Lymphatic Transport Research Articles

Real-Time Evaluation of Absolute, Cytosolic, Free Ca2+ and Corresponding Contractility in Isolated, Pressurized Lymph Vessels.

The lymphatic vasculature, now often referred to as "the third circulation," is located in many vital organ systems. A principal mechanical function of the lymphatic vasculature is to return fluid from extracellular spaces back to the central venous ducts. Lymph transport is mediated by spontaneous rhythmic contractions of lymph vessels (LVs). LV contractions are largely regulated by the cyclic rise and fall of cytosolic, free calcium ([Ca2+]i). This paper presents a method to concurrently calculate changes in absolute concentrations of [Ca2+]i and vessel contractility/rhythmicity in real time in isolated, pressurized LVs. Using isolated rat mesenteric LVs, we studied changes in [Ca2+]i and contractility/rhythmicity in response to drug addition. Isolated LVs were loaded with the ratiometric Ca2+-sensing indicator Fura-2AM, and video microscopy coupled with edge-detection software was used to capture [Ca2+]iand diameter measurements continuously in real time. The Fura-2AM signal from each LV was calibrated to the minimum and maximum signal for each vessel and used to calculate absolute [Ca2+]i. Diameter measurements were used to calculate contractile parameters (amplitude, end diastolic diameter, end systolic diameter, calculated flow) and rhythmicity (frequency, contraction time, relaxation time) and correlated with absolute [Ca2+]i measurements.

A Long-Acting Lyotropic Liquid Crystalline Implant Promotes the Drainage of Macromolecules by Brain-Related Lymphatic System in Treating Aged Alzheimer's Disease.

Numerous evidence has demonstrated that the brain is not an immune-privileged organ but possesses a whole set of lymphatic transport system, which facilitates the drainage of harmful waste from brains to maintain cerebral homeostasis. However, as individuals age, the shrinkage and dysfunction of meningeal and deep cervical lymphatic networks lead to reduced waste outflow and elevated neurotoxic molecules deposition, further inducing aging-associated cognitive decline, which act as one of the pathological mechanisms of Alzheimer's disease. Consequently, recovering the function of meningeal and deep cervical lymph node (dCLNs) networks (as an important part of the brain waste removal system (BWRS)) of aged brains might be a feasible strategy. Herein we showed that the drug brain-entering efficiency was highly related to administration routes (oral, subcutaneous, or dCLN delivery). Besides, by injecting a long-acting lyotropic liquid crystalline implant encapsulating cilostazol (an FDA-approved selective PDE-3 inhibitor) and donepezil hydrochloride (a commonly used symptomatic relief agent to inhibit acetylcholinesterase for Alzheimer's disease) near the deep cervical lymph nodes of aged mice (about 20 months), an increase of lymphatic vessel coverage in the nodes and meninges was observed, along with accelerated drainage of macromolecules from brains. Compared with daily oral delivery of cilostazol and donepezil hydrochloride, a single administered dual drugs-loaded long-acting implants releasing for more than one month not only elevated drug concentrations in brains, improved the clearing efficiency of brain macromolecules, reduced Aβ accumulation, enhanced cognitive functions of the aged mice, but improved patient compliance as well, which provided a clinically accessible therapeutic strategy toward aged Alzheimer's diseases.

Ivacaftor pharmacokinetics and lymphatic transport after enteral administration in rats.

Background: Ivacaftor is a modern drug used in the treatment of cystic fibrosis. It is highly lipophilic and exhibits a strong positive food effect. These characteristics can be potentially connected to a pronounced lymphatic transport after oral administration. Methods: A series of studies was conducted to describe the basic pharmacokinetic parameters of ivacaftor in jugular vein cannulated rats when dosed in two distinct formulations: an aqueous suspension and an oil solution. Additionally, an anesthetized mesenteric lymph duct cannulated rat model was studied to precisely assess the extent of lymphatic transport. Results: Mean ± SD ivacaftor oral bioavailability was 18.4 ± 3.2% and 16.2 ± 7.8%, respectively, when administered as an aqueous suspension and an oil solution. The relative contribution of the lymphatic transport to the overall bioavailability was 5.91 ± 1.61% and 4.35 ± 1.84%, respectively. Conclusion: Lymphatic transport plays only a minor role in the process of ivacaftor intestinal absorption, and other factors are, therefore, responsible for its pronounced positive food effect.

