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WO1998022124A1 - Utilisation d'un compose secretagogue de l'hormone de croissance pour le traitement de la defaillance cardiaque ou d'un dysfonctionnement vasculaire apparente - Google Patents

Utilisation d'un compose secretagogue de l'hormone de croissance pour le traitement de la defaillance cardiaque ou d'un dysfonctionnement vasculaire apparente Download PDF

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Publication number
WO1998022124A1
WO1998022124A1 PCT/SE1997/001957 SE9701957W WO9822124A1 WO 1998022124 A1 WO1998022124 A1 WO 1998022124A1 SE 9701957 W SE9701957 W SE 9701957W WO 9822124 A1 WO9822124 A1 WO 9822124A1
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Prior art keywords
growth hormone
compound
rats
reperfusion
heart
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PCT/SE1997/001957
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English (en)
Inventor
Ferruccio BERTI
Vito DE GENNARO COLONNA
Eugenio MÜLLER
Giuseppe ROSSONI
Muny Boghen
Magnus Nilsson
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Pfizer Health AB
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Pharmacia and Upjohn AB
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Priority claimed from SE9604300A external-priority patent/SE9604300D0/xx
Application filed by Pharmacia and Upjohn AB filed Critical Pharmacia and Upjohn AB
Priority to AU51424/98A priority Critical patent/AU5142498A/en
Publication of WO1998022124A1 publication Critical patent/WO1998022124A1/fr
Anticipated expiration legal-status Critical
Ceased 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/27—Growth hormone [GH], i.e. somatotropin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/25—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin

Definitions

  • the present invention relates to the use of growth hormone (GH) secretagogue compound or GH and Adrenocorticotropic hormone (ACTH) secretagogue compound for the manufacture of a medicament for treating cardiac failure or related vascular dysfunction.
  • GH growth hormone
  • ACTH Adrenocorticotropic hormone
  • GHRP Crowth hormone releasing peptide
  • Fig. 1 Cardiac function during moderate ischemia in isovolumic left heart preparations.
  • Example 1 Cardiac function during moderate ischemia in isovolumic left heart preparations.
  • Fig. 2 Cardiac function during moderate ischemia in isovolumic left heart preparations. Each point of the curves is the mean value of 10 experiments.
  • Example 1. Fig 4. Rate of formation of 6-keto-PGF 1 a.
  • Fig 6 Left ventricular pressure (LVP) during postischemic reperfusion in heart preparations from saline- or hexarelin-treated rats.
  • LVP Left ventricular pressure
  • Fig. 7 Left ventricular developed pressure (LVDP) and coronary perfusion pressure (CPP) in isovolumic left heart preparations.
  • LVDP left ventricular developed pressure
  • CPP coronary perfusion pressure
  • Example 2 Creatine kinase (CK) release profile in ischemic and reperfusion conditions of old rat hearts.
  • Adrenocorticotropic hormone (ACTH) secretagogue compound has a direct effect on heart is a novel finding, which has not been disclosed earlier and which must be regarded as surprising and of utmost importance.
  • Growth hormone (GH) secretagogue compounds and GH and Adrenocorticotropic hormone (ACTH) secretagogue compounds include peptides, non-peptides and peptoids. (See E Ghigo et al, J. of Clin. Endocrinology and metabolism, Vol 82, No 8, 1997). This group of compounds do not include natural growth hormone releasing compounds (GHRH/GRF). The claimed compounds are functioning at least partially via the Growth hormone releasing peptide (GHRP) mechanisms.
  • GHRP are meant peptidyl GH secretagogue synthetic, non-natural molecules with strong GH- and slight ACTH/Cortisol-releasing effect.
  • related vascular dysfunction all vascular lesions occurring during cardiac failure.
  • the protecting activity of the studied compound observed on impaired heart contractility is also related to its effect on endothelium functions.
  • the endothelium elaborates a panoply of proteins, prostanoids and other paracrine substances to maintain a delicate balance between vasoconstriction and vasodilation.
