Search

This paper presents the results of the kinematic analysis of an analogous Huygens pendulum using Inverted Tooth Chain (I.T.C); the simulation was done by the aid of MSC ADAMS VIEW. During the simulation process one could see the behaviour of the Inverted Tooth Chain by observing the motion of the chain plates in relation to the global coordinate axes. Also, it presents the possibility of obtaining various measurements of different angular displacements, velocities and accelerations of each plate individually, which in return give relevant information on the system behaviour. [ABSTRACT FROM AUTHOR]

Karim S Shalaby,1 Mahmoud E Soliman,1 Luca Casettari,2 Giulia Bonacucina,3 Marco Cespi,3 Giovanni F Palmieri,3 Omaima A Sammour,1 Abdelhameed A El Shamy1,† 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Ain Shams University, Cairo, Egypt; 2Department of Biomolecular Sciences, School of Pharmacy, University of Urbino, Urbino, Italy; 3School of Pharmacy, University of Camerino, Camerino, Italy †Abdel Hameed El-Shamy passed away on August 25, 2013 Abstract: In this study, di- and triblock copolymers based on polyethylene glycol and polylactide were synthesized by ring-opening polymerization and characterized by proton nuclear magnetic resonance and gel permeation chromatography. Nanoparticles containing noscapine were prepared from these biodegradable and biocompatible copolymers using the nanoprecipitation method. The prepared nanoparticles were characterized for size and drug entrapment efficiency, and their morphology and size were checked by transmission electron microscopy imaging. Artificial neural networks were constructed and tested for their ability to predict particle size and entrapment efficiency of noscapine within the formed nanoparticles using different factors utilized in the preparation step, namely polymer molecular weight, ratio of polymer to drug, and number of blocks that make up the polymer. Using these networks, it was found that the polymer molecular weight has the greatest effect on particle size. On the other hand, polymer to drug ratio was found to be the most influential factor on drug entrapment efficiency. This study demonstrated the ability of artificial neural networks to predict not only the particle size of the formed nanoparticles but also the drug entrapment efficiency. This may have a great impact on the design of polyethylene glycol and polylactide-based copolymers, and can be used to customize the required target formulations. Keywords: noscapine, polyethylene glycol (PEG), polylactide (PLA), biodegradable nanoparticles, artificial neural networks (ANNs)

Abstract Background Pulmonary function has been reported in mice using negative pressure-driven forced expiratory manoeuvres (NPFE) and the forced oscillation technique (FOT). However, both techniques have always been studied using separate cohorts of animals or systems. The objective of this study was to obtain NPFE and FOT measurements at baseline and following bronchoconstriction from a single cohort of mice using a combined system in order to assess both techniques through a refined approach. Methods Groups of allergen- or sham-challenged ovalbumin-sensitized mice that were either vehicle (saline) or drug (dexamethasone 1 mg/kg ip)-treated were studied. Surgically prepared animals were connected to an extended flexiVent system (SCIREQ Inc., Montreal, Canada) permitting NPFE and FOT measurements. Lung function was assessed concomitantly by both techniques at baseline and following doubling concentrations of aerosolized methacholine (MCh; 31.25 - 250 mg/ml). The effect of the NPFE manoeuvre on respiratory mechanics was also studied. Results The expected exaggerated MCh airway response of allergic mice and its inhibition by dexamethasone were detected by both techniques. We observed significant changes in FOT parameters at either the highest (Ers, H) or the two highest (Rrs, RN, G) MCh concentrations. The flow-volume (F-V) curves obtained following NPFE manoeuvres demonstrated similar MCh concentration-dependent changes. A dexamethasone-sensitive decrease in the area under the flow-volume curve at the highest MCh concentration was observed in the allergic mice. Two of the four NPFE parameters calculated from the F-V curves, FEV0.1 and FEF50, also captured the expected changes but only at the highest MCh concentration. Normalization to baseline improved the sensitivity of NPFE parameters at detecting the exaggerated MCh airway response of allergic mice but had minimal impact on FOT responses. Finally, the combination with FOT allowed us to demonstrate that NPFE induced persistent airway closure that was reversible by deep lung inflation. Conclusions We conclude that FOT and NPFE can be concurrently assessed in the same cohort of animals to determine airway mechanics and expiratory flow limitation during methacholine responses, and that the combination of the two techniques offers a refined control and an improved reproducibility of the NPFE.

Introduction: Plasma cell leukemia (PCL) is a rare malignancy with poor overall survival (OS). Recently, its diagnostic criteria were revised by lowering the threshold of circulating plasma cells from ≥ 20% to ≥ 5%., Methods: Between 2010 and 2024, patients with primary PCL (pPCL) and secondary PCL (sPCL) were identified at a tertiary center. We retrospectively analyzed baseline characteristics, treatment, and survival in months (m)., Results: We identified 30 patients with pPCL and 29 patients with sPCL. The median time to sPCL in patients who received Daratumumab (Dara)-containing regimens for multiple myeloma was 46.8m compared with 12.3m in patients who did not (P=0.007). Of the whole cohort, 51.9% received an induction regimen with novel agents without chemotherapy. Of the evaluable patients with pPCL and sPCL, 82.1% (23/28) and 64.7% (11/17) achieved partial response or better respectively. Median progression free survival was significantly worse in patients with sPCL than pPCL (2.2 vs. 38.3 months; HR 0.16; 95% CI (0.07-0.35), P < .001). Median OS was also worse in patients with sPCL compared with pPCL (3.1 months vs. NR [not reached]; HR 0.09; 95%CI 0.04-0.23, P < .001). The median post-SCT survival for patients with pPCL was NR compared with 6.7m for patients with sPCL (HR 0.17; 95% CI (0.03-0.83), P = .03). Dara-refractory status was associated with worse OS (HR 5.63; 95% CI (2.75-11.51), P < .0001)., Conclusion: Outcomes of pPCL are improving but remain dismal for sPCL. We explored the role of novel agents, especially Dara, in the treatment of PCL. More prospective trials are needed to improve its outcomes., Competing Interests: Disclosure K.S., F.A., S.P., C.W, H.Y., and K.A declare no competing conflicts of interest. J.H. is on the data safety and monitoring board for Janssen, the advisory board for Targeted Oncology, Angitia, Prothena, Sebia, Regeneron, and has given talks at Beigene, Targeted Oncology, Integrity Continuing Education, Inc, and Clinical Care Options., (Copyright © 2024 Elsevier Inc. All rights reserved.)

