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Biomedical subjects

S L Sacks

Publications and source records attributed to S L Sacks.

At least 55 records · Page 3Linked to original sources
PubMed1987

Clinical course of recurrent genital herpes and treatment with foscarnet cream: results of a Canadian multicenter trial.

Clinic-initiated topical treatment of recurrent genital herpes with foscarnet cream (concentration, 0.3% in men and 1% in women) was compared with a placebo in a Canadian multicenter trial involving 309 patients. Culture-positive episodes of herpes took significantly longer to heal than did the others. Lesions in men were larger and lasted longer but were less symptomatic than those in women. Foscarnet did not statistically improve the times to healing or the loss of symptoms overall but did result in a higher proportion of symptom-free individuals after one day of treatment. Foscarnet-treated patients had a reduced duration of shedding of virus, and this was significant for men. These clinical benefits do not, however, warrant general use of this agent for established lesions. Earlier, prodromal treatment might have been more effective, but patient-initiated studies include a greater proportion of culture-negative (shorter) episodes that often make results difficult to interpret.

Administration, Topical↗
PubMed1987

Comparative metabolism of E-5-(2-bromovinyl)-2'-deoxyuridine and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil in herpes simplex virus-infected cells.

The antiviral activities and metabolic fates of E-5-(2-bromovinyl)-2'-deoxyuridine (BrVdUrd) and 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BrVaraUra) were compared in a dThd kinase-deficient human fibroblast cell line, infected with parental strains of herpes simplex virus, and other strains expressing no viral dThd kinase activity. Metabolic experiments were performed at concentrations well above the ID50 for each compound because radiolabeled agents were not available. BrVaraUra and its nucleotides qualitatively displayed chromatographic and anabolic characteristics which closely paralleled those of BrVdUrd and its nucleotides. Monophosphorylation of both drugs was dependent upon the presence of viral dThd kinase activity except in the case of one dThd kinase-negative type 1 mutant (SC16R5C1) which retained BrVdUrd/BrVaraUra kinase activity. Intracellular uptake of either parent compound was absent during mock-infection and minimal in the cases of infection with mutants unable to phosphorylate the parent compound. Parental type 1 strains were able to induce diphosphorylation and triphosphorylation of both compounds to a similar, dose-dependent degree. Extracts of type 2-infected cells contained greater quantities of BrVdUrd and its monophosphate compared with BrVaraUra and its monophosphate, after identical drug exposure and infection conditions. As previously observed for BrVdUrd, diphosphorylated and triphosphorylated nucleotides of BrVaraUra were not detected after type 2 infection. BrVdUrd and BrVaraUra metabolic breakdown pathways differed, however, as evidenced by the formation of E-5-(2-bromovinyl)uracil (BrVUra). Unlike BrVdUrd, BrVaraUra formed no BrVUra in infected cells, suggesting that replacement of 2'-deoxyribose with arabinose makes the compound biologically more stable, presumably because of resistance to enzymatic breakdown by pyrimidine nucleoside phosphorylases. In this dThd kinase-negative cell line, BrVdUrd and BrVaraUra displayed qualitatively similar susceptibility profiles in that activities were type 1 selective and dThd kinase dependent. Antiviral activities against dThd kinase-positive type 1 strains were similar with both compounds. These data would suggest that BrVdUrd and BrVaraUra have identical type-specific dThd-dTMP kinase-dependent mechanisms of cellular uptake and phosphorylation, but that the latter is not subjected to phosphorolysis and resultant formation of an inactive metabolite. Furthermore, the absence of presence of phosphorolysis of the parent nucleoside does not apparently adversely affect in vitro antiviral activity.

Arabinofuranosyluracil↗
PubMed1985

Neurotoxic effects during vidarabine therapy for herpes zoster.

Two cases of neurotoxic effects resulting from therapy with vidarabine are described. Both patients were undergoing treatment for cutaneously disseminated herpes zoster complicating therapy for solid malignant tumours. Both had normal renal function. The serum levels of hepatic enzymes were normal in one patient and slightly elevated in the other. Neurotoxicity was first manifested in both patients by the development of intention tremors that progressed to gross tremors. Obtundation, coma and death ensued in one patient and pain syndromes in the other. Vidarabine-induced neurotoxic effects, which may occur in the absence of hepatic or renal dysfunction or treatment with another drug, may be mild initially but may progress rapidly to more serious, even life-threatening, conditions. Presentation of neurotoxic effects should be considered an indication for withdrawal of vidarabine.