  • a damage of endothelium-dependent vasoconstriction mechanism(s) regulated by nitric oxide (NO) and prostacyclin (PG12) formed by endothelial cells may initiate and contribute to different pathological states, including hypertension, vasopasm and atherosclerosis.
  • NO nitric oxide
  • PG12 prostacyclin
  • the heart contractility can be seen in figures 1, the upper panel in figure 2 and figure 3.
  • the endothelium functions can be seen in figure 2 lower panel and figures 4 and
  • GH-deficiency patients are patients included whose GH and
  • IGF-I response to spontaneous, physiological and pharmacological tests are GH deficient-like.
  • the invention is illustrated by the use of hexarelin.
  • Hexarelin is a low molecular weight peptide with six amino acids:
  • Trp at position 2 is D-2 methyl-Tip
  • Phe is D-Phe
  • Lys is Lys-NH 2 .
  • Hexarelin is a synthetic growth hormone-releasing peptide, shown to produce a substantial increase of growth hormone plasma levels in humans (Imbimbo et al,
  • hexarelin and biosynthetic human growth hormone (Pharmacia, Sweden); angiotensin II (Sigma Chem. Co., MA, USA); multiprime DNA labeling system (Rediprime; Amersham, Little Chalfont, UK); kit for 6-keto-PGF l ⁇ determination (Cayman, Chemical Company, Ann Arbor, MI); kit for creatine kinase determination (Boehringer-Mannheim, Germany).
  • the GHM-Ab was prepared by immunising rabbits with a mixture of synthetic rat GHRH (Spiess, J., J. et al, Nature 303, 532) and methylated BSA emulsified in
  • the biologic efficacy of the antiserum was assessed at various levels.
  • the GHRH-Ab has repeatedly been shown to significantly inhibit GH secretion and growth (Wehrenberg, W.B..et al 1984 , Endocrinology 115, 1218.; Wehrenberg, W.B. et al, 1986, Endocrinology 1 18, 489; Arsenijevic et al., 1989, Endocrinology 124, 3050).
  • the antiserum was tested for rat GHRH- binding capacity with l25 1-labelled rat GHRH. The antiserum dilution required to bind 30% of the tracer was approximately 1 :30.000.
  • the antiserum showed that it was directed toward the GHRH carboxyl terminal. It cross-reacted with synthetic human, bovine and porcine GHRH by less than 4%, and the dose-response curves were not paralleled with rat GHRH. The antiserum did not cross-react with peptides that have considerable sequence homology with GHRH, including secretin, glucagon, vasoactive intestinal peptide, gastrin motilin, bradykinin and angiotensin.
  • Rats were treated every other day by s.c. administration of the anti-GHRH serum (250 ⁇ l/rat) or isovolumetric amounts of normal rabbit serum from postnatal day 20 to 40.
  • a group of anti-GHRH serum treated rats was given in addition hexarelin (80 ⁇ g/kg s.c, bid) from postnatal day 25 to 40 (15 days).
  • hexarelin 80 ⁇ g/kg s.c, bid
  • rats were killed by decapitation. Pituitaries were removed, immediately frozen on dry ice, and stored at -20°C until used. Blood was collected into EDTA-containing tubes and plasma was separated and stored at -20 °C for insulin-like growth factor I (IGF-I) determination.
  • IGF-I insulin-like growth factor I
  • SSC saline sodium citrate
  • Filters were hybridised with a rat GH cDNA sequence (13 and 15) labelled by the Multiprime DNA labelling system with ⁇ [ 32 P] dCTP to a specific activity of lxl 0 9 dpm/ ⁇ g DNA. Hybridisation conditions were as previously reported (13 and 15). Quantification of the hybridisation signal was performed on a scanning densitometer (LKB XL Laser Densitometer, LKB, Uppsala, Sweden). Pituitary GH mRNA levels were expressed as percent value of normal rabbit serum-treated rats.
  • Plasma IGF-I levels were evaluated by a homologous radioimmunoassay in plasma extracted with 12.5% of 2N HCI plus 87.5% ethanol using reagents provided by the National Hormone and Pituitary Program (NHOP). The sensitivity of the assay was 100 pg/ml; intra- and interassay variation was less than 10%. The IGF-I plasma levels of 10 rats for each experimental group were determined.
