WO2000067770A1 - Treatment of acute myocardial infarction with a substance related to the growth hormone axis - Google Patents
Treatment of acute myocardial infarction with a substance related to the growth hormone axis Download PDFInfo
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- WO2000067770A1 WO2000067770A1 PCT/SE2000/000844 SE0000844W WO0067770A1 WO 2000067770 A1 WO2000067770 A1 WO 2000067770A1 SE 0000844 W SE0000844 W SE 0000844W WO 0067770 A1 WO0067770 A1 WO 0067770A1
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- Prior art keywords
- growth hormone
- substance
- treatment
- ischemic event
- functionally equivalent
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Classifications
-
- 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
- A61K38/30—Insulin-like growth factors, i.e. somatomedins, e.g. IGF-1, IGF-2
-
- 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
-
- 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
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Definitions
- Ischemic heart disease is the most common cause of death in both men and women in the Western world. Some of the clinical manifestations are angina pectoris, myocardial infarction, congestive heart failure (CHF) and sudden death. Despite marked improvements in the treatment including beta-blockers, trombolysis and PTCA, mortality of patients with acute myocardial infarction (MI) is still very high and almost 50% of patients surviving MI eventually develop CHF. Cardiac changes developing after MI include left ventricular dilatation and hypertrophy of the residual non-infarcted myocardium also known as remodeling. Moreover, contractile impairment often occurs after MI, clinically manifested as CHF.
- MI myocardial infarction
- a lowering of arterial blood pressure peripheral resistance by GH may also be beneficial for hemodynamics (see Caidahl K. et al . , Cardiovascular and renal effects of growth hormone, Clin. Endocrinol . (Oxf) 1994; 40:393-400; Jin H., et al . , Beneficial effects of growth hormone and insulin-like factor-1 in experimental heart failure in rats treated with chronic ACE inhibition, J. Cardiovasc . Pharmacol. 1995; 26:420-425). It may be speculated that this effect is more rapid and could be an important factor in studies demonstrating acute cardiovascular effects of GH (see Volterrani M., et al . Hemodynamic effects of intravenous growth hormone in congestive heart failure, Lancet 1997; 349:1067-1068).
- Insulin-like growth factor I stimulates myofibril development and decreases smooth muscle I -actin of adult cardiomyocytes, Proc. Natl. Acad. Sci . USA 1994; 91:1686-1690) and increases isometric force and free cytosolic Ca 2+ (see Freestone N. S., et al . , The effect of insulin-like growth factor- 1 on adult rat cardiac contractility, Molecular and Cellular Biochemistry 1996; 163/164:223-229).
- Apoptosis or programmed cell death, has been reported to occur in the myocardium of patients both after ischemic injury (see Saraste A., et al . , Apoptosis in human acute myocardial infarction, Circulation 1997; 95:320-323) and in conditions with dilated cardiomyopathy (see Narula J. , et al . , Apoptosis in myocytes in end- stage heart failure, N. Engl. J. Med. 1996; 335-1182- 1189) .
- Some of the genes involved in the apoptotic process have been identified including the Fas-receptor which has been shown to mediate signals for apoptosis (see Itoh N.
- Fas-receptor Upregulation of the Fas-receptor has been shown to be associated with apoptosis after myocardial infarction in rats (see Kajstura J., et al . , Apoptotic and necrotic myocyte cell deaths are independent contributing variables of infarct size in rats, Lab. Invest. 1996; 74:86-107).
- a possible mechanism contributing to the deterioration of heart function post MI may be altered energy metabolism and a reduction of energy reserve which have been observed in rats with experimental MI (see Neubauer S., et al . , Impairment of energy metabolism in intact residual myocardium of rat heart with chronic myocardial infarction, J. Clinical Invest. 1995; 95:1092-1100). However, until now the potential effects of GH on myocardial energy stores have not been evaluated.
- the invention thus relates to the use of a substance related to the growth hormone axis, or of a combination of two or more such substances, for the production of a pharmaceutical preparation for treatment of an acute ischemic event.
- the pharmaceutical preparation according to the invention should thus be administered to a patient shortly after the ischemic event first has occurred, and the sooner the better.
- the invention also relates to a method for treatment of an acute ischemic event, wherein a therapeutically active amount of a substance related to the growth hormone axis is administered to a patient, preferably within a short period of time from the first manifestation of the ischemic event.
- the invention relates to the use of substances related to the growth hormone axis.
