WO1988000830A1

WO1988000830A1 - Use of certain polysaccharides for the treatment of hepatic or renal failure

Info

Publication number: WO1988000830A1
Application number: PCT/GB1987/000550
Authority: WO
Inventors: Ranulph Michael Alsop; Raymond Brian Forrester; George Griffin; Jeremiah Milner
Original assignee: Fisons Plc
Priority date: 1986-08-02
Filing date: 1987-08-03
Publication date: 1988-02-11
Also published as: EP0276273A1; JPH01500751A

Abstract

Method of treatment of a patient suffering from hepatic or renal failure which comprises administration of a dextran of Mw in the range 10,000 to 50,000,000, optionally in admixture with glucose polymers other than dextran, and in particular those containing an average of 2 - 10 glucose units per molecule.

Description

Use of certain polysaccharides for the treatment of hepatic or renal failure.

Technical Field

This invention relates to novel compositions for, and to the use of certain polysaccharides in, the treatment of conditions arising from hepatic or renal failure.

Nitrogenous waste products, such as ammonia, are usually converted in the liver to products that may be excreted, eg urea. Such products are then transported to the kidneys where they are excreted from the body.

Failure of either of the kidneys or liver to carry out such functions may lead to an increased concentration of waste products which are toxic to the body.

Hepatic and/or portosystemic encephalopathy may occur where there is a high concentration of ammonia circulating in the blood stream. Ammonia is produced in the gut by the action of bacteria on ingested proteins and is absorbed into the portal blood stream from the large intestine. Patients suffering from hepatic failure or portosystemic shunting can not adequately convert the ammonia to urea in the liver for excretion, so that excess ammonia may enter the systemic blood system.

Patients who have defective kidneys or who have had their kidneys removed tend to have a high metabolic rate. This can lead to the metabolism of stored proteins, which the pati ent .

It is also known that patients suffering from renal failure can be treated by the oral administration of a low molecular weight dextrin which provides a rapidly available source of energy as absorbed glucose. The presence of the glucose reduces the metabolism of the stored body protein and thereby reduces some of the load of nitrogenous products on the kidneys.

We have now found a means of mitigating some of the problems of patients who have defective livers or kidneys. Disclosure of the Invention

According to the invention we provide a method of treatment of a patient suffering, from hepatic or renal failure, which comprises administration of an effective amount of a dextran of weight average molecular weight in the range 10,000 to 50,000,000 to a patient suffering from such a condition.

The dextran preferably has a weight average molecular weight in the range 50,000 to 1,000,000, more preferably in the range 60,000 to 400,000.

By dextran we mean a polyglucose or a derivative thereof in which the glucose units or their derivatives are predominantly linked in an alpha 1,6 configuration. Specific derivatives include hydrogenated dextran, dextran glucoheptonic acid, carboxymethyl dextran and hydroxyethyl dextran. Dextrans can be made by the action of the dextransucrase family of enzymes on sucrose. Dextransucrases are produced by various species of lactobacillae. We particularly prefer dextrans produced by Leuconostoc mesenteroides (and especially strain NRRL B512F). The dextrans produced by the action of the enzymes on sucrose are generally of very high molecular weight and may be partially hydrolysed and the hydrolysate fractionated, if desired, to produce fractions of relatively narrow bands of lower molecular weight. We prefer to use these fractionated dextrans. These dextrans are generally available in commerce and are of the same general type as, but are usually of a higher molecular weight than, the dextrans which are currently used for intravenous administration.

According to the invention we also provide a dextran of weight average molecular weight of from 10,000 to 50,000,000 for use in the manufacture of a medicament for the treatment of hepatic or renal failure. The medicament may be in a form suitable for i.v., rectal or preferably oral administration.

For oral administration the medicament may be in the form of a syrup, a tablet, a dry powder, which may be dissolved in a suitable solvent, eg water prior to administration, or a liquid, eg an aqueous solution. The medicament may be incorporated into either a liquid or solid foodstuff, eg bread, biscuits, yoghurt, tea or coffee.

For rectal administration we prefer the medicament to be in the form of an enema and in particular to be an aqueous solution. We prefer the enema to contain up to 15% w/v, eg 7.5% w/v of the dextran.

For i.v. administration we prefer the medicament to contain up to 15% w/v, eg 6 - 10% w/v of the dextran. The medicament may also contain a pharmaceutically acceptable adjuvant, diluent or carrier. For tablets suitable adjuvants, diluents and carriers are lactose, starch, talc or stearic acid and, for i.v. formulations or enemas, surfactants and preservatives. The i.v. formulations and enemas may be made isotonic with, for example, sodium chloride or phosphate.

The medicament may also contain other ingredients, such as flavours, eg fruit flavour; acids, eg phosphoric, citric, maleic, fumaric or tartaric acids; buffering agents, eg phosphates; sugars, eg fructose, sorbitol or sucrose. The medicament may also contain balanced nutrients such as fats, carbohydrates, proteins, minerals and vitamins. When the medicament is in the form of a dry powder it may also contain an effervescent couple, eg sodium bicarbonate/citric acid. effective amount of a mixture of a dextran of weight average molecular weight of from 10,000 to 50,000,000 with glucose polymers other than dextran, to such a patient. We also provide a composition suitable for the treatment of a patient with hepatic or renal failure, which comprises a dextran of weight average molecular weight of from 10,000 to 50,000,000 in admixture with glucose polymers other than dextran.

We further provide a dextran of weight average molecular weight of from 10,000 to 50,000,000 in admixture with glucose polymers other than dextran, for use in the manufacture of a medicament for the treatment of hepatic or renal failure.

The dextran in these mixtures is preferably as described above.

We prefer the glucose polymers other than dextran to be starch hydrolysates, and as such to be mixtures of glucose and polyglucose molecules having a wide range of numbers of glucose units per molecule. We prefer the glucose polymers to contain an average of 2 - 10 and more preferably 4 - 6 glucose units per molecule.

We prefer the ratio of dextran to glucose polymers other than dextran to be in the range 1:0.3 to 3, eg 1:1 by weight. The compositions or medicaments may be suitable for