Oral delivery of posaconazole-loaded phospholipid-based nanoformulation: Preparation and optimization using design of experiments, machine learning, and TOPSIS

Phospholipid-based nanosystems show promising potentials for oral administration of hydrophobic drugs. The study introduced a novel approach to optimize posaconazole-loaded phospholipid-based nanoformulation using the design of experiments, machine learning, and Technique for Order of Preference by Similarity to the Ideal Solution. These approaches were used to investigate the impact of various variables on the encapsulation efficiency (EE), particle size, and polydispersity index (PDI). The optimized formulation, with %EE of ∼ 74 %, demonstrated a particle size and PDI of 107.7 nm and 0.174, respectively. The oral pharmacokinetic profiles of the posaconazole suspension, empty nanoformulation + drug suspension, and drug-loaded nanoformulation were evaluated. The nanoformulation significantly increased maximum plasma concentration and the area under the drug plasma concentration–time curve (∼3.9- and 6.2-fold, respectively) and could be administered without regard to meals. MTT and histopathological examinations were carried out to evaluate the safety of the nanoformulation and results exhibited no significant toxicity. Lymphatic transport was found to be the main mechanism of oral delivery. Caco-2 cell studies demonstrated that the mechanism of delivery was not based on an increase in cellular uptake. Our study represents a promising strategy for the development of phospholipid-based nanoformulations as efficient and safe oral delivery systems.

Nasopharyngeal lymphatic plexus is a hub for cerebrospinal fluid drainage.

Cerebrospinal fluid (CSF) in the subarachnoid space around the brain has long been known to drain through the lymphatics to cervical lymph nodes1-17, but the connections and regulation have been challenging to identify. Here, using fluorescent CSF tracers in Prox1-GFP lymphatic reporter mice18, we found that the nasopharyngeal lymphatic plexus is a major hub for CSF outflow to deep cervical lymph nodes. This plexus had unusual valves and short lymphangions but no smooth-muscle coverage, whereas downstream deep cervical lymphatics had typical semilunar valves, long lymphangions and smooth muscle coverage that transported CSF to the deep cervical lymph nodes. α-Adrenergic and nitric oxide signalling in the smooth muscle cells regulated CSF drainage through the transport properties of deep cervical lymphatics. During ageing, the nasopharyngeal lymphatic plexus atrophied, but deep cervical lymphatics were not similarly altered, and CSF outflow could still be increased by adrenergic or nitric oxide signalling. Single-cell analysis of gene expression in lymphatic endothelial cells of the nasopharyngeal plexus of aged mice revealed increased type I interferon signalling and other inflammatory cytokines. The importance of evidence for the nasopharyngeal lymphatic plexus functioning as a CSF outflow hub is highlighted by its regression during ageing. Yet, the ageing-resistant pharmacological activation of deep cervical lymphatic transport towards lymph nodes can still increase CSF outflow, offering an approach for augmenting CSF clearance in age-related neurological conditions in which greater efflux would be beneficial.

Dual strategy to improve the oral bioavailability of efavirenz employing nanomicelles and curcumin as a bio-enhancer

The present investigation was focused on the development of Soluplus®-based nanomicelles (NMs) (10 % w/v) loaded with Efavirenz (EFV) (5 mg/mL) and Curcumin (natural bio-enhancer) (CUR) (5, 10 and 15 mg/mL) to improve the oral bioavalability of EFV. Micellar formulations were obtained employing an acetone-diffusion technique. Apparent aqueous solubility was increased up to ∼1250-fold and 25,000-fold for EFV and CUR, respectively. Drug-loaded nanoformulations showed an excellent colloidal stability with unimodal size distribution and PDI values < 0.30. In vitro drug release was 41.5 % (EFV) and 2.6 % (CUR) from EFV-CUR-NMs over 6 h in simulated gastrointestinal fluids. EFV-CUR-loaded NMs resulted as safe nanoformulations according to the in vitro cytocompatibility assays in Caco-2 cells. Furthermore, CUR bio-enhancer activity was demonstrated for those nanoformulations. A CUR concentration of 15 mg/mL produced a significant (p < 0.05) increment (2.64-fold) of relative EFV oral bioavailability. Finally, the active role of the lymphatic system in the absorption process of EFV, after its oral administration was assessed in a comparative pharmacokinetic study in presence and absence of cycloheximide, a lymphatic transport inhibitor.Overall our EFV-CUR-NMs denoted their potential as a novel nanotechnological platform, representing a step towards an optimized “nano-sized” therapy for AIDS patients.