  • the hearts from the three experimental groups were rapidly removed and perfused retrogradely through the aorta with Krebs-Henseleit solution (37°C) of the following composition (in mM): NaCl 118, KCI 1.2, CaCl 2 2.5, MgSO 4 1.2, NaHC0 3 25 and glucose 5.5.
  • the solution was gassed with a mixture of 95% 0 2 + 5% C0 2 and, after a 30 min equilibration period, the pH of the heart perfusate was 7.4.
  • Left ventricular pressure (LVP) was measured by a polyethylene catheter (with a small latex balloon on the top) inserted in the left ventricie cavity.
  • LVEDP left ventricular end-diastolic pressure
  • CPP Coronary perfusion pressure
  • LVP were monitored with Statham transducers (HP-1280C) connected to a Hewlett-Packard (Waltham, MA, USA) dynograph (HP-7754A).
  • the hearts were electrically paced at a frequency of 300 beats/min with rectangular impulses (1 ms duratio; voltage 10% above threshold) by a Grass stimulator (mod. S-88; Grass Instr., Quincy, MA, USA).
  • the perfusion rate of each heart was adjusted to yield a CPP of 55-60 mmHg with a flow rate of 12 ml/min.
  • Ischemia was induced by reducing the coronary flow to 2 ml/min with a perfusion pressure of 4-6 mmHg.
  • Each heart was reperfused 40 min after the onset of ischemia at the preischemic flow rate (12 ml/min) for another period of 20 min.
  • the vasopressor activity of angiotensin II (1 ⁇ g injected as a bolus in the perfusion system) was regularly recorded at the beginning of each experiment.
  • Prostacyclin (PGI 2 ) generation was measured in the heart perfusates as 6-Keto- PGF l ⁇ , according to the enzyme immunoassay previously described by (18). Particularly, the concentration of this eicosanoid was determined collecting the heart perfusates for 5 min immediately before flow reduction and during the first 10 min of reperfusion.
  • pituitary GH mRNA and plasma IGF-I levels were reduced of 51.2% (P ⁇ 0.01) and 43.5% (PO.01) respectively in GH-deficient rats as compared to normal rabbit serum-treated animals.
  • Administration of hexarelin to anti-GHRH serum-treated rats restored both pituitary GH mRNA and plasma IGF- I at the level of control animals.
  • bolus injections of angiotensin-II (1 ⁇ g) in the perfusion system of hearts excised from GH-deficient rats induced a vasopressor activity which was markedly increased (291%; PO.001) as compared with control hearts.
  • Fig. 1 Cardiac function during moderate ischemia and reperfusion in isovolumic left heart preparations of the rat electrically driven.
  • NRS the heart was excised from a rat treated with normal rabbit serum (control);
  • GHRH-Ab the heart was excised from a rat treated with anti-GHRH senim (GH- deficient);
  • GHRH-Ab +HEXA the heart was excised from a rat treated with antiGHRH serum + hexarelin.
  • angiotensin II All was injected as a bolus (1 ⁇ g) in the perfusion system.
  • LVP left ventricular pressure
  • CPP coronary perfusion pressure
  • LV dP/dt, nax first derivative of LVP.
  • LVEDP left ventricular end- diastolic pressure
  • CPP coronary perfusion pressure
  • the AUC was evaluated by the trapezoid method: in ordinate, LVEDP in mmHg; in abscissa, time from 0 to 60 min.
  • Left ventricular developed pressure (LVDP peak left ventricular systolic pressure minus LVEDP) in isovolumic left heart preparations of the rat electrically paced. Each point of the curve is the mean value of 10 experiments and vertical bars S.E.M. The legend as in Fig. 1.
  • the AUC was evaluated by the trapezoid method: in ordinate, LVEDP in mmHg; in abscissa, time from 40 to 60 min.
  • Fig. 4 Rate of formation of 6-Keto-PGF, ⁇ in isovolumic left heart preparations of the rat electrically paced.
