Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0018681 (headache)
 56,091 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

All-trans retinoic acid (ATRA) is a known inducer of differentiation in acute promyelocytic leukemia. To improve the outcome of children with acute promyelocytic leukemia, ATRA has been applied since 1994 as an additional induction element inthe AML-BFM 93 study. In a retrospective study, we compared 22 children treated with ATRA (median age: 9.3 years; range: 1.8-16.3) with 22 patients receiving conventional therapy (median age: 12.3 years; range: 3.2-16.7). Twenty-one of the children achieved complete remission. Only one patient died early from bleeding complications after 3 days administration of ATRA. In the control group, seven early deaths occurred (Fisher exact test; p<0.04). Two children died from intracerebral hemorrhages. Two patients suffered from sepsis during aplasia after induction therapy, and one child did not respond to treatment. The 5-year overall survival (OS) and event-free survival (EFS) of the children who received ATRA followed by chemotherapy were significantly bettercom-pared with conventionally treated children [OS: 0.87 +/- 0.9 vs 0.45 +/- 0.11, p (log rank) <0.003; EFS: 0.76 +/- 0.11 vs 0.43 +/- 0.11 p (log rank) <0.02]; the median observation time was 2.8 years (19-76 months). However, nearly all children suffered from common side effects such as headache, fever, joint, muscle and bone pain, weight gain, or dermatitis. In three patients, a retinoic acid syndrome was observed. Interruption of ATRA treatment and application of dexamethasone, necessary in 12 children, controlled theadverse effects. ATRA treatment could be resumed in 18 patients. In conclusion, ATRA treatment during induction could avoid early deaths in children with acute promyelocytic leukemia with considerable but manageable toxic side effects.
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PMID:Treatment with all-trans retinoic acid in acute promyelocytic leukemia reduces early deaths in children. 1152 68

We compared two doses of recombinant human granulocyte-stimulating factor (G-CSF) for stem cell mobilisation in 90 healthy donors for allogeneic stem cell transplantation in a retrospective analysis. Group I (n = 46) received 10 microg/kg G-CSF (filgrastim) given as 5 microg/kg twice daily, and group II (n = 44) received 16 microg/kg, given as 8 microg/kg twice daily with a 12-h interval. The groups were well-balanced for age and body-weight. G-CSF application was performed on an out-patient basis, and leukapheresis was started in all donors on day 5. The most frequent side-effects of G-CSF were grade I/II, bone pain, headache and fatigue in both groups, whereas grade III of bone pain, headache and fatigue occurred in the 2 x 8 microg/kg group only. One serious non-fatal event with non-traumatic spleen rupture occurred in the 2 x 5 microg/kg group. The CD34(+)cell count in the first apheresis of all donors was 5.1 x 10(6)/kg donor weight (range, 1.5-19.3). The CD34(+) cell harvest was higher in the 2 x 8 microg/kg group than in the 2 x 5 microg/kg group (7.1 x 10(6)/kg vs 4.9 x 10(6)/kg; P = 0.09). The target of collecting >5.0 x 10(6) CD34(+) cells/kg donor weight with one apheresis procedure was achieved in 45% of group I and in 61% of group II, respectively. Administering G-CSF at a dosage of 8 microg/kg twice daily leads to a higher CD34(+) cell yield than a dosage of 2 x 5 microg/kg, but is associated with increased toxicity and higher cost.
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PMID:Stem cell mobilisation with 16 microg/kg vs 10 microg/kg of G-CSF for allogeneic transplantation in healthy donors. 1204 Apr 68

