US20150306065A1 - A Combination of Adrenaline with an Antidepressant for Use in the Treatment of Shocks - Google Patents

A Combination of Adrenaline with an Antidepressant for Use in the Treatment of Shocks Download PDF

Info

Publication number
US20150306065A1
US20150306065A1 US14/433,549 US201314433549A US2015306065A1 US 20150306065 A1 US20150306065 A1 US 20150306065A1 US 201314433549 A US201314433549 A US 201314433549A US 2015306065 A1 US2015306065 A1 US 2015306065A1
Authority
US
United States
Prior art keywords
pharmaceutical composition
adrenalin
antidepressant
shock
treatment
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.)
Abandoned
Application number
US14/433,549
Other languages
English (en)
Inventor
Jean-Charles Schwartz
Xavier Ligneau
Laurent François Gérard LANDAIS
David Perrin
Jeanne-Marie Lecomte
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.)
Bioprojet SC
Original Assignee
Bioprojet SC
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 Bioprojet SC filed Critical Bioprojet SC
Assigned to BIOPROJET reassignment BIOPROJET COMBINATION DECLARATION AND ASSIGNMENT Assignors: LECOMTE, JEANNE-MARIE, PERRIN, DAVID, SCHWARTZ, JEAN-CHARLES, LANDAIS, LAURENT FRANCOIS GERARD, LIGNEAU, XAVIER
Publication of US20150306065A1 publication Critical patent/US20150306065A1/en
Abandoned legal-status Critical Current

Links

Images

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
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • 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
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • 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
    • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure

Definitions

  • the present invention concerns a novel combination of adrenalin with an antidepressant for use in the treatment of shocks.
  • Circulatory shocks are life-threatening medical emergencies wherein the organs and tissues of the body are not receiving an adequate flow of blood and thus an adequate level of oxygen.
  • shocks There are three major types of shocks: cardiogenic, hypovolemic, and distributive shocks.
  • distributive shocks the anaphylactic shock and septic shock can be cited.
  • tachycardia Among the symptoms of shocks, it can be cited tachycardia, hypotension and signs of poor end-organ perfusion such as low urine output, confusion or weakness.
  • the present invention concerns a novel combination of adrenalin with an antidepressant for use in the treatment of shocks, for which the emergency treatment comprises the administration of adrenalin.
  • Anaphylaxis is a severe allergic reaction of rapid onset affecting many body systems and may cause death. It is due to the release of inflammatory mediators and cytokines from mast cells and basophils, typically due to an immunologic reaction but also, sometimes, non-immunologic mechanisms.
  • immunoglobulin E binds to an antigen.
  • Antigen-bound IgE then activates Fc ⁇ RI receptors (Fc epsilon RI receptors) on mast cells and basophils. This leads to release of inflammatory mediators such as histamine. These mediators subsequently increase the contraction of bronchial smooth muscles, trigger vasodilation, increase the leakage of fluid from blood vessels, and cause heart muscle depression.
  • Non-immunologic mechanisms involve substances that directly cause the degranulation of mast cells and basophils. These include agents such as contrast media, penicillins, opioids, temperature (hot or cold), and vibration.
  • adrenalin also called epinephrine or adrenaline
  • an injection of adrenalin within minutes of the onset of symptoms can be lifesaving (Kemp S F et al. Allergy, 2008, 63, 1061-1070).
  • Administration of adrenalin will increase vascular tone, myocardial contractility, and cardiac output in most cases.
  • Adrenalin is a well-known emergency treatment of circulatory shocks such as anaphylactic shock, cardiac arrest, and cardiovascular distress associated with anaphylactic shock, hemorragic shock, traumatic shock, infectious shock and secondary shock due to cardiac surgery.
  • adrenalin may fail due to the delay required for the injected adrenalin dose to reach the general circulation from the injected site.
  • plasma levels of adrenalin increase slightly a few minutes after such injection but the bulk of the increase occurs after a delay of about 20 minutes in animals as well as in humans (Simons et al. J Allergy Clin Immunol. 2001; 108:871-3.).
  • Such a delay for the second peak seems attributable to the local vasoconstriction elicited by adrenalin at the injection site.
  • the inventors have hypothesized that the diffusion of adrenalin in general circulation could be improved by the inhibition of the alpha-1 adrenergic receptor and/or by the inhibition of adrenalin capture by the noradrenalin/monoamine transporters.
  • H1 histaminergic receptors H1-receptors or H1R
  • H1-receptors H1-receptors
  • H1R H1 histaminergic receptors
  • adrenalin and antidepressants are administrated separately, to recreate the usual conditions of medication (long-term treatment for the antidepressant): the antidepressant is administered several times a day for several days before the administration of adrenalin by intravenous route.
  • the present inventors discovered that the combination of adrenalin with an antidepressant improves the diffusion of adrenalin into the general circulation, leading to a rapid and sustained plasma level. Also, the combination of adrenalin with an antidepressant accelerates the diffusion of adrenalin into general circulation, and/or blocks the main deleterious actions of released histamine.
  • the combination of adrenalin and an antidepressant according to the invention is preferably administered by intramuscular or subcutaneous injection.
  • adrenalin preferably administered together via intramuscular or subcutaneous route potentiates the action of adrenalin, thus involving a synergy between the two active ingredients.
  • Such effects are of great interest as they can be life-saving.
  • one of the advantages of the invention is that the administration of adrenalin with the antidepressant is easy to perform.
  • Another advantage of the combination according to the invention is the local effect of the antidepressant that prevents the local vasoconstriction at the adrenalin site of injection, leading to an improved bioavailability of adrenalin.
  • the invention therefore allows the combination of a ready-to-use treatment of shocks with an improved bioavailability in the first ten minutes following the intramuscular or subcutaneous injection of the combination adrenalin-antidepressant.
  • the combination according to the invention is thus of great interest in shocks for which the treatment comprises the quick administration of adrenalin as it improves the bioavailability of adrenaline, and can thus be life-saving.
  • the present invention thus relates to an aqueous solution comprising adrenalin and an antidepressant.
  • Adrenalin (or epinephrine) is both a hormone and a neurotransmitter. It belongs to the group of catecholamines. Adrenalin as used herein refers to the formula:
  • antidepressant refers to an active principle which is used for the prevention and/or treatment of depression.
  • Depression is a mood disorder characterized by an all-encompassing low mood accompanied by low self-esteem, and by loss of interest or pleasure in normally enjoyable activities.
  • the antidepressant is an inhibitor of noradrenalin/monoamine transporters as well as an antagonist of the alpha-1 adrenergic receptors and an antagonist of the H1 receptors.
  • anti-agonist of the H1 receptor is meant a compound generally having a Ki inferior to 35 nM for the H1-receptors.
  • antagonist of the alpha-1 adrenergetic receptor is meant a compound having a Ki inferior to 200 nM for the alpha-1 adrenergetic receptors.
  • inhibitor of the noradrenalin/monoamine transporter is meant a compound having a Ki inferior to 100 nM for the noradrenalin/monoamine transporters.
  • Ki is meant the dissociation constant obtained by inhibiting the binding of a ligand or the inhibition constant obtained by inhibiting noradrenalin/adrenalin uptake.
  • the antidepressant can be chosen among the following classes:
  • the antidepressant is chosen among the tricyclic antidepressants (TCAs) or one of their pharmaceutically acceptable salts.
