Towards an International Consensus on the Prevention, Treatment, and Management of High-Risk Substance Use and Overdose among Youth.

Background and Objectives: Now more than ever, there is an obvious need to reduce the overall burden of disease and risk of premature mortality that are associated with mental health and substance use disorders among young people. However, the current state of research and evidence-based clinical care for high-risk substance use among youth is fragmented and scarce. The objective of the study is to establish consensus for the prevention, treatment, and management of high-risk substance use and overdose among youth (10 to 24 years old). Materials and Methods: A modified Delphi technique was used based on the combination of scientific evidence and clinical experience of a group of 31 experts representing 10 countries. A semi-structured questionnaire with five domains (clinical risks, target populations, intervention goals, intervention strategies, and settings/expertise) was shared with the panelists. Based on their responses, statements were developed, which were subsequently revised and finalized through three iterations of feedback. Results: Among the five major domains, 60 statements reached consensus. Importantly, experts agreed that screening in primary care and other clinical settings is recommended for all youth, and that the objectives of treating youth with high-risk substance use are to reduce harm and mortality while promoting resilience and healthy development. For all substance use disorders, evidence-based interventions should be available and should be used according to the needs and preferences of the patient. Involuntary admission was the only topic that did not reach consensus, mainly due to its ethical implications and resulting lack of comparable evidence. Conclusions: High-risk substance use and overdoses among youth have become a major challenge. The system's response has been insufficient and needs substantial change. Internationally devised consensus statements provide a first step in system improvement and reform.

Atorvastatin-loaded pro-nanolipospheres with ameliorated oral bioavailability and antidyslipidemic activity.

Despite significant advances in oral drug delivery technologies, many drugs are prone to limited oral bioavailability due to biological barriers that hinder drug absorption. Pro-nanolipospheres (PNL) are a form of delivery system that can potentiate the oral bioavailability of poorly water-soluble drugs through a variety of processes, including increased drug solubility and protecting them from degradation by intestinal or hepatic first-pass metabolism. In this study, pro-nanolipospheres were employed as a delivery vehicle for improving the oral bioavailability of the lipophilic statin, atorvastatin (ATR). Various ATR-loaded PNL formulations, composed of various pharmaceutical ingredients, were prepared by the pre-concentrate method and characterized by determining particle size, surface charge, and encapsulation efficiency. An optimized formula (ATR-PT PNL) showing the smallest particle size, highest zeta potential, and highest encapsulation efficiency was selected for further in vivo investigations. The in vivo pharmacodynamic experiments demonstrated that the optimized ATR-PT PNL formulation exerted a potent hypolipidemic effect in a Poloxamer® 407-induced hyper-lipidaemia rat model by restoring normal cholesterol and triglyceride serum levels along with alleviating serum levels of LDL while elevating serum HDL levels, compared to pure drug suspensions and marketed ATR (Lipitor®). Most importantly, oral administration of the optimized ATR-PT PNL formulation showed a dramatic increase in ATR oral bioavailability, as evinced by a 1.7- and 3.6-fold rise in systemic bioavailability when compared with oral commercial ATR suspensions (Lipitor®) and pure drug suspension, respectively. Collectively, pro-nanolipospheres might represent a promising delivery vehicle for enhancing the oral bioavailability of poorly water-soluble drugs.

Influence of Surface-Modification via PEGylation or Chitosanization of Lipidic Nanocarriers on In Vivo Pharmacokinetic/Pharmacodynamic Profiles of Apixaban.