Treatment of healthy donors with recombinant human granulocyte colony-stimulating factor (rhG-CSF) allows the mobilization and peripheralization into circulating blood of an adequate number of CD34+ cells that can then be collected by leukapheresis (PBSC). This procedure avoids the invasiveness of bone marrow harvest and the risks related to general anesthesia. The main adverse effects of rhG-CSF are: bone pain, 84%, headache, 54%, fatigue, 31%, and nausea, 13%, which are usually scored by the donors as moderate to severe, resolving within 2-3 days after discontinuation of the cytokine. Analgesics, mainly acetaminophen, are sufficient to control the pain. Less than 5% of the donors experience non-cardiac chest pain, a local reaction at the injection site, insomnia, dizziness or a low-grade fever. Discontinuation of the PBSC procedure because of adverse effects of rhG-CSF or leukapheresis is rarely necessary (0.5%) but this good tolerability can be hampered by the need, in 5-20% of cases, for an adequate venous access that requires insertion of a central or venous catheter. There are no absolute contraindications to the stimulation of healthy donors with rhG-CSF but the description of cases of non-traumatic splenic rupture, iritis, cardiac ischemia, and gouty arthritis suggests that further precautionary restrictions are advisable when deciding eligibility for PBSC collection. The main advantages for patients receiving an allogeneic PBSC transplant are the faster hematologic and immunologic recovery and the potential for a greater efficacy in advanced disease by lowering the transplant-related mortality. One of the major concerns regarding the use of rhG-CSF in unrelated healthy donors is the uncertainty about its possible role in triggering malignancy, in particular myelodysplastic syndrome and acute myeloid leukemia. There are no studies with an adequate sample size and follow-up that can answer this question but two recent retrospective studies reported that in the medium term rhG-CSF is not associated with an excess of lymphoproliferative disorders. Currently, caution on the long-term safety of the use of rhG-CSF in healthy donor is still warranted but the data so far accumulated on allogeneic PBSC transplants are encouraging both as far as concerns the good short-medium tolerability profile of G-CSF-stimulation of the donor and the potential major efficacy in leukemia patients.
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PMID:The use of cytokine-stimulated healthy donors in allogeneic stem cell transplantation. 1241 88

Recombinant human granulocyte colony-stimulating factor (rhG-CSF) mobilized peripheral blood progenitor cells (PBPCs) from healthy individuals are a rapidly emerging alternative source to bone marrow for allogeneic transplantation. Although widely applied in the meantime, only limited information on feasibility and safety of mobilization and collection of PBPCs is currently available from prospective multicenter studies specifically designed to investigate this donation modality. This ongoing multicenter study on the performance as well as the short- and long-term safety profile of rhG-CSF-induced mobilization and collection of PBPCs was initiated in October 1999. The study is designed to recruit a total of 300 healthy family donors who will be followed regularly for a period of 5 years after donation. The first interim report presented here summarizes results obtained after enrollment of 150 donors from nine German institutions. The study protocol allowed the individual choice between two dose regimens of rh-CSF (10 micro g/kg per day vs 2x8 micro g/kg per day of donor body weight). The primary endpoint was defined as a yield of > or =5x10(6) CD34(+) cells/kg of recipient body weight in a single leukapheresis product. This endpoint was attained by 50% of donors receiving the lower rhG-CSF dose regimen and by 75% of donors with the higher dose regimen ( p<0.0009). A total of 478 acute adverse events attributable to the mobilization procedure were recorded and manifested predominantly as transient bone pain and headaches (80%). No persistent hematologic or nonhematologic adverse events have occurred in this study so far. Thus, the current experience in a prospective multicenter study supports previous single-center and retrospective registry reports in that the collection of PBPCs after rhG-CSF mobilization is feasible and associated with frequent, but generally mild and acceptable side effects.
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PMID:Filgrastim mobilization and collection of allogeneic blood progenitor cells from adult family donors: first interim report of a prospective German multicenter study. 1248 66

