Rate Of Oral Absorption Research Articles

Computational and ADMET Predictions of Novel Compounds as Dual Inhibitors of BuChE and GSK-3β to Combat Alzheimer's Disease.

Alzheimer's disease is a serious and widespread neurodegenerative illness in the modern healthcare scenario. GSK-3β and BuChE are prominent enzymatic targets associated with Alzheimer's disease. Co-targeting GSK3β and BChE in Alzheimer's disease helps to modify disease progression and enhance cognitive function by addressing both tau pathology and cholinergic deficits. However, the treatment arsenal for Alzheimer's disease is extremely inadequate, with present medications displaying dismal success in treating this never-ending ailment. To create novel dual inhibitors, we have used molecular docking and dynamics analysis. Our focus was on analogs formed from the fusion of tacrine and amantadine ureido, specifically tailored to target GSK-3β and BuChE. In the following study, molecular docking was executed by employing AutoDock Vina and molecular dynamics and ADMET predictions were performed using the Desmond and Qikprop modules of Schrödinger. Our findings unveiled that compounds DKS1 and DKS4 exhibited extraordinary molecular interactions within the active domains of GSK-3β and BuChE, respectively. These compounds engaged in highly favorable interactions with critical amino acids, including Lys85, Val135, Asp133, and Asp200, and His438, Ser198, and Thr120, yielding encouraging docking energies of -9.6 and -12.3 kcal/mol. Additionally, through extensive molecular dynamics simulations spanning a 100 ns trajectory, we established the robust stability of ligands DKS1 and DKS4 within the active pockets of GSK-3β and AChE. Particularly noteworthy was DKS5, which exhibited an outstanding human oral absorption rate of 79.792%, transcending the absorption rates observed for other molecules in our study. In summary, our in silico findings have illuminated the potential of our meticulously designed molecules as groundbreaking agents in the fight against Alzheimer's disease, capable of simultaneously inhibiting both GSK-3β and BuChE.

Quality-by-Design-Driven Nanostructured Lipid Scaffold of Apixaban: Optimization, Characterization, and Pharmacokinetic Evaluation.

Apixaban, an anticoagulant, is limited in its efficacy due to poor solubility, low bioavailability, and extensive metabolism. This study investigates the application of nanostructured lipid carriers (NLCs) to enhance the bioavailability of Apixaban. NLCs were prepared using the high-pressure homogenization method. The influence of independent variables, viz., the amount of Tween 80, HPH pressure, and the number of HPH cycles, were studied using a 23 factorial design. The average particle size, PDI, zeta potential, and entrapment efficiency of the optimized NLCs were found to be 232 ± 23 nm, with 0.514 ± 0.13 PDI and zeta potential of about -21.9 ± 2.1 mV, respectively. Additionally, concerning the thermal and crystallographic properties of the drug, the NLCs showed drug entrapment without altering its potency. The in-vitro drug release studies revealed an immediate release pattern, followed by sustained release for up to 48 h. In-vivo pharmacokinetic experiments demonstrated that Apixaban-loaded NLCs exhibited higher values of t1/2 (27.76 ± 1.18 h), AUC0-∞ (19,568.7 ± 1067.6 ng·h/mL), and Cmax (585.3 ± 87.6 ng/mL) compared to free drugs, indicating improved bioavailability. Moreover, a decrease in the elimination rate constant (Kel) reflected the sustained effect of Apixaban with NLCs. NLCs offer improved oral absorption rates and enhanced therapeutic impact compared to free drugs, potentially reducing dose frequency and improving patient outcomes.

Computational Investigation of Novel Compounds as Dual Inhibitors of AChE and GSK-3β for the Treatment of Alzheimer's Disease

