MEDICAMENTS FOR THE TREATMENT AND PREVENTION OF LIVER DAMAGE

Abstract: This invention concerns the novel use of nicardipine and pharmaceutically acceptable non-toxic salts thereof for the manufacture of medicaments for the treatment and preven­ tion of liver damage induced by drugs, toxic chemicals, poisons, radiation, alcohol and viruses.

Description: Medicaments for the Treatment and Prevention of Liver Damage Field of The Invention This invention relates to novel medicaments for the treatment and prevention of liver damage caused or induced by drugs, toxic chemicals, poisons, radiation, alcohol and viruses. The known compound nicardipine of the formula EMI1.1 and nicardipine salts with non-toxic acids, paricularly nicardipine hydrochloride, were found to be active in the prevention and treatment of liver damage and would, therefore, be useful for the manufacture of medicaments for treatment of viral hepatitis, alcoholic liver disease, drug, poison, radiation and chemotherapy induced liver disease and toxic hepatitis. Related Disclosures The liver is the largest and metabolically the most complex and active organ of the body. The functions of the liver are manyfold and include metabolism, synthesis, detoxification, secretion and storage. All nutrients, toxins, poisons, drugs and viruses pass through the liver and there they are metabolized, detoxified, or converted to other substances by the liver cells (hepatocytes). Therefore, any damage or injury to the hepatocytes causes disturbance of liver function with severe consequences for normal functioning of the whole body. For clinical purposes, the liver can be considered in terms of blood st=pply, parenchymal cells, Kupffer cells and biliary passages. Specific liver diseases tend to affect these four components in z predictable manner, often with. characteristic clinical, biocheical and histological consequences. Symptoms and signs of hepatic dysfunction are numerous and while some may be seen only in chronic liver disease, the others will be observed in both acute and chronic liver disorders. The liver damage caused by viruses, drugs, toxic chemicals, poisons, alcohol or radiation are characterized by the elevation of the liver enzymes such as glutamic-pyruvic transaminase (GPT), glutamic-ooalic transaminase (GCT), alkaline phosphatase (AP), sorbitol dehydrogenase (SDH) and in the level of bilirubin. These tests are most useful in determination of the character and the extent of liver damage and are generally part of routine evaluation of the patient with liver disease. For example, increased activity of serum alkaline phosphatase suggests mechanical obstructicn of the extrahepatic biliary tree, an infiltrative lesicn of the liver, early manifestation of cirrhosis or drug induced cholestasis. Increase in the serum transaminases (GPT and GOT) and sorbitol dehydrogenase activity is common in all kinds of liver disease and indicates hepatocyte injury. The Merck Manual, 13th Ed., Section E:836 (1977). Therefore, any decrease in the elevated levels of these enzymes following the drug treatment would vindicate that the drug is effective in treatment of the liver damage. Jaundice, one of the most known and visible symptoms of liver disorder, is caused by excess of circulating bilirubin. Any abnormality due to the liver disorder in the bilirubin metabolism will cause hyperbilirubinemia. Thus, any increase in the level of bilirubin is considered a good indicator of liver damage and the determination of serum bilirubin is a necessary part of the routine evaluation of a patient with liver disease. Ibid. The liver injury iv also accompanied by the liver cell necrosis affecting particularly parenchynal liver cells. Such necrosis can be determined histologically and is an excellent indicator of the extent of liver injury. Moreover, the changes in the magnitude of the liver cells necrosis indicate whether the drug treatment was effective and to which extent. Successful drug treatment of liver damage is, therefore, accompanied by: 1. reducing the elevated liver enzymes; 2. decreasing levels of bilirubin. and 3. diminishing the extent of liver cells necrosis. Because of its importance, liver damage ha- been widely studied and models of simulating hepatic injuries similar or identical to the viral or chemical hepatitis were developed. The models of experimental hepatitis are numerous. Those, however, most resembling the actual viral or chemical hepatitis are those induced by hepatotoxins such as D-galactosamine, carton tetrachloride cr bromobenzene. The administration of D-galactosamine to rats results ina a reproducible liver cell injury. Moreover, the biochemical and morphological pattern of