Multiple myeloma (MM) is a plasma cell malignancy characterized by infiltration of bone marrow, bone destruction, infiltration of soft tissues with plasma cells, and suppression of normal hematopoiesis. The production of monoclonal immunoglobulins with or without light chains is a major feature of the disease. Full spectrum of plasma cell dyscrasias include monoclonal gammapathy of undetermined significance, smouldering myeloma, indolent multiple myeloma, and fully developed, symptomatic multiple myeloma. The usual presenting features of MM include bone pain, weakness, fatigue, fever and infection. Neurologic symptoms are less common but one must not forget that MM may present with a neurologic disease. Careful neurologic history and examination are mandatory in patients with MM. Neurologic symptoms may be a direct manifestation of MM or may be due to the immune effect of monoclonal proteins directed against different neural structures. Finally, metabolic consequences (uremia, hypercalcemia, hyperviscosity) of MM may produce a broad spectrum of different neurologic symptoms including headache, blurring of vision, drowsiness, precoma, coma, vertigo, ataxia, hemiparesis and epileptiform seizures. The most common location of bone changes in MM is the thoracic spine, where it causes osteolytic changes with consequent compressive fractures. The most disastrous sequel is paraplegia. Multiple vertebral involvement with the evidence of osteolytic changes in other bones is usual, but solitary vertebral myeloma may occur. Myeloma usually involves the bone of the vertebral body and then spreads into the extradural space. However, patients with solitary extradural myeloma have been reported. Skull myeloma is frequently asymptomatic. It may grow externally or, rarely, there is intracranial expansion. Involvement of the cranial nerves is not rare, with II, V, VI, VII and VIII cranial nerves being most often affected. Isolated intracerebral plasmacytomas are extremely rare. Diagnostic approach includes plain X-rays of the skeleton, which was found to be the method of choice for demonstration of osteolytic changes, whereas magnetic resonance with gadolinium enhancement most reliably displays the degree of vertebral involvement and demonstrates any associated soft tissue mass. Current treatment of osteolytic changes in multiple myeloma include chemotherapy, radiotherapy in combination with dexamethasone, monthly infusions of bisphosphonates, surgical decompression, and kyphoplasty. Therapeutic approach is dictated by the presenting symptoms. In case of pain as the predominant symptom, treatment with chemotherapy and radiotherapy may be appropriate. Compressive symptoms are relieved with dexamethasone followed by radiotherapy and chemotherapy. Surgical decompression is used in patients with vertebral collapse and vertebral instability. Kyphoplasty is a new method used in the treatment of osteolytic changes of vertebral bodies. A viscous cement is injected into the cavity by a balloon-like inflatable bone tampon. It has been successfully employed to improve the quality of life, to reduce pain, and to increase overall functioning in patients with vertebral compression fractures by restoring most of the original height of the vertebral body. Bisphosphonates reduce pain associated with osteolytic changes in multiple myeloma, but also significantly reduce skeletal events (pathologic fracture, spinal cord compression, surgery or irradiation of bone) via unknown mechanism. It seems that bisphosphonates, by inhibiting bone resorption, alter the microenvironment in which the MM cells grow.
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PMID:[Neurologic sequelae of bone changes in multiple myeloma and its therapy]. 1263 Mar 41

Increased bone marrow angiogenesis and vascular endothelial growth factor (VEGF) levels are adverse prognostic features in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDSs). VEGF is a soluble circulating angiogenic molecule that stimulates signaling via receptor tyrosine kinases (RTKs), including VEGF receptor 2 (VEGFR-2). AML blasts may express VEGFR-2, c-kit, and FLT3. SU5416 is a small molecule RTK inhibitor (RTKI) of VEGFR-2, c-kit, and both wild-type and mutant FLT3. A multicenter phase 2 study of SU5416 was conducted in patients with refractory AML or MDS. For a median of 9 weeks (range, 1-55 weeks), 55 patients (33 AML: 10 [30%] primary refractory, 23 [70%] relapsed; 22 MDS: 15 [68%] relapsed) received 145 mg/m2 SU5416 twice weekly intravenously. Grade 3 or 4 drug-related toxicities included headaches (14%), infusion-related reactions (11%), dyspnea (14%), fatigue (7%), thrombotic episodes (7%), bone pain (5%), and gastrointestinal disturbance (4%). There were 11 patients (20%) who did not complete 4 weeks of therapy (10 progressive disease, 1 adverse event); 3 patients (5%) who achieved partial responses; and 1 (2%) who achieved hematologic improvement. Single agent SU5416 had biologic and modest clinical activity in refractory AML/MDS. Overall median survival was 12 weeks in AML patients (range, 4-41 weeks) and not reached in MDS patients. Most observed toxicities were attributable to drug formulation (polyoxyl 35 castor oil or hyperosmolarity of the SU5416 preparation). Studies of other RTKI and/or other antiangiogenic approaches, with correlative studies to examine biologic effects, may be warranted in patients with AML/MDS.
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PMID:SU5416, a small molecule tyrosine kinase receptor inhibitor, has biologic activity in patients with refractory acute myeloid leukemia or myelodysplastic syndromes. 1264 63

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.
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PMID:A phase 2 clinical study of SU5416 in patients with refractory acute myeloid leukemia. 1284 1

