Valtrex or valacyclovir
Interactions of a nonpeptidic drug, valacyclovir, with the human intestinal peptide transporter (hPEPT1) expressed in a mammalian cell line.

Sinko PJ.

Department of Pharmaceutics, College of Pharmacy, Rutgers University, Piscataway, New Jersey, USA.

The results of previous work performed in our laboratory using an in situ perfusion technique in rats and rabbit apical brush border membrane vesicles have suggested that the intestinal uptake of valacyclovir (VACV) appears to be mediated by multiple membrane transporters. Using these techniques, it is difficult to characterize the transport kinetics of VACV with each individual transporter in the presence of multiple known or unknown transporters. The purpose of this study was to characterize the interaction of VACV and the human intestinal peptide transporter using Chinese hamster ovary (CHO) cells that overexpress the human intestinal peptide transporter (hPEPT1) gene. VACV uptake was significantly greater in CHO cells transfected with hPEPT1 than in cells transfected with only the vector, pcDNA3. The optimum pH for VACV uptake was determined to occur at pH 7.5. Proton cotransport was not observed in hPEPT1/CHO cells, consistent with previously observed results in tissues and Caco-2 cells. VACV uptake was concentration dependent and saturable with a Michaelis-Menten constant and maximum velocity of 1.64 +/- 0.06 mM and 23.34 +/- 0.36 nmol/mg protein/5 min, respectively. A very similar Km value was obtained in hPEPT1/CHO cells and in rat and rabbit tissues and Caco-2 cells, suggesting that hPEPT1 dominates the intestinal transport properties of VACV in vitro. VACV uptake was markedly inhibited by various dipeptides and beta-lactam antibiotics, and Ki values of 12.8 +/- 2.7 and 9.1 +/- 1.2 mM were obtained for Gly-Sar and cefadroxil at pH 7.5, respectively. The present results demonstrate that VACV is a substrate for the human intestinal peptide transporter in hPEPT1/CHO cells and that although transport is pH dependent, proton cotransport is not apparent. Also, the results demonstrate that the hPEPT1/CHO cell system has use in investigating the transport kinetics of drugs with the human intestinal peptide transporter hPEPT1; however, the extrapolation of these transport properties to the in vivo situation requires further investigation.

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Valtrex or valacyclovir
Antiviral therapy for herpes zoster: randomized, controlled clinical trial of valacyclovir and famciclovir therapy in immunocompetent patients 50 years and older.

Crooks RJ.

Department of Dermatology, University of Texas Medical Branch, Galveston, TX 77555, USA.

OBJECTIVE: To compare the efficacy and safety of valacyclovir hydrochloride and famciclovir for the treatment of herpes zoster. DESIGN: A double-blind, randomized, controlled, multicenter clinical trial in which patients received 7 days of treatment and were followed up for 24 weeks. SETTINGS: Patients reported directly to specialist centers or were referred from primary care centers. PATIENTS: There were 597 otherwise healthy immunocompetent outpatients, aged 50 years and older, who presented within 72 hours of onset of zoster rash. INTERVENTIONS: Treatment with valacyclovir hydrochloride (1 g 3 times daily) or famciclovir (500 mg 3 times daily) for 7 days. MAIN OUTCOME MEASURES: Resolution of zoster-associated pain and postherpetic neuralgia, rash healing, and treatment safety. RESULTS: Intent-to-treat analysis did not detect statistically significant differences for valacyclovir vs famciclovir on resolution of zoster-associated pain (hazard ratio, 1. 02; 95% confidence interval, 0.84-1.23; P =.84). Furthermore, no differences were evident between treatments on rash healing rates and on a range of analyses of postherpetic neuralgia. Safety profiles for valacyclovir and famciclovir were similar, with headache and nausea being the more common adverse events. CONCLUSIONS: Valacyclovir treatment is comparable to famciclovir treatment in speeding the resolution of zoster-associated pain and postherpetic neuralgia. Current wholesale prices indicate that valacyclovir is the more cost-effective treatment for herpes zoster ($83.90 vs $140.70 per course).

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Valtrex or valacyclovir
Effect of ionization on the variable uptake of valacyclovir via the human intestinal peptide transporter (hPepT1) in CHO cells.

Sinko P.

Department of Pharmaceutics, College of Pharmacy, Rutgers-The State University of New Jersey, Piscataway, NJ 08854, USA.

