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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 -
Cell Death & Disease Feb 2021Animal models are necessary to study cancer and develop treatments. After decades of intensive research, effective treatments are available for only a few types of...
Animal models are necessary to study cancer and develop treatments. After decades of intensive research, effective treatments are available for only a few types of leukemia, while others are currently incurable. Our goal was to generate novel leukemia models in immunocompetent mice. We had achieved abilities for overexpression of multiple driving oncogenes simultaneously in normal primary cells, which can be transplanted and followed in vivo. Our experiments demonstrated the induction of primary malignant growth. Leukemia lines that model various types of leukemia, such as acute myeloid leukemia (AML) or chronic lymphocytic leukemia (CLL), were passaged robustly in congenic wild-type immunocompetent mice. These novel leukemia lines, which may complement previous models, offer the flexibility to generate tailored models of defined oncogenes of interest. The characterization of our leukemia models in immunocompetent animals can uncover the mechanisms of malignancy progression and offer a unique opportunity to stringently test anti-cancer chemotherapies.
Topics: Animals; Antimetabolites, Antineoplastic; Cell Line, Tumor; Cell Proliferation; Cell Transformation, Viral; Gene Expression Regulation, Leukemic; Hematopoietic Stem Cells; Immunocompetence; Lentivirus; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Mice, Inbred C57BL; Mice, Transgenic; Neoplasm Transplantation; Oncogenes; Transplantation, Isogeneic; Vidarabine; Mice
PubMed: 33602907
DOI: 10.1038/s41419-021-03477-2 -
Journal of Korean Medical Science Feb 2020This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease...
Better Failure-Free Survival and Graft-versus-Host Disease-Free/Failure Free Survival with Fludarabine-Based Conditioning in Stem Cell Transplantation for Aplastic Anemia in Children.
BACKGROUND
This study aimed to assess the outcome of stem cell transplantation (SCT), including overall survival (OS), failure-free survival (FFS) and graft-versus-host disease (GvHD)-free/failure-free survival (GFFS), and to analyze prognostic factors in children with aplastic anemia (AA).
METHODS
From 1991 to 2018, 43 allogeneic SCT recipients were enrolled in the study to investigate the demographic characteristics, survival outcomes and prognostic factors.
RESULTS
With the median follow-up of 7.1 years, the estimated 10-year OS, FFS, GFFS were 86.0%, 60.5%, and 51.2%, respectively. Matched related donors (MRD, n = 28) showed better 10-year OS than unrelated donors (n = 15) (96.4% vs. 66.7%; = 0.006). Engraftment failure was seen in 13 patients (30.2%). Donor-type aplasia was seen in 13.8% (4/29) after fludarabine (Flu)-based conditioning (Flu-group), while in 42.6% (6/14) after cyclophosphamide (Cy)-based regimen (Cy-group) ( = 0.035). Six patients died. The 10-year OS in Cy-group was 92.9% (n = 14, all MRD), while that of Flu-group was 82.1% (n = 29; = 0.367). But Flu-group tended to have better FFS and GFFS than Cy-group, although Flu-group had less MRDs (41.4% vs. 100%; = 0.019), and higher proportion of previous immunosuppressive treatment (IST; 62% vs. 21.4%, = 0.012). In MRD transplants, OS was similar between Flu-group (100%, n = 14) and Cy-group (92.9%, n = 14), while FFS (100.0% vs. 42.9%; = 0.001) and GFFS (85.7% vs. 35.7%; = 0.006) were significantly better in Flu-group. Stem cell sources, irradiation in the conditioning, and method of GvHD prophylaxis did not significantly influence the outcome.
CONCLUSION
This study reviewed SCT outcomes for pediatric AA with changes of transplant strategies over the last 25 years. The FFS and GFFS were higher in Flu-group than in Cy-group, especially in matched related transplantation. Graft failure including donor-type aplasia remains troublesome even with Flu-based conditioning. Further refinement of transplant strategies to ensure better quality-of-life should be pursued.
