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Osteoporosis (OP), is a systemic bone disorder associated with low bone mass and bone tissue corrosion. Worsening of the disease condition leads to bone delicacy and fracture. Various drugs are available for the treatment of OP, however they have limitations including poor solubility, bioavailability and toxicity. Herein, Raloxifene-loaded polymeric nanoparticles (RLX-PNPs) were developed and investigated for the treatment of OP with possible solutions to the above mentioned problems. RLX-PNPs were prepared by modified ionic gelation method followed by determining their particle properties. FTIR, DSC and PXRD analysis of the RLX-PNPs were performed to check chemical interaction, thermal behavior and crystallinity, respectively. In-vitro release profile of RLX-PNPs was checked in lab setting, whereas its pharmacokinetics was investigated in Sprague-Dawley rats, in-vivo. Finally, the treatment potential of RLX-PNPs was analyzed in OP induced animal model. The optimized PNPs formulation indicated 134.5 nm particle size, +24.4 mV charge and 91.73% % EE. TEM analysis showed spherical and uniform sized particles with no interactions observed in FTIR analysis. In-vitro release of RLX from RLX-PNPs showed more sustained release behavior as compared to RLX-suspension. Moreover, pharmacokinetic investigations showed a significantly enhanced bioavailability of the RLX-PNPs as well as reduced serum levels of alkaline phosphatase and calcium in OP induced rats when compared with RLX-Suspension after oral administration. Findings of this study suggested that the developed RLX-PNPs have the potential to treat OP due to sustained release and improved bioavailability of the incorporated drug.

Non‐invasive management of intestinal microvascular injury with hemorrhage under constant biochemical‐mechanical encroachment of luminal contents is a major clinical challenge. Herein, an oral hydrogel microsphere is designed, encapsulating the platelet membrane fragment self‐assembled nanohydrogel fabricated by double‐crosslinking of methacrylated hyaluronic acid and Rebamipide‐loaded dendrimer (Rng@PMS), for self‐localization of hemorrhagic focus and intensive management of intestinal microvascular injury via suppression of inflammation‐mediated tissue injury and reintegration of the damaged mucosal barrier. The results indicate that Rng@PMS effectively adheres to exposed collagen on injured microvasculature and attaches to over 90% of activated macrophages within 10 min, endowing Rng@PMS with a significantly prolonged enteral dwell time (over 24 hours). Importantly, Rng@PMS generated from alginate is designed for oral colon‐targeted delivery to avoid the erosion of gastrointestinal contaminants. In vivo study reveals oral administration of microspheres in murine hematochezia model upregulates the intestinal barrier proteins zonula occludens‐1, Occludin, and muc2, and inhibits infiltration of neutrophils, dendritic cells, and macrophages in hemorrhagic foci, thereby reducing the hematochezia score from 4 to 0.8, and the pathology score from 5.3 to 0.5. Oral microspheres for in situ management of intestinal microvascular injury may be applicable more broadly to noninvasively treat diseases with symptoms of mucosal hemorrhage. [ABSTRACT FROM AUTHOR]

Bacterial vaginosis (BV) is a common infection of the lower genital tract with a vaginal microbiome dysbiosis caused by decreasing of lactobacilli. Previous studies suggested that supplementation with live Lactobacillus may benefit the recovery of BV, however, the outcomes vary in people from different regions. Herein, we aim to evaluate the effectiveness of oral Chinese-origin Lactobacillus with adjuvant metronidazole (MET) on treating Chinese BV patients. In total, 67 Chinese women with BV were enrolled in this parallel controlled trial and randomly assigned to two study groups: a control group treated with MET vaginal suppositories for 7 days and a probiotic group treated with oral Lactobacillus gasseri TM13 and Lactobacillus crispatus LG55 as an adjuvant to MET for 30 days. By comparing the participants with Nugent Scores ≥ 7 and < 7 on days 14, 30, and 90, we found that oral administration of probiotics did not improve BV cure rates (72.73% and 84.00% at day 14, 57.14% and 60.00% at day 30, 32.14% and 48.39% at day 90 for probiotic and control group respectively). However, the probiotics were effective in restoring vaginal health after cure by showing higher proportion of participants with Nugent Scores < 4 in the probiotic group compared to the control group (87.50% and 71.43% on day 14, 93.75% and 88.89% on day 30, and 77.78% and 66.67% on day 90). The relative abundance of the probiotic strains was significantly increased in the intestinal microbiome of the probiotic group compared to the control group at day 14, but no significance was detected after 30 and 90 days. Also, the probiotics were not detected in vaginal microbiome, suggesting that L. gasseri TM13 and L. crispatus LG55 mainly acted through the intestine. A higher abundance of Prevotella timonensis at baseline was significantly associated with long-term cure failure of BV and greatly contributed to the enrichment of the lipid IVA synthesis pathway, which could aggravate inflammation response. To sum up, L. gasseri TM13 and L. crispatus LG55 can restore the vaginal health of patients recovering from BV, and individualized intervention mode should be developed to restore the vaginal health of patients recovering from BV. [ABSTRACT FROM AUTHOR]

The important pathway toward liver fibrosis is the TGF-β1-induced activation of hepatic stellate cells (HSCs). To discover chemicals to inhibit liver fibrosis, we screened 3000 chemicals using cell array system where human HSCs line LX2 cells are activated with TGF-β1. We discovered 3,7-dimethoxyflavone (3,7-DMF) as a chemical to inhibit TGF-β1-induced activation of HSCs. In the thioacetamide (TAA)-induced mouse liver fibrosis model, 3,7-DMF treatment via intraperitoneal or oral administration prevented liver fibrosis as well as reversed the established fibrosis in the separate experiments. It also reduced liver enzyme elevation, suggesting protective effect on hepatocytes because it has antioxidant effect. Treatment with 3,7-DMF induced antioxidant genes, quenches ROS away, and improved the hepatocyte condition that was impaired by H 2 O 2 as reflected by restoration of HNF-4α and albumin. In the TAA-mouse liver injury model also, TAA significantly increased ROS in the liver which led to decrease of albumin and nuclear expression of HNF-4α, increase of TGF-β1 and hepatocytes death, accumulation of lipid, and extra-nuclear localization of HMGB1. Treatment of 3,7-DMF normalized all these pathologic findings and prevented or resolved liver fibrosis. In conclusion, we discovered 3,7-DMF that inhibits liver fibrosis based on dual actions; antioxidant and inhibitor of TGF-β1-induced activation of HSCs. [Display omitted] • We developed a cell array system to identify new compounds capable of inhibiting liver fibrosis, using the human hepatic stellate cells activated by TGF-β1. • We identified 3,7-DMF as a potential chemical to prevent liver fibrosis after injury. • Daily oral administration of 3,7-DMF effectively resolved established liver fibrosis after injury. • 3,7-DMF protected hepatocytes through two mechanisms: scavenging ROS and decreasing the expression of TGF-β1. • 3,7-DMF had a protective effect on injured liver tissues by restoring hepatocyte functional genes, inhibiting hepatic steatosis, regenerating injured hepatocytes, and inhibiting activated HSCs. [ABSTRACT FROM AUTHOR]

Overexpression of classically activated macrophages (M1) subtypes and assessed reactive oxygen species (ROS) levels are often observed in patients with ulcerative colitis. At present, the treatment system of these two problems has yet to be established. Here, the chemotherapy drug curcumin (CCM) is decorated with Prussian blue analogs in a straightforward and cost‐saving manner. Modified CCM can be released in inflammatory tissue (acidic environment), eventually causing M1 macrophages to transform into M2 macrophages and inhibiting pro‐inflammatory factors. Co(III) and Fe(II) have abundant valence variations, and the lower REDOX potential in CCM‐CoFe PBA enables ROS clearance through multi‐nanomase activity. In addition, CCM‐CoFe PBA effectively alleviated the symptoms of UC mice induced by DSS and inhibited the progression of the disease. Therefore, the present material may be used as a new therapeutic agent for UC. [ABSTRACT FROM AUTHOR]

The efficacy of orally administered drugs in cattle is thought to be slow because of the anatomical and physiological features of their forestomach. Thus, parenteral routes are mainly preferred to administer drugs. However, the effect of some drugs with unique physicochemical properties was promptly obtained even after oral administration in clinically ill cattle. Therefore, the present study aimed to investigate pharmacokinetically the usefulness of the oral route in cattle by comparing the oral pharmacokinetic properties of two sulfonamides with different physicochemical properties. Sulfadiazine (SDZ) and sulfamonomethoxine (SMM) were administered by intravenous and oral route to four female Holstein cows with a 4-weeks washout period. Blood samples were collected over time, and SDZ and SMM concentrations in plasma were analyzed by HPLC. Data obtained from the same animal after intravenous and oral administration were simultaneously analyzed with the one compartment model, and kinetic parameters were calculated. The Tmax (mean ± SD) of SMM (2.75 ± 0.96 hr) was significantly achieved earlier than that of SDZ (5.00 ± 1.15 hr). Further, the mean absorption time of SMM (5.24 ± 0.69 hr) was significantly shorter than that of SDZ (5.92 ± 1.11 hr). Also, the half-life of absorption of SMM (3.91 ± 0.51 hr) was significantly shorter than that of SDZ (4.51 ± 0.82 hr). These data suggest that the absorption rates of highly unionized drugs (such as SMM) from the forestomach of cattle may be markedly higher than less unionized ones (such as SDZ). [ABSTRACT FROM AUTHOR]

