Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0015672 (fatigue)
 51,768 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Imatinib (STI571, Gleevec/Glivec) and other small-molecule tyrosine kinase inhibitors are highly effective in the treatment of chronic myeloid leukemia (CML), gastrointestinal stromal tumors and, for example, eosinophilia-associated chronic myeloproliferative disorders. This molecularly targeted approach disrupts abnormal tyrosine kinase dependent signalling pathways, thus providing a preferred treatment option for selected neoplastic disorders with activating mutations of Abelson-, Abl-related-, Kit-, and platelet-derived growth factor receptor A and B genes. Loss of response to imatinib may be due to an acquired resistance of emerging mutant tumor cell clones. Therapy is generally well tolerated. However, toxicities including edema, skin rashes, fatigue, nausea and myelosuppression have been reported. Philadelphia/Bcr-Abl-negative clonal chromosomal abnormalities may develop. Bone marrow trephines obtained from CML patients in complete remission with prolonged pancytopenia secondary to imatinib generally show marrow hypoplasia. Morphological features may be in keeping with either aplastic anemia or myelodysplasia developing in Philadelphia-negative hematopoiesis. Single or multilineage myelodysplasia may be accompanied by an excess of blasts and rarely evolves into acute leukemia in CML patients. Severe adverse hematological effects of imatinib are extremely rare. Current questions involve the molecular mechanisms of hematological side effects of tyrosine kinase inhibitors with special regard to the emergence of distinct aberrant clones.
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PMID:[Hematological side effects of tyrosine kinase inhibition using imatinib]. 1642 5

PTK787/ZK 222584 (PTK/ZK) is an oral angiogenesis inhibitor targeting vascular endothelial growth factor (VEGF) receptor tyrosine kinases, including VEGFR-1/Flt-1, VEGFR-2/KDR, VEGFR-3/Flt-4, the platelet-derived growth factor receptor tyrosine kinase and the c-kit protein tyrosine kinase. The objective of this Phase I study was to evaluate the safety, tolerability, biologic activity and pharmacologic profile of PTK/ZK administered orally, twice daily, on a continuous dosing schedule in patients with primary refractory or relapsed acute myeloid leukemia (AML), secondary AML, poor-prognosis de novo AML or advanced myelodysplastic syndrome (MDS). Acute myeloid leukemia patients for whom PTK/ZK monotherapy was ineffective could receive PTK/ZK combined with standard induction chemotherapy. Sixty-three patients received PTK/ZK at doses of 500-1000 mg orally b.i.d. Safety and pharmacokinetic data were collected. Responses were evaluated according to standard bone marrow and peripheral blood criteria. At 1000 mg b.i.d., dose-limiting toxicities of lethargy, hypertension, nausea, emesis and anorexia were observed. Other adverse events related to PTK/ZK were dizziness, weakness, fatigue, diarrhea and pruritus; these were generally mild and reversible. Pharmacokinetic data showed that steady state was reached by day 14, there was no accumulation with repeat dosing and there was no significant increase in exposure at steady state beyond the maximum tolerated dose (MTD). Complete remission was observed in five of 17 AML patients treated with PTK/ZK combined with chemotherapy. In conclusion, the MTD of PTK/ZK is 750 mg orally b.i.d. The drug is generally well tolerated and can be given in combination with chemotherapy for patients with MDS and AML.
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PMID:Phase 1 study of PTK787/ZK 222584, a small molecule tyrosine kinase receptor inhibitor, for the treatment of acute myeloid leukemia and myelodysplastic syndrome. 1661 23

