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. 1994 Jun;38(6):1397–1401. doi: 10.1128/aac.38.6.1397

Aerosolized L-693,989 for Pneumocystis carinii prophylaxis in rats.

M A Powles 1, D C McFadden 1, P A Liberator 1, J W Anderson 1, E B Vadas 1, D Meisner 1, D M Schmatz 1
PMCID: PMC188217  PMID: 8092844

Abstract

Water-soluble pneumocandin L-693,989, a potent antipneumocystis agent in the rat model for Pneumocystis carinii pneumonia (PCP), inhibits P. carinii cyst development and effectively prevents the development of PCP when used as a prophylactic agent (D. M. Schmatz, M. A. Powles, D. C. McFadden, L. Pittarelli, J. Balkovec, M. Hammond, R. Zambias, P. Liberator, and J. Anderson, Antimicrob. Agents Chemother. 36:1964-1970, 1992). However, because of limited oral bioavailability, this compound would likely be restricted to parenteral use in humans. As an alternative, the aerosol delivery of L-693,989 was explored to determine the dosing regimen required to prevent the onset of PCP. Rats with latent P. carinii infections were immunosuppressed continuously with dexamethasone to promote the onset of PCP. During the 6-week immunosuppression period, L-693,989 was delivered to rats as a nebulized solution (volume median diameter of 3.8 microns) via a nose exposure inhalation chamber. The efficiency of aerosol delivery to the lungs and the rate of clearance were determined by using radiolabelled compound. It was found that a daily dose of 0.7 micrograms of L-693,989 per lung or a weekly dose of 77.9 micrograms/lung effectively prevented the development of P. carinii cysts and trophozoites as well as the associated pneumonia commonly seen in rats with acute P. carinii infections. These results demonstrate that L-693,989 is potentially useful as an aerosol prophylactic agent for PCP.

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Selected References

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  1. Abd A. G., Nierman D. M., Ilowite J. S., Pierson R. N., Jr, Bell A. L., Jr Bilateral upper lobe Pneumocystis carinii pneumonia in a patient receiving inhaled pentamidine prophylaxis. Chest. 1988 Aug;94(2):329–331. doi: 10.1378/chest.94.2.329. [DOI] [PubMed] [Google Scholar]
  2. Balkovec J. M., Black R. M., Hammond M. L., Heck J. V., Zambias R. A., Abruzzo G., Bartizal K., Kropp H., Trainor C., Schwartz R. E. Synthesis, stability, and biological evaluation of water-soluble prodrugs of a new echinocandin lipopeptide. Discovery of a potential clinical agent for the treatment of systemic candidiasis and Pneumocystis carinii pneumonia (PCP). J Med Chem. 1992 Jan;35(1):194–198. doi: 10.1021/jm00079a027. [DOI] [PubMed] [Google Scholar]
  3. Debs R., Brunette E., Fuchs H., Lin E., Shah M., Hargis A., Montgomery A. B. Biodistribution, tissue reaction, and lung retention of pentamidine aerosolized as three different salts. Am Rev Respir Dis. 1990 Nov;142(5):1164–1167. doi: 10.1164/ajrccm/142.5.1164. [DOI] [PubMed] [Google Scholar]
  4. Frenkel J. K., Good J. T., Shultz J. A. Latent Pneumocystis infection of rats, relapse, and chemotherapy. Lab Invest. 1966 Oct;15(10):1559–1577. [PubMed] [Google Scholar]
  5. Girard P. M., Brun-Pascaud M., Farinotti R., Tamisier L., Kernbaum S. Pentamidine aerosol in prophylaxis and treatment of murine Pneumocystis carinii pneumonia. Antimicrob Agents Chemother. 1987 Jul;31(7):978–981. doi: 10.1128/aac.31.7.978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. Jules-Elysee K. M., Stover D. E., Zaman M. B., Bernard E. M., White D. A. Aerosolized pentamidine: effect on diagnosis and presentation of Pneumocystis carinii pneumonia. Ann Intern Med. 1990 May 15;112(10):750–757. doi: 10.7326/0003-4819-112-10-750. [DOI] [PubMed] [Google Scholar]
  7. Liberator P. A., Anderson J. W., Powles M., Pittarelli L. A., Worley M., Becker-Hapak M., Graves D. C., Schmatz D. M. Comparative study of antipneumocystis agents in rats by using a Pneumocystis carinii-specific DNA probe to quantitate infection. J Clin Microbiol. 1992 Nov;30(11):2968–2974. doi: 10.1128/jcm.30.11.2968-2974.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Montaner J. S., Lawson L. M., Gervais A., Hyland R. H., Chan C. K., Falutz J. M., Renzi P. M., MacFadden D., Rachlis A. R., Fong I. W. Aerosol pentamidine for secondary prophylaxis of AIDS-related Pneumocystis carinii pneumonia. A randomized, placebo-controlled study. Ann Intern Med. 1991 Jun 1;114(11):948–953. doi: 10.7326/0003-4819-114-11-948. [DOI] [PubMed] [Google Scholar]
  9. Northfelt D. W. Extrapulmonary pneumocystosis in patients taking aerosolised pentamidine. Lancet. 1989 Dec 16;2(8677):1454–1454. doi: 10.1016/s0140-6736(89)92060-6. [DOI] [PubMed] [Google Scholar]
  10. Noskin G. A., Murphy R. L. Extrapulmonary infection with Pneumocystis carinii in patients receiving aerosolized pentamidine. Rev Infect Dis. 1991 May-Jun;13(3):525–525. doi: 10.1093/clinids/13.3.525. [DOI] [PubMed] [Google Scholar]
  11. Schmatz D. M., Powles M. A., McFadden D. C., Pittarelli L., Balkovec J., Hammond M., Zambias R., Liberator P., Anderson J. Antipneumocystis activity of water-soluble lipopeptide L-693,989 in rats. Antimicrob Agents Chemother. 1992 Sep;36(9):1964–1970. doi: 10.1128/aac.36.9.1964. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Smaldone G. C., Fuhrer J., Steigbigel R. T., McPeck M. Factors determining pulmonary deposition of aerosolized pentamidine in patients with human immunodeficiency virus infection. Am Rev Respir Dis. 1991 Apr;143(4 Pt 1):727–737. doi: 10.1164/ajrccm/143.4_Pt_1.727. [DOI] [PubMed] [Google Scholar]
  13. Telzak E. E., Cote R. J., Gold J. W., Campbell S. W., Armstrong D. Extrapulmonary Pneumocystis carinii infections. Rev Infect Dis. 1990 May-Jun;12(3):380–386. doi: 10.1093/clinids/12.3.380. [DOI] [PubMed] [Google Scholar]
  14. Witt K., Nielsen T. N., Junge J. Dissemination of Pneumocystis carinii in patients with AIDS. Scand J Infect Dis. 1991;23(6):691–695. doi: 10.3109/00365549109024295. [DOI] [PubMed] [Google Scholar]

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