Valtrex References

1: J Infect Dis. 2005 Jul 1;192(1):156-61. Epub 2005 May 27.

Recurrent antiviral-resistant genital herpes in an immunocompetent patient.

Kriesel JD, Spruance SL, Prichard M, Parker JN, Kern ER.

Department of Medicine, University of Utah, Salt Lake City, Utah, USA.

Herpes simplex virus type 2 (HSV-2) resistance to antiviral drugs has been described primarily in immunocompromised patients. We report an apparently immunocompetent, human immunodeficiency virus-negative male patient who has experienced repeated HSV-2 genital outbreaks despite receiving antiviral prophylaxis with several different drugs. Several of the HSV-2 genital isolates from this patient have been confirmed as resistant to acyclovir and penciclovir. Antiviral resistance occurred in the setting of long-term prednisone treatment and intermittent acyclovir prophylaxis at suboptimal doses and persisted despite the cessation of oral steroid treatment. The patient's genital herpes outbreaks were not controlled by high-dose prophylaxis with acyclovir, valacyclovir - Valtrex, and famciclovir. Cessation of antiviral prophylaxis resulted in reversion of this patient's HSV-2 isolates to acyclovir and penciclovir sensitivity, although resistant virus reappeared when antiviral prophylaxis was resumed. Transmission of a sensitive HSV-2 strain from this patient to a female sex partner was observed. These observations confirm previous reports that resistance to acyclovir may develop during prophylactic therapy in an otherwise well, immunocompetent patient. These findings support the conclusion that both drug-sensitive and drug-resistant HSV-2 strains established latency in this patient and that both strains are capable of frequent reactivation.

2: Am J Med. 2005 Jun;118(6):689-90.

Treatment of plantar warts with oral valacyclovir - Valtrex.

Tandeter H, Tandeter ER.

3: J Pharmacol Exp Ther. 2005 May 18;

Delineation of HPEPT1 Meditated Uptake and Transport of Substrates with Varying Transporter Affinities Utilizing Stably Transfected HPEPT1/MDCK Clones and Caco-2 Cells.

Bhardwaj RK, Herrera-Ruiz D, Sinko PJ, Gudmundsson OS, Knipp G.

Rutgers, the State University of New Jersey.

In the present investigation the uptake and transport kinetics of valacyclovir - Valtrex (VACV), 5-aminolevulinic acid (5-ALA) and benzylpenicillin (BENZ) were studied in stably transfected MDCK/hPepT1-V5/His clonal cell lines expressing varying levels of epitope-tagged hPepT1 protein (low, medium, and high expression) and in Caco-2 cells to delineate hPepT1 mediated transport kinetics. These compounds were selected due to the fact that they are known PepT1 substrates, yet also have affinity for other transporters. Caco-2 cells, traditionally used for studying peptide-based drug transport, were included for comparison purposes. The time, pH, sodium and concentration dependency of cellular uptake and permeability were measured using mock, clonal hPepT1-MDCK and Caco-2 cells. A pH dependent effect was observed in the hPepT1 expressing clones and Caco-2 cells, with an increase of 1.96, 1.84 and 2.05 fold for VACV, 5-ALA and BENZ uptake, respectively, at pH 6 vs. 7.4 in the high expressing hPepT1 cells. BENZ uptake was significantly decreased in Caco-2 and MDCK cells in Na(+)-depleted buffer, whereas VACV uptake only decreased in Caco-2 cells. Concentration dependent uptake studies in the mock-corrected hPepT1-MDCK and Caco-2 cells demonstrated hPepT1 affinity ranking of VACV>5-ALA>BENZ. The apical-to-basal Papp values of VACV, 5-ALA and BENZ in mock-corrected hPepT1-MDCK cells showed solely hPepT1 mediated transport in contrast to Caco-2 cells. Lower Km values and higher Papp in Caco-2 cells, as compared to mock-corrected hPepT1-MDCK cells suggested the multi-transporters involvement in Caco-2 cells. Thus hPepT1-MDCK cells corrected for endogenous transporter expression may be more appropriate model for screening compounds for their affinity to hPepT1.

4: J Clin Microbiol. 2005 May;43(5):2173-80.

Effect of prophylactic valacyclovir - Valtrex on the presence of human herpesvirus DNA in saliva of healthy individuals after dental treatment.

Miller CS, Avdiushko SA, Kryscio RJ, Danaher RJ, Jacob RJ.

Department of Microbiology, Immunology & MOlecular Genetics, University of Kentucky College of Medicine and College of Dentistry, Lexington, KY, USA.

