WO2005011659A1 - Utilisation des n-alkanols comme activateurs du canal cftr - Google Patents
Utilisation des n-alkanols comme activateurs du canal cftr Download PDFInfo
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- WO2005011659A1 WO2005011659A1 PCT/FR2004/001662 FR2004001662W WO2005011659A1 WO 2005011659 A1 WO2005011659 A1 WO 2005011659A1 FR 2004001662 W FR2004001662 W FR 2004001662W WO 2005011659 A1 WO2005011659 A1 WO 2005011659A1
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- cftr
- alkanols
- octanol
- channel
- cells
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
Definitions
- the present invention relates to a new use of n-alkanols as activators of the CFTR channel (cystic fibrosis ans'ansmembrane conductance regulator) and to the application of said use to the treatment of pathologies in which there is a dysfunction of said channel, such as cystic fibrosis.
- the CFTR protein located in the apical region of the epithelial cells, is a chloride channel controlled by the level of cAMP and involved in the hydration of the fluids secreted by the submucosal glands. A dysfunction of this CFTR channel is responsible for cystic fibrosis, an autosomal recessive genetic disease.
- Cystic Fibrosis in English terminology
- Cystic Fibrosis in English terminology
- Cystic Fibrosis gene called CF involved in cystic fibrosis has been identified, cloned and located on the long arm of chromosome 7 (Riordan et al, 1989). Cystic fibrosis is the most common autosomal recessive genetic disorder in Caucasian populations.
- CF gene consists of 250,000 base pairs defining 27 exons and codes for the protein CFTR (Cystic Fibrosis Transmembrane Conductance Regulator), which contains 1480 amino acids (Riordan et al., 1989).
- Cystic fibrosis is a canalopathy, that is, a pathology related to dysfunction of ion channels, insofar as the protein CFTR has been characterized as a chloride channel.
- CFTR a canalopathy
- more than 1300 mutations in the CF gene have already been reported, which alter the properties and function of the CFTR channel.
- the CFTR protein is expressed in many organs including the exocrine pancreas, lungs, sweat glands, intestine, liver tissue, reproductive system, kidney and heart tissue.
- the interest in cystic fibrosis had important consequences for the understanding of the secretory mechanisms of normal epithelial cells.
- the CFTR protein which is mainly located at the apical pole of the epithelial cells, is a chloride channel, of low conductance, activated by the cAMP pathway.
- CFTR is involved in the hydration of fluids secreted by the submucosal glands and is said to influence the secretion of mucins, glycoproteins which participate in particular in the formation of bronchial mucus.
- dysfunction of the CFTR channel affects the apical secretion of Cl ions, activated by cAMP.
- the electrolyte transport which has become abnormal, causes the thickening of the extracellular mucus and thus leads to obstructions in the lumens of the various tissues. These obstructions are the cause of chronic bronchitis due to opportunistic bacterial pulmonary infections, pancreatic and hepatic insufficiencies, abnormally concentrated sweat secretion and male infertility.
- the CFTR protein is a glycoprotein with a molecular weight of
- 170 kD comprising five domains (Riordan et al., 1989): two transmembrane domains each with 6 transmembrane segments or ⁇ helices (numbered from 1 to
- the CFTR protein has, in addition to its chloride channel activity, many other cellular functions which have not yet been elucidated. It would regulate other ion channels such as the outgoing rectifying chloride channel ORCC (Schwiebert et al., 1995), the epithelial sodium channel ENaC (Quinton et al., 1999) or the calcium-dependent chloride channel CaCC (Wei et al. , 1999). It also has a regulatory activity on the release of ATP from the inside to the outside of the cell (Schwiebert et al., 1995).
- the CFTR shares a sequence and structure homology, with the ABC transporters (for "ATP-binding cassette") which constitute a large family of membrane proteins very conserved in evolution.
- the absence of chloride current after stimulation of the epithelial cells of the exocrine glands by cAMP is the main characteristic showing the presence of an abnormality in the CF gene and in particular of the mutation ( ⁇ F508).
