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Journal of Pharmaceutical Sciences Nov 1979A physical model approach to the topical delivery of a vidarabine ester prodrug was investigated. It involved modeling, theoretical simulations, experimental method...
A physical model approach to the topical delivery of a vidarabine ester prodrug was investigated. It involved modeling, theoretical simulations, experimental method development for factoring and quantifying parameters, and, finally, employment of the deduced parameters to determine the steady-state species fluxes and concentration profiles in the target tissue. The present report describes the physical modeling and theoretical simulation aspects. The physical model for the simultaneous transport and bioconversion of a topically delivered prodrug was formulated assuming homogeneous enzyme distributions and constant diffusivities in the membrane. The mathematical problem was solved, and the solution yielded concentration profiles and fluxes of all species in the biomembrane. These results provided the prevailing levels of the prodrug, the drug, and the metabolite at the target site and the transport rates of all species into the bloodstream. Computations of concentration profiles and fluxes were carried out for a reasonable range of the parameters. The relative activities of the esterase and the deaminase enzymes, as well as the stratum corneum permeabilities, were important in influencing the concentration profiles and fluxes of all species.
Topics: Administration, Topical; Animals; Biological Transport; In Vitro Techniques; Mathematics; Mice; Mice, Nude; Models, Biological; Skin; Skin Absorption; Valerates; Vidarabine
PubMed: 512880
DOI: 10.1002/jps.2600681104 -
Biology of Blood and Marrow... Dec 2017
Topics: Adult; Female; Hematopoietic Stem Cell Transplantation; Humans; Male; Precision Medicine; Survival Analysis; Transplantation Conditioning; Vidarabine
PubMed: 29032061
DOI: 10.1016/j.bbmt.2017.10.005 -
Annals of Oncology : Official Journal... 1994Fludarabine monophosphate (fludarabine) is an adenine nucleoside analogue active in indolent lymphoproliferative diseases which has an increasing role in studies... (Review)
Review
BACKGROUND
Fludarabine monophosphate (fludarabine) is an adenine nucleoside analogue active in indolent lymphoproliferative diseases which has an increasing role in studies incorporating combinations of agents which exploit biochemical modulation, inhibition of DNA repair, and radiosensitizing effects.
PATIENTS AND METHODS
Patients with lymphoma and chronic lymphocytic leukemia (CLL) treated at the M. D. Anderson Cancer Center (MDACC) and reports in the literature form the basis of this report.
RESULTS
CLL has traditionally been treated with alkylating agents and corticosteroids. In this study, fludarabine has shown marked cytoreductive ability in both previously treated patients and untreated patients. In the former group, there has been a 55% response rate in 374 patients, and 79% in the untreated CLL group. Fludarabine has also been very active in the management of low-grade lymphomas, with two-thirds of patients with follicular lymphoma and half of those with other indolent lymphomas responding. Waldenstrom's macroglobulinemia is also sensitive to the effects of fludarabine. Combination regimens were developed incorporating the substantial effectiveness of fludarabine and mitoxantrone where in the previously treated low-grade lymphoma group 25 of 28 patients (89%) responded. Fludarabine has the effect of increasing the triphosphate form of cytosine arabinoside in acute and chronic leukemic cells. This modulation has now been translated into therapy for acute leukemia and combined with cisplatinum in refractory CLL. Fludarabine inhibits DNA repair and enhances cross-linking of DNA by cisplatinum. The combination of fludarabine, ara-C, and cis-platinum is now being used in refractory CLL. Fludarabine is a radiation sensitizer, inhibiting repair of DNA damage. Studies are ongoing with this combination.
CONCLUSIONS
Fludarabine is a potent molecule with a wide range of biochemical effects. Optimal use of this drug alone and in combination is continuing to be explored.
Topics: Adrenal Cortex Hormones; Alkylating Agents; Antineoplastic Combined Chemotherapy Protocols; Clinical Trials as Topic; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Drug Screening Assays, Antitumor; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma; Molecular Structure; Multicenter Studies as Topic; Radiation-Sensitizing Agents; Remission Induction; Tumor Cells, Cultured; Vidarabine; Waldenstrom Macroglobulinemia
PubMed: 8204523
DOI: 10.1093/annonc/5.suppl_2.s79 -
Blood Oct 1995
Review
Topics: Antineoplastic Agents; Cladribine; Clinical Trials as Topic; Drug Resistance; Humans; Lymphoproliferative Disorders; Pentostatin; Purine Nucleosides; Vidarabine
PubMed: 7670093
DOI: No ID Found -
Cancer Treatment Reviews Jun 2005
Comparative Study Meta-Analysis Review
Topics: Antineoplastic Agents; Antineoplastic Agents, Alkylating; Disease Progression; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Randomized Controlled Trials as Topic; Survival Analysis; Treatment Outcome; Vidarabine
PubMed: 15894429
DOI: 10.1016/j.ctrv.2005.04.002 -
Chemotherapy 19909 beta-D-Arabinofuranosyladenine (adenine arabinoside, vidarabine, ara-A), is employed as an antiviral compound mainly against herpes virus infections. Toxicity of ara-A...
9 beta-D-Arabinofuranosyladenine (adenine arabinoside, vidarabine, ara-A), is employed as an antiviral compound mainly against herpes virus infections. Toxicity of ara-A is of concern in clinical applications. This work reports quantitative changes of bone marrow hemopoietic progenitors in mice treated with ara-A. The experimental model is based on time survival curves following repeated intraperitoneal injections (200, 400 or 800 mg/kg twice a day for 4 days) of different doses of the drug. Our results show that ara-A causes damage to the hemopoietic progenitors. The induced damage is roughly proportional to the injected amount of the drug. Following termination of ara-A administration all tested populations rapidly recovered.
