TREATMENT OF DISEASE STATES

Abstract: The invention presents methods for the treatment of symptoms associated with diseases states including cardiomyopathy, Parkison's Disease and degenerative liver disease including cirrhosis comprising treatment with an effective amount of a composition comprising beta-amyloid, streptolysin O, and growth hormone.

Description: TREATMENT OF DISEASE STATES This is a continuation-in-part of U.S. Serial No. 08/810,725 filed March 4, 1997. FTELD OF INVENTION This invention relates generally to methods and materials for the treatment and amelioration of the symptoms associated with cardiomyopathy in non-human animals, Parkinson's Disease, and degenerative liver disease including cirrhosis. BACKGROUND OF THE INVENTION Cardiomyopathy is a disease of the heart muscle. This form of heart disease is often distinctive, both in general symptoms and in patterns of blood flow, to allow a diagnosis to be made. Increasing recognition of this disease, along with improved diagnostic techniques, has shown that cardiomyopathy is a major cause of morbidity and mortality. In some areas of the world it may account for as many as 30 percent of all deaths due to heart disease. Cardiomyopathy can result from a variety of structural or functional abnormalities of the ventricular myocardium. A large number of cardiomyopathies are apparently not related to an infectious process and are not well understood. Some are congenital and may cause enlargement of the heart. Metabolic diseases associated with endocrine disorders may also cause cardiomyopathies. Infections, such as acute rheumatic fever and several viral infections, may cause a number of types of myocarditis. Myocarditis may also occur as a manifestation of a generalized hypersensitivity reaction, allergic or immunologic. The heart may also be affected by any of a considerable number of collagen diseases. Collagen is the principal connective tissue protein, and collagen diseases are diseases of the connective tissues. They include diseases primarily of the joints, skin, and systemic disease. There are three clinical classifications of cardiomyopathy; hypertrophic, restrictive, and dilated congestive. Dilated congestive cardiomy- opathy is a disorder of myocardial function where ventricular dilation occurs, often following virus infection. Restrictive cardiomyopathy occurs as a consequence of the ventricular walls becoming rigid so that the chambers are unable to fill adequately. This is usually idiopathic. Hypertrophic cardiomyopathy is characterized by ventricular hypertrophy and may be congenital or acquired. The prognosis for all three types of disease is guarded at best and often poor. Treatment of cardiomyopathy involves restricted activity, stress avoidance, treatment with beta-blockers, prophylactic antibiotic therapy, use of anti-coagulants, calcium channel blockers, surgery, and cardiac transplantation. Of interest to the present application are the disclosure of co- owned published PCT international applications PCT/US91/01898 published November 14, 1991, PCT/US95/06689 published November 30, 1995, and PCT/US97/14005 filed August 8, 1997 and U.S. Patent No. 5,753,624 issued May 19, 1998 the disclosures of which are hereby incorporated by reference. These references relate in part to methods for alleviating symptoms associated with amyloid plaque formation and/or formation of arterial plaques comprising the step of administering to a patient an effective amount of amyloid protein. Recent literature reports have focused on the use of somatotro- pin, a growth hormone, for the treatment of cardiomyopathy. See: "A Preliminary Study of Growth Hormone in the Treatment of Dilated Cardiomy- opathy," N.E. J. of Medicine, 334(13), pp. 811-814 (1996). However, cautionary responses to such reports speak to the possibility, or even likelihood, of inducing cancer, arrhythmias, and other problems with growth hormone therapy using the concentrations now being evaluated by those authors. Accordingly, there remains a desire in the art for effective cardiomyopathy therapies that allow reduction in the amount of growth hormone administered and do not suffer from the limitations of the prior methods. SUMMARY OF THE INVENTION The present invention relates to the discovery that treatment of cardiomyopathy with a combination of compounds is effective in improving heart function. The therapeutic composition described herein is comprised of three compounds, each with a specific function relative to the amelioration of symptoms associated with cardiomyopathy. They are: beta-amyloid protein, streptolysm O, and growth hormone. It has been found that the admmistration of these compounds in combination is surprisingly effective in treating the symptoms associated with cardiomyopathy and allows a reduction in the amount of growth hormone required for a useful therapeutic effect. Beta-amyloid acts to reduce vascular plaquing that may be associated with the disease. Streptolysin O reduces or eliminates cardiac scarring associated with the heart disease. Streptolysin O is one of a group of filterable hemolysins derived from Group A beta-hemolytic