naphthoquinones and Acquired-Immunodeficiency-Syndrome

In this international, noncomparative, randomized phase II trial, we evaluated the effectiveness and tolerance of atovaquone suspension (1500 mg orally twice daily) plus either pyrimethamine (75 mg per day after a 200-mg loading dose) or sulfadiazine (1500 mg 4 times daily) as treatment for acute disease (for 6 weeks) and as maintenance therapy (for 42 weeks) for toxoplasmic encephalitis (TE) in patients infected with human immunodeficiency virus. Twenty-one (75%) of 28 patients receiving pyrimethamine (95% lower confidence interval [CI], 58%) and 9 (82%) of 11 patients receiving sulfadiazine (95% lower CI, 53%) responded to treatment for acute disease. Of 20 patients in the maintenance phase, only 1 experienced relapse. Eleven (28%) of 40 eligible patients discontinued treatment as a result of adverse events, 9 because of nausea and vomiting or intolerance of the taste of the atovaquone suspension. Although gastrointestinal side effects were frequent, atovaquone-containing regimens are otherwise well tolerated and safe and may be useful for patients intolerant of standard regimens for toxoplasmic encephalitis.

Topics: Acquired Immunodeficiency Syndrome; Acute Disease; Adult; AIDS-Related Opportunistic Infections; Animals; Antiprotozoal Agents; Atovaquone; Drug Therapy, Combination; Encephalitis; Female; Follow-Up Studies; Humans; Male; Naphthoquinones; Pyrimethamine; Sulfadiazine; Time Factors; Toxoplasma; Treatment Outcome

To evaluate if atovaquone (ATQ) interacts pharmacokinetically with azithromycin (AZ) in human immunodeficiency virus-infected children, 10 subjects (ages, 4 to 13 years) were randomized in a crossover study to receive AZ (5 mg/kg/day) alone (ALONE) or AZ (5 mg/kg/day) and ATQ (30 mg/kg/day) simultaneously (SIM) prior to receiving AZ and ATQ staggered by 12 h. Despite a lack of significant difference in the mean AZ pharmacokinetic parameters, the steady-state values of AZ's area under the concentration-time curve from 0 to 24 h and maximum concentration in serum were consistently lower (n = 7 of 7) for the SIM regimen than they were for the ALONE regimen. A larger study will be required to determine if ATQ affects AZ pharmacokinetics and efficacy in a clinically significant manner.

Topics: Acquired Immunodeficiency Syndrome; Adolescent; Anti-Bacterial Agents; Antifungal Agents; Atovaquone; Azithromycin; Child; Child, Preschool; Cross-Over Studies; Drug Interactions; HIV-1; Humans; Naphthoquinones

To evaluate the efficacy and tolerance of atovaquone used as long-term maintenance therapy in patients with toxoplasmic encephalitis and intolerant of conventional anti-Toxoplasma therapies.. Uncontrolled open-label study of atovaquone given through an expanded access programme; statistical analysis was performed on an intent-to-treat basis.. Sixty-five patients intolerant of conventional toxoplasmic encephalitis therapies-pyrimethamine, sulphadiazine or clindamycin-received atovaquone as maintenance therapy after resolution of an acute episode of toxoplasmic encephalitis. Patients were clinically and neurologically evaluated monthly. Toxoplasmic encephalitis relapse was defined as the occurrence of neurological abnormalities, except in the case of a proven alternative diagnosis.. Sixty-five patients were treated with atovaquone 750 mg four times daily and followed up for a mean period of 1 year. Mean CD4 lymphocytes count was 29 x 10(6)/l. Prior to starting atovaquone, patients had experienced a total of 129 episodes of intolerance to conventional anti-Toxoplasma drugs. Atovaquone was used as a single anti-toxoplasmic agent in 75% of the cases. Seventeen patients (26%) experienced a toxoplasmic encephalitis relapse. Sixty-three patients (97%) were able to tolerate and continued taking atovaquone. Two patients had to discontinue therapy because of side-effects. In a multivariate analysis, only the duration of pyrimethamine-sulphadiazine therapy during the acute therapy phase of toxoplasmic encephalitis was significantly associated with a decreased risk of toxoplasmic encephalitis relapse during maintenance therapy [relative risk, 0.64 for each week of pyrimethamine-sulphadiazine; 95% confidence interval (CI), 0.42-0.96; P = 0.03]. The survival probability was 70% at 1 year after the episode of toxoplasmic encephalitis (95% CI, 57-83).. These results suggest that atovaquone is a well-tolerated alternative anti-Toxoplasma treatment for maintenance therapy in patients who are intolerant to conventional anti-Toxoplasma drugs.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antiprotozoal Agents; Atovaquone; Clindamycin; Encephalitis; Female; Humans; Male; Naphthoquinones; Pyrimethamine; Recurrence; Risk Factors; Sulfadiazine; Survival Analysis; Time Factors; Toxoplasmosis, Cerebral