Aged↗
PubMed1985

Preclinical assessment of topical treatments of herpes simplex virus infection: 5% (E)-5-(2-bromovinyl)-2'-deoxyuridine cream.

The potential efficacy of topical therapy with (E)-5-w-bromovinyl)-2'-deoxyuridine (BVDU) for cutaneous herpesvirus infection was evaluated in vitro and in guinea pigs. Drug sensitivity testing against herpes simplex virus type 1 strain E115 revealed an ID50 of 0.008 microgram/ml for BVDU and 0.19 microgram/ml for acyclovir (ACV). In vitro drug diffusion studies showed poor penetration of guinea pig skin by BVDU from the cream compared to BVDU from dimethylsulfoxide (DMSO) (0.04 vs. 1.5 microgram/cm2 per h). 5% BVDU cream, 5% BVDU/DMSO, and 5% ACV in polyethylene glycol (PEG) were then compared in the treatment of experimental dorsal cutaneous HSV-1 infection in guinea pigs. Lesion number, total lesion area and virus titer were reduced by all three formulations compared to control sites treated with the corresponding drug vehicles (P less than or equal to 0.01). BVDU cream effected a greater reduction in lesion number (20+ vs. 13%) and total lesion area (40% vs. 28%) than did ACV/PEG and a significantly greater decrease in virus titer (990% vs. 55%, P less than 0.002). BVDU/DMSO was clinically twice as effective as BVDU cream (P less than or equal to 0.01) and reduced lesion virus titers to a similar degree. The results of these studies show that BVDU is a more potent virus-inhibitory agent than ACV in vitro and is superior to topical ACV in vivo when formulated in a simple aqueous cream. The marked efficacy of BVDU/DMSO in the animal model demonstrates the potential of this antiviral if drug delivery is improved.

Absorption↗
PubMed1985

Synthesis and antiviral activity of 11-azapentacyclo[6.2.1.0.0.0]decane.

11-Azapentacyclo[6.2.1.0.0.0]decane (6a) as well as its 6,7-dimethyl derivative 6b was synthesized by a novel, four-step sequence that holds promise for the construction of a variety of cage compounds with bridging nitrogen atoms. The hydrochloride salt of 6a was shown to possess no antiviral activity against either the influenza virus A/Victoria/3/75 or the herpes simplex viruses HSV-1 and HSV-2.

Antiviral Agents↗
PubMed1984

Frequency and duration of patient-observed recurrent genital herpes simplex virus infection: characterization of the nonlesional prodrome.

For assessment of the natural history of patient-observed episodes of genital herpes, 32 patients with culture-proven, recurrent herpes were studied during 340 disease episodes for approximately seven and one-half months. Prodromes were experienced by 29 patients (90.6%) in 201 episodes (59.1%). Nonlesional prodromes were observed in 67 episodes (19.7%) and occurred at least once in 14 patients (43.8%). Vesicles were more likely to occur in men, wet ulcers in women. When all episodes were considered, the time to total healing was 5.65 +/- 3.73 days. Excluding episodes of nonlesional prodrome, the time to total healing was 6.83 +/- 3.7 days. Nonlesional prodromes occur commonly and usually resolve without therapy. Recurrent disease as observed by the patient is shorter than recurrent disease as observed in the clinic; this observation may affect the outcome of patient-initiated therapeutic trials.

Adult↗
PubMed1984

Metabolic fate of (E)-5-(2-bromovinyl)-2'-deoxyuridine in herpes simplex virus- and mock-infected cells.

(E)-5-(2-Bromovinyl)-2'-deoxyuridine is a potent antiherpes compound with far better activity against herpes simplex virus type 1 than type 2. To understand the role of drug metabolism in this differential antiviral activity, we examined the metabolic fate of this drug in virus-infected and mock-infected Vero cells by high-pressure liquid chromatography. After 8 h of incubation in which cells were exposed to 10 micrograms of the drug per ml, 63 pmol/10(6) cells of the parent compound was detected in acid-soluble extracts of mock-infected cells. Herpes simplex virus-infected cells, however, incorporated or metabolized, or both, up to 11,310 pmol/10(6) cells. Type 1-infected cells metabolized the drug to the triphosphate where as many as 5,565 pmol/10(6) cells were detected. In contrast, three strains of type 2-infected cells metabolized the drug to the monophosphorylated nucleotide and no further. The amount of drug getting into the cells was virus strain and inoculum dependent. These studies indicate that poor substrate acceptance of (E)-5-(2-bromovinyl)-2'-deoxyuridine monophosphate by herpes simplex virus type 2-specified thymidylate kinase is an important factor in situ in infected cells, preventing anabolism of the parent compound to its active triphosphorylated form. This may account for its type specificity.

