The age-related down-regulation of the growth hormone/insulin-like growth factor-1 axis in the elderly male is reversed considerably by donepezil, a drug for Alzheimer's disease.

GH secretion declines by 14%/decade of adult life, leading to the suggestion that people over the age of 60 years are functionally GH deficient. Recently, rivastigmine, a novel cerebral selective cholinesterase-inhibitor (ChEI), was shown to be a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. The present study was designed as a randomised controlled trial to evaluate long term effects of donepezil, a cerebral selective ChEI, on basal GH and IGF-1 levels and on GH response to GHRH (1 microg/kg i.v., GHRH test) before and after an 8-week donepezil treatment period. Donepezil was given orally 5 mg per day for 4 weeks and 10 mg per day for another 4 weeks. Twenty four healthy male volunteers (n=2 x 12, placebo group vs. donepezil group, age: 61-70 years) were studied. Donepezil treatment group: basal GH levels taken at 08:30 a.m. doubled from 0.4+/-0.3 to 0.8+/-0.4 ng/ml (p=0.008). GHRH-test: GH-AUC was 318+/-227 ng/ml/h and increased by 53% to 485+/-242 ng/ml/h (p=0.009). Total serum IGF-1 levels, taken simultaneously with the basal GH levels, showed a considerable increase, too: the baseline IGF-1 levels increased by 31% from 84+/-19 to 110+/-21 ng/ml (p=0.007). This study demonstrated that the age-related down-regulation of the GH/IGF-1 axis is reversed considerably by donepezil in the elderly male. Future investigation will reveal whether such a new therapeutic intervention can delay the onset or even reverse some manifestations of the somatopause in the long term and evaluate its benefit/risk ratio concerning new treatment implications.

Endurance running acutely raises plasma osteoprotegerin and lowers plasma receptor activator of nuclear factor kappa B ligand.

Abstract The balance of the 2 cytokines, osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa B ligand (soluble (s)RANKL), is known to have considerable influence on bone formation and degradation. Plasma concentrations of OPG and (s)RANKL were determined in a total of 31 long-distance runners before and immediately after running distances of either 15 or 42.195 km, respectively. In both groups of endurance runners, a significant decrease of sRANKL was observed during the run, the extent of which correlated to the running distance. Furthermore, OPG increased only in runners covering the marathon distance of 42.195 km. We hypothesize that the known positive effect of long-distance running on the skeletal mass may be mediated by the OPG/sRANKL system.

The cholinergic system controls ghrelin release and ghrelin-induced growth hormone release in humans.

The stomach-derived peptide hormone ghrelin induces appetite and GH release. Several ghrelin actions are possibly mediated and modulated by the central cholinergic system. The aim of this study was to investigate the influence of the unspecific cholinergic antagonist atropine and the acetylcholine esterase inhibitor pyridostigmine, a cholinergic enhancer on ghrelin plasma concentrations and ghrelin-induced GH release. We investigated plasma ghrelin concentrations, ghrelin-induced GH release, and glucose and insulin concentrations after administration of atropine or pyridostigmine, and ghrelin (in two different doses, 0.25 and 1 microg/kg body weight), alone and in combination in a randomized, double-blind, placebo-controlled, crossover study design on 12 young, healthy male volunteers. Atropine alone significantly reduced fasting ghrelin levels by 25%, whereas under pyridostigmine alone ghrelin levels were unaltered. Ghrelin in combination with atropine induced significantly reduced GH concentrations compared with ghrelin administration alone for both ghrelin doses, whereas ghrelin-induced GH peak concentrations and areas under the curve were not enhanced by pyridostigmine treatment. These results suggest that, in humans, fasting ghrelin concentrations might be under cholinergic control and that the cholinergic system appears to modulate ghrelin-induced GH release.

Increases in plasma levels of atrial and brain natriuretic peptides after running a marathon: are their effects partly counterbalanced by adrenocortical steroids?

OBJECTIVE: Long-distance running results in considerable stress. Little evidence exists about the role of the atrial and brain natriuretic peptides, ANP and BNP, deriving from the myocardium. The aim of our study was to investigate the influence of running 42.195 km on changes in circulating natriuretic propeptides and adrenocortical steroids. DESIGN AND METHODS: We studied 17 male and 2 female runners (age: 28-62 Years) participating in a marathon. Blood samples were obtained before and immediately after the competition. proANP(1-98) and proANP(1-30) as well as Nt-proBNP(8-29) were determined by enzyme immunoassays. RESULTS: Runners finished the competition between 2 h 58 min and 4 h 25 min. We observed a more pronounced increase in proANP(1-98) (+58%) and proANP(1-30) (+99%, both P<0.001) compared with Nt-proBNP(8-29) (+6%; P=0.005). Increases in proANP(1-30) positively correlated with runners' age (r=0.53; P=0.02). We also observed a marked increase in cortisol (+73%) and especially in aldosterone (+431%, both P<0.001). CONCLUSIONS: Cardiac strain during long-distance running may explain the pronounced increase in proANP. Other explanations for the observed rise in plasma levels might be a change in the permeability of myocardial cells and an impaired clearance. A rise in adrenocortical steroids may compensate for the negative influence of ANP on natriuresis and blood pressure. Positive effects of ANP during a marathon could be the regulation of body temperature by influencing sweat glands as well as the stimulation of lipolysis compensating for the enormous energy demand.

