Pediatric obesity pharmacotherapy: current state of the field, review of the literature and clinical trial considerations.
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SUBMITTER: Kelly AS
PROVIDER: S-EPMC5546093 | biostudies-other | 2016 Jul
REPOSITORIES: biostudies-other
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Project description:Purpose of reviewChildhood obesity is escalating globally. Lifestyle and behavioral changes, which are the frequently used interventions in clinical practice, lead to only modest improvements in children with established obesity. Bariatric surgery is currently the most effective obesity treatment but has very limited utilization in pediatric obesity and is preferentially used for children with worsening comorbidities. There exists a massive treatment gap for children suffering with obesity especially after the failure of lifestyle modifications. Pharmacotherapy that is an established management tool in adults is very infrequently used in children. Only two medications, Phentermine and Orlistat are approved by the Food and Drug Administration (FDA) for use in adolescent obesity. Herein, we discuss the current landscape and available literature on the use of antiobesity pharmacotherapy in children.Recent findingsThere are emerging pediatric data about the efficacy of the many weight loss medications that are FDA approved in adults. Moreover, more clinical trials are underway on the rarer, intractable forms of obesity such as monogenic, syndromic, and hypothalamic obesity.SummaryWeight loss medications in children, like adults, have variable efficacy and similar side effect profiles. Rigorous research and improved education of providers about weight loss medications may address the huge treatment gap in severe pediatric obesity.
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Project description:A growing number of youth suffer from obesity and in particular severe obesity for which intensive lifestyle intervention does not adequately reduce excess adiposity. A treatment gap exists wherein effective treatment options for an adolescent with severe obesity include intensive lifestyle modification or metabolic and bariatric surgery while the application of obesity pharmacotherapy remains largely underutilized. These youth often present with numerous obesity-related comorbid diseases, including hypertension, dyslipidemia, prediabetes/type 2 diabetes, obstructive sleep apnea, nonalcoholic fatty liver disease, musculoskeletal problems, and psychosocial issues such as depression, anxiety, and social stigmatization. Current pediatric obesity treatment algorithms for pediatric primary care providers focus primarily on intensive lifestyle intervention with escalation of treatment intensity through four stages of intervention. Although a recent surge in the number of Food and Drug Administration-approved medications for obesity treatment has emerged in adults, pharmacotherapy options for youth remain limited. Recognizing treatment and knowledge gaps related to pharmacological agents and the urgent need for more effective treatment strategies in this population, discussed here are the efficacy, safety, and clinical application of obesity pharmacotherapy in youth with obesity based on current literature. Legal ramifications, informed consent regulations, and appropriate off-label use of these medications in pediatrics are included, focusing on prescribing practices and prescriber limits.
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Project description:Over the past decades, obesity has become a rising health problem as the accessibility to high calorie, low nutritional value food has increased. Research shows that some bioactive components in fruits and vegetables, such as carotenoids, could contribute to the prevention and treatment of obesity. Some of these carotenoids are responsible for vitamin A production, a hormone-like vitamin with pleiotropic effects in mammals. Among these effects, vitamin A is a potent regulator of adipose tissue development, and is therefore important for obesity. This review focuses on the role of the provitamin A carotenoid ?-carotene in human health, emphasizing the mechanisms by which this compound and its derivatives regulate adipocyte biology. It also discusses the physiological relevance of carotenoid accumulation, the implication of the carotenoid-cleaving enzymes, and the technical difficulties and considerations researchers must take when working with these bioactive molecules. Thanks to the broad spectrum of functions carotenoids have in modern nutrition and health, it is necessary to understand their benefits regarding to metabolic diseases such as obesity in order to evaluate their applicability to the medical and pharmaceutical fields.
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Project description:The rising tide of obesity and its related disorders is one of the most pressing health concerns worldwide, yet existing medicines to combat the problem are disappointingly limited in number and effectiveness. Recent advances in mechanistic insights into the neuroendocrine regulation of body weight have revealed an expanding list of molecular targets for novel, rationally designed antiobesity pharmaceutical agents. Antiobesity drugs act via any of four mechanisms: 1) decreasing energy intake, 2) increasing energy expenditure or modulating lipid metabolism, 3) modulating fat stores or adipocyte differentiation, and 4) mimicking caloric restriction. Various novel drug candidates and targets directed against obesity are currently being explored. A few of them are also in the later phases of clinical trials. This review discusses the development of novel antiobesity drugs based on current understanding of energy homeostasis.
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Project description:IntroductionThe past decades have witnessed a remarkable improvement in the health of patients with Gaucher disease, the inherited deficiency of the lysosomal enzyme glucocerebrosidase, resulting from the availability of enzyme replacement and substrate reduction therapies. Especially in pediatric populations, early diagnosis and initiation of treatment is essential to achieving optimal outcomes.Areas coveredThe authors review the literature pertaining to the effectiveness of currently available therapies and describe new pharmacotherapies under development, especially for young patients.Expert opinionFor pediatric patients with non-neuronopathic Gaucher disease, there may be new therapeutic options on the horizon in the form of gene therapy or small molecule glucocerebrosidase chaperones. These have the potential to result in a cure for systemic disease manifestations and/or to reduce the cost and convenience of treatment. For children with neuronopathic Gaucher disease, the challenge of targeting therapy to the central nervous system is being explored through new modalities including brain-targeted gene therapy, in-utero therapy, brain-penetrant small molecule chaperones, and other methods that convey enzyme across the blood-brain barrier. Indeed, these are exciting times for both pediatric patients with Gaucher disease and those with other lysosomal storage disorders.
