In vitro Interactions of Amantadine Hydrochloride, R-(-)-Deprenyl Hydrochloride and Valproic Acid Sodium Salt with Antifungal Agents Against Filamentous Fungal Species Causing Central Nervous System Infection

Abstract

The mortality rates of fungal infections that affect the central nervous system are high in consequence of the absence of effective antifungal drugs with good penetration across the blood-brain barrier and the blood-cerebrospinal fluid barrier. In the present work in vitro antifungal activities of three good penetrating non-antifungal drugs (amantadine hydrochloride, R-(-)-deprenyl hydrochloride, valproic acid sodium salt) and their combinations with three antifungal agents (amphotericin B, itraconazole, terbinafine) were tested with broth microdilution method against eight fungal isolates belonging to Zygomycetes (Lichtheimia corymbifera, Rhizomucor miehei, Rhizopus microsporus var. rhizopodiformis, Saksenaea vasiformis) and Aspergillus genus (A. flavus, A. fumigatus, A. nidulans, A. terreus). These are known to be possible agents of central nervous fungal infections (CNFI). When used alone, the investigated non-antifungal drugs exerted slight antifungal effects. In their combinations with antifungal agents they acted antagonistically, additively and synergistically against zygomyceteous isolates. Primarily antagonistic interactions were revealed between the investigated drugs in case of Aspergilli, but additive and synergistic interactions were also observed. The additive and synergistic combinations allowed the usage of reduced concentrations of antifungal agents to inhibit the fungal growth in our study. These combinations would be a basis of an effective, less toxic therapy for treatment of CNFI.

References

  1. 1.

    Abraham, O. C., Manavathu, E. K., Cutright, J. L., Chandrasekar, P. H. (1999) In vitro susceptibilities of Aspergillus species to voriconazole, itraconazole, and amphotericin B. Diagn. Microbiol. Infect. Dis. 33, 7–11.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  2. 2.

    Afeltra, J., Verweij, P. E. (2003) Antifungal activity of nonantifungal drugs. Eur. J. Clin. Microbiol. Infect. Dis. 22, 397–107.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  3. 3.

    Azzaro, A. J., Ziemniak, J., Kemper, E., Campbell, B. J., Van Den Berg, C. (2007) Pharmacokinetics and absolute bioavailability of selegiline following treatment of healthy subjects with the selegiline transdermal system (6 mg/24 h): a comparison with oral selegiline capsules. J. Clin. Pharmacol. 47, 1256–1267.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  4. 4.

    Baddley, J. W., Salzman, D., Pappas, P. G. (2002) Fungal brain abscess in transplant recipients: epidemiologic, microbiologic, and clinical features. Clin. Transplant. 16, 419–124.

    PubMed  Article  PubMed Central  Google Scholar 

  5. 5.

    Bazinet, R. P., Weis, M. T., Rapoport, S. I., Rosenberger, T. A. (2006) Valproic acid selectively inhibits conversion of arachidonic acid to arachidonoyl-CoA by brain microsomal long-chain fatty acyl-CoA synthetases: relevance to bipolar disorder. Psychopharmacology (Berl.) 184, 122–129.

    CAS  Article  Google Scholar 

  6. 6.

    Blum, G., Perkhofer, S., Haas, H., Schrettl, M., Wiirzner, R., Dierich, M. P., Lass-Florl, C. (2008) Potential basis for amphotericin B resistance in Aspergillus terreus. Antimicrob. Agents. Chemother. 52, 1553–1555.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  7. 7.

    Chakrabarti, A., Marak, R. S. K., Singhi, S., Gupta, S., Hurst, S. F., Padhye, A. A. (2005) Brain abscess due to Aspergillus nidulans. J. Mycol. Med. 16, 100–104.

    Article  Google Scholar 

  8. 8.

    Cohen, R. A., Fisher, M. (1989) Amantadine treatment of fatigue associated with multiple sclerosis. Arch. Neurol. 46, 676–680.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  9. 9.

    Crosby, N., Deane, K. H., Clarke, C. E. (2003) Amantadine in Parkinson’s disease. Cochrane Database Syst. Rev. 1, CD003468.

  10. 10.

