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  • 1
    Electronic Resource
    Electronic Resource
    Triple-helix formation and cooperative binding by oligodeoxynucleotides with a 3'-3' internucleotide junction (1992)
    s.l. : American Chemical Society
    Biochemistry 31 (1992), S. 1603-1609 
    Details
    ISSN: 1520-4995
    Source: ACS Legacy Archives
    Topics: Biology , Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/bi00121a004
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  • 2
    Electronic Resource
    Electronic Resource
    Specific, high-efficiency, triple-helix-mediated cross-linking to duplex DNA (1991)
    s.l. : American Chemical Society
    Journal of the American Chemical Society 113 (1991), S. 7765-7766 
    Details
    ISSN: 1520-5126
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1021/ja00020a051
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  • 3
    Electronic Resource
    Electronic Resource
    The adult α-globin locus of old world monkeys: An abrupt breakdown of sequence similarity to human is defined by an Alu family repeat insertion site (1991)
    Springer
    Journal of molecular evolution 33 (1991), S. 506-513 
    Details
    ISSN: 1432-1432
    Keywords: α-Globin ; DNA rearrangement ; Alu family repeats ; Genomic evolution
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology
    Notes: Summary The haploid genomes of all known primates have two or more adult α-globin genes contained within tandemly arranged duplication units. Although the tandem duplication event generating these α-globin loci is believed to occur prior to the divergence of primates, a number of length polymorphisms exist within the loci among different primate species. In order to understand the molecular basis of these length polymorphisms, we have cloned and determined the nucleotide sequence of a major portion of the rhesus monkey adult α-globin locus. Sequence comparison to human suggests that the length difference between the adult α-globin loci of human and Old World monkey is the result of one or more DNA recombination processes, all of which appeared to be related to the transposition of Alu family repeats. First, the finding of a monomeric Alu family repeat at the junction between nonhomology block I and homology block Y of the α2 genecontaining unit in rhesus macaque suggests that the dimeric Alu family repeat, Alu 3, at the orthologous position in human was generated by insertion of a monomeric Alu family repeat into the 3′ end of another preexisting Alu family repeat. Second, two Alu family repeats, Alu 1 and Alu 2, exist in human at the 3′ end of each of the two X homology blocks, respectively. However, this pair of paralogous Alu family repeats is absent at the corresponding positions in rhesus macaques. This raises interesting questions regarding the evolutionary origin of Alu 1 and Alu 2. Finally, DNA sequences immediately downstream from the insertion site of Alu 2 are completely different between human and rhesus macaque. This last event is similar to DNA rearrangements occurring nearby transposable element(s) in the chromosomes of bacteria, yeast, and plant cells. Its possible role in accelerating the genomic evolution of noncoding or spacer DNA is discussed.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF02102803
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  • 4
    Electronic Resource
    Electronic Resource
    Sequence organization and genomic complexity of primate Θ 1 globin gene, a novel α -globin-like gene (1986)
    [s.l.] : Nature Publishing Group
    Nature 321 (1986), S. 785-788 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The human a-globin cluster can be used to investigate the processes of gene duplication, insertion, and correction, in addition to the better-known molecular evolutionary processes13'16. To study these processes further, we have constructed genomic libraries of three non-human primates (orang-utan, ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/321785a0
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  • 5
    Electronic Resource
    Electronic Resource
    A Novel Oligodeoxynucleotide Inhibitor of Thrombin. I. In VitroMetabolic Stability in Plasma and Serum (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1937-1942 
    Details
    ISSN: 1573-904X
    Keywords: oligodeoxynucleotides ; nuclease degradation ; plasma stability ; kinetics ; in vitrometabolism ; thrombin inhibitor
