Novel pharmacologic formulation of cannabidiol (CBDloaded nanoparticles) and effect on antipsychotic-induced weight gain and related metabolic alterations

Datos básicos

Objetivos del proyecto

The exposure to antipsychotic medication has been widely associated with weight gain and cardiovascular and metabolic side effects, such as dyslipemia and insulin-resistance or new onset diabetes mellitus (type 2). However, two recent studies have reported that cannabis consumption, which is highly prevalent among psychotic patients, showed a protective on antipsychotic-induced weight gain and other metabolic sideeffects. This unexpected beneficial effect of cannabinoids on metabolism has been previously reported in animal models, where peripherally restricted CB1R antagonists or inverse agonists reduced food intake, weight, and the odds for dyslipemia and insulin-resistance in diet-induced obese animal models. Besides, it has been recently described a novel pharmacology formulation based on PEGylated PLGA nanoparticles containing synthetic cannabinoid CB13 with long-lasting effects in a neuropathic-pain animal model after oral administration. This methodology may solve one of the main drug delivery challenges in cannabinoids research; improving oral bioavailability. Regarding cannabinoid election, cannabidiol (CBD) stands out as one of the best current candidates; although it displays a low affinity for CB1 and CB2 receptors, it is capable of antagonizing cannabinoid CB1/CB2 receptor agonists with apparent low KB values, showing a beneficial effect on metabolic syndrome, and importantly, without producing psychoactivity. Based on the available scientific evidence, we hypothesise that CBD-nanoparticles will produce a protective effect on antipsychotic-induced weight gain and related lipid/glycaemic metabolic alterations, in rats exposed to olanzapine. Therefore, the main objective would be to develop CBD-loaded PLGA nanoparticles for long-lasting pharmacological effect. In a future step, we expect this novel CBD formulation to reduce metabolic syndrome in patients treated with olanzapine. Our research plan encompasses two main pre-clinical tasks: Task 1. To develop and produce CBD-loaded nanoparticles (Pharmacy School, Sevilla University); and Task 2. To implement an antipsychotic-induced weight gain animal model (rats) with/without adjuvant CBD-loaded nanoparticles (Neurosciences Department, Medicine School, Cádiz University), during a 24-months study period. The project would be based on an innovative pharmacological formulation approach, and would tests a pharmacological hypothesis finally directed to improve treatment tolerance in psychosis. This project takes advantage of a collaborative approach between three consolidated research groups in pharmacology, pre-clinical animal models and psychosis areas, with vast experience in biological research. The experience and the expertise of the applicant group with influential publications, the availability of the necessary infrastructure, and human resources, ensure the viability of the project. MEMORIA DEL PROYECTO (máxima extensión 20 caras. NO incluir imágenes)) ? Antecedentes y estado actual del tema y bibliografía ? Objetivos e hipótesis ? Metodología ? Cronograma y plan de trabajo ? Recursos disponibles ? Aplicabilidad y utilidad de los resultados y capacidad para ser protegidos y transferidos al mercado ? Experiencia del personal investigador sobre el tema ? Aportación de las empresas que participan. 1. Background Cannabis and lipid metabolism The exposure to antipsychotic medication has been associated with cardiovascular and metabolic side effects of clinical relevance. The metabolic disturbances described in psychotic patients include weight gain and obesity, dyslipemia (e.g.: increments in triglycerides, increments in LDL-cholesterol, and decrements in HDLcholesterol), and insulin-resistance or new onset diabetes mellitus (type 2), constituting in some cases a metabolic syndrome (Vazquez-Bourgon et al. 2018; Stahl et al. 2009). Among typical antipsychotics, olanzapine (OLA) has been increasingly relevant mainly to some patients with severe schizophrenia who are resistant to first-generation antipsychotic medications (Suzuki et al. 2012). Some reports have demonstrated that this antipsychotic can promote body weight gain and alterations in biochemical parameters, mainly in lipid and glucose metabolism (Salviato et al. 2014). Among psychotic population cannabis use is highly prevalent (Green et al. 2005; Setien-Suero et al. 2017). Interestingly, two recent studies have shown data suggesting a protective effect of cannabis on the metabolic syndrome emergence in psychosis (Waterreus et al. 2016; Bruins et al. 2016). Bruins and colleagues (2016) found that cannabis users had significantly lower body mass index (BMI), smaller waist circumference, and lower diastolic blood pressure than non-users. Waterreus and colleagues (2016) found, in a large populationbased sample of people with psychosis, that cannabis users were significantly less likely than non-users to have metabolic syndrome globally and each of its 5 criteria individually. In the same direction as previous studies, we have recently found similar results in a sample of drug-naïve patients presenting a first-episode of psychosis (Vázquez-Bourgon et al., under review). Moreover, this protective effect on metabolism have been also described in the general population; thus previous studies reported cannabis smoking associated to lower BMI and waist circumference (Hayatbakhsh et al. 2010; Le Strat and Le Foll 2011; Penner et al. 2013; Ngueta et al. 2015). However, other studies in the general population found cannabis use not associated to changes in weight over time (Jin et al. 2017) or even being associated to greater BMI and greater likelihood of being overweight/obese (Ross et al. 2016). Regarding the glycemic metabolism there are contradictory findings. Several studies have described the cannabis use associated to lower levels of fasting insulin and HOMA-IR (Penner et al. 2013) and lower prevalence on diabetes mellitus (Rajavashisthet al. 2012; Alshaarawy and Anthony 2015). However, other studies found no association to Diabetes Mellitus type 2 (Danielsson et al. 2016). And Ngueta and colleagues (2015) described an association between cannabis use and insulin-resistance, but indirectly mediated through its influence on weight (Ngueta et al. 2015). Longitudinal