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Journal of Neurology, Neurosurgery, and... Dec 1984Vidarabine (adenine arabinoside, ara-a) has been found to be useful in the treatment of various viral infections. Its adverse neurological effects include tremor and...
Vidarabine (adenine arabinoside, ara-a) has been found to be useful in the treatment of various viral infections. Its adverse neurological effects include tremor and encephalopathy. Two cases of vidarabine encephalopathy are reported and the five other cases in the literature are reviewed. The clinical features of the tremor and encephalopathy are discussed.
Topics: Adult; Electroencephalography; Evoked Potentials; Female; Herpes Zoster; Humans; Male; Middle Aged; Substance-Related Disorders; Tremor; Vidarabine
PubMed: 6512557
DOI: 10.1136/jnnp.47.12.1351 -
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 -
Blood Jun 2017Autoimmune hemolytic anemia (AIHA) is an uncommon entity that presents diagnostic, prognostic, and therapeutic dilemmas despite being a well-recognized entity for over... (Review)
Review
Autoimmune hemolytic anemia (AIHA) is an uncommon entity that presents diagnostic, prognostic, and therapeutic dilemmas despite being a well-recognized entity for over 150 years. This is because of significant differences in the rates of hemolysis and associated diseases and because there is considerable clinical heterogeneity. In addition, there is a lack of clinical trials required to refine and update standardized and evidence-based therapeutic approaches. To aid the clinician in AIHA management, we present four vignettes that represent and highlight distinct clinical presentations with separate diagnostic and therapeutic pathways that we use in our clinical practice setting. We also review the parameters present in diagnostic testing that allow for prognostic insight and present algorithms for both diagnosis and treatment of the AIHA patient in diverse situations. This is done in the hope that this review may offer guidance in regard to personalized therapy recommendations. A section is included for the diagnosis of suspected AIHA with negative test results, a relatively infrequent but challenging situation, in order to assist in the overall evaluation spectrum for these patients.
Topics: Aged; Algorithms; Anemia, Hemolytic, Autoimmune; Coombs Test; Erythrocyte Transfusion; Female; Glucocorticoids; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Male; Middle Aged; Rituximab; Serologic Tests; Splenectomy; Vidarabine
PubMed: 28360039
DOI: 10.1182/blood-2016-11-693689 -
The Cochrane Database of Systematic... Jul 2006Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Recent trials suggest improved response rates for purine antagonists compared to alkylator-based regimens in the treatment of B-CLL. However, none was able to show a survival advantage.
OBJECTIVES
To determine if there is any advantage of purine antagonists compared to alkylating agents (alone or in combination) in the treatment of patients with previously untreated B-CLL.
SEARCH STRATEGY
Medical databases (Cochrane Library, MEDLINE, EMBASE), conference proceedings and internet-based trial registers were searched electronically and/or by hand (1990-2003). All references were checked for further trial information. We also contacted experts in the field and pharmaceutical companies.
SELECTION CRITERIA
Randomised controlled trials comparing purine antagonists as single agents with alkylator-based regimens in patients with previously untreated B-CLL were included. We included full-text and abstract publications as well as unpublished data.
DATA COLLECTION AND ANALYSIS
Data extraction and quality assessment were done in duplicate by two independent reviewers. Missing data were obtained from original authors. Endpoints included overall survival, overall response rate, rate of complete remissions, progression-free survival, treatment-related morbidity and mortality.
MAIN RESULTS
Five trials with 1838 randomised patients were included. There is some evidence for improved overall survival after treatment with purine antagonists compared to alkylators, but statistical significance was not reached (HR 0.89 [95% CI 0.78-1.01], 4 trials, n=1638). However, the relative risk for achieving an overall response (RR 1.22 [95% CI 1.13-1.31], 5 trials, n=1751) and complete remission (RR 1.94 [95% CI 1.65-2.28], 5 trials, n=1751) was significantly higher, resulting in a longer progression-free survival (HR 0.70 [95% CI 0.61-0.82], 4 trials, n=1638). Incidence of grade III/IV infections was significantly higher in patients receiving treatment with purine antagonists (RR 1.83 [95% 1.30-2.58], 4 trials, n=1620). There was no significant difference concerning the relative risk for grade III/IV neutropenia (RR 1.14 [95% CI 0.98-1.34], 4 trials, n=1620) and therapy-related mortality (RR 0.94 [95% CI 0.45-1.95]). Overall incidence of hemolytic anemia was low, but significantly increased in the purine antagonist group (RR 3.36 [95% CI 1.27-8.91], 3 trials, n=1258).
AUTHORS' CONCLUSIONS
Despite significantly increased overall response and complete remission rates and longer progression-free survival with first-line treatment of B-CLL patients with single-agent purine antagonists, we were not able to detect a statistically significant improvement of overall survival compared to alkylator-based regimens. Furthermore, the use of purine antagonists also augments the risk for grade III/IV infections and hemolytic anemia.
