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Clinical Pharmacokinetics 2002In the past decade, fludarabine has had a major impact in increasing the effectiveness of treatment of patients with indolent B-cell malignancies. This has come about in... (Review)
Review
In the past decade, fludarabine has had a major impact in increasing the effectiveness of treatment of patients with indolent B-cell malignancies. This has come about in a variety of clinical circumstances, including use of fludarabine alone as well as in combinations with DNA-damaging agents or membrane-targeted antibodies. Other strategies have used fludarabine to reduce immunological function, thus facilitating non-myeloablative stem cell transplants. Fludarabine is a prodrug that is converted to the free nucleoside 9-beta-D-arabinosyl-2-fluoroadenine (F-ara-A) which enters cells and accumulates mainly as the 5'-triphosphate, F-ara-ATP. The rate-limiting step in the formation of triphosphate is conversion of F-ara-A to its monophosphate, which is catalyzed by deoxycytidine kinase. Although F-ara-A is not a good substrate for this enzyme, the high specific activity of this protein results in efficient phosphorylation of F-ara-A in certain tissues. F-ara-ATP has multiple mechanisms of action, which are mostly directed toward DNA. These include inhibition of ribonucleotide reductase, incorporation into DNA resulting in repression of further DNA polymerisation, and inhibition of DNA ligase and DNA primase. Collectively these actions affect DNA synthesis, which is the major mechanism of F-ara-A-induced cytotoxicity. Secondarily, incorporation into RNA and inhibition of transcription has been shown in cell lines. With the standard dose of fludarabine (25 to 30 mg/m(2)/day given over 30 minutes for 5 days), plasma concentrations of about 3 micromol/L F-ara-A are achieved at the end of each infusion. Serial sampling of leukaemia cells from patients receiving these standard doses of fludarabine has demonstrated that the peak concentrations of F-ara-ATP are achieved 4 hours after start of fludarabine infusion. Although there is heterogeneity among individuals with respect to rate of F-ara-ATP accumulation, the peak concentrations are generally proportional to the dose of the drug. Knowledge of the plasma pharmacokinetics of its principal nucleoside metabolite F-ara-A, and the cellular pharmacology of the proximal active metabolite, F-ara-ATP, has provided some understanding of the activity of fludarabine when used as a single agent. Preclinical studies directed toward learning the mechanisms of action of this agent have formed the basis for several mechanism-based strategies for its combination and scheduling with other agents. As a single agent fludarabine has been effective for the indolent leukaemias. Biochemical modulation strategies resulted in enhanced accumulation of cytarabine triphosphate and led to the use of fludarabine for the treatment of acute leukaemias. Combination of fludarabine with DNA damaging agents to inhibit DNA repair processes has been highly effective for indolent leukaemias and lymphomas. The current review brings together knowledge of the mechanisms of fludarabine, the state of understanding of the plasma pharmacokinetics, and cellular pharmacodynamics of fludarabine nucleotides. This may be useful in the design of future therapeutic approaches.
Topics: Antineoplastic Agents; Biological Availability; DNA (Cytosine-5-)-Methyltransferases; Deoxycytidine Kinase; Drug Evaluation, Preclinical; Humans; Leukemia; Lymphoma; Phosphorylation; Vidarabine; Vidarabine Phosphate
PubMed: 11888330
DOI: 10.2165/00003088-200241020-00002 -
Hematology. American Society of... 2011Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem... (Review)
Review
Despite the widespread use of highly effective chemoimmunotherapy (CIT), fludarabine-refractory chronic lymphocytic leukemia (CLL) remains a challenging clinical problem associated with poor overall survival (OS). The traditional definition, which includes those patients with no response or relapse within 6 months of fludarabine, is evolving with the recognition that even patients with longer remissions of up to several years after CIT have poor subsequent treatment response and survival. Approved therapeutic options for these patients remain limited, and the goal of therapy for physically fit patients is often to achieve adequate cytoreduction to proceed to allogeneic stem cell transplantation (alloSCT). Fortunately, several novel targeted therapeutics in clinical trials hold promise of significant benefit for this patient population. This review discusses the activity of available and novel therapeutics in fludarabine-refractory or fludarabine-resistant CLL as well as recently updated data on alloSCT in CLL.
