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Biomedical subjects

F S Philips

Publications and source records attributed to F S Philips.

At least 19 recordsLinked to original sources
PubMed1985

Biotransformation and elimination of [2-14C]-1-(2-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine in immunosuppressed patients with herpesvirus infections.

The metabolism of the drug [2-14C]-1-(2'-deoxy-2'-fluoro-beta-D -arabinofuranosyl)-5-iodocytosine (FIAC), a potent inhibitor of herpesvirus replication, was studied in immunosuppressed patients with herpesvirus infections. FIAC was administered intravenously by 15-min infusion and by mouth 24 h later to four patients at doses of 50 or 100 mg/m2. FIAC was cleared from the plasma primarily by biotransformation in liver, kidney, and peripheral blood, with a terminal-phase half-life of 0.92 to 1.80 h (mean, 1.36 h) after intravenous administration. The area under the concentration-time curve from zero to infinity (AUC0-infinity) for FIAC was 1.6 to 4.7% (mean, 3.4%) of the AUC0-infinity for total radioactivity. 1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was the major metabolite; the AUC0-infinity for FIAU was 54.3 to 72.5% (mean, 63.4%) of the AUC0-infinity for total radioactivity. The terminal-phase half-life for FIAU was 3.32 to 4.49 h (mean, 3.91 h); FIAU was cleared from plasma by renal elimination and further biotransformation. lesser amounts of 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)uracil, 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)cytosine, the glucuronide conjugates of these metabolites, and the glucuronide conjugates of FIAC and FIAU were also formed. A comparison of the AUC0-infinity for total radioactivity after intravenous and oral administration suggested that nearly all of the oral dose was absorbed. Plasma levels of FIAU, also a potent inhibitor of herpesvirus replication in vitro, exceeded the 50% effective dose for herpes simplex virus and varicella-zoster virus as late as 12 h after administration of FIAC.

Adult↗
PubMed1984

Metabolic competition studies of 2'-fluoro-5-iodo-1-beta-d-arabinofuranosylcytosine in vero cells and herpes simplex type 1-infected vero cells.

2'-Fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC) is a potent antiviral agent with minimal cytotoxicity. In Vero cells, incorporation of labeled dCyd and dThd into the acid-insoluble DNA fraction was, respectively, competitively and noncompetitively inhibited by FIAC. In herpes simplex type 1 (HSV-1) infected Vero cells, these inhibition patterns became noncompetitive. The inhibition constants of FIAC on dThd and dCyd incorporation into the acid-insoluble fraction during a 15-min period were greater than 30 microM which were much higher than the antiviral concentration of FIAC (ED90 = 0.003-0.013 microM) for continuous exposure. Incorporation of dUrd into acid-insoluble DNA was inhibited by 10 microM FIAC in HSV-1-infected Vero cells, but not in uninfected cells. The radioactivity of [2-14C]FIAC was incorporated into the acid-insoluble DNA fraction, and this incorporation in uninfected cells was strongly inhibited by 10 microM dCyd but not by dThd. By contrast, the incorporation in HSV-1-infected Vero cells was strongly inhibited by 10 microM dThd but not by dCyd. These data indicate that FIAC behaves metabolically like dThd, dUrd, or 5-iodo-dUrd in HSV-1-infected cells but like dCyd in noninfected cells. Thus, combined use of dCyd and FIAC may reduce cytotoxicity of FIAC or incorporation of FIAC into host cell DNA without affecting its antiviral activity. This finding is of significance since, for practical reasons, incorporation of FIAC into host cell DNA needs to be reduced as much as possible.

Animals↗
PubMed1983

Kinetic properties and inhibition of Acinetobacter glutaminase-asparaginase.

