WO1999055317A2 - Traitement de l'insuffisance cardiaque desequilibree avancee au moyen de donneurs d'oxyde nitrique - Google Patents

Traitement de l'insuffisance cardiaque desequilibree avancee au moyen de donneurs d'oxyde nitrique Download PDF

Info

Publication number
WO1999055317A2
WO1999055317A2 PCT/US1999/009330 US9909330W WO9955317A2 WO 1999055317 A2 WO1999055317 A2 WO 1999055317A2 US 9909330 W US9909330 W US 9909330W WO 9955317 A2 WO9955317 A2 WO 9955317A2
Authority
WO
WIPO (PCT)
Prior art keywords
nitric oxide
heart
patient
heart failure
positive inotropic
Prior art date
Application number
PCT/US1999/009330
Other languages
English (en)
Other versions
WO1999055317A3 (fr
Inventor
Joshua M. Hare
Original Assignee
The Johns Hopkins University
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 The Johns Hopkins University filed Critical The Johns Hopkins University
Priority to AU37717/99A priority Critical patent/AU3771799A/en
Publication of WO1999055317A2 publication Critical patent/WO1999055317A2/fr
Publication of WO1999055317A3 publication Critical patent/WO1999055317A3/fr

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

Definitions

  • This invention is related to treatment of heart failure.
  • this invention is related to treatment of advanced decompensated heart failure with drugs which are capable of nitrosylating proteins.
  • Congestive heart failure is a prevalent and serious condition. In the United States, 4.7 million people have congestive heart failure. Once the condition develops, the six-year mortality rate approaches 80% in men and 65% in women. (Kannel,
  • NASH New York Heart Association
  • ACE angiotensin-converting enzyme
  • Contraindications to treatment with ACE inhibitors include shock, angioneurotic edema, and significant hyperkalemia. Patients may be unable to tolerate ACE inhibitors because of symptomatic hypotension, azotemia, hyperkalemia, cough, rash, or angioneurotic edema.
  • Diuretic treatment is usually recommended for class IV heart failure patients; however, a variety of complications such as hypotension, vascular collapse, hypokalemia, and diuretic drug resistance can develop. While vasodilators can be used to treat NYHA class I-III heart failure, they are often detrimental to class IV patients.
  • One embodiment of the invention provides a method of treating advanced decompensated heart failure.
  • a nitric oxide donor which is a positive inotrope is administered to a patient with advanced decompensated heart failure in an amount sufficient to increase myocardial contractility.
  • Another embodiment of the invention provides a method for screening to identify candidate positive inotropic drugs for treating advanced heart failure.
  • a test substance is contacted with an L-type calcium channel. S-nitrosylation of the L-type calcium channel is determined.
  • a test substance which donates a nitric oxide radical to the L-type calcium channel is identified as a candidate positive inotropic drug.
  • Still another embodiment of the invention provides a method for screening to identify candidate positive inotropic drugs for treating advanced heart failure.
  • a test substance is contacted with a ryanodine receptor. S-nitrosylation of the ryanodine receptor is determined.
  • a test substance which donates a nitric oxide radical to the ryanodine receptor is identified as a candidate positive inotropic drug.
  • the invention provides novel means for treating advanced decompensated heart failure by increasing myocardial contractility using drugs which nitrosylate the L-type calcium channel or the ryanodine receptor.
  • the invention also provides novel means of screening for candidate positive inotropic drugs.
  • Figure 1 Representative pressure- volume data generated with transient occlusion of the inferior vena cava. Shown are pressure- volume loops before (solid loops) and after SIN-1 infusion (dotted loops, 160 ⁇ g/Kg/min). The solid line indicates slope of the end-systolic pressure volume relationship (Ees) obtained by non-linear regression of end-systolic pressure volume points. In this example, the end-systolic pressure volume relationship shifted to the left, resulting in near-complete emptying of the ventricle at end-systole. This positive inotropic effect dramatically increased stroke volume.
  • Ees end-systolic pressure volume relationship
  • SIN-1 was infused via the internal jugular vein and pressure- volume data were obtained during transient IVC occlusion at each infusion rate.
