TREATMENT OF SHOCK BY CYCLODEXTRINS AND THEIR DERIVATIVES

Abstract: A use of a cyclodextrin or a derivative thereof for the manufacture of a medicament for treatment of shock.

Description: The present invention relates to a use of a cyclodextrin or a derivative thereof for the manufacture of a medicament for treating shock. Shock refers to a condition of acute circutalory failure and in other words a condition wherein cardiac function is seriously damaged by hemorrhage, bacterial toxin, pathological cardiac alterations, anaphylaxis and cardiac output, which must be retained at a level essential for supporting normal function of organs, is reduced, thereby causing histonic circulatory failure and hence cellular metabolic disorder. Conveniently, shock symptoms have been treated by transfusion or administration of vasodilator etc., without satifactory effect. Accordingly, there has been a continuous need of developing a medicament useful in treatment of shock. As a result of extensive studies about the properties of cyclodextrin and their derivatives which have been used only as a complexing agent in the pharmaceutical field, the present inventor discovered that these compounds have beneficial action in prolonging the life of a patient who is in the condition of shock. The present invention provides the use of a cyclodextrin, an estherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin, or a sulfonated cyclodextrin for the manufacture of a medicament for treatment of shock. As used herein, the term "shock" refers to the condition as mentioned above and includes hypovolemic shock (traumatic shock) due to bleeding, thermal burn, dehydration etc., cardiogenic shock, endotoxic shock, and acute peripheral vasogenic shock, nerogenic shock, antigenic and drug induced shock due to hypersensitivity and anaphylaxis, as well as a shock induced by hormoral insufficiency. The term "treatment" includes prevention, cure and relief of disease and arrest or relief of development of disease. The term "cyclodextrin" includes α-cyclodextrin, β-cyclodextrin and γ-cyclodextrin. The term "derivatives" used in conjunction with the term cyclodextrin refers to etherified cyclodextrins, glucosyl cyclodextrins, maltosyl cyclodextrins acylated cyclodextrins and sulfonated cyclodextrins. Said etherified cyclodextrins include (lower)alkylcyclodextrins such as methylcyclodextrin, ethylcyclodextrin, propylcyclodextrin, dimethylcyclodextrin, trimethylcyclodextrin, (lower)alkenylcyclodextrins, hydroxy(lower)alkylcyclodextrins such as hydroxyethylcyclodextrin, hydroxypropylcyclodextrin, (lower)alkoxy(lower)alkylcyclodextrins, aralkylcyclodextrins such as benzylcyclodextrin, halo(lower)alkylcyclodextrins such as chloroethylcyclodextrin, and cylodextrinepichlorohydrine copolymer. These may be etherified cyclodextrins in which one, two or three hydroxy groups in any of the glucose units of the cyclodextrin molecule are converted into ether. Said acylated cyclodextrins include (lower)alkanoylcyclodextrins such as formylcyclodextin, acetylcyclodextrin, aromatically or heterocyclically acylated cyclodextrins such as benzoylcyclodextrin, nicotinoylcyclodextrin. The derivatives of cyclodextrin include also derivatives in which two or more of derivatizations selected from etherification, branching, acylation and sulfuration are co-existing. These derivatives are known or can be prepared by a method similar to that for the known derivatives. While the dosage of cyclodextrin or derivatives thereof will vary depending on age, weight, condition of particular subject, desired therapeutic effect, satisfactory effects will generally be obtained with the dosage of 1 µg/kg to 500 mg/kg, preferably 10 µg/kg to 50 mg/kg, administered once a day or 2 to 4 divided doses a day or as a sustained form. Administration may be effected by injection. For administration, the compound used in the invention can be given in the form of conventional pharmaceutical preparation which contains said compound, as an active ingredient, in admixture with a pharmaceutically acceptable carrier such as organic or inorganic, solid or liquid excipients suitable for the desired mode of administration such as injection. Such preparation may be in a solid form such as solid from which a solution can be made up before use, or in a liquid form such as solution, emulsion, suspension. Said carrier includes