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PubMed2001

[Valaciclovir in the treatment of initial infection by genital herpes virus: comparative study].

BASIS: To know the therapeutic efficiency in the genital herpes of two drugs: acyclovir and valaciclovir. METHODS: There were included in the study 142 patients with diagnostic of clinic first episode by genital herpes in two equal groups of 71 patients each one. The distribution in both groups was random to receive one of the following treatment standards: acyclovir 200 mg by verbal each 5 hours, during 7 days; valaciclovir: 500 mg by verbal each 12 hours during 7 days being valued objective and subjective response to the treatment. RESULTS: The prevailing symptom was the pain (45% and 46.4%), followed by the warmth or burning sensation. The most frequent lesions in both groups were blisters (39.4% and 46.4%). The analysis response to the treatment in relationship to the symptoms as well as in the lesions it could be appreciated that there are not significant differences in the patients treated in both groups (p = 0.3). The adverse effect communicated by the discussed patients were scarce and similar in both groups. CONCLUSIONS: Both drugs are suitable for the treatment of the genital herpes. The advantage observed with the valaciclovir is the dosing comfort and the facility of completing the treatment.

Acyclovir↗
PubMed1999

Rapid determination of valaciclovir and acyclovir in human biological fluids by high-performance liquid chromatography using isocratic elution.

A rapid high-performance liquid chromatographic assay with isocratic elution is developed for the simultaneous quantification of valaciclovir (VACV) prodrug and its active converted compound, acyclovir (ACV), in biological fluids of treated patients. For serum, the samples are deproteinized with perchloric acid in presence of 1-methylguanosine as the internal standard (IS). For urine and dialysis liquid, the samples are diluted with a mobile phase containing the IS, then filtered. VACV, ACV and the IS are separated on a SymmetryShield RP-8 column with acetonitrile-ammonium phosphate buffer as the mobile phase and detected at 254 nm. The chromatographic time is about 12 min. The relative standard deviations (RSD) of VACV and ACV standards are between 0.5 and 3.5%. Most endogenous nucleosides and their metabolites, psychotropic drugs and drugs of abuse are shown not to interfere with this technique. The method has been applied to study the pharmacokinetics of VACV and ACV in serum, dialysis liquid and urine of renal failure patients on continuous ambulatory peritoneal dialysis (CAPD) under oral treatment of VACV.

Acyclovir↗
PubMed2003

Health-related quality of life predicts survival, cytomegalovirus disease, and study retention in clinical trial participants with advanced HIV disease.

We tested whether health related quality of life (HRQOL) predicts mortality, development of active cytomegalovirus (CMV) disease, and study retention. We studied 957 patients with CD4 counts <100 cells/mm(3) in AIDS Clinical Trials Group Protocol 204, a randomized, double-blind trial comparing three prophylactic regimens against CMV end-organ disease. The MOS-HIV, a brief HRQOL questionnaire, generated physical health summary (PHS) and mental health summary (MHS) scores. We used Cox proportional hazards to predict events by baseline HRQOL, adjusted for treatment, demographics, and CD4. Each point increase in baseline PHS decreased the risk of death by 4%, CMV by 2%, and dropout by 2%. Each point increase in baseline MHS decreased the risk of death by 4% and study dropout by 1%. In conclusion, self-rated physical and mental health demonstrated predictive validity for survival, CMV end-organ disease, and retention in advanced HIV patients. The results show the clinical importance of HRQOL and may facilitate interpretation by clinicians.

Acute Disease↗
PubMed2003

Analysis of numbers of repeated units in R2 region among varicella-zoster virus strains.

BACKGROUND: A variable region, R2, on the varicella-zoster virus (VZV) genome contains a repeated 42-bp unit. OBJECTIVE: The purpose of this study is the derivation of significance from tandem reiteration structure in the R2 region. METHODS: Fifty-two specimens were collected from 52 patients with herpes zoster in Osaka and Tokyo, Japan. After treatment of the specimens to release viral DNA, the samples were amplified directly by polymerase chain reaction. In addition, 14 samples were collected from 7 of these zoster patients after valaciclovir or aciclovir therapy. RESULTS: Analyses of the 52 specimens revealed that the number of repeats ranged from 4 to 13. Interestingly, the numbers of repeats among various VZV strains showed a normal distribution pattern, so that 6-9 repeats were found to be predominant in both Osaka (85%) and Tokyo (72%). The pre- and post-treatment strains taken from the same individuals showed the same numbers of repeats (7-9 in 6 cases and 11 in one). CONCLUSION: Our results suggest that the 6-9 repetitions of the 42-bp unit, with presumed stability, may offer these virus strains an advantage in virulence to human skin.