streptococci. Specifically, streptolysin O is a 60kD peptide which is hemolytic in its reduced state but is inactivated upon oxidation. Streptolysin O is used in the art generally as an analytical reagent for permeabilizing cells. See, e.g. , Razin et al., Proc. Nafl. Acad. Sci. (USA), 91:7722-7726 (1994). Co-owned U.S. Patent No. 5,576,289, the disclosure of which is incorporated by reference, discloses the use of streptolysin O in methods for treating disease states characterized by motor deficit disorders. No disclosure is made in that patent of utility of streptolysin O in treating cardiomyopathy. Growth hormone stimulates healing of the compromised heart. Growth hormone functions to regulate somatic growth and also maintains muscle mass and strength. It can also act as a counterregulatory hormone opposing the action of insulin on carbohydrate and lipid metabolism. It has been discovered that by administration of a combination of the above compounds symptoms associated with cardiomyopathy are reduced or stabilized. The present invention provides methods for treating cardiomyopathy by administration of an effective amount of a composition comprising beta-amyloid, streptolysin O, and growth hormone. Methods of the invention result in amelioration of the symptoms associated with cardiomyopathy such as angina, fatigue, loss of strength, respiratory insufficiency, edema, interrupted sleep, recurrent respiratory infection, and the like. Noticeable improvement and/or stabilization of the disease symptoms were obtained after treatment. Improved Ejection Fraction (EF), blood pressure, and echo cardiogram readings were also noted in some cases. The invention comprises the step of administering an effective amount of beta-amyloid, streptolysin O, and growth hormone in combination, to a human or non-human subject suffering from cardiomyopathy. The precise dose will vary among patients and may readily be determined by those skilled in the art. Useful dosages generally range from about 1 x 10 ~π mg to 10 mg of beta-amyloid, about 0.0005 units to 50 units streptolysin O, and about 1 x 10 "16 I.U. to 100 I.U. growth hormone, with preferred dosages of from about 10 "7 mg to 1.0 mg, 0.1 units to 10 units, and 10 "4 I.U. to 10 I.U., of each compound respectively. It is particularly preferred that dosages of about 0.1 I.U. or less of growth hormone be used to minimize potential negative effects of growth hormone therapy. Most preferred is the use of growth hormone at dosages of 0.01 I.U. or less. The compositions of the invention may be administered by a variety of routes of admmistration including intravenous, intramuscular, subcutaneous, intrathecal, and oral, with sublingual administra- tion being preferred. It is also anticipated that alternative routes of administration may be by inhalation and topical application. The preferred dosage for sublingual application is 1-10 drops (0.05 ml/drop) per day according to the above formula. Subcutaneous injections are administered 1-3 times a day. The invention further provides Parkinson's Disease in a subject, comprising the step of administering to a subject diagnosed with Parkinson's Disease a composition comprising an effective amount of beta-amyloid, streptolysin O, and growth hormone. The precise dose will vary among patients and may readily be determined by those skilled in the art. Useful dosages generally range from about 1 x 10 ~n mg to 10 mg of beta-amyloid, about 0.0005 units to 50 units streptolysin O, and about 1 x 10 "16 I.U. to 100 I.U. growth hormone, with preferred dosages of from about 10 "7 mg to 1.0 mg, 0.1 units to 10 units, and 10 "4 I.U. to 10 1.U., of each compound respectively. It is particularly preferred that dosages of about 0.1 I.U. or less of growth hormone be used to minimize potential negative effects of growth hormone therapy. Most preferred is the use of growth hormone at dosages of 0.01 I.U. or less. The compositions of the invention may be administered by a variety of routes of administration including intravenous, intramuscular, subcutaneous, intrathecal, and oral, with sublingual administration being preferred. It is also anticipated that alternative routes of admmistration may be by inhalation and topical application. The preferred dosage for sublingual application is 1-10 drops (0.05 ml/drop) per day according to the above formula. Subcutaneous injections are administered 1-3 times a day. The invention further provides degenerative liver disease in a subject, comprising the step of administering to a subject diagnosed with degenerative liver disease a composition comprising an effective amount of beta-amyloid, streptolysin O, and growth hormone. Degenerative liver diseases which may be treated according to the invention include, but are not limited to cirrhosis. The precise dose will vary among patients and may readily be determined by those skilled in the art. Useful dosages generally range from about 1 x 10 "11 mg to 10 mg of beta-amyloid, about 0.0005 units to 50 umts streptolysin O, and about 1 x 10 "16 I.U. to 100 I.U. growth hormone, with preferred dosages of from about 10 7 mg to 1.0 mg, 0.1 umts to 10 umts, and 10 "4 I.U. to 10 I.U. , of