Replicating agents

Scenarios of the future may be complicated by the possible use of multiple agents, or the delivery of chemical and replicating agents and/or their toxins that have been carefully matched, based on their stability and ability to generate specific symptoms. Health effects could be potentiated. Therefore, from a medical perspective, detection requires the availability of rapid diagnostic methods and procedures to assess illnesses that will be the result of multiple agents. 

Genes producing particular immunogens can be inserted into replicating agents so that their products are expressed. Novel approaches include use of mammalian viruses, insect viruses (baculovirus expression), yeasts, E. coli. 

Howe JA, Demers GW, Johnson DE, Neugebauer SE, Perry ST, Vaillancourt MT, FahaB. Evaluation of El-mutantadenovimses as conditionally replicating agents for cancer therapy. Mol Ther2000 2 485 95. 

Pyrimidinopyrazines related to folic acid have been investigated in some detail for their antimeta-bolic and antineoplastic activities. A related compound, which lacks one nitrogen atom, has been described as an antiproliferative agent, indicating it too has an effect on cell replication. Aldol condensation of the benzaldehyde 99 with ethyl acetoacetate gives the cinnamate 100. This is then reduced catalytically to the acetoacetate 101. Reaction of that keto ester with 2,4,6- triami-nopyrimidine gives the product 102 which is subsequently chlorinated (103) and subjected to hydrogenolysls. There is thus formed piritrexim (104) [17]. 

Releasing agents 793 Replicate determinations number of, 142 reliability of, 137 Residual current 595 Resistance 504 Resistivity 519 Resonance line sources 790 Results, comparison of 139 Reverse osmosis 90 Reversible back e.m.f. 505 Rf values 234 Rotated electrode 511 R.U. powder 766, 772... 

These agents profoundly prevent production of bacterial nucleic acids and inhibit genetic replication. 

Cross-linkage - bifunctional agents may form covalent bonds with each of two adjacent guanine residues and such inter-strand cross-links will lead to inhibition of DNA replication and transcription. Intra-strand and DNA-protein cross-links may also be formed ... 

Viruses are small infectious agents composed of a nucleic acid genome (DNA or RNA) encased by structural proteins and in some cases a lipid envelope. They are the causative agents of a number of human infectious diseases, the most important for public health today being acquired immunodeficiency syndrome (AIDS), hepatitis, influenza, measles, and vituses causing diarrhoea (e.g., rotavirus). In addition, certain viruses contribute to the development of cancer. Antiviral drugs inhibit viral replication by specifically targeting viral enzymes or functions and are used to treat specific virus-associated diseases. 

The human immunodeficiency vims (HIV) is the causative agent of the acquired immunodeficiency syndrome (AIDS). HIV is a retrovirus, whose replication includes the transcription of the single-stranded RNA genome into double stranded DNA (reverse transcription) and the covalent insertion of the DNA... 

When amphotericin B or diuretics are administered with ACTH, the potential for hypokalemia is increased. There may be an increased need for insulin or oral antidiabetic drag s in the patient with diabetes who is taking ACTH. There is a decreased effect of ACTH when the agent is administered with the barbiturates. Profound muscular depression is possible when ACTH is administered with the anticholinesterase drugp. Live virus vaccines taken while taking ACTH may potentiate virus replication, increase vaccine adverse reaction, and decrease the patient s antibody response to the vaccine... 

Deres K, Schroder CH, Paessens A, Goldmann S, Hacker HJ, Weber O, Kramer T, Niewohner U, Pleiss U, Stoltefuss J et al. (2003) Inhibition of hepatitis B virus replication by drug-induced depletion of nucleocapsids. Science 299 893-896 Ehon GB, Furman PA, Fyfe JA, de Miranda P, Beauchamp L, Schaeffer HJ (1977) Selectivity of action of an antiherpetic agent, 9-(2-hydroxy ethoxy methyl) guanine, Proc Natl Acad Sci USA 74 5716-5720... 

Several excellent reviews have appeared recently (Condon et al. 2005 Huang et al. 2006 Koch and Narjes 2006 Meanwell et al. 2005 Neyts 2006 Shim et al. 2006 Wu et al. 2005), which summarize the development of agents to treat HCV infection. In this report we highlight the application of modem drug discovery tools and techniques to inhibit HCV replication by describing selected examples that have appeared recently in the scientific literature. 

Mitochondria-associated toxicities, such as pancreatitis, are frequently demonstrated in HlV/HCV-coinfected individuals, and may significantly influence treatment options (de Mendoza and Soriano 2005). Yet, no cell culture or animal models have been developed to predict nucleoside-induced pancreatitis. Nevertheless, an association of HCV replication and mitochondrial DNA depletion in primary human lymphocytes obtained from HIV/HCV-coinfected individuals under concomitant administration of HCV and HIV medications was demonstrated by de Mendoza and coworkers (de Mendoza et al. 2007). They claimed that the use of HCV medication together with certain antiretroviral agents seemed to enhance mitochondrial damage due to a synergistic deleterious interaction between the anti-HCV and anti-HIV drugs. In contrast, an improvement in mitochondrial content with effective... 

Stuyver LJ, Whitaker T, McBrayer TR, Hernandez-Santiago BI, Lostia S, Tharnish PM, Ramesh M, Chu CK, Jordan R, Shi J, Rachakonda S, Watanabe KA, Otto MJ, Schinazi RF (2003b) Ribonucleoside analogue that blocks replication of bovine viral diarrhea and hepatitis C viruses in culture, Antimicrob Agents Chemother 47 244-254... 

Fig. 8 HBV replication cycle and site of action of several anti-HBV agents...

Ludmerer SW, Graham DJ, Boots E, Murray EM, Simcoe A, Markel EJ, Grobler JA, Flores OA, Olsen DB, Hazuda DJ, LaFemina RL (2005) Replication fitness and NS5B drug sensitivity of diverse hepatitis C virus isolates characterized by using a transient replication assay. Antimicrob Agents Chemother 49 2059-2069... 

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