- the highest mutation density is found in the two nucleotide binding domains (NBD1 and NBD2). Seven other significant mutations are present with frequencies above 1%.
- the G551D mutation corresponds to the substitution of a glycine residue (G) at position 551 of the protein with an aspartic acid (D).
- CF patients carrying this mutant have a severe pathology with pancreatic insufficiency and serious pulmonary disorders (Cutting et al., 1990).
- Heterozygous people would have been more resistant to epidemics of typhoid fever, cholera, tuberculosis or secretory diarrhea.
- a correlation between heterozygous carriers for the CF gene and susceptibility to develop various pathologies such as asthma, nasal polyposis, chronic sinusitis and bronchitis, bronchiectasis, allergic bronchopulmonary aspergillosis or pancreatitis has been established by certain studies. (Griesenbach et al., 1999). Mutations occurring in flanking regions between exons-introns of the CF gene have also been described. For example, there are polymorphic variants 9-, 7- or 5-thymidines between intron 8 and exon 9.
- the polymorphic variant 5T decreases the synthesis of the protein CFTR, moreover normal.
- the association of the 5T variant on one allele with a CFTR mutation on the other allele leads to congenital agenesis of vas deferens (ACCD), characterized in male patients by secretory infertility without any other classic cystic fibrosis disorder. A certain proportion of sterile men could actually carry these mutations in the CF gene, without developing cystic fibrosis itself.
- This discovery opens a debate on the diagnosis and classification of cystic fibrosis, linked to physiological disorders listed in heterozygous individuals.
- bromotetramisole did not have the expected activating effect.
- - Benzimidazolones (NSOO4) (Gribkoff et al, 1994). These compounds, derived from the imidazole nucleus such as levamisole, can, under certain conditions, and in particular when the CFTR channel has been phosphorylated, open the channel. Benzimidazolones are however also activators of many potassium channels (Olesen et al., 1994) and are therefore not very specific to the CFTR channel.
- Substituted xanthines such as 1TBMX (3-isobutyl-1-methyl-xanthine) or theophylline are first known as inhibitors of intracellular phosphodiesterases (cAMP degradation enzymes), phosphatases and antagonists of membrane receptors which fix adenosine; they also act on the mobilization of intracellular calcium. Regardless of these properties, they are activators of the CFTR channel (Chappe et al., 1998). The mechanic nism of action of xanthines on CFTR is still poorly understood but could imply their fixation on the nucleotide binding domains (NBD1 and NBD2).
- transmembrane ionics in particular chloride, and in particular in epithelial cells in humans or animals.
- the present invention more particularly aims to provide new drugs which can be used in the context of the treatment of cystic fibrosis, cases of "atypical cystic fibrosis" (asthma, chronic sinusitis, bronchiectasis ...), prevention or treatment of obstructions of the bronchial or digestive tracts (in particular pancreatic or intestinal), cardiovascular or renal diseases.
- the inventors have in fact surprisingly found that certain n-alkanols specifically activate the CFTR chloride channel (cystic fibrosis transmembrane conductance regulator).
- the CFTR channel activity is measured using the radioactive iodide efflux technique ( 125 I) or the patch clamp technique.
- the order of activation of CFTR by the n-alkanols is hexanol-Kheptanol-Koctanol-Koctanol-2 ⁇ decanol-1 (1 mM).
- the present invention therefore relates to the use of n-alkanols with linear hydrocarbon chains, branched or not, or C 6 -C 10 cyclic, for the preparation of a medicament intended for the treatment of pathologies associated with disorders CFTR chloride channels (transmembrane chloride flow), in particular in epithelial cells, in humans or animals.
- n-alkanols are n-alkanols with linear hydrocarbon chains, branched or not, in which the OH group is in position 1 (primary alcohol) or in position 2 (secondary alcohol).
- said n-alkanols are n-alkanols with cyclic hydrocarbon chains carrying one or more alcohol groups (cyclohexane, for example).
