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PubMed1993

Review of research leading to new anti-herpesvirus agents in clinical development: valaciclovir hydrochloride (256U, the L-valyl ester of acyclovir) and 882C, a specific agent for varicella zoster virus.

Research leading to the new anti-herpesvirus compounds discussed here has come from three approaches. The first approach was directed towards improving the bioavailability of acyclovir by examining the potential of a variety of prodrugs, leading to the new compound valaciclovir hydrochloride. The second approach was to examine a large number of 5-substituted pyrimidines for activity against those viruses which were not as potently inhibited by acyclovir as are herpes simplex viruses, i.e., varicella zoster virus (VZV) and human cytomegalovirus (HCMV). This research led to the new chemical entity 882C for VZV. A third approach has been to examine drug combinations with acyclovir. This research led to the compound 348U, an inhibitor of herpes simplex virus ribonucleotide reductase which acts synergistically in combination with acyclovir. This manuscript will focus on the first two approaches leading to new compounds valaciclovir hydrochloride and 882C since Dr. Safrin details such background for 348U/acyclovir. Attempts to improve the bioavailability of acyclovir began a decade ago. Early prodrugs were compounds with alterations in the 6-substituent of the purine ring of acyclovir. The 6-amino congener required the cellular enzyme adenosine deaminase for conversion to acyclovir and the 6-deoxycongener was dependent on cellular xanthine oxidase for conversion. Neither of these prodrugs had a chronic toxicity profile in laboratory animals as good as acyclovir. Efforts were directed towards simpler esters and 18 amino acid esters were made. The pharmacokinetic profile of each prodrug was determined in rats by measuring the recovery of acyclovir in urine after oral dosing.(ABSTRACT TRUNCATED AT 250 WORDS)

Acyclovir↗
PubMed1993

Valaciclovir (BW256U87): the L-valyl ester of acyclovir.

Valaciclovir (BW256U87) is an L-valyl ester of acyclovir, which is extensively and almost completely converted to acyclovir. In healthy human volunteers, single valaciclovir doses of 100-1000 mg resulted in dose-proportional increases in acyclovir area under the curve (AUC). The 1,000 mg dose produced an acyclovir peak plasma concentration (Cmax) of 5-6 micrograms/ml, AUC6 of 19 hr. micrograms/ml, time to maximum plasma concentration (Tmax) of 1-2 hr, and half-life (T1/2) of 2.8 hr. Plasma valaciclovir peak levels were < 0.3 micrograms/ml, and the prodrug was undetectable after 3 hr. Multiple valaciclovir doses of 250-2,000 mg given four times daily for 10 days resulted in dose-proportional increases in acyclovir Cmax. There were less than proportional increases in the AUCs. No serious or unexpected adverse events or laboratory abnormalities were reported. In volunteers with advanced human immunodeficiency virus (HIV) disease (absolute CD4 lymphocyte count < 150 cells/microliters), acyclovir and valaciclovir pharmacokinetic results were nearly identical to those in healthy volunteers. At the 2 g dose administered four times daily, steady-state acyclovir Cmax = 8.4 micrograms/ml, Tmax = 2.0 hr, AUC6 = 30.5 hr. micrograms/ml, and T1/2 = 3.3 hr. Nausea, vomiting, diarrhoea, and abdominal pain were commonly reported; however, only one adverse event (diarrhoea) was causally linked to valaciclovir exposure. There were no renal or neurologic adverse events. Valaciclovir is well absorbed and is rapidly converted to acyclovir, resulting in three- to fourfold higher acyclovir levels than can be achieved with oral acyclovir, even in patients with advanced HIV disease. The safety profile is generally favourable, with no evidence of nephrotoxicity or neurotoxicity.

Acyclovir↗
PubMed2006

Two cases of varicella zoster virus meningitis found in pediatric patients after bone marrow transplantation despite valaciclovir prophylaxis and without skin lesions.

Two cases of varicella zoster virus (VZV) meningitis are described in an 18-year-old girl and an 18-year-old boy. They occurred, respectively, 9 days and 9 months after allogeneic bone marrow transplantation. VZV nucleic acid was detected in the cerebrospinal fluid during the 1st week of illness. This recurrence occurred despite valaciclovir prophylaxis and without skin lesions. The two patients received aciclovir intravenously and immunoglobulins infusion. They responded to treatment and their clinical state improved rapidly.

Acyclovir↗
PubMed1999

Therapeutic approaches to the management of herpes zoster.

