Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0002871 (anemia)
 52,094 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A nonradioactive micro-assay procedure for detection of released reverse transcriptase activity from cells infected with equine infectious anemia virus is described. This procedure utilizes biotinylated-dUTP in conjunction with a streptavidin-alkaline phosphatase conjugate. Detection of alkaline phosphatase is by autoradiography of the chemiluminescence produced during enzymatic dephosphorylation of Lumi Phos 530. This method, as with reverse transcriptase micro-assays employing 32P-labeled nucleotides, is suited to the processing of numerous samples, while having the advantages of safety and stability normally associated with nonradioactive methods of detection. Sensitivity is comparable to a reverse transcriptase micro-assay using 32P-dTTP.
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PMID:A nonradioactive micro-assay for released reverse transcriptase activity of a lentivirus. 138 69

A characterization of equine infectious anemia virus reverse transcriptase (EIAV RT) and its inhibition by 5'-triphosphate analogs was undertaken to explore the possibility of using EIAV RT as an in vitro model for studying human immunodeficiency virus (HIV). EIAV RT activity was found to be dependent on the bivalent cations Mg++ and Mn++. The optimal pH for enzyme reaction was pH 8.2. EIAV RT preferred a 70 mmol/L concentration of monovalent salts. Phosphonoformic acid (PFA) was an active inhibitor of EIAV RT, but phosphonoacetic acid (PAA) and N-ethylmaleimide (NEM) were not. The inhibition of EIAV RT activity by 5'-triphosphates of nucleoside derivatives was in the following decreasing order: FLTTP greater than AZTTP greater than nPrearaUTP greater than nPredUTP = CEdUTP greater than EtdUTP greater than nPrdUTP greater than HMdUTP. nPrearaUTP was a linear competitive and PFA a linear noncompetitive inhibitor of EIAV RT with respect to dTTP. Apparent Kis and Kii were 1.5 and 2.2 mumol/L respectively. The susceptibility pattern of EIAV RT to inhibitors was similar to that of HIV RT.
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PMID:The characterization of EIAV reverse transcriptase and its inhibition by 5'-triphosphates of 2'-deoxyuridine analogs, PFA and PAA. 171 94

Administration of 3'-azido-3'-deoxythymidine (AZT) to patients with acquired immunodeficiency syndrome (AIDS) causes significant anemia and neutropenia. The bone marrow cytotoxicity of AZT has been attributed to deoxyribonucleotide pool perturbations that might result in impaired DNA synthesis in normal bone marrow elements. We examined the effect of human recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on AZT-mediated biochemical perturbations and in vitro growth inhibition of normal bone marrow myeloid progenitor cells. Exposure of nonadherent, bone marrow mononuclear cells (BMMC) to 100 ng/ml of rGM-CSF for 6 h resulted in approximately twofold increments in the mean intracellular deoxycytidine triphosphate (dCTP) and thymidine triphosphate (dTTP) levels. Administration of 10 microM AZT alone to BMMC for 6 h markedly reduced dCTP and dTTP levels and generated significant levels of AZT triphosphate (AZT-TP). Coadministration of rGM-CSF (100 ng/ml) along with AZT (10 microM) partly restored dCTP and dTTP levels and significantly reduced AZT-TP levels. Furthermore, simultaneous exposure of BMMC for 4 h to 100 ng/ml of rGM-CSF reduced the mean DNA incorporation of [3H]AZT (10 microM) from 27.2 to 19.1 pmol/micrograms of DNA. Additionally, the inhibitory effects of AZT (10 microM) on granulocyte-macrophage colony-forming unit (CFU-GM) colony growth were significantly reduced in the presence of 100 ng/ml of rGM-CSF. These in vitro studies suggest that rGM-CSF partly corrects AZT-mediated biochemical perturbations as well as reduces the cytotoxicity of AZT in normal human bone marrow myeloid progenitor cells.
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PMID:The effect of recombinant human granulocyte-macrophage colony-stimulating factor (rGM-CSF) on 3'-azido-3'-deoxythymidine (AZT)-mediated biochemical and cytotoxic effects on normal human myeloid progenitor cells. 278 47

The kinetic properties of dUTPase from equine infectious anemia virus (EIAV) were investigated. K(M) (1.1 +/- 0.1 microM) and k(cat) (25 s(-1)) were found to be independent of pH in the neutral pH range. Above pH 8.0, K(M) increases slightly. Below pH 6.0, the enzyme is rapidly deactivated. Detergent was found to enhance activity, leaving K(M) and k(cat) unaffected. Compared to the Escherichia coli dUTPase, the EIAV enzyme is equally potent in hydrolyzing dUTP, but less specific. Inhibition of the viral enzyme by the nucleotides dTTP, dUMP and a synthetic analogue, 2'-deoxyuridine 5'-(alpha,beta-imido)triphosphate, is stronger by one order of magnitude.
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PMID:dUTPase from the retrovirus equine infectious anemia virus: specificity, turnover and inhibition. 931

