US20070185181A1 - Treatment or prevention of hypotension and shock - Google Patents

Treatment or prevention of hypotension and shock Download PDF

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Publication number
US20070185181A1
US20070185181A1 US11/641,953 US64195306A US2007185181A1 US 20070185181 A1 US20070185181 A1 US 20070185181A1 US 64195306 A US64195306 A US 64195306A US 2007185181 A1 US2007185181 A1 US 2007185181A1
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United States
Prior art keywords
effective amount
patient
administered
mammal
treatment
Prior art date
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Abandoned
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US11/641,953
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English (en)
Inventor
Riitta Heino
Tiina Leino
Tarja Lehtimaki
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Orion Oyj
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Orion Oyj
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Filing date
Publication date
Application filed by Orion Oyj filed Critical Orion Oyj
Priority to US11/641,953 priority Critical patent/US20070185181A1/en
Publication of US20070185181A1 publication Critical patent/US20070185181A1/en
Priority to US13/096,387 priority patent/US8470862B2/en
Priority to US13/925,271 priority patent/US9078883B2/en
Priority to US14/738,717 priority patent/US9446025B2/en
Abandoned legal-status Critical Current

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    • 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
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—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
    • A61K31/415—1,2-Diazoles
    • 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
    • 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
    • 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
    • A61P9/02—Non-specific cardiovascular stimulants, e.g. drugs for syncope, antihypotensives

