Nutraceutical Approaches to Dyslipidaemia: The Main Formulative Issues Preventing Efficacy.

Currently, the nutraceutical approach to treat dyslipidaemia is increasing in use, and in many cases is used by physicians as the first choice in the treatment of patients with borderline values. Nutraceuticals represent an excellent opportunity to treat the preliminary conditions not yet showing the pathological signs of dyslipidaemia. Their general safety, the patient's confidence, the convincing proof of efficacy and the reasonable costs prompted the market of new preparations. Despite this premise, many nutraceutical products are poorly formulated and do not meet the minimum requirements to ensure efficacy in normalizing blood lipid profiles, promoting cardiovascular protection, and normalizing disorders of glycemic metabolism. In this context, bioaccessibility and bioavailability of the active compounds is a crucial issue. Little attention is paid to the proper formulations needed to improve the overall bioavailability of the active molecules. According to these data, many products prove to be insufficient to ensure full enteric absorption. The present review analysed the literature in the field of nutraceuticals for the treatment of dyslipidemia, focusing on resveratrol, red yeast rice, berberine, and plant sterols, which are among the nutraceuticals with the greatest formulation problems, highlighting bioavailability and the most suitable formulations.

Prostatic Therapeutic Efficacy of LENILUTS®, a Novel Formulation with Multi-Active Principles.

Lower Urinary Tract Symptoms (LUTs) in men are usually associated to benign prostatic hyperplasia (BPH), a non-malignant prostate enlargement. Unfortunately, BPH etiology is still unclear. Recent works highlighted a relevant inflammation role in BPH onset and development. Consequently, to complement the 5-α reductase (and α-adrenergic receptor agonists-based therapy, an anti-inflammatory therapy should be devised. To reduce potential adverse effects of multi-drug treatment, plant extract-based therapies are becoming increasingly common. Serenoa repens, the main phytotherapic treatment for BPH, is not sufficient to front the multi-faceted etiology of BPH. In response to this, a novel, multiple phytotherapic agents-based formulation, LENILUTS®, was developed. In the present work, we compared, using an in vitro approach, the prostatic safety and efficacy of LENILUTS® with a commercial formulation, based only on Serenoa repens, and a 5αR inhibitor, Dutasteride. Furthermore, preliminary in vitro experiments to investigate the active principles, bioaccessibility and bioavailability of LENILUTS® were performed. Our results showed a better prostatic safety and therapeutic efficacy of LENILUTS® compared to the commercial formulation and Dutasteride, with increased anti-inflammatory, and pro-apoptotic activity, and a stronger inhibitory effect on the release of the key enzyme 5αR and Prostatic-Specific Antigen (PSA). The limited bioaccessibility and bioavailability of the active principles of LENILUTS® were highlighted. Considering the results obtained, the LENILUTS® formulation is more promising for BPH and LUTs therapy compared to formulations based on Serenoa repens only, but further efforts should be made to improve the bioaccessibility and bioavailability of the active principles.

Novel Adenosine Triphosphate-Based Nutraceutical Formulation to Prevent Non-Steroidal Anti-Inflammatory Drug Enteric Cell Toxicity: Preliminary In Vitro Evidence.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are the most commonly prescribed and self-prescribed drugs to treat inflammation and pain associated with several conditions. Although their efficacy and overall safety have been recognized when used according to medical prescriptions and for a short period time, their acute impact on enteric physiology has rarely been studied. NSAIDs are known to cause gastrointestinal side effects due to their intrinsic mechanism of action, which involves prostaglandins synthesis, leading to impaired mucopolysaccharide layer production. Despite this well-known and investigated side effect, the short- and long-term influences of acute administration of these drugs on the biochemical environment of enteric cells are not well understood. This study investigates the rate of adenosine triphosphate (ATP) loss and permeability alterations occurring in a model of human enteric cells, as a consequence of acute administration of NSAIDs as major perpetrators of enteric toxicity. For the first time, we investigate the ability of a novel ATP-containing formulation to prevent ATP hydrolysis in the stomach and ensure its delivery at the proximal duodenal site.

