Valtrex or valacyclovir
A novel nucleoside prodrug-activating enzyme: substrate specificity of biphenyl hydrolase-like protein.

Amidon GL.

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA.

Biphenyl hydrolase-like protein (BPHL, NCBI accession number NP_004323) is a novel human serine hydrolase recently identified as a human valacyclovirase, catalyzing the hydrolytic activation of the antiviral prodrugs valacyclovir and valganciclovir. The substrate specificity of BPHL was investigated with a series of amino acid ester prodrugs of the therapeutic nucleoside analogues: acyclovir, zidovudine, floxuridine, 2-bromo-5,6-dichloro-1-(beta-D-ribofuranosyl) benzimidazole, and gemcitabine. The hydrolysis of typical esterase and aminopeptidase substrates by BPHL was also investigated. The results indicate that the substrate specificity of BPHL is largely determined by the amino acid acyl promoiety, and is less sensitive to the nucleoside parent drugs. For all nucleoside parent drugs, BPHL preferred the hydrophobic amino acids valine, phenylalanine, and proline over the charged amino acids lysine and aspartic acid. The position and monoester or diester form of the prodrug were also important, with BPHL exhibiting higher affinity for the 5'-esters than for the 3'-esters and the 3',5'-diesters irrespective of amino acid type. Further, the presence of the 3'-amino acid ester considerably reduced the hydrolysis rate of the 5'-amino acid ester functionality. BPHL exhibited stereoselectivity with an L/D specificity ratio of 32 for 5'-valyl floxuridine and 1.5 for 5'-phenylalanyl floxuridine. The substrate specificity suggests that the substrate-binding pocket of BPHL has a hydrophobic acyl binding site which can accommodate the positively charged alpha-amino group, while having an alcohol leaving group binding site that can accommodate nucleoside analogues with a relatively generous spatial allowance. In conclusion, BPHL catalyzes the hydrolytic activation of amino acid esters of a broad range of therapeutic nucleoside analogues in addition to valacyclovir and valganciclovir and has considerable potential for utilization as an activation target for design of antiviral and anticancer nucleoside analogue prodrugs.

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

Jacob RJ.

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

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 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 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 therapy decreases the prevalence of EBV in saliva but has little effect on HHV-6 and HHV-7.

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Valtrex or valacyclovir
A randomized clinical trial of valacyclovir in multiple sclerosis.

Sheng D.

Department of Neurology, New York University School of Medicine, NY, NY 10010, USA. jef4 med.nyu.edu

OBJECTIVE: The human Herpesvirus type-6 (HHV-6) has been implicated in multiple sclerosis (MS). Valacyclovir is an antiviral agent with an excellent safety profile. A two-year placebo-controlled, double-blind study was conducted to (1) ascertain if high-dose, prolonged treatment with valacyclovir would be safe and (2) observe if valacyclovir would delay the progression of MS clinically or by magnetic resonance imaging (MRI). DESIGN/METHODS: Fifty-eight patients were stratified as to severity and randomly assigned to receive valacyclovir (3000 mg/day) or placebo for a period of two years. Patients were followed clinically over the two-year period by means of the Expanded Disability Status Scale (EDSS), the Ambulation Index (AI) and brain MRI scans. Patients underwent routine lab studies every three months. Patients continued on the medication for two years unless they had a sustained progression or repeated exacerbations. RESULTS: No patient discontinued the study due to side effects or toxicity. In Relative Ranking of Progression, time to first attack, attack rate, and time to withdrawal there were trends (but not statistically significant) toward drug effect over placebo in the Severe clinical category. MRI evaluation showed no significant drug effect. CONCLUSIONS: Although not statistically significant, positive trends were detected for acyclovir by clinical measures, but not by MRI.

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Valtrex or valacyclovir
A double-blind, randomized study assessing the equivalence of valacyclovir 1000 mg once daily versus 500 mg twice daily in the episodic treatment of recurrent genital herpes. Genival Study Group.

Chastang C.

Service de Dermatologie, Hopital Ambroise Pare, Universite Paris V, Boulogne, France. philippe.saiag apr.ap-hop-paris.fr

Valaciclovir is a prodrug of acyclovir with more favourable bioavailability. Twice daily oral administration of valacyclovir is recommended in patients with genital herpes. A double-blind, randomized, controlled, multicriteria equivalence trial was conducted to determine whether od treatment with valacyclovir 1000 mg is as effective as bd treatment with 500 mg in patients with recurrent genital herpes. A total of 922 immunocompetent outpatients were treated with either regimen for 5 days; treatment was self-initiated at the first symptoms of the next recurrence. The principal outcome measures were the percentage of lesions healed at day 6, time to healing, time to cessation of pain, discomfort or itching, the percentage of abortive episodes and safety. Equivalence was assessed by comparison of 80% confidence limits for each measure; the two regimens were regarded as equivalent if the lower confidence limit was higher than a pre-determined equivalence limit calculated to show a maximum 10% inferiority of valacyclovir 1000 mg od against valaciclovir 500 mg bd. Intention-to-treat analysis showed that the two treatments were equivalent for each outcome measure. Hence, it is concluded that valacyclovir 1000 mg od is as effective as 500 mg bd. as self-initiated therapy in patients with recurrent genital herpes.

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Valtrex or valacyclovir
Structure and specificity of a human valacyclovir activating enzyme: a homology model of BPHL.

Amidon GL.

Department of Pharmaceutical Sciences, College of Pharmacy, The University of Michigan, 428 Church Street, Ann Arbor, Michigan 48109-1065, USA.

Biphenyl hydrolase-like (BPHL) protein is a novel serine hydrolase which has been identified as human valacyclovirase (VACVase), catalyzing the hydrolytic activation of valine ester prodrugs of the antiviral drugs acyclovir and ganciclovir as well as other amino acid ester prodrugs of therapeutic nucleoside analogues. The broad specificity for nucleoside analogues as parent drugs suggests that BPHL may be particularly useful as a molecular target for prodrug activation. In order to develop an initial structural view of the specificity of BPHL, a homology model of BPHL based on the crystal structure of 2-hydroxy-6-oxo-7-methylocta-2,4-dienoate hydrolase was developed using the Molecular Operating Environment package (Chemical Computing Group, Montreal, Quebec), evaluated for its stereochemical quality and identification of free cysteines, and used in a molecular docking study. The BPHL model has residues S122, H255, and D227 comprising the putative catalytic triad in proximity and potential charge-charge interaction sites, M52 or D123 for the alpha-amino group. The model also suggested that the structural preference of BPHL for hydrophobic amino acyl promoieties and its limited activity for the secondary alcohol substrates may be attributed to the hydrophobic acyl-binding site formed by residues I158, G161, I162, and L229, and the spatial constraint around the catalytic site by a loop on one side, the active serine and histidine on the other side, and L53 and L179 on top. In addition, the broad specificity for nucleoside analogues may be due to the relatively less constrained nucleoside-binding site opening toward the entrance of the substrate-binding pocket. The homology model of BPHL provides a basis for further investigation of the catalytic and active site residues, can account for the observed structure activity profile of BPHL, and will be useful in the design of nucleoside prodrugs.

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