3D bioprinting of liver models: A systematic scoping review of methods, bioinks, and reporting quality.

Background: Effective communication is crucial for broad acceptance and applicability of alternative methods in 3R biomedical research and preclinical testing. 3D bioprinting is used to construct intricate biological structures towards functional liver models, specifically engineered for deployment as alternative models in drug screening, toxicological investigations, and tissue engineering. Despite a growing number of reviews in this emerging field, a comprehensive study, systematically assessing practices and reporting quality for bioprinted liver models is missing. Methods: In this systematic scoping review we systematically searched MEDLINE (Ovid), EMBASE (Ovid) and BioRxiv for studies published prior to June 2nd, 2022. We extracted data on methodological conduct, applied bioinks, the composition of the printed model, performed experiments and model applications. Records were screened for eligibility and data were extracted from included articles by two independent reviewers from a panel of seven domain experts specializing in bioprinting and liver biology. We used RAYYAN for the screening process and SyRF for data extraction. We used R for data analysis, and R and Graphpad PRISM for visualization. Results: Through our systematic database search we identified 1042 records, from which 63 met the eligibility criteria for inclusion in this systematic scoping review. Our findings revealed that extrusion-based printing, in conjunction with bioinks composed of natural components, emerged as the predominant printing technique in the bioprinting of liver models. Notably, the HepG2 hepatoma cell line was the most frequently employed liver cell type, despite acknowledged limitations. Furthermore, 51% of the printed models featured co-cultures with non-parenchymal cells to enhance their complexity. The included studies offered a variety of techniques for characterizing these liver models, with their primary application predominantly focused on toxicity testing. Among the frequently analyzed liver markers, albumin and urea stood out. Additionally, Cytochrome P450 (CYP) isoforms, primarily CYP3A and CYP1A, were assessed, and select studies employed nuclear receptor agonists to induce CYP activity. Conclusion: Our systematic scoping review offers an evidence-based overview and evaluation of the current state of research on bioprinted liver models, representing a promising and innovative technology for creating alternative organ models. We conducted a thorough examination of both the methodological and technical facets of model development and scrutinized the reporting quality within the realm of bioprinted liver models. This systematic scoping review can serve as a valuable template for systematically evaluating the progress of organ model development in various other domains. The transparently derived evidence presented here can provide essential support to the research community, facilitating the adaptation of technological advancements, the establishment of standards, and the enhancement of model robustness. This is particularly crucial as we work toward the long-term objective of establishing new approach methods as reliable alternatives to animal testing, with extensive and versatile applications.

Factors that Influence the Need to Start Adaptive Radiotherapy.

Introduction: Adaptive radiotherapy (ART) is an essential approach to account for anatomical and biological uncertainties. Adaptive radiotherapy is, however, time-consuming, and it is unclear which patients are eligible or when is the best time to start ART. Methods: This prospective study was conducted at Kasr El-Aini Center of Clinical Oncology and Nuclear Medicine, Cairo, Egypt from January 2019 to December 2020. Thirty patients with pathologically proven, limited-stage small cell or stage I-II non-small cell lung cancer who were either not fit for or refused surgery or had stage III disease were recruited and underwent treatment planning to receive 60 Gy on a conventional 3D conformal radiation schedule with platinum-based chemotherapy. All patients underwent computed tomography (CT) planning within 2 and 4 weeks of starting radiation therapy to assess the need for adaptation. Pulmonary function test and echocardiography findings were assessed at the end of treatment and at 3 and 6 months after treatment, and were compared to the baseline. Results: We found a significant reduction in mean value of the planning target volume (PTV) in the CT scans at the second (331 cm3) and fourth (257 cm3) weeks of treatment as compared to baseline (342 cm3) (p-value < 0.0001). Adaptation decreased the dose to the organ at risk with statistical significance and with improvement of the target coverage. At week 2 of radiotherapy, the need for adaptation was correlated to the conformity index (p = 0.0473), esophageal V35 (p = 0.0488), esophageal V50 (p = 0.0295), and its mean dose (p = 0.0087). At week 4 it was correlated to forced expiratory volume in 1 second (FEV1) (p = 0.0303), ratio between the forced expiratory volume in 1 second and the forced vital capacity (FEV1/FVC) (p = 0.0024), and echocardiography (p = 0.0183). Conclusions: Conformity index and esophageal dose constraints can predict the need for adaptation at week 2, whereas baseline pulmonary function parameters and echocardiography can predict the need for adaptation at week 4 of radiotherapy.

