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Biomedical subjects

C Shipman

Publications and source records attributed to C Shipman.

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

Pyrrolo[2,3-d]pyrimidine nucleosides as inhibitors of human cytomegalovirus.

Seven arabinosyl, 2'-deoxyribosyl, and ribosyl pyrrolo[2,3-d]pyrimidines were evaluated in vitro for activity against human cytomegalovirus and for cytotoxicity in primary and established cell lines of human origin. The parent ribosyl analogs exhibited little antiviral selectivity owing to high cytotoxicity. In contrast, ara-tubercidin, ara-toyocamycin, ara-sangivamycin, and deoxysangivamycin exhibited selectivity between antiviral effect (measured by plaque or titer reduction or both) and cytotoxicity (measured microscopically and by incorporation of radioactive precursors into DNA, RNA, and protein). The selectivity (in vitro therapeutic indexes) for these four compounds ranged from 2 to 40. The two sangivamycin analogs were the most potent and selective. Ara-sangivamycin, for example, inhibited virus replication 10(5)-fold at a concentration (10 microM) which produced only partial inhibition of cell growth and labeled precursor incorporation. The four arabinosyl and deoxyribosyl nucleosides appeared to act by inhibition of viral DNA synthesis as quantitated by DNA-DNA dot blot hybridization. These four analogs also were tested for activity against two strains of type 1 herpes simplex virus by a plaque reduction assay. Unexpectedly, all compounds inhibited herpes simplex virus to a lesser extent than human cytomegalovirus.

Animals↗
PubMed1987

Cost effectiveness of prevaccination screening for hepatitis B antibody.

The cost effectiveness of screening for hepatitis B antibodies prior to instituting a vaccination program was investigated. Prevaccination screening tests for anti-HBs were performed on sera from 295 faculty and staff. Anti-HBs positive titers were found for 58 persons, and 43 (14.6 percent) of these had titers high enough to confer immunity. The cost of screening 295 persons was $1,666.64, or $5.65 per participant. By not vaccinating 43 persons, $4,498.23 was saved. A prevaccination screening would be most cost effective if only faculty with patient contact were screened.

Cost-Benefit Analysis↗
PubMed1986

Selective inhibition of herpes simplex virus ribonucleoside diphosphate reductase by derivatives of 2-acetylpyridine thiosemicarbazone.

The effects of thiosemicarbazone derivatives of 2-acetylpyridine on mammalian and viral ribonucleoside diphosphate reductases were investigated. The enzymes were partially purified from uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells by sequential salt fractionation with streptomycin sulfate and ammonium sulfate and by affinity chromatography on ATP-agarose. The five thiosemicarbazone derivatives investigated were all potent inhibitors of the virus-induced reductase. Fifty percent inhibitory concentrations (IC50 values) range from 2 to 13 microM. Four of the five derivatives also were inhibitors of the host cell reductase (IC50 values = 7-34 microM). A semicarbazone was inactive against the cellular enzyme and relatively weak as an inhibitor of the viral enzyme (IC50 = 340 microM). Four of six compounds were preferential inhibitors of the viral reductase based on a comparison of IC50 values (5- to greater than 85-fold difference). Kinetic experiments revealed that inhibition of the HSV-1 reductase by the thiosemicarbazones was noncompetitive with respect to CDP and dithiothreitol. A comparison of the inhibitory effects of 2-acetylpyridine thiosemicarbazone itself on viral reductase and on virus replication in vitro demonstrated a similarity in the dose-response relationships for the two parameters. This observation supports the hypothesis that the HSV-induced ribonucleoside diphosphate reductase is an important target for the design of antiviral drugs.

Antiviral Agents↗
PubMed1986

Thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1-acetylisoquinoline, and related compounds as inhibitors of herpes simplex virus in vitro and in a cutaneous herpes guinea pig model.

A series of 111 thiosemicarbazones of 2-acetylpyridine, 2-acetylquinoline, 1-acetylisoquinoline, and related compounds were evaluated as inhibitors of herpes simplex virus in vitro and in a cutaneous herpes guinea pig model. All derivatives tested were potent inhibitors of virus replication with mean 50% inhibitory concentrations of 1.1 micrograms/ml for both type 1 and 2 herpes simplex virus. Inhibitory concentrations for cellular protein and DNA synthesis were considerably higher for many compounds resulting in in vitro therapeutic indices ranging from greater than 100 (highly selective) to less than 1 (negatively selective). All compounds were tested for dermal toxicity following topical administration of saturated solutions in 1,3-butanediol to the shaved, depilated skin of guinea pigs. Approximately 50% of the compounds produced slight to no dermal toxicity whereas the remaining compounds produced moderate to severe dermal toxicity. 28 compounds were evaluated in the cutaneous herpes guinea pig model against herpes simplex virus type 1. A number of N4-monosubstituted 2-acetylpyridine thiosemicarbazones produced highly significant reductions in days to healing and lesion score without producing untoward dermal toxicity. Structure-activity relationships revealed that a reduction of the azomethine bond in the molecule (i.e., conversion of a thiosemicarbazone to a thiosemicarbazide) greatly diminished dermal toxicity apparently without producing a proportional decrease in antiviral activity.

