Safety and efficacy of robotic anti-reflux surgery in geriatric patients: a comparative analysis.

INTRODUCTION: As our population ages, older adults are being considered for anti-reflux surgery (ARS). Geriatric patients typically have heightened surgical risk, and literature has shown mixed results regarding postoperative outcomes. We sought to evaluate the safety and efficacy of robotic ARS in the geriatric population. METHODS: We conducted a single-institution review of ARS procedures performed between 2009 and 2023. Patients ≥ 65 were assigned to the geriatric cohort. We compared operative details, lengths of stay (LOS), readmissions, reoperations, and complications between the two cohorts. The gastroesophageal reflux disease health-related quality of life (GERD-HRQL) survey and review of clinic notes were used to evaluate ARS efficacy. RESULTS: 628 patients were included, with 190 in the geriatric cohort. This cohort had a higher frequency of diabetes (16.3% vs 5.9% p < 0.0001), hypertension (50.0% vs 21.5% p < 0.0001), and heart disease (17.9% vs 2.3% p < 0.0001). Geriatric patients were more likely to exhibit hiatal hernias on imaging (51.6% vs 34.2% p < 0.0001) and were more likely to have large hernias (30.0% vs 7.1% p < 0.0001). Older adults were more likely to undergo Toupet fundoplications (58.4% vs 41.3%, p < 0.0001), Collis gastroplasties (9.5% vs 2.7% p < 0.0001), and relaxing incisions (11.6% vs 1.4% p < 0.0001). Operative time was longer for geriatric patients (132.0 min vs 104.5 min p < 0.0001). There were no significant differences in LOS, readmissions, or reoperations between cohorts. Geriatric patients exhibited lower rates of complications (7.4% vs. 14.6%, p = 0.011), but similar complication grades. Both groups had significant reduction in symptom scores from preoperative values. There were no significant differences in the reported symptoms between cohorts at any follow-up timepoint. CONCLUSION: Geriatric robotic ARS patients tend to do as well as younger adults regarding postoperative and symptomatic outcomes, despite presenting with larger hiatal hernias and shorter esophagi. Clinicians should be aware of possible need for lengthening procedures or relaxing incisions in this population.

Opium use and gastrointestinal cancers: a systematic review and meta-analysis study.

Aim: The current systematic review and meta-analysis aimed to assess the association between Gastrointestinal (GI) cancers and opium use. Background: GI malignancies are a global public health issue and are associated with many risk factors including genetic and lifestyle factors. Methods: PubMed, Web of Science, Embase and Scopus and the Google Scholar search engine in addition to Persian databases including Magiran and SID were searched using relevant keywords. The associations of opium use, long duration of opium use, high daily amount opium use and high cumulative opium use and GI cancer and various subtypes of GI cancers were estimated and pooled in format of odds ratios (OR) and their corresponding 95% confidence intervals (CI) with a random effects model. Results: 22 articles that were published between 1983 and 2022 entered the analyses. There were significant relationships between opium use based on crude effect sizes (OR: 2.53, 1.95-3.29) and adjusted effect sizes (OR: 2.64, 1.99-3.51), high daily opium use (or: 3.41, 1.92-6.06), long duration of opium use (OR: 3.03, 1.90-4.84) and high cumulative opium use (OR: 3.88, 2.35-6.41), all compared to never opium use, and GI cancer. The results were not sensitive to sensitivity analyses and no influential publication biases were found in these analyses. Conclusion: Our meta-analysis showed that opium use could be associated with increased risk of overall and some particular GI cancers including oropharyngeal, gastric, pancreatic and colorectal cancers. Opium use as a potentially modifiable factor, therefore, should be more emphasized.

Solubility vs Dissolution in Physiological Bicarbonate Buffer.

