Artículos de revistas: "Ganciclovir. Cytomegalovirus infections. Ocular pharmacology"

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Sahin, Afsun y Pedram Hamrah. "Acute Herpetic Keratitis: What is the Role for Ganciclovir Ophthalmic Gel?" Ophthalmology and Eye Diseases 4 (enero de 2012): OED.S7267. http://dx.doi.org/10.4137/oed.s7267.

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Herpes simplex keratitis (HSK) is a major cause of corneal blindness in the world. Following the primary infection, the virus enters into a latent phase. Recurrent infectious or immune keratitis cause structural damage to the cornea, scarring, and may lead to blindness. Several commercially available topical and oral antiviral drugs for HSK are currently available. However, toxicity and low patient compliance hamper their use in HSK. Further, oral antiviral drugs alone are not always effective in HSK. Thus, there had been a need for safe and effective topical antiviral agents against HSK. Systemic ganciclovir has been in use for the treatment of cytomegalovirus infections. Recently, topical ganciclovir has become available for use in patients with HSK. Ganciclovir 0.15% ophthalmic gel has been shown to be both safe and effective against viruses of the herpes family. Topical ganciclovir ophthalmic gel is well tolerated and does not cause significant toxic effects on the ocular surface. Several multicenter studies have revealed the potential role of ganciclovir ophthalmic gel in the treatment and prophylaxis of epithelial HSK. In this paper, we have reviewed the pharmacology, efficacy, side effects, and the role of ganciclovir ophthalmic gel 0.15% in the treatment of acute herpetic keratitis.

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Montero, Ma Carmen, Maite Pastor, Catalina Buenestado, Amparo Lluch y Manuela Atienza. "Intravitreal Ganciclovir for Cytomegalovirus Retinitis in Patients with AIDS". Annals of Pharmacotherapy 30, n.º 7-8 (julio de 1996): 717–23. http://dx.doi.org/10.1177/106002809603000701.

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OBJECTIVE: To assess the evolution of cytomegalovirus (CMV) retinitis and evaluate the possible complications associated with the use of intravitreal injections to treat this disease. DESIGN: A nonrandomized, retrospective study with case series was performed. The study took place over 34 months. SETTING: The study included patients with AIDS who developed CMV retinitis, and who were treated in the hospital, as outpatients, or both. PATIENTS: Twelve patients with AIDS and CMV retinitis diagnosed between June 1990 through April 1993 were included in the study. MAIN PATIENT PARAMETERS AND OUTCOME MEASURES: For each patient, the following data were recorded: age, risk factors, other systemic findings, dates of AIDS and CMV retinitis diagnoses, stage of AIDS, extent of the retinitis, CD4 lymphocyte count at the time of diagnosis of the retinitis, visual acuity, clinical evolution of the ocular infection, therapy, complications caused by the treatment, development of nonocular CMV, and the use of zidovudine or didanosine during the study period. RESULTS: Vision improved or remained stable in nine patients and worsened in three. Two patients developed optic neuritis. The retinitis progressed to the other eye in only one of the eight patients who had unilateral involvement. The rate of relapse with maintenance therapy was 8.3% (n = 1) within the first 8 weeks. Treatment was well tolerated. There was no evidence of toxicity after a total of 226 intravitreal ganciclovir injections. All patients were able to tolerate zidovudine or didanosine concomitantly with intravitreal ganciclovir. CONCLUSIONS: Intravitreal ganciclovir appears to be an effective alternative to systemic ganciclovir in patients with severe neutropenia and in patients who choose to continue receiving systemic zidovudine or didanosine. Early treatment and long-term maintenance therapy is essential for preserving sight.

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Fletcher, Courtney V. y Henry H. Balfour. "Evaluation of Ganciclovir for Cytomegalovirus Disease". DICP 23, n.º 1 (enero de 1989): 5–12. http://dx.doi.org/10.1177/106002808902300101.

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Cytomegalovirus (CMV) infections are a common cause of morbidity and mortality in immunosuppressed patients. Ganciclovir is an acyclic deoxyguanosine analog structurally similar to acyclovir but with superior activity against CMV. The median ganciclovir concentration required to inhibit viral replication by 50 percent is 2.15 μmol versus 72 μmol for acyclovir. Pharmacokinetic properties of ganciclovir include biexponential decay with a terminal half-life of 2.5 hours, tissue uptake, cerebrospinal fluid penetration, and renal dependence for elimination. CMV treatment approaches have commonly used dosages of 3–15 mg/kg/d. In uncontrolled trials, the response rate of CMV retinitis is approximately 80 percent. The overall response rate for CMV pneumonitis has been approximately 50 percent. However, AIDS (acquired immunodeficiency syndrome) and other immunosuppressed patients appear to respond more favorably (~ 70 percent) than do marrow transplant recipients. Relapse is common once ganciclovir is stopped and maintenance therapy may be required for sustained benefit. Neutropenia appears to be the drug-limiting adverse reaction. Although the development of ganciclovir-resistant CMV, risk factors for neutropenia, and alternative administration strategies all need further study, ganciclovir appears to have a role in the treatment of cytomegalovirus disease.

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Minces, Lucio R., M. Hong Nguyen, Dimitra Mitsani, Ryan K. Shields, Eun J. Kwak, Fernanda P. Silveira, Rima Abdel-Massih et al. "Ganciclovir-Resistant Cytomegalovirus Infections among Lung Transplant Recipients Are Associated with Poor Outcomes despite Treatment with Foscarnet-Containing Regimens". Antimicrobial Agents and Chemotherapy 58, n.º 1 (21 de octubre de 2013): 128–35. http://dx.doi.org/10.1128/aac.00561-13.

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ABSTRACTGanciclovir-resistant cytomegalovirus (CMV) infections are reported infrequently among lung transplant recipients receiving extended valganciclovir prophylaxis. We performed a single-center, retrospective review of ganciclovir-resistant CMV infections in a program that employed valganciclovir prophylaxis for ≥6 months after lung transplant. CMV infections were diagnosed in 28% (170/607) of patients. UL97 mutations were detected in 9.4% (16/170) of CMV-infected patients at a median of 8.5 months posttransplant (range, 5 to 21) and despite prophylaxis for a median of 7 months (range, 4 to 21). UL97 mutations were canonical; 25% (4/16) of strains carried concurrent UL54 mutations. Ganciclovir-resistant CMV was more likely with breakthrough infections (75% [12/16] versus 19% [30/154];P= 0.00001) and donor positive/recipient negative (D+/R−) serostatus (75% versus 45% [69/154];P= 0.03). The median whole-blood CMV load was 4.13 log10copies/cm3(range, 2.54 to 5.53), and 93% (14/15) of patients had low-moderate immune responses (Cylex Immunoknow). Antiviral therapy was successful, failed, or eradicated viremia followed by relapse in 12% (2/16), 31% (5/16), and 56% (9/16) of patients, respectively. Eighty-seven percent (14/16) of patients were treated with foscarnet-containing regimens; toxicity developed in 78% (11/14) of these. Median viral load half-life and time to viremia eradication among foscarnet-treated patients were 2.6 and 23 days, respectively, and did not correlate with protection from relapse. Sixty-nine percent (11/16) of patients developed CMV pneumonitis, and 25% (4/16) died of it. Serum viral load was independently associated with death among foscarnet-treated patients (P= 0.04). In conclusion, ganciclovir-resistant CMV infections remained a major cause of morbidity and mortality following lung transplantation. Foscarnet-based regimens often eradicated viremia rapidly but were ineffective in the long term and limited by toxicity.

