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Viruses Jun 2021Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the... (Review)
Review
Herpes simplex viruses-1 and -2 (HSV-1 and -2) are two of the three human alphaherpesviruses that cause infections worldwide. Since both viruses can be acquired in the absence of visible signs and symptoms, yet still result in lifelong infection, it is imperative that we provide interventions to keep them at bay, especially in immunocompromised patients. While numerous experimental vaccines are under consideration, current intervention consists solely of antiviral chemotherapeutic agents. This review explores all of the clinically approved drugs used to prevent the worst sequelae of recurrent outbreaks by these viruses.
Topics: Antiviral Agents; Biological Availability; DNA-Directed DNA Polymerase; Drug Resistance, Viral; Herpes Simplex; Herpesvirus 1, Human; Herpesvirus 2, Human; Humans; Nucleic Acid Synthesis Inhibitors; Virus Attachment; Virus Internalization
PubMed: 34202050
DOI: 10.3390/v13071228 -
Leukemia Jan 2022
Topics: Antineoplastic Combined Chemotherapy Protocols; Biomarkers, Tumor; Cyclophosphamide; Follow-Up Studies; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Variable Region; Integrin alpha4; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Neoplasm Recurrence, Local; Prognosis; Rituximab; Survival Rate; Telomere Homeostasis; Tumor Suppressor Protein p53; Vidarabine
PubMed: 34148055
DOI: 10.1038/s41375-021-01322-1 -
Cancer Medicine Jul 2021Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the...
Allogenic hematopoietic stem cell transplantation (allo-HCT) is the standard treatment for acute myeloid leukemia (AML) in non-complete remission (non-CR); however, the prognosis is inconsistent. This study aimed to develop and validate nomograms and a web application to predict the overall survival (OS) of patients with non-CR AML undergoing allo-HCT (cord blood transplantation [CBT], bone marrow transplantation [BMT], and peripheral blood stem cell transplantation [PBSCT]). Data from 3052 patients were analyzed to construct and validate the prognostic models. The common significant prognostic factors among patients undergoing allo-HCT were age, performance status, percentage of peripheral blasts, cytogenetic risk, chemotherapy response, and number of transplantations. The conditioning regimen was a significant prognostic factor only in patients undergoing CBT. Compared with cyclophosphamide/total body irradiation, a conditioning regimen of ≥3 drugs, including fludarabine, with CBT exhibited the lowest hazard ratio for mortality (0.384; 95% CI, 0.266-0.554; p < 0.0001). A conditioning regimen of ≥3 drugs with CBT also showed the best leukemia-free survival among all conditioning regimens. Based on the results of the multivariable analysis, we developed prognostic models showing adequate calibration and discrimination (the c-indices for CBT, BMT, and PBSCT were 0.648, 0.600, and 0.658, respectively). Our prognostic models can help in assessing individual risks and designing future clinical studies. Furthermore, our study indicates the effectiveness of multi-drug conditioning regimens in patients undergoing CBT.
Topics: Adult; Age Factors; Bone Marrow Transplantation; Busulfan; Cord Blood Stem Cell Transplantation; Cyclophosphamide; Cytarabine; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Karnofsky Performance Status; Leukemia, Myeloid, Acute; Male; Melphalan; Middle Aged; Nomograms; Peripheral Blood Stem Cell Transplantation; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation
PubMed: 34132501
DOI: 10.1002/cam4.3920 -
Transplantation and Cellular Therapy Oct 2021The recommended therapy for severe aplastic anemia (SAA) in younger patients with a matched sibling donor (MSD) is allogeneic hematopoietic cell transplantation...
The recommended therapy for severe aplastic anemia (SAA) in younger patients with a matched sibling donor (MSD) is allogeneic hematopoietic cell transplantation (allo-HCT). A number of conditioning regimens and protocols have been used for these patients. Here we report a homogeneous cohort of SAA patients receiving a uniform transplantation protocol. This study is a retrospective analysis of 82 consecutive patients with SAA who underwent MSD allo-HCT at a single center. The median duration of follow-up for survivors was 100 months, the 10-year overall survival (OS) was 87.5%, and the 10-year event-free survival was 75.3%. The OS was 97.4% for "mobilized" bone marrow (BM) graft recipients and 78.9% for "nonmobilized" BM graft recipients (P = .01. The cumulative incidence of acute graft-versus-host disease (GVHD) was 25.6%, that of chronic GVHD was 27.16%, and that of graft failure was 16.2%. Recipient age ≥30 years and transplantation at >6 months after SAA diagnosis were associated with a increased risk of events. In the presence of a fully matched sibling donor, allo-HCT with a mobilized BM graft and fludarabine-cyclophosphamide conditioning is an efficacious and safe approach. Early transplantation is associated with a better outcome, emphasizing the importance of not delaying transplantation in these patients. Prospective trials are needed to determine the optimal regimen.
