Efficacy of MK-991 (L-743,872), a Semisynthetic Pneumocandin,in Murine Models of Pneumocystis carinii |
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| Authors: | Mary Ann Powles Paul Liberator Jennifer Anderson Yashwant Karkhanis James F. Dropinski F. Aileen Bouffard James M. Balkovec Hisashi Fujioka Masamichi Aikawa Diane McFadden Dennis Schmatz |
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| Affiliation: | Merck Research Laboratories, Rahway, New Jersey 070651.; Institute of Pathology, Case Western Reserve University, Cleveland, Ohio 441062.; and Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, California 94305-54023. |
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| Abstract: | 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. carinii development 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.Pneumocystis carinii is one of the most common and serious opportunistic infections in patients with AIDS, as well as in those receiving immunosuppressive therapy as a result of organ transplantation or cancer chemotherapy. The most widely used agent for the treatment and prevention of P. carinii pneumonia (PCP), trimethoprim-sulfamethoxazole (TMP-SMZ), has a high incidence of adverse reactions in AIDS patients (2). Rapid oral desensitization to TMP-SMZ has been attempted (5, 8, 10), and while initial results are positive, studies have been limited to small numbers of patients, and there is clearly a need for a new class of compounds to treat PCP.A novel natural product, pneumocandin B0, originally isolated from a fermentation of Glarea lozoyensis, was found to have activity in an experimental rat model for PCP (13). Synthetic chemical modifications of the parent structure have resulted in more potent and soluble compounds (12). The pneumocandins act by inhibiting the synthesis of β- 1,3-glucan, a major component of the cyst wall of P. carinii (7). The lack of a mammalian β-1,3-glucan synthase counterpart should provide a superior therapeutic window over standard PCP treatments, such as TMP-SMZ and pentamidine.While β-1,3-glucan represents a major portion of the wall of the cyst, it is not found in great abundance in the trophozoite form of the organism. From previous studies (13), we know that short-term treatment (4 days) with pneumocandin analogs does not have a significant effect on trophozoites. Treatment over a period of 2 weeks (the standard length of treatment for known PCP agents) results in no significant increase or decrease in the level of trophozoites. This result suggests that inhibition of cyst proliferation has an effect on the ability of the trophozoites to multiply. Finally, when prophylactic effects of the pneumocandins were evaluated, inhibition of the cyst form of the organism was found to result in inhibition of the trophozoite form as well, implying that the cyst stage is required for trophozoite proliferation (11).The efficacy of one of the most potent semisynthetic pneumocandins, MK-991, against PCP is evaluated here. This compound was evaluated orally (p.o.) and parenterally in murine models for PCP. Short-term (4 day) and long-term (as much as 21 days) uses, as well as prophylactic use, were evaluated. In addition, the effects of the drug on the organization of the cyst and localization of the drug in the cyst wall after 2 days of drug treatment were evaluated. |
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