Topics: Adolescent; Anemia, Aplastic; Child; Disease-Free Survival; Enzyme Inhibitors; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Male; Retrospective Studies; Transplantation, Homologous; Vidarabine
PubMed: 32080987
DOI: 10.3346/jkms.2020.35.e46 -
Current Oncology Reports Mar 2020Chronic lymphocytic leukaemia is now recognised as a heterogenous disease with a variety of clinical outcomes. Here we summarise the way it is currently stratified... (Review)
Review
PURPOSE OF REVIEW
Chronic lymphocytic leukaemia is now recognised as a heterogenous disease with a variety of clinical outcomes. Here we summarise the way it is currently stratified according to genetic risk and patient characteristics and the treatment approaches used for these different subgroups.
RECENT FINDINGS
Certain patients appear to sustain MRD negativity after combination chemoimmunotherapy, leading to the suggestion that their CLL may be cured. However, 17p-deleted, p53-mutated or IGHV-UM subgroups are generally resistant to FCR, and much better responses are seen with ibrutinib and venetoclax, frequently inducing MRD negativity that hopefully will be translated into durable remissions. Small molecule inhibitors have already revolutionised CLL treatment. Going forward, we anticipate their use in the majority of patients, early after diagnosis and with curative intent.
Topics: Antineoplastic Combined Chemotherapy Protocols; Chromosome Deletion; Chromosomes, Human, Pair 17; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Mutation; Rituximab; Tumor Suppressor Protein p53; Vidarabine
PubMed: 32172299
DOI: 10.1007/s11912-020-0893-0 -
Molecules (Basel, Switzerland) Mar 2020The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from (UP) and a purine nucleoside...
The bi-enzymatic synthesis of the antiviral drug vidarabine (arabinosyladenine, ara-A), catalyzed by uridine phosphorylase from (UP) and a purine nucleoside phosphorylase from (PNP), was re-designed under continuous-flow conditions. Glyoxyl-agarose and EziG1 (Opal) were used as immobilization carriers for carrying out this preparative biotransformation. Upon setting-up reaction parameters (substrate concentration and molar ratio, temperature, pressure, residence time), 1 g of vidarabine was obtained in 55% isolated yield and >99% purity by simply running the flow reactor for 1 week and then collecting (by filtration) the nucleoside precipitated out of the exiting flow. Taking into account the substrate specificity of UP and PNP, the results obtained pave the way to the use of the UP/PNP-based bioreactor for the preparation of other purine nucleosides.
Topics: Aeromonas hydrophila; Antiviral Agents; Biocatalysis; Bioreactors; Biotransformation; Clostridium perfringens; Enzymes, Immobilized; Glyoxylates; Humans; Protein Engineering; Purine Nucleosides; Purine-Nucleoside Phosphorylase; Sepharose; Substrate Specificity; Vidarabine
PubMed: 32182773
DOI: 10.3390/molecules25051223 -
Blood Cancer Journal Aug 2023
Ibrutinib plus fludarabine, cyclophosphamide and rituximab (iFCR) as initial treatment in chronic lymphocytic leukemia/ small lymphocytic leukemia with or without TP53 aberrations: a prospective real-world study in Chinese cohort.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; East Asian People; Prospective Studies; Cyclophosphamide; Vidarabine; Antineoplastic Combined Chemotherapy Protocols; Tumor Suppressor Protein p53
PubMed: 37558684
DOI: 10.1038/s41408-023-00890-y -
The Journal of Physiological Sciences :... Feb 2022We recently reported a positive relationship between occlusal disharmony and cardiovascular disease via activation of β-adrenergic signaling in mice. Furthermore,...