Entry and exit of extracellular vesicles to and from the blood circulation.

Extracellular vesicles (EVs) are biological nanoparticles that promote intercellular communication by delivering bioactive cargo over short and long distances. Short-distance communication takes place in the interstitium, whereas long-distance communication is thought to require transport through the blood circulation to reach distal sites. Extracellular vesicle therapeutics are frequently injected systemically, and diagnostic approaches often rely on the detection of organ-derived EVs in the blood. However, the mechanisms by which EVs enter and exit the circulation are poorly understood. Here, the lymphatic system and transport across the endothelial barrier through paracellular and transcellular routes are discussed as potential pathways for EV entry to and exit from the blood circulatory system.

Giant Penoscrotal Lymphedema-What to Do? Presentation of a Curative Treatment Algorithm.

While rare, penoscrotal lymphedema (PL) is accompanied with devastating effects on the quality of life of patients. Moreover, especially for patients with excessive (giant) PL, no standardized curative treatment has been defined. This article therefore retrospectively evaluates the authors' surgical treatment approach for giant PL, which includes resection alone or in combination with a free vascularized lymph node transfer (VLNT). A total of ten patients met the inclusion criteria. One patient dropped out of the study before therapy commenced. Eight of the nine remaining patients presented with end-stage (giant) PL. One patient presented with manifest pitting edema. All patients were treated with penoscrotal resection and reconstruction. Additionally, five patients received VLNT into the groin or scrotum. The extent of the lymphedema was specified with a treatment-oriented classification system. The median follow-up was 49.0 months. No patient showed a recurrence. Patients who received VLNT into the scrotum displayed a significantly improved lymphatic transport of the scrotum. Advanced PL should be treated in a standardized surgical fashion as suggested by our proposed algorithm. VLNT from the lateral thoracic region into the scrotum must be considered. If treated correctly, surgical intervention of end-stage PL leads to good results with a low recurrence rate.

A 1D model characterizing the role of spatiotemporal contraction distributions on lymph transport

Lymphedema is a condition in which lymph transport is compromised. The factors that govern the timing of lymphatic contractions are largely unknown; however, these factors likely play a central role in lymphatic health. Computational models have proven useful in quantifying changes in lymph transport; nevertheless, there is still much unknown regarding the regulation of contractions. The purpose of this paper is to utilize computational modeling to examine the role of pacemaking activity in lymph transport. A 1D fluid–solid modeling framework was utilized to describe the interaction between the contracting vessel and the lymph flow. The distribution of contractions along a three-lymphangion chain in time and space was determined by specifying the pacemaking sites and parameters obtained from experimentation. The model effectively replicates the contractility patterns in experiments. Quantitatively, the flow rates were measured at 5.44 and 2.29 μL/h\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$${\\upmu L}/\\mathrm{h}$$\\end{document}, and the EF values were 78% and less than 33% in the WT and KO models, respectively, which are consistent with the literature. Applying pacemaking parameters in this modeling framework effectively captures lymphatic contractile wave propagations and their relation to lymph transport. It can serve as a motivation for conducting novel studies to evaluate lymphatic pumping function during the development of lymphedema.

Oral Drug Delivery via Intestinal Lymphatic Transport Utilizing Lipid-Based Lyotropic Liquid Crystals.

