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Biomedical subjects

S L Sacks

Publications and source records attributed to S L Sacks.

At least 37 records · Page 2Linked to original sources
PubMed1996

Spontaneous reactivation of thymidine kinase-deficient, acyclovir-resistant type-2 herpes simplex virus: masked heterogeneity or reversion?

Herpes simplex virus (HSV) strain 1737, acyclovir-resistant and uniformly thymidine kinase-deficient (tkD) by all conventional assays, clinically reactivated in an AIDS patient in the absence of antiviral drug pressure. Investigation of its neurovirulence and latency characteristics in a mouse model using a tkD plaque isolate (1737-14), however, yielded a neurovirulent, homogeneous, acyclovir-sensitive, tk wild type (tkWT) strain (1737-14ME), while trigeminal ganglia from a surviving animal yielded a heterogeneous tkD/tkWT population (1737-14/10(5)B). Heterogeneity may have arisen due to selection of a preexisting tkWT subpopulation or to genetic reversion. "Ultralow" levels of tk, undetectable by conventional means, may be sufficient for reactivation while retaining the acyclovir-resistant phenotype. A possible mechanism for spontaneous reactivation of 1737 is in vivo complementation between heterogeneous tk populations. Eradication of acyclovir-resistant, tkD virus does not ensure subsequent reactivations to be acyclovir-sensitive, and alternating antivirals may be required for effective therapy.

Acquired Immunodeficiency Syndrome↗
PubMed1996

New antiherpesvirus agents. Their targets and therapeutic potential.

Of the large number of agents under development for the treatment of herpes virus infections [herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV)], only ten have apparently reached clinical development. Aciclovir was approved for the treatment of HSV infections over 10 years ago, and it remains an important and reliable antiviral agent. Recent approvals in some countries of valaciclovir for VZV infection and famciclovir for both HSV and VZV infections demonstrate the rapidity of change in this field. Intravenous ganciclovir and foscarnet are approved for the treatment of CMV infection in the immunocompromised patient. Five of the antiherpetic drugs under current clinical development are nucleoside analogues or their prodrugs; another is a phosphorylated nucleoside (nucleotide). Four of the nucleoside agents-penciclovir, famciclovir, valaciclovir and lobucavir-are being developed for the management of HSV and VZV infections. Valaciclovir is also being developed for the prevention of CMV infections and famciclovir and lobucavir for the treatment of hepatitis B virus infection. Oral ganciclovir, lobucavir, ISIS 2922 and cidofovir are being developed for the suppression of CMV infections in immunocompromised patients. Sorivudine has been studied in VZV infections. n-Docosanol is under development for HSV infections, and cidofovir is being developed for both HSV and CMV infections, as well as for treatment of other viral diseases. Traditionally, the adverse effects associated with anti-CMV compounds have been more difficult to manage and are acceptable clinically only because of the severity of the underlying infection and lack of safer therapeutic alternatives. In general, toxicity issues continue to be problematic in the anti-CMV arena, although newer agents have improved the situation to some extent. In contrast, the safety of anti-HSV compounds has traditionally been excellent, establishing a safety standard that must be met by newer agents entering the field.

Antiviral Agents↗
PubMed1996

Genital herpes simplex virus and its treatment: focus on famciclovir.

The incidence of genital herpes continues to increase worldwide. Primary first-episode genital herpes are commonly associated with severe systemic symptoms. Primary first-episode lesions are usually bilateral and may from over a period of 10 days. Nonprimary first-episode genital herpes are often associated with less severe systemic symptoms and lesion formation. Although recurrent genital herpes episodes are generally limited to localized lesions without systemic symptoms, the frequent recurrence and chronicity may have a substantial psychosocial impact on a patient's well-being. Presently, there are no available treatments capable of abating the latent virus in human beings. Current management of genital herpes focuses on treatment with antiviral agents, which are effective in reducing the course of genital herpes.

2-Aminopurine↗
PubMed1995

Automated microneutralization: method and comparison with western blot for type-specific detection of herpes simplex antibodies in two pregnant populations.

A novel method for the detection of microneutralization was compared to Western blot for detection of type-specific antibodies to herpes simplex virus in two pregnant patient populations in Vancouver. From an unselected group of women in labor in a tertiary care obstetric hospital (426) and another group of women specially referred for assessment of genital herpes in pregnancy (195) 20 and 88%, respectively, were seropositive for herpes simplex virus type 2 antibodies by Western blot. During the study period, 93 (48%) of the high-risk group were culture positive for HSV-2 and all but one case was verified serologically by Western blot. Therefore, the sensitivity for Western blot in this high seroprevalence group was 99%. The false-negative case had longstanding recurrent infection and on retest was found to be a laboratory error. For microneutralization, type-specificity was especially difficult to distinguish among patients with mixed viral type patterns. Comparing microneutralization to Western blot as the gold standard, sensitivity, specificity, positive and negative predictive values were 84, 78, 97 and 40% respectively, for the referred group and 73, 82, 51 and 92%, respectively, for the unselected group. Poor negative and positive predictive values for the referred group and unselected populations, respectively, demonstrate that microneutralizations are not clinically acceptable for type-specific antibody detection. By contrast, serology by Western blot is very sensitive and apparently highly specific.