The past several years have provided exciting advances in the management of herpes zoster in the normal host. In spite of these advances, a significant portion of zoster patients still have persistent complications from this disease. Persistent pain is the most debilitating sequela and it occurs in at least 15% of individuals over 50 years of age. Future research efforts must embrace alternative approaches for pain control.

2-Aminopurine↗
PubMed2003

[Herpetic folliculitis barbae. A rare cause of folliculitis].

Viral folliculitis is a rare disease usually caused by herpes simplex, herpes zoster and molluscum contagiosum in immune-compromised patients. An otherwise healthy 30 year old patient without history of herpes simplex contracted a folliculitis in the beard region after a flu-like illness. He had no oral or labial lesions but instead showed a crusty erythematous folliculitis confined to the beard region with small grouped vesicles on the neck and reactive cervical lymph nodes. Bacterial and mycological analysis from swabs were negative. The culture was positive for herpes simplex virus and the immune fluorescence showed HSV type 1. Systemic therapy with valaciclovir 2x 500 mg/d and lotio alba locally led to rapid improvement. When confronted with folliculitis, non-bacterial causes such as viral (herpes simplex, herpes zoster, molluscum contagiosum), mycological (pityrosporon, candida), demodex and eosinophilic follicultitis should be taken under consideration.

Acyclovir↗
PubMed2003

Low-dose valaciclovir prophylaxis against cytomegalovirus disease in renal transplant recipients.

High-dose valaciclovir at up to 8 g/day has been shown to be effective in prophylaxis against cytomegalovirus (CMV) disease in renal transplant recipients. We report our experience with low-dose valaciclovir prophylaxis of up to 3 g/day, adjusted to creatinine clearance. A group of patients at high risk of developing CMV disease who received prophylaxis were selected as the study group. This included all CMV-positive patients who received antilymphocyte therapy (R+, n=20) and all CMV-negative recipients of CMV-positive organs (D+R-, n=15). D+R- patients receiving antilymphocyte therapy were excluded, as most of the patients in the control group had received ganciclovir prophylaxis. A historical control group was used, which consisted of patients who did not receive prophylaxis. Low-dose valaciclovir prophylaxis resulted in a statistically significant decrease (8.5 vs 37%, P=0.004) in CMV disease in the study group at 6 months. On subgroup analysis the decrease was statistically significant only in the R+ group (5 vs 45%, P=0.003), not in the D+R- group (13.3 vs 26.6%, P=0.651). Low-dose valaciclovir prophylaxis seems to be adequate for R+ patients receiving antilymphocyte therapy. The role of low-dose valaciclovir prophylaxis needs to be assessed further in a prospective trial.

Acyclovir↗
PubMed2005

Idiopathic facial paralysis (Bell's palsy) in the immediate puerperium in a patient with mild preeclampsia: a case report.

INTRODUCTION: Idiopathic peripheral facial palsy is the most common and frequent unilateral cranial neurological disorder characterized by an isolated facial nerve paralysis. CASE REPORT: We report a case of an idiopathic facial paralysis (Bell's palsy) in the immediate puerperium in a patient with mild preeclampsia and diagnosed fetal IUGR. Additionally, the presence of Bell's palsy in the puerperium of the mother of our patient suggests a familiar tendency. DISCUSSION: Every gynaecologist and obstetrician should be aware of this quite uncommon complication during pregnancy and the puerperium. This case report illustrates that Bell's palsy can occur in the immediate post-partum after mild preeclamptic symptoms. For these women, a maternal surveillance can be recommended. A fast and accurate diagnosis with a subsequent immediate treatment might be very important in avoiding worsening of the symptoms and therefore improve the recovery prognosis.

Acyclovir↗
PubMed2006

Acute retinal necrosis diagnosed in a child with chronic panuveitis.

BACKGROUND: To report the case of an immunocompetent child with herpes simplex virus-2 (HSV-2) acute retinal necrosis (ARN) syndrome, who was considered to have an idiopathic unilateral panuveitis sensitive to steroid treatment. METHODS: Polymerase chain reaction for detection of viral DNA was applied to ocular fluids and in situ hybridization was performed on a retinal sample. HSV serology was performed using the ELISA and Western blot techniques, and an in-house indirect immunofluorescence technique. RESULTS: In addition to the atypical clinical presentation, the serological assays for HSV were negative using ELISA at the time of diagnosis of ARN and 1 year after. HSV2 infection was confirmed by using polymerase chain reaction of aqueous humor specimen and in situ hybridization of a retinal biopsy. Retrospective analysis with the Western blot technique detected low titers of anti-HSV antibodies, when the sera were concentrated 5-fold. CONCLUSION: Herpes virus infections must be investigated in children with posterior or panuveitis. PCR analysis is a reliable technique for diagnosis. This case emphasizes that clinical presentation can be atypical and that a negative viral serology does not exclude an acute or a past herpetic infection.

