Safety and pharmacokinetics of 566C80, a hydroxynaphthoquinone with anti-Pneumocystis carinii activity: a phase I study in human immunodeficiency virus (HIV)-infected men

Article Abstract:

Patients who are infected with the human immunodeficiency virus (HIV), the agent that causes AIDS, are at risk of developing infections, such as Pneumocystis carinii pneumonia, that do not generally affect people with normal immune function. Most patients with AIDS will experience a bout with Pneumocystis carinii pneumonia which, if left untreated, is invariably fatal. Current drugs of choice do not effectively eliminate this parasite, and episodes of pneumonitis frequently recur, suggesting the need for more effective and long-lasting therapy. A new hydroxynaphthoquinone known as compound 566C80 has demonstrated antiprotozoal activity in experimental animals with murine P. carinii pneumonia; in doses of 100 milligrams per kilogram of body weight per day, 566C80 was fully effective in the prevention and treatment of the disease. Phase 1 multidose studies were conducted in five cohorts of four male patients with AIDS to assess dose levels and ascertain the safety and pharmacokinetics of the drug in humans. Participants had not received medical treatment for P. carinii pneumonia in the previous four weeks, and satisfied other experimental parameters. Daily doses of 100, 250, 750, l,500 and 3,000 milligrams of 566C80 were administered to the 5 cohorts, respectively, for 12 or 21 days, after they ate a standard breakfast. A sixth cohort received another dosage regimen to characterize the pharmacokinetic properties of the new compound. The drug was well tolerated up to the maximum dosage in the trial. No significant abnormal clinical findings were attributed to the new compound. Administration of 566C80 with food enhanced its absorption and produced higher blood levels of the drug. The action of this agent suggests that the parasite was killed rather than inhibited; this is an added advantage in the treatment of immunocompromised patients. The apparent successful application of this new class of compounds provides a new category of potentially effective antiprotozoal drugs and offers hope for an effective treatment for P. carinii pneumonitis. (Consumer Summary produced by Reliance Medical Information, Inc.)

HIV infection, HIV infections, Pneumocystis carinii pneumonia, Pneumocystis carinii

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Summary of the workshop on future directions in discovery and development of therapeutic agents for opportunistic infections associated with AIDS

Article Abstract:

The human immunodeficiency virus (HIV) is the agent that causes AIDS. The HIV attacks and destroys the immune system (the body's natural defense system for fighting infection). Therefore, patients with AIDS have a greater risk of developing life-threatening infections. Infections that frequently affect patients with immunodeficiency are known as opportunistic infections. One of the most common opportunistic infections in AIDS patients is pneumonia caused by Pneumocystis carinii; it is estimated to occur in 80 percent of all AIDS patients. Drugs such as trimethoprim/sulfamethoxazole and pentamidine are effective in treating Pneumocystis carinii pneumonia, but they may cause adverse side effects. New drugs that are effective, safe and inexpensive are needed. Another common infection in patients with AIDS is tuberculosis caused by Mycobacterium avium. This type of infection is resistant to many forms of drug treatment that are available, and new therapies are needed. The most common type of central nervous system infection in AIDS patients is toxoplasmic encephalitis (TE). It is characterized by inflammation in the brain and is caused by Toxoplasma gondii. Drugs used to treat TE include pyrimethamine and sulfadiazine. These drugs are effective in treating the infection, but are toxic to the patient. Fungal infections frequently occur in patients with AIDS. Infection with Candida albicans accounts for almost 40 percent of all infections affecting AIDS patients. While C. albicans frequently causes nonlife-threatening infection in patients with normal immune function, it causes meningitis (inflammation of the brain and spinal cord) and endocarditis (inflammation in the heart) in patients with immunodeficiency. Amphotericin B is the standard drug used for treatment, but its toxicity limits its use. It is apparent that there are many different types of opportunistic infections that can occur in patients with AIDS and that newer, safer, and more effective drugs are needed. (Consumer Summary produced by Reliance Medical Information, Inc.)

Opportunistic infections

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Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever

Article Abstract:

Neutropenia is an abnormal drop in the number of neutrophils, a type of white blood cell involved in fighting off infection. Patients with neutropenia who have fever are likely to have a bacterial infection in their blood. Typical signs of infection such as swelling may be reduced or absent in neutropenic patients, which tends to make diagnosis complicated. The infectious organisms in neutropenic patients are typically gram-negative bacilli and gram-positive cocci, which are generally restricted to just a few sites on the body, primarily the intestinal tract and skin. Treatment of neutropenic patients is complicated because excessive antibiotic therapy can predispose these patients to other types of infections (secondary infections), and it can make bacteria resistant to treatment, have adverse affects and cost a great deal of money. Since untreated infections can be life-threatening in the neutropenic patient, careful diagnosis and treatment are essential. The medical management of neutropenic patients having an unexplained episode of fever is reviewed. Although specific antibiotic plans cannot be determined in advance, a set of guidelines recommended by a committee working for the Infectious Diseases Society of America is presented. A four-star rating system was used to evaluate the validity of each antibiotic treatment for each type of bacterial infection. All patients with unexplained fever and a neutrophil count of less than 500 cells per microliter should be placed on a broad spectrum antibiotic. Specific antibiotic regimens are selected based on the type of bacteria, how often the infection occurs and the susceptibility of the bacteria to that particular antibiotic. The specific recommendations for antibiotic therapy, which is based on the committee's consensus, are not intended to be steadfast rules but a reasonable approach to the management of neutropenic patients. (Consumer Summary produced by Reliance Medical Information, Inc.)

Usage, Reports, Antibiotics, Causes of, Fever, Neutropenia, Infectious Diseases Society of America

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