Preparation, Characterization and Evaluation of Flavonolignan Silymarin Effervescent Floating Matrix Tablets for Enhanced Oral Bioavailability.

The convenient and highly compliant route for the delivery of active pharmaceutical ingredients is the tablet. A versatile platform of tablets is available for the delivery of therapeutic agents to the gastrointestinal tract. This study aimed to prepare gastro retentive drug delivery floating tablets of silymarin to improve its oral bioavailability and solubility. Hydroxypropyl methylcellulose (HPMCK4M and HPMCK15), Carbopol 934p and sodium bicarbonate were used as a matrix, floating enhancer and gas generating agent, respectively. The prepared tablets were evaluated for physicochemical parameters such as hardness, weight variation, friability, floating properties (floating lag time, total floating time), drug content, stability study, in vitro drug release, in vivo floating behavior and in vivo pharmacokinetics. The drug-polymer interaction was studied by Differential Scanning Calorimetry (DSC) thermal analysis and Fourier transform infrared (FTIR). The floating lag time of the formulation was within the prescribed limit (<2 min). The formulation showed good matrix integrity and retarded the release of drug for >12 h. The dissolution can be described by zero-order kinetics (r2 = 0.979), with anomalous diffusion as the release mechanism (n = 0.65). An in vivo pharmacokinetic study showed that Cmax and AUC were increased by up to two times in comparison with the conventional dosage form. An in vivo imaging study showed that the tablet was present in the stomach for 12 h. It can be concluded from this study that the combined matrix system containing hydrophobic and hydrophilic polymers min imized the burst release of the drug from the tablet and achieved a drug release by zero-order kinetics, which is practically difficult with only a hydrophilic matrix. An in vivo pharmacokinetic study elaborated that the bioavailability and solubility of silymarin were improved with an increased mean residence time.

The relationship between hydroxychloroquine plasma concentration and COVID-19 outcomes in rheumatoid arthritis patients in Saudi Arabia.

Background: The drug hydroxychloroquine (HCQ) is widely used to treat rheumatoid arthritis (RA) and has been repurposed for the treatment of COVID-19. This study aims to determine whether HCQ concentration levels in individuals with RA alter the incidence of COVID-19 or its complications. Methods: We collected plasma samples from 13 individuals with confirmed rheumatoid arthritis (RA) to measure HCQ concentration levels. The study included individuals at least 18 years old who had been taking HCQ for at least six months at daily doses ranging from 200 to 400 mg. Results: The study enrolled a total of 13 RA patients. All patients were chronic HCQ users. Among the 13 patients, 7 patients were receiving HCQ at a dose of 200 mg per day, and 6 patients were receiving HCQ at a dose of 400 mg per day. COVID-19 confirmed cases accounted for approximately 46% of all patients. Half of the infected patients (n = 3) were taking a daily dose of 200 mg daily, while the other half were taking 400 mg daily. COVID-19 symptoms ranged from mild to moderate, and the intensity of the symptoms was not severe enough to necessitate hospitalization. COVID-19 symptoms in RA patients included headache, fever, fatigue, dry cough, and loss of taste or smell. Conclusions: Our findings indicated that there was no correlation between HCQ concentrations in rheumatoid arthritis patients and the occurrence of COVID-19 or its complications.

Nephroprotective Effect of Bergapten Against Cyclophosphamide-Mediated Renal Stress, Inflammation, and Fibrosis in Wistar Rats: Probable Role of NF-kB and TGF-ß1 Signaling Molecules.

Cyclophosphamide (CPM) is a well-established antineoplastic drug with marked clinical outcomes in various types of cancers. Despite being a promising drug, its use is associated with significant renal toxicity and often limits its use, leading to compromised clinical outcomes. Therefore, this study explored the renal protective effect of bergapten (BGP), a natural bioactive compound that showed marked antioxidant, anti-inflammatory, anticancer, and neuroprotective effects. Till now, BGP has not been studied for its renal protective effect in an in vivo model. Animals were divided into control, toxic, BGP-3, BGP-10, and BGP Per se. The control group was treated with normal saline for 2 weeks. To the toxic group, CPM 200 mg/kg was given on day 7 as i.p. To BGP-3, 10, and Per se, BGP-3 and 10 mg/kg, ip was given 2 weeks with a single shot of CPM 200 day 7. To the Per se group, only BGP 10 mg/kg, ip was given from day 1 to day 14. After 14 days, animals were sacrificed, and kidneys were removed and studied for the markers of oxidative stress, inflammation, renal injury, renal fibrosis, and renal damage using biochemical, histopathological, and immunohistochemical studies. We found that BGP-10 effectively reversed the damage toward normal, whereas BGP-3 failed to exhibit a significant renal protective effect. We conclude that bergapten could be a potential renal protective drug, and hence, more detailed cellular molecular-based studies are needed to bring this drug from the bench to the bedside.