Antibodies, Viral↗
PubMed1995

Anti-infective therapy for viral pneumonia.

The recognition of viruses as causes of pneumonia in both immunocompetent and immunocompromised hosts has expanded dramatically. The number of therapeutic agents available for treatment of these illness also has increased in the last decade. Each of these agents has demonstrated a limited therapeutic indication for treatment of viral pneumonia. Many of these agents inhibit viral DNA synthesis through actions as nucleoside analogs (such as acyclovir and ganciclovir). However, a variety of alternative mechanisms of inhibition of viral replication are used. Ribavirin, while being a nucleoside analogue, also appears to exert broad antiviral activity by a variety of enzymatic inhibitory mechanisms. Foscarnet, an inorganic pyrophosphate analogue, offers additional treatment options for herpesviruses by acting as a direct virus DNA polymerase inhibitor. The tricyclic amines amantadine and rimantadine inhibit influenza A replication by interfering with viral uncoating after cell penetration. Thus, these two agents are largely effective as prophylaxis. The search for novel antiviral drugs, such as neuraminadases inhibitors with selective influenza activity, is currently in progress.

Acyclovir↗
PubMed1994

No-carrier-added [123I]1-(beta-D-arabinofuranosyl)-5(E)-(2- iodovinyl)uracil (IVaraU): high yield radiolabeling via organotin and exchange reactions.

Organotin intermediates for IVaraU synthesis were obtained following the reaction of 1-(2',3',5'-tri-O-toluyl-beta-D-arabinofuranosyl-5-iodouracil with (E)-1,2-bis(tri-(n-butyl) stannyl)ethene in the presence of catalytic (Ph3P)2PdCl2. A direct precursor for IVaraU, (E)-5-[2-tri-n-butylstannylvinyl]-arabinosyluridine, reacted with [123I]NaI (10 mCi) or alternatively [125I]NaI in the presence of methanol and chloramine T providing no-carrier-added (NCA) [123I]IVaraU in a radiolabeling yield up to 97%; the product was recovered following reversed phase HPLC. Unlabeled IVaraU was prepared in five steps from arabinosyluridine via an organotin intermediate with an overall yield of 22%. An exchange radioiodination was also identified, based on accessible BrVara U in the presence of water and a cuprous ion catalyst. [123I]NaI (up to 40 mCi) or alternatively [125I]NaI reacted under exchange conditions to give no-carrier-added [123,125I]IVaraU in a radiolabeling yield of 93%; the product was recovered following reversed phase HPLC.

Antiviral Agents↗
PubMed1993

Systemic antivirals in herpesvirus infections.

Over the last few years we have seen the advent of effective antiviral drug therapy, the major ramifications being in the area of herpes infections. Acyclovir has become an established part of clinical practice, and other compounds are being increasingly used in the immunocompromised host. An effective vaccine is available for chickenpox, but herpes simplex and cytomegalovirus vaccines are still in early development. Thus, antiviral agents will continue to play a major role in the management of all herpesvirus infections for the foreseeable future. Current work includes the development of increased bioavailability prodrugs (BW 256, famciclovir), which are converted to active drug once absorbed, enabling rapid high serum levels, and hence may turn out to have increased efficacy in HSV- and VZV-induced diseases, for which oral acyclovir currently is the treatment of choice. Markedly increased efficacy against VZV in vitro has been demonstrated by two current agents under study (BVaraU, BW 882). HPMPC is now entering clinical trials with a markedly improved efficacy profile against CMV and HSV in animal models. Finally, drug combinations that are being investigated in AIDS may offer a means to avoid resistance in herpes infections in immunocompromised patients.

Acquired Immunodeficiency Syndrome↗
PubMed1992

Heterogeneity of a herpes simplex virus clinical isolate exhibiting resistance to acyclovir and foscarnet.

Resistance of herpes simplex virus to acyclovir is a problem of growing clinical importance. Acyclovir-resistance can be due either to mutations in the viral thymidine kinase gene or in the viral DNA polymerase gene. Although clinical resistance has most frequently been associated with thymidine kinase alterations, heterogeneity in clinical isolates has not been addressed frequently. The potential for such heterogeneity has been emphasized by a report describing a pathogenic clinical isolate containing within its population at least one thymidine kinase-proficient DNA polymerase mutant as well as mutants exhibiting thymidine kinase-deficiency (Sacks, et al., 1989). We provide here additional characterization of this isolate and speculations regarding its significance.