We recently reported a positive relationship between occlusal disharmony and cardiovascular disease via activation of β-adrenergic signaling in mice. Furthermore, inhibition of type 5 adenylyl cyclase (AC5), a major cardiac subtype in adults, protects the heart against oxidative stress. Here, we examined the role of AC5 in the development of occlusal-disharmony-induced cardiovascular disease in bite-opening (BO) mice, prepared by cementing a suitable appliance onto the mandibular incisor. We first examined the effects of BO treatment on cardiac function in mice treated or not treated for 2 weeks with vidarabine, which we previously identified as an inhibitor of cardiac AC. Cardiac function was significantly decreased in the BO group compared to the control group, but vidarabine ameliorated the dysfunction. Cardiac fibrosis, myocyte apoptosis and myocyte oxidative DNA damage were significantly increased in the BO group, but vidarabine blocked these changes. The BO-induced cardiac dysfunction was associated with increased phospholamban phosphorylation at threonine-17 and serine-16, as well as increased activation of the Ca-calmodulin-dependent protein kinase II/receptor-interacting protein 3 signaling pathway. These data suggest that AC5 inhibition with vidarabine might be a new therapeutic approach for the treatment of cardiovascular disease associated with occlusal disharmony.
Topics: Adenylyl Cyclases; Animals; Apoptosis; Heart; Heart Diseases; Mice; Mice, Knockout; Myocytes, Cardiac; Vidarabine
PubMed: 35148678
DOI: 10.1186/s12576-022-00826-4 -
Computational Biology and Chemistry Jun 2023Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19)...
Nucleoside analogs/derivatives (NAs/NDs) with potent antiviral activities are now deemed very convenient choices for the treatment of coronavirus disease 2019 (COVID-19) arisen by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. At the same time, the appearance of a new strain of SARS-CoV-2, the Omicron variant, necessitates multiplied efforts in fighting COVID-19. Counteracting the crucial SARS-CoV-2 enzymes RNA-dependent RNA polymerase (RdRp) and 3'-to-5' exoribonuclease (ExoN) jointly altogether using the same inhibitor is a quite successful new plan to demultiplicate SARS-CoV-2 particles and eliminate COVID-19 whatever the SARS-CoV-2 subtype is (due to the significant conservation nature of RdRps and ExoNs in the different SARS-CoV-2 strains). Successive in silico screening of known NAs finally disclosed six different promising NAs, which are riboprine/forodesine/tecadenoson/nelarabine/vidarabine/maribavir, respectively, that predictably can act through the planned dual-action mode. Further in vitro evaluations affirmed the anti-SARS-CoV-2/anti-COVID-19 potentials of these NAs, with riboprine and forodesine being at the top. The two NAs are able to effectively antagonize the replication of the new virulent SARS-CoV-2 strains with considerably minute in vitro anti-RdRp and anti-SARS-CoV-2 EC values of 189 and 408 nM for riboprine and 207 and 657 nM for forodesine, respectively, surpassing both remdesivir and the new anti-COVID-19 drug molnupiravir. Furthermore, the favorable structural characteristics of the two molecules qualify them for varied types of isosteric and analogistic chemical derivatization. In one word, the present important outcomes of this comprehensive dual study revealed the anticipating repurposing potentials of some known nucleosides, led by the two NAs riboprine and forodesine, to successfully discontinue the coronaviral-2 polymerase/exoribonuclease interactions with RNA nucleotides in the SARS-CoV-2 Omicron variant (BA.5 sublineage) and accordingly alleviate COVID-19 infections, motivating us to initiate the two drugs' diverse anti-COVID-19 pharmacological evaluations to add both of them betimes in the COVID-19 therapeutic protocols.
Topics: Humans; COVID-19; SARS-CoV-2; Nucleosides; Exoribonucleases; RNA-Dependent RNA Polymerase; Antiviral Agents
PubMed: 36842392
DOI: 10.1016/j.compbiolchem.2022.107768 -
Cancer Discovery Aug 2020Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of...