Altered Pharmacokinetics Parameters of Vancomycin in Patients with Hematological Malignancy with Febrile Neutropenia, a Bayesian Software Estimation.

The pharmacokinetics of vancomycin vary significantly between specific groups of patients, such as critically ill patients and patients with hematological malignancy (HM) with febrile neutropenia (FN). Recent evidence suggests that the use of the usual standard dose of antibiotics in patients with FN may not offer adequate exposure due to pharmacokinetic variability (PK). Therefore, the purpose of this study is to assess the effect of FN on AUC0-24 as a key parameter for vancomycin monitoring, as well as to determine which vancomycin PK parameters are affected by the presence of FN using Bayesian software PrecisePK in HM with FN. This study was carried out in King Abdulaziz Medical City. All adult patients who were admitted to the Princess Norah Oncology Center PNOC between 1 January and 2017 and 31 December 2020, hospitalized and received vancomycin with a steady-state trough concentration measured before the fourth dose, were included. During the trial period, 297 patients received vancomycin during their stay at the oncology center, 217 of them meeting the inclusion criteria. Pharmacokinetic parameters were estimated for the neutropenic and non-FN patients using the precise PK Bayesian platform. The result showed that there was a significant difference (p < 0.05) in vancomycin clearance Clvan, the volume of distribution at a steady-state Vdss, the volume of distribution for peripheral compartment Vdp, half-life for the elimination phase t½ß, and the first-order rate constant for the elimination process ß in FN compared to non-FN patients. Furthermore, AUC0-24 was lower for FN patients compared to non-FN patients, p < 0.05. FN has a significant effect on the PK parameters of vancomycin and AUC0-24, which may require specific consideration during the treatment initiation.

Current clinical practice in the management of phyllodes tumors of the breast: an international cross-sectional study among surgeons and oncologists.

PURPOSE: Phyllodes tumors of the breast are rare fibroepithelial lesions that are classified as benign, borderline or malignant. There is little consensus on best practice for the work-up, management, and follow-up of patients with phyllodes tumors of the breast, and evidence-based guidelines are lacking. METHODS: We conducted a cross-sectional survey of surgeons and oncologists with the aim to describe current clinical practice in the management of phyllodes tumors. The survey was constructed in REDCap and distributed between July 2021 and February 2022 through international collaborators in sixteen countries across four continents. RESULTS: A total of 419 responses were collected and analyzed. The majority of respondents were experienced and worked in a university hospital. Most agreed to recommend a tumor-free excision margin for benign tumors, increasing margins for borderline and malignant tumors. The multidisciplinary team meeting plays a major role in the treatment plan and follow-up. The vast majority did not consider axillary surgery. There were mixed opinions on adjuvant treatment, with a trend towards more liberal regiments in patients with locally advanced tumors. Most respondents preferred a five-year follow-up period for all phyllodes tumor types. CONCLUSIONS: This study shows considerable variation in clinical practice managing phyllodes tumors. This suggests the potential for overtreatment of many patients and the need for education and further research targeting appropriate surgical margins, follow-up time and a multidisciplinary approach. There is a need to develop guidelines that recognize the heterogeneity of phyllodes tumors.

Chimeric Antigen Receptor Structure and Manufacturing of Clinical Grade CAR Engineered Cells using Different Bioreactors.