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the degradation rates and pathways of GS-522, a potent oligodeoxynucleotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, in serum and plasma. Methods. A stability-indicating, anion-exchange HPLC method was developed and used to determine concentrations of GS-522 and metabolites. Results. In monkey plasma at 2 µM or below, the degradation of GS-522 can be fit to a first-order exponential with a kp obs ~ 0.01 min−1. At 3 µM and above the degradation process deviates from a monoexponential decay profile. An initial fast degradation process is followed by a slower phase with an observed rate constant equal to that observed at 2 µM and below. In monkey serum, the KMand Vmaxare 8.4 µM and 0.87 µM min−1, respectively. Conclusions. The kinetics are consistent with an equilibrium binding of GS-522 to prothrombin in plasma (Kd = 50 nM) which saturates at GS-522 concentrations 〉2 µM. Compared to a scrambled sequence (GGTGGTGGTTGTGGT), with no defined tertiary structure, GS-522 is 4-fold more stable in serum. The metabolic profile in plasma is consistent with a 3′-exonuclease catalyzed hydrolysis of GS-522.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016243923195
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  • 6
    Electronic Resource
    Electronic Resource
    Metabolism and Pharmacokinetics of Novel Oral Prodrugs of 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA) in Dogs (1997)
    Springer
    Pharmaceutical research 14 (1997), S. 1824-1829 
    Details
    ISSN: 1573-904X
    Keywords: prodrug ; 9-[(R)-2-(phosphonomethoxy)propyl]adenine ; antiretroviral drug ; oral bioavailability
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. A series of prodrugs designed to enhance the oral bioavailability of the antiretroviral agent 9-[(R)-2-(phosphonomethoxy)propyl]adenine (PMPA; 1) have been synthesized, including a bis-(acyloxymethyl) ester 2 and a series of bis-(alkoxycarbonyloxymethyl) esters 3-9. The in vitro biological stability andin vivo pharmacokinetics of these prodrugs were evaluated to support selection of a prodrug candidate for clinical evaluation. Methods. The in vitrobiological stability of the prodrugs was examined in dog tissues (intestinal homogenate, plasma and liver homogenate). The apparent half-lives were determined based on the disappearance of prodrug using reverse-phase HPLC with UV detection. Oral bioavailability of PMPA from each prodrug was determined in fasted beagle dogs. Concentrations of PMPA in plasma were determined by HPLC following fluorescence derivatization. Data for prodrugs were compared to historical data for intravenous PMPA. Results. All prodrugs were rapidly hydrolyzed in dog plasma and tissues (t1/2 〈 60 min). In fasted beagle dogs, bis-[(pivaloyloxy)methyl] PMPA (bis-POM PMPA) 2 had the highest oral bioavailability as PMPA (37.8 ± 5.1%). The oral bioavailabilities of PMPA from bis-(alkoxycarbonyloxymethyl) esters ranged from 16.0% to 30.7% and PMPA was the major metabolite formed. Conclusions. There was a correlation between oral bioavailability and intestinal stability of bis-(alkoxycarbonyloxymethyl) ester prodrugs (r2 = 0.96). Lipophilicity (log P) was not a good predictor of oral bioavailability. The most labile prodrugs in dog intestinal homogenates, bis-(n-butyloxycarbonyloxymethyl) PMPA 5 and bis-(neo-pentyloxycarbonyloxymethyl) PMPA 8 (t1/2 〈 5 min) had the lowest oral bioavailabilities. Based on good oral bioavailability (30.1%), chemical and intestinal stability bis-(isopropyloxycarbonyloxymethyl) PMPA (bis-POC PMPA) 4 was selected as a candidate for clinical evaluation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1012108719462
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  • 7
    Electronic Resource
    Electronic Resource
    Oral Bioavailability of the Antiretroviral Agent 9-(2-phosphonylmethoxyethyl)adenine (PMEA) from Three Formulations of the Prodrug Bis(pivaloyloxymethyl)-PMEA in Fasted Male Cynomolgus Monkeys (1994)
    Springer
    Pharmaceutical research 11 (1994), S. 839-843 
    Details
    ISSN: 1573-904X
    Keywords: PMEA ; prodrug ; oral bioavailability ; formulation ; monkey ; antiviral
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract The bioavailability of PMEA from three oral formulations of the prodrug bis(POM)-PMEA has been evaluated in fasted male cynomolgus monkeys. The formulations examined included a hydroxy-propyl-β-cyclodextrin (HPBCD) complex, a PEG based cosolvent solution, and an aqueous suspension. Oral formulations containing 3H-bis(POM)-PMEA were compared to intravenous 3H-PMEA at 10.9 mg-eq/kg in a crossover study in four monkeys, with a 7 day washout period. No intact bis(POM)-PMEA or monoester were detected in plasma. Bioavailabilities of PMEA from the prodrug were 24.7 ± 6.5%, 27.3 ± 12.3% and 22.2 ± 15.6% for the HPBCD complex, PEG solution and aqueous suspension, respectively. The oral bioavailability of PMEA from bis(POM)-PMEA was not limited by dissolution rate of the prodrug. Data for the PEG cosolvent solution and suspension indicate that the prodrug could potentially be formulated as a soft gelatin capsule or a tablet.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018925723889
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  • 8
    Electronic Resource
    Electronic Resource
