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)

Breast cancer is the second leading cause of cancer death in women. Treatment options for advanced-stage disease, although numerous, remain suboptimal. Lapatinib and ixabepilone are two new agents approved by the United States Food and Drug Administration (FDA) in 2007 for the treatment of locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). When added to the existing endocrine therapies-single--agent cytotoxic therapies and combination chemotherapy regimens--lapatinib and ixabepilone offer potential treatment strategies for disease that has become resistant to trastuzumab and the taxanes, respectively. Lapatinib is an oral dual tyrosine kinase inhibitor against members of the human epidermal growth factor receptor (HER) family (HER1 or epidermal growth factor receptor [EGFR], and HER2). It is indicated for combination therapy with capecitabine for the treatment of patients with HER2-overexpressing LABC or MBC whose disease has progressed after receiving previous treatment with an anthracycline, a taxane, and trastuzumab. Of note, lapatinib is the first FDA-approved tyrosine kinase inhibitor indicated for use in MBC. Ixabepilone, the first FDA-approved analog of the antimicrotubule agent epothilone B, is indicated as monotherapy for the treatment of LABC or MBC in patients whose tumors are refractory or resistant to anthracyclines, taxanes, and capecitabine. It is also indicated in combination with capecitabine for treatment of LABC or MBC that is resistant to anthracycline and taxane. Both lapatinib and ixabepilone are fairly well tolerated. The most common toxicities with lapatinib are diarrhea (65%) and hand-and-foot syndrome (53%), whereas peripheral neuropathy (62%), fatigue (56%), and neutropenia (54%) are most common with ixabepilone. Though the conventional standard end point of overall survival has not yet been assessed in clinical trials, these agents have been shown to improve surrogate markers of clinical benefit: progression-free survival and the related time to progression. Future clinical trials should focus on elucidation of optimal combination or sequential therapies, as well as patient-specific therapies based on tumor characteristics, such as biomarkers and tumor subtypes.
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PMID:Lapatinib and ixabepilone for the treatment of metastatic breast cancer. 1882 21

Pazopanib, which is being developed by GlaxoSmithKline plc, is an oral, second-generation multi-targeted tyrosine kinase inhibitor that targets VEGFR, platelet-derived growth factor receptor and c-kit, key proteins responsible for tumor growth and survival. Pazopanib exhibited good potency against all of the human VEGFRs and closely related tyrosine receptor kinases in vitro, and demonstrated antitumor activity in several human tumor xenografts, including renal cell carcinoma (RCC), and breast and lung cancer. In phase I and II clinical trials, pazopanib was generally well tolerated with the main side effects being hypertension, fatigue or gastrointestinal disorders. Pazopanib alone caused a decrease in tumor size and stable disease in a significant number of patients, including those with RCC, NSCLC and gynecological tumors. The combination of pazopanib with lapatinib was effective in patients with breast cancer. At the time of publication, pazopanib monotherapy was being evaluated in phase III trials in patients with RCC and as combination therapy with lapatinib in patients with breast cancer. In addition, phase I and II trials were being conducted to assess pazopanib alone or in combination with a range of chemotherapeutics in patients with solid tumors or multiple myeloma.
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PMID:Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. 1903 39