Effects of 12 months of recombinant growth hormone therapy on parameters of bone metabolism and bone mineral density in patients on chronic hemodialysis.

BACKGROUND: Renal osteodystrophy is common in patients with chronic renal failure (CRF) on hemodialysis (HD), leading to reduced bone mineral density (BMD) and higher bone fracture incidences. Since growth hormone (GH) and insulin-like growth factor 1 (IGF-1) are known to enhance bone metabolism and BMD, and CRF patients exhibit GH and IGF-1 resistance, recombinant human GH (rhGH) therapy could be beneficial for these patients. METHODS: This study evaluated the effects of a 12-month rhGH therapy on bone metabolism parameters; alkaline phosphatase (AP), osteocalcin (OC), procollagen I carboxyterminal propeptide (PICP), telopeptide ICTP, serum crosslaps, n-terminal propeptide of type III procollagen (PIIINP) and intact parathyroid hormone (iPTH), as well as on BMD of the lumbar spine and the femoral neck in 19 malnourished HD patients (10 females, 9 males) with a mean age of 59.3 +/- 13.4 yrs. Fourteen patients completed the 12-month study. RhGH (0.25 IU/kg) was given subcutaneously 3x/week after each dialysis session. RESULTS: IGF-1 concentrations rose significantly from 169.2 +/- 95.6 to 262.9 +/- 144.4 ng/mL (p<0.01) after 3 months, followed by a slight decline over the next 9 months. PICP as a bone formation marker significantly increased after 3 months from 250.1 +/- 112.6 to 478.5 +/- 235.2 ug/L (p<0.01), as well as PIIINP, whereas OC and bone resorption parameters like ICTP showed only a slight increase (ICTP: 50.3 +/- 18.5 to 70.0 +/- 39.5 ug/L after 3 months (ns)). All bone metabolism parameters slightly declined in the following 9 months, but remained above baseline values after 12 months. PTH rose from 198.0 +/- 139.2 to 456.0 +/- 268.7 ng/ml, p<0.01 after 6 months. BMD of the lumbar spine showed a significant reduction after 3-month rhGH therapy (0.80 +/- 0.17 vs. 0.77 +/- 0.16 g/cm2, p<0.01), but returned to baseline values after 12 months. BMD of the femoral neck remained stable during the entire study. CONCLUSIONS: In summary, 12-month rhGH treatment in patients on chronic HD caused a significant increase in IGF-1, together with an increase in bone turnover. In addition, there was a temporary reduction in BMD of the lumbar spine seen, which returned to baseline values after 12 months.

One-year growth hormone therapy improves granulocyte function without major effects on nutritional and anthropometric parameters in malnourished hemodialysis patients.

BACKGROUND/AIMS: Growth hormone (GH) resistance leads to enhanced protein catabolism and contributes to the malnutrition of patients with chronic renal failure (CRF). In short-term trials anabolic effects of rhGH therapy have been demonstrated in patients on chronic hemodialysis. METHODS: This study was initiated to determine the effects of 12 months of rhGH therapy on polymorphonuclear leukocyte (PMNL) function as well as on nutritional and anthropometric parameters. 0.125 IU/kg rhGH was given 3 times a week during the first 4 weeks and 0.25 IU/kg thereafter to 19 malnourished hemodialysis patients with a mean age of 59.3 +/- 13.4 years. RESULTS: Insulin-like growth factor I (IGF-I) concentrations rose significantly from 169.2 +/- 95.6 to 262.9 +/- 144.4 ng/ml (p < 0.01) in the first 3 months, but declined thereafter. Phagocytic activity of PMNLs also increased significantly in response to rhGH therapy and this activation remained stable over the whole 12-month period. Other parameters of PMNL function were not influenced by rhGH therapy. In addition, nutritional parameters such as albumin, prealbumin, transferrin, cholesterol, HDL-cholesterol, cholinesterase, predialytic creatinine and blood urea nitrogen were not affected by rhGH therapy. A decline of total body fat (TBF) was observed after 3 and 9 months of rhGH therapy (17.5 +/- 10 vs. 16.7 +/- 10% after 3 months, p < 0.017 and 16.8 +/- 8.7% after 9 months, p < 0.049), whereas lean body mass remained stable. CONCLUSIONS: Twelve months of rhGH therapy caused a significant increase in IGF-I levels, stimulated phagocytic activity of PMNLs and induced a decline of TBF. Other anthropometric and nutritional parameters were not affected, which might be related to the persistence of GH resistance.