Lyotropic liquid crystals (LLCs) are liquids that have crystalline structures. LLCs as drug delivery systems that can deliver hydrophobic, hydrophilic, and amphiphilic agents. Due to their unique phases and structures, LLCs can protect both small molecules and biologics from the gastrointestinal tract's harsh environment, thus making LLCs attractive as carriers for oral drug delivery. In this review, we discuss the advantages of LLCs and LLCs as oral formulations targeting intestinal lymphatic transport. In oral LLC formulations, the relationship between the micelle compositions and the resulting LLC structures as well as intestinal transport and absorption were determined. In addition, we further demonstrated approaches for the enhancement of intestinal lymphatic transport: (1) lipid-based LLCs promoting chylomicron secretion and (2) the design of LLC nanoparticles with M cell-triggered ligands for targeting the M cell pathway. In this review, we introduce LLC drug delivery systems and their characteristics. Our review focuses on recent approaches using oral LLC drug delivery strategies targeting the intestinal lymphatic system to enhance drug bioavailability.

Robot-assisted rehabilitation of people with breast cancer developing upper limb lymphedema: protocol of a randomized controlled trial with a 6-month follow‑up

Upper limb lymphedema (ULLy) is an external (and/or internal) manifestation of lymphatic system insufficiency and deranged lymph transport for more than 3 months and frequently affects people as a consequence of breast cancer (BC). ULLy is often underestimated despite diminished motor skills, mood, and cognitive-behavioral complaints negatively condition the health-related quality of life (HRQoL) of persons. BC can also metastasize to the jawbone, further impacting on the HRQoL. In time, the implementation of robot-assisted rehabilitation (RR) for neurological diseases has grown to improve HRQoL and pain. This study aims to evaluate the effectiveness of a RR program in the treatment of individuals who develop an ULLy; as a further analysis, the study will assess the effectiveness of the same program in people with jawbone metastases from BC who will also develop ULLy. A randomized, parallel-group superiority-controlled trial will be conducted. 44 participants will be randomly allocated to either the experimental (receiving a RR program) or the control group (regular rehabilitation). Both groups will follow individual-based programs three times a week for 10 weeks. The main outcome measure will be the Lymphedema Quality of Life Questionnaire. Secondary outcomes will be a pain intensity numerical rating scale and the Cranio-Facial Pain Disability Inventory. Evaluations are before and after training and 6 months later. Findings may provide evidence on the effectiveness of a RR program on inducing improvements in the HRQoL and pain of individuals with ULLy due to BC. People with ULLy and jawbone metastases from BC are expected for similar or higher improvements as per the same comparisons above. This trial might contribute towards defining guidelines for good clinical rehabilitation routines and might be used as a basis for health authorities’ endorsements.Trial registration OSF REGISTRIES, osf-registrations-jz7ax-v1. Registered on 26 June 2023.

Design, Optimization and Characterization of Self-Nanoemulsifying Drug Delivery Systems of Bilastine

Self-nanoemulsifying drug delivery systems are innovative methods that have the potential to resolve a variety of drug formulation issues, including solubility, stability and bioavailability. Bilastine is a potent and highly selective H1-antihistamine. The aim of this study is to develop bilastine as an oral self-nanoemulsion to enhance its permeability from prepared formulas and possibility of lymphatic transport. Based on the solubility investigations of bilastine in some oils, surfactants and cosurfactants, fifteen formulae of liquid SNEDDS were created utilizing oleic acid, tween 60 and transcutol as oil, surfactant and co-surfactant respectively. Pseudoternary phase diagrams were used to evaluate the component phase behavior and the area of the nanoemulsion. The prepared formulas were evaluated for particle size, polydispersity index, zetapotential, self-emulsification time, drug content, and robustness to dilution. When compared to the pure drug powder, the produced SMEDDS formulations showed enhanced drug release. This study's findings showed that a formula 8 with a 20% oleic acid, 40% tween 60, and 40% transcutol composition exhibited lower particle size and higher zetapotential with acceptable drug content compared to other formulas and better in-vitro drug release characteristics than pure bilastine powder. All of these criteria favor the development of self-nano emulsifying drug delivery systems as a potential approach to enhance the bioavailability of drugs like bilastine that are poorly soluble. Keywords: Bilastine, SNEDDS

Self-Nano Emulsifying Drug Delivery System: A Potential Solution to the Challenges of Oral Delivery of Poorly Water-Soluble Drugs