Nanoengineered chitosan functionalized titanium dioxide biohybrids for bacterial infections and cancer therapy.

Nanoengineered chitosan functionalized titanium dioxide biohybrids (CTiO2@NPs) were prepared with Amomum subulatum Roxb extract via one-pot green method and assessed by UV-Vis spectroscopy, XRD, SEM and EDAX analyses. As revealed by XRD pattern, the nanohybrids exhibits a rutile TiO2 crystallites around 45 nm in size. The emergence of the Ti-O-Ti bond is identified by observing a peak between 400 and 800 cm-1. A wide bandgap (4.8 eV) has been observed in CTiO2@NPs, due to the quantum confinement effects and the oxygen vacancies reveal the intriguing potential of developed nanohybrids for various applications. Surface flaws were identified by observing an emission band at 382, 437, 482, 517, and 556 nm. They also exhibit better antibacterial performances using well diffusion method against Staphylococcus aureus, Bacillus substilis, Klebsiella pneumonia, and Escherichia coli. CTiO2@NPs were discovered to have free radical scavenging activity on DPPH analysis and exhibit IC50 value as 95.80 µg/mL and standard (Vitamin C) IC50 is 87.62 µg/mL. CTiO2@NPs exhibited better anticancer properties against the osteosarcoma (MG-63) cell line. All these findings suggest that there is a forum for further useful therapeutic applications. Therefore, we claim that nano-engineered carbohydrated TiO2 phytohybrid is a promising solution for bacterial infections and bone cancer.

Recent Progress in Chitosan-Based Nanomedicine for Its Ocular Application in Glaucoma.

Glaucoma is a degenerative, chronic ocular disease that causes irreversible vision loss. The major symptom of glaucoma is high intraocular pressure, which happens when the flow of aqueous humor between the front and back of the eye is blocked. Glaucoma therapy is challenging because of the low bioavailability of drugs from conventional ocular drug delivery systems such as eye drops, ointments, and gels. The low bioavailability of antiglaucoma agents could be due to the precorneal and corneal barriers as well as the low biopharmaceutical attributes of the drugs. These limitations can be overcome by employing nanoparticulate drug delivery systems. Over the last decade, there has been a lot of interest in chitosan-based nanoparticulate systems to overcome the limitations (such as poor residence time, low corneal permeability, etc.) associated with conventional ocular pharmaceutical products. Therefore, the main aim of the present manuscript is to review the recent research work involving the chitosan-based nanoparticulate system to treat glaucoma. It discusses the significance of the chitosan-based nanoparticulate system, which provides mucoadhesion to improve the residence time of drugs and their ocular bioavailability. Furthermore, different types of chitosan-based nanoparticulate systems are also discussed, namely nanoparticles of chitosan core only, nanoparticles coated with chitosan, and hybrid nanoparticles of chitosan. The manuscript also provides a critical analysis of contemporary research related to the impact of this chitosan-based nanomedicine on the corneal permeability, ocular bioavailability, and therapeutic performance of loaded antiglaucoma agents.

Predicting Hydroxychloroquine Clearance in Healthy and Diseased Populations Using a Physiologically Based Pharmacokinetic Approach.

Hydroxychloroquine (HCQ), a congener of chloroquine, is widely used in prophylaxis and the treatment of malaria, and also as a cure for rheumatoid arthritis, systemic lupus erythematosus, and various other diseases. Physiologically based pharmacokinetic modeling (PBPK) has attracted great interest in the past few years in predicting drug pharmacokinetics (PK). This study focuses on predicting the PK of HCQ in the healthy population and extrapolating it to the diseased populations, i.e., liver cirrhosis and chronic kidney disease (CKD), utilizing a systematically built whole-body PBPK model. The time vs. concentration profiles and drug-related parameters were obtained from the literature after a laborious search and in turn were integrated into PK-Sim software for designing healthy intravenous, oral, and diseased models. The model's evaluation was performed using observed-to-predicted ratios (Robs/Rpre) and visual predictive checks within a 2-fold error range. The healthy model was then extrapolated to liver cirrhosis and CKD populations after incorporating various disease-specific pathophysiological changes. Box-whisker plots showed an increase in AUC0-t in liver cirrhosis, whereas a decrease in AUC0-t was seen in the CKD population. These model predictions may assist clinicians in adjusting the administered HCQ doses in patients with different degrees of hepatic and renal impairment.