Increasing success of adaptive cell therapy (ACT), such as genetically engineered T cells to express chimeric antigen receptors (CARs) proven to be highly significant technological advancements and impressive clinical outcomes in selected haematological malignancies, with promising efficacy. The evolution of CAR designs beyond the conventional structures is necessary to address some of the limitations of conventional CAR therapy and to expand the use of CAR T cells to a wider range of malignancies. There are various obstacles with a wide range of engineering strategies in order to improve the safety, efficacy and applicability of this therapeutic modality. Here we describe details of modular CAR structure with all the necessary domains and what is known about proximal CAR signalling in T cells. Furthermore, the global need for adoptive cell therapy is expanding very rapidly, and there is an urgent increasing demand for fully automated manufacturing methods that can produce large scale clinical grade high quality CAR engineered immune cells. Despite the advances in automation for the production of clinical grade CAR engineered cells, the manufacturing process is costly, consistent and involves multiple steps, including selection, activation, transduction, and Ex-Vivo expansion. Among these complex manufacturing phases, the choice of culture system to generate a high number of functional cells needs to be evaluated and optimized. Here we list the most advance fully automated to semi-automated bioreactor platforms can be used for the production of clinical grade CAR engineered cells for clinical trials but are far from being standardized. New processing options are available and a systematic effort seeking automation, standardization and the increase of production scale, would certainly help to bring the costs down and ultimately democratise this personalized therapy. In this review, we describe in detail different CAR engineered T cell platforms available and can be used in future for clinical-grade CAR engineered ATMP production.

Posterior tibial nerve stimulation as a neuromodulation therapy in treatment of neurogenic overactive bladder in multiple sclerosis: A prospective randomized controlled study.

BACKGROUND: one of the major annoying disorders occurring in people with multiple sclerosis is lower urinary tract disorders (LUT). Urgency is considered the main one seriously influencing the quality of life. Neurogenic detrusor over activity (DOAB) is characterized by a hyperreflexic, overactive detrusor that responds quickly to low-intensity sensory input from general visceral afferent fibers. Overactivity has been claimed to induce random, uncontrolled contractions of the detrusor muscle, leading to intravesicular pressure rise, producing urgency, frequency, and consequently incontinence AIM: To demonstrate the therapeutic efficacy for posterior tibial nerve stimulation (PTNS) in neurogenic over active bladder (NOAB) in people with multiple sclerosis METHODS: The current trial is a prospective, randomized controlled study. Forty remitting relapsing males with MS with moderate NOAB symptoms were randomly assigned into two equal groups; control group (C) treated by selected therapeutic exercises program for strengthening pelvic floor muscles and an intervention group (ES) receiving an additional posterior tibial nerve electrical stimulation. Each session ranged from 45- 50 minutes, three days weekly for a month. Outcome measures were recorded before starting the treatment and after termination of the study intervention and included over active bladder symptoms score (OVBS) score, urodynamic parameters (uroflow, filling and voiding cystometry), and post voiding residual volume by abdominal ultrasound RESULTS: There was a significant improvement of all voiding parameters compared to baseline and the group C except frequency of urgency incontinence. A significant decrease was detected in post-treatment mean episodes number of nighttime frequency, urgency, urgency incontinence (1.65 ± 0.93, 1.2 ± 0.52 and 1.5 ± 0.76) respectively of the ES group compared to that of group C (3.05 ± 1.09, 2.25 ± 0.71 and 2.25 ± 1.06) (P < 0.01). There was a significant decrease in median post-treatment OVBS score 3 (3-3) compared to group C median score 5 (6-4). A statistically significant improvement was observed of all urodynamic parameters (bladder capacity and compliance, Detrusor overactivity (DO), maximum flow rate and post voidal residual volume in the ES group compared to the group C CONCLUSION: PTNS is a promising and potentially beneficial treatment option for NOAB symptoms in males with MS and superior to pelvic floor muscle training alone.

Augmented Renal Clearance and Hypoalbuminemia-Induced Low Vancomycin Trough Concentrations in Febrile Neutropenic Patients With Hematological Malignancies.

INTRODUCTION: Vancomycin administration in individuals with hematological malignancy or neutropenia is associated with a suboptimal trough concentration. Nonetheless, most studies did not distinguish whether low vancomycin trough concentrations were due to hematological malignancies or neutropenia. This study aimed to determine the association between types of hematological malignancy and febrile neutropenia with low vancomycin concentrations. METHODS: The present retrospective chart review study was conducted by using clinical data adopted from computerized physician order entries (BestCare®) for all of the patients who received intravenous vancomycin treatment between January 2017 and December 2020 at King Abdulaziz Medical City in Jeddah. RESULTS: Out of the 296 patients, 217 were included. There was no significant association between the type of hematological malignancy and the incidence of a low trough concentration (p > 0.05), while a significant association between febrile neutropenia and the incidence of a low trough concentration was observed (p < 0.05). Furthermore, the predictors for a low trough among febrile neutropenic patients were creatinine clearance (CrCI) and a low albumin concentration. In addition, there was a significant association between febrile neutropenia and augmented renal clearance (p < 0.05). CONCLUSIONS: The findings of this study conclude that febrile neutropenia is associated with low vancomycin concentrations. Interestingly, augmented renal clearance was observed in most of the febrile neutropenia patients with a significant association, which is considered the main driver for a low trough in neutropenic patients.