BACKGROUND: Phosphate buffer is often used as a replacement for the physiological bicarbonate buffer in pharmaceutical dissolution testing, although there are some discrepancies in their properties making it complicated to extrapolate dissolution results in phosphate to the in vivo situation. This study aims to characterize these discrepancies regarding solubility and dissolution behavior of ionizable compounds. METHODS: The dissolution of an ibuprofen powder with a known particle size distribution was simulated in silico and verified experimentally in vitro at two different doses and in two different buffers (5 mM pH 6.8 bicarbonate and phosphate). RESULTS: The results showed that there is a solubility vs. dissolution mismatch in the two buffers. This was accurately predicted by the in-house simulations based on the reversible non-equilibrium (RNE) and the Mooney models. CONCLUSIONS: The results can be explained by the existence of a relatively large gap between the initial surface pH of the drug and the bulk pH at saturation in bicarbonate but not in phosphate, which is caused by not all the interfacial reactions reaching equilibrium in bicarbonate prior to bulk saturation. This means that slurry pH measurements, while providing surface pH estimates for buffers like phosphate, are poor indicators of surface pH in the intestinal bicarbonate buffer. In addition, it showcases the importance of accounting for the H2CO3-CO2 interconversion kinetics to achieve good predictions of intestinal drug dissolution.

Comparative Evaluation of Dissolution Performance in a USP 2 Setup and Alternative Stirrers and Vessel Designs: A Systematic Computational Investigation.

The dissolution testing method described in the United States Pharmacopeia (USP) Chapter ⟨711⟩ is widely used for assessing the release of active pharmaceutical ingredients from solid dosage forms. However, extensive use over the years has revealed certain issues, including high experimental intervariability observed in specific formulations and the settling of particles in the dead zone of the vessel. To address these concerns and gain a comprehensive understanding of the hydrodynamic conditions within the USP 2 apparatus, computational fluid dynamic simulations have been employed in this study. The base design employed in this study is the 900 mL USP 2 vessel along with a paddle stirrer at a 50 rpm rotational speed. Additionally, alternative stirrer designs, including the hydrofoil, pitched blade, and Rushton impeller, are investigated. A comparison is also made between a flat-bottom tank and the USP round-bottom vessel of the same volume and diameter. Furthermore, this work examines the impact of various parameters, such as clearance distance (distance between the bottom of the impeller and bottom of the vessel), number of impeller blades, impeller diameter, and impeller attachment angle. The volume-average shear rate (Stv), fluid velocity (Utv), and energy dissipation rates (ϵtv) represent the key properties evaluated in this study. Comparing the USP2 design and systems with the same stirrer but flat-bottom vessel reveals more homogeneous mixing compared to the USP2 design. Analyzing fluid flow streamlines in different designs demonstrates that hydrofoil stirrers generate more suspension or upward movement of fluid compared to paddle stirrers. Therefore, when impellers are of a similar size, hydrofoil designs generate higher fluid velocities in the coning area. Furthermore, the angle of blade attachment to the hub influences the fluid velocity in the coning area in a way that the 60° angle design generates more suspension than the 45° angle design. The findings indicate that the paddle stirrer design leads to a heterogeneous shear rate and velocity distributions within the vessel compared with the other designs, suggesting suboptimal performance. These insights provide valuable guidance for the development of improved in vitro dissolution testing devices, emphasizing the importance of optimized design considerations to minimize hydrodynamic variability, enhance dissolution characterization, and reduce variability in dissolution test results. Ultimately, such advancements hold potential for improving in vitro-in vivo correlations in drug development.

Particle Size, Dose, and Confinement Affect Passive Diffusion Flux through the Membrane Concentration Boundary Layer.

