Drug – bio-affecting and body treating compositions – Antigen – epitope – or other immunospecific immunoeffector – Virus or component thereof
Reexamination Certificate
2000-04-12
2002-09-24
Stucker, Jeffrey (Department: 1647)
Drug, bio-affecting and body treating compositions
Antigen, epitope, or other immunospecific immunoeffector
Virus or component thereof
C424S085400, C424S085500, C514S894000
Reexamination Certificate
active
06455051
ABSTRACT:
TECHNICAL FIELD
The present invention relates to an ameliorant for hepatitis C therapeutic effects, the ameliorant being used in combination with interferon-&agr; (hereinafter referred to as “IFN-&agr;”). More specifically, the present invention relates to an ameliorant for hepatitis C therapeutic effects, which is used together with IFN-&agr; or before the administration of IFN-&agr; and has the action of improving or enhancing the therapeutic effects of IFN-&agr; on hepatitis C.
The present invention further relates to a therapeutic composition for the treatment of hepatitis C, which has high therapeutic effects on hepatitis C, as compared to conventional hepatitis C therapeutic agents comprising IFN-&agr; as an active ingredient.
The present invention further relates to a pharmaceutical kit for the treatment of hepatitis C, which comprises a pharmaceutical composition containing IFN-&agr; as an active ingredient and a pharmaceutical composition containing interferon-&ggr; (hereinafter referred to as “IFN-&ggr;”) as an active ingredient.
The present invention further relates to an effective therapeutic method for the treatment of hepatitis C.
BACKGROUND ART
In chronic hepatitis C, as long as hepatitis C virus (HCV) infection continues, liver lesion does not cure and the alleviation is rare. About 40% of chronic hepatitis C patients progress to liver cirrhosis, and further 25% develop hepatocellular carcinoma. Of the liver cirrhosis cases, 75% progress from chronic hepatitis. It is therefore recognized that chronic hepatitis should be actively treated without viewing the prognosis optimistically.
Since infection of hepatitis C virus (HCV) which is a RNA virus causes hepatitis C, IFN-&agr; or interferon-&bgr; (herein after referred to as “IFN-&bgr;”) presumably having the action of suppressing the proliferation of HCV may cure chronic hepatitis C. From such theoretical background, an IFN-&agr; therapy for the treatment of non-A non-B chronic hepatitis was reported in 1986 by Hoofnagle et al. (Hoofnagle, J. H., Mullen, K. D., et al.: N. Engl. J. Med., 315, 1575-1578, 1986), and attracted attention. HCV was identified in 1988, and it has been proven that 90% of the non-A non-B chronic hepatitis cases are chronic hepatitis C.
In Japan, various IFN-&agr; or IFN-&bgr; therapeutic methods have been tested since about 1988, and their clinical use was permitted in 1992.
At present, as IFN-&agr; therapy for the treatment of chronic hepatitis C, a method of administering IFN-&agr; three times weekly for a long period of time (Davis, G. L., Balart, L. A.,: N. Engl. J. Med., 321, 1501-1506, 1989) is used in the U.S., Europe and part of Japan, whereas a method of administering a large amount of IFN-&agr; every day for the first 2 to 4 weeks of IFN-&agr; administration (Iino, S., Hino, K., et al.: Gastroent. Jpn., 26(Suppl.3), 224-239, 1991) is employed in Japan.
In the former method, the daily dose of IFN-&agr; is 3~5×10
6
IU in many cases. In such cases, GPT (glutamic-pyruvic transaminase) decreases well during the administration of IFN-&agr;, but GPT increases again and HCV-RNA reappears in most cases when the administration of IFN-&agr; is stopped. In recent research, a report shows that administration of IFN-&agr; (3×10
6
IU) three times,weekly for 18 to 24 months makes 24% of the patients continuously HCV-RNA negative, thus enhancing therapeutic effects on chronic hepatitis C, as compared to the 6-month administration whereby the HCV-RNA continuous negative rate is 12.5% (F.D.C Reports, Mar. 31, 1997). Based on the report, the FDA has approved the 12-month administration as a preferable IFN-&agr; administration method.
