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- Selection and Recombinant Phenotyping of a Novel CMX001 and Cidofovir Resistance Mutation in Human Cytomegalovirus. [JOURNAL ARTICLE]
- Antimicrob Agents Chemother 2013 May 6.
CMX001 is an orally available lipid acyclic nucleotide phosphonate that delivers high intracellular levels of cidofovir (CDV)-diphosphate and exhibits enhanced in vitro antiviral activity against a wide range of double-stranded DNA viruses, including cytomegalovirus (CMV). Mutations in the DNA polymerase of CMV that impart resistance to CDV also render the virus resistant to CMX001. Here, we report a novel resistance mutation that arose under the selective pressure of CMX001. The wild-type CMV strain AD169 was propagated in human foreskin fibroblasts under increasing concentrations of CMX001 over 10 months and the resulting strain (CMX001(R)) was less susceptible to CDV and CMX001 in a plaque reduction assay. Genotypic analysis of CMX001(R) via conventional sequencing of the genes encoding the CMV DNA polymerase (UL54) and UL97 kinase (UL97) demonstrated one mutation which changed the wild-type aspartate to glutamate at position 542 in UL54. A recombinant virus with this novel D542E mutation was generated via bacterial artificial chromosome-mediated marker transfer experiments. Subsequent phenotypic resistance analysis of the D542E mutant demonstrated reductions in susceptibility of greater than 10-fold to CMX001 and CDV but no resistance to foscarnet (FOS) or ganciclovir (GCV). Analysis of replicative fitness showed that both CMX001(R) and the D542E mutant viruses demonstrated a smaller plaque phenotype and slower replication kinetics than their respective parent viruses. These data describe the first resistance mutation generated under the selective pressure of CMX001 and suggest that CMX001 may have a unique resistance profile associated with reduced viral replication and maintenance of sensitivity to FOS and GCV.
- Evaluation of intratympanic formulations for inner ear delivery: methodology and sustained release formulation testing. [JOURNAL ARTICLE]
- Drug Dev Ind Pharm 2013 Apr 30.
Abstract A convenient and efficient in vitro diffusion cell method to evaluate formulations for inner ear delivery via the intratympanic route is currently not available. The existing in vitro diffusion cell systems commonly used to evaluate drug formulations do not resemble the physical dimensions of the middle ear and round window membrane. The objectives of this study were to examine a modified in vitro diffusion cell system of a small diffusion area for studying sustained release formulations in inner ear drug delivery and to identify a formulation for sustained drug delivery to the inner ear. Four formulations and a control were examined in this study using cidofovir as the model drug. Drug release from the formulations in the modified diffusion cell system was slower than that in the conventional diffusion cell system due to the decrease in the diffusion surface area of the modified diffusion cell system. The modified diffusion cell system was able to show different drug release behaviors among the formulations and allowed formulation evaluation better than the conventional diffusion cell system. Among the formulations investigated, poly(lactic-co-glycolic acid)-poly(ethylene glycol)-poly(lactic-co-glycolic acid) triblock copolymer systems provided the longest sustained drug delivery, probably due to their rigid gel structures and/or polymer-to-cidofovir interactions.
- Poxvirus antigen staining of immune cells as a biomarker to predict disease outcome in monkeypox and cowpox virus infection in non-human primates. [Journal Article]
- PLoS One 2013; 8(4):e60533.