The authors present a steady-state-, particle-size-, and dose-dependent dissolution-permeation model that describes particle dissolution within the concentration boundary layer (CBL) adjacent to a semipermeable surface. It is critical to understand how particle size and dose affect the behavior of dissolving particles in the presence of a CBL adjacent to a semipermeable surface both in vivo and in vitro. Control of particle size is ubiquitous in the pharmaceutical industry; however, traditional pharmaceutical assumptions of particle dissolution typically ignore particle dissolution within the length scale of the CBL. The CBL does not physically prevent particles from traveling to the semipermeable surface (mucus, epithelial barrier, synthetic membrane, etc.), and particle dissolution can occur within the CBL thickness (δC) if the particle is sufficiently small (∼dparticle ≤ δC). The total flux (the time rate transport of molecules across the membrane surface per unit area) was chosen as a surrogate parameter for measuring the additional mass generated by particles dissolving within the donor CBL. Mass transfer experiments aimed to measure the total flux of drug using an ultrathin large-area membrane diffusion cell described by Sinko et al. with a silicone-based membrane ( Mol. Pharmaceutics 2020, 17, (7) 2319-2328, DOI: 10.1021/acs.molpharmaceut.0c00040). Suspensions of ibuprofen, a model weak-acid drug, with three different particle-size distributions with average particle diameters of 6.6, 37.4, and 240 µm at multiple doses corresponding to a range of suspension concentrations with dimensionless dose numbers of 2.94, 14.7, 147, and 588 were used to test the model. Experimentally measured total flux across the semipermeable membrane/CBL region agreed with the predictions from the proposed model, and at a range of relatively low suspension concentrations, dependent on the average particle size, there was a measurable effect on the flux due to the difference in δC that formed at the membrane surface. Additionally, the dose-dependent total flux across the membrane was up to 10% higher than the flux predicted by the standard Higuchi-Hiestand dissolution model where the effects of confinement were ignored as described by Wang et al. ( Mol. Pharmaceutics 2012, 9 (5), 1052-1066, DOI: 10.1021/mp2002818).

Impedance planimetry (EndoFLIPTM) and surgical outcomes after Hill compared to Toupet fundoplication.

INTRODUCTION: Endoluminal functional lumen imaging probe (EndoFLIP) provides a real-time assessment of gastroesophageal junction (GEJ) compliance during fundoplication. Given the limited data on EndoFLIP measurements during the Hill procedure, we investigated the impact of the Hill procedure on GEJ compliance compared to Toupet fundoplication. METHODS: Patients who underwent robotic Hill or Toupet fundoplication with intraoperative EndoFLIP between 2017 and 2022 were included. EndoFLIP measurements of the GEJ included cross sectional surface area (CSA), intra-balloon pressure, high pressure zone length (HPZ), distensibility index (DI), and compliance. Subjective reflux symptoms, gastroesophageal reflux disease-health related quality of life (GERD-HRQL) score, and dysphagia score were assessed pre-operatively as well as at short- and longer-term follow-up. RESULTS: One-hundred and fifty-four patients (71.9%) had a Toupet fundoplication while sixty (28%) patients underwent the Hill procedure. The CSA [27.7 ± 10.9 mm2 vs 42.2 ± 17.8 mm2, p < 0.0001], pressure [29.5 ± 6.2 mmHg vs 33.9 ± 8.5 mmHg, p = 0.0009], DI [0.9 ± 0.4 mm2/mmHg vs 1.3 ± 0.6 mm2/mmHg, p = 0.001], and compliance [25.9 ± 12.8 mm3/mmHg vs 35.4 ± 13.4 mm3/mmHg, p = 0.01] were lower after the Hill procedure compared to Toupet. However, there was no difference in post-fundoplication HPZ between procedures [Hill: 2.9 ± 0.4 cm, Toupet: 3.1 ± 0.6 cm, p = 0.15]. Follow-up showed no significant differences in GERD-HRQL scores, overall dysphagia scores or atypical symptoms between groups (p > 0.05). CONCLUSION: The Hill procedure is as effective to the Toupet fundoplication in surgically treating gastroesophageal reflux disease (GERD) despite the lower CSA, DI, and compliance after the Hill procedure. Both procedures led to DI < 2 mm2/mmHg with no significant differences in dysphagia reporting (12-24) months after the procedure. Further studies to elucidate a cutoff value for DI for postoperative dysphagia development are still warranted.

A Global, Regional, and National Burden and Quality of Care Index for Schizophrenia: Global Burden of Disease Systematic Analysis 1990-2019.