Human herpesviruses (HHVs) are ubiquitous pathogens that intermittently reactivate from latency. Transmission is believed to be facilitated by their frequent appearance in saliva. This study sought to understand the factors that influence the appearance of these viruses in saliva by examining the prevalence, pattern, and quantity of all eight HHVs in saliva of immunocompetent adults with a history of recurrent oral herpes simplex virus (HSV) infections following dental treatment and antiviral therapy. valacyclovir - Valtrex or matched placebo was given (2 g twice on the day of treatment and 1 g twice the following day) to 125 patients in a randomized, double-blind controlled trial. Saliva, collected on the day of dental treatment and 3 and 7 days later, was analyzed using real-time quantitative PCR. At all visits, HHVs coinfected saliva. Over the course of the week, the DNAs of HHV-6 and HHV-7 were detected significantly more often (97% to 99% of patients) than Epstein-Barr virus (EBV; 64.8%), HSV-1 (13.0%), HHV-8 (3.2%), cytomegalovirus (2.4%), HSV-2 (0%), and varicella-zoster virus (0%), irrespective of drug treatment (P < 0.002). Mean genome copy numbers were highest for HSV-1 and HHV-6. Dental treatment did not influence asymptomatic viral shedding patterns. However, valacyclovir - Valtrex treatment resulted in significantly fewer patients shedding EBV at both postoperative visits compared with placebo (P < 0.008). These results suggest that HHVs are simultaneously present in the saliva of healthy adults at levels that could facilitate transmission, and valacyclovir - Valtrex therapy decreases the prevalence of EBV in saliva but has little effect on HHV-6 and HHV-7.

5: Arch Virol. 2005 Apr 14;

Observations on recovery from and recurrence of HSV-2 infections in adult mice that were rescued from lethal vaginal infection by antiviral therapy.

Parr EL, Holliday EM, Collard MW, Parr MB.

Southern Illinois University, School of Medicine, Carbondale, Illinois, U.S.A..

An adult mouse model for studies of latency and recurrence after vaginal HSV-2 infection is not available at present, largely because the infection kills most mice within 14 days. We describe here an antiviral therapy that rescues most vaginally infected mice from death. Vaginally infected mice were nearly all rescued by combined treatment with one dose of monoclonal anti-HSV glycoprotein D 3 days after infection plus valacyclovir - Valtrex in the drinking water on days 3, 4, 5, 7, 9, 11, 13, and 15 after infection. At 60 days after infection, PCR measurements revealed that most rescued mice had viral DNA in their lumbosacral dorsal root ganglia, lumbosacral spinal cords, and paracervical autonomic ganglia, consistent with the possibility that latent infections were established. At this time, immunolabeling revealed CD45+ lymphoid cells in these neural tissues in rescued mice but not in normal control mice. In vivo depletion of T lymphocytes with monoclonal antibodies caused a recurrence of herpes illness symptoms earlier and in a larger proportion of rescued mice than was observed in non-depleted rescued mice. Interestingly, many rescued mice (46/114) spontaneously developed a syndrome of typical herpes illness symptoms that began with ruffled fur on a mouse that previously had sleek fur and progressed to arched backs, feeble gait, hindlimb paralysis, and death or euthanasia, or in some cases to recovery to health. This high incidence of apparent spontaneous recurrence of HSV-2 infection in rescued mice suggests that it may be possible, with some refinement of the procedure, to obtain an effective adult mouse model for studies of therapeutic vaccination to inhibit or prevent HSV-2 recurrence after genital tract infection.

6: Antimicrob Agents Chemother. 2005 Apr;49(4):1580-3.

Early selection of a new UL97 mutant with a severe defect of ganciclovir phosphorylation after valaciclovir prophylaxis and short-term ganciclovir therapy in a renal transplant recipient.

Hantz S, Michel D, Fillet AM, Guigonis V, Champier G, Mazeron MC, Bensman A, Denis F, Mertens T, Dehee A, Alain S.

Department of Bacteriology-Virology-Hygiene, EA 3175, Teaching Hospital Dupuytren, Limoges cedex, France.

We describe the emergence of a new ganciclovir resistance mutation in the UL97 gene of human cytomegalovirus, deletion of codon 601, after valaciclovir and short-term ganciclovir therapy following kidney transplantation. Its role in ganciclovir resistance was supported by decreased ganciclovir phosphorylation in a recombinant vaccinia virus system.

7: Lakartidningen. 2005 Mar 7-13;102(10):744-5.

Treatment of facial paresis--evidence-based recommendations

Hultcrantz M.

Karolinska Universitetssjukhuset Solna. malou.hultcrantz@karolinska.se

8: Antimicrob Agents Chemother. 2005 Mar;49(3):1081-6.

Susceptibilities of several clinical varicella-zoster virus (VZV) isolates and drug-resistant VZV strains to bicyclic furano pyrimidine nucleosides.

Andrei G, Sienaert R, McGuigan C, Clercq ED, Balzarini J, Snoeck R.

Rega Institute for Medical Research, Minderbroedersstraat 10, B-3000 Leuven, Belgium.