An RP-HPLC method with a UV detector was developed for the simultaneous quantification of diclofenac diethylamine, methyl salicylate, and capsaicin in a pharmaceutical formulation and rabbit skin samples. The separation was achieved using a Thermo Scientific ACCLAIM TM 120 C 18 column (Waltham, MA, USA, 4.6 mm × 150 mm, 5 µm). The optimized elution phase consisted of deionized water adjusted to pH = 3 using phosphoric acid mixed with acetonitrile in a 35:65% ( v / v ) ratio with isocratic elution. The flow rate was set at 0.7 mL/min, and the detection was performed at 205 nm and 25 °C. The method exhibits good linearity for capsaicin (0.05-70.0 µg/mL), methyl salicylate (0.05-100.0 µg/mL), and diclofenac diethylamine (0.05-100.0 µg/mL), with low LOD values (0.0249, 0.0271, and 0.0038 for capsaicin, methyl salicylate, and diclofenac diethylamine, respectively). The RSD% values were below 3.0%, indicating good precision. The overall greenness score of the method was 0.61, reflecting its environmentally friendly nature. The developed RP-HPLC method was successfully applied to analyze Omni Hot Gel ® pharmaceutical formulation and rabbit skin permeation samples.

Celecoxib (CLX), a selective inhibitor for cyclooxygenase 2 (COX-2), has manifested potential activity against diverse types of cancer. However, low bioavailability and cardiovascular side effects remain the major challenges that limit its exploitation. In this work, we developed ultra-elastic nanovesicles (UENVs) with pH-triggered surface charge reversal traits that could efficiently deliver CLX to colorectal segments for snowballed tumor targeting. CLX-UENVs were fabricated via a thin-film hydration approach. The impact of formulation factors (Span 80, Tween 80, and sonication time) on the nanovesicular features was evaluated using Box-Behnken design, and the optimal formulation was computed. The optimum formulation was positively coated with polyethyleneimine (CLX-PEI-UENVs) and then coated with Eudragit S100 (CLX-ES-PEI-UENVs). The activity of the optimized nano-cargo was explored in 1,2-dimethylhydrazine-induced colorectal cancer in Wistar rats. Levels of COX-2, Wnt-2 and β-catenin were assessed in rats' colon. The diameter of the optimized CLX-ES-PEI-UENVs formulation was 253.62 nm, with a zeta potential of -23.24 mV, 85.64% entrapment, and 87.20% cumulative release (24 h). ES coating hindered the rapid release of CLX under acidic milieu (stomach and early small intestine) and showed extended release in the colon section. In colonic environments, the ES coating layer was removed due to high pH, and the charge on the nanovesicular corona was shifted from negative to positive. Besides, a pharmacokinetics study revealed that CLX-ES-PEI-UENVs had superior oral bioavailability by 2.13-fold compared with CLX suspension. Collectively, these findings implied that CLX-ES-PEI-UENVs could be a promising colorectal-targeted nanoplatform for effective tumor management through up-regulation of the Wnt/β-catenin pathway., Competing Interests: The authors wish to declare that no interest is involved in this publication., (© 2023 The Authors. Published by Elsevier B.V.)

Growing evidence suggests quercetin and aspirin may have anticancer properties, notably in the case of colorectal cancer. The goal of this study was to create Pluronic F127 and polyethylene glycol4000 solid dispersion-loaded chitosan nanoparticles for colonic quercetin and aspirin delivery. In 1:1 polymeric stoichiometric ratio, solubility and complex formation were verified. Solid dispersion-loaded chitosan nanoparticles with a diameter of 244.45 ± 8.5 nm, a surface charge of 34.1 ± 3.3 mV, and encapsulation effectiveness of 76.3 ± 4.3% were generated under ideal conditions. In some cases, coating with Eudragit L100 resulted in a decrease in zeta potential and an increase in particle size. The coated formulation released the actives in a pH-dependent manner, considering their physicochemical features. Surprisingly, when compared to the actives' suspension and uncoated formulation, the coated formulation had greater anti-inflammatory efficacy, with a substantial reduction of PGE2 and IL-8 production in colonic tissues (16.9 ± 7.9 ng/g tissue and 134.9 ± 10.1 pg/g tissue, respectively). It also reversed most of the dimethyl hydrazine-induced histological alterations in the colon. It also demonstrated a greater reduction in TNF expression in colonic tissues. As a result, Eudragit L100-coated QT/AS-loaded chitosan nanoparticles are suggested to provide a potential platform for colonic delivery of quercetin and aspirin., (© 2023. Controlled Release Society.)

Depression is a serious mental disorder and the most prevalent cause of disability and suicide worldwide. Quercetin (QER) demonstrated antidepressant effects in rats exhibiting anxiety and depressive-like behaviors. In an attempt to improve QER's antidepressant activity, a QER-loaded transferosome (QER-TFS) thermosensitive gel for intranasal administration was formulated and optimized. The therapeutic effectiveness of the optimized formulation was assessed in a depressed rat model by conducting a behavioral analysis. Behavioral study criteria such as immobility, swimming, climbing, sucrose intake, number of crossed lines, rearing, active interaction, and latency to feed were all considerably enhanced by intranasal treatment with the QER-TFS in situ gel in contrast to other formulations. A nasal histopathological study indicated that the QER-TFS thermosensitive gel was safe for the nasal mucosa. An immunohistochemical analysis showed that the animals treated with the QER-TFS thermosensitive gel had the lowest levels of c-fos protein expression, and brain histopathological changes in the depressed rats were alleviated. According to pharmacodynamic, immunohistochemical, and histopathological experiments, the intranasal administration of the QER-TFS thermosensitive gel substantially alleviated depressive symptoms in rats. However, extensive preclinical investigations in higher animal models are needed to anticipate its effectiveness in humans.

Numerous neurological disorders have a pathophysiology that involves an increase in free radical production in the brain. Quercetin (QER) is a nutraceutical compound that shields the brain against oxidative stress-induced neurodegeneration. Nonetheless, its low oral bioavailability diminishes brain delivery. Therefore, the current study aimed to formulate QER-loaded transferosomal nanovesicles (QER-TFS) in situ gel for QER brain delivery via the intranasal route. This study explored the impacts of lipid amount, edge activator (EA) amount, and EA type on vesicle diameter, entrapment, and cumulative amount permeated through nasal mucosa (24 h). The optimum formulation was then integrated into a thermosensitive gel after its physical and morphological characteristics were assessed. Assessments of the optimized QER-TFS showed nanometric vesicles (171.4 ± 3.4 nm) with spherical shapes and adequate entrapment efficiency (78.2 ± 2.8%). The results of short-term stability and high zeta potential value (-32.6 ± 1.4 mV) of QER-TFS confirmed their high stability. Compared with the QER solution, the optimized QER-TFS in situ gel formulation exhibited sustained release behavior and augmented nasal mucosa permeability. CT scanning of rat brains demonstrated the buildup of gold nanoparticles (GNPs) in the brains of all treatment groups, with a greater level of GNPs noted in the rats given the transferosomal gel. Additionally, in vitro studies on PCS-200-014 cells revealed minimal cytotoxicity of QER-TFS in situ gel. Based on these results, the developed transferosomal nanovesicles may be a suitable nanocarrier for QER brain targeting through the intranasal route.

