Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1996 May;40(5):1194–1197. doi: 10.1128/aac.40.5.1194

Effects of pentoxifylline or dexamethasone in combination with amphotericin B in experimental murine cerebral cryptococcosis: evidence of neuroexcitatory pathogenic mechanisms.

L Ostrosky-Zeichner 1, J L Soto-Hernandez 1, V Angeles-Morales 1, F Teixeira 1, C Nava-Ruiz 1, C Rios 1, F Solis 1, J Sotelo 1
PMCID: PMC163290  PMID: 8723465

Abstract

In a murine model of intracerebral infection by Cryptococcus neoformans the therapeutic effects of pentoxifylline or dexamethasone were studied alone and in combination with amphotericin B. Assessed parameters were mean survival time, brain histopathology index, amounts of glutamate and gamma-aminobutyric acid in the brain, and yeast CFU per brain. Survival increased significantly in mice treated with dexamethasone, amphotericin B, amphotericin B plus dexamethasone, and amphotericin B plus pentoxifylline; the latter had significantly longer survival than other treated groups. Indices of histopathological damage were similar in all treated groups. In infected untreated mice, the amounts of glutamate in the brain were decreased, presumably by depletion. In mice treated with amphotericin B plus dexamethasone, glutamate levels returned to the range of control mice. No differences in the amounts of gamma-aminobutyric acid were found between control and treatment groups. Brain fungal counts were significantly lower in mice treated with amphotericin B, amphotericin B plus dexamethasone, and amphotericin B plus pentoxifylline than in untreated animals. In this model, pentoxifylline in combination with amphotericin B improved survival, decreasing the fungal burden, and has potential as adjuvant therapy in cerebral cryptococcosis.

