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 in elderly patients (70+) is a major health problem that will only increase in the future. Besides adequate local treatment and hormone therapy, there can be an indication for chemotherapy in this patient group. Due to concerns of excessive toxicity, there is often a defeatist attitude towards chemotherapy in elderly patients. As taxanes are considered to be the most effective drugs in breast cancer, and as the weekly regimens seem at least as effective as the 3-weekly regimens but with less toxicity, these weekly regimens are very attractive for elderly breast cancer patients. Many different doses have been used for the weekly taxane regimens in phase II trials. Although large comparative studies are lacking, pharmacological studies are suggestive for a decreased clearance of both paclitaxel and docetaxel in elderly patients compared to non-elderly patients. It seems therefore safe to use the lower range of proposed doses of the weekly regimens until further data provide stronger evidence for optimal dosing in elderly patients. A dose of paclitaxel 80 mg/m(2)/week and docetaxel 36 mg/m(2)/week seems tolerable for elderly patients without excessive toxicity and with impressive response rates. The dose limiting toxicity for 3-weekly taxanes, severe neutropaenia, is generally very limited in weekly regimens, also in the elderly or frail patients. However, neuropathy (paclitaxel) or fatigue and fluid retention (docetaxel) can be troublesome, and eventually require dose modifications. In general however, weekly taxanes are a reasonable option for older patients with metastatic breast cancer.
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PMID:Taxanes in elderly breast cancer patients. 1514 8

At the outset of the research programme into irritable bowel syndrome (IBS) it was perceived that there was a need to develop a symptom-based classification for the patients. Four groups of patients were identified, those with spastic colon syndrome, diarrhoea-predominant spastic colon syndrome, functional diarrhoea and midgut dysmotility. While working with outpatients with IBS it was noted how some of them had suffered symptoms for many years; specifically, a group of patients satisfying the criteria for midgut dysmotility had also suffered from particularly severe and intractable intestinal symptoms. These patients underwent 24 h ambulatory studies of small intestinal motility and the majority were found to have manometric features of chronic idiopathic intestinal pseudo-obstruction (CIIP). To characterise the cause, laparoscopic full-thickness small intestine and colonic biopsies have been obtained in forty-five of the latter group of patients. Of these patients 58% have been found to have complete or partial deficiency of alpha-actin epitope staining in the inner circular layer of small intestinal smooth muscle. This deficiency is believed to represent an important biomarker rather than the cause of CIIP, since alpha-actin epitope deficiency has been observed in association with enteric neuropathy and myopathies. In relation to the management of CIIP patients, a multidisciplinary model is proposed incorporating management of co-morbid psychological and psychiatric pathology, abdominal and musculoskeletal pain, fatigue, urological symptoms and nutrition. A six-stage nutritional management plan for these patients is presented.
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PMID:Chronic idiopathic intestinal pseudo-obstruction: the need for a multidisciplinary approach to management. 1537 60

Thalidomide has anti-angiogenic and immunomodulatory activity, exhibiting antitumour effects in patients with multiple myeloma and, more rarely, in several other solid tumours. We evaluated the single-agent antitumour activity and toxicity profile of thalidomide in patients with metastatic malignant melanoma, as well as its plasma pharmacokinetics and pharmacodynamic effects [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (b-FGF) levels]. A two-stage Gehan method was used with a stopping rule after 14 consecutive non-responding patients. Thalidomide was given orally at a daily dose of 200 mg/day, which was then escalated every 2 weeks by 200 mg/day as tolerated to a maximum of 800 mg/day. Patients were evaluated every 8 weeks for response using the World Health Organization (WHO)-27 criteria. Fourteen patients were enrolled and no objective responses were observed, with one stable disease and one mixed response. The dose-limiting toxicities were constipation, dizziness and somnolence. Other toxicities were oedema, neuropathy, dry skin, dry mouth, tremor and fatigue. The plasma pharmacokinetics of thalidomide were comparable with those of previous studies in normal volunteers and in patients with advanced prostate cancer. Serum levels of b-FGF and VEGF did not change significantly following drug administration. In conclusion, thalidomide showed poor activity, but acceptable toxicity, in patients with metastatic melanoma. Future studies should explore this agent in combination with other biological agents or cytotoxic agents, such as temozolomide.
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PMID:Phase II study of thalidomide in patients with metastatic malignant melanoma. 1557 25