starch, lactose, glucose, sucrose, dextrin cellulose, paraffin, aliphatic glyceride, water, alcohol, acacia etc. The above preparation may also contain auxiliary substance, stabilizer, emulsifier, lubricant, binder, pH-adjuster, isotonic agent and other conventional additives added as necessary. The present invention is illustrated in more detail by way of the following Examples and Test Examples. Example 1 The above ingredients are brought into solution by conventional way to form an injectable solution. Test Example 1 Male Crj-Wister rats (weighing 230 - 240 g, 7 weeks old, 13 - 20 rats per groups) were used. Predetermined amounts of commercial dimethyl-α-cyclodextrin [a mixture mainly comprising hexakis(2,6-di-O-methyl)-α-cyclodextrin and pentakis(2,6-di-O-methyl)-mono(2,3,6-tri-O-methyl)-α-cyclodextrin; hereinafter referred to as DMCD] or pentakis[2,6-di-O-methyl)-mono(2,3,6-tri-O-methyl)-α-cyclodextrin (purified from commercial DMCD; hereinafter referred to as P-DMCD], dissolved in the Ringer solution (2 ml/kg) was intravenously administered. The control group received the same amount of Ringer solution. After 5 minutes, lipopolyssacharide (15 mg/kg) was intravenously administered. After 24 hours, the rats were inspected for survival and rates were calculated. The results are shown in the following Table. Test Example 2 The survival rate in the treatment with α-cyclodextrin (3 mg/kg) was determined as described in Test Example 1. As a results, it was shown that the survival rate of α-cyclodextrin (3 mg/kg) group was 27% as compared with that of Ringer group which was 13%. Test Example 3 Lipopolysaccharide (3.75 mg/kg) was intravenously administered to male Beagle dogs (weighing 7.5 - 9.5 kg) and, after 15 minutes, a solution of commercial DMCD (10 mg/kg) in the Ringer solution (0.5 ml/kg) was intravenously administered over five minutes in order to evaluate the activity of DMCD against endotoxin shock. The control groups (4 Beagle dogs per group) received the same amount of Ringer solution. Two of four dogs of Ringer group died, while all four of the DMCD group survived. Test Example 4 The survival rates in the treatment with dimethyl-β-cyclodextrin (10 mg/kg), hydroxypropyl-α-cyclodextrin (1 mg/kg) and hydroxypropyl-β-cyclodextrin (10 mg/kg) were determined as described in Test Example 1. As a results, it was shown that the survival rates of dimethyl-β-cyclodextrin (10 mg/kg) group, hydroxypropyl-α-cyclodextrin (1 mg/kg) group, and hydroxypropyl-β-cyclodextrin (10 mg/kg) group were 27%, 27% and 33%, respectively, as compared with that of Ringer group which was 7%. Test Example 5 The survival rates in the treatment with β-cyclodextrin polymer [product obtained by polymerizing β-cyclodextrin by crosslinker] (1 mg/kg) and trimethyl-β-cyclodextrin (1 mg/kg) were determined as described in Test Example 1. As a results, it was shown that the survival rates of β-cyclodextrin polymer (1 mg/kg) group and trimethyl-β-cyclodextrin (1 mg/kg) group were 33% and 33%, respectively, as compared with that of Ringer group which was 13%. The above results indicate that the compounds used in the invention have an excellent action in prolonging the life of a shocked subject.

Claims: Claims for the following Contracting States : AT, BE, CH, DE, DK, FR, GB, IT, LI, LU, NL, SE The use of a cyclodextrin, an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin, or a sulfonated cyclodextrin for the manufacture of a medicament for treatment of shock. The use according to claim 1, in which the etherified cyclodextrin is used and is selected from the group consisting of dimethylcyclodextrin. The use according to claim 1, for treatment of endotoxin shock. Claims for the following Contracting States : ES, GR A method for the manufacture of a medicament for treatment of shock comprising admixing, cyclodextrin, an etherified cyclodextrin, a glucosyl cyclodextrin, a maltosyl cyclodextrin, an acylated cyclodextrin, or a sulfonated cyclodextrin, and a pharmaceutically acceptable excipient. A method according to claim 1 in which the etherified cyclodextrin is used and is selected from the group consisting of dimethylcyclodextrin. A method according to claim 1 wherein the medicament is for the treatment of endotoxin shock.

Inventors: UENO, RYUJI
Applicants: KABUSHIKI KAISHA UENO SEIYAKU OYO KENKYUJO
Application year: 1990
Main classification: A61K31
IPC codes: A61P3, A61P43, A61P9, A61K31