MXPA99000074A - A method for treating liver diseases and similar indications with vasodilated agents - Google Patents

Abstract

The present invention relates to: method for the treatment of liver disease selected from the group consisting of cirrhosis of the liver, toxic liver damage and by drugs, a parenchymal disorder of the liver or hepatitis, said method includes administering to a human or animal with the need thereof, a therapeutically active or prophylactically effective low dose amount of a vasodilating agent, which selectively increased the supply of oxygenated blood to the liver by increasing the hepatic arterial influx. In one aspect of the invention, the effective low dose amount of the vasodilator administered was reduced with increases in the severity of the disease condition being treated.

Description

A METHOD FOR TREATING LIVER DISEASES AND SIMILAR INDICATIONS WITH VASODY-ATTACKING AGENTS DESCRIPTION OF THE INVENTION The present invention relates to a method for the treatment of liver disease. The invention also relates to compositions suitable for use in the treatment of liver disease. Diltiazem is a generic name given to the active component of a composition that is primarily used for the treatment of heart disease. Specifically, it is known as 3-acetoxy-5- (2-dimethyl-a-minoethyl) -2,3-dihydro-2- (4-methoxyphenyl) -1,5-benzothiazepine-4) 5H-one. This compound is the active ingredient in the cardiac treatment drug Cardizem. Cardizem has particular efficacy in the treatment of ischemic heart disease including angina pectoris and hypertension. Diltiazem is a member of a broad class of benzothiazepine derivatives which are the subject of Australian patent 426146. The class of compounds is referred to in that specification as having particular utility as an antidepressant, tranquilizers and coronary vasodilators. Diltiazem mainly acts as a calcium channel blocker (a calcium blocker); Calcium being involved in several biological processes in the human body including vasoconstriction and va on to t a t ion. Calcium blockers interfere with the transport of calcium through the cell membrane, thus reducing the contraction of the vascular smooth muscle and causing the arteries to dilate. The discovery of calcium blockers was a major advance in cardiovascular treatment. Diltiazem contributed significantly to this advance. In general, during the cardiovascular trial using Diltiazem, a patient with the need for it is administered the drug in doses of 180 mg to 360 mg per day. The liver is a large gland located in the upper part of the abdomen on the right side. Its domed top surface fits tightly against the lower surface of the right diaphragm. It has a double blood supply from the hepatic artery (oxygenated arterial blood) and the portal vein (substances that carry - deoxygenated venous blood absorbed from the stomach, small intestine and large intestine). It comprises thousands of tiny lobes (liver lobes) the functional units of the liver. Its multiple functions include the storage and filtration of blood, the secretion of bile, the excretion of bilixubine and other substances formed anywhere in the body and numerous metabolic functions, including the conversion of sugars to glycogen, which stores. It is essential for life and therefore the malfunction of the liver weakens and endangers life. The prior art treatments of liver disease have included using a number of drugs. For example, choline has been administered as an adjunct to the dietary treatment of fatty acid infl uction and early cirrhosis of the liver. Methionine has a lipotropic action similar to choline. It has also been used as an aid in the treatment of diseases of the liver in patients who can not take an adequate diet, although it is evident that in cases of severe liver damage large doses of methionine can aggravate the taxoemia. Litrison is a composition of methionine, choline, B vitamins and Vitamin E. It has been used for the treatment of degenerative changes to restore liver function and to maintain liver function. Neurogem is a composition of the essential vitamin B complex of high potency and vitamin C, which has been used for supplement therapy or maintenance. Finally, Ripason is a total protein-free extract from the livers of healthy animals. It has been used to treat chronic hepatitis, cirrhosis, damage to the liver due to medications and upheavals in the liver. The treatment of liver disease, however, has been a growing challenge in the prior art and none of the drugs used has proven to be particularly effective. In particular, none of these agents reverses relative hypoxia, or lack of oxygen, which seems to contribute to the pathology and progression of chronic liver disease. Therefore, liver disease is a life-threatening disease and may eventually require transplant surgery in some cases.