  • the legend as in Fig. 1. Perfusates were collected for 5 min before reduction of the flow rate (ischemia) and during the first 10 min of reperfusion. Each columns represent the mean values of 10 hearts and vertical bars S.E.M. a PO.01 versus NRS and GHRH-Ab + HEXA.
  • Fig. 5 Vasopressor activity of angiotensin II (1 ⁇ g bolus) injected in the perfusion system of isovolumic left heart preparations of the rat electrically paced.
  • CPP coronary perfusion pressure during the preischemic period. a PO.001 versus NRS and GHRH-Ab + HEXA.
  • Example 1 Discussion of Example 1.
  • rats passively immunised against GHRH a suitable model of selective GH deficiency (12; Shakutsui et al., 1989: Acta Paediat. Scand. Suppl. 349, 101; 13 and 15 ), exhibited clear signs of cardiac dysfunction, consisting of an exacerbation of ischemic tissue damage during low- flow ischemia and reperfusion, with increased coronary artery resistance upon reperfusion. These heart abnormalities were reverted to normal by "ex vivo" replacement therapy with GH (4).
  • the anti-GHRH serum-treated rats used were truly GH-deficient as shown by decreased growth rate, pituitary GH mRNA and plasma IGF-1 levels, all features reported in previous studies (Arsenijevic et al., 1989, Endocrinology 124, 3050; ; Shakutsui et al., 1989: Acta Paediat. Scand. Suppl. 349, 101; 17).
  • somatotropic function was restored by hexarelin replacement as proved by normalisation of all biological markers investigated.
  • Restoration of GH mRNA levels in anti-GHRH serum young adult male rats at the same doses used in these experiments was already reported by Torsello, A., M.
  • end-diastolic pressure (LVEDP) during the ischemic period and a poor recovery of mechanical activity at reperfusion with a significative decrease of the left ventricular (LV)-developed pressure as compared to control hearts; 2) a decreased rate of formation of 6-Keto-PGF, ⁇ , the stable metabolite of prostacyclin, in perfusates of both preischemic and reperfusion periods; 3) an increased vasopressor activity of angiotensin II on the coronary vasculature.
  • Hexarelin 80 ⁇ g/kg, bid, sc), administered for 15 days (from 25"' postnatal day) to GHRH-Ab- treated rats reversed these signs of cardiac dysfunction.
  • Each figure is a mean value ⁇ S.E.M. of 10 determinations.
  • NRS rats treated with normal rabbit serum
  • GHRH-Ab rats treated with anti- GHRH serum a PO.01 versus NRS and GHM-Ab + HEXARELIN Table 2. Markers of somatotropic function of young male rats of 41 days of age.
  • Figures related to GH mRNA are the mean values ⁇ S.E.M. of 5 determinations.
  • Figures related to plasma IGF-I are the mean values ⁇ S.E.M. of 10 determinations.
  • Hexarelin His-D-2-Me-Trp-Ala-Trp-D-Phe-Lys-NH 2
  • GH GH were given to rats at the dose of 80 ⁇ g/kg and 0.4 ⁇ g/g bid respectively, for 21 days.
  • the dose of hexarelin or GH was chosen on the basis of previous results showing their adequacy to restore somatotropic function in neuroendocrine (12, 13) and cardiovascular studies (4). Animals were killed by cervical dislocation 14 h after the last injection. Pituitaries were removed, immediately frozen on dry ice and stored at -20°C until used for determination of GH mRNA levels. Blood was collected into EDTA-containing tubes and plasma was separated and stored at - 20°C for IGF-I determination. The hearts were isolated and used for ischemia and reperfusion experiments.
  • the membranes were hybridized with a rat cDNA sequence (13,15) labeled by random primer with [ ⁇ - 32 P] dCTP to a specific activity of 10 9 dpm/ ⁇ g DNA. Hybridization conditions were as previously reported (13, 15). Quantification of the hybridization signal was performed on a scanning densitometer (LKB XL Laser Densitometer, LKB, Uppsala, Sweden). Pituitary GH mRNA levels were expressed as percentage of controls values.