  • SIN-1 administration caused a biphasic positive inotropic response which was converted to a negative inotropic effect by pretreatment with SOD. *P ⁇ 0.05 vs. control.
  • LVEDP LV end-diastolic pressure
  • Ea effective arterial elastance
  • the present invention provides a method of treating patients with advanced decompensated heart failure. These are preferably patients who are classified as New
  • NYHA York Heart Association
  • These patients are hemodynamically decompensated, have low blood pressure, and deteriorating kidney function and mental status.
  • these patients cannot tolerate vasodilator drugs or angiotensin-converting enzyme inhibitors, and some patients cannot tolerate ⁇ - adrenergic blocking agents.
  • Many of these patients are not ambulatory and/or are refractory to outpatient therapy.
  • Nitric oxide donors activate the L-type Ca 2+ channel and the ryanodine receptor by nitrosylating the thiol moieties of these proteins.
  • NONOates are one class of nitric oxide donors which can nitrosylate proteins.
  • Sydnonimes are another class of nitric oxide donors.
  • 3-Morpholinosydnonimine (SIN-1) releases equimolar NO * and -O 2 - that react to form peroxynitrite, an effective nitrosating agent.
  • Nitrosothiols such as S-nitrosocysteamine, are a third class of nitric oxide donors.
  • Nitric oxide donors which can be used to treat patients with advanced decompensated heart failure include, but are not limited to, members of the classes above, such as SIN-1, ((Z)-l-N-[3-aminopropyl]-N-[4-(3- aminopropylammonio)butyl]-aminodiazen- 1 -ium- 1 ,2-diolate (spermine NONOate), diethylamine NONOate, S,S'-Dinitrosodithio ( ⁇ )-S-Nitroso-N-acetylpenicillinamine
  • SNAP Glyco-SNAP-1, Glyco-SNAP-2, NOC-9, NOR-3, sodium dinitroprusside dihydrate, S-Nitrosoglutathione (SNOG), S-Nitrosoglutathione monomethyl ester, 2- (dimethylamino)-ethylputreanine/NO (DMAEP/NO), ((Z)- 1 -N-Methyl-N-[6-(N- methylammoniohexyl)amino] diazen-l)-ium-l,2-diolate (MAHMA NONOate), S- nitrosocysteine, S-nitroso-N-acetylcysteine, S-nitrosocysteamine, S- nitrosohomocysteine, S-nitrosodithiothreitol, S-nitrosoalbumin, CAS 1609 (4- hydroxymethyl-furoxan-3-carboxamide), and diazeniumdi
  • Nitric oxide donors can be administered either alone or in combination with other therapies.
  • the patients are not treated with or are not concomitantly treated with other positive inotropic agents, such as digoxin or dobutamine.
  • the nitric oxide donor is preferably administered by intravenous infusion. Dosages of the nitric oxide donors can be determined, for example, by carrying out routine testing in animal models of heart failures, which are known and widely used in the art.
  • the dosage effective to increase myocardial contractility is between 10 and 200 ⁇ g/kg/min. or between 50 and 150 ⁇ g/kg/min.
  • the total amount administered is between 100 and 2000 ⁇ g/kg or 500 and 1500 ⁇ g/kg.
  • the amount of the nitric oxide donor is sufficient to stabilize the hemodynamics of the patient.
  • Hemodynamic stabilization can be assessed by means of common hemodynamic measurements, such as cardiac output, stroke output, stroke work, stroke power, ventricular end-diastolic pressure, ejection fraction, and ventricular end-diastolic volume, as is known in the art.
  • the method of the invention is especially effective for treatment of severely ill heart failure patients, such as those with a pulmonary wedge pressure of less than 18 or more than 28 mm Hg and/or a cardiac index of ⁇ 2 L/min/m 2 .
  • Pulmonary wedge pressure can be measured by methods known in the art, such as Doppler echocardiography or right heart catheterization. Cardiac index can be measured using the Fick method or other techniques known in the art. (See Hurst et al., eds., THE HEART, 4th ed., pp. 491-501, 1978).
  • the invention also provides a method for screening drugs to identify candidate positive inotropic drugs for treating advanced heart failure.
  • a test substance is contacted with an L-type calcium channel, and S-nitrosylation of the L-type calcium channel is determined.
  • the test substance can be contacted with a ryanodine receptor, and S-nitrosylation of t e ryanodine receptor is determined.
  • a test substance which donates a nitric oxide radical to the L-type calcium channel or the ryanodine receptor is identified as a candidate positive inotropic drug.
  • the test substance can be a pharmacologic agent already known in the art as a nitric oxide donor or can be a compound previously unknown to have any nitrosylating activity.