Performing an up-to-date meta-analysis of oral antioxidant therapies and determining whether they are effective in preventing and/or treating preeclampsia (PE). Search was performed in PubMed, CENTRAL, LILACS, Web of Science, and ScienceDirect databases. The risk of bias was assessed based on using Cochrane Collaboration's tool. A funnel plot was created, and Egger's and Peter's test was carried out to assess publication bias in the primary outcome of prevention studies. The overall quality of the evidence was assessed based on using the Grading of Recommendations Assessment, Developing and Evaluation (GRADE) tool; a formal protocol was published in the PROSPERO database (registration number CRD42022348992). In total, 32 studies were taken into consideration for analysis purposes; 22 studies focused on investigating preeclampsia prevention methods, whereas 10 focused on its treatment. Significant results associated with the incidence of preeclampsia were observed in prevention studies comprising 11,198 subjects and 1106 events in the control groups, as well as 11,156 subjects and 1048 events in the intervention groups (relative risk [RR]: 0.86, 95% confidence interval [CI]: [0.75, 0.99], P = 0.03; I2 = 44%, P = 0.02). With respect to outcomes associated with treatment studies, only intrauterine growth restriction has shown significant effects. Egger's and Peter's test has evidenced publication bias. Six outcomes in prevention studies were classified as having low quality and two as having moderate quality, whereas all three outcomes assessed in treatment studies were classified as having moderate quality. Antioxidant therapy has shown beneficial effects on preeclampsia prevention; moreover, the positive impact of this therapy on intrauterine growth restriction was observed during the disease treatment. [ABSTRACT FROM AUTHOR]

The newly developed vanadium dioxide (VO2), a material with excellent reversible and multi-stimuli responsible phase transition property, has been widely used in high-performance and energy-saving smart devices. The rapid growth of the VO2-based emerging technologies and the complex biological effect of vanadium to organisms urge a better understanding of the behavior of VO2 in vivo for safety purpose. Herein, we study the absorption, distribution, and excretion of two commercial VO2 (nanoscale SVO2 and bulk MVO2) in mice after consecutive gavage administration for up to 28 days. The absorption of both types of VO2 is as low as less than 1.5% of the injected dose within 28 days, while MVO2 is several times more difficult to be absorbed than SVO2. Almost all unabsorbed VO2 is excreted through feces. For the absorbed vanadium, bone is the organ with the largest accumulation, followed by liver, kidney, and spleen. The vanadium content in organs shows a size-, dosage-, and animal health condition-dependent manner, and increases gradually to a saturation value along with the consecutive administration. Generally, smaller particle size and higher dosage lead to higher vanadium contents in organs, and more vanadium accumulates in bone and liver in diabetic mice than in normal mice. After the treatment is stopped, the accumulated vanadium in organs decreases a lot within 14 days, even reaches to the background level in some organs, but the content of vanadium in the bone remains high after 14 days post-exposure. These findings provide basic information for the safety assessment and safe applications of VO2-based materials. [ABSTRACT FROM AUTHOR]

Genotoxicity and mutagenicity of monoterpene carvone along with the related monoterpene alcohols – carvacrol and thymol have been studied using Drosophila melanogaster as model system. The viability, pre-imaginal stage duration, level of dominant lethal mutations, unequal crossover in the Bar mutant of D. melanogaster and the influence of monocyclic terpenoids on the multiplication of the nuclear genome in salivary gland cells were investigated. The compounds tested after oral administration (0.02% in 1,2-propylene glycol) influence the degree of chromosome polyteny in salivary gland cells of D. melanogaster larvae. Among the terpenoids examined, carvacrol exhibited the most significant impact on imago lifespan, frequency of dominant lethal mutations, unequal crossover in the Bar mutant when added to the culture medium. Oral administration of terpenoids increases the average level of chromosome polyteny with the highest value for carvacrol – 1178 C compared to control (776 C). The conceivable mechanism of action for monocyclic terpenoids associated with the impact on juvenile hormone activity is debated.

Introduction: Aging, genetic mutations, and other pathological conditions cause impairment of skeletal growth and bone metabolism, which affect activities of daily living and quality of life in all life stages. Although several drugs have been used in clinical settings and new drugs have been developed for the treatment of skeletal degenerative disorders such as osteoporosis and genetic disorders such as osteogenesis imperfecta (OI), there is clear demand for development of new drugs, especially orally available anabolic drugs that are applicable for a wide range of skeletal disorders. Methods: To identify therapeutic candidates for skeletal disorders, peptide screening was performed. To validate the identified peptides, we performed a bone histomorphometric analysis with rat bone tissues and in vitro cell proliferation assays of skeletal cells. To understand the metabolism of the peptides, we performed a biochemical analysis, followed by in vitro assays for proliferation and differentiation of skeletal cells. We examined the therapeutic efficacy of the identified peptides with several mouse models representing skeletal disorders including bone fracture, osteoporosis, and osteogenesis imperfecta. In vivo therapeutic effects of the candidate were assessed with radiological analysis and mechanical property tests. Results: We identified the egg yolk-derived functional peptide PF201. PF201 promoted in vivo bone formation in rodents and enhanced proliferation of osteoblasts and chondrocytes in vitro. D2, a metabolite of PF201, was present and circulated after digestion and absorption in the digestive tract. D2 had positive impacts on the proliferation and differentiation of mesenchymal stem cells and preosteoblasts. Oral administration of D2 accelerated bone healing in a mouse fracture model. D2 also improved bone strength and fracture healing under ovariectomy-induced osteoporotic conditions in mice, and D2 showed a therapeutic effect in a mouse OI model. Conclusion: D2 is likely to be a candidate for an orally available therapeutic for a range of skeletal disorders.

Xiao Liang, Kai Wen, Yingxuan Chen, Guangxu Fang, Shengcai Yang, Quanshun Li Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun, People’s Republic of ChinaCorrespondence: Quanshun Li; Shengcai Yang, Tel/Fax +86-431-85155200, Email quanshun@jlu.edu.cn; yang_shengcai1990@163.comBackground: Oral administration of proteins/peptides is challenging in clinical application due to their instability and susceptibility in the gastrointestinal tract.Materials and Methods: The in situ polymerization on the surface of enzymes was used to encapsulate antioxidant enzymes (superoxide dismutase (SOD) and catalase (CAT)) in polymeric shells, and the reactive oxygen species (ROS) scavenging ability was monitored based on DCFH-DA probe using flow cytometry and confocal laser scanning microscopy. The mRNA expression level of pro-inflammatory factors was assessed by real-time qPCR, using lipopolysaccharide-induced RAW264.7 cells as a model. Finally, the enzyme capsules were orally administered for the treatment of inflammatory bowel disease using dextran sodium sulfate (DSS)-induced colitis mice as a model, based on the evaluation of the disease-associated index, ROS level and pro-inflammatory cytokines’ expression.Results: The enzyme capsules could effectively scavenge the intracellular reactive oxygen species (ROS) through the cascade catalysis of SOD and CAT, and thus protect the cells from ROS-induced oxidative damage. Meanwhile, the enzyme capsules could inhibit the secretion of pro-inflammatory cytokines from macrophages, thereby achieving favorable anti-inflammation effect. Oral administration of enzyme capsules could facilitate the accumulation of enzymes in the inflamed colon tissues of DSS-induced colitis mice. Moreover, the oral delivery of enzyme capsules could effectively alleviate the symptoms associated with colitis, attributing to the excellent ROS scavenging ability and the inhibition of pro-inflammatory cytokines’ level.Conclusion: In summary, our findings provided a promising approach to construct enzyme-based nano-formulations with favorable therapeutic efficacy and biocompatibility, exhibiting great potential in the treatment of gastrointestinal diseases in an oral administration manner.Keywords: antioxidant enzymes, in situ polymerization, oral administration, reactive oxygen species, anti-inflammation, colitis