Accordingly, it is an object of the present invention to overcome, or at least alleviate, one or more of the difficulties or deficiencies related to the prior art. Accordingly, in a first aspect of the invention, there is provided a method for the treatment of liver disease and similar indications, said method includes administering to a human or animal with the need thereof a low dose of a therapeutic amount or prophylactically effective of a vasodilator agent, which selectively increases the supply of oxygenated blood to the liver. The vasodilating agent may include a calcium blocker, for example, a thiazepine derivative, preferably a ben z or t i -acidine derivative, nufedipine, felodipine or verapamil. Other vasodilators can be used indirectly. The method of treatment can be used in the treatment of various diseases of the liver such as cirrhosis of the liver, toxic damage to the liver or by drugs or disorders of the liver and related diseases such as hepatitis, including chronic active hepatitis. The treatment method can be directional since significantly lower doses can be used which are usually administered in the treatment of heart disease or similar indications. _ In particular, it has been found that the required dose is reduced with increases in? severity of the condition of the disease being treated. Although not intended to be restricted by theory, it is believed that the class of vasodilated agents known as calcium bleachers are effective in the treatment of liver disease since they are selectively capable of increasing the oxygen content in the liver. In particular, it is believed that calcium blockers are effective in the treatment of liver disease since they are selectively capable of dilating the hepatic artery. An increase in the oxygen level can alleviate the progress of liver disease, since liver function generally increases with an increase in oxygen concentration. Common liver diseases, such as chronic hepatitis or cirrhosis of the liver, share as a pathological aspect a low oxygen concentration in the liver. Accordingly, in a further aspect of the present invention, there is provided a method for the treatment of liver disease, said method includes administering to a human or animal in need thereof a therapeutically or prophylactically effective amount of a derivative of in a cepi na of the formula: wherein R1 is a phenyl group substituted or not with 1 to 3 lower alkyl groups, lower alkoxy groups or halogen atoms, R2 is a hydrogen atom or a lower alkanoyl group, R and R are each a lower-alkyl group and they may be the same or different, X is a hydrogen atom or a halogen atom, and Y is an alkylene group of 2 or 3 carbon atoms, or its non-toxic acid addition salt. Preferably, R1 is a 4-a1 coxy f1 i or lower, R2 is lower alkanoyl, R3 and R4 are each lower alkyl, X is hydrogen, Y is ethylene. More preferably, R1 is 4-me t-oxy phenyl, R2 is acetyl and R3 and R4 are each methyl. Even more preferably, the benzyl or acetyl derivative is 3-acetoxy-5- (2- (dimethylaminoethyl) -2,3-dihydro-2- (4-methoxyphenyl) -1,5-beniazepine-4) 5H- ona The benzyl derivative may be converted to its acidic salts by addition with treatment with an organic or inorganic acid (eg acetic acid, oxalic acid, malonic acid, tartaric acid, malic acid, citric acid, lactic acid, acid). gluconic acid, aspartic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, etc.) in a suitable solvent (for example, water, methanol, ethanol, etc.). It has been found that the use of said derivatives of b in z or t i a c ep i na is effective to increase hepatic arterial blood flow to the liver. Said derivatives of b in z or t i a cepri na may be effective in the treatment of liver disease in doses significantly lower than that normally administered in the treatment of cardiac diseases. Significantly lower is meant to imply doses that will not have any significant effect on the heart or peripheral circulation.

In a further preferred aspect of the present invention, there is provided a method for the treatment of liver disease, said method includes administering to a patient with the need thereof a low dose of a vasodilating agent, for example of about 2.5 mg. at 30 mg per day, preferably around 2.5 to 15 mg / day of diltiazem or its non-toxic acid addition salt. Experimental studies in mice have currently indicated effective doses of approximately 1.5 to 2.5 mg / kg / day. However, it is common for doses for humans that are lower than for animals, including rodents. A lower dose may be used for patients with higher degrees of liver disease, the amount of effective low dose of the vasodilator agent being reduced with increases in the severity of the disease state-which is being treated.