From March 1993 to February 1997, 43 eligible patients with inoperable stage IIIA (ten patients) and stage IIIB (33 patients), histologically confirmed NSCLC received 3 courses of the ICE combination (ifosfamide 1.5 g m(-2) and mesna 750 mg m(-2) two times a day, cisplatin 25 mg m(-2) and etoposide 100 mg m(-2), all administered intravenously (i.v.) on days 1-3 every 3 weeks) with G-CSF support. After three cycles, patients were submitted to radical surgery or received two additional courses of the ICE regimen and/or curative radiotherapy. Grade 3-4 neutropenia occurred in 21% of 114 evaluable courses, but was of short duration, leading to neutropenic fever in 5% of the courses. Severe thrombocytopenia and anaemia were observed in 13% and 3% of the courses respectively. Non-haematological toxicity was generally mild with only two episodes of reversible renal impairment. The overall response rate after three chemotherapy courses was 69% (28 partial responses, one complete response). Ten patients (8/10 patients in stage IIIA, 2/33 patients in stage IIIB) underwent radical surgery. Median TTP for patients not undergoing surgery (n = 33) was 8 months (range 3-34+); median DFS for patients rendered NED by surgery (n = 10) was 26 months (range 1-54+). Median OS for the entire group was 12.5 months (range 2-57+). The ICE regimen is active in locally advanced NSCLC with acceptable toxicity and warrants further exploration as induction chemotherapy in larger series.
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PMID:Ifosfamide, cisplatin and etoposide combination in locally advanced inoperable non-small-cell lung cancer: a phase II study. 1057 61

Red cell hemolysis is classically diagnosed by a combination of nonspecific laboratory tests, including serum bilirubin, LDH, and the reticulocyte count. None of these tests alone or in combination has the specificity to reliably ascertain the presence of hemolysis. We have previously demonstrated that erythrocyte adenylate kinase (EAK) is a red cell specific enzyme released from damaged red cells. Its activity can be measured in serum by rapid electrophoresis or immunological methods and correlates linearly with the degree of hemolysis in vitro. We now report on a clinical study comparing EAK levels in patients with and without hemolysis. The clinical diagnosis of hemolysis was established in hospitalized patients with anemia by the combined elevation of the bilirubin, LDH, and reticulocyte count in the absence of liver disease and demonstrable blood loss. The normal range of serum EAK was determined in 30 healthy nonanemic voluntary blood donors and was 0-3.5 Units (mean = 0.5). In 25 patients with hemolytic anemia due to sickle cell disease, hemolytic transfusion reactions, or TTP, the mean EAK level was 62.4 with a range 0-298 Units (P < 0.001 compared to normals). Levels of EAK exceeded the normal range in 24 of 25 patients (96%). In a control group of 44 hospitalized patients with liver disease or myocardial infarction and no clinical evidence of hemolysis, the mean EAK level was 0.12 with a range of 0-3.2 (P = 0.1, NS compared to normals and P < 0.001 compared to patients with hemolysis). None of the control patients had EAK levels that exceeded the normal range. The diagnostic sensitivity of the EAK assay for hemolysis, as calculated according to Baye's algorithm, was 96%, with a specificity and accuracy of 97%. Measurement of serum EAK represents a highly sensitive and specific test for the diagnosis of hemolytic anemia.
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PMID:Diagnosis of the hemolytic state using serum levels of erythrocyte adenylate kinase. 1086 13

