FOSCARNET PENETRATES THE BLOOD-BRAIN-BARRIER - RATIONALE FOR THERAPY OF CYTOMEGALOVIRUS ENCEPHALITIS

Foscarnet (phosphonoformate) is a potent virustatic drug against herpe s-like viruses and is widely used in the therapy of cytomegalovirus in fections in immunosuppressed patients. To obtain data on its penetrati on across the blood-brain barrier, we determined concentrations of fos carnet 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 electrochem ical detection by high-pressure liquid chromatography. Penetration coe fficients were correlated with the integrity of the blood-brain barrie r. After a single infusion of foscarnet, levels in plasma ranged from 297 to 1,775 mug/ml (990 to 5,920 mumol/liter), with a mean of 766 +/- 400 mug/ml. Corresponding levels in cerebrospinal fluid were 57 to 22 5 mug/ml (190 to 750 mumol/liter), with a mean of 131 +/- 52 mug/ml. T he penetration coefficient was 0.05 to 0.72 (mean, 0.23 +/- 0.16). At steady state, mean foscarnet levels in plasma were 464 +/- 219 mug/ml (1,553 mumol/liter) and mean levels in cerebrospinal fluid were 308 +/ - 155 mug/ml (1,023 mumol/liter). The penetration coefficient was 0.66 +/- 0.11. Although penetration coefficients were highly variable afte r a single administration and at steady state, the concentrations of f oscarnet attained in cerebrospinal fluid are sufficient for complete i nhibition of cytomegalovirus replication in vitro. In conclusion, we s how that foscarnet seems to be the drug of choice for the treatment of cytomegalovirus encephalitis, because it penetrates the blood-brain b arrier and is found in the cerebrospinal fluid in virustatic concentra tions. Foscarnet might be considered for additive therapy for human im munodeficiency virus encephalitis in combination with zidovudine or di deoxyinosine.