Accordingly, in a further aspect of the present invention there is provided a pharmaceutical composition suitable for the treatment of liver disease and indications, if any, said composition includes a therapeutically or prophylactically effective amount of a vasodilating agent, which selectively increases the supply of - oxygenated blood towards the liver and a pharmaceutically acceptable diluent or vehicle of the same. The vasodilating agent may include a calcium blocker, for example a derivative of t-accepine, preferably a derivative of ben z or t i a cepin, nifedipine, felodipine or verapamil. 0 t no vasodilators can be used indirectly. The pharmaceutical composition can be used in the treatment of various liver diseases such as cirrhosis of the liver, toxic liver damage or by drugs or disorders of the liver and related diseases such as hepatitis, including chronic active hepatitis. * In a further preferred aspect of the present invention, there is provided a pharmaceutical composition suitable for the treatment of liver disease and similar indications, said composition includes a therapeutically or prophylactically effective amount of a ben z or thiol derivative of the formula: wherein R1 is a phenyl group substituted or not with 1 to 3 lower alkyl groups, lower alkoxy groups, or halogen atoms, R2 is a hydrogen atom or a lower alkanoyl group, R3 and R4 are each a lower alkyl group and they may be the same or different, X is a hydrogen atom or a halogen atom and Y is an alkylene group of 2 to 3 carbon atoms, or its non-toxic acid addition salt; and a pharmaceutically acceptable diluent or vehicle thereof.

Preferably, R1 is a 4-a1 coxy f1 i or lower, R2 is lower alkanoyl, R3 and R4 are each lower alkyl, X is hydrogen, Y is ethylene. More preferably, R 1 is 4-me t oxy phenyl 1, R 2 is acetyl and R 3 and R 4 each are methyl. Even more preferably, the benzoyl-a-cepin derivative is 3-acetoxy-5- (2- (dimethylaminoethyl) -2,3-dihydro-2- (4-methoxy-phenyl) -1,5-benzothiazepine-4) 5H-one. In a further preferred aspect of the present invention, a pharmaceutical composition suitable for the treatment of liver disease and similar indications is provided, said composition includes about 2.5 to 30 mg of diltiazem or its non-toxic acid addition salt, and a diluent or pharmaceutically acceptable vehicle thereof. A dose at the low level of the scale can be used in patients with higher degrees of liver disease. The pharmaceutically acceptable diluent or vehicle can be of any suitable type. The pharmaceutically acceptable diluent or carrier can be a suitable organic or inorganic carrier material for enteral, parenteral or transdermal applications.

Preferably, the composition is formulated in order to allow adequate administration to the patient. Said administration can be any suitable medium such as oral, subcutaneous, intravenous or cu r t o s t. Preferably, the administration is via the oral route since the active ingredient is able to reach the liver directly, ie through the portal vein. Oral administration through the use of tablets, capsules, powders or in liquid form such as suspensions, solutions, emulsions or syrups, is particularly advantageous. When formed into tablets, conventional excipients (e.g., sodium citrate, lactose, microcrystalline cellulose, starch, etc.), lubricating agents (e.g., anhydrous silicic acid, hydrolyzed castor oil, magnesium stearate, lauryl) can be used. sodium sulfate, talc, etc.), and binders (eg, starch grass, glucose, lactose, acacia gum, gelatin, mannitol, magnesium trisilicate, talc, etc.). When they are administered as liquids, conventional liquid vehicles can be used. In the case of solid preparations, each unit dose form of the active ingredient may contain from about 5 to about 95% thereof by weight of the total composition the remainder comprising conventional pharmaceutical carriers. When the therapeutic agent is used as an aqueous solution, i.e., injection, the solution may contain from about 0.05 to about 0.5% thereof by weight of the total composition. Preferably, the composition may be of the sustained release type, for example, to allow for "once-a-day administration." The sustained release composition may be suitable for oral or transdermal administration.A suitable low release formulation may be achieved, by example, when the active ingredient is bound to a suitable polymer.A composition once a day is capable of delivering a sufficient amount of the active ingredient to the patient and can avoid the possibility of toxic shock, when multiple doses are given on a daily basis to patients suffering from "liver disease. The present invention will now be described more fully with reference to the appended examples. However, it should be understood that the following description is illustrative only and should not be taken in any way as a restriction of the generality of the invention described hereinabove.

