990 results on '"Cytosine therapeutic use"'
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2. Brincidofovir inhibits polyomavirus infection in vivo .
- Author
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Butic AB, Katz ZE, Jin G, Fukushima K, Hazama M, Lukacher AE, and Lauver MD
- Subjects
- Animals, Mice, Virus Replication drug effects, Kidney virology, Kidney drug effects, Female, DNA, Viral genetics, Cells, Cultured, Disease Models, Animal, Mice, Inbred C57BL, Brain virology, Cytosine analogs & derivatives, Cytosine pharmacology, Cytosine therapeutic use, Polyomavirus Infections drug therapy, Polyomavirus Infections virology, Polyomavirus drug effects, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Organophosphonates pharmacology, Organophosphonates therapeutic use
- Abstract
Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases, there are no currently approved antivirals for treating polyomavirus infection. Brincidofovir (BCV) is an antiviral approved for the treatment of poxvirus infections and has shown activity against other double-stranded DNA viruses. In this study, we tested the efficacy of BCV against polyomavirus infection in vitro and in vivo using mouse polyomavirus (MuPyV). BCV inhibited virus production in primary mouse kidney cells and brain cortical cells. BCV treatment of cells transfected with MuPyV genomic DNA resulted in a reduction in virus levels, indicating that viral inhibition occurs post-entry. Although in vitro BCV treatment had a limited effect on viral DNA and RNA levels, drug treatment was associated with a reduction in viral protein, raising the possibility that BCV acts post-transcriptionally to inhibit MuPyV infection. In mice, BCV treatment was well tolerated, and prophylactic treatment resulted in a reduction in viral DNA levels and a potent suppression of infectious virus production in the kidney and brain. In mice with chronic polyomavirus infection, therapeutic administration of BCV decreased viremia and reduced infection in the kidney. These data demonstrate that BCV exerts antiviral activity against polyomavirus infection in vivo , supporting further investigation into the use of BCV to treat clinical polyomavirus infections., Importance: Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating polyomavirus infections, management of polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection in vivo using mouse polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic., Competing Interests: K.F. and M.H. are employees of Symbio, which owns the license to BCV.
- Published
- 2024
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3. NPP-669, a prodrug of cidofovir, is highly efficacious against human adenovirus infection in the permissive Syrian hamster model.
- Author
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Tollefson AE, Cline-Smith AB, Spencer JF, Reyna DM, Lipka E, and Toth K
- Subjects
- Animals, Humans, Adenoviruses, Human drug effects, Adenovirus Infections, Human drug therapy, Adenovirus Infections, Human virology, Disease Models, Animal, Cricetinae, Administration, Oral, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Prodrugs pharmacology, Prodrugs therapeutic use, Cidofovir pharmacology, Cidofovir therapeutic use, Mesocricetus, Organophosphonates pharmacology, Organophosphonates therapeutic use, Cytosine analogs & derivatives, Cytosine pharmacology, Cytosine therapeutic use
- Abstract
Human adenoviruses can cause serious, disseminated infections in immunocompromised patients. For pediatric allogeneic stem cell transplant patients, the case fatality rate can reach 80%. Still, there is no available antiviral drug that is specifically approved by the Food and Drug Administration for the treatment of adenovirus infections. To fill this pressing medical need, we have developed NPP-669, a prodrug of cidofovir with broad activity against double-stranded DNA viruses, including adenoviruses. Here, we report on the in vivo anti-adenoviral efficacy of NPP-669. Using the immunosuppressed Syrian hamster as the model, we show that NPP-669 is highly efficacious when dosed orally at 1 mg/kg and 3 mg/kg. In a delayed administration experiment, NPP-669 was more effective than brincidofovir, a similar compound that reached Phase III clinical trials. Furthermore, parenteral administration of NPP-669 increased its efficacy approximately 10-fold compared to oral dosing without apparent toxicity, suggesting that this route may be preferable in a hospital setting. Based on these findings, we believe that NPP-669 is a promising new compound that needs to be further investigated., Competing Interests: The authors declare no conflict of interest.
- Published
- 2024
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4. Brincidofovir for disease progression due to suspected tecovirimat resistance in association with advanced HIV.
- Author
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Harrison I, DeSear K, Santevecchi BA, Venugopalan V, Cherabuddi K, Iovine N, and Radhakrishnan N
- Subjects
- Humans, Male, Anti-HIV Agents therapeutic use, Antiviral Agents therapeutic use, HIV-1 drug effects, Treatment Outcome, Cytosine analogs & derivatives, Cytosine therapeutic use, Disease Progression, Drug Resistance, Viral, HIV Infections drug therapy, HIV Infections complications, Organophosphonates therapeutic use
- Abstract
A man with advanced HIV presented with verrucous plaques 2-3 months after initial mpox infection. He received two courses of tecovirimat without resolution of initial mpox lesions and development of new lesions raising concern for resistance. He was treated with two doses of brincidofovir and demonstrated improvement 6 months later., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
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- 2024
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5. Immune reconstitution and cidofovir administration rescue human adenovirus hepatitis after allogeneic hematopoietic cell transplantation.
- Author
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Tomoda T, Nishimura A, Kamiya T, Inoue K, Katano H, Iida S, Hoshino A, Isoda T, Imai K, Kajiwara M, Takagi M, Kanegane H, Hanaoka N, and Morio T
- Subjects
- Humans, Transplantation, Homologous, Adenoviruses, Human immunology, Male, Hepatitis, Viral, Human drug therapy, Hepatitis, Viral, Human immunology, Cidofovir therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Organophosphonates therapeutic use, Cytosine analogs & derivatives, Cytosine therapeutic use, Adenovirus Infections, Human drug therapy, Adenovirus Infections, Human immunology, Adenovirus Infections, Human therapy, Antiviral Agents therapeutic use, Immune Reconstitution
- Abstract
Human adenovirus infection (HAdV) may be fatal in patients undergoing allogeneic hematopoietic cell transplantation (HCT). Cidofovir is effective in only a part of the post-HCT HAdV infection. Therefore, posttransplant immune reconstitution is important for HAdV clearance. We describe the detailed immune reconstitution and response of adenovirus-specific T cells in a patient with inborn errors of immunity who had disseminated HAdV infection with hepatitis post-HCT and was treated with cidofovir. Though the patient received cidofovir for only 19 days starting from Day 72 after HCT because of renal dysfunction, we observed T-cell reconstitution, a decrease in HAdV copy number, and amelioration of the symptoms of HAdV infection after Day 90. We initially observed expanded NK and CD8
+ CD45RO+ memory subsets and later gradual increase of naïve T cells eveloped after cessation of cidofovir treatment. An increase in adenovirus-specific IFN-γ secretion from 2 to 4 months after HCT was confirmed by ELISpot assay. The progression of immune reconstitution and cidofovir treatment are considered to have contributed to survival in this patient. Optimization of transplantation methods, prompt appropriate antiviral medication, and virus-specific T-cell therapy would be necessary as the better strategy for systemic HAdV infection., Competing Interests: Declaration of competing interest We have no conflict of interest to disclose concerning this study., (Copyright © 2024 Elsevier B.V. All rights reserved.)- Published
- 2024
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6. The successful treatment of mpox with brincidofovir in renal transplant recipients-a report of 2 cases.
- Author
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Alameer RM, Yamani A, Al-Saud A, Alsobayeg S, Alamro B, Alali A, Hammad E, Shendi AM, and Almaghrabi RS
- Subjects
- Humans, Male, Adult, Transplant Recipients, Treatment Outcome, Middle Aged, Kidney Transplantation adverse effects, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Cytosine therapeutic use, Organophosphonates therapeutic use, Immunocompromised Host
- Abstract
An mpox outbreak was declared in July 2022 by the world health organization (WHO). It causes a mild self-limiting disease however; in immunosuppressed hosts, it tends to cause severe disseminated infection. Most cases of mpox in sold organ transplant (SOT) recipients reported in the literature were treated with tecovirimat. Here we report two cases of severe disseminated mpox infection in renal transplant recipients that were successfully treated with brincidofovir. Both patients were discharged from the hospital with no immediate significant side effects from brincidofovir reported until the submission of this report., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)
- Published
- 2024
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7. Computational analysis of antiviral drugs using topological descriptors.
- Author
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Fraz HM, Ali K, and Nadeem MF
- Subjects
- Humans, Acyclovir therapeutic use, Acyclovir chemistry, Acyclovir pharmacology, Computational Biology methods, Cidofovir therapeutic use, Cidofovir chemistry, Cytosine analogs & derivatives, Cytosine therapeutic use, Cytosine chemistry, Valacyclovir therapeutic use, Antiviral Agents therapeutic use, Antiviral Agents chemistry, Antiviral Agents pharmacology
- Abstract
Many health challenges are attributed to viral infections, which represent significant concerns in public health. Among these infections, diseases such as herpes simplex virus (HSV), cytomegalovirus (CMV), and varicella-zoster virus (VZV) infections have garnered attention due to their prevalence and impact on human health. There are specific antiviral medications available for the treatment of these viral infections. Drugs like Cidofovir, Valacyclovir, and Acyclovir are commonly prescribed. These antiviral drugs are known for their efficacy against herpesviruses and related viral infections, leveraging their ability to inhibit viral DNA polymerase. A molecular descriptor is a numerical value that correlates with specific physicochemical properties of a molecular graph. This article explores the calculation of distance-based topological descriptors, including the Trinajstic, Mostar, Szeged, and PI descriptors for the aforementioned antiviral drugs. These descriptors provide insights into these drugs' structural and physicochemical characteristics, aiding in understanding their mechanism of action and the development of new therapeutic agents., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)
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- 2024
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8. Cidofovir in Severe Hypoxemic Adenoviral Pneumonia.
- Author
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Gupta A, Khanna P, Parihar A, Singh DP, and Singhi SC
- Subjects
- Male, Humans, Cidofovir therapeutic use, Antiviral Agents therapeutic use, Cytosine therapeutic use, Organophosphonates therapeutic use, Adenoviridae Infections diagnosis, Pneumonia, Viral
- Abstract
The authors present a 16-mo-old boy with flu like symptoms, not responding to supportive management and progressed to severe hypoxemic pneumonia. Adenovirus was detected in the nasopharyngeal aspirate. He showed rapid improvement after intravenous cidofovir administration., (© 2023. The Author(s), under exclusive licence to Dr. K C Chaudhuri Foundation.)
- Published
- 2024
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9. Monkeypox: A re-emerging disease.
