MXPA00009416A - Treatment of cardiac hypertrophy - Google Patents
Treatment of cardiac hypertrophyInfo
- Publication number
- MXPA00009416A MXPA00009416A MXPA/A/2000/009416A MXPA00009416A MXPA00009416A MX PA00009416 A MXPA00009416 A MX PA00009416A MX PA00009416 A MXPA00009416 A MX PA00009416A MX PA00009416 A MXPA00009416 A MX PA00009416A
- Authority
- MX
- Mexico
- Prior art keywords
- ifn
- cardiac hypertrophy
- treatment
- cardiac
- hypertrophy
- Prior art date
Links
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Abstract
The invention concerns the treatment of cardiac hypertrophy by interferon-gamma (IFN-&ggr;). Cardiac hypertrophy may result from a variety of diverse pathologic conditions, including myocardial infarction, hypertension, hypertrophic cardiomyopathy, and valvular regurgitation. The treatment extends to all stages of the progression of cardiac hypertrophy, with or without structural damage of the heart muscle, regardless of the underlying cardiac disorder.
Description
THE USE OF IMIERFERON-GAMMA FOR THE TREATMENT OF CARDIAC HYPERTROPHY
FIELD OF THE INVENTION The present invention relates generally to the effect of IFN-? in cardiac hypertrophy. More - particularly, the invention involves the use of IFN-? for the prevention and treatment of cardiac hypertrophy and associated pathological conditions.
BACKGROUND OF THE INVENTION
Intexferon-gamma (IFN-J) Interferons are relatively small, single-chain glycoproteins released by cells invaded by viruses or certain other substances.The ferments are presently grouped into three main classes, the designated leukocyte interferon.
(interferon-alpha, a-interferon, IFN-a), fibroblast interferon (interferon-beta, beta-interferon, IFN-beta, and immune interferon (interferon-gamma,? -interferon, IFN-?). To the viral infection, the primary synthesized lymphocytes of α-methylferon (together with a smaller amount of one of the different species of interferon, usually called interferon omega), while the infection, of the fibroblasts normally
REF .: 123272 induces ß-interferon, ios a- and ß-interferons share approximately 2-2-30 percent of the homology of the amino acid sequence. The gene for human IFN-β lacks introns, and encodes a protein that possesses 29% of the identity of the amino acid sequence with human IFN-α, suggesting that the IFN-a and IFN-β genes have evolved from a common ancestor (Taniguchi et al., Nature 265, 547-549 [1980]). By contrast, the IFN-? it is not induced by viral infection, rather, it is synthesized by lymphocytes in response to mitogens, and is scarcely related to two other types of inférferons in the amino acid sequence. Interferons-a and -β are known to induce the MHC antigens "Ciase I, while the IFN-y induces the expression of the MHC Class II antigen, and also increases the efficiency with which the labeled cells present the viral peptide in association with MHC Class I molecules for recognition by cytotoxic T cells IFN-α is a member of the interferon family, which shows the characteristic antiviral and anti-proliferative properties of interferons-a and -ß (IFN-a and IFN -ß) but, in contrast to these interferons, it is PH 2 labile.The iFN-α is originally produced in the mitogenic induction of lymphocytes The recombinant production of human IFN-β first reported by Gray, Goeddel and co-workers (Gray et al., Nature 295 503-508 [1982]), and submitted to US Patents Nos. 4,762,791, 4,929,544, 4,727,138, 4,925,793, 4,855,238, 5,582,824, 5,096,705, 5,574,137 and 5,595,888 The human IFN-γ recombinating from Gray and Goedde As it was produced in E. coli, it consists of 146 amino acids, the N-terminal position of the molecule starts with the sequence CysTyrCys. It has been found after the IFN-? native human (i.e., arising from mitogenic induction of human peripheral blood lymphocytes and subsequent purification) is a polypeptide lacking the N-terminal CysTyrCys assigned by Gray et al., supra. More recently, the crystal structure of E. coli derived from recombinant human IFN-y (rhIFN-y) was determined (Ealick et al., Science 525, 698-702 [1991]), which shows that the protein exists as a non-covalent homodimer, hermetically interlaced, wherein the two identical polypeptide chains are oriented in an antiparallel manner. The IFN-? it is known to show a wide range of biological activities, including antitumor, antimicrobial, and inregulatory activities. A particular form of recombinant human IFN-γ (rhIFN-y-lb, Actimmune®, Genentech, Inc. South San Francisco, California) is commercially available as an immune-enhancing drug for the treatment of chronic granulomatous disease characterized by infections recurring, severe skin, lymph nodes, liver, lungs, and bones due to phagocyte dysfunction (Baehner, R.L., Pediatric Pathol, 10, 143-153 [1990]). IFN-y has also been proposed for the treatment of atopic dermatitis, a common inflammatory skin disease characterized by severe itching, a course that chronically relapses with frequent periods of exacerbation, a distinctive clinical morphology and distribution of skin lesions. (see PCT Publication No. WO 91/07984 published June 13, 1991), vascular stenosis, including treatment of restenosis followed by angioplasty and / or vascular surgery (PCT Publication No. WO 90/03189 published on 5 April 1990), various lung conditions, including respiratory pain syndromes (RDS), such as adult respiratory distress syndrome (ARDS) and a neonatal form, variablely terminated as idiopathic RDS or hyaline membrane disease (PCT Publication No. WO 89/01341, published February 23, 1989). In addition, IFN-? it has been proposed for use in the treatment of various allergies, for example asthma, and conditions related to HIV infection, co or opportunistic infections, for example Pneumocystis carinii pneumonia, and sepsis associated with trauma. The production of IFN-? damaged has been observed in patients with multiple sclerosis (MP), and it has been reported that the production of IFS-y is suppressed mostly in mononuclear cell suspensions stimulated with mitogen derived from patients with AIDS. For an analysis see, for example, Chapter 16, "The Presence of Possibie Pathogenic Role of Interferonsin Disease". In: Interferons and other Regulatory Cytokmes, Edward de Maeyer (1988, John Wilet and Sons Publishersj.) Interferon-y, along with other cytokines, have been implicated as inducible nitric oxide inducer (iNOS) which, in turn, has been described as an important mediator of the fundamental inflammatory mechanism in heart failure, cardiac response or sepsis or allograft rejection, as well as the progression of dilated cardiomyopathies of various etiologies Ungureanu-Longrois et al., Res. 77, 494-502 (1995): Pinsky et al., J. Clin Invest. 95, 677-685 (1995); Singh et al., J. Biol. Chem. 270, 28471-8 (1995); Birks. and Yacoub, Coronary Artery Disease 8_, t 389-402 (1997"; Hattori __y collaborators, J. Mol. Cell. Cardioi. 29, _ 1585-92 (1997) .In fact, IFN-y has been reported to be the only the most potent cytokine with respect to the induction of iNOS of the myocyte (Watkins et al., J. Mol. &Ceii. ~ Cardioi., 27, 2015-29 [1995]).
Cardiac Hypertrophy _ Hypertrophy is generally defined as an increase in the size of an organ or structure independent of natural growth that does not involve the formation of a tumor. The hypertrophy of an organ or tissue is due to an increase in the size of the individual cells (actual hypertrophy), or an increase in the number of cells that make up the tissue (hyperplasia), or both. Cardiac hypertrophy is the enlargement of the heart that is activated through both mechanisms and hormonal stimuli and allows the heart to adapt the demands for increased cardiac output or injury. Morgan and Baker, Circulation 8_3_y 13-25_ ^ (1991). This response is frequently associated with a variety of different pathological conditions, such as hypertension, aortic stenosis, myocardial infarction, cardiomyopathy, valvular regurgitation, cardiac deviation, congestive heart deficiency, etc. In a cellular level, the heart functions as a syncytium of myocytes and the surrounding support cells, called non-myocytes. While the nodules are mainly ibroblastic / mesenchymal cells, they also include endothelial and smooth muscle cells. In fact, although myocytes make up the majority of the adult myocardial mass, they only account for approximately 30% of the total cell numbers present in the heart. Enlargement of the embryonic heart is mainly dependent on an increase in myocyte number, which continues briefly until after birth, when the cardiac myocytes lose their proliferative capacity. In addition, growth occurs through the hypertrophy of individual cells. The hypertrophy of adult cardiac ventricular myocytes is a response to a variety of conditions that lead to chronic hemodynamic overload. A) Yes. In response to hormonal, physiological, hematomagic and pathological stimuli, adult ventricular muscle cells can adapt to increase workloads through the activation of a hypertrophic process. This response is characterized by an increase in the size of the myocyte cell and contractile protein content of the individual cardiac muscle cells, without division and concomitant cell activation of the embryonic genes, including the gene for the atrial natriuretic peptide.
(ANP). Chien et al., ETAPAB J. __5, 3037-3046
(1991); Chien and collaborators, Annu. King Physio1. 55,
77-95 (1993). An increase in myocardial mass as a result of an increase in myocyte size that is associated with an accumulation of interstitial collagen within the extracevian matrix and around the arteries of the intramyocardial coronary artery has been described in secondary left ventricular hypertrophy to press the excessive load in humans (Caspari et al., Cardiovasc., Res., 554-8. [1977], Schwarz et al., Am. J. Cardioi, 42, 895-903 [1973], Hess et al., Circulation 63, 360 -371 [1981]; Pearl an et al., Lab. Invest. 46, 158-164 [1982]). Cardiac hypertrophy due to chronic hemodynamic load is the result of the common extreme of most cardiac disorders and a consistent feature of cardiac deficiency. It has also been suggested that the paracrine factors produced by the non-myocyte support cells may be additionally involved in the development of cardiac hypertrophy, and various hypertrophic factors derived from the non-myocyte, such as, the leukocyte inhibiting factor (LIF). ) and endoteiino, have been identified. Metcalf, Growth Factors 7_, _ 169-173 (1992); Kurzrock et al., Endocrine Reyiews 12, 208-217 (1991): Inoue et al., Proc. Nati Acad Sci. USA 86: 2863-2867 (1989); Yanagisawa and Masakí, Trends Pharm. Sci. 10, _ 374-378. ^ (1989); __ Patent. North American No. 5,573,762 (issued November 12, 1996). In addition to the exemplary factors that have been identified as potential mediators of cardiac hypertrophy include cardiotrofin-1 (CT-1) (Pennica et al., Proc. Nal. Acad. Sci ^ USA 92: 1142-1146 ^ [19951], catecholamines, adrenocorticosteroids, angiotensin, and prsstaglandins. Hypertrophy of the adult myocyte is initially beneficial as a short-term response to impaired cardiac function, allowing a decrease in the load on the individual muscle fibers. With excessive, severe, lasting burden, however, the hypertrophied cells begin to deteriorate and die. Katz, "Heart Failure", in: Katz A.M. ed. , Physiology of the Heart (New York, Raven Press, 1992) pages 638-668. Cardiac hypertrophy is an important risk factor for mortality and cardiac. Katz, Trends Cardiovasc. Med. B_, 37-44 (1995). For additional details of the causes and pathologies of cardiac hypertrophy, see for example Heart Disease, A Text book of Cardiovascular Medicine.
Braunwald. E. ed., W.B. Saunders Co., 1988. Chapter 14. Pathophysiology of Heart Faiiure.
Treatment of cardiac hypertrophy At present, the treatment of cardiac hypertrophy "varies and depends on the fundamental heart disease." Catecholamines, adrenocorticosteroids, angiotensin, prostaglandins, leukemia inhibitory factor (LIF), endothelin
(including endoteiin-1, -2 and -3 and major endothelin), cardiotrofin-1 (CT-1) and cardiac hypertrophic factor
(CHF) are among the factors identified as potential mediators of hypertrophy. For example, the ß-adrenergic receptor blocks drugs (ß-biociders, eg, propranolol, timolol, tetralolol, carteolol, nadolol, betaxolol, penbutolol, acetobutolol, atenoloi, metoprolol, carvedilol, etc.) and verapamil has been used extensively in the treatment of hypertrophic cardiomyopathy. The beneficial effects of β-blockers on symptoms (eg, chest pain) and exercise tolerance are mainly due to a decrease in heart rate with a consequent prolongation of diastole and increased passive ventricular filling. Thompson et al., 3r. Heart J. 44 _ 4S8-98 (1980): Harrison et al., Circulation 22, 64-98 (1964). Verapamil has been described to improve ventricular filling and probably reduce myocardial ischemia. Bonow et al., Circuiation 72, 853-64 (1985). Nifedipine and diltiazem have also been used from time to time in the treatment of hypertrophic cardiomyopathy. Loreil et al. Reporters, Circulation 65, 499-507 (1982); Betocciii et al., Am. J. Cardioi. 78, 451 ^ -7 (1996 J. However, due to its potent vasodilating properties, nifedipine may be harmful, especially in patients with effluvial obstruction.Disopyramide has been used to relieve symptoms by virtue of its inotropic properties. Pollick, N. Engl. J. Med. 307, 997-9 (1982) __ In many patients, however, the initial benefits diminish over time.Wigle et al., Circulation 92, 1680-92 (1995). ).
Antihypertensive drug therapy has been reported to have beneficial effects on cardiac hypertrophy associated with elevated blood pressure. Examples of drugs used in antihypertensive therapy, alone or in combination, are calcium antagonists, for example nitrendipine; ß-adrenergic receptor blocking agents, for example, those listed above; inhibitors of angiotensin converting the enzyme (ACE), for example, quinapril, captopril, enalapril, ramipril, benazepril, fosinopril, lisinopril; diuretics, for example corothiazide, hydrochlorothiazide, hydroflu-etazide, ethyl-thiazide, benzthiazide, dichlorphenamide, acetazoiamide, indapamide; calcium channel blockers, eg diltiazem, nifedipine, verapamil, nicardipine For example, the treatment of hypertension with diltiazem and captopril showed a decrease in left ventricular muscle mass, but the Doppler indices of diastolic function were not Szlachcic and et al., Am. J. Cardi 63, 198-201 (1989), Shahi et al., Lancet 336, 458-61 (1990) These interpretations were interpreted to indicate that excessive amounts of interstitial collagen they can remain after the regression of left ventricular hypertrophy.
Rossi et al., Am. Heart J. 124, 700-709 (1992). Rossi et al., Supra, investigated the effect of captoprii on the prevention and regression of myocardial cell hypertrophy and interstitial fibrosis in cardiac hypertrophy of pre-ion overload in experimental rats. As there is no generally applicable therapy for the treatment of cardiac hypertrophy, the identification of the factors that can prevent or reduce hypertrophy to the cardiac myocyte is of paramount importance in the development of new therapeutic strategies to inhibit pathophysiological cardiac growth.
BRIEF DESCRIPTION OF THE INVENTION - We have unexpectedly found that IFN-y inhibits the prostaglandin Fa (PGF2a) - and the induced phe- iiefrina that spread from cardiac myocytes isolated from adult rats. We have also found that IFN-y inhibits in vitro both cardiac hypertrophies induced by fluprostenol, an agonist analog of PGF2a, and hypertrophy induced by pressure overload in a rat model. Therefore, the present invention involves the treatment of cardiac hypertrophy, without taking into account the fundamental cause, by administering a therapeutically effective dose of I N- ?. If the goal is the treatment of human patients, the ILFN-y is preferably human recombinant IFN-y (rhIFN-y), more preferably, rhIFN-α-lb, which is defined below. The concept of treatment is used in the broadest sense, and specifically includes the prevention (prophylactic), moderation, reduction, and cure of cardiac hypertrophy of any stage. IFN-? it is preferably administered in the form of a liquid pharmaceutical formulation which can be preserved to achieve extended storage stability. The preserved liquid pharmaceutical formulations may contain multiple doses of IFN-α and may, therefore, be suitable for repeated use. IFN-y may be administered in combination with one or more of the additional therapeutic agent used for the treatment of cardiac hypertrophy, or an instrumental physiological condition in the development of cardiac hypertrophy, such as elevated blood pressure, aortic stenosis, or infarction at myocardium The invention further involves a method for making a pharmaceutical composition for the treatment of cardiac hypertrophy, which comprises IFN-y as an active ingredient. The invention also involves a pharmaceutical * product comprising: _ _
(a) a pharmaceutical composition - comprising at least one therapeutically effective dosage of IFN-y; (b) a container containing the pharmaceutical composition: and (c) a label attached to the container, or an inserted package included in a pharmaceutical product referred to the use of IFN-? in the treatment of cardiac hypertrophy.
BRIEF DESCRIPTION OF THE FIGURES In the Figures and throughout the examples, the
"IFN" or "IFN-y" refers to the IFN-? of recombinant mouse
(Genentech Inc., South San Francisco, CA. or Genzyme,
Cambridge, MAj. Figure 1 Inhibition of prostaglandin F2a
(PGF2a) -induced propagated in response by IFN- ?. Myocytes were pre-incubated with saline vehicle or IFN-y
(500 U / mi) per day of isolation. A second addition of the vehicle or IFN-y was made 24 h after isolation, together with the addition of any vehicle or PGF2a (10"M.) After an additional 72 h incubation, the cells were fixed in glutaraldehyde, stained with eosin Y and seen by fluorescent microscopy, cardiac myocytes A, B, C after 4 days in culture, control, PGF2a, and PGF2a + IFN-y, respectively, Histograms showing the maximum amplitude of cardiac myocytes in the form of bar versus the percentage frequency of amplitude occurrence The maximum amplitude of the rod-shaped cells was determined by fluorescent microscopy and a set of image-forming software (software) At least 200 bar-shaped cells from a single experiment were examined by group, IFN-γ only had no noticeable effect on cell morphology, F < 0.001 for all group comparisons, Figure 2: Dose-sensitive inhibition of PGF2a in ducid in response to IFN-y (500-25 U / ml). The myocytes were pre-incubated with saline vehicle or IFN-y per day of isolation. A second amount of IFN-y was added 24 hr after isolation, along with the addition of any vehicle or PGF2a (10"" M). After an additional 72 hr incubation the cells were fixed in glutaraldehyde, stained with eosin Y and seen under fluorescence. The quantification of myocyte morphology: A control, B PGF2a, C PGF2a + IF -? (25 ü / ml), D PGF a-t-IFN- and ÚOO U / i J, E PGF2a + IFN-? (500 U / ml). The maximum amplitude shows the histograms of cardiac myocytes in the form of a bar against the percentage frequency of amplitude occurrence. The maximum amplitude of rod-shaped cells was determined by fluorescent microscopy- and a set of image-forming programs. At least 200 cells in the form of ~ bar from a single experiment were examined per group. The IFN-? It exclusively has no noticeable effect on the morphology of the cells. P <; 0.001 for all group comparisons. Figure 3 Inhibition of the induced propagation-response (PE) of phenylephedrine by IFN-y. The myocytes were pre-incubated with saline vehicle or IFN-y (500 U / ml) per day of isolation. A second addition of vehicle or IFN-? 2A Xx was performed after isolation, together with the addition of the vehicle or PE (10"M.) After an additional 72 h incubation, the cells were fixed in glutaraldehyde, stained with eosin Y and viewed by fluorescent microscopy. Cardiac myocytes A, B, C after 4 days in culture, control, PE, and PE + IFN- ?, respectively, Histograms showing the maximum amplitude of cardiac myocytes in the form of a bar against the percentage frequency of occurrence of The maximum amplitude of the rod-shaped cells was determined by fluorescent microscopy and a set of imaging programs.At least 200 bar-shaped cells from a single experiment were examined per group. had a remarkable effect on cell morphology P <0.001 for all group comparisons Figure 4 Effects of IFN-y on cardiac hypertrophy induced by fluprostenol in rats. omo lower ± SEM The number in parentheses is the number of animals in each group. * P < 0.05, * P < 0.01, compared to the vehicle group. #P < 0.05, ## P < 0.01, compared to the Flup group. Fiup: tiuprostenol: IFN = IFN- ?; H: weight of the heart; BW: corpsrai weight: VW: ventricular weight; LVW: left ventricular weight. Figure 5 Effects of Flup and / or IFN on MAP and HR. The data is presented as below ± SEM. The number in parentheses is the number of animals in each group. * P < 0.05, compared to the vehicle group. # P < 0.05, compared to the Flup group. + P < 0.05, compared to the Flup + IFN group. Flup: fluoprostenol; IFN: IFN-y; MAP: lower blood pressure; HR: proportion of the heart. Figure 6 The graphical bars showing the effect of fluprostenol (FLUP) and IFN-y on: A actin skeleton (SKA); B AT? Sarcoplasmicreticulo calcium cap (SRCA); C Collagen I (COL I); D expression of the natriuretic factor Atriai (ANFj.) Expression levels are normalized for the glyceraldehyde-3-phosphate dehydrogenase message (GAPDH), VEH is the vehicle, there were 7 animals per group and the date was presented as the lower one ± SEM, P <0.05 vs. the VEH group Figure 7 The effects of IFN-y on heart weight, ventricular weight, and left ventricular weight in rats with pressure overload.The data is presented as lower ± SEM. number "in parentheses is the number of animals in each group. ** p <0.01, compared to the stimulation group ## P <0.01, compared to the group Union + vehicle Stimulation: stimulation-operated rats: Junction: aortic-joined rats, IFN-IFN- ?; H: heart weight, VW: ventricular weight: LVW: left ventricular weight Figure 8 Effects of IFN-y on the proportion of heart weight, ventricular weight, and left ventricular weight to body weight in rats with overload of pres ion Data are presented as below: ± SEM. The number in parentheses is the number of animals in each group. ** P < 0.01, compared to the stimulation group, ## P < 0.01, compared to the Union + vehicle group.
Stimulation: stimulation-operated rats; Union: aortic-attached rats: IFN: IFN- ?; KW: weight of the heart: BW: body weight; V: ventricular weight; LV: left ventricular weight. Figure 9 Effects of IFN-y on systolic blood pressure, lower blood pressure, diastolic blood pressure in rats with pressure overload. The number in parentheses is the number of animals in each group. ** P < 0.01. compared to the stimulation group, Stimulation; stimulation-operated rats: Union: aortic-attached rats; IFN: IFN- ?, SAP: systolic blood pressure: MAP: lower blood pressure; DAP: diastolic blood pressure.
BRIEF DESCRIPTION OF THE INVENTION A. Definitions "Inferieron gamma", "interferon-gamma", or "IFN-y" refer variously to all forms of interferon gamma (human and non-human animal) that is shown to be biologically active in any test- of cardiac hypertrophy, for example the hypertrophy assay described herein, and is principal to include, but is not limited to, form, maturity, pro, meets and / or des (1-3) (also called desCysTyrCys IFN-y), if obtained from the natural source, chemically synthesized or produced by techniques of recombinant DNA technology. A complete description of the preparation of IFN-α is described. recombinant human (rhuIFN-?) including its cDNAs and amino acid sequences, for example, in U.S. Patent Nos. 4,727,138; 4,762,791; 4,925,793; 4,929,554; 5,532,824: 5,096,705; 4,855,238; 5,574,137; and 5,595,888. The IFN-? Recombinant human lacks CysTyrCy, for example, various truncated derivatives are included, described in European Patent Publication No. 146,354. Non-human animal interferons, including IFN- ?, are, for example, described in European Publication No. 88,622. The term includes various glycosylated forms and other variants (for example variants of the amino acid sequence) and derivatives of native interferons
(wild type), if known in the art or may be available in the future. The examples of the variants are allied, and the products of the mutagenesis at the directed site where the residues are deleted, inserted and / or replaced (see, for example, European Publication No. 146,354 referred to above). IFN-y is known to have a limited host range, therefore, IFN-α homologs should be used. the animal to be treated. In human therapy, the desCysTyrCys variant of the sequence shown in U.S. Patent No. 4,717,138 and its counterpart, EP 77,670, is preferably and optionally employed the C-terminal variant wherein the last four amino acid residues are deleted at the post-translation process. For human therapeutic use, IFN-y of the present invention is preferably IFN-? recombinant human (rhIFS-?), with or without the CysTyrCys amino acids as the N-terminus. More preferably, IFN-y is a species of IFN-? recombinant human (recombinant human interferon gamma-Ib, rhIFN-y-lb, containing 140 amino acids), which is the active ingredient of the commercial formulation, Actimmune® (Genentech, Inc. South San Francisco, California). Like the IFN-? it is known to be a highly specific species, in animal experiments, or for veterinary use, the IFN-? of the animal species to be treated is preferably employed. Thus, in the experiments in vi that use a rat animal model, murine (mouse) recombinant IFN-y (Genentech, Inc.) has been used. The rat and the mouse and sufficiently closely related to allow the use of the mouse IFN-y in a rat model. In a pharmacological sense, in the context of the present invention, a "therapeutically effective amount" of IFN-y refers to an effective amount in the treatment of hypertrophy, especially cardiac hypertrophy. "Hypertrophy", as used herein, is defined as an increase in the mass of an organ or structure independent of natural growth that does not involve the formation of tumors. The hypertrophy of an organ or tissue or is - due to an increase in the mass of the individual cells (real hypertrophy), or an increase in the number of cells that make up the tissue (hyperplasia), or both. Certain organs, such as the heart, lose the ability to divide briefly after birth. Therefore, "cardiac hypertrophy" is defined as an increase in heart mass, which, in adults, is characterized by an increase in the size of the myocyte cell and the content of contractile protrein without division of the heart. concomitant cell. The nature of the stress responsible for inciting hypertrophy, (for example, increased preload, after increased loading, loss of myocytes, as in myocardial infarction, or primary contractility depression), appears to play a critical role in determining the nature of the response. The early stage of cardiac hypertrophy is usually characterized morphologically by increasing the size of the microfibrils and mitochondria, as well as the enlargement of the mitochondria and nuclei. At this stage, while the muscle cells are larger than normal, the cellular organization is mainly conserved. In a more advanced stage of cardiac hypertrophy, the increa- ses are preferential in the specific size or number, such as a mitochondria, and new contractile elements are added in localized areas of the cells, in an irregular manner. Cells subjected to long-standing hypertrophy show cleavages more evident in cellular organization, including remarkably enlarged nuclei with highly lobulated membranes, which displace adjacent myofibers and damage the cause of normal Z-band registration. The phrase "cardiac hypertrophy" is used to include all stages of the progression of this condition, characterized by varying degrees of structural damage to the heart muscle, regardless of the underlying cardiac disorder. "J cardiac efficiency" refers to an abnormality of cardiac function where the heart does not pump blood at the rate needed for the requirements of metabolized tissues. Heart failure can be caused by several factors, including ischemic, congenital, rheumatic, or idiopathic forms. "Congestive heart deficiency" is a progressive pathological state where the heart has an increase incapable of providing adequate cardiac performance (the volume of blood pumped by the heart over time) to provide oxygenated blood to peripheral tissues. When congestive heart failure progresses, structural and hemodynamic damage occurs. While these damages have to a variety of manifestations, a characteristic symptom is ventricular hypertrophy. Congestive heart failure is a common end result of a number of various cardiac disorders. "Myocardial infarction" usually results from atherosclerosis of the coronary arteries, often with superimposed coronary thrombosis. It can be divided into two main types: transural infarctions, where myocardial necrosis involves the full thickness of the ventricular wall, subendocardial (non-transmural) e-infarcts, where myocardial necrosis involves the subendocardium, or both, without extending the trajectory through the ventricular wall to the epicardium. Myocardial infarction is known to cause both a change in hemodynamic effects and an alteration in the structure in damaged and healthy areas of the heart. Thus, for example, myocardial infarction minimizes the cardiac output and the volume of the heart attack. Also associated with myocardial infarction is a stimulus of DNA synthesis that occurs in the interstitium as well as an increase in collagen formation in unaffected areas of the heart. As a result of the increased tension or tension located in the heart due to prolonged hypertension, for example, to the total increase in peripheral resistance, "cardiac hypertrophy has long been associated with" hypertension. "A characteristic of the ventricle that becomes hypertrophic as a result of chronic pressure overload is a damaged diastolic performance." Fouad et al., J. Am. Coil. 4, 1500-6 (1984J; Smith and collaborators, J. Am. Coll. Cardioi o_, _869-74 __ (1985). A prolonged left ventricular relaxation that has been discovered in early essential hypertension, despite normal or supranormal systolic function.
Hartford et al., Hypertension 329-33Í
(1984) . However, there is no close parallel between the level of blood pressure and cardiac hypertrophy. Although improvement in left ventricular function in response to antihypertensive therapy has been reported in humans, patients treated variously with a diuretic (hydrochlorothiazide), a β-blocker (propranolol), or a calcium channel blocker (diltiazem), has shown a return of the left ventricular mass, without improvement in diastolic function. Lnouye et al., Am. J. Cardioi. 53, 1583-7 (1984). Another complex heart disease associated with cardiac hypertrophy is "hypertrophic cardiomyopathy". This condition is characterized by a great diversity of morphological, functional and clinical characteristics (Marón et al., N. Engl., J. Med. 316, 780-9 [1987], Spirito et al., N. Engl. J. Med. 320, 749-55 [1989]; Louie and Edwards, Prog.
Cardiovasc. Dis. 36, 275-308 [19941;, Wigle et al., Circulation 92, 1680-92 [1995]), the heterogeneity which is accentuated by the fact that it afflicts patients of all ages (Spirito et al., N. Engl. J. Med. 336. 775-785 [1997]). The causative factors of hypertrophic cardiomyopathy are also diverse and poorly understood. Recent data suggest that ß-myosin heavy chain mutations can be considered for approximately 30 to 40 percent of cases of familial hypertrophic cardiomyopathy (Watkins et al., N. Engl. J. Med. 326, 1108-14 [1992] Schwanz et al., Circulation 91, 532-40_ [1995], Marian and Roberts, Circulation 92, 1336-47"[1995], Thierfelder, et al., 77, 701-_12__ [1994]; collaborators, Nat. Gen. 11, 434-7 [1995]). Supravalvular "aortic stenosis" is a hereditary vascular disorder, which is also characterized by narrowing of the ascending aorta, but other arteries, including the pulmonary arteries, also The untreated aortic stenosis can lead to the increased intracardiac pressure produced in myocardial hypertrophy and eventually to heart infarction and death.The pathogenesis of this disorder is not fully understood, but hypertrophy and possibly Middle smooth muscle hyperplasia are prominent features of this disorder. It has been reported that molecular variants of the elastin gene are involved in the development and pathogenesis of aortic stenosis: (US Patent No. 5,650,282 issued July 22, 1997). "Valvular regurgitation" occurs as a result of heart diseases that cadisorders of the heart valves. Several diseases, such as rheumatic fever, may cashrinking or pulling away from the valve orifice, while other diseases may result in endocarditis, an inflammation of the endocardium or the lining membrane of the atrioventricular orifices, and the functioning of the heart. Defects such as narrowing of the valve stenosis or defective closure of the valve result in a buildup of blood in the heart cavity or regurgitation of the blood past to the valve. If the prolonged valvular stenosis is incorrect, or insufficient, it can produce cardiac hypertrophy and the damage associated with the heart muscle, which may eventually require valve replacement. The treatment of all these, and other cardiac disorders accompanied by cardiac hypertrophy is subject of the present invention. "Treatment" refers to both the therapeutic treatment and the prophylactic or preventive measures, wherein the object is to prevent or reduce the speed (decrease) of the hypertrophy. Those who need treatment already include those with the disorder as well as those who are prone to have the disorder or those in whom the disorder will be prevented. Hypertrophy can result from any cause, including idiopathic, cardiotrophic, or myotrophic, or ischemic or ischemic attacks, such as myocardial infarction. "Chronic" administration refers to the administration of the agent (s) in a continuous mode as opposed to an acute mode, to maintain the initial antihypertrophic effect for a prolonged period of time. "Mammal" for purposes of treatment refers to any animal classified as a mammal, including humans, domestic and farm animals, and zoo, sports, or domestic animals, such as dogs, cats, cows-, horses, sheep, pigs, etc. Preferably, the mammal is human. The administration "in combination with" one or more therapeutic agents further include simultaneously (concurrently) and consecutively administration in any order.
B. Modes of Carrying Out the Invention 1. Cardiac hypertrophy assay In vitro assay a. Induction of expansion of cardiac myocytes of the adult rat In this test, ventricular myocytes are isolated from a single rat (male Sprague-Dawley), following a modification of the procedure described in detail 'by Piper et al., "Aduit ventricuiar rat heart muscle cells. " in: Cell Culture Techniques in Heart and Vessel Research, H.M. Piper, ed., Berlin: Spinger-Verlag, 1990. Pages 36-60. This procedure allows the isolation of adult ventricular myocytes and the long-term culture of these cells in the bar-like phenotype. Phenylephrine and Prostaglandin F2 (PGFa) have been shown to induce an extensive response in these adult cells. Fiper et al., Supra; Lai and collaborators, A J. Physiol. nineteen ninety six; 271 (Heart Circ. Physiol. 4 -2 7 ~ H2208) The inhibition of myocyte propagation induced by the analogues PGF2"or PGF2a / (eg fluprostenol) and phenylephrine by several potential inhibitors of cardiac hypertrophy is then tested. A detailed protocol is described in the following examples: In vivo assays: Inhibition of cardiac hypertrophy induced by fluprostenol in vivo This pharmacological model tests the ability of IFN-y to inhibit cardiac hypertrophy induced in rats (eg Wistar or Male Sprague-Dawiey) by subcutaneous injection of fluprostenol (an agonist analogue of PGF2a) • It is known that rats with pathological cardiac hypertrophy induced by myocardial infarction have chronically elevated the levels of PGF2a extractadle in their myocardium Lai et al., Am. J. Physiol (Heart Circ. Physiol.) 271: H2I97-H2208 (1996) .Therefore, the factors that can inhibit the effects of fluprostenol in the Myocardial growth in vivo are potentially useful for treating cardiac hypertrophy. The effects of IFN-y on cardiac hypertrophy are determined by measuring the weight of the heart, ventricles, and left ventricle
(normalized by body weight) in relation to rats treated with fluprostenol that do not receive IFN-y. A detailed description of this test is given in the examples. b. Cardiac hypertrophy test for pressure overload. For in vivo testing it is common to induce cardiac hypertrophy of pressure overload by constriction of the abdominal aorta of test animals. In normal protocol rats (eg Wistar or Sprague-Dawley male) they are treated under anesthesia, and the abdominal aorta of each rat tapers down just below the diaphragm. Beznak M., Can. J. Biochem. _ Physiol. 33, 985-94 (1955). The. aorta _ is exposed through a surgical incision, and a blunt needle is placed next to the vessel. The aorta is narrowed with a ligature of wool thread around the needle, which is immediately removed - and where the lumen of the aorta is reduced to the diameter of the needle. This approach is described, for example, in Rossi et al., Am. Heart J. 124, 70J-70 JJL992). and O'Rourke and Reibel, P. S .E M B 200, 95-100 (1992). A detailed description of the protocol used by the present inventors is described in the following examples. b. Effect on cardiac hypertrophy that follows experimentally induced myocardial infarction (Ml). MI is induced in rats by the ligation of the left coronary artery and confirmed by the electrocardiographic examination. A surrogate group of animals is also prepared as control animals. The most recent data show that cardiac hypertrophy is present in the group of animals with Ml, as evidenced by an 18% increase in the weight of the heart and the proportion of body weight. Lai et al., Supra. The treatment of these animals with candidate blockers of cardiac hypertrophy, for example, IFN-y provides valuable information on the therapeutic potential of the candidates tested. 2. Therapeutic compositions, uses and administration of IFN-? According to the present invention, IFN-? it can be used for the treatment of cardiac hypertrophy, that is, the enlargement of the heart, without taking into account the etiology and pathogenesis. When excessive pressure or volume loading is imposed on the heart (ventricle), it develops cardiac hypertrophy (myocardium), providing a fundamental compensatory mechanism that allows the 1-ventricular to prolong its load, Krayenbuehl et al., Eur. Heart_ J. 4 (Suppl. A), 29 (1983). The character of the tension (increased preload, increased posterior load, loss of myocytes, as in myocardial infarction, or primary depression of the compression) that responds to the development of hypertrophy that plays a critical role in determining the nature of the response to hypertrophy. Scheuer and Bunrick, Circulation 75 (Suppl 1), 63 (1987). The present invention involves the treatment of cardiac hypertrophy associated with any fundamental pathological condition, including, without limitation, post-myocardial infarction, hypertension, aortic stenosis, cardiomyopathy, valvular regurgitation, cardiac deviation, and congestive heart failure. The main characteristics of these conditions have been discussed previously. Particularly important is the use of IFN-? for the prevention of heart failure followed by myocardial infarction. Approximately 750,000 patients suffer from acute myocardial infarction (AMI) annually, and approximately four of all deaths in the United States are due to AMI. In recent years, thrombolytic agents, for example streptokinase, urokinase, and in particular the tissue plasminogen activator (t-PA) have significantly increased the survival of patients who suffered myocardial infarction, when administered as a continuous intravenous infusion during 1.5 to 4 hours, t-PA produces the coronary opening for 90 minutes from 69% to 90% of the treated patients Topol et al., Am. J. Cardioi, 61, 723-8 (1988); Neuhauset and col aboradores, J. Am. Coll. Cardioi 12, 581-7 (1988); Neuhauset _ et al., J. Am. Col., Cardioi. 14, 15_66-9_ (1989). The highest patentable proportions have been reported with high doses or dosed regimens have been accelerated. Topol, J. Am Coll. Cardiol 15 ^ 922- ^ 4 (1990). t-PA can also be administered as a single bolus, although due to its relatively short life, it is more appropriate for infusion therapy. Tebbe et al., Am. J. Cardioi. 64, 448-53 U98_9). A variant of t-PA, specifically designed to have a higher average life and very high fibrin specificity. TKN t-PA (a T103N, N117Q, KHRR (296-299) AAAA variant of t-PA, Keyt et al., Proc Nati. Acad 5ci USA 91, 3670-3674 (1994)) is particularly convenient for administration of - bolus. However, despite all these advances, the long-term survival prognosis of the patient depends greatly on the post-infarction check-up and the treatment of the patients, which should include the check-up and treatment of cardiac hypertrophy. Another important therapeutic indication is the treatment of cardiac hypertrophy associated with hypertension. As noted above, prolonged hypertension is known to result in cardiac hypertrophy. Although certain hypotensive agents have been shown to reduce left ventricular mass, treatment does not always result in improved diastolic function. Accordingly, IFN-y can be administered in combination with the adrenergic receptor blocking agents, for example, propranolol, timolol, tetalolol, carteol !, nadolol, betaxoloi, penbutolol, acetobutolol, atenoloi, metoproloi, carvedilol; enzyme inhibitors that converts to angiotensin (ACE), for example, quinapril, captopril, enalapril, ramipril, benazepril, fosinopril, lisinopril,; diuretics, for example, chlorothiazide, hydrochlorothiazide, methyclothiazide, benzthiazide, acetazolamide, indapamide; and / or calcium channel blockers, for example, diltiazem, nifedipine, verapamil, nicardipine. The pharmaceutical compositions comprising the therapeutic agents identified their generic names are commercially available, and are administered following the instructions of the manufacturers for dosage, administration, adverse effects, contradictions, etc. (See, for example, Medical Economics Data Production Co., Montvale, N.J., 51 th edition, 1997.) IFN-? it can also be administered prophylactically to patients with cardiac hypertrophy, to prevent the progression of the condition, and to avoid sudden death, including the death of asymptotic patients. Preventive therapy is particularly warranted in the case of patients diagnosed with massive left ventricular hypertrophy (a maximum wall thickness of 35 mm or more in adults, or a comparable value in children), or in castrs when the hemodynamic burden in the heart It is particularly strong. IFN-? It may also be useful in the management of atrial fibrillation, which develops in a substantial portion of patients diagnosed with hypertrophic cardiomyopathy. IFN-? it is administered in the form of a pharmaceutical composition comprising IFN-? as an active ingredient, together with a pharmaceutically acceptable carrier. The therapeutic formulations of IFN-y are prepared to treat cardiac hypertrophy for storage by mixing IFN-y having the desired degree of purity with physiologically acceptable carriers, excipients, or optional stabilizers (Remingtop / s Pharmaceutical Sciences, supra) in the form of slice of lyophilized cake or aqueous solutions. The excipient carriers, or acceptable stabilizers, are not toxic to the recipients at the dosages and concentrations employed, and include buffers such as phosphate, citrate, and other organic acids; anti-oxidants including ascorbic acid; polypeptides of low molecular weight (less than about 10 residues); proteins, such as serum albumin, gelatin, or immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone; amino acids such as glycine, glutamine, asparagine, arginine or lysine; monosaccharides, disaccharides, and other carbohydrates including glucose, mannose, or dextrins; chelating agents- such as EDTA; sugar alcohols such as mannitol or sorbitoi; counterion that form salts like sodium; and / or nonionic surfactants such as Tween, Pluronics, or polyethylene glycol (PEG). The IFN- must be sterile? to be used for in vi ve administration. This is quickly accomplished by filtration through the sterile filtration membranes, before or after lyophilization and reconstitution. The IFN-y will ordinarily be stored in lyophilized form or in solution. IFN-y can be used in lyophilized form, in combination with other ingredients for reconstitution with an appropriate diluent at the time of use. Because IFN-y is known to be a labile acid, it has been traditionally handled at slightly alkaline or neutral pH. See, for example, US Patent No. 4,499,014 which describes the reactivation of an IFN-α solution. lyophilized at a pH of 6 to 9. Slightly alkaline or neutral solutions or of higher concentrations of IFN-y are generally not suitable as injectable formulations due to the immediate formation of a visible precipitate. The precipitate may cause thrombosis in the administration or decrease in potency. European Patent Publication No. 0196.203 discloses the reconstitution of IFN-iodinated at a pH of 4 to 6.0. They are described in U.S. Patent No. 5.15JT.265 issued September 29, 1995. Stable liquid pharmaceutical compositions comprise an effective amount of IFN-α. not lyophilized together with a buffer capable of maintaining the pH at 4.0-6-0, a stabilizing agent, and a non-ionic detergent. The stabilizing agent is usually a polyhydric sugar alcohol, such as mannitol, and the nonionic detergent can be a surfactant, for example, polysorbate 80 or polysorbate 20. The nonionic detergent preferably comes in a range of about 0.07 to 0.2 mg / ml. and more preferably at a concentration of about 0.1 mg / ml. Suitable buffers are the conventional buffers of organic acids and salts thereof, such as nitrate buffers (for example, the mixture of monosodium citrate disodium citrate, the mixture of citric acid trisodium citrate, the citrate mixture of monosodium-citric acid, etc.), succinate buffers (for example, the mixture of monosodium succinate-succinic acid, the mixture of sodium hydroxide-succinic acid, the mixture of disodium succinate-succinic acid, etc.) tartarate buffers (for example, the mixture of sodium tartarate-tartaric acid, the mixture of tartrate of potassium-tartaric acid, the mixture of sodium hydroxide-tartaric acid, etc.), fumarate buffers (for example, the mixture of monosodium fumarate-fumaric acid, the mixture of disodium fumarate-fumaric acid, the mixture of disodium fumarate-monosodium fumarate, etc.), gluconate buffers (for example, the mixture of gl sodium urea-gluconic acid, the mixture of sodium hydroxide-gluconic acid, the mixture of potassium gluconate-gluconic acid, etc.), oxalate buffers (for example, the mixture of sodium oxalate-oxalic acid, the mixture of sodium hydroxide-oxalic acid, the mixture of potassium oxalate-oxalic acid, etc.) lactate buffers (for example the mixture of sodium lactate-lactic acid, the mixture of sodium hydroxide-lactic acid, the mixture of potassium lactate-lactic acid, etc.) and acetate buffers (for example the mixture of sodium acetate-acetic acid, the mixture of sodium hydroxide-acetic acid, etc.). A known commercial liquid formulation of IFN-? (Acti mune © rhu IFN -? - lb. Genentech, Inc.) is a colorless solution, without preservation, ciara, sterile filled in a vial of a dose by subcutaneous injection. Each 0.5 ml vial of Actimmune contains 100 μg (3 million U, specific activity: 30 million U / mg) of IFN-? -Ib formulated in 20 mg of mannitbi, 0.36 mg of sodium succinate, 0.05 mg of polysorbate 20 and Sterile Water for Injection. Preserved pharmaceutical compositions to be used in accordance with the present invention, which are suitable for repeated use, preferably contain: a) IFN-y not subjected to prior lyophilization; b) an acetate buffer capable of maintaining the pH between about 4 and about 6 (the pH range of maximum stability of the protein in solution); c) a non-ionic detergent primarily to stabilize the protein against induced aggregation-agitation; d) an isotifier;
e) a condom selected from the group of phenol, benzyl alcohol and a benzethonium halide, for example chloride; and f) water. Nonionic detergents (surfactants) can, for example, be polysorbates (for example, polysorbate [Tween] 20, 80, etc.) or poloxamers (for example, poloxamer 188). The use of non-ionic surfactants allows the formulation to be exposed to the stresses of the cut surface without causing denaturation of the protein. In addition, the surfactant containing the formulations can be employed in aerosol devices such as those used in a pulmonary dosing, and needle-less jet injection guns (see, for example, EP 257,956). The isotonifier is present to ensure the isonicity of the liquid compositions of the present invention, and includes polyhydric sugar alcohols, preferably trihydric or higher sugar alcohols, such as glycerin, erythritol, arabitol, xylitol, sorbitol and mannitol. These sugar alcohols can be used alone or in combination. Alternatively, hate chloride or other appropriate inorganic salts can be used to provide the isotonic solutions.
The acetate buffer can, for example, be a mixture of acetic acid-sodium acetate, a mixture of acetic acid-sodium hydroxide, etc. The pH of the liquid formulation of this invention is buffered in the range of about 4.0 to 6.0, preferably 4.5 to 5.5. and more preferably at about pH 5. Condoms of phenol, benzyl alcohol and a benzethonium halide, for example chloride, are known antimicrobial agents. In a preferred embodiment, IFN-y is administered in the form of a liquid pharmaceutical composition comprising the following components: IFN-y 0.1-2.0 mg / ml sodium acetate (pH 5.0) 5-100 mM Tween 20 0.1 to 0.01% by weight phenol 0.05 to 0 4% by weight mannitol 5% by weight water for injection. USP up to 100%
wherein the percentage amounts are based on the weight of the composition. Phenol can be replaced by 0.5-1.0% by weight of benzyl alcohol and mannitol can be replaced by 0.9% by weight of sodium chloride.
More preferably, the compositions comprise IFN-y 0.1-1.0 mg / ml sodium acetate (pH 5.0) 10 mM Tween 20 0.01% by weight phenol 0 2% mannitol 5%
Phenol can be replaced by 0.75 by weight of benzyl alcohol and mannitol by 0.9% by weight of sodium chloride. The liquid formulations preserved preferably contain multiple doses of a therapeutic effective amount of IFN-y. In view of the reduced organization range of this polypeptide, for the treatment of human patients, liquid formulations comprising human IFN-γ, more preferably the native sequence of human IFN-γ, are preferred. As a biological response modifier, IFN-y exerts a wide variety of activity, it is on a wide range of cell types, in a variety of human and non-human mammalian species. The therapeutically effective dose, of course, will vary depending on factors such as the pathological condition to be treated (including prevention), the age of the patient, weight, general medical condition, medical history, etc. and its determination is good within ability of a practicing doctor. The effective dose is generally within the range of about 0.001 to about 1.0 mg / kg, preferably about 0.01-1 mg / kg, more preferably about 0.01-0.1 mg / kg. In the formulations huIFN-? preferably they will exhibit a specific activity in the order of about 2 x 10 U / mg protein or greater when tested in AS49 cells against the encephalomyocarditis virus. It should be appreciated that endotoxin contamination should be kept minimally at a safe level, eg, less than 0.5 ng / mg protein. In addition, for human administration, liquid formulations must comply with sterility, pyrogenicity, safety in general, and purity as required by the FDA Office and Biological standards. The administration route of IFN-? is according to known methods, for example, injection or infusion by intraperitoneal, intravenous, intracerebral, intramuscular, intraocular, intraarterial, or intralesional means, or by prolonged release systems as noted below.
The therapeutic compositions of IFN-y are generally located in a container having a sterile access port, for example, a bag of intravenous solution or vials having a plug penetrable by a hypodermic injection needle. The formulations are preferably administered as repeated intravenous injections (i.v.). subcutaneous (s.c.) or intramuscular (i.m.) injections, or as aerosol formulations appropriate for intranasal or intrapulmonary release (for intrapulmonary release see, for example, EP 257, 956). The stable aqueous compositions of IFN- and preferably in vials are contained, containing up to about 30 therapeutically effective doses of IFN-y. The bioactivity of IFN-? preferably it remains within about 20% of the bioactivity exhibited at the time of the first administration for at least about 14 days, more preferably for at least about 200 days followed by the "first administration." IFN-y can also be administered at The form of prolonged release preparations Suitable examples of sustained release preparations include semipermeable matrices of solid hydrophobic polymers containing the protein, the matrices are in the form of preformed articles, eg, films or microcapsules. Prolonged release include polyesters, hydrogels (eg, poly (2-hydroxyl) methacrylate) as described by Langer et al., J. Biomed, Mater. Res. 15: 167-277 [1981] and Langer, Chem_ Tech., 12: 9J3-105 [1982] or poly (vinylalcohol)), polyethylactides (U.S. Patent No. 3,773,919, EP 58,881), polymers of L-glutamic acid and gamma ethyl-L-glutamate (Sidman et al., Biopoiymers, 22: 547-556 T1983)), non-degradable vinylacetate-ethylene, (Langer et al., supra), copolymers of giicoic acid-lactic acid degradable such as Lupron Depot ™ (injectable microspheres composed of the copolymer of glycolic acid-lactic acid and acetate leuprolide), and poly-D- (-) -3-hydroxybutyric acid (EP 133,988). While polymers such as ethylene-vinyol acetate and lactic acid-glycolic acid are capable of releasing molecules for approximately 100 days, certain hydrogels release proteins for shorter periods of time. When the encapsulated proteins remain in the body for a long time, they can denature or aggregate as a result of exposure to moisture at 37 ° C, resulting in a loss of biological activity and possible changes in immunogenicity. Rational strategies can be invented for the stabilization of the protein that depends on the mechanism involved. For example, if the aggregation mechanism is discovered for the formation of the intermolecular SS bond through the exchanged thio-disulfide, stabilization can be achieved by modifying the sulfhydryl residues, lyophilizing from the solutions, controlling the moisture content, using appropriate additives, and developing specific compositions of polymer matrix. Sustained-release IFN-y compositions include IFN-γ and liposomatically entrapped. The liposomes containing IFN-? are prepared by methods known from: DE 3,218,121: Epstein et al., Proc. Nati Acad Sci. USA, 82: 3688-3692 (1985): Hwang et al., Proc. Nati. Acad Sci USA, 77: 4030 4054 (1980); EP 52,322; EP 36. ~ 676: EP 88,046; EP143,949; EP142,641; Japanese Patent Application 83-118008; U.S. Patent Nos. 4,485,045 and 4,544,545; and EP 102,324. Ordinarily the liposomes are of the small unilamellar type (approximately 200-800 Angstroms) wherein the lipid content is greater than about 30 mol% of cholesterol, the selected proportion is adjusted for the optimal therapy. An effective amount of IFN-y to be used therapeutically will depend, for example, on the therapeutic objectives, the route of administration, and the condition of the patient. Therefore, it will be necessary for the titular therapist to dose and modify the route of administration as required to obtain the optimal therapeutic effect. The recommended dosage for the administration "of IFN-y
(Actimmune © Genentech, Inc.) to treat patients with chronic granulomatous disease is 50 mcg / 1 (1.5 million U / m ') for patients whose surface area of the body is greater than 0.5 mz, and 1.5 mcg / kg / dose for patients whose surface area of the body is equal to or less than 0.5 m administered with a subcutaneous injection, three times a week. This is a valuable guide for a doctor to determine the optimal effective dose for the treatment of cardiac hypertrophy. The doctor will administer IFN-? until a dosage is reached to achieve the desired effect for the treatment of the heart disorder. For example, if the goal is the treatment of a congestive heart deficiency, the amount will be one that inhibits the cardiac hypertrophy p og esiv associated with this condition. The progress of this therapy is easily monitored by echo cardiography. Similarly, in patients with hypertrophic cardiomyopathy, ei I FN-y can be administered on an empirical basis, relying on the subjective perception of the patient. IFN-y can be administered in combination with other therapeutic agents used for the treatment (including prevention) of cardiac hypertrophy. For example, IFN-y therapy can be combined with the administration of inhibitors of known myocyte cardiac hypertrophy factors, for example, inhibitors of α-adrenergic agonists, for example, phenylephrine: endothelin-i CT-1; LIF; enzyme converted to angiotensin and angiotensin II. Inhibitors of cardiac hypertrophy factor (CHF, cardiotrophin or cardiotrophin-1, see, eg, US 5,67"9,545) are particularly preferred for combination therapy Preferred candidates for combination therapy in the treatment of cardiomyopathy hypertrophic drugs are ß-adrenergic blocking drugs (eg, propranolol, timolol, tertalolol, carteolol, nadolol, betamethanol, penbutoioi, acetobutolol, atenolol, metoprolol, carvedilol), verapamil, difedipine, diltiazem. high blood pressure may require the use of antihypertensive drug therapy, using "calcium channel blockers, for example, diltiazem, nifedipine, verapamil, nicardipine: ß-adrenergic blocking agents; diuretics, for example, chlorothiazide, hydrochlorothiazide, hydroflumetazide, methylclothiazide, benzthiazide, dichlorphenamide, acetazolamide, indapamide; and / or ACE inhibitors, for example, quiñapril, c ptopril, enalapril, ramipril, benazepril, fosinopril, lisinopril. The effective amount of the therapeutic agents administered in combination with IFN-? It will be at the discretion of the doctor or veterinarian. The administration of the dosage and adjustment is done to achieve optimal control of the conditions to be treated, ideally taking into account the use of diuretics or digital, and conditions such as hyper- or hypotension, renal deterioration. The dosage additionally will depend on factors such as the type of therapeutic agent to be used and the specific patient to be treated. Normally, the amount used will be the same dose as the one already used, if the given therapeutic agent is administered without IFN- ?.
EXAMPLES Example 1 Inhibition of PGF2a ~ propagated response _ _. induced adult myocytes of IFN-y < Materials and Methods _ Cul tients of adult myocyte. The procedure used for the isolation of ventricular myocytes from adult rats was a modification of a procedure described by Piper et al., Supra, and is detailed in Lai et al., Supra. For each myocyte preparation, a male Sprague-Dawley rat weighing approximately 250 g was anesthetized with sodium pentobarbital, and the heart was removed. The foreign tissue was removed from the heart, and was mounted in a Langendorff system at a controlled temperature at 37 ° C. The heart was penetrated with approximately 40 ml of Krebs buffer (110 mM NaCl, 2.6 mM KCl, 1.2 mM KH2P04, 1.2 mm MgSO4, 1R0, 25 mM NaHCO3} and 11 mM glucose). A solution containing 30 mg of collagenase and 12.5 μl of 100 mM CaCl 2 in 50 ml of Krebs buffer was then circulated through the heart for 30 minutes. The heart withdrew from Langendorff's apparatus, and the connective tissues and atria were removed. The ventricles were cut in 2 cubic mm with dissection scissors, and further collected in a fresh collagenase solution (30 mg collagenase and 400 mg of BSA dissolved in the Krebs buffer with 12.5 μl of 100 mM CaCl_) for five to 37 minutes. ° C. During digestion, the tissue suspension was gently shaken for one minute. After digestion, the supernatant was removed and saved, and the remaining tissue was further digested in the fresh collagenase solution for an additional five minutes. Isolated adult rat myocytes were electroplated on laminin coated plate at a density of 3x10 'cells / ml. After 72 hours of appropriate stimulation, the cells were fixed with gluteraidehyde and stained with Eosin Y. Images of the rod-shaped cells were captured under fluorescent microscopy and the maximum amplitude was determined using a set of imaging programs. (Simple 32, Compix Imaging, Mars, PA). Results IFN-α inhibits the propagation of adult cardiac myocyte induced by the factors of PGE hypertrophy & amp; amp;; and phenyl ephine PGF2a and phenylephrine a-adrenergic agonist have been shown to induce hypertrophy of cardiac myocytes from cultured neonatal rats (Adams et al., J. Biol. Chem, 271: 1179-1186 [1996]; Lai et al. Am. J. Physiol. (Hart Circ. Physiol.) 271: H2197-H220S [1996]; Meidell et al. ", Am. J Physiol. 251: H 1076-H 1084 [1986]: Simpson, J. Clin. Invest 72: 732-738 [1983]: Simpson, Circ. Res. 56: 884-894 [1985].) Ventrubic adult rat iocytes were propagated when exposed to these factors in culture (Lai et al., Supra; Piper and collaborate, "Adult ventricular rat heart muscle cell," in: Cell Culture Techniques in _Heart and Vessel, Research, HM Piper, Editor, 1990, Springer-Verlag,: Berlin, pp. 36-60.) Adult myocytes have A morphology similar to a bar When these cells are exposed to 0.1 μM PGFa, the rod-shaped cells flatten and expand (Figure 1). n was quantified by measuring the maximum cell width of at least 200 cells in bars and delineating this value against the percent frequency of cell breadth in the population. PGFa induces a significant change in the maximum width of the cell as evidenced by a change in the population distribution for this parameter compared to the control cells (P <0.001). The treatment of the cells with IFN-y significantly inhibits their response to PGF2a (P <0C01 FGF2a t IFN-y compared to PGF2a) • The inhibitory effect of IFN-y on the propagation of the induced myocyte of PGF2a was a dose-dependent ( Figure 2) with respect to a concentration range that is consistent with the biological response to IFN-y in cardiac myocytes and other cellular systems (Singh et al., J. Biol. Chem. 271: 1111-1117 [1996]; and collaborators, J. Clin. Invest, 95: 766-685 t
[995]; Ungureanu-Longrois et al., Circ. Res. 77: 494-502 [1995]; Soderber-Naucler and collaborators, J. Clin Invest. 100: 3154-3163 [1997]; Gou et al., J. Clin. Invest ,. i 00: 829-838 [1997]; Marra and collaborators, Can J. Cardioi. 12: 1259-1267 [1996]). The ability to inhibit the propagation of the induced myocyte of PGF2a appears to be specific for IFN-y since several other cytokines include IL-ia, IL-Iβ, IL-2, IL-6, TNF-α, IFN-α and IFN -β can not inhibit the propagation response. The inhibitory effect of IFN-y is nonspecific for PGF2a. IFN-y can also inhibit the spread induced by phenylephrine (Figure 3) Example 2 Inhibition of Cardiac Hypertrophy _Virvo Materials and Methods Animal All experimental procedures conformed to the guiding principles of the American Physiology Society, and approved by Gepentech's Institutional Anima *! Care and Use Committee The animals used in this study were male Sprague / Dawley (SD) rats (8 weeks old, Charles River Breeding Laboratories, Inc.) .The animals were acclimated to the environment at least once Week before the experiments, a rat was fed with pellets of food and water ad libi tum, and was housed in a room under controlled light and temperature Administration of fluprostenol and / or IFN-y The rats received a subcutaneous injection of fluprostenol ( Cayman Chemical, An Arbor, Ml) at 0.15 mg / kg of the IFN-y of the recombinant mouse tGcnentech Inc. South San Francisco, CA) at 0.08 mg / kg, combination of fluprostenol and IFN-y, or the saline vehicle, twice a day for 14 days. In the IFN-? and groups of fluprostenoi + IFN-y, the animals were penetrated with IFN-y for one day. Body weight was measured before and after treatment. A previous study has shown that the dose of fluprostenol used is the lowest dose that produces a significant cardiac hypertrophy in rats. Lai et al., Supra. A pilot study showed that IFN-y at the indicated dose with respect to inhibited fluprostenol-induced cardiac hypertrophy has small effects on the body weight of rats. Hemodynamic Valuation 30 days after treatment, the rats were anesthetized with an injection intraperitorea injection of 80 mg / kg ketamine (Aveco Co., Inc., Fort Dodge, Iowa) and 10 mg / kg xylazine (Rugby Laboratories, Inc., Rockville Center, NY.). A catheter (PE-10 fused with PE 50) filled with saline-heparin (50 U / ml) was implanted in the abdominal aorta, by means of the right femoral artery, for the measurement of mean arterial pressure (MAP) and heart rate (HR). The catheter was externalized and fixed to the back of the neck. One day after placing the catheter, the arterial catheter was connected to the Model CP10 Pressure Transducer (Century Technology Company, Inglewood, CA, USA) which was assembled to a Model 7 polygraph from Grass (Grass Instruments, Quincy, MA USA). MAP and HR were simultaneously measured in conscious and free rats. Measurement of organ weights Under anesthesia with ketamine / xiazine, the heart, kidney and spleen were removed, dissected and weighed. The left ventricle was stored at 80 ° C for the evaluation of gene expression. Model or animal pressure load The induction of pressure overload by the partial attachment of the abdominal aorta in the rats was as previously described, Kimura et al., Am. J. Physiol. 1989: 256 (Heart Circ. Physiol. 25): Hi 006-HI-II; Batra et al., J. Cardiovasc. Pharl. 17 (suppl.2), S15I-S153; (1991). In brief, the rats were anaesthetized with ketamine / xiazine as described above. A third midline incision of 3 cm was made in the abdominal wall. The abdominal aorta between the diaphragm and the renal artery was exposed and bent with 5-0 silk suture. The suture was tensioned around a measuring needle 23 and then the needle was removed. The fake animals received the surgery without tightening the suture. Protocol or experiment in rats with overload pressure. Rats with random aortic union received by hypodermic injection of IFN-y at 0.08 mg / k twice daily for one day before surgery and for 14 days after surgery. Fake animals were not treated. Thirteen days after treatment, a catheter was implanted in the right carotid artery under anesthesia as indicated above. One day after implantation, blood pressure and HR were measured in conscious rats. The heart and other organs including the liver, kidney, and spleen were removed, weighed and fixed in 10% buffered formalin for pathological studies. The left ventricle was dissected rapidly and frozen with liquid nitrogen in some animals and stored at -80 ° C for the evaluation of gene expression.Statistical analysis.The results are expressed as means + SEM.A way of variant analysis (ANOVA) was performed to evaluate the differences in parameters between the groups, after which the important differences were subjected to the post hoc analysis using the Newman-Keuls method.; P < 0.05 was considered important. RNA preparation Total RNA was isolated using RNeasy Maxi Columns (Qiagen) according to the manufacturing instructions. RT-PCR Real-time RT-PCR technology (TaqManj) was used to compare the expression of the gene between the various treatment groups.An oligonucleotide probe containing a fluorescent staining reported, 6-carboxitetramethyl-rhodamine (TAMRA), to the exremo -3 'was designed to hybridize to the amplicon defined by the first two PCRs A 3-blockade-phosphate prevents the extension of the probe.The reported dyeing is released from the probe by the 5'-exonuclease activity of Taq polymerase During the extension phase of the PCR reaction, the resulting fluorescence is monitored in the reaction tube by the sequence detector and quantified without further manipulation, hence the term "real time." The threshold cycle number (Ct) ), defined as the point where the fluorescence reported reaches a value greater than 10 times the normal deviation of the baseline, being proportional to the amount of amplicon produced in the example. When the amplification is detected during the exponential phase of the amplification, none of the reaction components is limited. In each experiment, one control is analyzed as lacking the RNA template to monitor for contamination, and another control is included where the RT stage is omitted to eliminate the amplification of the possible DNA contamination as the source of the signal. The reactions are optimized to give a greater fluorescence signal and Ct is smaller by magnesium titration and primer concentrations, and the product is run on an agarose gel to verify the presence of a single band at the predicted molecular weight. In addition, the amplicon sequence is protected against Genbank to eliminate the possibility of overlapping with closely related genes. For each sample, the mRNA for each designated gene is determined using a normal curve as described below and then normalized to the amount of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in the sample (see below for the specifications of this calculation). ). The relative abundance of each gene designated to GAPDH between the treatment groups can be compared. RT-PCR was performed on 1 ng of total RNA per reaction using the Sequence Detector-TaqMan Model 7700 (ABI-Perkin Elmer) (Gibson et al., Genome Res 6, 995-10uX ~ 11996]). The amplification reaction conditions (for 50 μl) were lx Shocker A of TaqMan, 200 μM dATP, dCTP, dGTP, and 400 μM of dUTP, 10% of giicerol, 6.5 mM of MgCl, 50 U of MuLV of reverse transcriptase, 20 U of RNase Inhibitor, 1.25 U of A pliTaq Goid, 100 nM of the forward and opposite primer, and 100 nM of fluorogenic probe. The RT-PCR and giicerol reagents were obtained from Perkin Elmer and Sigma, respectively. The reactions were performed in MicoAmp Optical Tubes and Caps (ABI-Perkin Elmer). The TaqMan primers and probes were designed according to the guidelines determined by Perkin Elmer and synthesized in Genentech, Inc. except those for the GAPDH rodent which was a generous gift of Perkin Eimer. Reverse transcription was performed at 48 ° C for 30 minutes followed by heat activation of AmpliTaq Gold at 95 ° C for 10 minutes. The thermal cycle was at 95 ° C for 30 seconds and 60 ° for 1.5 minutes for 40 cycles. The quantification of the TaqMan results was performed as described by Heid et al., Genome Res. 6: 986-994 (1996), with nqdj.fi¿aciones. Briefly, the normal curves (1: 5 of dilution series) for each designated gene of interest were run in duplicate. The Ct was delineated on the Y axis against the recording of the total RNA concentration (X axis), and the equation describing the line was determined. The MARN for each designated gene was determined from the appropriate normal curve by entering Ct (Y value) and solving for the input mRNA (X). The value for the designated gene was then normalized to GAPDH by solving the following equation: 10/10, where XI is the designated gene, and X2 is GAPDH.
Results _ __ __ _ IFN-? inhibits cardiac hypertrophy Viral chronic administration of "fluprostenoi, an agonist analog of PGF2a- has been shown to induce cardiac hypertrophy in vi, and rats with pathological cardiac hypertrophy induced by myocardial infarction have chronically elevated levels of PGF2a extractable in its myocardium (Lai et al., supra) Thus, the factors that can inhibit the effects of PGF2a on myocardial growth in vi may be useful to treat cardiac hypertrophy.The rats were dosed with fluprostenol in the presence and absence of IFN-y for two weeks, and the effects on cardiac hypertrophy are determined.The absolute weight of the heart, ventricles, and left ventricle tends to increase in rats treated with fluprostenol, compared to vehicle controls, and there was a significant decrease in these parameters in the rats treated with fluprostenol + IFN-γ in relation to the rats treated with flupr ostenol (Table 1) Treatment with fluprostenol results in a significant increase in heart rate, in ventricular weight, and left ventricular weight to body weight (BW), indicating cardiac hypertrophy induced by fluprostenol (Figure 4), and Hypertrophy induced by inhibited fiuprostenol of iFN- ?. Rats receiving fiuprostenol + IFN-y have a decrease in ventricular and left ventricular weight of the heart, normalized by BW, compared to animals in the fiuprostenol groups (Figure 4). The comparison between IFN-y and vehicle treated groups • showed that the administration of IFN-y alone did not significantly alter or the left ventricular or ventricular weights of the normalized BW heat (Table 1, Figure 1). 4) . Chronic administration of fluprostenol was associated with a significant decline in mean arterial pressure (MAP) compared to controls "treated with the vehicle (Figure 5) .IFN-? Had no MAP effect compared to the vehicle, and did not affect MAP of animals treated with fluprostenol There was a significant alteration in the heart rate in the fourth treatment of the groups (Figure 5) These results indicate that IFN-y did not inhibit the hypertrophy induced by fluprostenol neutralizing the hemodynamic effects of the treatment. and not only inhibits the increase in cardiac mass associated with the administration of fluprostenol, but also the alterations in the expression of the cardiac gene associated with fluprostenol-induced hypertrophy (Figure 6) .There was an increase in the abundance of mRNA by actin a- skeleton, collagen 1, and the natriuretic factor in the hearts of rats treated with fluprostenol compared to the vehicle.MARN for calcium ATPase Sarcoplasmic reticulum was significantly reduced in these rats. The IFN-? inhibited all but the response to atrial natriuretic factor. IFN-y was also tested in a rodent model of cardiac hypertrophy induced by a pressure overload generated by the abdominal aortic junction.The constriction of the aorta results in cardiac hypertrophy as evidenced by substantial increases in absolute heart weights, left ventricular and ventricular, and also the proportions of these weights to BW.The treatment with IFN-y is markedly accentuated cardiac hypertrophy in this model (Table 2 and Figures 7 and 8) .The effect of IFN-y in others Also, the union of the aorta and the IFN-γ treatment did not alter the weight of the kidney and the proportion of the weight of the kidney to B, compared to the operated surrogate animals, the actual weight and the weight of the kidney. The proportion of BW tended to decrease in rats with the aorta junction treated with vehicle, but not in those treated with IFN-α. The constriction of the aorta caused a significant elevation in the weight of the aorta. absolute and normalized spleen of BW, which was exaggerated by the treatment of IFN-y. So, the effects of IFN-? in the heart mass were not- due to a generalized effect on the weight of the organ. Mean arterial pressure, systolic pressure and diastolic pressure were markedly higher in rats with constriction of the aorta compared to the operated controls of the substitutes, and the incremental increase in blood pressure was not different between the treated rats treated with IFN-? or vehicle (Figure 9). This result indicates that the accentuation of cardiac hypertrophy observed in the bound rats receiving IFN-? it is not related to an alteration in the subsequent load. Aortic constriction results in several changes in the expression of the cardiac gene. The relative abundance of mRNA for the heavy chain of β-myosin, a-soft muscle and a-skeletal actin, atrial natriuretic factor, collagens I and III, and fibronectin were increased in the bound rats compared to the controls operated on. the substitutes. The effects on two of these genes; in soft muscle actin and collagen I were inhibited by IFN-?
(Table 3). Taken together, the results in the
Examples 1 2 show that I FN-y can inhibit cardiac hypertrophy. The effects of IFN-y are not limited to inhibit an increase in cardiac mass induced by hypertrophic stimuli, IFN-y can also inhibit certain molecular alterations that occur in the heart with hypertrophy ~ at the level of gene expression. It is especially remarkable that IFN-? inhibit the induction of collagen gene expression
1 in vi, both in response to the chronic stimulus with fluprostenol and in a hypertrophy model induced by pressure overload. Collagen 1 is counted by approximately 75% of myocardial collagen (Ju et al., Can J. Caridol 12: 1259-1267 [1996]). __? 1_ Increased extracellular matrix deposition and interstitial fibrosis accompanying cardiac hypertrophy may contribute to the pathophysiology of cardiac deficiency. Inhibiting the production of collagen 1, IFN-y can reduce interstitial fibrosis in the case of cardiac deficiency.
Table 1. Body Weight and Body Weight in Rats Treated with Flup and / or IFN
The data expressed as means + SEM, and animal numbers are 14, 14, 14 and 9 in the Vehicle group, Flup, Flup + IFN, and IFN, respectively. Vehicle, saline; Flup, fluprostenol; IFN, interferon and, BWO, fundamental levels of body weight; BW, post treatment weight; ? BW, BW-BWO; HW, weight of the heart; VW, ventricular weight; LVW, left ventricular weight; KW, kidney weight; SW, weight of the spleen, * p < 0.05, ** p < 0.01, compared to the vehicle group, #p < 0.05, ## p < 0.01, compared to the Flup group.
Table 2, Body Weight, Body Weight, and HR in Rats with Pressure Overload __ _ _
The data expressed as means + SEM. The_ numbers of animals are 16, 22, and 21 in the Substitute, the PO + vehicle group, and PO + IFN, respectively, for all parameters except HR for which the animal number is 7, 8, and 7, respectively, PO, pressure overload; IFN, interferon and; BWO, fundamental levels of body weight; BW, post-treatment body weight; ? BW, BW-BWO; AW, atrial weight; KW, kidney weight; LW, real weight; SW, spleen weight; HR, heart rate, ^ p < 0.05, or * P < 0.01, compared to the substitute group, # p < 0.05, ## p < 0.01, compared to the PO + vehicle group.
PO indicates pressure overload; 1FN, interferon-gamma; ANF, atrial natriuretic factor; ßMHC, ß-myosin heavy chain; SKA, a-skeleton actin; SMA, mild muscle actin; COLI, collagen 1; COLIII, collagen III; FIB, Fibronectin. The expression levels ~ were calculated as proportions to glyceraldehyde-3-phosphate dehydrogenase, n = 6 per group, Values are mean + SEM, + P < 0.05 against the group of substitutes + vehicle.
It is noted that in relation to this date, the best method known to the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers. Having described the invention as "antecedent, property is claimed as contained in the following:
Claims (30)
1. A method of treating cardiac hypertrophy characterized in that a therapeutically effective amount of interferon gamma (IFN-y) is administered to a patient having cardiac hypertrophy.
2. The method according to claim 1, characterized in that the patient is human.
3. The method according to claim 1, characterized in that the IFN-y is IFN-? recombinant human (rh-lFN-y).
The method according to claim 3, characterized in that IFN-y is r IFN -? - lb.
5. The method according to claim 3, characterized in that the cardiac hypertrophy is characterized by the presence of an elevated level of PGF2a-
6. The method according to claim 2, characterized in that the cardiac hypertrophy has been induced by myocardial infarction. .
7. The method according to claim 6, characterized in that the administration of IFN-y is initiated within 48 hours following myocardial infarction.
8. The method according to claim 7, characterized in that the administration of iFN-y is initiated within 24 hours after myocardial infarction.
9. The method according to claim 2, characterized in that the patient is at risk of developing cardiac hypertrophy.
10. The method according to claim 9, characterized in that the patient has suffered a myocardial infarction.
11. The method according to claim 10, characterized in that the administration of IFN-y is initiated within 48 hours following myocardial infarction.
12. The method according to claim 11, characterized in that the administration of IFN-y is initiated within 24 hours after myocardial infarction.
13. The method according to claim 2, characterized in that the IFN-y is administered in combination with at least one additional therapeutic agent used for the treatment of cardiac hypertrophy or a cardiac deficiency resulting in cardiac hypertrophy.
14. The method according to claim 13, characterized in that the additional therapeutic agent is selected from the group consisting of β-andrenergic blocking agents, verapamil, difedipine, and diltiazem.
15. The method according to claim 14, characterized in that the β-adrenergic blocking agent is carvedilol, propranolol, metoprolol, timolol, oxprenolol or tetratolol.
16. The method of compliance "with claim 13, characterized in that the IFN-y is administered in combination with an antihypertensive drug.
17. The method according to claim 13, characterized in that the IFN-y is administered with an ACE inhibitor.
18. The method according to claim 13, characterized in that IFN-y is administered with an endostelin receptor antagonist.
19. The method according to claim 13, characterized in that the IFN-? it is administered followed by the administration of a thrombolytic agent.
20. The method according to claim 18, characterized in that the thrombolytic agent is a plasminogen activator of recombinant human tissue (rht-PA).
21. The method according to claim 13, characterized in that the IFN-? is administered followed by angioplasty prrimaria 'for the treatment of acute myocardial infarction.
22. A method for making a pharmaceutical composition for the treatment of cardiac hypertrophy, characterized in that it comprises administering a therapeutically effective amount of gamma interferon (IFN-y) with a pharmaceutically acceptable carrier.
23. The method according to claim 22, characterized in that the pharmaceutical composition is liquid.
24. The method according to claim 22, characterized in that the pharmaceutical composition comprises a condom.
25. The method according to claim 23, characterized in that the pharmaceutical composition is an injectable formulation.
26. The use of a pharmaceutical product characterized in that it comprises: (a) a pharmaceutical composition comprising at least one therapeutically effective dose of IFN-y (b) a container containing the pharmaceutical composition; and (c) a label attached to the container, or an inserted package included in the pharmaceutical product that relates the use of IFN-y in the treatment of cardiac hypertrophy.
27. The use according to claim 26, characterized in that the container has a sterile access opening.
28. The use according to claim 26, characterized in that the container is an intravenous solution bag or vial having a cap penetrable by a hypodermic injection needle.
29. IFN-Iy- for use in a method of treating cardiac hypertrophy according to any of claims 1-21.
30. The use of IFN-y for the preparation of a medicament for the treatment of cardiac hypertrophy according to any of claims 1-21.
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US60/080,448 | 1998-04-02 |
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