Acyclovir↗
PubMed2001

CMV disease in CMV-mismatched renal transplant recipients with prophylactic low dose valaciclovir.

BACKGROUND: Valaciclovir (VACV) 2 g q.i.d. for 3 months after kidney transplantation has been shown, (Lowance et al., NEJM 1999; 340: 1462-70), to reduce CMV disease from 45 to 16% and rejection from 52 to 26% in CMV-negative (D+R-) recipients. Neurotoxic side effects, however, were frequent, and 5% of the patients experienced hallucinations. We hypothesised that a lower dosage of VACV would prevent CMV disease with fewer CNS side effects. METHODS: Since September 1998 all CMV-mismatched renal transplant recipients received VACV 1 g t.i.d. for 3 months posttransplantation (PT). The incidence of CMV disease, rejection and neurotoxic side effects during 6 months PT was studied retrospectively in, up to now, 25 patients. RESULTS: 24% (6/25) of the patients developed CMV disease. The mean time for onset of symptoms was 145 days (92-191). Five of the patients had mild-moderate symptoms and recovered after ganciclovir therapy for 3 weeks. One patient was diagnosed with a CMV-associated retinitis on day 191 PT. The rate of biopsy-confirmed acute graft rejection was 32% (8/25). 20% (5/25) of the patients had a serum creatinine of >200 micromol/l after 6 months, including one patient on hemodialysis. CNS adverse effects were not observed. None out of nine patients with basiliximab induction and VACV developed CMV disease. One patient with basiliximab that did not receive VACV, developed a symptomatic CMV-infection. CONCLUSIONS: The incidence of CMV disease was lower than in historical controls at our centre, and the time to onset of symptoms was prolonged. Compared to the 8 g VACV/day study, CMV disease and graft rejection was more frequent, but no neurotoxic side effects were observed. A combination with basiliximab induction and VACV 3 g/day shows promising results, but randomised studies are needed for confirmation.

Acyclovir↗
PubMedDate not supplied

Antiviral agents in women's health: pharmacotherapeutics of treating influenza and herpes.

This article updates the practitioner on the pharmacology of antiviral agents. The mechanism of action of the six different classifications of antiviral agents is described. Because influenza and herpes are the viral infections that are most frequently treated in clinical practice, the pharmacotherapeutics of common antiviral agents for these infections are described. This includes pharmacokinetics, adverse effects, preparations, and dosages. Other recommendations related to prescribing and client education surrounding each of the pharmaceutical agents is reviewed.

2-Aminopurine↗
PubMedDate not supplied

In vivo ocular pharmacokinetics of acyclovir dipeptide ester prodrugs by microdialysis in rabbits.

In vivo corneal absorption of the dipeptide prodrugs of acyclovir (ACV) was evaluated using microdialysis in rabbits. A corneal well was placed on the cornea of the anesthetized New Zealand White rabbits with implanted linear probes into the aqueous humor. Two hundred microliters of a 1% solution of L-valine-ACV (VACV), glycine-valine-ACV (GVACV), valine-valine-ACV (VVACV), and valine-tyrosine-ACV (VYACV) was placed in the corneal well and was allowed to diffuse for a period of 2 h, following which the drug solution was aspirated and well removed. Samples were collected every 20 min throughout the infusion and postinfusion phases and were analyzed by HPLC to obtain the aqueous humor concentrations. Absorption rate constants of all the compounds were found to be lower than the elimination rate constants. GVACV exhibited highest absorption rate (ka) compared with other prodrugs, but all the prodrugs showed similar terminal elimination rate (lambda(z)). The time of maximum absorption (Tmax) of ACV after administration of VACV and the dipeptide prodrugs did not vary significantly (p < 0.05). GVACV exhibited the highest concentration (Cmax) and area under curve (AUC) upon absorption (p < 0.05) compared to VACV, VVACV, and VYACV. Dipeptide prodrugs of ACV were absorbed through the cornea at similar rates but to varying extents. The dipeptide prodrug GVACV owing to its enhanced absorption of ACV seems to be a promising candidate for the treatment of ocular HSV infections.