    A Novel Oligodeoxynucleotide Inhibitor of Thrombin. II. Pharmacokinetics in the Cynomolgus Monkey (1995)
    Springer
    Pharmaceutical research 12 (1995), S. 1943-1947 
    Details
    ISSN: 1573-904X
    Keywords: GS-522 ; oligodeoxynucleotide ; thrombin ; pharmacokinetics ; monkey
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. To determine the pharmacokinetics of GS-522, an oligodeoxynucleotide (GGTTGGTGTGGTTGG) inhibitor of thrombin, after constant infusion and bolus administration in the cynomolgus monkey. Methods. Using a stability indicating HPLC method, the GS-522 plasma concentration versus time data were obtained after constant infusion (0.1, 0.3, 0.5 mg/kg/min) and bolus administration (11.25 and 22.5 mg/kg). Plasma data after bolus administration was fit to a three-compartment model. Results. The half-lives for the α and β phases were 1.4 and 5.4 min, respectively. Steady state GS-522 concentrations were reached within 10 minutes after initiation of constant infusions. Termination of infusions resulted in a rapid elimination of GS-522 with an average elimination half-life equal to 1.5 min. The Vss calculated from both the constant infusion and bolus data approximated the blood volume of the monkey. Substitution of the phosphodiester backbone at the 3′ end of GS-522 with two phosphorothioate linkages did not substantially effect the elimination half-life upon termination of infusion. Conclusions. These data in conjunction with published biodistribution data suggest that oligodeoxynucleotides are rapidly cleared from plasma by tissue uptake and that little efflux back into blood takes place. Additionally, strategies designed to increase oligodeoxynucleotide resistance to exonucleases will not dramatically increase plasma half-lives.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1016295907266
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  • 9
    Electronic Resource
    Electronic Resource
    Aryl Ester Prodrugs of Cyclic HPMPC. I: Physicochemical Characterization and In Vitro Biological Stability (1999)
    Springer
    Pharmaceutical research 16 (1999), S. 1687-1693 
    Details
    ISSN: 1573-904X
    Keywords: prodrug ; cyclic phosphonate ; reactivity ; salicylate esters ; cidofovir ; cyclic HPMPC ; nucleotides
    Source: Springer Online Journal Archives 1860-2000
    Topics: Chemistry and Pharmacology
    Notes: Abstract Purpose. The chemical, enzymatic, and biological stabilities and physical properties of a series of salicylate and aryl ester prodrugs of the antiviral agent, cyclic HPMPC, were evaluated to support the selection of a lead compound for clinical development. Methods. Chemical stabilities of the prodrugs in buffered solutions at 37°C were determined. Stability was also studied in the presence of porcine liver carboxyesterases (PLCE) at pH 7.4 and 25°C. Tissue stabilities were examined in both human and dog intestinal homogenates, plasmas and liver homogenates. Prodrug and product concentrations were determined by reverse phase HPLC. Results. Chemical degradation of the prodrugs resulted in the formation of both cyclic HPMPC and the corresponding HPMPC monoester. Chemical stability was dependent on the orientation of the exo-cyclic ligand; the equatorial isomers were 5.4- to 9.4-fold more reactive than the axial isomers. In the presence of PLCE, the salicylate prodrugs cleaved exclusively to give cyclic HPMPC and not the HPMPC monoester. In plasma, but not intestinal or liver homogenates, the salicylate esters of cyclic HPMPC cleaved readily with a rate dependent on the chain length of the alkyl ester substituent. Conclusions. The carboxylate function on the salicylate prodrugs of cyclic HPMPC provides an additional handle to chemically modify the lipophilicity, solubility and the biological reactivity of the prodrug. In tissue and enzymatic studies, the major degradation product is cyclic HPMPC. The salicylate ester prodrugs are attractive drug candidates for further in vivo evaluation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1023/A:1018945713623
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  • 10
    Electronic Resource
    Electronic Resource
    Evidence that the recently discovered Θ1-globin gene is functional in higher primates (1987)
    [s.l.] : Nature Publishing Group
    Nature 326 (1987), S. 717-720 
    Details
    ISSN: 1476-4687
    Source: Nature Archives 1869 - 2009
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Notes: [Auszug] The olive baboon, Papio anubis (Primates: Cercopithecidae), is a close relative of the apes and humans, having diverged from that lineage nearly 30 million years ago (refs 8-11; Fig. la). The structure of its adult a-globin gene region is similar to that of the human and orang-utan. They all ...
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1038/326717a0
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