Combination Therapy of Metastatic Castration-Recurrent Prostate Cancer: Hyaluronic Acid Decorated, Cabazitaxel-Prodrug and Orlistat Co-Loaded Nano-System.

PURPOSE: Prostate cancer (PCa) is the second leading cause of cancer-related death among men in developed countries. Cabazitaxel (CBZ) is recommended as one of the most active chemotherapy agents for PCa. This study aimed to develop a hyaluronic acid (HA) decorated, cabazitaxel-prodrug (HA-CBZ) and orlistat (ORL) co-loaded nano-system against the prostate cancer in vitro and in vivo. METHODS: Cabazitaxel-prodrug was firstly synthesized by conjugating HA with CBZ through the formation of ester bonds. HA contained ORL and CBZ prodrug co-loaded lipid-polymer hybrid nanoparticles (ORL/HA-CBZ/LPNs) were constructed and characterized in terms of particle size, zeta potential, drug loading capacity and stability. The antitumor efficiency and systemic toxicity of LPNs were evaluated in vitro and in vivo. RESULTS: The resulting ORL/HA-CBZ/LPNs were 150.9 nm in particle size with narrow distribution and high entrapment efficiency. The minimum combination index of 0.57 was found at a drug ratio of 1:2 (ORL:HA-CBZ, w/w) in the drug co-loaded formulations, indicating the strongest synergism effect. ORL/HA-CBZ/LPNs demonstrated an enhanced in vitro and in vivo antitumor effect compared with single drug loaded LPNs and free drug formulations. CONCLUSION: ORL/HA-CBZ/LPNs showed remarkable synergism cytotoxicity and the best tumor inhibition efficiency in mice with negligible systemic toxicity. ORL/HA-CBZ/LPNs can be highly useful for targeted prostate cancer therapy.

Arylacetamide deacetylase as a determinant of the hydrolysis and activation of abiraterone acetate in mice and humans.

AIM: Abiraterone acetate for metastatic castration-resistant prostate cancer is an acetylated prodrug to be hydrolyzed to abiraterone. Abiraterone acetate is known to be hydrolyzed by pancreatic cholesterol esterase secreted into the intestinal lumen. This study aimed to investigate the possibility that arylacetamide deacetylase (AADAC) expressed in enterocytes contributes to the hydrolysis of abiraterone acetate based on its substrate preference. MATERIALS AND METHODS: Abiraterone acetate hydrolase activity was measured using human intestinal (HIM) and liver microsomes (HLM) as well as recombinant AADAC. Correlation analysis between activity and AADAC expression was performed in 14 individual HIMs. The in vivo pharmacokinetics of abiraterone acetate was examined using wild-type and Aadac knockout mice administered abiraterone acetate with or without orlistat, a pancreatic cholesterol esterase inhibitor. KEY FINDINGS: Recombinant AADAC showed abiraterone acetate hydrolase activity with similar Km value to HIM and HLM. The positive correlation between activity and AADAC levels in individual HIMs supported the responsibility of AADAC for abiraterone acetate hydrolysis. The area under the plasma concentration-time curve (AUC) of abiraterone after oral administration of abiraterone acetate in Aadac knockout mice was 38% lower than that in wild-type mice. The involvement of pancreatic cholesterol esterase in abiraterone formation was revealed by the decreased AUC of abiraterone by coadministration of orlistat. Orlistat potently inhibited AADAC, implying its potential as a perpetrator of drug-drug interactions. SIGNIFICANCE: AADAC is responsible for the hydrolysis of abiraterone acetate in the intestine and liver, suggesting that concomitant use of abiraterone acetate and drugs potently inhibiting AADAC should be avoided.

Mouse Model for Efficient Simultaneous Targeting of Glycolysis, Glutaminolysis, and De Novo Synthesis of Fatty Acids in Colon Cancer.

Colon cancer is a highly anabolic entity with upregulation of glycolysis, glutaminolysis, and de novo synthesis of fatty acids, which also induces a hypercatabolic state in the patient. The blockade of either cancer anabolism or host catabolism has been previously proven to be a successful anticancer experimental treatment. However, it is still unclear whether the simultaneous blockade of both metabolic counterparts can limit malignant survival and the energetic consequences of such an approach. In this chapter, by using the CT26.WT murine colon adenocarcinoma cell line as a model of study, we provide a method to simultaneously perform a pharmacological blockade of tumor anabolism and host catabolism, as a feasible therapeutic approach to treat cancer, and to limit its energetic supply.

Obesity: The New Global Epidemic Pharmacological Treatment, Opportunities and Limits for Personalized Therapy.