  • the test substance can be naturally occurring or designed in the laboratory. It can be isolated from microorganisms, animals, or plants, or can be produced recombinantly or synthesized by chemical methods known in the art.
  • S-nitrosylation of the L-type calcium channel or ryanodine receptor can be determined, for example in isolated cardiac muscle strips, isolated cardiac myocytes, or non-cardiac muscle cells transfected with expression vectors encoding either of the two proteins.
  • S-nitrosylation can be measured in in vitro systems comprising purified or recombinantly expressed L-type calcium channels or ryanodine receptors. Purification of these proteins has been described. (See Tauna & Murphy, Can. J. Physiol Pharmacol 68, 1482-88, 1990; Xu et al., Science 279:234-237 (1998). Either protein can be expressed using recombinant DNA techniques well known in the art.
  • the candidate positive inotropic drug is administered to a mammalian heart, such as a rabbit, ferret, mouse, rat, guinea pig, hamster, dog, cat, cow, sheep, pig, or goat heart, and myocardial contractility is measured.
  • the heart can be an isolated, perfused heart or the heart can be in an intact animal.
  • Myocardial contractility can be measured by any means known in the art. Methods of measuring myocardial contractility are taught, for example, in Kojda et al., Cir. Res.
  • a candidate drug which increases myocardial contractility in the heart is identified as a positive inotrope.
  • a dissecting microscope for visualization, a limited substernal abdominal incision was performed, and the diaphragm cut at the anterior chest wall.
  • a combined micromanometer-conductance catheter (20) (SPR-719, Millar Instruments, Houston, TX) was then advanced retrograde into the left ventricle along the cardiac longitudinal axis with the distal tip in the aortic root and proximal electrode just within the endocardial wall of the LV apex. The pericardium was left as intact as possible.
  • the right jugular vein was cannulated with a 30G needle.
  • the recorded volume signal from the conductance catheter requires calibration for absolute volume (offset) and stroke volume (gain). Calibration was performed in 7 mice. Absolute volume was derived using a saline wash-in technique (21). This saline wash-in method allows determination of the "parallel-conductance," a measure of the conductance signal which derives from structures outside the left ventricular cavity (i.e., muscle, bone, blood in the right ventricle, etc.).
  • Stroke volume calibration was derived from cardiac output obtained from direct measurement of aortic flow. With the catheter fixed in place, the mice were turned to the left-lateral position. Special care was taken to maintain catheter position as evidenced by the shape and position of the pressure-volume loops visualized on-line. A limited lateral thoracotomy was then performed and the descending aorta dissected free from the spinal column just above the level of the diaphragm. A flow probe (AT01RB, Transonic Systems, Ithaca, NY) was placed around the aorta, and flow per minute was recorded (ATI 06, Transonic Systems).
  • Ea has been validated to closely approximate aortic impedance, which incorporates systemic vascular resistance and the reflected wave properties of the vasculature. Contractility was indexed using the load-independent parameters end-systolic elastance (Ees) and preload-recruitable stroke work (PRSW; slope of stroke work/end-diastolic volume relation) (23). Diastolic performance was measured by the time constant of isovolumic relaxation (tau) and the time to peak filling rate (ttpf) (25).
  • Table 1 summarizes baseline hemodynamic variables in all C57BL/6 mice studied. Heart rate was 699 ⁇ 17 bpm, SBP 98 ⁇ 3 mm Hg, Ees 18.7 ⁇ 4.2 mm Hg/ ⁇ l and
  • PRSW (Figure 2) increased by 27 ⁇ 13% (p ⁇ 0.05) from baseline at the peak response which occurred at the dose 160 ⁇ g/kg/min. At higher infusion rates of SIN-1 (320 ⁇ g/kg/min) this effect was partially reversed. In contrast, SIN-1 did not affect myocardial relaxation as indexed by tau and ttpf.
  • Rat Langendorff preparations can be used to measure myocardial contractility.
  • Hearts are excised from male Wistar rats and retrogradely perfused with oxygenated perfusion buffer at 37 °C .
  • a polyvinyl chloride balloon attached to PE-190 tubing balloon is placed through the left atrium and mitral valve into the left ventricle.
