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Transplantation and Cellular Therapy Jan 2021The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell...
The high incidence of human herpesvirus-6 (HHV-6) reactivation, potentially interfering with engraftment after umbilical cord blood (UCB) hematopoietic cell transplantation (HCT), remains a major challenge. To potentially address this problem, we evaluated the effect of prophylactic foscarnet administered twice daily beginning on day +7 and continuing through engraftment in 25 patients. To determine the impact of foscarnet on HHV-6, engraftment, and other transplantation outcomes, we compared results in 61 identically treated patients with hematologic malignancies. Treatment and control groups underwent reduced-intensity conditioning UCB HCT with a conditioning regimen of fludarabine, cyclophosphamide, and total body irradiation 200 cGy with or without antithymocyte globulin (ATG), using sirolimus plus mycophenolate mofetil immune suppression. The treatment and control groups were similar in terms of age, disease risk, use of ATG, Hematopoietic Cell Transplantation Comorbidity Index, and graft CD34 cell dose; however, foscarnet-treated patients were less likely to receive a double UCB graft and to be treated more recently (2016 to 2018). The cumulative incidence of HHV-6 reactivation by day +100 was 63% for all patients (95% confidence interval [CI], 51% to 75%) and was not significantly different between the 2 groups. HHV-6 reactivation occurred at a median of 34 days in the foscarnet group and 25.5 days in the control group. The incidence of neutrophil engraftment at day 42 was higher in the foscarnet group compared with the control group (96%; [95% CI, 83% to 100%] versus 75% [95% CI, 64% to 85%]; P< .01). The cumulative incidence of platelet engraftment by 6 months was 92% (95% CI, 69% to 100%) for the foscarnet group versus 75% (95% CI, 60% to 90%) for the control group (P= .08), and multivariate analysis identified the use of foscarnet as an independent predictor of better platelet engraftment. No patients died as a result of graft failure in recipients of foscarnet, whereas 5 patients died from graft failure in the control group. Six-month overall survival (OS) and nonrelapse mortality (NRM) were better in the foscarnet group (96% versus 72% [P= .02] and 4% versus 18% [P= .07], respectively). Even though foscarnet prophylaxis did not prevent HHV-6 viremia, we observed a delay in time to HHV-6 reactivation, a trend toward differences in engraftment, NRM, and OS compared with historical controls.
Topics: Cord Blood Stem Cell Transplantation; Foscarnet; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Herpesvirus 6, Human; Humans
PubMed: 33053448
DOI: 10.1016/j.bbmt.2020.10.008 -
Physiological Research Aug 2020Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms...
Lithium is mainly excreted into urine, and a large fraction of lithium filtered through glomeruli is reabsorbed in the proximal tubule. However, the mechanisms responsible for lithium reabsorption remain unclear. We previously reported that the reabsorption of lithium was biphasic in rats, and that foscarnet inhibited lithium reabsorption with a high affinity type. We herein evaluated the effects of acetazolamide and foscarnet on the renal excretion of lithium in rats treated with lithium chloride at 2 doses. In rats intravenously injected with a bolus of 25 mg/kg lithium chloride, acetazolamide facilitated the urinary excretion of lithium, and increased the fractional excretion of lithium from 0.446 to 0.953, near the theoretically maximum value. At a dose of 2.5 mg/kg lithium chloride, the fractional excretion of lithium was 0.241 in control rats, 0.420 in rats administered acetazolamide, and 0.976 in rats administered acetazolamide and foscarnet. These results showed the potent inhibition of lithium reabsorption by acetazolamide and foscarnet in rats. And, it was exhibited that the effects of acetazolamide on lithium reabsorption differed with the dosages of lithium administered.
Topics: Acetazolamide; Animals; Antiviral Agents; Disease Models, Animal; Diuretics; Drug Interactions; Foscarnet; Kidney Tubules, Proximal; Lithium Chloride; Male; Rats; Rats, Wistar; Renal Reabsorption
PubMed: 32584131
DOI: 10.33549/physiolres.934285 -
Investigative Ophthalmology & Visual... Jun 2020Herpes simplex virus type I (HSV-1) infection of corneal epithelial cells activates ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response...
PURPOSE
Herpes simplex virus type I (HSV-1) infection of corneal epithelial cells activates ataxia telangiectasia mutated (ATM), an apical kinase in the host DNA damage response pathway, whose activity is necessary for the progression of lytic HSV-1 infection. The purpose of this study is to investigate the mechanism of ATM activation by HSV-1 in the corneal epithelium, as well as its functional significance.