Development of a Curcumin-Loaded Lecithin/Chitosan Nanoparticle Utilizing a Box-Behnken Design of Experiment: Formulation Design and Influence of Process Parameters.

Curcumin (CUR) has impressive pharmacologic properties, including cardioprotective, neuroprotective, antimicrobial, and anticancer activity. However, the pharmaceutical application of CUR is limited due to its poor aqueous solubility and low bioavailability. The development of novel formulations has attracted considerable attention to the idea of applying nanobiotechnology to improve the therapeutic efficacy of these challenging compounds. In this study, CUR-loaded lecithin−chitosan nanoparticles (CUR/LCSNPs) were developed and optimized by the concentration of chitosan, lecithin, and stirring speed by a 3-factorial Box-Behnken statistical design, resulting in an optimal concentration of chitosan (A) and lecithin (B) with a 1200 rpm stirring speed (C), with applied constraints of minimal average particle size (Y1), optimal zeta potential (Y2), and maximum entrapment efficiency (%EE) (Y3). The mean particle size of the checkpoint formulation ranged from 136.44 ± 1.74 nm to 267.94 ± 3.72, with a zeta potential of 18.5 ± 1.39 mV to 36.8 ± 3.24 mV and %EE of 69.84 ± 1.51% to 78.50 ± 2.11%. The mean particle size, zeta potential, %EE, and % cumulative drug release from the optimized formulation were 138.43 ± 2.09 nm, +18.98 ± 0.72 mV, 77.39 ± 1.70%, and 86.18 ± 1.5%, respectively. In vitro drug release followed the Korsmeyer−Peppas model with Fickian diffusion (n < 0.45). The optimized technique has proven successful, resulting in a nanoformulation that can be used for the high loading and controlled release of lipophilic drugs.

Physicochemical Characterization of Chitosan-Decorated Finasteride Solid Lipid Nanoparticles for Skin Drug Delivery.

Finasteride is considered the drug of choice for androgenic alopecia and benign prostate hyperplasia. The aim of the study was to formulate nanodrug carriers of finasteride with enhanced retentive properties in the skin. The finasteride was formulated as solid lipid nanoparticles that were decorated with different concentrations of chitosan for improved retentive properties. Solid lipid nanoparticles (SLNs) were synthesized by "high-speed homogenization technique" using stearic acid as a solid lipid while PEG-6000 and Tween-80 were used as surfactants. The SLNs were evaluated for particle size, polydispersity index (PDI), zeta potential, drug entrapment efficiency, and drug release behavior. The mean particle size of SLNs was in the range of 10.10 nm to 144.2 nm. The PDI ranged from 0.244 to 0.412 while zeta potential was in the range of 8.9 mV to 62.6 mV. The drug entrapment efficiency in chitosan undecorated formulations was 48.3% while an increase in drug entrapment was observed in chitosan-decorated formulations (51.1% to 62%). The in vitro drug release studies of SLNs showed an extended drug release for 24 hours after 4 hours of initial burst release. The extended drug release was observed in chitosan-coated SLNs in comparison with uncoated nanoparticles. The permeation and retention study revealed higher retention of drug in the skin and low permeation with chitosan-decorated SLNs that ranged from 39.4 µg/cm2 to 13.2 µg/cm2. TEM images depicted spherical shape of SLNs. The stability study confirmed stable formulations in temperature range of 5°C and 40°C for three months. It is concluded from this study that the SLNs of finasteride were successfully formulated and chitosan decoration enhanced the drug retention in the skin layers. Therefore, these formulations could be used in androgenic alopecia and benign prostate hyperplasia to avoid the side effects, drug degradation, and prolonged use of drug with conventional oral therapy.

Effect of chronic hydroxychloroquine use on COVID-19 risk in patients with rheumatoid arthritis and systemic lupus erythematosus: a multicenter retrospective cohort.

