Dual Drug-Loaded Coaxial Nanofiber Dressings for the Treatment of Diabetic Foot Ulcer.

Introduction: Diabetes mellitus is frequently associated with foot ulcers, which pose significant health risks and complications. Impaired wound healing in diabetic patients is attributed to multiple factors, including hyperglycemia, neuropathy, chronic inflammation, oxidative damage, and decreased vascularization. Rationale: To address these challenges, this project aims to develop bioactive, fast-dissolving nanofiber dressings composed of polyvinylpyrrolidone loaded with a combination of an antibiotic (moxifloxacin or fusidic acid) and anti-inflammatory drug (pirfenidone) using electrospinning technique to prevent the bacterial growth, reduce inflammation, and expedite wound healing in diabetic wounds. Results: The fabricated drug-loaded fibers exhibited diameters of 443 ± 67 nm for moxifloxacin/pirfenidone nanofibers and 488 ± 92 nm for fusidic acid/pirfenidone nanofibers. The encapsulation efficiency, drug loading and drug release studies for the moxifloxacin/pirfenidone nanofibers were found to be 70 ± 3% and 20 ± 1 µg/mg, respectively, for moxifloxacin, and 96 ± 6% and 28 ± 2 µg/mg, respectively, for pirfenidone, with a complete release of both drugs within 24 hours, whereas the fusidic acid/pirfenidone nanofibers were found to be 95 ± 6% and 28 ± 2 µg/mg, respectively, for fusidic acid and 102 ± 5% and 30 ± 2 µg/mg, respectively, for pirfenidone, with a release rate of 66% for fusidic acid and 80%, for pirfenidone after 24 hours. The efficacy of the prepared nanofiber formulations in accelerating wound healing was evaluated using an induced diabetic rat model. All tested formulations showed an earlier complete closure of the wound compared to the controls, which was also supported by the histopathological assessment. Notably, the combination of fusidic acid and pirfenidone nanofibers demonstrated wound healing acceleration on day 8, earlier than all tested groups. Conclusion: These findings highlight the potential of the drug-loaded nanofibrous system as a promising medicated wound dressing for diabetic foot applications.

A Facile Synthesis and Molecular Characterization of Certain New Anti-Proliferative Indole-Based Chemical Entities.

Cancer cells frequently develop drug resistance, which leads to chemotherapeutic treatment failure. Additionally, chemotherapies are hindered by their high toxicity. Therefore, the development of new chemotherapeutic drugs with improved clinical outcomes and low toxicity is a major priority. Several indole derivatives exhibit distinctive anti-cancer mechanisms which have been associated with various molecular targets. In this study, target compounds 4a-q were obtained through the reaction of substituted benzyl chloride with hydrazine hydrate, which produces benzyl hydrazine. Subsequently, the appropriate substituted benzyl hydrazine was allowed to react with 1H-indole-2-carboxylic acid or 5-methoxy-1H-indole-2-carboxylic acid using 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide as a coupling agent. All compounds exhibited cytotoxicity in three cell lines, namely, MCF-7, A549, and HCT. Compound 4e exhibited the highest cytotoxicity, with an average IC50 of 2 µM. Moreover, a flow cytometry study revealed a significantly increased prevalence of Annexin-V and 7-AAD positive cell populations. Several derivatives of 4a-q showed moderate to high cytotoxicity against the tested cell lines, with compound 4e having the highest cytotoxicity, indicating that it may possess potential apoptosis-inducing capabilities.

Mesoporous Silica Nanoparticles Coated with Carboxymethyl Chitosan for 5-Fluorouracil Ocular Delivery: Characterization, In Vitro and In Vivo Studies.

This study investigates the development of topically applied non-invasive amino-functionalized silica nanoparticles (AMSN) and O-Carboxymethyl chitosan-coated AMSN (AMSN-CMC) for ocular delivery of 5-Fluorouracil (5-FU). Particle characterization was performed by the DLS technique (Zeta-Sizer), and structural morphology was examined by SEM and TEM. The drug encapsulation and loading were determined by the indirect method using HPLC. Physicochemical characterizations were performed by NMR, TGA, FTIR, and PXRD. In vitro release was conducted through a dialysis membrane in PBS (pH 7.4) using modified Vertical Franz diffusion cells. The mucoadhesion ability of the prepared nanoparticles was tested using the particle method by evaluating the change in zeta potential. The transcorneal permeabilities of 5-FU from AMNS-FU and AMSN-CMC-FU gel formulations were estimated through excised goat cornea and compared to that of 5-FU gel formulation. Eye irritation and ocular pharmacokinetic studies from gel formulations were evaluated in rabbit eyes. The optimum formulation of AMSN-CMC-FU was found to be nanoparticles with a particle size of 249.4 nm with a polydispersity of 0.429, encapsulation efficiency of 25.8 ± 5.8%, and drug loading capacity of 5.2 ± 1.2%. NMR spectra confirmed the coating of AMSN with the CMC layer. In addition, TGA, FTIR, and PXRD confirmed the drug loading inside the AMSN-CMC. Release profiles showed 100% of the drug was released from the 5-FU gel within 4 h, while AMSN-FU gel released 20.8% of the drug and AMSN-CMC-FU gel released around 55.6% after 4 h. AMSN-CMC-FU initially exhibited a 2.45-fold increase in transcorneal flux and apparent permeation of 5-FU compared to 5-FU gel, indicating a better corneal permeation. Higher bioavailability of AMSN-FU and AMSN-CMC-FU gel formulations was found compared to 5-FU gel in the ocular pharmacokinetic study with superior pharmacokinetics parameters of AMSN-CMC-FU gel. AMSN-CMC-FU showed 1.52- and 6.14-fold higher AUC0-inf in comparison to AMSN-FU and 5-FU gel, respectively. AMSN-CMC-FU gel and AMSN-FU gel were "minimally irritating" to rabbit eyes but showed minimal eye irritation potency in comparison to the 5 FU gel. Thus, the 5-FU loaded in AMSN-CMC gel could be used as a topical formulation for the treatment of ocular cancer.