Atovaquone (formerly 566C80) is a hydroxynaphthoquinone with potent activity against Toxoplasma in vitro and in laboratory animals. Eight patients with AIDS and presumed or biopsy confirmed toxoplasmosis who were intolerant of or had not responded to standard therapies were treated with oral atovaquone 750 mg four times a day. Seven patients showed radiographic improvement; the other remained radiographically stable. Six patients died 6-60 weeks after enrollment with no clinical (six) or necropsy (three) evidence of recurrent toxoplasmosis; two patients relapsed at 10 and 32 weeks. Toxicity was mild: only one patient required temporary discontinuation of drug due to a rash. Atovaquone is a well-tolerated drug that appears to be an effective alternative for patients with toxoplasmosis who are intolerant of standard therapies.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Anti-Infective Agents; Atovaquone; Biopsy; Enzyme-Linked Immunosorbent Assay; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Naphthoquinones; Recurrence; Toxoplasmosis, Cerebral

The drug 566C80 is an investigational hydroxynaphthoquinone that is active against Pneumocystis carinii in vitro and in animal models. Initial studies in humans indicate that 566C80 is safe and has adequate bioavailability after oral administration.. We conducted an open-label trial of 566C80 in 34 adults with the acquired immunodeficiency syndrome (AIDS) and untreated pneumocystis pneumonia. All the patients had a partial pressure of arterial oxygen of at least 60 mm Hg while breathing room air. They were enrolled sequentially in three cohorts taking 566C80 at different dosages, all administered orally: 750 mg three times daily for 5 days, then twice daily for 16 days; 750 mg three times daily for 21 days; and 750 mg four times daily for 21 days.. All 34 patients survived, and 27 (79 percent) were successfully treated with 566C80 alone. The mean partial pressure of oxygen in 33 patients was 78 mm Hg at entry and 93 mm Hg after the course of 566C80 (P less than 0.001). In five patients (15 percent) the drug was discontinued because of lack of response. In four patients (12 percent), the drug was discontinued because of toxicity (fever and rash in two patients each). In two of these, treatment was considered to have succeeded because 566C80 was not discontinued because of toxicity until after day 14. Five of the successfully treated patients had rashes that resolved despite continued therapy. In nine patients, serum alanine aminotransferase levels rose above 100 U per liter. During the first three months after the completion of therapy, pneumocystis pneumonia recurred in 4 of the 27 successfully treated patients, and another 3 patients had recurrences between month 3 and month 6 of follow-up. The mean (+/- SEM) steady-state plasma levels of 566C80 were similar in the three cohorts: 16.3 +/- 2.10, 20.4 +/- 2.48, and 18.9 +/- 3.08 micrograms per milliliter in the patients taking the drug twice daily, three times daily, and four times daily, respectively.. From these preliminary data, the investigational compound 566C80 appears to be a safe, effective, and well-tolerated therapy for P. carinii pneumonia of mild-to-moderate severity in patients with AIDS.

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adult; Atovaquone; Drug Administration Schedule; Drug Evaluation; Female; Follow-Up Studies; Humans; Male; Naphthoquinones; Partial Pressure; Pneumonia, Pneumocystis; Recurrence; Treatment Outcome

This retrospective cohort study was conducted to determine whether Pneumocystis carinii cytochrome b gene mutations in patients with AIDS and P. carinii pneumonia (PCP) are associated with atovaquone exposure. Portions of the P. carinii cytochrome b genes that were obtained from 60 patients with AIDS and PCP from 6 medical centers between 1995 and 1999 were amplified and sequenced by using polymerase chain reaction. Fifteen patients with previous atovaquone prophylaxis or treatment exposure were matched with 45 patients with no atovaquone exposure. Cytochrome b coenzyme Q binding site mutations were observed in 33% of isolates from patients exposed to atovaquone, compared with 6% from those who were not (P=.018). There was no difference in survival 1 month after treatment between patients with or without cytochrome b mutations (P=.14). Thus, cytochrome b mutations are significantly more common in patients with AIDS and PCP with atovaquone exposure, but the clinical significance of these mutations remains unknown.

