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)

The medical uses of bisphosphonates derive from their exceptional ability to inhibit bone resorption. However, bone resorption is essential for the healing of fractures, the repair of microscopic fatigue cracks in bone, nad the internal reorientation of trabecular and cortical bone in response to altered mechanical strains. In theory, overdose with bisphosphonates might interfere with the repair of fractures or weaken bone strength (by forcing bones to accumulate and propagate fatigue cracks or by abolishing the skeleton's adaptive powers). Regulatory agencies (particularly in the USA) have, therefore, set comprehensive and stringent safety criteria before the marketing of bisphosphonates can be approved. Some bisphosphonates can also inhibit bone mineralization, alter hepatic function, or cause gastritis/esophagitis. The safety profile of tiludronate will be described from this perspective, emphasizing the results of prolonged treatment in animals, and studies in humans.
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PMID:Skeletal safety of tiludronate. 857 27

The aim of this study was to determine whether it is feasible to reduce the overall treatment time from 7 to 4 weeks in patients with non-small cell lung cancer (NSCLC) receiving radiotherapy with cisplatin. This follows an EORTC phase III randomised trial (08844) in which cisplatin given before each radiation dose resulted in improved local control and survival, but which had a relatively long treatment period of 7 weeks [Schaake-Koning et al., N Engl J Med 1992, 326, 524-530]. 38 patients with confirmed NSCLC (2 stage I, 1 stage II, 18 stage IIIA, 17 stage IIIB) received a total tumour dose of 55 Gy/20 fractions/26 days, from January 1992 to March 1994. Daily fractions of 2 Gy (5 times/week) were given to the macroscopic tumour and the non-involved adjacent lymph node areas. During the same session, a dose of 0.75 Gy was given to the macroscopic tumour (simultaneous boost). Cisplatin 6 mg/m2 was administered 1-2 h before each fraction, in an escalating total dose, during week 1 in 3 patients, during weeks 1 and 2 in 6 patients, during weeks 1, 2 and 3 in 5 patients and during the whole treatment in 24 patients. 38 patients were evaluable for acute side-effects (WHO). Maximal therapy-related toxicity (WHO) was grade 3 (nausea/vomiting in 2 patients, oesophagitis in 3 patients, dyspnoea in 3 patients, cough in 1 patient). Late side-effects were evaluated in 34 patients. There was grade 2 oesophagitis in 2 patients; grade 3 toxicity in 8 patients (tiredness in 3 patients, dyspnoea in 3 patients, oesophagitis in 2 patients); grade 4 toxicity in 4 patients (dyspnoea in 3 patients, cough in 1 patient). Pulmonary fibrosis grade 3 occurred in 4 and grade 4 in 6 patients. One patient developed a severe (grade 3) radiation pneumonitis. The low incidence of acute and late side-effects with this treatment, combining daily administration of 6 mg cisplatin with radical radiotherapy using a simultaneous boost technique, indicates that escalation of the radiation dose seems feasible.
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PMID:Feasibility of escalating daily doses of cisplatin in combination with accelerated radiotherapy in non-small cell lung cancer. 886 92

In this case-report we describe the fatal outcome of systemic vasculitis. A 51-year-old man was hospitalised with constant abdominal pain, chest pain, anorexia, fatigue, weight loss, dyspeptic complaints, and a period of high fever at home. Bilateral adrenal enlargement was found without a plausible cause. Endoscopy revealed a reflux oesophagitis grade I, which was treated with famotidine. His complaints disappeared without further treatment. Five days after release from hospital the patient was re-admitted with subfebrile temperature followed by an Addison's crisis due to primary adrenal failure. Laboratory tests for systemic illness were all negative. He was treated with high-dose corticosteroids. Right adrenal biopsy revealed haemorrhage, possibly of older age. After 10 days he returned with severe kidney and heart failure. He was transported to another hospital for haemodialysis. Unfortunately the patient passed away because of cardiac arrhythmias. Postmortem investigation revealed inflammation of middle-sized and small arteries in the adrenal glands, heart, lung and thyroid. In the kidneys, mesangio-proliferative glomerulonephritis was found. A definite classification of the vasculitis could not be made because of the high-dose corticosteroids therapy. Possibly, the haemorrhage of both adrenal glands was caused by venous thrombosis due to the hypercoagulable state, which is often observed in vasculitis.
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PMID:Bilateral adrenal enlargement as a first sign of systemic vasculitis. 944 26

