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FEBS Open Bio Mar 2021Periodontitis is an autoimmune disease of periodontal tissues initiated by plaque. It is known that there is a close connection between periodontitis and CKD with...
Periodontitis is an autoimmune disease of periodontal tissues initiated by plaque. It is known that there is a close connection between periodontitis and CKD with hypertension, but the underlying mechanisms are unknown. STAT1 has been reported to play a regulatory role in hypertension and chronic kidney disease (CKD). Here, we investigated whether STAT1 regulates periodontitis-mediated aggravation of kidney injury with accompanying hypertension. A hypertensive renal injury mouse model was established with Nos3 knockout mice, and a periodontitis model was established by implantation with the oral bacteria Porphyromonas gingivalis. The mice were intraperitoneally injected with a STAT1 inhibitor. Periodontitis aggravated kidney injury in hypertensive mice, and upregulation of STAT1 was observed when both periodontitis and hypertension were present; furthermore, STAT1 inhibitor moderated this effect. Moreover, we observed that periodontitis promoted the upregulation of inflammatory and fibrosis gene expression in the kidneys of hypertensive mice. In addition, STAT1 inhibition decreased the expression of pro-inflammatory and pro-fibrotic cytokines in the kidney lesion area. Periodontitis augmented the expression of inflammatory and fibrosis genes by upregulating the expression of STAT1, thereby aggravating kidney injury in the hypertensive mouse model.
Topics: Animals; Disease Models, Animal; Gene Knockdown Techniques; Humans; Hypertension; Mice; Mice, Knockout; Nitric Oxide Synthase Type III; Periodontitis; Porphyromonas gingivalis; Renal Insufficiency, Chronic; STAT1 Transcription Factor; Up-Regulation; Vidarabine
PubMed: 33448153
DOI: 10.1002/2211-5463.13081 -
The Journal of Toxicological Sciences Feb 2016Vidarabine has been used for the treatment of patients with local and systemic herpes virus infection; moreover, it was recently reported that it inhibits cardiac type 5...
Antiviral drug vidarabine possessing cardiac type 5 adenylyl cyclase inhibitory property did not affect cardiohemodynamic or electrophysiological variables in the halothane-anesthetized dogs.
Vidarabine has been used for the treatment of patients with local and systemic herpes virus infection; moreover, it was recently reported that it inhibits cardiac type 5 adenylyl cyclase. Furthermore, vidarabine has been shown to suppress atrial fibrillation and improve congestive heart failure in experimental models of mice induced by the isoproterenol infusion. Since information that can explain its experimentally demonstrated efficacy against congestive heart failure and atrial fibrillation remains limited, in this study we precisely assessed cardio-electropharmacological effect using the halothane-anesthetized canine model. Vidarabine was intravenously administrated in three escalating doses of 1, 10, 100 mg/kg over 10 min with a pause between the doses (n = 4). Meanwhile, the vehicle dimethyl sulfoxide in volumes of 0.033, 0.033 and 0.33 mL/kg was intravenously administrated in the same manner as was vidarabine (n = 4). No significant difference was detected in any cardiohemodynamic or electrophysiological variables between the vehicle- and vidarabine-treated groups, which indicates that effective doses of vidarabine adequately inhibiting type 5 adenylyl cyclase did not affect the cardiovascular variables in vivo at all, showing its cardiac safety profile under physiological condition. Thus, the clinical utility of vidarabine might be limited to the pathological situation including congestive heart failure with increased adrenergic tone and/or sympathetic nerve-dependent atrial fibrillation.
Topics: Adenylyl Cyclase Inhibitors; Anesthesia, Inhalation; Animals; Antiviral Agents; Atrial Fibrillation; Dogs; Electrophysiological Phenomena; Halothane; Heart Failure; Hemodynamics; Infusions, Intravenous; Male; Models, Animal; Vidarabine
PubMed: 26763398
DOI: 10.2131/jts.41.115 -
Viruses Apr 2021Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses....
Viral infections are one of the leading causes in human mortality and disease. Broad-spectrum antiviral drugs are a powerful weapon against new and re-emerging viruses. However, viral resistance to existing broad-spectrum antivirals remains a challenge, which demands development of new broad-spectrum therapeutics. In this report, we showed that fludarabine, a fluorinated purine analogue, effectively inhibited infection of RNA viruses, including Zika virus, Severe fever with thrombocytopenia syndrome virus, and Enterovirus A71, with all IC values below 1 μM in Vero, BHK21, U251 MG, and HMC3 cells. We observed that fludarabine has shown cytotoxicity to these cells only at high doses indicating it could be safe for future clinical use if approved. In conclusion, this study suggests that fludarabine could be developed as a potential broad-spectrum anti-RNA virus therapeutic agent.