Acyclovir↗
PubMed1991

Nucleic acid related compounds. 65. New syntheses of 1-(beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil (IVAraU) from vinylsilane precursors. Radioiodine uptake as a marker for thymidine kinase positive herpes viral infections.

(Trimethylsilyl)acetylene was coupled with 1-(2,3,5-tri-O-acetyl-beta-D- arabinofuranosyl)-5-iodouracil to give 1- (2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)-5-[2-(trimethylsilyl)eth yny l] uracil. Lindlar hydrogenation of 4 gave 1-(2,3,4-tri-O-acetyl-beta-D-arabinofuranosyl)-5(Z)-[2- (trimethylsilyl)vinyl]uracil. Treatment of 5 with iodine monochloride (or sodium iodide/phenyliodine(III) dichloride) in benzene gave 1-(2,3,5-tri-O-acetyl-beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil (7), whereas polar solvents favored the (Z)-iodovinyl isomer 8. Deacetylation of 7 gave 1-(beta-D-arabinofuranosyl)-5(E)-(2-iodovinyl)uracil (IVAraU, 9). A microscale in situ synthesis with Na*I gave [*I]IVAraU. Treatment of HSV-infected cells with [125I]IVAraU resulted in virus-dependent uptake associated with nucleoside phosphorylation by wild type or acyclovir-resistant DNA polymerase mutants (but not with TK-HSV-1 mutants). Uptake was virus-inoculum dependent and was detectable within 4 h postinfection. The process was not completely reversible. Virus-specified uptake of [125I]IVAraU may allow automated in vitro detection of HSV isolates.

Animals↗
PubMed1991

Randomized, double-blind, placebo-controlled, clinic-initiated, Canadian multicenter trial of topical edoxudine 3.0% cream in the treatment of recurrent genital herpes. Canadian Cooperative Study Group.

Treatment for recurrent genital herpes using edoxudine 3% cream for 5 days was evaluated in 200 patients in a randomized, multicenter, double-blind, placebo-controlled, clinic-initiated trial. Lesion tenderness was predictive of and more sensitive and longer-lasting than the symptom of pain. Among patients receiving placebo, times to crusting (P = .043), cessation of investigator-observed signs (P = .005), lesion-associated signs (P = .02), and groin signs (P = .05) were longer in women. Edoxudine reduced viral shedding in men (mean 2.7 vs. 3.4 days, P = .009) and women (2.0 days vs. 3.5 days, P = .0001). Loss of investigator-observed signs (4.4 vs. 6.2 days, P = .002), investigator-observed lesion tenderness (P = .01), lesion signs (P = .02), groin adenopathy (P = .01), and tenderness (P = .01) occurred earlier in women taking edoxudine. Edoxudine was well-tolerated and reduced several signs of herpes in women. Its clinical role in recurrent genital herpes remains to be fully determined.

Administration, Topical↗
PubMed1991

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. II. Immunologic evaluation.

Immunologic functions are studied in conjunction with a placebo-controlled trial of lymphoblastoid interferon (IFN) in patients with chronic progressive (CP) multiple sclerosis. Prior to treatment, CD4+ cells are significantly increased and CD8+ cells decreased in the blood of MS patients. Both CD5+ and CD4+ cells increase significantly with IFN therapy early during the treatment phase of the trial, while the number of CD8+ cells decreases steadily, becoming significant at 6 months. CNS IgG synthesis rates increase with IFN treatment and maximize at 3 months. Serum antiviral activity also increases with IFN treatment. In the IFN-treated group, a trend toward improvement, determined clinically and by MRI, likely reflects the influence of a subpopulation of 10 patients. This subpopulation is now further characterized by an early increase in CNS IgG synthesis and numbers of CD5+ cells in the blood. Although these immune functions may identify a number of CP MS patients who might benefit from IFN, it is unlikely that these mechanisms actually mediate the potentially beneficial effects of this cytokine.

Adult↗
PubMed1990

Randomized, double-blind, placebo-controlled, patient-initiated study of topical high- and low-dose interferon-alpha with nonoxynol-9 in the treatment of recurrent genital herpes.

