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 studied the effect of CV 205-502 in 12 patients with macroprolactinomas and 8 patients with PRL-secreting tumors, who were selected because of previous repeatedly shown intolerance to bromocriptine in even small doses. We also investigated serum insulin-like growth factor-I (IGF-I) levels before and during CV 205-502 therapy. In 12 macroprolactinoma patients followed for 1 yr, 0.075-0.450 mg CV 205-502 lowered PRL levels by 91.2 +/- 5.4%. Only 3 of the patients had transient side-effects of nausea, dizziness, or fatigue. In eight patients with PRL-secreting tumors who were bromocriptine intolerant, CV 205-502 (0.075-0.300 mg daily) lowered PRL levels by 80.2 +/- 6.3%. Four of these patients showed transient side-effects (nausea, fatigue, and/or tachycardia). None of the patients discontinued therapy. There was a close correlation between pretreatment circulating PRL levels and tumor size, expressed in cubic millimeters. The decrease in pituitary tumor size after 52 weeks of CV 205-502 therapy (-74 +/- 6%) was also correlated with the decrease in PRL levels (P less than 0.01). In four patients with hypopituitarism, lowered IGF-I levels did not change during CV 205-502 therapy. However, in seven previously untreated patients with macroprolactinoma and normal CV 205-502 is a potent dopaminergic drug, which effectively controls PRL secretion and induces tumor shrinkage. At the doses used in our study, it causes only mild and transient side-effects in a minority of patients and can also be used to treat hyperprolactinemic patients who have shown intolerance to bromocriptine therapy.
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PMID:The efficacy and tolerability of CV 205-502 (a nonergot dopaminergic drug) in macroprolactinoma patients and in prolactinoma patients intolerant to bromocriptine. 167 85

The present study evaluates the effects of 2 years of growth hormone (GH) replacement therapy on psychological well-being and cognitive performance in adults with childhood-onset growth hormone deficiency (CO-GHD). A total of 48 GHD adult men (mean age: 27 years) were randomly assigned to one of four treatment groups: placebo treatment, or GH replacement in a dose of 1, 2, or 3 IU/m2, respectively. Placebo treatment was given for 6 months. Psychological assessments were made every 6 months. Assessments included somatic and psychological complaints, depression, fatigue, vigor, tension, state/trait anxiety, iconic memory, short-term memory, long-term memory and perceptual-motor skill. GH treatment was considered physiological if the observed insulin-like growth factor-I (IGF-I) levels were within the normal range. It was considered supraphysiological if serum IGF-I rose to a value exceeding the upper normal limit. During the placebo-controlled phase of the study the changes in memory performance were positively correlated to the GH induced changes in serum IGF-I concentration and, more weakly, to the daily GH substitution dose. At 6 months memory only had improved in the group receiving supraphysiological GH treatment, but not in the group of patients who had a normalization of serum IGF-I. However, after 1 year of treatment a normalization of memory functioning was found in both groups of patients and this was preserved during the 2nd year of treatment. No changes were observed in psychological well-being and perceptual-motor skill. We conclude that GH replacement improves memory function in adults with CO-GHD. It has no effect on psychological well-being or perceptual-motor skill. Supraphysiological treatment accelerates the recovery of memory performance. However, the long-term effects are not different from those achieved with physiological GH replacement.
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PMID:Cognitive changes during growth hormone replacement in adult men. 961 51

There is a high prevalence of protein-energy malnutrition in both nondialyzed patients with advanced chronic renal failure and in those individuals with end-stage renal disease who are receiving maintenance hemodialysis or chronic peritoneal dialysis therapy. Approximately one-third of maintenance dialysis patients have mild to moderate protein-energy malnutrition, and about 6 to 8 percent of these individuals have severe malnutrition. These statistics are of major concern because markers of protein-energy malnutrition are strong predictors of morbidity and mortality. The causes of protein-energy malnutrition in patients with chronic renal failure include: (1) decreased energy or protein intake; (2) concurrent chronic illnesses, and superimposed acute illnesses and possibly increased inflammatory cytokines; (3) the catabolic stimulus of hemodialysis; (4) losses of nutrients into dialysate, particularly amino acids, peptides, protein (with peritoneal dialysis), glucose (when hemodialysis is performed with glucose-free dialysate) and water-soluble vitamins; and (5) diagnostic or therapeutic (e.g., prednisone therapy) procedures that reduce nutrient intake or engender net protein breakdown. Other theoretically possible causes for protein-energy malnutrition include (6) chronic blood loss; (7) endocrine disorders (especially resistance to insulin and insulin-like growth factor-I, hyperglucagonemia, hyperparathyroidism and deficiency of 1,25-dihydroxycholecalciferol); (8) products of metabolism that accumulate in renal failure and may induce wasting, such as organic and inorganic acids; (9) loss of the metabolic actions of the kidney; and (10) the accumulation of toxic compounds that are taken up from the environment (e.g., aluminum).
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PMID:Pathophysiology of protein-energy wasting in chronic renal failure. 991 8