Varicella-zoster virus (VZV) is responsible for primary infections as well as reactivations after latency in the dorsal root ganglia. The treatment of such infections is mandatory for immunocompromised patients and highly recommended for elderly patients with herpes zoster infections (also called zona or shingles). The treatment of choice is presently based on four molecules, acyclovir (ACV), valaciclovir, famciclovir, and (in Europe) brivudine (BVDU). We present here our data on the antiviral activity of a new class of potent and selective anti-VZV compounds, bicylic pyrimidine nucleoside analogues (BCNAs), against a broad variety of clinical isolates and different drug-resistant virus strains. The results show that the BCNAs are far more potent inhibitors than ACV and BVDU against clinical VZV isolates as well as the VZV reference strains Oka and YS. The BCNAs were not active against ACV- and BVDU-resistant VZV strains bearing mutations in the viral thymidine kinase gene but kept their inhibitory potential against virus strains with mutations in the VZV DNA polymerase gene. Mutant virus strains selected in the presence of the BCNAs were solely cross-resistant to drugs, such as ACV and BVDU, that depend for their antiviral action on metabolic activation by the viral thymidine kinase.

9: Mol Pharm. 2005 Mar-Apr;2(2):157-67.

Amino acid ester prodrugs of the anticancer agent gemcitabine: synthesis, bioconversion, metabolic bioevasion, and hPEPT1-mediated transport.

Song X, Lorenzi PL, Landowski CP, Vig BS, Hilfinger JM, Amidon GL.

Department of Pharmaceutical Sciences, College of Pharmacy, University of Michigan, Ann Arbor, MI 48109, USA.

Gemcitabine, a clinically effective nucleoside anticancer agent, is a polar drug with low membrane permeability and is administered intravenously. Further, extensive degradation of gemcitabine by cytidine deaminase to an inactive metabolite in the liver affects its activity adversely. Thus, strategies that provide both enhanced transport and high metabolic bioevasion would potentially lead to oral alternatives that may be clinically useful. The objective of this study was to evaluate whether amino acid ester prodrugs of gemcitabine would (a) facilitate transport across intestinal membranes or across cells that express hPEPT1 and (b) provide resistance to deamination by cytidine deaminase. 3'-Monoester, 5'-monoester, and 3',5'-diester prodrugs of gemcitabine utilizing aliphatic (L-valine, D-valine, and L-isoleucine) and aromatic (L-phenylalanine and D-phenylalanine) amino acids as promoieties were synthesized and evaluated for their affinity and direct hPEPT1-mediated transport in HeLa/hPEPT1 cells. All prodrugs exhibited enhanced affinity (IC(50): 0.14-0.16 mM) for the transporter. However, only the 5'-L-valyl and 5'-L-isoleucyl monoester prodrugs exhibited (a) increased uptake (11.25- and 5.64-fold, respectively) in HeLa/hPEPT1 cells compared to HeLa cells and (b) chemical stability in buffers, that were comparable to valacyclovir - Valtrex, a commercially marketed oral amino acid ester prodrug. The widely disparate enzymatic bioconversion profiles of the 5'-L-valyl and 5'-L-isoleucyl prodrugs in Caco-2 cell homogenates along with their significant resistance to deamination by cytidine deaminase suggest that the disposition of gemcitabine following oral administration would be controlled by the rate of bioconversion following transport across the intestinal epithelial membrane. The combined results also suggest that it may be possible to modulate these characteristics by the choice of the amino acid promoiety.

10: Transplantation. 2005 Feb 15;79(3):317-24.

valacyclovir - Valtrex for cytomegalovirus prophylaxis reduces the risk of acute renal allograft rejection.

Reischig T, Jindra P, Mares J, Cechura M, Svecova M, Hes O, Opatrny K Jr, Treska V.

Department of Internal Medicine I, Charles University Hospital, Pilsen, Czech Republic.

BACKGROUND: Both oral ganciclovir and valacyclovir - Valtrex decrease the incidence of cytomegalovirus (CMV) disease after renal transplantation. Moreover, valacyclovir - Valtrex has been shown to reduce the risk of acute rejection. Our study was designed to compare the efficacy and safety of oral ganciclovir and valacyclovir - Valtrex in the prophylaxis of CMV disease after renal transplantation. METHODS: A total of 83 patients were prospectively randomized to 3-month treatment with oral ganciclovir (3 g/day, n=36, GAN) or oral valacyclovir - Valtrex (8 g/day, n=35, VAL). A control group (DEF, n=12) was managed by deferred therapy. RESULTS: No differences were found in demography, immunosuppression, or donor/recipient CMV serology. The 12-month incidence of CMV disease was 67% in the DEF group compared with 6% in the GAN group and 3% in the VAL group (P<0.001 GAN or VAL vs. DEF; P=0.575 GAN vs. VAL). The biopsy-confirmed acute rejection rate at 12 months was 12% in the VAL group compared with 34% in the GAN group (P=0.030) and 58% in the DEF group (P<0.001). The difference between the GAN and DEF groups was not significant (P=0.087). The average CMV-associated costs per patient were $3,072, $2,906, and $4,906 in the GAN, VAL, and DEF groups, respectively. CONCLUSIONS: valacyclovir - Valtrex and oral ganciclovir are equally effective in the prevention of CMV disease after renal transplantation. Both regimens are cost-effective. valacyclovir - Valtrex is associated with a significantly reduced risk of acute rejection compared with both ganciclovir prophylaxis and deferred therapy.