Lipid-based drug delivery systems (LBDDS) are the most promising technique to formulate the poorly water soluble drugs. Nanotechnology strongly influences the therapeutic performance of hydrophobic drugs and has become an essential approach in drug delivery research. Self-Nanoemulsifying drug delivery systems (SNEDDS) are a vital strategy that combines benefits of LBDDS and nanotechnology. SNEDDS are now preferred to improve the formulation of drugs with poor aqueous solubility. SNEDDS are isotropic mixtures composed of oils, surfactants, and occasionally cosolvents. The ability of these formulations and methods to produce nanoemulsions or fine oil-in-water (o/w) emulsions after moderate stirring and dilution by water phase along the GI tract. SNEDDS has garnered attention during recent years as it improves oral bioavailability, reduces drug dose, and increases drug protection from unsuitable environment in the gastrointestinal tract. It can solve the problems related to the dissolution and bioavailability of the Biopharmaceutics Classifcation System Class II and IV drugs. This review shortly describes the ambiguity between nanoemulsions and microemulsions, mechanism of self-emulsifications, composition and function of various excipients of SNEDDS. This review discusses characterization of SNEDDS, advantage of SNEEDS over other emulsion, biopharmaceutical aspects, and limitation as well as future views. The SNEDDS is a potential formulation for drug delivery. Owing to its small particle size, large surface area, high encapsulation efficiency, and high drug loading, the SNEDDS can improve the rate and extent of oral absorption by maximizing drug solubility in the intestinal absorption site. Moreover, because of the lipid-based formulation of SNEDDS, it can stimulate and enhance lymphatic transport of drugs to avoid hepatic first-pass metabolism, and thus improve their bioavailability.

Self emulsifying drug delivery system: norfloxacin model drug

Background Norfloxacin is a synthetic antibacterial fluoroquinolone that is poorly water soluble and active against a wide spectrum of gram-positive and gram-negative aerobic bacteria. The goal of this work was to create a self-nanoemulsion (SNE) as a colloidal dispersed drug delivery system for increasing norfloxacin dissolving rate, while also assuming intestinal lymphatic transport participation for such a nano-size system that would increase norfloxacin oral bioavailability. Methods Depending on the solubility of norfloxacin in various components, several formulations of liquid SNEDDS of the antibiotic were created using oleic acid (oil), tween20 (surfactant), and PEG200 (co-surfactant). To assess the presence of a nanoemulsion region, phase diagram was generated at various oil: surfactant: co-surfactant ratios. Results The in-vitro dissolution profile suggested an optimum norfloxacin SEDD formulation (F1) comprised of oleic acid (10%), tween 20 (45%), and PEG200 (45%), as opposed to commercially available traditional tablets. The F1 formula exhibited thermodynamic stability with a zeta potential of +60.78mV and a droplet size of 57.4nm. The F1 formula revealed an improved dissolving profile as compared to the commercial Tablet of norfloxacin. Conclusion Based on the findings, this study indicated that preparing norfloxacin as a liquid self-nanoemulsifying system improved the solubility and drug release of norfloxacin counteract the inconsistent bioavailability of the commercial tablet.

Para- and Transcellular Transport Kinetics of Nanoparticles across Lymphatic Endothelial Cells.

Lymphatic vessels have received significant attention as drug delivery targets, as they shuttle materials from peripheral tissues to the lymph nodes, where adaptive immunity is formed. Delivery of immune modulatory materials to the lymph nodes via lymphatic vessels has been shown to enhance their efficacy and also improve the bioavailability of drugs when delivered to intestinal lymphatic vessels. In this study, we generated a three-compartment model of a lymphatic vessel with a set of kinematic differential equations to describe the transport of nanoparticles from the surrounding tissues into lymphatic vessels. We used previously published data and collected additional experimental parameters, including the transport efficiency of nanoparticles over time, and also examined how nanoparticle formulation affected the cellular transport mechanisms using small molecule inhibitors. These experimental data were incorporated into a system of kinematic differential equations, and nonlinear, least-squares curve fitting algorithms were employed to extrapolate transport coefficients within our model. The subsequent computational framework produced some of the first parameters to describe transport kinetics across lymphatic endothelial cells and allowed for the quantitative analysis of the driving mechanisms of transport into lymphatic vessels. Our model indicates that transcellular mechanisms, such as micro- and macropinocytosis, drive transport into lymphatics. This information is crucial to further design strategies that will modulate lymphatic transport for drug delivery, particularly in diseases like lymphedema, where normal lymphatic functions are impaired.