Topics: Antineoplastic Agents; Chlorambucil; Cladribine; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Pentostatin; Randomized Controlled Trials as Topic; Vidarabine
PubMed: 16856041
DOI: 10.1002/14651858.CD004270.pub2 -
Journal of Hematology & Oncology Jul 2009Advances in the treatment of chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free... (Review)
Review
Advances in the treatment of chronic lymphocytic leukemia (CLL) have improved initial overall response (OR) rates, complete response (CR) rates and progression free survival (PFS). Despite these advances, CLL remains incurable with standard therapies. Thus, there remains a need for more effective therapies in both the upfront and relapsed setting, particularly for patients with high-risk cytogenetic abnormalities such as del(11q22) and del(17p13). The 2008 American Society of Hematology (ASH) Annual Meeting featured several presentations which highlighted the ongoing clinical advances in CLL. The benefit of adding rituximab to purine analog therapy in the upfront setting was demonstrated by a large randomized study which showed that the addition of rituximab to fludarabine and cyclophosphamide (FCR) significantly improved OR, CR and PFS. The improvement in PFS directly resulted from an improved ability to eliminate minimal residual disease (MRD) in the peripheral blood, highlighting the importance of MRD eradication. However, a multi-center study suggested that the high CR rates to chemoimmunotherapy regimens such as FCR obtained in academic centers may not be reproducible when the same regimens are given in the community setting. The immunomodulatory drug lenalidomide is active in relapsed high-risk CLL, but two studies of lenalidomide in previously untreated CLL patients failed to achieve a CR and were associated with significant tumor lysis, tumor flare and hematologic toxicity. In the relapsed setting, a combination study of the bifunctional alkylator bendamustine and rituximab (BR) demonstrated a high OR rate in patients with del(11q22) and del(17p13), indicating that further studies to define's bendamustine activity are warranted in high-risk CLL. Similarly, the CDK inhibitor flavopiridol demonstrated significant clinical activity and durable remissions in heavily treated, refractory CLL patients with high-risk cytogenetic features and bulky lymphadenopathy. The monoclonal anti-CD20 antibody ofatumumab appeared to be superior to rituximab in relapsed CLL patients with bulky nodal disease or high-risk cytogenetic features. Ongoing studies of these agents and other novel therapeutic agents in clinical development hold forth the promise that treatment options for CLL patients will continue to expand and improve.
Topics: Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Congresses as Topic; Humans; Immunotherapy; Leukemia, Lymphocytic, Chronic, B-Cell; Medical Oncology; Patient Selection; Vidarabine
PubMed: 19619273
DOI: 10.1186/1756-8722-2-29 -
Cancer Jul 2009The development of resistance to purine analogs defines a poor-risk subset of patients with chronic lymphocytic leukemia (CLL). Although in recent years... (Review)
Review
The development of resistance to purine analogs defines a poor-risk subset of patients with chronic lymphocytic leukemia (CLL). Although in recent years chemoimmunotherapeutic combinations such as fludarabine, cyclophosphamide, and rituximab have induced response rates of 95% in previously untreated patients and increased the rates of failure-free survival, CLL remains incurable for many patients because of a lack of disease response or the development of refractoriness to fludarabine. Fludarabine-refractory disease is defined as CLL that does not respond to fludarabine or that recurs within 6 months of treatment with a fludarabine-containing regimen. The natural course of the disease is associated with poor survival. Salvage therapeutic strategies include alemtuzumab-containing regimens, targeted agents, and allogeneic stem cell transplantation. Single-agent alemtuzumab induces response in up to 40% of patients with fludarabine-refractory CLL, but responses are not durable, and the median survival is approximately 1 to 2 years. Alemtuzumab is also combined with fludarabine, cyclophosphamide, and/or rituximab, and other agents such as lenalidomide and flavopiridol, as well as targeted agents, and used in fludarabine-refractory CLL. Cumulative evidence suggests that allogeneic stem cell transplantation is an efficacious therapeutic strategy for patients who do not respond to fludarabine or who develop disease recurrence within 12 months after purine analog treatment. In conclusion, chemoimmunotherapy regimens that include alemtuzumab and/or rituximab and allogeneic stem cell transplantation improve the prognosis of this disease, but there is a continued need for novel, more effective therapies.