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Prichard, Mark, Caroll Hartline, Randall Lanier y Earl Kern. "Evaluations of Combinations of CMX001 and Ganciclovir Against Cytomegalovirus Infections Using Real Time PCR". Antiviral Research 86, n.º 1 (abril de 2010): A64—A65. http://dx.doi.org/10.1016/j.antiviral.2010.02.462.

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Gentry, Brian G. y John C. Drach. "Metabolism of Cyclopropavir and Ganciclovir in Human Cytomegalovirus-Infected Cells". Antimicrobial Agents and Chemotherapy 58, n.º 4 (10 de febrero de 2014): 2329–33. http://dx.doi.org/10.1128/aac.02311-13.

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ABSTRACTHuman cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised patients. The current standard of therapy for the treatment of HCMV infections is ganciclovir (GCV). However, high incidence rates of adverse effects are prevalent and limit the use of this drug. Cyclopropavir (CPV) is 10-fold more effective against HCMVin vitrothan GCV (50% effective concentrations [EC50s] = 0.46 and 4.1 μM, respectively) without any observed increase in cytotoxicity (S. Zhou, J. M. Breitenbach, K. Z. Borysko, J. C. Drach, E. R. Kern, E. Gullen, Y. C. Cheng, and J. Zemlicka, J. Med. Chem. 47:566–575, 2004, doi:10.1021/jm030316s). We have previously determined that the viral protein kinase pUL97 and endogenous cellular kinases are responsible for the conversion of CPV to a triphosphate (TP), the active compound responsible for inhibiting viral DNA synthesis and viral replication. However, this conversion has not been observed in HCMV-infected cells. To that end, we subjected HCMV-infected cells to equivalently effective concentrations (∼5 times the EC50) of either CPV or GCV and observed a time-dependent increase in triphosphate levels for both compounds (CPV-TP = 121 ± 11 pmol/106cells; GCV-TP = 43.7 ± 0.4 pmol/106cells). A longer half-life was observed for GCV-TP (48.2 ± 5.7 h) than for CPV-TP (23.8 ± 5.1 h). The area under the curve for CPV-TP produced from incubation with 2.5 μM CPV was 8,680 ± 930 pmol · h/106cells, approximately 2-fold greater than the area under the curve for GCV-TP of 4,520 ± 420 pmol · h/106cells produced from incubation with 25 μM GCV. We therefore conclude that the exposure of HCMV-infected cells to CPV-TP is greater than that of GCV-TP under these experimental conditions.

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Reddy, Subhakar, Mudit Tyagi, Shashwat Behera y Rajeev Reddy Pappuru. "Cytomegalovirus retinitis in a patient of granulomatosis with polyangiitis on long-term immunosuppressants". BMJ Case Reports 14, n.º 2 (febrero de 2021): e236632. http://dx.doi.org/10.1136/bcr-2020-236632.

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A 69-year-old male patient presented to the retina clinic with a sudden decrease in vision in his right eye since 1 day. He was a known case of granulomatosis with polyangiitis and was on systemic immunosuppression for the past 3 years. The best-corrected visual acuity (BCVA) in his right eye was 20/60 and he has no perception of light in the left eye. Fundus examination revealed the presence of retinitis lesions in the right eye and total optic atrophy in the left eye. A vitreous biopsy was done and the PCR was found to be positive for cytomegalovirus (CMV). He was treated with intravitreal ganciclovir injections. Subsequently, the retinitis lesions regressed and BCVA in the right eye improved to 20/40.This case report elaborates on the risks of the development of opportunistic ocular infections in patients receiving long-term systemic immunosuppressants and the need for regular ocular examinations in such cases.

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Trofe, Jennifer, Lindsey Pote, Erin Wade, Emily Blumberg y Roy D. Bloom. "Maribavir: A Novel Antiviral Agent with Activity Against Cytomegalovirus". Annals of Pharmacotherapy 42, n.º 10 (26 de agosto de 2008): 1447–57. http://dx.doi.org/10.1345/aph.1l065.

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Objective: To review the pharmacology, pharmacokinetics, efficacy, and safety of maribavir, a novel antiviral agent in the benzimidazole drug class. Data sources: Articles were identified through searches of MEDLINE (January 1998-July 2008). Abstracts from recent scientific meetings and the manufacturer were also included. Study Selection and Data Extraction: All English-language in vitro and in vivo studies and abstracts evaluating maribavir were reviewed and considered for inclusion. All human studies were included. Data Synthesis: Maribavir has significant activity against both human cytomegalovirus (CMV) and Epstein-Barr virus, but not other herpesviruses Unlike ganaclovir. which needs to be phosphorated by UL 97 kinase to become an active inhibitor of DNA polymerase, maribavir directly inhibits UL 97 kinase. UL 97 kinase is an early viral gene product involved in viral DNA elongation, DNA packaging and egress or shedding of capsids from viral nuclei. Maribavir has also been found to be effective against ganciclovir-resistant CMV strains. Maribavir differs from current CMV antiwal agents in its adverse event profile. Maribavir is not associated with nephrotoxicity or hematologic toxicities, but has been associated with taste disturbances. In February 2007, maribavir was granted Food and Drug Administration orphan drug status for prevention of CMV viremia and diseases in at-risk populations. Maribavir Phase 2 trials in stem-cell transplant recipients have been completed, and there are ongoing Phase 3 trials in stem-cell and organ transplant recipients. Conclusions: Maribavir may be an option for treatment of ganciclovir-resistant CMV infections. Its bioavailability is greater than that of oral ganciclovir, but less than that of valganciclovir. No differences in pharmacokinetics were seen in renally impaired patients, although dialysis-dependent patients were not evaluated. Maribavir is not associated with hematologic toxicities; however, the high prevalence of taste disturbances may limit its tolerability.

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Smee, Donald F., Robert W. Sidwell y Bill B. Barnett. "Combination of antiviral immunotoxin and ganciclovir or cidofovir for the treatment of murine cytomegalovirus infections". Antiviral Research 32, n.º 3 (noviembre de 1996): 165–71. http://dx.doi.org/10.1016/s0166-3542(95)00986-8.

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Fan-Havard, P., M. C. Nahata y M. T. Brady. "GANCICLOVIR—A REVIEW OF PHARMACOLOGY, THERAPEUTIC EFFICACY AND POTENTIAL USE FOR TREATMENT OF CONGENITAL CYTOMEGALOVIRUS INFECTIONS". Journal of Clinical Pharmacy and Therapeutics 14, n.º 5 (octubre de 1989): 329–40. http://dx.doi.org/10.1111/j.1365-2710.1989.tb00256.x.

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Horvatits, Thomas, Reinhard Kitzberger, Andreas Drolz, Christian Zauner, Walter Jäger, Michaela Böhmdorfer, Stefanie Kraff et al. "Pharmacokinetics of Ganciclovir during Continuous Venovenous Hemodiafiltration in Critically Ill Patients". Antimicrobial Agents and Chemotherapy 58, n.º 1 (21 de octubre de 2013): 94–101. http://dx.doi.org/10.1128/aac.00892-13.