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

Circulating leptin, insulin, insulin-like growth factor-I (IGF-I), cortisol, and albumin concentrations and the growth hormone (GH) response to provocation were measured in 30 children with severe protein-energy malnutrition (PEM), 20 with marasmus and 10 with kwashiorkor, as well as 10 age-matched normal children (body mass index [BMI] >50th and <90th percentile for age and sex) and 10 prepubertal obese children (BMI >95th percentile for age and sex). Patients with PEM had a significantly lower BMI, midarm circumference (MAC), and skinfold thickness (SFT) compared with the age-matched control group. Basal cortisol and GH concentrations were significantly higher in the malnourished groups versus controls. Leptin and IGF-I were significantly lower in the marasmic and kwashiorkor groups versus normal children. Fasting insulin levels were significantly decreased in the kwashiorkor group compared with marasmic and normal children. The BMI correlated significantly with leptin (r = .77, P < .001), basal insulin (r = .61, P < .001), and IGF-I (r = .77, P < .001) and negatively with basal GH (r = -.52, P < .001). These findings suggest that during prolonged nutritional deprivation, the decreased energy intake, diminished subcutaneous fat mass, and declining insulin (and possibly IGF-I) concentration suppress leptin production. In support of this view, serum leptin levels were positively correlated with triceps, scapular, and abdominal SFT (r = .763, .75, and .744, respectively, P < .0001) in all of the children. Moreover, basal insulin and circulating IGF-I were correlated significantly with leptin concentrations (r = .47 and .62, respectively, P < .001). Basal levels of cortisol and GH were significantly elevated in the 2 groups with severe PEM. It is suggested that low leptin levels can stimulate the hypothalamic-pituitary-adrenal (HPA) axis and possibly the hypothalamic-pituitary-GH axis to maintain the high cortisol and GH levels necessary for effective lipolysis to ensure a fuel (fatty acids) supply for the metabolism of brain and peripheral tissue during nutritional deprivation. In summary, during prolonged PEM, the decreased synthesis of IGF-I and the low level of insulin and/or its diminished effect due to an insulin-resistant status in the presence of high circulating GH and cortisol levels ensure substrate diversion away from growth toward metabolic homeostasis. Leptin appears to be an important signal in the process of metabolic/endocrine adaptation to prolonged nutritional deprivation.
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PMID:Serum leptin concentrations during severe protein-energy malnutrition: correlation with growth parameters and endocrine function. 1090 89

Muscle has an intrinsic ability to change its mass and phenotype in response to activity. This process involves quantitative and qualitative changes in gene expression, including that of the myosin heavy chain isogenes that encode different types of molecular motors. This, and the differential expression of metabolic genes, results in altered fatigue resistance and power output. The regulation of muscle mass involves autocrine as well as systemic factors. We have cloned the cDNAs of local and systemic isoforms of insulin-like growth factor-I (IGF-I) from exercised muscle. Although different isoforms are derived from the IGF-I gene by alternative splicing, the RNA transcript of one of them is only detectable following injury and/or mechanical activity. Thus this protein has been called mechano growth factor (MGF). Because of a reading-frame shift, MGF has a different 3' sequence and a different mode of action compared with systemic or liver IGF-I. Although MGF has been called a growth factor, it may be regulated as a local repair factor.
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PMID:Gene expression in skeletal muscle. 1202 66

Acromegaly is a chronic disorder invariably caused by a growth hormone (GH)-secreting pituitary tumour and is characterised by disabling symptoms (sweating, arthralgia, headache, paraesthesiae, fatigue), significant comorbidities (diabetes mellitus, hypertension, sleep apnoea), and premature mortality. Symptomatic control can be achieved by lowering insulin-like growth factor-I (IGF-I) concentrations to within the age-adjusted normal range, and survival can be improved to match that of the general population. However, even with optimal surgery and current medical therapies (dopamine agonists, somatostatin analogues), 30% to 50% of patients do not achieve target concentrations of IGF-I and GH. Pegvisomant is a new GH-receptor antagonist that blocks GH activity by inhibiting functional dimerisation of GH-receptors. Given as subcutaneous injections at dosages of 10 mg, 15 mg, or 20 mg/day for 3 Months, pegvisomant normalised serum IGF-I concentrations in, respectively, 54%, 81%, and 89% of acromegalic patients. Moreover, long-term pegvisomant therapy normalised IGF-I concentrations in 97% of patients treated for 12 Months or longer, with no evidence of tachyphylaxis. Pegvisomant is the most effective medical therapy, reported to date, in terms of normalisation of circulating IGF-I concentrations. In addition, pegvisomant appears to be safe and well tolerated. Although additional long-term studies are required to further assess safety, the introduction of this innovative treatment should allow for optimal disease control in patients with acromegaly.
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PMID:Pegvisomant: an advance in clinical efficacy in acromegaly. 1267 Feb 98