In the latter method, i.e., method of administering a large amount of IFN-&agr; every day for the first 2 to 4 weeks of IFN-&agr; administration, a daily IFN-&agr; dose of as high as 10×10
6
IU is expected to achieve a continuous normalization of GPT in 40 to 50% of the patients even after the completion of administration and make 30 to 40% of the patients HCV-RNA negative. With such expectation, this method is used in Japan.
In Japan, a method of administering IFN-&bgr; every day for 6 to 8 weeks is also widely used as a therapy for chronic hepatitis C.
As regards IFN-&ggr;, it has been reported that IFN-&ggr; produced no effects when administered to 10 chronic hepatitis C patients for 6 months (F. Saez-Royuela, et al.: Hepatology, 13: 327-331, 1991). Michio Sata et al (International Hepatology Communications 6 (1997) 264-273) reported on the expression of the immunological action of IFN-&ggr;, but the effectiveness has not been officially recognized yet.
As shown above, IFN-&agr; therapy and IFN-&bgr; therapy are conventionally used for the treatment of chronic hepatitis C. In recent year, factors determining the therapeutic effects of IFN-&agr; and IFN-&bgr; have been elucidated.
The background factors affecting IFN-&agr; therapy were analyzed dividing the patients into an IFN-&agr; therapy responsive group whose IFN-&agr; intermittent administration period was less than 2 years and into an IFN-&agr; therapy resistant group whose IFN-&agr; intermittent administration period was 2 years or more. The analysis revealed that HCV genotype, HCV quantity before the treatment and liver image are important. More specifically, the analysis revealed that IFN-&agr; therapy and IFN-&bgr; therapy are effective against chronic hepatitis cases wherein the HCV genotype is 2a or 2b, the HCV amount is less than 10
6
copies/ml (1 Meq/ml) and the fibrillation is slight, whereas it is less effective against chronic hepatitis cases wherein the HCV genotype is 1a or 1b, the HCV amount is 10
6
copies/ml (1 Meq/ml) or more and the fibrillation is moderate to severe. Age, sex, contraction period, biochemical test values did not greatly affect IFN-&agr; or IFN-&bgr; therapeutic effects.
The antiviral action and side effects of IFN-&agr; or IFN-&bgr; are dose-dependent, although there are some individual differences. In IFN-&agr; or IFN-&bgr; therapies, it is therefore expected that an increased dose of IFN enhances antiviral effects and produces high therapeutic effects, whereas undesirable side effects of IFN-&agr; or IFN-&bgr; are worried about. A long-term administration of IFN is better as mentioned above, but causes various side effects, for example, (1) having the possibility that the antibody neutralizes recombinant IFN, (2) inducing autoimmune diseases, (3) producing side effects on the cardiovascular system and (4) inducing or worsening the side effects on patients with depression (Shiro Itano; liver bile pancreas, 21,899-904, 1990).
Therefore, an effective therapeutic method for treating chronic hepatitis C patients who have not responded to IFN-&agr; or IFN-&bgr; treatment is sought now.
There are few research reports on the retreatment cases of IFN-&agr;-ineffective chronic hepatitis C patients using IFN-&agr;. From the reports, however, there appear to be two types of IFN-&agr;-ineffective chronic hepatitis C patients, i.e., the cases in which IFN was ineffective because of an insufficient dosage or short administration period in the first treatment and the cases in which IFN was ineffective despite a sufficient IFN administration.
Kuroki et al. (Tetsuo Koroki: Medical Practice, 10,981, 1993) administered IFN-&agr; again to 18 out of 71 patients who had not responded to the first IFN-&agr; administration and examined their condition for 1 year or more. Kuroki et al. reported that of the 18 patients, only 1 patient (6%) had continuous normalization of GPT (remarkable efficacy) and there was no continuous HCV-RNA negative case.
Matsushima (Takashi Matsushima: Treatment, 77, 1187, 1983) reports the results of re-administration of IFN-&agr; to 37 patients who had been judged as unchanged cases in the first IFN-&agr; administration. The results show that the GPT continuous normalization rate achieved by re-administering IFN-&agr; to 27 patients who had shown transient effects in the first IFN-&agr; administration was 22.2% (6/27 cases), whereas re-administration
Furukawa Aya
Hayashi Norio
Kito Yuji
Otsuka Pharmaceutical Co. Ltd.
Seharaseyon Jegatheesan
Stucker Jeffrey
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