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Ganciclovir and Valganciclovir
Published in M. Lindsay Grayson, Sara E. Cosgrove, Suzanne M. Crowe, M. Lindsay Grayson, William Hope, James S. McCarthy, John Mills, Johan W. Mouton, David L. Paterson, Kucers’ The Use of Antibiotics, 2017
Camille E. Beauduy, Mark A. Jacobson
Resistance has been related to impaired monophosphorylation of GCV in some reports (Lurain et al., 1992; Baldanti et al., 1995). GCV resistance can arise from mutations in either the UL97 gene, which codes for CMV kinase (functionally homologous to the thymidine kinase [TK] gene of HSV), or the UL54 gene, which codes for DNA polymerase gene (herpes simplex and CMV) (Crumpacker et al., 1984; St Clair et al., 1984; Sullivan et al., 1992a). Mutations in the UL97 gene are more commonly associated with the development of resistance in clinical isolates than mutations in the DNA polymerase gene. The UL97 mutations reduce the intracellular phosphorylation of GCV, resulting in low-level GCV resistance (Limaye, 2002; Chou, 2008). Mutations at codons 460, 594, and 595 have been described in drug-resistant isolates (Lurain et al., 1994; Baldanti et al., 1995; Chou et al., 1995; Wolf et al., 1995); they have not been found in susceptible strains. Several reported mutations in the DNA polymerase gene of CMV (G987A and L501I) also confer GCV resistance. Although cross-resistance to cidofovir (Lurain et al., 1992) and foscarnet (Tatarowicz et al., 1992) has been described for CMV, other investigators have found that GCV-resistant strains remain susceptible to these drugs as well as to vidarabine, cidofovir, fialuridine, and the fluoroarabinose cytidine analog 2′-fluoro-5-iodo-aracytosine (Biron et al., 1986; Biron, 1991; Drew et al., 1991; Stanat et al., 1991). A complete summary of specific mutations involved in CMV resistance to GCV is provided in Table 215.2.
Mouse models for mesothelioma drug discovery and development
Published in Expert Opinion on Drug Discovery, 2021
Kenneth P. Seastedt, Nathanael Pruett, Chuong D. Hoang
In general, while humans and mice share virtually the same set of genes, it is not always true that a drug targeting a mouse gene would exert an identical effect on the same gene in humans. The function of genes in different organisms (i.e., human versus mouse) may differ and be utilized in physiologic processes in entirely disparate ways, which would confound the interpretation of drug effects [80]. Specifically, regulation of p53 target genes diverged along species-specific pathways with dramatically different DNA binding landscapes between human and mouse [81]. Another category of differential drug response is in the spatio-temporal location of proteins impacting drug metabolism and pharmacodynamics. A well-documented example is that of fialuridine that worked against hepatitis B in mice but was toxic to humans because the protein transporter of the drug was also located in human mitochondria and not in mouse leading to human-specific mitochondria poisoning [82]. The genes of mouse and human for this drug transporter differed by three base pairs resulting in proteins with a radically different location and function. Lastly, in human diseases like cancer, the genetic landscape(s) are intrinsically complex and depend on the orchestration of gene pathways to drive biologic behavior, some of which are known and many of which remain obscure in MPM [7]. Incomplete knowledge of the entire genetic profile underlying the MPM tumor phenotype explains why the GEM mice, for example, do not manifest mesothelioma that genuinely mimics human cancer.
Current state-of-the-art pharmacotherapy for the management of hepatitis B infection
Published in Expert Opinion on Pharmacotherapy, 2019
Hans L. Tillmann, Gbeminiyi Samuel
Of note, famciclovir, a nucleoside that is a less antivirally active nucleoside, whose resistance profile did not include the YMDD motif [31], but whose development for HBV was halted when more effective antivirals emerged. Other drugs with insufficient antiviral activity against HBV include ganciclovir [32]. Another noteworthy story, reminding that safety is always a concern in drug development is the story of Fialuridine [33], where unexpectedly seven of 15 patients developed liver failure resulting in death or need for liver transplantation.