    Dannaoui, E., Persat, F., Monier, M. F., Borel, E., Piens, M. A., Picot, S. (1999) In-vitro susceptibility of Aspergillus spp. isolates to amphotericin B and itraconazole. J. Antimicrob. Chemother. 44, 553–555.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  11. 11.

    Dannaoui, E., Meletiadis, J., Mouton, J. W., Meis, J. F., Verweij, P. E., Eurofung Network (2003) In vitro susceptibilities of zygomycetes to conventional and new antifungals. J. Antimicrob. Chemother. 51, 45–52.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  12. 12.

    Deyde, V M., Xu, X., Bright, R. A., Shaw, M., Smith, C. B., Zhang, Y., Shu, Y., Gubareva, L. V., Cox, N. J., Klimov, A. I. (2007) Surveillance of resistance to adamantanes among influenza A(H3N2) and A(H1N1) viruses isolated worldwide. J. Infect. Dis. 196, 249–257.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  13. 13.

    Dotis, J., Roilides, E. (2007) Immunopathogenesis of central nervous system fungal infections. Neurol. India 55, 216–220.

    PubMed  Article  PubMed Central  Google Scholar 

  14. 14.

    Eliopoulos, G. M., Moellering, R. C. (1996) Antimicrobial combinations. In: Lorian, V (ed.) Antibiotics in Laboratory Medicine, 4th edn. Williams and Wilkins, Baltimore MD, USA, pp. 330–396.

    Google Scholar 

  15. 15.

    Eltoukhy, N. S., Crank, C. W. (2010) Antifungal distribution into cerebrospinal fluid, vitreous humor, bone, and other difficult sites. Curr. Fungal. Infect. Rep. 4, 111–119.

    Article  Google Scholar 

  16. 16.

    Gallagher, C. G., Ashley, E. S. D., Drew, R. H., Perfect, J. R. (2003) Antifungal pharmacotherapy for invasive mould infections. Expert Opin. Pharm. 4, 147–164.

    CAS  Article  Google Scholar 

  17. 17.

    Garcia-Effron, G., Gomez-Lopez, A., Mellado, E., Monzon, A., Rodriguez-Tudela, J. L., Cuenca-Estrella, M. (2004) In vitro activity of terbinafine against medically important non-dermatophyte species of filamentous fungi. J. Antimicrob. Chemother. 53, 1086–1089.

    CAS  PubMed  Article  Google Scholar 

  18. 18.

    Gomez-Lopez, A., Cuenca-Estrella, M., Mellado, E., Rodriguez-Tudela, J. L. (2003) In vitro evaluation of combination of terbinafine with itraconazole or amphotericin B against Zygomycota. Diagn. Microbiol. Infect. Dis. 45, 199–202.

    CAS  PubMed  Article  Google Scholar 

  19. 19.

    Groll, A. H., Giri, N., Petraitis, V., Petraitiene, R., Candelario, M., Bacher, J. S., Piscitelli, S. C., Walsh, T. J. (2000) Comparative efficacy and distribution of lipid formulations of amphotericin B in experimental Candida albicans infection of the central nervous system. J. Infect. Dis. 182, 274–282.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  20. 20.

    Hosseini-Yeganeh, M., McLachlan, A. J. (2001) Tissue distribution of terbinafine in rats. J. Pharm. Sci. 90, 1817–1828.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  21. 21.

    Hosseini-Yeganeh, M., McLachlan, A. J. (2002) Physiologically based pharmacokinetic model for terbinafine in rats and humans. Antimicrob. Agents. Chemother. 46, 2219–2228.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Imbert, F., Jardin, M., Fernandez, C., Gantier, J. C., Dromer, F., Baron, G., Mentre, F., Van Beijsterveldt, L., Singlas, E., Gimenez, F. (2003) Effect of efflux inhibition on brain uptake of itraconazole in mice infected with Cryptococcus neoformans. DrugMetab. Dispos. 31, 319–325.

    CAS  Google Scholar 

  23. 23.

    Karaarslan, A., Arikan, S., Ozcan, M., Ozcan, K. M. (2004) In vitro activity of terbinafine and itraconazole against Aspergillus species isolated from otomycosis. Mycoses. 47, 284–287.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Kontoyiannis, D. P., Lewis, R. E., May, G. S., Osherov, N., Rinaldi, M. G. (2002) Aspergillusnidulans is frequently resistant to amphotericin B. Mycoses. 45, 406–107.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  25. 25.