Stroke was always a disease that threatened human life and health worldwide. We reported the synthesis of a new type of hyaluronic acid-modified multi-walled carbon nanotube. Then, we produced hydroxysafflor yellow A-hydroxypropyl-β-cyclodextrin phospholipid complex water-in-oil nanoemulsion with hyaluronic acid-modified multi-walled carbon nanotubes and chitosan (HC@HMC) for oral treatment of an ischemic stroke. We measured the intestinal absorption and pharmacokinetics of HC@HMC in rats. We found that the intestinal absorption and the pharmacokinetic behavior of HC@HMC was superior to that of HYA. We measured intracerebral concentrations after oral administration of HC@HMC and found that more HYA crossed the blood–brain barrier (BBB) in mice. Finally, we evaluated the efficacy of HC@HMC in middle cerebral artery occlusion/reperfusion (MCAO/R)-injured mice. In MCAO/R mice, oral administration of HC@HMC demonstrated significant protection against cerebral ischemia-reperfusion injury (CIRI). Furthermore, we found HC@HMC may exert a protective effect on cerebral ischemia-reperfusion injury through the COX2/PGD2/DPs pathway. These results suggest that oral administration of HC@HMC may be a potential therapeutic strategy for the treatment of stroke. [ABSTRACT FROM AUTHOR]

This study aims to prepare a nanodrug system for insulin delivery and controlled release with Poly(lactic acid-glycolic acid) (PLGA) as the shell and polyethylene glycol-chondroitin sulfate as the core to enhance its oral administration bioavailability. The insulin/CS-PLGA nanoparticles (NPs) with an average size of about 150 nm and regular spherical shape were obtained and showed good biocompatibility and relative high drug loading. Insulin can be controlled release according to the environmental pH and retained its original structure. The oral administration of insulin/CS-PLGA NPs showed a relatively higher hypoglycemic effect than that of insulin, indicating the NPs is a potential oral delivery system to enhance insulin bioavailability. [ABSTRACT FROM AUTHOR]

Simple Summary: pH-responsive hydrogel microparticles have great potential as drug delivery systems of anti-cancer drugs. Here, we use microfluidics for the generation of asymmetric microgels as carriers for oral administration of 5-fluorouracil (5-FU) in colorectal cancer. Due to their anisotropic shape, they show increased on-demand loading of the drug. The pH-responsiveness is ensured by the presence of alginate methacrylate within the gel network and represents the key factor for 5-FU release at the targeted location. Empty, asymmetric microgels do not show cytotoxicity even at high concentration, while upon treatment with 5-FU loaded microparticles, the viability of tumor cells notably decreases confirming the efficacy of drug release at certain pH. In the last 20 years, the development of stimuli-responsive drug delivery systems (DDS) has received great attention. Hydrogel microparticles represent one of the candidates with the most potential. However, if the role of the cross-linking method, polymer composition, and concentration on their performance as DDS has been well-studied, still, a lot needs to be explained regarding the effect caused by the morphology. To investigate this, herein, we report the fabrication of PEGDA–ALMA-based microgels with spherical and asymmetric shapes for 5-fluorouracil (5-FU) on-demand loading and in vitro pH-triggered release. Due to anisotropic properties, the asymmetric particles showed an increased drug adsorption and higher pH responsiveness, which in turn led to a higher desorption efficacy at the target pH environment, making them an ideal candidate for oral administration of 5-FU in colorectal cancer. The cytotoxicity of empty spherical microgels was higher than the cytotoxicity of empty asymmetric microgels, suggesting that the gel network's mechanical proprieties of anisotropic particles were a better three-dimensional environment for the vital functions of cells. Upon treatment with drug-loaded microgels, the HeLa cells' viability was lower after incubation with asymmetric particles, confirming a minor release of 5-FU from spherical particles. [ABSTRACT FROM AUTHOR]

Subcutaneous insulin (INS) injection as the main therapy method for diabetes shows adverse effects such as inconvenient use and hypoglycemia. Fortunately, the oral route of administration of insulin possesses more application potential. As one of the most mature drug delivery systems, liposomes exist some disadvantages in the oral administration of proteins or peptides, such as poor stability, low drug load, and limited mucus penetration. Herein, according to the phosphocholine (PC) component of the cell membrane, choline phospholipid with trifluoroethyl modified zwitterionic head (DPFCP) is designed and synthesized for constructing liposomes delivery system loaded with insulin (INS@DPFCP) for oral administration. By comparison with phosphate choline liposomes (INS@DPPC) and unfunctionalized choline phosphate liposomes (INS@DPCP), the physicochemical properties, drug release stability, mucus permeability, biocompatibility, endocytosis, and transport ability of INS@DPFCP are studied. The test results indicate that the particle size of INS@DPFCP is 185 nm, and drug entrapment efficiency is (47. 1±3. 9)%. Compared with INS@DPPC (27. 2%) and INS@DPCP (24. 5%), the amount of mucus aggregation for INS@DPFCP is 17. 15%. Hemolysis and cytotoxicity experiments show that INS@DPFCP gets good biocompatibility. When the mass concentration is as high as 1. 2 mg/mL, the hemolysis rate is 6. 88%, and the cell viability is above 90%. In addition, the endocytosis assay results demonstrate that INS@DPFCP is proved to be higher cellular uptake efficiency of Caco-2 cells, and the drug delivery accumulation reaches 47. 5% in 4 h. INS@DPFCP is expected to play an important role in diabetes treatment, and shows potential application in the field of proteins or peptides oral administration [ABSTRACT FROM AUTHOR]

The oral route is the most widely used and preferable way of drug administration. Several pharmacokinetic processes play a role in the distribution of administered drugs. Therefore, accurate quantification of absorption, distribution, metabolism, excretion, and characterisation of drug kinetics after oral administration is extremely important for developing new human drugs. In vivo methods, such as gamma-scintigraphy, magnetic resonance imaging (MRI), and positron emission tomography (PET), have been used to analyse gastrointestinal tract (GIT) absorption behaviour. This scoping review provides an overview of PET studies that used oral tracer administration. A systematic literature search was performed using PubMed, EMBASE, Scopus, Science Direct, and Web of Science databases. Extensive variation between these studies was seen concerning acquisition protocols, quantification methods, and pharmacokinetic outcome parameters. Studies in humans indicate that it takes 10 to 30 min for the tracer to be in the intestine and about 100 min to reach its maximum concentration in the brain. In rodent studies, different pharmacokinetic parameters for the brain, blood, and GIT were estimated, showing the potential of PET to measure the absorption and distribution of drugs and pharmaceuticals non-invasively. Finally, regarding radiation protection, oral administration has a higher absorbed dose in GIT and, consequently, a higher effective dose. However, with the recent introduction of Long Axial Field of View (LAFOV) PET scanners, it is possible to reduce the administered dose, making oral administration feasible for routine clinical studies. [Display omitted] • This route of administration results in delayed plasma peaks dependent on the tracer, population, fasting, use of anaesthetics, and GIT motility. • The approach can have clinical implications for therapeutic strategies, drug dosages, and the treatment of GIT diseases. [ABSTRACT FROM AUTHOR]

Autoimmune diseases are often accompanied by acute exacerbation. However, the mechanism underlying systemic lupus erythematosus (SLE) flares remains unclear. We investigated whether short-term enteric Toll-like receptor 7 (TLR7) stimulation can exacerbate SLE using B6SKG mice, which spontaneously develop SLE due to a mutation in the zeta‒chain‒associated protein kinase 70 (Zap70) gene. Imiquimod (IMQ) or phosphate-buffered saline (PBS) were orally administered on B6WT and B6SKG mice every other day for 2 weeks. SLE exacerbation was assessed via fluorescent immunohistochemical staining of glomeruli for IgG and C3, hematoxylin and eosin staining of kidneys, and enzyme-linked immunosorbent assay for antinuclear antibody (ANA). Flow cytometry was used to evaluate germinal center B cells (GCBs), plasma cells, follicular helper T cells (Tfhs), regulatory T cells (Tregs), effector T cells (Th1s and Th17s), plasmacytoid dendritic cells (pDCs), conventional dendritic cells (cDCs), and macrophages (Mφs) in spleens. Oral administration of IMQ every other day for 2 weeks resulted in exacerbation of splenomegaly, increased IgG and C3 deposition in glomeruli, and increased ANA production in the B6SKG IMQ (SKG-IMQ) group compared to the B6SKG PBS (SKG-PBS) group; the percentages of GCBs, plasma cells, Tfhs, Th1s, pDCs, and Mφs were also increased in the SKG-IMQ group. Splenomegaly, IgG, and C3 deposition in glomeruli, and the percentages of GCBs, plasma cells, Tfhs, and Th1s were enhanced in SKG-IMQ mice compared with B6SKG mice topically treated with IMQ (SKG-ear-IMQ). Oral TLR7 stimulation in a Zap70 genetic mutation background can cause acute exacerbations of SLE. Key Points • The mechanism of SLE flares is not well understood. • We have created a model that causes short-term SLE exacerbations in mice with a genetic background. • IMQ administered orally causes more SLE in mice than transdermally. [ABSTRACT FROM AUTHOR]