Background: Alzheimer's disease (AD) stands out as one of the most devastating and prevalent neurodegenerative disorders known today. Researchers have identified several enzymatic targets associated with AD among which Glycogen synthase kinase-3β (GSK-3β) and Acetylcholinesterase (AChE) are prominent ones. Unfortunately, the market offers very few drugs for treating or managing AD, and none have shown significant efficacy against it. Objectives: To address this critical issue, the design and discovery of dual inhibitors will represent a potential breakthrough in the fight against AD. In the pursuit of designing novel dual inhibitors, we explored molecular docking and dynamics analyses of tacrine and amantadine uredio-linked amide analogs such as GSK-3β and AChE dual inhibitors for curtailing AD. Tacrine and adamantine are the FDA-approved drugs that were structurally modified to design and develop novel drug candidates that may demonstrate concurrently dual selectivity towards GSK-3β and AChE. Methods: In the following study, molecular docking was executed by employing AutoDock Vina, and molecular dynamics and ADMET predictions were made using Desmond, Qikprop modules of Schrödinger. Results: Our findings revealed that compounds DST2 and DST11 exhibited remarkable molecular interactions with active sites of GSK-3β and AChE, respectively. These compounds effectively interacted with key amino acids, namely Lys85, Val135, Asp200, and Phe295, resulting in highly favourable docking energies of -9.7 and -12.7 kcal/mol. Furthermore, through molecular dynamics simulations spanning a trajectory of 100 ns, we confirmed the stability of ligands DST2 and DST11 within the active cavities of GSK-3β and AChE. The compounds exhibiting the most promising docking results also demonstrated excellent ADMET profiles. Notably, DST21 displayed an outstanding human oral absorption rate of 76.358%, surpassing the absorption rates of other molecules. Conclusion: Overall, our in-silico studies revealed that the designed molecules showed potential as novel anti-Alzheimer agents capable of inhibiting both GSK-3β and AChE simultaneously. So, in the future, the designing and development of dual inhibitors will harbinger a new era of drug design in AD treatment.

α-Glucosidase inhibitory potential of Oroxylum indicum using molecular docking, molecular dynamics, and in vitro evaluation

BackgroundAccording to the International Diabetes Federation, there will be 578 million individuals worldwide with diabetes by 2030 and 700 million by 2045. One of the promising drug targets to fight diabetes is α-glucosidase (AG), and its inhibitors may be used to manage diabetes by reducing the breakdown of complex carbohydrates into simple sugars. The study aims to identify and validate potential AG inhibitors in natural sources to combat diabetes. MethodsComputational techniques such as structure-based virtual screening and molecular dyncamic simulation were employed to predict potential AG inhibitors from compounds of Oroxylum indicum. Finally, in silico results were validated by in vitro analysis using n-butanol fraction of crude methanol extracts. ResultsThe XP glide scores of top seven hits OI_13, OI_66, OI_16, OI_44, OI_43, OI_20, OI_78 and acarbose were –14.261, –13.475, –13.074, –13.045, –12.978, –12.659, –12.354 and –12.296 kcal/mol, respectively. These hits demonstrated excellent binding affinity towards AG, surpassing the known AG inhibitor acarbose. The MM-GBSA dG binding energies of OI_13, OI_66, and acarbose were −69.093, −62.950, and −53.055 kcal/mol, respectively. Most of the top hits were glycosides, indicating that active compounds lie in the n-butanol fraction of the extract. The IC50 value for AG inhibition by n-butanol fraction was 248.1 μg/ml, and for that of pure acarbose it was 89.16 μg/ml. The predicted oral absorption rate in humans for the top seven hits was low like acarbose, which favors the use of these compounds as anti-diabetes in the small intestine. ConclusionIn summary, the study provides promising insights into the use of natural compounds derived from O. indicum as potential AG inhibitors to manage diabetes. However, further research, including clinical trials and pharmacological studies, would be necessary to validate their efficacy and safety before clinical use.

The influence of natural polymers on loratadine's solubility and dissolution profiles.

Second-generation tricyclic H1 antihistamine loratadine (LTD) has a high permeability, low water solubility, and an oral absorption rate dependent on the rate at which it dissolves in the gastrointestinal tract. One approach suggested for improving the drug's solubility and rate of dissolution is natural solid dispersion (NSD). The present study evaluated the use of hydrophilic natural polymers, sodium alginate (SA), hyaluronic acid (HA), and xyloglucan (XG), in natural solid dispersion to enhance LTD solubility and dissolution rate. A total of 12 formulations comprising varied drug-to-polymer ratios were produced and analyzed for percentage yield, water solubility, and in vitro dissolution rate. The solubility of LTD was improved in all formulations. Excellent results were achieved with NSD1 (LTD: SA 1:0.25), with a high yield (99%), superior solubility (0.187) compared to pure loratadine (0.0021), and a speedy dissolution rate (98%) within 30 minutes. These studies suggest natural polymers like SA, HA, and XG can considerably increase LTD solubility. When introduced into NSD, these polymers effectively augment LTD dissolving rates, presenting attractive prospects for better bioavailability and therapeutic efficacy.