each compound respectively. It is particularly preferred that dosages of about 0.1 I.U. or less of growth hormone be used to minimize potential negative effects of growth hormone therapy. Most preferred is the use of growth hormone at dosages of 0.01 I.U. or less. The compositions of the invention may be administered by a variety of routes of administration including intravenous, intramuscular, subcutaneous, intrathecal, and oral, with sublingual administration being preferred. It is also anticipated that alternative routes of admmistration may be by inhalation and topical application. The preferred dosage for sublingual application is 1-10 drops (0.05 ml/drop) per day according to the above formula. Subcutaneous injections are administered 1-3 times a day. Additional aspects and advantages of the invention will become apparent upon consideration of the following detailed description thereof. DETAILED DESCRIPTION OF THE INVENTION It has been discovered that treatment of a patient suffering from cardiomyopathy with a composition comprising beta-amyloid, streptolysin O, and growth hormone can reduce or stabilize the disease symptoms. Administra- tion of the composition of the invention has been shown to be effective in clinical improvement in angina, energy, and strength. It has also been shown to have a stabilizing effect on echocardiogram testing indicating improved cardial function and efficiency. A number of animal and human clinical trials have been conducted and the results are presented herein in the form of several examples. In each human test case, clinical histories of the patients were known or taken prior to treatment according to the invention. In the reported examples, reduction or stabilization of the adverse symptoms of cardiomyopathy were noted. In some cases, improved EF ratings were observed after treatment according to the invention, along with increased energy and strength. In treatment of dogs of various breeds, ages, and sizes, disease symptoms either remained stable or improved without adverse effects. In 70% of the cases, improved performance, endurance, and vitality were observed in dogs. Compositions according to the invention comprise effective combinations of from about 1 x 10 "10 to about 1 x 10 mg beta-amyloid, from about 0.0005 units to about 50 units streptolysin O, and from about 1 x 10 "6 International Units (I.U.) to about 100 I.U. growth hormone. According to a preferred embodiment, a composition is provided which comprises about 4 x 10 "9 mg beta-amyloid, about 2 umts streptolysin O, and less than 4 I.U. of human growth hormone with less than 0.1 I.U. being preferred and about 0.01 I.U. growth hormone being particularly preferred. Growth hormone used in this invention can be of a human, porcine, bovine, or other source, and can be produced by recombinant methods. Proper dosing of the composition of the present invention may easily be determined by the skilled artisan using standard procedures and upon evaluation of the severity of a patient's symptoms. The compositions of the invention may be formulated in an appropriate pharmaceutical vehicle, including water, saline, dextrose, and albumin. In the present invention, human patients in the foregoing examples were treated using relatively low doses of the compositions. Drops were administered daily of a composition comprising 4 x 10 "9 mg beta-amyloid, 2 units streptolysin O, and 0.01 I.U. growth hormone. The preferred route of administration was sublingually and patients were generally instructed to self- administer from one to about 6 drops daily. Provided below are case histories of patients being treated according to the invention which provide evidence of the effectiveness of the treatment methods described herein. The following Examples are intended to illustrate practice of the preferred embodiments of the invention. Numerous additional embodiments and improvements are apparent upon consideration of the following Examples. EXAMPLE 1 Cardiomyopathy Forty dogs of varied ages, breeds, and exhibiting symptoms of cardiomyopathy were treated with a 0.2cc subcutaneous injection of the composition of the invention comprising 4 x 10 "9 mg beta-amyloid, 2 units streptolysin O and 0.01 I.U. growth hormone. Prior to treatment, the dogs were lethargic, depressed, and easily exhausted. After treatment of several weeks to several months, the dogs exhibited noticeable improved performance and energy. Significant improved activity performance and vitality was observed in 70% of the dogs. EXAMPLE 2 A 74-year-old male with a history of cardiomyopathy was treated according to the methods and compositions of the invention. The patient received 4 drops a day of a composition comprising 4 x 10 ~9 mg beta-amyloid, 2 units streptolysin O, and 0.01 I.U. growth hormone. His initial ejection fraction (EF) by echocardiogram was 35 % , while three months later it had improved to 50%. A repeat echocardiogram was not readable at the six-month evaluation, however, a MUG A (multiple gated acquisition) scan revealed a normal EF of 53 % . This reading was significantly better than the baseline EF of 35%, even with the variation in echocardiogram