Acta Biologica Hungarica

, Volume 63, Issue 4, pp 490–500 | Cite as

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

  • L. GalgóczyEmail author
  • Liliána Tóth
  • M. Virágh
  • T. Papp
  • Cs. Vágvölgyi


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.


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


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


  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.PubMedCrossRefPubMedCentralGoogle Scholar
  2. 2.
    Afeltra, J., Verweij, P. E. (2003) Antifungal activity of nonantifungal drugs. Eur. J. Clin. Microbiol. Infect. Dis. 22, 397–107.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle Scholar
  8. 8.
    Cohen, R. A., Fisher, M. (1989) Amantadine treatment of fatigue associated with multiple sclerosis. Arch. Neurol. 46, 676–680.PubMedCrossRefPubMedCentralGoogle Scholar
  9. 9.
    Crosby, N., Deane, K. H., Clarke, C. E. (2003) Amantadine in Parkinson’s disease. Cochrane Database Syst. Rev. 1, CD003468.Google Scholar
  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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar
  13. 13.
    Dotis, J., Roilides, E. (2007) Immunopathogenesis of central nervous system fungal infections. Neurol. India 55, 216–220.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Hosseini-Yeganeh, M., McLachlan, A. J. (2001) Tissue distribution of terbinafine in rats. J. Pharm. Sci. 90, 1817–1828.PubMedCrossRefPubMedCentralGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.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.PubMedPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar
  27. 27.
    Mahmood, I. (1997) Clinical pharmacokinetics and pharmacodynamics of selegiline. An update. Clin Pharmacokinet. 33, 91–102.PubMedCrossRefPubMedCentralGoogle 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.PubMedPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle 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.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Murthy, J. M. (2007) Fungal infections of the central nervous system: the clinical syndromes. Neurol India 55, 221–225.PubMedCrossRefPubMedCentralGoogle Scholar
  34. 34.
    Nadkarni, T., Goel, A. (2005) Aspergilloma of the brain: an overview. J. Postgrad. Med. 51 Suppl. 1, S37-H.Google Scholar
  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.PubMedCrossRefPubMedCentralGoogle Scholar
  37. 37.
    Odds, F. C. (2003) Synergy, antagonism, and what the chequerboard puts between them. J. Anti-microb. Chemother. 52, 1.CrossRefGoogle 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.PubMedCrossRefGoogle Scholar
  39. 39.
    Ribes, J. A., Vanhover-Sams, C. L., Baker, D. J. (2000) Zygomycetes in human disease. Clin Microbiol. Rev. 13, 236–301.PubMedPubMedCentralCrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    Schwartz, S., Thiel, E. (2009) Cerebral aspergillosis: tissue penetration is the key. Med Mycol. 41 Suppl. 1, S387-393.Google Scholar
  43. 43.
    Scully, E. P., Baden, L. R., Katz, J. T. (2008) Fungal brain infections. Curr Opin Neurol. 21, 347–352.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle 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.CrossRefGoogle 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.PubMedPubMedCentralCrossRefGoogle 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.PubMedPubMedCentralGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Vazquez, J. A. (2007) Combination antifungal therapy: the new frontier. Future Microbiol. 2, 115–139.PubMedCrossRefPubMedCentralGoogle 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.CrossRefGoogle 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.PubMedCrossRefPubMedCentralGoogle Scholar

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© Akadémiai Kiadó, Budapest 2012

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Authors and Affiliations

  • L. Galgóczy
    • 1
    Email author
  • Liliána Tóth
    • 1
  • M. Virágh
    • 1
  • T. Papp
    • 1
  • Cs. Vágvölgyi
    • 1
  1. 1.Department of Microbiology, Faculty of Science and InformaticsUniversity of SzegedSzegedHungary

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