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• • A—HUMAN NECESSITIES
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  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
  • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
  • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
• • 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
  • A61K31/13—Amines
  • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
• • 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
  • A61K31/19—Carboxylic acids, e.g. valproic acid
  • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
• • 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
  • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
  • A61K31/36—Compounds containing methylenedioxyphenyl groups, e.g. sesamin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/425—Thiazoles
  • A61K31/426—1,3-Thiazoles
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4412—Non condensed pyridines; Hydrogenated derivatives thereof having oxo groups directly attached to the heterocyclic ring
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
• • 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
  • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
  • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
  • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine
  • A61K31/5517—1,4-Benzodiazepines, e.g. diazepam or clozapine condensed with five-membered rings having nitrogen as a ring hetero atom, e.g. imidazobenzodiazepines, triazolam
• • 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
  • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
• • 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
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives

Definitions

• the present invention falls within the field of medicine, more particularly, it relates to the treatment of pulmonary hypertension.
• Pulmonary hypertension defined as the increase in mean pulmonary arterial pressure (PAP) above normal values, encompasses a number of diseases characterized by increased pulmonary vascular resistance (RVP) and progressive deterioration of the Right ventricular function (RV) (McLaughlin 2009). In this sense, the majority of studies refer to HP for mean PAP values above 25 mmHg, considering that in man a typical average PAP is approximately 12 to 15 mmHg.
• PH secondary to left heart disease is of post-capillary origin, characterized by increased pulmonary capillary pressure.
• the invention relates to the use of a selective beta-3 adrenergic receptor agonist for the preparation of a medicament for the treatment and / or prevention of PH.
• the invention is directed to a selective beta-3 adrenergic receptor agonist for use in the treatment and / or prevention of PH.
• the invention is directed to the use of a selective beta-3 adrenergic receptor agonist for the treatment and / or prevention of PH.
• the invention is directed to a medicament or pharmaceutical composition
• a medicament or pharmaceutical composition comprising at least one selective beta-3 adrenergic receptor agonist and at least one pharmaceutically acceptable excipient for use in the treatment and / or prevention of PH.
• Another aspect of the invention is a method for the treatment and / or prevention of PH, which comprises administering to the patient in need of such a treatment or prevention a therapeutically effective amount of a selective beta-3 adrenergic receptor agonist.
• Figure 1 Pre and 10-minute post-treatment changes (placebo in continuous line and BRL37344 in discontinuous line) of mean PAP (A), cardiac output (B) and RVP (C) in 10 animals with acute PH.
• Figure 2 Effect of administration of BRL 37344 on mean PAP, RVP, cardiac output and arterial oxygen saturation (typical mediaierror) in chronic postcapillary PH.
• Figure 3 Effect of administration of BRL 37344 on mean PAP and arterial oxygen saturation (typical mediaierror) in chronic precapillary PH.
• Figure 4 Changes 14 days after the start of treatment with respect to the initial state (placebo in continuous line and BRL37344 in discontinuous line) of RVP in 8 animals with chronic postcapillary HP.
• Figure 5 Changes 14 days after the start of treatment with respect to the initial state (placebo in continuous line and Mirabegron in dashed line) of RVP in 8 animals with chronic postcapillary HP.
• Figure 6 Immunofluorescence of ⁇ 3 receptors in human pulmonary artery.
• ⁇ 3 selective agonist "beta-3 selective agonist” or similar expressions are used herein to refer to a "adrenergic beta-3 receptor selective agonist”.
• an agonist is a molecule that binds to the receptor and has an intrinsic effect and, therefore, increases the basal activity of a receptor when it comes into contact with the receptor.
• selective beta-3 adrenergic receptor agonist means a compound that exhibits preferential agonism towards the beta-3 receptor compared to beta-1 and beta-2 receptors.
• selective beta-3 agonists behave as beta-3 receptor agonists at lower concentrations than for beta-1 and beta-2 receptors.
