[go: up one dir, main page]

WO2008009071A2 - Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline - Google Patents

Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline Download PDF

Info

Publication number
WO2008009071A2
WO2008009071A2 PCT/BE2006/000082 BE2006000082W WO2008009071A2 WO 2008009071 A2 WO2008009071 A2 WO 2008009071A2 BE 2006000082 W BE2006000082 W BE 2006000082W WO 2008009071 A2 WO2008009071 A2 WO 2008009071A2
Authority
WO
WIPO (PCT)
Prior art keywords
release forms
endothelin antagonist
betaine
antagonist compound
group
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/BE2006/000082
Other languages
English (en)
Inventor
Jallal Messadek
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Priority to PCT/BE2006/000082 priority Critical patent/WO2008009071A2/fr
Publication of WO2008009071A2 publication Critical patent/WO2008009071A2/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/205—Amine addition salts of organic acids; Inner quaternary ammonium salts, e.g. betaine, carnitine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0065—Forms with gastric retention, e.g. floating on gastric juice, adhering to gastric mucosa, expanding to prevent passage through the pylorus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4808—Preparations in capsules, e.g. of gelatin, of chocolate characterised by the form of the capsule or the structure of the filling; Capsules containing small tablets; Capsules with outer layer for immediate drug release
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • Methods and compositions are provided for preventing or inhibiting cardiovascular events in a subject, in which a subject in need is administered a betaine and one or more endothelin receptor antagonist.
  • Methods and compositions for improving the efficacy of one or more endothelin antagonist are also provided, comprising administering to a subject in need thereof a betaine together with one or more endothelin receptor antagonist.
  • This invention relates to novel methods and compositions for treating hypertension, cardiovascular diseases, inflammation diseases, cancer diseases, metabolic diseases, pulmonary hypertension and endothelial abnormalities and/or for lessening adverse effects induced by administration of one or more endothelin receptors antagonists.
  • ET-1 , ET- 2 and ET-3 The three endogenous isoforms of endothelin (ET) in humans, ET-1 , ET- 2 and ET-3, mediate their actions via two receptor subtypes, ETA and ETB, that have been isolated and cloned from mammalian tissues. Both subtypes belong to the seven-transmembrane-domain spanning, G- protein-coupled receptor superfamily.
  • the only other endogenous peptides displaying a high degree of sequence similarity to the ETs are the sarafotoxins (S6a, S6b, S6c and S6d), a family of 21 -amino-acid peptides isolated from the venom of the snake Atractaspis engadensis.
  • ET receptors are widely expressed in all tissues, consistent with the physiological role of ET-1 ,the most abundant isoform, as a ubiquitous endothelium derived vasoactive peptide contributing to the maintenance of normal vascular tone. Receptors are also localized to non-vascular structures (such as epithelial cells) and expressed in the central nervous system (glia and neurons).
  • ETA receptors are present mainly on vascular smooth muscle cells, and are chiefly responsible for contraction. ETB receptors are also thought to be localized to the single layer of endothelial cells lining the vessel wall. Activation of endothelial ETB receptors may lead to the release of endothelium-derived relaxing factors (nitric oxide and prostanoids). Nonvascular ETB receptors in organs including the kidney may beneficially clear ET-1 from the circulation.
  • ET stimulates proliferation in a number of different cell types, including smooth muscle cells (mainly via the ETA subtype) and astrocytes (via
  • ET is thought to be co-mitogenic, potentiating the actions of other growth factors, such as platelet-derived growth factor.
  • Endothelins are polypeptides of 21 amino acid residues with two disulfide bridges connecting cystein residues. Three endothelins, I, Il and HI, different only by some amino acids, are described. Endotheline I (ET-1) is considered as the most active. They act on at least two types of receptors called ETA and ETB.
  • Endothelins are found primarily in vascular endothelium (which explains their denomination), but also in brain, kidney, intestine, adrenal gland.
  • An increase in plasma endothelins can be observed during arterial hypertension, myocardial infarction, congestive heart failure, Raynaud disease.
  • Endothelin activates ETA and ETB receptors:
  • ETA located in vascular smooth muscles, their stimulation gives vasoconstriction and a mitogenic effect.
  • ETB o present in vascular smooth muscles: their activation gives vasoconstriction
  • o present in endothelial cells their activation leads to the release of nitric oxide, NO, and of prostacyclin and leads to vasodilation.
  • the vasoconstrictive effect is widely predominant.
  • Endothelins by activating ETA and ETB receptors, elicit a general vasoconstriction of long duration, including coronary and pulmonary arteries. This long duration of action contrasts with their very short half- life, of about one minute. The vasoconstriction can be preceded by an hypotension of very short duration whose mechanism is not well known.
  • angiotensin As angiotensin, they could, by a mitogenic effect, induce development of cardiac hypertrophy and atherosclerosis.
  • Endothelins have a bronchoconstrictive effect but they do not seem to play a determining part in asthma. They constrict intestinal fibers. Endothelins elicit release of other transmitters such as nitric oxide, NOES, certain prostaglandins (prostacyclin), atrial natriuretic factor.