- substance related to the growth hormone axis relates to all substances related to, linked to or involved in the sequence of successive activation reactions wherein GH is involved, comprising GH it self, hormones from the hypothalamus affecting GH and hormones or growth factors affected by GH.
- Preferred examples of such substances are growth hormone (GH) , growth hormone secreta- gogues (GHSs) , or insulin like growth factor I (IGF-I) .
- GH growth hormone
- GHSs growth hormone secreta- gogues
- IGF-I insulin like growth factor I
- GH or an analogue thereof is especially preferred.
- the growth hormone (GH) used according to the invention is preferably human growth hormone. It is possible to use both naturally derived GH and synthetically produced GH.
- a growth hormone secretagogue is a substance that stimulates secretion of GH. According to the invention it is possible to use both naturally derived GHSs and synthetically produced GH. Furthermore, the GHS used may be either a peptidic or a non-peptidic substance.
- a peptidic GHS suitable for use according to the present invention is growth hormone release peptide (GHRP) , which is a substance that leads to increased secretion of GH.
- the insulin like growth factor I (IGF-I) used according to the invention is preferably human IGF-I. It is possible to use both naturally derived IGF-I and synthetically produced IGF-I.
- the pharmaceutical preparation produced according to the invention and the method according to the invention are suitable for treatment of ischemic events.
- Ischemic event is a term describing a condition with a relative shortage of oxygen supply to the myocardium manifested e.g. as angina pectoris, myocardial infarction, contractile dysfunction, arrythmia, fatigue, decreased exercise performance and breathlessness.
- the pharmaceutical preparation and the method according to invention are intended for treatment of acute ischemic events such as acute myocardial infarctions, angina pectoris and sudden cardiac decompensation.
- patient relates to any human or non-human mammal in need of treatment according to the invention.
- treatment used herein relates to measures taken in order to cure or alleviate a disease or a condition.
- a "therapeutically active amount" of the substance is used. This expression relates to a dose of the substance that will lead to the desired pharmacological effect.
- the desired pharmacological effect is, as stated above, to improve the systolic function by improving the myocardial energy handling.
- the pharmaceutical preparation according to the invention may also comprise other substances, such as an inert vehicle, or pharmaceutical acceptable adjuvants, carriers, preservatives etc., which are well known to persons skilled in the art.
- Fig. 1 is a diagram illustrating the creatine phosphate to ATP ratio measured with 31 P-MRS in MI rats treated with rhGH; the values are mean ⁇ SEM, **p ⁇ 0.01 compared to effect of saline treatment;
- Fig. 2 is a diagram illustrating the fractional shortening measured with echocardiography in MI rats treated with rhGH; the values are mean ⁇ SEM, **p ⁇ 0.01 compared to effect of saline treatment.
- MI myocardial infarction
- the rats were anesthetized with ketamine hydrochloride 100 mg/kg (Parke-Davis, Morris Plains, NJ, USA) and xylazine hydrochloride (Bayer AG, Leverkusen, Germany) 10 mg/kg i.p., intubated and connected to a respirator for artificial ventilation with room air and oxygen using a Carlsson ventilator (Astra-Hassle, Goteborg, Sweden) . A 2.5 cm long parasternal incision was made in the left thoracic area to the skeletal muscle. The muscle layers were separated with minimal damage using blunt dissection. Left thoracotomy was than performed between the fourth and fifth ribs, exposing the left ventricular wall .
- ECHO Transthoracal echocardiography
- Pulsed wave Doppler spectra of mitral inflow from the apical four- chamber view were used to asses LV diastolic flow characteristics. Stroke volume (SV) was calculated using Doppler recording from the pulmonary artery (as described by Baily R. G. , et al . in Non- invasive assessment of ventricular damage in rats with myocardial infarction, Car- diovasc . Res. 1993; 27: 851-855). All investigations were stored as cine- loop pictures, M-mode tracings and Doppler spectra on optical disc for off-line analysis. All measurements were averaged at least on 3 consecutive cardiac cycle using EchoPac 5.4 off-line analysis system (GE Ving Med, USA) .
- EchoPac 5.4 off-line analysis system GE Ving Med, USA
- WS Left ventricular meridional wall-stress
- P is the systolic blood pressure
- Am is the myocardial area determined by subtraction of the LV cavity area (Ac) from the total LV area and 1.33 is conversion constant from millimeters of mercury to dynes/cm 2 . Echocardiographic estimation of infarct size
- the size of MI was estimated according to the score system as described by Baily R. G. (supra) .
