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Biomedical subjects

Stephen L Sacks

Publications and source records attributed to Stephen L Sacks.

14 recordsLinked to original sources
PubMed2005

Clinic-initiated, twice-daily oral famciclovir for treatment of recurrent genital herpes: a randomized, double-blind, controlled trial.

BACKGROUND: Famciclovir, the oral prodrug of penciclovir, is effective for the treatment of recurrent genital herpes. This randomized, clinic-initiated, double-blind trial compared the therapeutic efficacy and safety of treatment with famciclovir at dosages of 125 mg, 250 mg, and 500 mg twice daily for 5 days with placebo in immunocompetent adults with a recurrent episode of genital herpes. METHODS: Efficacy and tolerability were assessed in 308 patients with lesions present for no more than 6.5 h at the time of the first dose. Two assessments per day were performed to increase the precision of the determination of study end points. RESULTS: All doses of famciclovir were significantly more effective than placebo in reducing the time to cessation of viral shedding, complete lesion healing, and loss of all lesion-associated symptoms, particularly lesion tenderness, pain, and itching. Patients receiving treatment with famciclovir were significantly less likely to experience new lesions than were patients receiving placebo. All doses of famciclovir were tolerated as well as placebo was. There was no difference in efficacy or tolerability among the different doses of famciclovir; the lowest effective dose was 125 mg twice per day. CONCLUSIONS: In immunocompetent adults with recurrent genital herpes, a 5-day course of famciclovir at a dosage of 125 mg, 250 mg, or 500 mg twice per day was significantly more effective than was placebo in reducing the duration of viral shedding and symptoms and in accelerating lesion healing. These results support the use of treatment with famciclovir at a dosage of 125 mg for 5 days as an effective, well-tolerated treatment for episodes of recurrent genital herpes.

2-Aminopurine↗
PubMed2004

Quantitation of hepatitis B virus (HBV) covalently closed circular DNA (cccDNA) in the liver of HBV-infected patients by LightCycler real-time PCR.

Antivirals for hepatitis B virus (HBV) reduce viral load and improve liver histology, however, their effect on covalently closed circular DNA (cccDNA), the HBV transcriptional template, has not been extensively examined. This study evaluated a newly designed LightCycler based quantitative cccDNA PCR assay. A linear range of 2.5 x 10(1) to 1 x 10(9) copies/assay using primers specific for HBV cccDNA and 2.5 x 10(1) to 2.5 x 10(9) copies/assay using primers specific for total HBV DNA (tDNA) was established. beta-Globin was used to estimate the number of cells in each PCR reaction. Enzymatic digestion with an ATP-dependent DNase improved the analytic specificity to a greater than 1:10000 ratio of cccDNA:RC DNA (relaxed circular DNA). One-tenth of the extracted DNA from 1mg of liver biopsy, was analyzed from six patients, three HBV-infected and three uninfected individuals, under blinded conditions; three were found positive and three negative for cccDNA and tDNA. Approximately 6 x 10(3) copies of cccDNA/mg of tissue were detected in a pre-transplant biopsy from an HBV-infected patient treated with lamivudine. Sequential post-transplant liver biopsies were negative for both HBV cccDNA and tDNA. An HBV-infected patient with cirrhosis who was antiviral therapy naïve had 3.7 x 10(4) copies of cccDNA/mg of liver tissue. Another treatment-naïve patient with a history of high HBV viral load had 1 x 10(5) copies of cccDNA/mg of tissue (4 x 10 (6) copies of tDNA/mg of tissue). Further studies are warranted but the high level of sensitivity, specificity, rapidity and accuracy provided by this novel assay with the LightCycler system indicate that it could be useful for monitoring antiviral therapy.

DNA, Circular↗
PubMed2004

Famciclovir suppression of asymptomatic and symptomatic recurrent anogenital herpes simplex virus shedding in women: a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, single-center trial.

Genital herpes is most often transmitted while the patient is asymptomatic, presumably during episodes of viral shedding. To determine whether famciclovir is effective in reducing asymptomatic shedding, women with frequent, recurrent genital outbreaks were enrolled in a randomized, double-blind, double-dummy, placebo-controlled, parallel-group, 112-day trial of suppressive treatment with famciclovir for anogenital viral shedding. Sixty women received 125 mg of famciclovir 3 times daily, 59 received 250 mg of famciclovir 3 times daily, and 58 received placebo. Patients recorded symptoms and self-obtained cultures daily. Famciclovir reduced asymptomatic shedding, compared with placebo (P < .0001). The onset of asymptomatic shedding was also delayed (P < .0001). Famciclovir reduced symptomatic shedding in a dose-dependent manner (0.72% for 125 mg 3 times daily vs. 0.19% for 250 mg 3 times daily [P < .0001] vs. 5.53% for placebo [P < .0001]). In conclusion, suppressive treatment with famciclovir reduced both asymptomatic and symptomatic viral shedding and delayed the onset of asymptomatic shedding in women with frequently recurring genital herpes. Studies to examine the effects of suppression by famciclovir on the transmission of genital herpes are warranted.