Sorafenib (Nexavar) is an orally active multikinase inhibitor that is approved in the EU for the treatment of hepatocellular carcinoma. Monotherapy with sorafenib prolongs overall survival and delays the time to progression in patients with advanced hepatocellular carcinoma who are not candidates for potentially curative treatment or transarterial chemoembolization. Sorafenib is generally well tolerated in patients with advanced hepatocellular carcinoma. Thus, sorafenib represents an important advance in the treatment of advanced hepatocellular carcinoma and is the new standard of care for this condition. The bi-aryl urea sorafenib is an oral multikinase inhibitor that inhibits cell surface tyrosine kinase receptors (e.g. vascular endothelial growth factor receptors and platelet-derived growth factor receptor-beta) and downstream intracellular serine/threonine kinases (e.g. Raf-1, wild-type B-Raf and mutant B-Raf); these kinases are involved in tumour cell proliferation and tumour angiogenesis. In vitro, dose-dependent inhibition of cell proliferation and induction of apoptosis was seen with sorafenib in human hepatocellular carcinoma cells lines. Sorafenib demonstrated dose-dependent antitumour activity in a murine xenograft model of human hepatocellular carcinoma. Steady-state plasma concentrations were reached within 7 days in patients with advanced, refractory solid tumours who received twice-daily oral sorafenib. Metabolism of sorafenib occurs primarily in the liver and is mediated via cytochrome P450 (CYP) 3A4 and uridine diphosphate glucuronosyltransferase 1A9. In advanced hepatocellular carcinoma, differences in sorafenib pharmacokinetics between Child-Pugh A and B patients were not considered clinically significant. Sorafenib may be associated with drug interactions. For example, sorafenib exposure was reduced by an average 37% with concomitant administration of the CYP3A4 inducer rifampicin (rifampin); sorafenib concentrations may also be decreased by other CYP3A4 inducers. Monotherapy with oral sorafenib 400 mg twice daily prolonged median overall survival and delayed the median time to progression in patients with advanced hepatocellular carcinoma, according to the results of two randomized, double-blind, placebo-controlled, multicentre, phase III trials (the SHARP trial and the Asia-Pacific trial). There was no significant difference between sorafenib and placebo recipients in the median time to symptomatic progression in either trial. The vast majority of patients included in these trials were Child-Pugh A. Combination therapy with sorafenib plus doxorubicin did not delay the median time to progression to a significant extent compared with doxorubicin alone in patients with advanced hepatocellular carcinoma, according to the results of a randomized, double-blind, phase II trial. However, the median durations of overall survival and progression-free survival were significantly longer in patients receiving sorafenib plus doxorubicin than in those receiving doxorubicin alone. Combination therapy with sorafenib plus tegafur/uracil or mitomycin also showed potential in advanced hepatocellular carcinoma, according to the results of noncomparative trials. Monotherapy with oral sorafenib was generally well tolerated in patients with advanced hepatocellular carcinoma, with a manageable adverse effect profile; diarrhoea and hand-foot skin reaction were consistently the most commonly occurring drug-related adverse events in clinical trials. In the SHARP trial, drug-related adverse events of any grade occurring in significantly more sorafenib than placebo recipients included diarrhoea, hand-foot skin reaction, anorexia, alopecia, weight loss, dry skin, abdominal pain, voice changes and 'other' dermatological events. A similar tolerability profile was seen in the Asia-Pacific trial. As expected given the addition of a chemotherapy agent, the adverse event profile in patients with advanced hepatocellular carcinoma who received combination therapy with sorafenib plus doxorubicin differed somewhat to that seen with sorafenib monotherapy in the SHARP trial. In patients receiving sorafenib plus doxorubicin, the most commonly occurring all-cause adverse events (all grades) included fatigue, neutropenia, diarrhoea, elevated bilirubin levels, abdominal pain, hand-foot skin reaction, left ventricular dysfunction, hypertension and febrile neutropenia.
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PMID:Sorafenib: a review of its use in advanced hepatocellular carcinoma. 1922 77

Myasthenia gravis (MG) is an autoimmune disorder usually caused by antibodies against either the acetylcholine receptor (AChR) or muscle-specific tyrosine kinase (MuSK) at the neuromuscular junction. Neuromuscular transmission failure results in muscle fatigue and weakness that can be treated symptomatically with acetylcholinesterase inhibitors (AChEIs). Long-term treatment with nonselective AChEIs may have considerable drawbacks; thus, this medication is ideally tapered when strength improves. Patients with AChR antibodies respond beneficially to treatment, whereas patients with MuSK antibodies generally do not. Recently, the selective AChEI EN101, which specifically targets the isoform of "read-through" AChE (AChE-R), has been developed and may be of importance for symptomatic relief in AChR-antibody seropositive MG. This article is a review of the mechanisms, therapeutic effects, and drawbacks, with both old and new AChEIs in MG.
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PMID:Acetylcholinesterase inhibitors in MG: to be or not to be? 1926 48

