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      Effects of Methylphenidate on Weight Gain and Food Intake in Hypothalamic Obesity

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          Abstract

          For patients with a craniopharyngioma (CP), treatment of hypothalamic obesity (HO) and hyperphagia following resection and/or radiotherapy is extremely difficult and few reports have been published on potential drug therapies. Psychomotor stimulant methylphenidate (MPH) has been reported to inhibit food intake (FI). In this paper, we report reduction of body mass index (BMI) and appetite in an adolescent CP patient suffering from HO. We then tested the ability of MPH to attenuate the FI and body weight (BW) gain in a rat model consistent with the neuroanatomical and metabolic disturbances commonly observed in obese CP patients. Specifically, we used a novel electrolytically generated combined medial hypothalamic lesion (CMHL) affecting the arcuate nucleus, ventromedial hypothalamic nucleus, and dorsomedial hypothalamic nucleus to induce hyperphagia, rapid weight gain, and adiposity. Both CMHL and control animals ( n = 7 per group) were administered either methylphenidate HCl (MPH; 20 mg kg −1 day −1) or saline for 4 days in a crossover design experiment 28 weeks post-surgery. A significant decrease in percent baseline FI (CMHL −23%, p = 0.008; control −20%, p = 0.002) and percent change in BW (CMHL −1.97%/4 days, p = 0.011; control −1.75%/4 days, p = 0.003) was observed during MPH treatment as compared to saline. Conclusion: This study shows MPH treatment of severely obese CMHL rats resulted in significantly reduced FI and BW loss.

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          Most cited references28

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          Effects of methylphenidate on the catecholaminergic system in attention-deficit/hyperactivity disorder.

          Stimulants are part of the standard-of-care treatment for attention-deficit/hyperactivity disorder (ADHD). Methylphenidate, with a history of use spanning approximately 5 decades, is a first-line stimulant treatment for ADHD. Methylphenidate chiefly affects the prefrontal cortex and striatum, the mechanism of action being modulation of catecholaminergic tone. Methylphenidate treatment produces an increase in dopamine (DA) signaling through multiple actions, including blockade of the DA reuptake transporter and amplification of DA response duration, disinhibition of DA D2 autoreceptors and amplification of DA tone, and activation of D1 receptors on the postsynaptic neuron. The actions of methylphenidate may also be mediated by stimulation of the noradrenergic alpha2 receptor and DA D1 receptor in the cortex. The role of other neurotransmitters such as histamine, acetylcholine, serotonin, and alpha-agonists in modulating catecholamine pathophysiology in ADHD and ADHD treatment needs to be elucidated. Overall, the changes in catecholaminergic tone clinically manifest as improvements in attention deficit, distractibility, and motor hyperactivity in patients with ADHD.
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            Childhood Craniopharyngioma

            Background: Craniopharyngioma are embryogenic malformations of the sellar area. With an overall incidence of 0.5–2 new cases per million population per year, 30–50% of all cases occur in childhood. Overall survival rates are high. However, quality of life (QoL) is substantially reduced in many survivors due to sequelae such as extreme obesity caused by hypothalamic lesions. Methods: Based on retrospective analysis of 306 patients with childhood craniopharyngioma (HIT ENDO), we found that QoL was negatively related to hypothalamic involvement, tumor size and the number of neurosurgical interventions. Results: Irradiation had no significant impact on long-term QoL. The prospective surveillance of 98 patients in KRANIOPHARYNGEOM 2000 revealed frequent and early events in terms of tumor relapse after apparently complete resection (EFS: 0.60 ± 0.09 at 3 years) and tumor progression after incomplete resection (EFS: 0.22 ± 0.09). Conclusion: We conclude that radical surgery in patients with hypothalamic involvement has a major negative impact on long-term QoL. Innovative treatment strategies are warranted to improve QoL in these patients at risk. Accordingly, the appropriate time point of irradiation after incomplete resection will be analyzed in KRANIOPHARYNGEOM 2007.
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              Weight gain in craniopharyngioma--a model for hypothalamic obesity.

              To evaluate (1) the pattern of post-operative weight gain and (2) the risk factors associated with the development of post-operative weight gain and obesity in children treated for craniopharyngioma. The records of 43 children who had primary craniopharyngioma resection were reviewed. Neurological, endocrine, anthropometric and radiological risk factors for the development of obesity and for post-operative increase in BMI SDS were analyzed. Twenty-five patients (58%) became obese post-operatively. Obesity was significantly associated with higher BMI SDS at presentation and pre-operative hydrocephalus (p < 0.05). Increased BMI SDS from 0-12 months was significantly associated with post-operative MRI evidenced hypothalamic damage and higher BMI at presentation (p < 0.05). Children who developed hypothalamic obesity had a significant, rapid BMI increase over the first 6 months, followed by stabilization, with no regression of BMI SDS.
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                Author and article information

                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrin.
                Frontiers in Endocrinology
                Frontiers Research Foundation
                1664-2392
                13 September 2011
                14 December 2011
                2011
                : 2
                : 78
                Affiliations
                [1] 1simpleSeattle Children’s Research Institute, Center for Integrative Brain Research, University of Washington, School of Medicine Seattle, WA, USA
                Author notes

                Edited by: Hermann Lothar Mueller, Klinikum Oldenburg gGmbH, Germany

                Reviewed by: Günter K. Karl Stalla, Max-Planck-Institute of Psychiatry, Germany; Carlos Dieguez, University of Santiago de Compostela, Spain

                *Correspondence: Christian Ludwig Roth, Division of Endocrinology, Seattle Children’s Hospital Research Institute, 1900 Ninth Avenue, Seattle, WA 98101, USA. e-mail: christian.roth@ 123456seattlechildrens.org

                This article was submitted to Frontiers in Pituitary Endocrinology, a specialty of Frontiers in Endocrinology.

                Article
                10.3389/fendo.2011.00078
                3355874
                22649386
                b160bf70-e141-4c52-8fb7-71b28992a91d
                Copyright © 2011 Elfers and Roth.

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.

                History
                : 25 August 2011
                : 06 November 2011
                Page count
                Figures: 2, Tables: 1, Equations: 0, References: 33, Pages: 5, Words: 4479
                Categories
                Endocrinology
                Original Research

                Endocrinology & Diabetes
                food intake,weight gain,hypothalamic lesion,methylphenidate,hyperphagia
                Endocrinology & Diabetes
                food intake, weight gain, hypothalamic lesion, methylphenidate, hyperphagia

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