• a selective beta-3 agonist includes compounds that behave as beta-3 receptor agonists and as beta-1 and beta-2 receptor antagonists.
• the selectivity of the compounds useful in the present invention towards the beta-3 receptor is clearly superior compared to the beta-1 and beta-2 receptors.
• the ⁇ 3 selective agonists according to the present invention show a selectivity towards the beta-3 receptor approximately ⁇ 10 times higher, more preferably approximately ⁇ 100 times higher, and still more preferably approximately ⁇ 1000 times higher, with respect to the other beta adrenergic receptors. Even more preferably for the purpose of the invention, ⁇ 3 selective agonists show superior "infinitely" beta-3 receptor selectivity (approximately ⁇ 10000 times) with respect to the other beta receptors.
• the ⁇ 3 selective agonist shows values in constant inhibition and / or average effective concentration for the ⁇ 3, ⁇ 1 and ⁇ 2 receptors respectively of approximately Ki 287/1750/1 120 nM and / or EC 50 18 /> 10000 / > 10000 nM.
• the ability to exert selective beta-3 agonism of a given compound can be easily evaluated by conventional techniques.
• General bibliographic references related to receptor ligand binding assays include for example: Masood N. Khan, John W. Findlay (2010).
• Ligand-Binding Assays Development, Validation, and Implementation in the Drug Development Arena: John Wiley &Sons; Assay Guidance Manual Version 5.0, 2008: Eli Lilly and Company and NIH Chemical Genomics Center, available at: http://ncgcweb.nhgri.nih.gov/guidance/manual toc.html.
• selective beta-3 agonists useful in the present invention include, but are not limited to:
• the compounds useful in the present invention can be, for example, in neutral form, the form of a base or acid, in the form of a salt, preferably a salt physiologically acceptable, in the form of a solvate or a polymorph and / or in different isomeric forms.
• salt should be understood as any form of an active compound used according to this invention in which said compound is in ionic form or is charged and coupled to a counterion (a cation or anion) or is in solution.
• This definition also includes quaternary ammonium salts and complexes of the active molecule with other molecules and ions, particularly complexes formed by ionic interactions.
• the definition includes, in particular, physiologically acceptable salts; This term should be understood as equivalent to "pharmacologically acceptable salts” or “pharmaceutically acceptable salts”.
• physiologically acceptable salt or “pharmaceutically acceptable salt” is understood in particular, in the context of this invention, as a salt (as defined above) formed or with an acid that is physiologically tolerated, ie salts of the particular active compound with organic or inorganic acids that are physiologically tolerated, particularly if used in humans and / or mammals, or with at least one cation, preferably inorganic, that is physiologically tolerated, particularly if used in humans and / or mammals
• salts that are physiologically tolerated of particular acids are salts of: hydrochloric acid, hydrobromic acid, sulfuric acid, bromohydrate, monobromohydrate, monohydrochloride or hydrochloride, methodide, methanesulfonic acid, formic acid, acetic acid, oxalic acid, succinic acid, malic acid , tartaric acid, mandelic acid, fumaric acid, lactic acid, citric acid, glutamic acid, hippuric acid, picric acid and / or as
• solvate should be understood as meaning any form of the active compound according to the invention in which this compound is linked by a non-covalent bond to another molecule (usually a polar solvent), especially including hydrates and alcoholates, as per example, methanolate. It is also within the scope of the invention, any compound that is a prodrug of a selective beta-3 adrenergic receptor agonist.
• prodrug is used in its broadest sense and encompasses those derivatives that are converted in vivo into the compounds of the invention.
• prodrugs include, but are not limited to, derivatives and metabolites of the beta-3 selective agonist compounds that include biohydrolysable moieties such as biohydrolysable amides, biohydrolysable esters, biohydrolysable carbamates, biohydrolysable carbonates, biohydrolysable ureides and biohydrolysable phosphate analogs.