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ABSTRACTGanciclovir is an antiviral agent that is frequently used in critically ill patients with cytomegalovirus (CMV) infections. Continuous venovenous hemodiafiltration (CVVHDF) is a common extracorporeal renal replacement therapy in intensive care unit patients. The aim of this study was to investigate the pharmacokinetics of ganciclovir in anuric patients undergoing CVVHDF. Population pharmacokinetic analysis was performed for nine critically ill patients with proven or suspected CMV infection who were undergoing CVVHDF. All patients received a single dose of ganciclovir at 5 mg/kg of body weight intravenously. Serum and ultradiafiltrate concentrations were assessed by high-performance liquid chromatography, and these data were used for pharmacokinetic analysis. Mean peak and trough prefilter ganciclovir concentrations were 11.8 ± 3.5 mg/liter and 2.4 ± 0.7 mg/liter, respectively. The pharmacokinetic parameters elimination half-life (24.2 ± 7.6 h), volume of distribution (81.2 ± 38.3 liters), sieving coefficient (0.76 ± 0.1), total clearance (2.7 ± 1.2 liters/h), and clearance of CVVHDF (1.5 ± 0.2 liters/h) were determined. Based on population pharmacokinetic simulations with respect to a target area under the curve (AUC) of 50 mg · h/liter and a trough level of 2 mg/liter, a ganciclovir dose of 2.5 mg/kg once daily seems to be adequate for anuric critically ill patients during CVVHDF.

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Schindele, Birgit, Luise Apelt, Jörg Hofmann, Andreas Nitsche, Detlef Michel, Sebastian Voigt, Thomas Mertens y Bernhard Ehlers. "Improved Detection of Mutated Human Cytomegalovirus UL97 by Pyrosequencing". Antimicrobial Agents and Chemotherapy 54, n.º 12 (27 de septiembre de 2010): 5234–41. http://dx.doi.org/10.1128/aac.00802-10.

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ABSTRACT Ganciclovir (GCV) resistance frequently occurs upon prolonged treatment of ongoing active human cytomegalovirus (HCMV) infection in individuals with immature or compromised immune functions (e.g., recipients of solid-organ and hematopoietic stem cell transplants). Using pyrosequencing (PSQ), we established fast and sensitive detection of GCV resistance-associated mutations occurring in the HCMV open reading frame UL97. These mutations have been repeatedly associated with clinical treatment failure. We designed four PSQ assays and evaluated them by analyzing mixtures of plasmids or bacterial artificial chromosome-derived viruses containing UL97 wild-type and mutant sequences. A minimum level of 6% mutant sequence variants could be detected in these mixtures. In order to further evaluate the novel PSQ assays, we tested clinical specimens from patients with active HCMV infections. The results were compared with those obtained by conventional dideoxy chain terminator sequencing. As the PSQ method was more sensitive in detecting minor HCMV mutant fractions in a wild-type population, it is suggested that pyrosequencing is a useful tool for the early detection of emerging GCV-resistant HCMV in GCV-treated patients.

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Lurain, Nell S., Adriana Weinberg, Clyde S. Crumpacker y Sunwen Chou. "Sequencing of Cytomegalovirus UL97 Gene for Genotypic Antiviral Resistance Testing". Antimicrobial Agents and Chemotherapy 45, n.º 10 (1 de octubre de 2001): 2775–80. http://dx.doi.org/10.1128/aac.45.10.2775-2780.2001.

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ABSTRACT The widespread use of ganciclovir (GCV) to treat cytomegalovirus (CMV) infections in immunosuppressed patients has led to the development of drug resistance. Phenotypic assays for CMV drug resistance are presently too time-consuming to be therapeutically useful. To support the development of genotypic assays for GCV resistance, the complete sequences of the UL97 phosphotransferase genes in 28 phenotypically GCV-sensitive CMV clinical isolates were determined. The gene was found to be highly conserved, with nucleotide sequence identity among strains ranging from 98.6 to 100% and amino acid sequence identity of >99%. Primers for a genotypic assay were designed to amplify codons 400 to 707, because all known UL97 mutations conferring drug resistance occur at three sites within this region. This part of the UL97 gene was amplified from over 50 clinical isolates, and two sequencing reactions for the coding strand were successfully used to identify GCV resistance mutations. This genotypic assay can be performed in 48 h using genomic DNA extracted from cell monolayers at very low levels of virus infectivity, thus rapidly providing therapeutically useful results.

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Kern, Earl R., Deborah J. Bidanset, Caroll B. Hartline, Zhaohua Yan, Jiri Zemlicka y Debra C. Quenelle. "Oral Activity of a Methylenecyclopropane Analog, Cyclopropavir, in Animal Models for Cytomegalovirus Infections". Antimicrobial Agents and Chemotherapy 48, n.º 12 (diciembre de 2004): 4745–53. http://dx.doi.org/10.1128/aac.48.12.4745-4753.2004.

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ABSTRACT We reported previously that purine 2-(hydroxymethyl)methylenecyclopropane analogs have good activity against cytomegalovirus infection. A second-generation analog, (Z)-9-{[2,2-bis-(hydroxymethyl)cyclopropylidene]methyl}guanine (ZSM-I-62, cyclopropavir [CPV]), has particularly good activity against murine and human cytomegaloviruses (MCMV and HCMV) in vitro. To determine the oral activity of this compound in vivo, BALB/c or severe combined immunodeficient (SCID) mice infected with MCMV and two models using SCID mice implanted with human fetal tissue and subsequently infected with HCMV were used. In MCMV-infected normal mice, CPV at 10 mg/kg of body weight was highly effective in preventing mortality when administered at 24, 48, or 72 h post-viral inoculation and reduced titers of virus in tissues of SCID mice by 2 to 5 log10. In one HCMV model, human fetal retinal tissue was implanted into the anterior chamber of the mouse eye and inoculated with the Toledo strain of HCMV, and in the second, human fetal thymus and liver tissues were implanted under the kidney capsule of mice and then inoculated with HCMV. In general, replication of HCMV in both types of implant tissue increased from 7 through 21 to 28 days and then gradually decreased to undetectable levels by 8 weeks postinfection. Oral treatment with 45 or 15 mg of CPV/kg initiated 24 h after infection was highly effective in reducing replication to undetectable levels in both models and was generally more effective than ganciclovir. These data indicate that the methylenecyclopropane analog, CPV, was highly efficacious in these four animal models and should be evaluated for use in HCMV infections in humans.

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Kern, Earl R., Caroll B. Hartline, Rachel J. Rybak, John C. Drach, Leroy B. Townsend, Karen K. Biron y Deborah J. Bidanset. "Activities of Benzimidazole d- and l-Ribonucleosides in Animal Models of Cytomegalovirus Infections". Antimicrobial Agents and Chemotherapy 48, n.º 5 (mayo de 2004): 1749–55. http://dx.doi.org/10.1128/aac.48.5.1749-1755.2004.