The combination of CPT-11 with 5-fluorouracil (5-FU) in advanced colorectal cancer (ACC) represents an attractive approach. A phase II study was conducted to assess the tolerance and efficacy of CPT-11 in combination with leucovorin-modulated bolus plus infusional 5-FU given according to the de Gramont regimen in chemonaive patients with ACC. Fifty-four patients with histologically confirmed ACC were enrolled. The patients' median age was 65 years; 30 (55.5%) patients were men; performance status (World Health Organization) was 0 in 27 (50%) patients, 1 in 22 (41%), and 2 in 5 (9%). Patients received leucovorin (200 mg/m2/d) as a 2-hour intravenous infusion, followed by 5-FU as an intravenous bolus at 400 mg/m2/d, and then as a 22-hour continuous infusion at 600 mg/m2/d, repeated on 2 consecutive days. CPT-11 (180 mg/m2; 30-minute intravenous infusion) was administered on day 1, simultaneously with leucovorin administration. This cycle was repeated every 2 weeks. Complete response was achieved in 4 patients (8%) and partial response in 19 (37%) (overall response rate: 45%; 95% CI: 24-50.5%). Stable disease was achieved in 16 (31%) patients and progressive disease in 13 (25%). The median duration of response and the median TTP were 5 and 8 months, respectively. After a median follow-up period of 11 months, 33 (61%) patients are still alive; the median overall survival has not yet been reached. Thrombocytopenia and anemia were very rare. Grade III/IV neutropenia developed in 19 patients (36%); febrile neutropenia developed in 4 patients, and 1 of them died of sepsis. Grade IV diarrhea was seen in 7 (13%) patients, and 4 of them required hospitalization. Grade III and IV mucositis was observed in two (4%) and one (2%) patients, respectively. Other toxicities were mild. The combination of CPT-11 and bolus plus infusional 5-FU is a relatively well-tolerated and effective first-line treatment in ACC. Final results from large phase III trials are awaited to clarify whether the CPT-11/5-FU combinations should be considered as "standard" first-line treatment in ACC.
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PMID:Irinotecan (CPT-11) in combination with infusional 5-fluorouracil and leucovorin (de Gramont regimen) as first-line treatment in patients with advanced colorectal cancer: a multicenter phase II study. 1182

Systematic evaluations of anemia, thrombocytopenia, and coagulopathy are essential to identifying and managing their causes successfully. In all cases, clinicians should evaluate RBC measurements alongside WBC and platelet counts and WBC differentials. Multiple competing factors may coexist; certain factors affect RBCs independent of those that affect WBCs or platelets. Ideally, clinicians should examine the peripheral blood smear for morphologic features of RBCs, WBCs, and platelets that provide important clues to the cause of the patient's hematologic disorder. Thrombocytopenia arises from decreased platelet production, increased platelet destruction, or dilutional or distributional causes. Drug-induced thrombocytopenias present diagnostic challenges, because many medicines can cause thrombocytopenia and critically ill patients often receive multiple medications. If they suspect type II HIT, clinicians must promptly discontinue all heparin sources, including LMWHs, without awaiting laboratory confirmation, to avoid thrombotic sequelae. Because warfarin anticoagulation induces acquired protein C deficiency, thereby exacerbating the prothrombotic state of type II HIT, warfarin should be withheld until platelet counts increase to more than 100,000/microL and type II HIT is clearly resolving. The presence of a consumptive coagulopathy in the setting of thrombocytopenia supports a diagnosis of DIC, not TTP-HUS, and is demonstrated by decreasing serum fibrinogen levels, and increasing TTs, PTs, aPTTs, and fibrin degradation products. Increasing D-dimer, levels are the most specific DIC parameter and reflect fibrinolysis of cross-linked fibrin. Elevated PTs or a PTTs can result from the absence of factors or the presence of inhibitors. Clinicians should suspect factor inhibitors when the prolonged PT or aPTT does not correct or only partially corrects following an immediate assay of a 1:1 mix of patient and normal plasma. In addition to factor inhibitors, antiphospholipid antibodies (e.g., lupus anticoagulant) can produce a prolonged aPTT that does not correct with normal plasma but is overcome by adding excess phospholipid or platelets. Paradoxically, a tendency to thrombosis, not bleeding, accompanies lupus anticoagulants and the antiphospholipid antibody syndrome. Transfusion of red blood cells, platelets, or plasma products is sometimes warranted, but clinicians must carefully weigh potential benefits against known risks. In critically ill patients, administering RBCs can enhance oxygen delivery to tissues. Among euvolemic patients who do not have ischemic heart disease, guidelines recommend a transfusion threshold of HGB levels in the range of 6.0 to 8.0 g/dL; patients who have HGB that is at least 10.0 g/dL are unlikely to benefit from blood transfusion. The use of rHuEPO to increase erythropoiesis offers an alternative to RBC transfusion, assuming normal, responsive progenitor cells and adequate iron, folate, and cobalamin stores. Future research should examine whether clinical outcomes from rHuEPO use in critically ill patients are important and cost-effective. Because platelets play an instrumental role in primary hemostasis, platelet transfusions are often important in managing patients who are bleeding or at risk of bleeding with thrombocytopenia or impaired platelet function. Platelet transfusions carry risks, and decisions to transfuse platelets must consider clinical circumstances. Most important, platelet transfusions are generally contraindicated if the underlying disorder is TTP or type II HIT, because platelet transfusion in these settings may fuel thrombosis and worsen clinical signs and symptoms. Plasma products can correct hemostasis when bleeding arises from malfunction, consumption, or underproduction of plasma coagulation proteins. Choice of plasma product for transfusion depends on clinical circumstances. FFP is the most commonly used plasma product to correct clotting factor deficiencies, particularly coagulopathies that are attributable to multiple clotting factor deficiency states as in liver disease, DIC, or warfarin anticoagulation. PCC or rFVIIa that is administered in small volumes may provide advantages over FFP when coagulopathies require quick reversal without risk of volume overload. Factor concentrates can replace specific factor deficiencies. Recombinant FVIIa bypasses inhibitors to factors VIII and IX and vWF. Use of rFVIIa in managing hemostatic abnormalities from severe liver dysfunction; extensive surgery, trauma, or bleeding; excessive warfarin anticoagulation; and certain platelet disorders requires further study to determine optimal and cost-effective dosing regimens. Recombinant activated protein C reduces mortality from severe sepsis that is associated with organ dysfunction in adults who are at high risk for death (APACHE scores of at least 25). In severe sepsis, levels of protein C decrease, as do fibrinogen and platelet levels. Because of its anticoagulant effect, however, drotrecogin alfa may induce bleeding. Guidelines for drotrecogin alfa use must take into account bleeding risks.
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PMID:Critical issues in hematology: anemia, thrombocytopenia, coagulopathy, and blood product transfusions in critically ill patients. 1471 Jun 93