Cross-Linked Chitosan/Gelatin Beads Loaded with Chlorella vulgaris Microalgae/Zinc Oxide Nanoparticles for Adsorbing Carcinogenic Bisphenol-A Pollutant from Water.

Water polluted by phenolic compounds is a global threat to health and the environment; accordingly, we prepared a green novel sorbent biological system from a chitosan (CS), gelatin (GT), and Chlorella vulgaris freshwater microalgae (m-Alg) composite impregnated with zinc oxide nanoparticles (ZnO-NPs) for the remediation of bisphenol-A (BPA) from water. C. vulgaris was selected to be one of the constituents of the prepared composite because of its high capability in phytoremediation. The morphology and the structure of CS/GT*m-Alg/ZnO beads were characterized by SEM, FTIR, XRD, and TGA. Different monitoring experimental conditions, such as contact time, pH, BPA concentration, and sorbent dosage, were optimized. The optimum conditions for the adsorption process showed outstanding removal efficiency toward BPA at pH 4.0, contact time 40.0 min, and 40.0 mg L-1 BPA initial concentration. Langmuir, Freundlich, and Temkin isotherm models have been studied for adsorption equilibrium, and the best fit is described by the Langmuir adsorption isotherm. The adsorption kinetics has been studied using pseudo-first-order (PFO), pseudo-second-order (PSO), Elovich, and intraparticle diffusion (IPD) models. The pseudo-second-order kinetic model shows the optimum experimental fit. The monolayer adsorption capacity of the prepared CS/GT*m-Alg/ZnO for BPA was determined to be 38.24 mg g-1. The prepared CS/GT*m-Alg/ZnO beads show advantageous properties, such as their high surface area, high adsorption capacity, reusability, and cost-effectiveness.

Fabrication of Polyaniline@ß-cyclodextrin Nanocomposite for Adsorption of Carcinogenic Phenol from Wastewater.

We synthesized a stable, eco-friendly, and low-cost polyaniline@ß-cyclodextrin (PANI@ß-CD) nanocomposite via oxidative polymerization for phenol adsorption from water waste since phenol pollution is a global danger to human and animal health and the environment. The production of the composite and synergistic alteration of PANI with ß-CD resulted in 66% reduction in particle size from 59 nm (PANI) to 20 nm (PANI@ß-CD) as well as better phenol adsorption. Fourier transform infrared spectroscopy (FT-IR), X-ray diffraction (XRD), scanning electron microscope (SEM), and thermogravimetric analysis (TGA) were used to analyze the produced PANI@ß-CD nanocomposite. Our results show the optimum conditions for phenol adsorption: time (50 min), pH (8.0), nanosorbent dose (0.5 g), and the sorption isotherm fitted with Langmuir model; the monolayer adsorption capacity of the prepared PANI@ß-CD for phenol was determined to be 8.56 mg g-1. The average pore size, total pore volume, and surface area of PANI/ßCD nanocomposite are 15.62 nm, 0.1586 cm3/g, and 90.901 m2/g, respectively, for the pseudo second order model. Finally, modifying PANI nanoparticles with ßCD allowed reusability up to four cycles with superior adsorption performance of ∼95% using (0.01 N) HNO3.

A novel ß-cyclodextrin/alginate-combined-nickel oxide nanosorbent for adsorptive remediation of 51Cr and 56Mn radionuclides.

A Promising nanocomposite from ß-Cyclodextrin/Alginate (ß-CD/Alg) composite impregnated with nickel oxide nanoparticles (NiO) has been synthesized and characterized using diverse techniques like FT-IR, XRD, TGA, and SEM. The new nanocomposite has been investigated for the efficient remediation of 51Cr and 56Mn radionuclides from simulated contaminated radioactive water. All the controlling experimental parameters such as solution pH, contact time, initial radionuclides concentration and adsorbent mass have been investigated and optimized. The distribution coefficient values Kd (mL/g) for 51Cr and/or 56Mn radionuclides have been calculated for all factors it was found that the optimum pH values were at 5 and 6 with Kd 5300, and 4500, for 51Cr and/or 56Mn, respectively and the equilibrium was at 90 and 100 (min) with Kd values 5600 and 4800 for 51Cr and/or 56Mn, respectively.

