Skip to main content
PMC home page
Antimicrobial Agents and Chemotherapy logoLink to Antimicrobial Agents and Chemotherapy
. 1993 May;37(5):1010–1014. doi: 10.1128/aac.37.5.1010

Foscarnet penetrates the blood-brain barrier: rationale for therapy of cytomegalovirus encephalitis.

U R Hengge 1, N H Brockmeyer 1, R Malessa 1, U Ravens 1, M Goos 1
PMCID: PMC187882  PMID: 8390807

Abstract

Foscarnet (phosphonoformate) is a potent virustatic drug against herpes-like viruses and is widely used in the therapy of cytomegalovirus infections in immunosuppressed patients. To obtain data on its penetration across the blood-brain barrier, we determined concentrations of foscarnet in cerebrospinal fluid and in plasma specimens from 26 patients with human immunodeficiency virus (stages 2 to 6 by Walter Reed Army Institute of Research classification) after a single infusion of 90 mg of foscarnet per kg of body weight and at steady state by electrochemical detection by high-pressure liquid chromatography. Penetration coefficients were correlated with the integrity of the blood-brain barrier. After a single infusion of foscarnet, levels in plasma ranged from 297 to 1,775 micrograms/ml (990 to 5,920 mumol/liter), with a mean of 766 +/- 400 micrograms/ml. Corresponding levels in cerebrospinal fluid were 57 to 225 micrograms/ml (190 to 750 mumol/liter), with a mean of 131 +/- 52 micrograms/ml. The penetration coefficient was 0.05 to 0.72 (mean, 0.23 +/- 0.16). At steady state, mean foscarnet levels in plasma were 464 +/- 219 micrograms/ml (1,553 mumol/liter) and mean levels in cerebrospinal fluid were 308 +/- 155 micrograms/ml (1,023 mumol/liter). The penetration coefficient was 0.66 +/- 0.11. Although penetration coefficients were highly variable after a single administration and at steady state, the concentrations of foscarnet attained in cerebrospinal fluid are sufficient for complete inhibition of cytomegalovirus replication in vitro. In conclusion, we show that foscarnet seems to be the drug of choice for the treatment of cytomegalovirus encephalitis, because it penetrates the blood-brain barrier and is found in the cerebrospinal fluid in virustatic concentrations. Foscarnet might be considered for additive therapy for human immunodeficiency virus encephalitis in combination with zidovudine or dideoxyinosine.

