RESUMO
Different backbone modified antisense oligonucleotides (AS-ODNs) directed against the hepatitis C virus genome were 5'-conjugated to cholesterol, cholic acid or taurocholic acid to enhance liver specific drug targeting and hepatocellular uptake. The lipophilic character of modified AS-ODNs was determined from RP-HPLC retention times and duplex stability was correlated with Tm-values from UV melting curves.
Assuntos
Hepacivirus/genética , Fígado/metabolismo , Oligonucleotídeos Antissenso/química , Oligonucleotídeos Antissenso/genética , Colesterol/análogos & derivados , Colesterol/química , Colesterol/farmacocinética , Ácido Cólico/química , Ácido Cólico/farmacocinética , Cromatografia Líquida de Alta Pressão , Desenho de Fármacos , Hepacivirus/efeitos dos fármacos , Oligonucleotídeos Antissenso/farmacocinética , Especificidade de Órgãos , Ácido Taurocólico/análogos & derivados , Ácido Taurocólico/química , Ácido Taurocólico/farmacocinéticaRESUMO
Repeat coronary artery bypass (RCAB) procedures were performed on 323 patients from March 1984 through December 1990. The mean interval between bypass operations was 7.8 years. The operative mortality rate was 4.6%; six of the 15 deaths (40%) occurred in the operating room. Fourteen of the 15 operative deaths (93.3%) were cardiac, all but one of which were due to ventricular failure. Follow-up data for 83 of 91 (91.2%) patients at least five years following RCAB show that 64 (77.1%) are still alive, 39 (60.9%) of whom remain free of cardiac symptoms. Findings in this report, which are notably consistent with those of previous reports, are a significantly higher operative mortality rate and higher risk of death in the operating room in patients undergoing repeat bypass compared with those having initial coronary artery bypass. The challenge of reducing the mortality risk following coronary reoperation is discussed in this report.
Assuntos
Ponte de Artéria Coronária , Adulto , Idoso , Idoso de 80 Anos ou mais , Ponte de Artéria Coronária/mortalidade , Ponte de Artéria Coronária/estatística & dados numéricos , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Reoperação/mortalidadeAssuntos
Idoso de 80 Anos ou mais , Procedimentos Cirúrgicos Cardíacos , Idoso , Procedimentos Cirúrgicos Cardíacos/efeitos adversos , Procedimentos Cirúrgicos Cardíacos/métodos , Procedimentos Cirúrgicos Cardíacos/mortalidade , Estudos de Avaliação como Assunto , Feminino , Humanos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
Recently, we synthesized antisense oligonucleotides (AS-ODNs) directed against the non-coding-region (NCR) and the adjacent core region of the hepatitis C virus (HCV) RNA. Backbone modifications like phosphorothioates, methyl- and benzylphosphonates were introduced three at each end of the sequence. For improvement of liver specific drug targeting and/or hepatocellular uptake efficient AS-ODNs were covalently conjugated to biomolecules such as cholesterol or bile acids. The use of base-labile alkylphosphonates afforded mild conditions for deprotection of bile acid conjugated AS-ODNs. Here, we describe a convenient synthesis of new cholic acid and taurocholic acid phosphoramidites. Derivatization to taurocholic acid was effected directly before phosphitylation reaction, which is the last step of the phosphoramidite synthesis. These building blocks were coupled to the 5'-position of AS-ODNs in the last step of solid-phase synthesis. After mild deprotection, purification and characterization the properties of these modified AS-ODNs like their lipophilicity or their ability to form stable duplices to DNA and RNA were investigated. Enhanced lipophilicity and formation of stable duplices and heteroduplices makes bile acid conjugated AS-ODNs interesting as antiviral antisense therapeutics against HCV.
Assuntos
Ácidos e Sais Biliares/síntese química , Ácidos e Sais Biliares/farmacologia , Hepacivirus/genética , Oligonucleotídeos Antissenso/química , Compostos Organofosforados/síntese química , Compostos Organofosforados/farmacologia , Ácidos e Sais Biliares/química , Espectroscopia de Ressonância Magnética , Oligonucleotídeos Antissenso/genética , Compostos Organofosforados/químicaRESUMO
Phosphorothioate and benzyl-modified antisense-oligodeoxynucleotides directed against nucleotides 334-350 of the Hepatitis C Virus RNA form surprisingly stable hairpins. These data contribute to solve a structural detail information in search for a global secondary structure model of the Non Coding Region (NCR) of HCV.