Infection of non-human primates (NHPs) such as rhesus and cynomolgus macaques with monkeypox virus (MPXV) or cowpox virus (CPXV) serve as models to study poxvirus pathogenesis and to evaluate vaccines and anti-orthopox therapeutics. Intravenous inoculation of macaques with high dose of MPXV (>1-2×10(7) PFU) or CPXV (>10(2) PFU) results in 80% to 100% mortality and 66 to 100% mortality respectively. Here we report that NHPs with positive detection of poxvirus antigens in immune cells by flow cytometric staining, especially in monocytes and granulocytes succumbed to virus infection and that early positive pox staining is a strong predictor for lethality. Samples from four independent studies were analyzed. Eighteen NHPs from three different experiments were inoculated with two different MPXV strains at lethal doses. Ten NHPs displayed positive pox-staining and all 10 NHPs reached moribund endpoint. In contrast, none of the three NHPs that survived anticipated lethal virus dose showed apparent virus staining in the monocytes and granulocytes. In addition, three NHPs that were challenged with a lethal dose of MPXV and received cidofovir treatment were pox-antigen negative and all three NHPs survived. Furthermore, data from a CPXV study also demonstrated that 6/9 NHPs were pox-antigen staining positive and all 6 NHPs reached euthanasia endpoint, while the three survivors were pox-antigen staining negative. Thus, we conclude that monitoring pox-antigen staining in immune cells can be used as a biomarker to predict the prognosis of virus infection. Future studies should focus on the mechanisms and implications of the pox-infection of immune cells and the correlation between pox-antigen detection in immune cells and disease progression in human poxviral infection.
- The Acyclic Nucleoside Phosphonates (ANPs): Antonín Holý's Legacy. [JOURNAL ARTICLE]
- Med Res Rev 2013 Apr 8.
The name of Antonín Holý has become synonymous for the era of acyclic nucleoside phosphonates (ANPs), which started with (S)-HPMPA as the prototype and (S)-HPMPC (cidofovir) as the first marketed compound. It has now evolved to a number of compounds clinically used in the treatment of HIV and hepatitis B virus infections, either as such [tenofovir disoproxil fumarate (TDF, Viread®)] or in combination [Truvada®, Atripla®, Complera®, Stribild®]. Truvada has also been approved for the prevention of HIV infections. Forthcoming is a new formulation of tenofovir (TAF: tenofovir alafenamide). Also forthcoming are several "quad" drug combinations containing either TDF or TAF. Other ANPs, based on either an alkoxy side chain or 5-azacytosine heterocycle seem highly promising and worth further pursuing.
- Use of cidofovir in recurrent respiratory papillomatosis. [JOURNAL ARTICLE]
- Eur Arch Otorhinolaryngol 2013 Apr 2.
- Screening for BK viremia reduces but does not eliminate the risk of BK nephropathy: a single-center retrospective analysis. [Journal Article]
- Transplantation 2013 Apr 15; 95(7):949-54.
This study reviewed the outcomes of a screening protocol for BK viremia to determine if early diagnosis, followed by immunosuppression minimization, would prevent progression to nephropathy and graft loss.This review included 369 renal transplant recipients tested for BK virus at serial time points after transplantation. Management included immunosuppression minimization plus cidofovir treatment for BK nephropathy.Recipients received tacrolimus-based immunosuppression, with 8% prednisone-free and 6% who received desensitization. With a mean follow-up of 22 ± 10 months, 16% (n = 57) of recipients became BK viremia positive. The median (range) time to diagnosis was 3 (1-17) months. Because renal biopsy was performed selectively, 59% of recipients underwent biopsy, with 47% showing BK nephropathy. Seventy-four percent of recipients cleared the virus at a median (range) time of 9 (3-33) months, with four grafts lost to BK nephropathy. Cidofovir-treated recipients displayed a higher viral load at diagnosis but showed equivalent renal function at last evaluation. In multivariate analysis, recipient age, Asian ethnicity, deceased donor, and prednisone use were factors independently associated with BK viremia. Actuarial survival of BK-positive grafts was worse than that of BK-negative grafts (P<0.01, log-rank test). At 9 and 12 months, the mean estimated glomerular filtration rate of the BK-positive group was lower than that of the BK-negative cohort (P = 0.02).Despite using a screening protocol combined with immunosuppression minimization, BK-positive recipients had a greater risk of graft loss and impaired function than recipients free of infection. Future investigations should focus on practices to prevent BK viremia.
- Research on substances with activity against orthopoxviruses. [Journal Article]
- Ann Agric Environ Med 2013; 20(1):1-7.