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ABSTRACT Since human cytomegalovirus (HCMV) does not infect or replicate in nonhuman cells and tissues, there are few animal models currently available for evaluation of antiviral therapies for these infections. In the present studies, we utilized two different models in which severe combined immunodeficient (SCID) mice were implanted with human fetal tissue that was subsequently infected with HCMV. In one model, human fetal retinal tissue was implanted into the anterior chamber of the SCID mouse eye, and in the second, human fetal thymus and liver (thy/liv) tissues were implanted under the kidney capsule. After the implants were established, they were infected with 2,000 to 9,000 PFU of HCMV. To determine the efficacy of three benzimidazole nucleosides, 2-bromo-5,6-dichloro-(1-β-d-ribofuranosyl)benzimidazole (BDCRB), GW275175X (175X), and GW257406X (1263W94, maribavir [MBV]) treatment was initiated 24 h after infection of the implants and continued for 28 days. Treatment consisted of either placebo, 25 mg of ganciclovir (GCV)/kg of body weight administered intraperitoneally (i.p.) twice daily, 33 or 100 mg of BDCRB/kg administered i.p. twice daily, or 75 mg of either MBV or 175X/kg administered orally twice daily. GCV was effective in both models, inhibiting HCMV infection by 5- to 3,000-fold. In the retinal tissue model, MBV and BDCRB reduced HCMV replication about fourfold through 21 days postinfection compared with results for the vehicle control. In the thy/liv tissue model, all three benzimidazole nucleosides were effective in inhibiting HCMV replication by approximately 30- to 3,000-fold in comparison to the vehicle control. These data indicate that the benzimidazole nucleosides were efficacious in these animal models and suggest that this class of compounds should be active against the various HCMV infections that occur in the immunocompromised host.

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Williams-Aziz, Stephanie L., Caroll B. Hartline, Emma A. Harden, Shannon L. Daily, Mark N. Prichard, Nicole L. Kushner, James R. Beadle, W. Brad Wan, Karl Y. Hostetler y Earl R. Kern. "Comparative Activities of Lipid Esters of Cidofovir and Cyclic Cidofovir against Replication of Herpesviruses In Vitro". Antimicrobial Agents and Chemotherapy 49, n.º 9 (septiembre de 2005): 3724–33. http://dx.doi.org/10.1128/aac.49.9.3724-3733.2005.

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ABSTRACT Cidofovir (CDV) is an effective therapy for certain human cytomegalovirus (HCMV) infections in immunocompromised patients that are resistant to other antiviral drugs, but the compound is not active orally. To improve oral bioavailability, a series of lipid analogs of CDV and cyclic CDV (cCDV), including hexadecyloxypropyl-CDV and -cCDV and octadecyloxyethyl-CDV and -cCDV, were synthesized and found to have multiple-log-unit enhanced activity against HCMV in vitro. On the basis of the activity observed with these analogs, additional lipid esters were synthesized and evaluated for their activity against herpes simplex virus (HSV) types 1 and 2, human cytomegalovirus, murine cytomegalovirus, varicella-zoster virus (VZV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and HHV-8. Using several different in vitro assays, concentrations of drug as low as 0.001 μM reduced herpesvirus replication by 50% (EC50) with the CDV analogs, whereas the cCDV compounds were generally less active. In most of the assays performed, the EC50 values of the lipid esters were at least 100-fold lower than the EC50 values for unmodified CDV or cCDV. The lipid analogs were also active against isolates that were resistant to CDV, ganciclovir, or foscarnet. These results indicate that the lipid ester analogs are considerably more active than CDV itself against HSV, VZV, CMV, EBV, HHV-6, and HHV-8 in vitro, suggesting that they may have potential for the treatment of infections caused by a variety of herpesviruses.

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Gentry, Brian G., Quang Phan, Ellie D. Hall, Julie M. Breitenbach, Katherine Z. Borysko, Jeremy P. Kamil, Leroy B. Townsend y John C. Drach. "Human Cytomegalovirus Resistance to Deoxyribosylindole Nucleosides Maps to a Transversion Mutation in the Terminase Subunit-Encoding GeneUL89". Antimicrobial Agents and Chemotherapy 59, n.º 1 (27 de octubre de 2014): 226–32. http://dx.doi.org/10.1128/aac.03686-14.

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ABSTRACTHuman cytomegalovirus (HCMV) infection can cause severe illnesses, including encephalopathy and mental retardation, in immunocompromised and immunologically immature patients. Current pharmacotherapies for treating systemic HCMV infections include ganciclovir, cidofovir, and foscarnet. However, long-term administration of these agents can result in serious adverse effects (myelosuppression and/or nephrotoxicity) and the development of viral strains with reduced susceptibility to drugs. The deoxyribosylindole (indole) nucleosides demonstrate a 20-fold greater activityin vitro(the drug concentration at which 50% of the number of plaques was reduced with the presence of drug compared to the number in the absence of drug [EC50] = 0.34 μM) than ganciclovir (EC50= 7.4 μM) without any observed increase in cytotoxicity. Based on structural similarity to the benzimidazole nucleosides, we hypothesize that the indole nucleosides target the HCMV terminase, an enzyme responsible for packaging viral DNA into capsids and cleaving the DNA into genome-length units. To test this hypothesis, an indole nucleoside-resistant HCMV strain was isolated, the open reading frames of the genes that encode the viral terminase were sequenced, and a G766C mutation in exon 1 ofUL89was identified; this mutation resulted in an E256Q change in the amino acid sequence of the corresponding protein. An HCMV wild-type strain, engineered with this mutation to confirm resistance, demonstrated an 18-fold decrease in susceptibility to the indole nucleosides (EC50= 3.1 ± 0.7 μM) compared to that of wild-type virus (EC50= 0.17 ± 0.04 μM). Interestingly, this mutation did not confer resistance to the benzimidazole nucleosides (EC50for wild-type HCMV = 0.25 ± 0.04 μM, EC50for HCMV pUL89 E256Q = 0.23 ± 0.04 μM). We conclude, therefore, that the G766C mutation that results in the E256Q substitution is unique for indole nucleoside resistance and distinct from previously discovered substitutions that confer both indole and benzimidazole nucleoside resistance (D344E and A355T).

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Fletcher, Courtney V. "Treatment of Herpesvirus Infections in Hiv-Infected Individuals". Annals of Pharmacotherapy 26, n.º 7-8 (julio de 1992): 955–62. http://dx.doi.org/10.1177/106002809202600720.

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OBJECTIVE: To discuss strategies available for the treatment of herpesvirus infections in individuals infected with HIV. DATA SOURCES: Information was obtained from controlled and uncontrolled clinical trials, abstracts, conference proceedings, and review articles. STUDY SELECTION: Emphasis was placed on controlled investigations in subjects infected with HIV. DATA EXTRACTION: Data from human studies were extracted by the author and evaluated according to the patient population studied, sample size, dosage regimen, and therapeutic response. DATA SYNTHESIS: Herpes group viruses are common opportunistic pathogens in HIV-infected individuals. Zoster, caused by varicella-zoster virus (VZV), is an early indication of the loss of cell-mediated immunity and HIV disease progression. Anorectal mucocutaneous disease is the most common manifestation caused by herpes simplex virus (HSV). Acyclovir is the drug of choice for treatment of both VZV and HSV infections. Cytomegalovirus (CMV) is the most common life-threatening viral infection in patients with AIDS; retinitis is the most frequent clinical manifestation. The response rate of CMV retinitis to initial treatment with either ganciclovir or foscarnet is equivalent, approximately 60–90 percent. Recent data suggest that the survival benefit may be greater with foscarnet. CONCLUSIONS: Advances in the development and application of antiviral drugs for herpes group viruses have made treatment and, in some cases, prevention of infections possible. Future efforts, aimed at earlier intervention and suppression of latent virus, may offer additional improvement in quality of life for the HIV-infected individual.