Antiviral Agents↗
PubMed1984

Cytomegalovirus hepatitis: evidence for direct hepatic viral infection using monoclonal antibodies.

Cytomegalovirus-induced hepatitis presented as acute right upper quadrant pain with a cholestatic profile in a middle-aged woman. The presentation was confused by the presence of gallstones. Her course was complicated by pleuritis, atypical lymphocytosis, lymphadenopathy, and transient arthritis. Urine virus cultures grew cytomegalovirus and seroconversion of indirect immunofluorescent antibody to late cytomegalovirus antigen was demonstrated. Biopsies of the patient's liver failed to grow cytomegalovirus or to show viral inclusions. Electron micrographic studies were negative. Biopsy specimens were stained with monoclonal antibodies to cytomegalovirus by an indirect fluorescence technique. Clearly defined inclusions were specifically stained. Both nuclear and cytoplasmic inclusions were demonstrated using monoclonal antibodies CH16 and CH12, respectively. Insofar as we are aware, this is the first reported direct evidence for hepatic viral infection with this virus in a previously healthy adult.

Antibodies, Monoclonal↗
PubMed1983

Drug resistance in malaria: three cases and a review.

Drug resistance has been well documented in two species of malarial parasites. Of greatest concern are the rapid developments in the resistance of Plasmodium falciparum to commonly used therapeutic and chemoprophylactic agents. This species, which is capable of producing life-threatening disease, has shown various levels of resistance in different parts of the world. Also, some strains of the most common species causing relapsing disease, P. vivax, exhibit resistance to primaquine. Three cases of malaria that demonstrate various types of drug resistance are presented in this paper.

Adult↗
PubMed1983

Serotyping of herpes simplex virus isolates: a comparison of BVDU sensitivities, indirect immunofluorescence with monoclonal antibodies, and indirect immunofluorescence with cross-adsorbed rabbit antibodies.

Four methods for typing of herpes simplex virus (HSV) isolates were compared for 43 recent clinical isolates and 3 reference strains of HSV. These isolates were subjected to indirect immunofluorescence using both monoclonal antibodies and cross-adsorbed rabbit antisera. Sensitivity to E-5-(2-bromovinyl)-2'-deoxyuridine (BVDU) was also examined. All isolates which fluoresced with HSV-1 monoclonals were found to be sensitive to BVDU with ID50's ranging from 0.001 to 0.006 micrograms/ml. All isolates labelled as HSV-2 using monoclonal antibodies had ID50's to BVDU ranging from 0.4 to 3.5 micrograms/ml. Results of typing with rabbit cross-adsorbed antisera were less accurate, however. When dilutions were predetermined according to manufacturer's instructions, only 3 of 22 isolates (14%) of HSV-1 were correctly typed. HSV-2 isolates were correctly labelled in 24 of 26 situations (92%). When fluorescence dilution endpoints were compared, however, 21 of 22 (95%) HSV-1 isolates had fluorescence endpoints at a greater dilution with HSV-1 antiserum. Twenty-three of 24 HSV-2 isolates were also correctly typed (96%).

Animals↗
PubMed1983

Susceptibility of recent clinical isolates of herpes simplex virus to 5-ethyl-2'-deoxyuridine: preferential inhibition of herpes simplex virus type 2.

We examined the in vitro susceptibilities of three reference strains and 41 recent clinical isolates of herpes simplex virus types 1 and 2 to 5-ethyl-2'-deoxyuridine. This thymidine analog exerts a type 2-preferential but not a type 2-specific antiviral effect. Utilizing a microtiter assay with BHK-21 cells, we found that the mean (+/- standard deviation) 50% inhibitory dose for herpes simplex virus type 1 isolates was 0.58 +/- 0.30 micrograms/ml as compared with 0.33 +/- 0.20 microgram/ml for herpes simplex virus type 2 isolates. Isolates were typed according to their susceptibilities to (E)-5-(2-bromovinyl)-2'-deoxyuridine and by an indirect fluorescent-antibody technique in which monoclonal antibody combinations were used. A cytotoxicity assay in which the incorporation of [1',2'-3H]deoxyuridine was measured revealed a 50% inhibitory dose of 37.5 micrograms/ml, suggesting a favorable therapeutic index for this compound.

Antibodies, Monoclonal↗
PubMed1983

Prospective randomized trial of piperacillin monotherapy versus carboxypenicillin-aminoglycoside combination regimens in the empirical treatment of serious bacterial infections.

