Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution... – Containing or obtained from hypericum
Reexamination Certificate
2000-04-04
2002-08-06
Lankford, Jr., Leon B. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
Containing or obtained from hypericum
C435S235100, C435S238000, C514S732000, C514S738000
Reexamination Certificate
active
06428819
ABSTRACT:
FIELD AND BACKGROUND OF THE INVENTION
The present invention involves the use of extracts of the plant
Hypericum perforatum
in the preparation of improved pharmaceutical compositions for the treatment, prevention and control of hepatisis C, chronic hepatitis and related viruses.
Hepatitis C is a debilitating liver disease that begins as an acute infection and can develop into a chronic disease. As many of 50% of acutely infected individuals develop a state of chronic infection [Alter HJ 1988. Transfusions-associated non-A, non-B hepatitis: the first decade In Viral Hepatitis and Liver Disease. Zuckerman A. J. ed. Alan R. Liss, New York, p. 537-542] of which up to 20% may proceed to hepatic cirrhosis (destruction of the liver) with its complications of portal hypertension, ascites, encephalopathy, and bleeding disorders. The infection also poses a high risk for development of liver cancer (hepatocellular carcinoma). The prevalence of infection in the general population is so high that prior to the availability of screening tests, the risk of hepatitis C following blood transfusion in the United States was 5-10% or about 150,000-300,000 transfusion recipients per year acquired the disease. In Japan 4% of screened blood donors over age 55 had serologic evidence of HCV infection [Tabor E. and K. Kabayashi 1992. Hepatitis C virus, a causative infectious agent for non-A, non-B hepatitis: Prevalence and structure—Summary of a conference on hepatitis C virus as a causative of hepatocellular carcinoma. J. Natl. Cancer Inst. 84: 86-90] In some endemic regions of the Third World as many as 20% of the population can be infected. The healthy appearance of some chronic carriers may change after contraction of other illnesses that can reduce their immunity. The carriers can transmit the hepatitis C virus to others with whom they have close contact, thereby spreading the disease.
Hepatitis C is caused by a virus known as hepatitis C virus (HCV). HCV is non-integrating, lipid-enveloped positive sense RNA virus, similar to flavivirus and pestiviruses in gene organization and in mechanisms of cell invasion, with a single open reading frame [Choo QL, G Kuo, A J Weiner, L R Overby, D W Bradley and M Houghton 1989. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science 244: 359-362, Tabor/Kabayashi 1992]. The virus is transmitted by the parenteral route in the case of transfusion and drug abuse; and by uncertain mechanisms that probably include a sexual mode of transmission in other cases.
Treatment of Chronic Hepatitis C
A search for effective means of treating chronic hepatitis C is essential due to the high prevalence of hepatitis C, its major morbidity for symptomatic patients, the insidiously progressive course, the infectious potential of carriers, and the long-term risk for development of hepatocellular carcinoma. The primary goals of therapy should be to reduce the release of liver enzymes into the blood circulation bringing about a biologic and histologic improvement of disease activity, and secondary objectives should be to decrease viral replication and viral load with the ultimate goal of complete elimination of the virus. Virus load emerges as the most reliable means of evaluating treatment response. Techniques to characterize and quantify hepatitis C infection continue to evolve. Newly developed assays utilizing branched DNA technology (bDNA) (Chiron Ltd.), and Roche's HCV-RNA RT-PCR assay may permit simple quantification of viral RNA levels in serum. The clinical significance of these assays is beginning to be established in larger, multicenter, prospective studies.