2-Aminopurine↗
PubMed2004

Once-daily valacyclovir to reduce the risk of transmission of genital herpes.

BACKGROUND: Nucleoside analogues against herpes simplex virus (HSV) have been shown to suppress shedding of HSV type 2 (HSV-2) on genital mucosal surfaces and may prevent sexual transmission of HSV. METHODS: We followed 1484 immunocompetent, heterosexual, monogamous couples: one with clinically symptomatic genital HSV-2 and one susceptible to HSV-2. The partners with HSV-2 infection were randomly assigned to receive either 500 mg of valacyclovir once daily or placebo for eight months. The susceptible partner was evaluated monthly for clinical signs and symptoms of genital herpes. Source partners were followed for recurrences of genital herpes; 89 were enrolled in a substudy of HSV-2 mucosal shedding. Both partners were counseled on safer sex and were offered condoms at each visit. The predefined primary end point was the reduction in transmission of symptomatic genital herpes. RESULTS: Clinically symptomatic HSV-2 infection developed in 4 of 743 susceptible partners who were given valacyclovir, as compared with 16 of 741 who were given placebo (hazard ratio, 0.25; 95 percent confidence interval, 0.08 to 0.75; P=0.008). Overall, acquisition of HSV-2 was observed in 14 of the susceptible partners who received valacyclovir (1.9 percent), as compared with 27 (3.6 percent) who received placebo (hazard ratio, 0.52; 95 percent confidence interval, 0.27 to 0.99; P=0.04). HSV DNA was detected in samples of genital secretions on 2.9 percent of the days among the HSV-2-infected (source) partners who received valacyclovir, as compared with 10.8 percent of the days among those who received placebo (P<0.001). The mean rates of recurrence were 0.11 per month and 0.40 per month, respectively (P<0.001). CONCLUSIONS: Once-daily suppressive therapy with valacyclovir significantly reduces the risk of transmission of genital herpes among heterosexual, HSV-2-discordant couples.

Acyclovir↗
PubMed2004

A phase II dose-escalating trial of clevudine in patients with chronic hepatitis B.

Current therapies available for the treatment of chronic hepatitis B are limited in their ability to result in a cure. Clevudine is a new pyrimidine analog with potent anti-hepatitis B virus (HBV) activity in vitro. A multicenter dose-escalation study evaluated clevudine at 10, 50, 100, and 200 mg once daily for 28 days. Eligible patients had HBV DNA levels of 3 x 10(6) copies/mL or more, had not undergone nucleoside treatment, and were without human immunodeficiency or hepatitis C virus coinfection. Thirty-two patients were enrolled (5, 10, 10, and 7 patients in the 10-, 50-, 100-, and 200-mg dose groups, respectively), 81% were male, 81% Asian, and 88% were hepatitis Be antigen (HBeAg) positive at baseline. Median pretreatment serum HBV DNA levels ranged from 7.3 to 8.8 log(10) copies/mL. After 28 days, the median HBV DNA log(10) change from baseline was -2.5, -2.7, -3.0, and -2.6 log(10). Six months after dosing, median changes from baseline were -1.2, -1.4, -2.7 and -1.7 log(10) in the 10-, 50-, 100-, and 200-mg cohorts, respectively. Six of 27 patients lost HBeAg, and 3 of 27 patients seroconverted to HBe antibody. Clevudine was well tolerated, with no dose-limiting toxicities. A transient increase in alanine aminotransferase of up to 7.8 times the upper limit of normal (increase ranged from 20 to 186 IU/L) was observed in six patients in the 100-mg cohort, without signs of liver failure. These increases were associated with improved viral suppression. The pharmacokinetic profile of clevudine was proportional to the dose. In conclusion, these results demonstrate the tolerability and potent activity of clevudine in HBV-infected patients and support further clinical study.

Adult↗
PubMed2004

The synergistic effects of betulin with acyclovir against herpes simplex viruses.