- the n-alkanols have, in this application, a certain number of advantages: - no activation by n-alkanols is detected in CHO control cells which do not express CFTR, whereas activation of CFTR by n-alkanols in CHO Chinese Hamster Ovary cells) expressing the CFTR channel is blocked by the addition of glibenclamide (100 ⁇ M), used to specifically block the CFTR channel.
- n-alkanols do not modify the basic level of cAMP; n-alkanols thus specifically activate the CFTR channel by a route independent of cAMP.
- the activation of CFTR by n-alkanols is independent of the potential effect of these molecules on cellular decoupling.
- the n-alkanols act by a mechanism independent of the protein kinase C.
- octanol which has already been proposed in numerous applications: 1. as anesthetic molecules; it exerts complex effects on biological membranes. A physico-chemical theory had been advanced to explain the effective power of anesthetics.
- n-alkanols are involved in the relaxation of smooth muscles in the airways by notably reducing the intracellular concentration of calcium ([Ca 2+ ] j) (Sakihara et al., 2002). action at the level of cell junctions by altering the conductance of communicating junctions in numerous tissues including the epithelial tissue (Weingart et al., 1998); this effect relates more specifically to lipophilic agents, such as n- long-chain alkanols The molecular mechanism resulting from cellular decoupling remains unclear 5. Alcohols such as octanol, as anti-emulsifying agents, have already been used, as an aerosol, in patients suffering from pulmonary edema (Miller and al.
- n-alkanols in the treatment of pathologies associated with transmembrane chloride ion flow disorders in epithelial cells and in particular cystic fibrosis and atypical cystic fibrosis has just been found by the inventors. Indeed, surprisingly, the n-alkanols in C ⁇ -C t o, in particular nebulized in the bronchi of patients in the form of an aerosol or nebuliser, activate or potentiate the activity of wild or mutated CFTR channels but present at the cell membrane especially in patients with cystic fibrosis.
- n-alkanols Activation of the CFTR channel by n-alkanols, could further promote a bronchodilator effect on the smooth muscle fibers of the bronchi and bronchioles, and contribute to the improvement of the respiratory function of patients suffering from cystic fibrosis as well as patients with respiratory failure not related to cystic fibrosis, such as asthma.
- said n-alkanols can be administered parenterally: intradermal, intravenous, intramuscular or subcutaneous administration; by intranasal and oral route: aspiration or nebulization by aerosol; orally; sublingually.
- said n-alkanols are administered in a form suitable for intra-nasal or buccal administration, so as to obtain direct contact between said n-alkanols and the surface of the bronchopulmonary mucous membranes.
- said n-alkanols are presented in a liquid form, for administration in the form of an aerosol or in the form of a nebulizer, and this using a nebulizing device, of the type of those used in the treatment of both asthma and cystic fibrosis.
- said n-alkanols are associated with at least one pharmaceutically acceptable vehicle suitable for said intra nasal or buccal administration.
- said n-alkanols are preferably administered at a concentration of between 0.001% and 0J% (v / v), corresponding to a value of between 10 and 1000 ppm (parts per million ), i.e. from 10 mg / kg to 1 g / kg.
- the invention also comprises other provisions, which will emerge from the description which follows, which refers to examples of implementation of the use which is the subject of the present invention, as well as to the accompanying drawings.
- FIG. 1 illustrates: (A) Comparison of the effect of octanol-1 and FSK on the efflux of I25 I (% on the ordinate) as a function of time (min, on the abscissa) in CHO-CFTR (+) cells. (B) Effect of octanol-1 and FSK on the efflux of 125 I (% on the ordinate) as a function of time (min on the abscissa) in the CHO-CFTR (-) control cells.
- FIG. 4 illustrates: (A) Effect of the length of the hydrocarbon chain of n-alkanols (on the abscissa) in the activation of l efflux of I25 I (efflux speed in min "1 on the ordinate). (B) Effect of octanol-2 on the activation of the efflux of I (efflux speed in min " on the ordinate).
- - Figure 5 illustrates the effect of octanol-1 (1 mM) and 18-alpha glycerrhetinic acid ( ⁇ -GA 10 ⁇ M) on the calcium response induced by a stimulation of ATP which involves communication intercellular.
