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  • 1
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The biologically active form of most purine or pyrimidine analogs is the nucleoside 5′-mono, di- or triphosphate. The nucleoside form is most often administered because of the ease with which it penetrates cells by facilitated transport. However, many nucleoside derivatives fail to exhibit significant antiviral or antitumor activity because they are not phosphorylated by cellular enzymes to the active nucleotide form. In this review, the potential use of suitable nucleotide analogs as selective inhibitors of ribonucleotide reductase and viral reverse transcriptase is considered. Masked nucleotides such as phosphoramidates or methyl phosphates could be employed to allow transport across cellular membranes. Furthermore, phosphonocarboxamide, phosphonoformate or sulfamidophosphoramidate may mimic nucleotide di- and triphosphates. Tumor cells and virally infected cells are often more permeable to nucleotides and their analogs than normal cells, which could provide a therapeutic advantage. There could be considerable therapeutic potential for nucleotide analogs that can penetrate the tumor cell membranes and that are resistant to enzymatic hydrolysis and are non-incorporable into DNA or RNA.
    Type of Medium: Electronic Resource
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  • 2
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The proposed tautomeric equilibrium between the microsomal metabolite of cyclophosphamide, 4-hydroxycyclophosphamide, and the open chain aldophosphamide, and the subsequent facile β-elimination to generate acrolein and phosphoramide mustard have been confirmed by proton magnetic resonance studies. When 4-hydroxycyclophosphamide, initially maintained in CDC13 at −20°C, was allowed to equilibrate at 15°C, a singlet at 9.76 δ and a triplet at 2.88 δ appeared concomitantly which were assigned to the aldehydic proton and the protons α to the carbonyl of aldophosphamide, respectively. Further reaction led to the appearance of several NMR signals that indicated the irreversible formation of acrolein (multiplet at 9.55 δ) and phosphoramide mustard. Polymerization occurred approximately 2 hours after the initiation of the reaction. The kinetic data of the reaction sequence are discussed.
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  • 3
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pharmacokinetic disposition of the anthracyclines, adriamycin (doxorubicin), daunorubicin, 4′-epi-adriamycin, carminomycin, and 4-demethoxy-daunorubicin, and the formation of their reduced C13 hydroxy metabolites were studied in dogs. The presence of a C14hydroxy group (adriamycin and 4′epi-adriamycin) drastically reduces the appearance of the C13 hydroxy metabolites in plasma. Substitution of the C4-H with C4-OH and C4-OCH3, in this rank order, decreases the area under the plasma concentration-time curves of the parent compounds and their C13 hydroxy metabolites.
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  • 4
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The opiate antagonist WIN 44,441–3 is a potent, stereospecific antagonist of mu, delta, and kappa opiate receptors. This antagonist activity is of long duration (〉 4 h) with no agonist activity being observed. It therefore appears that WIN 44,441–3 will be a useful long-acting opiate antagonist for in vivo studies.
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  • 5
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Metoclopramide has recently been approved at dose levels of 1 to 2 mg/kg for the treatment of nausea and vomiting resulting from cancer chemotherapeutic agents. A rapid, sensitive reverse phase HPLC quantitative procedure for metoclopramide in serum is described. The method involves a single-step extraction of metoclopramide and disopyramide (internal standard) from alkalinized serum into benzene and utilizes a reverse-phase C-8 system with a mobile phase of 11:22:66, methanol: acetonitrile: pH 3.7 acetate buffer, and UV detection at 268 nm. The method is highly reproducible and has a limit of sensitivity of 2.5 ng/ml from a 2.0 ml serum sample. The method has been successfully applied to clinical pharmacokinetic studies involving administration of IV oral metoclopramide to cancer patients receiving highly emetogenic cis-diamminedichloroplatinum.
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  • 6
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 1 (1984), S. 50-50 
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The pyrrolo(l,4)benzodiazepine (P(1,4)B) antitumor antibiotics, anthramycin, tomaymycin, sibiromycin and the neothramycins A and B, are potent anticancer agents that form covalent adducts through the exocyclic amino group of guanine in DNA. This review describes the chemistry important for both the DNA reactivity and synthesis of the carbinolamine containing drugs and the strategy for elucidation of the three-dimensional form of the adduct with DNA. The high DNA sequence specificity as well as some of the observed biological consequences of DNA damage caused by these agents in human and yeast cells are rationalized through the proposed structure of the drug-DNA adducts. Parallel toxicological studies have led to a proposal for the underlying mechanism for the cardiotoxicity of certain members of this group of agents. A rationale for designing drugs which should retain their potent antitumor activity without the associated cardiotoxicity is also proposed. Lastly, the application of the P(l,4)B's as probes for monitoring drug binding to DNA and drug-induced conformational changes is described.
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  • 8
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract A series of benzenetricarboxylic acids was shown to be potent hypolipidemic agents in rodents. Terephthalic acid proved to be one of the more potent agents, lowering serum cholesterol 42% and serum triglyceride 33 % at 20 mg/kg/day for 16 days. The ability to lower serum lipids by this agent appeared to be due to multiple modes of action: (1) terephthalic acid suppressed the activities both in vivo and in vitro of a number of regulatory enzymes involved in cholesterol, fatty acid, and triglyceride syntheses; (2) the drug inhibited cholesterol absorption from the GI tract by 43 %; and (3) the drug accelerated lipid excretion in the feces leading to a reduction of cholesterol in the tissue. Terephthalic acid was effective in lowering lipids in normal and hyperlipidemic animals and possessed a safe therapeutic index.
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  • 9
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The effect of uridine on the incorporation of 5-fluorouracil into RNA and the inhibition of DNA synthesis by the FdUMP block of thymidylate synthetase was studied in the CD8F1 murine mammary carcinoma system. The administration of exogenous uridine resulted in about a one third reduction of 5-fluorouracil in RNA of tumor and normal tissues. However, unlike thymidine, uridine was unable to reverse the early, partial inhibition of DNA synthesis. The amount of fluorouridine nucleotides and (5-fluorouracil)RNA formed in various tissues correlates with the level of orotate phosphoribosyl transferase activity suggesting that the major pathway for activation of 5-fluorouracil to nucleotide form in these tissues is via phosphoribosyl transferase. Enzyme preparations from three different murine tumors convert about 15 times as much 5-fluorouracil to FUMP as they do uracil to UMP. In contrast, the ratio of FUMP to UMP formed in enzyme preparations from gut and bone marrow is lower, 2–6 fold. However, in none of these tissues was the in vitro conversion of 5-fluorouracil to FUMP or incorporation into RNA substantially inhibited by uracil. Examination of tumor, gut and bone marrow uridine nucleotide pools showed that the thymidine-uridine-5-fluorouracil schedule does increase uridine nucleotide pools. Thus, the reduction in 5-fluorouracil in RNA is probably not due to inhibition of the conversion of 5-fluorouracil to FUMP by uracil (derived from phosphorylase cleavage of uridine) but, rather, is probably due to the elevated levels of UTP. We conclude that the protection from 5-fluorouracil toxicity afforded by the addition of uridine is due to the reduction in 5-fluorouracil in RNA rather than by reversal of the FdUMP block on thymidylate synthetase.
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  • 10
    Electronic Resource
    Electronic Resource
    Springer
    Pharmaceutical research 1 (1984), S. 101-101 
    ISSN: 1573-904X
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
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