BACKGROUND AND HYPOTHESIS: Schizophrenia is a mental disorder usually presented in adulthood that affects roughly 0.3 percent of the population. The disease contributes to more than 13 million years lived with disability the global burden of disease. The current study aimed to provide new insights into the quality of care in Schizophrenia via the implementation of the newly introduced quality of care index (QCI) into the existing data. STUDY DESIGN: The data from the global burden of disease database was used for schizophrenia. Two secondary indices were calculated from the available indices and used in a principal component analysis to develop a proxy of QCI for each country. The QCI was then compared between different sociodemographic index (SDI) and ages. To assess the disparity in QCI between the sexes, the gender disparity ratio (GDR) was also calculated and analyzed in different ages and SDIs. STUDY RESULTS: The global QCI proxy score has improved between 1990 and 2019 by roughly 13.5%. Concerning the gender disparity, along with a rise in overall GDR the number of countries having a GDR score of around one has decreased which indicates an increase in gender disparity regarding quality of care of schizophrenia. Bhutan and Singapore had 2 of the highest QCIs in 2019 while also showing GDR scores close to one. CONCLUSIONS: While the overall conditions in the quality of care have improved, significant disparities and differences still exist between different countries, genders, and ages in the quality of care regarding schizophrenia.

Tehranolid and Artemisinin Effects on Ameliorating Experimental Autoimmune Encephalomyelitis by Modulating Inflammation and Remyelination.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. Artemisinin (ART) is a natural sesquiterpene lactone with an endoperoxide bond that is well-known for its anti-inflammatory effects in experimental autoimmune encephalomyelitis (EAE), the most commonly used animal model of MS. Tehranolide (TEH) is a novel compound with structural similarity to ART. In this study, we aimed to investigate the ameliorating effect of TEH on EAE development by targeting proteins and genes involved in this process and compare its effects with ART. Female C57BL/6 mice were immunized with MOG35-55. Twelve days post-immunization, mice were treated with 0.28 mg/kg/day TEH and 2.8 mg/kg/day ART for 18 consecutive days, and the clinical score was measured daily. The levels of pro-inflammatory and anti-inflammatory cytokines were assessed in mice serum and splenocytes by ELISA. We also evaluated the mRNA expression level of cytokines, as well as genes involved in T cell differentiation and myelination in the spinal cord tissue by qRT-PCR. Administration of TEH and ART significantly alleviated EAE signs. A significant reduction in IL-6 and IL-17 secretion and IL-17 and IL-1 gene expression in spinal cord were observed in the TEH-treated group. ART had similar or less significant effects. Moreover, TGF-ß, IL-4, and IL-10 genes were stimulated by ART and TEH in the spinal cord, while the treatments did not affect IFN-γ expression. Both treatments dramatically increased the expression of FOXP3, GATA3, MBP, and AXL. Additionally, the T-bet gene was reduced after TEH administration. The compounds made no changes in RORγt, nestin, Gas6, Tyro3, and Mertk mRNA expression levels in the spinal cord. The study revealed that both TEH and ART can effectively modulate the genes responsible for inflammation and myelination that play a crucial role in EAE. Interestingly, TEH demonstrated a greater potency compared to ART and hence may have the potential to be evaluated in interventions for the management of MS.

Evaluation of ASGE Criteria for Prediction of Choledocholithiasis: Can Early Endoscopic Ultrasound Utilization Make the Prediction More Accurate?

Background: ASGE predictive model for the detection of choledocholithiasis is a reasonable approach for the management of patients with cholelithiasis. Surgeons do not pursue cholecystectomy without evaluation of the biliary system when laboratory tests and diagnostic imaging evidence show biliary duct involvement. Literature revisions reveal that the prediction of choledocholithiasis based on ASGE criteria suffers from poor accuracy which results in unnecessary ERCPs. We decided to estimate the sensitivity and specificity of the ASGE predictive model for the detection of choledocholithiasis with the hope that early EUS would obviate the need for unnecessary ERCPs among highly probable patients for choledocholithiasis based on ASGE criteria. Methods: This is a prospective intervention and control study on the accuracy of ASGE criteria for the prediction of choledocholithiasis. To evaluate the sensitivity and specificity of ASGE criteria, patients were followed in two groups of controls who were treated based on ASGE guidelines and cases who underwent primary EUS. The clinical relevance of the ASGE criteria was estimated by sensitivity and specificity using SPSS Statistics 28 software. Then, absolute risk reduction utilizing primary EUS was also calculated. Results: The sensitivity and specificity of the ASGE predictive guideline for choledocholithiasis were estimated to be 62.31% and 51.85%, respectively. Evaluation of the ASGE guideline also revealed that patients in the intermediate probability group who finally required ERCP based on EUS results (false-negatives) were estimated to be 49.1% and patients who were predicted to require ERCP but finally did not need ERCP (false positives) were estimated to be 37.68%. The comparison of the two groups revealed the need for ERCP in about 55.56% of the primary EUS group and 77.42% in the ASGE group. Utilization of primary EUS reduced the need for ERCP by an absolute risk reduction of 0.299. (Primary Endpoint). Conclusion: ASGE guideline is associated with the overestimation of ERCP in cholelithiasis. The usage of primary EUS will reduce the need for ERCP.