- FIG. 7 illustrates: (A) Effect of the inhibition of protein kinase A by H-89 (30 ⁇ M, 30 min) on the activation of the efflux of I (efflux rate in min " in ordered) induced by octanol-1 (1 mM), FSK (1 ⁇ M) or co-stimulation octanol-1 + FSK.
- FIG. 9 illustrates:
- the arrow represents the moment when octanol-1 (1 mM) is added, with or without glibenclamide and with or without DIDS.
- FIG. 11 illustrates the reversibility of the effect of octanol-1 (1 mM) on the activation of CFTR studied by patch clamp in whole cell configuration in CHO-BQ1 cells.
- - Figure 12 illustrates the structure of n-alkanols in C2-CK). It should be understood, however, that these examples are given only by way of illustration of the subject of the invention, of which they do not in any way constitute a limitation.
- CHO-CFTR (-) and are cultured in DMEM / F12 medium under the same conditions as above.
- CFTR studies are also carried out on Calu-3 cells (ATCC No. HTB-55) which are human pulmonary epithelial cells endogenously expressing the CFTR channel. These cells are cultivated under the same culture conditions as CHO cells.
- Study of the mutated CFTR channel is carried out on JME / CF15 cells, epithelial cells extracted from the respiratory airways of patients suffering from cystic fibrosis (homozygous ⁇ F508) (Jefferson et al., 1990). These cells therefore express the mutated CFTR channel ⁇ F508.
- the resistance of a pipette or a microelectrode makes it possible to appreciate the fineness of the tip: the greater the resistance, the finer the tip or the electrode is blocked.
- the diameter of the patch-clamp pipette does not allow it to enter the cell, but on the other hand, it effectively allows a piece of membrane to be trapped in the tip. Interactions between the membrane and the glass will form, helped by a slight suction or negative pressure of the pipette.
- the quality of this interaction (or sealing) is also appreciated by measuring the resistance between the glass and the membrane. To measure global currents in whole cell configuration, a sealing resistance of 1 G ⁇ is sufficient.
- electrical current records are measured through a patch containing, for example, a channel.
- amp ) is generally in millivolts.
- E c The imposed membrane potential
- amp is generally in millivolts.
- the current oscillates weakly around a basic level (state F). This tiny basic current flows through the "leaks" between the patch and the tip of the pipette.
- the channel opens (state O) the current jumps to another level, then returns to the basic level when the channel closes and so on.
- the measurements can be carried out in one of the following configurations: attached cell (cell-attached), whole cell (whole-cell), excised patch inside-outside (inside-ouf) or excised patch outside-outside (outside-ouf) . Patch-clamp experiments are carried out on confluent cells.
- the culture dishes are placed in an experimental tank (volume 1 ml) on the stage of an inverted microscope (Nikon) equipped with phase contrast lighting.
- the whole-cell configuration is used for recording cell currents (Hamill et al., 1981).
- the experiments are carried out at room temperature (20-22 ° C).
- the currents are amplified with an Axopatch 200B amplifier (Axon Instrument LTd) having a 2-5 kHz low-pass filter (6-pole Bessel filter) and recorded on the hard drive of a PC computer after digitization at 10-25 kHz. .
- the pipettes are made from 1 mm diameter glass tubes (Clark Electromedical Instrument) in four stages with a horizontal drawing machine (Bruwn Flaming 97, CA).
- the drugs to be tested are dissolved according to the desired concentration, at 37 ° C, in medium B at pH 7.4, containing in mM: 137 NaCl, 5.36 KCl, 0, 8 mM MgCl 2 1.8 mM CaCl 2 , 5.5 glucose and 10 HEPES-NaOH.
- the wells are washed 4 times with 500 ⁇ l of medium B.
- the solution is then replaced by 500 ⁇ l of loading solution containing 1 ⁇ M Kl and 0.5 ⁇ Ci of 125 INa / ml for 30 min.
- the exit kinetics of i are carried out after eliminating the loading solution and washing the wells 4 times with 500 ⁇ l of medium B.
