Famvir
Hepatitis B virus mutants associated with 3TC and famciclovir administration are replication defective.

Melegari M, Scaglioni PP, Wands JR.

Molecular Hepatology Laboratory, Massachusetts General Hospital Cancer Center, and Harvard Medical School, Charlestown 02129, USA.

Hepatitis B virus (HBV) variant strains may develop during therapy for chronic infection with the nucleoside analog 2',3'-dideoxy-3'-thiacytidine (3TC). HBV mutants result from isoleucine (I) or valine (V) substitutions in the methionine (M) of the YMDD motif in the viral reverse-transcriptase catalytic domain. In addition, other mutations in the reverse-transcriptase "B domain" involving either a phenylalanine (F)-to-leucine (L) at amino acid 501 (F501L) or an L-to-M substitution at amino acid 515 (L515M) have been observed during 3TC and Famciclovir therapy as well. To determine the biologic consequences of these mutations on viral replication, variant viral genomes were constructed and transiently transfected into hepatocellular carcinoma (HCC) and HEK 293 human embryo kidney-derived cell lines. In transiently transfected HCC cells, the viruses bearing the YI/VDD or F501L mutations had greatly impaired replication as compared to wild-type virus, whereas the virus carrying the L515M substitution showed the least defect. Double mutants with the L515M substitution showed intermediate defect between the YI/VDD or F501L and the L515M single-mutant strains. In contrast, when transfected into HEK 293 cells, the viruses bearing the YI/VDD or L515M mutation replicated as wild-type. However, under conditions of deoxynucleotide depletion produced by hydroxyurea treatment of HEK 293 cells, all mutants but not the wild-type virus exhibited a reduced replication phenotype similar to that observed in HCC cells. In both HCC and HEK 293 cells, the mutant viruses carrying the F501L substitution showed a decreased pregenomic RNA encapsidation level, suggesting that the defect in HBV DNA synthesis occurs at the RNA packaging level. These findings show that 3TC and Famciclovir selected mutations alter the properties of the HBV reverse transcriptase, resulting in impaired viral replication within the cell.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9462667&dopt=Abstract famciclovir Famvir



Famvir
Use of famciclovir to prevent HBV reactivation in HBsAg-positive recipients after allogeneic bone marrow transplantation.

Lau GK, Liang R, Wu PC, Lee CK, Lim WL, Au WY.

Department of Medicine, Queen Mary Hospital, Hong Kong. gkklau hkstar.com

BACKGROUND/AIMS: Reactivation of chronic hepatitis B viral infection causes significant morbidity and mortality after bone marrow transplantation. Recently, nucleoside analogues, such as famciclovir, were found to have a direct suppressive effect on hepatitis B virus replication in both in vitro and in vivo studies. We have studied the effect of famciclovir on the incidence of hepatitis B virus reactivation and hepatitis after allogeneic bone marrow transplantation. METHODS: Eight hepatitis B surface antigen (HBsAg)-positive patients who received allogeneic bone marrow transplantation were given oral famciclovir 250 mg three times daily, starting at least 1 week prior to bone marrow transplantation and continuing for 24 weeks after transplantation. Clinical and serological outcomes in these patients were compared with 24 HBsAg-positive recipients of allogeneic bone marrow transplantation who did not receive famciclovir (historical controls). RESULTS: After bone marrow transplantation, there were five patients with hepatitis B virus reactivation among those who received famciclovir 250 mg three times daily. Four of these patients responded to increased dosages of 500 mg three times daily and did not develop hepatitis. The remaining patient suffered from hepatitis related to hepatitis B virus reactivation. Compared to historical controls, there were fewer cases of hepatitis due to hepatitis B virus reactivation and veno-occlusive disease. The median follow-up was 701.6 days (range: 50-2346 days) with ten deaths (three due to hepatic failure related to HBV reactivation) in those who did not receive famciclovir and one death (due to hepatic failure related to graft-versus-host disease) in those who received famciclovir. CONCLUSIONS: Use of famciclovir significantly reduced hepatitis due to hepatitis B virus reactivation in HBsAg-positive recipients after allogeneic bone marrow transplantation.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9551671&dopt=Abstract famciclovir Famvir



Famvir
Famciclovir and valaciclovir differ in the prevention of herpes simplex virus type 1 latency in mice: a quantitative study.

