Trial Information

Evaluation of 4-Methylumbelliferone for Treatment of Chronic Hepatitis B (HBV) and Chronic Hepatitis C (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].