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Project description:IN BRIEF This article reinforces the dosing guidance from the package inserts of available insulin products and supplemental information provided by the manufacturers of insulin products. It reviews and evaluates pertinent primary literature detailing algorithms for the initiation and titration of insulin therapy that have helped to shape current clinical practice guidelines. The article discusses the clinical applicability of the evidence on insulin pharmacotherapy and offers recommendations for initiation and titration of various insulin products for insulin-requiring people with type 2 diabetes in the ambulatory care setting.
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Project description:Pediatric heart failure (HF) represents an important cause of morbidity and mortality in childhood. There is an overlapping relationship of HF, congenital heart disease, and cardiomyopathy. The goal of treatment of HF in children is to maintain stability, prevent progression, and provide a reasonable milieu to allow somatic growth and optimal development. Current management and therapy for HF in children are extrapolated from treatment approaches in adults. There are significant barriers in applying adult data to children because of developmental factors, age variation from birth to adolescence, and differences in the genetic expression profile and β-adrenergic signaling. At the same time, there are significant challenges in performing well-designed drug trials in children with HF because of heterogeneity of diagnoses identifying a clinically relevant outcome with a high event rate, and a difficulty in achieving sufficient enrollment. A judicious balance between extrapolation from adult HF guidelines and the development of child-specific data on treatment represent a wise approach to optimize pediatric HF management. This approach is helpful as reflected by the increasing role of ventricular assist devices in the management of advanced HF in children. This review discusses the causes, epidemiology, pathophysiology, clinical manifestations, conventional medical treatment, clinical trials, and the role of device therapy in pediatric HF.
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Project description:Schizophrenia is a debilitating psychiatric disorder, leading to both physical and social morbidity. Despite its importance, the etiology of schizophrenia remains poorly understood. Furthermore, its mainstream treatments fail to address all aspects of the disorder and are associated with significant side-effects. Recently, there has been growing interest in the relationship between the gut microbiome and mental health, including in schizophrenia. In this article, we review the existing evidence implicating dysbiosis in schizophrenia and discuss how the presumed dysbiosis could fit within known hypotheses of its pathogenesis, focusing on inflammation, tryptophan metabolites, and BDNF levels. We also evaluate the clinical potential of manipulating the gut microbiome with probiotics and prebiotics as adjunctive treatments in schizophrenia, based on existing clinical and pre-clinical studies. Overall, the current data showing microbiome alterations in schizophrenia are highly discrepant and insufficient to conclude whether microbiome changes are associated with increased risk of the disorder, or are simply the result of external factors or treatment. Despite some encouraging results of pro/prebiotic supplementation, there is also inconclusive evidence for their efficacy in schizophrenia. Thus, further research and more clinical trials are needed to test the validity of manipulating the gut microbiome to improve the treatment of this disorder.
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Project description:ImportanceThe pediatric obesity disease burden imposes the necessity of new effective strategies.ObjectiveTo determine whether oral butyrate supplementation as an adjunct to standard care is effective in the treatment of pediatric obesity.Design, setting, and participantsA randomized, quadruple-blind, placebo-controlled trial was performed from November 1, 2020, to December 31, 2021, at the Tertiary Center for Pediatric Nutrition, Department of Translational Medical Science, University of Naples Federico II, Naples, Italy. Participants included children aged 5 to 17 years with body mass index (BMI) greater than the 95th percentile.InterventionsStandard care for pediatric obesity supplemented with oral sodium butyrate, 20 mg/kg body weight per day, or placebo for 6 months was administered.Main outcomes and measuresThe main outcome was the decrease of at least 0.25 BMI SD scores at 6 months. The secondary outcomes were changes in waist circumference; fasting glucose, insulin, total cholesterol, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, triglyceride, ghrelin, microRNA-221, and interleukin-6 levels; homeostatic model assessment of insulin resistance (HOMA-IR); dietary and lifestyle habits; and gut microbiome structure. Intention-to-treat analysis was conducted.ResultsFifty-four children with obesity (31 girls [57%], mean [SD] age, 11 [2.91] years) were randomized into the butyrate and placebo groups; 4 were lost to follow-up after receiving the intervention in the butyrate group and 2 in the placebo group. At intention-to-treat analysis (n = 54), children treated with butyrate had a higher rate of BMI decrease greater than or equal to 0.25 SD scores at 6 months (96% vs 56%, absolute benefit increase, 40%; 95% CI, 21% to 61%; P < .01). At per-protocol analysis (n = 48), the butyrate group showed the following changes as compared with the placebo group: waist circumference, -5.07 cm (95% CI, -7.68 to -2.46 cm; P < .001); insulin level, -5.41 μU/mL (95% CI, -10.49 to -0.34 μU/mL; P = .03); HOMA-IR, -1.14 (95% CI, -2.13 to -0.15; P = .02); ghrelin level, -47.89 μg/mL (95% CI, -91.80 to -3.98 μg/mL; P < .001); microRNA221 relative expression, -2.17 (95% CI, -3.35 to -0.99; P < .001); and IL-6 level, -4.81 pg/mL (95% CI, -7.74 to -1.88 pg/mL; P < .001). Similar patterns of adherence to standard care were observed in the 2 groups. Baseline gut microbiome signatures predictable of the therapeutic response were identified. Adverse effects included transient mild nausea and headache reported by 2 patients during the first month of butyrate intervention.Conclusions and relevanceOral butyrate supplementation may be effective in the treatment of pediatric obesity.Trial registrationClinicalTrials.gov Identifier: NCT04620057.
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Project description:Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-XL/BCL-2 inhibitor, may potentiate therapeutic BCL-2 and BCL XL inhibition without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase 1 dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase 2 dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adult-equivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen (28%) patients proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population.
2021-02-17 | GSE162894 | GEO