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Kuljic-Kapulica, Nada, Dragana Stamatovic, Dejana Savic, Dragutin Jovanovic, Ljiljana Tukic y Nebojsa Andjelkovic. "Monitoring of cytomegalovirus infection after allogeneic stem cell transplantation". Vojnosanitetski pregled 67, n.º 5 (2010): 375–78. http://dx.doi.org/10.2298/vsp1005375k.

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Background/Aim. More than 90% of worldwide population is infected with human cytomegalovirus (CMV), one of the most common agents which complicate immunocompromised patients. Viral infections, in particular CMV ones are still a major cause of moratality and morbidity after stem cell transplantation (SCT). Monitoring is performed by detecting CMVAg or virus DNA in peripheral blood. Risk factors are donor/ recipient CMV status, type of transplant and acute graft versus host disease. The aim of the study was to determine the extent of validity of CMV infection monitoring after transplantation as a reliable parameter of further CMV replication course in patients with hematopoietic stem cell transplantation. Methods. A total of 49 patients with stem cell transplantation were studied prospectively during a 2-year period after transplantation for the presence of CMV DNA. Polymerase chain reaction (PCR) CMV DNA was performed on 222 full blood samples using Cobas Amplicor assay. Results. Activation of CMV was detected in 10/49 (20.48%) of the patients. The median posttransplantation time for the first positive PCR result was 6 weeks for the stem cell transplant patients. Viremia became negative in all the cases after the antiviral therapy with ganciclovir. Conclusion. Our data show that the level of CMV-DNA load at the time of initial CMV detection after transplantation could be a possible predictor for further course of CMV replication in patients receiving hematopoietic stem cell.

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Rybak, Rachel J., Caroll B. Hartline, Yao-Ling Qiu, Jiri Zemlicka, Emma Harden, Gwen Marshall, Jean-Pierre Sommadossi y Earl R. Kern. "In Vitro Activities of Methylenecyclopropane Analogues of Nucleosides and Their Phosphoralaninate Prodrugs against Cytomegalovirus and Other Herpesvirus Infections". Antimicrobial Agents and Chemotherapy 44, n.º 6 (1 de junio de 2000): 1506–11. http://dx.doi.org/10.1128/aac.44.6.1506-1511.2000.

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ABSTRACT Human cytomegalovirus (HCMV) infection does not generally cause problems in the immunocompetent adult but can result in severe clinical disease in the fetus, neonate, and immunocompromised host. Ganciclovir (GCV), the agent currently used to treat most HCMV infections, has resulted in much therapeutic success; however, efficacy remains suboptimal. Therefore, there is still a need to develop new compounds for use against HCMV infections. In the present study, severalZ- and E-series methylenecyclopropane analogues and their phosphoroalaninate prodrugs were tested initially for activity against HCMV, strain AD169, and murine cytomegalovirus (MCMV) in vitro. Many were found to exhibit efficacy comparable to that of GCV against HCMV in plaque assays and were active against MCMV as well. The compounds were also tested for efficacy against herpes simplex virus types 1 and 2, varicella-zoster virus, and Epstein-Barr virus, and some had levels of activity that were comparable to that of acyclovir. In addition, the compounds synguanol (QYL-438) and 2-amino-6-cyclopropylamino analogue (QYL-769) were chosen for further evaluation and were found to be effective against additional laboratory and clinical isolates of HCMV and GCV-resistant isolates. QYL-438 and QYL-769 were found to be nontoxic in human and mouse fibroblasts and were considerably less toxic than GCV in granulocyte macrophage CFUs and erythroid burst-forming units. These results provide evidence for the high activity of some of these methylenecyclopropane analogues against various herpesviruses, particularly HCMV, in tissue culture and suggest that further evaluation is warranted to determine their potential for use in future clinical studies.

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Beadle, James R., Caroll Hartline, Kathy A. Aldern, Natalie Rodriguez, Emma Harden, Earl R. Kern y Karl Y. Hostetler. "Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir Exhibit Multiple-Log Enhancement of Antiviral Activity against Cytomegalovirus and Herpesvirus Replication In Vitro". Antimicrobial Agents and Chemotherapy 46, n.º 8 (agosto de 2002): 2381–86. http://dx.doi.org/10.1128/aac.46.8.2381-2386.2002.

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ABSTRACT The incidence of cytomegalovirus (CMV) retinitis is declining in AIDS patients but remains a significant clinical problem in patients with organ transplants and bone marrow transplants. Prophylaxis with ganciclovir (GCV) or valganciclovir reduces the incidence of CMV disease but may lead to the emergence of drug-resistant virus with mutations in the UL97 or UL54 gene. It would be useful to have other types of oral therapy for CMV disease. We synthesized hexadecyloxypropyl and octadecyloxyethyl derivatives of cyclic cidofovir (cCDV) and cidofovir (CDV) and found that these novel analogs had 2.5- to 4-log increases in antiviral activity against CMV compared to the activities of unmodified CDV and cCDV. Multiple-log increases in activity were noted against laboratory CMV strains and various CMV clinical isolates including GCV-resistant strains with mutations in the UL97 and UL54 genes. Preliminary cell studies suggest that the increase in antiviral activity may be partially explained by a much greater cell penetration of the novel analogs. 1-O-Hexadecyloxypropyl-CDV, 1-O-octadecyloxyethyl-CDV, and their corresponding cCDV analogs are worthy of further preclinical evaluation for treatment and prevention of CMV and herpes simplex virus infections in humans.

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Neyts, Johan, Graciela Andrei y Erik De Clercq. "The Novel Immunosuppressive Agent Mycophenolate Mofetil Markedly Potentiates the Antiherpesvirus Activities of Acyclovir, Ganciclovir, and Penciclovir In Vitro and In Vivo". Antimicrobial Agents and Chemotherapy 42, n.º 2 (1 de febrero de 1998): 216–22. http://dx.doi.org/10.1128/aac.42.2.216.