resulting liver cell injury is qualitatively related to the dose cf D-galactosamine. Since the high dose of D-galactosamine induces a reversible structural and functional change in rat livers, it makes it analyzable model for the study of effect cf drugs and pharmaceuticals on the liver damage. Carbon tetrachloride is a known model hepatotoxin widel used for studies of acute chemical liver injuries In the liver, carton tetrachloride is converte by the liver cells to a metabolize which peroxidizes and alkylates tissue macromolecules. This conversion initiates te stereotypical events cf acute lethal liver cell injury. Aside from D-galactosamine, the carbon tetrachloride model is considered most suitable for studies of liver injuries particularly those due to chronic alcoholic ingestion. The galactosamine and carbon tetrachloride hepatitis models are described, for example, in Amer. J. Path., 79:579,(1975); Virchows Arch. B. Cell. Path., 26:331(1978), and in Seminars in Liver disease, 1:143(1981). Using the above models, Applicant has found that nicardipine and nicardipine salts, particularly micardipine hydrochloride, administered before the liver damage occurred, effectively prevent the increase in liver enzymes and bilirubin and is thus useful in obviating the liver damage. The nicardipine and nicardipine hydrochloride are equally effective in decreasing elevated liver enzymes and bilirubin when administered after the damage to the liver has already occured and are, therefore, also useful for treatment of liver damage. These conclusicns are supported by both biochemical and histological findings that the administration of nicardipine and particularly nicardipine hydrochloride, regardless whether before or after the liver injury occurs, was able to decrease the levels of GPT, GCT, SDH and bilirubin and also diminish the magnitude of the hepatocellular necrosis. Compounds which are the subject cf this invention, namely nicarcip ne and nicardipine salts are known peripheral vascular dilatcrs, anti-anginal agents and antihypertensive. Their preparation and above utility have been described in the U.S. Patent 3,985,756. Hepato-protective properties of compounds somehow structurally related was disclosed in European Patent 0 087 156-A. Therefrom, however, ist was not possible to predict any new effect of the nicardipine and its salts. It has now been found that nicardipine and nicardipine salts, particularly nicardipine hydrochloride, are active in diminishing the symptoms appearing during the liver damage and injury. Thus, medicaments containing these compounds significantly decrease the elevated levels of liver enzymes; such as, for example glutamic-oxalacetic transaminase (GOT); glutamic-pyruvic transaminase (GPT) and sorbitol dehydrogenase (SDH). These medicaments also lower the bilirubin level and decrease the magnitude of hepatocellular necrosis. DETAILED DESCRIPTION OF THE INVENTION Definitions "Nicardipine" as used herein means the compound named as: 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydropyridine3,5-dicarboxylic acid 3-B (N-benzyl-N-methylamino) ethyl ester 5 methyl ester (U.S. Patent 3,985,758); or 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)-3,5-pyridine dicartbxylic acid methyl 2- methyl-(phenylmethyl )-amino) ethyl ester (Merck Index); or 3,5-pyridinedicarboxylic acid, 1,4-dihydro-2,6-dimethyl4(3-nitrophenyl)-, methyl 2- ±methyl-(phenylmethyl)-amino) ethyl ester (SUSAN}; or 2-(Benzylmethylamino)ethyl methyl 1,4-dihydro-2,6-dimethyl4-(m-nitrophenyl)-3,5-pryridine dicarboxylate (USAN) "Nicardipine salt" means pharmaceutically acceptable non-toxic salt of the nicardipine. "Pharmaceuticalb; acceptable non-toxic salts21 refers to pharmaceutically acceptable hydrogen-anion addition salts which do not adversely effect the pharmaceutical properties of the parent compounds. With respect to the addition salts, suitable inorganic anions include, for example, chloride, bromide, iodide, sulfate, phosphate, nitrate and the like. Suitable organic anions include, for example, acetate, benzoate, lactate, picrate, propionate, butyrate, valerate, tartarate, maleate, fumarate, citrate, succinate, tosylate, asccrbate, nicotinate, adipate, gluconate and the like. The term "Ma=als" means a class of warm-blooded vertebrates characterized by mamnary glands, including but not limited to humans,-laboratcy or domestic animals such as dogs, cats, mice, rats or rabbits, and livestcck. 