BIOANALYTICAL METHOD DEVELOPMENT AND VALIDATION OF 2-(4-ETHOXYPHENYL SULPHONAMIDO) PENTANE-DIAMIDE, A NOVEL ANTITUMOR AND ANTIANGIOGENIC AGENT, IN RAT SERUM AND APPLICATION OF THE METHOD IN DETERMINATION OF PHARMACOKINETIC PARAMETERS

Objective: The present study focuses on the development and validation of a bioanalytical method for the quantification of 2-(4-ethoxyphenyl sulphamido) pentane-diamide, a candidate antitumor and antiangiogenic agent, in rat serum. The developed method was subsequently applied to determine the pharmacokinetic parameters of the compound. Methods: To quantify the compound and determine its pharmacokinetic properties in rats, a liquid chromatography-mass spectrometry (LC-MS) bioanalytical method has been developed and the pharmacokinetic parameters were computed by compartmental model analysis. Results: A linear relationship was detected within the concentration range of 10 to 5000 ng/ml prepared by adding standard solutions of the test compound to the pooled serum of 10 SD rats, which exhibits high levels of precision, accuracy, and reproducibility. An appreciable recovery in the range of 97.20±0.63 to 93.22±1.48 percent was determined, with no noticeable impact from the matrix. The pharmacokinetic parameters, namely oral absorption rate constant (Ka) (5.054±0.238 1/h), elimination rate constant (KE) (2.585±0.357 h), volume of distribution (V) (8.173±0.333 L/kg), and bioavailability of (73.2%), were determined by the utilization of PK-solver software. Conclusion: We developed a simple yet precise and validated LC-MS method to analyze the drug candidate in rat serum. Simple protein precipitation and extraction were cost-effective. This bioanalytical approach was successful due to its good linearity, high recoveries, no matrix influence, and matrix stability. PK solver derived I. V. and oral pharmacokinetics parameters from the best-fit one-compartment model. Because of its high oral absorption, biological half-life, and bioavailability, the compound is suitable for oral administration.

Enhancing oral bioavailability of Ca-DTPA by self double emulsifying drug delivery system (SDEDDS)

Objective BCS class III drug (highly soluble, poorly permeable) possesses low oral bioavailability. The research work highlights the utility of self-double emulsifying drug delivery system (SDEDDS) which are stable isotropic mixture of w/o primary emulsion and hydrophilic surfactants for improving oral bioavailability of Ca-DTPA (Calcium diethylenetriamine pentaacetate). Upon oral administration, SDEDDS rapidly emulsifies into w/o/w double emulsions in the aqueous gastrointestinal environment, with hydrophilic drugs entrapped inside oil reservoirs. Methods SDEDDS formulation was successfully developed using excipients, that is, medium chain triglycerides, oleic acid, phospholipids, Span 80, Tween 80 using double emulsification technique. Results The optimized formulation F4 (Aq. phase: 11.6%w,w; MCT & oleic acid: 70.9%w/w; Span 80:17.5%w/w; Lecithin:16%w/w and Tween 80 (10%w/w)) appeared bright yellow liquid which upon dilution appeared milky white within 2 min, droplet size (501.7 nm), pdi value (0.044), zeta potential (-52 mV), entrapment efficiency (79.6 ± 1.63), viscosity (72.2 ± 1.8 mpA.s), significant high cumulative in vitro drug permeation (CDP) and 2.17-fold increase in apparent permeability coefficient. Pharmacokinetic studies in rats showed 1.17-fold increases in AUC of F4 and comparatively higher plasma levels (Cmax) compared with pure drug administered orally. The Absolute (OF4, OD) and Relative bioavailability was found to be 14.52%, 12.35%, and 117.47%, respectively. Conclusion The present studies have clearly demonstrated that SDEDDS could readily form w/o/w double emulsions in vivo with enhanced in vitro and in vivo oral bioavailability. Therefore, considerable augmentation in the rate and extent of oral drug absorption ratified the better performance of the SDEDDS in enhancing the bioavailability of Ca-DTPA.

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.