versus MUGA EF determinations. After approximately 6 months of treatment, the patient's blood pressure was 140/70 with a heart rate of 68. One month later, his blood pressure was 122/82 with only one episode of chest pain. A significant improvement in left ventricular function was noted. The patient has reported increased energy and strength and reported no angina symptoms for one month. EXAMPLE 3 Cardiomyopathy A 73-year-old male with a history of multiple cardiomyopathic symptoms was treated according to the procedure set out in Example 2. His initial EF by echocardiogram was 25%, while three months after treatment, his EF was 20%. At the six-month evaluation, he had 2+ edema (nonpitting) and a repeat echocardiogram revealed an EF of 25-30% compared to a baseline of 25 % . The patient's blood pressure was 142/70. The patient reported dramatic clinical improvement in angina, energy, and strength. After another month of treatment, his echocardiogram EF remained unchanged, but he continued to have no angina, good energy levels, and strength. He also reported that when he stopped using the composition after 2-3 days, he had pain across his anterior chest and became more fatigued and complained of less strength. EXAMPLE 4 Cardiomyopathy A 70-year-old female with a history of multiple medical problems, including cardiomyopathy, was treated according to the procedure set out in Example 2. This patient had multiple admissions to the hospital with recurrent angina and congestive heart failure. Her EF remained severely depressed at 10-15% after seven months treatment. She had severe coronary artery disease and prognosis was poor. The patient had periods of improvement clinically, but this was earlier in treatment according to the invention. Her initial EF by echocardiogram was 15-20% , while three months later it was 10- 15 %. It has remained stable for an additional three months. She recently suffered another episode of angina and her EF remains at 10% . It is believed advanced coronary disease prevented a more positive response to the compositions of the invention. EXAMPLE 5 Cardiomyopathy An 86-year-old male with a history of a dilated cardiomyopathy and an EF of 25 % by a chemical stress sestamibi prior to treatment according to the invention. He also had moderately severe chrome obstructive pulmonary disease (COPD). His main symptoms include dyspnea and palpitations, especially during exertion, extreme fatigue, lethargy, and shortness of breath. After one month of treatment with 1 drop of a composition, according to Example 2, four times daily, his blood pressure was 142/80 and his lungs were clear but decreased. His pulse was 72. After two months of treatment, he was slightly improved and continued to have less severe dyspnea and less lethargy. He continued to be fatigued, but needed less sleep. Palpitations were present, but less frequent. His energy level was similar, although he was more active. There appeared to be slight clinical improvement overall after two months of treatment according to the therapy. EXAMPLE 6 Cardiomyopathy A 69-year-old male with a history of ischemic cardiomyopathy, chronic atrial fib/flutter, COPD, diabetes mellitus type 2, congestive heart failure, and hyperlipidemia was treated with 1 drop four times daily according to the procedure in Example 2. An initial echocardiogram revealed an EF of 10-20% . Prior to treatment, this patient had been a virtual invalid and practically confined to a chair. He had tachycardia intermittently, extreme fatigue, and dyspnea with minimal exertion. He also had extreme shortness of breath. On the first day of treatment, his blood pressure was 102/70. His lung sounds were decreased and the heart rhythm was atrial fibrillation. A month after treatment began, he was walking without shortness of breath and his energy improved. His palpitations, which were occurring daily, had occurred only once in two weeks. He had no chest pain. He continued to improve and had no palpitations or chest pain after two months of treatment. He developed dyspnea and palpitations, however, after physical exertion using a treadmill. After an additional two weeks of treatment, the patient continued to significantly improve. He was no longer confined to a chair and is able to walk about throughout the day. His lungs were clear, but had a trace of edema. His blood pressure remained good. The following examples are directed to treatment of Parkinson's Disease using the compositions of the invention comprising the combination of beta-amyloid, streptolysin O, and growth hormone. EXAMPLE 7 Parkinson's Disease According to this example a 71 year-old female diagnosed with Parkinson's Disease had been treated with medications including Sinemet 50/200 CR BID and Permax .25 BID for three years. Her initial complaints were difficulty moving her left side, problems with handwriting and trouble with gait. Prior to treatment with the composition of the invention she continued to have a slight left tremor (upper extremity), cogwheel rigidity on the left and masked facies. Upon examination, she complained of numbness bitemporalfy, heavy tired feeling in the afternoon, difficulty