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)

We examined the effect of recovery following reversible ATP depletion on MAP kinase activity in cultured renal cells of proximal tubular origin (LLC-PK1). We induced ATP depletion by 0.1 micromol/l antimycin A in combination with substrate deprivation, and obtained recovery by restoration of substrate supply. MAP kinase activity increased from 374+/-45 pmol/mg protein/mm during ATP depletion to 768 +/- 77 pmol/mg protein/mm after 15 min of recovery. We used ATP to activate a representative G-protein coupled receptor, or epidermal growth factor (EGF) to activate receptors with intrinsic tyrosine kinase activity, and measured the effect of these manipulations on MAP kinase activity during ATP depletion or following recovery. ATP and EGF stimulated MAP kinase activity under control conditions, but not during ATP depletion or after recovery. This shows that two distinct signal transduction pathways represented by ATP and EGF are blocked during ATP depletion and recovery. The lack of energy during ATP depletion and the already maximally stimulated MAP kinase during recovery is likely to be the reason for these results. In summary, these findings suggest that MAP kinase may be involved in the physiological response of cells injured by hypoxia.
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PMID:Activation of MAP kinase after reversible ATP depletion in LLC-PK 1 cells. 1084 98

SUGEN is developing SU-6668, a tyrosine kinase inhibitor that inhibits three distinct growth factor receptor targets, for the potential treatment of cancer [304530]. The compound is in phase I trials in the UK and US [321260], [374505]. A report in January 2001 stated that phase I/II trials for hematological and solid tumors were expected to commence shortly thereafter [395657]. In May 2001, phase I data from a dose-escalation study conducted at UCLA were presented at the 37th ASCO meeting in San Francisco, CA. By that time, 74 patients had been enrolled in this study which aimed to determine the toxicities of SU-6668 when delivered to fed and fasting patients. SU-6668 was administered orally either once or twice-daily at doses of 100 to 2400 mg/m2 to patients diagnosed as having advanced malignancies. Accrual in phase I is continuing to define the toxicities of doses > 200 mg/m2 twice-daily [409984], [411418]. In December 1998, SUGEN filed an IND with the FDA for the clinical testing of this compound with oral and iv formulations [310237]. In November 1998, SUGEN entered into a collaboration with the Cancer Research Campaign (CRC) to conduct a phase I trial of SU-6668 at the Royal Marsden Hospital, UK using an iv formulation [304530]. After the first six patients had been treated, the trial was halted owing to problems with the iv formulation. Some toxicities, including nausea, vomiting, fatigue and tumor pain were observed [413538]. No licensing agreement as involved between the CRC and SUGEN for this trial [408572].
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PMID:Su-6668. SUGEN. 1189 27

Colorectal cancers (CRC) express the epidermal growth factor receptor (EGF-R), a type I transmembrane receptor with tyrosine kinase activity. EGF-R signaling inhibition is a promising target for cancer therapy. ZD1839 (Iressa, AstraZeneca) and OSI-774 (Tarceva, Roche) are small molecular weight molecules with selective and reversible tyrosine kinase inhibition properties directed to EGF-R. Orally administered, these molecules induce sustained tumor stabilizations in previously treated metastatic CRC patients. The most frequent treatment-related toxicities are fatigue, diarrhea and acne-like follicular rash. The addition in the clinic of 5-FU, lOHP or CPT-11 to ZD1839 or OSI-774 does not seem to increase the own toxicity of each cytotoxic agents. Cetuximab (Erbitux, Merck) is an intravenously administered humanized monoclonal antibody which bind with high affinity with the extracellular domain of the EGF-R. The most frequent treatment-related toxicities are diarrhea, fatigue, nausea and cutaneous toxicity (allergic or acne-like follicular rashes, folliculitis). Most, if not all of these adverse events are mild. Partial responses were observed with cetuximab either alone (RR: 10%) or in combination with CPT-11 (RR: 22%) in patients with CPT-11 refractory advanced CRC which expressed EGF-R. The combination of cetuximab to folinic acid, 5-FU and CPT-11 seems tolerable at the cost of a slight increase of severe diarrhea and neutropenia. Finally, the promising activity of these EGF-R inhibitors has to be confirmed throughout randomized studies.
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PMID:[Inhibitors of epidermal growth factor receptor and colorectal cancer]. 1476 44