- the tracer contained in the cell layer at the start of the efflux is calculated as the sum of the samples and extracts counted.
- the efflux curves are constructed by expressing the percentage of the content remaining in the cell layer (1%) over time.
- the cells are incubated in culture medium DMEM / F12 without serum in the presence of the permeable form of fura-2 (fura- 2 / AM, 2.5 ⁇ M) for 1 h at 37 ° C.
- CHO-CFTR (+) cell line CHO-CFTR (-) cells not expressing the CFTR protein were used as control cells.
- 1 L ⁇ 23187 (2 ⁇ M) (a calcium ionophore) has no effect on the efflux of I in both CHO-CFTR (+) and CHO-CFTR (-) cells, showing that there is no Cl channels "dependent intracellular calcium (Chappe et al., 1998).
- the CFTR channel is mainly regulated by protein kinase A, the control experiments have used the KSF to boost the level of intracellular cAMP.
- Figure 1 A shows an activation of CFTR obtained by applying either 1 ⁇ M of FSK (FSK), octanol-1 (1 mM) or a combined application of FSK (1 ⁇ M) and octanol-1 (1 mM) in CHO-CFTR (+) cells.
- Activation of the CFTR channel measured by the efflux of 125 I induces an increase in the amplitude of the iodide efflux (expressed as% of 125 I released in the medium) and of the exit speed of 125 I.
- FIG. 1 A shows an activation of CFTR obtained by applying either 1 ⁇ M of FSK (FSK), octanol-1 (1 mM) or a combined application of FSK (1 ⁇ M) and octanol-1 (1 mM) in CHO-CFTR (+) cells.
- FIG. 2 represents a dose-response curve of octanol-1 (0.1 to 5 mM) or FSK (0.1 to 5 ⁇ M) on the activation of CFTR. It can be seen in FIG. 2 that the activation of CFTR by FSK or by octanol-1 is dependent on the concentration with an EC 5 o of approximately 0.5 ⁇ M for FSK and of 0.5 mM for octanol-l. The effects of octanol-1 on the activation of CFTR are observable for concentrations of octanol-1 from 0.3 mM to 5 mM, with a plateau reached at 1 mM and a half-activation dose of 0, 5 mM.
- FIGS. 3A and 3B respectively show that FSK (1 ⁇ M) and octanol-1 (I mM) produce an increase of approximately 10 times in the membrane conductance compared to the control.
- the reversion potential of the current induced by FSK or by octanol-1 is 1 ⁇ 0.6 mV, showing that Cl " is the main ion which contributes to this current.
- FIG. 3B shows that an application octanol-1 alone (1 mM), ie without FSK, induces full activation of the CFTR channel 2.2)
- Octanol-l specifically stimulates the CFTR channel in human bronchial epithelial cells (Calu- The capacity of octanol-1 to stimulate CFTR in a human bronchial epithelial cell line (Calu-3) was also tested. As shown in FIG.
- octanol-1 activates the output of iodide in Calu-3 cells.
- efflux activated by octanol-1 is strongly blocked by treatment (1 hour) with glibenclamide (100 ⁇ M), a CFTR channel inhibitor, while treatment (1 hour) with 500 ⁇ M DIDS (4.4 '-diisothiocyanatostilbene-2,2'-disulfonic acid), used to block Cl channels " except the CFTR channel which is insensitive to it, has no effect (Figure 9B). All of these results show that octanol-l specifically activates the endogenous human CFTR channel expressed in human bronchial epithelial cells Calu-3.
- octanol-1 activates the human CFTR channel of in a dose-dependent manner (0.1 to 10 mM) in Calu-3 cells ( Figures 9C, D)
- a dose-response curve of octanol-1 performed in the presence of FSK (1 ⁇ M) shifts towards the left the dose-response curve of octanol-1, indicating a potency by forskolin of the activation of CFTR by octanol-1.
- the ⁇ F508 mutation is found in more than 70% of patients with cystic fibrosis.
- a large majority of the mutated CFTR channel ⁇ F508 is degraded by the ubiquitin-pr ⁇ téasome system inside the cell, and only a very small amount of mutated channel reaches the surface of the membrane where it can be activated.
