Preparation and In Vitro and In Vivo Evaluation of Rectal In Situ Gel of Meloxicam Hydroxypropyl-ß-cyclodextrin Inclusion Complex.

Meloxicam (MLX) is one of the most effective NSAIDs, but its poor water solubility and low bioavailability limit its clinical application. In this study, we designed a thermosensitive in situ gel of the hydroxypropyl-ß-cyclodextrin inclusion complex (MLX/HP-ß-CD-ISG) for rectal delivery to improve bioavailability. The best method for preparing MLX/HP-ß-CD was the saturated aqueous solution method. The optimal inclusion prescription was optimized using an orthogonal test, and the inclusion complex was evaluated via PXRD, SEM, FTIR and DSC. Then, MLX/HP-ß-CD-ISG was characterized regarding the gel properties, release in vitro, and pharmacokinetics in vivo. The inclusion rate of the inclusion complex obtained via the optimal preparation process was 90.32 ± 3.81%. The above four detection methods show that MLX is completely embedded in the HP-ß-CD cavity. The developed MLX/HP-ß-CD-ISG formulation has a suitable gelation temperature of 33.40 ± 0.17 °C, a gelation time of 57.33 ± 5.13 s, pH of 7.12 ± 0.05, good gelling ability and meets the requirements of rectal preparations. More importantly, MLX/HP-ß-CD-ISG significantly improved the absorption and bioavailability of MLX in rats, prolonging the rectal residence time without causing rectal irritation. This study suggests that the MLX/HP-ß-CD-ISG can have a wide application prospect with superior therapeutic benefits.

The neurobiological drive for overeating implicated in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a genetic imprinting disorder characterized mainly by hyperphagia and early childhood obesity. Previous fMRI studies examined the activation of eating-related neural circuits in PWS patients with or without exposures to food cues and found an excessive eating motivation and a reduced inhibitory control of cognitive processing of food. However, the effective connectivity between various brain areas or neural circuitry critically implicated in both the biological and behavioral control of overeating in PWS is largely unexplored. The current study combined resting-state fMRI and Granger causality analysis (GCA) techniques to investigate interactive causal influences among key neural pathways underlying overeating in PWS. We first defined the regions of interest (ROIs) that demonstrated significant alterations of the baseline brain activity levels in children with PWS (n = 21) as compared to that of their normal siblings controls (n = 18), and then carried out GCA to characterize the region-to-region interactions among these ROIs. Our data revealed significantly enhanced causal influences from the amygdala to the hypothalamus and from both the medial prefrontal cortex and anterior cingulate cortex to the amygdala in patients with PWS (P < 0.001). These alterations offer new explanations for hypothalamic regulation of homeostatic energy intake and impairment in inhibitory control circuit. The deficits in these dual aspects may jointly contribute to the extreme hyperphagia in PWS. This study provides both a new methodological and a neurobiological perspective to aid in a better understanding of neural mechanisms underlying obesity in the general public. This article is part of a Special Issue entitled 1618.

Obesity: pathophysiology and intervention.

Obesity presents a major health hazard of the 21st century. It promotes co-morbid diseases such as heart disease, type 2 diabetes, obstructive sleep apnea, certain types of cancer, and osteoarthritis. Excessive energy intake, physical inactivity, and genetic susceptibility are main causal factors for obesity, while gene mutations, endocrine disorders, medication, or psychiatric illnesses may be underlying causes in some cases. The development and maintenance of obesity may involve central pathophysiological mechanisms such as impaired brain circuit regulation and neuroendocrine hormone dysfunction. Dieting and physical exercise offer the mainstays of obesity treatment, and anti-obesity drugs may be taken in conjunction to reduce appetite or fat absorption. Bariatric surgeries may be performed in overtly obese patients to lessen stomach volume and nutrient absorption, and induce faster satiety. This review provides a summary of literature on the pathophysiological studies of obesity and discusses relevant therapeutic strategies for managing obesity.