The chronic myeloproliferative diseases (CMDs) are a group of conditions characterized by unregulated blood cell production, that due either to excessive numbers of erythrocytes, leukocytes or platelets, or their defective function cause symptoms and signs of fatigue, headache, ruddy cyanosis, hemorrhage, abdominal distension, and the complications of vascular thrombosis. In the late 19th century Vaquez provided the first description of polycythemia vera (PV) and Hueck defined idiopathic myelofibrosis (IMF). In 1920, di Guglielmo established criteria for patients with essential thrombocythemia (ET). In 1951, Dameshek argued that these disorders, along with chronic myelogenous leukemia (CML) display many similar clinical and laboratory features [Dameshek W. Some speculations on the myeloproliferative syndromes. Blood 1951;6:372-5], and grouped them. In 2002, the World Health Organization expanded the definition of CMDs to also include chronic neutrophilic leukemia (CNL), chronic eosinophilic leukemia/hypereosinophilic syndrome (CEL/HES) and systemic mast cell disorder (SMCD) [Vardiman JW, Harris NL, Brunning RD. The World Health Organization (WHO) classification of the myeloid neoplasms. Blood 2002;100:2292-302]. While the molecular pathogenesis of CML is well known [Melo JV, Deininger MW. Biology of chronic myelogenous leukemia-signaling pathways of initiation and transformation. Hematol Oncol Clin North Am 2004;18:545-68], and the causes of CEL/HES and SMCD have been identified in about half of all cases [Gotlib J, Cools J, Malone III JM, Schrier SL, Gilliland DG, Coutre SE. The FIP1L1-PDGFRalpha fusion tyrosine kinase in hypereosinophilic syndrome and chronic eosinophilic leukemia: implications for diagnosis, classification, and management. Blood 2004; 103:2879-91; Valent P, Akin C, Sperr WR, Horny HP, Metcalfe DD. Mast cell proliferative disorders: current view on variants recognized by the World Health Organization. Hematol Oncol Clin North Am 2003; 17:1227-41], until very recently the etiologies of the three classically defined CMDs, PV, IMF and ET, were poorly understood. Each of these disorders is characterized by excessive hematopoiesis, a process usually dependent on one or more hematopoietic growth factors (HGFs). This review will focus on how our knowledge of the molecular mechanisms by which HGFs are produced, bind cell surface receptors and transduce survival and proliferative signals have provided the platform on which the multiple origins of CMDs can be understood and novel therapeutic interventions designed.
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PMID:Hematopoietic growth factors, signaling and the chronic myeloproliferative disorders. 1705 68

Gastrointestinal stromal tumors (GISTs) represent a distinct oncogenetic entity that is now center stage in clinical trials of kinase-targeted therapies. These neoplasms express the c-KIT oncoprotein and occur predominantly in adults, more rarely in children. Two selected cases of GIST expressing c-KIT, including one adult patient and a 9-year-old boy are presented. The adult patient was admitted for palpable abdominal mass without other clinical symptoms. On biopsies obtained by scanner-guided procedure, diagnosis of ganglioneurinoma was proposed with the remark that GIST tumor could not be categorically excluded. At surgery, voluminous encapsulated tumor located at the jejunal wall was found and totally excised. The second patient presented with acute upper gastrointestinal hemorrhage associated with several months history of general fatigue and loss of appetite. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a tumoral mass arising from the lesser curvature of the stomach compatible with GIST. Two small metastatic lesions in the liver were also detected. Combined treatment by surgery and systemic therapy by the tyrosine kinase inhibitor imatinib mesylate was applied.
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PMID:Expression of c-KIT oncoprotein in gastrointestinal stromal tumors in adults and children: guideline for diagnosis and treatment. 1721 Dec 92

The addition of antiangiogenic agents has improved overall survival in a wide variety of tumor types, including non-small-cell lung cancer (NSCLC). Antibodies to the vascular endothelial growth factor (VEGF) were the first targeted agent to yield a significant improvement in overall survival when combined with first-line chemotherapy for metastatic NSCLC. Anti-VEGF antibodies and tyrosine kinase inhibitors blocking VEGF receptor (VEGFR) activity are also being investigated in pretreated NSCLC. Initial experience with anti-VEGF antibodies suggested a mild adverse event profile. However, it has become clear with additional experience that antiangiogenic agents are associated with a distinct array of toxicities, such as hemorrhage, hypertension, thromboembolic events, and proteinuria. Furthermore, an increase in chemotherapy-associated toxicities such as neutropenia has been observed with the addition of anti-VEGF antibodies. Multitargeted small-molecule inhibitors that block activity of the VEGFR tyrosine kinase are associated with fatigue and other toxicities in addition to the aforementioned class-effect toxicities, possibly because of their inhibition of multiple signaling pathways. Currently, only patients without predominant squamous cell histology are eligible to receive bevacizumab. Trials are ongoing to address the feasibility of bevacizumab in patients who were excluded from the phase III pivotal trial. Additionally, further investigation is necessary to determine risk factors for hemorrhage with antiangiogenic agents.
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PMID:Toxicities of antiangiogenic therapy in non-small-cell lung cancer. 1723 87