- Author
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Kaur N, Dabar J, and Bassi P
- Subjects
- Humans, Animals, Cytosine therapeutic use, Monkeypox virus, Isoindoles therapeutic use, Organothiophosphorus Compounds, Organophosphonates therapeutic use, Benzamides therapeutic use, Mpox (monkeypox) epidemiology, Mpox (monkeypox) transmission, Antiviral Agents therapeutic use, Communicable Diseases, Emerging epidemiology, Cytosine analogs & derivatives, Phthalimides
- Abstract
Abstract: The virus known as monkeypox is the source of the zoonotic disease monkeypox, which was historically widespread in Central Africa and West Africa. The cases of monkeypox in humans are uncommon outside of West and Central Africa, but copious nonendemic nations outside of Africa have recently confirmed cases. People when interact with diseased animals, then, they may inadvertently contact monkeypox. There are two drugs in the market: brincidofovir and tecovirimat and both of these drugs are permitted for the cure of monkeypox by the US Food and Drug Administration. The present review summarizes the various parameters of monkeypox in context with transmission, signs and symptoms, histopathological and etiological changes, and possible treatment. Monkeypox is clinically similar to that of smallpox infection but epidemiologically, these two are different, the present study also signifies the main differences and similarities of monkeypox to that of other infectious diseases. As it is an emerging disease, it is important to know about the various factors related to monkeypox so as to control it on a very early stage of transmission., (Copyright © 2024 Copyright: © 2024 Indian Journal of Pharmacology.)
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- 2024
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10. Oral USC-093, a novel homoserinamide analogue of the tyrosinamide (S)-HPMPA prodrug USC-087 has decreased nephrotoxicity while maintaining antiviral efficacy against human adenovirus infection of Syrian hamsters.
- Author
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Tollefson AE, Riemann SB, Ying B, Spencer JF, Overhulse JM, Kashemirov BA, Wold WSM, McKenna CE, and Toth K
- Subjects
- Cricetinae, Animals, Humans, Cidofovir pharmacology, Cidofovir therapeutic use, Mesocricetus, Antiviral Agents therapeutic use, Adenoviridae, Virus Replication, Cytosine pharmacology, Cytosine therapeutic use, Amino Acids pharmacology, Nucleotides therapeutic use, Adenovirus Infections, Human drug therapy, Prodrugs pharmacology, Prodrugs therapeutic use, Organophosphonates pharmacology, Organophosphonates therapeutic use, Adenoviridae Infections drug therapy, Adenine analogs & derivatives, Tyrosine analogs & derivatives
- Abstract
Adenovirus infections of immunocompromised humans are a significant source of morbidity and mortality. Presently, there is no drug specifically approved for the treatment of adenovirus infections by the FDA. The state-of-the-art treatment of such infections is the off-label use of cidofovir, an acyclic nucleotide phosphonate. While cidofovir inhibits adenovirus replication, it has dose-limiting kidney toxicity. There is an apparent need for a better compound to treat adenovirus infections. To this end, we have been developing acyclic nucleotide phosphonate prodrugs that utilize an amino acid scaffold equipped with a lipophilic modifier. Here, we compare the antiviral potential of two prodrugs of HPMPA that differ only in the amino acid-based promoiety: USC-087, based on an N-hexadecyl tyrosinamide, and USC-093, based on an N-hexadecyl serinamide. Oral administration of both compounds was very efficacious against disseminated HAdV-C6 infection in immunosuppressed Syrian hamsters, suppressing virus replication and mitigating pathology even when treatment was withheld until 4 days after challenge. We saw only marginal efficacy after respiratory infection of hamsters, which may reflect suboptimal distribution to the lung. Importantly, neither compound induced intestinal toxicity, which was observed as the major adverse effect in clinical trials of brincidofovir, a prodrug of cidofovir which also contains a C-16 modifier. Notably, we found that there was a significant difference in the nephrotoxicity of the two compounds: USC-087 caused significant kidney toxicity while USC-093 did not, at effective doses. These findings will be valuable guidepoints in the future evolution of this new class of potential prodrugs to treat adenovirus infections., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Published
- 2024
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11. Clinical evaluation of pediatric patients with recurrent respiratory papillomatosis.: A longitudinal study at a Saudi Arabian tertiary care center.
- Author
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Almutairi N, Alshathri A, Alshareef W, Sindi A, Aljasser A, and Alammar A
- Subjects
- Male, Child, Humans, Female, Cidofovir therapeutic use, Saudi Arabia epidemiology, Cytosine therapeutic use, Longitudinal Studies, Retrospective Studies, Tertiary Care Centers, Organophosphonates therapeutic use, Papillomavirus Infections drug therapy, Respiratory Tract Infections drug therapy
- Abstract
Objectives: To study the clinical evaluation of recurrent respiratory papillomatosis (RRP) patients and the factors associated with the improvement in the Derkay's score as a measure of disease severity., Methods: A retrospective cohort that included all juvenile RRP patients who were admitted to King Abdulaziz University Hospital, Riyadh, Saudi Arabia, between September 2015 and June 2022 and underwent surgical debulking., Results: A total of 16 patients were eligible to join our study. Among them, 7 patients were males. Hoarseness of voice was the most frequent symptom. The median period of the follow-up was 56 months. Complete remission was achieved in 31.3%. The univariate linear regression model revealed that the cidofovir-treated patients had a significant reduction in the change value of Derkay's score compared to those without treatment (regression coefficient= -5.83, 95% confidence interval [CI]: [-11.5 to -0.143], p =0.045). Also, the increased first Derkay's score decreased the change value and subsequently increased the improvement chance of the disease (regression coefficient= -0.424, 95% CI: [-0.764 to -0.083], p =0.018). However, in the multivariate regression model, both variables showed non-significant results., Conclusion: cidofovir treatment and higher Derkay's scores affected the disease improvement., (Copyright: © Saudi Medical Journal.)
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- 2024
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12. Successful Treatment of Recalcitrant Mpox Lesions With Intralesional Cidofovir in a Patient With HIV/AIDS.
- Author
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Buechler CR, Anderson ZJ, Kullberg SA, Miller DD, Ahiskali A, Schut R, and Hylwa SA
- Subjects
- Humans, Cidofovir, Antiviral Agents therapeutic use, Cytosine therapeutic use, Injections, Intralesional, Acquired Immunodeficiency Syndrome, Mpox (monkeypox), Papillomavirus Infections
- Published
- 2024
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13. Treatment and Vaccination for Smallpox and Monkeypox.
- Author
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Saalbach KP
- Subjects
- Humans, Vaccination methods, Variola virus immunology, Variola virus genetics, Animals, Cytosine analogs & derivatives, Cytosine therapeutic use, Monkeypox virus immunology, Monkeypox virus pathogenicity, Monkeypox virus genetics, Immunization, Passive methods, Organophosphonates therapeutic use, Isoindoles therapeutic use, Cidofovir therapeutic use, Immunoglobulins, Intravenous therapeutic use, Benzamides, Phthalimides, Smallpox prevention & control, Smallpox epidemiology, Smallpox immunology, Smallpox history, Antiviral Agents therapeutic use, Smallpox Vaccine immunology, Smallpox Vaccine therapeutic use, Mpox (monkeypox) epidemiology, Mpox (monkeypox) prevention & control, Mpox (monkeypox) immunology
- Abstract
The smallpox infection with the variola virus was one of the most fatal disorders until a global eradication was initiated in the twentieth century. The last cases were reported in Somalia 1977 and as a laboratory infection in the UK 1978; in 1980, the World Health Organization (WHO) declared smallpox for extinct. The smallpox virus with its very high transmissibility and mortality is still a major biothreat, because the vaccination against smallpox was stopped globally in the 1980s. For this reason, new antivirals (cidofovir, brincidofovir, and tecovirimat) and new vaccines (ACAM2000, LC16m8 and Modified Vaccine Ankara MVA) were developed. For passive immunization, vaccinia immune globulin intravenous (VIGIV) is available. Due to the relationships between orthopox viruses such as vaccinia, variola, mpox (monkeypox), cowpox, and horsepox, the vaccines (LC16m8 and MVA) and antivirals (brincidofovir and tecovirimat) could also be used in the mpox outbreak with positive preliminary data. As mutations can result in drug resistance against cidofovir or tecovirimat, there is need for further research. Further antivirals (NIOCH-14 and ST-357) and vaccines (VACΔ6 and TNX-801) are being developed in Russia and the USA. In conclusion, further research for treatment and prevention of orthopox infections is needed and is already in progress. After a brief introduction, this chapter presents the smallpox and mpox disease and thereafter full overviews on antiviral treatment and vaccination including the passive immunization with vaccinia immunoglobulins., (© 2024. The Author(s), under exclusive license to Springer Nature Switzerland AG.)
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- 2024
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14. Use of cidofovir in a patient with severe mpox and uncontrolled HIV infection.
- Author
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Stafford A, Rimmer S, Gilchrist M, Sun K, Davies EP, Waddington CS, Chiu C, Armstrong-James D, Swaine T, Davies F, Gómez CHM, Kumar V, ElHaddad A, Awad Z, Smart C, Mora-Peris B, Muir D, Randell P, Peters J, Chand M, Warrell CE, Rampling T, Cooke G, Dhanji S, Campbell V, Davies C, Osman S, and Abbara A
- Subjects
- Male, Humans, Middle Aged, Cidofovir therapeutic use, State Medicine, Cytosine therapeutic use, Antiviral Agents therapeutic use, HIV Infections complications, HIV Infections drug therapy, Organophosphonates therapeutic use, Mpox (monkeypox) drug therapy
- Abstract
A 48-year-old man with poorly controlled HIV presented with severe human monkeypox virus (hMPXV) infection, having completed 2 weeks of tecovirimat at another hospital. He had painful, ulcerating skin lesions on most of his body and oropharyngeal cavity, with subsequent Ludwig's angina requiring repeated surgical interventions. Despite commencing a second, prolonged course of tecovirimat, he did not objectively improve, and new lesions were still noted at day 24. Discussion at the UK National Health Service England High Consequence Infectious Diseases Network recommended the use of 3% topical and then intravenous cidofovir, which was given at 5 mg/kg; the patient made a noticeable improvement after the first intravenous dose. He received further intravenous doses at 7 days and 21 days after the dose and was discharged at day 52. Cidofovir is not licensed for use in treatment of hMPXV infection. Data for cidofovir use in hMPXV are restricted to studies in animals. Four other documented cases of cidofovir use against hMPXV have been reported in the USA in 2022, but we present its first use in the UK. The scarcity of studies into the use of cidofovir in this condition clearly shows the need for robust studies to assess efficacy, optimum dosage, timing, and route of administration., Competing Interests: Declaration of interests DA-J has received consultancy fees or honoraria from Gilead and Pulmocide and has stock or stock options in Pulmocide. MG has received consultancy fees from Pfizer. FD receives a Clinical Academic Research Partnerships Fellowship from the Medical Research Council. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)
- Published
- 2023
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15. BILATERAL UVEITIS AND HYPOTONY FOLLOWING TREATMENT WITH TOPICAL CIDOFOVIR.
