Development of an improved rat model of Pneumocystis carinii pneumonia and investigations of novel chemotherapeutic agents.

摘要

Pneumocystis carinii pneumonia (PCP) is the most common opportunistic infection associated with AIDS. PCP is often fatal because AIDS patients frequently are intolerant to drugs that would otherwise be effective. Consequently, new and better tolerated therapies are urgently needed.In an attempt to improve the activity of eflornithine, I tested three combinations of drugs that were known to be individually active against African sleeping sickness and synergistic when combined. Furthermore, all were either known to be active against PCP or I demonstrated this activity. In my experimental model pentamidine, a drug currently used for PCP, was as active as the control treatment, but the combination of eflornithine and pentamidine was no more active than pentamidine alone. Diminazene aceturate, a compound related to pentamidine, showed high activity in my animal model of PCP, which was a novel finding. Disappointingly, eflornithine and diminazene aceturate were antagonistic. Suramin showed weak anti-PCP activity which was not enhanced by combination with eflornithine. In addition, I tested dapsone, a well known drug related to SMZ, which is sometimes used to treat PCP. However, in my experimental model dapsone was not very active so that combinations of dapsone with other drugs were not tested.Although I failed to find synergistic drug combinations, my research laid the groundwork for further work designed to improve the activity of eflornithine and related compounds.Eflornithine (difluoromethylornithine, DMFO) is a new drug which had shown activity in a small trial treating PCP in AIDS patients. However, when more extensive clinical trials indicated that the activity was only moderate and two animal studies failed to show any activity against PCP enthusiasm for this drug waned. I developed a reliable animal model of PCP and re-tested eflornithine under conditions more likely to reveal activity. As a positive control, I used the combination of trimethoprim plus sulfamethoxazole (TMP/SMZ), the most common treatment for PCP. Eflornithine was definitely active, but not as effective as TMP/SMZ.