The barrier functionalities of the skin offer a major but not insuperable hindrance for fabrication of skin delivery effective systems. This work aimed to develop an optimized lipid polymer hybrid nanoparticle and assess the skin delivery effectiveness of hydrocortisone (9.872 ± 0.361 × 10 -3 cm 2 /h) of a drug through the skin from an optimized formulation when compared with a drug solution. Meanwhile, histological examination after topical application of the optimized formulation showed a safe increase in epidermal thickness. In vivo, the optimized formulation showed promising anti-inflammatory activity in a croton oil-induced ear rosacea model. As an excellent anti-inflammatory agent, these findings propose that the use of lipomers could be a promising strategy to improve the topical effectiveness of hydrocortisone acetate (HCA) against inflammatory diseases. Collectively, these results support our view that lipid polymer hybrid nanoparticles can proficiently deliver hydrocortisone to the skin in treating skin inflammatory conditions., Competing Interests: The authors declare no competing financial interest., (© 2023 The Authors. Published by American Chemical Society.)

COVID-19 infection is now considered one of the leading causes of human death. As an attempt towards the discovery of novel medications for the COVID-19 pandemic, nineteen novel compounds containing 1,2,3-triazole side chains linked to phenylpyrazolone scaffold and terminal lipophilic aryl parts with prominent substituent functionalities were designed and synthesized via a click reaction based on our previous work. The novel compounds were assessed using an in vitro effect on the growth of SARS-CoV-2 virus-infested Vero cells with different compound concentrations: 1 and 10 μM. The data revealed that most of these derivatives showed potent cellular anti-COVID-19 activity and inhibited viral replication by more than 50% with no or weak cytotoxic effect on harboring cells. In addition, in vitro assay employing the SARS-CoV-2-Main protease inhibition assay was done to test the inhibitors' ability to block the common primary protease of the SARS-CoV-2 virus as a mode of action. The obtained results show that the one non-linker analog 6h and two amide-based linkers 6i and 6q were the most active compounds with IC 50 values of 5.08, 3.16, and 7.55 μM, respectively, against the viral protease in comparison to data of the selective antiviral agent GC-376. Molecular modeling studies were done for compound placement within the binding pocket of protease which reveal conserved residues hydrogen bonding and non-hydrogen interactions of 6i analog fragments: triazole scaffold, aryl part, and linker. Moreover, the stability of compounds and their interactions with the target pocket were also studied and analyzed by molecular dynamic simulations. The physicochemical and toxicity profiles were predicted, and the results show that compounds behave as an antiviral activity with low or no cellular or organ toxicity. All research results point to the potential usage of new chemotype potent derivatives as promising leads to be explored in vivo that might open the door to rational drug development of SARS-CoV-2 Main protease potent medicines.

In the last few decades, several natural bioactive agents have been widely utilized in the treatment and prevention of many diseases owing to their unique and versatile therapeutic effects, including antioxidant, anti-inflammatory, anticancer, and neuroprotective action. However, their poor aqueous solubility, poor bioavailability, low GIT stability, extensive metabolism as well as short duration of action are the most shortfalls hampering their biomedical/pharmaceutical applications. Different drug delivery platforms have developed in this regard, and a captivating tool of this has been the fabrication of nanocarriers. In particular, polymeric nanoparticles were reported to offer proficient delivery of various natural bioactive agents with good entrapment potential and stability, an efficiently controlled release, improved bioavailability, and fascinating therapeutic efficacy. In addition, surface decoration and polymer functionalization have opened the door to improving the characteristics of polymeric nanoparticles and alleviating the reported toxicity. Herein, a review of the state of knowledge on polymeric nanoparticles loaded with natural bioactive agents is presented. The review focuses on frequently used polymeric materials and their corresponding methods of fabrication, the needs of such systems for natural bioactive agents, polymeric nanoparticles loaded with natural bioactive agents in the literature, and the potential role of polymer functionalization, hybrid systems, and stimuli-responsive systems in overcoming most of the system drawbacks. This exploration may offer a thorough idea of viewing the polymeric nanoparticles as a potential candidate for the delivery of natural bioactive agents as well as the challenges and the combating tools used to overcome any hurdles.

Treatment options for the management of breast cancer are still inadequate. This inadequacy is attributed to the lack of effective targeted medications, often resulting in the recurrence of metastatic disorders. Cumulative evidence suggests that epidermal growth factor receptor (EGFR-TK) and cyclin-dependent kinases-9 (CDK-9) overexpression correlates with worse overall survival in breast cancer patients. Pyranopyrazole and pyrazolone are privileged options for the development of anticancer agents. Inspired by this proven scientific fact, we report here the synthesis of two new series of suggested anticancer molecules incorporating both heterocycles together with their characterization by IR, 1 H NMR, 13 C NMR, 13 C NMR-DEPT, and X-ray diffraction methods. An attempt to get the pyranopyrazole-gold complexes was conducted but unexpectedly yielded benzylidene-2,4-dihydro-3 H -pyrazol-3-one instead. This unexpected result was confirmed by X-ray crystallographic analysis. All newly synthesized compounds were assessed for their anti-proliferative activity against two different human breast cancer cells, and the obtained results were compared with the reference drug Staurosporine. The target compounds revealed variable cytotoxicity with IC 50 at a low micromolar range with superior selectivity indices. Target enzyme EGFR-TK and CDK-9 assays showed that compounds 22 and 23 effectively inhibited both biological targets with IC 50 values of 0.143 and 0.121 µM, respectively. Molecular docking experiments and molecular dynamics simulation were also conducted to further rationalize the in vitro obtained results.Communicated by Ramaswamy H. Sarma.