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ABSTRACT The immunosuppressive agent mycophenolate mofetil (MMF) has been approved for use in kidney transplant recipients and may thus be used concomitantly for the treatment of intercurrent herpesvirus infections with drugs such as acyclovir (ACV), ganciclovir (GCV), and penciclovir (PCV). We found that MMF and its parent compound mycophenolic acid (at concentrations that are attainable in plasma) strongly potentiate the antiherpesvirus (herpes simplex virus [HSV] type 1 [HSV-1], HSV-2, thymidine kinase-deficient [TK−] HSV-1, both wild-type and TK− varicella-zoster virus, and human cytomegalovirus) activities of ACV, PCV, and GCV (up to 350-fold increases in their activities). The mechanism of potentiation was found to reside in the depletion of endogenous dGTP pools, which favored the inhibitory effect of the triphosphate of ACV, GCV, or PCV on the viral DNA polymerase. The combination of topically applied 5% MMF with 0.1% ACV strongly protected against HSV-1-induced cutaneous lesions in hairless mice, whereas therapy with either compound used singly had no protective effect. Interestingly, the combination of topically applied 5% MMF with 5% ACV was also highly effective in protecting against TK− HSV-2-induced cutaneous lesions (that were refractory to ACV treatment) in athymic nude mice. Topical therapy with MMF was very well tolerated, and no signs of irritation were observed. When given perorally at 200 mg/kg of body weight/day, MMF potentiated to some extent the growth retardation induced by GCV in young NMRI mice. These observations may have clinical implications (i) for those transplant recipients who receive both MMF and either ACV, GCV, or PCV and (ii) for the treatment of ACV-resistant mucocutaneous HSV infections.

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Gentry, Brian G., Laura E. Vollmer, Ellie D. Hall, Katherine Z. Borysko, Jiri Zemlicka, Jeremy P. Kamil y John C. Drach. "Resistance of Human Cytomegalovirus to Cyclopropavir Maps to a Base Pair Deletion in the Open Reading Frame ofUL97". Antimicrobial Agents and Chemotherapy 57, n.º 9 (1 de julio de 2013): 4343–48. http://dx.doi.org/10.1128/aac.00214-13.

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ABSTRACTHuman cytomegalovirus (HCMV) is a widespread pathogen in the human population, affecting many immunologically immature and immunocompromised patients, and can result in severe complications, such as interstitial pneumonia and mental retardation. Current chemotherapies for the treatment of HCMV infections include ganciclovir (GCV), foscarnet, and cidofovir. However, the high incidences of adverse effects (neutropenia and nephrotoxicity) limit the use of these drugs. Cyclopropavir (CPV), a guanosine nucleoside analog, is 10-fold more active against HCMV than GCV (50% effective concentrations [EC50s] = 0.46 and 4.1 μM, respectively). We hypothesize that the mechanism of action of CPV is similar to that of GCV: phosphorylation to a monophosphate by viral pUL97 protein kinase with further phosphorylation to a triphosphate by endogenous kinases, resulting in inhibition of viral DNA synthesis. To test this hypothesis, we isolated a CPV-resistant virus, sequenced its genome, and discovered that bp 498 ofUL97was deleted. This mutation caused a frameshift inUL97resulting in a truncated protein that lacks a kinase domain. To determine if this base pair deletion was responsible for drug resistance, the mutation was engineered into the wild-type viral genome, which was then exposed to increasing concentrations of CPV. The results demonstrate that the engineered virus was approximately 72-fold more resistant to CPV (EC50= 25.8 ± 3.1 μM) than the wild-type virus (EC50= 0.36 ± 0.11 μM). We conclude, therefore, that this mutation is sufficient for drug resistance and that pUL97 is involved in the mechanism of action of CPV.

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Yu, Zhenwei, Jianping Zhu, Jiayi Jin, Lingyan Yu y Gang Han. "Trends in Outpatient Prescribing Patterns for Ocular Topical Anti-Infectives in Six Major Areas of China, 2013–2019". Antibiotics 10, n.º 8 (28 de julio de 2021): 916. http://dx.doi.org/10.3390/antibiotics10080916.

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Topical anti-infectives are important in the management of ocular infections, but little is known about their current status and trends in their use in China. Thus, we carried out a prescription-based, cross-sectional study using the database of Hospital Prescription Analysis Projection of China, and aimed to analyze the trend in the use of ocular topical anti-infectives for outpatients of the ophthalmology department from 2013 to 2019. A total of 2,341,719 prescriptions from 61 hospitals located in six major areas written by ophthalmologists for outpatients were identified, and 1,002,254 of the prescriptions contained at least one anti-infective. The yearly anti-infective prescriptions increased continuously from 126,828 prescriptions in 2013 to 163,434 prescriptions in 2019. The cost also increased from 4,503,711 Chinese Yuan (CNY) in 2013 to CNY 5,860,945 in 2019. However, the use rate of anti-infectives decreased slightly from 46.5% in 2013 to 41.1% in 2019. Patients aged between 19 and 45 years old had the highest anti-infective use rate. Levofloxacin was the most frequently used anti-infective and kept on increasing among all age groups, occupying 67.1% of the total cost at the end of the study. Tobramycin was more frequently used in pediatric patients than in adults, but the use still decreased. Ganciclovir was the preferred anti-viral drug over acyclovir. In conclusion, the prescriptions and cost of ocular topical anti-infectives for outpatients both increased progressively. The increasingly widespread use of levofloxacin raised concerns regarding safety in pediatrics and resistance development. The observed trends can lead to the more efficient management of ocular anti-topical anti-infectives in China.

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Gentry, Brian G., Jeremy P. Kamil, Donald M. Coen, Jiri Zemlicka y John C. Drach. "Stereoselective Phosphorylation of Cyclopropavir by pUL97 and Competitive Inhibition by Maribavir". Antimicrobial Agents and Chemotherapy 54, n.º 8 (14 de junio de 2010): 3093–98. http://dx.doi.org/10.1128/aac.00468-10.

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ABSTRACT Human cytomegalovirus (HCMV) is a widespread pathogen that can cause severe disease in immunologically immature and immunocompromised individuals. Cyclopropavir (CPV) is a guanine nucleoside analog active against human and murine cytomegaloviruses in cell culture and efficacious in mice by oral administration. Previous studies established that the mechanism of action of CPV involves inhibition of viral DNA synthesis. Based upon this action and the structural similarity of CPV to ganciclovir (GCV), we hypothesized that CPV must be phosphorylated to a triphosphate to inhibit HCMV DNA synthesis and that pUL97 is the enzyme responsible for the initial phosphorylation of CPV to a monophosphate (CPV-MP). We found that purified pUL97 phosphorylated CPV 45-fold more extensively than GCV, a known pUL97 substrate and the current standard of treatment for HCMV infections. Kinetic studies with CPV as the substrate for pUL97 demonstrated a Km of 1,750 ± 210 μM. Introduction of 1.0 or 10 nM maribavir, a known pUL97 inhibitor, and subsequent Lineweaver-Burk analysis demonstrated competitive inhibition of CPV phosphorylation, with a Ki of 3.0 ± 0.3 nM. Incubation of CPV with pUL97 combined with GMP kinase [known to preferentially phosphorylate the (+)-enantiomer of CPV-MP] established that pUL97 stereoselectively phosphorylates CPV to its (+)-monophosphate. These results elucidate the mechanism of CPV phosphorylation and help explain its selective antiviral action.

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Prichard, Mark N., Debra C. Quenelle, Caroll B. Hartline, Emma A. Harden, Geraldine Jefferson, Samuel L. Frederick, Shannon L. Daily et al. "Inhibition of Herpesvirus Replication by 5-Substituted 4′-Thiopyrimidine Nucleosides". Antimicrobial Agents and Chemotherapy 53, n.º 12 (21 de septiembre de 2009): 5251–58. http://dx.doi.org/10.1128/aac.00417-09.