• the prodrugs of compounds with carboxyl functional groups are the lower alkyl esters of the carboxylic acid.
• the carboxylate esters are conveniently formed by esterifying any of the carboxylic acid residues present in the molecule.
• prodrugs can be prepared using well known, such as those described in Burger methods "Medicinal Chemistry and Drug Discovery 6 ed.
• Selective beta-3 agonists useful in the present invention may include optical isomers depending on the presence of chiral centers or geometric isomers depending on the presence of multiple bonds (eg Z, E). Isomers, enantiomers or individual diastereoisomers and mixtures thereof, such as a racemic mixture, are within the scope of the present invention.
• any compound referred to herein may exist as tautomers.
• tautomer refers to one of two or more structural isomers of a compound that exists in equilibrium and that are easily converted from one isomeric form to another. Common tautomeric pairs are amine-imine, amide-imidic acid, keto-enol, lactam-lactime, etc.
• the compounds of the invention include isotopically labeled forms, that is, compounds that differ only in the presence of one or more isotopically enriched atoms.
• compounds having the present structures are within the scope of this invention except for the replacement of at least one hydrogen atom with a deuterium or tritium, or the substitution of at least one carbon for a carbon enriched in 13 C or 14 C , or the replacement of at least one nitrogen with nitrogen enriched in 15 N.
• the beta-3 selective agonists in the context of the invention are preferably in pharmaceutically acceptable or substantially pure form.
• Pharmaceutically acceptable means, among others, that it has a pharmaceutically acceptable level of purity excluding normal pharmaceutical additives such as diluents and carriers, and does not include any material considered toxic at normal dosage levels.
• the purity levels for the active ingredient are preferably greater than 50%, more preferably greater than 70%, most preferably greater than 90%. In a preferred embodiment, it is greater than 95% of the selective beta-3 agonist.
• prodrugs, solvates or pharmaceutically acceptable salts refers to any salt, solvate or any other compound that, upon administration to the recipient, can provide (directly or indirectly) a selective beta-3 agonist. It will be appreciated that prodrugs, solvates and non-pharmaceutically acceptable salts are also within the scope of the invention since they can be useful in the preparation of prodrugs, solvates and pharmaceutically acceptable salts. The preparation of prodrugs, solvates and salts can be carried out by methods known in the art.
• the beta-3 selective agonist is selected from a compound derived from phenylethanolamine (2-amino-1-phenylethanol).
• beta-3 selective agonist is selected from a compound derived from phenylethanolamine, with the following general formula:
• R ⁇ is selected from hydrogen and halogen (F, Cl, Br or I); preferably, the halogen is chlorine.
• R ⁇ can be in any position (ortho, goal or para); In a preferred embodiment, R ⁇ is in the target position.
• R 2 is an aralkyl, which may be substituted in the aryl part and / or in the alkyl part, or a radical selected from:
• R represents chloro in the meta position and R 2 is a radical 1 - methyl-2-phenylethyl optionally substituted on the phenyl.
• R represents hydrogen and R 2 is a 2-phenylethyl radical optionally substituted on the phenyl.
• the agonist used in the present invention is the compound identified as BRL37344 ([4 - [(2R) -2 - [[(2R) -2- (3-chlorophenyl) -2-hydroxyethyl] amino] propyl] phenoxy] acetic), which is described in EP 023 385 and in Drugs of the Future, Vol. 16, 797-800 (1991) and having the following molecular formula:
• Compound BRL 37344 is a potent and selective agonist of beta-3 adrenergic receptors (Ki values are 287, 1750 and 1 120 nM for ⁇ 3, ⁇ 1 and ⁇ 2 receptors respectively) that can be purchased commercially as sodium salt (CAS number 127299-93-8):
• the known compound CL316243 is preferred, which is described in EP 0 455 006 and J. Med. Chem. 35, 3081-3084 (1992) and having the following molecular formula:
• the agonist used in the present invention is YM178 (Mirabegron) or a salt thereof.
