naphthoquinones and Toxoplasmosis

Topics: Acyclovir; AIDS-Related Opportunistic Infections; Anti-HIV Agents; Anti-Infective Agents; Antitubercular Agents; Antiviral Agents; Atovaquone; Azithromycin; Chickenpox; Clarithromycin; Cytomegalovirus Infections; Drug Therapy, Combination; Ganciclovir; Herpes Simplex; Humans; Mycobacterium avium-intracellulare Infection; Naphthoquinones; Pneumonia, Pneumocystis; Rifabutin; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Pulmonary; Valacyclovir; Valine

Topics: 2-Aminopurine; Acyclovir; AIDS-Related Opportunistic Infections; Anti-Infective Agents; Antifungal Agents; Antiprotozoal Agents; Antiretroviral Therapy, Highly Active; Antitubercular Agents; Antiviral Agents; Atovaquone; Azithromycin; Clarithromycin; Cytomegalovirus Infections; Drug Therapy, Combination; Famciclovir; Herpes Simplex; Herpes Zoster; Humans; Mycobacterium avium-intracellulare Infection; Mycoses; Naphthoquinones; Pneumonia, Pneumocystis; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination; Tuberculosis, Pulmonary; Valacyclovir; Valine

Atovaquone has been investigated as an alternative agent for oral use in the treatment of both mild to moderate Pneumocystis carinii pneumonia (PCP) and toxoplasmosis, opportunistic infections commonly experienced by patients with AIDS. In patients with mild to moderate PCP, a dosage of 750mg 3 times daily (administered in tablet form) has similar overall therapeutic efficacy (defined as clinical response without a treatment-limiting adverse event) to the conventional therapies oral cotrimoxazole (trimethoprim-sulfamethoxazole) and intravenous pentamidine, respectively. Response rates to atovaquone are lower than those achieved with cotrimoxazole, but atovaquone has superior tolerability. Atovaquone recipients experienced significantly fewer treatment-limiting adverse effects than patients treated with cotrimoxazole (7 vs 20%) or pentamidine (4 vs 36%). Mortality rates were higher among atovaquone-treated patients than in cotrimoxazole recipients (7 vs 0.6%) 4 weeks after completion of therapy in a large comparative trial, although most deaths were caused by bacterial infections. However, a similar rate of mortality was reported for atovaquone- and pentamidine-treated patients (16 vs 17% 8 weeks after discontinuation of therapy) in another study. In predominantly small numbers of patients with toxoplasmosis, of whom most were unresponsive to conventional agents, atovaquone 750mg 4 times daily (administered as tablets) produced a complete or partial radiological response rate of 37 to 87.5% 52% of patients achieved a complete or partial clinical response after 6 weeks of treatment in the largest trial (n = 87), although the incidence of toxoplasmosis-related death was 24% 18 weeks after therapy was initiated. Thus, atovaquone will be a useful option for the treatment of patients with mild to moderate PCP who are intolerant or unresponsive to cotrimoxazole, especially if the increased plasma drug concentrations observed with the suspension further improve response rates. Atovaquone should also be considered a promising agent for the treatment of toxoplasmosis.

Topics: AIDS-Related Opportunistic Infections; Antifungal Agents; Antiprotozoal Agents; Atovaquone; Clinical Trials as Topic; Drug Evaluation; Drug Interactions; Humans; Naphthoquinones; Pneumonia, Pneumocystis; Toxoplasmosis