- Author
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Santilli CM, Koozekanani D, and Armbrust KR
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- Male, Humans, Middle Aged, Cidofovir adverse effects, Cytosine therapeutic use, Organophosphonates adverse effects, Ocular Hypotension drug therapy, Ocular Hypotension etiology, AIDS-Related Opportunistic Infections complications, AIDS-Related Opportunistic Infections drug therapy, Uveitis chemically induced, Uveitis diagnosis, Uveitis drug therapy, Uveitis, Anterior complications, Uveitis, Anterior drug therapy, Choroidal Effusions complications, Choroidal Effusions drug therapy
- Abstract
Purpose: To report a case of bilateral uveitis and hypotony associated with topical cidofovir treatment., Methods: Case report., Results: A 59-year-old diabetic man with HIV/AIDS presented with photophobia, ocular pain, and decreased vision. He was found to have bilateral hypotony, anterior uveitis, and serous choroidal detachments. Infectious disease workup, patient-reported history, and review of the patient's electronic medication list did not identify the etiology. Treatment with intensive topical corticosteroids led to resolution of uveitis and choroidal effusions within 3 months and resolution of hypotony within 9 months. Two years after his initial presentation, the patient developed acute recurrence of bilateral hypotony, anterior uveitis, and serous choroidal detachments shortly after intravenous cidofovir treatment. Careful reevaluation of the patient's outside medical records revealed that he had initiated treatment for rectal herpes simplex virus with compounded topical cidofovir one month before his initial presentation., Conclusion: To our knowledge, this is the first reported case of topical cidofovir causing ocular toxicity. Compounded and topical medications, like cidofovir in this case, may not appear on a patient's electronic medication list, so a focused review of outside medical records may be beneficial when a particular medication toxicity is suspected.
- Published
- 2023
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16. Assessment of immunomodulation and regulation of cell cycle in epithelium and stroma after Cidofovir injection in patients with recurrent respiratory papillomatosis-Pilot study.
- Author
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Solarz P, Bodnar M, Czech J, Mackiewicz-Nartowicz H, Sinkiewicz A, Szylberg Ł, Borowczak J, Rutkiewicz P, Zwierz A, and Burduk P
- Subjects
- Humans, Cidofovir therapeutic use, Pilot Projects, Cytosine therapeutic use, Antiviral Agents therapeutic use, Epithelium pathology, Cell Cycle, Immunomodulation, Papillomavirus Infections drug therapy, Organophosphonates therapeutic use, Laryngeal Neoplasms pathology
- Abstract
Recurrent respiratory papillomatosis is strictly connected with human papillomavirus (HPV) infection of the epithelium of the upper respiratory tract. The main treatment of lesions located in the larynx or lower pharynx includes microsurgical excision by using a CO
2 laser. To decrease the amount of surgical procedures gain in importance combined therapy with antiviral agents. The aim of this study was to investigate the effect of the intralesional application of Cidofovir on the tissue of laryngeal papillomas. We have shown that simultaneous microsurgery with adjuvant therapy of Cidofovir reduces chronic inflammation (by measuring the expression of CD4 and CD8 in tissue samples), cell proliferation, and regulates the cell cycle of HPV-infected cells by reducing the expression of p53 and p63 proteins. In addition, this strategy reduces the multiple surgical procedures and regrowth of the pathology., (© 2022 Wiley Periodicals LLC.)- Published
- 2023
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17. Resistant herpes simplex virus infections - who, when, and what's new?
- Author
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Kotton BD and Kotton CN
- Subjects
- Humans, Cytosine therapeutic use, Acyclovir therapeutic use, Foscarnet therapeutic use, Antiviral Agents therapeutic use, Organophosphonates therapeutic use, Herpes Simplex diagnosis, Herpes Simplex drug therapy, Herpesviridae Infections
- Abstract
Purpose of Review: This review summarizes the literature on acyclovir resistant herpes infections and the most recent data pertinent to diagnosis and treatment in the immunocompromised patient population., Recent Findings: Although fairly rare, acyclovir resistant herpes infections can be challenging to diagnose. Clinicians should be aware of this entity when facing refractory herpes infections. With updated diagnostics, the diagnosis is usually made through viral culture and sequencing. Therapeutic choices depend on the extent of disease. Topical therapy may be appropriate for mucocutaneous disease. Intravenous antiviral therapies such as foscarnet and cidofovir may be necessary for disseminated, ophthalmologic, central nervous system, or visceral disease. Experimental therapies such as pritelivir are in clinical trials., Summary: Immunosuppressed patients are at risk for developing acyclovir-resistant herpes, which can be challenging to diagnose and treat, although emerging therapeutic options look promising., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)
- Published
- 2022
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18. Mutation detection and minimum inhibitory concentration determination against linezolid and clofazimine in confirmed XDR-TB clinical isolates.
- Author
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Singh K, Sharma S, Banerjee T, Gupta A, and Anupurba S
- Subjects
- Agar, Antitubercular Agents pharmacology, Clofazimine pharmacology, Clofazimine therapeutic use, Cytosine therapeutic use, Drug Resistance, Multiple, Bacterial genetics, Humans, Linezolid pharmacology, Linezolid therapeutic use, Microbial Sensitivity Tests, Mutation, Thymine therapeutic use, Extensively Drug-Resistant Tuberculosis drug therapy, Extensively Drug-Resistant Tuberculosis microbiology, Mycobacterium tuberculosis, Tuberculosis, Multidrug-Resistant microbiology
- Abstract
Background: The emergence of multidrug-resistant tuberculosis (MDR-TB) has complicated the situation due to the decline in potency of second-line anti-tubercular drugs. This limits the treatment option for extensively drug-resistant tuberculosis (XDR-TB). The aim of this study was to determine and compare the minimum inhibitory concentration (MIC) by agar dilution and resazurin microtiter assay (REMA) along with the detection of mutations against linezolid and clofazimine in confirmed XDR-TB clinical isolates., Results: A total of 169 isolates were found positive for Mycobacterium tuberculosis complex (MTBC). The MIC was determined by agar dilution and REMA methods. The isolates which showed non-susceptibility were further subjected to mutation detection by targeting rplC gene (linezolid) and Rv0678 gene (clofazimine). The MIC for linezolid ranged from 0.125 µg/ml to > 2 µg/ml and for clofazimine from 0.25 µg/ml to > 4 µg/ml. The MIC
50 and MIC90 for linezolid were 0.5 µg/ml and 1 µg/ml respectively while for clofazimine both were 1 µg/ml. The essential and categorical agreement for linezolid was 97.63% and 95.26% and for clofazimine, both were 100%. The sequencing result of the rplC gene revealed a point mutation at position 460 bp, where thymine (T) was substituted for cytosine (C) while seven mutations were noted between 46 to 220 bp in Rv0678 gene., Conclusion: REMA method has been found to be more suitable in comparison to the agar dilution method due to lesser turnaround time. Mutations in rplC and Rv0678 genes were reasons for drug resistance against linezolid and clofazimine respectively., (© 2022. The Author(s).)- Published
- 2022
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19. Functional Phosphoproteomics in Cancer Chemoresistance Using CRISPR-Mediated Base Editors.
- Author
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Li J, Lin J, Huang S, Li M, Yu W, Zhao Y, Guo J, Zhang P, Huang X, and Qiao Y
- Subjects
- Humans, Clustered Regularly Interspaced Short Palindromic Repeats, Fluorouracil pharmacology, Fluorouracil therapeutic use, Protein Kinases genetics, Protein Kinases metabolism, Protein Kinases pharmacology, Adenine pharmacology, Adenine therapeutic use, Amino Acids genetics, Amino Acids pharmacology, Amino Acids therapeutic use, Cytosine pharmacology, Cytosine therapeutic use, p21-Activated Kinases genetics, p21-Activated Kinases metabolism, p21-Activated Kinases pharmacology, Drug Resistance, Neoplasm genetics, Colorectal Neoplasms drug therapy, Colorectal Neoplasms genetics, Colorectal Neoplasms pathology
- Abstract
Selective inhibition of targeted protein kinases is an effective therapeutic approach for treatment of human malignancies, which interferes phosphorylation of cellular substrates. However, a drug-imposed selection creates pressures for tumor cells to acquire chemoresistance-conferring mutations or activating alternative pathways, which can bypass the inhibitory effects of kinase inhibitors. Thus, identifying downstream phospho-substrates conferring drug resistance is of great importance for developing poly-pharmacological and targeted therapies. To identify functional phosphorylation sites involved in 5-fluorouracil (5-FU) resistance during its treatment of colorectal cancer cells, CRISPR-mediated cytosine base editor (CBE) and adenine base editor (ABE) are utilized for functional screens by mutating phosphorylated amino acids with two libraries specifically targeting 7779 and 10 149 phosphorylation sites. Among the top enriched gRNAs-induced gain-of-function mutants, the target genes are involved in cell cycle and post-translational covalent modifications. Moreover, several substrates of RSK2 and PAK4 kinases are discovered as main effectors in responding to 5-FU chemotherapy, and combinational treatment of colorectal cancer cells with 5-FU and RSK2 inhibitor or PAK4 inhibitor can largely inhibit cell growth and enhance cell apoptosis through a RSK2/TP53BP1/γ-H2AX phosphorylation signaling axis. It is proposed that this screen approach can be used for functional phosphoproteomics in chemotherapy of various human diseases., (© 2022 The Authors. Advanced Science published by Wiley-VCH GmbH.)
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- 2022
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20. Evaluation of cytosine base editing and adenine base editing as a potential treatment for alpha-1 antitrypsin deficiency.
