In addition to its potent efficacy in animal models against Candida sp., Aspergillus fumigatus, and Histoplasma capsulatum, the clinical candidate pneumocandin MK-991 (formerly L-743,872) was also extremely potent against Pneumocystis carinii in models of immune-compromised animals. MK-991 was approximately 14 times more potent than the original natural product lead, pneumocandin B0. The 90% effective dose (ED90) of MK-991 for cyst clearance in the rat model for pneumocystis was 0.011 mg/kg of body weight when delivered parenterally for 4 days twice a day (b.i.d.). In a mouse model, under the same experimental parameters, the ED90 was 0.02 mg/kg. MK-991 was also effective orally, with an ED90 for cyst clearance of 2.2 mg/kg against acute infection in rats (b.i.d. for 4 days). Complete prevention of P. cariniidevelopment was achieved in immunocompromised mice at a daily oral dose of 2.25 mg/kg. As reported previously for other pneumocandins and echinocandins, MK-991 selectively prevented the development of P. carinii cysts. When used as a prophylactic agent, neither stage of the organism appeared in the lungs of animals. In response to an acute infection, cysts were eliminated rapidly, while trophozoite forms persisted. Despite good efficacy as an oral agent in murine models, the low oral absorption of this class may limit the use of MK-991 to parenteral therapy.
A new series of semisynthetic, water-soluble pneumocandin analogs has been found to be extremely potent against Pneumocystis carinii in an immunocompromised-rat model. These compounds are 5 to 10 times more potent than the parent natural product, pneumocandin B 0 (L-688,786) (R. E. Schwartz et al., J. Antibiot. 45:1853-1866, 1992), and >100 times more potent than cilofungin. One compound in particular, L-733,560, had a 90% effective dose against P. carinii cysts of 0.01 mg/kg of body weight when delivered parenterally (subcutaneously, twice daily for 4 days). This compound was also effective when given orally for the treatment and prevention of P. carinii pneumonia. For treating acute P. carinii pneumonia, oral doses of 2.2 mg/kg twice daily for 4 days were required to eliminate 90% of the cysts. A once-daily oral prophylactic dose of 2.2 mg/kg prevented cyst development, and a dose of 6.2 mg/kg prevented any development of P. carinii organisms (cysts and trophozoites), as determined through the use of a P. carinii-specific DNA probe (P. Among the most promising classes of compounds for the potential treatment and prevention of systemic fungal infections and Pneumocystis carinii pneumonia (PCP) are the echinocandins and the closely related pneumocandins (1,3,4,11,15). These compounds are believed to function by inhibiting the biosynthesis of -1,3-glucan, a major component of the cell walls of many fungi and of P. carinii cyst walls (13). Many of the echinocandins have potent in vivo efficacy against Candida albicans (3) and P. carinii (15) in murine models. The semisynthetic echinocandin cilofungin has also been shown to effectively treat candidiasis in humans (6,7,10). Despite the significant efficacies of compounds in this class, the poor water solubility of compounds in this class has hindered their development for clinical use. Clinical trials with cilofungin for intravenous use in humans were abandoned because of side effects attributable to the cosolvent (9, 10).AThe lack of water solubility of this class was overcome by the development of pneumocandin prodrugs such as L-693,989 (2) and, more recently, by the addition of charged amino groups to the peptide core of pneumocandin B 0 (L-688,786), resulting in water-soluble, nonprodrug compounds which are substantially more efficacious (5). This additional potency has also resulted in an expanded spectrum for these drugs, which have been shown to have potent activity against Aspergillus fumigatus in murine models (1). Prior to this, only modest in vivo antiAspergillus activity had been reported with extremely high doses of cilofungin (8). The broadened spectrum of these pneumocandins with amino substitutions, which encompasses both Aspergillus spp. and Candida spp., may, for the first time, make echinocandins useful for empiric treatment of systemic fungal infections.These amino compounds are also substantially more efficacious against P. carinii and may represent a new class of agents for the safe, effective control of this organism in immunocompromised host...
A series of lipopeptide compounds co-produced during the fermentation of pneumocandin Ao (L-671 ,329) and related semisynthetic compounds were evaluated in vivo against Pneumocystis carinii pneumonia and systemic candidiasis. In addition, they were tested in vitro against a panel ofpathogenic Candidaspecies and in a Candida membrane 1,3-jS-D-glucan synthesis assay. The results of these studies demonstrate that pneumocandin Ao and pneumocandin Bo (L-688,786) are the most potent compoundswhenconsidering both antipneumocystis and anticandida activity. Other compoundsin the series are selectively more potent against P. carinii or Candida albicans suggesting a diverging structure-activity relationship. Evaluation of these compoundsfor their ability to inhibit C. albicans l,3-/?-D-glucan synthesis in vitro demonstrates that they inhibit this process. A positive correlation between l,3-/?-D-glucan synthesis inhibition and in vitro antifungal activity was also demonstrated for some of the pneumocandins.
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.
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