Use of Gastrointestinal Simulator, Mass Transport Analysis, and Absorption Simulation to Investigate the Impact of pH Modifiers in Mitigating Weakly Basic Drugs' Performance Issues Related to Gastric pH: Palbociclib Case Study.

It is well known that reduced gastric acidity, for example with concomitant administration of acid reducing agents, can result in variable pharmacokinetics and decreased absorption of weakly basic drugs. It is important to identify the risk of reduced and variable absorption early in development, so that product design options to address the risk can be considered. This article describes the utilization of in vitro and in silico tools to predict the effect of gastric pH, as well as the impact of adding pH modifiers, in mitigating the effect of acid reducing agents on weak base drugs' dissolution and absorption. Palbociclib, a weakly basic drug, was evaluated in low and high gastric pH conditions in a multicompartmental dissolution apparatus referred to as a gastrointestinal simulator (GIS). The GIS permits the testing of pharmaceutical products in a way that better assesses dissolution under physiologically relevant conditions of pH, buffer concentration, formulation additives, and physiological variations including GI pH, buffer concentrations, secretions, stomach emptying rate, residence time in the GI, and aqueous luminal volume. To predict drug dissolution in the GIS, a hierarchical mass transport model was used and validated using in vitro experimental data. Dissolution results were then compared to observed human clinical plasma data with and without proton pump inhibitors using a GastroPlus absorption model to predict palbociclib plasma profiles and pharmacokinetic parameters. The results showed that the in silico model successfully predicted palbociclib dissolution in the GIS under low and high gastric pH conditions with and without pH modifiers. Furthermore, the GIS data coupled with the in silico tools anticipated (1) the reduced palbociclib exposure due to proton pump inhibitor coadministration and (2) the mitigating effect of a pH-modifying agent. This study provides tools to help in the development of orally administered formulations to overcome the effect of elevated gastric pH, especially when formulating with pH modifiers.

Education case: a case-based approach to overlap syndromes in autoimmune liver disease in patient with ulcerative colitis.

Simultaneous occurrence of immune-based gastrointestinal diseases and autoimmune hepatitis, although not common, is of clinical importance. Some clinical and laboratory findings such as severe pruritus and elevated alkaline phosphatase raise suspicion of a biliary disease which overlaps autoimmune hepatitis. A strong clinical suspicion of overlap syndrome in a patient with autoimmune hepatitis prompts more diagnostic evaluations like MRCP, liver biopsy, and secondary laboratory tests. Patients who fall into the category of overlap syndrome proceed with timely monitoring of known complications including colorectal carcinomas, cholangiocarcinomas, and gallbladder cancers. It is strongly recommended that all simultaneous immune-based involvements be searched prior to labeling a patient as having pure autoimmune hepatitis. The current study attempted to express all challenges about a case with overlap syndrome referred to the gastroenterology ward of Taleghani Hospital and to review the latest articles and related guidelines about the diagnosis, treatment, complications, and surveillance of the mentioned patient with autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC), and inflammatory bowel disease (IBD).

Effect of Statins on Helicobacter pylori Eradication Rate: A Systematic Review and Meta-Analysis.