Acyclovir↗
PubMed2006

Herpes simplex and varicella-zoster virus infections during pregnancy: current concepts of prevention, diagnosis and therapy. Part 1: herpes simplex virus infections.

Primary herpes simplex virus (HSV) infection may lead to severe illness in pregnancy and may be associated with transplacental virus transmission and fetal infection. The consequences may be abortion, stillbirth and congenital malformations. In neonates, the clinical findings after intrauterine HSV infection are characterized by skin lesions, diseases of the eye and neurologic damage. Herpes genitalis of pregnant women at the time of labor may result in life-threatening neonatal herpes. Currently, neither active nor passive immunization is available to prevent HSV infections during pregnancy and in the newborn infant. Therefore, antiviral treatment using aciclovir and/or valaciclovir must be considered in all primary episodes of genital herpes as well as in neonates who show signs of either infection. Clinical herpes lesions of the genitalia and/or positive test for virus detection at the time of delivery are an indication for cesarean section. However, this surgical intervention may be reduced by suppressive treatment of recurrent genital herpes with aciclovir or valaciclovir.

Acyclovir↗
PubMed2005

The cost-effectiveness of prophylaxis with valaciclovir in the management of cytomegalovirus after renal transplantation.

Prophylaxis-based antiviral treatment and intensive monitoring followed by pre-emptive antiviral treatment are both commonly used management strategies to reduce risk of cytomegalovirus (CMV) infection following renal transplantation. This study employed a decision-model approach using published efficacy data and information from a recent survey of French clinical practice to consider the relative costs and outcomes associated with CMV prevention strategies for high-risk patient groups. The cost per case of treating tissue invasive and symptomatic CMV disease was estimated at euro 15,431 and euro 10,852, respectively. In the highest infection-risk patient group (positive donor with no previous CMV history) prophylactic oral valaciclovir was shown to avoid the greatest number of CMV disease cases (35 cases per 100 transplanted patients) and reduced the overall CMV-related costs per transplanted patient by around 14% over a'wait-and-treat' baseline strategy. In contrast, intensive monitoring and preemptive treatment resulted in a much higher cost per transplanted patient. This analysis suggests that prophylactic treatment remains the most cost-effective approach to the management of CMV in renal-transplanted patients. Further comparative studies between prophylactic and pre-emptive treatment would be a valuable addition to the current evidence based on CMV prevention.

Acyclovir↗
PubMed2006

Topical iontophoresis of valaciclovir hydrochloride improves cutaneous aciclovir delivery.

PURPOSE: To investigate the topical iontophoresis of valaciclovir (VCV) as a means to improve cutaneous aciclovir (ACV) delivery. METHODS: ACV and VCV electrotransport experiments were conducted using excised porcine skin in vitro. RESULTS: While the charged nature of the prodrug, VCV, enabled it to be more efficiently iontophoresed into the skin than the parent molecule, ACV, only the latter was detectable in the receptor chamber, suggesting that VCV was enzymatically cleaved into the active metabolite during skin transit. Iontophoresis of VCV was significantly more efficient than that of ACV; the cumulative permeation of ACV after 1, 2 and 3 h of VCV iontophoresis at 0.5 mA cm(-2) and using an aqueous 2 mM (approximately 0.06%) formulation was 20+/-10, 104+/-47 and 194+/- 82 microg cm( -2), respectively (cf. non-quantifiable levels, 0.1 and 1.0+/-0.7 microg cm(-2) after ACV iontophoresis). CONCLUSIONS: These delivery rates provide ample room to reduce either current density or the duration of current application. Preliminary in vitro data serve to emphasize the potential of VCV iontophoresis to improve the topical therapy of cutaneous herpes simplex infections and merit further investigation to demonstrate clinical efficacy.

Acyclovir↗
PubMed2006

Validation of the genital herpes treatment satisfaction questionnaire (GHerpTSQ) in status and change versions.