1Treatment" covers any treatment of the disease in a mammal, particularly hunan, and include: (i) preventing the disease from occuring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease, i.e. arresting the development of said disease; or (iii) relieving the disease, i.e. causing regression of the disease. "Liver damage", "liver disorders", or "liver disease" as used herein mean hepatic and biliary disorders which are caused by viruses, drugs, toxic chemicals, poisons, radiation or alcohol and are meant to include all hepatic disease and disorders as described in The Merch Manual, 13th Ed., Section 8, pp:836-886 (1977). Preferre Earcdiments of the Invention The broadest aspect of this invention is given in the Summary of this invention. Most preferred compound useful in the method of the current invention is nicardipine hydrochloride. preparation procedures Sicardipine and nicardipine salts are disclosed and their detailed preparation is described in U.S. Patent 3,985,758 which is hereby incorporated by reference. Sustained release pharmaceutical composition containing ncardipine salts is described in U.S. Patent 4,393,789 which is hereby inccrporated by reference. The nicardipine in free base form may be converted to the acid addition salts by treating it with a stoichiometric excess cf the appropriate organic or inorganic acid, such as, for example, phosphoric, pyruvic, hydrochloric cr sulfuric acid and the like. Typically, the free base is dissolved in a polar organic solvent such as ethanol or methanol, and the acid added thereto. The temperature is maintained between about 0 C and 100 C. The resulting acid addition salt precipitates spontaneously or may be brought out of solution with a less polar sclvect The acid addition salts of nicardipine may be decomposed to the corresponding free base by treating it with a stoichiometric excess of a suitable base, such as potassium carbonate or sodium hydroxide, typically in the presence of 2queous solvent, and at a temperature of between about 0 C and 1OOeC. The free base form is isolated by conventional means, such as extraction with an organic solvent. Nicardipine salts may be interchanged by taking advantage of differential solubilities of the salts, volatilities or acidities of the acids, or by treating with the appropriately loaded ion exchange resin. For example, the interchange is effected by te reaction of a nicardipine salt with a slight stoichiometric excess of an acid cf a lower pKa than the acid component of the starting salt. This conversion is carried out at a temperature between about O-C and the boiling point of the solvent being used as the medium for the procedure. UTILITY This invention relates to a novel medicament for a treatment and prevention of liver damage caused or induced by drugs, toxic chemicals, poisons, radiation, alcohol and viruses. Nicardipine and nicardipine salts, particularly nicardipine hydrochloride, compounds previcusly kncwn as peripheral and cerebral vascular dilators, antihypertensives and anti-anginal agents were now found to be active in prevention and treatment of liver disorders and would be, therefore, useful for treatment of such liver disorders as, for example: : 1. viral hepatitis type A or type B, herpes, mononucleosis, rutella, mumps and coxsacsie; 2. alcoholic liver disease, such as fatty liver, steatosis, hepatomegaly, intrahepatic obstructive jaundice, portal hypertension, cirrhosis, fibrosis and acute hepatccellular failure; 3. drug induced liver disease, such as drug induced acute hepatitis, drug induced jaundice or cholestasis; 4. toxic hepatitis caused b such toxic agents as carbon tetrachloride and related hydrocarbons, industrial solvents and phosphorus or other toxic chemicals; ; or 5. poison hepatitis caused by mushroom poisoning, by poisoning with fungal products known as aflatoxins or by other poisons; 6. radiation end chemotherapy induced liver injury. Administration Administration of nicardipine or its salt, preferably nicardipine hydrochloride, can be via any of the accepted modes of administration suitable for treatment of the liver disorder. These methods include oral routes, parenteral routes such as intravenous, subcutaneous, intradermal, or intramuscular and other systemic routes of administration such as, for example, by suppositories. The amount of nicardipine cr its salt administered will, of course, be dependent on the subject being treated, on the severity of the affliction, on the manner of administration and on the judgment of the prescribing physician. However, an effective dosage is in the range cf 0.001-5 mg/kg/day1 preferably 0.03-1 mg/kg/day. For an average 70 kg human, this would anount to 0.07-350 mg/day, preferably 2-7G mg/day. For oral administration, which is preferred, a pharmaceutical composition takes the form of sclutions, suspensions, tablets, pills, capsles, powders, sustained release formulations and the like. Parenteral