Topics: Adult; Anemia, Aplastic; Cyclophosphamide; Humans; Prospective Studies; Retrospective Studies; Siblings; Vidarabine
PubMed: 34126277
DOI: 10.1016/j.jtct.2021.06.004 -
Cancer Science Aug 2021To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed... (Clinical Trial)
Clinical Trial
To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).
Topics: Administration, Intravenous; Cell Culture Techniques; Cyclophosphamide; Feasibility Studies; Gene Regulatory Networks; Humans; Immune Checkpoint Inhibitors; Immunotherapy, Adoptive; Interleukin-2; Lymphocytes, Tumor-Infiltrating; Male; Melanoma; Middle Aged; Pilot Projects; Transplantation Conditioning; Treatment Outcome; Vidarabine
PubMed: 34101300
DOI: 10.1111/cas.15009 -
Frontiers in Pharmacology 2021The current pandemic caused by SARS-CoV2 and named COVID-19 urgent the need for novel lead antiviral drugs. Recently, United States Food and Drug Administration (FDA)... (Review)
Review
The current pandemic caused by SARS-CoV2 and named COVID-19 urgent the need for novel lead antiviral drugs. Recently, United States Food and Drug Administration (FDA) approved the use of remdesivir as anti-SARS-CoV-2. Remdesivir is a natural product-inspired nucleoside analogue with significant broad-spectrum antiviral activity. Nucleosides analogues from marine sponge including spongouridine and spongothymidine have been used as lead for the evolutionary synthesis of various antiviral drugs such as vidarabine and cytarabine. Furthermore, the marine sponge is a rich source of compounds with unique activities. Marine sponge produces classes of compounds that can inhibit the viral cysteine protease (M) such as esculetin and ilimaquinone and human serine protease (TMPRSS2) such as pseudotheonamide C and D and aeruginosin 98B. Additionally, sponge-derived compounds such as dihydrogracilin A and avarol showed immunomodulatory activity that can target the cytokines storm. Here, we reviewed the potential use of sponge-derived compounds as promising therapeutics against SARS-CoV-2. Despite the reported antiviral activity of isolated marine metabolites, structural modifications showed the importance in targeting and efficacy. On that basis, we are proposing a novel structure with bifunctional scaffolds and dual pharmacophores that can be superiorly employed in SARS-CoV-2 infection.
PubMed: 34079462
DOI: 10.3389/fphar.2021.666664 -
British Journal of Clinical Pharmacology Jan 2022We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant...
AIMS
We studied melphalan pharmacokinetics (PK) and feasibility of melphalan full-dose adjustment based on test-dose PK in children and young adults with non-malignant disorders (NMD) undergoing allogeneic hematopoietic cell transplantation (HCT) using reduced intensity conditioning (RIC) containing alemtuzumab, fludarabine and melphalan.
METHODS
Patients received test-dose melphalan (10% of planned full-dose) prior to conditioning. Blood samples for PK were obtained around test and full-dose melphalan (140 mg/m or 4.7 mg/kg in patients <10 kg). Melphalan concentration was measured by liquid chromatography electrospray ionization tandem mass-spectrometry assay and data were analysed using a population-PK model and Bayesian estimation. Test and full-dose melphalan clearance estimates were evaluated by pairwise Wilcoxon test and Bland-Altman plot.
RESULTS
Twenty-four patients undergoing 25 transplants were included in the final analysis. Patients received standard full-dose melphalan in 17 transplants, with median area under the concentration-time curve (AUC) of 5.5 mg*h/L (range, 3.0-9.5 mg*h/L). Patients received test-dose melphalan in 23 transplants with a test-dose PK predicted full-dose AUC range of 2.9-16.8 mg*h/L. In seven transplants where patients had baseline organ impairment, test-dose PK predicted higher exposure for standard full-dose (median AUC 13.8 mg*h/L). Melphalan full-dose was adjusted in these patients, with achievement of desired target AUC (3.6-5.4 mg*h/L) and no excess toxicity. Mean ratio of test-dose clearance to full-dose clearance was 1.03. Twenty of 22 patients (91%) were within the 95% confidence intervals of the clearance ratio.
CONCLUSION
Melphalan test-dose PK reliably predicts full-dose PK and allows for accurate adjustment of full-dose melphalan in RIC-HCT for NMD. This approach can avoid excess toxicity from increased systemic exposure, especially in patients with organ impairment.
Topics: Bayes Theorem; Child; Hematopoietic Stem Cell Transplantation; Humans; Melphalan; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult
PubMed: 34075614
DOI: 10.1111/bcp.14932 -
Cellular & Molecular Immunology Jul 2021
Topics: A549 Cells; Angiotensin-Converting Enzyme 2; Antiviral Agents; Binding Sites; COVID-19; Enzyme Induction; HEK293 Cells; HeLa Cells; Humans; Interferon Type I; Phosphorylation; Promoter Regions, Genetic; Receptors, Virus; STAT1 Transcription Factor; Vidarabine; COVID-19 Drug Treatment
PubMed: 34059790
DOI: 10.1038/s41423-021-00698-5 -
Asian Pacific Journal of Cancer... May 2021The side effects of conditioning regimens on the success rate of allogeneic transplantation around the world have been challenging. In this study, we aimed to...