  • Plasma IGF-I levels were evaluated by a homologous radioimmunoassay in plasma after acid-ethanol extraction according to the method described by Daughaday (16).
  • the reagents were provided by the National Hormone and Pituitary Program.
  • the sensitivity of the assay was 100 pg/ml; intra- and inter- assay variation was less than 10%.
  • the IGF-I plasma levels of 6-10 rats for each experimental group were determined and expressed in ng/ml.
  • the perfusion medium contained (in mM): NaCl 118, KC1 2.8, KH 2 PO ⁇ 1.2, CaCl, 2.5, MgSO 4 1.2, NaHCO 3 25 and glucose 5.5. After a period of equilibration with 5% C0 2 and 95% O 2 gas mixture, the pH of the perfusate was 7.35 and the perfusion was maintained at 15 ml/min with a roller pump (Minipuls 3, Gilson V Amsterdam, le Bel, France).
  • LVP left ventricular pressure
  • CPP coronary perfusion pressure
  • the hearts were electrically paced at the frequency of 300 beats/min with rectangular impulses (1 msec duration, voltage 10% above threshold) by a Grass stimulator (model S-88, Grass Instruments, Quincy, Mass, USA).
  • a moderate ischemia was induced by global reduction of the perfusion flow to 1 ml/min for a period of 20 min.
  • a normal flow rate (15 ml/min) was then restored and reperfusion continued for 30 min.
  • Prostacyclin (PGL) generation by the cardiac tissues was measured in heart perfusates as 6-keto-PGF , consequent according to the enzyme immunoassay method (detection limit 0.05 ng/ml) of Pradelles et al. (18). The concentration of this stable metabolite was determined collecting the perfusates for 5 min immediately before flow reduction and during the first 10 min of reperfusion. The rate of formation of 6-keto-PGF lu was expressed in ng/min.
  • the perfusate was collected every 150 sec in an ice-cooled beaker before flow reduction and during reperfusion and the activity of creatine kinase
  • CPP was increased of 65% (PO.01) over the basal values at the beginning of reperfusion and was still markedly elevated after 30 min (46% increase; PO.01) (Fig. 7).
  • results were also reflected by a marked increase of CK in the effluent (433% over basal values; PO.001), peaking between 8 and 15 min of reperfusion, and still evident at 30 min (109% increase; PO.01) (Fig. 8).
  • Fig. 6 Left ventricular pressure (LVP) during postischemic reperfusion in heart preparations from saline- or hexarelin-treated rats.
  • the area under the curve (AUC) related to LVDP are: a, 765 ⁇ 46; b, 1 147 ⁇ 88; c, 2272 ⁇ 66.
  • the AUC related to CPP (increase in mmHg over the pre-schemic values ) are: a, 1284 ⁇ 79; b, 1008 ⁇ 47; c, 235 ⁇ 35.
  • AUC was estimated according the trapezoid method: in ordinate, LVDP or CPP in mmHg; in abscissa, time from 20 to 50 min.
  • the area under the curve (AUC) related to CK release during reperfusion are: a, 4454 ⁇ 352; b, 3520 ⁇ 278; c, 278 ⁇ 56.
  • Fig. 9 Rate of release of 6-keto-PGF l ⁇ in perfusates of isovolumic left heart preparations from old-rats of the three experimental groups. Columns represent mean values and vertical bars standard error of the mean. Perfusates were collected during preischemia (5 min) and reperfusion (first 10 min). Values obtained during preischemia are statistically different from those of reperfusion: PO.001.
  • Myocardial ischemia defined as an imbalance between fractional uptake of oxygen and the rate of cellular oxidation, may have several potential outcomes, especially in senescent hearts which are the ones more prone to this pathological event. Under these circumstances, when ischemia is brief, a transient postischemic ventricular dysfunction may occur and this condition (stunning) reflects many disturbances of cardiomyocytes and insufficient cellular antioxidant activity (2, 20). In the present model of ischemia-reperfusion in hearts from old rats chronically treated with hexarelin, a considerable protection against mechanical stunning was achieved. It is noteworthy that complete recovery of left ventricular function was present upon reperfusion. Simultaneous blunting of the release of CK in the heart effluents underlined the integrity of myocardial cell membranes and the preservation from the contractile impairment which follows oxygen readmission.