    Kornhuber, J., Quack, G., Danysz, W., Jellinger, K., Danielczyk, W., Gsell, W., Riederer, P. (1995) Therapeutic brain concentration of the NMDA receptor antagonist amantadine. Neuropharmacology. 34, 713–721.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Kurita, M., Nishino, S., Ohtomo, K., Rai, M., Shirakawa, F.L., Mashiko, H., Niwa, S., Nakahata, N. (2007) Sodium valproate at therapeutic concentrations changes Ca2+ response accompanied with its weak inhibition of protein kinase C in human astrocytoma cells. Prog. Neuropsychopharmacol. Biol Psychiatry 31, 600–604.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  27. 27.

    Mahmood, I. (1997) Clinical pharmacokinetics and pharmacodynamics of selegiline. An update. Clin Pharmacokinet. 33, 91–102.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Meletiadis, J., te Dorsthorst, D. T. A., Verweij, P. E. (2006) The concentration-dependent nature of in vitro amphotericin B-itraconazole interaction against Aspergillus fumigatus: isobolographic and response surface analysis of complex pharmacodynamic interactions. Int. J. Antimicrob. Agents. 28, 439–149.

    CAS  PubMed  PubMed Central  Google Scholar 

  29. 29.

    Minassian, B., Huczko, E., Washo, T., Bonner, T., Fung-Tome, J. (2003) In vitro activity of ravueon-azole against Zygomycetes, Scedosporium and Fusarium isolates. Clin. Microbiol. Infect. 9, 1250–1252.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Misra, R., Malik, A., Singhal, S. (2011) Comparison of the activities of amphotericin B, itraconazole, and voriconazole against clinical and environmental isolates of Aspergillus species. Indian. J. Pathol Microbiol. 54, 112–116.

    PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Moosa, M. Y., Alangaden, G. J., Manavathu, E., Chandrasekar, P. H. (2002) Resistance to amphotericin B does not emerge during treatment for invasive aspergillosis. J. Antimicrob. Chemother. 49, 209–213.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  32. 32.

    Moreno, A. B., del Pozo, A. M., Borja, M., San Segudo, B. (2003) Activity of the antifungal protein from Aspergillus giganteus against Botrytis cinerea. Phytopathology 93, 1344–1353.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Murthy, J. M. (2007) Fungal infections of the central nervous system: the clinical syndromes. Neurol India 55, 221–225.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  34. 34.

    Nadkarni, T., Goel, A. (2005) Aspergilloma of the brain: an overview. J. Postgrad. Med. 51 Suppl. 1, S37-H.

  35. 35.

    National Committee for Clinical Laboratory Standards. Reference method for broth dilution antifungal susceptibility testing of filamentous fungi; approved standard (2002) NCCLS document M38-A. NCCLS, Wayne, Pennsylvania, USA.

    Google Scholar 

  36. 36.

    Nosanchuk, J. D. (2006) Current status and future of antifungal therapy for systemic mycoses. Recent Pat. Antiinfect. Drug Discov. 1, 75–84.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  37. 37.

    Odds, F. C. (2003) Synergy, antagonism, and what the chequerboard puts between them. J. Anti-microb. Chemother. 52, 1.

    CAS  Article  Google Scholar 

  38. 38.

    Rath, P. M. (1998) Susceptibility of Aspergillus strains from culture collections to amphotericin B and itraconazole. J. Antimicrob. Chemother. 41, 567–570.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Ribes, J. A., Vanhover-Sams, C. L., Baker, D. J. (2000) Zygomycetes in human disease. Clin Microbiol. Rev. 13, 236–301.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Sabatelli, F., Patel, R., Mann, P. A., Mendrick, C. A., Norris, C. C., Hare, R., Loebenberg, D., Black T. A., McNicholas, P. M. (2006) In vitro activities of posaconazole, fluconazole, itraconazole, voriconazole, and amphotericin B against a large collection of clinically important molds and yeasts. Antimicrob. Agents Chemother. 50, 2009–2015.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Schwartz, S., Ruhnke, M., Ribaud, P., Reed, E., Troke, P., Thiel, E. (2007) Poor efficacy of amphotericin B-based therapy in CNS aspergillosis. Mycoses. 50, 196–200.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  42. 42.