Despite recent advances in combined modality therapy, long-term survival remains elusive in most patients with limited-stage small cell lung cancer (SCLC). The present study was designed to evaluate the activity and toxicity of concurrent hyperfractionated radiotherapy and weekly, alternating-regimen chemotherapy. Twelve patients with limited-stage SCLC and performance status 0-1 were treated with cyclophosphamide 250 mg/m2, etoposide 100 mg/m2, and cisplatin 50 mg/m2 on day 1 every other week, and vincristine 1 mg/m2 on day 8, and ifosfamide 1.2 mg/m2 on days 8 and 9 every other week. Hyperfractionated thoracic radiotherapy, consisting of three daily doses of 1.1 Gy for 20 days to a total dose of 66 Gy, was started on day 1 of chemotherapy. Ten patients (83%) exhibited an objective response (9 CRs and 1 PR) with a median duration of response of 8.6 months. Two complete responders died at 50 and 53 months without evidence of progression and two remain alive and free of SCLC at 73 and 87 months. Median survival was 19.8 months with 2- and 5-year survival rates of 50 and 17%, respectively. Severe toxicity, including grade 3-4 esophagitis (67%) and granulocytopenia (83%), as well as debilitating fatigue and pneumonitis, prompted early termination of the trial. Hyperfractionated radiotherapy and concurrent weekly alternating-regimen chemotherapy resulted in promising response and survival rates, but induced excessive toxicity, in patients with limited-stage SCLC.
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PMID:Phase II study of hyperfractionated radiotherapy and concurrent weekly alternating chemotherapy in limited-stage small cell lung cancer. 986 6

CHS 828 is a cyanoguanidine, which has demonstrated potent antitumor activity in preclinical tumor models. The activity of CHS 828 in vitro showed only low to moderate correlation to other antineoplastic agents suggesting a unique mechanism of action. Ten females and 6 males (median age 58 years) with solid tumors refractory to standard therapy were included in this Phase I study. The study drug was administered to fasting patients as a single oral dose on days 1-5 of each treatment cycle. Patients received one to six cycles of treatment. The doses ranged from 30 mg to 200 mg (total dose within a cycle). Hematological toxicity was generally mild and dominated by transient thrombocytopenia and lymphocytopenia. Nonhematological toxicity most frequently consisted of nausea, vomiting, diarrhea, fatigue, and localized genital mucositis. The dose-limiting toxicities were thrombocytopenia, thrombosis, esophagitis, diarrhea, and constipation. The recommended Phase II dose of CHS 828 was 20 mg once daily for 5 days in cycles of 28 days duration. The extent of systemic exposure of CHS 828 across patients was approximately dose proportional. The time at which the highest drug concentration occurs was 2.2 +/- 1.3 h and half-life was 2.1 +/- 0.52 h (mean +/- SD). Large intra- and interindividual variation in dose level-adjusted maximum plasma concentration and the area under the curve from time 0 h to infinity were observed. There was an apparent inverse relationship between systemic exposure of CHS 828, and thrombocyte and lymphocyte nadir levels. No objective tumor responses were observed, and 7 patients showed stable disease after two courses of therapy.
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PMID:A Phase I study of CHS 828 in patients with solid tumor malignancy. 1223 25

