EP1233815A1 - Utilisation d'antagonistes du recepteur d3 de la dopamine pour la therapie de l'hypertonie liee a l'absorption de sel - Google Patents

Utilisation d'antagonistes du recepteur d3 de la dopamine pour la therapie de l'hypertonie liee a l'absorption de sel

Info

Publication number
EP1233815A1
EP1233815A1 EP00975979A EP00975979A EP1233815A1 EP 1233815 A1 EP1233815 A1 EP 1233815A1 EP 00975979 A EP00975979 A EP 00975979A EP 00975979 A EP00975979 A EP 00975979A EP 1233815 A1 EP1233815 A1 EP 1233815A1
Authority
EP
European Patent Office
Prior art keywords
salt
rats
dopamine
hypertension
dahl
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.)
Withdrawn
Application number
EP00975979A
Other languages
German (de)
English (en)
Inventor
Bernd Mühlbauer
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.)
Abbott GmbH and Co KG
Original Assignee
Abbott GmbH and Co KG
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 Abbott GmbH and Co KG filed Critical Abbott GmbH and Co KG
Publication of EP1233815A1 publication Critical patent/EP1233815A1/fr
Withdrawn legal-status Critical Current

Links

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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • 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
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to the use of dopamine D 3 receptor agonists for the manufacture of a medicament for the diagnosis and treatment of salt-dependent hypertension.
  • salt-dependent hypertension is present in approximately 10 to 15% of cases.
  • the diagnosis has so far been made in such a way that the patients have to follow a low-salt diet for several weeks, which in the case of salt-dependent hypertension results in a reduction in hypertension.
  • all agonists which are selective for this receptor subtype can be considered as dopamine D receptor agonists.
  • Such an agonist is, for example, R (+) -7-hydroxy-2-dipropylamino-tetra-lin (7 OH-DPAT). Those agonists which have high peripheral plasma levels are particularly suitable.
  • the Dahl rat (see Dahl et al., Nature 1962, 194: 480-482) represents an animal model for salt-dependent hypertension.
  • sodium-enriched food can cause hypertension even in adolescence be generated during this effect be the so-called salzre ⁇ sistenten Dahl rats does not occur.
  • Dopamine-D 3 receptor agomes can be used for the diagnosis of salt-sensitive forms of hypertension. This is a
  • D 3 -Agomst to be administered orally or parenterally and to measure urine volume and sodium excretion under standardized conditions.
  • An increase in urine volume and sodium excretion would suggest a normal response; failure to do so would indicate a salt-sensitive form of hypertension.
  • Such a distinction is important for further therapy decisions
  • the D -receptor agones can be processed into customary pharmaceutical dosage forms, for example for peroral, parenteral, subcutaneous, mtrape ⁇ toneal or topical administration.
  • customary pharmaceutical dosage forms for example tablets, capsules, infusion and Injekti ⁇ onsaten, drinking molds or sprays.
  • the pharmaceutical preparations according to the invention contain the usual carriers and diluents in addition to the active ingredient.
  • pharmaceutical-technical auxiliaries such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycostearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used.
  • pharmaceutical-technical auxiliaries such as ethanol, isopropanol, ethoxylated castor oil, ethoxylated hydrogenated castor oil, polyacrylic acid, polyethylene glycol, polyethylene glycostearate, ethoxylated fatty alcohols, paraffin oil, petroleum jelly and wool fat can be used.
  • internal use e.g. Milk sugar, propylene glycol, ethanol, starch, talc and polyvinyl pyrrolidone.
  • Antioxidants such as tocopherol and butylated hydroxyanisole and butylated hydroxytoluene, taste-improving additives, stabilizers, emulsifiers and lubricants can also be present.
  • the substances contained in the preparation in addition to the active substance and the substances used in the manufacture of the pharmaceutical preparation are toxicologically safe and compatible with the respective active substance.
  • the pharmaceutical preparations are prepared in the usual way, e.g. by mixing the active ingredient with the other conventional carriers and diluents.
  • the rats (80 mg / kg body weight; Trapanal®, Byk guilders, Konstanz, DE.) By an intraperitoneal injection of sodium thiopental anesthetized and trium-sheet on a heat table pla ⁇ to a rectal temperature of 37.1 ° C. A tracheostomy was performed to facilitate spontaneous breathing.
  • Two catheters were inserted into the right jugular vein.
  • Ringer's saline solution (111 mmol NaCl, 30 mmol NaHC0 3 , 4.7 mmol KCl) was infused through the first catheter at a rate of 1.5 to 3.0 ml / h, corresponding to 0.8% by weight of the body weight.
  • [ 3 H] inulin (1.2 ⁇ Ci / ml) dissolved in Ringer's solution was infused at a rate of 0.6 ml / h throughout the experiment to determine the glomerular filtration rate.