Lymphatic Transport and Immune Activation Effect by Locally Administered Extracellular Vesicles from Saccharomyces cerevisiae as Biocompatible Vaccine Adjuvants.

The yeast strain Saccharomyces cerevisiae is an eukaryotic organism that has been widely used for the production of fermented foods. Most cells secrete extracellular vesicles (EVs), small particles composed of lipid membranes. Elucidating the role of EVs as a new intercellular communication system and developing novel EV-based therapies have attracted the increased attention of researchers. Although recent studies have reported the secretion of EVs from S. cerevisiae, their in vivo fate and subsequent EV-mediated biological responses in the host are unclear. In this study, we characterized both the biodistribution of locally (intradermally and subcutaneously) administered Saccharomyces cerevisiae-derived EVs (S-EVs) and the EV-mediated immune responses to evaluate their potential use as biocompatible vaccine adjuvants. S-EVs were round but heterogeneous in size and contained glucan, DNA, and RNA. Their mean particle sizes and zeta potentials were approximately 177.5 nm and -14.6 mV, respectively. We provided evidence that locally administered S-EVs were delivered to the lymph nodes, mainly reaching the B-cell zone. Measurement of host immune reactions revealed that administration of S-EVs increased the expression of cytokine (tumor necrosis factor (TNF)-α) and costimulatory molecules (CD40, CD80, CD86), which are indicators of immune activation. Especially, subcutaneously injected S-EVs showed potent adjuvanticity, indicating that subcutaneous administration of S-EVs is the desirable approach for achieving effective immune stimulation. These findings will facilitate the development of novel EV-based immunotherapies.

ENOS Regulates Lymphatic Valve Specification by Controlling β-Catenin Signaling During Embryogenesis in Mice.

Lymphatic valves play a critical role in ensuring unidirectional lymph transport. Loss of lymphatic valves or dysfunctional valves are associated with several diseases including lymphedema, lymphatic malformations, obesity, and ileitis. Lymphatic valves first develop during embryogenesis in response to mechanotransduction signaling pathways triggered by oscillatory lymph flow. In blood vessels, eNOS (endothelial NO synthase; gene name: Nos3) is a well-characterized shear stress signaling effector, but its role in lymphatic valve development remains unexplored. We used global Nos3-/- mice and cultured human dermal lymphatic endothelial cells to investigate the role of eNOS in lymphatic valve development, which requires oscillatory shear stress signaling. Our data reveal a 45% reduction in lymphatic valve specification cell clusters and that loss of eNOS protein inhibited activation of β-catenin and its nuclear translocation. Genetic knockout or knockdown of eNOS led to downregulation of β-catenin target proteins in vivo and in vitro. However, pharmacological inhibition of NO production did not reproduce these effects. Co-immunoprecipitation and proximity ligation assays reveal that eNOS directly binds to β-catenin and their binding is enhanced by oscillatory shear stress. Finally, genetic ablation of the Foxo1 gene enhanced FOXC2 expression and partially rescued the loss of valve specification in the eNOS knockouts. In conclusion, we demonstrate a novel, NO-independent role for eNOS in regulating lymphatic valve specification and propose a mechanism by which eNOS directly binds β-catenin to regulate its nuclear translocation and thereby transcriptional activity.

Preparation of Dihydromyricetin-Loaded Self-Emulsifying Drug Delivery System and Its Anti-Alcoholism Effect.