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Packer MS, Chowdhary V, Lung G, Cheng LI, Aratyn-Schaus Y, Leboeuf D, Smith S, Shah A, Chen D, Zieger M, Cafferty BJ, Yan B, Ciaramella G, Gregoire FM, and Mueller C
- Subjects
- Adenine chemistry, Adenine therapeutic use, Animals, Cytosine chemistry, Cytosine therapeutic use, Humans, Liposomes, Mice, Mutation, Nanoparticles, alpha 1-Antitrypsin genetics, Gene Editing methods, alpha 1-Antitrypsin Deficiency genetics, alpha 1-Antitrypsin Deficiency pathology, alpha 1-Antitrypsin Deficiency therapy
- Abstract
Alpha-1 antitrypsin deficiency (AATD) is a rare autosomal codominant disease caused by mutations within the SERPINA1 gene. The most prevalent variant in patients is PiZ SERPINA1, containing a single G > A transition mutation. PiZ alpha-1 antitrypsin (AAT) is prone to misfolding, leading to the accumulation of toxic aggregates within hepatocytes. In addition, the abnormally low level of AAT secreted into circulation provides insufficient inhibition of neutrophil elastase within the lungs, eventually causing emphysema. Cytosine and adenine base editors enable the programmable conversion of C⋅G to T⋅A and A⋅T to G⋅C base pairs, respectively. In this study, two different base editing approaches were developed: use of a cytosine base editor to install a compensatory mutation (p.Met374Ile) and use of an adenine base editor to mediate the correction of the pathogenic PiZ mutation. After treatment with lipid nanoparticles formulated with base editing reagents, PiZ-transgenic mice exhibited durable editing of SERPINA1 in the liver, increased serum AAT, and improved liver histology. These results indicate that base editing has the potential to address both lung and liver disease in AATD., Competing Interests: Declaration of interests M.S.P., G.L., L.C., Y.A.S., D.L., S.S., A.S., D.C., B.J.C., B.Y., G.C., and F.M.G. are employees of and shareholders in Beam Therapeutics. This work was funded in part by Beam Therapeutics, which develops base editing therapeutics., (Copyright © 2022 The American Society of Gene and Cell Therapy. Published by Elsevier Inc. All rights reserved.)
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- 2022
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21. Photoreactive Cytosine-Functionalized Self-Assembled Micelles with Enhanced Cellular Uptake Capability for Efficient Cancer Chemotherapy.
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Manayia AH, Ilhami FB, Lee AW, and Cheng CC
- Subjects
- Cytosine therapeutic use, Drug Carriers chemistry, Drug Delivery Systems, Drug Liberation, Humans, Micelles, Neoplasms drug therapy
- Abstract
Design, fabrication, and control of photoreactive supramolecular macromers─which are composed of a thermoresponsive polymer backbone and photoreactive nucleobase end-groups─to achieve the desired physical-chemical performance and provide the high efficiency required for chemotherapy drug delivery purposes still present challenges. Herein, a difunctional cytosine-terminated supramolecular macromer was successfully obtained at high yield. UV-irradiation induces the formation of cytosine photodimers within the structure. The irradiated macromer can self-assemble into nanosized spherical micelles in water that possess a number of interesting and unique features, such as desired micellar size and morphology, tunable drug-loading capacity, and excellent structural stability in serum-containing medium, in addition to well-controlled drug-release behaviors in response to changes in environmental temperature and pH; these extremely desirable, rare features are required to augment the functions of polymeric nanocarriers for drug delivery. Importantly, a series of in vitro studies demonstrated that photodimerized cytosine moieties within the drug-loaded micelles substantially enhance their internalization and accumulation inside cells via endocytosis and subsequently lead to induction of massive apoptotic cell death compared with the corresponding nonirradiated micelles. Thus, this newly developed "photomodified" nanocarrier system could provide a potentially fruitful route to enhance the drug delivery performance of nanocages without the need to introduce targeting moieties or additional components.
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- 2021
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22. Safety and efficacy of brincidofovir for Adenovirus infection in children receiving allogeneic stem cell transplantation: an AIEOP retrospective analyses.
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Perruccio K, Menconi M, Galaverna F, Pagliara D, Carraro F, Fagioli F, Calore E, Biffi A, Baretta V, Massei MS, Capolsini I, Faraci M, Verna M, Soncini E, Caniglia M, Locatelli F, and Cesaro S
- Subjects
- Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Cytosine pharmacology, Cytosine therapeutic use, Humans, Organophosphonates, Retrospective Studies, Adenoviridae Infections drug therapy, Hematopoietic Stem Cell Transplantation
- Published
- 2021
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23. Results of a randomized phase 3 study of oral sapacitabine in elderly patients with newly diagnosed acute myeloid leukemia (SEAMLESS).
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Kantarjian HM, Begna KH, Altman JK, Goldberg SL, Sekeres MA, Strickland SA, Arellano ML, Claxton DF, Baer MR, Gautier M, Berman E, Seiter K, Solomon SR, Schiller GJ, Luger SM, Butrym A, Gaidano G, Thomas XG, Montesinos P, Rizzieri DA, Quick DP, Venugopal P, Gaur R, Maness LJ, Kadia TM, Ravandi F, Buyse ME, and Chiao JH
- Subjects
- Aged, Azacitidine, Cytosine analogs & derivatives, Cytosine therapeutic use, Decitabine, Humans, Treatment Outcome, Arabinonucleosides, Leukemia, Myeloid, Acute
- Abstract
Background: Acute myeloid leukemia (AML) is fatal in elderly patients who are unfit for standard induction chemotherapy. The objective of this study was to evaluate the survival benefit of administering sapacitabine, an oral nucleoside analogue, in alternating cycles with decitabine, a low-intensity therapy, to elderly patients with newly diagnosed AML., Methods: This randomized, open-label, phase 3 study (SEAMLESS) was conducted at 87 sites in 11 countries. Patients aged ≥70 years who were not candidates for or chose not to receive standard induction chemotherapy were randomized 1:1 to arm A (decitabine in alternating cycles with sapacitabine) received 1-hour intravenous infusions of decitabine 20 mg/m
2 once daily for 5 consecutive days every 8 weeks (first cycle and subsequent odd cycles) and sapacitabine 300 mg twice daily on 3 consecutive days per week for 2 weeks every 8 weeks (second cycle and subsequent even cycles) or to control arm C who received 1-hour infusions of decitabine 20 mg/m2 once daily for 5 consecutive days every 4 weeks. Prior hypomethylating agent therapy for preexisting myelodysplastic syndromes or myeloproliferative neoplasms was an exclusion criterion. Randomization was stratified by antecedent myelodysplastic syndromes or myeloproliferative neoplasms, white blood cell count (<10 × 109 /L and ≥10 × 109 /L), and bone marrow blast percentage (≥50% vs <50%). The primary end point was overall survival (OS). Secondary end points were the rates of complete remission (CR), CR with incomplete platelet count recovery, partial remission, hematologic improvement, and stable disease along with the corresponding durations, transfusion requirements, number of hospitalized days, and 1-year survival. The trial is registered at ClinicalTrials.gov (NCT01303796)., Results: Between October 2011 and December 2014, 482 patients were enrolled and randomized to receive decitabine administered in alternating cycles with sapacitabine (study arm, n = 241) or decitabine monotherapy (control arm, n = 241). The median OS was 5.9 months on the study arm versus 5.7 months on the control arm (P = .8902). The CR rate was 16.6% on the study arm and 10.8% on the control arm (P = .1468). In patients with white blood cell counts <10 × 109 /L (n = 321), the median OS was higher on the study arm versus the control arm (8.0 vs 5.8 months; P = .145), as was the CR rate (21.5% vs 8.6%; P = .0017)., Conclusions: The regimen of decitabine administered in alternating cycles with sapacitabine was active but did not significantly improve OS compared with decitabine monotherapy. Subgroup analyses suggest that patients with baseline white blood cell counts <10 × 109 /L might benefit from decitabine alternating with sapacitabine, with an improved CR rate and the convenience of an oral drug. These findings should be prospectively confirmed., (© 2021 American Cancer Society.)- Published
- 2021
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24. Topical cidofovir for benign human papillomavirus-associated skin lesions.
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Napolitano L, Schroedl L, Kerman A, and Shea CR
- Subjects
- Cidofovir therapeutic use, Cytosine adverse effects, Cytosine therapeutic use, Humans, Papillomaviridae, Alphapapillomavirus, Organophosphonates therapeutic use, Papillomavirus Infections drug therapy
- Abstract
Cidofovir is a broad-spectrum antiviral agent that has shown efficacy against skin lesions caused by human papillomavirus (HPV). We present a case of extensive verruca vulgaris lesions refractory to imiquimod that was responsive to topical cidofovir therapy, and analyze other case series in the literature of successful treatment of benign HPV-associated skin lesions with topical cidofovir. Topical cidofovir's favorable response rate and tolerability make it a useful treatment option for patients of differing ages and immune status who have nonmalignant HPV-associated skin lesions and desire topical therapy.
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- 2021
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25. Benefit-risk assessment for brincidofovir for the treatment of smallpox: U.S. Food and Drug Administration's Evaluation.
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Chan-Tack K, Harrington P, Bensman T, Choi SY, Donaldson E, O'Rear J, McMillan D, Myers L, Seaton M, Ghantous H, Cao Y, Valappil T, Birnkrant D, and Struble K
- Subjects
- Animals, Cytosine therapeutic use, Disease Eradication, Disease Models, Animal, Humans, Risk Assessment, Treatment Outcome, United States, United States Food and Drug Administration, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Drug Approval, Organophosphonates therapeutic use, Smallpox drug therapy
- Abstract
The development and approval of brincidofovir for the treatment of smallpox, a disease that was eradicated from the world over 40 years ago, has resulted in the second antiviral approved via the Medical Countermeasure Initiative (MCMi) to combat this disease. Approval of brincidofovir required a unique regulatory approach based on the FDA Animal Rule, and development was supported by many years of research and collaboration among academic investigators, the pharmaceutical industry and multiple government agencies. This article summarizes the FDA regulatory pathway and describes the challenges involved., (Published by Elsevier B.V.)
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- 2021
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26. Safety and efficacy of intravenously administered cidofovir in adult haematopoietic cell transplant recipients: a retrospective multicentre cohort study.