BACKGROUND
The side effects of conditioning regimens on the success rate of allogeneic transplantation around the world have been challenging. In this study, we aimed to investigate the side effect of Bu/Cy and Bu/Flu regimens on our patients who underwent allogeneic bone marrow transplantation.
METHODS
We analyzed 180 patients receiving bone marrow transplantation in Taleghani Hospital, in Tehran, Iran between April 2016 and December 2019. Patients in group A received a combination of intravenous busulfan 0.8 mg/kg QID over two hours for 4 consecutive days (12.8 mg/kg in total)(Savani et al., 2006) and cyclophosphamide 60 mg/kg per day for two consecutive days. Patients in group B received busulfan the same as the first group in combination with fludarabine equal to 40 mg/m² per day. Patients were followed up at regular intervals up to two years after transplantation.
RESULT
Various items were evaluated for patients, including cardiopulmonary function, psychological disorders, GVHD, and endocrine disorders such as hypothyroidism, fertility, or gonad dysfunction. Primary hypothyroidism developed in 13.3% and 11.1% of the Bu/Cy and Bu/Flu groups, respectively (p=0.230). None of the patients in either group experienced infertility or gonad dysfunction. In group A versus group B, pulmonary diseases were detected in 4.4% versus 6.6% of BMT recipients, respectively (p = 0.223). In both groups, mitral and tricuspid regurgitation were observed in patients (8.9% vs. 11.1%; p = 0.189). Incidence of Psychological disorders was no significant difference between the two groups. 32.2% of group A versus 34.45% of group B had skin and liver GVHD, respectively (p = 0.235).
CONCLUSION
The therapeutic-related adverse effects of the two conditioning regimens in patients who underwent allogeneic bone marrow transplant were almost similar. To improve quality of life and overall survival among BMT patients, careful evaluation of treatment-related complications should be part of the regular follow-up of them.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Bone Marrow Transplantation; Busulfan; Combined Modality Therapy; Cyclophosphamide; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Hematologic Neoplasms; Humans; Iran; Male; Middle Aged; Prognosis; Quality of Life; Retrospective Studies; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult
PubMed: 34048196
DOI: 10.31557/APJCP.2021.22.5.1639 -
Transplantation and Cellular Therapy Sep 2021Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients.... (Observational Study)
Observational Study
Higher Fludarabine and Cyclophosphamide Exposures Lead to Worse Outcomes in Reduced-Intensity Conditioning Hematopoietic Cell Transplantation for Adult Hematologic Malignancy.
Reduced-intensity conditioning regimens using fludarabine (Flu) and cyclophosphamide (Cy) have been widely used in hematopoietic cell transplantation (HCT) recipients. The optimal exposure of these agents remains to be determined. We aimed to delineate the exposure-outcome associations of Flu and Cy separately and then both combined on HCT outcomes. This is a single-center, observational, pharmacokinetic (PK)-pharmacodynamic (PD) study of Flu and Cy in HCT recipients age ≥18 years who received Cy (50 mg/kg in a single dose), Flu (150 to 200 mg/m given as 5 daily doses), and total body irradiation (TBI; 200 cGy). We measured trough concentrations of 9-β-D-arabinosyl-2-fluoradenine (F-ara-A), an active metabolite of Flu, on days -5 and -4 (F-ara-A and F-ara-A, respectively), and measured phosphoramide mustard (PM), the final active metabolite of Cy, and estimated the area under the curve (AUC). The 89 enrolled patients had a nonrelapse mortality (NRM) of 9% (95% confidence interval [CI], 3% to 15%) at day +100 and 15% (95% CI, 7% to 22%) at day +180, and an overall survival (OS) of 73% (95% CI, 63% to 81%) at day +180. In multivariate analysis, higher PM area under the curve (AUC) for 0 to 8 hours (PM AUC) was an independent predictor of worse NRM (P < .01 at both day +100 and day +180) and worse day +180 OS (P < .01), but no associations were identified for F-ara-A trough levels. We observed lower day +100 NRM in those with both high F-ara-A trough levels (≥40 ng/mL; >25th percentile) and low PM AUC (<34,235 hr ng/mL; <75th percentile), compared with high exposures to both agents (hazard ratio, 0.06; 95% CI, 0.01 to 0.48). No patients with low F-ara-A (<40 ng/mL; <25th percentile) had NRM by day +100, regardless of PM AUC. The interpatient PK variability was large in F-ara-A trough and PM AUC (29-fold and 5.0-fold, respectively). Flu exposure alone was not strongly associated with NRM or OS in this reduced Flu dose regimen; however, high exposure to both Flu and Cy was associated with a >16-fold higher NRM. These results warrant further investigation to optimize reduced-intensity regimens based on better PK-PD understanding and possible adaptation to predictable factors influencing drug clearance.
Topics: Adolescent; Adult; Cyclophosphamide; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Vidarabine
PubMed: 34044184
DOI: 10.1016/j.jtct.2021.05.013