Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A 61 year old man with long standing common variable immunodeficiency presented with pyrexia, anaemia and leucopenia. A diagnoses of Hodgkin's disease of the bone marrow was made. The typical histopathological and immunophenotypic appearances were clearly distinct from those of T cell lymphoma with Reed-Sternberg-like cells which, in contrast to Hodgkin's disease, is a known complication of common variable immunodeficiency. Complete clinical and histological remission was achieved with combination chemotherapy. The latter was complicated by severe myelosuppression, unusually severe erosive mucositis and viral retinitis.
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PMID:Hodgkin's disease in a patient with common variable immunodeficiency. 903 46

A prospective, randomized study was conducted to evaluate the role of vitamin B12 and folinic acid supplementation in preventing zidovudine (ZDV)-induced bone marrow suppression. Seventy-five human immunodeficiency virus (HIV)-infected patients with CD4+ cell counts < 500/mm3 were randomized to receive either ZDV (500 mg daily) alone (group I, n = 38) or in combination with folinic acid (15 mg daily) and intramascular vitamin B12 (1000 micrograms monthly) (group II, n = 37). Finally, 15 patients were excluded from the study (noncompliance 14, death 1); thus, 60 patients (31 in group I and 29 in group II) were eligible for analysis. No significant differences between groups were found at enrollment. During the study, vitamin B12 and folate levels were significantly higher in group II patients; however, no differences in hemoglobin, hematocrit, mean corpuscular volume, and white-cell, neutrophil and platelet counts were observed between groups at 3, 6, 9 and 12 months. Severe hematologic toxicity (neutrophil count < 1000/mm3 and/or hemoglobin < 8 g/dl) occurred in 4 patients assigned to group I and 7 assigned to group II. There was no correlation between vitamin B12 or folate levels and development of myelosuppression. Vitamin B12 and folinic acid supplementation of ZDV therapy does not seem useful in preventing or reducing ZDV-induced myelotoxicity in the overall treated population, although a beneficial effect in certain subgroups of patients cannot be excluded.
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PMID:Study of the role of vitamin B12 and folinic acid supplementation in preventing hematologic toxicity of zidovudine. 762 95

The didanosine Expanded Access Program was the largest AIDS treatment program to prospectively evaluate the safety of an antiretroviral agent among patients with advanced human immunodeficiency virus (HIV) disease in whom therapy with zidovudine was failing. A total of 21,198 patients who had infections refractory to zidovudine or who were intolerant of the drug received didanosine as a buffered powder for oral solution (sachet), with total daily doses of 6.6-10 mg/kg; the median CD4 lymphocyte count was 0.04 x 10(9)/L for this population. At the currently recommended dose (6.6-8.29 mg/[kg.d]), 6-month estimated rates of pancreatitis ranged from 1.2% for patients with AIDS-related complex (ARC) and CD4 lymphocyte counts of > or = 0.1 x 10(9)/L to 6.7% for patients with AIDS and CD4 lymphocyte counts of < 0.05 x 10(9)/L. Laboratory toxicities of World Health Organization grades 3 and 4 developed in fewer than 4% of patients entering the study with normal baseline values; the sole exception was leukopenia, which was documented in 8% of these patients. The results of this program demonstrated that patients with CD4 lymphocyte counts of < 0.10 x 10(9)/L or with a diagnosis of AIDS (defined by the 1987 classification system of the Centers for Disease Control and Prevention) were less tolerant of didanosine and significantly more likely to develop adverse clinical reactions and myelosuppression than other patients.
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PMID:Rates and risk factors for adverse events associated with didanosine in the expanded access program. 788 37

Nineteen young human immunodeficiency virus-infected patients were randomized to receive 400 mg of oral diethyldithiocarbamate (DTC) per m2 or placebo weekly for 12 weeks. Changes in blood CD4+ lymphocytes were not significantly different between groups. However, neutrophil, monocyte, and platelet counts consistently decreased during DTC treatment, suggesting DTC-mediated myelosuppression.
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PMID:Decreased counts of blood neutrophils, monocytes, and platelets in human immunodeficiency virus-infected children and young adults treated with diethyldithiocarbamate. 797 99

Myelosuppression is the dose-limiting side effect for most anti-cancer and many anti-human immunodeficiency virus agents, which can be quantitated with optimized colony-forming assays (granulocyte-macrophage, late erythroid, and megakaryocytic [for murine only] colony-forming units and early erythroid burst-forming units (BFUs)). When applied to new drug development, the assays are used for therapeutic index-based screening (e.g., less myelosuppressive analogues, structure-toxicity studies, new drug leads), interpreting efficacy data from xenotransplant models, and selecting the most accurate animal model for human hematopoietic toxicity. However, other types of assays may be required to identify the mechanism underlying myelosuppression. In clinical trial planning, in vitro colony-forming assays can be used to elucidate schedule dependency of myelotoxicity (which in turn provides clues about mechanism of action), to plan cytokine support, and to estimate dose-escalation effects. The inhibition of colony formation can be measured relative to a compound with known clinical myelotoxicity and schedule dependency to provide some idea of the toxicity expected at particular doses, and the degree of heterogeneity between individuals, during clinical trials. The predictive accuracy of the in vitro data has been proven by validation studies with alkylating agents.
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PMID:Roles for in vitro myelotoxicity tests in preclinical drug development and clinical trial planning. 821 Sep 45

