Valtrex or valacyclovir
Syntheses, chemical and enzymatic stability of new poly(ethylene glycol)-acyclovir prodrugs.

Boccu E.

Department of Pharmaceutical Sciences, University of Trieste, Italy. zacchign univ.trieste.it

Two known antiherpetic agents, acyclovir and valaciclovir, were coupled with activated poly(ethylene glycol). In vitro drug release studies demonstrated the conjugates to be stable in buffer solutions at pH 7.4 and 5.5, while only PEG-valacyclovir2 was stable in a buffer solution at pH 1.2. The ability of the macromolecular conjugate to release the free drug was also evaluated in plasma, in which the most stable prodrug also proved to be PEG-valacyclovir2. The derivatives are degraded in the presence of proteolytic enzyme. The rate of hydrolysis was monitored by HPLC-analysis.

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Valtrex or valacyclovir
European best practice guidelines for renal transplantation. Section IV: Long-term management of the transplant recipient. IV.6.1. Cancer risk after renal transplantation. Post-transplant lymphoproliferative disease (PTLD): prevention and treatment.

EBPG Expert Group on Renal Transplantation.

GUIDELINES: A. In the first year after organ transplantation, recipients are at the greatest risk of developing lymphoproliferative diseases (PTLDs), which are induced most often by Epstein-Barr virus (EBV) infection, and patients should therefore be screened prior to or at the time of transplantation for EBV antibodies. B. In the rare cases (<5%) where the recipient is EBV seronegative, he or she has a 95% likelihood of receiving an organ from an EBV-seropositive donor, which translates into a high risk of primary EBV infection with seroconversion soon after transplantation. In such cases, the recipient should receive a prophylactic antiviral treatment with acyclovir, valacyclovir or ganciclovir, starting at the time of transplant and lasting for at least 3 months. The specific recommendations given for CMV prophylaxis could be applicable in this situation. C. The treatment of PTLD should be based on accurate pathology with extensive cell markers and phenotyping. The treatment modalities are as follows. Reduction of basal immunosuppression in all cases (either maintain only steroids, or decrease by at least 50% the anti-calcineurin drugs and stop other immunosuppressive drugs). In the case of EBV-positive B-cell lymphoma, antiviral treatment with acyclovir, valacyclovir or ganciclovir may be initiated for at least 1 month or according to the blood level of EBV replication when available. In the case of rare lymphomas from the mucosal-associated lymphoid tissue (MALT) with positive Helicobacter pylori, full eradication of H. pylori should be carried out with a validated protocol. Subsequent H. pylori prophylaxis should be implemented to avoid relapse. In the case of CD20-positive lymphomas, treatment with rituximab, a chimeric monoclonal antibody directed against CD20, should be carried out with one i.v. injection per week for 4 weeks. In the case of diffuse lymphomas or improper response to previous treatment, CHOP chemotherapy should be used alone or in combination with rituximab. The CHOP regimen is cyclophosphamide, doxorubicine, vincristine and prednisone. Complete cessation of immunosuppression with or without graft nephrectomy should also be considered.

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Valtrex or valacyclovir
Synthesis of analogs of L-valacyclovir and determination of their substrate activity for the oligopeptide transporter in Caco-2 cells.

Borchardt RT.

Department of Medicinal Chemistry, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100, Copenhagen, Denmark. gerda.friedrichsen leo-pharma.com

L-Valacyclovir, a prodrug of acyclovir, is a substrate for the peptide transporter (PepT1) in the intestinal mucosa, which accounts for its higher than expected oral bioavailability. The substrate activity of L-valacyclovir for PepT1 is surprising, particularly when one considers that the molecule has the structural features of a nucleoside rather than a peptide. In an attempt to better understand the structure-transport relationships (STR) for the interactions of L-valacyclovir with PepT1, analogs of this molecule with structural changes in the guanine moiety were synthesized and their substrate activity for PepT1 in Caco-2 cell monolayers was determined. The analogs synthesized include those that had the guanine moiety of L-valacyclovir substituted with purine, benzimidazole, and 7-azaindole. All three analogs (purine, benzimidazole, and 7-azaindole) exhibited affinity for PepT1 in binding studies, but only the purine analog (as the L-valine ester) showed PepT1-associated transcellular transport across Caco-2 cell monolayers. The benzimidazole and 7-azaindole analogs (as their L-valine esters) were rapidly metabolized by esterase when applied to the apical surface of Caco-2 cells, which probably explains their low penetration as the intact prodrugs via PepT1.

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Valtrex or valacyclovir
Once-daily valacyclovir hydrochloride for suppression of recurrent genital herpes.

Miller JM.

State University of New York, Stony Brook 11794, USA. david.baker sunysb.edu

OBJECTIVE: To document the frequency of genital herpes recurrences in men and women with histories of recurrent genital herpes during 1 year of continuous, suppressive therapy with valacyclovir hydrochloride (HCl). METHODS: In an open-label clinical trial conducted at 11 centers, 127 subjects (46 women and 81 men) with histories of recurrent genital herpes (at least 6 recurrences per year) were treated with valacyclovir HCl (500 mg once daily), and their clinical status was followed up for 1 year. Genital herpes recurrences were documented in diaries, and quarterly clinic visits were made for evaluating lesion recurrences and drug safety. In cases of recurrence, subjects self-treated with valacyclovir HCl 500 mg twice daily for 5 days, then resumed once-daily treatment. RESULTS: After the first 3 months of suppressive therapy, 81% of subjects were free of recurrence. Recurrence-free rates remained undiminished during the second, third, and fourth quarters (84%, 84%, and 91%, respectively) and were similar for men and women. Thirty of 46 women (65%) and 56 of 81 men (69%) remained recurrence free during the study and therapy was well tolerated. Adverse events were mild, infrequent, and not considered related to the study drug. CONCLUSION: Valacyclovir HCl was highly effective and well tolerated as continuous suppressive therapy in men and women with recurrent genital herpes. Potential benefits of the once-daily regimen of valacyclovir HCl include improved patient compliance.

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Valtrex or valacyclovir
Valacyclovir versus acyclovir for HSV prophylaxisin neutropenic patients.

Marra F.

Faculty of Pharmaceutical Sciences, University of British Columbia, Vancouver, British Columbia, Canada.

BACKGROUND: It is common practice to administer acyclovir as prophylaxis to patients with hematologic malignancies during neutropenia; however, effective therapy requires frequent dosing, which is difficult in this setting. Valacyclovir has greater oral bioavailability and requires less frequent dosing. OBJECTIVE: To evaluate the efficacy and safety of valacyclovir compared with acyclovir. METHODS: Patients who had been treated with chemotherapy or stem-cell transplantation were randomized to receive acyclovir 400 mg orally 3 times daily (n = 51), valacyclovir 500 mg orally twice daily (n = 48), or valacyclovir 250 mg orally twice daily (n = 52) during neutropenia. RESULTS: Clinical success, defined as the absence of an active herpes simplex virus (HSV) lesion or asymptomatic viral shedding, was similar between the 3 groups (acyclovir 96%, valacyclovir 500 mg 95%, valacyclovir 250 mg 100%). The overall rates of adverse events were similar in the 3 groups. CONCLUSIONS: Prophylactic treatment with valacyclovir is an effective and safe alternative to acyclovir for the prevention of HSV reactivation in patients with hematologic malignancies.

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