Statins have been used as adjuvants to standard treatment in order to increase the eradication rates of Helicobacter pylori infection. This study aimed to summarize the results of the efficacy of adding statins to standard treatments used for the eradication of H. pylori infection. We conducted a systematic search using a comprehensive combination of keywords in PubMed/MEDLINE, Web of Science, and Scopus to retrieve relevant studies from 1990 to 2020. The estimate of pooled relative risk (RR), as the effect measure, was calculated using random effects meta-analyses in Stata 14. We finally included 5 studies (all of them were randomized controlled trials). The meta-analysis of all studies showed that the pooled RR (95% confidence interval) was 1.03 (0.64-1.68) in the random effects model, which was not statistically significant. In other words, based on our meta-analysis, the addition of statins as an adjuvant therapy to the standard treatment regimens does not increase the rate of H. pylori eradication. However, further evidence is needed to confirm this result as the number of available studies was small.

As estatinas têm vindo a ser usadas como adjuvantes à terapêutica convencional para aumentar a taxa de erradicação da infeção por Helicobacter pylori. Este estudo sumariza os resultados da eficácia de adicionar estatinas à terapêutica convencional na erradicação da infeção por Helicobacter pylori. Usando uma combinação compreensiva de palavras-chave, efetuamos uma revisão sistemática da PubMed/MEDLINE, Web of Science e Scopus de forma a encontrar estudos relevantes na área de 1990 a 2020. A estimativa do risco relativo (RR) global, como medida de eficácia, foi calculada usando o random effects meta-analyses no Stata 14. No final incluímos 5 estudos (todos ensaios randomizados e controlados). A meta-análise de todos os estudos mostrou um RR global (Intervalo confiança (IC) 95%) de 1.03 (0.64­1.68) no random effects model, que não foi estatisticamente significativo. Portanto, baseado nesta meta-análise, a adição de estatinas às duas terapêuticas convencionais mais utilizadas não aumenta a taxa de erradicação de Helicobacter pylori. Contudo, mais evidência é necessária para confirmar estes resultados já que o número de estudos disponíveis é pequeno.

A case of posterior reversible encephalopathy syndrome during endoscopic retrograde cholangiopancreatography after anesthesia.

Posterior reversible encephalopathy syndrome (PRES) is a neurological disorder that occurs following cerebral vasogenic edema. It has diverse clinical presentations from headache and vomiting to seizure and mental status alteration. Herein, we report a 54-year-old woman with no prior disease who developed PRES in the parieto-occipital lobes and brain stem after a second attempt endoscopic retrograde cholangiopancreatography (ERCP). To our knowledge, no case of PRES during ERCP has been reported to date. This case reminds us of unusual complications that are likely to occur after ERCP. It is believed that blood pressure fluctuations and anesthetic medications, fentanyl in particular, were the main precipitating factors causing the syndrome in the current case. Even if there is no specific treatment for this condition, a diagnosis is critical to start supportive treatment.

Multi-method simulation modelling of circular manufacturing systems for enhanced decision-making.

Circular manufacturing systems (CMS) constitute complex value networks comprising a large and diverse set of stakeholders that collaborate to close the loop of products through multiple lifecycles. Complex systems modelling and simulation play a crucial role in providing quantitative and qualitative insights into the behaviour of such systems. In particular, multi-method simulation modelling that combines agent-based, discrete-event, and system dynamics simulation methods is considered more suitable to model and simulate CMS as it allows to capture their complex and dynamic nature. This paper provides a step-by-step approach on how to build a CMS multi-method simulation model in order to assess their economic, environmental, and technical performance for enhanced decision-making. To model and simulate CMS three main elements need to be considered:•A multi-method model architecture where the CMS stakeholders with heterogeneous characteristics are modelled individually as autonomous agents using agent-based, discrete-event, and system dynamics.•An agent environment defined by a Geographic Information System (GIS) to establish connections based on agents' geographic location.•The product journey resulting from the product's interaction with various CMS stakeholders in the circular value network is traced throughout its multiple lifecycles.

Naringenin and cryptotanshinone shift the immune response towards Th1 and modulate T regulatory cells via JAK2/STAT3 pathway in breast cancer.