Full Text

The Full Text of this article is available as a PDF (181.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Blasi E., Barluzzi R., Mazzolla R., Bistoni F. Differential host susceptibility to intracerebral infections with Candida albicans and Cryptococcus neoformans. Infect Immun. 1993 Aug;61(8):3476–3481. doi: 10.1128/iai.61.8.3476-3481.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bozzette S. A., Sattler F. R., Chiu J., Wu A. W., Gluckstein D., Kemper C., Bartok A., Niosi J., Abramson I., Coffman J. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. N Engl J Med. 1990 Nov 22;323(21):1451–1457. doi: 10.1056/NEJM199011223232104. [DOI] [PubMed] [Google Scholar]
  3. Chalkiadakis G. E., Kostakis A., Karayannacos P. E., Chalkiadakis M. E., Sgouromali S., Giamarellou H., Skalkeas G. D. Pentoxifylline in the treatment of experimental peritonitis in rats. Arch Surg. 1985 Oct;120(10):1141–1144. doi: 10.1001/archsurg.1985.01390340039007. [DOI] [PubMed] [Google Scholar]
  4. Chan K. H., Mann K. S., Yue C. P. Neurosurgical aspects of cerebral cryptococcosis. Neurosurgery. 1989 Jul;25(1):44–48. doi: 10.1097/00006123-198907000-00008. [DOI] [PubMed] [Google Scholar]
  5. Chao C. C., Hu S., Close K., Choi C. S., Molitor T. W., Novick W. J., Peterson P. K. Cytokine release from microglia: differential inhibition by pentoxifylline and dexamethasone. J Infect Dis. 1992 Oct;166(4):847–853. doi: 10.1093/infdis/166.4.847. [DOI] [PubMed] [Google Scholar]
  6. Denning D. W., Armstrong R. W., Lewis B. H., Stevens D. A. Elevated cerebrospinal fluid pressures in patients with cryptococcal meningitis and acquired immunodeficiency syndrome. Am J Med. 1991 Sep;91(3):267–272. doi: 10.1016/0002-9343(91)90126-i. [DOI] [PubMed] [Google Scholar]
  7. Dezube B. J. Pentoxifylline for the treatment of infection with human immunodeficiency virus. Clin Infect Dis. 1994 Mar;18(3):285–287. doi: 10.1093/clinids/18.3.285. [DOI] [PubMed] [Google Scholar]
  8. Diamond R. D., Bennett J. E. Prognostic factors in cryptococcal meningitis. A study in 111 cases. Ann Intern Med. 1974 Feb;80(2):176–181. doi: 10.7326/0003-4819-80-2-176. [DOI] [PubMed] [Google Scholar]
  9. Guerra-Romero L., Tureen J. H., Fournier M. A., Makrides V., Täuber M. G. Amino acids in cerebrospinal and brain interstitial fluid in experimental pneumococcal meningitis. Pediatr Res. 1993 May;33(5):510–513. doi: 10.1203/00006450-199305000-00018. [DOI] [PubMed] [Google Scholar]
  10. Huston E., Cullen G., Sweeney M. I., Pearson H., Fazeli M. S., Dolphin A. C. Pertussis toxin treatment increases glutamate release and dihydropyridine binding sites in cultured rat cerebellar granule neurons. Neuroscience. 1993 Feb;52(4):787–798. doi: 10.1016/0306-4522(93)90529-o. [DOI] [PubMed] [Google Scholar]
  11. LOURIA D. B., FALLON N., BROWNE H. G. The influence of cortisone on experimental fungus infections in mice. J Clin Invest. 1960 Sep;39:1435–1449. doi: 10.1172/JCI104163. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Louie A., Baltch A. L., Franke M. A., Smith R. P., Gordon M. A. Comparative capacity of four antifungal agents to stimulate murine macrophages to produce tumour necrosis factor alpha: an effect that is attenuated by pentoxifylline, liposomal vesicles, and dexamethasone. J Antimicrob Chemother. 1994 Dec;34(6):975–987. doi: 10.1093/jac/34.6.975. [DOI] [PubMed] [Google Scholar]
  13. Mahaffey K. W., Hippenmeyer C. L., Mandel R., Ampel N. M. Unrecognized coccidioidomycosis complicating Pneumocystis carinii pneumonia in patients infected with the human immunodeficiency virus and treated with corticosteroids. A report of two cases. Arch Intern Med. 1993 Jun 28;153(12):1496–1498. [PubMed] [Google Scholar]
  14. Mitchell D. H., Sorrell T. C., Allworth A. M., Heath C. H., McGregor A. R., Papanaoum K., Richards M. J., Gottlieb T. Cryptococcal disease of the CNS in immunocompetent hosts: influence of cryptococcal variety on clinical manifestations and outcome. Clin Infect Dis. 1995 Mar;20(3):611–616. doi: 10.1093/clinids/20.3.611. [DOI] [PubMed] [Google Scholar]
  15. Powderly W. G. Therapy for cryptococcal meningitis in patients with AIDS. Clin Infect Dis. 1992 Mar;14 (Suppl 1):S54–S59. doi: 10.1093/clinids/14.supplement_1.s54. [DOI] [PubMed] [Google Scholar]
  16. Rothman S. M., Olney J. W. Glutamate and the pathophysiology of hypoxic--ischemic brain damage. Ann Neurol. 1986 Feb;19(2):105–111. doi: 10.1002/ana.410190202. [DOI] [PubMed] [Google Scholar]
  17. Saag M. S., Powderly W. G., Cloud G. A., Robinson P., Grieco M. H., Sharkey P. K., Thompson S. E., Sugar A. M., Tuazon C. U., Fisher J. F. Comparison of amphotericin B with fluconazole in the treatment of acute AIDS-associated cryptococcal meningitis. The NIAID Mycoses Study Group and the AIDS Clinical Trials Group. N Engl J Med. 1992 Jan 9;326(2):83–89. doi: 10.1056/NEJM199201093260202. [DOI] [PubMed] [Google Scholar]
  18. Sathe S. S., Sarai A., Tsigler D., Nedunchezian D. Pentoxifylline aggravates impairment in tumor necrosis factor-alpha secretion and increases mycobacterial load in macrophages from AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. J Infect Dis. 1994 Aug;170(2):484–487. doi: 10.1093/infdis/170.2.484. [DOI] [PubMed] [Google Scholar]
  19. Stern J. J., Hartman B. J., Sharkey P., Rowland V., Squires K. E., Murray H. W., Graybill J. R. Oral fluconazole therapy for patients with acquired immunodeficiency syndrome and cryptococcosis: experience with 22 patients. Am J Med. 1988 Oct;85(4):477–480. doi: 10.1016/s0002-9343(88)80081-0. [DOI] [PubMed] [Google Scholar]
  20. Sullivan G. W., Carper H. T., Mandell G. L. Pentoxifylline modulates activation of human neutrophils by amphotericin B in vitro. Antimicrob Agents Chemother. 1992 Feb;36(2):408–416. doi: 10.1128/aac.36.2.408. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sáez-Llorens X., Ramilo O., Mustafa M. M., Mertsola J., de Alba C., Hansen E., McCracken G. H., Jr Pentoxifylline modulates meningeal inflammation in experimental bacterial meningitis. Antimicrob Agents Chemother. 1990 May;34(5):837–843. doi: 10.1128/aac.34.5.837. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Tan C. T. Intracranial hypertension causing visual failure in cryptococcus meningitis. J Neurol Neurosurg Psychiatry. 1988 Jul;51(7):944–946. doi: 10.1136/jnnp.51.7.944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tang L. M. Ventriculoperitoneal shunt in cryptococcal meningitis with hydrocephalus. Surg Neurol. 1990 May;33(5):314–319. doi: 10.1016/0090-3019(90)90198-x. [DOI] [PubMed] [Google Scholar]
  24. Zuger A., Louie E., Holzman R. S., Simberkoff M. S., Rahal J. J. Cryptococcal disease in patients with the acquired immunodeficiency syndrome. Diagnostic features and outcome of treatment. Ann Intern Med. 1986 Feb;104(2):234–240. doi: 10.7326/0003-4819-104-2-234. [DOI] [PubMed] [Google Scholar]
  25. van der Heyden J. A., Korf J. Regional levels of GABA in the brain: rapid semiautomated assay and prevention of postmortem increase by 3-mercapto-propionic acid. J Neurochem. 1978 Jul;31(1):197–203. doi: 10.1111/j.1471-4159.1978.tb12448.x. [DOI] [PubMed] [Google Scholar]

Articles from Antimicrobial Agents and Chemotherapy are provided here courtesy of American Society for Microbiology (ASM)

RESOURCES