route of administration is the administration of drugs to Z patient by injection under or through one or more layers cf the skin or mucous mmbrane. Parenteral administration would preferably be reserved for crisis situaticns, wherein the subJect is unable to swallow Cr administer the medication to himself. Systemic administration via suppository is the administration of the drug in a solid but readily meltable cone or cylinder made of suitable pharmaceutical excipient. Suppository must be suitable for insertion into a bodily passage or cavity, any is usually inserts into the rectum. This way of administration would be preferred in the Fatient with severe ingestion disturbance such as repeated vomiting usually occurring in cases of poisoining. Pharmaceutical Composition Depending on the intended mode of administration, the manufacture of the pharmaceutical compositions in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, pills, capsules, powders1 liquids, suspensions, or the like, preferably in unit dosage forms suitable for single administration of precise dosages may be performed in the usual way. The pharmaceutical compositions will include a conventional pharmaceutical carrier or excipient, nicardipine cr the pharmaceutically acceptable salt, preferably nicardipine hydrochloride, as an active ingredient thereof. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc. A pharmaceutical composition may contain 0.l%o.S% of nicardipine or nicardipine salt, preferably 1%-70%. In any event, the composition or formulation to be administered will contain a quantity of nicardipine or nicardipine salt in an amount effective to alleviate the symptoms of the subject being treated. For solid pharmaceutical compositions, conventional non-toxic solid carriers include, for example1 pharmaceutical grades cf mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium carbonate, and the like. Liquid pharmaceutically administerable compositions can he prepared by dissolving or dispersing, or otherwise preparing a nicardipine or nicardipine salt, and mixing it optionally with a pharmaceutical adjutant in a carrier, such as, for example, water, saline, aqueous-- dextrose, glycerol, ethanol, and the like, to there form a solution or suspension. For parenteral administration, suc as, for example, intravenous injections, the nicardipine or nicardipine salt is dissolved in a vehicle. Vehicle may be, for example, aqueous vehicle, such as sodium chloride injection, Ringer's injection, dextrose injection and others, water miscible vehicle, such as ethyl alcohol, polyethylene glycol of the liquid series or propylene glycol, or nonaqueous vehicles such a corn oil, peanut oil or sesame oil. Vehicle will be buffered to the proper pH in order to stabilize a solution against chemical degradation and formed in such a way as to control isotcnicity of inection. Other substances may also be added as antimicrobial or antioxidant agents. A more recently devised approach for parenteral administration employs the implantaticn of a slow-release or sustained-release system, such that a constant level of dosage is maintained. See, e.g., U.S. Patent No. 3,710,795. For systemic administration via suppository, the nicardipine or nicardipine salt may be formulated as suppositories using as the carrier traditional binders and carriers such as, for example, polyalkylene glycols, or triglycerides. Such suppositories may be formed from mixtures containing nicardipine or nicardipine salt in the range of 0.5%-10%; preferably 1-2%. Methods of preparing various pharmaceutical compositions with a certain amount of active ingredient are known, or will he apparent, to those skilled in this art. For examples, see Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania, 15th Edition (1975). The fowllowing2pharmaceutical tests illustrate the surprising effect of medicaments according to the invention. TEST 1 Prevention of Experimental Liver Damage in Rats This test illustrates the ability of a medicament of the current invention to prevent an experimentally induced liver damage. The procedure used in this test is the modified procedure of Lier et al, Virchows Arch B. Cell Path., 26:331, (1978). Experimental protocol The experimental liver damage was induced either with D-galactosamine or with carbon tetrachloride as the challenging agents. Liver damage caused b D-galactosamine resembled that sen after acute hepatitis. Carbon tetrachloride caused the liver damage resembled that of alcchol-induced liver injury. Male Bantin-Kingman Sprague Dawley rats weighing between 220-220 grams were divided in six groups with 10 rats per group. RXats were starved 18 hours prior to sacrifice otherwise food