  • TCAs include in particular:
  • amitriptyline amoxapine, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, desipramine, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin, imipramine, imipraminoxide, lofepramine, maprotiline, mianserin, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, quinupramine, amineptine (norepinephrine-dopamine reuptake inhibitor), and trimipramine.
  • TCAs include:
  • amitriptyline amoxapine, amitriptylinoxide, butriptyline, clomipramine, demexiptiline, dibenzepin, dimetacrine, dosulepin/dothiepin, doxepin, imipraminoxide, lofepramine, maprotiline, mianserin, melitracen, metapramine, nitroxazepine, nortriptyline, noxiptiline, pipofezine, propizepine, protriptyline, quinupramine, amineptine (norepinephrine-dopamine reuptake inhibitor), and trimipramine.
  • the antidepressant is chosen among the group consisting of: amitryptyline, amoxapine, clomipramine, doxepin, imipramine, maprotiline, mianserin nortriptyline, protriptyline and trimipramine. More preferably the antidepressant is chosen among the group consisting of doxepin, trimipramine, amitriptyline and mianserin.
  • the antidepressant is chosen among doxepin or one of its pharmaceutically acceptable salts, preferably doxepin chlorhydrate, imipramine or one of its pharmaceutically acceptable salts, preferably imipramine chlorhydrate or amitryptiline or one of its pharmaceutically acceptable salts, preferably amitryptiline chlorhydrate.
  • the antidepressant is doxepin or doxepin chlorhydrate.
  • pharmaceutically acceptable salts refers to salts which retain the biological effectiveness and properties of the active ingredient and which are not biologically or otherwise undesirable.
  • Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids, while pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases.
  • pharmaceutically acceptable salts see Berge, et al. ((1977) J. Pharm. Sd, vol. 66, 1).
  • the salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, and the like, as well as salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, fumaric, methanesulfonic, and toluenesulfonic acid and the like.
  • the preferred pharmaceutically acceptable salts for the antidepressant are chosen among chlorhydrate, mesilate, maleate and fumarate.
  • the preferred pharmaceutically acceptable salts for adrenalin are chlorhydrate and tartrate.
  • the present invention also encompasses hydrates or hydrated salts or polymorphic crystalline structures, racemates, diastereomers or enantiomers of the active ingredients.
  • the solution of the invention further comprises one or more pharmaceutically acceptable excipient(s) such as preservative agents, buffers, substance to make the solution isotonic with blood such as sodium chloride, solvents, stabilizers, or antimicrobial preservatives. It can be cited: sodium, hydrochloric acid or water for injection.
  • the excipients used are well-known to the skilled person. They should not adversely affect the stability, bioavailability, safety, or efficacy of the active ingredients, or cause toxicity or undue local irritation when the solution is to be administered by injection.
  • the solution of the invention further comprises at least one preservative agent.
  • the preservative agents are chosen among sodium metabisulfite, sodium bisulfite, ascorbic acid and/or their mixture.
  • the preservative agent is sodium metabisulfite.
  • the solution of the invention consists of adrenalin, an antidepressant, sodium chloride, a preservative agent and water.
  • adrenalin in the solution of the invention, is at a concentration comprised between 0.05 mg/ml and 1.0 mg/ml. In a particular embodiment, adrenalin is at a concentration between 0.15 mg/ml and 1.0 mg/ml. In another embodiment, adrenalin is at a concentration between 0.6 mg/ml and 1.0 mg/ml in formulations suitable for adults. In another embodiment, adrenalin is at a concentration between 0.1 mg/ml and 0.6 mg/ml in formulations suitable for children.
  • the antidepressant in the solution as defined above, is at a concentration comprised between 0.1 mg/ml and 10 mg/ml. Preferably, the antidepressant is at a concentration comprised between 0.3 mg/ml and 3 mg/ml.
  • the invention also relates to a pharmaceutical composition comprising the solution as defined above.
  • the invention relates to a pharmaceutical composition comprising the solution as defined above, wherein the solution is suitable for injection.
  • An injection is an instrumental method used to introduce into the body a liquid pharmaceutical composition by parenteral administration.
  • injection is preferably meant a method of administration which can be intramuscular, subcutaneous or a transcutaneous penetration.
  • transcutaneous penetration is to be understood an injection by local pressure using devices without skin perforation by needle.
  • the pharmaceutical composition of the invention is suitable for intramuscular injection and/or subcutaneaous injection.
  • the pharmaceutical composition as defined above is administered by intramuscular injection.
  • the injection of the above defined pharmaceutical composition is not an intravenous injection.
  • the pharmaceutical composition of the invention is in a unit dosage form in which the injected volume is comprised between 0.1 ml and 0.5 ml. More preferably, the injected volume is of 0.3 ml.
  • the invention also relates to the pharmaceutical composition as defined above, for use in the treatment of shocks.
  • the invention also relates to the use of a solution as defined above for the preparation of a pharmaceutical composition to treat shocks.
  • the invention also relates to the solution as defined above for its use in the treatment of shocks.
  • shock it is understood a circulatory shock, which may be characterized by a decrease of the organ perfusion. Circulatory shocks are acute and severe pathologies, often life-threatening, and are well-known by physicians.
  • shock refers to every shock as defined herein, for which the emergency treatment comprises the administration of adrenalin, more particularly for which adrenalin is administered by injection, subcutaneously or by intramuscular route.
  • the shock is chosen from the group consisting of: anaphylactic shock, cardiac arrest, and cardiovascular distress associated with anaphylactic shock, hemorragic shock, traumatic shock, infectious shock and secondary shock due to cardiac surgery.
  • the shock is the anaphylactic shock.