Carrier-mediated transport of valacyclovir (vacv), the L-valyl ester prodrug of acyclovir (acv), via the human peptide transporter (hPepT1) has been shown in Xenopus laevis oocytes and in cell lines such as Chinese hamster ovary (CHO) and Caco-2 transfected with the hPepT1 gene. However, significant differences in vacv uptake were observed in those models as extracellular pH varied. The purpose of this work was to characterize the interactions of various ionic species of vacv with the peptide transporter by overexpressing the transporter gene, hPepT1, in CHO cells. Based on the pK(a) values of vacv, it was determined that vacv exists as four different ionic species (di-cationic, cationic, neutral and anionic) with a predominance of cationic and neutral species at physiologically relevant pH conditions. Vacv uptake was shown to increase with increasing pH of the extracellular medium from 5.5 to 7.2. The uptake value was maximal at around pH 7.2 and did not vary for studies done at higher pH. Vacv uptake was concentration dependent and saturable at all pH conditions (5.5, 6.2, 6.8, 7.5 and 7.9) with apparent Michaelis-Menten constants, mean (S.D.), of 7.42(0.32), 6.64(1.20), 5.38(0.88), 2.69(0.23) and 2.23(0.33) mM, respectively. The current results demonstrate that the estimated affinities of the cationic and the neutral species of vacv with hPepT1 are significantly different (7.4 versus 1.2 mM, respectively). Given the axial and radial (microclimate) pH gradients known to exist in the intestine, the greater than six-fold difference in affinity constants suggests that intestinal pH fluctuations may significantly impact upon the variability of vacv uptake. Copyright 2000 John Wiley & Sons, Ltd.

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Valtrex or valacyclovir
Valacyclovir for the prevention of recurrent herpes simplex virus eye disease after excimer laser photokeratectomy.

Asbell PA.

Department of Ophthalmology, Mount Sinai School of Medicine, New York, USA.

PURPOSE: A variety of factors have been reported as inducing the reactivation of latent herpes simplex virus (HSV), among them stress, trauma, and UV radiation. Excimer laser photorefractive keratectomy (PRK) is a surgical procedure utilizing a 193 nm ultraviolet light to alter the curvature of the cornea and hence correct vision. Reactivation of ocular herpes simplex keratitis following such excimer laser PRK has been reported. All published cases of HSV reactivation following excimer laser treatment in humans are reviewed. The present study evaluates whether stress, trauma of the corneal de-epithelialization prior to the laser, or the excimer laser treatment itself to the stromal bed induces this ocular reactivation of the latent HSV, and whether a systemic antiviral agent, valacyclovir, would prevent such laser PRK-induced reactivation of the HSV. METHODS: Forty-three normal 1.5- to 2.5-kg New Zealand white rabbits were infected on the surface of the cornea with HSV-1, strain RE. The animals were monitored until resolution, and then all animals were divided into 5 treatment groups: (1) de-epithelialization only, intraperitoneal (i.p.) saline for 14 days; (2) de-epithelialization plus laser, i.p. saline for 14 days; (3) de-epithelialization plus laser, valacyclovir 50 mg/kg per day i.p. for 14 days; (4) de-epithelialization plus laser, valacyclovir 100 mg/kg per day i.p. for 14 days; (5) de-epithelialization plus laser, valacyclovir 150 mg/kg per day i.p. for 14 days. Animals were evaluated in a masked fashion by clinical examination biweekly and viral cultures biweekly through day 28. RESULTS: The reactivation rates were as follows: group 1, 0%; group 2, 67%; group 3, 50%; group 4, 17%; and group 5, 0%. Viral titers were negative in animals that had no reactivation but persistently positive in those that had reactivation (day 6 through day 28). CONCLUSIONS: Excimer laser (193 nm) treatment can trigger reactivation of ocular herpes disease (67%) and viral shedding in the latently infected rabbit. De-epithelialization alone is not sufficient to cause reactivation or viral shedding. Prophylaxis with intraperitoneal valacyclovir decreases the recurrence rate in a dose-response fashion. At 150 mg/kg per day, there are no recurrences. The presence of persistent viral shedding in reactivated animals may correlate with cases of late HSV recurrence reported in humans undergoing excimer treatment. The data suggest that humans undergoing excimer laser procedures for correction of refractive errors or treatment of corneal scars with a history of herpetic keratitis are at increased risk for reactivation. Such patients, however, may appropriately be considered for prophylactic systemic antiviral medication at the time of the laser procedure in order to decrease the possibility of recurrence.

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Valtrex or valacyclovir
[Neurologic toxicity caused by zelitrex (valaciclovir) in 3 patients with renal failure. Is overdose associated with improvement of product bioavailability improvement?]

[Article in French]

Peyriere H, Branger B, Bengler C, Vecina F, Pinzani V, Hillaire-Buys D, Blayac JP.

Centre regional de pharmacovigilance, hopital Saint-Charles, CHU, 300, rue Auguste-Broussonnet, 34295 Montpellier, France. je;eme[euroere voila.fr

INTRODUCTION: We report three cases of neurotoxicity in patients with renal failure, treated with Zelitrex (valacyclovir). EXEGESIS: The patients are two women and a man, aged 76 +/- 4.6 years, who presented acute mental confusion during a treatment with valacyclovir. In two cases, the patients previously had altered renal function and were under peritoneal dialysis. In the last case, the patient had simultaneous neurotoxicity and acute renal failure. After the discontinuation of the drug, the outcome was favourable in all cases. CONCLUSION: Our cases focus attention on the possible neurotoxicity of valacyclovir, which is an amino acid ester prodrug of acyclovir, rapidly and almost completely hydrolysed to acyclovir prior to systemic exposure. The bioavailability of valacyclovir is 54% compared to approximately 20% for oral acyclovir and may account for unexpected overdoses, which may lead to serious neurological toxicity.

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