorometric quantification of Caspase3 / 7 activity. The apoptosis rate in relation to solvent-treated control cells is shown.
- the presence of Icilin in QGP-1 cells causes a marked concentration-dependent induction of apoptosis, while hardly any effects were observed in control cells.
- Example 9 Iclin has an anti-proliferative effect on neuroendocrine tumor cells
- Human neuroendocrine QGP-1 P-u ⁇ J reagent tumor cells were plated out in 96 well plates as a ⁇ - fold approach in 100 ⁇ l medium (5000 cells / well) and the next day Icilin, dissolved in DMSO in the final concentrations 100 nm, 100 ⁇ m, 100 ⁇ m and 100 ⁇ m were added.
- Icilin dissolved in DMSO in the final concentrations 100 nm, 100 ⁇ m, 100 ⁇ m and 100 ⁇ m were added.
- As a control completely vin-treated cells (Ko) and cells to which DMSO was added in a dilution corresponding to the highest icinin concentration were included. After 48 hours of incubation, cell proliferation was determined by luminometric quantification of the intracellular ATP concentration. The proliferation rate in relation to solvent-treated control cells is shown.
- the presence of Icilin causes a concentration-dependent inhibition of proliferation in QGP-1 cells, while no effect on control cells was observed. Similar results were observed with other proliferation assays
Abstract
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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AU2003296545A AU2003296545A1 (en) | 2002-12-18 | 2003-12-16 | Use of a trpm8-activating substance for the treatment of tumours |
US10/539,874 US20070010574A1 (en) | 2002-12-18 | 2003-12-16 | Use of a trpm8-activating substance for the treatment of tumours |
EP03813082A EP1575673A2 (de) | 2002-12-18 | 2003-12-16 | Verwendung einer trpm8 aktivierenden substanz zur tumorbehandlung |
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DE10259619.0 | 2002-12-18 | ||
DE10259619A DE10259619A1 (de) | 2002-12-18 | 2002-12-18 | Verwendung einer TRPM8 aktivierenden Substanz zur Tumorbehandlung |
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WO2004054497A2 true WO2004054497A2 (de) | 2004-07-01 |
WO2004054497A3 WO2004054497A3 (de) | 2004-12-23 |
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US (1) | US20070010574A1 (de) |
EP (1) | EP1575673A2 (de) |
AU (1) | AU2003296545A1 (de) |
DE (1) | DE10259619A1 (de) |
WO (1) | WO2004054497A2 (de) |
Cited By (3)
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WO2005002582A3 (en) * | 2003-07-02 | 2005-05-26 | Genentech Inc | Trp-p8 active compounds and therapeutic treatment methods |
WO2006040103A1 (en) * | 2004-10-13 | 2006-04-20 | Bayer Healthcare Ag | Use of cold menthol receptor modulators for the treatment of respiratory disorders |
JP2009526859A (ja) * | 2006-02-15 | 2009-07-23 | デンドレオン コーポレイション | Trp−p8活性の低分子モジュレーター |
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CN104147016B (zh) * | 2008-08-26 | 2017-07-11 | 巴斯夫欧洲公司 | 冷薄荷醇受体trpm8的低分子量调节剂的检测和用途 |
ES2377785B2 (es) * | 2010-09-08 | 2012-09-26 | Universidad Miguel Hernández De Elche | Composición farmacéutica para el tratamiento del ojo seco. |
EP2875803A1 (de) * | 2013-11-26 | 2015-05-27 | OTC GmbH | Polyol-in-Öl-Emulsionen zur dermalen Verabreichung |
CN107308165B (zh) * | 2017-06-22 | 2020-06-02 | 华中科技大学 | 一种抗肿瘤药物的增强剂及其应用 |
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2002
- 2002-12-18 DE DE10259619A patent/DE10259619A1/de not_active Ceased
-
2003
- 2003-12-16 US US10/539,874 patent/US20070010574A1/en active Pending
- 2003-12-16 AU AU2003296545A patent/AU2003296545A1/en not_active Abandoned
- 2003-12-16 WO PCT/DE2003/004233 patent/WO2004054497A2/de not_active Application Discontinuation
- 2003-12-16 EP EP03813082A patent/EP1575673A2/de not_active Withdrawn
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WO2000033857A1 (en) * | 1998-12-07 | 2000-06-15 | Ecosmart Technologies, Inc. | Cancer treatment composition and method using natural plant essential oils |
DE10215321A1 (de) * | 2002-04-02 | 2003-10-23 | Metagen Pharmaceuticals Gmbh | Trp-p8 Splice Varianten und regulatorische RNA |
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WO2005002582A3 (en) * | 2003-07-02 | 2005-05-26 | Genentech Inc | Trp-p8 active compounds and therapeutic treatment methods |
US7893072B2 (en) | 2003-07-02 | 2011-02-22 | Genentech, Inc. | Trp-p8 active compounds and therapeutic treatment methods |
WO2006040103A1 (en) * | 2004-10-13 | 2006-04-20 | Bayer Healthcare Ag | Use of cold menthol receptor modulators for the treatment of respiratory disorders |
JP2009526859A (ja) * | 2006-02-15 | 2009-07-23 | デンドレオン コーポレイション | Trp−p8活性の低分子モジュレーター |
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AU2003296545A1 (en) | 2004-07-09 |
WO2004054497A3 (de) | 2004-12-23 |
US20070010574A1 (en) | 2007-01-11 |
AU2003296545A8 (en) | 2004-07-09 |
EP1575673A2 (de) | 2005-09-21 |
DE10259619A1 (de) | 2004-07-08 |
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