Potential Treatment of Herpes Simplex Virus Encephalitis by Brain‐Specific Delivery of Trifluorothymidine Using a Dihydropyridine ⇆ Pyridinium Salt Type Redox Delivery System

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Abstract
A newly described, drug-carrier delivery system in which a lipophilic derivative is enzymatically converted to a hydrophilic compound was used to treat experimental herpes simplex virus (HSV) encephalitis. Because trifluorothymidine (TFT) does not cross the blood brain barrier, the lipophilic dihydropyridine derivative 3 ′hyphen;(N-methyl- 1, 4-dihydronicotinoyl)hyphen;5hyphen;'pivaloyltrifluorothymidine (DHTFT) was synthesized and characterized by HPLC. After intravenous administration of 20 mg/kg of DHTFT to rats, the quaternary, intermediate compound 3'-N-methyl-1,4-nicotinoyltrifluorothymidine was measured at levels of 7–8 m̈/g brain at 1 hour and 13.5 ± 0.8 m̈g/g brain at 4 hours. This compound had antiviral activity equivalent to that of TFT against HSV-1 in a plaque reduction assay (ID 50 = 0.5–1.0 m̈g/ml), either directly or by conversion to TFT. Although survival was not prolonged in a rat model of HSV encephalitis, a statistically significant reduction in titer of HSV/g brain was achieved with daily intravenous treatment with DHTFT. TFT was not detected in brains of rats at 1 and 4 hours after intravenous DHTFT, but a low level was observed at 18 hours, 0.3 ± 0.05 pg/g brain. These data suggest that the lipophilic compound DHTFT or a lipophilic metabolite crossed the blood brain barrier and was converted to a quaternary.