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)

One hundred and three acromegalic patients from 14 medical centers were enrolled in this study to determine the efficacy and safety of the somatostatin analog, octreotide acetate, during long term treatment. Seventy percent of the patients had undergone previous surgery or radiation treatment. Octreotide was initiated at a dose of 100 micrograms, sc, every 8 h and gradually increased to a maximum of 1500 micrograms daily depending upon the individual patient's clinical and biochemical response [GH and insulin-like growth factor I (IGF-I) reduction]. The mean duration of treatment was 24 months (range, 3-30 months). However, most patients were treated for a mean of 30 months, because this study took place after an initial 6-month study previously reported. Mean serum GH fell from 30.9 micrograms/L (range, 2.7-350) to 5.7 micrograms/L (range, 0.6-59) at the 3 months visit and remained suppressed (P < 0.001). Plasma IGF-I concentrations were also significantly reduced and remained in the normal range for at least half of the treatment visits in 56 of 87 patients (64%) treated for 12-30 months. Patients with higher initial GH concentrations were less likely to normalize IGF-I concentrations during treatment (P < 0.001). There was no evidence of drug tachyphylaxis in those patients who continued taking stable doses of medication. With some exceptions, dose increments above 800 micrograms daily in 31 patients did not provide additional benefit in terms of GH and IGF-I reduction. Headache, excessive perspiration, fatigue, and joint pain were ameliorated in 83-95% of patients. Mean finger circumference was decreased significantly at the 12 month visit (P < 0.05). The most common adverse events reported were diarrhea, abdominal discomfort, loose stools, and nausea; these symptoms usually disappeared within 3 months of treatment. Five patients discontinued octreotide because of adverse events. Of 102 patients with normal baseline ultrasound examinations of the gallbladder, 24 patients (23.5%) developed gallstones (usually during the first year of treatment), and 21 patients developed sludge alone. Gallstone formation was not related to the dose of octreotide. Most patients with cholelithiasis were asymptomatic, and none developed cholecystitis. These observations suggest that octreotide is a valuable long term medical treatment for acromegaly.
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PMID:Safety and efficacy of long-term octreotide therapy of acromegaly: results of a multicenter trial in 103 patients--a clinical research center study. 767 22

Data from studies in diabetic rodents and evidence from clinical situations of severe resistance to insulin suggest that insulin-like growth factor I (IGF-I) is able to at least partly overcome insulin resistance. To assess the efficacy of recombinant human IGF-I in subjects with the most common form of insulin resistance, e.g., obese, type II diabetic patients, we administered recombinant human IGF-I (rhIGF) in doses of 120 and 160 micrograms/kg twice daily for 4-52 days to seven such individuals who had been treated previously with high doses of insulin (> 0.7 U.kg-1 x day-1). Four patients exhibited comparable or enhanced, whereas three had diminished, blood glucose control on rhIGF-I relative to that while on twice daily NPH insulin during the six-week control period. The occurrence of adverse effects in all patients compelled us to discontinue rhIGF-I administration before completing the 8-week treatment period. These adverse effects included edema primarily on the face and hands, mild weight gain, occasional dyspnea, bilateral jaw tenderness, arthralgias and myalgias, fatigue, tachycardia, flushing, orthostatic hypotension, and local burning at the injection site. We conclude that the frequency and severity of side effects associated with administering high-dose subcutaneous rhIGF-I to obese insulin-resistant diabetic patients make it an unacceptable therapeutic agent for these patients despite its ability to produce reasonable blood glucose control in approximately 50% of them.
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PMID:Adverse effects of recombinant human insulin-like growth factor I in obese insulin-resistant type II diabetic patients. 831 9

Fetal cerebellar cell suspensions, prepared from wild-type (+/+) mice, were implanted bilaterally into the cerebellum of Purkinje cell degeneration' (pcd) mutant mice, a model of adult-onset recessively inherited cerebellar ataxia, to study the functional effects of the grafts on motor coordination and fatigue resistance in a rotating rod treadmill paradigm. The viability of transplanted Purkinje cells was verified with immunocytochemistry for calbindin-D28k and for glutamate receptor 2/3 subunits and with in situ hybridisation histochemistry for insulin-like growth factor I mRNA, biochemical markers normally expressed by Purkinje cells in the cerebellum. Sham injections of vehicle did not appreciably modify the performance of pcd mutants in the rota-rod tests. On the other hand, bilateral cerebellar grafts led to a 3.5-fold increase in the time period that recipient pcd mice were able to stay on the rotating drum based on the comparison of mean scores (of three trials) or a 5.5-fold increase based on the comparison of maximum scores (of the three trials). These findings provide evidence for a motor enhancement in the pcd mouse model of hereditary cerebellar ataxia following intracerebellar transplantation of primordial Purkinje cells.
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PMID:Graft-induced restoration of function in hereditary cerebellar ataxia. 854 77