  • a cannula was inserted into the left carotid artery to take blood samples and to continuously measure systemic blood pressure. Urine samples were taken through a bladder catheter. After the rats have been exposed to each other for a period of 80 to 100 min. had recovered from this procedure, two successive clearance periods of 20 min each. examined to establish the baseline. Then, instead of Ringer's saline solution, a solution of the D3 receptor agonist R (+) - 7-hydroxy-2-dipropyl-aminotetralin, dissolved in Ringer's solution, in two successive doses of 0.01 to 0.1 ⁇ g / kg body weight / min infused. Then Ringer's solution was infused again and after 10 min. a clearance period. During each 20 minute clearance period, a blood sample of 180 ⁇ l was taken after 10 minutes.
  • Renal [ 3 H] inulin clearance was used to determine the glomerular filtration rate (GFR).
  • Mean arterial blood pressure (MAP) and heart rate (HR) were continuously measured during the experiments.
  • MAP mean arterial blood pressure
  • HR heart rate
  • the urine volume was determined gravimetrically.
  • the blood samples were centrifuged and the hematocrit determined.
  • the sodium concentrations in urine and plasma were determined by flame photometry using an ELEX 6361 device from Eppendorf, Hamburg.
  • the 3H inulin radioactivity was determined by liquid phase scanning.
  • Rats were first anesthetized to obtain kidney tissue. Using sterile working material, the kidneys were exposed, removed, weighed and the capsule removed.
  • RNA isolation was carried out according to the method of Chomczynski and Sacchi (1987). The tissue is homogenized and centrifuged in the presence of an acidic phenol / chloroform mixture. The upper aqueous phase contains the RNA. This is cleaned of phenol residues with isopropanol and precipitated with ethanol. This can then be recorded in DEPC-H0 and used in RT-PCR after quantification. All operations were carried out sterile, contamination with RNases was excluded.
  • RNA 500 ng of total RNA were transcribed into complementary DNA (cDNA) in 15 ⁇ l batches.
  • the primers for the subsequent RT-PCR were selected either from the relevant literature or with the aid of published sequences in gene databases and synthesized by MWG-Biotech (Ebersberg).
  • the relative quantification of the D 3 receptor mRNA expression was carried out according to the "primer dropping" method as described by (Wong et al., 1994). In the first stage, the target sequence is amplified over a certain number of cycles, in the second stage the primer pair for the amplification of the "hoppinging gene", in this case beta-actin, is added and the PCR is continued for further cycles.
  • Kidneys from animals of both Dahl strains (DS and DR) after normal and salt-rich diet were homogenized immediately after removal using a potter in buffer solution (TRIS 25 mM / HEPES 40 mM (pH 4.7), sucrose 320 mM, EDTA 0.5 mM) and centrifuged at 1,000 xg for 15 minutes (4 ° C). After discarding the supernatant, the pellet was resuspended with buffer and centrifuged again. The second supernatant was centrifuged at 100,000 x g for 30 minutes (4 ° C). The final pellet was resuspended in buffer without sucrose and EDTA and stored at -80 ° C until binding experiments. Binding studies were carried out with 100 mg membrane protein. Saturation experiments were performed at 0.5 to 50 nM
  • [3H] -7-OH-DPAT carried out, using 10 uM unlabeled 7-OH-DPAT to determine the non-specific binding. Specific binding was calculated by subtracting non-specific from total binding.
  • the dissociation constant (K D ) as an expression of the affinity of the ligand for its receptor was not found to be significantly different and was around 10 nM in both Dahl strains.
  • the specific binding (bmax) was significantly lower in DS compared to DR. The difference became even clearer if the rats were previously fed a salt-rich diet. Here the specific binding in DS rats was only 50% of that in DR animals.
  • Salt-resistant Dahl rats were given a normal diet for one week with the dopamine D3 antagonist 5-amino-3- (4- (4- (2-t-butyl-6-trifluoromethyl) pyrimidin-4-yl) pipe - razin-1-yl) 2-methyl-but-2-en-l-yl-mercapto) -4-methyl -1, 2, 4 (4H) triazole in a dosage of 40 mg / kg per day treated the drinking water.
  • tail plethysmometry was used to measure arterial blood pressure.
  • the animals were then exposed to a salt-rich diet (4% by weight NaCl in the feed) ad libitum. Arterial blood pressure was determined weekly up to 4 weeks after the start of the experiments.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Chemical & Material Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Emergency Medicine (AREA)
  • Urology & Nephrology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Cardiology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne l'utilisation d'antagonistes du récepteur D3 de la dopamine pour produire un médicament servant au diagnostic et à la thérapie de l'hypertonie liée à l'absorption de sel.
EP00975979A 1999-11-04 2000-10-31 Utilisation d'antagonistes du recepteur d3 de la dopamine pour la therapie de l'hypertonie liee a l'absorption de sel Withdrawn EP1233815A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19953254 1999-11-04
DE19953254 1999-11-04
PCT/EP2000/010770 WO2001032263A1 (fr) 1999-11-04 2000-10-31 Utilisation d'antagonistes du recepteur d3 de la dopamine pour la therapie de l'hypertonie liee a l'absorption de sel