Allogeneic hematopoietic stem cell transplantation is an effective treatment for hematological malignancies. Peripheral blood stem cells (PBSCs) are increasingly used as an alternative to bone marrow for allogeneic transplantation. However, predictive factors for the response to recombinant human granulocyte stimulating factor (rHuG-CSF) in healthy donors have not been extensively studied. We analyzed the side effects, laboratory test results after administration of rHuG-CSF and the factors influencing mobilization of peripheral blood stem cells in 30 healthy donors. Bone pain, fever and headache were observed with high frequency after administration of rHuG-CSF. WBCs and reticulocytes increased, and RBCs and platelets decreased significantly after administration rHuG-CSF. Biochemical examination revealed significant elevations of LDH, CRP, ALP and UA. Univariate analysis showed the age of donors (< 50 vs. > 50, p = 0.041) and the lymphocyte counts before administration of rHuG-CSF (p = 0.032) to be correlated with the number of CD34 positive cells. From a multivariate analysis, the tendency for good mobilization with a twice daily dose of rHuG-CSF (p = 0.065) was observed. The rHuG-CSF schedule may be the most important factor affecting peripheral blood stem cell mobilization and collection in healthy donors.
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PMID:[Analysis of factors for poor mobilization after administration of recombinant human granulocyte stimulating factor (rHuG-CSF) in healthy donors]. 1285 51

We investigated whether anti-inflammatory effects of treatment with granulocyte colony-stimulating factor (G-CSF, filgrastim) are mediated via prostaglandin E(2) (PGE(2)) induction. In a double-blind crossover study, 10 healthy volunteers received 300 microg of filgrastim or saline 1 week apart. This was repeated after oral administration of 50 mg of flurbiprofen 1 h before injection. The increase in neutrophilic granulocytes initiated by G-CSF was augmented significantly by flurbiprofen. Lipopolysaccharide-induced PGE(2) and thromboxane (TxB(2)) release were increased 8 h after G-CSF treatment. This increase was abrogated by flurbiprofen. However, flurbiprofen did not affect G-CSF-mediated decrease in tumor necrosis factor-alpha or interferon-gamma release. Of the volunteers treated with G-CSF, eight reported side effects (headache and bone pain) against none in the saline group. When flurbiprofen was given before injection, one volunteer each reported side effects in the G-CSF and in the saline group. These data show that G-CSF primes for increased PGE(2) and TxB(2) release. Cyclooxygenase inhibition counteracts neither the hematopoietic nor the anti-inflammatory activity of G-CSF but reduces side effects.
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PMID:Granulocyte colony-stimulating factor (filgrastim) treatment primes for increased ex vivo inducible prostanoid release. 1461 Feb 36

Both granulocyte colony-stimulating factor (G-CSF) and dexamethasone (DXM) are used for neutrophil (PMN) mobilization and collection. This prospective study was aimed to evaluate and compare the rate, severity and clinical significance of adverse reactions of these drugs alone and in combination in healthy donors. PMN mobilization was carried out using dexamethasone alone (8 mg orally; n=25) or glycosylated G-CSF alone (Lenograstim, 5 microg/kg subcutaneously, n=24) or in combination (n=23) prior to a standard granulocyte apheresis on the Spectra cell separator. The number of PMNs counted in the mobilized peripheral blood of the donors was 7.0 (3.6-20.4) x10(9)/L (DXM), 25.2 (15.5-49.7) x10(9)/L (G-CSF), and 31.6 (20.0-43.0) x10(9)/L (G-CSF+DXM), corresponding to PMN apheresis yields of 13 (8-43) x10(9)/U, 56 (34-118) x10(9)/U, and 83 (33-117) x10(9)/U, respectively. The three groups had comparable percentages of donors with at least one adverse effect (ranging from 75 to 80%), but the G-CSF-containing regimens were generally more toxic, as was reflected by higher percentages of donors with moderate to severe adverse reactions and higher overall severity scores of 2.28 (G-CSF) and 2.08 (G-CSF+DXM) compared with 1.33 in the DXM group ( p<or=0.001). With G-CSF alone, pain symptom complexes were more frequent, more severe, and more often triggered requests for analgesics (9/47 donors; 19%) and unwillingness to give further neutrophil donations (2/47 donors; 4%). The addition of DXM to G-CSF diminished some symptoms, particularly bone pain, headache and the frequency of requests for analgesics. The predominant symptoms in the DXM alone group were mild gastrointestinal complaints. We conclude that G-CSF stimulation improved neutrophil mobilization and apheresis yields at the expense of donor tolerability. Compared with G-CSF alone, the combination G-CSF and DXM did not increase the quantity or the severity of donor symptoms.
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PMID:A comparative study of adverse reactions occurring after administration of glycosylated granulocyte colony stimulating factor and/or dexamethasone for mobilization of neutrophils in healthy donors. 1506 Jul 47


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