  • Endothelins act via the G proteins and phospholipase C and release of intracellular calcium; they also inhibit adenylcyclase activity.
  • ANTAGONISTS Antagonists are currently classified as ETA-selective, ETB-selective, or mixed antagonists that display similar affinities for both receptor subtypes. However, only ETA-selective or ETAJETB antagonists are currently being evaluated in clinical trials.
  • the most highly selective peptide antagonists (4 ⁇ 5 orders of selectivity) for the ETA receptors are the cyclic pentapeptide BQ123 and the modified linear peptide FR139317.
  • a peptide structurally similar to FR139317 has been radiolabeled, PD151242, which displays subnanomolar affinity for the ETA subtype.
  • BQ123 is also available as a tritiated analogue, and a non-peptide antagonist, PD164333, displays high affinity and selectivity for this subtype.
  • non-peptide ETA receptor-selective antagonists Unlike peptide antagonists, many non-peptide ETA receptor-selective antagonists have oral bioavalibility, and some may cross the blood ⁇ brain barrier. The majority are more potent than peptide antagonists, with pA 2 values of up to 10, compared with 7 ⁇ 8 for BQ123 or FR139317 (where PA2 is defined as - log-io of the molar concentration of an antagonist that makes it necessary to double the concentration of agonist required to elicit the original submaximal response). However, they are less selective, and plasma binding may be significant in vivo. A limited number of peptide and non-peptide ETB receptor antagonists have been developed, reflecting the lack of clinical need for this type of compound.
  • the first drug of this group is bosentan.
  • Bosentan is an antagonist of type A and B receptors, ETA and ETB (ET for endothelins) but it has an affinity approximately 50 times more important for type A receptors than for type B.
  • the international common name of antagonists of endothelins receptors ends by "-sentan”.
  • endothelin antagonists display some undesired side effects such as liver enzymes elevations or drug interactions leading to limitations in their uses.
  • the present invention describes, provides and claims methods and compositions for treating and/or preventing one or more trouble/disease selected selected from cardiovascular diseases, pulmonary hypertension, pulmonary arterial hypertension, metabolic diseases, diabetes, chronic kidney disease, pulmonary vascular resistance, hypertension, chronic heart failure, congestive heart failure, stroke, restenosis of arteries after balloon angioplasty, stent implantation, cancer, prostate cancer, benign prostate hyperplasia, digital ulcers, pulmonary fibrosis, Raynaud's Disease, Raynaud's phenomenon, human immunodeficiency virus infection (HIV), metastatic melanoma, scleroderma, connective tissue diseases, collagen diseases, blood flow disturbances, thrombosis, asthma, asthmatic complications, bronchoconstriction, Arthritis, rheumatic and musculoskeletal diseases, diabetic complications, diabetic hyperglycaemia, diabetes-induced vascular complications, insulin resistance, defects in functional cardiac performances, obstructive sleep apnoea, sleep a
  • the endothelin antagonist can targets and/or antagonises one or more endothelin receptor.
  • the invention provides pharmacological combinations of one or more betaine in therapeutically effective amount with one or more endothelin antagonist in therapeutically effective amount which favourably ameliorated patients in need.
  • the combinations effects were more efficient than the effects of one or more endothelin antagonist when administrated alone.
  • the combinations showed fewer side effects than the effects of one or more endothelin antagonist when administrated alone.
  • the invention provides compositions and methods for preventing and/or alleviating and/or inhibiting a trouble and/or a disease in a subject in need, comprising administering to said subject a betaine and one or more endothelin antagonist such as, but non limited to, bosentan (RO470203), ambrisentan, sitaxsentan (TBC 11251), tezosentan (RO 610612), darusentan (LU 135 252), enrasentan (SB 217 242), astrasentan (ABT627), TAK-044, A-127722 , A-182086, CM 020, BQ123, BQ788
  • the troubles and/or diseases are endothelin mediated.
  • the general aims of the invention are to provide compositions ando methods for treating endothelin related disorders and diseases in a subject, comprising administering to a subject in need thereof a betaine and one or more endothelin receptor antagonist compound/agent.
  • the betaine and the endothelin antagonist and/or peptide-based endothelin antagonists may be administered sequentially, or may be co-5 administered.
  • the betaine and the endothelin antagonist and/or peptide- based endothelin antagonists may be administered as a single dosage unit or according to different paths.
  • the betaine can be partially and/or completely in slow release dosage forms and/or controlled release dosages forms0 and the endothelin antagonist and/or peptide-based endothelin antagonists may be in immediate release dosage forms.
  • the betaine and the endothelin antagonist and/or peptide-based endothelin antagonists may be administered as a single dosage unit or according to different paths.
  • the betaine can be partially and/or completely in slow release dosage forms and/or controlled release dosages forms and the endothelin antagonist and/or peptide-based endothelin antagonists may partially and/or completely in slow release dosage forms and/or controlled release dosages forms.
  • the betaine and the endothelin antagonist and/or peptide-based endothelin antagonists may be administered as a single dosage unit or according to different paths