Normal regulation of elevated plasma ghrelin concentrations in dialysis patients.

BACKGROUND: Chronic renal failure is often associated with malnutrition, and malnourished patients are subject to increased morbidity and mortality. Therefore plasma concentrations of the stomach-derived peptide hormone ghrelin, which has been shown to exert potent GH-releasing and appetite-stimulating effects, were determined and correlated with nutritional parameters. METHODS: Twenty-four patients (15 male, 9 female) undergoing hemodialysis (HD) were studied. In addition, six patients were studied before and one hour after ingestion of a meal and five were studied immediately before and at the end of the dialysis session. RESULTS: Chronic renal insufficiency was associated with significantly elevated ghrelin levels (320.1 +/- 57 fmol/mL vs. 75.6 +/- 12.4 fmol/mL in controls; p < 0.007). Plasma ghrelin concentrations were also significantly higher in the 16 normal-weight patients than in the eight overweight or obese patients (399.6 +/- 76.3 fmol/mL vs. 161.1 +/- 41.3 fmol/mL; p < 0.03). Ingestion of food induced a decrease in five out of six patients tested (mean 242.3 +/- 66.5 fmol/mL vs. 186 +/- 30.7 fmol/mL; n.s.). HD also resulted in a significant decrease of elevated ghrelin concentrations: ghrelin was in the normal range at the end of HD in four of the five patients tested. Plasma ghrelin concentrations did not correlate with nutritional parameters except for cholinesterase which was negatively correlated to ghrelin. CONCLUSION: Plasma ghrelin concentrations are elevated in HD. The fact that ghrelin concentrations are higher in normal-weight than in overweight or obese HD patients and suppressed after ingestion of a meal suggests that the regulation of ghrelin release is retained in HD patients, albeit shifted to a higher level.

Prediction of clinical outcome in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) using the TIMI risk score extended by N-terminal pro-brain natriuretic peptide levels.

BACKGROUND: N-terminal pro-brain natriuretic peptide (Nt-proBNP) is a strong independent predictor of death in acute coronary syndromes. In order to improve risk assessment in patients with unstable coronary artery disease we investigated the role of the additional determination of Nt-proBNP levels in patients sub-grouped into high-, medium- and low-risk groups according to the TIMI risk score. METHODS: Nt-proBNP was determined in 145 consecutive patients admitted to our clinic with typical anginal pain in the past 24 hours and normal left ventricular function. Using classification and regression tree analysis, we investigated whether Nt-proBNP levels provide clinically relevant prognostic information in addition to the TIMI risk score. Nt-proBNP concentrations were determined using a commercially available assay from Biomedica, Austria. The normal range of this assay is <2827 pg/ml. RESULTS: Multivariate logistic regression analysis revealed that TIMI scores and Nt-proBNP levels are independent predictors of mortality (P = 0.001 and P < 0.001, respectively). Patients with Nt-proBNP levels >5225 pg/ml had the highest mortality rate, independent of their TIMI risk classification. In the subset of patients with Nt-proBNP < or =5225 pg/ml, patients at TIMI medium risk but with Nt-proBNP above 2827 pg/ml had significantly higher mortality than patients with lower levels of Nt-proBNP (P = 0.03). Accordingly, we developed a combined risk score consisting of four risk groups: very high (Nt-proBNP > or =5225 pg/ml), high (TIMI high-risk group or TIMI medium-risk group and Nt-proBNP >2827 pg/ml), medium (TIMI medium-risk group and Nt-proBNP < or =2827 pg/ml) and low (TIMI low-risk group). The area under the receiver operating characteristic curve was 0.772 for the TIMI score alone and 0.863 for the combined risk score (P < 0.001). CONCLUSION: Determination of plasma Nt-proBNP levels and incorporation of these into TIMI risk classification by creating a combined risk score significantly improves risk assessment of patients with unstable coronary artery disease.

Risk assessment in patients with unstable angina/non-ST-elevation myocardial infarction and normal N-terminal pro-brain natriuretic peptide levels by N-terminal pro-atrial natriuretic peptide.

