Subject(s)
Adrenergic Agents/therapeutic use , Exercise Tolerance/drug effects , Heart Failure/drug therapy , Stroke Volume/physiology , Ventricular Function, Left/drug effects , Aged , Echocardiography , Female , Heart Failure/diagnostic imaging , Heart Failure/physiopathology , Humans , Male , Middle Aged , Prognosis , Stroke Volume/drug effectsABSTRACT
OBJECTIVE: The quantitative and qualitative aspects of the pituitary response in children and adults with Prader-Willi syndrome (PWS) are compared in order to verify the possible age-dependent and genotype-related differences in terms of GH secretion. DESIGN: 29 young subjects (21 males and 8 females) and 65 adults (24 males and 41 females) with PWS were studied. All subjects underwent a standard GH Releasing Hormone (GHRH 1-29, 1 µg/kg as i.v. bolus at 0 minutes)+arginine (0.5 g/kg) test. Peak GH values, standard GH area under the curve (AUC), AUC of the instantaneous secretion rate (ISR), and secretion response analysis (i.e. half-secretion time) were evaluated. A regression analysis was performed to investigate which are the patient characteristics that affect the amplitude and shape of the GH secretion response. RESULTS: Peak GH values and AUCGH were significantly higher in PWS children than in PWS adults, these differences being also significant both in PWS DEL15 (only peak GH value) and PWS UPD15. Moreover, PWS children showed significantly lower half secretion time than PWS adults, this delayed response being present both in PWS DEL15 and PWS UPD15. Significant negative correlations between AUCGH and BMISDS were observed in the two groups (adults and children), as well as in adults and children DEL15, but not in adults and children PWS UPD15. A regression analysis performed on the whole dataset showed that for PWS DEL15 the statistically significant variable explaining GH responsiveness was BMISDS (p<0.0001), while for UPD15 no statistically significant covariate was found. Conversely, when the delay of the secretion response was considered, the regression model yielding the best performances was the one with only age as a regressor (p<0.001). CONCLUSIONS: The quantitative and qualitative analyses of GH responsiveness to GHRH+arginine highlight relevant differences between PWS children and PWS adults and genotype-related traits. The negative influence of BMISDS on GH secretion reinforces the need for an early start of life-long weight management in PWS subjects.
Subject(s)
Arginine/administration & dosage , Growth Hormone-Releasing Hormone/administration & dosage , Human Growth Hormone/metabolism , Pituitary Gland/metabolism , Prader-Willi Syndrome/genetics , Prader-Willi Syndrome/metabolism , Adolescent , Adult , Age Factors , Area Under Curve , Body Mass Index , Child , Child, Preschool , Female , Follow-Up Studies , Genotype , Humans , Male , Prader-Willi Syndrome/diagnosis , Prognosis , Young AdultABSTRACT
Many difficulties may arise during the modeling of the time course of Hamilton Rating Scale for Depression (HAM D)scores in clinical trials for the evaluation of antidepressant drugs: (i) flexible designs, used to increase the chance of selecting more efficacious doses, (ii) dropout events, and (iii) adverse effects related to the experimental compound.It is crucial to take into account all these factors when designing an appropriate model of the HAM D time course and to obtain a realistic description of the dropout process. In this work, we propose an integrated approach to the modeling of a double-blind, flexible-dose, placebo-controlled, phase II depression trial that comprises response,tolerability, and dropout. We investigate three different dropout mechanisms in terms of informativeness. Goodness of fit is quantitatively assessed with respect to response (HAM D score) and dropout data. We show that dropout is a complex phenomenon that may be influenced by HAM D evolution, dose changes, and occurrence of drug-related adverse effects.
Subject(s)
Antidepressive Agents/administration & dosage , Depression/drug therapy , Patient Dropouts , Antidepressive Agents/adverse effects , Double-Blind Method , Humans , Psychiatric Status Rating Scales , Research DesignABSTRACT
The aim of the present study was to characterize the muscarinic acetylcholine receptor subtypes present in the caput and cauda of rat epididymis. The specific binding of [3H]quinuclidinyl benzilate ([3H]QNB) to epididymal membranes was time dependent, temperature dependent, and saturable. The cauda epididymis showed higher affinity to [3H]QNB and higher muscarinic receptor density when compared to the caput region. The [3H]QNB binding was tested in competition studies with different muscarinic receptor antagonists. Each antagonist tested displaced [3H]QNB bound to caput and cauda epididymal membrane with similar affinity. Correlation among the negative logarithm of inhibition constant values (pK(i)) for these antagonists obtained in the epididymis with their correspondent published pK(i) values obtained in tissues that expressed each receptor subtype (M1, M2, M3, and M4) indicated that the muscarinic receptors present in caput and cauda epididymis belong to the muscarinic M2 receptor subtype. When reverse transcription-polymerase chain reaction was used to identify muscarinic receptor mRNA subtypes in the epididymis, only m2 transcripts were detected in the caput region, while both m2 and m3 mRNA subtypes were observed in the cauda region. In conclusion, these results demonstrate that muscarinic receptors are present in the rat epididymis, with expression levels dependent on the region of the epididymis analyzed. Thus, the cholinergic neurotransmitter in the epididymis may be a factor controlling contractility and/or the luminal fluid microenvironment.