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ABSTRACT A series of 4′-thionucleosides were synthesized and evaluated for activities against orthopoxviruses and herpesviruses. We reported previously that one analog, 5-iodo-4′-thio-2′-deoxyuridine (4′-thioIDU), exhibits good activity both in vitro and in vivo against two orthopoxviruses. This compound also has good activity in cell culture against many of the herpesviruses. It inhibited the replication of herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus with 50% effective concentrations (EC50s) of 0.1, 0.5, and 2 μM, respectively. It also inhibited the replication of human cytomegalovirus (HCMV) with an EC50 of 5.9 μM but did not selectively inhibit Epstein-Barr virus, human herpesvirus 6, or human herpesvirus 8. While acyclovir-resistant strains of HSV-1 and HSV-2 were comparatively resistant to 4′-thioIDU, it retained modest activity (EC50s of 4 to 12 μM) against these strains. Some ganciclovir-resistant strains of HCMV also exhibited reduced susceptibilities to the compound, which appeared to be related to the specific mutations in the DNA polymerase, consistent with the observed incorporation of the compound into viral DNA. The activity of 4′-thioIDU was also evaluated using mice infected intranasally with the MS strain of HSV-2. Although there was no decrease in final mortality rates, the mean length of survival after inoculation increased significantly (P < 0.05) for all animals receiving 4′-thioIDU. The findings from the studies presented here suggest that 4′-thioIDU is a good inhibitor of some herpesviruses, as well as orthopoxviruses, and this class of compounds warrants further study as a therapy for infections with these viruses.

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Williams, Stephanie L., Caroll B. Hartline, Nicole L. Kushner, Emma A. Harden, Deborah J. Bidanset, John C. Drach, Leroy B. Townsend, Mark R. Underwood, Karen K. Biron y Earl R. Kern. "In Vitro Activities of Benzimidazole d- and l-Ribonucleosides against Herpesviruses". Antimicrobial Agents and Chemotherapy 47, n.º 7 (julio de 2003): 2186–92. http://dx.doi.org/10.1128/aac.47.7.2186-2192.2003.

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ABSTRACT Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella-zoster virus (VZV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), human herpesvirus 6 (HHV-6), and human herpesvirus 8 (HHV-8) are responsible for a number of clinical manifestations in both normal and immunocompromised individuals. The parent benzimidazole ribonucleosides evaluated in this series, 2-bromo-5,6-dichloro-1-(β-d-ribofuranosyl)benzimidazole (BDCRB) and maribavir (1263W94), are potent and selective inhibitors of human CMV replication. These nucleosides act by two different mechanisms. BDCRB blocks the processing and maturation of viral DNA, whereas 1263W94 inhibits the viral enzyme pUL97 and interferes with DNA synthesis. In the present study, we have evaluated the in vitro antiviral activity of BDCRB, an analog, GW275175X (175X), and 1263W94 against the replication of HSV-1, HSV-2, VZV, CMV, EBV, HHV-6, and HHV-8. By using various methodologies, significant activity was observed against human CMV and EBV but not against HSV-1, HSV-2, VZV, HHV-6, or HHV-8. Plaque reduction assays performed on a variety of laboratory and clinical isolates of human CMV indicated that all strains, including those resistant to ganciclovir (GCV) and foscarnet, were sensitive to all three benzimidazole ribonucleosides, with mean 50% effective concentration values of about 1 to 5 μM compared to that of GCV at 6 μM. The toxicity of these compounds in tissue culture cells appeared to be similar to that observed with GCV. These results demonstrate that the benzimidazole ribonucleosides are active against human CMV and EBV and suggest that they may be useful for the treatment of infections caused by these herpesviruses.

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Smee, Donald F., Stephan T. Sugiyama, Robert W. Sidwell y Bill B. Barnett. "Effects of Monoclonal Antibody Combined with Ganciclovir or (S)-1-[3-Hydroxy-(2-phosphonylmethoxy)-propyl]cytosine against Murine Cytomegalovirus Infections in Cell Culture and in Severe Combined Immunodeficient Mice". Chemotherapy 41, n.º 2 (1995): 141–48. http://dx.doi.org/10.1159/000239335.

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Garvey, Michael J., Paul G. Ambrose y Jack L. Ulmer. "Topical Fumagillin in The Treatment of Microsporidial Keratoconjunctivitis in Aids". Annals of Pharmacotherapy 29, n.º 9 (septiembre de 1995): 872–74. http://dx.doi.org/10.1177/106002809502900909.

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Objective: To report microsporidial keratoconjunctivitis in a patient infected with HIV who was treated with topical fumagillin. Case Summary: A 37-year-old white man who was experiencing redness, pain, irritation, decreased vision, and a foreign body sensation occurring in both eyes was referred to the ophthalmology clinic. The patient had a medical history significant for AIDS, Pneumocystis carinii pneumonia, and Cytomegalovirus retinitis. Conjunctival smears were taken and stained positive for the presence of Microsporidia. The patient was diagnosed with bilateral microsporidial keratoconjunctivitis and fumagillin therapy was initiated. After 5 days of therapy, the patient repotted significant improvements characterized by a decrease in blurred vision with only slight blurring in the left eye, decrease in headache, and decreased foreign body sensation. The patient continued topical fumagillin therapy for more than 14 months, with only slight blurring in the left eye and no apparent ocular toxicity as a result of fumagillin therapy. Discussion: Although rare in occurrence, increasing numbers of documented microsporidial infections are being reported in the medical literature, particularly in individuals who are seropositive for HIV. Clinicians need to be cognizant of microsporidial keratoconjunctivitis as another opportunistic infection in this patient population. Conclusions: Although a curative agent has yet to be discovered, fumagillin represents a safe, effective, low-cost, topical agent for the treatment of microsporidial keratoconjunctivitis.

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"▾Ganciclovir for cytomegalovirus infection". Drug and Therapeutics Bulletin 27, n.º 20 (2 de octubre de 1989): 79–80. http://dx.doi.org/10.1136/dtb.27.20.79.

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Cytomegalovirus (CMV) infection is usually trivial, but in patients whose immune system is suppressed, e.g. by AIDS, it can cause lethal lung and gut infections and blindness from retinitis. Ganciclovir (Cymevene - licensed to Syntex; discovered by Wellcome) is the first drug with useful activity against CMV. In vitro it is ten times as active against CMV as acyclovir, a related nucleoside analogue used in other herpes virus infections.1

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"Studies of Ocular Complications of AIDS Foscarnet-Ganciclovir cytomegalovirus retinitis trial: 1. Rationale, design, and methods". Controlled Clinical Trials 13, n.º 1 (febrero de 1992): 22–39. http://dx.doi.org/10.1016/0197-2456(92)90027-w.

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Nguyen, T., M. Oualha, C. Briand, M. Bendavid, A. Béranger, S. Benaboud, J.-M. Tréluyer et al. "Population Pharmacokinetics of intravenous Ganciclovir and oral Valganciclovir in pediatric population to optimize dosing regimens". Antimicrobial Agents and Chemotherapy, 14 de diciembre de 2020, AAC.02254–20. http://dx.doi.org/10.1128/aac.02254-20.