Topics: Animals; Antiviral Agents; Cell Line; Cell Survival; Cells, Cultured; Enterovirus A, Human; Humans; Phlebovirus; RNA Viruses; Vidarabine; Virus Replication; Zika Virus
PubMed: 33925713
DOI: 10.3390/v13050774 -
Molecular Pharmaceutics Jun 2016Lymphoma research has advanced thanks to introduction of [(18)F]fludarabine, a positron-emitting tool. This novel radiotracer has been shown to display a great... (Comparative Study)
Comparative Study
Lymphoma research has advanced thanks to introduction of [(18)F]fludarabine, a positron-emitting tool. This novel radiotracer has been shown to display a great specificity for lymphoid tissues. However, in a benign process such as inflammation, the uptake of this tracer has not been questioned. Indeed, in inflammatory zones, elevated glucose metabolism rate may result in false-positives with [(18)F]FDG-PET Imaging. In the present investigation, it has been argued that cells, involved in inflammation, might be less avid of [(18)F]fludarabine. To generate inflammation, Swiss mice were intramuscularly injected with 0.1 mL of turpentine oil into the right front paw. Imaging sessions with (18)F-labeled tracers named above were conducted on days 5 and 25 after inoculation. For each animal, volumes of interest (VOI), delineating the muscle of the inflamed (IP) and normal paws (NP), were determined on PET scans. For characterization of inflammation, muscle samples from IP and NP were stained with hematoxylin and eosin (H&E). In early (day 5) inflammation, [(18)F]FDG accumulation was 4.00 ± 1.65 times greater in the IP than in the contralateral NP; for [(18)F]fludarabine, this IP/NP ratio was 1.31 ± 0.28, resulting in a significant difference between radiotracer groups (p < 0.01). In late (day 25) inflammation, the IP/NP ratios were 2.07 ± 0.49 and 1.03 ± 0.07, for [(18)F]FDG and [(18)F]fludarabine, respectively (p < 0.001). [(18)F]Fludarabine showed significantly weaker uptake in inflammation when compared with [(18)F]FDG. This encouraging finding suggests that [(18)F]fludarabine-PET might well be a robust approach for distinguishing tumor from inflammatory tissue, avoiding false-positive PET results and thus enabling an accurate imaging of lymphoma.
Topics: Animals; Fluorodeoxyglucose F18; Inflammation; Mice; Positron-Emission Tomography; Radiopharmaceuticals; Sensitivity and Specificity; Tissue Distribution; Vidarabine
PubMed: 27080099
DOI: 10.1021/acs.molpharmaceut.6b00050 -
Blood Dec 2021E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in... (Randomized Controlled Trial)
Randomized Controlled Trial
E1912 was a randomized phase 3 trial comparing indefinite ibrutinib plus 6 cycles of rituximab (IR) to 6 cycles of fludarabine, cyclophosphamide, and rituximab (FCR) in untreated younger patients with CLL. We describe measurable residual disease (MRD) levels in E1912 over time and correlate them with clinical outcome. Undetectable MRD rates (<1 CLL cell per 104 leukocytes) were 29.1%, 30.3%, 23.4%, and 8.6% at 3, 12, 24, and 36 months for FCR, and significantly lower at 7.9%, 4.2%, and 3.7% at 12, 24, and 36 months for IR, respectively. Undetectable MRD at 3, 12, 24, and 36 months was associated with longer progression-free survival (PFS) in the FCR arm, with hazard ratios (MRD detectable/MRD undetectable) of 4.29 (95% confidence interval [CI], 1.89-9.71), 3.91 (95% CI, 1.39-11.03), 14.12 (95% CI, 1.78-111.73), and not estimable (no events among those with undetectable MRD), respectively. In the IR arm, patients with detectable MRD did not have significantly worse PFS compared with those in whom MRD was undetectable; however, PFS was longer in those with MRD levels <10-1 than in those with MRD levels above this threshold. Our observations provide additional support for the use of MRD as a surrogate end point for PFS in patients receiving FCR. In patients on indefinite ibrutinib-based therapy, PFS did not differ significantly by undetectable MRD status, whereas those with MRD <10-1 tended to have longer PFS, although continuation of ibrutinib would very likely be necessary to maintain treatment efficacy.
Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Female; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Neoplasm, Residual; Piperidines; Prognosis; Progression-Free Survival; Protein Kinase Inhibitors; Rituximab; Treatment Outcome; Vidarabine
PubMed: 34407545
DOI: 10.1182/blood.2020010146 -
Bone Marrow Transplantation Jan 2023
Fludarabine- and low-dose cyclophosphamide-based conditioning regimens provided favorable survival and engraftment for unmanipulated hematopoietic cell transplantation from unrelated donors and matched siblings in patients with Fanconi anemia: results from the CBMTR.