Animals↗
PubMed1986

Structure-activity relationships among alpha-(N)-heterocyclic acyl thiosemicarbazones and related compounds as inhibitors of herpes simplex virus type 1-specified ribonucleoside diphosphate reductase.

2-Acetylpyridine thiosemicarbazone, a potent antiviral drug, and 13 analogues were examined as inhibitors of partially purified herpes simplex virus type 1-specified ribonucleoside diphosphate reductase. N4,N4-Azacycloheptane derivatives were more active than their N4-unsubstituted analogues. Selenosemicarbazones were similar in potency to their thiosemicarbazone congeners, whereas a related semicarbazone was much less active. Maximum inhibition was observed when an ethylidene side-chain was present in the compounds. No discernible trend in potency was observed when the pyridine moiety was replaced by quinoline or isoquinoline. Thiosemicarbazide derivatives were less potent than their unsaturated thiosemicarbazone analogues. Inhibitory potencies increased at longer incubation times consistent with the hypothesis that thiosemicarbazones inactivate the enzyme in a time-dependent manner.

Ribonucleoside Diphosphate Reductase↗
PubMed1984

Metabolism of arabinosyladenine in herpes simplex virus-infected and uninfected cells. Correlation with inhibition of DNA synthesis and role in antiviral selectivity.

The metabolism of 9-beta-D-arabinofuranosyladenine (ara-A, vidarabine) and its effects on DNA synthesis were compared in uninfected and herpes simplex virus type-1 (HSV-1)-infected KB cells. In the absence of an inhibitor of adenosine deaminase, ara-A was deaminated to 9-beta-D-arabinofuranosylhypoxanthine and phosphorylated to ara-A-5'-mono-, di- and triphosphates in both types of cells. When an inhibitor of adenosine deaminase (coformycin) was added to cell cultures, nucleotides were the only metabolites detected--primarily the 5'-triphosphate of ara-A (aATP). Detailed studies performed in the presence of coformycin established that the net rate and extent of aATP formation were the same in uninfected and HSV-1-infected cells. After a 12-hr exposure to 50 microM ara-A, intracellular concentrations of aATP were approximately 40 microM. Levels of aATP correlated directly with inhibition of total DNA synthesis. Approximately 0.7 microM aATP was required for 50% inhibition of total DNA synthesis in both uninfected and HSV-1-infected cells. Following removal of ara-A-containing culture medium, aATP levels in uninfected cells declined with a half-life of 3.2 hr. In marked contrast, the half-life in HSV-1-infected cells was 9.3 hr; this may explain why as little as a 3-hr exposure to ara-A resulted in a significant HSV-1 titer reduction. Taken together, the data show that when ara-A was removed from culture medium, levels of aATP persisted longer in HSV-1-infected cells thereby prolonging antiviral activity. This effect could be important in vivo where levels of ara-A oscillate with dosing schedule.

Arabinose↗
PubMed1981

Tritiated thymidine incorporation does not measure DNA synthesis in ribavirin-treated human cells.

When the incorporation of tritiated thymidine into acid insoluble material was measured, ribavirin appeared to be a potent inhibitor of DNA synthesis in KB cells and human lymphocytes. Inhibition was nearly 100-fold less, however, when DNA synthesis was measured by incorporation of phosphorus-32-labeled phosphate or by DNA fluorescence. The potent inhibition detected by incorporation of tritiated thymidine into DNA actually was the result of a potent effect on the labeling of deoxythymidine triphosphate, not on the synthesis of DNA.

Cells, Cultured↗
PubMed1979

A clinical trial of topically applied 3 percent vidarabine against recurrent herpes labialis.

Seventy-six participants were enrolled in a clinical trial to determine therapeutic effectiveness of 3 percent vidarabine applied topically to recurrent perioral herpetic lesions. Following a 6- to- 12-month natural history phase, a 12-month clinical trial was conducted. Seventy participants developed 463 lesions during 361 episodes. Three percent vidarabine in a water-miscible gel was applied six times daily for 7 days to each lesion in the experimental group. Identically packaged placebo was used by the control group. Group assignment was by computer-generated randomization. Lesion size was reduced when vidarabine, rather than placebo, was applied. The difference was statistically significant (Student's t test, P = 0.02). Vesiculation followed tingling more rapidly when vidarabine, rather than placebo, was applied prior to vesiculation (P = 0.05). No significant difference between the two groups was found in episode frequency or lesion duration. Adverse reactions to vidarabine were not experienced.

Administration, Topical↗
PubMed1978

Kinetics of drug transport and concurrent metabolism in human cell cultures I: theory.

A method for evaluating the passive permeability and single-step metabolism of drugs in suspension cultures of mammalian cells was formulated assuming linear kinetics. It was assumed that the metabolizing enzymes are driven by endogenous substrates present in steady-state quantities. The presence of the drug in radiolabeled tracer quantities was assumed to cause only a small perturbation from the endogenous steady-state operating point. The time course solutions for the drug and its metabolite are given in terms of macroscopic constants, and their physical interpretations are given in terms of metabolic and transport parameters.

Biological Transport↗