GEM 231 is a second-generation antisense oligonucleotide targeted against the RIalpha regulatory subunit of cAMP-dependent protein kinase type I (PKA-I). Excessive expression of PKA-I is associated with cell proliferation and transformation, and increased levels of secreted extracellular PKA (ECPKA) are found in the serum of cancer patients. Preclinical studies have demonstrated single-agent antitumor activity of GEM 231 in a variety of human cancer xenograft models, and additive or synergistic antitumor activity has been observed with taxane and/or camptothecin-based combinations. Based on prior safety (MTD) data demonstrating dose-dependent, reversible, and cumulative transaminitis, and high peak plasma concentration (Cmax)-dependent changes in activated partial thromboplastin time (aPTT) with GEM 231 2-h twice-weekly infusions, an alternative schedule of GEM 231 given as a single agent was evaluated in patients with advanced solid tumors. Fourteen patients (median age approximately 60 yrs) with advanced solid malignancies received a total of 78 weeks of therapy. GEM 231 was infused via a CADD pump at 80 mg/m2/day (d) for 3 d/wk (n = 1), then for 5 d/wk at 80 (n = 3), 120 (n = 8), and 180 mg/m2/d (n = 2). One cycle was defined as 4 weeks of therapy. Apparent dose dependency for the occurrence of transaminitis was readily reversible. At 180 mg/m2/d, 2 of 2 patients had cycle 1 dose-limiting toxicity (DLT) transaminitis. One patient treated at 120 mg/m2/d experienced grade 3 transaminase elevations after 8 weeks of therapy, but when serum transaminase values rapidly improved he resumed treatment at 80 mg/m2/d for 6 weeks until tumor progression was documented. Another patient at 120 mg/m2/d developed grade 3 esophagitis after 3 weeks, limiting further dosing. One patient (lung cancer) demonstrated stable disease for 9 weeks. Overall, plasma aPTT was minimally prolonged and changes were transient, peaked at the end of each infusion, and were not associated with spontaneous bleeding. A constitutive symptom (e.g., low-grade fatigue) was common, cumulative, and reversible following discontinuation of therapy. Serum ECPKA was measured by enzymatic assay and Western blotting from blood drawn at the beginning and end of each infusion. Serum ECPKA levels demonstrated a trend to decline with the treatment. In addition to single agent schedules, combination trials were undertaken to assess safety and possible interaction of GEM 231 with taxanes (paclitaxel, docetaxel), given once every 3 weeks (one cycle). While trials using the 2-h twice-weekly GEM 231 infusions are ongoing, preliminary results from both studies show that it is safe to combine paclitaxel or docetaxel with GEM 231. Overall, it is also feasible to administer GEM 231 in combination with taxane or nontaxane chemotherapy (e.g., camptothecins). Phase I combination studies are currently underway to further explore the clinical, pharmacokinetic, and biologic profile of GEM 231 with chemotherapy.
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PMID:Clinical studies in patients with solid tumors using a second-generation antisense oligonucleotide (GEM 231) targeted against protein kinase A type I. 1475 40

Concurrent chemoradiotherapy plays an important role in the treatment of unresectable NSCLC. This phase II study was conducted to evaluate the efficacy and toxicity of paclitaxel (PTX) and carboplatin (CBDCA) at a recommended dose, based on other previous phase I studies. Twenty-two unresectable stage III NSCLC patients participated in this trial. Of those 22 patients, 19 were evaluable, with a median age of 57 (with ages ranging between 42 and 74), in stages IIIA/IIIB: 6/13. Every patient displayed adequate organ functions. Treatment consisted of a 1-hour i.v. infusion of 50 mg/m2 of PTX followed by a half-hour infusion of CBDCA AUC 2 administered weekly concurrently with radiation treatment, every first day of those weeks in which the patient underwent radiotherapy. Concurrent thoracic radiation therapy was performed in daily doses of 2 Gy to a total dose of 66 Gy over a period of 6.5 weeks. After completion of chemoradiotherapy, consolidation chemotherapy was administered via a 3-hour i.v. infusion of 175 mg/2 PTX on days 1 and 22, in combination with a 1-hour i.v. infusion of CBDCA AUC 6 on days 1 and 22, q 4 weeks for 4 cycles. The overall response rate was 78.9% (95% CI: 62-87.7) with 5 CR (26.3%), 10 PR (52.6%), 2 SD (15.8%), and 1 PD (5.3%). The median survival rate of the patients was 13.9 months, and the 1-year survival rate was 65.1%. Toxicity was moderate: grade 2 neutropenia was seen in 8, and grade 3 neutropenia in 5 patients. Grade 2 thrombocytopenia was seen in 3 patients, and grade 3 thrombocytopenia was not observed. Nonhematologic toxicities were moderate: esophagitis was the most common, and significant toxicity was noted in this study (89.4%). Grade 1 asthenia/fatigue was observed in 5, and grade 2 asthenia/fatigue in 3 patients; furthermore, grade 1 peripheral neuropathy was seen in 4 of the cases and grade 2 peripheral neuropathy in 3 of the cases. Concurrent chemoradiotherapy with weekly PTX/CBDCA, followed by consolidation chemotherapy with the same regimen in patients with stage III unresectable NSCLC is feasible and well tolerated.
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PMID:Preliminary results of a phase II study of weekly paclitaxel (PTX) and carboplatin (CBDCA) administered concurrently with thoracic radiation therapy (TRT) followed by consolidation chemotherapy with PTX/CBDCA for stage III unresectable non-small-cell lung cancer (NSCLC). 1557 39

