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September 1999 Bruce H. Woolley, Pharm.D., Editor Vol. 6, No.9
Marv Orrock, Pharm.D, Associate Editor -- Kenneth Hunt, Associate Editor


Chronic viral hepatitis is responsible for at least half of all deaths attributed to chronic liver disease. Viral hepatitis, now the predominant chronic liver disease in the United States, impairs health-related quality of life. Once the illness progresses to cirrhosis, end-stage liver disease, or cancer, life expectancy is significantly reduced. End-stage liver disease caused by viral hepatitis is now the single most common indication for liver transplantation in the United States and Western Europe.

Chronic viral hepatitis is responsible for at least half of all deaths attributed to chronic liver disease, even though there has been a recent decline in new infections. Currently, the most prominent therapy involves Alfa interferons which exhibit a wide range of biological activities. Advances in treatment, expanded treatment options, evidence of long-term benefits, and cost-effectiveness analyses are changing management strategies.

Infection by the hepatitis C virus (HCV), hepatitis B virus (HBV), and co-infections of HBV and hepatitis D virus (HDV) are responsible for about 90% of cases of chronic viral hepatitis in the United States. No other viruses have been implicated. Candidates for treatment usually display elevated serum alanine aminotransferase (ALT) levels and qualitative tests indicating the presence of circulating hepatitis RNA. Hepatitis A is responsible for about 60% of US cases of acute viral hepatitis and superinfection by HAV may lead to acute liver failure in patients with chronic liver disease, so patients who are susceptible should be vaccinated against hepatitis A virus.

Treatment of HCV may involve any of the approved type 1 interferons (alfa-2b, alfa-2a, and alfacon-1), given in subcutaneous doses of 3 MU. The combination of interferon alfa-2b in its conventional dose and the guanosine analog ribavirin in an oral divided total dose of 1000 to 1200 mg has improved sustained virological response rates. Treatment of HBV involves injections of 5 MU (daily) or 10 MU (3 times weekly) of interferon alfa-2b for 4 to 6 months. This treatment has resulted in HBV clearance by 30% to 40% of cases and saves costs. There have been few advances in treatment of HDV and 10 MU o f interferon alfa 3 times weekly remains the only effective therapy. Treatment for a year or longer may be necessary.

Recent and future gains in understanding the biology of the hepatitis viruses and the natural history of chronic viral hepatitis may permit development of safe and more effective therapies. New approaches may include combinations of antiviral compounds and immunity-enhancing drugs and vaccines. Gene therapy to deliver antivirals to sites of viral replication may also be attempted.

Koff, Raymond S. Advances in the Treatment of Chronic Viral Hepatitis. JAMA 1999;282:511-512.


Hypertension is a diverse and heterogeneous disease and carries with it a dramatic variability in response to therapy with a single agent. Administering more than one antihypertensive therapy has several theoretical benefits, including enhanced efficacy, improved tolerability, increased compliance and, in many cases, beneficial changes in biochemical variables associated with increased cardiovascular risk such as improvements in lipid profiles. Drugs of the alpha1-Blocker class, such as doxazosin, have several properties that may be advantageous when used with other agents. Their mechanism of action is complementary to that of each of the other four main groups of antihypertensive drugs and, in clinical trials, enhanced efficacy has been observed when alpha1-blockers have been added to monotherapy with other drug classes.

Synergistic effects have been observed when an alpha1-blocker is administered coincidently with either a calcium channel blocker or angiotensin-converting enzyme (ACE) inhibitor. Alpha1-blockers often induce regression of left ventricular hypertrophy, the possibility of enhanced effects during multiple therapy has not yet been explored. Alpha1-Blockers exert positive effects on lipids, and some investigators purport that they are able to reverse the adverse lipid effects of diuretics and beta-blockers.

The factors implicated in the pathogenesis of hypertension vary widely between individuals. Individual response to antihypertensive monotherapy with any first-line drug also varies. Additional therapy is often used to widen the spectrum and allow an individualized treatment according to underlying diseases and risk factors. Tolerability, compliance and end-organ effects may also be enhanced. Administering alpha1-blockers with other types of antihypertensive drugs offers more efficacy than single-drug therapy and is well tolerated and may offer particular benefits with respect to cardiovascular risk factors such as hyperlipidemia and glucose intolerance.

Further studies are needed to determine whether alpha1-blockers can alleviate the adverse effects of beta-blockers or diuretics on glucose homeostasis. alpha1-Blockers, when given concomitantly with other antihypertensive drugs, are well tolerated, conferring advantages with respect to patient compliance. The current data favor the use of alpha1-blockers as an additional component of antihypertensive therapy, but further studies are needed to address the metabolic and end-organ effects of such treatment regimens. Long-term outcome trials such as the Antihypertensive and Lipid Lowering Treatment to Prevent Heart Attack Trial (ALLHAT) will greatly increase our state of knowledge regarding the benefits of additional antihypertensive therapies.

Thanks to Sever, Peter S. Current Medical Research and Opinion 15(2):95-103, 1999.


