SummaryObjectives: There is no licensed, dose-appropriate formulation of hydrocortisone for children with adrenal insufficiency (AI) and patients rely on compounded adult medication. The aim of this study was to evaluate the absorption, palatability and safety of Infacort ® , an immediate-release, granule formulation of hydrocortisone with taste masking. Study design:Single site with satellites attended by a "flying" doctor from investigator site. Open-label, single-dose study in three consecutive child cohorts (n = 24) with AI;Cohort 1, children aged 2 to <6 years (n = 12); Cohort 2, infants aged 28 days to <2 years (n = 6); Cohort 3, neonates aged 1 to <28 days (n = 6). Methods:Fasted children were given a single dose of Infacort ® as dry granules administered directly from a capsule or spoon followed by a drink. The primary end-point was the maximum serum cortisol concentration up to 240 minutes after Infacort ® administration. Secondary end-points were palatability and adverse events (AEs).Results: All children showed an increase in cortisol above baseline after Infacort Conclusions: Infacort ® is well tolerated, easy to administer to neonates, infants and children and shows good absorption, with cortisol levels at 60 minutes after administration similar to physiological cortisol levels in healthy children. K E Y W O R D Sadrenal insufficiency, congenital adrenal hyperplasia, infants, neonates, oral hydrocortisone granules This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
The effects of a single dose of scopolamine alone and in combination with ZK 93426 (a beta-carboline antagonist at the GABAA/BZ receptor complex with weak inverse agonist activity) were tested in two studies. In one study (study 1) the emphasis of enquiry was on different stages of information processing measured by a psychometric battery; in the second study (study 2) performance at different stages of memory and psychomotor abilities was tested and electroencephalogram recordings and video-tracking were also performed. Each study consisted of two parts, part I in which scopolamine (0.5 mg; 1 ml) or placebo were administered subcutaneously, and part II in which scopolamine (0.5 mg; 1 ml) was administered subcutaneously followed by an intravenous injection of ZK 93426 (0.04 mg; 0.04 ml/kg) or placebo. Thirty-six volunteers, who were randomly allocated to receive one of the two treatments (n = 18 per treatment), participated in each part. In study 1 attention was measured by a continuous attention task and a rapid information processing task, vigilance was measured by a visual vigilance task, and working memory and reasoning were evaluated by a logical reasoning task. A visual memory task was also included to measure acquisition and retention. In study 2 acquisition and short term storage and retrieval were measured by a word lists-Buschke restricted reminding procedure, and retention was tested by delayed recall and recognition. Psychomotor performance was assessed by measuring tapping speed (related to gross motoric abilities) and a pegboard task (related to fine motoric abilities). A task to measure working memory, the Pauli test, was also included. In study 1 scopolamine significantly impaired performance in the attentional and vigilance tasks (P < 0.05), but there was no effect in the logical reasoning task main measurements of time and accuracy. In study 2, scopolamine also impaired performance in the psychomotor tasks (P < 0.05) and the Pauli test. ZK 93426 partially antagonised most of the effects of scopolamine on memory and attention, suggesting that an interaction between the GABA-ergic and cholinergic systems is reflected in measurements of both attention and memory. In general a dissociation was found in the effects of scopolamine on memory, i.e. scopolamine impaired performance during all acquisition measurements but left retention unaffected.
In a prospective multi-center observational study, we evaluated the frequency, severity, and impact on activities of daily living (ADL) of adverse effects (AEs) of high-dose intravenous methylprednisolone (IVMP) in relapsing remitting multiple sclerosis (MS) patients with a relapse. Online self-report questionnaires stating IVMP’s most common AEs were completed at baseline, the 2nd day of treatment, and 1 day and 1 week after treatment. Eighty-five patients were included, 66 completed the baseline questionnaire, and 59 completed at least one post-baseline questionnaire. Patients reported on average 4 (median) AEs; two (3.4 %) reported no AE. Most frequent was change in taste (61 %), facial flushing (61 %), sick/stomach pain (53 %), sleep disturbance (44 %), appetite change (37 %), agitation (36 %), and behavioral changes (36 %). Of all AEs, 34.3 % were severe and 37.9 % impacted on ADL. A 3-day course resulted in 4 (median) AEs and a 5-day course in 7. All patients with high disease impact had two or more AEs, compared with 79 % of those with low impact (p < 0.01). Of patients with high disability, 45 % had severe AEs, compared with 16 % of those with low disability. Severe central nervous system (CNS)-related AEs occurred two times more frequently in patients with high disease impact, and two-and-a-half times more frequently in patients with high disability. Therefore, in virtually all patients, high-dose IVMP leads to AEs, with about one of three AEs being severe with impact on ADL. Patients with high disease impact or high disability may experience more (severe) AEs, due to a higher occurrence of severe CNS-related AEs.Electronic supplementary materialThe online version of this article (doi:10.1007/s00415-016-8183-3) contains supplementary material.
The effects of a single dose of scopolamine (0.5 mg) SC and of lorazepam (2.5 mg) PO were tested in two independent studies for their effects on performance in a psychometric battery which measured functions related to different stages of information processing. Attention and vigilance were measured by a continuous attention task and a vigilance task, respectively. Working memory and reasoning were evaluated by the rapid information processing and logical reasoning task; memory acquisition and storage were measured by pre- and post-drug immediate and delayed recall using visual material. The following pattern of effects was revealed; both scopolamine and lorazepam impaired performance in attentional and vigilance tasks as well as in the rapid information processing task significantly (P < 0.05) when compared with their own placebo; in the logical reasoning task lorazepam significantly prolonged the time required to solve a problem; scopolamine did not have any effect on this task. Scopolamine impaired performance in the immediate recall but left delayed recall unaffected; lorazepam impaired only delayed recall, immediate recall remaining unaffected. These data suggest that scopolamine at this dose impaired mostly attention and early stages of information processes; lorazepam at the dose tested impaired also the later acquisition and encoding aspects of memory.
Context Children with congenital adrenal hyperplasia (CAH) and adrenal insufficiency (AI) require daily hydrocortisone replacement with accurate dosing Objective Prospective study of efficacy and safety of hydrocortisone granules in children with AI and CAH monitored by 17-OHP saliva profiles Methods 17 children with CAH (9 male) and 1 with hypopituitarism (male) aged from birth to 6 years, had their hydrocortisone medication changed from pharmacy compounded capsules to hydrocortisone granules. Patients were followed prospectively for 2 years. In children with CAH therapy was adjusted by 3-monthly 17-OHP profiles. The following parameters were recorded: hydrocortisone dose, height, weight, pubertal status, adverse events, and incidence of adrenal crisis Results Study medication was given thrice daily, median duration of treatment (range) was 795 (1-872) days with 150 follow-up visits. Hydrocortisone doses were changed on 40/150 visits, 32 based on salivary measurements and 8 on serum 17-OHP levels. Median daily hydrocortisone dose mg/m 2 (range) at study entry in different age groups: 2-8 years, 1months-2years, <28 days was 11.9 (7.2-15.5), 9.9 (8.6-12.2) and 12.0 (11.1-29.5) and at end of study was 10.2 (7.0-14.4), 9.8 (8.9-13.1) and 8.6 (8.2-13.7). There were no trends for accelerated or reduced growth. No adrenal crises were observed despite 193 treatment-emergent adverse events, which were mainly common childhood illnesses Interpretation This first prospective study of glucocorticoid treatment in children with AI and CAH demonstrates that accurate dosing and monitoring from birth results in hydrocortisone doses at the lower end of the recommended dose range, normal growth, without occurrence of adrenal crises
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