EXAMPLE 1 OBJECTIVE A pilot study was conducted to examine the effect on the hepatic artery and the flow of the mesenteric artery in anesthetized dogs when exposed to cumulative doses of diltiazem.

METHODS: Preparation: Greyhounds were used in this pilot study. All dogs were present in an animal shelter during < 1 week before surgery, and all seemed clinically well. The dogs were given 15 minutes of exercise before arriving at the amphitheater. When they arrived, they were fastened to the abdomen, front legs and hindquarters, and anesthesia was induced with a sodium tonic (Nembutal for T injection) given intravenously to be performed. The subjects were fitted with tubes and connected to a respirator. A heating table was used to maintain body temperature. An initial infusion of one liter of a Hartmann's solution was given through the surgical procedure, bicarbonate being administered as required according to the blood gas estimation. The abdomen was opened, and the ga s t r o-duodena 1 branch of the common hepatic artery was localized and ligated. Electromagnetic flux probes were placed on the common hepatic artery and the anterior mesenteric artery. A branching was exposed to the vein and a catheter was introduced and advanced towards the portal vein. A catheter was also placed in the left hepatic vein using a bag sequence technique. A resident catheter was placed in a branch of the mesenteric vein, very close to the other catheter placed in the lumen of the jejunum. The abdomen was then closed and a catheter was inserted into the femoral artery. The subject was then covered with gauze, and the circulation and temperature of the dogs were allowed to stabilize before the start of the experimental stage.

At the end of the study, the dogs were slaughtered with sodium carbonate.

Experimental procedure: Infused theophylline was used as a marker for liver extraction. A bolus was provided (for 15 minutes) at a rate of 3.42 mg / minute, then an infusion into the mesenteric vein at a rate of 11 mg / minute. After 90 minutes of stabilization, the first dose of diltiazem (0.25 mg / kg) was given in a lumen of the jejunum. Time was allowed for changes in blood flow before the next dose was given. The effects on the flow reached a platform at 2.0 minutes, when the next dose was provided. Cumulative doses were given, that is to say 0.25, 0.5, 1.0, 2.0, 4.0 mg / kg. Blood samples were taken throughout the procedure of the portal vein, posterior hepatic vein and arterial line at 20, 40, 60, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180 and 190 minutes, time zero being the start of the infusion of theophylline.

RESULTS: Studies were conducted in 6 dogs, as follows: Dog Experimental Dog Preparation 3/92 Good surgery No flow response Dog 4/92 Good surgery Excellent flow response to diltiazem Dog 1/93 Good surgery Flow response to diltiazem Dog 2/93 Good surgery Excellent flow response to diltiazem Dog 3/93 Unsuccessful surgery - Dog 4/93 Good surgery Flow response to diltiazem STATISTICAL OBSERVATIONS Mean flows were obtained in both the hepatic and mesenteric arteries for 10 to 20 minutes before providing dil-tiazem. This was taken as baseline flows, and all the measurements that were used in it were baseline. The maximum flow responses were measured. The results are summarized in the table below and are presented schematically in Figures 1-5.