BACKGROUND: Use of natural products has been proposed as an efficient method in modulation of immune system and treatment of cancers. The aim of this study was to investigate the potential of cryptotanshinone (CPT), naringenin, and their combination in modulating the immune response towards Th1 cells and the involvement of JAK2/STAT3 signaling pathway in these effects. METHODS: Mouse models of delayed type hypersensitivity (DTH) were produced and treated with naringenin and CPT. The proliferation of spleen cells were assessed by Bromodeoxyuridine (BrdU) assay. Flowcytometry and enzyme-linked immunosorbent assay (ELISA) tests were employed to evaluate subpopulation of T-lymphocytes and the levels of cytokines, respectively. The JAK/STAT signaling pathway was analyzed by Western blotting. RESULTS: We showed higher DTH, increased lymphocyte proliferation, decreased tumor growth and reduced JAK2/STAT3 phosphorylation in mice treated with naringenin and CPT. Moreover, a significant decline in the production of IL-4 and an upsurge in the production of IFN-γ by splenocytes were observed. Additionally, the population of intra-tumor CD4+CD25+Foxp3+ T cells was significantly lower in naringenin + CPT treated animals than that in controls. CONCLUSION: Naringenin-CPT combination could exert immunomodulatory effects, suggesting this combination as a novel complementary therapeutic regimen for breast cancer.

Evaluating the IVIVC by Combining Tiny-tim Outputs and Compartmental PK Model to Predict Oral Exposure for Different Formulations of Ibuprofen.

Nowadays, the ever-increasing costs of research and development in the pharmaceutical industry have created a big demand for predicting the performances of drug candidates. Of those, the desire to establish an in vitro-in vivo correlation (IVIVC) to better predict the oral drug exposure for different drug products is a growing need. Once a robust IVIVC is established, the performance of different drug products can be predicted and selected for testing in clinical trials with greater confidence. This tool will significantly reduce the cost and speed of drug development and provide new therapy to the patient faster. In this study, we explore combining the outputs of Triskelion's Gastro-Intestinal Model (Tiny-TIM) and multi-compartment pharmacokinetic model for a 200 mg ibuprofen product. The Loo-Riegelman method was used to calculate the amount of ibuprofen absorbed and was combined with the Tiny-TIM data to establish the IVIVC. The IVIVC was used to predict the exposures of both fast release and liquid gel formulations in humans. In general, the predicted exposure using Tiny-TIM-based IVIVC has good agreement with the clinical findings.

Anticancer properties of novel zinc oxide quantum dot nanoparticles against breast cancer stem-like cells.

Cancer stem cells (CSCs) play an essential role in cancer development, metastasis, relapse, and resistance to treatment. In this article, the effects of three synthesized ZnO nanofluids on proliferation, apoptosis, and stemness markers of breast cancer stem-like cells are reported. The antiproliferative and apoptotic properties of ZnO nanoparticles were evaluated on breast cancer stem-like cell-enriched mammospheres by MTS assay and flowcytometry, respectively. The expression of stemness markers, including WNT1, NOTCH1, ß-catenin, CXCR4, SOX2, and ALDH3A1 was assessed by real-time PCR. Western blotting was used to analyze the phosphorylation of Janus kinase 2 (JAK2) and Signal Transducer and Activator of Transcription 3 (STAT3). Markers of stemness were significantly decreased by ZnO nanofluids, especially sample (c) with code ZnO-148 with a different order of addition of polyethylene glycol solution at the end of formulation, which considerably decreased all the markers compared to the controls. All the studied ZnO nanofluids considerably reduced viability and induced apoptosis of spheroidal and parental cells, with ZnO-148 presenting the most effective activity. Using CD95L as a death ligand and ZB4 as an extrinsic apoptotic pathway blocker, it was revealed that none of the nanoparticles induced apoptosis through the extrinsic pathway. Results also showed a marked inhibition of the JAK/STAT pathway by ZnO nanoparticles; confirmed by downregulation of Mcl-1 and Bcl-XL expression. The present data demonstrated that ZnO nanofluids could combat breast CSCs via decreasing stemness markers, stimulating apoptosis, and suppressing JAK/STAT activity.

