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Biomedical subjects

H Machida

Publications and source records attributed to H Machida.

At least 109 records · Page 6Linked to original sources
PubMed1988

Effects of various nucleosides on antiviral activity and metabolism of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against herpes simplex virus types 1 and 2.

Uptake of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) into herpes simplex virus type 1 (HSV-1)- and 2 (HSV-2)-infected cells was elevated about 190 to 40 times, compared with that into mock-infected human embryo lung fibroblast cells. Uptake was not enhanced by infection with thymidine kinase-negative HSV-1 and HSV-2 mutants, however. In HSV-1-infected cells, 9.7% of BV-araU was phosphorylated to BV-araU triphosphate, but only 1.1% was phosphorylated in HSV-2-infected cells. The antiviral effect, uptake, and turnover of BV-araU were inhibited significantly by thymidine (dThd), moderately by deoxyuridine, and not at all by deoxycytidine. On the other hand, the antiviral activity of acyclovir (ACV) was inhibited only by dThd. The effect of BV-araU was influenced by dThd and dThd phosphates (mono-, di-, and triphosphates), and the effect of ACV was influenced only by dThd, which competitively inhibited the phosphorylation of ACV to ACV monophosphate. The combination of 5-fluorodeoxyuridine (FUdR)-BV-araU or FUdR-ACV had a synergistic effect on HSV-1 and HSV-2 replication. The effect of FUdR on the turnover of BV-araU in HSV-1- and HSV-2-infected cells was analyzed by high-performance liquid chromatography. In HSV-1-infected cells, 86% of the BV-araU was phosphorylated to BV-araU triphosphate, but no effect was observed in HSV-2-infected cells, in which 98% of the BV-araU remained as BV-araU monophosphate.

Antiviral Agents↗
PubMed1988

Efficacies of antiherpesvirus nucleosides against two strains of herpes simplex virus type 1 in Vero and human embryo lung fibroblast cells.

Antiviral activities of five nucleoside analogs against the VR-3 and WT-34 strains of herpes simplex virus type 1 (HSV-1) were investigated in Vero and human embryo lung fibroblast (HEL) cells. In HEL cells, the compounds showed antiviral activities against both strains of HSV-1, but in Vero cells, the antiviral activities of the compounds were reduced in proportion to their antiviral indexes (the 50% inhibitory dose [ID50] for cell growth divided by the 50% plaque reduction dose for virus). The ratio of the ID50 in Vero cells to the ID50 in HEL cells was larger in VR-3-infected cells than in WT-34-infected cells. The following results were obtained. (i) Thymidine kinase (TK; EC 2.7.1.21) activity in the VR-3- or WT-34-infected Vero cells was about half that in VR-3- or WT-34-infected HEL cells. Induction of viral TK was especially low in the VR-3-infected Vero cells. (ii) The ID50 of the plaque reduction assay in hypoxanthine, aminopterin, and thymidine medium revealed that the activity of cellular thymidylate synthetase (EC 2.1.1.45) was important in viral replication in VR-3-infected Vero cells. (iii) The VR-3-infected cells required larger thymidine and thymidine phosphate pools for viral replication than the WT-34-infected cells did, although uptake of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl) uracil into infected cells was equal for both strains. (iv) In the VR-3-infected Vero cells, the quantity of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil triphosphate was smaller than that in VR-3-infected HEL cells and WT-34-infected Vero and HEL cells.

Acyclovir↗
PubMed1988

Comparison of two bromovinyl nucleoside analogs, 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil and E-5-(2-bromovinyl)-2'-deoxyuridine, with acyclovir in inhibition of Epstein-Barr virus replication.

The effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU), a new antiviral drug, on Epstein-Barr virus (EBV) was studied and compared with those of E-5-(2-bromovinyl)-2'-deoxyuridine (BVdU) and acyclovir (ACV). BV-araU effectively inhibited EBV replication both in superinfected Raji cells and in virus producer P3HR-1(LS) cells, as determined by density gradient centrifugation, in situ cytohybridization with an EBV DNA probe, and cRNA-DNA hybridization. The 50% effective doses for viral DNA replication were 0.26, 0.06, and 0.3 microM for BV-araU, BVdU, and ACV, respectively. The relative efficacy on the basis of the in vitro therapeutic index was BVdU (6,500) greater than BV-araU (1,500) greater than ACV (850). Synthesis of EBV-induced polypeptides with molecular weights of 145,000 and 140,000 was inhibited by these drugs. Kinetic analysis of reversibility of inhibition of EBV DNA replication after removal of the drugs indicated that BV-araU, like BVdU, has a more prolonged inhibitory effect than ACV. These results indicate that the 2' OH group in the arabinosyl configuration of BV-araU results in marked reduction in anti-EBV activity while slightly diminishing cytotoxicity.

Acyclovir↗
PubMed1987

Antiviral activity of various 1-beta-D-arabinofuranosyl-E-5-halogenovinyluracils and E-5-bromovinyl-2'-deoxyuridine against salmon herpes virus, Oncorhynchus masou virus (OMV).

1-beta-D-Arabinofuranosyl-E-5-bromovinyluracil (BVaraU), 1-beta-D-arabinofuranosyl-E-5-iodovinyluracil (IVaraU), 1-beta-D-arabinofuranosyl-E-5-chlorovinyluracil (CVaraU) and 1-beta-D-arabinofuranosyl-5-vinyluracil (VaraU) were examined for antiviral activity against salmon herpesvirus, Oncorhynchus masou virus (OMV) in vitro using Yamame (Oncorhynchus masou) kidney cells (YNK). BVaraU, IVaraU, CVaraU and VaraU were highly active against OMV; 50% inhibitory concentration (IC50): 0.01, 0.003, 0.003, 0.003 microgram/ml, respectively. The IC50 of 5-bromovinyl-2'-deoxyuridine (BVDU) was 0.3 microgram/ml. The lower activity may be due to cleavage of it N-glycosyl linkage by pyrimidine nucleoside phosphorylases (i.e. thymidine phosphorylase) during the incubation period. The arabinofuranosyl counterparts are resistant to this (these) enzyme(s). Both OMV-induced DNA polymerase and cellular DNA polymerase alpha were strongly inhibited by BVaraU 5'-triphosphate (BVaraUTP). In an in vivo study, daily immersion of OMV-infected chum salmon (Oncorhynchus keta) fry into aqueous solution of BVaraU (5 micrograms/ml, 30 min/day, 30 times) did not increase the life span of infected fish.

Animals↗
PubMed1987

Esophageal function following Livaditis repair of long gap esophageal atresia.

Proximal pouch esophagomyotomy (Livaditis) allows for repair of long gap esophageal atresia (EA). Postoperative esophageal functional studies in these patients are lacking. Six such infants were followed for up to 42 months. Esophageal function was assessed clinically and by barium swallow, manometry, 24 hr pH monitoring, esophagoscopy, and biopsy. Operative complications included two minor anastomotic leaks and two asymptomatic diverticula at the myotomy site. All patients had dysmotility on barium swallow. Gastroesophageal reflux (GER) was seen in four. Manometry showed a variable aperistaltic segment in each infant but lower esophageal sphincter pressures and relaxation were retained. Twenty-four hour pH monitoring showed an increase in frequency and duration of GER. All four patients biopsied had esophagitis. Five of the six patients showed normal growth velocity. Livaditis modified repair of EA was not associated with significant surgical complications. Esophageal motility showed abnormalities similar to those reported after the standard repair of EA. Myotomy did not adversely affect the esophageal function.

Biopsy↗
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↗
PubMed1987

Palatopharyngeal incompetence in association with esophageal dysmotility, acquired glucocorticoid deficiency, and deficient tear production.

An 8 1/2-year-old male is described with the rare triad of acquired adrenal insufficiency, esophageal dysfunction, and alacrima. In addition, he had velopharyngeal insufficiency, which is a previously unreported feature of this syndrome. Although the pathophysiology of this disorder remains to be demonstrated, a defect may be present, linking hormone-receptor cyclic AMP-mediated processes with abnormalities in parasympathetic and voluntary neuronal innervation or transmission.

Child↗
PubMed1986

Comparison of susceptibilities of varicella-zoster virus and herpes simplex viruses to nucleoside analogs.