OBJECTIVE: Hydroxychloroquine (HCQ) has been used during the coronavirus disease 2019 (COVID-19) pandemic because of its reported anti-viral activity. This study examined the association of chronic HCQ use with the incidence and complications of COVID-19. METHODS: This retrospective cohort study included adults with rheumatoid arthritis and/or systemic lupus erythematosus who visited rheumatology clinics in three tertiary hospitals in Riyadh, Saudi Arabia between January 2019 and December 2020. Patients were categorized into two groups based on HCQ use. Data were obtained from the electronic health record and by interviews with patients. The primary study objective was the incidence of COVID-19 and its complications from March 2020 to February 2021. RESULTS: Almost 11% of the study cohort was positive for COVID-19, and the incidence of COVID-19 was similar between HCQ users (11.11%) and nonusers (10.86%). Disease complication rates were similar in the study arms, and they mainly included fever, dry cough, fatigue, and breathing difficulty. CONCLUSIONS: This study revealed no significant association between chronic HCQ use and the incidence of COVID-19, and disease complications were similar in the study arms.

Roflumilast protects from cisplatin-induced testicular toxicity in male rats and enhances its cytotoxicity in prostate cancer cell line. Role of NF-κB-p65, cAMP/PKA and Nrf2/HO-1, NQO1 signaling.

Cisplatin (CIS)-induced testicular injury is a major obstacle in its application as antineoplastic agent. In this study, we investigated the protective effect and mechanism of roflumilast (ROF), a PDE4 inhibitor, against CIS-induced testicular toxicity in rats. Besides, the cytotoxic effect of CIS, with and without ROF, was evaluated on PC3 cell line. ROF reversed CIS-induced abnormalities in sperm characteristics, normalized serum testosterone level, and ameliorated CIS-induced alterations in testicular and epidydimal weights and restored normal testicular structure. Moreover, ROF increased intracellular cAMP level, PKA and HO-1 activities and Nrf2, NQO-1 and HO-1 gene expression, improved testicular oxidative stress parameters (TBARS, NO, GSH levels, and CAT activity) and inflammatory mediators (IL-1ß and TNF-α, and NF-κß p65gene expression) and reduced the proapoptotic proteins, caspase-3, Bax and increased Bcl-2. Lastly, in vitro analyses showed that ROF augmented the anticancer efficacy of CIS and enhanced the increase in gene expression of Nrf2, HO-1, and NQO-1 and the inhibition of gene expression of NF-κß p65 induced by CIS and enhanced its apoptotic effect in PC3 cells. Conclusively, PDE4 inhibition with induction of Nrf2/HO-1, NQO-1 is a potential therapeutic approach to protect male reproductive system from the detrimental effects with augmenting, the antineoplastic effect of CIS.

Piclamilast mitigates 1,2-dimethylhydrazine induced colon cancer in rats through modulation of Ras/PI3K/Akt/mTOR and NF-κß signaling.

Colorectal cancer (CRC) is the third leading type of adult cancer in both genders with high morbidity and mortality worldwide. Even though the discovery of many antineoplastic drugs for CRC, the current therapy is not adequately efficient.This study was designed to investigate the effect and mechanism of Piclamilast (PIC), a selective PDE4 inhibitor, on a DMH-induced colorectal cancer (CRC) rat model. The rats were grouped (n = 10) into group 1 (control), group 2 (PIC 3 mg/kg, p.o.), groups 3-5 received DMH (20 mg/kg/week, S.C.), and groups 4 and 5 received PIC (1 and 3 mg/kg/day, p.o.) for 15 weeks. The DMH treatment increased aberrant crypt foci (ACF), Proliferating cell nuclear antigen (PCNA), and TBARS levels, along with decreased antioxidant defenses (GSH, GSH-Px, and catalase). Increased NF-κß expression and inflammatory cytokines were also evident. PIC dose-dependently reduced ACF and restored oxidative stress and inflammatory markers favorably. Moreover, PIC in its large, tested dose only significantly increased the intracellular level of cAMP and suppressed the activation of Ras and PI3K and its downstream Akt/mTOR signaling. Furthermore, PIC promoted CRC apoptosis, and increased the gene expression of the apoptotic factors, caspase-3 and Bax, and decreased the anti-apoptotic factor Bcl-2. The results of this study show that PIC may be a promising therapeutic agent for the treatment of CRC. PIC might inhibit the proliferation of CRC cells and induce apoptosis via multiple mechanisms that involve its antioxidant effect and inhibition of NF-κß and Ras/PI3K/Akt/mTOR signaling.

Exploitation of Design-of-Experiment Approach for Design and Optimization of Fast-Disintegrating Tablets for Sublingual Delivery of Sildenafil Citrate with Enhanced Bioavailability Using Fluid-Bed Granulation Technique.