Improving Dissolution Behavior and Oral Absorption of Drugs with pH-Dependent Solubility Using pH Modifiers: A Physiologically Realistic Mass Transport Analysis.

Orally dosed drugs must dissolve in the gastrointestinal (GI) tract before being absorbed through the epithelial cell membrane. In vivo drug dissolution depends on the GI tract's physiological conditions such as pH, residence time, luminal buffers, intestinal motility, and transit and drug properties under fed and fasting conditions (Paixão, P. et al. Mol. Pharm.2018 and Bermejo, et al. M. Mol. Pharm.2018). The dissolution of an ionizable drug may benefit from manipulating in vivo variables such as the environmental pH using pH-modifying agents incorporated into the dosage form. A successful example is the use of such agents for dissolution enhancement of BCS class IIb (high-permeability, low-solubility, and weak base) drugs under high gastric pH due to the disease conditions or by co-administration of acid-reducing agents (i.e., proton pump inhibitors, H2-antagonists, and antacids). This study provides a rational approach for selecting pH modifiers to improve monobasic and dibasic drug compounds' dissolution rate and extent under high-gastric pH dissolution conditions, since the oral absorption of BCS class II drugs can be limited by either the solubility or the dissolution rate depending on the initial dose number. Betaine chloride, fumaric acid, and tartaric acid are examples of promising pH modifiers that can be included in oral dosage forms to enhance the rate and extent of monobasic and dibasic drug formulations. However, selection of a suitable pH modifier is dependent on the drug properties (e.g., solubility and pKa) and its interplay with the pH modifier pKa or pKas. As an example of this complex interaction, for basic drugs with high pKa and intrinsic solubility values and large doses, a polyprotic pH modifier can be expected to outperform a monoacid pH modifier. We have developed a hierarchical mass transport model to predict drug dissolution of formulations under varying pH conditions including high gastric pH. This model considers the effect of physical and chemical properties of the drug and pH modifiers such as pKa, solubility, and particle size distribution. This model also considers the impact of physiological conditions such as stomach emptying rate, stomach acid and buffer secretion, residence time in the GI tract, and aqueous luminal volume on drug dissolution. The predictions from this model are directly applicable to in vitro multi-compartment dissolution vessels and are validated by in vitro experiments in the gastrointestinal simulator. This model's predictions can serve as a potential data source to predict plasma concentrations for formulations containing pH modifiers administered under the high-gastric pH conditions. This analysis provides an improved formulation design procedure using pH modifiers by minimizing the experimental iterations under both in vitro and in vivo conditions.

STAT3-mediated Apoptotic-enhancing Function of Sclareol Against Breast Cancer Cells and Cell Sensitization to Cyclophosphamide.

Sclareol is an organic compound with potential anti-tumor effects against various cancer types. However, its precise molecular mechanism in the suppression of tumor growth has not been fully elucidated. In the present study, the anti-proliferative and apoptosis-inducing effects of sclareol with cyclophosphamide were investigated in breast cancer cells and the involvement of the JAK/STAT pathway was evaluated. For this purpose, MCF-7 breast cancer cells were cultured and treated with various concentrations of sclareol to determine its IC50. Cell viability was measured by MTT assay and apoptosis was assessed by flow cytometric analysis of annexin V binding. Gene and protein expression were examined by real-time PCR and Western blotting, respectively. The activity of caspase enzymes was also measured. The results showed that sclareol significantly reduced cell viability and triggered cell death and its co-administration with cyclophosphamide enhanced its anti-cancer properties. Additionally, sclareol up-regulated the expression of p53 and BAX and reduced the expression of Bcl-2. Docking studies indicated an interaction between sclareol and STAT3 which was proved by attenuation of STAT3 phosphorylation after treatment of the cells with sclareol. Sclareol was also capable of suppressing the function of IL-6 in modulating the expression of apoptosis-associated genes. Altogether these data suggest the potential of sclareol as an anti-cancer agent and demonstrate that a combination of sclareol with cyclophosphamide might serve as an effective chemotherapeutic approach resulting in improvements in the treatment of breast cancer.