Kenneth H. Rand1,2, Nicholas Bodor2, Alaaeldin A. Ei Koussi2, Issam Raad3, Akio Miyake4,2, Herbert Houck2, Nancy Gildersteeve2
1University of Florida
2VA Medical Center
3Department of Medicine, College of Medicine, University of Florida and the Gainesville Veterans Administration Hospital, Gainesville, Florida
4Takeda Pharmaceutical Company, Limited
Tóm tắt
AbstractA 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.