METHODS
Mechanistic studies were performed in cultured human corneal epithelial cell lines (hTCEpi, HCE), as well as in esophageal (EPC2) and oral (OKF6) cell lines. Transfection-based experiments were performed in HEK293 cells. HSV-1 infection was carried out using the wild-type KOS strain, various mutant strains (tsB7, d120, 7134, i13, n208), and bacterial artificial chromosomes (fHSVΔpac, pM24). Inhibitors of ATM (KU-55933), protein synthesis (cycloheximide), and viral DNA replication (phosphonoacetic acid) were used. Outcomes of infection were assayed using Western blotting, qRT-PCR, immunofluorescence, and comet assay.
RESULTS
This study demonstrates that HSV-1-mediated ATM activation in corneal epithelial cells relies on the viral immediate early gene product ICP4 and requires the presence of the viral genome in the host nucleus. We show that ATM activation is independent of viral genome replication, the ICP0 protein, and the presence of DNA lesions. Interestingly, ATM activity appears to be necessary at the onset of infection, but dispensable at the later stages.
CONCLUSIONS
This study expands our understanding of HSV-1 virus-host interactions in the corneal epithelium and identifies potential areas of future investigation and therapeutic intervention in herpes keratitis.
Topics: Cells, Cultured; DNA Damage; DNA Replication; DNA, Viral; Epithelium, Corneal; Eye Infections, Viral; Herpesvirus 1, Human; Humans; Keratitis, Herpetic; Virus Replication
PubMed: 32543665
DOI: 10.1167/iovs.61.6.39 -
Biology of Blood and Marrow... Sep 2020Despite a well-established risk of chronic kidney disease (CKD) after allogeneic hematopoietic cell transplant (allo-HCT), the benefits of using nephrotoxic...
Despite a well-established risk of chronic kidney disease (CKD) after allogeneic hematopoietic cell transplant (allo-HCT), the benefits of using nephrotoxic anti-infective agents to treat serious peritransplant infections often outweigh this risk. While there is no consensus on the optimal management of post-allo-HCT human herpes virus 6 (HHV6) reactivation, the nephrotoxic drug foscarnet is often used, although its long-term impact on renal function has not been established. We retrospectively reviewed 987 adult patients who underwent transplantation between 2002 and 2016, of whom 45.3% (n = 447) were exposed to foscarnet. The most frequent indications for foscarnet treatment were cytomegalovirus (n = 257, 57.5%) and HHV6 (n = 139, 31.1%). In the first 3 months post-transplant, patients exposed versus unexposed had similar rates of acute kidney injury and acute kidney failure (defined as 3 times baseline creatinine or <75% baseline estimated glomerular filtration rate [eGFR], 61.6% versus 58.7%, P = .42 and 28.1% versus 26.6%, P = .64, respectively). There was no difference in the eGFR at 3 months (P = .36), but patients treated with foscarnet had significantly lower median eGFRs (mL/min/1.73 m) at 6 months (69.3, interquartile range [IQR] 51.4 to 92.8 versus 77.4, IQR 57.3 to 99.3; P = .009) and 12 months (67.8, IQR 52.7 to 85.0 versus 80.7, IQR 63.1 to 102.0; P < .001), respectively. There was also a significant difference in the decline in eGFR from baseline to 12 months (median 32.8, IQR 14.6 to 53.2 versus 21.9, IQR 6.4 to 37.4; P < .001), irrespective of the duration of foscarnet treatment. Multivariate analysis revealed that patients treated with foscarnet were more likely to experience a >30% decrease in eGFR from baseline to 12 months compared to those who were not (odds ratio, 2.30; 95% CI, 1.40 to 3.78; P = .001). We conclude that foscarnet use following allo-HCT had a profound impact on long-term renal function independent of other transplant-related factors.
Topics: Adult; Foscarnet; Glomerular Filtration Rate; Hematopoietic Stem Cell Transplantation; Humans; Retrospective Studies; Transplantation, Homologous
PubMed: 32450288
DOI: 10.1016/j.bbmt.2020.05.007 -
Scientific Reports Feb 2020Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no...