  • the invention provides pharmaceutical compositions and methods of treatments for improving the efficacy of one or more endothelin antagonist, consisting in administering to a subject in need thereof one or more betaine together with one or more endothelin antagonist.
  • the invention provides pharmaceutical compositions and methods of treatments for improving the pharmacological efficiency of one or more endothelin antagonist, consisting in administering to a subject in need thereof one or more betaine together with one or more endothelin antagonist.
  • the invention provides pharmaceutical compositions and methods of treatments for improving the pharmacological efficiency of one or more endothelin antagonist, consisting in administering to a subject in need thereof one or more betaine together with one or more endothelin antagonist
  • the invention provides pharmaceutical compositions and methods of treatments for lowering the amount needed for pharmacological effective effect of one or more endothelin antagonist, consisting in administering to a subject in need thereof one or more betaine together with one or more endothelin antagonist.
  • the invention provides pharmaceutical compositions and methods of treatments for lowering the side effects of one or more endothelin antagonist, consisting in administering to a subject in need thereof one or more betaine together with one or more endothelin antagonist.
  • the invention provides combinations and/or methods for treating cancer, tumour angiogenesis, metastasis, prostate cancer or benign prostate hyperplasia (BPH) in a subject, comprising administering to a subject in need thereof a betaine and one or more endothelin antagonist.
  • the combinations and/or methods for treating cancer, tumour angiogenesis, metastasis, prostate cancer or benign prostate hyperplasia (BPH)) in a subject can further comprise an anti-cancerous agent.
  • the compositions of the invention may be administered sequentially, or may be co-administered with the anti-cancerous agent.
  • the compositions of the invention may be administered as a single dosage unit with the anti-cancerous agent or according to different paths.
  • betaine alone can be combined with one or more prostaglandin such as epoprostenol (prostacyclin), iloprost, teprostinil, beraprost and their mixtures for achieving the therapeutical goals of the invention.
  • prostaglandin such as epoprostenol (prostacyclin), iloprost, teprostinil, beraprost and their mixtures for achieving the therapeutical goals of the invention.
  • betaine alone can be combined with one or more phosphodiesterase inhibitor such as sildenafil, tadalafil or with other compounds such as losartan,, aviptadil, iloprost, teprostinil, beraprost, UK-369003, ABT-306552, PRX-08066, PulmoLAR, Gleevec (imatinib) and their mixtures for achieving the therapeutical goals of the invention.
  • one or more phosphodiesterase inhibitor such as sildenafil, tadalafil or with other compounds such as losartan,, aviptadil, iloprost, teprostinil, beraprost, UK-369003, ABT-306552, PRX-08066, PulmoLAR, Gleevec (imatinib) and their mixtures for achieving the therapeutical goals of the invention.
  • the one or more endothelin receptor antagonist and their pharmaceutically acceptable salts can be administered substantially simultaneously with the betaine and its pharmaceutically acceptable salts (i.e., co-administered), or the two or more agents, as their pharmaceutically acceptable salts, can be administered sequentially according to a suitable schedule readily determined by one of ordinary skill in the art.
  • compositions and/or methods of treatments are provided in which pharmaceutical effective amounts of one or more endothelin antagonist and pharmaceutical effective amounts of one or more betaine are acting synergistically for obtaining a better pharmacological effect than each compound alone.
  • a pharmaceutical composition comprising, in synergistic effective amounts, an endothelin antagonist, and its pharmaceutically acceptable salts, and a betaine, and its pharmaceutically acceptable salts, said pharmaceutical composition as a single dosage unit.
  • the single dosage unit can further comprise any pharmaceutically acceptable vehicle.
  • the single dosage unit provides for simultaneous or substantially simultaneously administration of the endothelin antagonist and a betaine.
  • treating is intended to mean inhibiting, reducing, preventing (e.g., prophylaxis), reversing (e.g., alleviating), ameliorating, controlling, or managing.
  • betaine is intended to mean compounds of formula CH 3 ) 3 N + (CH 2 ) n COO ' with n an integer from 1 to 5 pharmaceutically acceptable salts thereof, esters thereof, precursors thereof, and mixtures thereof.
  • Betaine as employed refers also to lipidic betaines and betaine lipids which are structural components of membranes commonly found in ferns, mosses, fungi, amoeba, eukaryotes such as nonseed plants and algae. Betaine lipids are ether-linked, nonphosphorous glycerolipids that resemble the more commonly known phosphatidylcholine in overall structure.
  • glycerolipids are containing a diacyl-glycerol moiety to which a polar head group is attached.
  • This head group can be a carbohydrate moiety as in the very abundant plant galactolipids or a phosphorylester as in the glycerophospholipids, the most common lipid class in animals.
  • Betaine lipids represent a third class of glycerolipids in which a quaternary amine alcohol is bound in an ether linkage to the diacylglycerol moiety. They can be obtained by extraction, by biosynthesis or by synthesis.