Young growing animals appear to have significantly reduced "nutritional to short periods of unstressed starvation compared with adults, with resultant growth arrest and/or atrophy of diaphragm (Dia) muscle fibers. The aim of this study was to assess in an adolescent rat model of acute nutritional deprivation (ND; 72 h) the impact of insulin-like growth factor I (IGF-I), with or without added growth hormone (GH), on the cross-sectional areas (CSA) of individual Dia muscle fibers. Five groups were studied: 1) control (Ctr); 2) ND; 3) ND given IGF-I (ND/IGF-I); 4) ND given GH (ND/GH); and 5) ND given a combination of IGF-I and GH (ND/IGF-I/GH). IGF-I was given by a subcutaneously implanted osmotic minipump (200 microg/day), whereas GH was administered twice daily by a subcutaneous injection (250 microg every 12 h). Isometric contractile and fatigue properties of the Dia were determined in vitro. Forces were normalized for muscle CSA (i.e., specific force). Dia fiber type proportions were determined histochemically, and fiber CSA was quantified by using a computer-based image-processing system. Total serum IGF-I concentrations were significantly reduced in ND and ND/GH animals, compared with Ctr, and elevated in the groups receiving IGF-I. The provision of growth factors did not alter the contractile or fatigue properties of ND animals. Dia fiber type proportions were similar among the groups. In ND animals, there was a significant reduction in the CSA of types I, IIa, IIx, and IIc Dia fibers compared with Ctr. The administration of IGF-I alone or in combination with GH to ND animals significantly diminished the reduction in Dia fiber size. GH alone had no effect on Dia fiber size in ND animals. We conclude that with acute ND the peripheral resistance to the action of GH appears to be bypassed by the administration of IGF-I alone or in combination with GH.
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PMID:Effect of insulin-like growth factor I and/or growth hormone on diaphragm of malnourished adolescent rats. 910 40

It is controversial whether insulin-like growth factor I (IGF-I), growth hormone (GH), or their combination might enhance body growth and/or tissue anabolism in the well-fed animal with an intact somatotrophic axis. To assess this further, we studied four groups of adolescent rats: 1) control (Ctr), 2) GH, 3) IGF-I, and 4) GH/IGF-I. IGF-I was given via an osmotic minipump, whereas GH was injected subcutaneously for a period of 72 h. Diaphragm (Dia) contractile and fatigue properties were determined in vitro. Quantitative histochemical and morphometric analyses were performed on Dia fibers. Total serum IGF-I levels were significantly increased in the groups receiving growth factors. Although body weight increased to a greater extent in the animals receiving growth factors, a further synergistic effect was noted in the GH/IGF-I animals compared with either GH or IGF-I groups. Costal Dia mass was greater in the groups receiving growth factors. The Dia of GH/IGF-I animals was more fatigue resistant than the Dia in Ctr. The cross-sectional area of types IIa and IIx fibers were increased to a similar extent in all groups receiving growth factors compared with Ctr. Succinate dehydrogenase activity of type IIa fibers was significantly greater in the GH/IGF-I animals compared with the other groups. We conclude that the short-term provision of growth factors to well-nourished, normally growing adolescent rats can accelerate body growth and promote selective hypertrophy of predominantly type II Dia fibers.
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PMID:Anabolic influences of insulin-like growth factor I and/or growth hormone on the diaphragm of young rats. 917 66

Resistance to the anabolic effects of growth hormone (GH) occurs with severe caloric deficit. This study examined whether moderate caloric deficit (50% of daily intake for 7 days) in the adolescent rat exceeds a critical threshold for GH action and whether a combination of GH and insulin-like growth factor I (IGF-I) would have enhanced anabolic effects on the diaphragm (Dia). Five groups of rats (4 wk old) were studied: 1) control (Ctl), 2) nutritionally deprived (ND), 3) ND + GH, 4) ND + IGF-I, and 5) ND + GH + IGF-I. IGF-I was given by continuous infusion (200 microg/day). GH was injected subcutaneously (250 microg every 12 h). Contractile and fatigue properties of the Dia were determined in vitro. Quantitative histochemical methods were used to determine Dia fiber type proportions, cross-sectional areas, and succinate dehydrogenase activities. The body weight of Ctl rats increased 46% compared with 7% in ND animals, whereas that of ND rats receiving growth factors was intermediate. Serum IGF-I levels were reduced 54% in ND animals and maintained with the provision of growth factors. Dia fatigue resistance was improved in ND animals receiving growth factors. There were no differences in Dia contractile properties, fiber type proportions, or succinate dehydrogenase activities across groups. ND resulted in atrophy/growth arrest of all Dia fibers (20-32%) compared with Ctl. Administration of IGF-I and/or GH completely prevented atrophy/growth arrest of all Dia fibers. No additive or synergistic effects were noted. We propose that these growth factors may provide useful short-term adjunctive nutritional support in circumstances in which the provision of optimal nutrition may be delayed or inadequate.
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PMID:IGF-I and/or growth hormone preserve diaphragm fiber size with moderate malnutrition. 965 74