Common Hepatic Artery Subject +% CHA +% CHA +% CHA +% CHA +% CHA 0.25mg / kg 0.5mg / kg 1.0mg / kg 2.0mg / kg 4.0mg / kg 4/92 t12.4 121.7 123.2 134.0 119.6 1/93 99.9 86.0 71.2 73.2 * 140.7 2/93 151.5 178.7 201.3 227.6 156.0 4/93 104.7 110.1 112.8 112.8 93.5 MEDIA 117.1 + 11.7 124.1 + 19.7 127.1 + 27.2 136.9 + 32.8 127.5 + 13.6 Anterior Mesenteric Artery Subject +% AMA +% AMA +% AMA +% AMA +% AMA 0.25mg / kg 0.5mg / kg 1.Omg / kg 2.0mg / kg 4.0mg / kg 4/92 114.6 112.9 120.9 116.6 118.1 • 1/93 114.9 132.4 177.8 161.5 168.3 2/93 121.1 127.0 129.3 125.1 123.2 4/93 106.7 106.7 103.3 104.1 82.8 MEDIA 114.3 + 3.0 119.8 + 6.0 132.9 + 15.9 126.8 + 12.3 123.1 + 17.5 EXAMPLE 2 Two types of experiments were performed. Both were conducted in dogs anesthetized with barbiturates. In the first series, nitroglycerin was infused into both the portal vein (draining into the liver from the intestine) and the femoral vein (systemic circulation). When nitroglycerin was given in the portal vein, blood flow through the hepatic artery (ie, a measure of liver blood flow and oxygenation) was increased. In contrast, when nitroglycerin was given systematically, the hepatic blood flow was reduced. It can be concluded that liver flux and liver oxygenation can both be augmented by drugs, but this can not be achieved through systemic administration of nitroglycerin. In a second series, diltiazem was administered through a gastric tube to the stomach, effectively and orally. The level of blood flow through the hepatic artery increased by up to 50%, and this occurred at very small doses. In this way, the increase in the perfusion of the liver can be achieved through small doses of oral diltiazem and this will have a benefit in the diseased liver.

EXAMPLE 3 A third group of experiments was then conducted in rats after the first studies in dogs showed that low doses of diltiazem increased the blood flow of the liver. The objective of the study was to induce liver disease through the administration of carbon tetrachloride (CC14) and then test the hypothesis that low doses of diltiazem. They can improve the functional status of the liver.

METHODS Se. used Spregue Dawley male rats in this study, where liver disease was induced after the method of Proctor and Chatamra (1982). First hepatic enzymes were induced through the addition of sodium phenobarbitone to water to drink at a concentration of 350 mg / 100 ml. All animals were provided with phenobarbitone water for 10 weeks. No other type of water was available for the animals. The animals were randomly placed for the induction of liver disease by receiving CCI4 added to corn oil, and administered orally through a stainless steel feeding tube during carbon dioxide stunning. The CCI4 was given for 10 weeks as the weekly doses began after two weeks of enzyme induction with phenobarbitone. The starting dose of. CC14 was Q.5 ml, but the dose was then adjusted according to a protocol to obtain a weight loss of 6 to 9% during the 3 days after each dose, with a weight gain on 'day 7. Previous studies showed that during a period of 10 weeks, this regimen will produce liver disease with ascites, spl enomega 1 a, plasma albumin reduction, plasma alanine transaminase increase, and the isthological aspects of severe liver disease. For the determination of the effects of diltiazem, the animals were separated into 5 groups, each of 8 rats. Group 1 (normal) received phenobarbitone in drinking water but not CCI4 or diltiazem. Group 2 (control) received CCI4 but not diltiazem. Groups 3, 4 and 5 respectively received 0.5, 1.0 and 2.0 mg / kg of diltiazem added to drinking water. The animals were weighed daily for 4 days after each dose of CC14, and were sacrificed after two weeks, ie after 10 weeks of CCI4 +/- diltiazem, or at the equivalent time in normal animals. At autopsy, liver and vessel weights, the presence of ascites and the condition of the coating were recorded, and blood samples were taken to measure albumin, liver enzymes and coagulation factors. The differences between the groups for each variable were examined using analysis of variance.