Clostridioides difficile infection (CDI) is one of the most common hospital-acquired infections. Its incidence has increased during the last decade in the community among individuals with no previous risk factors; however, morbidity and mortality are still considered high in elderly patients. Oral Vancomycin and Fidaxomicin are the first lines of treatment for CDI. The systemic bioavailability of oral Vancomycin is thought to be undetectable due to its poor absorption in the gastrointestinal tract; therefore, routine monitoring is not warranted. Only 12 case reports were found in the literature that described adverse reactions associated with oral Vancomycin and its related risk factors. We present a case of a 66-year-old gentleman with severe CDI and acute renal failure who was started on oral Vancomycin upon admission. On day five of treatment, he developed leukocytosis associated with neutrophilia, eosinophilia, and atypical lymphocytes, with no evidence of active infection. Three days later, he developed a pruritic maculopapular rash in more than 50% of his body surface area. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) was ruled out since the patient only had three inclusion criteria for this diagnosis. No clear inciting agent was found. Oral Vancomycin was stopped and supportive treatment was supplied for a presumed Vancomycin-induced allergic reaction. The patient had an excellent response, with complete resolution of the rash and leukocytosis in less than 48 h. By reporting this case, we want to raise awareness among clinicians to remember that, albeit rare, oral Vancomycin can be the cause of adverse drug reactions in patients with severe illnesses. [ABSTRACT FROM AUTHOR]

Background: Oral insulin administration has recently become one of the most exciting research subjects. Different approaches have been carried out to get an effective oral insulin delivery system using nanotechnology. The development of a delivery system that overcomes the difficulties of oral insulin administration, achieving high stability and minimal side effects, is still an urgent need. Therefore, this study is considered one of the efforts to design a new prospective drug delivery nano-composite (silica-coated chitosan-dextran sulfate nanoparticles). Methods: Chitosan-dextran sulfate nanoparticles (CS-DS NPs) were prepared via a complex coacervation method and then coated with silica. Uncoated and silica-coated CS-DS NPs were physically characterized via different techniques. Transmission electron microscopy (TEM), scanning electron microscopy (SEM), energy-dispersive X-ray (EDX) analysis, and atomic force microscopy (AFM) have been used to investigate the chemical elements, size, morphology, and surface properties of the prepared formulations. Differential scanning calorimetry (DSC) to assess the thermal properties of formed nano-formulations. Fourier transform infrared (FT-IR) spectroscopy investigated the silica coat and chitosan interaction. The encapsulation efficiency was evaluated using high-performance liquid chromatography (HPLC) analysis. The insulin release profile of nano-formulations was performed with and without silica coat at two different pHs (5.5,7), nearly simulating the environment of the gastrointestinal tract (GIT). Results: The silica-coated CS-DS NPs revealed interesting physicochemical properties exemplified by suitable core particle size obtained by TEM images (145.31 ± 33.15 nm), hydrodynamic diameter (210 ± 21 nm), high stability indicated by their zeta potential value (-32 ± 3.2 mV), and adequate surface roughness assessed by AFM. The encapsulation efficiency of insulin-loaded chitosan nanoparticles (ICN) was (66.5%) higher than that of insulin-chitosan complex nanoparticles (ICCN). The silica-coated ICN demonstrated a controlled insulin release profile at pHs (5.5 and 7) compared with uncoated ICN. Conclusion: The silica-coated ICN can be an efficient candidate as a desired oral delivery system, overcoming the common obstacles of peptides and proteins delivery and achieving high stability and controlled release for further applications. [ABSTRACT FROM AUTHOR]

In today's aging society, dementia is an urgent problem to be solved because no treatment or preventive methods have been established. This review focuses on oral administration of lipopolysaccharide (LPS), an outer membrane component of Gram-negative bacteria, as a novel preventive drug for dementia. LPS is also called endotoxin and is well known to induce inflammation when administered systemically. On the other hand, although we humans routinely ingest LPS derived from symbiotic bacteria of edible plants, the effect of oral administration of LPS has hardly been studied. Recently, oral administration of LPS was reported to prevent dementia by inducing neuroprotective microglia. Furthermore, it has been suggested that colony stimulating factor 1 (CSF1) is involved in the dementia prevention mechanism by oral administration of LPS. Thus, in this review, we summarized the previous studies of oral administration of LPS and discussed the predicted dementia prevention mechanism. In addition, we showed the potential of oral LPS administration as a preventive drug for dementia by highlighting research gaps and future issues for clinical application development. [ABSTRACT FROM AUTHOR]

Protein and peptide drugs are predominantly administered by injection to achieve high bioavailability, but this greatly compromises patient compliance. Oral and transdermal drug delivery with minimal invasiveness and high adherence represent attractive alternatives to injection administration. However, oral and transdermal administration of bioactive proteins must overcome biological barriers, namely the gastrointestinal and skin barriers, respectively. The rapid development of new materials and technologies promises to address these physiological obstacles. This review provides an overview of the latest advances in oral and transdermal protein delivery, including chemical strategies, synthetic nanoparticles, medical microdevices, and biomimetic systems for oral administration, as well as chemical enhancers, physical approaches, and microneedles in transdermal delivery. We also discuss challenges and future perspectives of the field with a focus on innovation and translation. [ABSTRACT FROM AUTHOR]

Insulin is one of the most important drugs in the treatment of diabetes. There is an increasing interest in the oral administration of insulin as it mimics the physiological pathway and potentially reduces the side effects associated with subcutaneous injection. Therefore, insulin-loaded polyelectrolyte complex (PEC) nanoparticles were prepared by the ionic cross-linking method using protamine sulfate as the polycationic and sodium alginate as the anionic polymer. Taguchi experimental design was used for the optimization of nanoparticles by varying the concentration of sodium alginate, the mass ratio of sodium alginate to protamine, and the amount of insulin. The optimized nanoparticle formulation was used for further in vitro characterization. Then, insulin-loaded PEC nanoparticles were placed in hard gelatin capsules and the capsules were enteric-coated by Eudragit L100-55 (PEC-eCAPs). Hypoglycemic effects PEC-eCAPs were determined in vivo by oral administration to diabetic rats. Furthermore, in vivo distribution of PEC nanoparticles was evaluated by fluorescein isothiocyanate (FITC) labelled nanoparticles. The experimental design led to nanoparticles with a size of 194.4 nm and a polydispersity index (PDI) of 0.31. The encapsulation efficiency (EE) was calculated as 95.96%. In vivo studies showed that PEC-eCAPs significantly reduced the blood glucose level of rats at the 8th hour compared to oral insulin solution. It was concluded that PEC nanoparticles loaded into enteric-coated hard gelatin capsules provide a promising delivery system for the oral administration of insulin. [Display omitted] [ABSTRACT FROM AUTHOR]

Small extracellular vesicles (sEVs) have burst into biomedicine as a natural therapeutic alternative for different diseases. Considered nanocarriers of biological origin, various studies have demonstrated the feasibility of their systemic administration, even with repeated doses. However, despite being the preferred route of physicians and patients, little is known about the clinical use of sEVs in oral administration. Different reports show that sEVs can resist the degradative conditions of the gastrointestinal tract after oral administration, accumulating regionally in the intestine, where they are absorbed for systemic biodistribution. Notably, observations demonstrate the efficacy of using sEVs as a nanocarrier system for a therapeutic payload to obtain a desired biological (therapeutic) effect. From another perspective, the information to date indicates that food-derived vesicles (FDVs) could be considered future nutraceutical agents since they contain or even overexpress different nutritional compounds of the foods from which they are derived, with potential effects on human health. In this review, we present and critically analyze the current information on the pharmacokinetics and safety profile of sEVs when administered orally. We also address the molecular and cellular mechanisms that promote intestinal absorption and that command the therapeutic effects that have been observed. Finally, we analyze the potential nutraceutical impact that FDVs would have on human health and how their oral use could be an emerging strategy to balance nutrition in people. [ABSTRACT FROM AUTHOR]

Bloodstream infections (BSIs) due to Gram‐positive organisms have traditionally been treated with prolonged courses of intravenous antimicrobials. However, this dogma is associated with substantial burden to the patient and health care system. Consequently, there is growing interest in the utilization of oral stepdown therapy, defined as the transition of intravenous therapy to an active oral agent, for this indication. This review highlights available literature examining oral stepdown in adult patients with BSI due to commonly encountered Gram‐positive pathogens, including Staphylococcus aureus, Streptococcus spp., and Enterococcus spp. Support for oral stepdown in this setting is primarily derived from observational studies subject to selection bias. Nevertheless, this treatment strategy exhibits promising potential in carefully selected patients as it is consistently associated with reductions in hospital length of stay without jeopardizing clinical cure or survivability. Prospective, randomized trials are needed for validation of oral stepdown in Gram‐positive BSI and to identify the optimal patient population and regimen. [ABSTRACT FROM AUTHOR]