AIMS: To compare the accuracy of the N-terminal fragment of its pro-hormone (Nt-proBNP) and N-terminal pro-atrial natriuretic peptide (Nt-proANP) in the prediction of the 2 year mortality and to investigate whether additional measurement of Nt-proANP to troponin I (TnI) could improve risk assessment in the subgroups of patients with unstable coronary artery disease (UCAD) and normal Nt-proBNP. METHODS AND RESULTS: Plasma levels of the TnI, Nt-proANP, and Nt-proBNP were determined in 120 consecutive patients with UCAD without ST-segment elevations and normal left ventricular function. In multivariable logistic regression analysis, TnI and Nt-proBNP were independent predictors of mortality (P=0.01 and P=0.02, respectively). However, in the group of patients with normal Nt-proBNP levels, only Nt-proANP and TnI were independently associated with mortality (P=0.007 and P=0.03, respectively). Accordingly, patients with elevated Nt-proANP levels in this group of patients had significantly higher mortality rate than patients with normal Nt-proANP levels (P=0.003). CONCLUSION: Our results suggest that determination of Nt-proANP might improve risk assessment in patients with UCAD, especially when Nt-proBNP is in the normal range.

The reduced release of GH by GHRH in 8 subjects aged 65-69 years is augmented considerably by rivastigmine, a drug for Alzheimer's disease.

BACKGROUND: The growth hormone (GH) secretion declines by 14% with each decade of adult life. Several attempts have been made to reverse the manifestations of the senile GH deficiency, termed somatopause, but GH substitution treatment in old age has not yet developed an established regimen. Cholinesterase inhibitors like pyridostigmine are able to elicit GH secretion when administered alone and to enhance the GH response to growth hormone releasing hormone (GHRH), but its clinical use is limited due to the strong peripheral cholinergic side effects. OBJECTIVE: The aims of our experiments were to find out whether the GH response to GHRH can be augmented by rivastigmine, a new orally applicable and well-tolerated selective inhibitor of cerebral acetylchoinesterase. METHODS: Eight healthy volunteers (age range 65-69 years) were studied. After an overnight fast, GHRH tests were done: 1 microg/kg GHRH was injected as an intravenous bolus. Blood samples for an immunoradiometric GH assay were taken at the time of GHRH injection (time 0) and after 15, 30, 45, 60, and 120 min. First, the baseline experiment was done: it consisted of two subsequent GHRH tests which were carried out within an interval of 120 min. Four weeks later the rivastigmine experiment was done identically, but 60 min before performing the second GHRH test, rivastigmine (4.5 mg) was administered orally. The GH secretory responses were expressed as areas under the curve (AUC; median, interquartile range), Wilcoxon's signed-rank test was used for statistical comparisons. RESULTS: Baseline experiment: The GH AUC of the first GHRH test was 1040 (range 420-1250) ng/ml/h. The repeated GHRH stimulation after 120 min (second GHRH test) showed a 13-fold decrease to 80 (range 60-130) ng/ml/h. Rivastigmine experiment: The GH AUC of the first GHRH test was 950 (range 540-1430) ng/ml/h and, therefore, similar to that of the baseline experiment. 60 min after ingestion of the single oral dose of rivastigmine (4.5 mg), the following GHRH stimulation (second GHRH test) nearly doubled the GH AUC to 1580 (range 860-3330) ng/ml/h. Comparing the DeltaGH AUC values (DeltaGH AUC = GH AUC of the first GHRH test minus GH AUC of the second GHRH test), baseline experiment versus rivastigmine experiment, there was a 20-fold (p = 0.018) increase in GH AUC after rivastigmine pretreatment. CONCLUSIONS: Rivastigmine is a powerful drug to enhance GH release to repeated GHRH stimulation in healthy elderly human subjects. Future investigations are necessary to find out whether rivastigmine can restore the senile decline of the circadian GH secretion in the long term and, therefore, has new implications for patient treatment.

Estudo multicêntrico com três doses diferentes de ketanserin em hipertensäo arterial essencial / Multicenter study with 3 different doses of ketanserin in essential arterial hypertension

Os autores avaliaram em estudo randomizado, simples-cego, com grupos paralelos, a atividade anti-hipertensiva de ketanserin, um novo medicamento bloqueador dos receptores 5-HT2 de serotonina, em comprimidos de 40 mg. Noventa e um pacientes de ambulatório, portadores de hipertensäo arterial essencial näo complicada, após receberem placebo por período de 4 semanas, foram incluídos aleatoriamente em um de três grupos: 40 mg uma vez, duas vezes ou três vezes ao dia. O tratamento com ketanserin foi mantido durante 12 semanas. As três doses de ketanserin reduziram a pressäo arterial, havendo pequenas diferenças entre os esquemas escolhidos. Da mesma maneira, näo ocorreu diferença apreciável entre a incidência e a natureza das reaçöes adversas entre os grupos