Oral bioavailability and egg drug residue of lincomycin in laying hens after different treatment

Lincomycin (LCM) is an antibiotic used to treat severe bacterial infections in livestock and companion animals. In this study, we aimed to investigate the oral bioavailability of LCM with PK data after IV and PO administration and to compare differences in drug residue patterns in eggs. To ensure food safety, an additional study on egg residue was conducted using 3 different commercial LCM drugs. For bioavailability study, laying hens were divided into oral and intravenous (n=8/group) groups and received single dose (10 mg/kg) of LCM. The limits of quantification for LCM were 0.729 μg/mL and 0.009 mg/kg in plasma and eggs, respectively. The oral group exhibited a significantly lower average serum drug concentration than the IV group, with a bioavailability of 2.6%. Furthermore, the egg residue profiles confirmed reduced systemic drug exposure after oral administration. For the commercial LCM drug egg residue experiment, laying hens were divided into low- and high-dose groups (n=12/group) for each drug and treated with the recommended dosage and administration method for each respective drug. The eggs were collected and analyzed until 14 d after the last drug treatment. Despite differences in the LCM content and formulation among commercial drugs, all the tested commercial drugs showed average concentrations below the MRL in eggs within approximately 3 d after the last drug treatment. In this study, we have confirmed that LCM has a low oral absorption rate in laying hens, and this was consistent with the findings from the egg residue profiles. Further studies are requested to elucidate the exact reasons for evidently low oral drug absorption in laying hens.

New sulfonamide derivatives based on 1,2,3-triazoles: synthesis, in vitro biological activities and in silico studies

Eight new hybrid constructs containing a series of sulfonamide and 1,2,3-triazole units were designed and synthesized. Anticancer, antioxidant and cholinesterase activities of these hybrid structures were investigated. In our design, the Cu(I)-catalyzed click reaction between N,4-dimethyl-N-(prop-2-yn-1-yl)benzenesulfonamide (6) and aryl azides 8a–h was used. Antioxidant activity values of 9f (IC50: 229.46 ± 0.001 μg/mL) and 9h (IC50: 254.32 ± 0.002 μg/mL) hybrid structures were higher than BHT (IC50: 286.04 ± 0.003 μg/mL) and lower than Ascorbic acid (IC50: 63.53 ± 0.001 μg/mL) and α-Tocopherol (IC50: 203.21 ± 0.002 μg/mL). We determined that the cytotoxic effects of hybrid constructs 9d (IC50: 3.81 ± 0.1084 µM) and 9g (IC50: 4.317 ± 0.0367 µM) against A549 and healthy cell line (HDF) are much better than standard cisplatin (IC50: 6.202 ± 0.0705 µM). It was determined that the AChE inhibitory activities of all synthesized compounds were much better than Galantamine used as a standard. In particular, 9c (IC50: 13.81 ± 0.0026 mM) had ten times better activity than the standard Galantamine (IC50: 136 ± 0.008 mM). The ADMET properties of the molecules have been thoroughly examined and met the criteria for drug-like substances. They also have a high oral absorption rate, as they can effectively cross the blood–brain barrier and are easily absorbed in the gastrointestinal tract. In vitro experiments were confirmed by in silico molecular docking studies. Communicated by Ramaswamy H. Sarma

Selective Delivery of Tofacitinib Citrate to Hair Follicles Using Lipid-Coated Calcium Carbonate Nanocarrier Controls Chemotherapy-Induced Alopecia Areata.

Chemotherapy-induced alopecia (CIA) is one of the common side effects in cancer treatment. The psychological distress caused by hair loss may cause patients to discontinue chemotherapy, affecting the efficacy of the treatment. The JAK inhibitor, Tofacitinib citrate (TFC), showed huge potential in therapeutic applications for treating baldness, but the systemic adverse effects of oral administration and low absorption rate at the target site limited its widespread application in alopecia. To overcome these problems, we designed phospholipid-calcium carbonate hybrid nanoparticles (PL/ACC NPs) for a topical application to target deliver TFC. The results proved that PL/ACC-TFC NPs showed excellent pH sensitivity and transdermal penetration in vitro. PL/ACC NPs offered an efficient follicular targeting approach to deliver TFC in a Cyclophosphamide (CYP)-induced alopecia areata mouse model. Compared to the topical application of TFC solution, PL/ACC-TFC NPs significantly inhibited apoptosis of mouse hair follicles and accelerated hair growth. These findings support that PL/ACC-TFC NPs has the potential for topical application in preventing and mitigating CYP-induced Alopecia areata.