Lipopolysaccharide (LPS), an endotoxin, induces systemic inflammation by injection and is thought to be a causative agent of chronic inflammatory diseases, including type 2 diabetes mellitus (T2DM). However, our previous studies found that oral LPS administration does not exacerbate T2DM conditions in KK/Ay mice, which is the opposite of the response from LPS injection. Therefore, this study aims to confirm that oral LPS administration does not aggravate T2DM and to investigate the possible mechanisms. In this study, KK/Ay mice with T2DM were orally administered LPS (1 mg/kg BW/day) for 8 weeks, and blood glucose parameters before and after oral administration were compared. Abnormal glucose tolerance, insulin resistance progression, and progression of T2DM symptoms were suppressed by oral LPS administration. Furthermore, the expressions of factors involved in insulin signaling, such as insulin receptor, insulin receptor substrate 1, thymoma viral proto-oncogene, and glucose transporter type 4, were upregulated in the adipose tissues of KK/Ay mice, where this effect was observed. For the first time, oral LPS administration induces the expression of adiponectin in adipose tissues, which is involved in the increased expression of these molecules. Briefly, oral LPS administration may prevent T2DM by inducing an increase in the expressions of insulin signaling-related factors based on adiponectin production in adipose tissues. [ABSTRACT FROM AUTHOR]

The use of nanoparticles as drug delivery systems has increased in importance in the last decades. Despite the disadvantages of difficulty swallowing, gastric irritation, low solubility, and poor bioavailability, oral administration stands out as the most widely used route for therapeutic treatments, though it may not always be the most effective route. The effect of the first hepatic pass is one of the primary challenges that drugs must overcome to carry out their therapeutic effect. For these reasons, controlled-release systems based on nanoparticles synthesized from biodegradable natural polymers have been reported to be very efficient in enhancing oral delivery in multiple studies. Chitosan has been shown to have an extensive variability of properties and roles in the pharmaceutical and health fields; of its most important properties are the ability to encapsulate and transport drugs within the body and enhance the drug interaction with the target cells, which improves the efficacy of the encapsulated drugs. The physicochemical properties of chitosan give it the ability to form nanoparticles through multiple mechanisms, which will be addressed in this article. The present review article focuses on highlighting the applications of chitosan nanoparticles for oral drug delivery. [ABSTRACT FROM AUTHOR]

The delivery of curcumin (CUR) using the solid dispersion system (CUR solid dispersions; C-SDs) has been shown to improve CUR bioavailability. However, it is unclear how different particle sizes of C-SDs affect the bioavailability and biological activities of CUR. Hence, we prepared C-SDs in different sizes using food-grade excipients and evaluated their bioavailability and biological activities. By pulverizing large particle sizes of C-SDs using zirconia beads, we successfully prepared C-SDs I-IV (particle size: (I) 120, (II) 447, (III) 987, (IV) 1910 nm). When administrated orally in rats, the bioavailability of CUR was increased with decreasing C-SDs size, most likely by improving its solubility in micelles. When administrated intravenously in rats, blood concentrations of CUR were increased with increasing particle size, suggesting that larger C-SDs presumably control the metabolic conversion of CUR. In RAW264 cells, more CUR was taken up by cells as their sizes reduced, and the more potent their anti-inflammatory activities were, suggesting that smaller C-SDs were taken up through a number of cellular uptake pathways. Altogether, the present study showed an evident effect of C-SDs size on their bioavailability and anti-inflammatory activities—information that serves as a basis for improving the functionality of CUR. [ABSTRACT FROM AUTHOR]

Abstract Overexpression of classically activated macrophages (M1) subtypes and assessed reactive oxygen species (ROS) levels are often observed in patients with ulcerative colitis. At present, the treatment system of these two problems has yet to be established. Here, the chemotherapy drug curcumin (CCM) is decorated with Prussian blue analogs in a straightforward and cost‐saving manner. Modified CCM can be released in inflammatory tissue (acidic environment), eventually causing M1 macrophages to transform into M2 macrophages and inhibiting pro‐inflammatory factors. Co(III) and Fe(II) have abundant valence variations, and the lower REDOX potential in CCM‐CoFe PBA enables ROS clearance through multi‐nanomase activity. In addition, CCM‐CoFe PBA effectively alleviated the symptoms of UC mice induced by DSS and inhibited the progression of the disease. Therefore, the present material may be used as a new therapeutic agent for UC.

Sun stroke the high emergency clinical condition is a cascade of six prominent symptom groups with failed gravity & intramuscular routes; gut constriction; grave prognosis. 2%KCL+5% NaCl +2% CaOH with diluted milk as vector is proposed. Institutional framework is absent. Nurses are called upon.

ABSTRACT Alcohol is an essential drug in human life with multiple medical functions, but excessive alcohol intake, even a single episode of binge drinking, can cause serious damage. Reducing alcohol consumption or absorption is a direct way to alleviate the related harm. Alcohol is decomposed successively by alcohol dehydrogenase (ADH) and acetaldehyde dehydrogenase (ALDH) in the liver. Here, we produced a human ADH1B (hADH1B)-expressing probiotic, a recombinant Lactococcus lactis, that aimed to enhance alcohol degradation in the intestinal tract after oral administration. Our results showed that the oral hADH1B-expressing probiotic reduced alcohol absorption, prolonged the alcohol tolerance time, and shortened the recovery time after acute alcohol challenge. More importantly, the liver and intestine were protected from acute injury caused by alcohol challenge. Therefore, the engineered probiotic has the potential to protect organ damage from alcohol consumption. Furthermore, this engineered probiotic may have beneficial effects on alcohol-related diseases such as alcoholic fatty liver disease. IMPORTANCE Alcohol plays an important role in medical treatment, culture, and social interaction. However, excessive alcohol consumption or improper alcohol intake patterns can lead to serious damage to health. Aiming to reduce the harm of alcohol consumption, we designed a recombinant probiotic expressing hADH1B. Our results showed that this recombinant probiotic can reduce alcohol absorption and protect the body from alcohol damage, including hangover, liver, and intestinal damage. Reducing alcohol damage is helpful to the health of people with difficulty in abstinence. The engineered probiotic may provide new strategies for treatment and prevention of the negative effects of alcohol, and it also has the potential for widespread application.

Orally administered compounds represent the great majority of all pharmaceutical compounds produced for human use and are the most popular among patients since they are practical and easy to self-administer. Following ingestion, orally administered drugs begin a “perilous” journey down the gastrointestinal tract and their bioavailability is modulated by numerous factors. The gastrointestinal (GI) tract anatomy can modulate drug bioavailability and accounts for interpatient drug response heterogeneity. Furthermore, host genetics is a contributor to drug bioavailability modulation. Importantly, a component of the GI tract that has been gaining notoriety with regard to drug treatment interactions is the gut microbiota, which shares a two-way interaction with pharmaceutical compounds in that they can be influenced by and are able to influence administered drugs. Overall, orally administered drugs are a patient-friendly treatment option. However, during their journey down the GI tract, there are numerous host factors that can modulate drug bioavailability in a patient-specific manner.

The montmorillonite-sodium alginate (MMT-SA) colon-targeting microcapsules have been designed as a WGX-50 encapsulation and controlled release vehicle used in oral administration. The MMT-SA microcapsule was formed from a cross-linking reaction, and the stable micropore in the microcapsule changed with a different MMT-SA mixed mass ratio. The MMT-SA microcapsule has a reinforced micropore structure and an enhanced swell–dissolution in SIF and SCF with alkaline environment, which is attributed to the incorporated MMT. The MMT-SA microcapsule exhibited a high WGX-50 encapsulation rate up to 98.81 ± 0.31% and an obvious WGX-50 controlled release in the simulated digestive fluid in vitro. The WGX-50 loaded with MMT-SA microcapsule showed a weak minimizing drug loss in SGF (Simulated Gastric Fluid) with an acidic environment, while it showed a strong maximizing drug release in SIF (Simulated Intestinal Fluid) and SCF (Simulated Colonic Fluid) with an alkaline environment. These features make the MMT-SA microcapsule a nominated vehicle for colon disease treatment used in oral administration.

Carvacryl acetate (CA) is a monoterpene obtained from carvacrol, which exhibits anti-inflammatory activity. However, its low solubility in aqueous media limits its application and bioavailability. Herein, we aimed to develop a carvacryl acetate nanoemulsion (CANE) and assess its anti-inflammatory potential in preclinical trials. The optimized nanoemulsion was produced by ultrasound, and stability parameters were characterized for 90 days using dynamic light scattering after hydrophilic–lipophilic balance (HLB) assessment. To evaluate anti-inflammatory activity, a complete Freund’s adjuvant-induced inflammation model was established. Paw edema was measured, and local interleukin (IL)-1β levels were quantified using ELISA. Toxicity was assessed based on behavioral changes and biochemical assays. The optimized nanoemulsion contained 3% CA, 9% surfactants (HLB 9), and 88% water and exhibited good stability over 90 days, with no signs of toxicity. The release study revealed that CANE followed zero-order kinetics. Dose–response curves for CA were generated for intraperitoneal and oral administration, demonstrating anti-inflammatory effects by both routes; however, efficacy was lower when administered orally. Furthermore, CANE showed improved anti-inflammatory activity when compared with free oil, particularly when administered orally. Moreover, daily treatment with CANE did not induce behavioral or biochemical alterations. Overall, these findings indicate that nanoemulsification can enhance the anti-inflammatory properties of CA by oral administration.