Neurotrophins modulate acute and sustained synaptic plasticity. In cultured Xenopus laevis neuromuscular junctions, neurotrophins improve neuromuscular transmission. Whether this influence exists at the mammalian neuromuscular junction is unknown. We hypothesized that neurotrophins improve neuromuscular transmission at neuromuscular junctions of adult rat diaphragm muscle fibers. A diaphragm muscle-phrenic nerve preparation was used to determine the effects of brain-derived neurotrophic factor (BDNF), neurotrophin-4 (NT-4) and K252a [tyrosine kinase (Trk) receptor inhibitor] on the extent of neuromuscular transmission failure induced by repetitive nerve stimulation. We found significant enhancement of neuromuscular transmission with BDNF or NT-4 treatment, whereas K252a treatment worsened neuromuscular transmission. In contrast, diaphragm muscle contractile and fatigue properties were unaffected by neurotrophin or K252a treatment. These results demonstrate that BDNF and NT-4 improve synaptic transmission in the adult rat diaphragm muscle, likely in a Trk-dependent fashion. Neurotrophins may constitute a novel therapeutic target to improve neuromuscular function in the diaphragm.
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PMID:Neurotrophins improve neuromuscular transmission in the adult rat diaphragm. 1498 37

(1) For many years the reference first-line treatment for patients with chronic myeloid leukaemia who do not qualify for bone marrow transplantation was interferon alfa-2, possibly combined with cytarabine. (2) Imatinib, a tyrosine kinase inhibitor, was initially approved for second-line treatment of adults with chronic myeloid leukaemia and in the accelerated phase or blast crisis. This indication has now been extended to cover first-line treatment and children. (3) An unblinded trial in 1106 adults compared imatinib (400 mg/day by mouth) as a first-line treatment with the combination of interferon (5 MIU/m2/day) and cytarabine (20 mg/m2/day, 10 days a month) subcutaneously. After 18 months, imatinib significantly increased progression-free survival rate (92.1% versus 73.5%) and quality of survival, but not overall survival. (4) In the paediatric setting, there are follow-up data from only 17 children who received imatinib as a first- or second-line treatment. The results were similar to those obtained in adults. (5) In the only available trial in adults, the number of treatment withdrawals for adverse events was lower among patients taking imatinib. Fatigue and depression were the two serious adverse events reported more commonly by people taking interferon + cytarabine. (6) Imatinib is given by mouth, which is more convenient than subcutaneous route required for interferon + cytarabine. (7) In practice, pending a second comparative trial and further follow-up, imatinib seems a therapeutic advance in the first-line treatment of chronic myeloid leukaemia.
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PMID:Imatinib: new indication. Chronic myeloid leukaemia, first-line option: favourable findings to be confirmed. 1498 92

Patients with advanced non-small cell lung cancer (NSCLC) who fail to respond to cytotoxic chemotherapy or who cannot tolerate chemotherapy have limited treatment options. In addition, patients with advanced NSCLC often experience disease-related symptoms that impact their quality of life. Treatment goals in this setting include palliation of symptoms and improvement in quality of life, in addition to tumor response or disease stabilization and increased survival. ZD1839 (Iressa, gefitinib) is an orally active, small-molecule, epidermal growth factor receptor-tyrosine kinase inhibitor that has shown single-agent efficacy for previously treated advanced NSCLC. In phase I clinical trials, ZD1839 provided relief from symptoms often associated with lung cancer, including fatigue, shortness of breath, and chest pain. The IRESSA Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2 clinical trials evaluated ZD1839 treatment at 250 mg/day and 500 mg/day in patients with advanced NSCLC for objective tumor response and safety, as well as for improvements in NSCLC-related symptoms and health-related quality of life. The majority of patients enrolled in these studies had received multiple prior treatments. Rapid, sustained symptom improvement was documented for many patients receiving ZD1839 at 250 mg/day or 500 mg/day in both IDEAL trials and was positively associated with clinical benefits, such as tumor response and increased survival.
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PMID:Effects of ZD1839 (Iressa, gefitinib) treatment on symptoms and quality of life in patients with advanced non-small cell lung cancer. 1520 79