  • betaine lipid diacylglyceryl- 0-4' - (N, N, N- trimethyl) homoserine and a closely related isoform diacylglyceryl - O-2' - (hydroxymethyl) (N, N, N- trimethyl)- ⁇ -alanine are the most common.
  • "lipidic betaines” and “betaine lipids” are suitable for the methods and combinations of the invention.
  • salts are meant to include salts of the active compounds which are prepared with relatively nontoxic acids or bases, depending on the particular substituents found on the compounds described herein.
  • base addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired base, either neat or in a suitable inert solvent.
  • pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amino, or magnesium salt, or a similar salt.
  • acid addition salts can be obtained by contacting the neutral form of such compounds with a sufficient amount of the desired acid, either neat or in a suitable inert solvent.
  • Examples of pharmaceutically acceptable acid addition salts include, but are not limited to, those derived from inorganic acids like hydrochloric, hydrobromic, nitric, carbonic, monohydrogencarbonic, phosphoric, monohydrogenphosphoric, dihydrogenphosphoric, hydriodic, sulfuric, monohydrogensulfuric, or phosphorous acids and the like, as well as the salts derived from relatively nontoxic organic acids like acetic, propionic, isobutyric, oxalic, maleic, malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic, benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, and the like. Also included are salts of amino acids such as arginate and the like, and salts of organic acids like glucuronic or galactunoric acids and the like (see, for example, Berge, S. M., et al.,
  • the neutral forms of the compounds can be regenerated by contacting the salt with a base or acid and isolating the parent compound in the conventional manner.
  • the parent form of the compound differs from the various salt forms in certain physical properties, such as solubility in polar solvents, but otherwise the salts are equivalent to the parent form of the compound for the purposes of the present invention.
  • the present invention provides compounds, either betaine or endothelin antagonist, that are in a prodrug form.
  • Prodrugs of the compounds described herein are those compounds that readily undergo chemical changes under physiological conditions to provide the compounds of the present invention.
  • prodrugs can be converted to the compounds of the present invention by in vivo, chemical or biochemical methods in an ex vivo environment. For example, prodrugs can be slowly converted to the compounds of the present invention when placed in a reservoir such as transdermal patch and/or enteral reservoir and/or an implantable reservoir with a suitable enzyme or chemical reagent.
  • one or more endothelin antagonist can be synthesised, linked, extracted and/or combined to one or more betaine moieties to form new chemical entities, such new chemical entities being advantageously used in combination with one or more betaine for achieving the goals of the present invention.
  • Certain compounds of the present invention can exist in unsolvated forms as well as solvated forms, including hydrated forms. In general, the solvated forms are equivalent to unsolvated forms and are intended to be encompassed within the scope of the present invention. Certain compounds of the present invention can exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated by the present invention and are intended to be within the scope of the present invention.
  • Certain compounds of the present invention possess asymmetric carbon atoms (optical centers) or double bonds; the racemates, diastereomers, geometric isomers and individual isomers are all intended to be encompassed within the scope of the present invention.
  • the compounds of the present invention can also contain unnatural proportions of atomic isotopes, stable isotopes etc., at one or more of the atoms that constitute such compounds.
  • the compounds may be radiolabeled with radioactive isotopes, such as for example tritium (.sup.3 H), iodine-125 (.sup.125 I) or carbon-14 (.sup.14 C). All isotopic variations of the compounds of the present invention, whether radioactive or not, are intended to be encompassed within the scope of the present invention.
  • prodrug refers to compounds that are drug precursors, which, following administration, release the drug in vivo via a chemical or physiological process (e.g., a prodrug on being brought to the physiological pH is converted to the desired drug form).
  • terapéuticaally effective combination amount or "an effective amount of the combination of” all refer to a combined amount of both a compound of Formula . I and the endothelin antagonist agent that is effective to ameliorate symptoms associated with diabetic diseases.
  • the term "combination" of compound of Formula I with an endothelin antagonist agent means the two compounds can be delivered in a simultaneous manner, in combination therapy wherein the compound of Formula I is administered first, followed by the endothelin antagonist agent, as well as wherein the endothelin antagonist agent is delivered first, followed by a compound of Formula I.
  • the desired result can be either a subjective relief of a symptom(s) or an objectively identifiable , improvement in the recipient of the dosage.
  • synergistic effective amount refers to a combined amount of both a compound of Formula I and an endothelin antagonist agent that is effective to cause a synergistic effect.
  • Synergy is a biological phenomenon, in which the effectiveness of two or more active components in a mixture is more than additive, i.e., the effectiveness is greater than the equivalent concentration of either component alone.