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Stern A, Alonso CD, Garcia-Vidal C, Cardozo C, Slavin M, Yong MK, Ho SA, Mehta Steinke S, Avery RK, Koehler P, Scheid C, Cornely OA, Maertens J, Abi Aad Y, Epstein DJ, Papanicolaou GA, and Neofytos D
- Subjects
- Antiviral Agents adverse effects, Cidofovir, Cohort Studies, Cytosine therapeutic use, Humans, Retrospective Studies, Transplant Recipients, Hematopoietic Stem Cell Transplantation adverse effects, Organophosphonates adverse effects
- Abstract
Objectives: To evaluate the safety and efficacy of cidofovir for the treatment of double-stranded DNA (dsDNA) viral infections following allogeneic haematopoietic cell transplant (HCT)., Methods: This was a retrospective multicentre cohort study including adult HCT recipients who received ≥1 dose of IV-administered cidofovir for any dsDNA viral infection from 2006 to 2019. The objectives were to describe the rate of and risk factors for nephrotoxicity and virological response by the end of treatment (EOT)., Results: We included 165 patients from nine centres. Cidofovir was administered at 5 mg/kg/week (N = 115; 69.7%), 1 mg/kg/week (18; 10.9%), 3 mg/kg/week (12; 7.3%) or 1 mg/kg three times/week (11; 6.7%). Cidofovir was administered for adenovirus, cytomegalovirus (CMV) and BK virus infection in 75 (45.5%), 64 (38.8%) and 51 (30.9%) patients, respectively. Among 158 patients with renal function data at baseline and EOT, 40 (25.3%) developed nephrotoxicity. In multivariable analyses, age (OR 1.04; P = 0.05), weight (OR 1.05; P = 0.01), CMV infection (OR 3.6; P = 0.02), liposomal amphotericin B (OR 8.06; P = 0.05) and IV voriconazole/posaconazole (OR 13.0; P = 0.003) were predictors of nephrotoxicity. Creatinine concentration was significantly higher at EOT (1.16 ± 0.95 mg/dL) compared with baseline (0.91 ± 0.39 mg/dL; P < 0.001), but improved by 2 weeks (0.91 ± 0.84 mg/dL; P = 0.007) and 4 weeks (0.96 ± 0.89 mg/dL; P = 0.03) post-EOT. Median viral load significantly declined for patients with adenovirus DNAaemia by EOT (P < 0.0001) and for patients with CMV DNAaemia by EOT + 4 weeks (P = 0.003), but not for patients with BK virus DNAaemia., Conclusions: One in four HCT recipients treated with IV cidofovir developed largely reversible nephrotoxicity. Careful selection of patients and close follow-up of renal function may minimize toxicity., (© The Author(s) 2021. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)
- Published
- 2021
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27. Brincidofovir for the treatment of human adenovirus infection in pediatric solid organ transplant recipients: A case series.
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Londeree J, Winterberg PD, Garro R, George RP, Shin S, Liverman R, Serluco A, Romero R, and Yildirim I
- Subjects
- Adenovirus Infections, Human etiology, Adolescent, Antiviral Agents therapeutic use, Cytosine therapeutic use, Female, Follow-Up Studies, Humans, Infant, Male, Retrospective Studies, Transplantation, Homologous, Young Adult, Adenovirus Infections, Human drug therapy, Cytosine analogs & derivatives, Kidney Transplantation, Liver Transplantation, Organophosphonates therapeutic use, Postoperative Complications, Transplant Recipients
- Abstract
HAdV viremia can cause significant morbidity among pediatric recipients of SOT with variability in incidence and severity of disease based on the type of allograft. Currently, there are no US FDA-approved treatments for HAdV infections, and historically, the mainstay of treatment has been decreasing immunosuppression, with antiviral therapies reserved for those with severe disease. We describe the treatment of four pediatric SOT recipients (two kidney, one combined kidney-liver, and one liver) presenting with HAdV disease at our institution using brincidofovir. Our case series highlights the variability in presentation and the potential for severe disease in pediatric SOT recipients as we review disease presentation, disease course, complications, and treatment with brincidofovir., (© 2020 Wiley Periodicals LLC.)
- Published
- 2020
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28. Failure of antiviral therapy with brincidofovir in non-HIV progressive multifocal leukoencephalopathy.
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Talarmin JP, Rezig S, Tran-Minoui A, Berthou C, and Eveillard JR
- Subjects
- Cytosine therapeutic use, Fatal Outcome, Female, Humans, Male, Middle Aged, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Leukoencephalopathy, Progressive Multifocal drug therapy, Organophosphonates therapeutic use, Treatment Failure
- Published
- 2020
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29. Brincidofovir: understanding its unique profile and potential role against adenovirus and other viral infections.
- Author
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Alvarez-Cardona JJ, Whited LK, and Chemaly RF
- Subjects
- Adenovirus Infections, Human virology, Animals, Clinical Trials as Topic, Cytosine adverse effects, Cytosine pharmacokinetics, Cytosine pharmacology, Cytosine therapeutic use, DNA Virus Infections virology, Humans, Immunocompromised Host, Adenovirus Infections, Human drug therapy, Antiviral Agents adverse effects, Antiviral Agents pharmacokinetics, Antiviral Agents pharmacology, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, DNA Virus Infections drug therapy, DNA Viruses drug effects, Organophosphonates adverse effects, Organophosphonates pharmacokinetics, Organophosphonates pharmacology, Organophosphonates therapeutic use
- Abstract
Brincidofovir (BCV) is a lipid conjugate of cidofovir with good oral bioavailability, enabling optimal intracellular levels of the active drug. Lower rates of nephrotoxicity and myelotoxicity make it a favorable alternative. Despite a greater safety profile among pediatric hematopoietic cell transplant recipients, the oral formulation has been associated with increased gastrointestinal toxicity in adult hematopoietic cell transplant recipients. Oral BCV continues to be developed as a countermeasure against smallpox, while a potentially safer intravenous preparation has been out licensed to another company. BCV has demonstrated great in vitro potency against double-stranded DNA viruses, especially adenovirus. Because of its importance for immunocompromised patients, this review aims to evaluate BCV's clinical and safety profile to support its continued development.
- Published
- 2020
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30. Brincidofovir as a Salvage Therapy in Controlling Adenoviremia in Pediatric Recipients of Hematopoietic Stem Cell Transplant.
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Meena JP, Phillips RS, and Kinsey S
- Subjects
- Adolescent, Child, Child, Preschool, Cytosine therapeutic use, Female, Hematopoietic Stem Cell Transplantation adverse effects, Humans, Infant, Male, Salvage Therapy methods, Viremia drug therapy, Viremia immunology, Adenovirus Infections, Human drug therapy, Adenovirus Infections, Human immunology, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Immunocompromised Host, Organophosphonates therapeutic use
- Abstract
Adenovirus infection is a well-known complication in patients receiving hematopoietic stem cell transplantation (HSCT). Brincidofovir (BCV) is an orally bioavailable lipid conjugate of cidofovir, which has activity against adenoviruses. We present a review of adenovirus infections treated with BCV which were unresponsive to cidofovir initially in 4 patients and it was used upfront in one patient. Children with adenovirus infection following HSCT treated with BCV, between July 2014 and February 2018 were recognized. Five patients including 3 male and 2 female with a median age of 10 years (range, 2.2 to 10 y) were identified. The median days of adenoviremia detection was 18 days (range, 7 to 303 d) posttransplant. The median peak viral load by quantitative polymerase chain reaction was 21,38,000 copies/mL (range, 1,77,200 to 31,97,000 copies/mL). The median time from first detection of adenoviremia to become negative was 30 days (range, 15 to 113 d). The sites involved were gastrointestinal tract in all patients and 2 patients had additional respiratory tract involvement. Two patients survived and 3 patients died of sepsis. All patients responded well to BCV and no adverse effect was noticed. We saw the good safety profile and excellent antiadenoviral activity of BCV in pediatric patients receiving HSCT without the nephrotoxicity and it may have a role in preemptive therapy.
- Published
- 2019
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31. HSP90 inhibition depletes DNA repair proteins to sensitize acute myelogenous leukemia to nucleoside analog chemotherapeutics.
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Lai TH, Mitchell S, Wu PJ, Orwick S, Liu C, Ravikrishnan J, Woyach J, Mims A, Plunkett W, Puduvalli VK, Byrd JC, Lapalombella R, and Sampath D
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Arabinonucleosides therapeutic use, Benzamides therapeutic use, Cell Line, Tumor, Cytosine pharmacology, Cytosine therapeutic use, DNA Breaks, Double-Stranded drug effects, DNA Repair drug effects, Drug Resistance, Neoplasm genetics, HSP90 Heat-Shock Proteins metabolism, Humans, Isoindoles therapeutic use, Leukemia, Myeloid, Acute genetics, Leukemia, Myeloid, Acute pathology, Antineoplastic Combined Chemotherapy Protocols pharmacology, Arabinonucleosides pharmacology, Benzamides pharmacology, Cytosine analogs & derivatives, Drug Resistance, Neoplasm drug effects, HSP90 Heat-Shock Proteins antagonists & inhibitors, Isoindoles pharmacology, Leukemia, Myeloid, Acute drug therapy
- Published
- 2019
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32. Successful Brincidofovir Treatment of Metagenomics-detected Adenovirus Infection in a Severely Ill Signal Transducer and Activator of Transcription-1-deficient Patient.
- Author
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Averbuch D, Safadi R, Dar D, Wolf D, Cherniak M, Sorek R, and Amit S
- Subjects
- Adenoviridae Infections immunology, Cytosine therapeutic use, Humans, Immunocompromised Host, Liver immunology, Liver virology, Male, Metagenomics, Osteomyelitis drug therapy, Osteomyelitis microbiology, Treatment Outcome, Young Adult, Adenoviridae Infections diagnosis, Adenoviridae Infections drug therapy, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Organophosphonates therapeutic use, STAT1 Transcription Factor deficiency
- Abstract
A signal transducer and activator of transcription-1-deficient patient presented with prolonged fever, cachexia, anemia, hypoalbuminemia and finally relapsing debilitating mycobacterial osteomyelitis while receiving a previously effective antimycobacterial treatment. Progression despite rigorous workup and multiple antibiotics prompted shotgun metagenomics revealing adenovirus in liver samples. Brincidofovir led to a complete, sustained clinical recovery, including osteomyelitis, probably attributed to reversal of adenovirus-induced immune dysregulation.
- Published
- 2019
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33. Maribavir, brincidofovir and letermovir: Efficacy and safety of new antiviral drugs for treating cytomegalovirus infections.