  • the balloon is filled with saline to achieve a maximum isovolumic developed pressure, which typically occurs at an end-diastolic pressure of 10-15 mm Hg.
  • Hearts are perfused at a constant flow with a peristaltic pump titrated to a coronary perfusion pressure of 80 mm Hg. Constant flow is used to avoid confounding alterations in contractility due to the Gregg effect .
  • the perfusate contains (mmol/L) sodium 144, potassium 5, calcium 1.5, bicarbonate 17.5, magnesium 1.2, and chloride 134, along with 5 ⁇ g/ml lidocaine. This is equilibrated with a gas mixture of 95% O 2 /5% CO 2 , resulting in a perfusate pH of 7.4.
  • the hearts are placed in a heated bath to maintain the temperature at " ° C and paced at 300 beats per minute with an electrode placed in the bath.
  • the left ventricular pressure, the rate of change of left ventricular pressure (dP/dt), and the mean coronary perfusion pressure are measured continuously on a physiograph (Gould Electronics Corporation) and simultaneously digitized at 1000 Hz. After a 15 min. stabilization period, drugs can be infused at 1% of coronary flow using a Harvard 11 pump.
  • SIN-1 an effective nitrosating species
  • SOD superoxide dismutase
  • the purpose of this study was to test the hypothesis that nitrosating Nitric oxide donors would have positive inotropic effects in vivo.
  • SOD blocked SIN-1 positive inotropic effects supports a nitrosylation-dependent mechanism of action.
  • the physiologic roles of nitrosylation-based reactions are being increasingly appreciated.
  • Thiol nitrosylation (S-NO) reactions have been shown to confer NO-like vasodilator activity to albumin (5) and other low molecular-weight thiols (31), as well as to enhance tissue plasminogen activator function (6).
  • the second messenger most often attributed to be responsible for the cardiovascular actions of the NO signaling pathway is cGMP, produced by NO activation of soluble gaunylyl cyclase.
  • cGMP actions on contractility also suggest a biphasic response (33).
  • a role for NO in myocardial contractility is more apparent in the setting of ⁇ -adrenergic (18, 34) or heart rate (force-frequency response) (35, 36) stimulated myocardial contractility.
  • This index is also relatively load-independent but is derived from the entire area of the PV loop, rather than a single point as is the case for Ees.
  • SIN-1 had a positive inotropic effect which was not sustained at high concentrations.
  • Peroxynitrite may also lead to cellular toxicity due to its potent oxidizing properties (27), shown both in isolated hearts (38) and intact animal studies (39), and to inhibition of mitochondrial respiration (40). The latter two actions could contribute to reversal of positive inotropic effects.
  • a similar dual response has been noted with regard to peroxynitrite effects on vascular tone, acting as a vasodilator on the one hand and a cause of endothelial dysfunction on the other (41-43).
  • Heart rate HR
  • Systolic blood pressure SBP
  • Nitric oxide-dependent parasympathetic signaling is due to activation of constitutive endothelial (type III) nitric oxide synthase in cardiac myocytes. J.Biol.Chem. 1995;270:14582-14586. 2. Stamler JS. Redox signaling: nitrosylation and related target interactions of nitric oxide. Cell 1994;78:931-936.
  • Nitric oxide circulates in mammalian plasma primarily as an s-nitroso adduct of serum albumin. Proc.Natl.Acad.Sci.USA 1992;89:7674-7677.
  • Nitric oxide inhibits the contractile response to ⁇ -adrenergic stimulation in humans with left ventricular dysfunction. Circulation 1995;92:2198-2203.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Selon cette invention, on peut utiliser des composés donneurs d'oxyde nitrique, qui sont des agents inotropes positifs, pour traiter des patients souffrant d'une grave insuffisance cardiaque déséquilibrée avancée, et ce en nitrosylant le canal à calcium de type L ou le récepteur de ryanodine de manière à augmenter la contractilité du myocarde. On peut également mesurer la nitrosylation du canal à calcium de type L ou du récepteur de ryanodine pour cribler des médicaments candidats inotropes positifs.
PCT/US1999/009330 1998-04-30 1999-04-30 Traitement de l'insuffisance cardiaque desequilibree avancee au moyen de donneurs d'oxyde nitrique WO1999055317A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU37717/99A AU3771799A (en) 1998-04-30 1999-04-30 Treatment of advanced decompensated heart failure with nitric oxide donors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US8361898P 1998-04-30 1998-04-30
US60/083,618 1998-04-30