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Context: Ganciclovir is indicated for curative or preventive treatment of cytomegalovirus (CMV) infections. This study aimed to characterize ganciclovir pharmacokinetics, following intravenous ganciclovir and oral valganciclovir administration, in order to optimize dosing scheme.Method: All children aged <18 years receiving ganciclovir or valganciclovir were included in this study. Pharmacokinetics were described using non-linear mixed-effect modelling. Monte Carlo simulations were used to optimize dosing regimen in order to maintain area under the concentration curve (AUC) in the preventive or therapeutic target.Results: Among the 105 children (374 concentration-time observations) included, 78 received intravenous (IV) ganciclovir, 19 oral valganciclovir and 6 both drugs. A two-compartment model with first-order absorption for valganciclovir and first-order elimination best described the data. An allometric model was used to describe bodyweight (BW) effect. Estimated glomerular filtration rate (eGFR) and critically-ill children medical status were significantly associated with ganciclovir elimination.Conclusion: Recommended doses were adapted for prophylactic treatment. To obtain a therapeutic exposure, doses should be increased to 40 mg/kg/day oral or 15-20 mg/kg/day IV in children with normal eGFR and to 56 mg/kg/day oral or 20-25 mg/kg/day IV in children with augmented eGFR. These doses should be prospectively confirmed and a therapeutic drug monitoring could be used to refine them individually.

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Mercorelli, Beatrice, Anna Luganini, Marta Celegato, Giorgio Palù, Giorgio Gribaudo, Galina I. Lepesheva y Arianna Loregian. "The Clinically Approved Antifungal Drug Posaconazole Inhibits Human Cytomegalovirus Replication". Antimicrobial Agents and Chemotherapy 64, n.º 10 (20 de julio de 2020). http://dx.doi.org/10.1128/aac.00056-20.

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ABSTRACT Posaconazole (PCZ) is a clinically approved drug used predominantly for prophylaxis and salvage therapy of fungal infections. Here, we report its previously undescribed anti-human cytomegalovirus (HCMV) activity. By using antiviral assays, we demonstrated that PCZ, along with other azolic antifungals, has a broad anti-HCMV activity, being active against different strains, including low-passage-number clinical isolates and strains resistant to viral DNA polymerase inhibitors. Using a pharmacological approach, we identified the inhibition of human cytochrome P450 51 (hCYP51), or lanosterol 14α demethylase, a cellular target of posaconazole in infected cells, as a mechanism of anti-HCMV activity of the drug. Indeed, hCYP51 expression was stimulated upon HCMV infection, and the inhibition of its enzymatic activity by either the lanosterol analog VFV {(R)-N-(1-(3,4′-difluoro-[1,1′-biphenyl]-4-yl)-2-(1H-imidazol-1-yl)ethyl)-4-(5-phenyl-1,3,4-oxadiazol-2-yl)benzamide} or PCZ decreased HCMV yield and infectivity of released virus particles. Importantly, we observed that the activity of the first-line anti-HCMV drug ganciclovir was boosted tenfold by PCZ and that ganciclovir (GCV) and PCZ act synergistically in inhibiting HCMV replication. Taken together, these findings suggest that this clinically approved drug deserves further investigation in the development of host-directed antiviral strategies as a candidate anti-HCMV drug with a dual antimicrobial effect.

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"147 A comparison of ganciclovir and a phosphonate analogue, SR 3745A, for treatment of experimental cytomegalovirus infections". Antiviral Research 20 (abril de 1993): 123. http://dx.doi.org/10.1016/0166-3542(93)90525-n.

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"13 Phosphonate derivatives of ganciclovir and acyclovir inhibit murine cytomegalovirus (MCMV) infections in cell culture and in mice". Antiviral Research 23 (febrero de 1994): 42. http://dx.doi.org/10.1016/0166-3542(94)90137-6.

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"107 Treatment of murine cytomegalovirus (MCMV) infections in cell culture and in immunocompromised mice using antibodies to MCMV alone and in combination with ganciclovir (GCV) or (S)-1-(3-hydroxy-2-phosphonylmethoxypropy1)cytosine (HPMPC)". Antiviral Research 23 (febrero de 1994): 92. http://dx.doi.org/10.1016/0166-3542(94)90230-5.

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Beharry, Karen, Simerdip Kaur, Efrosini Papagiannuli, Samuel Moses y Denise De Lord. "P048 Cytomegalovirus retinitis in a patient with rheumatoid arthritis on tofacitinib". Rheumatology 60, Supplement_1 (1 de abril de 2021). http://dx.doi.org/10.1093/rheumatology/keab247.045.

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Abstract Background/Aims Cytomegalovirus (CMV) retinitis is one of the most common opportunistic ocular infections and has traditionally been associated with immunocompromised individuals. We present a case of CMV retinitis following 3 months of treatment with tofacitinib in conjunction with methotrexate (MTX) for rheumatoid arthritis (RA) in an elderly lady with no other co-morbidities. Methods The case is presented below. Results 69-year-old lady with long standing seronegative, anti-cyclic citrullinated peptide negative, erosive RA since 2016. She was intolerant of sulphasalazine, leflunamide, methotrexate and etanercept. Hydroxychloroquine was avoided due to idiopathic cystoid macular oedema in the right eye with a baseline visual acuity of 6/18. Baseline fundus fluorescein angiogram (FFA) was negative for any vascular, inflammatory or occlusive disease. She was escalated to tofacitinib in August 2019. Approximately 3 months later, she noticed significantly reduced vision in her right eye from 6/18 down to 6/60. She had an FFA and Indocyanine Green Angiography, which showed quite extensive retinal ischaemia and vasculitis. Her bloods revealed a raised serum ACE and a T-spot test from 2018 was reactive followed by a repeat in 2019 which was equivocal. Tofacitinib was discontinued. She was commenced on rifampicin and isoniazid as 3 months prophylaxis for latent tuberculosis (LTBI). Additionally, she was started on oral prednisolone 60mg daily for presumed sarcoid related retinal vasculitis. She failed to improve despite a week’s treatment and subsequently had a vitreous aspirate which was strongly positive for CMV PCR. Her CMV viral load was 267copies/ml. The aspirate was negative for other infectious agents. She was commenced on valganciclovir for CMV retinitis. Unfortunately, her vision remained unchanged despite the viral load becoming undetectable a few weeks later. Despite having LTBI, there was no reactivation of this with her immunosuppressive therapy. Conclusion CMV retinitis is usually associated with immunocompromised individuals and is rarely encountered related to tofacitinib therapy for rheumatoid arthritis. Tofacitinib suppresses T cell function by inhibiting STAT signalling pathways, modulating T cell activation and cytokine production. Our case highlights the preferential development of CMV retinitis over active TB in the presence of LTBI, which is a recognised risk with the use of JAK kinase inhibitors. TB risk has been associated with genetic mutations in IL-12, IFN-γ and STAT1 pathways while CMV activation may be influenced by mutations in HLA ,Toll-like receptors, immunoglobulin light chain antibodies, IFN lambda region as well as alternative transcripts of the CMV viral major immediate early genes. Disclosure K. Beharry: None. S. Kaur: None. E. Papagiannuli: None. S. Moses: None. D. De Lord: None.

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