Betulin, a pentacyclic triterpenoid, was isolated from the bark of Betula papyrifera. The antiviral efficacies of betulin on herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) were evaluated using viral plaque reduction assays on Vero cells. The results indicate that betulin is active against both HSV-1 and HSV-2 infections with the 50% effective concentrations (EC(50)) of 0.40 and 4.15 microg/ml, respectively. The cytotoxicity of betulin was examined on Vero cells using a neutral red uptake assay. The 50% cytotoxic concentration (CC(50)) of betulin was 73.1 microg/ml. A synergistic antiviral effect between betulin and acyclovir (ACV) was determined by drug combination studies. Strong and moderate synergistic antiviral effects were observed for betulin and ACV against HSV-1 when the concentrations of ACV and betulin were higher than 0.068 and 0.4 microg/ml, respectively. At the concentrations lower than these, additive effect was found. Synergistic antiviral effects were also found against HSV-2 at higher concentrations than for HSV-1, i.e. 0.45 microg/ml of ACV combined with 8.4 microg/ml of betulin.

Acyclovir↗
PubMed2004

Docosanol: a topical antiviral for herpes labialis.

Recurrent herpes labialis is a painful and potentially disfiguring infection affecting an estimated 40 million people in the US alone. The majority of recurrences are caused by herpes simplex virus type 1. Various oral and topical formulations of nucleoside analogues have demonstrated efficacy for this indication. Over-the-counter treatments are palliative in nature and do not reduce time to healing. Docosanol is a compound with a unique mechanism of action involving viral fusion inhibition. In randomised, clinical trials, a 10% docosanol cream formulation, initiated within 12 h of symptoms onset, demonstrated efficacy in reduction of time-to-healing compared with a polyethylene glycol control. Despite its potential to be a mild irritant, this novel antiviral was well-tolerated in clinical trials. Docosanol is the first topical antiviral approved for over-the-counter use in recurrent herpes labialis.

Administration, Topical↗
PubMed2003

A double-blind, randomized, placebo-controlled trial of acyclovir in late pregnancy for the reduction of herpes simplex virus shedding and cesarean delivery.

OBJECTIVE: The purpose of this study was to assess the efficacy of acyclovir in the reduction of herpes simplex virus culture and polymerase chain reaction positivity and cesarean delivery. STUDY DESIGN: Women with recurrent genital herpes simplex virus were randomized to acyclovir 400 mg three times daily or placebo from 36 weeks of gestation until delivery. A subset of daily specimens for herpes simplex virus culture and DNA polymerase chain reaction was self-collected. Analyses used chi(2), Fisher exact, and Mann-Whitney U tests. RESULTS: Lesions occurred at delivery among 11 of 78 women (14%) who received placebo and 4 of 84 women (5%) who received acyclovir (P =.08). Herpes simplex virus culture and polymerase chain reaction positivity near delivery occurred in 7% and 34% women in the placebo group and 0 and 2% in the acyclovir group (P =.03 and <.01, respectively). Cesarean delivery for herpes simplex virus occurred in 8 of the women (10%) in the placebo group and in 3 of the women (4%) in the acyclovir group (P =.17). Despite reductions in herpes simplex virus detection, 6% of the women who received acyclovir had herpes simplex virus detected by polymerase chain reaction on >20% of days. Neonatal outcomes were similar between groups. CONCLUSION: Acyclovir significantly reduced, but did not eliminate, herpes simplex virus lesions and detection in late pregnancy.

Acyclovir↗
PubMed2003

Current treatment options to prevent perinatal transmission of herpes simplex virus.

Neonatal herpes is a potentially devastating consequence of perinatal transmission of the herpes simplex virus (HSV), with significant morbidity and mortality. Treatment options are available, but must begin early in disease with manifestations that are often protean. Thus, preventive measures need to be optimised. Antiviral suppression in late pregnancy of women with a history of recurrent genital herpes will decrease symptomatic recurrence at delivery and appears to reduce caesarian section rates. However, primary HSV Type 2 and primary HSV Type 1 episodes have the highest neonatal transmission rates and thus, effective prevention may require the identification and suppression of the discordant partner. Significant experience has been gained with the use of acyclovir in pregnancy and it is recommended for both episodic and suppressive therapy in pregnant women. Its use has been demonstrated to be cost-effective in suppressive therapy, although issues regarding compliance and the potential for neonatal neutropenia need to be addressed. The more conveniently dosed prodrugs valacyclovir and famciclovir are being evaluated for use in pregnancy.

Antiviral Agents↗
PubMed2002

Development and validation of a plasma assay for acyclovir using high-performance capillary electrophoresis with sample stacking.

A sensitive plasma assay for acyclovir has been developed and validated. Acyclovir was separated from plasma components using Oasis HLB columns. Separation was obtained with no plasma interference using micellar electrokinetic chromatography (175 mM SDS) and hydroxypropyl-beta-cyclodextrin (100 mM) in 90 mM borate buffer (pH 8.8) containing 0.2% NaCl. High sensitivity was achieved by large volume sample introduction and stacking. The linear range was from 20 to 10000 ng/ml with a limit of quantitation of 20 ng/ml. This method is a viable alternative to HPLC because of its high separation and sensitivity, reproducibility, and adaptability to other nucleoside analogs.