The number of VEGFR tyrosine kinase inhibitors (TKIs) used as an anti-cancer agent is rapidly increasing, but several issues in clinical practice remain to be elucidated. VEGFR TKIs are multikinase inhibitors that have additional targets such platelet-derived growth factor receptors, which may result in an increased efficacy as well as an increased toxicity. Efficacy in several cancers has been shown, but acquired resistance also occurs during treatment with this new class of drugs. Tumor response evaluation can be a challenge, because VEGFR TKIs can cause extensive tumor necrosis without a marked decrease in tumor size. Therefore, new response criteria and functional imaging techniques are required. In this review we will also focus on the specific toxicities and their management: hypertension, proteinuria, cardiac toxicity, fatigue, hypothyroidism, voice changes, gastrointestinal toxicity, cutaneous reactions, wound healing, hemorrhage and thromboembolic events, hematological toxicity and cerebral toxicity. Furthermore we will discuss some issues regarding the pharmacology and dosing of these drugs. This review may provide important information to clinicians who prescribe VEGFR TKIs to their patients.
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PMID:Tyrosine kinase inhibitors of VEGF receptors: clinical issues and remaining questions. 1927 99

Despite their inherent selectivity, targeted therapies such as tyrosine kinase inhibitors (TKIs) can cause unusual adverse effects. Sunitinib and sorafenib are multitargeted TKIs that have been demonstrated to induce hypothyroidism and thyroid dysfunction. Retrospective studies indicate that sunitinib can induce hypothyroidism in 53-85% of patients, and in prospective studies this complication has been reported in 36-71% of patients. Sorafenib has been reported to be responsible for hypothyroidism in 18% of patients with metastatic renal-cell carcinoma. Furthermore, imatinib and sunitinib seem to increase the requirement of levothyroxine in hypothyroid patients. The management of thyroid dysfunction and possible related symptoms, such as fatigue, represents a challenge to oncologists. We propose a diagnostic and therapeutic algorithm for the management of TKI-related hypothyroidism. Prospective trials are needed to define the incidence of overt and subclinical hypothyroidism and thyroid dysfunction during therapy with sunitinib, sorafenib and potentially other TKIs. The safety and efficacy, and optimal dosing and timing of starting replacement therapy in patients affected by TKI-related hypothyroidism need accurate appraisal and should be evaluated prospectively in appropriately designed trials.
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PMID:Hypothyroidism related to tyrosine kinase inhibitors: an emerging toxic effect of targeted therapy. 1933 28

Vandetanib is a novel, orally available inhibitor of different intracellular signaling pathways involved in tumor growth, progression, and angiogenesis: vascular endothelial growth factor receptor-2, epidermal growth factor receptor, and REarranged during Transfection tyrosine kinase activity. Phase I clinical trials have shown that vandetanib is well tolerated as a single agent at daily doses < or =300 mg. In the phase II setting, negative results were observed with vandetanib in small cell lung cancer, metastatic breast cancer, and multiple myeloma. In contrast, three randomized phase II studies showed that vandetanib prolonged the progression-free survival (PFS) time of patients with non-small cell lung cancer (NSCLC) as a single agent when compared with gefitinib or when added to chemotherapy. Rash, diarrhea, hypertension, fatigue, and asymptomatic QTc prolongation were the most common adverse events. Antitumor activity was also observed in medullary thyroid cancer. Four randomized phase III clinical trials in NSCLC are exploring the efficacy of vandetanib in combination with docetaxel, the Zactima in cOmbination with Docetaxel In non-small cell lung Cancer (ZODIAC) trial, or with pemetrexed, the Zactima Efficacy with Alimta in Lung cancer (ZEAL) trial, or as a single agent, the Zactima Efficacy when Studied versus Tarceva (ZEST) and the Zactima Efficacy trial for NSCLC Patients with History of EGFR-TKI chemo-Resistance (ZEPHYR) trials. Based on a press release by the sponsor of these trials, the PFS time was longer with vandetanib in the ZODIAC and ZEAL trials; the ZEST trial was negative for its primary superiority analysis, but was successful according to a preplanned noninferiority analysis of PFS. Ongoing phase II and III clinical trials will better define the appropriate schedule, the optimal setting of evaluation, and the safety of long-term use of vandetanib.
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PMID:Vandetanib (ZD6474), a dual inhibitor of vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) tyrosine kinases: current status and future directions. 1934 11