Kinetic parameters, substrate specificity and exclusivity of ligands at binding sites of L-glutaminase-L-asparaginase purified from Acinetobacter glutaminasificans were studied in order to gain knowledge about the dual activities of this enzyme and its inhibition by structural analogs. Both L-glutamine and L-asparagine, which showed similar Km (4 approximately 7 X 10(-5) M) and Vmax (molecular activity 1.0 min-1) values, were competitive with each other for the substrate binding site. The products, L-glutamic acid and L-aspartic acid, showed competitive inhibition with respect to either L-glutamine or L-asparagine as substrates. Multiple inhibition of the glutaminase activity by L-glutamic acid and L-aspartic acid indicated that these ligands are mutually exclusive at the product-releasing site. The initial rates of both of the enzyme's activities were competitively inhibited by the following inhibitors (in rates of both of the enzyme's activities were competitively inhibited by the following inhibitors (in decreasing order of activity): 6-diazo-5-oxo-L-norleucine (DON), L-methionine sulfoximine, azaserine, and Acivicin. DON and azaserine inhibited both the asparaginase and glutaminase activities in a time-dependent and irreversible manner. The kinetic data suggest an ordered mechanism with glutamine or asparagine as the first substrate and glutamic acid or aspartic acid, respectively, as the last product. These results also suggest that a single mechanism and a single set of binding sites are responsible for catalyzing both of the enzyme's activities. The data also showed that succinylated enzyme, which has a 10-fold increase of plasma half-life in animals and humans and, thus, has benefit as a cancer chemotherapeutic agent, retained its catalytic activity and maintained Km and Vmax values similar to the native enzyme.

Acinetobacter↗
PubMed1983

Uptake, initial effects, and chemotherapeutic efficacy of harringtonine in murine leukemic cells sensitive and resistant to vincristine and other chemotherapeutic agents.

[3H]Harringtonine was shown to be taken up rapidly by L1210/0 cells using a fast-mixing, fast-separating technique and was retained with a slow rate of limited release to the medium. Cells resistant to vincristine (L1210/VCR) showed impaired capability to take up the drug at 20 degrees. Its initial uptake in L1210 sublines in vitro was: L1210/0 greater than L1210/cyclophosphamide, L1210/1-beta-D-arabinofuranosylcytosine, L1210/6-mercaptopurine greater than L1210/5-fluorouracil, L1210/Adriamycin greater than L1210/VCR. In [3H]harringtonine-preloaded cells, L1210/0 retained significantly more radioactivity than did L1210/VCR cells after repeated washing with fresh medium at 37 degrees. The radioactivity appeared to be predominantly bound to the microsomal fractions. [3H]Leucine incorporation into protein in L1210/0 cells was inhibited 90% within 15 min by harringtonine (0.5 micrograms/ml); incorporation of [3H]thymidine into DNA and [3H]cytidine into RNA was much less inhibited and showed an apparent lag of onset for 5 and 10 min, respectively. The relative potency of harringtonine to inhibit [3H]leucine incorporation in the above sublines in vitro follows an order similar to their rates of uptake of harringtonine by these sublines of cells. The efficacy of harringtonine, 2.4 or 3.6 mg/kg i.p., in increasing the life span of C57BL/6 X DBA/2 F1 mice bearing the sublines of leukemic cells, on the average, was: L1210/0 greater than L1210/cyclophosphamide, L1210/6-mercaptopurine greater than L1210/1-beta-D-arabinofuranosylcytosine, L1210/5-fluorouracil greater than L1210/Adriamycin, L1210/VCR. These results suggest that: (a) protein synthesis is the major initial target for the effect of harringtonine; (b) harringtonine bound more tightly to the cellular components of VCR-sensitive leukemic cells than to VCR-resistant cells; and (c) cellular uptake of harringtonine and the relative potency of inhibiting protein synthesis in sublines have a rank order similar to the chemotherapeutic efficacy of harringtonine in these cells.

Alkaloids↗
PubMed1983

Phase I evaluation of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine in immunosuppressed patients with herpesvirus infection.