Definitions

  • the present invention relates lo a method for the prevention or treatment of hypotension and shock due to low peripheral resistance. Further, the present invention relates to a method for the treatment of cardiopulmonary resuscitation. Accordingly, the present invention relates to a method for the prevention or treatment of hypotension and shock due to low peripheral resistance by administering an imidazole derivative of the formula 1: wherein R is hydrogen or methyl, or a pharmaceutically acceptable ester or salt thereof.
  • the present invention relates to a method for the treatment of cardiopulmonary resuscitation by administering an imidazole derivative of formula 1 or a pharmaceutically acceptable ester or salt thereof.
  • the present invention also relates to the use of an imidazole derivative of formula 1, or a pharmaceutically acceptable ester or salt thereof, in the manufacture of a medicament for the prevention or treatment of hypotension and shock due to low peripheral resistance. Further, the present invention also relates to the use of an imidazole derivative of formula 1, or a pharmaceutically acceptable ester or salt thereof, in the manufacture of a medicament for the treatment of cardiopulmonary resuscitation.
  • ⁇ 2 -Adrenoceptor agonists such as dexmedetomidine
  • dexmedetomidine are known to induce a characteristic pattern of cardiovascular responses including e.g., bradycardia and hypotension and therefore they are typically considered as potential candidates for the treatment of hypertension.
  • MAP mean arterial pressure
  • HR heart rate
  • MAP mean arterial pressure
  • HR heart rate
  • the imidazole derivatives of formula 1 do not decrease the blood pressure after intravenous, intramuscular Or subcutaneous administration in a mammal. Accordingly, they cause an increase in the blood pressure with a reflectory decrease in heart rate after the administration.
  • the imidazole derivatives of formula 1, or a pharmaceutically acceptable ester or salt thereof can be used in situations where returning the blood from peripheral circulation to the central circulation is needed, like in circulatory shock due to low resistance of peripheral circulation and cardiac arrest.
  • an object of the invention is to provide a method for the prevention or treatment of hypotension and shock due to low peripheral resistance by administering an imidazole derivative of formula 1, or a pharmaceutically acceptable ester or salt thereof to a mammal. Further, an object of the invention is to provide a method for the treatment of cardiopulmonary resuscitation by administering an imidazole derivative of formula 1, or a pharmaceutically acceptable ester or salt thereof to a mammal.
  • the preferred compound of the present invention is 3-(1H-imidazol-4-ylmethyl)-indan-5-ol.
  • hypotension and shock due to low peripheral resistance encompasses all of the potential conditions that require the treatment of hypotension and shock. e.g., hypotension due to vasodilatation, anaphylatic shock, septic shock and post heart surgery shock.
  • the precise amount of the drug to be administered to a mammal for the prevention and treatment of hypotension and shock due to low peripheral resistance and for the treatment of cardiopulmonary resuscitation is dependent on numerous factors known to one skilled in the art, such as, the compound to be administered, the general condition of the patient, the condition to be treated, the desired duration of use, the type of mammal, the method of administration etc.
  • the desired dose can be administered intravenously, using a bolus dose or by a steady infusion, intramuscularly or subcutaneously.
  • the dose of 3-(1-imidazol-4-ylmethyl)-indan-5-ol administered intravenously to a human can be from about 10 to 500 ⁇ g/patient, preferably about 30-200 ⁇ g/patient.
  • the injections or infusions may contain one or more diluents or carriers.
  • mice Male Spraque-Dawley rats (B&K, Sweden), weighing 290-400 g, were anaesthetized with sodium pentobarbital (Mebunat® 60 mg/ml) 75 mg/kg i.p..
  • the left femoral vein was cannulated (PE-50) for slow drug injections.
  • the left femoral artery was cannulated (PE-60) and the mean arterial blood pressure (MAP) and heart rate (HR) were recorded continuously via a Micro MP-15 transducer connected to a Grass Model 7D Polygraph.
  • MAP mean arterial blood pressure
  • HR heart rate
  • Arterial pressure was sampled at a rate 150 samples/second and recorded on a Pinus PC computer using the software program Acqknowledge version 3.5.3 and a MP100A data acquisition unit for analog/digital conversion (BIOPAC Systems, Inc.). Pulse waves of the blood pressure were used for displaying heart rate continuosly.
  • the body temperature (rectal) was kept constant at 37 ⁇ 0.5° C. by warming with a lamp above the animal's chest. Only rats with MAP of 73 mmHg or higher were used for the tests.
  • 3-(1-imidazol-4-ylmethyl)-indan-5-ol (1 and 3 ⁇ g/kg, as hydrochloride) or dexmedetomidine (3 and 10 ⁇ g/kg, as hydrochlorides) dose was given as slow intravenous injection (during 5 min) by an infusion pump (Perfusor®, ED 2, B. Braun). The total injection volume was adjusted to 1 ml in each experimental group.
  • 3-(1H-imidazol-4-ylmethyl)-indan-5-ol induced an immediate and dose-dependent increase in MAP (maximally +31%) and long-lasting decrease in HR (maximally ⁇ 19%) after slow (during 5 minutes) i.v. dosing of 1 and 3 ⁇ g/kg (see FIG. 1 and Table 1).
  • the reference compound dexmedetomidine 3 and 10 ⁇ g/kg decreased both MAP and HR (maximally 37% and ⁇ 21% respectively) immediately and dose-dependently (see FIG. 2 and Table 1) after slow intravenous administration at the tested doses.
  • Dose Time MPV-2426 Al Dose Time Dexmedetomidine ( ⁇ g/kg) (min) MAP(mmHg) HR (beats/min) ( ⁇ g/kg) (min) MAP (mmHg) HR (beats/min) 1 0 97 ⁇ 4 373 ⁇ 8 3 0 89 ⁇ 5 348 ⁇ 12 3 114 ⁇ 3 324 ⁇ 9 3 86 ⁇ 5 310 ⁇ 6 5 112 ⁇ 3 321 ⁇ 9 5 79 ⁇ 7 310 ⁇ 5 10 83 ⁇ 4 327 ⁇ 7 10 61 ⁇ 4 308 ⁇ 4 20 84 ⁇ 4 319 ⁇ 9 20 65 ⁇ 2 309 ⁇ 5 30 80 ⁇ 3 317 ⁇ 9 30 67 ⁇ 2 309 ⁇ 5 3 0 94 ⁇ 5 366 ⁇ 11 10 0 92 ⁇ 2 383 ⁇ 11 3 123 ⁇ 9 309 ⁇ 7 2 94 ⁇ 4 308 ⁇ 5 5 117 ⁇ 12
  • 3-(1H-imidazol-4-ylmethyl)-indan-5-ol produces both hypertensive and bradycardic actions, unlike dexmedetomidine, which in turn has typical cardiovascular effects of an alpha-2-adrenoceptor agonist.