Burnout and Depressive Symptoms in Healthcare Professionals: A Cross-Sectional Study in Saudi Arabia.

OBJECTIVES: The study objectives were to examine the prevalence of burnout among healthcare professionals, analyze the association of depression and burnout among healthcare professionals, and explore the factors related to burnout. METHODS: A prospective cross-sectional study using a validated questionnaire was conducted among healthcare professionals in a tertiary teaching hospital in Saudi Arabia's central region. The Maslach Burnout Inventory (MBI) questionnaire was used to measure burnout through emotional exhaustion, depersonalization, and personal accomplishment. Descriptive and inferential statistics were carried out using SAS version 9.4. RESULTS: The study sample was composed of 139 healthcare professionals. Around 48% of the study sample were nurses, 26% were physicians, 19% were pharmacists, and 6% were other healthcare professionals. About 61% screened positive for depression. Overall, one third of the participants had a high risk of burnout. Around 61.8% of the participants were in the high-risk group of the EE, 58.3% of the DP, and 41.0% of the PA subscales. Scores for the overall MBI were significantly different between various age groups, gender, those with social and financial responsibility, income, job titles, or years of experience. A higher risk of burnout in all subscales was observed among those with depression. CONCLUSIONS: A high risk of burnout was observed among healthcare professionals. The level of burnout was connected to workplace factors and the presence of depression. The burnout suffering among these healthcare professionals underlines the need to study further how to reduce the factors that contribute to burnout and the impact of interventions to reduce healthcare professionals' burnout levels. The burnout scientific literature would benefit from further high-quality research with larger samples using longitudinal study designs to identify the causal risk factors.

New Isatin-Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity.

BACKGROUND: Cancer remains the leading cause of human morbidity universally. Hence, we sought to assess the in vitro antiproliferative activity of new isatin-based conjugates (5a-s) against three human cancer cell lines. METHODS: The antiproliferative activities of compounds 5a-s were evaluated in vitro and their ADME (absorption, distribution, metabolism and excretion) was carried out using standard protocols. Subsequently, Western blot analysis was conducted to elucidate the potential antiproliferative mechanism of compounds 5a-s. RESULTS: The in vitro antiproliferative activities of compounds 5a-s against the tested cancer cell lines ranged from 20.3 to 95.9%. Compound 5m had an IC50 value of 1.17 µM; thus, its antiproliferative potency was approximately seven-fold greater than that of sunitinib (IC50 = 8.11 µM). In-depth pharmacological testing was conducted with compound 5m to gain insight into the potential antiproliferative mechanism of this class of compounds. Compound 5m caused an increase in the number of cells in the G1 phase, with a concomitant reduction of those in the G2/M and S phases. Additionally, compound 5m significantly and dose-dependently reduced the amount of phosphorylated retinoblastoma protein detected. Compound 5m enhanced expression of B cell translocation gene 1, cell cycle-associated proteins (cyclin B1, cyclin D1, and phosphorylated cyclin-dependent kinase 1), and a pro-apoptotic protein (Bcl-2-associated X protein gene), and activated caspase-3. ADME predictions exposed the oral liability of compounds 5a-s. CONCLUSION: Herein, we revealed the antiproliferative activity and ADME predictions of the newly-synthesized compounds 5a-s and provided a detailed insight into the pharmacological profile of compound 5m. Thus, compounds 5a-s can potentially be exploited as new antiproliferative lead compounds for cancer chemotherapeutic.

Thermosensitive hydrogels a versatile concept adapted to vaginal drug delivery.

Vaginal drug delivery represents an attractive strategy for local and systemic delivery of drugs otherwise poorly absorbed after oral administration. The rather dense vascular network, mucus permeability and the physiological phenomenon of the uterine first-pass effect can all be exploited for therapeutic benefit. However, several physiological factors such as an acidic pH, constant secretion, and turnover of mucus as well as varying thickness of the vaginal epithelium can impact sustained drug delivery. In recent years, polymers have been designed to tackle challenges mentioned above. In particular, thermosensitive hydrogels hold great promise due to their stability, biocompatibility, adhesion properties and adjustable drug release kinetics. Here, we discuss the physiological and anatomical uniqueness of the vaginal environment and how it impacts the safe and efficient vaginal delivery and also reviewed several thermosensitive hydrogels deemed suitable for vaginal drug delivery by addressing specific characteristics, which are essential to engage the vaginal environment successfully.