Medicinal plant-based drug delivery system for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a chronic recurrent intestinal disease. The incidence rate of IBD is increasing year by year, which seriously endangers human health worldwide. More and more studies have shown that medicinal plants or their main phytochemicals have great potential in the treatment of intestinal diseases. However, the disadvantages of low oral absorption rate, low biological distribution and low systemic bioavailability limit their clinical application to a certain extent. In recent years, the application of nanotechnology has made it possible to treat IBD. Nanoparticles (NPs) drug delivery system has attracted special attention in the treatment of IBD due to its small size, low immunogenicity, surface modification diversity, targeting and other advantages. Synthetic nanoparticles and extracellular vehicles (EVs) can deliver drug components to colon, and play a role in anti-inflammation, regulation of oxidative stress, improvement of intestinal flora, etc. In addition, some medicinal plants can secrete EVs by themselves, and carry biological molecules with therapeutic effects to act on the intestine. Some clinical trials to evaluate the safety, tolerance, toxicity and effectiveness of EVs-loaded drugs in IBD are also progressing steadily. This review introduces that synthetic nanoparticles and medicinal plants derived EVs can play an important role in the treatment of IBD by carrying the effective active phytochemicals of medicinal plants, and discuss the limitations of current research and future research needs, providing a scientific and reliable basis and perspective for further clinical application and promotion.

Virtual screening for novel FGFR2 inhibitors: Exploring Gefitinib-like compounds as promising therapeutic candidates

Gefitinib, an established anticancer medication targeting Epidermal Growth Factor Receptor (EGFR), has faced challenges due to tumor resistance and relapse over time. A notable factor in Gefitinib resistance is the elevated expression of FGFR2. Combining Gefitinib with an FGFR2 inhibitor has been proposed to counteract this resistance and prolong the efficacy of EGFR-targeted therapy.To identify potential FGFR2 inhibitors, our study adopted a virtual screening approach using the PubChem database and a KNIME Workflow to filter compounds for Lipinski Violations. These selected compounds underwent evaluation for their binding affinity to FGFR2, with the aid of the AutoQSAR module to predict bioactivity. For comparison, Derazantinib, a known FGFR2-targeting anticancer agent, was used as a benchmark. Moreover, bioisosteric replacements were conducted for the top two compounds to enhance ADMET profiles and binding affinity.Results indicated that the leading compounds exhibited notably improved binding affinities toward FGFR2, surpassing Derazantinib's performance. These compounds engaged in significant interactions with specific amino acids, such as ASP 644, LYS 157, ASN 157, and TYR 566, forging unique connections. Additionally, ADMET predictions highlighted favorable oral absorption rates exceeding 75% for all tested compounds, including Derazantinib. Also, the bioisosteres demonstrated enhanced binding affinity compared to the original structures.This study uncovers potential FGFR2 inhibitors with good binding affinities, shedding light on their interactions with the target protein. While promising, further in vivo and in vitro investigations are essential to validate the anticancer potential of these compounds.

Effect of a high-fat meal on the relative bioavailability of HMPL-689 in Chinese healthy volunteers.

The aim of this study was to investigate the effect of a high-fat meal on the single-dose pharmacokinetics (PK) and tolerability of HMPL-689 in Chinese healthy volunteers. In this study, 34 eligible male volunteers received a single 30-mg dose of HMPL-689 capsules following an overnight fast or a high-fat breakfast prior to dosing. Blood samples were collected at the designated time points for pharmacokinetic analysis. Safety and tolerability were assessed throughout the study. Total 32 healthy male volunteers were completed in the study. The GMRs of AUC0-t , AUC0-∞ , and Cmax and their 90% CIs were 1.12 (1.09, 1.15), 1.12 (1.09, 1.15), and 0.64 (0.58, 0.70), respectively, in healthy male subjects after oral administration of HMPL-689 following intake of a high-fat diet versus under fasting state. The 90% CI of Cmax GMR fell outside the acceptable equivalent range (0.8-1.25). In addition, the median Tmax of HMPL-689 was 1.0 and 4.0h under the fasting and the fed conditions. The study indicated that intake of a high-fat diet had an impact on the in vivo PK profile of HMPL-689 in healthy Chinese male subjects, which could obviously reduce the oral absorption rate of HMPL-689 and had little effect on the extent of oral absorption (AUC).