To explore further topical antiviral therapy for recurrent genital herpes, 188 culture-proven patients were randomized to receive treatment with topical interferon-alpha in high-dose (10(6) IU/g with 1% nonoxynol-9 in 3.5% methylcellulose) or low-dose (10(3) IU/g with 0.1% nonoxynol-9 in 3.5% methylcellulose) treatments or placebo (3.5% methylcellulose, alone), applied three times daily for 5 days. Of these, 105 experienced prodromal symptoms within the study period and applied the medication, of whom 99 could be evaluated for efficacy. Patients were followed with daily clinical assessments and cultures until reepithelialization. The median time to negative virus culture in high-dose recipients was 2.5 days compared with 3.9 days for placebo recipients (P = .023), and a significant dose response was observed (P = .016). Antiviral effects were more prominent in men than women. High-dose recipients also had reduced median duration of symptoms to 2.7 days from 3.7 days for placebo recipients (P = .03), with a significant dose-response relationship (P = .047). Effects on duration of symptoms were more prominent in women. Times to complete reepithelialization in those who applied the drug during the prodromal phase were 5.8 days for high-dose recipients compared with 6.5 days for placebo recipients (P = .053). A multivariate ranked linear model analysis of four efficacy variables (crusting, healing, virus shedding, symptom duration) also favored the high-dose gel (P = .015). High-dose topical interferon-alpha preparation is effective for patients with recurrent genital herpes. Applied early in the course of a recurrent episode, this treatment is safe and may provide a topical alternative to other types of therapy in the future.

Administration, Topical↗
PubMed1990

Systemic lymphoblastoid interferon therapy in chronic progressive multiple sclerosis. I. Clinical and MRI evaluation.

A randomized, double-blind, placebo-controlled, noncrossover trial determined the efficacy of lymphoblastoid interferon (IFN) in chronic progressive multiple sclerosis (CP MS). Fifty patients received 5 X 10(6) IU IFN subcutaneously daily for 6 months while 50 received placebo. After 2 years, there were no significant differences between the 2 groups based on clinical evaluations and quantitative MRI analysis of the brain, although a trend was observed in the IFN group. Clinically, the IFN group was worse at 1 and 3 months and improved at 6 to 18 months, when compared with the placebo group. Results of MRI evaluations of the brain at 6 months support this trend. This trend likely resulted from a subpopulation of 10 IFN-treated patients, characterized by a higher women:men ratio and a lower EDSS score at entry into the trial. We cannot recommend lymphoblastoid IFN as treatment for CP MS at this time.

Adult↗
PubMed1989

Progressive esophagitis from acyclovir-resistant herpes simplex. Clinical roles for DNA polymerase mutants and viral heterogeneity?

Clinically acquired acyclovir resistance in herpes simplex has usually been associated with a deficiency in viral thymidine kinase, which, in turn, has been linked with attenuated virulence in animal models. Diminished pathogenicity in thymidine kinase-deficient isolates has been partly responsible for controversies about the clinical significance of antiviral resistance. We report on a series of resistant virus isolates from a patient who had severe, progressive esophagitis. These isolates had various thymidine kinase activities, ranging from 2.8% to 130% when compared with the activity of the isolate obtained before treatment; the resistant isolate 615 retained enzyme activity as well as neurovirulence in an encephalitis model. Plaque purification showed a heterogeneous mixture containing at least one acyclovir-resistant, foscarnet-resistant plaque isolate (615.8) fully able to phosphorylate acyclovir. The 3.3-kbp BamHI fragment containing most of the DNA polymerase gene from isolate 615.8 was purified and used to successfully transfer both acyclovir and foscarnet resistance. Acquisition of in-vitro acyclovir resistance was associated with progression of clinical disease, as well as with maintenance of pathogenicity in an animal model and at least one mutation in viral DNA polymerase. Patients with herpes simplex infections that progress during acyclovir therapy should be observed for acquisition of resistance in the setting of antiviral chemotherapy; future studies should also consider the presence of heterogeneous virus populations in such patients.

Acyclovir↗
PubMed1987

The role of oral acyclovir in the management of genital herpes simplex.

Oral acyclovir is an antiviral nucleoside analogue that has recently been released in Canada for use in selected patients with genital infections by the herpes simplex virus. First episodes of genital herpes should be treated with oral acyclovir as soon as the diagnosis is considered. Most people with recurrent genital herpes do not require systemic drug therapy. Selected patients with severe or long-lasting recurrences, recurrences associated with long prodromal periods (greater than 12 to 24 hours) or systemic complications such as erythema multiforme and eczema herpeticum may receive measurable benefit from treatment at the onset of symptoms. In most patients frequently recurrent disease can be suppressed with long-term therapy. Since long-term safety beyond 1 year has not been established, suppressive therapy should be stopped at least once per year to reassess the recurrence pattern. Acyclovir has not been adequately tested for safety in pregnancy and should not be prescribed for pregnant women unless the potential benefits outweigh the risks. Careful attention to disease severity, accurate diagnosis and exclusion of other causes of genital lesions will ensure that the drug is used only when beneficial.

Acyclovir↗