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Canadian Medical Association Journal May 1985
Topics: Herpes Zoster; Humans; Vidarabine
PubMed: 3995428
DOI: No ID Found -
Journal of Pharmaceutical Sciences Apr 1979A physicochemical procedure for the analysis of vidarabine in aqueous parenteral formulations was needed to assure potency and to define stability. Concurrent with the...
A physicochemical procedure for the analysis of vidarabine in aqueous parenteral formulations was needed to assure potency and to define stability. Concurrent with the development of this method, its decomposition products and route in aqueous solution were determined. A quantitative procedure was developed to determine intact drug in the presence of decomposition products, and the results obtained were validated by microbial assay. Spectral (UV and polarimetric) and TLC evidence indicated that, in aqueous solution, hydrolysis without racemization occurs, yielding adenine and arabinose. The sensitivity of the method to decomposition is improved by ion-exchange separation of adenine and drug before UV measurement. Analysis of partially decomposed solutions of the drug by both ion-exchange and microbiological methods gave comparable results.
Topics: Chromatography, Thin Layer; Drug Stability; Methods; Polarography; Solubility; Solutions; Spectrophotometry, Ultraviolet; Vidarabine
PubMed: 438978
DOI: 10.1002/jps.2600680429 -
Drugs 2003Fludarabine is an antimetabolite antineoplastic agent used in the treatment of various haematological malignancies, particularly B-cell chronic lymphocytic leukaemia... (Review)
Review
Fludarabine is an antimetabolite antineoplastic agent used in the treatment of various haematological malignancies, particularly B-cell chronic lymphocytic leukaemia (CLL). An oral formulation of fludarabine has recently become available in the majority of European countries for the treatment of patients with relapsed or refractory B-cell CLL after initial treatment with an alkylating agent-based regimen. It is the first oral formulation of a purine analogue available for clinical use in B-cell CLL. Pharmacokinetic studies evaluating the bioavailability of oral fludarabine indicate that an oral dose of 40 mg/m2/day would provide similar systemic drug exposure to the standard intravenous dose of 25 mg/m2/day. A phase II study evaluated the clinical efficacy of six to eight cycles of oral fludarabine 40 mg/m2/day for 5 days of each 28-day cycle in 78 patients with previously treated B-cell CLL. Depending on the criteria used, the overall response rate was 46.2% (20.5% complete response [CR], 25.6% partial response [PR]) or 51.3% (17.9% CR, 33.3% PR). These results were similar to the 48% overall response rate reported in a similar historical control group treated with intravenous fludarabine. Myelosuppression (WHO grade 3 or 4) was the most frequently reported adverse effect with oral fludarabine therapy. Other common adverse effects included infection and gastrointestinal disturbances, although these were usually of mild to moderate severity (WHO grade 1 or 2). Overall, the tolerability profile of oral fludarabine is similar to that of the intravenous formulation.
Topics: Administration, Oral; Antineoplastic Agents; Area Under Curve; Biological Availability; Clinical Trials as Topic; Half-Life; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Vidarabine
PubMed: 14524733
DOI: 10.2165/00003495-200363210-00004 -
Gene Therapy Jun 2018Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity....
Adoptive T-cell therapy, incorporating engineered T cell receptors (TCRs) or chimeric antigen receptors (CARs), target tumor antigens with high affinity and specificity. To increase the potency of adoptively transferred T cells, patients are conditioned with lymphodepleting chemotherapy regimens prior to adoptive T-cell transfer (ACT), and data suggest that fludarabine is an important component of an effective regimen. In a recent clinical trial using CAR-T cells engineered to target the CD19 B-cell antigen to treat acute lymphoblastic leukemia, JCAR-015 (NCT02535364), two patient deaths due to cerebral edema led to trial suspension. The lymphodepleting agent fludarabine was suggested as the causative agent, in part due to its known association with neurotoxicity and its ability to induce greater potency. In a similar CAR-T study also incorporating fludarabine in the preconditioning regimen, ZUMA-1 (NCT02348216), one patient died of cerebral edema. However, subsequent deaths in the JCAR-015 study after removal of fludarabine and improved understanding behind the mechanisms of CAR-T-related encephalopathy syndrome (CRES) indicate that fludarabine is not the primary causative agent of cerebral edema and that it can be safely incorporated into the preconditioning regimen for ACT. Since entering clinical use in the late 1980s as a chemotherapy agent, fludarabine and similar analogs have been associated with lethal neurological toxicity, yet the manifestation and timing of symptoms are distinct to those observed recently in ACT. Herein, we review the history of fludarabine development as a chemotherapeutic agent, and discuss the safety of its continued use in preconditioning regimens for ACT.