Intraperitoneal injection of dihydromyricetin (DMY) has shown promising potential in the treatment of alcoholism. However, its therapeutic effect is limited due to its low solubility, poor stability, and high gut-liver first-pass metabolism, resulting in very low oral bioavailability. In this study, we developed a DMY-loaded self-emulsifying drug delivery system (DMY-SEDDS) to enhance the oral bioavailability and anti-alcoholism effect of DMY. DMY-SEDDS improved the oral absorption of DMY by facilitating lymphatic transport. The area under the concentration-time curve (AUC) of DMY in the DMY-SEDDS group was 4.13-fold higher than in the DMY suspension group. Furthermore, treatment with DMY-SEDDS significantly enhanced the activities of alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in the liver of mice (p < 0.05). Interestingly, DMY-SEDDS also increased ADH activity in the stomach of mice with alcoholism (p < 0.01), thereby enhancing ethanol metabolism in the gastrointestinal tract and reducing ethanol absorption into the bloodstream. As a result, the blood alcohol concentration of mice with alcoholism was significantly decreased after DMY-SEDDS treatment (p < 0.01). In the acute alcoholism mice model, compared to saline treatment, DMY-SEDDS prolonged the onset of LORR (loss of righting reflex) (p < 0.05) and significantly shortened the duration of LORR (p < 0.01). Additionally, DMY-SEDDS treatment significantly reduced gastric injury in acute alcoholism mice. Collectively, these findings demonstrate the potential of DMY-SEDDS as a treatment in the treatment of alcoholism.

A review on recent advantages and evaluation of microparticles and their applications

Microparticles are free spherical dust between 1 and 1000 microns made of synthetic, non-biodegradable, and non-biodegradable polymers. There are two types of microparticles: microcapsules and micro matrix. The main types of microparticles are magnetic microparticles, polymer microparticles, bio-adhesive microparticles, biodegradable polymer microparticles, synthetic polymer microparticles, floating microparticles, and radioactive microparticles. The advantage of microcarriers over nanoparticles is that they do not cross the 100 nm interstitium during lymphatic transport and therefore act locally. Toxic substances can be solidified in the form of micro-encapsulated and dried particles. Moreover, methods to characterize numerous physicochemical parameters like drug release, thermal properties, and particle size are introduced, along with new tests like in vitro leaching tests and floating tests.

Development of lipophilic ester prodrugs of dolutegravir for intestinal lymphatic transport

The establishment of latent cellular and anatomical viral reservoirs is a major obstacle to achieving a cure for people infected by HIV. Mesenteric lymph nodes (MLNs) are one of the most important anatomical reservoirs of HIV. Suboptimal levels of antiretroviral (ARVs) drugs in these difficult-to-penetrate viral reservoirs is one of the limitations of current antiretroviral therapy (ART) regimens. This study aimed to design and assess highly lipophilic ester prodrugs of dolutegravir (DTG) formulated with long-chain triglyceride (LCT) for delivery of DTG to the viral reservoir in mesenteric lymph and MLNs. A number of alkyl ester prodrugs of DTG were designed based on the predicted affinity to chylomicrons (CM), and the six most promising prodrugs were selected and synthesised. The synthesised prodrugs were further assessed for their intestinal lymphatic transport potential and biotransformation in biorelevant media in vitro and ex vivo. DTG and the most promising prodrug (prodrug 5) were then assessed in pharmacokinetic and biodistribution studies in rats. Although oral administration of 5 mg/kg of unmodified DTG (an allometrically scaled dose from humans) with or without lipids achieved concentrations above protein binding-adjusted IC90 (PA-IC90) (64 ng/mL) in most tissues, the drug was not selectively targeted to MLNs. The combination of lipophilic ester prodrug and LCT-based formulation approach improved the targeting selectivity of DTG to MLNs 4.8-fold compared to unmodified DTG. However, systemic exposure to DTG was limited, most likely due to poor intestinal absorption of the prodrug following oral administration. In vitro lipolysis showed a good correlation between micellar solubilisation of the prodrug and systemic exposure to DTG in rats in vivo. Thus, it is prudent to include in vitro lipolysis in the early assessment of orally administered drugs and prodrugs in lipidic formulations, even when intestinal lymphatic transport is involved in the absorption pathway. Further studies are needed to clarify the underlying mechanisms of low systemic bioavailability of DTG following oral administration of the prodrug and potential ways to overcome this limitation.