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Cardiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Heart & Thoracic Surgery (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Dermatology (AREA)
  • Pulmonology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)
US11/641,953 1999-10-29 2006-12-20 Treatment or prevention of hypotension and shock Abandoned US20070185181A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US11/641,953 US20070185181A1 (en) 1999-10-29 2006-12-20 Treatment or prevention of hypotension and shock
US13/096,387 US8470862B2 (en) 1999-10-29 2011-04-28 Treatment or prevention of hypotension and shock
US13/925,271 US9078883B2 (en) 1999-10-29 2013-06-24 Treatment or prevention of hypotension and shock
US14/738,717 US9446025B2 (en) 1999-10-29 2015-06-12 Treatment or prevention of hypotension and shock

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US16212099P 1999-10-29 1999-10-29
PCT/FI2000/000935 WO2001030347A1 (en) 1999-10-29 2000-10-27 Treatment or prevention of hypotension and shock
US11162802A 2002-08-23 2002-08-23
US11/641,953 US20070185181A1 (en) 1999-10-29 2006-12-20 Treatment or prevention of hypotension and shock

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
PCT/FI2000/000935 Continuation WO2001030347A1 (en) 1999-10-29 2000-10-27 Treatment or prevention of hypotension and shock
US10111628 Continuation 2002-08-23
US11162802A Continuation 1999-10-29 2002-08-23

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/096,387 Continuation US8470862B2 (en) 1999-10-29 2011-04-28 Treatment or prevention of hypotension and shock

Publications (1)

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US20070185181A1 true US20070185181A1 (en) 2007-08-09

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US11/641,953 Abandoned US20070185181A1 (en) 1999-10-29 2006-12-20 Treatment or prevention of hypotension and shock
US13/096,387 Expired - Fee Related US8470862B2 (en) 1999-10-29 2011-04-28 Treatment or prevention of hypotension and shock
US13/925,271 Expired - Fee Related US9078883B2 (en) 1999-10-29 2013-06-24 Treatment or prevention of hypotension and shock
US14/738,717 Expired - Lifetime US9446025B2 (en) 1999-10-29 2015-06-12 Treatment or prevention of hypotension and shock

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US13/096,387 Expired - Fee Related US8470862B2 (en) 1999-10-29 2011-04-28 Treatment or prevention of hypotension and shock
US13/925,271 Expired - Fee Related US9078883B2 (en) 1999-10-29 2013-06-24 Treatment or prevention of hypotension and shock
US14/738,717 Expired - Lifetime US9446025B2 (en) 1999-10-29 2015-06-12 Treatment or prevention of hypotension and shock

Country Status (11)

Country Link
US (4) US20070185181A1 (ru)
EP (1) EP1223931B1 (ru)
JP (1) JP4741131B2 (ru)
AT (1) ATE312606T1 (ru)
AU (1) AU778522B2 (ru)
CA (1) CA2388979C (ru)
DE (1) DE60024855T2 (ru)
NO (1) NO329889B1 (ru)
NZ (1) NZ518447A (ru)
RU (1) RU2259827C2 (ru)
WO (1) WO2001030347A1 (ru)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060178417A1 (en) * 2002-12-05 2006-08-10 Tomi Jarvinen Imidazol derivatives having affinity for alpha 2 receptors activity

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5485827A (en) * 1990-12-05 1996-01-23 The General Hospital Corporation Methods and devices for treating plumonary vasoconstriction and asthma
US5571840A (en) * 1993-06-22 1996-11-05 The Regents Of The University Of Michigan Method for treating central nervous system ischemia
US5713907A (en) * 1995-07-20 1998-02-03 Endotex Interventional Systems, Inc. Apparatus and method for dilating a lumen and for inserting an intraluminal graft

Family Cites Families (16)