Sildenafil citrate undergoes first-pass metabolism, resulting in poor oral bioavailability at 25-41% of the administered dose. This study aimed to design and optimize fast-disintegrating tablets for the sublingual delivery of sildenafil citrate to improve bioavailability and facilitate rapid onset of action. The design-of-experiment (DoE) approach using 32 full factorial design was conducted to develop a new formulation of sildenafil fast-disintegrating sublingual tablets (FDSTs) using the fluid-bed granulation technique. The levels of partially pre-gelatinized starch (5-15%) and microcrystalline cellulose (10-60%) were selected as independent formulation variables. The prepared FDSTs were investigated for physical properties. Further, the optimum formulation was chosen for in vivo study in rabbits. Regression analysis showed that independent variables have a significant (p < 0.05) influence on critical attributes of FDSTs. The optimized formulation showed acceptable mechanical strength (friability < 1.0%) with very fast disintegration (14.561 ± 0.84 s) and dissolution (94.734 ± 2.76% after 15 min). Further, the optimized formulation demonstrated a significant increase (p < 0.01) in Cmax and AUC0-∞ with short tmax compared to the market product (Viagra®). Based on these results, using the DoE approach, a high level of assurance was achieved for FDSTs' product quality and performance.

Microwave Enabled Physically Cross Linked Sodium Alginate and Pectin Film and Their Application in Combination with Modified Chitosan-Curcumin Nanoparticles. A Novel Strategy for 2nd Degree Burns Wound Healing in Animals.

This study reports microwave assisted physically cross-linked sodium alginate and pectin film and their testing in combination with modified chitosan-curcumin nanoparticles for skin tissue regeneration following 2nd degree burn wound. Film was formulated by solution casting method and physically cross-linked using microwave irradiation at frequency of 2450 MHz, power 750 Watt for different time intervals for optimization. The optimized formulation was analyzed for various physiochemical attributes. Afterwards, the optimized film and optimized modified chitosan-curcumin nanoparticles were tested in combination for skin regeneration potential following burn wound in vivo and skin samples extracted and tested for different attributes. The results indicated that the optimized film formulation (5 min microwave treatment) physicochemical attributes significantly enhanced addressing the properties required of a wound healing platform. The vibrational analysis indicated that the optimized film experienced significant rigidification of hydrophilic domains while the hydrophobic domains underwent significant fluidization which also resulted in significant increase in the transition temperatures and system enthalpies of both polymer moieties with microwave treatment. The combined film and nanoparticles application significantly increased protein content in the wounds which were evident from higher absorbance ratios of amide-I and amide-II (2.15 ± 0.001), significantly higher melting transition temperature and enthalpy (∆T = 167.2 ± 15.4 °C, ∆H = 510.7 ± 20.1 J/g) and higher tensile strength (14.65 ± 0.8 MPa) with significantly enhanced percent re-epithelization (99.9934 ± 2.56) in comparison to other treatments. The combined application of film and nanoparticles may prove to be a new novel treatment strategy for 2nd degree burn wound healing.

Oral nano-delivery of anticancer ginsenoside 25-OCH3-PPD, a natural inhibitor of the MDM2 oncogene: Nanoparticle preparation, characterization, in vitro and in vivo anti-prostate cancer activity, and mechanisms of action.

The Mouse Double Minute 2 (MDM2) oncogene plays a critical role in cancer development and progression through p53-dependent and p53-independent mechanisms. Both natural and synthetic MDM2 inhibitors have been shown anticancer activity against several human cancers. We have recently identified a novel ginsenoside, 25-OCH3-PPD (GS25), one of the most active anticancer ginsenosides discovered thus far, and have demonstrated its MDM2 inhibition and anticancer activity in various human cancer models, including prostate cancer. However, the oral bioavailability of GS25 is limited, which hampers its further development as an oral anticancer agent. The present study was designed to develop a novel nanoparticle formulation for oral delivery of GS25. After GS25 was successfully encapsulated into PEG-PLGA nanoparticles (GS25NP) and its physicochemical properties were characterized, the efficiency of MDM2 targeting, anticancer efficacy, pharmacokinetics, and safety were evaluated in in vitro and in vivo models of human prostate cancer. Our results indicated that, compared with the unencapsulated GS25, GS25NP demonstrated better MDM2 inhibition, improved oral bioavailability and enhanced in vitro and in vivo activities. In conclusion, the validated nano-formulation for GS25 oral delivery improves its molecular targeting, oral bioavailability and anticancer efficacy, providing a basis for further development of GS25 as a novel agent for cancer therapy and prevention.