Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Radical -xh acid – or anhydride – acid halide or salt thereof...
Patent
1996-12-18
1999-06-29
Spivack, Phyllis G.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Radical -xh acid, or anhydride, acid halide or salt thereof...
A61K 31195
Patent
active
059169214
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to therapeutic agents for liver regeneration containing valine, which is a branched-chain amino acid, as an active ingredient. To be more precise, the invention relates to valine-containing preparations that are capable of regenerating hepatocytes in cases such as after the removal of the liver due, for example, to hepatopathy, hepatitis and cirrhosis.
BACKGROUND ART
Some factors and drugs are known to have a hepatocyte regenerating action. For example, Archive of Pathology, 16, 226-231 (1993) teaches that when a diet containing 1 wt % of a dried thyroid gland powder was continuously fed after partial hepatectomy, the liver weight increased significantly over the control from the seventh day of the partial hepatectomy.
Journal of Biological Chemistry, 247, 1757-1766 (1972) reports that a liquid mixture of triiodothyronine (T3), mixed amino acids in solution, glucagon and heparin caused DNA synthesis in the liver.
In addition, a growth factor for the primary culture of hepatocytes in mature rats was purified from rat sera 24 hours after 70% partial hepatectomy and designated HGF (hepatocyte growth factor) or hepatotropin, as described in Biochemical and Biophysical Research Communications, 122, 1450-1459 (1984).
Insulin and glucagon are also important factors to liver regeneration, as described in Advances in Enzyme Regulation, 13, 281-293 (1975), and in Japan, ever since Okita et al. reported the application of an insulin-glucagon therapy to fulminating hepatitis in Gastroenterologia Japan., 14, 453 (1979), they have been commonly used in clinical cases.
Valine, isoleucine and leucine, which are branched-chain amino acids, have been reported to be capable of ameliorating hepatic encephalopathy and septic encephalopathy or saving proteins during invasion, and Hepatoamine (registered trademark), Hepan (registered trademark), Aminoleban (registered trademark), Amiparen (registered trademark), Amizet (registered trademark) and Aminic (registered trademark) are commercially available as amino acids in solution. However, it is entirely unknown that valine has a hepatocyte regenerating action.
In recent years, hepatocyte growth factor (HGF) was purified from rats and humans, followed by successful cloning of cDNA, and in view of its capability for proliferating primary cultured hepatocytes, as well as the results of increased blood HGF activity in hepatopathy and induced expression of HGF mRNA, clinical application of the HGF is expected to materialize in the future but, as of today, this has not been commercialized.
The only treatment that is presently held in Japan to have a liver regenerating effect is glucagon-insulin therapy (GI therapy). However, the effectiveness of this GI therapy has not yet been recognized in Europe and the United States of America.
DISCLOSURE OF INVENTION
The object of the present invention is to provide a drug that is safe and which exhibits a potent liver regenerating effect on diseases of the liver that involves various degrees of hepatopathy.
In order to attain this object, various concentrations of valine were given to rats. The effects of valine on the weights of the livers and the histopathological findings were analyzed. As a result, the present inventors found that valine caused marked liver regeneration, which led to the accomplishment of the present invention.
The valine to be used in the invention may be commercially available or synthesized products and any types of valine can be employed irrespective of the method of their preparation. In addition, either of D-, L- and DL-forms of valine is usable.
BEST MODE FOR CARRYING OUT THE INVENTION
When the valine is used as a therapeutic agent for liver regeneration, it is generally preferred to perform intravenous administration, but other routes of administration such as peroral and parenteral are also possible. Valine may be used singly as a preparation in which it is the sole ingredient, but preferably it is used either in combination with a preparation for infusion such as a hi
REFERENCES:
patent: 4259353 (1981-03-01), Kleinberger
patent: 4499076 (1985-02-01), Ohashi et al.
Fujiwara et al, "Evaluation of Administration Ratio of BCAA Enriched Solution in Partially Hepatectomized Rats", Journal of Japan Vein-Enteral Nutrition Research Society, No. 4:104-107 (Feb. 1989).
Doi Hideyuki
Komatsu Hiromichi
Nishihira Tetsuro
Chugai Seiyaku Kabushiki Kaisha
Spivack Phyllis G.
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