Deconvolution of Systemic Pharmacokinetics Predicts Inhaled Aerosol Dosimetry of Nicotine

Absorption of inhaled compounds can occur from multiple sites based on upper and lower respiratory tract deposition, and clearance mechanisms leading to differential local and systemic pharmacokinetics. Deriving inhaled aerosol dosimetry and local tissue concentrations for nose-only exposure in rodents and inhaled products in humans is challenging. In this study we use inhaled nicotine as an example to identify regional respiratory tract deposition, absorption fractions, and their contribution toward systemic pharmacokinetics in rodents and humans. A physiologically based pharmacokinetic (PBPK) model was constructed to describe the disposition of nicotine and its major metabolite, cotinine. The model description for the lungs was simplified to include an upper respiratory tract region with active mucociliary clearance and a lower respiratory tract region. The PBPK model parameters such as rate of oral absorption, metabolism and clearance were fitted to the published nicotine and cotinine plasma concentrations post systemic administration and oral dosing. The fractional deposition of inhaled aerosol in the upper and lower respiratory tract regions was estimated by fitting the plasma concentrations. The model predicted upper respiratory tract deposition was 63.9% for nose-only exposure to nicotine containing nebulized aqueous aerosol in rats and 60.2% for orally inhaled electronic vapor product in humans. A marked absorption of nicotine from the upper respiratory tract and the gastrointestinal tract for inhaled aqueous aerosol contributed to the differential systemic pharmacokinetics in rats and humans. The PBPK model derived dosimetry shows that the current aerosol dosimetry models with their posteriori application using independent aerosol physicochemical characterization to predict aerosol deposition are insufficient and will need to consider complex interplay of inhaled aerosol evolutionary process. While the study highlights the needs for future research, it provides a preliminary framework for interpreting pharmacokinetics of inhaled aerosols to facilitate the analysis of in vivo exposure-responses for pharmacological and toxicological assessments.

Fabrication of Ginsenoside-Based Nanodrugs for Enhanced Antitumor Efficacy on Triple-Negative Breast Cancer.

There is an urgent need to identify chemotherapeutic agents with improved efficacy and safety against triple-negative breast cancer (TNBC). Ginsenosides can reportedly induce tumor cell death, invasion, and metastasis; however, poor water solubility, low oral absorption rate, and rapid blood clearance limit their clinical application. Utilizing the amphiphilic property of ginsenosides as building blocks of biomaterials, we fabricated a carrier-free nanodrug composed of ginsenosides Rg3 and Rb1 using a nano-reprecipitation method without any additional carriers. After characterizing and demonstrating their uniform morphology and pH-sensitive drug release properties, we observed that Rg3-Rb1 nanoparticles (NPs) exhibited stronger antitumor and anti-invasive effects on TNBCs in vitro than those mediated by free ginsenosides. Consequently, Rg3-Rb1 NPs afforded superior inhibition of tumor growth and reduction of pulmonary metastasis than the Rg3 and Rb1 mixture, with no obvious systematic toxicity in vivo. Collectively, our results provide a proof-of-concept that self-assembled engineered ginsenoside nanodrugs may be efficient and safe for TNBC therapy.

Sub-Inhibitory Concentrations of Amoxicillin and Tylosin Affect the Biofilm Formation and Virulence of Streptococcus suis.

Streptococcus suis (S. suis) can form a protective biofilm during infection and lead to prolonged disease. Oral antibiotics are often used for treatment in clinical practice, but sub-inhibitory concentration levels often exist due to low oral absorption rate, resulting in disease deterioration. The purpose of this study was to investigate the effects of Amoxicillin and Tylosin on the biofilm formation and virulence of S. suis HA9801 at sub-inhibitory concentration. We first determined that the test groups (1/4MIC Amoxicillin and Tylosin) could significantly increase the amount of biofilm formation without affecting bacterial growth. The LD50 value of the test groups was significantly higher than that of the control group in the mouse infection model. In the mouse infection model, the LD50 value of the experimental group was significantly increased, but the tissue bacterial load was significantly decreased. Further RT-PCR analysis showed that the expression levels of virulence-related genes in the experimental group were significantly reduced. Our study suggests that both Amoxicillin and Tylosin at sub-inhibitory concentrations could enhance the biofilm formation ability of S. suis HA9801 and reduce its virulence to form persistent infection.