• Mirabegron is a compound marketed for the treatment of overactive bladder that has the following molecular formula:
• the agonist used in the present invention is GW427353 (Solabegron) or a salt thereof, such as its hydrochloride.
• Solabegron has the following molecular formula:
• the agonist used in the present invention is SR 5861 1A (Amibegron) or a salt thereof.
• Amibegron is an antidepressant agent that has the following molecular formula:
• selective beta-3 adrenergic receptor agonists are commercially available and / or can be prepared by known methods, such as those described in the cited patents and applications.
• the inventors have demonstrated in different scenarios that the administration of selective beta-3 agonists allows to significantly reduce pulmonary arterial pressure as well as pulmonary vascular resistance, in turn increasing oxygen saturation. As an additional advantage, no significant changes in cardiac output or systemic blood pressure are observed, which means that the possible harmful side effects on systemic circulation are very low, compared to other vasodilators used for the treatment of pulmonary hypertension.
• the present invention proposes the use of selective beta-3 adrenergic receptor agonists as a broad-spectrum therapeutic agent against pulmonary hypertension (PH).
• PH pulmonary hypertension
• the results obtained show the enormous utility of selective beta-3 agonists in the treatment and / or prevention of PH of any etiology.
• the HP can be of any type: arterial HP; HP secondary to left heart disease; PH secondary to pneumopathy; Chronic thromboembolic HP; and HP of unknown or multifactorial origin.
• the invention is directed to the use of a selective beta-3 adrenergic receptor agonist for the treatment and / or prevention of acute PH.
• the invention is directed to the use of a selective beta-3 adrenergic receptor agonist for the treatment and / or prevention of chronic PH.
• the invention is directed to the use of a selective beta-3 adrenergic receptor agonist under an acute pulmonary thromboembolism scenario.
• pharmaceuticals or pharmaceutical compositions are provided for use in the treatment and / or prevention of HP comprising a selective beta-3 adrenergic receptor agonist and a pharmaceutically acceptable excipient.
• pharmaceutical compositions include any solid composition (tablets, pills, capsules, granules, etc.) or liquid (solutions, suspensions or emulsions) for oral, topical or parenteral administration.
• excipient refers to components of a pharmacological compound other than the active substance (definition obtained from the European Medicines Agency - EMA). They preferably include a "carrier, adjuvant and / or vehicle". Carriers are ways in which substances are incorporated to improve the administration and efficacy of drugs. Drug carriers are used in drug delivery systems such as controlled release technology to prolong the actions of the drug in vivo, decrease the metabolism of the drug and reduce the toxicity of the drug. Carriers are also used in designs to increase the effectiveness of drug administration to the target sites of pharmacological actions (US National Library of Medicine. National Institutes of Health). Adjuvant is a substance added to a formulation of pharmacological products that affects the action of the active substance in a predictable way.
• Vehicle is an excipient or a substance, preferably without therapeutic action, used as a means to provide volume for medication administration (Stedman's Medical Spellchecker, ⁇ 2006 Lippincott Williams & Wilkins).
• Such carriers, adjuvants or pharmaceutical vehicles may be liquids.
• sterile such as water and oils, including those of petroleum or animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like, excipients, disintegrants, wetting agents or diluents.
• Suitable pharmaceutical carriers are described in "Remington's Pharmaceutical Sciences” by EW Martin. The selection of these excipients and the amounts to be used will depend on the form of application of the pharmaceutical composition.
• the daily dosage for humans and animals may vary depending on factors that are based on the respective species or other factors, such as age, sex, weight or degree of disease and etc.
• the daily dosage for humans may preferably be in the range of from 1 to 2000, preferably from 1 to 1500, more preferably from 1 to 1000 milligrams of active ingredient to be administered for one or several intakes per day.
