Treatment of hepatic cirrhosis

Abstract

A composition for treating hepatic fibrosis and a method of using and manufacturing the composition are provided. The composition includes a quinazolinone derivative, preferably Halofuginone.

Description

[0001] This is a Continuation Application of U.S. patent application Ser. No. 08 / 862,382, filed on May 23, 1997, now abandoned, and a Continuation-in-Part Application of U.S. patent application Ser. No. 09 / 229,894, filed on Jan. 14, 1999, currently pending.FIELD AND BACKGROUND OF THE INVENTION[0002] The present invention relates to the treatment of hepatic cirrhosis and, in particular, to the treatment of hepatic cirrhosis with quinazolinone derivatives such as Halofuginone.[0003] Hepatic cirrhosis has a number of causes, including hepatic fibrosis caused by chronic alcoholism, malnutrition, hemochromatosis, passive congestion, hypercholesterolemia, exposure to hepatotoxic chemical substances, exposure to drugs, immune reactions, genetically determined sensitivities to certain substances as seen with copper in Wilson's disease and infections such as viral hepatitis, syphilis and various parasitic infections including, but not limited to, Schistosomiasis mansoni and S. japonica. For ...

AI Technical Summary

Problems solved by technology

For reasons given in greater detail below, the disease is currently incurable and frequently fatal.

Next, overt fibrosis is evident with a concomitant decrease in liver function.

Portal circulation is reduced as fibrotic tissue is formed in the liver, further reducing liver functionality.

These esophageal blood vessels can rupture, causing fatal hemorrhage.

In hepatic fibrosis, connective tissue accumulates in the liver, replacing normal hepatic parenchymal tissue, and reducing liver functionality.

For example, clinical conditions and disorders associated with primary or secondary fibrosis, such as systemic sclerosis, graft-versus-host disease (GVHD), lung fibrosis and a large variety of autoimmune disorders, are distinguished by excessive production of connective tissue, which results in the destruction of normal tissue architecture and function.

Unfortunately, only a few inhibitors of collagen synthesis are available, despite the importance of this protein in sustaining tissue integrity and its involvement in various disorders.

Unfortunately, none of these inhibitors are collagen-type specific.

Also, there are serious concerns about the toxic consequences of interfering with biosynthesis of other vital collagenous molecules, such as Clq in the classical complement pathway, acetylcholine esterase of the neuro-muscular junction endplate, conglutinin and liver surfactant apoprotein.

Their prolonged use causes lathritic syndrome and interferes with elastogenesis, since elastin, another fibrous connective tissue protein, is also cross-linked.

However, the in vitro action of Halofuginone does not always predict its in vivo effects.

However, chickens treated with Halofuginone were not reported to have an increased rate of bone breakage, indicating that the effect is not seen in vivo.

Thus, the exact behavior of Halofuginone in vivo cannot always be accurately predicted from in vitro studies.

Furthermore, the ability of Halofuginone or other related quinazolinone to block or inhibit pathological processes related to hepatic cirrhosis has not been demonstrated.

Other inhibitors of collagen synthesis, cross-linking and deposition, such as corticosteroids, penicillamine, methotrexate and colchicine, have been tested for their therapeutic effect on hepatic fibrosis, but have not proved effective [S. L. Friedman, New Eng. J. Med., 328:1828-35, 1993].

Although Halofuginone has been shown to have a specific inhibitory effect on the synthesis of type I collagen, such inhibition has not been otherwise shown to be efficacious in the treatment of hepatic cirrhosis.

Indeed, hepatic cirrhosis has a high mortality rate, as currently available therapeutic options have significant side effects and are not generally efficacious in slowing or halting the progression of the fibrosis.

Thus, simply administering known in vitro inhibitors of collagen synthesis, deposition and cross-linking in an attempt to treat hepatic cirrhosis is ineffective.

However, chickens treated with Halofuginone were not reported to have an increased rate of bone breakage, indicating that the effect is not seen in vivo.

Thus, the exact behavior of Halofuginone in vivo cannot always be accurately predicted from in vitro studies.

Second, other inhibitors of collagen synthesis, deposition and cross-linking have not proved effective for the treatment of hepatic cirrhosis, demonstrating that inhibition of collagen production alone is not sufficient for determining the success or failure of a treatment for hepatic fibrosis.

Thus, the ability of Halofuginone to inhibit collagen type I synthesis and deposition cannot predict the ability of Halofuginone to slow, reduce or other ameliorate the pathogenesis of hepatic fibrosis.

Finally, all other prior art references have only taught the efficacy of Halofuginone on cells such as fibroblasts.

Even if the behavior of Halofuginone on cells of a certain type could be predicted, such a prediction would certainly not be reliable for cells outside of that type.

Thus, the effect of Halofuginone on Ito cells is not predictable from its effect on fibroblasts.

Thus, nothing in the prior art taught that Halofuginone would be useful in the treatment of hepatic fibrosis in vivo.

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