The majority of human immunodeficiency virus (HIV)-seropositive patients develop bone marrow abnormalities associated with hematopoietic malfunction during the progression of disease. One important manifestation of HIV-associated hematopoietic dysfunction is that after myelosuppression, bone marrow recovery, a process known to be mediated in part by the production of stromal cell-derived hematopoietic growth factors, is impaired. We sought to test the hypothesis that bone marrow stromal cells are infected by HIV-1 in vivo and that production of certain stromal cell-derived hematopoietic growth factors is deficient as a consequence. In this report, we demonstrate that bone marrow microvascular endothelial cells (MVEC), a key element of the stroma, are the predominant cells infected by HIV (5% to 20%) in bone marrow stromal cultures obtained from 11 consecutive HIV-seropositive patients. Although HIV-infected stromal cultures enriched for MVEC constitutively express normal levels of interleukin (IL)-4, IL-6, granulocyte (G)-colony-stimulating factor (CSF), granulocyte-macrophage (GM)-CSF, tumor necrosis factor (TNF)-alpha, transforming growth factor (TGF)-beta, and Steel factor, IL-1 alpha-induced release of IL-6 and G-CSF is significantly reduced in these cultures. These observations suggest that HIV infection of bone marrow MVEC reduces the capacity of hematopoietic stroma to respond to regulatory signals that normally augment blood cell production during periods of increased demand.
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PMID:Human immunodeficiency virus infection of bone marrow endothelium reduces induction of stromal hematopoietic growth factors. 878 52

beta-D-Uridine protected human granulocyte-macrophage lineage cells in both semi-solid (granulocyte-macrophage colony-forming units, CFU-GM) and liquid cultures against the toxic effects of 3'-azido-3'-deoxythymidine (AZT), 3'-fluoro-3'-deoxythymidine (FLT) and a combination of AZT and FLT, without impairment of the activities of these respective drugs against human immunodeficiency virus (HIV) replication. In addition, beta-D-uridine also protected human CFU-GM against toxicity of the in vivo AZT metabolite, 3'-amino-3'-deoxythymidine (AMT). Beta-L-uridine and alpha-D-uridine, two stereoisomers of the natural form, and the base uracil, were unable to protect cells against either AZT or FLT toxicity, whereas beta-D-uridine-5'-bis(SATE)phosphotriester, a prodrug of beta-D-uridine-5'-monophosphate, successfully protected cells against AZT toxic effects, suggesting that beta-D-uridine needs to be metabolized to its nucleotides to exert a pharmacological effect. These data suggest in addition that AZT, FLT and AMT share a common target site(s) of toxicity involved in myelosuppression.
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PMID:Selective protection of toxicity of 2',3'-dideoxypyrimidine nucleoside analogs by beta-D-uridine in human granulocyte-macrophage progenitor cells. 873 4

Zidovudine is the cornerstone of current antiretroviral treatment of human immunodeficiency virus (HIV) infection. Its use, however, frequently leads to adverse reactions, including myelosuppression. Zidovudine pharmacokinetics show large interindividual variation with indications of pharmacokinetic-pharmacodynamic relationships, but a clear therapeutic window has not yet been defined. Individualisation of zidovudine therapy with monitoring of drug concentrations might be desirable. This review considers (intracellular) monitoring of zidovudine and anabolites for individualisation of zidovudine therapy and the achievements in describing pharmacokinetic-pharmacodynamic relationships so far.
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PMID:Pharmacokinetic individualisation of zidovudine therapy. Current state of pharmacokinetic-pharmacodynamic relationships. 898 61

Multilineage hematopoietic defects occur in patients with human immunodeficiency virus (HIV) infection and affect therapy of the disease and of associated opportunistic infections and neoplasms. Anemia and neutropenia are common in HIV patients, and can occur as a result of HIV-related myelosuppression or complications or may be secondary effects of antiretroviral or other agents used in management of the disease. With the advent of combination drug therapy for the treatment of HIV infection and prophylaxis and treatment of infectious complications, myelosuppression is frequently encountered and may be treated with synthetic hematopoietic growth factors. Erythropoietin has been shown to increase mean hematocrit levels and to reduce transfusion requirements in anemic HIV-infected patients receiving zidovudine. Granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor have been shown to increase neutrophil counts in patients with AIDS-related bone marrow failure and those receiving zidovudine, interferon-alpha, or ganciclovir. Although recent research using interleukin-2 (IL-2) has shown that use of this cytokine in AIDS patients can lead to increases in CD4 cell counts that appear to be functional, further study is needed to determine whether cytokines can play a role other than palliation in HIV-infected patients.
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PMID:Cytokine use in the management of HIV disease. 938 9

The therapeutic potential achievable by efficient transfer and expression of genes into haemopoietic stem cells (HSC) is enormous. In addition to inherited disorders such as haemoglobinopathies and lysosomal storage disorders, this technology can be applied to acquired disorders such as myelosuppression induced by anticancer chemotherapy or infection with human immunodeficiency virus (HIV). To date retroviral vectors are the most attractive modality for gene transfer into HSC. Unfortunately, the expectations of gene therapy are more advanced than the methodology needed to fulfil the goals. In this chapter, the current concepts and limitations in the genetic manipulation of haemopoietic cells are presented. Overcoming these limitations requires not only improvement in isolation and expansion of HSC that contribute to long-term repopulation, but also development of better retroviral transfer systems. Current restrictions occur at various levels in the viral transfer process, including efficient cell entry, regulated expression levels, and sustained expression. The analysis of retroviral mutants has proven to be a successful approach to developing effective retroviral vectors for HSC gene therapy.
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PMID:Gene transfer into haemopoietic cells. 942 10


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