Topics: Acquired Immunodeficiency Syndrome; Adult; Antifungal Agents; Atovaquone; Case-Control Studies; Cohort Studies; Cytochrome b Group; Female; Gene Amplification; Humans; Male; Middle Aged; Molecular Sequence Data; Naphthoquinones; Pneumocystis; Pneumonia, Pneumocystis; Polymerase Chain Reaction; Polymorphism, Genetic; Retrospective Studies; Survival; Treatment Outcome; Ubiquinone

A rapid high-performance liquid chromatography assay has been developed for the drug atovaquone, which is currently being used to treat Pneumocystis carinii pneumonia and Toxoplasma gondii encephalitis associated with the acquired immunodeficiency syndrome (AIDS). Protein is precipitated from plasma with acetonitrile-aqueous 1% acetic acid (85:15). The supernatant is assayed on a C6 column using methanol-10 mM triethylamine in aqueous 0.2% trifluoroacetic acid (76:24) with detection at 254 nm. The working assay range was 0.5 to 50 micrograms/ml. Recovery was 97% and the between-day coefficients of variation were 2.1% at 50 micrograms/ml and 10.3% at 1 microgram/ml. A number of drugs commonly used to treat AIDS and its complications did not interfere with the assay.

Topics: Acquired Immunodeficiency Syndrome; Antifungal Agents; Atovaquone; Chromatography, High Pressure Liquid; Naphthoquinones; Pneumonia, Pneumocystis; Reproducibility of Results; Spectrophotometry, Ultraviolet

To report the clinical response to atovaquone in HIV-1-infected patients with symptomatic intestinal microsporidiosis.. A retrospective review of a cohort of AIDS patients with symptomatic intestinal microsporidiosis who received atovaquone.. Infectious Disease Program of the Grady Memorial Hospital, Veterans Affairs Medical Center and private physicians' offices in Atlanta, Georgia.. HIV-1-infected patients (n = 371) were offered a complete stool evaluation and monthly follow-up. Among them, 22 were diagnosed with intestinal microsporidial infection using stool smears stained with modified trichrome stain. Species confirmation was made by light microscopy or electron microscopy on small intestinal biopsy specimens in some patients.. Differences in symptoms, number of stools, and body weight were compared before and after a minimum of 1 month of atovaquone therapy.. Eight patients received atovaquone treatment. The mean onset of clinical improvement after beginning treatment was 13 days (SEM, +/- 2). The mean number of stools per day decreased from 10 +/- 2.5 to 2 +/- 1 (P = 0.02, paired t test). The mean weight gain was 3 +/- 2 kg. The parasite was continuously present in the repeated stool specimens. However, semiquantitative analysis performed on two patients' stool specimens showed a decreased parasite burden. Four patients underwent small intestinal endoscopy was consistent with Enterocytozoon bieneusi in all four patients. Only one out of these four patients demonstrated a decrease in parasite burden in the biopsy specimen. Ultrastructural analysis performed in another of these four patients following treatment demonstrated the presence of electron-dense granules in spores, suggestive of toxic effects.. Atovaquone demonstrates promise as a symptomatic treatment for intestinal microsporidiosis. A double-blind and placebo-controlled clinical trial is currently in progress.

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Animals; Antiprotozoal Agents; Atovaquone; Cohort Studies; HIV-1; Humans; Intestines; Male; Microsporida; Naphthoquinones; Protozoan Infections; Retrospective Studies

Nineteen cases of cerebral toxoplasmosis (CTOX) are reported from a group of Edinburgh AIDS patients. All patients were severely immunodeficient at the time of presentation with CD4 count < 50 cells/mm3. Thirteen patients had suffered a previous AIDS-defining illness. In Edinburgh, CTOX has developed in 48% of patients who are seropositive for toxoplasma and have a CD4 count < 50 cells/mm3. It is estimated that at least half of the toxoplasma seropositive patients will develop CTOX if they survive for 21 months after reaching a time in their illness when the CD4 count = 50 cells/mm3. The incidence of CTOX in toxoplasma-seronegative patients with a CD4 count < 50 cells/mm3 is 1.3%. All patients showed improvement on treatment and there was no correlation between clinical or radiological features and patient survival. Those patients unable to tolerate first choice anti-toxoplasma therapy had a significantly shorter survival than the remainder but there was no single therapeutic regimen which conferred a survival advantage. Eighteen patients had died at the time of study and the median survival following diagnosis of cerebral toxoplasmosis was 10 months (range 3-38 months). Postmortem examination of the brain was available in 8, 4 of whom had concomitant cerebral lymphoma. The survival from AIDS or CD4 count = 50 cells/mm3 did not differ significantly between those with treated CTOX and a control group who had no toxoplasma infection, suggesting that treatment is reasonably effective. CTOX is a disease associated with severe HIV-related immunodeficiency and, in those with a CD4 count < 50 cells/mm3, occurs more than 35 times as frequently in toxoplasma-seropositive than toxoplasma-seronegative patients. Treatment is effective but the outcome of treated disease cannot be predicted from presenting clinical or radiological features. Concomitant space-occupying cerebral pathology is evident in 50% of post-mortem examinations.