Although smallpox was eradicated over 30 years ago, the disease remains a major threat. High mortality, high infectivity and low resistance of the contemporary population make the smallpox virus very attractive to terrorists. The possible presence of illegal stocks of the virus or risk of deliberate genetic modifications cause serious concerns among experts. Hence, it is reasonable to seek effective drugs that could be used in case of smallpox outbreak. This paper reviews studies on compounds with proven in vitro or in vivo antipoxviruses potential, which show various mechanisms of action. Nucleoside analogues, such as cidofovir, can inhibit virus replication. Cidofovir derivatives are developed to improve the bioavailability of the drug. Among the nucleoside analogues under current investigation are: ANO (adenozine N1-oxide) and its derivatives, N-methanocarbothymidine [(N)-MCT], or derivatitives of aciklovir, peninclovir and brivudin. Recently, ST-246 - which effectively inhibits infection by limiting release of progeny virions - has become an object of attention. It has been also been demonstrated that compounds such as: nigericin, aptamers and peptides may have antiviral potential. An interesting strategy to fight infections was presented in experiments aimed at defining the role of individual genes (E3L, K3L or C6L) in the pathogenesis, and looking for their potential blockers. Additionally, among substances considered to be effective in the treatment of smallpox cases, there are factors that can block viral inhibitors of the human complement system, epidermal growth factor inhibitors or immunomodulators. Further studies on compounds with activity against poxviruses are necessary in order to broaden the pool of available means that could be used in the case of a new outbreak of smallpox.
- Adenovirus Infections in Heart Transplantation. [JOURNAL ARTICLE]
- Cardiol Rev 2013 Mar 27.
Adenovirus infections have been associated with significant morbidity and mortality in immunocompromised hosts. The clinical significance of adenoviral disease in heart transplantation is not well defined; in particular, the significance of adenovirus identification in myocardium remains unclear. Although severe adenovirus disease has been described in heart transplant recipients, adenovirus infections seem to be more frequently associated with increased risk of adverse cardiac events such as rejection, ventricular dysfunction, coronary vasculopathy, need for re-transplantation and graft loss because of death. Cidofovir is currently considered the standard of treatment for adenovirus disease not responding to reduction of immunosuppression.
- First description of Merkel Cell polyomavirus DNA detection in a patient with Stevens-Johnson syndrome. [Journal Article, Research Support, Non-U.S. Gov't]
- J Med Virol 2013 May; 85(5):918-23.
Merkel Cell polyomavirus (MCPyV), a ubiquitous DNA tumor virus, has been found to be associated with Merkel cell carcinoma and chronic lymphocytic leukaemia while other associations are still being explored. MCPyV sequences have also been detected in normal tissues of tumor patients and in the blood of healthy donors. This report documents a new MCPyV association with the Stevens-Johnson syndrome, a rare immune-modulated mucocutaneous process particularly associated with specific drugs and infective agents. A high MCPyV viral load was detected simultaneously in fluid from skin lesions (2.0 × 10(4) copies/ml) and in matched blood (7.4 × 10(5) copies/ml) from a young adult patient after bone marrow transplant for a relapsed T-cell acute lymphatic leukaemia. MCPyV clearance concurred with the complete resolution of skin lesions after 5 days of cidofovir treatment. DNA sequencing classified the amplicons as the European/Italian MKL-1 strain. Given its ubiquitous nature, MCPyV could account for part of Stevens-Johnson syndrome idiopathic cases.
- What do we know about adenovirus in renal transplantation? [JOURNAL ARTICLE]
- Nephrol Dial Transplant 2013 Mar 13.
Adenoviruses are common pathogens that have the potential to cause opportunistic infections with significant morbidity and mortality in immunocompromised hosts. The significance of adenoviral infection and disease is incompletely known in the setting of kidney transplantation. Reported adenovirus infections in renal transplant recipients have typically manifested as hemorrhagic cystitis and tubulointerstitial nephritis, less severe diseases than often seen in other solid organ transplant recipients (i.e. pneumonia, hepatitis and enteritis). The prevalent adenovirus subgroups associated with cystitis and nephritis are B1 and B2 with the serotypes 7, 11, 34, 35. However, disseminated or severe adenovirus infections, including fatal cases, have been described in renal transplant recipients. There is uncertainty regarding monitoring of and treatment of this virus. Although not supported by randomized clinical trials, cidofovir is used for the treatment of adenovirus disease not responding to reduction of immunosuppression.