Nanostructured lipid carriers (NLCs) have been proven to significantly improve the bioavailability and efficacy of many drugs; however, they still have many limitations. These limitations could hinder their potential for enhancing the bioavailability of poorly water-soluble drugs and, therefore, require further amendments. From this perspective, we have investigated how the chitosanization and PEGylation of NLCs affected their ability to function as a delivery system for apixaban (APX). These surface modifications could enhance the ability of NLCs to improve the bioavailability and pharmacodynamic activity of the loaded drug. In vitro and in vivo studies were carried out to examine APX-loaded NLCs, chitosan-modified NLCs, and PEGylated NLCs. The three nanoarchitectures displayed a Higuchi-diffusion release pattern in vitro, in addition to having their vesicular outline proven via electron microscopy. PEGylated and chitosanized NLCs retained good stability over 3 months, versus the nonPEGylated and nonchitosanized NLCs. Interestingly, APX-loaded chitosan-modified NLCs displayed better stability than the APX-loaded PEGylated NLCs, in terms of mean vesicle size after 90 days. On the other hand, the absorption profile of APX (AUC0-inf) in rats pretreated with APX-loaded PEGylated NLCs (108.59 µg·mL-1·h-1) was significantly higher than the AUC0-inf of APX in rats pretreated with APX-loaded chitosan-modified NLCs (93.397 µg·mL-1·h-1), and both were also significantly higher than AUC0-inf of APX-Loaded NLCs (55.435 µg·mL-1·h-1). Chitosan-coated NLCs enhanced APX anticoagulant activity with increased prothrombin time and activated partial thromboplastin time by 1.6- and 1.55-folds, respectively, compared to unmodified NLCs, and by 1.23- and 1.37-folds, respectively, compared to PEGylated NLCs. The PEGylation and chitosanization of NLCs enhanced the bioavailability and anticoagulant activity of APX over the nonmodified NLCs; this highlighted the importance of both approaches.

Egyptian Students Open to Digital Mental Health Care: Cross-Sectional Survey.

BACKGROUND: In Egypt, the shortage of mental health services, particularly for adolescents and young adults, is apparent. Electronic mental health (EMH) has been proposed as a solution to bridge the gap and better address the needs of young people. However, EMH is new to Egypt and its acceptability among target populations is crucial to its implementation and success. OBJECTIVE: The objective of this study is to explore the interest of Egyptian youth in EMH, identify perceived barriers to EMH, and inform the design of EMH tools to best address the needs of youth. METHODS: A web-based cross-sectional survey was distributed among medical students at Tanta University in Egypt. Chi-square and one-way analysis of variance tests were performed for inferential analyses using a significance level of .05. RESULTS: Of the 707 individuals who completed the survey (90.9% response rate), 60.5% (428) were female, 62% (438) lived in urban and suburban areas, and the mean age of the sample was 20.5 (SD 1.8) years. The vast majority of participants (522/707, 73.8%) had already used the internet to find information about mental health problems, but the information was unsatisfactory for about half of them (386/707, 54.6%). Almost all students reported that they would prefer web-based therapy if EMH were available through a trustworthy national web-based platform for youth mental health (601/707, 85%). Students believed that emotional difficulties, social support, and coping strategies were the main topics that EMH should help with. The most common perceived barriers for EMH use in Egypt were concerns about privacy (382/707, 54%) and a lack of technology literacy and unfamiliarity with EMH (352/707, 50%). CONCLUSIONS: EMH is a promising strategy for addressing gaps in the mental health care for young people. To construct and implement a digital system of care that addresses the unique needs and preferences of youth, adolescents and young adults should be involved in the co-development and design.

Tailoring Apixaban in Nanostructured Lipid Carrier Enhancing Its Oral Bioavailability and Anticoagulant Activity.