Publications (2)

Publication Number Publication Date
WO1999055317A2 true WO1999055317A2 (fr) 1999-11-04
WO1999055317A3 WO1999055317A3 (fr) 2000-01-27

Family

ID=22179553

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1999/009330 WO1999055317A2 (fr) 1998-04-30 1999-04-30 Traitement de l'insuffisance cardiaque desequilibree avancee au moyen de donneurs d'oxyde nitrique

Country Status (2)

Country Link
AU (1) AU3771799A (fr)
WO (1) WO1999055317A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6656966B2 (en) 2000-06-22 2003-12-02 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
US20100316622A1 (en) * 2007-11-02 2010-12-16 University Of Miami Diagnosis and treatment of cardiac disorders

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
HIMBERT ET AL.: "Acute hemodynamic effects of SIN-1 vs. Isosorbide dinitrate: a double blind, crossover study in stable chronic left ventricular failure" J. CARDIOVASCULAR PHARMACOLOGY, vol. 17, no. Suppl.3, 1991, pages S279-S286, XP002110615 *
IBRAHIM ET AL.: "Hemodynamic effects of SIN-1 in acute left heart failure" CARDIOVASCULAR DRUGS AND THERAPY, vol. 3, no. 4, 1989, pages 557-561, XP002110616 *
MOHAN ET AL.: "Myocardial contractile response to nitric oxide and cGMP" CIRCULATION, vol. 93, no. 6, 15 March 1996 (1996-03-15), pages 1223-1229, XP002110617 cited in the application *
MOORE K P ET AL: "Formation of F2-isoprostanes during oxidation of human low-density lipoprotein and plasma by peroxynitrite." CIRCULATION RESEARCH, (1995 AUG) 77 (2) 335-41., XP002110618 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6656966B2 (en) 2000-06-22 2003-12-02 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
US6869973B2 (en) 2000-06-22 2005-03-22 Nitromed, Inc. Nitrosated and nitrosylated taxanes, compositions and methods of use
US20100316622A1 (en) * 2007-11-02 2010-12-16 University Of Miami Diagnosis and treatment of cardiac disorders

Also Published As

Publication number Publication date
AU3771799A (en) 1999-11-16
WO1999055317A3 (fr) 2000-01-27

Similar Documents

Publication Publication Date Title
Stamler et al. Nitric oxide regulates basal systemic and pulmonary vascular resistance in healthy humans.
EP0719558B1 (fr) Ranolazine et pipérazines apparentées pour le traitement des conditions du choc
Douglas et al. A role for endogenous endothelin-1 in neointimal formation after rat carotid artery balloon angioplasty. Protective effects of the novel nonpeptide endothelin receptor antagonist SB 209670.
CA2201784C (fr) Procede et formulation pour stimuler la synthese de l'oxyde d'azote
US6617337B1 (en) Use of nitroxides for the treatment of essential hypertension
US6425881B1 (en) Therapeutic mixture useful in inhibiting lesion formation after vascular injury
US20090246296A1 (en) Method of treating ischemia/reperfusion injury with nitroxyl donors
Janero et al. Nitric oxide and postangioplasty restenosis: pathological correlates and therapeutic potential
Seki et al. FK409, a new nitric-oxide donor, suppresses smooth muscle proliferation in the rat model of balloon angioplasty
Guimaraes et al. Nitrite exerts antioxidant effects, inhibits the mTOR pathway and reverses hypertension-induced cardiac hypertrophy
PT1467728E (pt) Composições farmacêuticas compreendendo valsartan e inibidores da nep
RU2252783C2 (ru) Фармацевтический препарат, содержащий низкомолекулярный ингибитор тромбина и его пролекарство
Bianchi et al. A novel peroxynitrite decomposer catalyst (FP-15) reduces myocardial infarct size in an in vivo peroxynitrite decomposer and acute ischemia-reperfusion in pigs
US20160067215A1 (en) Method and Composition for Treating Heart Failure
WO1999055317A2 (fr) Traitement de l'insuffisance cardiaque desequilibree avancee au moyen de donneurs d'oxyde nitrique
US20050182136A1 (en) N-acetylcysteine compositions and methods for the treatment and prevention of endothelial dysfunction
JP2002543148A (ja) カルボキシペプチダーゼｕ阻害剤とトロンビン阻害剤とを含有する医薬製剤
CN114072205A (zh) 用tie-2激活剂治疗高血压的方法
JP2002536325A (ja) 疾患を治療するためのｌ−アルギニン基盤の処方およびその使用方法
CN113116885A (zh) 一种茶多酚类化合物在制备抗血栓药物中的应用
WO2001097831A1 (fr) Agents therapeutiques et prophylactiques destines a l'insuffisance cardiaque
JPH0296537A (ja) プロタミンの使用における有害作用の予防または減少用組成物
JP2003527420A (ja) 鬱血性心不全の治療方法
Jones et al. Update on Nitrite Reduction in Ischemic Disease: Mechanisms and Clinical Translation
WO2018139477A1 (fr) Nouvel agent thérapeutique pour l'anémie néphrogénique ciblant un récepteur d'érythropoïétine via no et la stimulation de la voie no

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A2

Designated state(s): AU BR CA JP ZA

AL Designated countries for regional patents

Kind code of ref document: A2

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

121 Ep: the epo has been informed by wipo that ep was designated in this application
DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
AK Designated states

Kind code of ref document: A3

Designated state(s): AU BR CA JP ZA

AL Designated countries for regional patents

Kind code of ref document: A3

Designated state(s): AT BE CH CY DE DK ES FI FR GB GR IE IT LU MC NL PT SE

122 Ep: pct application non-entry in european phase