Topics: Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antineoplastic Combined Chemotherapy Protocols; Drug Resistance, Neoplasm; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Salvage Therapy; Stem Cell Transplantation; Vidarabine
PubMed: 19402170
DOI: 10.1002/cncr.24329 -
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 -
Marine Drugs Oct 2010Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often... (Review)
Review
Marine sponges are currently one of the richest sources of pharmacologically active compounds found in the marine environment. These bioactive molecules are often secondary metabolites, whose main function is to enable and/or modulate cellular communication and defense. They are usually produced by functional enzyme clusters in sponges and/or their associated symbiotic microorganisms. Natural product lead compounds from sponges have often been found to be promising pharmaceutical agents. Several of them have successfully been approved as antiviral agents for clinical use or have been advanced to the late stages of clinical trials. Most of these drugs are used for the treatment of human immunodeficiency virus (HIV) and herpes simplex virus (HSV). The most important antiviral lead of marine origin reported thus far is nucleoside Ara-A (vidarabine) isolated from sponge Tethya crypta. It inhibits viral DNA polymerase and DNA synthesis of herpes, vaccinica and varicella zoster viruses. However due to the discovery of new types of viruses and emergence of drug resistant strains, it is necessary to develop new antiviral lead compounds continuously. Several sponge derived antiviral lead compounds which are hoped to be developed as future drugs are discussed in this review. Supply problems are usually the major bottleneck to the development of these compounds as drugs during clinical trials. However advances in the field of metagenomics and high throughput microbial cultivation has raised the possibility that these techniques could lead to the cost-effective large scale production of such compounds. Perspectives on biotechnological methods with respect to marine drug development are also discussed.
Topics: Animals; Antiviral Agents; Aquatic Organisms; Biotechnology; Drug Discovery; HIV Infections; Herpes Simplex; Humans; Metagenomics; Porifera; Simplexvirus; Symbiosis; Vidarabine
PubMed: 21116410
DOI: 10.3390/md8102619 -
Medical Sciences (Basel, Switzerland) Mar 2022Autophagy is a known mechanism of cells under internal stress that regulates cellular function via internal protein recycling and the cleaning up of debris, leading to...
Autophagy is a known mechanism of cells under internal stress that regulates cellular function via internal protein recycling and the cleaning up of debris, leading to healthy live cells. However, the stimulation of autophagy by external factors such as chemical compounds or viral infection mostly tends to induce apoptosis/cell death. This study hypothesizes that manipulation of the autophagy mechanism to the pro-cell survival and/or decreased pro-viral niche can be a strategy for effective antiviral and anticancer treatment. Cells susceptible to viral infection, namely LLC-MK2, normal monkey epithelium, and K562, human immune-related lymphocyte, which is also a cancer cell line, were treated with fludarabine nucleoside analog (Fdb), interferon alpha (IFN-α), and a combination of Fdb and IFN-α, and then were evaluated for signs of adaptive autophagy and STAT1 antiviral signaling by Western blotting and immunolabeling assays. The results showed that the low concentration of Fdb was able to activate an autophagy response in both cell types, as demonstrated by the intense immunostaining of LC3B foci in the autophagosomes of living cells. Treatment with IFN-α (10 U/mL) showed no alteration in the initiator of mTOR autophagy but dramatically increased the intracellular STAT1 signaling molecules in both cell types. Although in the combined Fdb and IFN-α treatment, both LLC-MK2 and K562 cells showed only slight changes in the autophagy-responsive proteins p-mTOR and LC3B, an adaptive autophagy event was clearly shown in the autophagosome of the LLC-MK2 cell, suggesting the survival phase of the normal cell. The combined effect of Fdb and IFN-α treatment on the antiviral response was identified by the level of activation of the STAT1 antiviral marker. Significantly, the adaptive autophagy mediated by Fdb was able to suppress the IFN-α-mediated pSTAT1 signaling in both cell types to a level that is appropriate for cellular function. It is concluded that the administration of an appropriate dose of Fdb and IFN-α in combination is beneficial for the treatment of some types of cancer and viral infection.
Topics: Antiviral Agents; Autophagy; Cell Survival; Humans; Interferon-alpha; K562 Cells; TOR Serine-Threonine Kinases; Vidarabine
PubMed: 35323219
DOI: 10.3390/medsci10010020 -
Advances in Therapy Jul 2011Rituximab (Rituxan; iogen Idec, San Diego, CA, USA) is a human-mouse chimeric monoclonal antibody specific for CD20, a surface glycoprotein expressed on B lymphocytes.... (Review)
Review
Rituximab (Rituxan; iogen Idec, San Diego, CA, USA) is a human-mouse chimeric monoclonal antibody specific for CD20, a surface glycoprotein expressed on B lymphocytes. Administration of rituximab as a single agent to patients with chronic lymphocytic leukemia (CLL) has limited clinical activity, but generally does not eradicate leukemia from the marrow. However, when administered in combination with chemotherapy, rituximab can improve the survival of patients relative to those treated with chemotherapy alone. As a result of this, the US Food and Drug Administration approved the use of rituximab in previously untreated and previously treated CD20-positive CLL in combination with fludarabine monophosphate and cyclophosphamide. The results of clinical studies evaluating the activity of rituximab when used alone or in combination with other antileukemia agents for the treatment of this disease are reviewed here.
Topics: Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Cyclophosphamide; Humans; Leukemia, Lymphocytic, Chronic, B-Cell; Rituximab; Vidarabine
PubMed: 21725721
DOI: 10.1007/s12325-011-0032-2