The primary objective of these trials was to determine the 1-year survival of advanced non-small cell lung cancer (ANSCLC) patients (> or =70 years with PS 0-2 or > or =18 years with PS 2) receiving sequential paclitaxel and carboplatin (P --> C) or concurrent P + C. The secondary objectives were assessment of toxicities and quality of life. A total of 121 patients with NSCLC were treated. P--> C patients received paclitaxel (80 mg/m(2)) weekly x 3, followed by 1 week of rest; these 4-week cycles were repeated until relapse. At relapse, patients received carboplatin (AUC = 5, IV) on Day 1 of each 3-week cycle until evidence of further progression or lack of improvement. P + C patients received paclitaxel (80 mg/m(2)) and carboplatin (AUC = 2), weekly x 3, followed by 1 week of rest, until relapse. Patients in both studies were premedicated prior to paclitaxel administration. Sequential P + C resulted in a median survival of 8.2 months (range: <1-18.8) and P + C patients had a median survival of 9.2 months (range: <1-22.0). In both groups (P--> C) and P + C), the 1-year survival was 31%. For patients treated sequentially, treatment-related AEs (TRAE, > or =Grade 3) included fatigue (7%), neuropathy (5%), and leukopenia and diarrhea (3%, each). Grade 4 AEs were limited to neutropenia, febrile neutropenia, and sepsis (1 episode each). For patients receiving concurrent P + C, TRAE included neutropenia and leukopenia (15%, each) and shortness of breath and bilateral bone pain (10%, each). Leukopenia (n = 2) and neutropenia (n = 1) were the only Grade 4 events reported. The analysis of quality of life (QOL) questionnaires indicated that there were no obvious differences between treatment groups during the study. These drugs and treatment schema were well-tolerated when administered in the community setting and resulted in survival rates that were similar to what is reported in the literature with combination therapy administered to "high risk" patients. Finding the optimal chemotherapy regimen, that can be tolerated, remains a challenge in elderly patients.
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PMID:Sequential versus concurrent paclitaxel and carboplatin for the treatment of advanced non-small cell lung cancer in elderly patients and patients with poor performance status: results of two Phase II, multicenter trials. 1560 61

Fifteen patients with advanced multiple myeloma were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 every 3 weeks for eight cycles in combination with dexamethasone. One patient (7%) achieved a complete response, 10 (67%) a partial response, and one (7%) a minor response (MR) resulting in an overall response rate (> or = MR) of 80% (9/9 with > or = 2nd untreated and 3/6 with refractory relapse). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters including deletion of chromosome 13. Adverse events, mainly myelosuppression, neuropathy and fatigue, were manageable.
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PMID:Bortezomib in combination with dexamethasone for relapsed multiple myeloma. 1575 12

Muscle weakness is a common complaint among patients presenting to family physicians. Diagnosis begins with a patient history distinguishing weakness from fatigue or asthenia, separate conditions with different etiologies that can coexist with, or be confused for, weakness. The pattern and severity of weakness, associated symptoms, medication use, and family history help the physician determine whether the cause of a patient's weakness is infectious, neurologic, endocrine, inflammatory, rheumatologic, genetic, metabolic, electrolyte-induced, or drug-induced. In the physical examination, the physician should objectively document the patient's loss of strength, conduct a neurologic survey, and search for patterns of weakness and extramuscular involvement. If a specific cause of weakness is suspected, the appropriate laboratory or radiologic studies should be performed. Otherwise, electromyography is indicated to confirm the presence of a myopathy or to evaluate for a neuropathy or a disease of the neuromuscular junction. If the diagnosis remains unclear, the examiner should pursue a tiered progression of laboratory studies. Physicians should begin with blood chemistries and a thyroid-stimulating hormone assay to evaluate for electrolyte and endocrine causes, then progress to creatine kinase level, erythrocyte sedimentation rate, and antinuclear antibody assays to evaluate for rheumatologic, inflammatory, genetic, and metabolic causes. Finally, many myopathies require a biopsy for diagnosis. Pathologic evaluation of the muscle tissue specimen focuses on histologic, histochemical, electron microscopic, biochemical, and genetic analyses; advances in technique have made a definitive diagnosis possible for many myopathies.
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PMID:Evaluation of the patient with muscle weakness. 1583 36

Oxaliplatin plus fluorouracil/folinic acid (5-FU/FA) every 2 weeks has shown promising activity in advanced gastric cancer. This study assessed the efficacy and safety of weekly oxaliplatin plus 5-FU/FA (FUFOX regimen) in the metastatic setting. Patients with previously untreated metastatic gastric cancer received oxaliplatin (50 mg m(-2)) plus FA (500 mg m(-2), 2-h infusion) followed by 5-FU (2000 mg m(-2), 24-h infusion) given on days 1, 8, 15 and 22 of a 5-week cycle. The primary end point of this multicentre phase II study was the response rate according to RECIST criteria. A total of 48 patients were enrolled. Median age was 62 years and all patients had metastatic disease, with a median number of three involved organs. The most common treatment-related grade 3/4 adverse events were diarrhoea (17%), deep vein thrombosis (15%), neutropenia (8%), nausea (6%), febrile neutropenia (4%), fatigue (4%), anaemia (4%), tumour bleeding (4%), emesis (2%), cardiac ischaemia (2%) and pneumonia (2%). Grade 1/2 sensory neuropathy occurred in 67% of patients but there were no episodes of grade 3 neuropathy. Intent-to-treat analysis showed a response rate of 54% (95% CI, 39-69%), including two complete responses. At a median follow-up of 18.1 months (range 11.2-26.2 months), median survival is 11.4 months (95% CI, 8.0-14.9 months) and the median time to progression is 6.5 months (95% CI, 3.9-9.2 months). The weekly FUFOX regimen is well tolerated and shows notable activity as first-line treatment in metastatic gastric cancer.
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PMID:Phase II study of weekly oxaliplatin plus infusional fluorouracil and folinic acid (FUFOX regimen) as first-line treatment in metastatic gastric cancer. 1601 22

