Premium
Potential Treatment of Herpes Simplex Virus Encephalitis by Brain‐Specific Delivery of Trifluorothymidine Using a Dihydropyridine ⇆ Pyridinium Salt Type Redox Delivery System
Author(s) -
Rand Kenneth H.,
Bodor Nicholas,
Ei Koussi Alaaeldin A.,
Raad Issam,
Miyake Akio,
Houck Herbert,
Gildersteeve Nancy
Publication year - 1986
Publication title -
journal of medical virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.782
H-Index - 121
eISSN - 1096-9071
pISSN - 0146-6615
DOI - 10.1002/jmv.1890200102
Subject(s) - herpes simplex virus , encephalitis , metabolite , virus , pyridinium , blood–brain barrier , chemistry , virology , dihydropyridine , aciclovir , titer , medicine , pharmacology , stereochemistry , herpesviridae , biochemistry , viral disease , medicinal chemistry , central nervous system , organic chemistry , calcium
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.