  • the effectiveness of the combination therapy of a compound of Formula I and an endothelin antagonist agent is synergistic.
  • synergism is a result, or function, that is more than the sum of the results, or functions of individual elements.
  • the period can be longer such as a week, a month, 3 months, 6 months, etc. Such longer periods are necessary when the compounds of the invention are administrated with implanted mini-pumps and/or devices and/or dosages forms suitable for long period deliveries in the body.
  • the pharmaceutical combinations of betaine and endothelin antagonists can be but non limited to, oral, parenteral, subcutaneous, inhaled, transdermal, slow release, controlled release, delayed release dosages forms suitable for oral, parenteral, subcutaneous, transdermal, rectal and vaginal administrations according to different paths.
  • cardiovascular diseases is intended to encompass for example, hypertension, congestive heart failure, stroke, coronary revascularization, peripheral artery disease, fatal and non-fatal myocardial infarction, vasospasm, thrombotic events, syncope, endothelial dysfunction, atherosclerosis, angina, systemic pathogenic vascular remodeling, sexual dysfunction, or an increase in the subject's probability of acquiring any such disease.
  • Sepsis refers to the systemic response to an infection or to circulating bacterial products.
  • endothelin antagonist or “endothelin receptors antagonist” are intended to mean any pharmaceutically acceptable compound which effectively inhibits, prevents or blocks the actions of endothelin, either directly or indirectly, including any pharmaceutically acceptable salt, ester, or prodrug thereof.
  • an endothelin antagonist according to the invention may act at the level of inhibiting endothelin-receptor binding, inhibiting endothelin converting enzyme, inhibiting release of endothelin from endothelial cells or inhibiting post-receptor intracellular signal transduction pathways. Both peptidic and non-peptidic compounds are encompassed by this term.
  • endothelin antagonists such as endothelin receptor A (ET.sub.A) and endothelin receptor B (ET.sub.B) antagonists, and pharmaceutically acceptable salts thereof, have been identified and can be obtained commercially (e.g., Sigma, American Peptide Company Inc.). Attention is also directed to U.S. Pat. 5,284,828 (Hemmi et al.), U.S. Pat. 5,378,715
  • ET.sub.A and ET.sub.B antagonists are available commercially from various sources such as American Peptide Company Inc.
  • Endothelin Antagonists suitable to be utilised in the methods and/or combinations of the present invention are:
  • Endothelin Antagonist (JKC-301) c(Dlle-Leu-DTrp-DAsp-Pro) 88-2-30
  • Endothelin Antagonist (JKC-302) c(DVal-Leu-DTrp-DSer-Pro) 88-2-31
  • Endothelin Antagonist (BQ-610) (N,N-hexamethylene)carbamoyl-Leu- 88- 2-32 DTrp(CHO)-DTrp
  • Endothelin Antagonist (DGIu-Ala-DVal-Leu-DTrp) 88-2-40 (W-7338A) ET.sub.B [Cys11 , Cys 15]
  • Endothelin-1 (DGIu-Ala-DVal-Leu-DTrp) 88-2-41 (8-21), (1 RL-1038) [AIaH 1 15]
  • Bosentan is a non-peptide, orally active antagonist of both ETA and ETB receptors.
  • ETRA endothelin receptor A antagonists
  • endothelin antagonists are endothelin receptors A and B antagonists (ETRA ET A /ET B antagonists).
  • the invention provides a treatment for hypertension in which such risk is reduced.
  • a method for treating hypertension in a subject comprising administering to the subject a betaine and an endothelin antagonist.
  • endothelin antagonists suitable for use in accordance with the present invention include ABT-627 (Abbott, III.), Bosentan (Ro 47-0203; Roche, N.J.) and SB209670 (SmithKline Beecham, Pa.), and GTN.
  • the ratios betaine/endothelin antagonists can vary from 4:1 to 100:1 based on dry weight, preferably between 60:1 and 40:1.
  • compositions comprise advantageously more than 98% by weight betaine (especially glycine betaine), preferably more than 95% by weight betaine (especially glycine betaine), most preferably between 90% and 85% by weight betaine (glycine betaine), such as 80 %by weight, 75% by weight, 70 % by weight, 65 % by weight, 60 % by weight, 55% by weight, 50% by weight.
  • betaine especially glycine betaine
  • betaine especially glycine betaine
  • compositions for the administration of one or more endothelin antagonist in combination with a betaine in accordance with the methods of the present invention may take the form of ointments, transdermal patches, transbuccal patches, injectables, nasal inhalant forms, spray forms for deep lung delivery through the mouth, orally administered ingestible tablets and capsules, sachets, pouches, tablets or lozenges, slow release formulations, controlled release formulations, "lollipop" formulations for administration through the oral mucosal tissue.
  • the latter formulations included tablets, lozenges and the like which are dissolved while being held on or under the tongue, or in the buccal pouch.
  • compositions of the present invention comprise a therapeutically effective amount of an endothelin antagonist in combination with a therapeutically effective amount of betaine formulated together with one or more pharmaceutically acceptable carriers.
  • pharmaceutically acceptable carrier means a nontoxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type.
  • materials which can serve as pharmaceutically acceptable carriers are sugars such as lactose, glucose and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; powdered tragacanth; malt; gelatin; talc; excipients such as cocoa butter and suppository waxes; oils such as peanut oil, cottonseed oil; safflower oil; sesame oil; olive oil; corn oil and soybean oil; glycols; such as propylene glycol; esters such as ethyl oleate and ethyl laurate; agar; buffering agents such as magnesium hydroxide and aluminum hydroxide; alginic acid; pyrogen- free water; isotonic saline; Ringer's solution; ethyl alcohol, and phosphate buffer solutions, as well as other non-toxic compatible lubricants such as sodium lauryl sulf