Absorption↗
PubMed1998

Cellular uptake mechanism of amino acid ester prodrugs in Caco-2/hPEPT1 cells overexpressing a human peptide transporter.

PURPOSE: This study characterized the cellular uptake mechanism and hydrolysis of the amino acid ester prodrugs of nucleoside antiviral drugs in the transiently transfected Caco-2 cells overexpressing a human intestinal peptide transporter, hPEPT1 (Caco-2/hPEPT1 cells). METHODS: Amino acid ester prodrugs of acyclovir and AZT were synthesized and their apical membrane permeability and hydrolysis were evaluated in Caco-2/hPEPT1 cells. The cellular uptake mechanism of prodrugs was investigated through the competitive inhibition study in Caco-2/hPEPT1 cells. RESULTS: L-Valyl ester of acyclovir (L-Val-ACV) was approximately ten fold more permeable across the apical membrane than acyclovir and four times more permeable than D-valyl ester of acyclovir (D-Val-ACV). Correspondingly, L-valyl ester of AZT (L- Val-AZT) exhibited three fold higher cellular uptake than AZT. Therefore, amino acid ester prodrugs significantly increased the cellular uptake of the parent drugs and exhibited the D,L-stereoselectivity. Furthermore, prodrugs were rapidly hydrolyzed to the parent drugs by the intracellular hydrolysis, following the apical membrane transport. In the inhibition studies, cephalexin and small dipeptides strongly inhibited the cellular uptake of L-Val-ACV while L-valine had no effect, indicating that the peptide transporter is primarily responsible for the apical membrane transport of L-Val-ACV. In addition, the cellular uptake of L-Val-ACV was five times higher in Caco-2/hPEPT1 cells than the uptake in the untransfected Caco-2 cells, implying the cellular uptake of L-Val-ACV was related to the enhancement of the peptide transport activity in Caco-2/hPEPT1 cells. CONCLUSIONS: Caco-2/hPEPT1 system is an efficient in vitro model for the uptake study of peptidyl derivatives. Amino acid ester prodrugs significantly improved the cellular uptake of the parent drugs via peptide transport mechanism and were rapidly converted to the active parent drugs by the intracellular hydrolysis.

Acyclovir↗
PubMed2002

Mechanism of corneal permeation of L-valyl ester of acyclovir: targeting the oligopeptide transporter on the rabbit cornea.

PURPOSE: To delineate mechanisms associated with the corneal transport of a L-valine prodrug of an antiviral agent, acyclovir. METHOD: The permeability and enzymatic hydrolysis of L-Val-ACV were evaluated using freshly excised rabbit cornea. Transport mechanism across rabbit cornea was investigated through a competitive inhibition study of L-Val-ACV with other substrates of human peptide transporter (hPepT1). RESULTS: L-Valyl ester of Acyclovir (L-Val-ACV) was approximately threefold more permeable across the intact rabbit cornea than acyclovir (ACV). Dipeptides, beta-lactam antibiotics, and angiotensin converting enzyme (ACE) inhibitors, strongly inhibited the transport of L-Val-ACV indicating that a carrier mediated transport system specific for peptides is primarily responsible for the corneal permeation of L-Val-ACV. L-Val-ACV transport was found to be saturable (Km = 2.26 +/- 0.34 mM, Jmax = 1.087 +/- 0.05 nmoles cm(-2) min(-1)), energy and pH dependent. CONCLUSIONS Functional evidence of an oligopeptide transport system present on the rabbit cornea has been established. The peptide transporter on the corneal epithelium may be targeted to improve the ocular bioavailability of poorly absorbed drugs.

Acyclovir↗
PubMed2004

Clostridium difficile colitis associated with valaciclovir.

OBJECTIVE: To report a case of Clostridium difficile colitis associated with valaciclovir treatment. CASE SUMMARY: A 73-year-old man with lumbar herpes-zoster started valaciclovir 1 g tid. After three days he began vomiting and developed diarrhea, three to four stools per day. Symptoms worsened over the following days and he was admitted. Valaciclovir was stopped and fluid and electrolyte replacement was started. He continued 6 days later with diarrhea of 7 to 13 stools per day and a stool test for diagnosis of C. difficile infection was performed with a positive result. The patient received oral metronidazole (500 mg/t.i.d. for 10 days) and rapid improvement and eventual resolution of his diarrhea was observed after 3 days of therapy. DISCUSSION: Although no conclusive reports of this reaction exist, we think this is a case of C difficile colitis that appeared three days after valaciclovir was initiated. Colitis improved with metronidazole. Other causes of diarrhea were excluded, such as diabetes mellitus, renal failure, intestinal surgery and intestinal obstruction. Infection was confirmed by a positive test for C. difficile. The application of Naranjo's algorithm asserts the reaction as 'probable'. CONCLUSIONS: Valaciclovir-associated C. difficile colitis, although rare, can have severe consequences for the patient's health. It should be included as a possible adverse effect of valaciclovir treatment by health professionals.