Acyclovir↗
PubMed2002

Comparison of methods for identifying resistant herpes simplex virus and measuring antiviral susceptibility.

BACKGROUND: A number of in vitro assays are used to determine susceptibility of HSV to antiviral agents, but results from these in vitro assays do not necessarily correlate with treatment outcome. OBJECTIVES: A method with improved capability for identifying an isolate as acyclovir (ACV) or penciclovir (PCV) resistant when resistance is borderline could greatly improve the management of HSV disease. STUDY DESIGN: A comparative evaluation of four in vitro assays, plaque reduction (PRA), DNA hybridization, plating efficiency (PEA) and plaque autoradiography (PAR) was performed to accurately identify and measure resistance of a TK-altered clinical HSV isolate (HSV-1 N4) from a patient who was non-responsive to ACV treatment. Two established criteria for the prediction of antiviral resistance, IC(50)> or =2.0 microg/ml or an IC(50) greater than 10x above a sensitive virus IC(50), as well as testing in human (MRC-5) and nonhuman (Vero and CV-1 monkey kidney) cell lines were evaluated. RESULTS: The PRA and DNA hybridization assays accurately identified HSV-1 N4 as ACV(r) in human cells when using the 10x above sensitive virus IC(50) resistance criterion. Moreover, the PEA and PAR assays failed to classify HSV-1 N4 as drug resistant and indicate that these technologies alone are inadequate for identifying resistant virus. CONCLUSIONS: The data presented herein indicate that the PRA and DNA hybridization assays most accurately identified an otherwise borderline-resistant isolate as drug resistant: (i) when a sensitive virus is used within each individual assay as a control, (ii) when ACV and PCV susceptibility is evaluated in human cells, and (iii) when the 10x above sensitive IC(50) criterion is used to classify a virus as drug-resistant. Testing of additional clinical samples is warranted to further confirm these findings.

Acyclovir↗
PubMed2002

Antivirals in the prevention of genital herpes.

Genital herpes remains one of the most common sexually transmitted infections. Despite best efforts to prevent sexually transmitted diseases in the era of AIDS, the incidence of genital herpes continues to rise, and evidence that herpes simplex virus type 2 is a significant cofactor in the transmission of HIV infection is mounting. Because of the common psychosocial consequences of genital herpes transmission, prevention modalities against transmission of genital herpes are urgently required from both personal and public health perspectives. Most discordant couples are either unaware of genital herpes in one partner or unaware of clinical activity of the virus during sexual exposure that results in transmission. Yet, the body of evidence available suggests that the antiviral drugs currently used in the treatment of genital herpes are effective in suppressing asymptomatic virus shedding and, thus, could play a future role in reducing transmission. The first study to examine that possibility has recently been made public.

Antiviral Agents↗
PubMedDate not supplied

Oral famciclovir for the suppression of recurrent genital herpes: the combined data from two randomized controlled trials.

BACKGROUND: Genital herpes is a very common sexually transmitted disease. Safe and effective therapies are needed for patients with frequent recurrences. OBJECTIVE: The aim of our study was to determine the efficacy and safety of famciclovir for suppression of herpes simplex virus (HSV) infection in patients with history of clinically diagnosed recurrent genital HSV infection. METHOD: An analysis was conducted of the combined data from two randomized, double-blind, placebo-controlled studies of 52 weeks' duration involving a total of 469 patients (201 men, 268 women) from 47 university, hospital, or private referral centers in Europe and North America. The patients were 18 years or older with a history of six or more episodes of genital herpes during 12 of the 14-months prior to study entry and were not receiving suppressive therapy. They were randomized to receive oral famciclovir 250 mg twice daily or placebo for 52 weeks. The primary outcome measures were (1) the proportion of patients who remained free from clinical HSV recurrences, confirmed by viral culture, for at least 6 months after the start of study medication; (2) the time to first clinically confirmed lesional episode; and (3) the frequency of adverse events. RESULTS: A significantly greater proportion of famciclovir-treated patients (151/191, 79%) were free from HSV recurrences at 6 months compared with placebo recipients (48/184, 26%) (p<0.001); efficacy was maintained at 12 months. The median time for the first clinically confirmed lesional episode was significantly prolonged for famciclovir recipients (more than one year) compared with placebo recipients (59 days; p<0.0001). Famciclovir was well tolerated, with an adverse-experience profile comparable with placebo. CONCLUSIONS: Oral famciclovir 250 mg twice daily is an effective, well-tolerated treatment for the suppression of genital HSV infection in patients with frequent recurrences.

2-Aminopurine↗