• the formulations can be prepared according to conventional methods such as those described in the Spanish, European or United States Pharmacopoeias, or in similar reference texts, for example "Galenic Pharmacy Treaty", by C. Faul ⁇ i Trillo, 10 Edition, 1993, Luzán 5, SA of Editions.
• the compounds and compositions of this invention can be used with other drugs to provide a combination therapy.
• the other drugs may be part of the same composition, or they may be provided as a separate composition for administration at the same time or at a different time.
• the terms “treat”, “treating” and “treatment” generally include eradication, elimination, inversion, relief, modification or control of PH in a subject.
• the terms “prevention”, “preventing”, “preventive”, “prevent” and prophylaxis refer to the ability of a given substance to prevent, minimize or hinder the appearance or development of HP in a subject.
• the term “subject” or “patient” in the context of the invention includes any animal, in particular, vertebrate animals, preferably mammals, such as mice, rats, horses, pigs, rabbits, cats, sheep, dogs, cows, beings. humans, etc.
• the mammal is a pig or a human being. In another even more preferred embodiment, the mammal is the human being.
• Pre-capillary HP model The pre-capillary HP model was generated by pulmonary arterial embolization with synthetic microspheres 300 microns in diameter (Sephadex G50 coarse; Pharmacia Biotech; Freiburg, Germany), a variant of a previously described model (Bernd W. Bottiger, MD; Johann Motsch, MD; Joachim Dorsam, MD; UlfMieck, MD; Andre Gries, MD, forg Weimann, MD; and Eike Martin, MD. Inhaled Nitric Oxide Selectively Decreases Pulmonary Artery Pressure and Pulmonary Vascular Resistance Following Acute Massive Pulmonary Microembolism in Piglets. CHEST1996 ; 1 10: 1041-47)
• the protocol began in pigs Large-White breed, Sus Scrofa species, 3 months old ( « 40 Kg of weight). After general anesthesia and analgesia, and under cardiac monitoring and orotracheal intubation, the femoral artery and vein was cannulated by percutaneous puncture in the cardiac hemodynamics laboratory. Through the venous access, a Swan-Ganz catheter was placed in one of the main branches of the pulmonary artery (AP), which was connected to a monitor for continuous recording of PAP and for quantification of pulmonary capillary pressure and cardiac output. The arterial route allowed continuous recording of systemic blood pressure. The venous access served to administer the microspheres to the pulmonary arterial circulation.
• AP pulmonary artery
• a solution with 500 mg of microspheres in 200 ml of physiological serum was prepared and the amount needed to achieve an average PAP maintained> 40 mmHg in approximately 20 minutes was administered. This procedure was repeated weekly (3-5 embolizations) until the generation of chronic HP (mean PAP> 25 mmHg at rest). The animals were followed for 2 months. At the end of the follow-up the animals received euthanasia and the heart was removed for histological analysis.
• Histopathological lesions that we have observed in the lung reproduce those evidenced in arterial HP or chronic thromboembolic HP in humans: proliferation of arterial intima with media hypertrophy and perivascular fibrosis, vascular occlusions, and complex lesions such as vascular aneurysms or plexiform lesions. Post-capillary HP model.
• the post-capillary HP model was generated by the non-restrictive surgical cerclage of the main pulmonary vein in piglets of 4 weeks of age (approximately 10 kg of weight). This vein drains the blood of both lower pulmonary lobes, which constitute approximately 80% of the pulmonary mass. With analgesia and General anesthesia and under cardiac monitoring and orotracheal intubation, the external jugular vein and the right common carotid artery were located by surgical dissection. Through the venous access, the Swan-Ganz catheter was introduced for continuous monitoring of PAP, pulmonary capillary pressure and cardiac output. Likewise, the arterial route was used to monitor systemic blood pressure during surgery.
• the non-restrictive cerclage of the main pulmonary vein was performed by placing a 5 mm wide polyester tape around the vessel adjusted to the resting diameter of the pulmonary venous confluent just before its Left atrial entrance.