Imatinib and other Abl tyrosine kinase inhibitors (TKIs), such as dasatinib and nilotinib, have significantly improved the outcome of patients with chronic myeloid leukemia. Imatinib and dasatinib are currently Food and Drug Administration (FDA) approved, and nilotinib is expected to gain FDA approval soon. In addition, several other Abl TKIs are being evaluated in various clinical trials. Imatinib has also shown efficacy in the therapy of gastrointestinal stromal tumors, Philadelphia chromosome-positive acute lymphocytic leukemia and hypereosinophilic syndrome. Because of their efficacy, more patients will receive Abl TKIs for a longer period of time. Imatinib was FDA approved after a short follow-up because of its exceptional efficacy and safety profile. The most common adverse events reported included fluid retention, fatigue, diarrhea, and muscle cramps. With longer follow-up, issues related to the long-term use of imatinib have been discussed. Our aim is to review the emerging safety issues of Abl TKIs after a longer follow-up.
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PMID:Emerging safety issues with imatinib and other Abl tyrosine kinase inhibitors. 1738 19

To assess tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and clinical activity of the dual epidermal growth factor receptor (EGFR) 1 and 2 (HER2) tyrosine kinase inhibitor BIBW 2992. An escalating schedule of once-daily (OD) BIBW 2992 for 14 days followed by 14 days off medication was explored. Thirty-eight patients were enrolled. Dose levels were 10, 20, 30, 45, 70, 85, and 100 mg. At 100 mg dose-limiting toxicity (DLT) (common toxicity criteria grade 3 skin rash and grade 3 diarrhoea despite treatment with loperamide) occurred in two patients. In the next-lower dose of 70 mg, DLT (grade 3 fatigue and ALAT elevation) occurred in one of six patients. An intermediate dose level of 85 mg was studied. Here DLT occurred in two patients (grade 3 diarrhoea despite treatment and grade 2 diarrhoea lasting more than 7 days despite treatment). An additional 12 patients were treated at 70 mg. BIBW 2992 PK after single and multiple doses revealed moderately fast absorption, and no deviation from dose proportionality. Pharmacodynamics analysis in skin biopsies did not show significant changes in EGFR-associated biomarkers. However, a significant inhibitory effect on the proliferation index of epidermal keratinocytes was observed. No partial or complete responses were observed, stable disease lasting more than four cycles was seen in seven patients. The recommended dose for studies with BIBW 2992 for 14 days followed by 14 days off medication is 70 mg OD.
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PMID:A phase I dose escalation study of BIBW 2992, an irreversible dual inhibitor of epidermal growth factor receptor 1 (EGFR) and 2 (HER2) tyrosine kinase in a 2-week on, 2-week off schedule in patients with advanced solid tumours. 1802 90