Both induction chemotherapy and concurrent platinating agents have been shown to improve results of thoracic irradiation in the treatment of locally advanced non-small-cell lung cancer (NSCLC). This phase II study investigated activity and feasibility of a novel chemoradiation regimen, including platinum and paclitaxel, both as induction chemotherapy and concurrently with thoracic radiotherapy. Previously untreated patients with histologically/cytologically proven unresectable stage I-III NSCLC were eligible. Induction chemotherapy consisted of 2 courses of 200 mg/m2 paclitaxel and carboplatin at AUC of 6 mg/mL/min every 3 weeks. From day 43, continuous thoracic irradiation (60 Gy in 30 fractions radiotherapy for 6 weeks) was given concurrently with daily cisplatin at a dose of 5 mg/m2 intravenously and weekly paclitaxel at a dose of 45 mg/m2 for 6 weeks. Fifteen patients were accrued in the first stage of the trial. According to the previous statistical considerations, accrual at the second stage of the study was halted as a result of the achievement an insufficient number of successes. Major toxicity of combined chemoradiation was grade III-IV esophagitis requiring hospitalization for artificial nutrition, which occurred in 58% of patients. Other toxicities included grade II-IV fatigue in 75% of patients and grade I-IV neuromuscular toxicity in 67%. Only 7 patients completed the treatment program as scheduled. Eight patients (53.3%; 95% confidence interval, 26.5-78.7%) had a major response (5 partial response, 3 complete response), 2 patients had disease progression, and 1 was stable at the end of treatment. Four patients died early. With a median follow up of 38 months, the median survival was 12 months. A combined chemoradiation program, including platinum and paclitaxel, appears difficult to deliver at full dose as a result of toxicity, mainly esophagitis. More active and less toxic combined modality treatments need to be developed for inoperable NSCLC.
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PMID:Induction chemotherapy with carboplatin-paclitaxel followed by standard radiotherapy with concurrent daily low-dose cisplatin plus weekly paclitaxel for inoperable non-small-cell lung cancer. 1568 36