Luteolin is an excellent flavone possessing several beneficial properties such as antioxidant and anti-inflammatory effects which are interesting for skin delivery. Development of an appropriate skin delivery system could be a promising strategy to improve luteolin cutaneous performance.So, the main aim of this work was to fabricate, characterize and evaluate phospholipid-based luteolin-loaded lipid nanocapsules for skin delivery. The influence of phospholipid/oil ratio, surfactant type and chitosan coating were investigated. The prepared formulations underwent in vitro assessment and the selected formulations were evaluated ex vivo and in vivo. The mean diameters of investigated formulations varied between 174 nm and 628 nm while zeta potential varied between -25.7 ± 4.8 mV and 6.8 ± 1.7 mV. Increasing in phospholipid/oil ratios resulted in decrease in particles size with little effect on zeta potential and drug encapsulation. Cremophor EL showed the lowest particle sizes and the highest drug encapsulation. Chitosan coating shifted zeta potential towards positive values. Structural analyses showed that luteolin is incorporated into lipid core of nanocapsules. Selected formulations (LNC4 and LNC13) exhibited sustained in vitro release and antioxidant activity. LNC13 (chitosan coated) showed higher flux (0.457 ± 0.113 µg/cm 2 /h), permeability (45.70 ± 11.66 *10 -5 cm 2 /h) and skin retention (121.66 ± 7.6 µg/cm 2 after 24 h) when compared to LNC4 and suspension. It also showed disordered the integrity of the stratum corneum, increased epidermal thickness and relieving most of inflammatory features in animal model. In conclusion, this study proves that lipid nanocapsules could effectively deliver luteolin into skin and then can be established as a potential system in the pharmaceutical and cosmeceutical horizons., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Diabetes mellitus is a life-threatening metabolic disease. At the moment, there is no effective treatment available to combat it. In this study, we aimed to develop berberine-loaded bilosomes (BER-BLS) to boost the oral bioavailability and therapeutic efficacy of berberine, a natural antidiabetic medication. The BER-BLS was fabricated using a thin-film hydration strategy and optimized using a central composite design (face-centered). The average vesicle size, entrapment efficiency, and surface charge of the optimized BER-BLS preparation were 196.5 nm, 89.7%, (-) 36.4 mV, respectively. In addition, it exhibited higher stability and better-sustained release of berberine than the berberine solution (BER-SOL). BER-BLS and BER-SOL were administered to streptozocin-induced diabetic rats. The optimized BER-BLS formulation had a significant hypoglycemic impact, with a maximum blood glucose decrease of 41%, whereas BER-SOL only reduced blood glucose by 19%. Furthermore, the pharmacological effect of oral BER-BLS and BER-SOL corresponded to 99.3% and 31.7%, respectively, when compared to subcutaneous insulin (1 IU). A pharmacokinetic analysis found a 6.4-fold rise in the relative bioavailability of berberine in BER-BLS when compared to BER-SOL at a dosage of 100 mg/kg body weight. Histopathological investigation revealed that BER-BLS is suitable for oral administration. Our data demonstrate that BLS is a potential nanocarrier for berberine administration, enhancing its oral bioavailability and antidiabetic activity.

Cabergoline (CAB) is effective prolactin lowering drug. Evaluation of the bioequivalence for the new test product (0.5 mg CAB film-coated tablets) in Egypt is strongly needed for approval of the drug by the official health authority. Therefore, a highly sensitive and rapid (LC-MS/MS) method was validated for CAB analysis in human plasma. CAB was extracted from plasma via diethyl ether using Quetiapine (QUE) as an internal standard. Multiple reaction monitoring (MRM) in positive ion mode was used, m/z 452.3 → 381.2 for CAB and 384.2 → 253.1 for QUE. Separation was accomplished on a reversed-phase C 18 . FDA procedures for the bio-analytical method were followed. The method was used in the bioequivalence study to compare the test product (0.5 mg CAB) versus Dostinex tablets, on 24 healthy Egyptian volunteers. The total analysis time was 5.5 min for each sample which permits analysis of various samples per day. The linearity range was from 2.00 to 200.00 pg/mL for CAB. LOD and LOQ were found to be 0.5 and 1.6 pg/mL, respectively. The final greenness numerical value was 0.63 using AGREE tool. The results of pharmacokinetic parameter T max were 2.17, and 2.33 h; for test and reference products, respectively. The generic formulation of test product is considered bioequivalent to the reference product Dostinex 0.5 mg tablets and satisfies the requirements of the Egyptian market. The merits of the method over the previous published methods are low cost; availability of cheap internal standard; rapidness; use of acetonitrile-free solvents mobile phase., (© 2022. The Author(s).)

This work designates EthoLeciplex, a vesicular system consisting of phospholipid, CTAB, ethanol and water, as an innovative vesicular system for cutaneous/transfollicular minoxidil (MX) delivery. MX-loaded EthoLeciplex was fabricated by one-step fabrication process. Formulations were designed to study the effects of drug/phospholipid ratio, CTAB/phospholipid ratio, and ethanol concentration on vesicular size, PDI, surface charge and EE%. The optimized formulation was characterized by in vitro release, drug/excipient compatibility, ex vivo skin permeability and safety. A size of 83.6 ± 7.3 to 530.3 ± 29.4 nm, PDI of 0.214 ± 0.01 to 0.542 ± 0.08 and zeta potential of +31.6 ± 4.8 to +57.4 ± 12.5 mV were observed. Encapsulation efficiency was obtained in its maximum value (91.9 ± 16.2%) at the lowest drug/phospholipid ratio, median CTAB/phospholipid and the highest ethanol concentration. The optimized formulation was consisted of 0.3 as drug/lipid ratio, 1.25 as CTAB/lipid ratio and 30% ethanol concentration and showed responses' values in agreement with the predicted results. Differential scanning calorimetry studies suggested that EthoLeciplex existed in flexible state with complete incorporation of MX into lipid bilayer. The cumulative amount of MX permeated from EthoLeciplex, conventional liposome and ethanolic solution after 12 h were 36.3 ± 1.5 µg/ml, 21 ± 2.0 µg/ml and 55 ± 4.0 µg/ml respectively. Based on the remaining amount, the amount of MX accumulated in different skin layers can be predicted in descending order as follows; EthoLeciplex > conventional liposome > MX solution. EthoLeciplex produced marked disorder in the stratum corneum integrity and swelling with no features of skin toxicity. This new cationic system is a promising carrier for cutaneous/transfollicular drug delivery.