Paraquat (PQ) is a non-selective herbicide and is exceedingly toxic to humans. The mechanism of PQ toxicity is very complex and has not been clearly defined. There is no specific antidote for PQ poisoning. 5-hydroxy-1-methylhydantoin (HMH) is an intrinsic antioxidant and can protect against renal damage caused by PQ. The mechanism of PQ toxicology and the possible effects of HMH on PQ-induced lung injury were determined in this study. It was found that PQ decreased superoxide dismutase (SOD) activity and elevated the level of malondialdehyde (MDA), while HMH elevated SOD activity and decreased the level of MDA. Based on metabolomics, the citrate cycle, glutathione metabolism, taurine and hypotaurine metabolism, regulation of lipolysis in adipocytes, inflammatory mediator regulation of TRP channels, purine and pyrimidine metabolism, aldosterone synthesis and secretion, and phenylalanine metabolism were changed in the PQ group. Compared with the PQ group, the levels of N-acetyl-l-aspartic acid, L-glutamic acid, L-aspartic acid, mesaconic acid, adenosine 5' monophosphate, methylmalonic acid, cytidine, phosphonoacetic acid, hypotaurine, glutathione (reduced) and cysteinylglycine increased, while the levels of corticosterone, xanthine, citric acid, prostaglandin G2, 4-pyridoxic acid and succinyl proline decreased in the HMH group. These metabolites revealed that HMH can alleviate inflammation caused by PQ and elevate the activity of intrinsic antioxidants. In conclusion, our results revealed PQ toxicology and the pharmacology underlying the protective effect of HMH on lung injury due to PQ. Toxicity caused by PQ results in lipid peroxidation and an increase in reactive oxygen species (ROS), nitric oxide (NO), damage to the biliary system, gastrointestinal system and nervous system, in addition to lungs, kidneys, and the liver. HMH is a good antioxidant and protects against lung injury caused by PQ. In summary, HMH efficiently reduced PQ-induced lung injury in mice.
Topics: Acute Lung Injury; Glutathione; Herbicides; Humans; Hydantoins; Lipid Peroxidation; Malondialdehyde; Metabolomics; Paraquat; Protective Agents; Superoxide Dismutase; Taurine
PubMed: 32019966
DOI: 10.1038/s41598-020-58599-y -
Antimicrobial Agents and Chemotherapy Mar 2020Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of...
Herein, we phenotypically and enzymatically characterize the theoretical mutation Q579I in helix K and the already described clinical mutation K805Q in helix P of cytomegalovirus DNA polymerase for susceptibility to foscarnet. Q579I and K805Q recombinant viruses were hypersusceptible to foscarnet (respective mean 50% effective concentrations [EC] of 0.12- and 0.19-fold that of the wild type). Three-dimensional modeling analysis suggested that both mutations favor the closed conformation of the enzyme to which foscarnet binds with a higher affinity.
Topics: Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; DNA, Viral; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Foscarnet; Humans; Models, Molecular; Mutation
PubMed: 32015044
DOI: 10.1128/AAC.01910-19 -
Current Hematologic Malignancy Reports Apr 2020CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often... (Review)
Review
PURPOSE OF REVIEW
CMV DNA polymerase inhibitors such as ganciclovir and foscarnet have dramatically reduced the burden of CMV infection in the HCT recipient. However, their use is often limited by toxicities and resistance. Agents with novel mechanisms and favorable toxicity profiles are critically needed. We review recent developments in CMV antivirals and immune-based approaches to mitigating CMV infection.
RECENT FINDINGS
Letermovir, an inhibitor of the CMV terminase complex, was approved in 2017 for primary CMV prophylaxis in adult seropositive allogeneic HCT recipients. Maribavir, an inhibitor of the CMV UL97 kinase, is currently in two phase 3 treatment studies. Adoptive immunotherapy using third-party T cells has proven safe and effective in preliminary studies. Vaccine development continues, with several promising candidates currently under study. No longer limited to DNA polymerase inhibitors, the prevention and treatment of CMV infections in the HCT recipient is a rapidly evolving field which should translate into improvements in CMV-related outcomes.
Topics: Animals; Antiviral Agents; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Drug Resistance, Viral; Foscarnet; Ganciclovir; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Immunotherapy; Immunotherapy, Adoptive; Molecular Targeted Therapy; Opportunistic Infections; Risk Factors; T-Lymphocytes; Treatment Outcome
PubMed: 31981100
DOI: 10.1007/s11899-020-00557-6 -
RSC Advances 2020Adenosine 5'-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD). Synthetic ADPR analogues can shed...
