Randomised clinical study: GR-MD-02, a galectin-3 inhibitor, vs. placebo in patients having non-alcoholic steatohepatitis with advanced fibrosis.

BACKGROUND: Non-alcoholic steatohepatitis (NASH) and resultant liver fibrosis is a major health problem without approved pharmacotherapy. Pre-clinical results of GR-MD-02, a galectin-3 inhibitor, suggested potential efficacy in NASH with advanced fibrosis/cirrhosis and prompted initiation of a clinical development programme in NASH with advanced fibrosis. AIM: To evaluate the safety, pharmacokinetics and exploratory pharmacodynamic markers of GR-MD-02 in subjects having NASH with bridging fibrosis. METHODS: The GT-020 study was a first-in-human, sequential dose-ranging, placebo controlled, double-blinded study with the primary objective to assess the safety, tolerability and dose limiting toxicity of GR-MD-02, in subjects with biopsy-proven NASH with advanced fibrosis (Brunt stage 3). The secondary objectives were to characterise first-dose and multiple-dose pharmacokinetic profiles and to evaluate changes in potential serum biomarkers and liver stiffness as assessed by FibroScan. RESULTS: GR-MD-02 single and three weekly repeated of 2, 4 and 8 mg/kg revealed no meaningful clinical differences in treatment emergent adverse events, vital signs, electrocardiographic findings or laboratory tests. Pharmokinetic parameters showed a dose-dependent relationship with evidence of drug accumulation following 8 mg/kg (~twofold). CONCLUSIONS: GR-MD-02 doses were in the upper range of the targeted therapeutic dose determined from pre-clinical data and were safe and well tolerated with evidence of a pharmacodynamic effect. These results provide support for a Phase 2 development programme in advanced fibrosis due to NASH.

Three-decade metabolic outcome of neonatal gastrectomy and early Roux-en-Y.

Little information is available about long-term outcomes of major gastric surgery when performed very early in life and adverse consequences in growing children might be expected. In this case, gastrectomy with Roux-en-Y esophagojejunostomy was performed in early childhood. Despite stomach loss, growth velocity paralleled the third percentile for age during development. Maintained on a daily multivitamin and monthly B12 injections, no overt nutritional deficiencies were detected in adulthood. However, dual energy X-ray absorptiometry scan at age 31 revealed that the patient had abnormally low bone mineral density. This case study demonstrates that even after gastrectomy and reconstruction early in life, linear growth can be achieved. However, bone density can be adversely affected, even in the face of normal serum calcium and vitamin D levels.

Bariatric surgery for pediatric extreme obesity: now or later?

Obesity is a multifactorial disease of epidemic and global proportions that poses the most significant threat to the health of our younger generations. Those who are the most extremely affected bear the largest burden of health problems. In the US, extreme obesity affects approximately 9 million adults and 2 million children, and is associated with both immediate health problems and later health risk, including premature mortality. Present medical and behavioral interventions for extreme obesity in adults and children rarely result in the significant, durable weight loss necessary to improve health outcomes, prompting a search for more aggressive measures. Weight loss (bariatric) surgery has been advocated as an intervention for those with extreme obesity. In adults, bariatric surgery results in prolonged weight control and improvement in serious obesity comorbidities, namely type 2 diabetes, dyslipidemias, hypertension and obstructive sleep apnea syndrome. A surge in weight loss operations for adolescents has been observed recently, with a threefold increase in case volumes nationwide from 2000 to 2003. Current evidence suggests that after bariatric surgery, adolescents lose significant weight and serious obesity-related medical conditions and psychosocial status are improved. Thus it is reasonable to propose that bariatric surgery performed in the adolescent period may be more effective treatment for childhood-onset extreme obesity than delaying surgery for extremely obese youth until adulthood. This position has been echoed by a number of groups and an independent systematic review. Finally, it is conceivable that bariatric surgery performed in adulthood for childhood onset extreme obesity may not be as effective for comorbidity treatment as surgery performed earlier during adolescence. The purpose of this review is to examine the evidence, which supports early rather than later use of bariatric surgery in the treatment of extreme obesity, and to present this information in light of the medical and surgical risks of bariatric surgery.