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Medicinal compositions containing diuretic and insulin resistance-improving agent

a technology of diuretic and insulin resistance, which is applied in the direction of drug compositions, biocides, metabolic disorders, etc., can solve the problems of increased heart weight, cardiac enlargement, and sometimes adverse events of insulin sensitizers

Inactive Publication Date: 2005-12-29
SANKYO CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is also known that insulin sensitizers sometimes elicit adverse events such as increase in heart-weight, cardiac enlargement, edema, hydrothorax and the like, when used clinically.

Method used

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  • Medicinal compositions containing diuretic and insulin resistance-improving agent
  • Medicinal compositions containing diuretic and insulin resistance-improving agent
  • Medicinal compositions containing diuretic and insulin resistance-improving agent

Examples

Experimental program
Comparison scheme
Effect test

example

Example 1

Improving Effects of Co-Administration of a Diuretic, Furosemide, on Increasing Heart-Weight and Edema Elicited by 5-[4-(6-methoxy-1-methyl-1H-benzimidazol -2-ylmethoxy)benzyl]thiazolidine-2,4-dione Hydrochloride (Compound A)

(1) Increases in Heart-Weight and Circulating Serum Volume

[0289] After 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione hydrochloride (200 mg / kg) was repeatedly and orally administered by gavage for 3 or 7 successive days to female Wistar rats (7 weeks old, Charles River Japan, Inc.), circulating serum volume was determined by Evans blue methods and heart-weight recorded. The results are summarized in Table 1.

TABLE 1Duration ofRatio aganist controlAdministrationCirculating(day)Heart-WeightSerum volume31.03a)1.18a)*71.22b)**1.30b)**

Note:

a)n = 5-6;

b)n = 12;

*p < 0.05;

**p < 0.01 (Student's t-test)

[0290] Circulating serum volume and heart-weight were increased after administration for both 3 and 7 days. Therefore ...

example 2

Effects of a Co-Administering a Diuretic, Amiloride, on Increases in Circulating Serum Volume, Heart-Weight, and Edema Caused by Administration of 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione Hydrochloride (Compound A)

[0294] Zucker fatty rats (7 weeks old, SLC, Shizuoka, Japan) were grouped as 5 rats a group. Mean body weight, plasma glucose and glyceride levels, hematocrit value, and the number of red blood cells in each group were similar among the groups. The rats were allowed to take food pellets (F2, Funabashi Farm) and water ad libitum. In the control group, the rats were given only food pellets, while the rest of rats were administered 5-[4-(6-methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione hydrochloride (suspended in 0.5% solution of carboxymethylcellulose (CMC)) at a volume of 1 ml / kg orally by gavage. In the groups of rats administered the above compound with furosemide (100 mg / ml, suspended in 0.5% CMC solu...

reference example 1

5-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione•hydrochloride

Reference Example 1(1)

5-[4-(6-Methoxy-1-methyl-1H-benzimidazol-2-ylmethoxy)benzyl]thiazolidine-2,4-dione

[0300] A reaction mixture of 5-methoxy-N-methyl-1,2-phenylenediamine (21.8 g) (see Reference example 9 of Japanese Patent Application Publication No. Hei 9-295970), 5-(4-methoxycarbonylmethoxybenzyl)thiazolidine-2,4-dione (63.4 g) (see Reference example 21 of Japanese Patent Application Publication No. Hei 9-295970), 1,4-dioxane (250 ml) and concentrated hydrochloric acid (750 ml) was heated under reflux for 60 hours. The reaction mixture was cooled in an ice bath, and the resulting precipitate was filtered off. To this precipitate was added 5% aqueous sodium hydrogencarbonate solution (800 ml), and the mixture was stirred at room temperature for 2 hours. The precipitate was filtered off, dissolved in a mixed solvent of N,N-dimethylformamide (1000 ml) and methanol (200 ml), and then ...

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Abstract

The present invention relates to a pharmaceutical composition comprising an insulin sensitizer and a diuretic which can prevent or treat side effects such as edema, cardiac enlargement, body fluid retension or hydrothorax caused by administration of an insulin sensitizer.

Description

[0001] This is a Continuation-in-Part Application of International Application PCT / JP01 / 11296 filed Dec. 21, 2001, which is incorporated herein by reference in its entirety.BACKGROUND OF INVENTION [0002] The present invention relates to new pharmaceutical agents for prophylaxis or treatment of diabetes mellitus comprising an insulin sensitizer and a diuretic, said diuretic having the activity of preventing or treating edema caused by the insulin sensitizer. [0003] It is known that insulin sensitizers are useful as agents for the prevention and / or treatment of diabetes mellitus. However, it is also known that insulin sensitizers sometimes elicit adverse events such as increase in heart-weight, cardiac enlargement, edema, hydrothorax and the like, when used clinically. These adverse events are considered to be associated with retention of body fluid due to increased sensitivity to insulin. On the other hand, diuretics are agents that promote excretion of excess body fluid (hydrothorax...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/4965A61K45/06A61P3/10A61P43/00
CPCA61K31/4965A61K45/06A61K2300/00A61P3/10A61P43/00
Inventor TAKAOKA, MASAYAARAKI, KAZUSHIKANDA, SHOICHI
Owner SANKYO CO LTD
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