Acyclovir↗
PubMed2004

Medication error due to ambiguous labelling of a commercial product.

Medication errors may involve prescribing, dispensing, preparation and administration of drugs. We report a case in which an administration error occurred due to ambiguous labelling of a commercial drug. Tablets were packed in sets of two tablets per blister with the print on the blister 'Zelitrex 500', making the amount of drug per tablet unclear. A short survey among nurses and pharmacy technicians showed that the majority interpreted the strength of the tablets incorrectly. This case shows that, despite regulations for controlling and accepting labelling before marketing, ambiguous labelling may occur and can lead to medication errors.

Acyclovir↗
PubMed1993

Pharmacokinetics of the acyclovir pro-drug valaciclovir after escalating single- and multiple-dose administration to normal volunteers.

The pharmacokinetics and safety of the L-valyl ester pro-drug of acyclovir, valaciclovir (256U87), were investigated in two phase I, placebo-controlled trials in normal volunteers. These included a single-dose study with doses from 100 to 1000 mg (single cohort) and a multiple-dose investigation with doses from 250 to 2000 mg (five separate cohorts). In each cohort, eight subjects received valaciclovir and four subjects received placebo. Pharmacokinetic findings for valaciclovir and acyclovir were consistent in the two studies. Valaciclovir was rapidly and extensively converted to acyclovir, resulting in significantly greater acyclovir bioavailability (approximately threefold to fivefold) compared with that historically observed with high-dose (800 mg) oral acyclovir. At the higher valaciclovir doses, acyclovir maximum concentration and daily area under the concentration-time curve approximated those obtained with intravenous acyclovir. The favorable safety profile and enhanced acyclovir bioavailability from valaciclovir administration has prompted additional clinical evaluations for zoster and herpes simplex virus treatment, as well as cytomegalovirus suppression in immunocompromised patients.

Acyclovir↗
PubMed2000

Varicella-zoster infection after allogeneic bone marrow transplantation: incidence, risk factors and prevention with low-dose aciclovir and ganciclovir.

We examined the incidence of herpes varicella-zoster virus (VZV) infection in 151 patients undergoing allogeneic BMT between August 1990 and September 1997 and who survived at least 3 months. Median follow-up was 17 (range 3.3-80.7) months. Herpes simplex virus antibody positive (HSV+) patients received aciclovir 1200 mg p.o. daily or 750 mg i.v. daily, in divided doses from day 0 to engraftment. Ganciclovir (5 mg/kg i.v. three times per week) was given in CMV+ patients (or if the donor was CMV+) from engraftment to day 84. Ganciclovir was continued or recommenced if a dose of greater than 20 mg of prednisone was used for the treatment of GVHD otherwise aciclovir was recommenced. In HSV+ patients not receiving ganciclovir, aciclovir 600 mg p.o. daily in divided doses was given until at least 6 months after BMT. Thirty-two patients developed VZV infection from 4.1 to 28 months after transplant. The estimated cumulative incidence of VZV was 13% (95% confidence interval 6-19%) at 12 months, 32% (22-42%) at 24 months and 38% (27-50%) at 28 months, with no further cases beyond that time. No patient developed VZV whilst receiving aciclovir or ganciclovir (P < 0.0001). However, there was a rapid onset of VZV following cessation of antiviral therapy (33% (20-46%) at 1 year post cessation). The presence of GVHD and the prior duration of antiviral prophylaxis were significant and independent risk factors for the development of VZV. Age, underlying disease, conditioning therapy or donor type were not. We conclude that 3-6 months of low-dose aciclovir and ganciclovir are effective at delaying the onset of VZV after allogeneic BMT, but may not affect the overall incidence of infection. Prolonged prophylaxis may be warranted in patients at high risk of infection, for example those patients with GVHD.

2-Aminopurine↗