Topics: Antigens, CD19; Humans; Immunotherapy, Adoptive; Neurotoxicity Syndromes; Receptors, Antigen, T-Cell; T-Lymphocytes; Vidarabine
PubMed: 29789639
DOI: 10.1038/s41434-018-0019-6 -
DICP : the Annals of Pharmacotherapy May 1991The new fluorinated adenine analog, fludarabine, has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are... (Review)
Review
The new fluorinated adenine analog, fludarabine, has been tested for efficacy in many tumor types over the past ten years. Two other similar nucleoside analogs are currently available for commercial use. Cytarabine is used principally as an antileukemic agent, and vidarabine as an antiviral. Unlike vidarabine, fludarabine is resistant to deactivation by adenosine deaminase. Data from Phase I and II trials suggest that fludarabine is potentially effective in a number of leukemias, including acute lymphocytic leukemia, acute nonlymphocytic leukemia, and chronic lymphocytic leukemia (CLL). Unfortunately, the doses required to achieve adequate response in the acute leukemias (greater than 75 mg/m2) were above the maximum tolerated dose, resulting in intolerable granulocytopenia, thrombocytopenia, and a life-threatening neurotoxic syndrome. In CLL: however, the dose required to achieve a satisfactory response is well within tolerated limits. Long-term survival statistics are not yet available, but historical perspective strongly correlates response to other agents with increased survival times. Toxicities seen at dose regimens of 15-40 mg/m2/d for five consecutive days include somnolence, metabolic acidosis, confusion, fatigue, nausea, vomiting, increase in serum creatinine and aminotransferase concentrations, and pulmonary and hepatic abnormalities. Mild to severe hematologic toxicity has been observed at all dose levels.
Topics: Antineoplastic Agents; Clinical Trials as Topic; Drug Evaluation; Humans; Leukemia; Neoplasms; Remission Induction; Vidarabine
PubMed: 2068837
DOI: 10.1177/106002809102500512 -
The Medical Letter on Drugs and... Sep 1991
Topics: Antineoplastic Agents; Clinical Trials as Topic; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Middle Aged; Vidarabine
PubMed: 1886506
DOI: No ID Found -
ACS Chemical Biology Sep 2019Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of...
Nucleoside analogues are widely used in clinical practice as chemotherapy drugs. Arabinose nucleoside derivatives such as fludarabine are effective in the treatment of patients with acute and chronic leukemias and non-Hodgkin's lymphomas. Although nucleoside analogues are generally known to function by inhibiting DNA synthesis in rapidly proliferating cells, the identity of their targets and mechanism of action are often not known in molecular detail. Here we provide a structural basis for arabinose nucleotide-mediated inhibition of human primase, the DNA-dependent RNA polymerase responsible for initiation of DNA synthesis in DNA replication. Our data suggest ways in which the chemical structure of fludarabine could be modified to improve its specificity and affinity toward primase, possibly leading to less toxic and more effective therapeutic agents.
Topics: Adenosine Triphosphate; Antineoplastic Agents; Antiviral Agents; Catalytic Domain; Crystallography, X-Ray; DNA Primase; Enzyme Assays; Humans; Protein Binding; Vidarabine
PubMed: 31479243
DOI: 10.1021/acschembio.9b00367 -
The Journal of Infectious Diseases Oct 1983The pharmacokinetics of vidarabine were studied on 22 occasions in nine infants and three older children with herpesvirus infection. The drug was administered for 10...
The pharmacokinetics of vidarabine were studied on 22 occasions in nine infants and three older children with herpesvirus infection. The drug was administered for 10 days in doses of 15-30 mg/kg per day. Vidarabine was not detected in the serum of any patient, although small quantities were detected in the urine of two of the older children. Peak serum concentrations of arabinosyl hypoxanthine, the major metabolite of vidarabine, ranged from 2.3 to 11.4 micrograms/ml. Concentrations of this metabolite were higher in two preterm infants than in full-term infants receiving comparable doses. The mean elimination half-life estimated from cumulative urinary excretion was 2.4 hr in a preterm infant, 3.1 hr in full-term infants, and 2.8 hr in older children. Neither clearance nor half-life changed when multiple doses were administered. Vidarabine and arabinosyl hypoxanthine did not accumulate during therapy. The rates of recovery of drug from the urine and of renal clearance of arabinosyl hypoxanthine were directly related to the age and maturity of the patient. Arabinosyl hypoxanthine readily diffused into cerebrospinal fluid.
Topics: Arabinonucleosides; Dose-Response Relationship, Drug; Half-Life; Herpesviridae Infections; Humans; Infant; Infant, Newborn; Infant, Premature; Infusions, Parenteral; Kinetics; Time Factors; Vidarabine
PubMed: 6313815
DOI: 10.1093/infdis/148.4.721 -
Archives of Neurology Oct 1977Vidarabine, an antiviral chemotherapeutic agent shown to have in vitro activity against the herpes group of viruses, was administered to five patients with brain...
Vidarabine, an antiviral chemotherapeutic agent shown to have in vitro activity against the herpes group of viruses, was administered to five patients with brain biopsy-proved herpes simplex virus encephalitis. The mortality in this small number of patients (one of five or 20%) was less than that in most published reports of patients receiving other treatment modalities or no treatment other than supportive measures. No apparent toxicity was found that was attributable to vidarabine. Neuropsychological impairment of varying degree was noted in four surviving patients tested at two months after treatment and again 12 to 21 months later. Progressive improvement had occurred in three.
Topics: Adolescent; Adult; Drug Evaluation; Encephalitis; Female; Herpes Simplex; Humans; Male; Middle Aged; Vidarabine
PubMed: 907532
DOI: 10.1001/archneur.1977.00500220042006 -
The New England Journal of Medicine Mar 1983
Topics: Adrenal Cortex Hormones; Herpes Zoster; Humans; Vidarabine
PubMed: 6823274
DOI: No ID Found