- JME / CF15 human bronchial epithelial cells extracted from patients with cystic fibrosis and homozygous for the ⁇ F508 mutation were used.
- the molecule MPB-91 known to address a certain number of CFTR- ⁇ F508 channels to the plasma membrane, (Donner et al., 2001) has also been used.
- FIG. 10A shows that octanol-1 specifically activates the mutated CFTR channel ⁇ F508.
- a cocktail of stimulators (FSK 10 ⁇ M + genistein 30 ⁇ M) makes it possible to obtain the maximum activity for the mutated channel CFTR- ⁇ F508.
- Octanol-1 (1 mM) alone is capable of activating approximately 50% of the maximum activity of the mutated CFTR- ⁇ F508 channel ( Figure 10B).
- Octanol-1 is therefore of great interest in considering a pharmacotherapeutic treatment for cystic fibrosis.
- the activating effect of octanol-1 on CFTR is reversible
- FIG. 4A shows that the use of n-alkanols having lengths of hydrocarbon chains equal to or greater than those of hexanol-1 (C6) to decanol-1 (C10), significantly activates the CFTR channel.
- the activation of CFTR increases as a function of the length of the hydrocarbon chain (that is to say as a function of the hydrophobicity) of the alcohol.
- Figure 4 shows an increasing activation of CFTR following the application of hexanol-1 (C6), heptanol-1 (C7), octanol-1 (C8), or decanol-1 (C10) .
- n-alkanols having short hydro-carbon chains ethanol, butanol-1
- the efflux of I is not significantly different from the unstimulated efflux, indicating that ethanol and butanol do not activate the CFTR channel.
- FIG. 4B it can be seen that octanol-2 also activates the protein CFTR. This shows that the position of the OH radical on the molecule in position 1 or in position 2 is not critical for the activation of the CFTR channel.
- the activation of CFTR by n-alkanols is not due to cellular decoupling Octanol and the other n-alkanols can modify the cellular decoupling due to communicating junctions (gap junction).
- Octanol has been shown to activate certain subtypes of PKC.
- a strong PKC inhibitor in the presence of octanol-1 was therefore used. Under these conditions, the activation of CFTR by octanol-1 is not inhibited (FIG. 7).
- octanol-1 activates CFTR well by a mechanism independent of PKCs.
- Octanol and n-alkanols can interact directly with the CFTR channel at the hydrophobic sites of the protein, in order to induce a change in conformation favorable to its activation.
- n-alkanols do not induce an increase in cAMP, the activation of CFTR by the n-alkanols is therefore not due to an increase in the level of cAMP induced by the n-alkanols.
- the literature indicates that long chain n-alkanols are not potential activators of adenylate cyclase and therefore of the level of intracellular cAMP but rather have an inhibiting effect.