Topics: Acquired Immunodeficiency Syndrome; Adult; Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Atovaquone; Autopsy; Azithromycin; Brain; CD4 Lymphocyte Count; Clindamycin; Drug Therapy, Combination; Female; Humans; Incidence; Lymphoma, AIDS-Related; Male; Middle Aged; Naphthoquinones; Pyrimethamine; Retrospective Studies; Sulfadiazine; Toxoplasmosis, Cerebral; United Kingdom

Topics: Acquired Immunodeficiency Syndrome; Adult; AIDS-Related Opportunistic Infections; Antifungal Agents; Atovaquone; CD4 Lymphocyte Count; Female; Humans; Naphthoquinones; Pneumonia, Pneumocystis

The anticryptosporidial activity of four macrolides alone and in combination with other antimicrobial agents was investigated against ten clinical isolates of Cryptosporidium parvum recovered from stools of AIDS patients. The susceptibility tests were performed by inoculation of the protozoa on to cell monolayers and determining the parasite count after 72 h incubation at 37 degrees C. The culture medium was supplemented with Dulbecco's modified Eagle's medium containing serial dilutions of azithromycin, clarithromycin, roxithromycin, spiramycin, alone or in combination with artemisin, atovaquone, dapsone, minocycline or pyrimethamine. Most of the agents had an inhibitory effect on parasite growth, but only at high concentrations. No agent was able to inhibit parasite growth completely, even at the highest concentrations used. The more effective agents, azithromycin, clarithromycin, roxithromycin, minocycline and pyrimethamine, produced no more than a 13.1-27.8% reduction in oocyst count and no more than a 15.1-35.7% in schizont count. Positive interaction was clearly demonstrated when macrolides were tested in combination with minocycline or pyrimethamine.

Topics: Acquired Immunodeficiency Syndrome; Animals; Anti-Bacterial Agents; Anti-Infective Agents; Artemisinins; Atovaquone; Cryptosporidiosis; Cryptosporidium parvum; Dapsone; Dose-Response Relationship, Drug; Drug Therapy, Combination; Humans; Lactones; Macrolides; Minocycline; Naphthoquinones; Pyrimethamine; Sesquiterpenes

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

Topics: Acquired Immunodeficiency Syndrome; AIDS-Related Opportunistic Infections; Antiprotozoal Agents; Atovaquone; Drug Resistance, Microbial; Humans; Naphthoquinones; Toxoplasmosis, Cerebral

Topics: Acquired Immunodeficiency Syndrome; Antifungal Agents; Atovaquone; Humans; Naphthoquinones; Pneumonia, Pneumocystis

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Adolescent; Antiprotozoal Agents; Atovaquone; Eye Infections, Parasitic; Follow-Up Studies; Fundus Oculi; Humans; Male; Naphthoquinones; Toxoplasmosis, Ocular

Topics: Acquired Immunodeficiency Syndrome; Antifungal Agents; Atovaquone; Clinical Protocols; Drugs, Investigational; Humans; Naphthoquinones; Pneumonia, Pneumocystis

Topics: Acquired Immunodeficiency Syndrome; Antifungal Agents; Atovaquone; Drugs, Investigational; Humans; Naphthoquinones; Pneumonia, Pneumocystis

566C80 is a novel hydroxynaphthoquinone with broad-spectrum anti-parasitic properties. In vitro the compound was more potent against Plasmodium falciparum than any of the established anti-malarial drugs. It had good activity against the pathogen in Aotus monkeys and was also effective in rodents infected with various drug-resistant strains of P. yoelii and P. berghei. In mice the compound showed significant activity against Toxoplasma gondii. Evaluation of the metabolic stability of 566C80 to NADPH-mediated oxidative metabolism was made using microsome preparations from a number of species including man. Unlike other quinones examined, 566C80 was shown to be inert in these assays. In Phase 1 clinical studies up to 750mg of compound were given as a single oral dose to fasted healthy male adults. This was well tolerated and the plasma drug elimination half-life was approximately 70h. In these subjects a 450mg dose gave plasma concentrations of 0.1-0.3 micrograms/ml which were achieved 1 h post-dosing and remained so for at least 7 days. Volunteers ingesting food prior to drug administration had quinone plasma levels which were significantly higher. Phase II trials are now underway to assess 566C80 for use against malaria and opportunistic infections in AIDS patients.

Topics: 4-Quinolones; Acquired Immunodeficiency Syndrome; Adult; Animals; Anti-Infective Agents; Antimalarials; Aotus trivirgatus; Atovaquone; Dogs; Humans; Malaria, Falciparum; Male; Microsomes, Liver; Middle Aged; NADP; Naphthoquinones; Opportunistic Infections; Plasmodium; Rats; Toxoplasma

Topics: Acquired Immunodeficiency Syndrome; Administration, Oral; Atovaquone; Drugs, Investigational; Humans; Naphthoquinones; Pneumonia, Pneumocystis

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