Spontaneous Formation of 3D Breast Cancer Tissues on Electrospun Chitosan/Poly(ethylene oxide) Nanofibrous Scaffolds.

Three-dimensional (3D) tissue culture has attracted a great deal of attention as a result of the need to replace the conventional two-dimensional cell cultures with more meaningful methods, especially for understanding the sophisticated nature of native tumor microenvironments. However, most techniques for 3D tissue culture are laborious, expensive, and limited to spheroid formation. In this study, a low-cost and highly effective nanofibrous scaffold is presented for spontaneous formation of reproducible 3D breast cancer microtissues. Experimentally, aligned and non-aligned chitosan/poly(ethylene oxide) nanofibrous scaffolds were prepared at one of two chitosan concentrations (2 and 4 wt %) and various electrospinning parameters. The resulting fabricated scaffolds (C2P1 and C4P1) were structurally and morphologically characterized, as well as analyzed in silico. The obtained data suggest that the fiber diameter, surface roughness, and scaffold wettability are tunable and can be influenced based on the chitosan concentration, electrospinning conditions, and alignment mode. To test the usefulness of the fabricated scaffolds for 3D cell culture, a breast cancer cell line (MCF-7) was cultured on their surfaces and evaluated morphologically and biochemically. The obtained data showed a higher proliferation rate for cells grown on scaffolds compared to cells grown on two-dimensional adherent plates (tissue culture plate). The MTT assay revealed that the rate of cell proliferation on nanofibrous scaffolds is statistically significantly higher compared to tissue culture plate (P ≤ 0.001) after 14 days of culture. The formation of spheroids within the first few days of culture shows that the scaffolds effectively support 3D tissue culture from the outset of the experiment. Furthermore, 3D breast cancer tissues were spontaneously formed within 10 days of culture on aligned and non-aligned nanofibrous scaffolds, which suggests that the scaffolds imitate the in vivo extracellular matrix in the tumor microenvironment. Detailed mechanisms for the spontaneous formation of the 3D microtissues have been proposed. Our results suggest that scaffold surface topography significantly influences tissue formation and behavior of the cells.

Castor oil for labor initiation in women with a previous cesarean section: a double-blind randomized study.

Objective: To evaluate the efficacy of castor oil in initiation of labor in women who had one previous cesarean section. This study was conducted as a trial to increase the rate of vaginal birth after cesarean (VBAC) and decrease the rate of elective repeated cesarean section (ERCS).Methods: A double-blinded randomized controlled study was conducted in an Egyptian University Hospital from July 2019 to July 2020. The participants were 70 pregnant women who had one previous cesarean section, singleton pregnancy in cephalic presentation, with a Bishop score ≤6 attempting to perform a trial of labor. Sixty mL castor oil was administered to group A and 60 mL sunflower oil was administered to group B (as a placebo) for initiation of labor at the start of week 39. Primary outcomes were the percentage of women entering the active phase of labor within 24 h after receiving castor oil or placebo and the number of successful VBAC deliveries.Results: Labor started in 16 patients (45.7%) within 24 h in the castor oil group and in 3 patients in the placebo group (8.5%), while the rate of successful VBAC was 65.7% (23 patients) in the castor oil group and 48.5% (17 patients) in the placebo group.Conclusion: Castor oil appears to be an effective, low-cost, and non-harmful method for the initiation of labor in patients with a previous cesarean section.

Proposed Geometrical Tool for Cases of Laterally Adapted Tibial Tubercle during Total Knee Replacement.