Despite its high prevalence and moribund clinical course, there is no established form of effective therapy for hepatitis C infections. Acyclovir treatments were unsatisfactory [Pappas SC, J H Hooffiagle, N Young, S E Straus, and E A Jones, 1985. Treatment of chronic non-A, non-B hepatitis with acyclovir: A pilot study. J. Med Virol 15: 1-9], and IFN-gamma, despite its known antiviral activity, has also proven ineffective (Saez-Royuela F, J C Porres, A Moreno, I Castillo, G Martinez, F Gallana and V Carreno. 1991. High doses of recombinant alfa-interferon or gamma-interferon for chronic hepatitis C: A randomized controlled trial Hepatology 13: 327-331). The best results to date have been obtained with IFN-a, although relief was temporary, long-term response rates have been disappointing and generally run between 15-25% (Dusheiko G and P. Simmons 1994. Sequence variability of hepatitis C virus and its clinical significance (Review). J Viral Hepatitis 1: 3-15). The responses were found to be related to the HCV genotypes (Kanai K, M Kato and H Okamoto 1992. HCV genotypes in chronic hepatitis C and response to interferon, Lancet 339: 1543, Takada N, S Takase, N Enomoto, A Takada and T Date. 1992. Clinical backgrounds of the patients having different types of hepatitis C virus genomes. J Hepatol. 14: 3540, and Yoshioka K, S Kakumu, T Wakita et al. 1992, detection of hepatitis C virus by polymerase chain reaction and response to IFN-a therapy: relationship to genotypes of hepatitis C virus. Hepatology 16: 293-299), to HCV titres and to the duration of disease. A long duration of disease is an adverse prognostic factor and a prediction of therapy failure. Thus, the time factor for interferon therapy is crucial and therapy should begin early to succeed. Most recently interferon-&bgr; treatments have been given in combination with ribavirin. The results were not encouraging as sustained responses occurred in only one third of the patients (Kakumu S., Yoshioka K., Wakita T., Ishikawa T., Takayanagi M, and Hygashi Y. A pilot study of Ribavirin and interferon beta for the treatment of chronic hepatitis C. Gastroenterology 1993, 105: 507-512). This form of treatment has been associated with quite severe side effects and could be given for limited time intervals.
The present invention predicted and discovered that treatment of patients with chronic active hepatitis C with preparations from
Hypericum perforatum
led to dramatic declines in HCV blood levels in these patients. In some cases the patients tested negative to HCV in extremely sensitive molecular assays such as the quantitative RT-PCR for hepatitis C virus or the branched DNA technology, inferring that no virus particles could be detected in their blood by these most sensitive and sophisticated detection techniques. The virus appears to have been completely eliminated The preparations that were used are in most cases dried alcoholic extracts of the aerial parts of the plant
Hypericum perforatum
. They contain, among other compounds also hypericin and pseudohypericin. These are two photodynamic compounds which are activated by light and are known to act as virucidal agents (Moraleda G, T T Wu, A R Jilbert, C E Aldrich, L D Condreay. S H Larsen, J C Tang, M Colacino, W S Mason, 1993: Inhibition of duck hepatitis B virus replication by hypericin. Antiviral Res. 20: 235-247; Lavie, G, F. Valentine, B. Levin, Y. Mazur, G. Gallo, D. Lavie, D. Weiner, D. Meruelo. 1989: Studies of the mechanisms of action of the antiretroviral agents hypericin and pseudohypericin. Proc. Natl. Acad. Sci. (USA) 86: 5963-5967), however, the inventor has discovered that the plant extracts contain potentiating activity that obviates the need for light and renders the plant extracts with potent antiviralactivity against HCV without any need for light which is required with synthetic hypericin or pseudohypericin.
The healing process in this disease appears to be the result of inhibition of hepatitis C virus replication by the hypericum dried preparations. Over time the reservoir of infected cells dies due to the toxic effect of the virus. Prevention of infection of new liver cells or other bloods mononuclar cells by free hepatitis C virus that circulates in the blood will bring about elimination of the infected state. The liver then has a chance to slowly regenerate and return to normal function.
SUMMARY OF THE INVENT
Lavie David
Steinbeck-Klose Anne
Amster Rothstein & Ebenstein
Lankford , Jr. Leon B.
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