The effects of octreotide (up to 5 yr) as primary treatment in 26 patients with acromegaly were compared with those in 81 patients with acromegaly who received octreotide as secondary or adjunctive therapy after previous surgery and/or pituitary radiation. These patients were part of a multicenter study that took place between 1989-1995. The study was divided into 3 phases beginning with a 1-month placebo-controlled treatment period followed by a 1-month washout period. In the second phase, patients were randomized to treatment with either 100 or 250 micrograms octreotide, sc, every 8 h for 6 months. Octreotide was then discontinued for 1 month and reinitiated at the lower dose for a total mean treatment duration of 39 months. The dose was titrated by each investigator to improve each patient's individual response, which included improvement in symptoms and signs of acromegaly as well as reduction of GH and insulin-like growth factor I (IGF-I) into the normal range. In the second phase of the study, in which patients were randomized to either 100 or 250 micrograms octreotide, three times daily, mean integrated GH and IGF-I concentrations after 3 and 6 months were equivalent in the primary and secondary treatment groups. During long term open label treatment, mean GH fell from 32.7 +/- 5.2 to 6.0 +/- 1.7 micrograms/L 2 h after octreotide injection in the primary therapy group and remained suppressed for a mean period of 24 months (range, 3-60 months). The mean final daily dose was 777 micrograms. In the patients receiving secondary treatment, mean GH fell from 30.2 +/- 7.6 to 5.6 +/- 1.1 micrograms/L after 3 months and remained suppressed for the remainder of the study (average dose, 635 micrograms daily). Mean IGF-I concentrations fell from 5.2 +/- 0.5 x 10(3) U/L (primary treatment group) and 4.7 +/- 0.4 x 10(3) U/L (secondary treatment group) to a mean of 2.2 +/- 0.3 x 10(3) U/L in both groups after 3 months of open label treatment and remained suppressed. IGF-I was reduced into the normal range during at least half of the study visits in 68% of the primary treatment group and in 62% of the secondary treatment group. Patients whose GH levels fell to at least 2 SD below the baseline mean GH were considered responders. There was no significant difference in the percentage of responders in the primary and secondary treatment groups (70% vs. 61%), nor was there a statistical difference in the mean GH concentrations between the groups. Symptoms of headache, increased perspiration, fatigue, and joint pain were reported at baseline by 46%, 73%, 69%, and 85%, respectively, of patients in the primary therapy group and improved during 3 yr of octreotide treatment in 50-100%. Similarly, these acromegaly-related symptoms were reported by 62%, 58%, 78%, and 60% of patients in the secondary therapy group, and improvement was noted in 62-88%. Pituitary magnetic resonance imaging scans were available in 13 of 26 patients in the primary treatment group before and after 6 months of octreotide treatment. Tumor shrinkage was observed in 6 of 13 patients, with reduction in tumor volume greater than 25% in only 3. Of 6 patients with documented tumor shrinkage, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 4 patients. Of the 7 remaining patients in whom tumor shrinkage was less than 10%, IGF-I was reduced into the normal range in 5 patients. The degree of tumor shrinkage did not correlate with the percent reduction in IGF-I or GH. In summary, octreotide was equally effective in 26 previously untreated acromegalic patients (primary treatment group) and 81 patients previously treated with either surgery or pituitary radiation (secondary treatment group). These observations call into question the current practice of surgical resection of all newly diagnosed GH-secreting pituitary adenomas regardless of the likelihood of cure. (AB
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PMID:Octreotide as primary therapy for acromegaly. 974 96