A new measure of treatment satisfaction (GHerpTSQ) for recurrent genital herpes simplex virus (HSV) was validated and used to evaluate two therapeutic strategies widely used for the management of HSV: episodic treatment, where individual herpes outbreaks are treated as they arise; suppressive therapy, where treatment is taken daily to prevent HSV outbreaks. Satisfaction with treatment is important since daily dosing with suppressive therapy is necessary in the absence of symptoms. A 12-item questionnaire was designed using a modified form of the Diabetes treatment satisfaction questionnaire (DTSQ). The psychometric properties of the GHerpTSQ were evaluated within a sample of 125 Canadians with a history of HSV (type 1, 2) infection participating in a 48 week randomised cross-over trial. Factor analysis suggested that the items can be analysed as two separate subscales corresponding to Control/effectiveness, and Convenience/lifestyle; the single item concerning side effects was retained for separate analysis. Forced one-factor analysis showed that the two subscales can be combined to obtain a total score relating to overall treatment satisfaction. The GHerpTSQ has good internal reliability, clear structure with little overlap of subscales and evidence of good sensitivity to changes in treatment.

Acyclovir↗
PubMed2004

Valaciclovir for chronic hepatitis B virus infection after lung transplantation.

We report on a chronic asymptomatic hepatitis B surface antigen (HBsAg) carrier who developed an increase in aminotransferase and HBsAg levels 1 year after lung transplantation. During treatment for cutaneous herpes simplex virus (HSV) infection with oral valaciclovir there was a marked decrease in replicating hepatitis B virus (HBV)-DNA and aminotransferase levels, which was sustained for 9 months by continuing low-dose valaciclovir. A second rise in aminotransferase levels again responded to a valaciclovir dose increase and the HBV-DNA levels declined further. Although we cannot exclude a spontaneous variation of the serologic parameters, our observation suggests that valaciclovir may represent a valuable therapeutic option in the treatment of chronic hepatitis B after lung transplantation.

Acyclovir↗
PubMed1996

Cytogenetic genotoxicity of antiherpes virostatics in Chinese hamster V79-E cells. I. Purine nucleoside analogues.

The antiherpes virostatics acyclovir (ACV), valaciclovir (VACV), penciclovir (PCV), famciclovir (FCV) and ganciclovir (GCV), which belong to the group of purine acyclic nucleoside analogues, were tested for clastogenic and sister chromatid exchange (SCE)-inducing activity in Chinese hamster V79-E cells upon chronic application with and without a recovery period. ACV induced borderline effects in both cytogenetic assays, a dose-dependent reduction of the mitotic index and an increasing cell cycle delay. With VACV and PCV only a decrease of the mitotic index and an increase of cell cycle delay were observed. FCV was negative with respect to the four parameters studied, presumably due to the incapacity of the target cells of metabolizing FCV to PCV. GCV was a very potent genotoxin in both assays. It induced a statistically significant SCE response even in the range of the cytomegalovirus IC50 of < 10 microM. By variation of the experimental protocol it was shown that SCEs are induced in the second cell cycle following exposure to GCV but not in the first one. It is assumed that the drugs under study are metabolized to their respective triphosphates and then inhibit DNA replication as detected by decreasing mitotic index and increasing cell cycle delay. In the case of GCV it is suggested that GCV-TP is incorporated into the target cell DNA and that chromosomal aberrations and SCEs are secondary lesions due to repair processes at the substituted template.

2-Aminopurine↗
PubMed1996

Scintillation proximity radioimmunoassay for the measurement of acyclovir.

A homogeneous, single-tube scintillation proximity radioimmunoassay (SPRIA) to quantitate acyclovir (Zovirax), ACV, (9-[(2[hydroxyethoxy)]methylguanine)] in human plasma is described. The reagents for the SPRIA are an anti-ACV monoclonal antibody (WACO4 MAb), tritiated ACV, and scintillation proximity reagent (goat anti-mouse immunoglobulin G (IgG) coupled to fluoromicrospheres). The ACV standard curve range in the SPRIA is from 0.7 ng ml-1 (3.0 nmol l-1) to 90.0 ng ml-1 (0.4 mumol l-1) with a 50% inhibitory concentration of 5.0 ng ml-1 (22.2 nmol l-1). However, the lower limit of quantification is 7 ng ml-1 at 1:10 dilution of plasma. Analytical recovery of ACV in spiked human plasma controls ranges between 90-110%. Intra- and inter-assay relative standard deviations were < 8%. This high throughput homogeneous assay is a rapid, convenient and simple alternative to the current radioimmunoassay that uses ammonium sulfate precipitation as the separation method. This technique is particularly attractive because it requires neither separation of bound from free drug nor use of scintillation fluid. The procedure was applied to quantitate ACV in samples from pre-clinical and clinical studies after the administration of valaciclovir, a prodrug of ACV (256U87, Valtrex, L-valyl ester of ACV). Automation of this assay will further improve efficiency in processing a larger number of samples.

Acyclovir↗