  • compositions of this invention can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as by powders, ointments, or drops), supralingually (on the tongue) sublingually (under the tongue), buccally (held in the buccal pouch), or as an oral or nasal spray.
  • the oral spray may be in the form of a powder or mist which is delivered to the deep lungs by oral inhalation.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs.
  • the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents
  • the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents.
  • injectable preparations for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water, Ringer's solution, U.S. P.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil can be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid are used in the preparation of injectables.
  • the injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.
  • the absorption of the drug from subcutaneous or intramuscular injection can be slowed. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the drug then depends upon its rate of dissolution which, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is accomplished by dissolving or suspending the drug in an oil vehicle.
  • Injectable depot forms are made by forming micro-encapsulated matrices of the drug in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of drug to polymer and the nature of the particular polymer employed, the rate of drug release can be controlled. Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the drug in liposomes or micro-emulsions which are compatible with body tissues.
  • compositions for rectal or vaginal administration are preferably suppositories which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules.
  • the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and/or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and gly
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • Examples of embedding compositions which can be used include polymeric substances and waxes.
  • Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.
  • the active compounds can also be in micro-encapsulated form with one or more excipients as noted above.
  • the solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • additional substances other than inert diluents e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose.
  • the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner.
  • embedding compositions which can be used include polymeric substances and waxes.
  • Powders and sprays can contain, in addition to the compounds of this invention, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates and polyamide powder, or mixtures of these substances.
  • Sprays can additionally contain customary propellants such as chlorofluorohydrocarbons.
  • Dosage forms for topical or transdermal administration of a compound of this invention include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches.
  • the active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required.
  • Ophthalmic formulation, ear drops, eye ointments, powders and solutions are also contemplated as being within the scope of this invention.
  • Transdermal patches have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.
  • the ointments, pastes, creams and gels may contain, in addition to an active compound of this invention, excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • excipients such as animal and vegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, talc and zinc oxide, or mixtures thereof.
  • a preferred mode of delivery is one which provides a reasonably steady- state delivery of therapeutic agents, so as to maintain steady-state plasma concentrations. Such delivery avoids any substantial initial spike in plasma concentration of the agent, as it would be desirable to avoid any spike supra-threshold for negative side effects.
  • Solid dosage forms, including sustained-release solid dosage foms, for oral administration include capsules, tablets, pills, powders, and granules, and are a preferred mode of delivery.
  • bosentan has been used. However, it is obvious that said examples can be repeated with ambrisentan, sitaxsentan, tezosentan, darusentan, enrasentan, astrasentan and mixtures therof. The examples can also be repeated with other endothelin antagonists.
  • anhydrous glycine betaine has been used, as being the preferred betaine. (CAS Number: 107-43-7) - (CHg) 3 N + CH 2 COO "
  • Bosentan film coated tablet (Tracleer) was placed in a capsule.
  • the capsule was filled then with glycine betaine powder.
  • the capsule was then sealed.
  • the capsule content was 62.5 mg Bosentan and 500 mg glycine betaine.
  • the glycine betaine content was 250 mg, 500 mg, 750 mg and 1000 mg.
  • the kit comprises a sealed bag containing 3g glycine betaine (powder - anhydrous form) and a film coated tablet of 62.5 mg or 125 mg Bosentan
  • Example 3 (Tracleer®). The tablet is intended to be administered with a glass water in which glycine betaine has been dissolved.
  • Example 3 (Tracleer®). The tablet is intended to be administered with a glass water in which glycine betaine has been dissolved.
  • Example 2 has been repeated except that the sealed bag comprised glycine betaine.
  • the bag had a MVTR value inferior to 0.001 g/m 2 at a temperature of 38 C° and at 90% relative humidity during 24 hours.
  • Bosentan tablet contains 50 mg Bosentan
  • Partitioned capsules have been used, so as to separate Bosentan from Glycine Betaine.