The alignment of tibial component in total knee replacement operation must be achieved in three planes to ensure optimum results. In coronal plane, the alignment depends on three anatomical landmarks. These landmarks are tibial tuberosity, leg shin, and midtalar point. In eastern community, people get used to sit cross-legged which causes additional tension in the quadriceps muscle which is attached distally to the tibial tuberosity. This tension causes adaptation of the tuberosity laterally. Tuberosity adaptation causes the three anatomical landmarks being not collinear. In this work, eight cases of lateral adapted tubercle were diagnosed of this condition before the surgery and their X-ray images after the surgery were checked regarding tibial alignment. Tibial alignment has been checked by measuring the medial proximal tibial angle (MPTA) which is the angle between the mechanical tibial axis and the tibial component plateau. MPTAs for the eight cases were (86.9°-93.6°). Three cases had MPTA less than 90° indicating varus alignment and five of them had MPTA more than 90° indicating valgus alignment. A geometrical tool was designed using the DesignSpark Mechanical software as a proposed solution to solve the adaptation problem. The tool can give a method for fixing the tibial component precisely without any varus\valgus malalignment.

Role of polymeric materials in preventing COVID-19 infection.

The safety of personal protective equipment (PPE) is very important, and so is the choice of materials used. The ability of electrostatic charges (ESCs) generated from the friction of engineered materials to attract or repel viruses has a significant impact on their applications. This study examined the ESCs generated on the surface of PPE used by healthcare workers to enhance their potential effectiveness in protecting the wearer from viruses. This is a crucial consideration for the newly emerged severe acute respiratory syndrome corona virus 2 (SARS-CoV-2), which has a negative charge. The magnitudes and signs of generated ESCs on the surfaces of the PPE were determined experimentally using an Ultra Stable Surface DC Voltmeter. The high negative ESCs acquired by the polyethylene disposable cap and facemask are expected to repel negatively charged viruses and prevent them from adhering to the outer layer of the material. Also, the choice of polypropylene for facemasks and gowns is excellent because it is an aggressively negatively charged material in the triboelectric series. This property guarantees that facemasks and gowns can repel viruses from the wearer. However, the positive ESCs generated on latex glove surfaces are of great concern because they can attract negatively charged viruses and create a source of infection. In conclusion, it is necessary to ensure that PPE be made of materials whose surfaces develop a negative ESC to repel viruses, as well as to select polyethylene gloves.

Protective Effects of Low Dose Vorinostat on Cisplatin-Induced Nephrotoxicity in Rats.

BACKGROUND AND AIM: Cisplatin (cis-diamminedichloroplatinum [II]; CDDP) is the most widely used drug in cancer chemotherapy. The nephrotoxicity of CDDP is one of its major side effects. Vorinostat (VST) has been reported to have antioxidant and anti-inflammatory effects in bothin-vitro and in vivo models. The present study aimed to explore the potential protective effects of VST against CDDP-induced nephrotoxicity in rats. MATERIALS AND METHODS: The rats were randomly divided into 4 groups; control group, CDDP group (received CDDP 7.5 mg/kg IP single dose 5 days before the end of the experiment), VST group, (received VST 15 mg/kg/day by gastric gavage for 28 days), and CDDP + VST group (received CDDP + VST as above). Blood and kidney samples were collected on the 28th day for biochemical and histopathological examinations. RESULTS: Administration of CDDP single dose (7.5 mg/kg IP) 5 days before the end of the experiment (at day 23) produced a significant decrease in renal glutathione levels and a significant increase in serum urea nitrogen, creatinine, renal malondialdehyde, tumor necrosis factor-alpha, tumor suppressor protein (p53) and nuclear factor kappa B levels compared to the control group. Pretreatment with VST for 28 days significantly attenuated all unfavorable changes of these parameters. Histopathological analysis showed that VST significantly decreased kidney inflammatory and degenerative changes induced by CDDP. VST also significantly increased Bcl-2 and decreased Caspas- 3 immunoexpression in renal tissues. CONCLUSION: These results suggest that VST alleviates CDDP-induced nephrotoxicity in rats showing a novel therapeutic potential for the management of nephrotoxicity induced by CDDP.

Colon-Targeted Therapy of Tacrolimus (FK506) in the Treatment of Experimentally Induced Colitis.