RESULTS The body weight profiles are shown in Figure X. Group 1 animals (normal) progressively increased the weight of less than 200 g "approximately 440 g of body weight during the study period. ) lost weight after each dose of CC14 and did not gain as much weight as group 1, being 50 to 60 grams lighter at the end of the study period.The treatment with 0.5 mg / kg / day of diltiazem (Group 2) It seemed to have no significant effect to prevent weight loss induced by CCI.4 In contrast, in Group 3 (treated with 1.0 mg / kg / day of diltiazem), there was a transient loss in weight after each dose of CC14. However, at the end of the study, the body weights were not significantly different from the normal (Group 1), but were significantly stronger than those of the control animals (Group 2, p <0.05). 2.0 mg / kg / day (Group 5) seemed less than those of 1.0 mg / kg / day a. Autopsy and biochemical variables are listed in Table Y. In Groups 1 (normal) and 4 (diltiazem, 1.0 mg / kg / day), liver and vessel appeared normal on inspection, and no significant ascites were present. In contrast, Group 2 (control) showed evidence of severe liver disease. The macroscopic changes seen in the control group are supported by the reduction of plasma albumin and coagulation factors and plasma alanine transaminase increase compared to levels in the normal group of animals. Diltiazem offered significant protection against the development of severe functional liver disease and this effect appeared to be greater at a dose of 1.0 mg / kg / day.

DISCUSSION AND CONCLUSION The results of this study in rats show in conclusion that low doses of diltiazem significantly prevented the development of liver disease in rats with the administration of CC14. Particularly important is the observation that the greater effect of diltiazem appeared to be at a dose of 1.0 mg / kg / day instead of 0.5 or 2.0 mg / kg / day. Previous studies in dogs suggest that the mechanism of action is probably found in an increase in blood flow to the liver, and, therefore, improved oxygenation of the liver. These observations in animals should now be tested in human patients with liver disease. The variables that are measured should include determination of liver function, hepatic blood flow, and hepatic vein oxygen tension. Finally, it should be understood that various other modifications and / or alterations may be made without departing from the spirit of the present invention as indicated herein.

EXAMPLE 4 Phase I Clinical Studies of Diltiazem at Low Doses in Patients with Liver Disease Two studies were conducted to test the hypothesis that a low dose of diltiazem may be effective in the management of patients with chronic liver disease. In January 1996, the first study of patients with chronic hepatitis (hepatitis C) was completed and showed a highly significant response in two thirds of patients after only two weeks of treatment. This compares favorably with a regime of. 30% response after 12 weeks of treatment with inferred. The result after diltiazem is even more significant since all the patients were refractory to the treatment with inferieron. A second study in patients with cirrhosis of the liver is being conducted. However, the results in the first two patients indicate that diltiazem administered as 50 mg per day in the 24 hour release formulation is increasing the liver clearance of antipyrin, a marker dye of liver function.

Details of the Study a) Chronic Hepatitis The study of the effects of diltiazem at low doses in chronic hepatitis was performed, in 24 patients with chronic viral hepatitis (hepatitis C) who did not respond to treatment with inferred, and who had stable but high blood levels of the amino t r ans f e r of alanine enzyme in the liver (ALT) and other enzymes. The study was conducted at Alfred Hospital, Melbourne, Australia and was approved by the Ethics Review Committee at that hospital. Each patient who entered the study experienced an operation phase of two weeks followed by four periods, each lasting two weeks. Diltiazem was administered in incremental doses of 12.5, 25, 50 and 100 mg per day in each of the two week periods. The formulation of diltiazem was in Cardicem CD granules reformulated in the respective doses thus giving a low dose, but with a drug release of 24 hours. Blood samples were taken twice for the measurement of ALT in serum and liver enzymes, during the period of operation, and then at the end of each incremental dose period. A final ALT measurement was made two weeks after completing the study. A full report is not yet available until January 1996, but the main results can be summarized as follows. Twenty-four patients introduced to the study, and 19 completed it. Five patients withdrew due to symptoms of hepatitis and social pressure unrelated to diltiazem. The reasons cited included headache and impotence during the placebo operation phase. Four patients had a modest increase in ALT and two had no significant change. Thirteen had a fall in ALT which appeared to be higher after doses of 50 and 100 mg. Six patients had a fall in ALT greater than 20% and this appeared to be greater after a dose of 50 mg, although the response after 25 mg was almost as large. These data approximate one-half of the ALT evaluation after only two weeks of treatment. Table 4 shows the responses in those patients who had a fall in ALT.