  • the solution and/or the pharmaceutical composition as defined above is used in the treatment of a pathology chosen from the group consisting of: anaphylactic shock, cardiac arrest, and cardiovascular distress associated with anaphylactic shock, hemorragic shock, traumatic shock, infectious shock and secondary shock due to cardiac surgery.
  • a pathology chosen from the group consisting of: anaphylactic shock, cardiac arrest, and cardiovascular distress associated with anaphylactic shock, hemorragic shock, traumatic shock, infectious shock and secondary shock due to cardiac surgery.
  • the pathology is the anaphylactic shock.
  • treatment it may be understood the treatment of the causes of the shock and/or the treatment of its symptoms, more particularly the treatment of its symptoms.
  • the use of the pharmaceutical composition as defined above comprises administering a dose of adrenalin comprised between 0.05 mg and 0.35 mg.
  • the use of the pharmaceutical composition as defined above comprises administering a dose of adrenalin comprised between 0.05 mg and 0.15 mg for children and between 0.1 mg and 0.30 mg for adults.
  • the use of the pharmaceutical composition as defined above comprises administering a dose of adrenalin of 0.1 mg for children and of 0.2 mg for adults.
  • the pharmaceutical composition for use as defined above comprises administering the antidepressant at a dose comprised between 0.1 mg and 3 mg.
  • the unit dosage form is contained in an auto-injection device.
  • Auto-injection devices or autoinjectors are medical devices designed to deliver a single dose of a pharmaceutical composition. They are easy and ready to use and are intended for self-administration by patients, or administration by untrained personnel. The site of injection depends on the pharmaceutical composition, but it typically is administered into the thigh or the buttocks.
  • Auto-injection devices for adrenalin are well-known by a man skilled in the art such as Anapen®, Epipen®, Twinject®, Intelliject® or Crossject®. They allow the administration of injectable solutions by intramuscular injection, subcutaneous injection or transcutaneous penetration.
  • the invention thus also relates to an auto-injection device comprising the pharmaceutical composition of the invention.
  • the auto-injection device comprises a container prefilled with the pharmaceutical composition as defined above.
  • said container is a prefilled syringe.
  • the auto-injection device comprises two containers wherein one container is prefilled with an aqueous solution of adrenalin, the other one container is prefilled with an aqueous solution of an antidepressant and wherein the pharmaceutical composition of the invention is formed by mixing the two solutions within the device.
  • aqueous solutions may be the commercially available solutions for injection comprising adrenalin on one hand and the antidepressant on the other hand and/or may exhibit similar concentrations, dosage unit forms, excipients as the solution of the invention disclosed above.
  • the auto-injection device as defined above comprises at least one prefilled container which is (are) suitable for injection of a volume of the pharmaceutical composition as defined above comprised between 0.1 ml and 0.5 ml.
  • the injected volume of the pharmaceutical composition of the invention is of 0.3 ml.
  • an aqueous solution of adrenalin and another aqueous solution of antidepressant may also be separate, provided they are administered at the same time, and at the same point of injection.
  • the area of action of the antidepressant which is the area where the antidepressant blocks totally or partially the local vasoconstriction induced by injected adrenalin, therefore accelerating the systemic bioavailability and potentiates the activity of adrenalin.
  • the time of action of the antidepressant which is the time it takes for the antidepressant to block totally or partially the local vasoconstriction induced by injected adrenalin, therefore accelerating the systemic bioavailability and potentiating the activity of adrenalin.
  • the present invention also encompasses the combination of these separate aqueous solutions for use for the treatment of shocks for simultaneous administration.
  • the combination of these separate aqueous solutions is used for the treatment of anaphylactic shock for simultaneous administration.
  • the invention also relates to an auto-injection device comprising two containers wherein the pharmaceutical composition of the invention is prepared from an aqueous solution of adrenalin and an aqueous solution of an antidepressant, one container being prefilled with the aqueous solution of adrenalin, the other one container being prefilled with the aqueous solution of the antidepressant.
  • the containers are preferably prefilled syringes.
  • the invention also relates to a method of treatment of shocks comprising the administration of a pharmaceutical composition as defined above in a patient in need thereof.
  • the invention also relates to a method of treatment of the anaphylactic shock comprising the administration of a pharmaceutical composition as defined above in a patient in need thereof.
  • FIG. 1 shows the bioavailability of adrenalin when the combination according to the invention is injected in rabbits compared with adrenalin injected alone during the 10 minutes following the injection.
  • a first narrow peak in plasma adrenalin level occurred a few minutes following the injection and immediately decreased to basal level.
  • a second much larger peak of similar height occurred 20 min later.
  • the area under the curve (AUC) of this second peak was about 20 times higher than the first one indicating that the bulk of the injected dose reached the general circulation in a delayed manner, during this second period.
  • the AUC of plasma adrenalin calculated on the first 10 min following the intramuscular injection, was increased by more than 500% whereas the total AUC remained unchanged when compared to AUCs obtained after the injection of adrenalin alone (see FIG. 1 )
  • the AUC of the hypertensive response during the first 10 min following the injection was enhanced by more than three folds.
  • Plasma doxepin levels also peaked during these first 10 min and were maintained during the following two hours at concentrations several fold higher than required for continuous blockade of histamine H1 receptor, taking into account the below nanomolar affinity of the drug for this receptor.
  • Guinea pigs received intramuscularly saline solution with adrenalin at 30 ⁇ g/kg alone or in association with amitriptyline (1 mg/kg) or imipramine (1 mg/kg). Plasma levels of adrenalin were monitored.