2'-Fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine (FIAC) is a potent selective inhibitor of the replication of herpes simplex virus types 1 and 2 (HSV-1, HSV-2), varicella zoster virus, and cytomegalovirus in cell culture systems. FIAC produces an unequivocal therapeutic effect in mice that have been inoculated with a lethal burden of HSV-1. We have administered FIAC to 32 host compromised patients, 30 with advanced cancer, who were experiencing acute herpesvirus infections (varicella zoster, 29; HSV-1, 2; HSV-2, 1); the drug was given by 20 min i.v. infusion twice a day for 7 days. The dosage levels explored were 60, 120, 240, 400, and 600 mg/sq m/day. Drug-induced myelosuppression became evident at 600 mg/sq m/day; thrombocytopenia exceeded leukopenia. The toxic low dose was 400 mg/sq m/day with mild nausea and rare myelosuppression. All 24 varicella zoster patients with cutaneous disease receiving FIAC, greater than or equal to 120 mg/sq m/day, experienced stabilization of cutaneous lesions within 48 to 72 hr; healing began promptly thereafter.

Antiviral Agents↗
PubMed1982

Quantitative autoradiographic mapping of herpes simplex virus encephalitis with a radiolabeled antiviral drug.

2'-Fluoro-5-methyl-l-beta-D-arabinosyluracil (FMAU) labeled with carbon-14 was used to image herpes simplex virus type 1-infected regions of rat brain by quantitative autoradiography. FMAU is a potent antiviral pyrimidine nucleoside which is selectively phosphorylated by virus-coded thymidine kinase. When the labeled FMAU was administered 6 hours before the rats were killed, the selective uptake and concentration of the drug and its metabolites by infected cells (defined by immunoperoxidase staining of viral antigens) allowed quantitative definition and mapping of HSV-1-infected structures in autoradiograms of brain sections. These results show that quantitative autoradiography can be used to characterize the local metabolism of antiviral drugs by infected cells in vivo. They also suggest that the selective uptake of drugs that exploit viral thymidine kinase for their antiviral effect can, by appropriate labeling, be used in conjunction with clinical neuroimaging techniques to define infected regions of human brain, thereby providing a new approach to the diagnosis of herpes encephalitis in man.

Animals↗
PubMed1982

Incorporation of metabolites of 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine into deoxyribonucleic acid of neoplastic and normal mammalian tissues.

The radioactivity of 14C-labeled 2'-fluoro-5-iodo-1-beta-D-arabinofuranosylcytosine ([2-14C]-FIAC), a new and potent antiherpetic agent, was shown previously to be incorporated into the DNA fractions of mammalian and neoplastic tissues. The present work was undertaken to learn the nature of the incorporated moieties. Enzyme degradation of highly purified DNA from the small intestine of mice treated with [2-14C]FIAC and analysis of the resulting nucleosides failed to reveal the presence of unchanged FIAC. Rather, three metabolites were found, namely, the 2'-fluoro-1-beta-D-arabinofuranosyl nucleosides of cytosine (FAC), thymine (FMAU) and 5-iodouracil (FIAU). Labeled metabolites of FIAC were also found in the DNA isolated from P815 leukemic cells in mice given [2-14C]FIAC. It is of interest to note that FMAU, FIAU and FAC are, like FIAC, potent antiherpetic agents.

Animals↗
PubMed1982

Phase I clinical trial and pharmacokinetics of 4'-carboxyphthalato(1,2-diaminocyclohexane)platinum(II).

4'-Carboxyphthalato(1,2-diaminocyclohexane)platinum(II) is a new, second generation platinum analog which had demonstrated in vitro activity in L1210 cell lines resistant to cisplatin and had less nephrotoxicity than did cisplatin in preclinical animal testing. A Phase I trial with this agent has been performed in 45 patients with advanced refractory cancers. Nine dosage levels, ranging from 40 to 800 mg/sq m, were studied. Major toxicities seen were myelosuppression, nephrotoxicity (which was generally mild), nausea and vomiting (which was quantitatively less than that seen with cis-platin), allergic reactions, and a peripheral neuropathy. The dose-limiting toxicity was thrombocytopenia. Pharmacokinetics performed at three dosage levels indicates that 4'-carboxyphthalato-(1,2-diaminocyclohexane)platinum(II) has a long t1/2 of 20 to 30 hr (total platinum) and is only partially excreted in the urine and that a high proportion of the drug is nonfilterable within 30 to 60 min of administration. Therapeutic responses were seen in nasopharyngeal carcinoma, adenocarcinoma of the cervix, and lung and gastric cancer. As a starting dose for Phase II studies, which are planned for patients with ovarian, testicular, lung, gastric, and esophageal cancers, 640 mg/sq m given every 3 to 4 weeks is recommended.