BACKGROUND: The increase in global obesity rates over the past three decades has been remarkable, a true epidemic, both in developed and in developing countries. The projections, based on current trends, suggest an increase in the prevalence of obesity at 60% in adult men, 40% in adult women and 25% in children in 2050. Given the limitations of lifestyle and surgery interventions bariatric, drug therapy approaches for the treatment of obesity, therefore become important options. AIM: The purpose of this review is a review of the literature, based on research on MEDLINE until 2019, on the possible pharmacological options in the treatment of obesity. RESULTS: Currently, the FDA has approved several molecules for the treatment of obesity, both in monotherapy and in combination. Pharmacological monotherapies focus mainly on a single protein target and include orlistat, lorcaserin and liraglutide while the combination molecules propose a multitarget approach and include phentermine/topiramate and naltrexone/bupropion. All the approved drugs showed, in the different studies, a weight reduction of at least 5%, compared to placebo, in 52 weeks of observation. Phentermine-topiramate and liraglutide have been associated with the highest probability of at least 5% weight loss. Liraglutide and naltrexone-bupropion had the lowest rates of therapy discontinuation due to adverse events. CONCLUSION: The drugs, associated with the standard diet and/or exercise protocols, represent a good therapeutic opportunity to allow not only weight loss but also to reduce the risk of developing diseases caused by obesity, particularly cardiovascular diseases, and to maintain the set objectives over time. However, future research on the pharmacological treatment of obesity should encourage greater personalization of therapy, given the differences in safety, efficacy and response to therapy, in the different subpopulations of patients with obesity.

Pharmacological Treatment for Obesity in Adults: An Umbrella Review.

Objective: To synthesize the evidence from systematic reviews of clinical trials investigating the effectiveness of pharmacological therapies approved by the Australian Therapeutic Goods Administration and the US Food and Drug Administration for the management of obesity in adults. Data Sources: A 3-step literature search of the MEDLINE, EMBASE, CINAHL, and PubMed databases was conducted between March and May 2019. The key terms used were obesity, pharmacological therapy, antiobesity agent, antiobesity medication, weight loss, and systematic review. Study Selection and Data Extraction: Systematic reviews that evaluated the effectiveness of pharmacological therapies for the management of obesity in patients with a body mass index of or greater than 25 kg/m2. Data Synthesis: Nine systematic reviews involving three pharmacotherapies, liraglutide, orlistat, and naltrexone-bupropion were identified. The results indicate that the pharmacotherapies reduced weight when compared with placebo. Orlistat was effective in significantly reducing fasting blood glucose, HbA1c, total cholesterol, triglycerides, and systolic and diastolic blood pressure. All reviews discussed the presence or risk of gastrointestinal adverse effects including diarrhea, vomiting, and nausea related to orlistat and liraglutide. Relevance to Patient Care and Clinical Practice: This umbrella review compares the efficacy and safety of antiobesity medications for reducing weight and a discussion on their weight loss and metabolic control to guide clinicians when prescribing medications for obesity. Conclusions: All pharmacological therapies included in this review are superior to placebo in reducing weight. Clinicians should consider patient comorbidities and risk of adverse events when recommending medications for weight loss.

The Anti-Obesity Effect of Polysaccharide-Rich Red Algae (Gelidium amansii) Hot-Water Extracts in High-Fat Diet-Induced Obese Hamsters.

This study investigated the anti-obesity effect of a polysaccharide-rich red algae Gelidium amansii hot-water extract (GHE) in high-fat (HF) diet-induced obese hamsters. GHE contained 68.54% water-soluble indigestible carbohydrate polymers. Hamsters were fed with a HF diet for 5 weeks to induce obesity, and then randomly divided into: HF group, HF with 3% guar gum diet group, HF with 3% GHE diet group, and HF with orlistat (200 mg/kg diet) group for 9 weeks. The increased weights of body, liver, and adipose in the HF group were significantly reversed by GHE supplementation. Lower plasma leptin, tumor necrosis factor-α, and interleukin-6 levels were observed in the GHE+HF group compared to the HF group. GHE also increased the lipolysis rate and decreased the lipoprotein lipase activity in adipose tissues. GHE induced an increase in the phosphorylation of AMP-activated protein kinase (AMPK) and the protein expressions of peroxisome proliferator-activated receptor alpha (PPARα) and uncoupling protein (UCP)-2 in the livers. The decreased triglyceride and total cholesterol in the plasma and liver were also observed in obese hamsters fed a diet with GHE. These results suggest that GHE exerts a down-regulation effect on hepatic lipid metabolism through AMPK phosphorylation and up-regulation of PPARα and UCP-2 in HF-induced obese hamsters.

PET Imaging of Hepatocellular Carcinomas: 18F-Fluoropropionic Acid as a Complementary Radiotracer for 18F-Fluorodeoxyglucose.