Landscapes

  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Cardiology (AREA)
  • Emergency Medicine (AREA)
  • Immunology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Hospice & Palliative Care (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Infusion, Injection, And Reservoir Apparatuses (AREA)
US14/433,549 2012-10-03 2013-10-02 A Combination of Adrenaline with an Antidepressant for Use in the Treatment of Shocks Abandoned US20150306065A1 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
EP12306207.7 2012-10-03
EP12306207 2012-10-03
PCT/EP2013/070598 WO2014053579A1 (en) 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP2013/070598 A-371-Of-International WO2014053579A1 (en) 2012-10-03 2013-10-02 A combination of adrenalin with an antidepressant for use in the treatment of shocks

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US16/223,750 Division US10952987B2 (en) 2012-10-03 2018-12-18 Combination of adrenalin with an antidepressant for use in the treatment of shocks

Publications (1)

Publication Number Publication Date
US20150306065A1 true US20150306065A1 (en) 2015-10-29

Family

ID=47073380

Family Applications (2)

Application Number Title Priority Date Filing Date
US14/433,549 Abandoned US20150306065A1 (en) 2012-10-03 2013-10-02 A Combination of Adrenaline with an Antidepressant for Use in the Treatment of Shocks
US16/223,750 Active US10952987B2 (en) 2012-10-03 2018-12-18 Combination of adrenalin with an antidepressant for use in the treatment of shocks