and water were available ad libitum. The challenge was administered either only once at 24 hours prior sacrifice, or twice 24 hours and 18 hours prior sacrifice, depending on the regimen. The tested compound was administered in varicus defined intervals prior to sacrifice depending on the challenging agent and on the chosen regimen. At the time of the sacrifice the rats were anesthetized with ether, bled vi the orbital sinus of the eye and then sacrificed. The collected blood was spun down and the plasma was saved for liver enzyme ar.d/or liver metabolic function determination. The levels of GPT, GCT, SSE. and bilirubin were determined in controls and in experimental groups. The bilirubin and all enzymes were determined using the Autoanalyser Gemeni (manufactured by Electronucleonics; Inc). The instrument utilizes the modified methods of Walters and Gerarde, Microchem. J., 15:231 (1970) for determination of bilirubin and modified method of Henry, Amer. J. Clin. Path., 34:381 (1960) for determination of GPT, GOT and SDH. Independently, these enzymes were also measured with Signa colorinetric methods, Sigma Diagnostic Kits and Feagents, Siama Catalog (1983) Protccol - D-Galactosamine Challenge Challence: D-gulactosamine: Dose: 375 mg/kg, given twice; Administered 24 hours and 18 hours pricr sacrifice; Poute of administration: intraperitoneal; Tested Compound: Nicardipine Hydrochloride; Dose: Four times 50 mg/kg/ml; Administered: 36 hours, 25.5 hours, 19.5 hours and 12 hours prior to sacrifice; Route of administration: peroral; Control vehicle: Distilled water; Dose: ml/kg. Results (MeanS.E.) Test Controls Nicardipine EC1 Significance GPT 828 + 309 ull 86 + 16 u/l p < 0.05 GOT 556 + 170 u/l 199 + 28 u/l p < 0.07 NS SDH 200 + 68 u/l 41 + 11 u/l p < O.05 Bilirubin 0.3S ; 0.05 mc/dl 0.21 + 0.03mg/dl p < 0.01 All values are expressed in units of enzyme per liter of plasma or in mg of bilirubin per deciliter of plasma. Following the administration of 50 mg/kg of nicardipine hydrochloride 12 hours, 1.5 before, 1.5 after the first challenge and 6 hours after the second challenge with D-galactosamine, GPT, SDH and bilirubin were significantly lowered in plasma. GOT was also lower but, at least in this study, the decrease was nct significant. In the subsequent study with the same experimental setup except with decreased dose of nicardipine hydrochloride to four times 25 mg/kg/ml, the decrease seen in the level of GOT was significant. The degree of significance was p0.O5. The absolute values for ccntrol group of 10 animals were 919 + 299 units of GCT per liter of plasma versus 251 + 63 units of GOT per liter of plasma for experimental group of'8 animals. Postmortem histological examination of the liver supported the above biochemical findings. The extent of hepatocellular necrosis in controls was significantly larger than the extent of cecrcsis seen in the experimental liver. These results show that the administration of the nicardipine hydrochloride before the experimental liver D-galactasamine injury was afflicted was able to reduce significantly the extent of such liver injury. It can be, therefore, concluded that the liver injury resembling that of the acute hepatitis responds to the pretreatment with the nicardipine hydrochloride and that such pretreatment can prevent the extensive damage of the liver by the viruses or other hepatotoxine. Protocol - Carbon Tetrachloride Challenge Challenge: Carbon tetrachloride; Dose: 1.8 g/kg peroral; Administered: 24 hours prior sacrifice; use of Route of administration: peroral; Tested compound: Nicardipine hydrochloride; Dose: 25 mg/kg/ml; Administered: 48 hours, 36 hours, 25.5 hours, 18 hours and 12 hours before sacrifice; Route of administration: peroral; Control vehicle: 1% gelatin suspension medium containing hydroxypropylmethylcellulose, dioctyl sodium suiphosuccinate and benzylalcohol; Dose: 1 ml/kg; Route of administration: peroral. Results Mean S.E.) Test Controls Nicardipine h:Cl Significance GPT 333 + 20 u/l 204 + 32 u/l pc0.005 The results are expressed in units of GPT per liter of plasma. Following the administration of 25 mg/kg of the nicardipine hydrochloride 24 hours, 12 hours and 1.5 hour before challenge, and 6 and 12 hours after the challenge with the carbon tetrachloride, GPT was found to be significantly lower in the experimental groups of treated animals than in untreated controls. The results of this study show that the liver injury resembling that of alcohol induced liver damage responds to the pre-treatment with nicardipine hydrochloride TEST 2 Treatment of Experimental Liver Damage in Rats This test illustrates the ability of the medicament of the current invention to prevent