Topics: Animals; Bone Marrow Examination; Bone Marrow Transplantation; Female; Hematopoietic Stem Cells; Injections, Intraperitoneal; Leukocyte Count; Male; Mice; Mice, Inbred DBA; Time Factors; Vidarabine
PubMed: 2338032
DOI: 10.1159/000238772 -
Journal of Molecular Neuroscience : MN Feb 2015Cerebral ischemic injury involves a variety of cellular and molecular events. Signal transducers and activators of transcription-1 (STAT-1) activation is associated with...
Cerebral ischemic injury involves a variety of cellular and molecular events. Signal transducers and activators of transcription-1 (STAT-1) activation is associated with neuronal cell death and contributes to ischemic injury. The effects of fludarabine, a specific inhibitor of STAT1 protein, on cerebral ischemic/reperfusion (I/R) injury were studied in a rat model. Rats subjected to I/R injury were either treated with intra-cerebroventricular injection of fludarabine (5,000 μM, 10 μl) or saline 20 min before middle cerebral artery occlusion (MCAO). MR examinations including T2-weighted imaging (T2WI), diffusion-weighted imaging (DWI), and perfusion-weighted imaging (PWI) were performed after I/R period. Then rat brains were sectioned for triphenyltetrazolium chloride (TTC) stains, analyzed by Western blot and TUNEL staining of apoptosis. It was found that fludarabine treatment decreased the infarct volume of the cerebrum and the number of apoptotic neural cells in the ischemic brain. Compared to saline-treated group, the apparent diffusion coefficient (ADC) and cerebral blood volume (CBV) in the ischemic region were greater, and the mean transit time (MTT) was shortened in the fludarabine-treated group. Moreover, fludarabine inhibited the expression level of phosphorylated STAT1 (P-STAT1) in neural cells after I/R injury, whereas the expression of phosphorylated STAT3 (P-STAT3) was increased. Therefore, we concluded that fludarabine administrated in early stage of cerebral ischemia had neuroprotective effects, and the underlying mechanism could be mediated through inhibiting STAT1 phosphorylation and activating the cross regulation between STAT1 and STAT3 in neural cells.
Topics: Animals; Apoptosis; Brain; Infarction, Middle Cerebral Artery; Male; Phosphorylation; Rats; Rats, Sprague-Dawley; STAT1 Transcription Factor; STAT3 Transcription Factor; Vidarabine
PubMed: 24825839
DOI: 10.1007/s12031-014-0320-9 -
Clinical Lymphoma, Myeloma & Leukemia Oct 2021
Efficacy and Safety of Azacytidine in Combination With Fludarabine and High-Dose Cytarabine With G-CSF (FLAG) in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study.
Topics: Adolescent; Adult; Female; Humans; Male; Middle Aged; Young Adult; Azacitidine; Cytarabine; Granulocyte Colony-Stimulating Factor; Leukemia, Myeloid, Acute; Vidarabine
PubMed: 34417161
DOI: 10.1016/j.clml.2021.07.019 -
Bone Marrow Transplantation Aug 2022In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher...
Comparison of fludarabine-melphalan and fludarabine-treosulfan as conditioning prior to allogeneic hematopoietic cell transplantation-a registry study on behalf of the EBMT Acute Leukemia Working Party.
In recent years considerable variations in conditioning protocols for allogeneic hematopoietic cell transplantation (allo-HCT) protocols have been introduced for higher efficacy, lower toxicity, and better outcomes. To overcome the limitations of the classical definition of reduced intensity and myeloablative conditioning, a transplantation conditioning intensity (TCI) score had been developed. In this study, we compared outcome after two frequently used single alkylator-based conditioning protocols from the intermediate TCI score category, fludarabine/melphalan 140 mg/m (FluMel) and fludarabine/treosulfan 42 g/m (FluTreo) for patients with acute myeloid leukemia (AML) in complete remission (CR). This retrospective analysis from the registry of the Acute Leukemia Working Party (ALWP) of the European Society of Bone Marrow Transplantation (EBMT) database included 1427 adult patients (median age 58.2 years) receiving either Flu/Mel (n = 1005) or Flu/Treo (n = 422). Both groups showed similar 3-year overall survival (OS) (54% vs 51.2%, p value 0.49) for patients conditioned with FluMel and FluTreo, respectively. However, patients treated with FluMel showed a reduced 3-year relapse incidence (32.4% vs. 40.4%, p value < 0.001) and slightly increased non-relapse mortality (NRM) (25.7% vs. 20.2%, p value = 0.06) compared to patients treated with FluTreo. Our data may serve as a basis for further studies examining the role of additional agents/ intensifications in conditioning prior to allo-HCT.
Topics: Acute Disease; Adult; Bone Marrow Transplantation; Busulfan; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid, Acute; Melphalan; Middle Aged; Registries; Retrospective Studies; Transplantation Conditioning; Vidarabine
PubMed: 35568756
DOI: 10.1038/s41409-022-01646-1 -
Biology of Blood and Marrow... Sep 2013
Topics: Antineoplastic Agents; Female; HLA Antigens; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation Conditioning; Vidarabine; Whole-Body Irradiation
PubMed: 23892048
DOI: 10.1016/j.bbmt.2013.07.011