4-Methylumbelliferone as a Treatment for Chronic HBV/HCV

(i). Chronic hepatitis B Chronicity of HBV following acute infection is strongly age-related; the majority (90%) of infants acquiring HBV perinatally go on to develop chronic infection, while most persons who acquire HBV later in life resolve their infection \[ref 1\]. Patients with chronic HBV have a 15-25% lifetime risk of liver cirrhosis and hepatic cancer. An estimated 5,000 people die each year from complications of chronic HBV infection (cirrhosis and hepatocellular carcinoma). Three drugs have been approved by the Food and Drug Administration (FDA) for treatment of chronic HBV: interferon-α (IFN-α), lamivudine, and adefovir dipivoxil. Only one-third of chronic HBV patients develop a sustained response to IFN-α treatment, and adverse effects are common \[ref 2\]. Use of the newer orally-administered nucleoside analogues (lamivudine or adefovir dipivoxil) typically causes rapid initial clearance of virus and is associated with fewer adverse effects; however, seroconversion rates are low, and long-term therapy with lamivudine (required for sustained responses) frequently results in resistance \[ref 2\]. Adefovir dipivoxil has, so far, not shown the high rate of resistance observed with lamivudine, but it is expected that resistance will eventually develop \[ref 3\]. In summary, major problems with currently approved therapy of HBV include expense, toxicity, and development of resistance. (ii). Chronic hepatitis C Chronic viral hepatitis due to hepatitis C is an enormous medical problem, affecting approximately 170 million people worldwide (WHO) \[ref 4\]. In the U.S., an estimated 2.7 million people suffer from chronic HCV, with 10,000-12,000 deaths per year attributable to the disease (ref 5). Chronic HCV infections in the U.S. are usually acquired through injectable drug use, sexual contact, or receipt of contaminated blood products (before antibody screening was initiated in 1990). Most persons exposed to HCV (75%) develop asymptomatic chronic infection. Eventually, 15%-20% will die of cirrhosis and liver cancer without intervention \[ref 4\]. Only two drugs are licensed for treatment of chronic hepatitis C: IFN-α (standard or pegylated) and ribavirin. Sustained responses to IFN-α monotherapy have occurred in up to 35% of patients; higher responses can be observed with combination treatment (pegylated IFN-α and ribavirin) \[ref 6,7\]. Responses to combination therapy is closely linked with HCV genotype (types 2 and 3 most responsive). A significant number of patients relapse or do not respond to standard treatment, and retreatment is typically less effective than initial therapy \[ref 8\]. (iii). 4-methlyumbelliferone Umbelliferones (7-hydroxycoumarins) \[ref 9\] are substances present in many species of plants, especially umbelliferae, fabaceae, and oleaceae, which include such common plants as manna ash, sweet woodruff, German chamomile, celery, parsley, and others. In nature, umbelliferones help protect plants from cellular damage, infestation, trauma, and infection. Their 7-hydroxycoumarin derivatives (4-methylumbelliferones) \[ref 10\] are used in liver therapy, as reagents, plant growth factors, sunscreens, choleretics, and spasmolytics. They are also used as light-protective agents, in the calibration of medical lasers, and in analytical chemistry for the quantitation of nitric acid. Products containing 4-methylumbelliferone as their active substance have been available in the USA and Europe since 1990, as dietary supplements (under trade names Heparvit®, Heparmed®, DetoxPro®). These products are promoted as supporting liver function and improving detoxification. In many parts of Europe, products containing 4-methylumbelliferone are also available as drugs, and used as spasmolytics and choleretics \[ref 11\] (improving liver detoxification systems through increased bile production). 7-hydroxycoumarins are also natural metabolites in the body that play important roles in the metabolism of ethanol, chemotherapeutic drugs, acetaminophen, anabolic steroids, and other hepatotoxic drugs \[ref 12\]. Indeed, measurement of concentrations of 4-methylumbelliferyl glucuronide (a metabolic product of 4-methylumbelliferone) is a common assay for determining the level of toxicity of liver-toxic drugs \[ref 13\]. The broad potential medical benefits of 4-methylumbelliferone as a hepatoprotectant, anti-inflammatory agent, chemotherapeutic agent, and antiviral substance have been described \[ref 13,14\]. More recent studies indicate that 4-methylumbelliferone (and other 7-hydroxycoumarin derivatives) may be effective against Helicobacter pylori \[ref 15\], several types of cancer \[ref 15-19\], and Alzheimer's disease \[ref 20\].