The impact of GH on functional performance in GH-deficient adults is not well understood. To investigate the effects of GH on skeletal muscle, physical, and functional capacity, we randomized 28 GH-deficient adults to receive 3 months of recombinant human GH [rhGH: somatotropin, 6.25 microg/kg lean body mass (LBM) for 1 month, 12.5 microg/kg LBM thereafter] in a double-blind placebo-controlled crossover trial. We measured muscle fiber type, size, and insulin-like growth factor I messenger RNA, aerobic capacity [maximal oxygen uptake (VO2max), ventilation threshold (VeT)], isokinetic strength, oxygen-cost-of-walking at normal and fast speeds, and fatigue determined by the profile of mood states questionnaire. As expected, GH treatment decreased body fat, increased LBM, increased muscle fiber size, and increased muscle insulin-like growth factor-I messenger RNA 5-fold; however, muscle strength remained unchanged. At baseline, VeT occurred at a high percentage of maximal VO2max (73.3% +/-2.6) because of low VO2max (1.74+/-0.1 L/min or 20.7+/-1.3 mL/ kg x min). Walking required high oxygen consumptions representing from 83+/-4% of VeT at normal speeds to 120+/-5% of VeT at fast speeds. After rhGH, there was a significant (P = 0.03) increase in VeT (18%), compared with placebo. This was paralleled by a nonsignificant rise in VO2max. Functionally, rhGH treatment decreased the oxygen cost of walking, relative to VeT, at normal (14% decrease, P = 0.019) and fast (21% decrease, P = 0.004) SPW speeds. A 3-variable model (baseline fast SPW speed, VeT/VO2max, and VeT) accounted for 39% of the variance of change in self-reported fatigue. These data indicate that GH-deficient adults require a high fraction of VeT for daily activities, explaining the perception of increased fatigue and impaired physical performance. The actions ofrhGH on muscle fiber size translate into physiological improvement in submaximal aerobic capacity and result in functional improvement in walking ability but do not necessarily alter strength. Thus, measures of effort-independent submaximal aerobic performance provide novel objective determinants of functional impairment and fatigue and can be used to evaluate and predict response to GH treatment.
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PMID:Measures of submaximal aerobic performance evaluate and predict functional response to growth hormone (GH) treatment in GH-deficient adults. 1129 32

GH deficiency states and chronic fatigue syndrome (CFS) share several characteristics, and preliminary studies have revealed aspects of GH dysfunction in CFS. This study assessed indexes of GH function in 37 medication-free CFS patients without comorbid psychiatric illness and 37 matched healthy controls. We also assessed GH function before and after treatment with low dose hydrocortisone, which has been shown recently to reduce fatigue in CFS. We measured basal levels of serum insulin-like growth factor I (IGF-I), IGF-II, IGF-binding protein-1 (IGFBP-1), IGFBP-2 and IGFBP-3 together with 24-h urinary GH excretion. We also performed 2 dynamic tests of GH function: a 100-microg GHRH test and an insulin stress test using 0.15 U/kg BW insulin. There were no differences between patients and controls in basal levels of IGF/IGFBP or in urinary GH excretion. GH responses to both the GHRH test and the insulin stress test were no different in patients and controls. CFS patients did have a marginally reduced suppression of IGFBP-1 during the insulin stress test. Hydrocortisone treatment had no significant effect on any of these parameters. There is no evidence of GH deficiency in CFS. At the doses used, hydrocortisone treatment appears to have little impact on GH function.
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PMID:Integrity of the growth hormone/insulin-like growth factor system is maintained in patients with chronic fatigue syndrome. 1077 Jan 78

The rise in male life expectancy is paralleled by increased age-related clinical signs and symptoms such as muscle weakness, osteoporosis, benign prostatic hyperplasia, changes in body composition, fatigue, decreased sexual interest and activity, and increased prevalence of erectile dysfunction, all of which limit the quality of life. Many of these symptoms are similar to those of clinically well-defined hormone deficiencies, e.g. Kallman syndrome, Prader--Labhart--Willi syndrome or deficiencies due to treatment of pituitary tumors. Three male endocrine axes are characterized by age-related changes in concentrations of circulating hormones: (i) the hypothalamic--pituitary--testicular axis with lower serum levels of testosterone (T) and higher serum levels of luteinizing and follicle-stimulating hormone, (ii) the hypothalamic--pituitary--adrenal axis with its gradual decline in dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS), (iii) the growth hormone (GH)/insulin-like growth factor I (IGF-I) axis showing decreased hormone production concomitant with symptoms similar to those of GH-deficient adults. The beneficial effects of hormone replacement in nonelderly hormone-deficient individuals and in postmenopausal women raised hope that hormone substitution might prevent or even reverse some of the symptoms of male aging. However, this approach is hampered by the lack of individual age-related hormone reference values and reliable clinical read-out parameters. The findings so far do not support the need for widespread hormone replacement in elderly men. Larger long-term prospective studies are needed to identify clinically useful read-out parameters, and then demonstrate that hormone replacement can translate into functional parameters, thereby providing the individual benefit of treatment for aging men.
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PMID:Hormonal changes in aging men: a therapeutic indication? 1140 52


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