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FR2542738A1 (fr) * 1983-03-18 1984-09-21 Synthelabo Indanyl-2 d2-imidazoline, procede pour la preparer, et compositions pharmaceutiques qui la contiennent
GB2206880B (en) 1987-07-16 1991-04-24 Farmos Oy Optical isomers of an imidazole derivative
US5124157A (en) 1989-08-18 1992-06-23 Cygnus Therapeutic Systems Method and device for administering dexmedetomidine transdermally
FI894911A0 (fi) 1989-10-17 1989-10-17 Farmos Oy En terapeutiskt vaerdefull foerening.
GB2281206A (en) 1993-08-25 1995-03-01 Orion Yhtymae Oy Use of dexmedetomidine
GB9520150D0 (en) * 1995-10-03 1995-12-06 Orion Yhtymae Oy New imidazole derivatives
US20050281752A1 (en) 1997-10-01 2005-12-22 Dugger Harry A Iii Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system
US20030077227A1 (en) 1997-10-01 2003-04-24 Dugger Harry A. Buccal, polar and non-polar spray or capsule containing drugs for treating disorders of the central nervous system
US6716867B1 (en) 1998-04-01 2004-04-06 Orion Corporation Use of dexmedetomidine for ICU sedation
AR015744A1 (es) 1998-04-01 2001-05-16 Orion Corp Uso de dexmedetomidina para sedacion en terapia intensiva
US7001609B1 (en) 1998-10-02 2006-02-21 Regents Of The University Of Minnesota Mucosal originated drug delivery systems and animal applications
US6582457B2 (en) 2001-02-15 2003-06-24 Radiant Medical, Inc. Method of controlling body temperature while reducing shivering
US20030022926A1 (en) 2001-05-07 2003-01-30 Lavand'homme Patricia Method for treating neuropathic pain and pharmaceutical preparation therefor
FR2834212B1 (fr) 2001-12-27 2004-07-09 Besins Int Belgique Utilisation d'une poudre a liberation immediate dans des compositions pharmaceutiques et nutraceutiques
IL147921A0 (en) 2002-01-31 2002-08-14 Abdulrazik Mohammad A method for treating central nervous system disorders by ocular dosing
WO2008003093A2 (en) 2006-06-29 2008-01-03 Questcor Pharmaceuticals, Inc. Pharmaceutical compositions and related methods of treatment

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5485827A (en) * 1990-12-05 1996-01-23 The General Hospital Corporation Methods and devices for treating plumonary vasoconstriction and asthma
US5571840A (en) * 1993-06-22 1996-11-05 The Regents Of The University Of Michigan Method for treating central nervous system ischemia
US5713907A (en) * 1995-07-20 1998-02-03 Endotex Interventional Systems, Inc. Apparatus and method for dilating a lumen and for inserting an intraluminal graft

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060178417A1 (en) * 2002-12-05 2006-08-10 Tomi Jarvinen Imidazol derivatives having affinity for alpha 2 receptors activity
US7759496B2 (en) * 2002-12-05 2010-07-20 Orion Corporation Imidazole derivatives having affinity for alpha 2 receptors activity

Also Published As

Publication number Publication date
CA2388979C (en) 2010-09-14
AU1149201A (en) 2001-05-08
JP2003527333A (ja) 2003-09-16
EP1223931B1 (en) 2005-12-14
DE60024855D1 (de) 2006-01-19
AU778522B2 (en) 2004-12-09
CA2388979A1 (en) 2001-05-03
EP1223931A1 (en) 2002-07-24
ATE312606T1 (de) 2005-12-15
NZ518447A (en) 2004-10-29
NO20021920D0 (no) 2002-04-23
WO2001030347A1 (en) 2001-05-03
US9078883B2 (en) 2015-07-14
RU2259827C2 (ru) 2005-09-10
US9446025B2 (en) 2016-09-20
NO20021920L (no) 2002-06-14
JP4741131B2 (ja) 2011-08-03
US8470862B2 (en) 2013-06-25
US20110294862A1 (en) 2011-12-01
US20160030392A1 (en) 2016-02-04
NO329889B1 (no) 2011-01-17
DE60024855T2 (de) 2006-08-31
US20140100257A1 (en) 2014-04-10

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