In 1995 and 1997, the United States Public Health Service (USPHS) and the Infectious Disease Society of America (IDSA) published recommendations for primary prophylaxis of Pneumocystis carinii pneumonia (PCP), Mycobacterium avium complex (MAC), and toxoplasmosis in HIV-infected adults. We evaluated their implementation at four hospital-based HIV clinics in New York City in patients who initially met the CD4+ criterion for prophylaxis between January, 1995 and April, 1997. Medical records were reviewed at 6-month intervals to determine drugs prescribed. We identified 149 patients for the PCP sample, 130 for MAC, and 138 for toxoplasmosis. In the three samples, 91% were black and Hispanic, 75% to 81% were male, and 43% to 47% had a history of injection drug use (IDU); median age was between 39 and 40 years. PCP prophylaxis was prescribed during 93% of intervals and did not vary significantly by clinic or patient characteristics. Over the study period, MAC prophylaxis increased from 22% to 62%, and prescriptions for macrolides increased from 38% to 87% of all prescriptions. In the logistic regression analysis, prescription for MAC prophylaxis at any time during the study period was less likely in blacks compared with whites (odds ratio [OR] = .08; 95% confidence interval [CI] = .01, .52) and patients attending the clinic with the lowest rate of MAC prophylaxis (clinic D) compared with the clinic with the highest rate (clinic B; OR = .04; 95% CI = .01, .26). Toxoplasmosis prophylaxis was prescribed in 73% of intervals and did not differ significantly by antibody status (p = .42). Prescribing patterns were uniform across gender, HIV risk behavior, and age for PCP and MAC prophylaxis but differed by clinic and race for MAC prophylaxis. Trends in prophylaxis for opportunistic illnesses must continue to be monitored in light of the success of antiretroviral therapy in reducing the morbidity and mortality associated with HIV/AIDS.

Topics: Adolescent; Adult; AIDS-Related Opportunistic Infections; Analysis of Variance; Anti-Infective Agents; Atovaquone; Azithromycin; Clarithromycin; Dapsone; Ethnicity; Female; HIV Infections; Humans; Longitudinal Studies; Male; Medical Records; Mycobacterium avium-intracellulare Infection; Naphthoquinones; New York City; Pentamidine; Pneumonia, Pneumocystis; Practice Guidelines as Topic; Regression Analysis; Rifabutin; Risk-Taking; Time Factors; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination; United States; United States Public Health Service

The mouse-virulent RH strain of Toxoplasma gondii is generally considered to have lost its cyst-forming capacity, and conversion of RH tachyzoites into cysts in non-immune mice has previously been shown exclusively following early treatment with sulfadiazine (SDZ). We here describe the development of tissue cysts in mice infected with RH strain parasites and treated with atovaquone (ATO) combined with pyrrolidine dithiocarbamate (PDTC). Groups of Swiss-Webster mice infected intraperitoneally (i.p.) with 10(2) RH tachyzoites were treated with 5, 25 and 100 mg of ATO/kg per day alone or combined with PDTC at 250 mg/kg per day from day 1 postinfection (p.i.) for 14 days. A total of 19 mice survived the 6-week observation period. Of these, brain cysts were recovered in nine (47%), with burdens ranging from 50 to 3120 (mean +/- S.D. = 622 +/- 963). All cyst-harboring mice had high specific IgG antibody levels (1:10,240-1:40,960, corresponding to 500-2000 IU/ml), as did one mouse in which cysts were not demonstrated, which was therefore included in the group of mice with residual infection. Bioassay performed to test the infectivity of these cysts produced acute lethal toxoplasmosis following i.p. inoculation in all instances (100%), and importantly, following peroral inoculation in four (29%). The recovered tachyzoites were highly infectious. In addition, significantly elevated interferon gamma (IFN-gamma) in the treated mice which developed residual infection compared with any group of infection-free (treated or subinoculated) mice, indicates immunological control of the parasite in the latent form. In conclusion, early treatment of mice infected with T. gondii RH tachyzoites with ATO and PDTC induces conversion into tissue cysts, thus providing a new model for studying the mechanism(s) of T. gondii stage conversion.

Topics: Animals; Antiprotozoal Agents; Atovaquone; Brain; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Female; Mice; Naphthoquinones; Oocysts; Pyrrolidines; Thiocarbamates; Toxoplasma; Toxoplasmosis

Research results to determine the best prophylactic regimen for Pneumocystis carinii pneumonia (PCP) are reported. Overall results from these studies indicate patients who are eligible for PCP prophylaxis should be advised to take double-strength trimethoprim/sulfamethoxazole (TMP/SMX) on a daily basis, a dosage found more effective than thrice-weekly. To handle problems with side effects, one study demonstrated the success of using a 6-day dose escalation method that allowed 80 percent of the participants to complete treatment for 6 months. Patients remaining intolerant to TMP/SMX have the options of using atovaquone (not yet FDA-approved for PCP prophylaxis) or aerosolized pentamidine (not approved for treatment of PCP), which have been shown to be safe and effective in PCP prophylaxis. Due to recent FDA reforms, the use of off-label drugs may increase, but patients and physicians are cautioned that problems with insurance reimbursement may develop.