    Schwartz, S., Thiel, E. (2009) Cerebral aspergillosis: tissue penetration is the key. Med Mycol. 41 Suppl. 1, S387-393.

  43. 43.

    Scully, E. P., Baden, L. R., Katz, J. T. (2008) Fungal brain infections. Curr Opin Neurol. 21, 347–352.

    PubMed  Article  PubMed Central  Google Scholar 

  44. 44.

    Sharma, R.R. (2010) Fungal infections of the nervous system: current perspective and controversies in management. Int. J. Surg. 8, 591–601.

    Article  Google Scholar 

  45. 45.

    Skiada, A., Vrana, L., Polychronopoulou, H., Prodromou, P., Chantzis, A., Tofas, P., Daikos, G. L. (2009) Disseminated zygomycosis with involvement of the central nervous system. Clin. Microbiol Infect. 15 Suppl. 5, 46–19.

    Article  Google Scholar 

  46. 46.

    Smith, J., Andes, D. R. (2006) Pharmacokinetics of antifungals: Implications for drug selections. Infect. Med. 23, 328–333.

    Google Scholar 

  47. 47.

    Sun, Q. N., Fothergill, A. W., McCarthy, D. I., Rinaldi, M. G., Graybill, J. R. (2002) In vitro activities of posaconazole, itraconazole, voriconazole, amphotericin B, and fluconazole against 37 clinical isolates of zygomycetes. Antimicrob. Agents. Chemother. 46, 1581–1582.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  48. 48.

    Sutton, D. A., Sanche, S. E., Revankar, S. G., Fothergill, A. W., Rinaldi, M. G. (1999) In vitro amphotericin B resistance in clinical isolates of Aspergillus terreus, with a head-to-head comparison to voriconazole. J. Clin. Microbiol. 37, 2343–2345.

    CAS  PubMed  PubMed Central  Google Scholar 

  49. 49.

    van der Linden, J. W., Jansen, R. R., Bresters, D., Visser, C. E., Geerlings, S. E., Kuijper, E. J., Melchers, W. J., Verweij, P. E. (2009) Azole-resistant central nervous system aspergillosis. Clin Infect. Dis. 48, 1111–1113.

    PubMed  Article  PubMed Central  Google Scholar 

  50. 50.

    Vazquez, J. A. (2007) Combination antifungal therapy: the new frontier. Future Microbiol. 2, 115–139.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  51. 51.

    Vyzantiadis, T. A., Kioumi, A., Papadakis, E., Braimi, M., Dermitzakis, E., Tsitouridis, I., Antoniadis, A. (2002) Rhino-cerebral zygomycosis resistant to antimycotic treatment: a case report. Mycoses. 52, 87–90.

    Article  Google Scholar 

  52. 52.

    Yasar, S., Justinova, Z., Lee, S. H., Stefanski, R., Goldberg, S. R., Tanda, G. (2006) Metabolic transformation plays a primary role in the psychostimulant-like discriminative-stimulus effects of selegiline [(R)-(-)-deprenyl]. J. Pharmacol. Exp. Ther 317, 387–394.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

Download references

Acknowledgement

L. G. holds a postdoctoral fellowship from the Hungarian Scientific Research Fund (OTKA PD 83355).

Author information

Affiliations

Authors

Corresponding author

Correspondence to L. Galgóczy.

Rights and permissions

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

Reprints and Permissions

About this article

Cite this article

Galgóczy, L., Tóth, L., Virágh, M. et al. In vitro Interactions of Amantadine Hydrochloride, R-(-)-Deprenyl Hydrochloride and Valproic Acid Sodium Salt with Antifungal Agents Against Filamentous Fungal Species Causing Central Nervous System Infection. BIOLOGIA FUTURA 63, 490–500 (2012). https://doi.org/10.1556/ABiol.63.2012.4.8

Download citation

Keywords

  • Zygomycetes
  • Aspergillus spp.
  • central nervous fungal infection
  • non-antifungal drugs
  • antifungal agents
  • drug interaction