with left arm and left leg movement, tremor with fatigue, trouble typing letters and trouble getting her words out at times. Further, she swayed with walking with arms at her sides, had mild flexion/extension weakness of her left arm and left leg and minimal to no spasticity. Neither significant cogwheel rigidity or tremor was detected. The subject was treated with sublingual administration of a composition comprising 4 x 10 "9 mg beta-amyloid, 2 umts streptolysin O, and 0.01 I.U. growth hormone three times daily. Upon follow-up examination four weeks later the subject was able to type a letter for the first time in 3 to 4 months. Previously, the subject could not coordinate the left hand with the right. Upon follow-up examination one month later the subject reported that she felt fatigued after her vacation and was unable to type since she felt tired but that there were no other changes including tremor. Her dosage was then increased to four times daily. EXAMPLE 8 Parkinson's Disease According to this example a 67 year-old female diagnosed with Parkinson's Disease initially declined treatment but was treated with Sinemet which helped her tremor. After one year of treatment the subject developed side effects and discontinued treatment with Sinemet although she continued treatment for other conditions including Synthroid for hypothyroid, Isoptin for hypertension, Navane (paranoia), Benadryl, Cogentin, Lescol and estrogen. Her mental state has been stable for years. Upon evaluation, three years after her original diagnosis, her complaints included upper extremity tremor at rest which caused her to spill coffee on herself, falling to the left side, fatigue and tremor in her legs while she sat in a chair. On exam, she had cogwheel rigidity, right arm greater than left arm. She had tremor at rest in her legs and cogwheeling in both legs. She had noticeable bobbing of her head. The subject was treated with sublingual administration of a composition comprising 4 x 10 "9 mg beta-amyloid, 2 umts streptolysin O, and 0.01 I.U. growth hormone three times daily. Upon follow-up examination three weeks later the subject noted complete resolution of her lower extremity tremor 2-3 days after initiating therapy according to the invention. She said she was not swaying to the side and had not fallen. On examination, there was no change in the upper extremities, but the legs had no tremor. One month later, she still had resolution of tremor in her legs at home, but mild tremor was noted by the attending physician. She still was staggering at times. She noted a 20% decrease in hand tremor which was not obvious to the attending physician but could have been accurate given that the subject was no longer spilling coffee on herself. Her assessment could be accurate since she no longer spilled coffee on herself. No other changes were noted. The following examples are directed to treatment of degenerative liver conditions, including cirrhosis, using the compositions of the invention comprising the combination of beta-amyloid, streptolysin O, and growth hormone. EXAMPLE 9 Cirrhosis According to this example, a female subject about 60 years old suffering from advanced cirrhosis and extreme physical weakness and was projected to die within two months and was sent home from the hospital to undergo hospice care. The subject was treated with sublingual admmistration of a composition comprising 4 x 10 "9 mg beta-amyloid, 2 umts streptolysin O, and 0.01 I.U. growth hormone four times daily and began to respond favorably after three days and regained strength. The subject was treated with no other medication and continued to lead a near normal life for over two years. EXAMPLE 10 Degenerative Liver Function According to this example, a male subject about 45 years old suffered from degenerative liver function and placed on the waiting list for liver transplant was treated with sublingual admmistration of a composition comprising 4 x 10 "9 mg beta-amyloid, 2 umts streptolysin O, and 0.01 I.U. growth hormone. Reports from the subject indicate that after three months of treatment with the composition of the invention all indicators of liver function had improved substantially. In particular, platelet count which had been considered critically low at between 58 and 66 K/cmm for eight years prior to treatment according to the invention had risen to about 100 K/cmm (normal is considered 172-376). EXAMPLE 11 Degenerative Liver Function in Canines According to this example, several old dogs exhibiting abnormal liver profiles and compromised health were treated by one subcutaneous injection daily of the composition of the invention comprising 4 x 10 "9 mg beta- amyloid, 2 umts streptolysin O, and 0.01 I.U. growth hormone. The dogs responded positively to the treatment when evaluated both by performance criteria and lab results. Numerous modifications and variations in the practice of the invention are expected to occur to those skilled in the art upon consideration of the presently preferred embodiments thereof. Consequently, the only limitations which should be placed upon the scope of the invention are those which appear in the appended claims.