The phenanthroindolizidine alkaloid (-)-tylophorine has been reported for its significant anticancer activity working through different biomechanistic pathways. The current study aimed to evaluate the anticancer activity of phenanthroindolizidine alkaloids isolated from Tylophora indica . Six phenanthroindolizidine alkaloid (compounds 1 - 6 ) in addition to septicine ( 7 ), chlorogenic acid ( 8 ), and chlorogenic acid methyl ester ( 9 ) were isolated from Tylophora indica using different chromatographic techniques including vacuum liquid chromatography (VLC) and preparative high performance liquid chromatography (HPLC). The isolated compounds structures' were determined using various spectro-analytical techniques, i.e., 1 H-NMR, 13 C-NMR, and mass spectrometry. The isolates' structural stereochemistry and structural geometries were determined with the help of chiroptical techniques together with comparisons with the available standard samples. The in vitro anti-proliferative activity on three different cell lines, MCF-7, HepG2, and HCT-116 were evaluated. Among all the isolated compounds, tylophorinidine ( 5 ) was the most active cytotoxic agent with the lowest IC 50 values at 6.45, 4.77, and 20.08 μM against MCF-7, HepG2, and HCT-116 cell lines, respectively. The bioactivities were also validated by the in vitro kinase receptors inhibition assay. Compound ( 5 ) also exhibited the highest activity with lowest IC 50 values (0.6 and 1.3 μM against the Aurora-A and Aurora-B enzymes, respectively), as compared with all the isolated alkaloidal products. The structure activity relationship on the molecular properties, molecular attributes, and bioactivity levels were analyzed, interrelated, and the molecular docking studies on two different receptors, Aurora-A and Aurora-B, were determined, which provided the confirmations of the bioactivity with receptor-ligand geometric disposition, energy requirements, lipophilicity, and detailed the binding pharmacophore involvements responsible for bioactivity elicitations.

Anticancer therapy has the potential to cause unwanted cardiovascular side effects. Utilization of radiation therapy to treat tumors near the heart can result in radiation-induced valvular heart disease among other cardiovascular pathologies. The aim of this review is to describe the epidemiology, pathophysiology, risk prediction, non-invasive imaging modalities and management of radiation-induced valvular heart disease with a focus on pre-operative risk assessment and contemporary treatment options., (© 2022. The Author(s).)

Oxidative stress is a leading cause of different diseases. Genistein is a valuable bioflavonoid possessing antioxidant and anti-inflammatory activity but unfortunately, it suffers from low aqueous solubility, extremely poor bioavailability and first pass effect when used in its pure state. The aim of this work was to formulate and characterize genistein-loaded highly phospholipid-containing lipid nanocarriers to improve oral bioavailability and pharmacodynamic performance. Lipid nanocarriers were prepared by the emulsification/sonication technique. The influence of phospholipid percentage (1%-10%) on physicochemical properties, drug release and stability was investigated. The particle size, zeta potential and EE% were in ranges from 211.9 ± 21.6 to 342.3 ± 7.9 nm, -11.6 ± 1.7 to -19.4 ± 3.1 mV and 78.5 ± 4.7% to 92.2 ± 1.9%, respectively. Drug release was less predominant in the case of SLN formulations when compared to corresponding NLC formulations. High phospholipid percentage produced less stable formulations in terms of particle size growth, gelation and heterogeneous particle distributions. DSC, FT-IR and XRD tools revealed that genistein has existed in an amorphous form in NLC4. The bioavailability of NLC4 was approximately 2.6-fold greater than that of conventional suspension. Additionally, lipid peroxidation in liver homogenate and histopathological alterations in liver and kidney sections were particularly improved, providing a promising strategy for oral administration of genistein.

Introduction: Lung cancer is the leading cause of cancer-related deaths with non-small cell lung cancer (NSCLC) being the most common of them. About a third of NSCLC cases have an epidermal growth factor (EGFR) mutation, which is usually susceptible to tyrosine kinase inhibitors (TKIs). In rare cases where patients progress through TKI therapy, the use of immune checkpoint inhibitors (ICIs) remains controversial., Case Report: We describe a case of a patient with significant history of smoking and EGFR mutated programmed death ligand-1 (PD-L1) positive NSCLC who was initially treated with TKI therapy., Management/outcome: While patient progressed on TKI therapy, he was able to achieve a durable response with a single PD-L1 agent, pembrolizumab. Contrary to the available evidence, the presented EGFR mutant NSCLC responded to PD-L1 pathway inhibition., Discussion: From our observation Pembrolizumab could be promising in patients with rare EGFR mutations who do not respond to EGFR directed therapy. Our report provides supporting data for the use of immunotherapies in patients with EGFR mutated NSCLC.

The renin angiotensin aldosterone system has a localized key regulatory action, especially in liver and body circulation. Furthermore, it accomplishes a significant role in the downregulation of the PI3K/AKT/mTOR signaling pathway that is involved in type II diabetes mellitus pathogenesis. The current study aimed to evaluate the effect of a synthetic pioglitazone analogue (benzenesulfonamide derivative) compared to the standard pioglitazone hypoglycemic drug on enhancing liver insulin sensitivity via ACE 2/Ang (1-7)/PI3K/AKT/mTOR in experimental STZ-induced diabetes. After the model was established, rats were distributed into the normal control group, diabetic group, pioglitazone group (20 mg/kg), and a benzenesulfonamide derivative group (20 mg/kg), with the last 2 groups receiving oral treatment for 14 consecutive days. Our results suggested enhancing liver insulin sensitivity against the ACE2/Ang (1-7)/PI3K/AKT/mTOR pathway. Moreover, the synthetic compound produced a reduction in blood glucose levels, restored hyperinsulinemia back to normal, and enhanced liver glycogen deposition. In addition, it up regulated the ACE2/Ang (1-7)/PI3K/AKT/mTOR signaling pathway via increasing insulin receptor substrate 1 and 2 sensitivity to insulin, while it increased glucose transporter 2 expression in the rat pancreas. The study findings imply that the hypoglycemic effect of the benzenesulfonamide derivative is due to enhancing liver sensitivity to regulate blood glucose level via the ACE2/Ang (1-7)/PI3K/AKT/mTOR pathway.

Rheumatoid arthritis (RA) is a chronic inflammatory illness affecting the joints. The characteristic of RA is gradual joint deterioration. Current RA treatment alleviates signs such as inflammation and pain and substantially slows the progression of the disease. In this study, we aimed to boost the transdermal delivery of berberine (a natural product) by encapsulating it in chitosan, surface-modified bilosomes nanogel for better management of the inflammation of RA. The chitosan-coated bilosomes loaded with berberine (BER-CTS-BLS) were formulated according to the thin-film hydration approach and optimized for various causal variables, considering the effect of lipid, sodium deoxycholate, and chitosan concentrations on the size of the particles, entrapment, and the surface charge. The optimized BER-CTS-BLS has 202.3 nm mean diameter, 83.8% entrapment, and 30.8 mV surface charge. The optimized BER-CTS-BLS exhibited a delayed-release profile in vitro and increased skin permeability ex vivo. Additionally, histological examination revealed that the formulated BLS had no irritating effects on the skin. Furthermore, the optimized BER-CTS-BLS ability to reduce inflammation was evaluated in rats with carrageenan-induced paw edema. Our results demonstrate that the group treated with topical BER-CTS-BLS gel exhibited a dramatic reduction in rat paw edema swelling percentage to reach 24.4% after 12 h, which was substantially lower than other groups. Collectively, chitosan-coated bilosomes containing berberine have emerged as a promising therapeutic approach to control RA inflammation.