Creatinine↗
PubMed1981

Low dose injectable contraceptive norethisterone enanthate 20mg monthly--I. Clinical trials.

Clinical trials were undertaken with an injectable low dose progestational contraceptive, norethisterone enanthate 20 mg monthly (Net-en - 20). Data from the study indicate that Net-en - 20 is an effective contraceptive with lower incidence of menstrual cycle disturbances than the currently used injectable progestogens. There was a prompt return of fertility after the withdrawal of the drug. Net-en - 20 did not have any adverse effect on maternal nutritional status as assessed by anthropometric indices of nutritional status, and clinical sign of nutritional deficiencies or on lactational performance as assessed by mothers' impression on milk output and mean duration of lactation.

Actuarial Analysis↗
PubMed1979

Metabolism and effects of 5-(beta-D-ribofuranosyl)isocytosine in P815 cells.

5-(beta-D-Ribofuranosyl)isocytosine (psi l Cyd), a C-nucleoside, has been shown to be active against P815 leukemia in mice. In P815 cells treated with [2-14C]psi l Cyd, we have detected radioactivity in nucleotide fractions and in RNA and DNA. Degradation to nucleosides of the labeled triphosphate nucleotide fraction and of RNA showed that the radioactivity present was chromatographically identical to psi l Cyd. Half-saturation concentrations for the incorporation of [2-14C]psi l Cyd into the triphosphate nucleotide fraction and into RNA and DNA were 370, 280, and 94 microgram/ml, respectively, which were greater than 100-fold higher than those for tritiated cytidine. The incorporation of psi l Cyd was competitively inhibited by cytidine. Phosphorylation and incorporation of psi l Cyd into nucleic acids of P815 cells and of a P815 subline resistant to 1-beta-D-arabinofuranosylcytosine are about 2- to 20-fold higher than in P815 sublines resistant to psi l Cyd or to both 5-azacytidine and 1-beta-D-arabinofuranosylcytosine. These data suggest that the phosphorylation of psi l Cyd and possibly its incorporation into nucleic acids are essential for therapeutic activity in P815 leukemias. In vitro metabolic studies also suggest that psi l Cyd and 5-azacytidine are cross-resistant and that P815 cells resistant to psi l Cyd are collaterally sensitive to 1-beta-D-arabinofuranosylcytosine. These predictions were confirmed by therapeutic experiments carried out in mice bearing P815 leukemias.

Animals↗
PubMed1978

Effects of adriamycin on DNA synthesis in mouse and rat heart.

Adriamycin induces an inhibition of DNA synthesis in mouse tissues within one hr after treatment. While the effects are short-lived in liver and small intestine, DNA synthesis in heart remains below control values for up to 7 days. After this period DNA synthesis in hearts of treated mice is elevated and remains above control values for as long as 4 weeks. Both 1-beta-D-arabinofuranosylcytosine and actinomycin D also induce inhibition of cardiac DNA synthesis soon after treatment; the effects of 1-beta-D-arabinofuranosylcytosine are over by the end of 24 hr while the effects of actinomycin D persist for at least 4 days. Actinomycin D treatment also induces an "over-shoot" of DNA synthesis in mouse heart. Adriamycin can induce a loss of prelabeled DNA from heart, although no pathological alterations are immediately obvious. The small intestine, however, shows extensive karyorrhexis. The initial effects on cardiac DNA synthesis occur in adrenalectomized animals, indicating that the effects are not mediated via the adrenal gland. We did find, however, that DNA synthesis in heart was sensitive to the effects of starvation. The results of this study indicate that inhibition of mouse heart DNA synthesis is not specific for Adriamycin and that the effects of Adriamycin in heart following a single treatment are long-lived.

Animals↗