Publications (1)

Publication Number Publication Date
EP1233815A1 true EP1233815A1 (fr) 2002-08-28

Family

ID=7928007

Family Applications (1)

Application Number Title Priority Date Filing Date
EP00975979A Withdrawn EP1233815A1 (fr) 1999-11-04 2000-10-31 Utilisation d'antagonistes du recepteur d3 de la dopamine pour la therapie de l'hypertonie liee a l'absorption de sel

Country Status (15)

Country Link
EP (1) EP1233815A1 (fr)
JP (1) JP2003513053A (fr)
KR (1) KR20020062300A (fr)
CN (1) CN1387450A (fr)
AU (1) AU1390801A (fr)
BR (1) BR0015310A (fr)
CA (1) CA2389643A1 (fr)
CZ (1) CZ20021521A3 (fr)
HU (1) HUP0203024A2 (fr)
IL (1) IL149266A0 (fr)
MX (1) MXPA02004103A (fr)
NO (1) NO20022142L (fr)
RU (1) RU2002114818A (fr)
WO (1) WO2001032263A1 (fr)
ZA (1) ZA200204455B (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1180599A1 (fr) * 2000-08-16 2002-02-20 Siemens Building Technologies AG Dispositif de sécurité pour une pompe pouvant être utilisée dans une transmission à fluide
JP2010184889A (ja) * 2009-02-12 2010-08-26 Nihon Univ 高血圧症予防治療薬
JP5738875B2 (ja) * 2009-10-16 2015-06-24 エピオメド セラピューティクス， インク． 催吐治療

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU5147196A (en) * 1995-03-27 1996-10-16 Smithkline Beecham Plc Bicyclic amine derivatives and their use as anti-psychotic a gents
FR2742149B1 (fr) * 1995-12-11 1998-02-13 Inst Nat Sante Rech Med Nouveaux derives de 2-naphtamides et leurs applications therapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO0132263A1 *

Also Published As

Publication number Publication date
CN1387450A (zh) 2002-12-25
WO2001032263A1 (fr) 2001-05-10
NO20022142D0 (no) 2002-05-03
KR20020062300A (ko) 2002-07-25
JP2003513053A (ja) 2003-04-08
IL149266A0 (en) 2002-11-10
HUP0203024A2 (hu) 2003-02-28
CA2389643A1 (fr) 2001-05-10
AU1390801A (en) 2001-05-14
CZ20021521A3 (cs) 2003-05-14
ZA200204455B (en) 2003-09-04
RU2002114818A (ru) 2004-01-10
NO20022142L (no) 2002-05-03
MXPA02004103A (es) 2003-08-20
BR0015310A (pt) 2002-07-09

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