OI Backgrounder, Opportunistic Infections Research

Preclinical 01

Among their accomplishments, contractors have:
* Screened more than 800 compounds and plant extracts last year for in vitro activity
against organisms causing Ols. These evaluations included both confirmatory and
primary screens.
* Identified potent inhibitors of the folate metabolizing enzymes of Pneumocystis
carinii and Toxoplasma gondii.
* Identified and developed the combination of clindamycin and primaquine as
treatment and prophylaxis for PCP. These drugs appear to have fewer adverse
reactions than the present standard-of-care regimens.
* Identified additional anti-malarial analogs of primaquine that have more potent antiPneumocystis activity than primaquine.
* Developed a standardized method of infecting immunosuppressed rats with
Pneumocystis carinii for drug evaluations, allowing for more reliable and
reproducible experiments.
* Confirmed the similarity of Pneumocystis carinii to fungi. This has led to the
development of a method for laboratory culture of the organism using fungal
media. This will contribute to the study of the organism's metabolism and
sensitivity to antimicrobials, which will enable the design of more effective and
specific therapies.
* Identified the potential of severe combined immunodeficiency (SCID) mice as
models of Pneumocystis infections in AIDS patients.
* Synthesized, evaluated, and developed a pentamidine analog that is less toxic and
more efficacious in animals and can be administered orally for treating PCP.
Further development and testing of this compound in rats is necessary before
human clinical trials can be considered.
* Developed less toxic amphotericin B delivery systems for treatment of fungal
infections.
* Identified thiacetazone (an anti-tuberculosis drug) and azithromycin as potential
treatments for Mycobacterium avium infections.
* Identified plant extracts with anti-Candida activity to serve as prototypes for future
drug development.
Other Preclinical Resources
NIAID and the National Cancer Institute reached an agreement last year that NIAID
would assume primary responsibility for discovery and preclinical development of therapies
for HIV-associated Ols. To carry out this mission, DAIDS has established resources to
conduct chemical synthesis and formulation studies. DAIDS is planning to expand these
resources, contingent upon the availability of funds, to include all studies required in an
Investigational New Drug application.