Claims: WHAT IS CLAIMED IS: 1. A method of ameliorating the symptoms of cardiomyopathy in non-human animals, comprising the step of administering to a patient diagnosed with cardiomyopathy a composition comprising an effective amount of beta-amyloid, streptolysin O, and growth hormone wherein said amount of growth hormone is less than or equal to 0.1 International Units. 2. The method according to claim 1 wherein said amount of beta-amyloid is from about 1 x 10 "π mg to about 10 mg, and streptolysin O is from about 0.005 to about 50 units. 3. The method according to claim 1 wherein said amount of beta-amyloid is about 4 X 10 "9 mg streptolysin O is 2 Umts, and growth hormone is 0.01 International Units. 4. The method of claim 1 wherein said growth hormone is less than or equal to 0.01 International Units. 5. The method according to claim 1 wherein said composition is administered by a method selected for the group consisting of intramuscular, sublingual, intravenous, subcutaneous, intrathecal, inhalation and topical. 6. The method of claim 5 wherein said compound is administered intravenously. The method of claim 6 in a pharmaceutically acceptable vehicle. 8. A method of ameliorating the symptoms of Parkinson's Disease in a subject, comprising the step of administering to a subject diagnosed with Parkinson's Disease a composition comprising an effective amount of beta- amyloid, streptolysin O, and growth hormone. 9. The method according to claim 8 wherein said amount of beta-amyloid is from about 1 x 10" mg to about 10 mg, streptolysin O is from about 0.005 to about 50 units, and growth hormone is from about 1 x 10 "6 to about 100 International Units. 10. The method according to claim 9 wherein said amount of beta-amyloid is about 4 X 10 "9 mg streptolysin O is 2 Units, and growth hormone is 0.01 International Units. 11. The method according to claim 9 wherein the amount of said growth hormone is less than 4 International Units. 12. The method according to claim 10 wherein said growth hormone is less than or equal to 0.1 International Units. 13. The method according to claim 8 wherein said composition is admimstered by a method selected for the group consisting of intramuscular, sublingual, intravenous, subcutaneous, intrathecal, inhalation and topical. 14. The method of claim 13 wherein said composition is admimstered sublingually. 15. The method of claim 8 wherein said composition is admimstered in a pharmaceutically acceptable vehicle. 16. A method of ameliorating the symptoms of degenerative liver disease in a subject, comprising the step of administering to a subject diagnosed with degenerative liver disease a composition comprising an effective amount of beta-amyloid, streptolysin O, and growth hormone. 17. The method according to claim 16 wherein said amount of beta-amyloid is from about 1 x 10 "π mg to about 10 mg, streptolysin O is from about 0.005 to about 50 units, and growth hormone is from about 1 x 10 "6 to about 100 International Units. 18. The method according to claim 16 wherein said amount of beta-amyloid is about 4 X 10 "9 mg streptolysin O is 2 Umts, and growth hormone is 0.01 International Units. 19. The method according to claim 16 wherein the amount of said growth hormone is less than 4 International Units. 20. The method according to claim 19 wherein said growth hormone is less than or equal to 0.1 International Units. 21. The method according to claim 16 wherein said composition is administered by a method selected for the group consisting of intramuscular, sublingual, intravenous, subcutaneous, intrathecal, inhalation and topical. 22. The method of claim 16 wherein said composition is administered sublinguaUy. 23. The method of claim 26 wherein said composition is administered in a pharmaceutically acceptable vehicle. 24. The method of claim 16 wherein the degenerative liver disease is cirrhosis.

Inventors: GURNEY HARRY C, MCMICHAEL JOHN, GURNEY, HARRY, C., MCMICHAEL, JOHN
Applicants: MILKHAUS LAB INC, MILKHAUS LABORATORY, INC.
Application year: 1998
Main classification: A61K38
IPC codes: A61K38, A61P1, A61P9, A61P25