Bisphosphonates are the most commonly prescribed medications for the treatment of osteoporosis. Although evidence supports a good safety profile for these agents, numerous tolerability issues have been associated with their use. This review provides an overview of the safety issues associated with the nitrogen-containing class of bisphosphonates and discusses the potential effect of these issues on adherence. The review specifically considers upper gastrointestinal (UGI) adverse events (AEs), renal toxicity, influenza-like illness, osteonecrosis of the jaw and evidence on how to treat or prevent these events. In clinical trials, UGI AEs, including severe events such as oesophageal ulcer, oesophagitis and erosive oesophagitis, have been reported at similar frequencies in placebo- and active-treatment arms. However, postmarketing studies have highlighted UGI AEs as a concern. These studies show that a significant portion of patients are less compliant with administration instructions outside strict clinical trial supervision, and when oral bisphosphonates are not administered as directed, patients are more likely to experience UGI AEs. Some clinical trials with oral bisphosphonates have suggested that a decrease in the frequency of administration may lead to improvement in gastrointestinal tolerability. In the authors' experience, the issue of UGI tolerability can be minimised by explaining to the patient and/or caregiver the importance of following administration instructions. Intravenous (IV) bisphosphonates have been recently approved for use in osteoporosis, offering an alternative regimen for patients with osteoporosis. Earlier generation IV bisphosphonates (e.g. etidronate) have been associated with acute renal failure. Alternatively, late-generation IV bisphosphonates (i.e. ibandronate) have shown a better safety profile in relation to renal toxicity. Influenza-like illness, often referred to as an acute-phase reaction, covers symptoms such as fatigue, fever, chills, myalgia and arthralgia. These symptoms are transitory and self-limiting and usually do not recur after subsequent drug administration. Symptoms of influenza-like illness have been associated with both IV and oral bisphosphonates. Osteonecrosis of the jaw has also been associated with IV bisphosphonate treatment, particularly in patients treated with high doses. A small number of patients with cancer and osteoporosis using oral bisphosphonates have also reported this AE. As osteonecrosis of the jaw is difficult to treat and is often associated with dental procedures and poor oral hygiene, preventive measures seem to be the best management option for patients taking bisphosphonates.Overall, the safety and tolerability profile of the nitrogen-containing bisphosphonates is good, and long-term treatment does not appear to carry a risk of serious AEs. By encouraging adherence to administration instructions physicians can minimise certain complications, such as UGI intolerability. By being aware of other potential safety issues, such as renal impairment, influenza-like illness and osteonecrosis of the jaw, physicians can detect these AEs early in the course of treatment.
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PMID:Safety considerations with bisphosphonates for the treatment of osteoporosis. 1772 68

There is an evidence that increased capillary permeability in the standing position is related to a deficit in the sympathetic nervous system. The leakage of this fluid leads to various clinical conditions which frequently puzzle the consulting physician because despite the frequency of this condition intelligent physicians and patients are unaware of the cause of their condition. One of the most common manifestations is the inability to lose weight despite proper dieting. A randomized study comparing the efficacy of a diuretic, a converting enzyme inhibitor, spironolactone and a sympathomimetic amine on weight loss in diet refractory women found that only the latter in the form of dextroamphetamine sulfate demonstrated significant weight reduction over a six month time span. In fact, the dextroamphetamine sulfate proved effective when given in the next 6 months to the three groups failing to respond for the first 6 months. The diagnosis of a deficit in sympathomimetic amines is established by demonstrating an abnormal clearance of a water load in the erect position and exclusion of other conditions that are associated with an abnormal free water clearance, e.g., hypothyroidism, renal or liver disease or congestive heart failure. The original definition of an abnormal water load test was excretion of <55% of a 1500 ml water load in 6h but we found that <75% defines a greater population who suffer from this problem. There are several conditions that have proven refractory to conventional theory that respond quickly and effectively to sympathomimetic amines. There have been many anecdotal reports of relieving interactable pain syndromes quickly and efficiently with sympathomimetic amine theory, despite failure with a multitude of other therapies. These include interstitial cystitis and pelvic pain that was attributed to endometriosis, gastrointestinal pain including esophagitis and gastroparesis, headaches, joint pain, fibromyalgia, and carpal tunnel syndrome. It is not clear if the improvement in pain is related to a decrease in fluid retention or a direct effect of the sympathomimetic amines on the sympathetic nervous system. Sympathomimetic amine theory has helped other conditions besides pain, e.g., chronic fatigue, vasomotor symptoms in young women not associated with decreased ovarian egg reserve, and chronic urticaria resistant to all other therapies. Thus, these studies strongly suggest that physicians be aware of this condition involving a deficit in the sympathetic nervous system when faced with various enigmatic complaints especially if standard therapy has not proven effective.
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PMID:A disorder of sympathomimetic amines leading to increased vascular permeability may be the etiologic factor in various treatment refractory health problems in women. 1776 3


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