Background: Cancer-associated pulmonary embolism (PE) places a significant burden on patients and health care systems., Methods: A retrospective cross-sectional analysis of the National Inpatient Sample (NIS) database was performed in patients with acute PE from 2002 to 2014. Among patients hospitalized with PE, we investigated the differences in clinical outcomes and healthcare utilization in patients with and without cancer. A multivariate logistic regression model was applied to calculate adjusted odds ratios (OR) to estimate the impact of cancer on clinical outcomes. Wilcoxon rank sum tests were used to determine the differences in healthcare utilization between the two cohorts., Results: Among 3,313,044 patients who were discharged with a diagnosis of acute PE, 84.2% did not have cancer, while 15.8% had cancer as a comorbidity (56% metastatic cancer, 35% solid tumor without metastasis, and 9% lymphoma). Patients with cancer had a higher mean age but lower rates of common comorbidities except for coagulation deficiency than patients without a cancer diagnosis. In patients with cancer, the rate of IVC filter placement was higher (21.7% vs. 13.11%, OR 1.76 (95% CI 1.73-1.79); p < 0.0001) and thrombolytic use lower (1.34% vs. 2.15%, OR 0.68 (95% CI 0.64-0.72); p < 0.0001). Patients with cancer hospitalized for PE had a higher all-cause in-hospital mortality (11.8% vs. 6.6%, OR 1.79 (95% CI 1.75-1.83); p < 0.0001), longer length of stay (6 vs. 5 days; p < 0.0001), higher total charge per hospitalization ($30,885 vs. $27,273; p < 0.0001), and higher rates of home health services upon discharge (35.8% vs. 23.2%; p < 0.0001) compared with those without cancer., Conclusion: Concurrent cancer diagnosis in patients hospitalized for acute PE was associated with a 90% increase in all-cause mortality, longer length of stay, higher total charge per hospitalization, and higher rates of home health services upon discharge. The majority (56%) of patients with cancer had metastatic disease. Furthermore, there were identifiable differences in the intervention for acute PE between the two groups., (© 2021. The Author(s).)

Olive oil is a vegetable oil which has been successfully used as a skin penetrating agent. Acidity of olive oil is considered as one of the characteristic properties of olive oil. Olive oil acidity was selected as a parameter under investigation for evaluation of skin permeability. The acidities of the three investigated olive oils are varying from 0.75±0.16 to 2±0.17. Olive oil with acidity equals 2.0 showed the highest skin permeation for 12 h and cutaneous deposition with significant difference compared to the permeation values of 0.75 and F1.4 acidities. Results of cutaneous secretion of cytokines suggested that higher penetration was accompanied higher cytokines' secretions. Olive oil with acidity equals 2.0 also showed more prominent skin changes which suggested to be due to acidity and fatty acids' content. These results suggest that olive oil might improve the epidermal permeability, which is more pronounced in highly acidic olive oil, through weakening of skin barriers followed by acting of cytokines on re-building effective barriers. Finally, based on the current study, highly acidic olive oil is more efficient skin permeation enhancer vehicle than less acidic ones and can be efficiently used in formulation of cutaneous drug delivery systems.

Luteolin is a natural drug used as an antioxidant and anti-inflammatory, but unfortunately, it possesses low water solubility, which hinders its delivery via the skin. The main objective of this study was to prepare a luteolin-loaded nanosuspension by the antisolvent precipitation/sonication technique and study the effects of four stabilizers (two nonionic stabilizers, Pluronic F127 and Tween 80, and two polymeric stabilizers, HPMC and alginate) on the physicochemical properties of the prepared formulations. The selected formulations were incorporated into a gel base to evaluate their skin permeability and anti-inflammatory efficacy. The particle size was in the nanosize range (in the range from 468.1 ± 18.6 nm to 1024.8 ± 15.9 nm), while the zeta potential was negative and in the range from -41.7 ± 6.3 mV to -15.3 ± 1.9 mV. In particular, alginate-stabilized nanosuspensions showed the smallest particle size, the highest zeta potential value, and excellent stability due to the dual stabilizing effects (electrostatic and steric effects). The DSC results revealed a less crystalline structure of luteolin in lyophilized NS2 and NS12. Formulations stabilized by 1% Pluronic (NS2) and 2% alginate (NS12) were incorporated into a carbopol 940 gel base and showed good organoleptic character (homogenous with no evidenced phase separation or grittiness). In vitro dissolution studies showed that NS12 enhanced luteolin release rates, indicating the effect of particle size on the drug release pattern. On the other hand, NS2 showed enhanced skin permeability and anti-inflammatory effect in a carrageenan-induced paw edema model, revealing the surface activity role of the stabilizers. In conclusion, while alginate increased the nanosuspension stability by means of dual stabilizing effects, Pluronic F127 improved the skin delivery and pharmacodynamic efficacy of luteolin.

The main objective of this study was to prepare and characterize oleogel as potential carrier for quercetin skin delivery. The formulations were prepared by adding olive oil (5-30%) to Pluronic F127 hydrogel and were evaluated for particle size, zeta potential, viscosity in vitro quercetin release and stability, and were compared with that of Pluronic F127 hydrogel. The selected formulation was characterized for its interaction possibility, ex vivo skin permeation and skin histological changes and safety. The particle sizes ranged from 345.3 ± 5.3 nm to 401.5 ± 2.8 nm, and possessed negative charges. The viscosities of the formulations were found in the range of 6367-4823 cps with inverse proportionality to olive oil percentage while the higher percentages showed higher quercetin release. Percentages of 25% and 30% olive oil showed instability pattern under the conditions of accelerated stability studies. Differential scanning calorimetry verified the existence of quercetin in micellar aggregation and the network in the case of hydrogel and oleogel respectively. Ex vivo skin permeation showed an improved skin permeation of quercetin when 20% olive oil containing oleogel was used. Skin histology after 10 days of application showed stratum corneum disruption and good safety profile. Based on these findings, the proposed oleogel containing 20% olive oil denotes a potential carrier for topical delivery of quercetin.

