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Browsing by Subject "Pneumocystis carinii"
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Item Item Effect of Pneumocystis carinii on alveolar macrophage function during infection(1999) Lasbury, Mark EdwardItem Immunology of murine Pneumocystis carinii infection(1998) Bellagamba, Juan Miguel PascaleItem Molecular typing of Pneumocystis carinii(1995) Lu, Jang-JihItem Over-expressed genes in pneumocystis carinii-infected rat lung(2001) Jiang, TaoItem The Pneumocystis Carinii cyst: infectivity and role in lung damage in a rat model of infection(2002) Hsueh, Yi-chung JohnItem Pneumocystis carinii vimentin: isolation and identification of a primaquine-binding protein(1996) Bolyard, Lori AnnItem Scalable Preparation and Differential Pharmacologic and Toxicologic Profiles of Primaquine Enantiomers(American Society for Microbiology (ASM), 2016-03) Dhammika Nanayakkara, N. P.; Tekwani, Babu L.; Bandara Herath, H. M. T.; Sahu, Rajnish; Gettayacamin, Montip; Tungtaeng, Anchalee; Van Gessel, Yvonne; Baresel, Paul; Wickham, Kristina S.; Bartlett, Marilyn S.; Fronczek, Frank R.; Melendez, Victor; Ohrt, Colin; Reichard, Gregory A.; McChesney, James D.; Rochford, Rosemary; Walker, Larry A.; Department of Pathology & Laboratory Medicine, IU School of MedicineHematotoxicity in individuals genetically deficient in glucose-6-phosphate dehydrogenase (G6PD) activity is the major limitation of primaquine (PQ), the only antimalarial drug in clinical use for treatment of relapsing Plasmodium vivax malaria. PQ is currently clinically used in its racemic form. A scalable procedure was developed to resolve racemic PQ, thus providing pure enantiomers for the first time for detailed preclinical evaluation and potentially for clinical use. These enantiomers were compared for antiparasitic activity using several mouse models and also for general and hematological toxicities in mice and dogs. (+)-(S)-PQ showed better suppressive and causal prophylactic activity than (−)-(R)-PQ in mice infected with Plasmodium berghei. Similarly, (+)-(S)-PQ was a more potent suppressive agent than (−)-(R)-PQ in a mouse model of Pneumocystis carinii pneumonia. However, at higher doses, (+)-(S)-PQ also showed more systemic toxicity for mice. In beagle dogs, (+)-(S)-PQ caused more methemoglobinemia and was toxic at 5 mg/kg of body weight/day given orally for 3 days, while (−)-(R)-PQ was well tolerated. In a novel mouse model of hemolytic anemia associated with human G6PD deficiency, it was also demonstrated that (−)-(R)-PQ was less hemolytic than (+)-(S)-PQ for the G6PD-deficient human red cells engrafted in the NOD-SCID mice. All these data suggest that while (+)-(S)-PQ shows greater potency in terms of antiparasitic efficacy in rodents, it is also more hematotoxic than (−)-(R)-PQ in mice and dogs. Activity and toxicity differences of PQ enantiomers in different species can be attributed to their different pharmacokinetic and metabolic profiles. Taken together, these studies suggest that (−)-(R)-PQ may have a better safety margin than the racemate in human.