Table 4 - Average change in respondents Upper limit than normal for ALT is 40 lu / ml Data from patients who experienced more than 20% drop in ALT are shown in Table 5. Table 5 - Mean change in responders Time Dose n Average level of pre ALT 'mean ALT at that time 4 weeks 12.5 170.3 126.7 0.002 6 weeks 25 157.1 104.5 0.003 8 weeks 50 142.1 95.6 0.001 weeks 100 153.1 105.0 0.008 post (average) 7 160.0 106.3 0.003 The total data are consistent with an auxiliary and therapeutic effect, and coincide with the effects * of diltiazem at low doses seen in animals. The study can not show whether a higher response regimen or a greater therapeutic effect can be achieved after longer periods of therapy. However, the results need to be compared with those of the inferred study, a curative therapy, where the response time is reported as 12 weeks. It is also interesting to note that ALT did not appear to increase immediately after the interruption of diltiazem. This is consistent with reoxygenation through dilation of the hepatic artery thus allowing a healing effect, instead of directly interfering with the disease process. There was no evidence that 100 mg was more effective than 50 mg. The increase of enzymes in four patients indicates that the dose of the drug should be kept as low as possible. The patients also reported that they felt better while taking the drug. Several individuals reported less fatigue and headache, and more energy, b) Cirrhosis of the Liver This study is logically difficult to perform and is incomplete. Ten patients with chronic, but stable cirrhosis of the liver were recruited and each received 50 mg of diltiazem formulated from Cardizem-CD pellets for 24-hour release. A clear de-antipyrin study was performed on each patient in the recruitment, after the first dose of treatment and then again for two weeks of treatment. At the same time a possible measurement of propanolol clear could be made. The purpose of antipyretic clearance is to measure liver function in terms of the ability of the liver to excrete substances into bile. The purpose of the propranolol clearing is to measure the capacity of the cytochrome p450 system, which is critical for the oxidation process and the oxidation with the liver. A clear study involves intravenous injection of a dye or marker (in this case, antipyrine or radiolabeled propanolol), followed by repeated blood tests of up to 12 hours. The reduction in the levels of the marker in the blood allows the measurement of the clearance regime of the dye from the body, and in this case by the liver. In January 1996, two patients completed the clear study, and both showed an increase in antipyrin clearance. The first patient increased the antipyrin clearance of 468.2 units before treatment to 494 units after the first dose, and 730.4 units after 2 weeks of t r a tten. This represents a 56% increase in the clearance of antipyrine in a patient with severe disease. The second patient with a more severe disease had a smaller but impor tant increase.

Claims (3)

1. A method for the treatment of liver disease selected from the group that 5 consists of cirrhosis of the liver, damage of the toxic liver and by drugs, parenchymal disorder of the liver or hepatitis, said method includes admiering to a human or animal with the need thereof a therapeutically active low dose or (flfc 10 prophylactically effective on the scale of * 2.5 to 30 mg per day of a vasodilating agent to selectively increase the supply of oxygenated blood to the liver by increasing the arterial blood pressure

2. The method according to claim 1, wherein the vasodilating agent is a calcium blocker.

3. The method according to claim 2, wherein the blocker of. Calcium is a related thiazepine derivative or calcium blocker.

4. The method according to rei indication 2, wherein the calcium blocker is selected from a ben z or t i a cepi na derivative, nifedipine, felodipine or verapamil.