There are data suggesting that inhibition of epidermal growth factor receptor (EGFR) tyrosine kinase signalling may reverse resistance to fluoropyrimidine treatment. To investigate this further, the INFORM study was an open-label, non-comparative phase II study of gefitinib (Iressa, ZD1839; AstraZeneca, Wilmington, DE, USA) 250 mg daily in combination with 5-fluorouracil (5-FU administered as an intravenous 400 mg m(-2) bolus injection followed by 2800 mg m(-2) infusion over 46 h and folinic acid administered as a 350 mg infusion over 2 h) every 2 weeks for up to 12 cycles in 24 patients with metastatic colorectal cancer refractory to previous fluoropyrimidine treatment. There were no objective responses. The stable disease rate was 37.5% (95% CI: 18.80, 59.41), median progression-free survival measured 116 days and overall survival was 226 days. Quality of life was unchanged compared to baseline values, and the commonest toxicities were diarrhoea, rash and fatigue with 7 out of 24 (29%) patients having a grade 3 or 4 toxicity. Gefitinib does not sensitise patients with fluoropyrimidine refractory metastatic colorectal cancer to 5-FU chemotherapy.
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PMID:A phase II study to determine the ability of gefitinib to reverse fluoropyrimidine resistance in metastatic colorectal cancer (the INFORM study). 1825 19

Treatments for metastatic renal cell carcinoma (MRCC) are limited. RCCs frequently overexpress epithelial growth factor receptor and express c-Kit and platelet-derived growth factor receptor-beta. Combination of interferon with tyrosine kinase inhibitors of epithelial growth factor receptor [gefitinib (Iressa)] or c-Kit and platelet-derived growth factor receptor-beta [imatinib (Gleevec)] was evaluated for efficacy and safety. Patients with MRCC received 12-week cycles of interferon [3 million units (MU) subcutaneously thrice in week 1 and 6 MU thrice weekly thereafter] and either gefitinib (500 mg daily) or imatinib (600 mg daily). The gefitinib/imatinib dose was reduced as needed owing to toxicity. The primary endpoint was objective tumor response. Secondary endpoints were time to tumor progression, overall survival, and safety. Seventeen patients were enrolled. Most had clear cell [36% (6/17)] or papillary [36% (6/17)] tumors. Most (n=14) were treated on the gefitinib arm, including two patients who crossed over from the imatinib arm after experiencing disease progression. Objective tumor responses were evaluable in 14 patients (82%). Of these 14, partial responses occurred in three (21%), stable disease in seven (50%), and progressive disease in four (29%). The most frequent treatment-related adverse events were skin rash, flu-like symptoms, and fatigue (both treatment arms); diarrhea (gefitinib arm only); and thrombocytopenia and leukopenia (imatinib arm only). Median time to tumor progression (range) for patients on the gefitinib arm only was 4.27 (1.13-15.97) months and median overall survival (range) was 11.42+ (1.13-29.07+) months. Combination of gefitinib with interferon safely delays progression of refractory MRCC. Further studies in this setting are warranted.
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PMID:Interferon-alpha in combination with either imatinib (Gleevec) or gefitinib (Iressa) in metastatic renal cell carcinoma: a phase II trial. 1841 19

Disorders affecting the postsynaptic side of the neuromuscular junction include autoimmune myasthenia gravis (MG) as well as some of the congenital myasthenic syndromes (CMS). Lambert-Eaton myasthenic syndrome (LEMS) is an acquired autoimmune neuromuscular disorder in which autoantibodies are directed against the presynaptic calcium channels. Here we describe two monozygous twin brothers: case 1 was diagnosed with an indeterminate form of acquired postsynaptic neuromuscular junction defect at age 32 and case 2 with LEMS at age 47. Case 1 presented clinically with mild generalized myasthenic weakness, neurophysiological examination revealed disturbed neuromuscular transmission along with probable myositis and serum analysis regarding antibodies against the acetylcholine receptor and muscle-specific tyrosine kinase was negative. Case 2 presented with proximal muscle fatigue accompanied by areflexia at rest and antibodies against the P/Q-type voltage-gated calcium channels were present. Neurophysiologically, case 2 had reduced baseline compound motor action potential amplitudes on neurography, decrement on low-frequency repetitive nerve stimulation (RNS) and pathological increment on high frequency RNS. To our knowledge this is the first case report of its kind and adds an intriguing contrast to the more common diagnosis of CMS in monozygous twins.
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PMID:Monozygous twins with neuromuscular transmission defects at opposite sides of the motor endplate. 1868 14


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