• This method avoided causing acute post-surgical lung edema since pulmonary vein stenosis is not present immediately after surgery but progresses as the animal grows. It is therefore a progressive HP model (the severity increases throughout the follow-up).
• the hemodynamic study was performed by right heart catheterization using strictly the same methodology as in humans. Once the HP was generated, the following parameters were duplicated at baseline and after administration of the ⁇ 3 agonist: PAP, pulmonary capillary pressure and right atrial pressure. The quantification of cardiac output was performed by the thermodilution technique. Five measurements were made and the average of 3 measurements was considered after excluding the upper and lower extreme determinations. Telediastolic pressure of the left ventricle was determined by placing a pig-tail catheter in the inside of the left ventricle through the femoral artery. Pulmonary vascular resistance was calculated as the difference between mean PAP and left ventricular telediastolic pressure, all divided by cardiac output and expressed in Wood units.
• BRL 37344 in the form of sodium salt
• 5 ⁇ g / kg of the drug diluted in physiological serum intravenously was administered in all cases. This dose was established after a pilot study aimed at selecting the maximum dose that would not generate systemic hemodynamic involvement (to avoid possible side effects). The effect of the drug was evaluated at 10 minutes after its administration in acute HP and at 20 minutes in chronic HP.
• BRL 37344 To assess the chronic effect of administration of BRL 37344, a cohort of animals with post-capillary HP was randomized to BRL 37344 or placebo (physiological serum). All animals were implanted with a subcutaneous osmotic pump (Alzet 2 ml) coupled to a vascular catheter inserted into the internal jugular vein. Those animals randomized to BRL 37344 received a dose of 10 ⁇ g / kg / day for 14 days. The hemodynamic change was evaluated, blindly, at 2 weeks it was monitored.
• a subcutaneous osmotic pump Alzet 2 ml
• a 50 mg tablet was administered orally every 12 hours in all cases.
• the fixed dose for all animals was based on doses used in humans for different pathologies (never HP has never been tested in this entity) and that has resulted in no adverse effects.
• the dose used for the treatment of neurogenic vegija is 25 to 50 mg / day, while in studies designed to evaluate the effect of this drug on heart failure (see "Beta 3 Agonist Treatmente in Heart Failure (Beat-HF) NCT01876433 ”) the expected starting dose is 25 mg / 12 hours titrating up to a maximum of 150 mg / 12 hours.
• the 50 mg / 12h dose is intended to be an easily extrapolated average dose to patients with whom an efficacy study could be performed knowing that the adverse effect profile is favorable.
• Continuous variables are expressed as mean ⁇ SD and qualitative variables as frequency (%).
• Chronic HP was generated in 8 pigs by surgical stenosis of the inferior pulmonary venous confluent as described above.
• the animals were randomized to BRL37344 (10 ⁇ g / Kg / day) vs. physiological serum for 14 days, administered by means of ALZET® osmotic pumps coupled to a catheter inserted in the jugular vein. Pre and post treatment a right cardiac catheterization was performed.
• Table 2 Baseline characteristics of animals with chronic HP randomized to chronic treatment with BRL37344 or physiological serum, using osmotic pumps.
• RV ejection fraction (%) 61.4 ⁇ 9.9 56.5 ⁇ 5.0 0.42 DV Mass (g / m2) 28.6 ⁇ 10.8 27.0 ⁇ 3.3 0.80

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Citations (34)

• 2012
  • 2012-08-29 ES ES201231343A patent/ES2394349B1/es not_active Withdrawn - After Issue
• 2013
  • 2013-08-28 DK DK13785891.6T patent/DK2891490T3/da active
  • 2013-08-28 US US14/424,861 patent/US10532038B2/en active Active
  • 2013-08-28 ES ES13785891T patent/ES2863749T3/es active Active
  • 2013-08-28 WO PCT/ES2013/070611 patent/WO2014033343A1/es not_active Ceased
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