Impact Sibutramine Therapy in Children with Hypothalamic Obesity or Obesity with Aggravating Syndromes

Department of Pediatrics and the National Childhood Obesity Centre, B57, Karolinska University Hospital, Huddinge, S-141 86 Stockholm, Sweden.
Journal of Clinical Endocrinology &amp Metabolism (Impact Factor: 6.21). 11/2007; 92(11):4101-6. DOI: 10.1210/jc.2007-0826
Source: PubMed

ABSTRACT Behavioral treatment of children suffering from hypothalamic obesity or uncomplicated obesity in combination with syndromes that aggravate this condition has proven to be ineffective. The combination of comorbidities and severe obesity lower the quality of these children's lives drastically. The present goal was to determine whether treatment with sibutramine has a beneficial effect on such children.
A double-blind, placebo-controlled, cross-over study (20 + 20 wk), followed by a 6-month open phase, was performed. The primary indicator of efficacy was the body mass index (BMI) sd score (SDS) value, which was analyzed using an ANOVA repeated-measures design [intention to treat (ITT)]. The 50 children (7-20 yr of age) involved included 22 with hypothalamic obesity and 28 with uncomplicated obesity plus aggravating syndromes. Forty-five patients completed the first phase, and 42 participated in the entire study.
The group that initially received the placebo demonstrated an insignificant decrease (-0.06) in BMI SDS during this treatment but a significant decrease (-0.68; P < 0.001) when treated with sibutramine. The other group demonstrated a reduction in their BMI SDS of -0.72 during administration of sibutramine and a rebound of +0.43 when placed on the placebo (P < 0.001 in both cases). The response of children with hypothalamic obesity was also significant but was less pronounced than that of children with nonhypothalamic obesity. During the open phase, a continuous reduction in weight was observed. The treatment was tolerated well.
The clinically and statistically significant weight reduction caused by sibutramine in this short-term study indicates that treatment of hypothalamic and syndromal obesity with this drug may be beneficial.

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Available from: Annika Janson, May 23, 2015
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    • "Sibutramine is a nonspecific inhibitor of the presynaptic reuptake of serotonin and norepinephrine. A double-blind, placebo-controlled trial of 21 subjects showed significant weight reduction through the administration of sibutraimine52). However, sibutramine has been withdrawn from the market due to its adverse cardiovascular effects. "
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    ABSTRACT: The hypothalamus plays a key role in the regulation of body weight by balancing the intake of food, energy expenditure, and body fat stores, as evidenced by the fact that most monogenic syndromes of morbid obesity result from mutations in genes expressed in the hypothalamus. Hypothalamic obesity is a result of impairment in the hypothalamic regulatory centers of body weight and energy expenditure, and is caused by structural damage to the hypothalamus, radiotherapy, Prader-Willi syndrome, and mutations in the LEP, LEPR, POMC, MC4R and CART genes. The pathophysiology includes loss of sensitivity to afferent peripheral humoral signals, such as leptin, dysregulated insulin secretion, and impaired activity of the sympathetic nervous system. Dysregulation of 11β-hydroxysteroid dehydrogenase 1 activity and melatonin may also have a role in the development of hypothalamic obesity. Intervention of this complex entity requires simultaneous targeting of several mechanisms that are deranged in patients with hypothalamic obesity. Despite a great deal of theoretical understanding, effective treatment for hypothalamic obesity has not yet been developed. Therefore, understanding the mechanisms that control food intake and energy homeostasis and pathophysiology of hypothalamic obesity can be the cornerstone of the development of new treatments options. Early identification of patients at-risk can relieve the severity of weight gain by the provision of dietary and behavioral modification, and antiobesity medication. This review summarizes recent advances of the pathophysiology, endocrine characteristics, and treatment strategies of hypothalamic obesity.
    12/2013; 18(4):161-167. DOI:10.6065/apem.2013.18.4.161
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    • "Even more distressing, attempts at weight loss through caloric restriction and exercise are largely unsuccessful (Lustig et al., 2003; Eyal et al., 2006). Pharmacological treatment of HO and hyperphagia has shown success in a few clinical studies and case reports (Mason et al., 2002; Lustig et al., 2003; Danielsson et al., 2007; Hamilton et al., 2011) though weaker weight reductions were observed compared to uncomplicated obesity (Danielsson et al., 2007). A recent study of both normal weight and obese CP patients showed that insulin resistance and altered gut hormone secretion are not exclusively a result of obesity but hypothalamic disruption caused by the tumor and/or its treatment (Roth et al., 2011b). "
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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.
    Frontiers in Endocrinology 12/2011; 2:78. DOI:10.3389/fendo.2011.00078
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    • "As discussed earlier, additional therapies to target HO have been studied. Their mechanisms of action include increasing sympathetic tone (Mason et al., 2002; Ismail et al., 2006; Danielsson et al., 2007; Schultes et al., 2009), reducing insulin secretion, and improving sensitivity (Lustig et al., 1999, 2003a; Inge et al., 2007; Hamilton et al., 2011). Patients have experienced a decrease in weight gain or weight stabilization but without dramatic weight reduction. "
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    ABSTRACT: Craniopharyngioma are rare histologically benign brain tumors that develop in the pituitary-hypothalamic area. They may invade nearby anatomical structures causing significant rates of neurological, neurocognitive, and endocrinological complications including remarkable hypothalamic damage. Information regarding long term implications of the tumors and treatment in the pediatric population is accumulating, and treatment goals appear to be changing accordingly. In this review we aim to present data regarding long term complications of craniopharyngioma in children and adolescents and our experience from a large tertiary center. Hypothalamic dysfunction was noted to be the most significant complication, adversely affecting quality of life in survivors. Obesity, fatigue, and sleep disorders are the most notable manifestations of this dysfunction, and treatment is extremely difficult. Changes in management in recent years show a potential for improved long term outcomes; we found a trend toward less aggressive surgical management and increasing use of adjuvant treatment, accompanied by a decrease in complication rates.
    Frontiers in Endocrinology 11/2011; 2:81. DOI:10.3389/fendo.2011.00081
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