Pneumocystis carini pneumonia is a major cause of death in AIDS patients in the United States. The presently available treatments have limited use due to a high incidence of adverse reactions. Therefore, there is an urgent need for a safer method for treatment and prevention of this disease. Recent evidence has suggested that P. carinn is related to fungi and that the wall ofthe cyst form contains 1,3-13-glucan as a major constituent. Based on this, several proposed 1,3-f3-glucan synthesis inhibitors were evaluated for their ability to control P. carinu pneumonia in vivo. Compounds from two classes of 1,3-13-glucan synthesis inhibitors, the echinocandins and papulacandins, were found to be effective against P. carinii.Pneumocystis carinii pneumonia is the most prevalent opportunistic infection and a frequent cause of death in AIDS

Water-soluble lipopeptide L-693,989 was evaluated for its antipneumocystis activity in rats. Rats from colonies with latent Pneumocystis carinii infections were immunosuppressed with dexamethasone for 6 weeks to facilitate the development of acute P. carinii pneumonia (PCP). After 6 weeks, the rats were maintained on dexamethasone and were treated twice daily for 4 days with various concentrations of L-693,989. At a dose of 0.15 mg/kg of body weight, the compound effectively eliminated 90%o of the cysts in 4 days. Trophozoite forms of P. carinii were still present in these animals, as determined by using a P. carinii-specific DNA probe. A 3-week therapy study showed that the trophozoite load did not expand during treatment and that the trophozoites already present at the initiation of therapy appeared to persist. This may be a consequence of the stage specificity of the compound for cyst development and the severe immunosuppressive effects of dexamethasone on rats. When evaluated as a daily parenteral prophylactic agent, L-693,989 was effective in preventing the development of both P. carinii cysts and trophozoites, demonstrating its potential for use in prophylaxis and implying that the cyst stage ofP. carinii is an obligatory step in trophozoite multiplication. The foamy exudate commonly associated with P. carinii infections was absent in the lungs of rats on prophylaxis. The compound was also evaluated via oral administration and was found to have a 90%Yo effective dose of 32 mg/kg for therapy of acute infections and 5 mg/kg for daily prophylaxis.Pneumocystis carinii pneumonia (PCP) is a life-threatening disease which occurs in immunocompromised patients, especially those afflicted with AIDS. Although agents are available for the treatment and prevention of PCP, there is an unusually high incidence of adverse reactions to these treatments, particularly in patients with AIDS (14). Consequently, safer agents for controlling this disease are needed. We recently reported a novel method for controlling P.cainni infections in rodents using 1,3-p-glucan synthesis inhibitors (12). The more potent of these inhibitors, the lipopeptide natural product L-671,329 (Fig. 1), rapidly eliminates P. carinii cysts in 4 days when it is used to treat immunosuppressed rats with acute PCP. In addition to the antipneumocystis activity, L-671,329 is also effective against Candida infections in animal models (2). The lack of a counterpart for 1,3-p-glucan synthesis in humans should allow for selective killing of P. carinii and Candida spp. A shortcoming of L-671,329 and similar lipopeptides is their insolubility in aqueous solution, limiting their potential use as intravenous agents. Although cosolvent systems have been used for some insoluble drugs in the past, many of these formulations may no longer be acceptable because of adverse reactions (4, 8, 10); thus, water-soluble compounds are much more desirable. Therefore, a semisynthetic watersoluble prodrug, L-693,989 (Fig. 1 To determine the potential clinical use of L-693,989 in tre...

Animal models for Pneumocystis carinii, for the most part, have been limited to immunosuppressed rats and ferrets, while a dependable mouse model has been more difficult to develop. A P. carinii mouse model has now been established with several strains of mice, including C3Heb/FeJ, C3HeN, BALB/c, DBA12N, and BALB/c nu/nu (athymic). In lieu of using invasive methods for initiating P. carinii infections, mice harboring P. carinii transmitted the disease to mice without latent infection via short-term cohabitation. After the exposure period, the seed mice were sacrificed to confirm the presence of acute P. carinii pneumonia. Acute infections in recipient mice developed at approximately 7 to 8 weeks, while control unseeded littermates remained uninfected. All recipient mice and their littermates were maintained in isolation hoods to eliminate the possibility of exposure to other sources of P. carinii. This approach allows investigators to consistently transmit P. carinii to mice and to select the strain of mouse desired for use in a particular study. The results presented here suggest that more attention should be given to the potential for patient-to-patient transmission of P. carinii in immunocompromised patients such as those with AIDS.

An increased incidence of intermediate to high-grade Non Hodgkin's Lymphoma is found in individuals with AIDS. Although immune function in AIDS patients can be improved through the use of antiretroviral therapy, the contribution of these drugs to lymphoma regression is not known. Here we describe the complete regression and subsequent recurrence of high grade, Burkitt-like lymphoma during antiretroviral therapy in a patient with AIDS. Antiretroviral therapy resulted in diminished viral load and modest improvement in CD4+ T cell counts. Lymphoma regressed initially, but relapsed 3 months later. Tissue taken from the initial and recurrent tumor demonstrated different clonal rearrangements. The recurrent lymphoma did not respond to continued antiretroviral therapy. In Conclusion, antiretroviral therapy may contribute to lymphoma regression in AIDS lymphoma. Clinically recurrent disease may be clonally distinct.

A repetitive genomic DNA clone (B12-2) that specifically hybridizes to Pneumocystis carinii DNA has been identified. No cross-hybridization to genomic DNA prepared from bacteria, other fungi, protozoa, or mammals was observed. Clone B12-2 is multiply represented in the P. carinii genome. By direct hybridization to DNA prepared from the lungs of immunosuppressed rats, the probe can detect the equivalent of fewer than 1,000 P. carinii organisms. A hybridization assay employing clone B12-2 has been developed to quantitate organism load in the rat model for P. carinii. Application of the assay to track the accumulation of organisms during the immunosuppression regimen as well as to monitor the efficacy of two drug therapies used clinically for the treatment ofP. carinii pneumonia is described here. The clone B12-2 hybridization assay for the determination of P. carinii organism load possesses several advantageous features and thus should serve to complement conventional staining and immunohistochemical methods.