Gastrointestinal stromal tumor (GIST), the most common mesenchymal tumor of the human gastrointestinal tract, is thought to originate from the interstitial cells of Cajal. The mutation of c-kit, cording KIT, is essential in the development of GIST. Imatinib mesylate (IM), an agent for chronic myeloid leukemia, was reported to inhibit tyrosine kinase activity of KIT and to be highly effective for GIST. We report, here, a case of huge gastric GIST who underwent neoadjuvant therapy followed by surgical resection. The patient was a 62-year-old man with GIST in cardia (KIT+, CD34+, mitotic rate 5/50 HPF), whose chief complaint was general fatigue. Because the huge tumor, 7.5 cm in size, directly invaded the pancreas, total gastrectomy with distal pancreatosplenectomy was necessary for curative resection. IM was administered (400 mg/body/day) as a neoadjuvant treatment for down-staging of the tumor. Leucopenia (grade 2) and diarrhea (grade 1) were observed as the adverse effects of IM. Partial response was obtained. He underwent proximal gastrectomy without pancreatosplenectomy since CT no longer showed direct invasion to the pancreas. Histological examination of the resected specimen revealed the extensive degeneration of the tumor, in which tumor cells containing condensed nuclei had decreased remarkably. Interestingly, mitotic rate decreased to 0/50 HPF in the effective area of the resected specimen, indicating that recurrent risk might be decreased. A part of the viable tumor cells, however, had the same feature to that in the biopsied specimen before treatment. The results suggest that the heterogeneity of GIST induces different sensitivity to IM. The postoperative course was uneventful and no sign of recurrence was observed 3 months after surgery. Neoadjuvant therapy with IM may become a useful strategy for GIST, as it reduces the tumor size and decreases the recurrence rate.
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PMID:[A case of gastric GIST treated preoperatively by imatinib mesylate]. 1533 47

Despite improvements in conventional treatment, patients with advanced non-small-cell lung cancer (NSCLC) have a poor prognosis, leaving a significant unmet need for novel treatments. One such novel, biologically targeted agent is the orally active epidermal growth factor receptor tyrosine kinase inhibitor gefitinib. This open-label pilot trial investigated the safety, pharmacokinetics, and efficacy of 2 doses of gefitinib (250 and 500 mg per day) combined with docetaxel (75 mg/m2) in patients with locally advanced or metastatic NSCLC as first- and second-line chemotherapy. Eighteen patients were recruited: 6 received gefitinib 250 mg per day plus docetaxel; 12 received gefitinib 500 mg per day plus docetaxel. Combination therapy was feasible with no overlapping toxicities. No patients experienced dose-limiting toxicities (DLTs) at 250 mg per day; 1 patient had 2 DLT events at 500 mg per day (grade 3 rash and diarrhea for >4 days). Adverse events were mild to moderate, including fatigue, mucositis, nausea, anorexia, rash, diarrhea, and fever. Docetaxel did not appear to alter steady-state exposure to gefitinib. The effect of gefitinib on exposure to docetaxel was equivocal; with the exception of 2 patients in the gefitinib 250 mg per day dose group, there appeared to be no trend toward a higher or lower exposure to docetaxel when given in the presence of gefitinib compared with that when given alone. Combination therapy was associated with antitumor activity and responses were seen with gefitinib in 2 of 6 patients at 250 mg per day and 4 of 12 patients at 500 mg per day. This combination is feasible and has an acceptable and predictable safety profile, as well as associated antitumor activity.
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PMID:A pilot trial of gefitinib in combination with docetaxel in patients with locally advanced or metastatic non-small-cell lung cancer. 1594 94