  • a high vulnerability to moderate ischemia in senescent rat hearts is supported by the increased calcium regulating protein gene expression associated with a strong impairment of contractile function (26).
  • hexarelin very likely through a mechanism divorced from its GH-releasing effect, strikingly reduces the reperfusion injury in isolated hearts from senescent rats.
  • the protective effect of hexarelin which under our experimental conditions, overrides that exhibited by GH, opens new perspectives in the therapy of postischemic heart dysfunction in the elderly.
  • This subject is of increasing interest since the aged population is continuously growing and is becoming one of the major target of pharmacology; moreover, cardiac diseases are the first cause of mortality after 65 years of age (37).
  • hexarelin a recently synthetized hexapeptide with a strong growth hormone (GH)-releasing activity, or of GH itself to display a protectant activity against post-ischemic ventricular dysfunction in senescent hearts was studied in 24-month-old male rats.
  • LVDP post-ischemic left ventricular developed pressure
  • CPP coronary perfusion pressure
  • CK creatine kinase
  • the protection afforded by the peptide is likely due to a direct cardiotropic action and is far greater than that of GH. Either compound does not appear capable to interfere with the endothelium-dependent relaxant mechanism.
  • Table 3 Body and heart weights and markers of somatotropic function of 24-month-old male rats treated with hexarelin (HEXA) or growth hormone (GH).
  • Data are mean values ⁇ standard error of the mean. In brackets the number of rats. Drugs were given subcutaneously twice a day for 21 days.
  • GH growth hormone
  • ACTH Adrenocorticotropic hormone
  • Merola B Cittadini A, Colao A. Longobardi S, Fazio S, Sabatini D, Sacca L, Lombardi G. Cardiac structural and functional abnormalities in adult patients with growth hormone deficiency. J Clin Endocrinol Me tab 1993;77: 1658-61.

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Abstract

L'invention concerne l'utilisation d'un composé sécrétagogue de l'hormone de croissance ou de l'hormone de croissance et d'un composé sécrétagogue de l'hormone adrénocorticotrope, pour la fabrication d'un médicament pour le traitement de la défaillance cardiaque ou d'un dysfonctionnement vasculaire apparenté.
PCT/SE1997/001957 1996-11-22 1997-11-21 Utilisation d'un compose secretagogue de l'hormone de croissance pour le traitement de la defaillance cardiaque ou d'un dysfonctionnement vasculaire apparente Ceased WO1998022124A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU51424/98A AU5142498A (en) 1996-11-22 1997-11-21 Use of growth hormone secretagogue compound for treating cardiac failure or related vascular dysfunction

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Application Number Priority Date Filing Date Title
SE9604300-5 1996-11-22
SE9604300A SE9604300D0 (sv) 1996-11-22 1996-11-22 Therapeutical use and method
SE9703929A SE9703929D0 (sv) 1996-11-22 1997-10-28 Therapeutical use and method
SE9703929-1 1997-10-28

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Cited By (13)

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US5932548A (en) * 1998-06-03 1999-08-03 Deghenghi; Romano Lysine containing peptides for treatment of heart disease
US6025471A (en) * 1998-06-03 2000-02-15 Deghenghi; Romano Diazaspiro, azepino and azabicyclo therapeutic peptides
EP1143998A4 (fr) * 1998-11-26 2002-06-26 Auckland Uniservices Ltd Traitement de l'hypertension
WO2002053167A3 (fr) * 2001-01-03 2002-11-14 Ct Ingenieria Genetica Biotech Combinaison pharmaceutique pour le traitement des dommages tissulaires dus au defaut d'irrigation arterielle