Effectiveness and Safety of Novel Nutraceutical Formulation Added to Ezetimibe in Statin-Intolerant Hypercholesterolemic Subjects with Moderate-to-High Cardiovascular Risk.

The effectiveness of statins in the primary and secondary prevention of cardiovascular (CV) diseases has been widely proven. However, the onset of adverse events associated with their use prevents to achieve the therapeutic targets recommended by the guidelines (GL) for the management of dyslipidemia. In the event of statin intolerance, the GL recommend to use bile acid sequestrants, fibrates, and ezetimibe in monotherapy, but their benefits in improving lipid pattern are quite modest. This study aims at evaluating the effectiveness and safety of a nutraceutical compound (NC) associated with ezetimibe (EZE) on the lipid profile in statin-intolerant patients with moderate-to-high CV risk. Ninety-six statin-intolerant hypertensive and hypercholesterolemic subjects treated pharmacologically with EZE 10 mg daily were randomized in open label (n = 48) to take for 3 months a NC containing Monacolin-K (MK), Berberine Hydrochloride (BC), t-Resveratrol (RES), Quercetin (QUER), and Chromium (CH) in the form of a gastro-resistant tablet that improves enteric bioaccessibility and bioavailability of these substances. The control group (n = 48) took only EZE in monotherapy at the same dosage; both groups followed a standardized lipid-lowering diet. The total serum cholesterol (TC), low density lipoprotein cholesterol (LDLC), high density lipoprotein cholesterol (HDLC), triglycerides (TG), aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine phosphokinase (CPK) levels were compared at the follow-up in both groups using Student's t-test. TC and LDL levels reduced in both groups, but were lower in the group treated with EZE + NC (-25.9% vs. -15%, P < .05 and -38.7% vs. -21.0%, P < .05, respectively). No changes were observed in either group regarding a decrease in TG (-9.4% vs. -11.7%, NS) and an increase in HDLC (+4.2% vs. +1.1%, NS). The AST, ALT, and CPK levels increased in the group treated with the EZE + NC compared to the control group, but were still within the acceptable range. There was no difference concerning the lipid-lowering treatment between gender, and no patient withdrew from the study. In the short term, the EZE + NC combination therapy is well tolerated and effective in improving TC and LDLC levels in statin-intolerant patients with moderate-to-high CV risk.

Effectiveness of the integration of quercetin, turmeric, and N-acetylcysteine in reducing inflammation and pain associated with endometriosis. In-vitro and in-vivo studies.

BACKGROUND: to evaluate the efficacy of oral administration of a novel composition composed of quercetin, curcumin, acetylcysteine in reducing pain in women affected by endometriosis, through the reduction of the inflammatory-hyperproliferative component of the ectopic endometrial tissue. METHODS: Thirty-three women with clinical diagnosis of endometriosis from at least 3 months have been enrolled. Patients have been treated daily with 200 mg of quercetin, 210 mg of dry extract of Curcuma longa (titrated at 95% in curcuminoids) and 150 mg of acetylcysteine (1 tablet of ALLIENDO®) for 2 months. The overall symptomatology with specific reference to dysmenorrhea, pelvic pain and dyspareunia, together with the frequency of nonsteroidal anti-inflammatory drugs (NSAID) drugs assumption have been evaluated at the beginning and at the end of the treatment. RESULTS: Overall, the results collected at the end of the treatment according to the parameters evaluated and above mentioned on the 33 patients enrolled, show a significative improvement in the reduction of pain symptoms associated to endometriosis (P<0.001 for dysmenorrhea, pelvic pain and dyspareunia). The use of NSAIDs together with an overall reduction of their dosage and time of assumption has been reduced as well. No significative side effects have been observed. CONCLUSIONS: The aforementioned results suggest that administration of the composition described can represent a valuable adjuvant treatment in the reduction of pain symptomatology associated to endometriosis, triggered by inflammatory cascade and hyperproliferation of ectopic tissue.

Sublingual Delivery of Astaxanthin through a Novel Ascorbyl Palmitate-Based Nanoemulsion: Preliminary Data.