Muscle fatigue occurs in many neuromuscular diseases, including the muscular dystrophies, and it contributes to a loss of functional capacity and reduced quality of life for affected patients. An improvement in fatigue resistance has been observed in diaphragm muscles of mdx mice following insulin-like growth factor-I (IGF-I) administration. Whether similar treatment can improve locomotor muscle function in mdx mice is not known. We examined the efficacy of IGF-I administration (1 mg/kg daily s.c. for 8 weeks) on structural, metabolic, and functional properties of extensor digitorum longus (EDL) and soleus muscles of mdx mice, and tested the hypothesis that IGF-I treatment would improve function in these muscles. After treatment, muscles were more resistant to fatigue during repeated maximal contractions than muscles from untreated mice, an improvement associated with increased muscle fiber succinate dehydrogenase activity in the absence of changes in cellular (single-fiber) contractile activation characteristics. The findings have important clinical implications, not just for the dystrophinopathies, but for all neuromuscular pathologies where fatigue of locomotor muscles limits functional capacity and decreases quality of life.
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PMID:Administration of insulin-like growth factor-I improves fatigue resistance of skeletal muscles from dystrophic mdx mice. 1531 40

The absence of dystrophin and resultant disruption of the dystrophin glycoprotein complex renders skeletal muscles of dystrophic patients and dystrophic mdx mice susceptible to contraction-induced injury. Strategies to reduce contraction-induced injury are of critical importance, because this mode of damage contributes to the etiology of myofiber breakdown in the dystrophic pathology. Transgenic overexpression of insulin-like growth factor-I (IGF-I) causes myofiber hypertrophy, increases force production, and can improve the dystrophic pathology in mdx mice. In contrast, the predominant effect of continuous exogenous administration of IGF-I to mdx mice at a low dose (1.0-1.5 mg.kg(-1).day(-1)) is a shift in muscle phenotype from fast glycolytic toward a more oxidative, fatigue-resistant, slow muscle without alterations in myofiber cross-sectional area, muscle mass, or maximum force-producing capacity. We found that exogenous administration of IGF-I to mdx mice increased myofiber succinate dehydrogenase activity, shifted the overall myosin heavy chain isoform composition toward a slower phenotype, and, most importantly, reduced contraction-induced damage in tibialis anterior muscles. The deficit in force-producing capacity after two damaging lengthening contractions was reduced significantly in tibialis anterior muscles of IGF-I-treated (53 +/- 4%) compared with untreated mdx mice (70 +/- 5%, P < 0.05). The results provide further evidence that IGF-I administration can enhance the functional properties of dystrophic skeletal muscle and, compared with results in transgenic mice or virus-mediated overexpression, highlight the disparities in different models of endocrine factor delivery.
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PMID:Systemic administration of IGF-I enhances oxidative status and reduces contraction-induced injury in skeletal muscles of mdx dystrophic mice. 1662 99

Complex changes occur within the endocrine system of ageing individuals. This article explores the changes that occur in the metabolism and production of various hormones and discusses the resulting clinical consequences. As individuals age there is a decline in the peripheral levels of oestrogen and testosterone, with an increase in luteinizing hormone, follicle-stimulating hormone and sex hormone-binding globulin. Additionally there is a decline in serum concentrations of growth hormone, insulin-like growth factor-I and dehydroepiandrosterone and its sulphate-bound form. Even though there are complex changes within the hypothalmo-pituitary-adrenal/thyroid axis, there is minimal change in adrenal and thyroid function with ageing. The clinical significance of these deficiencies with age are variable and include reduced protein synthesis, decrease in lean body mass and bone mass, increased fat mass, insulin resistance, higher cardiovascular disease risk, increase in vasomotor symptoms, fatigue, depression, anaemia, poor libido, erectile deficiency and a decline in immune function. For each endocrine system, studies have been carried out in an attempt to reverse the effects of ageing by altering the serum hormonal levels of older individuals. However, the real benefits of hormonal treatment in older individuals are still being evaluated.
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PMID:The endocrine system and ageing. 1720 Sep 39


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