Although it is a front-line in tuberculosis treatment, rifampicin (RF) exhibits poor oral bioavailability and hepatotoxicity. Rectal mucoadhesive and in situ rectal gels were developed to overcome drug drawbacks. A RF/polyethylene glycol 6000 co-precipitate was first prepared in different ratios. Based on the drug solubility, the selected ratio was investigated for drug/polymer interaction and then incorporated into in situ rectal gels using Pluronic F127 (15%) and Pluronic F68 (10%) as a gel base and mucoadhesive polymers (HPMC, sodium alginate and chitosan). The formulations were assessed for gelation temperature and gel strength. The selected formulation was investigated for in vivo assessments. The results showed that a 1:1 drug/polymer ratio exhibited satisfying solubility with the recorded drug/polymer interaction. Depending on their concentrations, adding mucoadhesive polymers shifted the gelation temperature to lower temperatures and improved the gel strength. The selected formulation (F4) did not exhibit any anal leakage or marked rectal irritation. Using a validated chromatographic analytical method, F4 exhibited higher drug absorption with a 3.38-fold and 1.74-fold higher bioavailability when compared to oral drug suspension and solid suppositories, respectively. Toxicity studies showed unnoticeable hepatic injury in terms of biochemical, histopathological and immunohistochemical examinations. Together, F4 showed a potential of enhanced performance and also offered lower hepatic toxicity, thus offering an encouraging therapeutic alternative.

There are many synthetic drugs in literature have been utilized in healing of the wounds although the natural product specially antioxidants can offer similar if not better biological activity in that regard. Genus Sophora is well known to contain flavonoids and phenolic compounds which have antioxidant and inflammatory effects. So, the aim of the current study was to develop and evaluate chitosan/gelatin based Sophora gibbosa extract-loaded microemulsion as wound dressing. Sophora gibbosa extract (SGE) contained 16 major compounds which have reasonable antioxidant activity. The developed microemulsion showed that Tween 80 produced significant ( p  < 0.05) lower particle size than Pluronic F127 at the same SGE concentration whereas high concentration of extract results in large particle size. Thermodynamic stability studies showed that using higher concentration of the extract produced less stable formulations. The selected formulation was impregnated in the dressing base (chitosan/gelatin; 2:1 w/w ratio) which exhibited more water absorption. In vivo evaluation revealed that the dressing displayed superior wound repair compared to the control in terms histological examination and determination of alpha smooth muscle actin (α-SMA) and proliferating cell nuclear antigen (PCNA). Thus, SGE-loaded microemulsion-impregnated gelatin/chitosan could be a potential candidate for the wound healing.

The aim of this work was to prepare and optimize mucoadhesive nanostructured lipid carrier (NLC) impregnated with fluconazole for better management of oral candidiasis. The NLCs were fabricated using an emulsification/sonication technique. The nanoparticles consisted of stearic acid, oleic acid, Pluronic F127, and lecithin. Box-Behnken design, artificial neural networking, and variable weight desirability were employed to optimize the joint effect of drug concentration in the drug/lipid mixture, solid lipid concentration in the solid/liquid lipid mixture, and surfactant concentration in the total mixture on size and entrapment. The optimized NLCs were coated with chitosan. The nanoparticles were characterized by surface charge, spectroscopic, thermal, morphological, mucoadhesion, release, histopathological, and antifungal properties. The nanoparticles are characterized by a particle size of 335 ± 13.5 nm, entrapment efficiency of 73.1 ± 4.9%, sustained release, minor histopathological effects on rabbit oral mucosa, and higher fungal inhibition efficiency for an extended period of time compared with fluconazole solution. Coating the nanoparticles with chitosan increased its adhesion to rabbit oral buccal mucosa and improved its anti-candidiasis activity. It is concluded that mucoadhesive lipid-based nanoparticles amplify the effect of fluconazole on Candida albicans in vitro . This finding warrants pre-clinical and clinical studies in oral candidiasis disease models to corroborate in vitro findings.

Conjunctivitis is considered as a common infection of ocular surfaces. Eye drop is most commonly used for treatment of conjunctivitis, but has some drawback like 95% drug eliminated after administration. Administration of levofloxacin to the anterior site in form of chitosan coated poly (lactic-co-glycolic acid) nanoparticles (LFV-CS-PLGA-NPs) expected to overcome these problem and increasing corneal contact time and permeability for effective treatment of bacterial conjunctivitis. The Nanoparticles were developed by single emulsion solvent evaporation technique and optimized for different variables (chitosan, poly (lactide-co-glycolic acid) and polyvinyl alcohol concentration) by employing three factors, three levels Box-Behnken statistical design. The nanoparticles were evaluated for particle size, drug loading, entrapment efficiency, drug release, ex-vivo permeation, ocular tolerance, antimicrobial study, confocal laser microscopy, and Gamma scintigraphy study. The particle size and PdI of the optimized nanoparticles were 169.968 ± 15.23 nm and 0.13 ± 0.03, respectively, where as entrapment efficiency and drug loading is 49.54 ± 2.43% and 11.29 ± 2.13% with extended release profile and strong mucoadhesion. DSC data indicated levofloxacin formed molecular dispersion within coated nanoparticles. Corneal flux showed significantly ( P < 0.05) higher permeation as compared to marketed formulation. Formulation was nonirritant and possessed good antibacterial activity. Gamma Scintigraphy showed slow drainage compared to drug solution, indicating reduction in nasolachrymal drainage. The Gamma Scintigraphy study indicated the CS coated PLGA-NPs have high corneal residence time as compared to drug solution. So, it is revealed that LFV-CS-PLGA-NPs increase the drug concentration over ocular tissue and potential usefulness for sustained drug delivery.

The Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) genome editing system has been the focus of intense research in the last decade due to its superior ability to desirably target and edit DNA sequences. The applicability of the CRISPR-Cas system to in vivo genome editing has acquired substantial credit for a future in vivo gene-based therapeutic. Challenges such as targeting the wrong tissue, undesirable genetic mutations, or immunogenic responses, need to be tackled before CRISPR-Cas systems can be translated for clinical use. Hence, there is an evident gap in the field for a strategy to enhance the specificity of delivery of CRISPR-Cas gene editing systems for in vivo applications. Current approaches using viral vectors do not address these main challenges and, therefore, strategies to develop non-viral delivery systems are being explored. Peptide-based systems represent an attractive approach to developing gene-based therapeutics due to their specificity of targeting, scale-up potential, lack of an immunogenic response and resistance to proteolysis. In this review, we discuss the most recent efforts towards novel non-viral delivery systems, focusing on strategies and mechanisms of peptide-based delivery systems, that can specifically deliver CRISPR components to different cell types for therapeutic and research purposes.