Topics: Antineoplastic Agents; Drug Resistance, Neoplasm; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Recurrence; Vidarabine
PubMed: 22160021
DOI: 10.1182/asheducation-2011.1.110 -
Biology of Blood and Marrow... Mar 2011Toxic leukoencephalopathy has been more thoroughly investigated during the last decade because of the advance of magnetic resonance imaging (MRI) techniques. We analyzed... (Comparative Study)
Comparative Study Review
Toxic leukoencephalopathy has been more thoroughly investigated during the last decade because of the advance of magnetic resonance imaging (MRI) techniques. We analyzed fludarabine (Flu)-associated hematopoietic cell transplantation (HCT), resulting in severe leukoencephalopathy (n = 39/1596, 2.4%), and describe 3 clinical syndromes with unique clinical and radiographic characteristics. Posterior reversible encephalopathy syndrome (PRES) presents predominantly with seizures, persistent headache, and vision changes, along with variable mental status alterations. PRES is likely to be reversible, particularly after withholding cyclosporine (CsA). Acute toxic leukoencephalopathy (ATL) presents with cognitive dysfunction, decreased levels of consciousness, and vision changes. Other leukoencephalopathy (OLE) includes patients who behave similar to the ATL group, but with less prominent deep white matter changes on MRI. ATL and OLE are less likely to be reversible. The neurologic syndromes correlate with different MRI patterns. In PRES, subcortical and cortical involvement on MRI is associated with seizure, blurred vision, and dysarthria versus ATL and OLE, which involve deep white matter and cause mainly cognitive dysfunction. The different syndromes also carry different prognoses. All patients with Flu-associated encephalopathy had a median overall survival of only 169 days. Those with ATL had shorter overall survival (median 66 days) than patients with PRES (median 208 days). Potential risk factors for Flu-associated encephalopathy were older age, poor renal function, Flu dose, previously treated central nervous system (CNS) disease, or previous Flu-based transplant conditioning. Additional risk factors for PRES CNS toxicity are CsA use and acute hypertension. Flu pharmacokinetic studies may be useful to reduce life-threatening Flu-associated risks of neurotoxicity.
Topics: Antineoplastic Agents; Hematopoietic Stem Cell Transplantation; Humans; Leukoencephalopathies; Posterior Leukoencephalopathy Syndrome; Prodrugs; Vidarabine
PubMed: 20399878
DOI: 10.1016/j.bbmt.2010.04.003 -
Leukemia Research Sep 2013Fludarabine successfully treats chronic lymphocytic leukemia (CLL); however, its use may lead to significant myelosuppression and other toxicities. This article weighs... (Review)
Review
BACKGROUND
Fludarabine successfully treats chronic lymphocytic leukemia (CLL); however, its use may lead to significant myelosuppression and other toxicities. This article weighs the benefits against potential harms, highlighting strategies for appropriate patient selection and administration.
METHODS
Relevant studies were identified upon literature review, which were combined with our clinical and institutional experience.
RESULTS
Fludarabine-based regimens result in an overall response rate of approximately 95% and of untreated CLL patients. Fludarabine also causes potentially irreversible grade 3 or 4 cytopenias and infection in the majority of patients. Furthermore, future hematopoietic cell mobilization may be difficult and secondary myelodysplastic syndrome and leukemia occur in at least 3% of patients.
CONCLUSION
Fludarabine should be used judiciously in older patients, and avoided entirely in patients with renal insufficiency. Close monitoring of blood cell counts with appropriate dose reduction/omission is vital. Finally, alternatives such as pentostatin and bendamustine should be considered.
Topics: Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myeloid, Acute; Myelodysplastic Syndromes; Prognosis; Vidarabine
PubMed: 23787174
DOI: 10.1016/j.leukres.2013.05.004 -
The New England Journal of Medicine Apr 1979
Topics: Child; Encephalitis; Herpes Simplex; Humans; Vidarabine
PubMed: 423915
DOI: 10.1056/nejm197904053001415 -
Drugs 1994An understanding of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, knowledge of... (Review)
Review
An understanding of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, knowledge of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as arabinosylcytosine, arabinosyladenine, and fludarabine are prodrugs that must enter cells and be phosphorylated to the respective triphosphates before they can elicit biological activity. DNA synthesis is the major metabolic target for this class of compounds. Common to members of the arabinosyl nucleoside class is the finding in experimental systems of a relationship between incorporation of each drug into DNA and the loss of clonogenicity. Although additional inhibitory mechanisms have been identified, they all require formation of the respective triphosphate. Thus, knowledge of the pharmacokinetics of the triphosphates in target cells and an understanding of the mechanisms by which these active forms of arabinosyl nucleosides kill cells are indispensable to the rational design of treatment protocols. This article considers the clinical development of arabinosyl nucleosides with respect to investigations of their pharmacokinetics and mechanisms of action. An understanding of these elements of arabinosyl nucleoside metabolism should provide a rationale for combinations with other chemotherapeutic agents and anticancer modalities.
Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Biological Availability; Cytarabine; Humans; Leukemia; Vidarabine
PubMed: 7525187
DOI: 10.2165/00003495-199400476-00006 -
Annals of the New York Academy of... Mar 1977
Topics: Adenosine Deaminase Inhibitors; Animals; Blood Proteins; Drug Interactions; Erythrocytes; Humans; In Vitro Techniques; Kinetics; Male; Nucleoside Deaminases; Protein Binding; Rats; Tissue Distribution; Vidarabine
PubMed: 280160
DOI: 10.1111/j.1749-6632.1977.tb21932.x -
Archives of Ophthalmology (Chicago,... Mar 1986Intravitreal injections of the antiviral drug vidarabine in doses of 10, 50, 100, and 200 micrograms dissolved in 100% dimethyl sulfoxide (DMSO) were administered to the...
Intravitreal injections of the antiviral drug vidarabine in doses of 10, 50, 100, and 200 micrograms dissolved in 100% dimethyl sulfoxide (DMSO) were administered to the eyes of 12 Dutch and New Zealand pigmented rabbits to determine ocular toxicity. The eyes were examined one week, one month, and two months after inoculation with slit-lamp biomicroscopy, indirect ophthalmoscopy, electroretinography, and histopathologic examination with light and electron microscopy. No permanent damage to ocular tissue was found at a vidarabine concentration of 100 micrograms/mL. The antiviral activity and the toxicity of the vidarabine dissolved in DMSO were tested in vitro on herpes simplex virus type 1-infected rabbit corneal fibroblast monolayers. Vidarabine dissolved in DMSO was found to possess in vitro antiviral activity against herpes simplex virus type 1. Our results suggest that the intravitreal administration of vidarabine dissolved in DMSO may be a safe and effective means of drug therapy.
Topics: Animals; Cells, Cultured; Dimethyl Sulfoxide; Eye; Female; Keratitis, Dendritic; Male; Rabbits; Solubility; Vidarabine; Vitreous Body
PubMed: 3954645
DOI: 10.1001/archopht.1986.01050150128043 -
Seminars in Oncology Oct 1993Knowledge of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, an understanding of... (Review)
Review
Knowledge of the pharmacokinetics of a drug is essential to the optimal design of the dose and schedule of chemotherapy protocols. As an extension, an understanding of the mechanism of drug action is necessary to construct the optimal strategy for combination chemotherapy. Nucleoside antimetabolites such as fludarabine are pro-drugs that must enter cells and be phosphorylated to the nucleoside triphosphate before they can elicit biologic activity. Thus, knowledge of the pharmacokinetics of the triphosphate in target cells and an understanding of the mechanisms by which this active form of the drug act are indispensable to the rational design of treatment protocols. This article reviews the essential elements of the pharmacokinetics and mechanisms of action of fludarabine to provide a rationale for combinations of fludarabine with other chemotherapeutic agents and anti-cancer modalities.
Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Humans; Neoplasms; Vidarabine
PubMed: 8235690
DOI: No ID Found -
The Journal of Infectious Diseases May 1984Acyclovir and vidarabine exerted a less-than-additive effect on the replication of herpes simplex virus type 1 (HSV-1) in green monkey kidney cells. The synthesis of...
Acyclovir and vidarabine exerted a less-than-additive effect on the replication of herpes simplex virus type 1 (HSV-1) in green monkey kidney cells. The synthesis of viral DNA was reduced much more (97%) than that of cellular DNA (45%) by combined acyclovir and vidarabine in cell culture. Furthermore, the combined drugs, given topically or systemically, were more effective than the individual drugs in diminishing the development of clinical signs of HSV-1 infection in hairless mice. However, mortality among animals given topical acyclovir plus vidarabine was not significantly lower than that among animals given topical acyclovir only. Systemic acyclovir (50 mg/kg per day) plus vidarabine (100 mg/kg per day), given for five consecutive days starting 24 hr after viral inoculation, significantly reduced the frequency of development of latent HSV-1 infection in the trigeminal ganglia of mice, whereas systemic acyclovir or vidarabine alone did not.
Topics: Acyclovir; Animals; Cell Line; Chlorocebus aethiops; DNA; DNA, Viral; Drug Therapy, Combination; Face; Herpes Simplex; Mice; Simplexvirus; Trigeminal Ganglion; Vidarabine; Virus Replication
PubMed: 6327850
DOI: 10.1093/infdis/149.5.757