Myeloid-derived suppressor cells (MDSC) that block antitumor immunity are elevated in glioblastoma (GBM) patient blood and tumors. However, the distinct contributions of monocytic (mMDSC) versus granulocytic (gMDSC) subsets have yet to be determined. In mouse models of GBM, we observed that mMDSCs were enriched in the male tumors, whereas gMDSCs were elevated in the blood of females. Depletion of gMDSCs extended survival only in female mice. Using gene-expression signatures coupled with network medicine analysis, we demonstrated in preclinical models that mMDSCs could be targeted with antiproliferative agents in males, whereas gMDSC function could be inhibited by IL1β blockade in females. Analysis of patient data confirmed that proliferating mMDSCs were predominant in male tumors and that a high gMDSC/IL1β gene signature correlated with poor prognosis in female patients. These findings demonstrate that MDSC subsets differentially drive immune suppression in a sex-specific manner and can be leveraged for therapeutic intervention in GBM. SIGNIFICANCE: Sexual dimorphism at the level of MDSC subset prevalence, localization, and gene-expression profile constitutes a therapeutic opportunity. Our results indicate that chemotherapy can be used to target mMDSCs in males, whereas IL1 pathway inhibitors can provide benefit to females via inhibition of gMDSCs...
Topics: Animals; Antineoplastic Agents; Brain Neoplasms; Cell Line, Tumor; Coculture Techniques; Female; Gene Expression Regulation, Neoplastic; Glioblastoma; Humans; Immunotherapy; Interleukin-1beta; Male; Mice, Inbred C57BL; Mice, Transgenic; Myeloid-Derived Suppressor Cells; Sex Characteristics; T-Lymphocytes; Vidarabine
PubMed: 32300059
DOI: 10.1158/2159-8290.CD-19-1355 -
Journal of Preventive Medicine and... Dec 2019The burden of diarrheal diseases is very high, accounting for 1.7 to 5 billion cases per year worldwide. Typhoid fever (TF) and cholera are potentially life-threatening... (Review)
Review
The burden of diarrheal diseases is very high, accounting for 1.7 to 5 billion cases per year worldwide. Typhoid fever (TF) and cholera are potentially life-threatening infectious diseases, and are mainly transmitted through the consumption of food, drink or water that have been contaminated by the feces or urine of subjects excreting the pathogen. TF is mainly caused by Salmonella typhi, whereas cholera is caused by intestinal infection by the toxin-producing bacterium Vibrio cholerae. These diseases typically affect low- and middle-income countries where housing is overcrowded and water and sanitation are poor, or where conflicts or natural disasters have led to the collapse of the water, sanitation and healthcare systems. Mortality is higher in children under 5 years of age. Regarding their geographical distribution, TF has a high incidence in sub-Saharan Africa, India and south-east Asia, while cholera has a high incidence in a few African countries, particularly in the Horn of Africa and the Arabian Peninsula. In the fight against these diseases, preventive measures are fundamental. With modern air travel, transmissible diseases can spread across continents and oceans in a few days, constituting a threat to global public health. Nowadays, people travel for many reasons, such as tourism and business. Several surveys have shown that a high proportion of travelers lack adequate information on safety issues, such as timely vaccination and prophylactic medications. The main objective of this overview is to provide information to help European travelers to stay healthy while abroad, and thus also to reduce the potential importation of these diseases and their consequent implications for public health and society. The preventive measures to be implemented in the case of travel to countries where these diseases are still endemic are well known: the adoption of safe practices and vaccinations. It is important to stress that an effective preventive strategy should be based both on vaccinations and on hygiene travel guidelines. Furthermore, the emergence of multidrug-resistant strains is becoming a serious problem in the clinical treatment of these diseases. For this reason, vaccination is the main solution.
Topics: Anti-Bacterial Agents; Antineoplastic Combined Chemotherapy Protocols; Azithromycin; Bicarbonates; Cephalosporins; Cholera; Cholera Vaccines; Ciprofloxacin; Drinking Water; Drug Resistance, Bacterial; Endemic Diseases; Epidemics; Europe; Global Burden of Disease; Glucose; Humans; Idarubicin; Potassium Chloride; Prednisone; Ringer's Lactate; Sanitation; Sodium Chloride; Travel; Travel Medicine; Travel-Related Illness; Typhoid Fever; Typhoid-Paratyphoid Vaccines; Vidarabine
PubMed: 31967084
DOI: 10.15167/2421-4248/jpmh2019.60.4.1333