Family Applications After (1)

Application Number Title Priority Date Filing Date
US16/223,750 Active US10952987B2 (en) 2012-10-03 2018-12-18 Combination of adrenalin with an antidepressant for use in the treatment of shocks

Country Status (31)

Country Link
US (2) US20150306065A1 (enrdf_load_stackoverflow)
EP (1) EP2903607B1 (enrdf_load_stackoverflow)
JP (1) JP6419074B2 (enrdf_load_stackoverflow)
KR (1) KR102145786B1 (enrdf_load_stackoverflow)
CN (1) CN104780916B (enrdf_load_stackoverflow)
AU (1) AU2013326470B2 (enrdf_load_stackoverflow)
BR (1) BR112015007524B1 (enrdf_load_stackoverflow)
CA (1) CA2887330C (enrdf_load_stackoverflow)
CY (1) CY1119514T1 (enrdf_load_stackoverflow)
DK (1) DK2903607T3 (enrdf_load_stackoverflow)
EA (1) EA030763B1 (enrdf_load_stackoverflow)
ES (1) ES2647597T3 (enrdf_load_stackoverflow)
HR (1) HRP20171442T1 (enrdf_load_stackoverflow)
HU (1) HUE034638T2 (enrdf_load_stackoverflow)
IL (1) IL238120B (enrdf_load_stackoverflow)
IN (1) IN2015DN02849A (enrdf_load_stackoverflow)
LT (1) LT2903607T (enrdf_load_stackoverflow)
MA (1) MA37970B2 (enrdf_load_stackoverflow)
MX (1) MX359198B (enrdf_load_stackoverflow)
NO (1) NO2903607T3 (enrdf_load_stackoverflow)
NZ (1) NZ707124A (enrdf_load_stackoverflow)
PH (1) PH12015500755A1 (enrdf_load_stackoverflow)
PL (1) PL2903607T3 (enrdf_load_stackoverflow)
PT (1) PT2903607T (enrdf_load_stackoverflow)
RS (1) RS56392B1 (enrdf_load_stackoverflow)
SG (1) SG11201502645VA (enrdf_load_stackoverflow)
SI (1) SI2903607T1 (enrdf_load_stackoverflow)
SM (1) SMT201700502T1 (enrdf_load_stackoverflow)
TN (1) TN2015000126A1 (enrdf_load_stackoverflow)
WO (1) WO2014053579A1 (enrdf_load_stackoverflow)
ZA (1) ZA201502441B (enrdf_load_stackoverflow)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070293582A1 (en) * 2006-06-05 2007-12-20 Malcolm Hill Epinephrine dosing regimens comprising buccal, lingual or sublingual and injectable dosage forms
US20100190860A1 (en) * 2009-01-09 2010-07-29 The Brigham And Women's Hospital, Inc. Methods for selectively enhancing antinociceptive potency of local anesthetics

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3705942A (en) * 1969-09-29 1972-12-12 Ciba Geigy Corp Treatment of glaucoma employing imipramine or desmethylimipramine
TW200744568A (en) * 2006-02-28 2007-12-16 Verus Pharmaceuticals Inc Epinephrine dosing regimens
PT2818184T (pt) * 2007-11-16 2019-01-28 Aclaris Therapeutics Inc Composições e métodos para o tratamento de púrpura
SE533552C2 (sv) * 2008-12-30 2010-10-26 Igeloesa Transplantation Science Ab Förfarande och lösning för behandling av en potentiell organdonator
CN101987198B (zh) * 2009-08-06 2014-08-13 北京美倍他药物研究有限公司 药物组合物

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070293582A1 (en) * 2006-06-05 2007-12-20 Malcolm Hill Epinephrine dosing regimens comprising buccal, lingual or sublingual and injectable dosage forms
US20100190860A1 (en) * 2009-01-09 2010-07-29 The Brigham And Women's Hospital, Inc. Methods for selectively enhancing antinociceptive potency of local anesthetics