and to treat an experimentally induced liver damage. Essentially, the procedure and experimental protocol used in this example are the same as used in the test except.that each group of rats was injected only once with 25 mg/kg of nicardipine hydrochloride at intervals of 5 hours before challenge (Group 1), 1.5 hour before challenge (Group 2), 1 hour after the challenge (Group 3), 2 hours before the challenge (Group 4) and 4 hours after the challenge (Group 5). The animals in Control Group were injected with. distilled water in the same intervals. All animals were sacrificed 24 hours after the challenge. The challenging agent used to induce experimental liver damage was D-galactosamine Protocol - D-Galactosamine Challenge Challenge: D-galactosamine; Dose: 5CO mg/kg; Administered: 24 hours prior sacrifice: Route of administration: intraperitoneal: 0 Tested Compound: Nicardipine Hydrochloride: Dose: 25 mg/kg/ml; Administered: 27 hours, 25.5 hours, 23 hours, 22 hours and 20 hours prior sacrifice; Route of administration: peroral; Control vehicle: 1% gelatin suspension medium lml/kg. Results (Mean i S.E.) Group Time prior or post GPT/units/ Significance sacrifice/hours 1/plasma (CO) 2001 + 407 (1) 3.0 prior 458 + 161 F < 0.002 (2) 1.5 prior 423 + 165 p < O.OC1 (3) 1.0 post 1620 + 405 tt.S (4) 2.0 post 686 + 225 p < O.Ol (5) 4.0 post 959 + 253 p < 0.04 All results are expressed in units of the enzyme per liter of the plasma. The administration of nicardipine hydrochloride to the experimental animals 3 hours, and 1.5 hours prior to the inducement of the experimental liver injury prevented the increase in GPT level in both Groups (1) and (2) and thus prevented the development of the extensive liver injury which was seen in the control group. The administration of nicardipine hydrochloride to the experimental animals 1 hour (Group 3), 2 hours (Group 4) and 4 hours (Groups 5) after the inducement of the experimental liver injury was able to decrease the level of the GPT from approx 2001 units/l of plasma to 1620 units of GPT per liter of plasma in Group (3), to 686 units per liter of plasma in Group (4) and to 959 units per liter of plasma in Group (5). The above results show that nicardipine hydrochloride was able not only to prevent the development of the liver injury following the challenge but also to treat already incurred liver injury. In the following Examples for the manufacture of medicaments according to the invention nicardipine hydrochloride is used as active ingredient. Example 1 Quantity in mg Ingredients per tablet Active ingredient 25 cornstarch 20 lactose, spray-dried 153 magnesium stearate 2 The above ingredients are thoroughly mixed and pressed into single scored tablets. EXAMPLE 2 Quantity in mg Incredients per tablet Active ingredient 100 lactose, spray-dried -- 148 magnesium stearate 2 The above ingredients are mixed and introduced into a hard-shell gelatin capsule. EXAMPLE 3 Quantity in mS Ingredients per tablet Active ingredient 200 cornstarch 50 lactose 145 magnesium stearate 5 0 The above ingredients are mixed intimately and pressed into single scored tablets. EAXMPLE 4 Quantity in mg Ingredients per tablet Active ingredient 108 lactose 15 cornstarch 25 magnesium stearate 2 The above ingredients are mixed and introduced into a hard-shell gelatin capsule. EXAMPLE 5 Quantity in mg Ingredients per tablet Active ingredient 150 lactose 92 The above ingredients are mixed and introduced into a hard-shell gelatin capsule. EXAMPLE 6 An injectable preparation buffered to a pH of 7 is prepared having the following composition: Ingredients Active ingredient 0.2 g KH2P04 buffer (0.4 M solution) 2 ml KOH (1 N) q.s. to pH 7 water (distilled, sterile) q.s. to 20 ml EXAMPLE 7 An oral suspension is prepared having the following composition: Ingredients Active ingredient 0.1 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.1 g granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distilled water q.s. to 100 ml

Claims: CLAIMS: 1. The use of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-di hydropyridine-3, 5-dicarboxylic acid 3-ss-(N-benzyl-N-methyl- amino)ethylester-5-methyl ester - nicardipine - or a pharmaceutically acceptable non-toxic salt thereof for the manufacture of a medicament for the prevention and treatment of liver damage in mammals. 2. The use of 2,6-dimethyl-4-(3'-nitrophenyl)-1,4-dihydro- pyridine-3,5-dicarboxylic acid 3-B-(N-benzyl-N-methylamino)ethylester-5-methyl ester hydrochloride for the manufacture of a medicament according to claim 1.

Inventors: GARAY, GABRIEL L.
Applicants: YAMANOUCHI PHARMACEUTICAL CO. LTD.
Application year: 1985
Main classification: A61K31
IPC codes: A61P1, C07D211, A61K31