Cancer vaccines, a burgeoning strategy in cancer treatment, are exploring innovative administration routes to enhance patient and medical staff experiences, as well as immunological outcomes. Among these, oral administration has surfaced as a particularly noteworthy approach, which is attributed to its capacity to ignite both humoral and cellular immune responses at systemic and mucosal tiers, thereby potentially bolstering vaccine efficacy comprehensively and durably. Notwithstanding this, the deployment of vaccines through the oral route in a clinical context is impeded by multifaceted challenges, predominantly stemming from the intricacy of orchestrating effective oral immunogenicity and necessitating strategic navigation through gastrointestinal barriers. Based on the immunogenicity of the gastrointestinal tract, this review critically analyses the challenges and recent advances and provides insights into the future development of oral cancer vaccines.

Chronic osteomyelitis in adults is managed with prolonged courses of intravenous antibiotics in conjunction with surgical debridement of necrotic bone. Over the past 40 years, there has been no paradigm shift in this approach, as randomized controlled trials of this standard of care compared to alternatives such as prolonged oral antibiotics are scarce. However, there have been many small trials, case reports, and review papers evaluating the effectiveness of oral treatment for chronic osteomyelitis. The oral route for infections requiring prolonged treatment is intuitively and practically more favorable due to several advantages, the most important of which is the avoidance of long-term IV antimicrobial therapy with its complications, inconvenience, and cost. In this paper, we review the literature evaluating oral antibiotic therapy in the management of chronic bone infections since 1975. The majority of osteomyelitis infections are caused by Staphylococcus aureus, hence we focus on its treatment using oral antibiotics; however, we also emphasize subpopulations of patients with diabetes, implanted hardware, and with less common bacterial organisms. The primary objective of this review is to promulgate clinical recommendations on the use of oral antibiotics in bone infections in the context of initial therapy, transition from intravenous therapy, and the role of chronic suppression. The secondary objective is to summarize current knowledge of the specific oral antimicrobial agents that are commonly utilized, together with a synopsis of the available literature pertaining to their pharmacokinetic/pharmacodynamic properties and duration of therapy in bone infection.

Qingyun Yang,&ast; Jian Yang,&ast; Shuigen Sun, Jingyi Zhao, Shuang Liang, Yi Feng, Minchen Liu, Jiquan Zhang Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yi Feng; Jiquan Zhang, Engineering Research Center of Modern Preparation Technology of TCM of Ministry of Education, Shanghai University of Traditional Chinese Medicine, 1200 Cailun Road, Shanghai, 201203, People’s Republic of China, Tel +86-21-51322431 ; +86 13816062506, Email fyi@vip.sina.com; jqzhang@shutcm.edu.cnBackground: Rhodojaponin III (RJ-III) is a bioactive diterpenoid, which is mainly found in Rhododendron molle G. Don (Ericaceae), a potent analgesia in traditional Chinese medicine with several years of clinical applications in the country. However, its clinical use is limited by its acute toxicity and poor pharmacokinetic profiles. To reduce such limitations, the current study incorporated RJ-III into the colloidal drug delivery system of hydroxypropyl trimethyl ammonium chloride chitosan (HACC)-modified solid lipid nanoparticles (SLNs) to improve its sustained release and antinociceptive effects in vivo for oral delivery.Results: The optimized RJ-III@HACC-SLNs were close to spherical, approximately 134 nm in size, and with a positive zeta potential. In vitro experiments showed that RJ-III@HACC-SLNs were stable in the simulated gastric fluid and had a prolonged release in PBS (pH = 6.8). Pharmacokinetic results showed that after intragastric administration in mice, the relative bioavailability of RJ-III@HACC-SLNs was 87.9%. Further, it was evident that the peak time, half-time, and mean retention time of RJ-III@HACC-SLNs were improved than RJ-III after the administration. In addition, pharmacodynamic studies revealed that RJ-III@HACC-SLNs markedly reduced the acetic acid, hot, and formalin-induced nociceptive responses in mice (P < 0.001), and notably increased the analgesic time (P < 0.01). Moreover, RJ-III@HACC-SLNs not only showed good biocompatibility with Caco-2 cells in vitro but its LD50 value was also increased by 1.8-fold as compared with that of RJ-III in vivo.Conclusion: These results demonstrated that RJ-III@HACC-SLNs improved the pharmacokinetic characteristics of the RJ-III, thereby exhibiting toxicity-attenuating potential and antinociceptive enhancing properties. Consequently, HACC-SLNs loaded with RJ-III could become a promising oral formulation for pain management that deserves further investigation in the future.Graphical Abstract: Keywords: rhodojaponin III, multimodal antinociceptive, oral administration, solid lipid nanoparticles, hydroxypropyl trimethyl ammonium chloride chitosan, pharmacokinetic

Introduction/Background Vitiligo is an autoimmune disease characterized by depigmentation of skin due to the progressive loss of melanocytes. The often highly visible and chronic nature of vitiligo as well as its unpredictable disease course have negative psychosocial impacts on most patients, affecting quality of life. Disease pathogenesis is largely regulated by interferon-γ activation of the Janus kinase (JAK) signaling pathway. Povorcitinib is an oral, small-molecule, selective JAK1 inhibitor with potential activity in the treatment of nonsegmental vitiligo. Objectives To evaluate the efficacy and safety of povorcitinib in patients with extensive nonsegmental vitiligo in a phase 2b, dose-ranging study (NCT04818346). Methods Adults with nonsegmental vitiligo affecting ≥0.5% facial and ≥8% total body surface areas were eligible. Patients were randomized 1:1:1:1 to once daily povorcitinib 15/45/75 mg or placebo for 24 weeks; subsequently, patients received povorcitinib 45 or 75 mg for an additional 28 weeks, with a 24-week off-treatment follow-up period. The primary endpoint was the percentage change from baseline in total Vitiligo Area Scoring Index (T-VASI) at Week 24. Other endpoints included percentage of patients achieving ≥50% reduction from baseline in T-VASI (T-VASI50), ≥50%/≥75% reduction in facial VASI (F-VASI50/75), and safety. Results Of 171 randomized patients, 54.4% were female and 66.7% had Fitzpatrick skin types I–III. Median (range) age was 50 (23–74) years and disease duration was 16.4 (0.8–58.9) years. At Week 24, the primary efficacy endpoint, T-VASI percentage change from baseline with povorcitinib (15 mg, –19.1%; 45 mg, –17.8%; 75 mg, –15.7%; least square means povorcitinib vs placebo, P <0.01), was statistically superior to placebo (+2.3%). Percentages of patients achieving F-VASI50 at Week 24 were higher for povorcitinib (16.3%, 34.9%, and 23.8% for 15, 45, and 75 mg, respectively) than placebo (7.0%). Improved repigmentation was seen across treatment groups at Week 52; mean percentage changes from baseline in T-VASI for povorcitinib 15-to-75-mg, 45-mg, 75-mg, and placebo-to-75-mg subgroups were –40.7%, –42.7%, –41.3%, and –18.1%, respectively; F-VASI mean percentage changes from baseline were –63.6%, –63.8%, –64.4%, and –54.8%, respectively. T-VASI50 was achieved by 45.2%, 37.0%, 37.9%, and 15.2%; F-VASI50 by 71.0%, 77.8%, 69.0%, and 63.6%; and F-VASI75 by 48.4%, 55.6%, 58.6%, and 45.5% of patients, respectively. A total of 34 patients entered the follow-up period, with 32 completing Week 76. T-VASI mean percentage changes from baseline to Week 76 were –41.3%, –43.6%, –27.1%, and –34.8%, respectively; F-VASI mean changes were –48.9%, –63.0%, –46.4%, and –73.5%, suggesting durability of response after discontinuation of povorcitinib. Treatment-emergent adverse events (TEAEs) occurred in 89.2% and serious adverse events in 2.4% among patients who received povorcitinib 45 or 75 mg through 52 weeks. The most common TEAEs were COVID-19 (36.1%), blood creatine phosphokinase increased (13.3%), acne (12.0%), fatigue (10.8%), and headache (9.6%). Conclusions Oral povorcitinib was associated with substantial facial and total body repigmentation in patients with extensive nonsegmental vitiligo through 52 weeks of treatment in this phase 2b study. Patients who were off treatment for 24 weeks demonstrated durable response, maintaining their level of response achieved at Week 52. All doses of povorcitinib were generally well tolerated. [ABSTRACT FROM AUTHOR]