Topics: Aerosols; AIDS-Related Opportunistic Infections; Antifungal Agents; Atovaquone; CD4 Lymphocyte Count; Clinical Trials as Topic; Dapsone; Drug Administration Schedule; Encephalitis; Humans; Naphthoquinones; Pentamidine; Pneumonia, Pneumocystis; Toxoplasmosis; Trimethoprim, Sulfamethoxazole Drug Combination

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Amphotericin B; Antifungal Agents; Antiprotozoal Agents; Antiviral Agents; Atovaquone; Candidiasis, Oral; Clindamycin; Clotrimazole; Cryptosporidiosis; Cytomegalovirus Infections; Dapsone; Didanosine; Drug Combinations; Drug Therapy, Combination; Fluconazole; Flucytosine; Folic Acid Antagonists; Foscarnet; Glucuronates; Herpes Simplex; Herpes Zoster; Humans; Isoniazid; Itraconazole; Ketoconazole; Lamivudine; Mycobacterium avium-intracellulare Infection; Naphthoquinones; Nystatin; Pentamidine; Pneumocystis Infections; Pneumonia, Pneumocystis; Prednisone; Primaquine; Reverse Transcriptase Inhibitors; Stavudine; Syphilis; Toxoplasmosis; Trimetrexate; Tuberculosis; Zalcitabine; Zidovudine

Studies being conducted on opportunistic infections among people with HIV are presented in list form. The list includes new studies, those still in development, and those slated to begin in 1995. Areas of interest include candidiasis, cryptosporidiosis/microsporidiosis, cytomegalovirus (CMV), Mycobacterium avium complex (MAC) infection, Pneumocystis carinii pneumonia (PCP), toxoplasmosis, and tuberculosis (TB). Enrollment information can be obtained by calling 1-(800)-TRIALS-A (TDD 1- 800-448-0440).

Topics: AIDS-Related Opportunistic Infections; Amphotericin B; Antitubercular Agents; Atovaquone; Candidiasis; Clinical Trials as Topic; Cryptosporidiosis; Cytomegalovirus; Cytomegalovirus Infections; Ganciclovir; Humans; Immunotherapy; Mycobacterium avium-intracellulare Infection; Naphthoquinones; Paromomycin; Pneumonia, Pneumocystis; Pyrimethamine; Toxoplasmosis; Tuberculosis

Compound 566C80, 2-[trans-4-(4-chlorophenyl)cyclohexyl]-3-hydroxy-1,4-naphthoquinone, was studied for its in vitro and in vivo activities against Toxoplasma gondii. Replication within human foreskin fibroblasts of tachyzoites of seven different strains, five of them isolated from AIDS patients, was inhibited by concentrations as low as 4.8 x 10(-9) M. In vivo, a dose of 100 mg/kg of body weight per day, administered by gavage for 10 days, protected 100% of mice against death due to infection with five different strains of T. gondii, including the highly virulent RH strain. A dose of 50 mg/kg/day protected at least 80% of mice infected with the same inoculum, and a dose as low as 9.3 mg/kg/day protected 40 to 60% of mice. Treatment with 50 mg/kg/day for 30 days completely eradicated parasites from mice infected with four of five strains of T. gondii. 566C80 was active in vitro against the cyst stage of T. gondii at concentrations of 50 to 100 micrograms/ml. In vivo activity against this form of T. gondii was examined in mice infected for 6 weeks with strain ME49 and then treated orally with 100 mg of 566C80 per kg per day for 8 weeks. Treated mice sacrificed at 2-week intervals revealed a steady decline in the numbers of cysts in their brains compared with untreated controls. In addition, mortality as well as clinical signs of brain infection was absent from treated mice, whereas control mice had a high mortality rate and showed clinical signs of central nervous system infection. These results reveal remarkable in vitro and in vivo activities of 566C80 against T. gondii.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-Infective Agents; Atovaquone; Brain; Cell Division; Female; Humans; Mice; Mice, Inbred CBA; Naphthoquinones; Toxoplasma; Toxoplasmosis; Uracil