Beta-Cyclodextrin As An Excipient In Drug Formulation

After its discovery nearly 30 years ago, (2-Hydroxy –propyl) Beta –Cyclodextrin, a highly soluble derivative of Beta –Cyclodextrin, has been an authorized excipients of drug formulation in both the US and European pharmacopoeia. It is recommended for use in oral and parenteral formulations as a solubilizer and stabilizer. The majority of medications taken by mouth have low aqueous solubility and dissolution rates. Beta-Cyclodextrin that has been chemically modified Dynamic complex formation used to enchance the Low aqueous solubility, slow dissolution rate, and reduced drug stability. Cyclodextrin form inclusion complexes with appropriately sized guest molecules to improve aqueous solubility, physical chemical stability, and bioavailability of drugs. Cyclodextrin is a group of compounds made up of glucose monomers arranged in a donut form. They are non-reducing, crystalline cyclic oligosaccrides with a truncated core that produces a hydrophilic outer surface. Cyclodextrin and its derivatives have become common modalities for increasing oral bio availability and absorption rate as a result of these effects. Cyclodextrin has been positioned as an effective facilitating and usable excipients. This article discusses the widespread use of Cyclodextrin as excipients in drug formulations as well as recent Cyclodextrin developments.

An Overview on Dietary Polyphenols and Their Biopharmaceutical Classification System (BCS).

Polyphenols are natural organic compounds produced by plants, acting as antioxidants by reacting with ROS. These compounds are widely consumed in daily diet and many studies report several benefits to human health thanks to their bioavailability in humans. However, the digestion process of phenolic compounds is still not completely clear. Moreover, bioavailability is dependent on the metabolic phase of these compounds. The LogP value can be managed as a simplified measure of the lipophilicity of a substance ingested within the human body, which affects resultant absorption. The biopharmaceutical classification system (BCS), a method used to classify drugs intended for gastrointestinal absorption, correlates the solubility and permeability of the drug with both the rate and extent of oral absorption. BCS may be helpful to measure the bioactive constituents of foods, such as polyphenols, in order to understand their nutraceutical potential. There are many literature studies that focus on permeability, absorption, and bioavailability of polyphenols and their resultant metabolic byproducts, but there is still confusion about their respective LogP values and BCS classification. This review will provide an overview of the information regarding 10 dietarypolyphenols (ferulic acid, chlorogenic acid, rutin, quercetin, apigenin, cirsimaritin, daidzein, resveratrol, ellagic acid, and curcumin) and their association with the BCS classification.

Population Pharmacokinetic Model of N-acetylmannosamine (ManNAc) and N-acetylneuraminic acid (Neu5Ac) in Subjects with GNE Myopathy.

BackgroundGNE myopathy is a rare genetic muscle disease resulting from deficiency in an enzyme critical for the biosynthesis of N-acetylneuraminic acid (Neu5Ac, sialic acid). The uncharged Neu5Ac precursor, N-acetylmannosamine (ManNAc), is under development as an orphan drug for treating GNE myopathy.MethodsA semi-mechanistic population pharmacokinetic model was developed to simultaneously characterize plasma ManNAc and its metabolite Neu5Ac following oral administration of ManNAc to subjects with GNE myopathy. Plasma ManNAc and Neu5Ac pharmacokinetic data were obtained from two clinical studies (ClinicalTrials.gov identifiers NCT01634750, NCT02346461) and were simultaneously modeled using NONMEM.ResultsManNAc and Neu5Ac plasma concentrations were obtained from 34 subjects with GNE myopathy (16 male, 18 female, median age 39.5 years). The model parameter estimates included oral absorption rate (ka) = 0.256 h−1, relative bioavailability relationship with dose (F-Dose) slope = −0.405 (where F = 1 for 6-g dose), apparent clearance (CLM/F) = 631 L/h, volume of distribution (VM/F) = 506 L, Neu5Ac elimination rate constant (kout) = 0.283 h−1, initial ManNAc to Neu5Ac conversion (SLP0) = 0.000619 (ng/mL)−1 and at steady-state (SLPSS) = 0.00334 (ng/mL)−1, with a rate-constant of increase (kinc) = 0.0287 h−1. Goodness-of-fit plots demonstrated an acceptable and unbiased fit to the plasma ManNAc and Neu5Ac concentration data. Visual predictive checks demonstrated reasonable agreement between the 5th, 50th, and 95th percentiles of the observed and simulated data.ConclusionsThis population pharmacokinetic model can be used to evaluate ManNAc dosing regimens and to calculate Neu5Ac production and exposure following oral administration of ManNAc in subjects with GNE myopathy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-021-00343-6.