- Author
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Frange P and Leruez-Ville M
- Subjects
- Cytosine therapeutic use, Ganciclovir therapeutic use, Humans, Acetates therapeutic use, Antiviral Agents therapeutic use, Benzimidazoles therapeutic use, Cytomegalovirus Infections drug therapy, Cytosine analogs & derivatives, Organophosphonates therapeutic use, Quinazolines therapeutic use, Ribonucleosides therapeutic use
- Abstract
Cytomegalovirus (CMV) infection is a common complication in immunocompromised patients, especially after hematopoietic stem cell or solid organ transplantation. Therapeutic antiviral options [(val)ganciclovir, foscarnet, cidofovir] are still limited and can expose to severe toxicities. Moreover, prolonged antiviral drug exposure and ongoing viral replication are key factors in the development of antiviral drug resistance. After many years of few tangible advances in terms of new antiviral drugs, we are now experiencing an exciting period characterized by a series of phase III clinical trials incorporating three novel agents: maribavir, brincidofovir, and letermovir. This article summarizes the current state of the prevention and treatment of CMV infections as well as data of investigational drugs in clinical development., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)
- Published
- 2018
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34. Efficacy of brincidofovir as prophylaxis against HSV and VZV in hematopoietic cell transplant recipients.
- Author
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Lee YJ, Neofytos D, Kim SJ, Cheteyan L, Huang YT, Papadopoulos EB, Jakubowski AA, and Papanicolaou GA
- Subjects
- Adult, Aged, Child, Child, Preschool, Cytosine pharmacology, Cytosine therapeutic use, Female, Herpes Simplex epidemiology, Herpes Simplex virology, Herpesvirus 3, Human drug effects, Herpesvirus 3, Human isolation & purification, Humans, Infant, Male, Middle Aged, Organophosphonates pharmacology, Retrospective Studies, Simplexvirus drug effects, Simplexvirus isolation & purification, Treatment Outcome, Varicella Zoster Virus Infection epidemiology, Varicella Zoster Virus Infection virology, Young Adult, Antibiotic Prophylaxis methods, Cytosine analogs & derivatives, Hematopoietic Stem Cell Transplantation adverse effects, Herpes Simplex prevention & control, Organophosphonates therapeutic use, Varicella Zoster Virus Infection prevention & control
- Abstract
Allogeneic hematopoietic cell transplant (HCT) recipients are at risk for herpes simplex virus (HSV) and varicella-zoster virus (VZV) infections. Routine prophylaxis with acyclovir is recommended during periods of immunosuppression. Brincidofovir (BCV, CMX001), a lipid conjugate of cidofovir, has shown in vitro activity against HSV/VZV, but has not been formally studied for HSV/VZV prophylaxis. We report our clinical experience of BCV for HSV/VZV prophylaxis in HCT recipients. This was a retrospective review of 30 hematopoietic cell transplant (HCT) recipients between 8/2010 and 8/2015 who received BCV doses not exceeding 200 mg/week for adults/adolescents and 4 mg/kg/week for pediatric (<12 years) patients, for ≥14 days BCV without concomitant acyclovir under clinical trials or single patient use. HSV/VZV cases during BCV treatment were confirmed by viral culture or PCR and clinical symptoms. Of 30 patients who met the inclusion criteria, 27 (90%) patients were adults and 22 (73%) patients received T-cell depleted HCT. The most common indications for BCV were cytomegalovirus in 12 patients (40%) and adenovirus in 11 patients (37%). One patient was treated for acyclovir-resistant HSV and one for disseminated VZV. There were two breakthrough cases of HSV infection during 2170 patient-days. There were no cases of breakthrough VZV infection. The overall rate of breakthrough HSV infection was 1.0 per 1000 patient-days, without any breakthrough VZV infections. Our study provides the only available-albeit limited-evidence on the potential efficacy of BCV for HSV/VZV prophylaxis in HCT patients. Additional studies are needed to further assess the efficacy and safety of BCV in the setting., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2018
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35. The efficacy of sapacitabine in treating patients with acute myeloid leukemia.
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Czemerska M, Robak T, and Wierzbowska A
- Subjects
- Aged, Antineoplastic Agents pharmacology, Arabinonucleosides pharmacology, Cytosine pharmacology, Cytosine therapeutic use, Humans, Prognosis, Treatment Outcome, Antineoplastic Agents therapeutic use, Arabinonucleosides therapeutic use, Cytosine analogs & derivatives, Leukemia, Myeloid, Acute drug therapy
- Abstract
Introduction: Acute myeloid leukemia (AML) remains a poor prognosis hematological malignancy. The introduction of aggressive chemotherapy with allogeneic stem cell transplantation has resulted in improved clinical outcomes in younger patients. However, the treatment results in unfit elderly AML population remain disappointing. New strategies should be introduced to improve the prognosis in this group of patients. Areas covered: This review presents and discusses the mechanism of action, safety and efficacy of sapacitabine in AML patients. Expert opinion: Sapacitabine, a novel nucleoside analog, seemed to be a promising new agent for AML treatment. Its oral bioavailability and tolerable toxicity profile allow the drug to be used in an outpatient setting, especially in elderly unfit patients. Sapacitabine is known to have antileukemic activity in randomized clinical trials. In AML patients, sapacitabine monotherapy offered no advantage over low-intensity cytarabine treatment, and the combination of sapacitabine with decitabine was not significantly more effective than decitabine alone. However, the oral administration of sapacitabine allows it to be used in AML maintenance therapy.
- Published
- 2018
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36. The spectre of smallpox lingers.
- Subjects
- Animals, Benzamides pharmacology, Benzamides therapeutic use, Cytosine analogs & derivatives, Cytosine pharmacology, Cytosine therapeutic use, Disease Eradication trends, Disease Models, Animal, Drug Approval legislation & jurisprudence, Female, History, 20th Century, History, 21st Century, Humans, Isoindoles pharmacology, Isoindoles therapeutic use, Organophosphonates pharmacology, Organophosphonates therapeutic use, Rabbits, Smallpox epidemiology, Smallpox Vaccine supply & distribution, Synthetic Biology trends, United States, United States Food and Drug Administration legislation & jurisprudence, Disease Eradication history, Disease Reservoirs virology, Smallpox drug therapy, Smallpox history
- Published
- 2018
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37. Adenovirus infection in pediatric transplant recipients: are effective antiviral agents coming our way?
- Author
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Lopez SMC, Michaels MG, and Green M
- Subjects
- Adenoviridae Infections immunology, Child, Cidofovir therapeutic use, Cytosine adverse effects, Cytosine analogs & derivatives, Cytosine therapeutic use, Humans, Immunocompromised Host, Organophosphonates adverse effects, Organophosphonates therapeutic use, Pediatrics, Transplant Recipients, Adenoviridae Infections drug therapy, Antiviral Agents therapeutic use, Hematopoietic Stem Cell Transplantation adverse effects, Organ Transplantation adverse effects
- Abstract
Purpose of Review: Adenoviruses (AdVs) infection is a self-limited disease in the majority of immunocompetent children and adults, but can cause disseminated and life-threatening illness in immunocompromised hosts. This article will discuss therapeutic strategies for AdV infection in the pediatrics transplant recipient., Recent Findings: Currently, there is no FDA approved antiviral therapy for AdV infection. Accordingly, the primary initial therapy would be decreasing immunosuppression, whenever possible. Cidofovir (CDV) is an antiviral drug whose use has been associated with significant reductions of AdV viral load and, in some series improved survival in recipients of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT). However, its use is also associated with significant toxicity. Brincidofovir (BCV) is a lipid formulation of CDV, which has an improved oral bioavailability and favorable toxicity profile compared with CDV. However, studies have only shown modest benefit from BCV for AdV disease or viremia. Immunotherapy is a growing field in the management of this virus infection on HSCT patients with promising results., Summary: Current evidence support the use of CDV and BCV, as rescue therapy, on SOT and HSCT transplant patients. Immunotherapy had only been proven successful in HSCT patients, as an option for refractory cases or rescue therapy for AdV infection.
- Published
- 2018
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38. Successful treatment of disseminated adenovirus infection with cidofovir and intravenous immunoglobulin in an infant following heart transplant.
- Author
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Serrano RM, Darragh RK, and Parent JJ
- Subjects
- Antiviral Agents therapeutic use, Cidofovir, Cytosine therapeutic use, Humans, Immunocompromised Host, Infant, Male, Adenovirus Infections, Human drug therapy, Cytosine analogs & derivatives, Heart Transplantation adverse effects, Immunoglobulins, Intravenous therapeutic use, Opportunistic Infections drug therapy, Organophosphonates therapeutic use
- Abstract
For most patients, adenoviruses cause few acute health concerns and are often self-limiting. Patients who are immunocompromised or immunosuppressed, however, are at risk for disseminated adenovirus and suffer high morbidity and mortality, without well-defined treatment options. We report the case of a 9-month-old boy who was successfully treated for disseminated adenovirus infection with intravenous immunoglobulin and cidofovir 3 months post heart transplant, tailored to serum adenoviral load and clinical response. We emphasise the importance of early identification, monitoring, and a potentially novel treatment in the paediatric cardiac transplant population with disseminated adenovirus infection.
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- 2018
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39. Intravesicular cidofovir for BK hemorrhagic cystitis in pediatric patients after hematopoietic stem cell transplant.
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Foster JH, Cheng WS, Nguyen NY, Krance R, and Martinez C
- Subjects
- Administration, Intravesical, Adolescent, Antiviral Agents therapeutic use, Child, Cidofovir, Cystitis etiology, Cytosine administration & dosage, Cytosine therapeutic use, Female, Humans, Male, Organophosphonates therapeutic use, Polyomavirus Infections etiology, Tumor Virus Infections etiology, Antiviral Agents administration & dosage, BK Virus, Cystitis drug therapy, Cytosine analogs & derivatives, Hematopoietic Stem Cell Transplantation adverse effects, Organophosphonates administration & dosage, Polyomavirus Infections drug therapy, Tumor Virus Infections drug therapy
- Abstract
BK virus hemorrhagic cystitis is a complication of HCST. Response to IV cidofovir is unpredictable, and treatment carries risk of toxicity. We report the largest series of pediatric patients with BKHC after HSCT successfully treated with intravesicular cidofovir. There was no significant decrease in urine or plasma BK PCR. There was significant decrease in pain score on days 3 and 7, with associated decrease in morphine use. No patients experienced toxicities associated with IV cidofovir. Intravesicular cidofovir appears to be safe and effective for symptomatic treatment of BKHC in pediatric patients after HSCT., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2018
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40. Brincidofovir as Salvage Therapy for Adenovirus Disease in Intestinal Transplant Recipients.