Adenosine 5'-diphosphate ribose (ADPR) is an intracellular signalling molecule generated from nicotinamide adenine dinucleotide (NAD). Synthetic ADPR analogues can shed light on the mechanism of activation of ADPR targets and their downstream effects. Such chemical biology studies, however, are often challenging due to the negatively charged pyrophosphate, also sensitive to cellular pyrophosphatases, and prior work on an initial ADPR target, the transient receptor potential cation channel TRPM2, showed complete pyrophosphate group replacement to be a step too far in maintaining biological activity. Thus, we designed ADPR analogues with just one of the negatively charged phosphate groups removed, by employing a phosphonoacetate linker. Synthesis of two novel phosphonoacetate ADPR analogues is described tandem -dicyclohexylcarbodiimide coupling to phosphonoacetic acid. Neither analogue, however, showed significant agonist or antagonist activity towards TRPM2, underlining the importance of a complete pyrophosphate motif in activation of this particular receptor.
PubMed: 31934327
DOI: 10.1039/C9RA09284F -
Transplant Infectious Disease : An... Apr 2020Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic...
BACKGROUND
Ganciclovir (GCV) and foscarnet (FOS) are the most commonly used antivirals for preemptive treatment of cytomegalovirus (CMV) viremia in recipients of allogeneic hematopoietic cell transplantation (alloHCT). The current literature indicates similar efficacy between these agents. Thus, the primary consideration for choice of initial anti-CMV treatment is the safety profile, time period after alloHCT, and concern of myelosuppression or renal dysfunction.
METHODS
Herein, we retrospectively reviewed medical records of 124 alloHCT recipients who received GCV or FOS between April 27, 2014, and December 31, 2015, during the first year post-transplant. Healthcare resource use included drug, hospitalization, home health, dialysis, and growth factor costs.
RESULTS
Total duration of therapy was longer in the GCV group (37 days vs 28 days, P = .21) but hospitalization days were similar (9 days) in both groups. The total treatment cost was significantly lower in the GCV group ($38 100 vs $59 400, P < .05).
CONCLUSION
Preemptive anti-CMV therapy is associated with major healthcare resource costs, which were greater in patients who required FOS than those who were treated with GCV.
Topics: Adolescent; Adult; Aged; Antiviral Agents; Chemoprevention; Child; Costs and Cost Analysis; Cytomegalovirus Infections; Female; Foscarnet; Ganciclovir; Health Care Costs; Hematopoietic Stem Cell Transplantation; Hospitalization; Humans; Male; Middle Aged; Retrospective Studies; Transplant Recipients; Viremia; Young Adult
PubMed: 31840347
DOI: 10.1111/tid.13233 -
BMJ Case Reports May 2019A 60-year-old man with a history of severe herpes simplex virus type 1 (HSV-1) encephalitis 2 years prior presented with acute onset of visual loss in the left eye....
A 60-year-old man with a history of severe herpes simplex virus type 1 (HSV-1) encephalitis 2 years prior presented with acute onset of visual loss in the left eye. Dilated funduscopic examination showed retinitis and occlusive vasculitis with retinal necrosis. PCR of the vitreous fluid was positive for HSV-1, and he was diagnosed with acute retinal necrosis (ARN) due to HSV-1. The patient was treated with intravenous acyclovir and intravitreous foscarnet for 2 weeks, followed by high dose oral valacyclovir for 2 weeks. He was subsequently placed on planned life-long suppressive valacyclovir. His case demonstrates that acute visual loss concomitant with or subsequent to HSV-1 encephalitis warrants suspicion of ARN. Prompt therapy with effective antiviral medication is necessary to reduce the risk of sight-threatening complications. Chronic suppression with oral antiviral therapy after ARN is recommended to prevent involvement of the contralateral eye, though there is no consensus on the duration and dosage of antivirals.
Topics: Acute Disease; Acyclovir; Antiviral Agents; Diagnosis, Differential; Encephalitis, Herpes Simplex; Eye Infections, Viral; Foscarnet; Herpesvirus 1, Human; Humans; Intravitreal Injections; Male; Middle Aged; Ophthalmoscopes; Rare Diseases; Retinal Necrosis Syndrome, Acute; Treatment Outcome; Valacyclovir
PubMed: 31138593
DOI: 10.1136/bcr-2018-229137