Introduction/Background Orismilast is a potent selective phosphodiesterase 4 (PDE4)-B and -D inhibitor, showing significant efficacy in a Phase 2b psoriasis study.1,2 PDE4-B and PDE4-D isoforms are over-expressed in the skin of patients with atopic dermatitis (AD), compared to healthy individuals.3 Enhanced PDE4 activity has also been observed in peripheral blood leukocytes in AD. Orismilast inhibits PDE4-B/D isoforms up to 39 times more potently than apremilast,1 leading to potent suppression of Th1, Th17, and Th2 effector cytokines.1 Objectives To evaluate efficacy and safety of orismilast versus placebo in adults with moderate-to-severe AD. Methods ADESOS is a 16-week, phase 2b, double-blinded, placebo-controlled, dose-finding study assessing efficacy and safety of orismilast in adults with moderate-to-severe AD. Patients were randomized (1:1:1:1) to orismilast 20, 30, 40 mg, or placebo, twice daily. Randomized and dosed patients were included in the Intent-to-Treat Population. Missing data were handled using Multiple Imputation (MI) for the analysis of primary and secondary efficacy endpoints. Results Baseline demographics and disease characteristics were generally balanced across groups for the 233 dosed patients. Significantly more patients achieved IGA0/1 responses at Week 16 in orismilast 20 (n=58), 30 (n=61), and 40 mg (n=59) groups, compared to placebo (n=55) (26.3%, 24.3%, 30.9%, and 9.5%, respectively; all p-values <0.05). All active arms demonstrated a significant ≥4-point reduction in itch NRS at Week 2, compared to placebo (p <0.05). Similarly, Patient Global Impression of Change of "much or very much improved" was significant in active arms compared to placebo at Week 16. Mean percentage changes in EASI at Week 16 were -55.1%, - 52.2%, -61.4%, and -50.4%, in orismilast 20, 30, 40 mg and placebo groups, respectively (p>0,05). Mean EASI at baseline was 23, the least severe reported in Phase 2b/3 studies in moderate-to-severe AD.4 In a subgroup analysis of patients with baseline EASI >21 separation from placebo was increased in the 20 and 40 mg arms, as patients on placebo achieving EASI75 and EASI90 were reduced by 50% and 67%, for the severe population versus the full population. At Week 16, percentages of patients experiencing any Treatment Emergent Adverse Event (TEAE) were orismilast 20 mg, 76%; 30 mg, 79%; 40 mg, 86%; and placebo, 64%. Infection rates were numerically lower in the orismilast groups compared to placebo groups. The most common TEAEs were diarrhea, nausea, and headache, mainly seen within the first month, mostly mild in severity, with few leading to treatment discontinuation. Conclusion Orismilast demonstrated early itch reduction NRS≥4 and statistically significant efficacy versus placebo at Week 16 as measured by IGA0/1. The study was impacted by a high EASI placebo rate; however, in severe patients, the 20 and 40 mg doses separated from placebo for EASI75 and EASI90 measurements, consistent with the overall findings as measured by IGA 0/1, patient-reported efficacy, and objective biomarkers. No new safety signals were identified, and the profile was aligned with the well-established experience from the PDE4 inhibitor class. The most frequent TEAEs were gastrointestinal-related and headache. These data confirm the clinical relevance of high potency PDE4B/D selective inhibition with orismilast, potentially offering a convenient, novel, oral therapy for the treatment of AD and other inflammatory diseases. [ABSTRACT FROM AUTHOR]

Although Steamed Codonopsis lanceolata (SCL) has been shown to protect against acute kidney injury (AKI), Its poor stability and susceptibility to decomposition in the GI tract significantly reducing its therapeutic efficacy. Nanoscale/microscale drug delivery systems may overcome the difficulties of oral administration of phytochemicals and avoid premature drug release and degradation. In this study, we mainly loaded SCL into sodium alginate (SA) micron particles (SCL-SA), which showed significant gut-targeting and anti-gastric acid ability from in vitro and in vivo imaging fluorescence adhesion experiments. Our results showed that the levels of serum blood urea nitrogen (BUN) and creatinine (CRE) were evidently increased in cisplatin-intoxicated mice, which were reversed by SCL-SA. Renal oxidative stress, evidenced by increasing malondialdehyde (MDA) level and decrease of glutathione (GSH), catalase (CAT) and superoxide dismutase (SOD) activities, were significantly alleviated by SCL-SA pretreatment. Immunohistochemical staining showed that SCL-SA could improve cell apoptosis by decrease the expressions of BCL2-Associated X (Bax) and B-cell lymphoma-2 (Bcl-2). In addition, SCL-SA pretreatment can also inhibit the increase of serum tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) induced by cisplatin. Additionally, SCL-SA was found to reduce the expressions of nuclear factor-κB (NF-κB) signal pathways and inflammatory protein levels of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) induced by cisplatin. Meanwhile, the contents of lobetyolin and syringin in Codonopsis lanceolata were increased after steaming. In conclusion, the reduction of AKI by SCL-SA may be due to the synergistic effect of lobetyolin and syringin. Based on the advantages of microparticles, this study provides important insights into the treatment of AKI with oral natural compounds.

Methotrexate (MTX) by oral taking has been employed as the first‐line medication for various chronic inflammatory diseases treatment, such as Crohn's disease and rheumatoid arthritis (RA). However, the oral administration of MTX has very limited clinical benefits and will be discontinued due to the suboptimal response and severe adverse effects on intestinal mucosa. Herein, a multistage albumin nanomedicine depot (denoted as MAND) is formulated by encapsulating MTX‐loaded human serum albumin nanoparticles (MTX@HSA NPs) into calcium alginate chitosan microcapsules using a gas‐shearing technology. The MANDs can provide protection to MTX@HSA NPs with well‐persisted biologic activity against gastric acid erosion and realize specific boost release of MTX@HSA NPs in the intestinal tract in response to the mild basic circumstance. The MTX@HSA NPs absorbed by intestine can selectively accumulate in inflammation lesion by exploiting the inflammation targeting ability of HSA. In the animal experiments, the MANDs show improved therapeutic efficacy for the treatment of both RA and colitis with minimized intestinal side effects in respect to the free MTX by oral administration. Therefore, this conceived oral MANDs can promote a more clinic popularity and enhanced benefits of MTX for the treatment of chronic inflammatory diseases. [ABSTRACT FROM AUTHOR]

Here, we report on the development of lipid-based nanostructures containing zidovudine (1 mg/mL) and lamivudine (0.5 mg/mL) for oral administration in the pediatric population, eliminating the use of organic solvents, which is in accordance with green chemistry principles. The formulations were obtained by ultrasonication using monoolein (MN) or phytantriol (PN), which presented narrow size distributions with similar mean particle sizes (~150 nm) determined by laser diffraction. The zeta potential and the pH values of the formulations were around −4.0 mV and 6.0, respectively. MN presented a slightly higher incorporation rate compared to PN. Nanoemulsions were obtained when using monoolein, while cubosomes were obtained when using phytantriol, as confirmed by Small-Angle X-ray Scattering. The formulations enabled drug release control and protection against acid degradation. The drug incorporation was effective and the analyses using an electronic tongue indicated a difference in palatability between the nanotechnological samples in comparison with the drug solutions. In conclusion, PN was considered to have the strongest potential as a novel oral formulation for pediatric HIV treatment. [ABSTRACT FROM AUTHOR]

We evaluated the whole-body distribution of orally-administered radioiodine-125 labeled acetaminophen (125I-AP) to estimate gastrointestinal absorption of anionic drugs. 125I-AP was added to human embryonic kidney (HEK)293 and Flp293 cells expressing human organic anion transporting polypeptide (OATP)1B1/3, OATP2B1, organic anion transporter (OAT)1/2/3, or carnitine/organic cation transporter (OCTN)2, with and without bromosulfalein (OATP and multidrug resistance-associated protein (MRP) inhibitor) and probenecid (OAT and MRP inhibitor). The biological distribution in mice was determined by oral administration of 125I-AP with and without bromosulfalein and by intravenous administration of 125I-AP. The uptake of 125I-AP was significantly higher in HEK293/OATP1B1, OATP1B3, OATP2B1, OAT1, and OAT2 cells than that in mock cells. Bromosulfalein and probenecid inhibited OATP- and OAT-mediated uptake, respectively. Moreover, 125I-AP was easily excreted in the urine when administered intravenously. The accumulation of 125I-AP was significantly lower in the blood and urinary bladder of mice receiving oral administration of both 125I-AP and bromosulfalein than those receiving only 125I-AP, but significantly higher in the small intestine due to inhibition of OATPs and/or MRPs. This study indicates that whole-body distribution after oral 125I-AP administration can be used to estimate gastrointestinal absorption in the small intestine via OATPs, OATs, and/or MRPs by measuring radioactivity in the urinary bladder. [ABSTRACT FROM AUTHOR]