BACKGROUND/AIMS: Inflammatory bowel disease is a chronic or remitting/relapsing intestinal inflammation, which comprises Crohn's disease and ulcerative colitis (UC). Severe UC is a life-threatening condition that requires corticosteroids (CS) as a first-line rescue therapy. Some patients are refractory to CS and may require alternative immunosuppressive therapy. Oral tacrolimus (FK506), an immunosuppressive agent, has been reported to be effective in the management of severe refractory UC, but it can cause serious adverse effects. This work aims to study the effect of tacrolimus delivered by a colon-targeted delivery system (CTDS) in a dextran sulfate sodium (DSS)-induced animal model of colitis. MATERIALS AND METHODS: We developed and evaluated an oral CTDS of tacrolimus (FK506) loaded pH-dependent polymeric microspheres, composed of Eudragit® S100 as a pH-sensitive polymer using the oil-in-water emulsion method. The physicochemical properties and drug release profiles of these microparticles in gastrointestinal tract (GIT) conditions were examined. A DSS-induced colitis rat model was used to evaluate the potential remedial and in vivo distribution of microspheres. RESULTS: The pH-microspheres prevented a burst drug release in acidic pH conditions and showed sustained release at a colonic pH. The in vivo distribution study in the rat GIT demonstrated that pH-microspheres were successfully delivered to the inflamed colon. Moreover, it also demonstrated a significant decrease of disease activity and expression of proinflammatory cytokines, such as tumor necrosis factor α, interleukin-1ß (IL-1ß), and IL-6, and minimized the histological and morphometric changes. CONCLUSION: The results confirmed the efficacy of tacrolimus (FK506) CTDs in the management of DSS-induced colitis.

A randomized controlled trial of the safety and efficacy of preoperative rectal misoprostol for prevention of intraoperative and postoperative blood loss at elective cesarean delivery.

OBJECTIVE: To assess the safety and efficacy of preoperative rectal misoprostol for the prevention of intraoperative and postoperative blood loss in women undergoing elective cesarean delivery. METHODS: A single-blind randomized controlled trial of 200 full-term pregnant women scheduled for elective cesarean delivery. Computer-generated randomization allocated women to receive 400 µg rectal misoprostol at urinary catheter insertion plus 400 µg rectally after abdominal closure (preoperative group, n=100) or 800 µg of rectal misoprostol after abdominal closure (postoperative group, n=100). Primary outcome was intraoperative blood loss. RESULTS: Intraoperative blood loss was significantly lower in the preoperative misoprostol group compared with the postoperative group (528.7 ± 114.8 mL vs 788.6 ± 165.8 mL; P<0.001). Blood loss during the first 24 hours after delivery was also lower in the preoperative group (199.3 ± 84.5 mL vs 302.9 ± 125.6 mL; P<0.001). Fewer women in the preoperative group needed additional uterotonics (7 vs 21; P<0.001). After delivery, the decrease in both hemoglobin and hematocrit levels was significantly less in the preoperative group (-6.8 vs -12.8% and -6.05 vs -17.8%, respectively; P<0.001). CONCLUSION: Preoperative rectal administration of misoprostol significantly reduced intraoperative and postoperative blood loss during and after elective cesarean delivery. ClinicalTrial.gov ID: NCT03680339. Date of registration 9/2018.

Impact of thymoquinone on cyclosporine A pharmacokinetics and toxicity in rodents.

OBJECTIVES: Cyclosporine A (CsA) is an immunosupprsant drug used to prevent graft rejection and in the treatment of several autoimmune diseases. Thyomquinone (TQ), a bioactive component of Nigella sativa, has strong antioxidant properties and has been used in prevention of many toxicities, hence its protective effect and pharmacokinetic interactions with CsA was investigated in this study. METHODS: For bioavailability study, the rats were divided into four groups: TQ (PO, 10 mg/kg) was given alone for 7 days, then TQ plus CsA for another 5 days, CsA was given by two routes (po) and (IP) in a dose of 10 mg/kg 1 h after administration of TQ. Blood samples were taken at the 12th day at specified times, CsA level was determined by immune assays. The protective effect of TQ was studied. Blood samples for lab investigations and histopathology were taken at the 28th day. KEY FINDINGS: Thyomquinone reduced the bioavailability of oral CsA by around 32% (P > 0.05). However, bioavailability of IP administered CsA was not affected. Chronic administration of CsA increased concentrations of fasting glucose and Cystatin C and produced marked s kidney alteration of parenchyma which was reversed by concomitant administration of TQ. CONCLUSIONS: A potential drug interaction between TQ and CsA, which may reduced its oral bioavailability. Independently TQ caused significant attenuation of CsA induced renal toxicity and diabetogenic effect.