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Sulejmani N, Nagai S, Safwan M, Rizzari MD, Raoufi M, Abouljoud MS, and Ramesh M
- Subjects
- Adult, Cytosine therapeutic use, Female, Humans, Male, Salvage Therapy, Adenoviridae Infections drug therapy, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Immunocompromised Host, Organophosphonates therapeutic use, Transplant Recipients
- Abstract
Background: Adenoviruses are double-stranded DNA viruses that typically cause mild self-limiting respiratory, ocular, and gastrointestinal infections. In immunocompromised patients, especially transplant recipients, the infection can be severe, with dissemination and multiorgan failure. In intestinal transplant recipients, the incidence is as high as 57%. To our knowledge, no standardized guidelines or U.S. Food and Drug Administration-approved medications exist for the treatment of adenovirus disease., Aims: We describe two isolated intestinal transplant recipients who developed adenovirus disease (viremia with viral enteritis) that was managed with a new experimental drug, brincidofovir (an oral lipid conjugate prodrug of cidofovir), as salvage therapy., Results: The first patient was a 44-year-old woman who developed adenoviral enteritis 1 month after transplantation, which resolved with ribavirin therapy. Two weeks later, the infection recurred, and brincidofovir was initiated. While receiving this therapy for 3 months, she developed severe acute rejection, which was managed with rabbit antithymocyte globulin followed by infliximab. Eventually, complete resolution of the rejection and adenoviral enteritis was achieved. At 12 months posttransplantation, the patient was healthy and tolerating enteral feeding. The second patient was a 28-year-old man who had undergone isolated intestinal transplantation 6 years before he presented with generalized weakness and an increased ostomy output; he was diagnosed with adenoviral enteritis. Maintenance immunosuppression was reduced, and brincidofovir was started. The infection resolved with a month of therapy. Six months after the infection, he was healthy and tolerating enteral feeding., Conclusion: This is the first publication, to our knowledge, to describe two cases in which brincidofovir was used to successfully treat adenovirus infection in intestinal transplant recipients. Thus, these cases demonstrate that brincidofovir appears to be a safe and effective option in the management of adenoviral enteritis in these patients., (© 2018 Pharmacotherapy Publications, Inc.)
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- 2018
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41. Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
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Smith SDB, Erdag G, Cuda JD, Rangwala S, Girardi N, Bibee K, Orens JB, Prono MD, Toptan T, and Loss MJ
- Subjects
- Administration, Topical, Adult, Aged, Antiviral Agents administration & dosage, Antiviral Agents therapeutic use, Cidofovir, Cytosine administration & dosage, Cytosine therapeutic use, Exanthema drug therapy, Exanthema virology, Female, Humans, Immunocompromised Host, Immunosuppressive Agents therapeutic use, Male, Middle Aged, Organophosphonates administration & dosage, Polyomavirus Infections etiology, Pruritus drug therapy, Pruritus virology, Transplant Recipients, BK Virus drug effects, Cytosine analogs & derivatives, Lung Transplantation adverse effects, Organophosphonates therapeutic use, Polyomavirus Infections drug therapy, Tumor Virus Infections drug therapy
- Abstract
Human polyomavirus-7-associated rash and pruritus (PVARP) is a chronic superficial viral skin infection, which primarily impacts immunocompromised individuals. We report on a case of PVARP in a lung transplant recipient. Our patient developed symptoms 13 years after being on his immunosuppressive regimen, with an insidious course of progressive gray lichenification with marked islands of sparing and quality of life-altering pruritus. Treatment for PVARP is not established; however, topical cidofovir combined with immunomodulation may offer sustained therapeutic benefit., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
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- 2018
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42. Case report: a fatal case of disseminated adenovirus infection in a non-transplant adult haematology patient.
- Author
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Joffe M, Wagner SD, and Tang JW
- Subjects
- Adenoviridae genetics, Adenoviridae isolation & purification, Adenovirus Infections, Human complications, Adenovirus Infections, Human virology, Antineoplastic Agents therapeutic use, Bronchoalveolar Lavage Fluid chemistry, Bronchoalveolar Lavage Fluid microbiology, Cidofovir, Cytosine analogs & derivatives, Cytosine therapeutic use, DNA, Viral genetics, DNA, Viral metabolism, Drug Therapy, Combination, Fatal Outcome, Haemophilus influenzae isolation & purification, Humans, Leukemia, Lymphocytic, Chronic, B-Cell complications, Leukemia, Lymphocytic, Chronic, B-Cell drug therapy, Male, Middle Aged, Organophosphonates therapeutic use, Polymerase Chain Reaction, Tomography, X-Ray Computed, Trimethoprim, Sulfamethoxazole Drug Combination therapeutic use, Adenovirus Infections, Human diagnosis, Leukemia, Lymphocytic, Chronic, B-Cell diagnosis
- Abstract
Background: We report a fatal case of disseminated adenovirus infection in a non-transplant haematology adult patient with chronic lymphocytic leukaemia who had completed combination chemoimmunotherapy a few months before developing respiratory symptoms. In such non-transplant patients, monitoring for adenovirus in the blood is not routine. However, with adenoviruses, when there is a more peripheral (i.e. non-blood) site of infection such as the chest, serial adenovirus monitoring in blood for the duration of that illness may be warranted., Case Presentation: This case started with an initial bacterial chest infection that responded to treatment, followed by an adenovirus pneumonitis that disseminated to his blood a week later with levels of up to 92 million adenovirus DNA copies/ml. Despite prompt treatment with cidofovir, his respiratory function continued to deteriorate over the next two weeks and he was moved to intensive care. Intravenous immunoglobulin and ribavirin were subsequently added to his treatment. However, he died soon after this with a final adenovirus load of 20 million copies/ml in his blood., Conclusions: We recommend that even in non-transplant haematology patients, where such patients present with an acute respiratory adenovirus infection, teams should consider checking the blood for adenovirus to check for signs of disseminated infection. The earlier this can be tested, the earlier treatment can be initiated (if adenovirus positive), which may produce more successful clinical outcomes.
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- 2018
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43. Case 1-2018. A 39-Year-Old Woman with Rapidly Progressive Respiratory Failure.
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Hibbert KA, Shepard JO, Lane RJ, and Azar MM
- Subjects
- Adenoviridae Infections drug therapy, Adult, Antiviral Agents adverse effects, Antiviral Agents therapeutic use, Cidofovir, Cytosine adverse effects, Cytosine analogs & derivatives, Cytosine therapeutic use, Diagnosis, Differential, Female, Humans, Immunocompromised Host, Leukemia, Myeloid, Acute complications, Leukemia, Myeloid, Acute therapy, Lung diagnostic imaging, Nasopharynx virology, Opportunistic Infections drug therapy, Organophosphonates adverse effects, Organophosphonates therapeutic use, Radiography, Thoracic, Renal Insufficiency chemically induced, Stem Cell Transplantation adverse effects, Tomography, X-Ray Computed, Viral Load, Adenoviridae isolation & purification, Adenoviridae Infections diagnosis, Lung pathology, Opportunistic Infections diagnosis, Respiratory Insufficiency etiology
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- 2018
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44. Treatment of Refractory Acute Retinal Necrosis with Intravenous Foscarnet or Cidofovir.
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Stryjewski TP, Scott NL, Barshak MB, Tobin EH, Mali JO, Young LH, Foster CS, Kim IK, and Durand ML
- Subjects
- Aged, Aged, 80 and over, Cidofovir, Cytosine therapeutic use, Eye Infections, Viral diagnosis, Eye Infections, Viral virology, Herpes Simplex virology, Herpes Zoster Ophthalmicus virology, Herpesvirus 3, Human genetics, Herpesvirus 3, Human isolation & purification, Humans, Infusions, Intravenous, Male, Middle Aged, Polymerase Chain Reaction, Retinal Necrosis Syndrome, Acute diagnosis, Retinal Necrosis Syndrome, Acute virology, Retrospective Studies, Simplexvirus genetics, Simplexvirus isolation & purification, Vitreous Body virology, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Eye Infections, Viral drug therapy, Foscarnet therapeutic use, Herpes Simplex drug therapy, Herpes Zoster Ophthalmicus drug therapy, Organophosphonates therapeutic use, Retinal Necrosis Syndrome, Acute drug therapy
- Abstract
Purpose: To report use of intravenous foscarnet or cidofovir for the treatment of refractory acute retinal necrosis (ARN)., Methods: Retrospective chart review., Results: Four immunocompetent men aged 45-90 years presented with ARN from 2008-2014. One patient with two prior episodes of herpes simplex virus (HSV) ARN developed ARN after 6 years of antiviral prophylaxis. His condition worsened on acyclovir followed by intravenous foscarnet but responded to intravenous cidofovir (final VA in involved eye 20/20). Another patient with HSV ARN had received prolonged acyclovir prophylaxis for HSV keratitis; ARN improved after switching from acyclovir to intravenous foscarnet (final VA 20/125). Two patients with varicella zoster virus (VZV) ARN initially responded to acyclovir but developed fellow eye involvement 2-8 weeks later that worsened on acyclovir but responded to intravenous foscarnet (fellow eye final VA 20/20, 20/40)., Conclusions: Cases of HSV or VZV ARN that worsen despite intravenous acyclovir treatment may respond to intravenous foscarnet or cidofovir.
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- 2018
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45. In Vitro and In Vivo Comparison of Gemcitabine and the Gemcitabine Analog 1-(2'-deoxy-2'-fluoroarabinofuranosyl) Cytosine (FAC) in Human Orthotopic and Genetically Modified Mouse Pancreatic Cancer Models.