Testing the excitability of axons can provide insights into the ionic mechanisms underlying the pathophysiology of axonal dysfunction in human neuropathies and motor neuron diseases. Threshold tracking, which was developed in the 1990's, non-invasively measures a number of axonal excitability indices, which depend on membrane potential and on the Na+ and K+ conductances. This paper reviews recent advances in ionic-pathophysiological studies in human subjects in vivo. Membrane potential of human axons can be estimated, because most of the ion channels expressed on the axolemma are voltage-dependent, and patterns of changes in multiple excitability indices can suggest whether axons are depolarized or hyperpolarized. This has been clearly demonstrated in a single patient with acute hypokalemia (hyperpolarization) and patients with chronic renal failure (depolarization due to hyperkalemia). Muscle cramps/fasciculations arise from hyperexcitability of the motor axons. The enhanced excitability can result from altered ion channel function; an increase in persistent Na+ conductance, a decrease in accommodative K+ conductance, and focal membrane depolarization, all of which increase excitability, have been demonstrated in amyotrophic lateral sclerosis or other disorders affecting lower motor neurons. Patients with demyelinating neuropathy often complain of muscle fatigue. During voluntary contraction, the activation of the electrogenic Na+-K+ pump and resulting membrane hyperpolarization can cause activity-dependent conduction block when the safety factor for impulse transmission is critically reduced. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms is of clinical relevance, because once a specific ionic conductance is identified, blocking or activating it may provide a new therapeutic option for a variety of neuromuscular diseases.
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PMID:Axonal ionic pathophysiology in human peripheral neuropathy and motor neuron disease. 1618 Oct 85

Fatigue has been shown to be more frequent than previously thought in immune-mediated polyneuropathies. However, fatigue has not been reported as the main cause of referral in chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients. Between January 2001 and December 2003, we investigated 11 patients referred for fatigue, for which we established a final diagnosis of CIDP. All patients had at least two clinical examinations including assessment of the fatigue severity scale (FSS) and one electrophysiological and laboratory work up. Additionally, 10 of the 11 patients had a nerve biopsy. There were 11 male patients. Mean age at onset was 53 +/- 11 years. Main cause of referral was fatigue in all patients. Additional symptoms included cramps (one case), distal paresthesias (six cases), limb pain (seven cases) and vasomotor disturbances (one case). Cerebrospinal fluid (CSF) analysis displayed a moderate increase in protein content in four patients. Electrophysiological analysis showed abnormalities in all patients. Among 11 patients, one fulfilled the American Academy of Neurology electrodiagnostic criteria for CIDP and three fulfilled the inflammatory neuropathy cause and treatment group or the Nicolas et al. criteria. In the eight remaining patients, a nerve biopsy confirmed the diagnosis of CIDP. Ten patients were treated, among which seven showed a significant improvement based on the FSS scale. This study shows that fatigue is a possible cause of referral for patients with CIDP and, like previous reports, emphasizes the lack of sensitivity of widely accepted electrophysiological criteria of CIDP. Long-term follow up of these patients is warranted to determine the prognosis of these minimal forms of CIDP and establish the best therapeutic strategy in such cases.
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PMID:Fatigue as the main presenting symptom of chronic inflammatory demyelinating polyradiculoneuropathy: a study of 11 cases. 1622 Dec 92

Tipifarnib is an oral nonpeptidomimetic farnesyl transferase inhibitor developed to inhibit a variety of farnesylated targets potentially relevant to the therapy of various malignancies. The agent has, thus far, been tested in a wide array of both solid tumors and myeloid malignancies. Phase I trials have demonstrated that tipifarnib is best given in a twice-daily fashion in doses of 600-1200 mg/day to avoid significant neuropathy, fatigue and myelosuppression. Subsequent trials demonstrated that pauses in therapy (with staccato dosing schedules) seem to increase tolerability without a clear decrease in efficacy. Phase II and III trials of tipifarnib as monotherapy for breast, colorectal, lung (both non-small cell and small cell), brain, pancreatic and urothelial cancers have all been disappointing. Combination trials of tipifarnib with cytotoxic, hormonal or biological therapies are ongoing. Tipifarnib has displayed the most interesting activity in the myeloid malignancies of myelodysplastic syndrome, myelofibrosis with myeloid metaplasia and elderly/high-risk acute myeloid leukemia. Overall clinical response rates of approximately 20-30% have been reported in myelodysplastic syndrome and acute myeloid leukemia patients who have few alternative therapeutic options. US FDA approval for tipifarnib awaits results of subsequent Phase III trials of the agent in elderly acute leukemia.
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PMID:Tipifarnib: farnesyl transferase inhibition at a crossroads. 1650 48


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