Full text

PDF
1012

Selected References

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

  1. Behar R., Wiley C., McCutchan J. A. Cytomegalovirus polyradiculoneuropathy in acquired immune deficiency syndrome. Neurology. 1987 Apr;37(4):557–561. doi: 10.1212/wnl.37.4.557. [DOI] [PubMed] [Google Scholar]
  2. Chrisp P., Clissold S. P. Foscarnet. A review of its antiviral activity, pharmacokinetic properties and therapeutic use in immunocompromised patients with cytomegalovirus retinitis. Drugs. 1991 Jan;41(1):104–129. doi: 10.2165/00003495-199141010-00009. [DOI] [PubMed] [Google Scholar]
  3. Davis C. L., Springmeyer S., Gmerek B. J. Central nervous system side effects of ganciclovir. N Engl J Med. 1990 Mar 29;322(13):933–934. doi: 10.1056/NEJM199003293221315. [DOI] [PubMed] [Google Scholar]
  4. Delpech B., Lichtblau E. Etude quantitative des immunoglobulines G et de l'albumine du liquide cephalo rachidien. Clin Chim Acta. 1972 Mar;37:15–23. doi: 10.1016/0009-8981(72)90410-x. [DOI] [PubMed] [Google Scholar]
  5. Eidelberg D., Sotrel A., Vogel H., Walker P., Kleefield J., Crumpacker C. S., 3rd Progressive polyradiculopathy in acquired immune deficiency syndrome. Neurology. 1986 Jul;36(7):912–916. doi: 10.1212/wnl.36.7.912. [DOI] [PubMed] [Google Scholar]
  6. Fanning M. M., Read S. E., Benson M., Vas S., Rachlis A., Kozousek V., Mortimer C., Harvey P., Schwartz C., Chew E. Foscarnet therapy of cytomegalovirus retinitis in AIDS. J Acquir Immune Defic Syndr. 1990;3(5):472–479. [PubMed] [Google Scholar]
  7. Fletcher C., Sawchuk R., Chinnock B., de Miranda P., Balfour H. H., Jr Human pharmacokinetics of the antiviral drug DHPG. Clin Pharmacol Ther. 1986 Sep;40(3):281–286. doi: 10.1038/clpt.1986.177. [DOI] [PubMed] [Google Scholar]
  8. Gaub J., Pedersen C., Poulsen A. G., Mathiesen L. R., Ulrich K., Lindhardt B. O., Faber V., Gerstoft J., Hofmann B., Lernestedt J. O. The effect of foscarnet (phosphonoformate) on human immunodeficiency virus isolation, T-cell subsets and lymphocyte function in AIDS patients. AIDS. 1987 May;1(1):27–33. [PubMed] [Google Scholar]
  9. Graveleau P., Perol R., Chapman A. Regression of cauda equina syndrome in AIDS patient being treated with ganciclovir. Lancet. 1989 Aug 26;2(8661):511–512. doi: 10.1016/s0140-6736(89)92129-6. [DOI] [PubMed] [Google Scholar]
  10. Jacobsen M. A., van der Horst C., Causey D. M., Dehlinger M., Hafner R., Mills J. In vivo additive antiretroviral effect of combined zidovudine and foscarnet therapy for human immunodeficiency virus infection (ACTG Protocol 053). J Infect Dis. 1991 Jun;163(6):1219–1222. doi: 10.1093/infdis/163.6.1219. [DOI] [PubMed] [Google Scholar]
  11. Koeppen A. H., Lansing L. S., Peng S. K., Smith R. S. Central nervous system vasculitis in cytomegalovirus infection. J Neurol Sci. 1981 Sep;51(3):395–410. doi: 10.1016/0022-510x(81)90117-9. [DOI] [PubMed] [Google Scholar]
  12. Koshida R., Vrang L., Gilljam G., Harmenberg J., Oberg B., Wahren B. Inhibition of human immunodeficiency virus in vitro by combinations of 3'-azido-3'-deoxythymidine and foscarnet. Antimicrob Agents Chemother. 1989 May;33(5):778–780. doi: 10.1128/aac.33.5.778. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Laskin O. L., Cederberg D. M., Mills J., Eron L. J., Mildvan D., Spector S. A. Ganciclovir for the treatment and suppression of serious infections caused by cytomegalovirus. Am J Med. 1987 Aug;83(2):201–207. doi: 10.1016/0002-9343(87)90685-1. [DOI] [PubMed] [Google Scholar]
  14. Masdeu J. C., Small C. B., Weiss L., Elkin C. M., Llena J., Mesa-Tejada R. Multifocal cytomegalovirus encephalitis in AIDS. Ann Neurol. 1988 Jan;23(1):97–99. doi: 10.1002/ana.410230118. [DOI] [PubMed] [Google Scholar]
  15. McKenzie R., Travis W. D., Dolan S. A., Pittaluga S., Feuerstein I. M., Shelhamer J., Yarchoan R., Masur H. The causes of death in patients with human immunodeficiency virus infection: a clinical and pathologic study with emphasis on the role of pulmonary diseases. Medicine (Baltimore) 1991 Sep;70(5):326–343. doi: 10.1097/00005792-199109000-00004. [DOI] [PubMed] [Google Scholar]
  16. Morgello S., Cho E. S., Nielsen S., Devinsky O., Petito C. K. Cytomegalovirus encephalitis in patients with acquired immunodeficiency syndrome: an autopsy study of 30 cases and a review of the literature. Hum Pathol. 1987 Mar;18(3):289–297. doi: 10.1016/s0046-8177(87)80012-6. [DOI] [PubMed] [Google Scholar]
  17. Myerson D., Hackman R. C., Nelson J. A., Ward D. C., McDougall J. K. Widespread presence of histologically occult cytomegalovirus. Hum Pathol. 1984 May;15(5):430–439. doi: 10.1016/s0046-8177(84)80076-3. [DOI] [PubMed] [Google Scholar]
  18. Pantoni L., Inzitari D., Colao M. G., De Mayo E., Marini P., Mazzota F. Cytomegalovirus encephalitis in a non-immunocompromised patient: CSF diagnosis by in situ hybridization cells. Acta Neurol Scand. 1991 Jul;84(1):56–58. doi: 10.1111/j.1600-0404.1991.tb04903.x. [DOI] [PubMed] [Google Scholar]
  19. Pettersson K. J., Nordgren T., Westerlund D. Determination of phosphonoformate (foscarnet) in biological fluids by ion-pair reversed-phase liquid chromatography. J Chromatogr. 1989 Mar 24;488(2):447–455. doi: 10.1016/s0378-4347(00)82968-0. [DOI] [PubMed] [Google Scholar]
  20. Post M. J., Hensley G. T., Moskowitz L. B., Fischl M. Cytomegalic inclusion virus encephalitis in patients with AIDS: CT, clinical, and pathologic correlation. AJR Am J Roentgenol. 1986 Jun;146(6):1229–1234. doi: 10.2214/ajr.146.6.1229. [DOI] [PubMed] [Google Scholar]
  21. Sjövall J., Bergdahl S., Movin G., Ogenstad S., Saarimäki M. Pharmacokinetics of foscarnet and distribution to cerebrospinal fluid after intravenous infusion in patients with human immunodeficiency virus infection. Antimicrob Agents Chemother. 1989 Jul;33(7):1023–1031. doi: 10.1128/aac.33.7.1023. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Taburet A. M., Katlama C., Blanshard C., Zorza G., Gazzard D., Dohin E., Gazzard B. G., Frostegard C., Singlas E. Pharmacokinetics of foscarnet after twice-daily administrations for treatment of cytomegalovirus disease in AIDS patients. Antimicrob Agents Chemother. 1992 Sep;36(9):1821–1824. doi: 10.1128/aac.36.9.1821. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Vinters H. V., Kwok M. K., Ho H. W., Anders K. H., Tomiyasu U., Wolfson W. L., Robert F. Cytomegalovirus in the nervous system of patients with the acquired immune deficiency syndrome. Brain. 1989 Feb;112(Pt 1):245–268. doi: 10.1093/brain/112.1.245. [DOI] [PubMed] [Google Scholar]
  24. Wahren B., Oberg B. Reversible inhibition of cytomegalovirus replication by phosphonoformate. Intervirology. 1980;14(1):7–15. doi: 10.1159/000149156. [DOI] [PubMed] [Google Scholar]
  25. Wilkes M. S., Fortin A. H., Felix J. C., Godwin T. A., Thompson W. G. Value of necropsy in acquired immunodeficiency syndrome. Lancet. 1988 Jul 9;2(8602):85–88. doi: 10.1016/s0140-6736(88)90014-1. [DOI] [PubMed] [Google Scholar]

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

RESOURCES