(1) Background: Many drugs possess poor bioavailability, and many strategies are available to overcome this issue. In this study, smartFilm technology, i.e., a porous cellulose matrix (paper), in which the active compound can be loaded onto in an amorphous state was utilised for oral administration to improve the solubility and bioactivity of a poorly soluble BSC class IV antibiotic. (2) Methods: Norfloxacin was used as the model drug and loaded into commercially available paper. The resulting norfloxacin-loaded smartFilms were transformed into smartFilm granules via wet granulation and the resulting norfloxacin-loaded smartFilm granules were transformed into norfloxacin-loaded tablets made from paper, i.e., smartFilm tablets. The crystalline state of norfloxacin was investigated, as well as the pharmaceutical properties of the granules and the tablets. The bioactivity of the smartFilm tablets was assessed in vitro and ex vivo to determine the antibacterial activity of norfloxacin. The results were compared to a physical mixture tablet that contained non-loaded paper granules and equal amounts of norfloxacin as a crystalline powder. (3) Results: Norfloxacin-loaded smartFilm granules and norfloxacin-loaded smartFilm tablets contained norfloxacin in an amorphous state, which resulted in an improved and faster release of norfloxacin when compared to the physical mixture tablet. The bioactivity was up to three times higher when compared to the physical mixture tablet. The ex vivo model was demonstrated to be a useful tool that allows for a fast and cost-effective discrimination between "good" and "bad" formulations. It provides realistic physiological conditions and can therefore yield meaningful, additional biopharmaceutical information that cannot be assessed in classical in vitro experiments. (4) Conclusions: smartFilm tablets are a promising, universal, industrially feasible and cost-effective formulation strategy for improved solubility and enhanced bioactivity of poorly soluble drugs. [ABSTRACT FROM AUTHOR]

Di (2-ethylhexyl) phthalate (DEHP) is one of the most prevalent xenoestrogen endocrine disruptor in daily life. A growing number of studies showed that DEHP could exhibit long-term adverse health effects on the human body, particularly in the liver, kidneys, heart and reproductive systems. However, the impact of oral intake of DEHP on the nervous system is extremely limited. In the present study, the adult C57BL/6J male mice were intragastrically administered with two dosages of DEHP for 35 days. The behavioral parameters were assessed using the elevated plus maze and open-field test. The mRNA expression levels of neuropeptides and the oxidative stress-associated proteins were detected by qPCR and western blot seperately. The histopathologic alterations of the brain were observed by H&E and Nissl staining. The results demonstrated that DEHP exposure could result in neurobehavioral impairments such as locomotor increase and anxiety-like behavior. Furthermore, pathological damages were clearly observed in the cerebral cortex and hippocampus, accompanied by a decrease in neuropeptides and an increase in oxidative stress, which were all positively correlated with the dose of DEHP. Together, these findings provide valuable clues into the DEHP-induced neurotoxicity. [ABSTRACT FROM AUTHOR]

Cryptotanshinone (CTS) is a plant product extracted from Salvia miltiorrhiza Bunge with various pharmacological significances. In addition to its activities against coronary heart disease, hyperlipidemia, stroke, hepatitis and chronic renal failure, it demonstrates antimetastatic effects. However, its clinical use is limited due to its poor aqueous solubility and oral bioavailability. Herein, CTS nanocrystals were prepared with the precipitation method followed by high-pressure homogenization using Poloxamer 407 as the stabilizer. A stable product was further obtained by lyophilization. The particle size of the CTS nanocrystals was 315.67 ± 11.02 nm, and the zeta potential was near 0 mV. The crystallinity was confirmed by DSC and PXRD. The saturation solubility was substantially increased from 0.97 ± 0.12 µg/ml to 62.29 ± 1.91 µg/ml, and the dissolution rate was also significantly accelerated. A pharmacokinetic study in rats revealed an improvement in oral bioavailability (2.87-fold) with CTS nanocrystals compared to the raw drug. In conclusion, the results of this study suggest a feasible formulation for the oral delivery of CTS. [ABSTRACT FROM AUTHOR]

Simple Summary: The use of a dietary supplement containing S-acetyl-glutathione (SAG), silybin, and other antioxidant ingredients increased the level of erythrocyte glutathione (GSH) and improved key biochemical parameters in dogs with liver disease. Oxidative stress is often involved in liver disease progression. Liver is the primary site for the synthesis of glutathione (GSH), the major intracellular antioxidant. GSH erythrocyte concentration can decrease in case of liver damage. So, the use of food supplements with antioxidant capacity has been reported in the veterinary literature. In this case–control study, we tested a new supplement containing S-acetyl-glutathione (SAG), silybin, and other antioxidant ingredients in dogs affected by liver disease. After two weeks of supplement administration, we were able to report a significant increase in the level of erythrocyte GSH in the treated (TRT) group, nearly reaching the physiological limit at the end of the study. In addition, most of the key liver parameters are significantly reduced in the TRT group by the end of the trial. The results of this study support the effectiveness of the tested complementary feed, which may be helpful in managing dogs with liver conditions. [ABSTRACT FROM AUTHOR]

Sacha inchi is a plant native to the Peruvian Amazon. The oil obtained from its seeds contains high levels of alpha-linolenic acid and linoleic acid, which may provide protective effects against inflammation, cardiovascular disease, and cancer. In Cuba, the plant has been cultivated and the oil has been obtained, so it is important to carry out preclinical studies to evaluate its toxicity. The objective of this work was to determine the toxic effects of Sacha inchi oil, after a single oral administration to NMRI mice of both sexes. The dose administered to the animals was 2000 mg/kg of body weight, then they were observed at different intervals during the first 24 hours and daily for up to 14 days. Body weight was recorded at the beginning, after seven days and at the end of the experience, and food consumption was controlled throughout the experience. There were no deaths or signs indicative of toxicity in any animal. No macroscopic findings were observed during necropsy. In the analysis of body weight and food consumption there were no significant differences between the treated groups and the controls. The administration of single oral doses of Sacha inchi oil to NMRI mice did not show signs indicative of toxicity in either sex, showing an acute oral toxicity greater than 2000 mg/kg of body weight, so according to the method of the acute toxicity classes is not classifiable. [ABSTRACT FROM AUTHOR]

The two-spotted spider mite (TSSM), Tetranychus urticae Koch (Acari: Tetranychidae), is an agricultural pest distributed almost worldwide. Because of the frequent use of synthetic pesticides for its control, it has developed resistance to almost all types of active ingredients, making its chemical control very difficult. RNA interference (RNAi) is a sequence-specific gene silencing process triggered by double-stranded RNA (dsRNA). Since RNAi is induced in TSSM by orally ingested dsRNA, the use of dsRNA with sequences specific to essential genes in TSSM has potential as an alternative to synthetic pesticides. Here, we evaluated the effects of RNAi targeting the TSSM gene encoding a β-adrenergic-like octopamine receptor (TuOctβ2R), a target of the synthetic pesticide amitraz, by oral administration of dsRNA for the gene (dsTuOctβ2R). Survival and fecundity rates and feeding activity in mites fed on dsTuOctβ2R were significantly lower than those in a control group fed on dsRNA targeting an intergenic region, even in an amitraz-resistant population. Mites fed on dsTuOctβ2R moved significantly faster than the controls, suggesting that downregulation of TuOctβ2R induces hyperactivity while suppressing feeding behavior. These results indicate that the TuOctβ2R gene is a possible candidate for RNAibased biopesticides to control TSSM. [ABSTRACT FROM AUTHOR]

Paroxetine is a one of well-known anti-depressant but due to extensive hepatic first pass metabolism it suffers with shortcoming of poor oral bioavailability. Aim of current study was to develop and evaluate paroxetine loaded SNEDDS to increase oral bioavailability. SNEDDS were formulated by using caproyl 90 as oil phase, Cremophore EL as surfactant and propylene glycol as co-surfactant. Optimized SNEDDS exhibited spherical globules with diameter of 67.17 nm, PDI of 0.283 and zeta potential values of − 13.7 mV. SNEDDS showed good transmittance (higher than 99%). Enhanced paroxetine release was obtained with SNEDDS. Intestinal permeability studies and everted gut sac studies showed that there was increment in drug permeation in case of paroxetine loaded SNEDDS as compared to suspension. Results of behavioural study revealed that the depressed rats received paroxetine SNEDDS orally improved the behavioural activities in comparison to drug suspension by decreasing depletion of serotonin and norepinephrine therefore assisting in treatment of depression. Pharmacokinetic studies indicated that oral bioavailability of paroxetine SNEDDS increased 2.3 times as compared to paroxetine suspension. Cell line toxicity confirmed no sign of toxicity of developed formulation. In this way, oral paroxetine SNEDDS delivery can play a critical role in improving depression management. [ABSTRACT FROM AUTHOR]