Several times per year, the Journal of the American Medical Association will devote an entire issue to a certain medical theme. The August 4, 1999 edition focused on the cost of violence to our health care system. In the aftermath of several gruesome violent acts of our nation, this edition of JAMA includes many worth reading articles on the medical, psychosocial and financial burdens induced by unnecessary violence. Articles address issues such as handguns, violence in school and abuse in the home.

On of the articles addressed the high cost of treating gunshot injuries. The article estimated national acute-care and follow-up treatment costs and payment sources for gunshot injuries. The determined average medical cost per injury was around $17,000. This means that the roughly 135,000 gunshot injuries in the United States in 1994 produced nearly $2.3 billion in medical costs. Almost half of this was paid by US taxpayers. Gunshot injuries due to assaults accounted for 74% of total costs. Gunshot injury costs represent a substantial burden to the medical care system; much of this burden is shouldered by taxpayers. [1]

Another of the articles pointed out that there is a steady and substantial decline in violent crime in the country, including the number of fights in schools and the number of people who carry handguns. Unfortunately, violent crime remains a costly issue to American health professionals. For its statistics and focus on violence in health care, the August 4 issue of JAMA is worth reading.

(1) JAMA. 1999;282:447-454


With the spreading fear of infection with HIV, home tests have been developed that are purported to be a fast, convenient and accurate method of testing for HIV. The Federal Trade Commission recently issued a warning advising people who used these home HIV tests to get a professional opinion.

The consumer alert issued by the FTC has warned that some of the home-use HIV tests give inaccurate results. According to the alert, members of the commission recently tested some of the HIV kits advertised and sold on the Internet for self diagnosis at home. In each such attempt, the kits showed a negative result when used on a known HIV-positive sample. The FTC stated that the kits could give an HIV-positive individual a false impression that he or she is not infected.

The FTC also noted that some Internet ads indicate that the World Health Organization or US Food and Drug Administration have approved home-use tests. The WHO does not ever approve or license such kits and the FDA has not approved home-use HIV tests for sale in the United

States. The FDA has approved the Home Access Express HIV-1 Test System, in which the user collects a sample in the home and sends it to a laboratory for analysis. Patients seeking a reliable HIV test should do so through a medical professional or the FDA-approved system.

Outtakes. JAMA. 1999;282:317


Thimerosal is a preservative that contains ethyl mercury and has been an additive to biologics and vaccines since the 1930's. Thimerosal is very effective in killing bacteria, and in preventing bacterial contamination, particularly in opened multi-dose containers.

There is no evidence of any harm caused by thimerosal that some children may have encountered in following the current immunization schedule. The larger risk of not vaccinating children, far outweighs the unknown and probably much small risk, if any, of cumulative exposure to thimerosal-containing vaccines over the first six months of life.

The Publish Health Service, The American Academy of Pediatrics, and vaccine manufacturers agree that the use of Thimerosal as a preservative should be removed as soon as possible. The manufacturers of Hepatitis B vaccines have indicated that they will have available Thimerosal-free Hepatitis B vaccines in a month or two.

1. The Joint Statement of the Pu blic Health Serice (PHS) and the American Academy of Pediatrics (AAP) - MMWR 1999; 48:563-565.

2. Centers for Disease Control and Prevention (CDC) - "Implementation Guidance for Immunization Grantees During the Transition Period to Vaccines Without Thimerosal" July 14, 1999.

3. American Academy of Pediatrics (AAP) - "Thimerosal in Vaccines - An Interim Report" July 12, 1999.


The FDA has approved zanamivir inhalation (Relenza/GlaxoWellcome) for the treatment of uncomplicated acute illness due to influenza virus in adults and adolescents over 12 years of age. This is the first approved product for the treatment of influenza since 1993. Its mechanism of action is thought to be through inhibition of the breakage of the bond that holds virus particles to the infected cell. This is thought to interrupt the spread of infection within the respiratory tract. It should not be used in patients with severe or decompensated asthma or chronic obstructive pulmonary disease.

Topiramate (Topamax/Otho-McNeil) has been approved as an add-on treatment for partial onset seizures in pediatric patients 2 to 16 years of age. It is the first agent approved for patients as young as 2 years.

Ganirelix (Antagon/Organon), which is a gonadotropin-releasing-hormone [GnRH] antagonist, has been approved as an injection for inhibiting premature luteinizing hormone [LH] surges in women undergoing controlled ovarian hyperstimulation. It is anticipated that the new product will significantly reduce the number of medication days necessary to suppress LH surges and therefore maintain eggs in the ovaries.

Temozolomide (Temodar/Schering-Plough) has received accelerated approval for the treatment of adult patients with refractory anaplastic astrocytoma who have relapsed following chemotherapy with nitrosourea drugs.

Rabeprazole (Aciphex/Eisai-Janssen) has been granted approval as another proton pump inhibitor for the healing of duodenal ulcers and for maintenance of erosive or ulcerative GERD.

Pyrazolopyrimidine (Zalepion/Sonata-Wyeth-Ayerst) has been approved as a nonbenzodiazepine pyrazolopyrimidine for the short-term treatment of insomnia in adults. It is not a sleep maintenance drug but is rapidly eliminated so the patient’s natural sleep processes can take over.

The information and opinions expressed in the Therapeutics Letter do not necessarily reflect the official policy of the sponsoring organizations