Thackray AM, Field HJ.

Centre for Veterinary Science, Cambridge University Veterinary School, United Kingdom.

Famciclovir (FCV) and valaciclovir (VACV) have previously been shown to be potent inhibitors of herpes simplex virus type 1 (HSV-1) in a murine cutaneous model. In the present study, mice were inoculated in the skin of the left ear pinna with herpes simplex virus (HSV) type 1. Antiviral therapy was started on different days postinoculation (p.i.), terminating at the end of day 10 p.i. The compounds were administered twice daily by oral gavage at 50 mg/kg of body weight/dose. Mice were sampled on day 5 p.i., during the acute phase of the infection, and the titers of infectious virus in the target tissues (ear, brain stem, and trigeminal ganglia) were determined. At 2 to 3 months p.i., the ipsilateral and contralateral trigeminal and cervical dorsal root ganglia were explanted, and four different methods were used to detect latent HSV. The methods were (i) conventional explant culture for 5 days followed by homogenization, (ii) long-term culture (up to 73 days) of whole ganglia, followed by homogenization, (iii) dissociation by enzymatic disaggregation and an infectious center assay, and (iv) in situ hybridization to detect latency-associated transcripts (LATs). The conventional explant culture method was the least sensitive method, while in situ staining for LAT was the most sensitive, and all mice, including those treated from early times with FCV, were shown to be latently infected. Significantly less latent virus was detected by all four methods, however, in ganglia obtained from mice that had been treated with FCV in comparison with the amount detected in ganglia from mice that had been treated with VACV. However, in no case was latency completely eliminated.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9660982&dopt=Abstract famciclovir Famvir



Famvir
Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.

Kim DK, Lee N, Kim YW, Chang K, Kim JS, Im GJ, Choi WS, Jung I, Kim TS, Hwang YY, Min DS, Um KA, Cho YB, Kim KH.

Life Science Research Center, SK Chemicals, 600 Jungja-Dong, Changan-Ku, Suwon-Si, Kyungki-Do 440-745, Korea.

A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) of 88, >200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O (138.8 mg/mL, 20 degrees C).

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9719596&dopt=Abstract famciclovir Famvir



Famvir
Persistence of infectious herpes simplex virus type 2 in the nervous system in mice after antiviral chemotherapy.

Thackray AM, Field HJ.

Centre for Veterinary Science, Cambridge University Veterinary School, Cambridge CB3 0ES, United Kingdom.

Young adult mice were inoculated with herpes simplex virus type 2 (HSV-2) in the ear pinna. A relatively severe infection resulted, and 45% of the mice died by 11 days postinfection. Therapy at 1 mg/ml by means of the drinking water with either famciclovir for periods of 5 or 10 days or valaciclovir for 5, 10, 15, or 20 days decreased clinical signs and reduced mortality to 15% or less. Throughout a period of 27 days, mice were tested daily for the presence of infectious virus in the ear pinna, brain stem, and ipsilateral trigeminal ganglia. Virus was cleared from these tissues in surviving, untreated animals by 12 days postinfection, and no infectious virus was detected subsequently in any tissue. Furthermore, no infectious virus was detected after day 9 in mice that had been treated with famciclovir. In mice that had received valaciclovir therapy, however, infectious virus was repeatedly detected in the trigeminal ganglia and brain stem tissue samples up to 7 days after treatment was discontinued. To date, no specific mechanism to account for these results has been discovered; however, possible mechanisms for the persistence of potentially infectious virus in neural tissue of treated mice are discussed.

Online source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10602729&dopt=Abstract famciclovir Famvir