EP0898963A3 (fr) * 1997-08-19 2003-07-09 Eli Lilly And Company Traitement de l'insuffisance cardiaque congestive
WO2004014412A1 (fr) * 2002-08-09 2004-02-19 Kaken Pharmaceutical Co., Ltd. Agent de protection des cellules myocardiques
WO2004017986A1 (fr) * 2002-08-23 2004-03-04 Valorisation-Recherche, Societe En Commandite Peptides liberant l'hormone de croissance pour le traitement ou la prevention de l'atherosclerose et de l'hypercholesterolemie
US6878689B2 (en) 2000-06-23 2005-04-12 Kaken Pharmaceutical Co., Ltd. Preventives or remedies for heart failure
WO2005039625A1 (fr) * 2003-10-28 2005-05-06 Rheoscience A/S Agonistes du recepteur des secretagogues de l'hormone de croissance
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
WO2013190520A3 (fr) * 2012-06-22 2014-02-27 The General Hospital Corporation Agents de libération de gh dans le traitement d'une sténose vasculaire et d'états associés

Citations (1)

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US5932548A (en) * 1998-06-03 1999-08-03 Deghenghi; Romano Lysine containing peptides for treatment of heart disease
WO1999062539A1 (fr) * 1998-06-03 1999-12-09 Romano Deghenghi Peptides contenant de la lysine pour le traitement des troubles cardiaques
US6025471A (en) * 1998-06-03 2000-02-15 Deghenghi; Romano Diazaspiro, azepino and azabicyclo therapeutic peptides
JP2002516872A (ja) * 1998-06-03 2002-06-11 デゲンギ，ロマノ 心疾患の治療のためのリシン含有ペプチド
EP1616571A3 (fr) * 1998-06-03 2008-08-13 Ardana Bioscience Limited Peptides contenant de la lysine pour le traitement des maladies cardiaques
EP1143998A4 (fr) * 1998-11-26 2002-06-26 Auckland Uniservices Ltd Traitement de l'hypertension
JP2002530306A (ja) * 1998-11-26 2002-09-17 オークランド ユニサーヴィスィズ リミテッド 高血圧の治療
US6878689B2 (en) 2000-06-23 2005-04-12 Kaken Pharmaceutical Co., Ltd. Preventives or remedies for heart failure
US7361638B2 (en) 2001-01-03 2008-04-22 Centro De Ingenieria Genetica Y Biotecnologia Pharmaceutical combination for the treatment of tissue damage owing to an arterial irrigation defect
WO2002053167A3 (fr) * 2001-01-03 2002-11-14 Ct Ingenieria Genetica Biotech Combinaison pharmaceutique pour le traitement des dommages tissulaires dus au defaut d'irrigation arterielle
WO2004014412A1 (fr) * 2002-08-09 2004-02-19 Kaken Pharmaceutical Co., Ltd. Agent de protection des cellules myocardiques
WO2004017986A1 (fr) * 2002-08-23 2004-03-04 Valorisation-Recherche, Societe En Commandite Peptides liberant l'hormone de croissance pour le traitement ou la prevention de l'atherosclerose et de l'hypercholesterolemie
US7785567B2 (en) 2002-08-23 2010-08-31 Valorisation-Recherche, Société en Commandite Growth hormone-releasing peptides in the treatment or prevention of atherosclerosis and hypercholesterolemia
WO2005039625A1 (fr) * 2003-10-28 2005-05-06 Rheoscience A/S Agonistes du recepteur des secretagogues de l'hormone de croissance
EP2457925A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Procédé pour la préparation d'un modulateur macrocyclique du récepteur de ghréline et intermédiaires
EP2457893A1 (fr) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermédiaires pour des modulateurs macrocycliques du récepteur de ghréline
WO2007098716A1 (fr) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Composés analogues aux sécrétagogues peptidiques de l'hormone de croissance et préparations contenant ceux-ci
EP2644618A1 (fr) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. Intermédaires dans la synthese de modulateurs macrocycliques du récepteur de la ghréline
WO2013190520A3 (fr) * 2012-06-22 2014-02-27 The General Hospital Corporation Agents de libération de gh dans le traitement d'une sténose vasculaire et d'états associés

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