Model informed quantification of the feed-forward stimulation of growth hormone by growth hormone-releasing hormone

Aims: Growth hormone (GH) secretion is pulsatile and secretion varies highly between individuals. To understand and ultimately predict GH secretion, it is important to first delineate and quantify the interaction and variability in the biological processes underlying stimulated GH secretion. This study reports on the development of a population nonlinear mixed effects model for GH stimulation, incorporating individual GH kinetics and the stimulation of GH by GH-releasing hormone (GHRH). Methods: Literature data on the systemic circulation, the median eminence, and the anterior pituitary were included as system parameters in the model. Population parameters were estimated on data from 8 healthy normal weight and 16 obese women who received a 33 μg recombinant human GH dose. The next day, a bolus injection of 100 μg GHRH was given to stimulate GH secretion. Results: The GH kinetics were best described with the addition of 2 distribution compartments with a bodyweight dependent clearance (increasing linearly from 24.7 L/h for a 60-kg subject to 32.1 L/h for a 100-kg subject). The model described the data adequately with high parameter precision and significant interindividual variability on the GH clearance and distribution volume. Additionally, high variability in the amount of secreted GH, driven by GHRH receptor activation, was identified (coefficient of variation = 90%). Conclusion: The stimulation of GH by GHRH was quantified and significant interindividual variability was identified on multiple parameters. This model sets the stage for further development of by inclusion of additional physiological components to quantify GH secretion in humans

Severe tracheal and bronchial collapse in adults with type II mucopolysaccharidosis

Background: Mucopolysaccharidosis type II (MPSII) patients frequently suffer from dyspnoea caused by restrictive airway disease due to skeletal abnormalities as well as glycosaminoglycans (GAG) accumulation at different levels of the airway, including the trachea. In this study we describe the extent of the tracheal and bronchial narrowing, the changes in airway diameter during respiration and the effects of these obstructions on respiratory function in adult MPSII patients. Methods: Five adult MPSII patients (mean age 40 years) were included. Pulmonary function tests and in- and expiratory chest CT scans were obtained. Cross-sectional areas of trachea and main bronchi were measured at end-inspiration and -expiration and percentage collapse was calculated. Results: There was diffuse narrowing of the entire intra-thoracic trachea and main bronchi and severe expiratory collapse of the trachea in all patients. At 1 cm above the aortic arch the median % collapse of the trachea was 68 (range 60 to 77 %), at the level of the aortic arch 64 (range 21-93 %), for the main bronchi this was 58 (range 26-66 %) on the left and 44 (range 9-76 %) on the right side. The pulmonary function tests showed that this airway collapse results in obstructive airway disease in all patients, which was severe (forced expiratory volume <50 % of predicted) in four out of five patients. Conclusion: In adult MPS II patients, central airways diameters are strikingly reduced and upon expiration there is extensive collapse of the trachea and main bronchi. This central airways obstruction explains the severe respiratory symptoms in MPSII patients

Afamelanotide for Erythropoietic Protoporphyria

BACKGROUND: Erythropoietic protoporphyria is a severe photodermatosis that is associated with acute phototoxicity. Patients with this condition have excruciating pain and a markedly reduced quality of life. We evaluated the safety and efficacy of an α-melanocyte-stimulating hormone analogue, afamelanotide, to decrease pain and improve quality of life. METHODS: We conducted two multicenter, randomized, double-blind, placebo-controlled trials of subcutaneous implants containing 16 mg of afamelanotide. Patients in the European Union (74 patients) and the United States (94 patients) were randomly assigned, in a 1:1 ratio, to receive a subcutaneous implant containing either afamelanotide or placebo every 60 days (a total of five implants in the European Union study and three in the U.S study). The type and duration of sun exposure, number and severity of phototoxic reactions, and adverse events were recorded over the respective 180-day and 270-day study periods. Quality of life was assessed with the use of validated questionnaires. A subgroup of U.S. patients underwent photoprovocation testing. The primary efficacy end point was the number of hours of direct exposure to sunlight without pain. RESULTS: In the U.S. study, the duration of pain-free time after 6 months was longer in the afamelanotide group (median, 69.4 hours, vs. 40.8 hours in the placebo group; P=0.04). In the European Union study, the duration of pain-free time after 9 months was also longer in the afamelanotide group than in the placebo group (median, 6.0 hours vs. 0.8 hours; P=0.005), and the number of phototoxic reactions was lower in the the afamelanotide group (77 vs. 146, P=0.04). In both trials, quality of life improved with afamelanotide therapy. Adverse events were mostly mild; serious adverse events were not thought to be related to the study drug. CONCLUSIONS: Afamelanotide had an acceptable side-effect and adverse-event profile and was associated with an increased duration of sun exposure without pain and improved quality of life in patients with erythropoietic protoporphyria. (Funded by Clinuvel Pharmaceuticals and others; ClinicalTrials.gov numbers, NCT01605136 and NCT00979745.)