Astaxanthin is a carotenoid extracted from several seaweeds with ascertained therapeutic activity. With specific reference, astaxanthin is widely used in clinical practice to improve ocular tissue health and skin protection from UV ray damages. Despite its well-documented pleiotropic actions and demonstrated clinical efficacy, its bioavailability in humans is low and limited because of its hydrophobicity and poor dissolution in enteric fluids. Furthermore, astaxanthin is very unstable molecule and very sensitive to light exposure and thermal stress. Taken together, these pharmacological and chemical-physical features strongly limit pharmaceutical and nutraceutical development of astaxanthin-based products and as a consequence its full clinical usage. This work describes the preliminary in vitro investigation of sublingual absorption of astaxanthin through a novel ascorbyl palmitate (ASP) based nanoemulsion.

Lipomatrix: A Novel Ascorbyl Palmitate-Based Lipid Matrix to Enhancing Enteric Absorption of Serenoa Repens Oil.

The class of lipophilic compounds coming from vegetal source represents a perspective in the adjuvant treatment of several human diseases, despite their poor bioavailability in humans. These compounds are generally soluble in fats and poorly soluble in water. The major reason for the poor bioavailability of lipophilic natural compounds after oral uptake in humans is related to their reduced solubility in enteric water-based fluids, leading to an ineffective contact with absorbing epithelium. The main goal to ensure efficacy of such compounds is then creating technological conditions to deliver them into the first enteric tract as hydro-dispersible forms to maximize epithelial absorption. The present work describes and characterizes a new technological matrix (Lipomatrix, Labomar Research, Istrana, TV, Italy) based on a molten fats core in which Ascorbyl Palmitate is embedded, able to deliver lipophilic compounds in a well-dispersed and emulsified form once exposed to duodenal fluids. Authors describe and quantify Lipomatrix delivery of Serenoa repens oil through an innovative in vitro model of human gastro-enteric digestion, reporting results of its improved bioaccessibility, enteric absorption and efficacy compared with not formulated Serenoa repens oil-containing commercial products using in vitro models of human intestine and prostatic tissue.

Effect of resveratrol on blood pressure: A systematic review and meta-analysis of randomized, controlled, clinical trials.

Introduction: Results of previous clinical trials evaluating the effect of resveratrol supplementation on blood pressure (BP) are controversial. Purpose: We aimed to assess the impact of resveratrol on BP through systematic review of literature and meta-analysis of available randomized, controlled clinical trials (RCTs). Methods: Literature search included SCOPUS, PubMed-Medline, ISI Web of Science and Google Scholar databases up to 17th October 2017 to identify RCTs investigating the impact of resveratrol on BP. Two review authors independently extracted data on study characteristics, methods and outcomes. Overall, the impact of resveratrol on BP was reported in 17 trials. Results: Administration of resveratrol did not significantly affect neither systolic BP [weighted mean difference (WMD): -2.5 95% CI:(-5.5, 0.6) mmHg; p=0.116; I2=62.1%], nor diastolic BP [WMD: -0.5 95% CI:(-2.2, 1.3) mmHg; p=0.613; I2=50.8], nor mean BP [MAP; WMD: -1.3 95% CI:(-2.8, 0.1) mmHg; p=0.070; I2=39.5%] nor pulse pressure [PP; WMD: -0.9 95% CI:(-3.1, 1.4) mmHg; p=0.449; I2=19.2%]. However, significant WMDs were detected in subsets of studies categorized according to high resveratrol daily dosage (≥300 mg/day) and presence of diabetes. Meta-regression analysis revealed a positive association between systolic BP-lowering resveratrol activity (slope: 1.99; 95% CI: 0.05, 3.93; two-tailed p= 0.04) and Body Mass Index (BMI) at baseline, while no association was detected neither between baseline BMI and MAP-lowering resveratrol activity (slope: 1.35; 95% CI: -0.22, 2.91; two-tailed p= 0.09) nor between baseline BMI and PP-lowering resveratrol activity (slope: 1.03; 95% CI: -1.33, 3.39; two-tailed p= 0.39). Resveratrol was fairly well-tolerated and no serious adverse events occurred among most of the eligible trials. Conclusion: The favourable effect of resveratrol emerging from the current meta-analysis suggests the possible use of this nutraceutical as active compound in order to promote cardiovascular health, mostly when used in high daily dose (≥300 mg/day) and in diabetic patients.