Non-alcoholic steatohepatitis (NASH) is one of the most common liver disorders. This is highly prevalent in obese and diabetic subjects. Persons with central obesity are at particular risk. Other clinical predictors are age more than 40-50 years and hyperlipidemias, but none of these factors is invariable for causation of NASH. Other reported associations are, celiac disease, Wilson's Disease and few other metabolic diseases. Drugs, particularly amiodarone, tamoxifen, nucleoside analogues and methotrxate have also been linked to NASH. The disease is evenly distributed in both sexes but advanced disease is more common in women. Ethnic variation exists and African Americans are less affected than Hispanic Americans. Specific clinical features of NASH are infrequent. Patients usually come to clinical attention by elevated liver enzymes found on routine evaluation but on history, about two third of patients will admit to have mild fatigue and about half will report right upper quadrant pain. Rarely, patient may present with a complication of cirrhosis. Physical examination may reveal hepatomegaly and splenomegaly. Research in last few years has stressed that development of steatosis, stetohepatitis, fibrosis with subsequent cirrhosis are most probably the result of insulin resistance. Therefore, clinical features may reflect existence of insulin resistance. Obesity, particularly central obesity is most important of these. Patients may have sleep apnea syndrome. Hypertension and manifestations of diabetes mellitus like polyuria, polydypsia, and neurological deficits may occur. Patients may have varying combination of obesity, diabetes, hyperlipidemia, hypertension and impaired fibrinolysis (syndrome X). Children with insulin resistance may show acanthosis nigricance. Patients with polycystic ovary syndrome, which consists of insulin resistance, diabetes, obesity, hirsutism, oligo or polymenorrha and hyperlipidemia may have NASH. Other rare manifestations of insulin resistance, which can be seen in patients of NASH are lipomatosis, lipoatrophy/lipodystrophy and panniculitis. Most other rare conditions known to cause NASH like peroxisomal diseases, mitochondialpathies, Weber-Christian disease, Mauriac syndrome, Madelung's lipomatosis and abetaliopprotenemia also have insulin resistance. This is believed that primary defect underlying insulin resistance is impairment in postreceptor pathways (through tyrosine kinase activity) of insulin action. Primary defect in insulin receptors appear uncommon. This results in down regulation of insulin receptor substance 1 (IRS-1) signaling by excess free fatty acids. In muscle, activated IRS-1 promotes translocation of glucose transporter protein 4 (GLUT4) to cell membrane. As a result, monocyte glucose uptake by GLUT4 increases glucose disposal from blood and reduced need for insulin. PKC-0 is a likely candidate as serine kinase in muscle regulated by fatty acids that can impair the activation of IRS-1. Insulin resistance is usually evaluated by fasting insulin levels, Quantitative Insulin Check Index (QUICKI) and Homeostasis Model Assessment of Insulin Resistance (HOMA), C-peptid/insulin ratio oral glucose tolerance test and hyper insulinemic euglycemic clamp. The clamp technique is considered the gold standard.
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PMID:Insulin resistance and clinical aspects of non-alcoholic steatohepatitis (NASH). 1619 20

Chronic myelogenous leukemia (CML) represents about 14% of all leukemias and occurs with a frequency of about 1 in 100,000. It is rare in children. Symptoms include fatigue, weight loss, sweating, and abdominal discomfort from an enlarged spleen. The white blood cell count can range from 100-600 ul. CML has three phases: the chronic phase, accelerated phase, and blast phase. Most patients are diagnosed during the chronic phase. Ionizing radiation has been implicated in some cases of CML, but in most individuals no cause is known. The Philadelphia chromosome, an acquired genetic mutation represented by a translocation of chromosome 22 and chromosome 9, drives the leukemic changes in CML. Imatinib mesylate, a tyrosine kinase inhibitor, was approved in 2002 for the treatment of all phases of CML. Because of its effectiveness, imatinib has become the treatment of choice for most patients with CML. Stem cell transplantation also is an option for eligible patients. It is the only curative treatment for CML. Two drugs under study for patients who cannot tolerate or who become resistant to imatinib are BMS-354825 and AMN107. Oncology nurses who are knowledgeable about new therapies for CML can be effective resources for their patients.
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PMID:Chronic myelogenous leukemia. 1623 80


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