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Khan et. al. (Anesthesiology (2002) 96: 109-116). *
Serdyuk et. al. (Bulletin of Experimental Biology and Medicine (2007) 144:692-694). *

Also Published As

Publication number Publication date
KR102145786B1 (ko) 2020-08-19
US10952987B2 (en) 2021-03-23
ES2647597T3 (es) 2017-12-22
PH12015500755B1 (en) 2015-05-25
LT2903607T (lt) 2017-10-25
MX359198B (es) 2018-09-19
CA2887330A1 (en) 2014-04-10
HUE034638T2 (en) 2018-02-28
CN104780916B (zh) 2019-02-26
US20190117614A1 (en) 2019-04-25
MA37970B2 (fr) 2017-10-31
PL2903607T3 (pl) 2018-01-31
BR112015007524B1 (pt) 2022-06-21
ZA201502441B (en) 2015-12-23
IN2015DN02849A (enrdf_load_stackoverflow) 2015-09-11
HK1211846A1 (en) 2016-06-03
MA20150396A1 (fr) 2015-11-30
EP2903607B1 (en) 2017-08-16
CY1119514T1 (el) 2018-03-07
PT2903607T (pt) 2017-11-14
JP2015536907A (ja) 2015-12-24
AU2013326470A1 (en) 2015-04-30
WO2014053579A1 (en) 2014-04-10
PH12015500755A1 (en) 2015-05-25
AU2013326470B2 (en) 2017-08-24
TN2015000126A1 (en) 2016-10-03
SI2903607T1 (sl) 2017-12-29
NO2903607T3 (enrdf_load_stackoverflow) 2018-01-13
EP2903607A1 (en) 2015-08-12
CN104780916A (zh) 2015-07-15
MA37970B1 (fr) 2016-06-30
SMT201700502T1 (it) 2017-11-15
RS56392B1 (sr) 2017-12-29
NZ707124A (en) 2017-12-22
DK2903607T3 (en) 2017-10-09
JP6419074B2 (ja) 2018-11-07
KR20150093656A (ko) 2015-08-18
SG11201502645VA (en) 2015-05-28
IL238120B (en) 2018-08-30
CA2887330C (en) 2021-03-09
EA201500374A1 (ru) 2015-07-30
BR112015007524A2 (pt) 2017-07-04
HRP20171442T1 (hr) 2018-01-12
MX2015004323A (es) 2015-06-10
EA030763B1 (ru) 2018-09-28

Similar Documents

Publication Publication Date Title
US10881647B2 (en) Neosaxitoxin combination formulations for prolonged local anesthesia
CA2930900C (en) Combinations of ziconotide and opioids for reducing pain
CN102196819A (zh) 局部麻醉用组合物
EP3062791B1 (en) Novel treatments for attention and cognitive disorders, and for dementia associated with a neurodegenerative disorder
US10952987B2 (en) Combination of adrenalin with an antidepressant for use in the treatment of shocks
US12171807B2 (en) Use of bremelanotide in patients with controlled hypertension
HK1211846B (zh) 用於治疗休克的肾上腺素与抗抑郁剂的组合
JP2009537601A (ja) 神経因性疼痛の治療用のミルタザピン
US20230099367A1 (en) Purmorphamine as a small compound positive allosteric modulator of secretin receptor for the treatment of hypertension

Legal Events

Date Code Title Description
AS Assignment

Owner name: BIOPROJET, FRANCE

Free format text: COMBINATION DECLARATION AND ASSIGNMENT;ASSIGNORS:SCHWARTZ, JEAN-CHARLES;LIGNEAU, XAVIER;LANDAIS, LAURENT FRANCOIS GERARD;AND OTHERS;SIGNING DATES FROM 20150521 TO 20150601;REEL/FRAME:035882/0063

STPP Information on status: patent application and granting procedure in general

Free format text: DOCKETED NEW CASE - READY FOR EXAMINATION

STPP Information on status: patent application and granting procedure in general

Free format text: NON FINAL ACTION MAILED

STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION