Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
• • 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

• the present invention relates to pharmaceutical compositions useful for treating or preventing cardiovascular disease, and to methods for using these compositions in treating or preventing cardiovascular disease.
• AMI acute myocardial infarctions
• AMI exhibits a mortality rate of approximately 30%; more than half of these deaths occur before the patient reaches the hospital. Of those patients who survive the initial hospitalization, approximately 1 in 25 will die in the first year after suffering an AMI, and elderly patients fare even worse, with 30% dying within one year of an AMI.
• ventricular remodeling This involves the dilation of the left ventricle, initially from expansion of the infarct with resulting thinning and elongation of the infarct region, and subsequently from lengthening of noninfarcted segments as a result of an architectural rearrangement of the myocardium, including cardiomyocytes and interstitial cells. In cases of large AMI, this progressive dilation often results in increasing hemodynamic impairment, more frequent progression to heart failure, and a poor prognosis.
• Gene therapy offers a potential alternative for the treatment of cardiovascular disease, especially the treatment of AMI. To this end, it would be desirable to identify genes related to cardiovascular disease and develop methods of altering the expression patterns of those genes so as to prevent the development of the disease or reduce its effects once it has occurred.
• compositions are provided that are useful in preventing and treating cardiovascular disease.
• the compositions comprise a pharmaceutically acceptable carrier, and an effective therapeutic or prophylactic amount of an agent that changes the expression pattern of a gene related to cardiovascular disease.
• Methods are also provided for the use of the pharmaceutical compositions in the alteration of intracellular levels of cardiovascular disease-related proteins.
• the agent is a nitroxide antioxidant, such as Tempol (4-hydroxy ⁇ 2,2,6,6- tetramethylpiperidine-1-oxyl).
• Tempol (4-hydroxy ⁇ 2,2,6,6- tetramethylpiperidine-1-oxyl).
• Use of nitroxide antioxidants such as Tempol has been proposed as a treatment for ischemic cell damage in cases of acute resuscitation, such as myocardial infarction.
• Tempol as a treatment after the primary ischemic situation has been resolved, in order to ameliorate the longer-term effects of cardiovascular disease by reducing ventricular remodeling, has not been proposed.
• the agent used to downregulate genes related to cardiovascular disease is a nitroxide antioxidant.
• Tempol is a stable nitroxide radical characterized by the chemical formula 4- hydroxy-2,2,6,6-tetramethylpiperidine-l-oxyl that has antioxidative properties. The present applicants have discovered that Tempol also possesses the novel property of altering the expression of genes encoding for proteins associated with the development or progression of cardiovascular disease (see Tables 1 and 2 below). Previous therapies have generally not focused on altering the expression patterns of such cardiovascular disease- related genes.
• nitroxide compound can be selected from the following formulas:
• X is selected from O- and OH, and R is selected from COOH, CONH 5 CN, and CH 2 NH 2 .
• X is selected from O- and OH
• R 1 is selected from CH 3 and spirocycl ⁇ hexyl
• R 2 is selected from C 2 H 5 and spirocyclohexyl.
• X is selected from O- and OH and R is selected from CONH.
• X is selected from O- and OH and R is selected from H, OH, and NH 2 .
• Suitable nitroxide compounds can also be found in Proctor, U.S. Patent No. 5,352,442, and Mitchell et al, U.S. Patent No. 5,462,946, both of which are hereby incorporated by reference in their entireties.
• a non-limiting list of nitroxide compounds include: 2-ethyl-2,5,5- trimethyl-3-oxazolidine- 1 -oxyl (OXANO), 2,2,6,6-tetramethylpiperidine- 1 -oxyl (TEMPO), 4-hydroxy-2,2,6,6-tetramethyl ⁇ i ⁇ eridine-l-oxyl (TEMPOL), 4-amino-2,2,6,6- tetramethyl-1-piperidinyloxy (Tempamine), 3-Aminomethyl-PROXYL, 3-Cyano- PROXYL 5 3-Carbamoyl-PROXYL, 3-Carboxy-PROXYL, and 4-Oxo-TEMPO.
• OXANO 2-ethyl-2,5,5- trimethyl-3-oxazolidine- 1 -oxyl
• TEMPO 2,2,6,6-tetramethylpiperidine- 1 -oxyl
• TEMPOL 4-hydroxy-2,2,6,6-tetramethyl ⁇ i ⁇ eridine-l-oxy
• TEMPO can also be substituted, typically in the 4 position, for example, 4-amino, 4-(2- bromoacetamido), 4-(ethoxyfluorophosphonyloxy), 4-hydroxy, 4-(2-iodoacetamido), 4- isothiocyanato, 4-maleimido, 4-(4-nitrobenzoyloxyl), 4-phosphonooxy, and the like.
• Tempol was administered to experimental mice at a dose of 5 mg/g of food from 14 months to 31 months after birth. Mice receiving the same food without the addition of Tempol were used as a negative control. At the age of 31 months, the experimental animals were sacrificed and the hearts were surgically removed. The expression of a broad spectrum of genes in the cardiac tissue was assessed using chip-based microarray technology. Such chips are well known in the art and are widely used to assess gene expression. The experimental results showed that a gene related to cardiovascular disease, hepatocyte growth factor, exhibited a more than threefold increase in expression. This gene is shown in Table 1. TABLE 1: CARDIOVASCULAR DISEASE-RELATED GENE EXHIBITING INCREASED EXPRESSION IN CARDIAC TISSUE AFTER TEMPOL
• Tempol was administered to experimental mice at a dose of 5 g/kg of diet from 12 months through 15 months. Mice receiving the same diet without the addition of Tempol were used as a negative control. At the age of 15 months, the adipose tissue of the experimental animals was obtained. The expression of a broad spectrum of genes in the adipose tissue was assessed using chip-based microarray technology. Specifically, in this case an Affymetrix MOE430A 2.0 array, containing 12,960 genes, was employed. Such chips are well known in the art and are widely used to assess gene expression. The experimental results on the adipose tissue show that genes related to cardiovascular disease, caspase 3 and adiponectin, exhibited altered expression. These genes are shown in Table 2.
• HGF Hepatocvte Growth Factor
• HGF has been implicated in tissue regeneration, angiogenesis and apoptosis.
• mice were given adenovirus encoding human HGF intramuscularly three days following the induction of myocardial infarction, while in a control group, the LacA gene was used.
• the mice receiving the human HGF gene showed persistently increased plasma HGF, and improved left ventricular remodeling and less cardiac dysfunction was also observed at four weeks post-treatment, as indicated by a smaller left ventricular cavity and heart/body weight ratio, greater percent fractional shortening and left ventricular ⁇ dP/dt, and lower left ventricular end-diastolic pressure.
• the cardiomyocytes proximate to the myocardial infarct in the treated mice were also greatly hypertrophied, and the infarct wall was thicker due to an increased density of both cardiomyocytes and blood vessels.
• ADIPOQ is an adipocyte-derived peptide that regulates energy metabolism and endothelial activation. ADIPOQ levels have been shown to be decreased in patients with cardiovascular disease. For example, a recent study showed that a population of patients with arteriosclerosis obliterans, a typical disorder of arteriosclerosis in which arterial obstruction occurs in arteries supplying blood in lower extremities, had a significantly lower level of serum adiponectin than that found in control subjects (Kawano et al., Metabolism Clinical and Experimental 54 (2005) 653-656).
• Caspase 3 is a member of the cystene-aspartic acid (caspase) family of proteases. Caspases exist as inactive proenzymes which undergo proteolytic processing and dimerization to form the active enzymes, and are activated in a sequential manner and play a central role in the execution phase of apoptotic death by cleaving many structural and regulatory proteins.
• the proapoptotic proteases are organized in a hierarchical cascade: the apical or initiator caspases 8 and 9 cleave and activate the effector caspases 3, 6, and 7.
• Caspase 3 has been shown to be the primary executioner caspase. Mice engineered to overexpress caspase 3 in the heart have been shown to have an increased susceptibility to death when subjected to cardiac ischemia-reperfusion injury: only 45% and 30% of caspase 3-overexpressing mice were alive after 2 and 24 hours of reperfusion, respectively, versus 90% and 70% of control mice (Condorelli et al., PNAS 98:17 (2001) 9977-9982). The infarct size of the caspase 3 overexpressing mice was also increased.
• Tempol has the effect of altering the expression of genes related to cardiovascular disease. Since the expression of these genes is altered, administration of Tempol will have a beneficial effect by altering concentrations of gene products that are linked to the amelioration of cardiovascular disease. Specifically, Tempol will have at least the beneficial effects of increasing HGF and ADIPOQ concentrations and thereby reducing the extent of ventricular remodeling and the risk of developing cardiovascular disease, and of reducing the concentration of caspase 3 and thereby reducing the extent of apoptosis subsequent to ischemia-reperfusion injury. In a preferred embodiment of the present invention, therefore, Tempol is administered to a mammalian host, such as a human, exhibiting no symptoms of cardiovascular disease in order to prevent the development of cardiovascular disease.
• a mammalian host such as a human
• Particularly preferred patients are those who are predisposed or otherwise at risk for cardiovascular disease, such as those with a family history of cardiovascular disease, those with genetic or serum markers associated with cardiovascular disease, or those scheduled to undergo medical procedures in which cardiovascular disease is a possible side effect.
• Tempol may be administered to a human exhibiting cardiovascular disease, such as post- AMI, after primary treatment of ischemia has been conducted, in order to improve the recovery of the patient from the cardiovascular disease.
• Tempol, non- toxic salts thereof, acid addition salts thereof or hydrates thereof may be administered systemically or locally, usually by oral or parenteral administration.
• the doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment, hi the human adult, the dose per person at a time is generally from about 0.01 to about 1000 mg, by oral administration, up to several times per day.
• Specific examples of particular amounts contemplated via oral administration include about .02, .03, .04, .05, .10, .15, .20, .25, .30, .35, .40, .45, .50, .55, .60, .65, .70, .75, .80, .85, .90, .95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82,
• the dose per person at a time is generally from about 0.01 to about 300 mg/kg via parenteral administration (preferably intravenous administration), from one to four or more times per day.
• parenteral administration preferably intravenous administration
• Specific examples of particular amounts contemplated include about .02, .03, .04, .05, .10, .15, .20, .25, .30, .35, .40, .45, .50, .55, .60, .65, .70, .75, .80, .85, .90, .95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 205, 210, 215,
• Continuous intravenous administration is also contemplated for from 1 to 24 hours per day to achieve a target concentration from about 0.01 mg/L to about 100 mg/L.
• Specific examples of particular amounts contemplated via this route include about .02, .03, .04, .05, .10, .15, .20, .25, .30, .35, .40, .45, .50, .55, .60, .65, .70, .75, .80, .85, .90, .95, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 61, 68
• Tempol may be administered in the form of, for example, solid compositions, liquid compositions or other compositions for oral administration, injections, liniments or suppositories for parenteral administration.
• Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders and granules.
• Capsules include hard capsules and soft capsules.
• Tempol may be admixed with an excipient (e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch), combining agents (hydroxypropyl cellulose, polyvinyl pyrrolidone or magnesium metasilicate aluminate), disintegrating agents (e.g. cellulose calcium glycolate), lubricating agents (e.g. magnesium stearate), stabilizing agents, agents to assist dissolution (e.g. glutamic acid or aspartic acid), or the like.
• an excipient e.g. lactose, mannitol, glucose, microcrystalline cellulose, starch
• combining agents hydroxypropyl cellulose, polyvinyl pyrrolidone or magnesium metasilicate aluminate
• disintegrating agents e.g. cellulose calcium
• the agents may, if desired, be coated with coating agents (e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. Further, coating may include containment within capsules of absorbable materials such as gelatin.
• coating agents e.g. sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate
• coating may include containment within capsules of absorbable materials such as gelatin.
• Liquid compositions for oral administration include pharmaceutically acceptable solutions, suspensions, emulsions, syrups and elixirs.
• Tempol is dissolved, suspended or emulsified in a commonly used diluent (e.g. purified water, ethanol or mixture thereof).
• a commonly used diluent e.g. purified water, ethanol or mixture thereof.
• such liquid compositions may also comprise wetting agents or suspending agents, emulsifying agents, sweetening agents, flavoring agents, perfuming agents, preserving agents, buffer agents, or the like.
• injections for parenteral administration include solutions, suspensions, emulsions and solids which are dissolved or suspended.
• Tempol may be dissolved, suspended and emulsified in a solvent.
• the solvents are, for example, distilled water for injection, physiological salt solution, vegetable oil, propylene glycol, polyethylene glycol, alcohol such as ethanol, or a mixture thereof.
• the injections may also include stabilizing agents, agents to assist dissolution (e.g. glutamic acid, aspartic acid or POLYSORBATE80 (registered trade mark)), suspending agents, emulsifying agents, soothing agents, buffer agents, preserving agents, etc. They are sterilized in the final process or manufactured and prepared by sterile procedure. They may also be manufactured in the form of sterile solid compositions, such as a freeze-dried composition, and they may be sterilized or dissolved immediately before use in sterile distilled water for injection or some other solvent.
• compositions for parenteral administration include liquids for external use, and ointment, endermic liniments, inhale, spray, suppositories for rectal administration and pessaries for vaginal administration which comprise Tempol and are administered by methods known in the art.
• Spray compositions may comprise additional substances other than diluents: e.g. stabilizing agents (e.g. sodium sulfite hydride), isotonic buffers (e.g. sodium chloride, sodium citrate or citric acid).
• stabilizing agents e.g. sodium sulfite hydride
• isotonic buffers e.g. sodium chloride, sodium citrate or citric acid.
• a small aerosol particle size useful for effective distribution of the medicament may be obtained by employing self-propelling compositions containing the drugs in micronized form dispersed in a propellant composition.
• Effective dispersion of the finely divided drug particles may be accomplished with the use of very small quantities of a suspending agent, present as a coating on the micronized drug particles. Evaporation of the propellant from the aerosol particles after spraying from the aerosol container leaves finely divided drug particles coated with a fine film of the suspending agent. In the micronized form, the average particle size is less than about 5 microns.
• the propellant composition may employ, as the suspending agent, a fatty alcohol such as oleyl alcohol.
• the minimum quantity of suspending agent is approximately 0.1 to 0.2 percent by weight of the total composition.
• the amount of suspending agent is preferably less than about 4 percent by weight of the total composition to maintain an upper particle size limit of less than 10 microns, and preferably 5 microns.
• Propellants that may be employed include hydrofluoroalkane propellants and chlorofluorocarbon propellants. Dry powder inhalation may also be employed. Example 1
• a 70-kilogram patient three days post myocardial infarction is administered a dose of 1500 mg of Tempol per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the protein level of hepatocyte growth factor and adiponectin in the plasma is increased, and the protein level of caspase 3 is decreased.
• a 70-kilogram patient at risk for myocardial infarction is administered a dose of 1500 mg of Tempol per day for 180 days. This may be administered in a single dose, or may be administered as a number of smaller doses over a 24-hour period: for example, three 500-mg doses at eight-hour intervals. Following treatment, the protein level of hepatocyte growth factor and adiponectin in the plasma is increased, and the protein level of caspase 3 is decreased.

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• 2006
  • 2006-02-02 JP JP2007554271A patent/JP2008528704A/ja active Pending
  • 2006-02-02 WO PCT/US2006/003975 patent/WO2006084200A2/en not_active Ceased
  • 2006-02-02 US US11/815,446 patent/US20090062338A1/en not_active Abandoned

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