Thrombotic microangiopathy (TMA) is a recognized complication of malignant hypertension (HTN). Such patients have blood pressures > or = 200/140 mmHg but the condition is defined by the presence of papilledema and is frequently complicated by acute renal failure. Here we report two patients with severe HTN (systolic > or = 180 mmHg or diastolic > or = 120 mmHg), TMA, thrombocytopenia, renal failure, and, in one case, neurological changes (4 of 5 manifestations of the TTP pentad). A 50-year-old male with HTN presented with blurred vision, dizziness, headache, confusion, renal failure, and a TMA (PLT = 39 x 10(9)/L and LD = 2,781 normal <600 U/L). On presentation, BP was 214/133 mmHg and an ophthalmic exam demonstrated no papilledema. With HTN control over 7 days, his platelet count rebounded (220 x 10(9)/L), LD declined (1,730 U/L), and mental status improved. A 60-year-old female with diabetes, HTN, Lupus erythematosus, mild chronic anemia, and thrombocytopenia presented with abdominal pain, shortness of breath, renal failure, and a TMA (PLT = 83 x 10(9)/L and LD = 2,929 U/L). Blood pressures were 180-210/89-111 mmHg and ophthalmic exam demonstrated no papilledema. With HTN control over 8 days, her platelet count rebounded (147 x 10(9)/L), and LD declined (1,624 U/L). Although in both cases a diagnosis of TTP was considered because of overlap with the classic diagnostic pentad, neither received plasmapheresis. TTP is a diagnosis of exclusion, where there is no other likely diagnosis to explain the TMA. In cases of severe HTN (with or without papilledema), the diagnosis of TTP should be held in abeyance until the effect of HTN control can be assessed.
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PMID:Differentiating thrombotic microangiopathies induced by severe hypertension from anemia and thrombocytopenia seen in thrombotic thrombocytopenia purpura. 1549 50

Patients with cancer-related anemia have an inadequate Epo response that is further impaired by cancer treatments such as chemotherapy. Significant number of studies have demonstrated that treatment of anemia in cancer patients using recombinant human EPO(rHuEPO, epoetin alfa) significantly increases hemoglobin(Hb) levels,reduces transfusion requirements,and improves quality of life,particularly by relieving fatigue. However,the findings of several studies have raised the possibility of an adverse effect of thromboembolism. The American Society of Clinical Oncology and the American Society of Hematology developed an evidence-based clinical practice guideline for the use of epoetin in patients with cancer. In cancer patients, the risk of bleeding depends not only on the platelet count, but also on the underlying disease, in accordance with coagulation defects. The cause of thrombocytopenia must be established prior to platelet transfusion since platelet transfusions may be relatively contraindicated in certain conditions e. g., heparin-induced thrombocytopenia(HIT), and thrombotic thrombocytopenic purpura/hemolytic uremic syndrome(TTP/HUS).
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PMID:[Approaches to anemia, thrombocytopenia, and DIC in cancer patients]. 1641 Jun 90


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