Piperacillin as a single agent was compared in a prospective randomized trial with carboxypenicillin-aminoglycoside combinations in empirical therapy of serious bacterial infections. The difference in the clinical response rates with piperacillin (77% of 26 infection episodes) and combination therapy (75% of 24 infection episodes) were not statistically significant. Fewer adverse effects occurred in the piperacillin-treated group (42%) than in the combination-treated group (71%) (P = 0.0399 by Fisher's exact test), although neither nephrotoxicity nor hypokalemia alone was significantly less frequent in patients receiving piperacillin. However, the emergence of resistant organisms during therapy was more frequent among patients receiving piperacillin alone (42% of patients) than among patients receiving combination therapy (17% of patients) (P = 0.465 by Fisher's exact test). Moreover, emergence of resistance accounted for 5 of 9 patients with treatment failure, superinfection, or both when piperacillin was used as a single agent, compared with 2 of 10 similar patients in the combination group (P = 0.1299 by Fisher's exact test). The use of piperacillin as a single agent in the treatment of serious bacterial infections is not advocated, and the addition of an aminoglycoside to prevent emergence of resistance during empirical therapy of such infections is strongly recommended.

Adult↗
PubMed1982

Antiviral treatment of chronic hepatitis B virus infection: pharmacokinetics and side effects of interferon and adenine arabinoside alone and in combination.

In an uncontrolled trial, 29 patients with chronic hepatitis B virus infection were treated with 93 courses of adenine arabinoside at doses ranging from 2.5 to 15 mg/kg per day. Most patients were treated concomitantly with human leukocyte interferon. Significant, but transient, neurotoxicity was seen with adenine arabinoside therapy in 44% of all courses. Manifestations of toxicity were mainly neurological and ranged from pain syndromes to tremors and, rarely, seizures. Suppression of numbers of lymphocytes was also noted. All effects were reversible with time. The extent of toxicity was dependent upon the dosage of adenine arabinoside. Treatment with interferon appeared to potentiate the occurrence of toxicity with adenine arabinoside. Arabinofuranosylhypoxanthine serum levels increased in a dose-dependent manner and tended to accumulate in interferon-treated hepatitis patients during a course of therapy. Elevated blood levels and drug accumulation were associated with toxicity in a significant fashion. Human leukocyte interferon was administered to 38 patients in 113 separate courses. Interferon side effects were rapidly reversible upon cessation of therapy. These included initial fever, myalgias, and hair loss as well as suppression of granulocytes, platelets, and lymphocytes in the blood.

Drug Therapy, Combination↗
PubMed1982

Inactivation of S-adenosylhomocysteine hydrolase during adenine arabinoside therapy.

To assess for possible inhibition of cellular transmethylation during adenine arabinoside (ara-A) therapy, S-adenosylhomocysteine hydrolase activity was analyzed in 10 patients with chronic hepatitis B virus infection. In six patients receiving ara-A, enzyme activity was suppressed to 0-2% of control erythrocyte enzyme activity. This decrease in enzyme activity was evident within 4 h of starting the drug infusion and continued for 7 d after cessation of therapy. S-adenosylhomocysteine hydrolase activity of peripheral mononuclear cells was also measured in two patients receiving ara-A. Suppression to as low as 3.5% of pretreatment levels was found; however, marked fluctuations with partial return of enzyme activity during therapy was also observed in mononuclear cells. Inhibition of an enzyme involved in transmethylation reactions was observed in patients during ara-A therapy. This could contribute to the side effects and antiviral properties of ara-A.

Adenosylhomocysteinase↗
PubMed1981

Antiviral treatment of chronic hepatitis B virus infection. I. Changes in viral markers with interferon combined with adenine arabinoside.

Twenty patients with chronic active hepatitis and 12 patients with chronic persistent hepatitis associated with hepatitis B virus (HBV) infection were treated with human leukocyte interferon or adenine arabinoside alone or in combination. With interferon alone, four of 16 patients showed a permanent disappearance of HBV-associated DNA polymerase (DNAP) activity from serum. Of six patients treated with adenine arabinoside alone, only one patient became permanently DNAP-negative. With a regimen of multiple cycles of combined interferon and adenine arabinoside, seven of 16 male patients became permanently DNAP-negative. Of 69 patients who met the criteria for admission to the program, spontaneous decreases in DNAP activity without treatment were observed in only 9% during a mean observation period of 10 months. In general, patients with chronic active hepatitis, those who are female, and those with a history of recent steroid therapy responded to the antiviral agents significantly better than did the other patients.

Adult↗