Effects of a New Nutraceutical Formulation (Berberine, Red Yeast Rice and Chitosan) on Non-HDL Cholesterol Levels in Individuals with Dyslipidemia: Results from a Randomized, Double Blind, Placebo-Controlled Study.

Increased non high-density lipoprotein (HDL)/low-density lipoprotein (LDL) cholesterol levels are independent risk factors for cardiovascular (CV) mortality with no documented threshold. A new combination of nutraceuticals (berberine 200 mg, monacolin K 3 mg, chitosan 10 mg and coenzyme Q 10 mg) with additive lipid-lowering properties has become available. The aim of the study is to test the efficacy of the nutraceutical formulation (one daily) in lowering non-HDL cholesterol vs. placebo at 12 weeks in individuals with non-HDL-cholesterol levels ≥160 mg/dL. 39 subjects (age 52 ± 11 years; 54% females; body mass index 27 ± 4 kg/m²) were randomized (3:1) in a double blind phase II placebo-controlled study. At baseline, 4 and 12 weeks main clinical/biohumoral parameters, pro-inflammatory cytokines, (gut)-hormones, proprotein convertase subtilisin/kexin type 9 (PCSK9) levels and endothelial progenitor cell (EPC) number were assessed. Baseline characteristics were comparable in the two groups. The intervention significantly decreased non-HDL cholesterol (-30 ± 20 mg/dL; p = 0.012), LDL cholesterol (-31 ± 18 mg/dL, p = 0.011) and apolipoprotein (Apo) B (-14 ± 12 mg/dL, p = 0.030) levels compared to the placebo. Pro-inflammatory, hormonal, PCSK9 and EPC levels remained stable throughout the study in both groups. The intervention was well tolerated. Three adverse events occurred: Epstein Barr virus infection, duodenitis and asymptomatic but significant increase in creatine phosphokinase (following intense physical exercise) which required hospitalization. The tested nutraceutical formulation may represent a possible therapeutic strategy in dyslipidemic individuals in primary prevention.

New chitosan salt in gastro-resistant oral formulation could interfere with enteric bile salts emulsification of diet fats: preliminary laboratory observations and physiologic rationale.

Chitosan (CH) is a polymer of glucosamine that is extracted from the shells of several sea fruits. It is well recognized as a nutritional supplement that is used to reduce body weight and blood lipid levels, but its clinical efficacy has not been clearly demonstrated. The true mechanism of action and physiological processes involved in these properties of CH are not yet understood or explained. The most accepted theories assume that CH reduces dietary fat absorption by trapping the fat in the gastric lumen. The very low pH of the gastric lumen induces CH jellification and, therefore, entrapment of the fats. This article describes the most plausible mechanism by which CH interferes with fat absorption in the first part of the enteric tract while interacting with cholic acids. We emphasize the weak points of the classic CH-containing formulations, which are unable to prove this theory. We also report preliminary experimental data of a new CH salt-containing formulation that is capable of effectively interfering with bile salt emulsification processes and, as a result, reducing dietary fat absorption.

New association of surfactants for the production of food and cosmetic nanoemulsions: preliminary development and characterization.

A new nanoemulsifing system has been developed. This study refers to an innovative association of polysorbate 80 and palmitic ester of l-ascorbic acid for the production of good stability and very thin nanostructured emulsions with average micellar diameter size ranging from 100 to 300 nm. This system has showed to be very performing to create nanoemulsions with moderate stirring rate and warming regimen thanks to the high efficiency of the association between ascorbyl palmitate and polysorbate-80 (PS-80). This nanoemulsified system is very easy to achieve and shows a very good capability to encapsulate several substrates of both nutritional and cosmetic usage such as melatonin, resveratrol, essential oils and steroidic terpenes such as boswellic acids and others. This system has been optimally applied to nutraceutical and cosmetic formulations and particularly to develop sprayable sublingual delivery systems for melatonin and the aforesaid molecules. This study describes developing and analytical characterization of this system containing melatonin.