Topics: Humans; Fanconi Anemia; Unrelated Donors; Siblings; Hematopoietic Stem Cell Transplantation; Vidarabine; Cyclophosphamide; Transplantation Conditioning; Graft vs Host Disease
PubMed: 36257981
DOI: 10.1038/s41409-022-01838-9 -
The Lancet. Oncology Sep 2019
Randomized Controlled Trial
Topics: Adenine; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Piperidines; Progression-Free Survival; Pyrazoles; Pyrimidines; Rituximab; Vidarabine
PubMed: 31402323
DOI: 10.1016/S1470-2045(19)30528-5 -
Leukemia & Lymphoma Jan 2022Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of...
Increased early mortality after fludarabine and melphalan conditioning with peripheral blood grafts in haploidentical hematopoietic cell transplantation with post-transplant cyclophosphamide.
Due to the evolving use of haploidentical donor grafts in hematopoietic cell transplantation, there is increased need to better understand the risks and benefits of using bone marrow versus peripheral blood grafts, as well as how specific pre-transplantation conditioning regimens impact patient safety and treatment outcomes. We performed a retrospective analysis of 38 patients at two centers who underwent haploidentical hematopoietic cell transplantation using fludarabine plus melphalan-based conditioning regimens with post-transplant cyclophosphamide and peripheral blood donor grafts. We observed an unexpectedly high rate of early non-relapse mortality and severe cytokine release syndrome. The poor outcomes with 1-year overall survival of 34%, disease-free survival of 29%, and non-relapse mortality of 34% motivate us to reconsider the appropriateness of the combination of fludarabine and melphalan conditioning with T-cell replete peripheral blood grafts in the setting of haploidentical hematopoietic cell transplant with post-transplant cyclophosphamide.
Topics: Cyclophosphamide; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 34794373
DOI: 10.1080/10428194.2021.1978087 -
American Journal of Hematology Feb 2015We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165... (Comparative Study)
Comparative Study
We compared survival outcomes following myeloablative allotransplant (MAT) or cyclophosphamide/fludarabine (Cy/Flu) nonmyeloablative allotransplant (NMAT) for 165 patients with acute myelogenous leukemia (AML) in remission or without frank relapse. Patients who received NMAT were more likely to be older and have secondary AML and lower performance status. At a median follow-up of 61 months, median event-free survival and overall survival survival were not different between NMAT and MAT in univariate as well as multivariate analyses. Cy/Flu NMAT may provide similar disease control and survival when compared with MAT in patients with AML in remission or without frank relapse.
Topics: Adult; Analysis of Variance; Antineoplastic Agents; Cyclophosphamide; Drug Administration Schedule; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Male; Middle Aged; Neoplasm Recurrence, Local; Remission Induction; Survival Analysis; Transplantation Conditioning; Transplantation, Homologous; Vidarabine
PubMed: 25345651
DOI: 10.1002/ajh.23875 -
Annals of Transplantation Aug 2019BACKGROUND Graft rejection and graft versus host disease (GvHD) have impeded the success of hematopoietic cell transplantation for severe aplastic anemia (SAA) patients....
BACKGROUND Graft rejection and graft versus host disease (GvHD) have impeded the success of hematopoietic cell transplantation for severe aplastic anemia (SAA) patients. There is no sufficient data to identify the outcomes of peripheral blood stem cell transplantation (PBSCT) in SAA patients, especially for adult SAA patients. The aim of this study was to evaluate the outcomes of adult SAA patients undergoing PBSCT with the FCA regimen. The FCA regimen includes fludarabine, cyclophosphamide, and anti-thymocyte globulin (ATG). MATERIAL AND METHODS We report our experience with 46 adult SAA patients who underwent PBSCT with the FCA regimen. Thirty SAA patients who received only cyclophosphamide and ATG (CA) regimen were used as controls. Complications and survival outcomes were evaluated and compared. RESULTS There was a significantly higher percentage of patients who achieved >95% donor chimerism by day 30 in the FCA group. The 5-year event-free survival (EFS) rate in the FCA group was higher than that in the CA group (95.4% versus 73.3%). In addition, the 5-year rejection rate (RR) in the FCA group was lower than that in the CA group (4.6% versus 23.6%). A multivariable model identified the FCA regimen as an independent factor affecting EFS and RR. However, GvHD and serious infection did not differ between the 2 groups. For patients with an unrelated donor, the FCA regimen had a higher EFS and a lower RR than the CA regimen. CONCLUSIONS The FCA regimen for PBSCT in adult SAA patients compared favorably to the CA regimen. It can improve EFS and reduce graft rejection, especially for unrelated donor PBSCT.
Topics: Adolescent; Adult; Anemia, Aplastic; Antilymphocyte Serum; Cyclophosphamide; Female; Humans; Male; Middle Aged; Peripheral Blood Stem Cell Transplantation; Transplantation Conditioning; Treatment Outcome; Vidarabine; Young Adult
PubMed: 31395850
DOI: 10.12659/AOT.915696