The susceptibilities of varicella-zoster virus (VZV) and herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) to 17 nucleoside analogs were compared by a plaque reduction assay with human embryonic lung fibroblast cells. The susceptibility of VZV to certain nucleoside analogs was different from that of HSV-1. Against VZV the 5-halogenovinyl-arabinosyluracils were the most potent of the compounds tested.

Antiviral Agents↗
PubMed1986

Susceptibility of varicella-zoster virus to thymidine analogues.

Ten strains of varicella-zoster virus (VZV) were tested for susceptibility to 17 nucleoside analogues by a plaque reduction assay using human embryonic lung fibroblast cells. The compounds employed were 5-substituted arabinosyluracils and 2'-deoxyuridines, 2'-fluoro-arabinosylpyrimidines (F-araPyr) and acyclovir. In terms of the 50% plaque reduction dose (PD50), 4- to 40-fold difference were found between the 10 strains of VZV in susceptibilities to each compound. VZV was highly susceptible to 5-halogenovinyl-arabinosyluracils (XV-araUs); the PD50 values of these compounds were less than 0.001 micrograms/ml. VZV was much more susceptible than herpes simplex virus (HSV) type 1 to XV-araUs, but less susceptible than either HSV type 1 or type 2 to 5-ethyl-2'-deoxyuridine, 5-ethyl-arabinosyluracil and acyclovir.

Acyclovir↗
PubMed1984

In vitro and in vivo antiviral activity of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (BV-araU) and related compounds.

BV-araU and related compounds such as CV-araU, IV-araU and BV-araUMP showed marked activity against herpes simplex virus type 1 (HSV-1) in human embryonic lung fibroblast cells. BV-araU, CV-araU and BV-araUMP were also effective in mice infected intracerebrally with HSV-1. Especially, when mice were infected with a low dose of virus, both intravenous and oral treatment with BV-araU proved capable of increasing the mean survival time and decreasing the final mortality of the infected mice. The in vivo anti-HSV-1 activity of BV-araU was comparable to that of BVDU. BV-araU exhibited little toxicity for mice.

Animals↗
PubMed1984

Antigenicity of mouse interferons induced in vitro and in vivo by poly(I).poly(C).

Various mouse IFNs induced by poly(I).poly(C) or poly(ICLC) were analyzed for the antigenic types by neutralization tests using anti-IFN-alpha and anti-IFN-beta antibodies. The IFN samples included IFNs produced by L cells, by spleen cells in vitro and ex vivo, and in plasma of mice injected with the inducers. L-cell IFN was estimated to consist of IFN-beta and IFN-alpha at a ratio of about 80:20. Spleen IFNs also consisted of both IFN species, but IFN-alpha was the major component. Blood IFN samples obtained 1-4 h after injection of poly(I).poly(C) or poly(ICLC) consisted of the two molecular species, whereas the samples 8 and 24 h after injection contained only IFN-alpha. High levels of IFN activity (IFN-alpha) persisted much longer in the circulation of mice injected with poly(ICLC) than in mice injected with poly(I).poly(C).

Animals↗
PubMed1983

Oxidation of acetylpolyamines by extracellular polyamine oxidase produced by Penicillium sp. No. PO-1.

The oxidation of acetylpolyamines by an extracellular polyamine oxidase of Penicillium sp. No. PO-1 was investigated. The optimal pH value for oxidation of acetylpolyamines was 6.0. The purified enzyme oxidized spermidine, spermine, N1-acetylspermidine, N8-acetylspermidine, N1,8-diacetylspermidine, N1-acetylspermine and N1,12-diacetylspermine. The relative velocities for oxidation of acetylpolyamines were lower than those of spermidine and spermine. The Km values for oxidation of acetylpolyamines were higher than those of spermidine and spermine. The enzyme split N1-acetylspermidine and N8-acetylspermidine at the same position of the linkage as in spermidine oxidation. N1-Acetylspermine was changed to N1-acetylspermidine. This oxidation mechanism was different from that of rat liver polyamine oxidase. N1-Acetylspermine inhibited the oxidation of spermine. Putrescine, N8-acetylspermidine and N1,12-diacetylspermine also inhibited the N1-acetylspermidine oxidation by the enzyme.

Animals↗