- Author
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Russell J, Pillarsetty N, Kramer RM, Romesser PB, Desai P, Haimovitz-Friedman A, Lowery MA, and Humm JL
- Subjects
- Animals, Cell Line, Tumor, Cytosine pharmacology, Deoxycytidine pharmacology, Deoxycytidine therapeutic use, Female, Humans, Mice, Nude, Mice, Transgenic, Pancreatic Neoplasms pathology, Gemcitabine, Cytosine therapeutic use, Deoxycytidine analogs & derivatives, Pancreatic Neoplasms drug therapy, Xenograft Model Antitumor Assays
- Abstract
Purpose: Although gemcitabine is a mainstay of pancreatic cancer therapy, it is only moderately effective, and it would be desirable to measure drug uptake in patients. 1-(2'-deoxy-2'-fluoroarabinofuranosyl) cytosine (FAC), is an analog of gemcitabine, and when labeled with F-18, it may be a potential surrogate PET tracer for the drug., Procedures: [
18 F]FAC was synthesized to a radiochemical purity of >96 %. The human tumor lines AsPC1, BxPC3, Capan-1, Panc1, and MiaPaca2 were grown orthotopically in nude mice. KPC mice that conditionally express oncogenic K-ras and p53 mutations in pancreatic tissue were also used. The intra-tumoral distributions of [14 C]gemcitabine and [18 F]FAC were mapped with autoradiography. The inter-tumor correlation between [14 C]gemcitabine and [18 F]FAC was established in the orthotopic tumors. Expression of the equilibrative and concentrative nucleoside transporters (ENT, CNT) in vitro was detected by western blotting. Drug uptake was characterized in vitro using [3 H]gemcitabine and the effect of transporter inhibition on gemcitabine and FAC uptake was investigated. The relative affinity of cells for gemcitabine and FAC was tested in competition assays. The cell lines differed in sensitivity to transport inhibitors and in competition studies. There was a good in vivo correlation between the total uptake of [18 F]FAC and [14 C]gemcitabine, measured across all orthotopic tumors. Using the KPC and BxPC3 models, we found that [14 C]gemcitabine and [18 F]FAC were largely co-localized., Conclusions: In the lines examined here, [18 F]FAC uptake correlates well with gemcitabine in vivo, supporting the notion that [18 F]FAC can serve as a PET radiotracer surrogate to determine the uptake and distribution of gemcitabine within pancreatic tumors.- Published
- 2017
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46. The alpha-herpesviridae in dermatology : Varicella zoster virus.
- Author
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El Hayderi L, Rübben A, and Nikkels AF
- Subjects
- Adult, Child, Child, Preschool, Cytosine analogs & derivatives, Cytosine therapeutic use, Herpes Zoster Vaccine therapeutic use, Humans, Infant, Low-Level Light Therapy, Middle Aged, Organophosphonates therapeutic use, Pyrimidine Nucleosides therapeutic use, Recurrence, Risk Factors, Varicella Zoster Virus Infection diagnosis, Varicella Zoster Virus Infection drug therapy, Virulence, Herpesvirus 3, Human pathogenicity, Varicella Zoster Virus Infection virology
- Abstract
The second part of this publication deals with varicella zoster virus (VZV) and presents an overview of new, rare, and atypical clinical manifestations, including photolocalized varicella, hemorrhagic bullae during varicella, the implication of VZV in immunoglobulin A vasculitis, VZV-related alopecia, ulcerative varicella skin lesions, childhood herpes zoster (HZ), prolonged prodromal pains, recurrent HZ, VZV implication in burning mouth syndrome, verruciform VZV lesions, the significance of satellite lesions during HZ, and late HZ complications, either neurological or internal. Furthermore, certain associations between the occurrence of HZ and subsequent internal pathologies, as well as risk factors for HZ and new developments in vaccination against HZ will be addressed.
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- 2017
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47. Renal Toxicity in Pediatric Patients Receiving Cidofovir for the Treatment of Adenovirus Infection.
- Author
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Vora SB, Brothers AW, and Englund JA
- Subjects
- Adolescent, Antiviral Agents adverse effects, Child, Child, Preschool, Cidofovir, Cytosine adverse effects, Cytosine therapeutic use, Humans, Infant, Infant, Newborn, Organophosphonates adverse effects, Retrospective Studies, Young Adult, Acute Kidney Injury chemically induced, Adenovirus Infections, Human drug therapy, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Organophosphonates therapeutic use
- Abstract
Treatment options for adenovirus infection in immunocompromised children are limited. Nephrotoxicity has been associated with cidofovir use, but the rate of cidofovir-associated nephrotoxicity in pediatric patients is unclear. In a retrospective review of patients with adenovirus infection treated with cidofovir, neonates (n = 5) had higher viral loads and shorter times to renal insufficiency than older children (n = 24). Higher weekly doses of cidofovir were associated with greater increases in creatinine levels. Of 29 courses of cidofovir, 9 were complicated by acute kidney injury; in these children, mortality was high. Cidofovir dosing in children needs to be optimized, and other therapeutic alternatives should be developed., (© The Author 2017. Published by Oxford University Press on behalf of The Journal of the Pediatric Infectious Diseases Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)
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- 2017
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48. Disseminated adenovirus infection after allogeneic stem cell transplant and the potential role of brincidofovir - Case series and 10 year experience of management in an adult transplant cohort.
- Author
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Ramsay ID, Attwood C, Irish D, Griffiths PD, Kyriakou C, and Lowe DM
- Subjects
- Adenoviridae Infections pathology, Adult, Cohort Studies, Cytosine therapeutic use, Female, Humans, Male, Middle Aged, Treatment Outcome, Young Adult, Adenoviridae Infections diagnosis, Adenoviridae Infections drug therapy, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Hematopoietic Stem Cell Transplantation adverse effects, Organophosphonates therapeutic use, Transplantation, Homologous adverse effects
- Abstract
Background: Adenovirus infection is a recognized complication following haematopoietic stem cell transplantation. We present a review of our experience of these infections in our transplant cohort over 10 years including 3 patients treated with the novel antiviral brincidofovir., Objectives: We aimed to describe the presentation, response to treatment and outcomes of adult stem cell transplant patients with disseminated adenovirus infection., Study Design: All adult cases of disseminated adenovirus infection following haematopoietic stem cell transplant in our unit between 2005 and 2015 were identified. Transplant details and data on timing of diagnosis, course of infection, viral co-infection and treatment were collected., Results: Of 733 patients transplanted, 10 patients had disseminated infection, including 4 male and 6 female patients with median age of 36.5 (range 19-59) years. 6/10 received an allograft from an unrelated donor. Median post-transplant time to detection of viraemia was 67days (range 20-1140days). Median peak viral load was 3133 copies/ml (352-11,000,000) in survivors received cidofovir alone, one cidofovir then brincidofovir and two brincidofovir alone. 8/10 p and 1,580,000 copies/ml (41,999-3,000.000) in those who died. Five patientsatients had a decrease in viral load following antivirals and/or reduction in immunosuppression including all on brincidofovir. Three died on treatment., Conclusions: Disseminated adenovirus infection is uncommon in adult transplant patients and uncertainties remain surrounding effective treatment. In our cohort, brincidofovir has shown promise in treatment of adenoviral infection. However, randomized controlled studies are required to confirm this impression., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
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49. The Role of Brincidofovir in Preparation for a Potential Smallpox Outbreak.
- Author
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Foster SA, Parker S, and Lanier R
- Subjects
- Animals, Antiviral Agents pharmacokinetics, Benzamides therapeutic use, Cytosine pharmacokinetics, Cytosine therapeutic use, Databases, Pharmaceutical, Drug Resistance, Viral drug effects, Drug Resistance, Viral genetics, Drug Therapy, Combination, Humans, Isoindoles therapeutic use, Models, Animal, Organophosphonates pharmacokinetics, Variola virus drug effects, Variola virus genetics, Antiviral Agents therapeutic use, Biological Warfare Agents, Cytosine analogs & derivatives, Disease Outbreaks prevention & control, Organophosphonates therapeutic use, Smallpox prevention & control, Smallpox therapy
- Abstract
Smallpox (variola) virus is considered a Category A bioterrorism agent due to its ability to spread rapidly and the high morbidity and mortality rates associated with infection. Current recommendations recognize the importance of oral antivirals and call for having at least two smallpox antivirals with different mechanisms of action available in the event of a smallpox outbreak. Multiple antivirals are recommended due in large part to the propensity of viruses to become resistant to antiviral therapy, especially monotherapy. Advances in synthetic biology heighten concerns that a bioterror attack with variola would utilize engineered resistance to antivirals and potentially vaccines. Brincidofovir, an oral antiviral in late stage development, has proven effective against orthopoxviruses in vitro and in vivo, has a different mechanism of action from tecovirimat (the only oral smallpox antiviral currently in the US Strategic National Stockpile), and has a resistance profile that reduces concerns in the scenario of a bioterror attack using genetically engineered smallpox. Given the devastating potential of smallpox as a bioweapon, preparation of a multi-pronged defense that accounts for the most obvious bioengineering possibilities is strategically imperative., Competing Interests: Scott A. Foster and Randall Lanier are employees of Chimerix, the developer of brincidofovir. Scott Parker has provided consulting services to Chimerix. The authors declare no other conflict of interest.
- Published
- 2017
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50. Combination therapy with brincidofovir and valganciclovir against species C adenovirus infection in the immunosuppressed Syrian hamster model allows for substantial reduction of dose for both compounds.
- Author
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Toth K, Tollefson AE, Spencer JF, Ying B, and Wold WSM
- Subjects
- Adenoviridae Infections virology, Adenoviruses, Human physiology, Animals, Antiviral Agents administration & dosage, Antiviral Agents pharmacology, Cytosine administration & dosage, Cytosine pharmacology, Cytosine therapeutic use, Disease Models, Animal, Drug Therapy, Combination, Ganciclovir administration & dosage, Ganciclovir pharmacology, Ganciclovir therapeutic use, HEK293 Cells, Humans, Immunocompromised Host, Mesocricetus, Organophosphonates administration & dosage, Organophosphonates pharmacology, Valganciclovir, Viral Load drug effects, Virus Replication drug effects, Adenoviridae Infections drug therapy, Adenoviruses, Human drug effects, Antiviral Agents therapeutic use, Cytosine analogs & derivatives, Ganciclovir analogs & derivatives, Organophosphonates therapeutic use
- Abstract
Adenovirus infections of immunocompetent adults are usually mild and resolve without serious sequelae. However, adenovirus infections of immunocompromised patients often develop into life-threatening multi-organ disease. Pediatric hematopoietic transplant patients are especially threatened, with high incidence of infection and high mortality rates. Presently, there is no drug specifically approved by the FDA to treat adenovirus infections; thus there is an urgent need to develop effective antivirals against the virus. Previously, we demonstrated that brincidofovir and valganciclovir were efficacious against lethal intravenous challenge with human type 5 adenovirus in the Syrian hamster model. Here, we tested the in vivo efficacy of the combination of these two drugs and showed that the combination of brincidofovir and valganciclovir is more efficacious than either drug alone, thus potentially allowing decreased patient exposure to the drugs while maintaining antiviral efficacy. As antiviral compounds often have toxic side effects, a decrease in dose or duration of therapy allowed by the combination could also improve tolerability., (Copyright © 2017 Elsevier B.V. All rights reserved.)
- Published
- 2017
- Full Text
- View/download PDF
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