Apixaban (Apx), an oral anticoagulant drug, is a direct factor Xa inhibitor for the prophylaxis against venous thromboembolism. Apx has limited oral bioavailability and poor water solubility. The goal of this study was to improve the formulation of an Apx-loaded nanostructured lipid carrier (NLC) to increase its bioavailability and effectiveness. As solid lipid, liquid lipid, hydrophilic, and lipophilic stabilizers, stearic acid, oleic acid, Tween 80, and lecithin were used, respectively. Utilizing Box-Behnken design, the effects of three factors on NLC particle size (Y1), zeta potential (Y2), and entrapment efficiency percent (Y3) were examined and optimized. The optimized formula was prepared, characterized, morphologically studied, and pharmacokinetically and pharmacodynamically assessed. The observed responses of the optimized Apx formula were 315.2 nm, -43.4 mV, and 89.84% for Y1, Y2, and Y3, respectively. Electron microscopy revealed the homogenous spherical shape of the NLC particles. The in vivo pharmacokinetic study conducted in male Wistar rats displayed an increase in AUC and Cmax by 8 and 2.67 folds, respectively, compared to oral Apx suspension. Moreover, the half-life was increased by 1.94 folds, and clearance was diminished by about 8 folds, which makes the NLC formula a promising sustained release system. Interestingly, the pharmacodynamic results displayed the superior effect of the optimized formula over the drug suspension with prolongation in the cuticle bleeding time. Moreover, both prothrombin time and activated partial thromboplastin time are significantly increased. So, incorporating Apx in an NLC formula significantly enhanced its oral bioavailability and pharmacodynamic activity.

Preparation and Characterization of a Novel Mucoadhesive Carvedilol Nanosponge: A Promising Platform for Buccal Anti-Hypertensive Delivery.

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.

Factors affecting liposomes particle size prepared by ethanol injection method.

Ethanol injection is one of the techniques frequently used to produce liposomes which favors both simplicity and safety. In this process, an ethanolic solution of lipids is rapidly injected into an aqueous medium through a needle, dispersing the phospholipids throughout the medium and promoting the vesicle formation. Being a critical parameter that determines the fate of liposome and its distribution, we studied different factors affecting the particle size of liposomes including different phospholipid (Phosal® 53 MCT) and cholesterol concentrations and the use of different types of non-ionic surfactants at fixed Phosal® 53 MCT concentration of 50 mg per formulation. Both Phosal® 53 MCT and cholesterol concentration had direct effect on liposomes particle size. Non-ionic surfactants produced liposomes of smaller particle size when compared to conventional liposomes formed using Phosal® 53 MCT 300 mg per formulation only, whereas this effect was diminished when higher Phosal® 53 MCT to cholesterol ratios were used that obviously increased liposomes size. Smaller liposomes sizes were obtained upon using non-ionic surfactants of lower hydrophilic/hydrophobic balance (HLB) as both Tween 80 and Cremophor RH 40 produced liposomes of smaller particle size compared to Poloxamer 407. The smallest liposomes particle size was successfully obtained in the formulation comprising 300 mg Phosal® MCT, 150 mg cholesterol and 50 mg Tween 80.

Efficacy and In Vitro Cytotoxicity of Nanostructured Lipid Carriers for Paclitaxel Delivery

Paclitaxel (PTX) is an anticancer drug having poor aqueous solubility and low bioavailability. Formulation of PTX into Nanostructure lipid carriers (NLC) could be a potential way to enhance PTX aqueous solubility and bioavailability hence increases efficacy and decreases side effects. Eight PTX-NLC formulae were prepared using homogenization-ultrasonication technique. Characterization of the nanoparticles was done by transmission electron microscopy and by measurement of particle size, poly dispersibility index and zeta potential. Encapsulation efficiency, drug loading, and In Vitro release were measured. Particle size ranged between 172.8 ± 0.8 to 378.2 ± 1.8 nm and zeta potential between -18.6 ± 0.4 to -28.1 ± 1.2 mV. High EE and DL were obtained due to incorporation of liquid lipid and the In Vitro release showed prolonged time dependent release compared to Taxol®. NLC-3 had the best results among the eight prepared formulae. In Vitro cytotoxicity of NLC-3 was evaluated on MCF-7 cell line and compared to pure PTX powder and Taxol®. These findings show that NLC is a potential carrier to improve efficacy and enhance PTX delivery.