Sunitinib is an orally administered multitargeted tyrosine kinase inhibitor that has demonstrated substantial antitumour activity in patients with metastatic renal cell carcinoma. The more common grade 3 or 4 adverse effects of sunitinib include hypertension, fatigue, hand-foot syndrome, elevated lipase and lymphopenia. We report the case of a 69-year-old patient with metastatic renal clear-cell carcinoma, treated with nephrectomy and three lines of therapy (interleukin-2 plus interferon-alpha2a, vinorelbine plus gemcitabine, and capecitabine), who started a fourth-line therapy with oral sunitinib because of disease progression. At the end of his fifth cycle of sunitinib therapy, the patient complained of the development of abnormally large mammary glands associated with pain and peri-areolar erythema. After 2 weeks' off therapy, a partial reduction in mammary gland enlargement, local pain and erythema was observed. However, re-initiation of sunitinib treatment was followed by bilateral breast enlargement again. The mechanism by which sunitinib induces gynaecomastia is thought to be associated with an unknown direct action on breast hormonal receptors. To the best of our knowledge, this is the first report of an association between sunitinib and gynaecomastia.
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PMID:Onset of male gynaecomastia in a patient treated with sunitinib for metastatic renal cell carcinoma. 1949 66

Myasthenia gravis is an autoimmune disease characterized by weakness and fatigue of the skeletal muscles of the face and extremities. Pregnancy is associated with 19-41% of exacerbations. We present a 19-year-old woman who was seen at the neurology clinic 10 days after her last cesarean section with diplopia and trouble swallowing liquids and solids for the previous 3 months. On examination she had slurred speech, bilateral palpebral ptosis, and mild droop of her shoulders. An arterial blood sample showed a PCO2 of 50 mmHg and a PO2 of 70 mmHg. The tensilon test was positive, Intravenous methylprednisolone and immunoglobulin and oral pyridostigmine effectively relieved her myasthenic signs and symptoms. Five assays for acetylcholine or anti-striational antibodies in her serum were negative. A test for muscle-specific tyrosine kinase antibody was positive. In 10-20% of patients with myasthenia gravis no antibodies to acetylcholine receptors are detectable. Forty percent of this group has an antibody to muscle-specific tyrosine kinase.
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PMID:"Seronegative" anti-MUSK positive myasthenia gravis presenting during pregnancy. 1961 May 60

Sunitinib is a novel, oral, multi-targeted tyrosine kinase inhibitor with antiproliferative effects against cancer cells and antiangiogenic properties. Sunitinib was recently approved for the first-line treatment of patients with advanced renal cell carcinoma (RCC) and for the treatment of patients with gastrointestinal stromal tumours (GIST) after disease progression or intolerance to imatinib therapy. The main purpose of this benefit-risk assessment is to review data on sunitinib efficacy along with its toxicity in patients with GIST and RCC. Sunitinib demonstrates a high level of efficacy with acceptable tolerability using either the 50 mg daily oral dosing for 4 weeks every 6 weeks or a continuous daily administration schedule at a lower dose. Hypertension and asthenia appear to be the most common adverse effects with sunitinib. Diarrhoea, anorexia, disgeusia, stomatitis and skin toxicity are other clinically relevant toxicities. Fatigue may, at least in part, be related to the development of hypothyroidism during sunitinib therapy. Skin toxicity consists of bullous lesion in the soles and palms that may require treatment discontinuation for a few days and/or dose reduction. Thyroid hormone levels should be monitored during treatment with sunitinib, with the occurrence of clinical signs of hypothyroidism needing treatment with levothyroxine sodium. Hypertension usually requires standard antihypertensive therapy and treatment discontinuation is less frequently necessary. Mild neutropenia and thrombocytopenia usually require no intervention. A decrease in left ventricular ejection fraction is a rare but potentially life-threatening complication. Although usually well tolerated, sunitinib needs to be administered cautiously with medical follow-up in patients with cancer to prevent, avoid and treat adverse effects in order to improve patient compliance. Its established antitumor activity requires attempting to maintain the highest tolerable dose in individual patients. Current oral formulations allow physicians to modulate dosages (between 25 and 50 mg/day) and/or schedules (4 weeks on, 2 weeks off or continuous administration) to optimize the benefit-risk profile of sunitinib in individual patients.
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PMID:Benefit-risk assessment of sunitinib in gastrointestinal stromal tumours and renal cancer. 1967 Sep 13


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