  • Bosentan compartment contained 50 mg or 100 mg Bosentan, while the glycine betaine compartment contained respectively 300 mg, 500 mg,
  • the compression strength was 3.04 kN.
  • the tablets were floating immediately after adding a simulated gastric fluid. The floating continued for 24 hours.
  • Said floating betaine tablet was attached to a Bosentan tablet of 62.5 mg (Tracleer)
  • the tablets were floating immediately after adding a simulated gastric fluid. The floating continued for 24 hours.
  • the so obtained glycine betaine tablet was attached to a Tracleer tablet of 62.5 mg Bosentan.
  • a mixture comprising 38% of compactable Eudragit RPL RTM 1 60% anhydrous betaine, 1% talc stearate and 1% magnesium is prepared. After treatment in a Turbula T2C mixer, the mixture was compacted by means of an EKO apparatus of Korsch at 40,000 N/cm 2 and then converted into granules by means of a granulator Erweka TG Il S. The granules have then been dressed by means of a vibrator keeping only the fractions having a diameter between 100 and 150/vm.
  • Bosentan granules formed by wet granulation were overcoated with an Eudragit RPL layer
  • the so obtained granules of Bosentan and glycine betaine were used for filling capsules and for preparing tablets.
  • Betaine powder (particle size of less than 250 ⁇ m, in particular of less than 100 ⁇ m) has been mixed with oil or wax or an alcohol solid at room temperature, for example coconut oil or stearylic alcohol.
  • oil, alcohol or wax was melted so as obtain a liquid form, Betaine in powder was added to the molten oil, wax or alcohol.
  • the weight ratio betaine / oil or wax or alcohol was varied between 0.05 and 2 (ratios lower than 1 being preferred such as 0.2, 0.3, 0.4 and 0.5).
  • the liquid mixture is converted in micro-spheres, for example by spraying or by extrusion - spheronization, etc.
  • the so prepared micro-spheres have a size of 500 ⁇ m, 750 ⁇ m and 1 mm.
  • micro-spheres have been coated in one or more steps, with a layer of a hydrophilic polymer swellable in water, but insoluble in gastric medium (for example acrylic polymer or copolymer such as Eudragit®).
  • a hydrophilic polymer for example acrylic polymer or copolymer such as Eudragit®.
  • the dry weight ratio hydrophilic polymer / betaine micro-sphere was varied between 1 and 10.
  • the so obtained balls have then been provided with a thin layer of a polymer insoluble in water, but soluble or degradable in gastric medium, for example a Eudragit polyacrylate coating.
  • a capsule was filled with a film coated tablet of Bosentan, with glycine powder (immediate release) and with glycine betaine microspheres (extended release).
  • the Bosentan content was 62.5 mg, while the glycine betaine content was from 200 and 500 mg for the immediate release powder and from 400 to 800 mg for the microspheres.
  • the weight ratio immediate release glycine betaine / extended release glycine betaine was respectively 2:1 ; 1.25:1 ; 1 :1 ; 1 :2 and 1 :4.
  • Bosentan powder (particle size of less than 250 ⁇ m, in particular of less than 100 ⁇ m) has been mixed with oil or wax or an alcohol solid at room temperature, for example coconut oil or stearylic alcohol.
  • oil or wax or an alcohol solid at room temperature for example coconut oil or stearylic alcohol.
  • the oil, alcohol or wax was melted so as obtain a liquid form, Bosentan in powder was added to the molten oil, wax or alcohol.
  • the weight ratio betaine / oil or wax or alcohol was varied between 0.05 and 2 (ratios lower than 1 being preferred such as 0.2, 0.3, 0.4 and 0.5).
  • the liquid mixture is converted in micro-spheres, for example by spraying or by extrusion - spheronization, etc.
  • the so prepared micro-spheres have a size of 500//m, 750/ym and 1 mm.
  • micro-spheres have been coated in one or more steps, with a layer of a hydrophilic polymer swellable in water, but insoluble in gastric medium (for example acrylic polymer or copolymer such as Eudragit®).
  • a hydrophilic polymer for example acrylic polymer or copolymer such as Eudragit®.
  • the dry weight ratio hydrophilic polymer / bosentan micro-sphere was varied between 1 and 10.
  • the so obtained balls have then been provided with a thin layer of a polymer insoluble in water, but soluble or degradable in gastric medium, for example a Eudragit polyacrylate coating.
  • a capsule was filled with Bosentan microspheres with glycine powder (IE immediate release) and/or with glycine betaine microspheres (ER extended release - see example 9).
  • the capsule comprised for example: 50 mg Bosentan / 500 mg betaine IE
  • Sachets containing 3 g of anhydrous glycine betaine and 62.5 mg of Bosentan were realised.
  • pharmaceutical acceptable excipients can be added.
  • Sachets material Clay coated Paper 50g/PR 12g/ Alufoil 7 my / Co +PE 5g + 18g
  • Bosentan bid Nine patients suffering from Pulmonary Arterial Hypertension and taking 125 mg Bosentan bid were randomly assigned to placebo (lactose monohydrate) 6 g bid (4 patients) or to anhydrous betaine 6 g bid (5 patients) during two weeks. They were assessed for haemodynamic variables and for 6 minutes walking test at inclusion and after the two weeks of medication with placebo or betaine. Pulmonary Artery Pressure (PAP) and Heart rate were non-invasively estimated by Doppler echocardiography method. 6MWT was performed on a treadmill. The results of the study are given in the table below:
  • FT. 84 71 85 84 360 380 mean 82,4 66,8 83,2 73,2 409,2 413
  • the combinations of the invention may represent a true benefit for Pulmonary Hypertension patients, when providing more effective treatment while preserving and/or ameliorating patients' safety, quality of life and survival.