- the left ventricle was arbitrary divided into 4 regions in LAX and SAX.
- Each of the segments in parasternal LAX and SAX views was assigned a point for the presence of akinesis and/or dyskinesis. Additional point was assigned for the presence of LV dilatation on the M-mode tracing. Dilatation was defined as 15% more than the average of the left ventricular internal diameter (LVDd) in end diastole of the control group.
- a myocardial infarction was considered to be small if the total score was 1-2 points, moderate if 3 or 4 and large if > 5 points.
- MI > 1/3 of LV is associated with progressive LV remodeling and hemodynamic abnormalities characteristic for heart failure while MI ⁇ 1/3 of LV or nontransmural infarcts do not consistently cause this changes (see Pfeffer M. A., et al . , Myocardial infarct size and ventricular function in rats, Circ. Res. 1979; 44:503-512).
- the inclusion criteria for rats with MI were that > 1/3 of the LV circumference was showing signs of irreversible ischemia.
- MR imaging and volume-selective cardiac 31 P-MRS were performed on a 2.35 Tesla (T) horizontal magnet with a 20 cm bore (Bruker Biospec 24/30) according to the method previously described by our laboratory.
- the magnetic field homogeneity was optimized until line width of the water 1 H-signal at half height was ⁇ 0.5 ppm.
- a surface coil of 5 cm diameter dual tuned ( 1 H and 31 P) was used for radio frequency transmission and reception.
- Rats were given induction anesthesia with fenta- nyl/fluanizon (Hypnorm, Janssen) 0.5 mg/kg and diazepam (Stesolid) 2.5 mg/kg. Constant body temperature (36.5 ⁇ 0.5C°) was maintained by specially adapted homeothermic blanket system (Harvard Apparatus) . The animals were placed with heart region lying on the surface coil in prone position to minimize respiratory movements of the chest wall. The paws were wrapped in thin copper foil and connected via carbon electrodes to the Physiogard SM 785 MR monitoring system (Bruker, Düsseldorf, Germany) . Continuous ECG signal was then acquired and used for synchronization of RF pulses and monitoring of HR. The animals were maintained anaesthetized by continuous gas anesthesia with isoflurane delivered in the mixture of oxygen and nitrous oxide (1:1) in the concentration 0.4-1 % and at flow rate 0.4 1/min.
- a gradient echo imaging method was used for visualization of the heart and selection of VOI for 31 P-MRS. All images as well as spectroscopic data acquisition were obtained with synchronized RF pulses to the cardiac rhythm with triggering delay of 1 ms after the R wave. Five images (2.5 mm slice thickness and field of view of 8 cm) were acquired in the sagittal plane in order to visualize the thoraco-abdominal region and the heart. Starting from the scout image in the sagittal plane 5 additional (2.5 mm) images were taken perpendicular on the LV long axis. Image selected in vivo spectroscopy (ISIS) (see Ordridge R. J., et al .
- ISIS Image-Selected In vivo Spectroscopy
- Accumulation parameters were 512 scans, 4k data points and 2500 Hz sweep width with a 4.5 s repetition time giving the total scan time 38 min.
- Spectroscopic processing consisted of Fourier transformation followed by first order phase correction, Lorenzian curve fitting and integration of PCr, ⁇ -ATP, 2,3-DPG + and Pi peaks.
- Phosphocreatine, ATP, and 2,3-DPG were calculated by computer integration of the areas under the respective peaks.
- Myocardial PCr/ATP ratio was corrected for partial saturation for each animal separately by use of the correction factor calculated from PCr/ATP measured from unlocalized spectra of the chest region acquired at 4.5 s and 15 s repetition time (see Bottomley P.