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Abstract
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US10/562,085 US20070191493A1 (en) | 2003-07-02 | 2004-06-29 | Use of n-alkanols as activators of the cftr channel |
EP04767506A EP1638542A1 (fr) | 2003-07-02 | 2004-06-29 | Utilisation des n-alkanols comme activateurs du canal cftr |
CA2530882A CA2530882C (fr) | 2003-07-02 | 2004-06-29 | Utilisation des n-alkanols comme activateurs du canal cftr |
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FR0308064A FR2856926B1 (fr) | 2003-07-02 | 2003-07-02 | Utilisation des n-alkanols comme activateurs du canal cftr |
FR0308064 | 2003-07-02 |
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WO2005011659A1 true WO2005011659A1 (fr) | 2005-02-10 |
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PCT/FR2004/001662 WO2005011659A1 (fr) | 2003-07-02 | 2004-06-29 | Utilisation des n-alkanols comme activateurs du canal cftr |
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US (1) | US20070191493A1 (fr) |
EP (1) | EP1638542A1 (fr) |
CA (1) | CA2530882C (fr) |
FR (1) | FR2856926B1 (fr) |
WO (1) | WO2005011659A1 (fr) |
Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4897426A (en) * | 1986-03-06 | 1990-01-30 | New York University | Method for blocking calcium channels |
US4939146A (en) | 1987-01-29 | 1990-07-03 | Kramer Richard S | Method for alleviating ischemic-reperfusion injury |
WO1998005642A1 (fr) | 1996-08-01 | 1998-02-12 | Centre National De La Recherche Scientifique | Composes activateurs du canal cftr, et compositions pharmaceutiques les contenant |
US6359015B1 (en) * | 2000-02-28 | 2002-03-19 | The United States Of America As Represented By The Department Of Veterans Affairs | Method for antagonizing inhibition effects of alcohol on cell adhesion |
WO2002062327A2 (fr) * | 2001-02-07 | 2002-08-15 | Likhodi Serguei S | Methode de traitement de troubles neurologiques |
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AU740783B2 (en) * | 1996-09-18 | 2001-11-15 | Applied Genetics Incorporated Dermatics | Pharmaceutical compositions and methods |
US5945088A (en) * | 1997-03-31 | 1999-08-31 | Pfizer Inc | Taste masking of phenolics using citrus flavors |
WO1999024041A1 (fr) * | 1997-11-10 | 1999-05-20 | Cellegy Pharmaceuticals, Inc. | Systeme ameliorant l'administration de medicaments et reduisant les irritations |
US7150888B1 (en) * | 2000-04-03 | 2006-12-19 | Inhalation, Inc. | Methods and apparatus to prevent colds, influenzaes, tuberculosis and opportunistic infections of the human respiratory system |
-
2003
- 2003-07-02 FR FR0308064A patent/FR2856926B1/fr not_active Expired - Fee Related
-
2004
- 2004-06-29 CA CA2530882A patent/CA2530882C/fr not_active Expired - Fee Related
- 2004-06-29 WO PCT/FR2004/001662 patent/WO2005011659A1/fr active Application Filing
- 2004-06-29 EP EP04767506A patent/EP1638542A1/fr not_active Withdrawn
- 2004-06-29 US US10/562,085 patent/US20070191493A1/en not_active Abandoned
Patent Citations (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4897426A (en) * | 1986-03-06 | 1990-01-30 | New York University | Method for blocking calcium channels |
US4939146A (en) | 1987-01-29 | 1990-07-03 | Kramer Richard S | Method for alleviating ischemic-reperfusion injury |
WO1998005642A1 (fr) | 1996-08-01 | 1998-02-12 | Centre National De La Recherche Scientifique | Composes activateurs du canal cftr, et compositions pharmaceutiques les contenant |
US6359015B1 (en) * | 2000-02-28 | 2002-03-19 | The United States Of America As Represented By The Department Of Veterans Affairs | Method for antagonizing inhibition effects of alcohol on cell adhesion |
WO2002062327A2 (fr) * | 2001-02-07 | 2002-08-15 | Likhodi Serguei S | Methode de traitement de troubles neurologiques |
Non-Patent Citations (3)
Title |
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GRIBKOFF V K ET AL: "THE SUBSTITUTED BENZIMIDAZOLONE NS004 IS AN OPENER OF THE CYSTIC FIBROSIS CHLORIDE CHANNEL", JOURNAL OF BIOLOGICAL CHEMISTRY, AMERICAN SOCIETY OF BIOLOGICAL CHEMISTS, BALTIMORE, MD, US, vol. 269, no. 15, 15 April 1994 (1994-04-15), pages 10983 - 10986, XP000611985, ISSN: 0021-9258 * |
SAKIHARA ET AL., J. AM. SOC. ANESTHESIOL., vol. 95, 2001, pages A1303 |
See also references of EP1638542A1 |
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Publication number | Publication date |
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FR2856926B1 (fr) | 2005-09-30 |
CA2530882C (fr) | 2012-11-20 |
EP1638542A1 (fr) | 2006-03-29 |
FR2856926A1 (fr) | 2005-01-07 |
US20070191493A1 (en) | 2007-08-16 |
CA2530882A1 (fr) | 2005-02-10 |
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