To enhance human prostate-specific membrane antigen (hPSMA)-specific chimeric antigen receptor (CAR) T cell therapy in a hPSMA + MyC-CaP tumor model, we studied and imaged the effect of lactate dehydrogenase A (LDH-A) depletion on the tumor microenvironment (TME) and tumor progression. Effective LDH-A short hairpin RNA (shRNA) knockdown (KD) was achieved in MyC-CaP:hPSMA + Renilla luciferase (RLuc)-internal ribosome entry site (IRES)-GFP tumor cells, and changes in tumor cell metabolism and in the TME were monitored. LDH-A downregulation significantly inhibited cell proliferation and subcutaneous tumor growth compared to control cells and tumors. However, total tumor lactate concentration did not differ significantly between LDH-A knockdown and control tumors, reflecting the lower vascularity, blood flow, and clearance of lactate from LDH-A knockdown tumors. Comparing treatment responses of MyC-CaP tumors with LDH-A depletion and/or anti-hPSMA CAR T cells showed that the dominant effect on tumor growth was LDH-A depletion. With anti-hPSMA CAR T cell treatment, tumor growth was significantly slower when combined with tumor LDH-A depletion and compared to control tumor growth (p < 0.0001). The lack of a complete tumor response in our animal model can be explained in part by (1) the lower activity of human CAR T cells against hPSMA-expressing murine tumors in a murine host, and (2) a loss of hPSMA antigen from the tumor cell surface in progressive generations of tumor cells., (© 2020 The Authors.)

Long-acting preparations containing the antipsychotic paliperidone for intramuscular injection has drawn considerable attention to achieve harmless long-term treatment. This study aimed to develop paliperidone loaded polycaprolactone (PCL) nanoparticles and investigate the influence of PCL/drug ratio, stabilizer type, and chitosan coating on physicochemical properties, protein adsorption, and cellular toxicity. Results showed that chitosan coating produced enlarged particle sizes, shifted the surface charges from negative into positive and did not influence encapsulation efficiencies. Chitosan coating relatively sustained the drug release especially in pluronic stabilized formulations. Pluronic F127 based formulations exhibited the least protein adsorption (384.3 μg/mL). Chitosan coating of Tween 80 and polyvinyl alcohol stabilized formulations significantly ( p < 0.05) increased protein adsorption. Cellular viability was concentration-dependent and negatively affected by stabilizers. All formulations did not show cellular death at 1.56 μg/mL. Inflammatory responses and oxidative stress were less affected by Tween 80 compared with other stabilizers. Chitosan minimized all aspects of cellular toxicity. Collectively, stabilizer type and chitosan coating play critical roles in developing safe and effective long-acting PCL nanoparticles intended for parenteral drug delivery. The coated formulations containing Tween 80 and Pluronic F127 as stabilizers are warranted a future in vivo study to delineate its safety and efficacy profiles.

The main objective of this study was to develop, characterize and evaluate the potential use of dapsone-loaded nanostructured lipid carriers (NLCs) as a topical treatment for acne. Differently charged NLC formulations were successfully prepared using an emulsification/sonication method. The particle sizes ranged from 106.2 ± 5.6 nm to 151.3 ± 7.4 nm, and the NLCs possessed the predicted surface charges, depending on the emulsifier used (Tween 80, Transcutol P, or cetyltrimethylammonium bromide). The entrapment efficiencies ranged from 76.5 ± 3.8% to 91.1 ± 3.9%. Selected formulations were assessed for possible interactions, in vitro release, ex vivo skin permeation, pharmacological efficacy and safety compared with a hydroalcoholic solution. Dapsone was embedded in the lipid matrix of NLCs and behaved as controlled release system with a good occlusive effect. Dapsone-loaded cationic NLC formulation enhanced the skin permeation of dapsone, increase the amount of dapsone retained in the skin in controlled manner, and improved the anti-rosacea activity. Based on these encouraging results, cationic NLC represents a promising carrier for the safe topical delivery of dapsone., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background. The development of coronary collaterals is variable among patients with coronary artery disease and remains incompletely understood. We aimed to demonstrate the predictors of poorly developed coronary collateral circulation (CCC) in patients with subclinical hypothyroidism suffered from chronic stable angina. Methods. The study was conducted on 226 patients with subclinical hypothyroidism suffered from chronic stable angina, coronary angiography documented total occlusion at any major coronary artery or coronary artery lumen diameter stenosis >90%. Patients were divided into two groups according to grade of CCC, group A: 138 patients with (good collaterals) and group B: 88 patients with (poor collaterals). To classify CCC, we used Rentrop's classification. Results. Multivariate regression analysis was performed and identified the independent predictors of poor coronary collaterals: N/L ratio (OR 0.413, CI 95% [0.172-0.993], p = 0.048), and TSH (OR 2.511, CI 95% [1.784-3.534], p = 0.001). The ROC analysis provided a cut-off value of >4.6 for N/L ratio, and >9 µIU/mL for TSH to predict poor coronary collaterals. Conclusion. An elevated level of N/L ratio >4.6 and TSH level >9 µIU/mL were the independent predictors of poorly developed CCC in patients with subclinical hypothyroidism suffered from chronic stable angina., Competing Interests: The authors declare no conflicts of interest., (Copyright ©2019 The Author(s).)

Objectives: This study aims to develop thermosensitive gel containing soy isoflavone (antioxidant and anti-inflammatory natural agent) alginate microspheres for enhancement of wound-healing performance., Methods: Soy isoflavone microspheres were prepared by ionic cross-linking method and optimized using the Box-Behnken optimization design. Formulations were characterized in terms of particle size, encapsulation efficiency and equilibrium swelling degree. The optimized formula was incorporated in Pluronic F127 gel base and examined for in vivo wound-healing efficacy., Key Findings: Results showed mean particle size between 18 and 25 μm, encapsulation efficiency of over 75% and equilibrium swelling degree over 1.9. Thermal analysis indicated interaction between alginate and CaCl 2 and embedding of soy isoflavone in microspheres. In vivo wound-healing efficacy showed significant advance in re-epithelization, mature collagen synthesis and proangiogenesis. Immunohistochemical investigation exhibited promising alpha-smooth muscle actin immunopositive cells expression, fibroblast activation and expression of proliferating cell nuclear antigen (proliferation marker) in the epidermis and in the dermis., Conclusions: The developed formulation would appear to be a promising topical preparation for accelerating healing process., (© 2019 Royal Pharmaceutical Society.)