5. The method according to claim 4, wherein the benz or t i a cepin derivative is a compound of the formula: wherein R1 is a phenyl group substituted or not with 1 to 3 lower alkyl groups, lower alkoxy groups or halogen atoms, R2 is a hydrogen atom or a lower alkanoyl group, R3 and R4 each are a lower alkyl group and can be the same or different, X is a hydrogen atom or a halogen atom, and Y is an alkylene group of 2 or 3 carbon atoms, or its non-toxic acid addition salt. "The method according to the rei indication 5, wherein R is 4-lower alkoxyphenyl, R 2 is lower alkanoyl, R 3 and R 4 are each lower alkyl, X is hydrogen, Y is ethylene; more preferably, R 1 is 4-methyl t-phenyl, R 2 is acetyl and R 3 and R 4 are each methyl.

7. The method according to the rei indication 6, wherein the benz or thiazepine derivative is 3-ace t oxy-5 - (2 - (dime ti 1 aminoe ti 1) -2, 3-dihydro-2- (4- methoxyphenyl) -1,5-benzothiazepine-4-5H-one or a non-toxic acid addition salt thereof The method according to claim 1, wherein the treatment is admiered to a human being suffering from liver disease.

9. The method according to claim 1, wherein the vasodilating agent is in the form of a slow release formulation for oral admiration.

10. The method according to any of the preceding indications, wherein the vasodilator agent is admiered through the oral route.

11. A composition for the treatment of liver disease selected from the group consisting of cirrhosis of the liver, toxic liver damage or by drugs, parenchymal liver disorder or hepatitis, said composition includes a therapeutically or prophylactically effective dose amount of an agent vasodilator, which selectively increases the supply of oxygenated blood to the liver by increasing the hepatic arterial influx and a pharmaceutically acceptable carrier thereof, in the form of a sustained release composition for oral admiration.

12. The composition according to claim 11, wherein the vasodilating agent is a calcium blocker.

13. The composition according to claim 12, wherein the calcium blocker is a thiazepine derivative or related calcium blocker.

14. The composition according to the rei indication 13, wherein the thiazepine derivative is selected from a ben z or t i -acidine derivative, difedipine, felodipine or verapamil.

15. The composition according to claim 14, wherein the ben z or thiiphenyl derivative is a compound of the formula wherein R1 is a phenyl group substituted or not with 1 to 3 lower alkyl groups, lower alkoxy groups or halogen atoms, R2 is a hydrogen atom or a lower alkanoyl group, R3 and R4 are each a lower alkyl group and can be the same or different, X is a hydrogen atom or a halogen atom, Y is an alkylene group of 2 or 3 carbon atoms, or its non-toxic acid addition salt.

16. The composition according to claim 15, wherein R1 is a lower 4-alkoxyphenyl, R is lower alkanoyl, R3 and R4 are each lower alkyl, X is hydrogen and Y is ethylene. More preferably R1 is 4-me t-oxy phenyl, R2 is acetyl and R3 and R4 are each methyl

17. The composition according to the rei indication 16, wherein the benzothiazepine derivative is 3 -acetyloxy-5 - (2-dimethyl-1-amino-1-yl) -2,3-dihydro-2- (4-methylphenyl) - 1, 5-benzothiazepine-4) 5H-one or a non-toxic acid addition salt of the same

18. . The composition according to any of the rei indications 11 to 17, wherein the benzothiazepine derivative is present in an amount of about 2.5 to 30 mg.

19. The composition according to any of claims 11 to 17, wherein the benzothiazepine derivative is present in an amount of about 2.5 to 15 mg.

20. The composition according to any of claims 11 to 19, wherein the composition is in the form of a tablet, capsule, powder, suspension, emulsion or syrup.

21. The composition according to any of the rei indications 11 to 19, wherein the composition is in the unit dosage solid form and wherein the vasodilating agent is present in an amount of about 5 to about 95% by weight and the remainder comprising conventional pharmaceutical vehicles.

22. The composition according to any of the rei indications 11 to 19, in the form of an aqueous solution containing about 0.05 to about 0.5% of the vasodilating agent.