- FS fractional shortening
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Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| AU47908/00A AU4790800A (en) | 1999-05-05 | 2000-05-03 | Treatment of acute myocardial infarction with a substance related to the growth hormone axis |
| EP00930008A EP1173190A1 (en) | 1999-05-05 | 2000-05-03 | Treatment of acute myocardial infarction with a substance related to the growth hormone axis |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE9901634-7 | 1999-05-05 | ||
| SE9901634A SE9901634D0 (sv) | 1999-05-05 | 1999-05-05 | Treatment of myocardial infarction with a substance related to the growth hormone axis |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2000067770A1 true WO2000067770A1 (en) | 2000-11-16 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/SE2000/000844 WO2000067770A1 (en) | 1999-05-05 | 2000-05-03 | Treatment of acute myocardial infarction with a substance related to the growth hormone axis |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP1173190A1 (sv) |
| AU (1) | AU4790800A (sv) |
| SE (1) | SE9901634D0 (sv) |
| WO (1) | WO2000067770A1 (sv) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004017986A1 (en) * | 2002-08-23 | 2004-03-04 | Valorisation-Recherche, Societe En Commandite | Growth hormone-releasing peptides in the treatment of prevention of atherosclerosis and hypercholesterolemia |
| EP1529533A1 (en) * | 2003-11-06 | 2005-05-11 | Sahltech I Göteborg AB | Use of GH secretagogues in hypoxic-ischemic brain injury |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992011865A1 (en) * | 1991-01-11 | 1992-07-23 | Kabi Pharmacia Ab | Use of human igf-i |
| WO1995028174A1 (en) * | 1994-04-15 | 1995-10-26 | Genentech, Inc. | The combination of growth hormone and insulin-like growth factor, for treating congestive heart failure |
| WO1999001151A1 (en) * | 1997-07-04 | 1999-01-14 | Pharmacia & Upjohn Ab | Use of growth hormone in compositions for treating insulin resistance in the heart and for enhancing protein kinase b (pkb) activity |
-
1999
- 1999-05-05 SE SE9901634A patent/SE9901634D0/sv unknown
-
2000
- 2000-05-03 WO PCT/SE2000/000844 patent/WO2000067770A1/en not_active Application Discontinuation
- 2000-05-03 EP EP00930008A patent/EP1173190A1/en not_active Withdrawn
- 2000-05-03 AU AU47908/00A patent/AU4790800A/en not_active Abandoned
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1992011865A1 (en) * | 1991-01-11 | 1992-07-23 | Kabi Pharmacia Ab | Use of human igf-i |
| WO1995028174A1 (en) * | 1994-04-15 | 1995-10-26 | Genentech, Inc. | The combination of growth hormone and insulin-like growth factor, for treating congestive heart failure |
| WO1999001151A1 (en) * | 1997-07-04 | 1999-01-14 | Pharmacia & Upjohn Ab | Use of growth hormone in compositions for treating insulin resistance in the heart and for enhancing protein kinase b (pkb) activity |
Non-Patent Citations (6)
| Title |
|---|
| CITTADINI A. ET AL.: "Growth hormone and the heart", MINER. ELECTROLYT. METAB., vol. 25, no. 1-2, 1999, pages 51 - 55, XP002931983 * |
| H.E. CASTAGNINO ET AL.: "Preservation of the myocardial collagen framework by human growth hormone in experimental infarctions and reduction in the incidence of ventricularaneurysms", INTERNATIONAL JOURNAL OF CARDIOLOGY, vol. 35, 1992, pages 101 - 114, XP002931985 * |
| HO K.K. ET AL.: "Metabolic actions of growth hormone in man", ENDOCR. J., vol. 43 (SUPPL), October 1996 (1996-10-01), pages S57 - S63, XP002931984 * |
| HUGO E. CASTAGNINO: "Great expectations from a different approach to the treatment of acute myocardial infarction: cytoprotection", INTERNATIONAL JOURNAL OF CARDIOLOGY, vol. 69, 1999, pages 15 - 18, XP002931986 * |
| ISGAARD J. ET AL.: "The role of the GH/IGF-I axis for cardiac function and structure", HORM. METAB. RES., vol. 31, no. 2-3, 1999, pages 50 - 54, XP002931982 * |
| M. SCHWEINOWITZ ET AL.: "The role of insulin-like and basic fibroblasts growth factors on ischemic and infarcted myocardium: a mini review", INTERNATIONAL JOURNAL OF CARDIOLOGY, vol. 59, 1997, pages 1 - 5, XP002931981 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2004017986A1 (en) * | 2002-08-23 | 2004-03-04 | Valorisation-Recherche, Societe En Commandite | Growth hormone-releasing peptides in the treatment of prevention of atherosclerosis and hypercholesterolemia |
| 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 |
| EP1529533A1 (en) * | 2003-11-06 | 2005-05-11 | Sahltech I Göteborg AB | Use of GH secretagogues in hypoxic-ischemic brain injury |
Also Published As
| Publication number | Publication date |
|---|---|
| SE9901634D0 (sv) | 1999-05-05 |
| AU4790800A (en) | 2000-11-21 |
| EP1173190A1 (en) | 2002-01-23 |
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