OBJECTIVE: To evaluate the preclinical value of 18F-fluoropropionic acid (18F-FPA) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET) for imaging HCCs. METHODS: The 18F-FPA and 18F-FDG uptake patterns in 3 HCC cell lines (Hep3B, HepG2, and SK-Hep1) were assessed in vitro and in vivo. The 18F-FPA uptake mechanism was investigated using inhibition experiments with orlistat and 5-tetradecyloxy-2-furoic acid. The 18F-FPA PET imaging was performed in different tumor animal models and compared with 18F-FDG. We also evaluated the expressions of glucose transporter-1 (GLUT1), fatty acid synthase (FASN), and matrix metalloproteinase-2 (MMP2) in these cell lines. RESULTS: In vitro experiments showed that the radiotracer uptake patterns were complementary in the HCC cell lines. Orlistat and 5-tetradecyloxy-2-furoic acid decreased the uptake of 18F-FPA. The tumor-to-liver ratio of 18F-FPA was superior to that of 18F-FDG in the SK-Hep1 and HepG2 tumors ( P < .05). However, in the Hep3B tumors, the tumor-to-liver normalized uptake of 18F-FDG was higher than 18F-FPA ( P < .01). FASN was highly expressed in cell lines with high 18F-FPA uptake, whereas GLUT1 was highly expressed in cell lines with high 18F-FDG uptake. The 18F-FPA uptake correlated with FASN ( r = 0.89, P = .014) and MMP2 ( r = 0.77, P = .002) expressions. CONCLUSIONS: PET imaging with 18F-FPA combined with 18F-FDG can be an alternative for detecting HCC.

Características demográficas, clínicas y reacciones adversas de personas con sobrepeso y obesidad: consumidores de orlistat atendidos por centro de atención telefónica (2009 ­ 2017) / Demographic and clinical characteristics, and adverse reactions of people with overweight and obesity consumers of orlistat, attended by a call center (2009 ­ 2017)

Resumen Introducción Las enfermedades crónicas van en ascenso y están asociadas al incremento ponderal. Se requieren estrategias multidisciplinarias para su control. Métodos El diseño es descriptivo, observacional y retrospectivo. Los objetivos de esta comunicación son describir las características demográficas, clínicas y reacciones adversas de personas con sobrepeso y obesidad consumidores de orlistat, atendidos por un centro de atención telefónica durante el periodo 2009 a 2017; e identificar al profesional de la salud más consultado por ellos. La información se obtuvo desde una base de datos existente de un programa de atención a personas con sobrepeso u obesidad, interesadas en usar orlistat (prospectos) o usuarios (pacientes). El estudio se llevó a cabo en México y duró siete años. Las variables estudiadas fueron demográficas, clínicas y reacciones adversas. Resultados Se reunieron 311 913 solicitudes de 126 607 sujetos (104 711 prospectos interesados en consumir orlistat y 21 896 pacientes que ya lo tomaban). Las principales actividades fueron llamadas al sujeto (35,9%). Hubo 104 711 solicitudes: 82 810 (79,1%) prospectos y 21 896 (20,9%) pacientes. El 79,9% fue de sexo femenino. El intervalo de edad predominante fue de 32 a 45 años. Se detectaron 43 reacciones adversas (0,02%); las más comunes fueron dolor abdominal (0,05%) y cefalea (0,03%). Conclusiones La población más interesada en el control ponderal en este estudio es la femenina (79,9%) y el grupo etario de 32 a 45 años. El profesional más consultado fue el nutriólogo. Solo se obtuvo el índice de masa corporal (29,2 kilogramos por metro cuadrado) de los sujetos que desarrollaron 43 reacciones adversas, las más comunes fueron dolor abdominal y cefalea.

Introduction Chronic diseases are on the rise and are associated with weight gain. Multidisciplinary strategies are required for its control. Methods The design was descriptive, observational and retrospective. The objectives of this communication were to describe the demographic and clinical characteristics and adverse reactions of overweight and obese people who were consumers of orlistat, attended by a call center during the period 2009 to 2017; and to identify the healthcare professional most consulted by them. The information was obtained from an existing database of a program of attention to people with overweight or obesity, interested in using orlistat (prospects) or users (patients). The study was carried out in Mexico and lasted seven years. The variables studied were demographic, clinical and adverse reactions. Results A total of 311,913 requests were collected from 126 607 subjects (104 711 prospects interested in consuming orlistat and 21 896 patients who already took it). The main activities were phone calls to the subject (35.9%). There were 104 711 requests: 82 810 (79.1%) prospects and 21 896 (20.9%) patients. 79.9% of all were female. The predominant age interval was 32 to 45 years. 43 adverse reactions (0.02%) were detected; the most common were abdominal pain (0.05%) and headache (0.03%). Conclusions The population most interested in weight control in this study was the female population (79.9%) and the age group from 32 to 45 years. The most consulted healthcare professional was the nutritionist. Only the body mass index (29.2 kilograms per square meter) of the subjects who developed 43 adverse reactions was obtained. There were 43 adverse reactions, the most common being abdominal pain and headache.