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne des procédés et des compositions destinés à la prévention ou à l'inhibition d'épisodes cardiovasculaires chez un sujet au cours desquels un sujet nécessitant des soins reçoit de la bétaïne et un ou plusieurs antagonistes du récepteur de l'endothéline. L'invention concerne également des procédés et des compositions permettant d'améliorer l'efficacité d'un ou de plusieurs antagonistes de l'endothéline, les procédés consistant à administrer à un sujet nécessitant des soins un composé de bétaïne conjointement avec un ou plusieurs antagonistes du récepteur de l'endothéline.
PCT/BE2006/000082 2006-07-20 2006-07-20 Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline Ceased WO2008009071A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/BE2006/000082 WO2008009071A2 (fr) 2006-07-20 2006-07-20 Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/BE2006/000082 WO2008009071A2 (fr) 2006-07-20 2006-07-20 Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US11/747,167 Continuation-In-Part US8318805B2 (en) 2004-11-10 2007-05-10 Modulation of nitric oxide synthases by betaines

Publications (1)

Publication Number Publication Date
WO2008009071A2 true WO2008009071A2 (fr) 2008-01-24

Family

ID=38957118

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/BE2006/000082 Ceased WO2008009071A2 (fr) 2006-07-20 2006-07-20 Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline

Country Status (1)

Country Link
WO (1) WO2008009071A2 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2012139736A1 (fr) * 2011-04-11 2012-10-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique comprenant du bosentan
CN107157977A (zh) * 2017-06-20 2017-09-15 宁夏医科大学 甜菜碱治疗肺动脉高压的制药用途
US10181543B2 (en) 2009-11-03 2019-01-15 Lg Electronics Inc. Solar cell module having a conductive pattern part

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10181543B2 (en) 2009-11-03 2019-01-15 Lg Electronics Inc. Solar cell module having a conductive pattern part
WO2012139736A1 (fr) * 2011-04-11 2012-10-18 Alfred E. Tiefenbacher (Gmbh & Co. Kg) Composition pharmaceutique comprenant du bosentan
CN107157977A (zh) * 2017-06-20 2017-09-15 宁夏医科大学 甜菜碱治疗肺动脉高压的制药用途

Similar Documents

Publication Publication Date Title
CA2678722C (fr) Combinaison antihypertensive a base de valsartan et d'un inhibiteur calcique
ES2290429T3 (es) Composiciones farmaceuticas que comprenden valsartan e inhibidores de nep.
TW200911732A (en) Compositions and methods of use for treating or preventing lipid related disorders
CN1474690A (zh) 用于治疗心血管疾病的含有肾素抑制剂的协同性药物联合形式
TW200827344A (en) Administration of dipeptidyl peptidase inhibitors
KR20150046039A (ko) 심방 확장 또는 재형성을 특징으로 하는 질환을 치료하기 위한 nep 억제제
US6204281B1 (en) Method of treatment and pharmaceutical composition
WO2007106708A2 (fr) Combinaison de composes organiques
CN110234636B (zh) 包含哌醋甲酯前药的组合物，其制造和使用方法
TW200846000A (en) Weekly administration of dipeptidyl peptidase inhibitors
WO2002017913A1 (fr) Compositions medicinales utilisees dans la prevention ou le traitement de l'insuffisance cardiaque
JP2010515682A (ja) 喘息などの５−リポキシゲナーゼ活性上昇および／またはロイコトリエン活性上昇に関連する状態における使用のためのｒ−ジロートン
RU2331438C2 (ru) Альфа-2-дельта лиганд для лечения симптомов нижних мочевыводящих путей
US20140200256A1 (en) Acetylated amino acids as Anti-platelet agents, Nutritional And Vitamin Supplements
CN101102755B (zh) 肾素抑制剂在制备预防或治疗舒张功能障碍或舒张性心力衰竭的药物中的用途
WO2018209355A1 (fr) Méthodes thérapeutiques et compositions associees
WO2008009071A2 (fr) Thérapie combinée utilisant de la betaïne et des antagonistes de l'endothéline
JP2010501557A (ja) 血液脳関門を通過しないｋｗ−３９０２コンジュゲート
JP2024504424A (ja) 哺乳動物における体重減少を引き起こすための外因性ケトンエステルの使用
ES2372004T3 (es) Usos de derivados de metilfenidato.
US20110312890A1 (en) Acetylated amino acids as anti-platelet agents, nutritional and vitamin supplements
TWI250162B (en) Beta-lactamase inhibitor prodrug
WO2001079263A1 (fr) Derives peptidiques et compositions medicinales
CN101072564A (zh) 内皮缩血管肽a受体(eta)拮抗剂与磷酸二酯酶5(pde5)抑制剂的联合及其用途
CN111278465A (zh) mIDH1抑制剂和DNA低甲基化剂（HMA）的组合

Legal Events

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

Ref country code: DE

NENP Non-entry into the national phase in:

Ref country code: RU

122 Ep: pct application non-entry in european phase

Ref document number: 06761019

Country of ref document: EP

Kind code of ref document: A2