Preparation, characterization and ex vivo-in vivo assessment of candesartan cilexetil nanocrystals via solid dispersion technique using an alkaline esterase activator carrier.

The objective of this study was to improve candesartan cilexetil (CC) efficacy by formulating nanocrystals via solid dispersion (SD) technique using tromethamine (Tris). SD was prepared by solvent evaporation at different drug carrier ratios, evaluated for particle size, vitro dissolution studies, TEM, FTIR, and X-ray powder diffraction. Ex vivo, in vivo pharmacokinetic parameters were conducted on selected formulae compared to drug suspension and marketed product. Size analysis demonstrated formation of particles in the nanorange lower than 300 nm. A burst drug release followed by an improved dissolution was observed indicating instant formation of nanocrystals along with amorphization as confirmed by X-ray diffraction. FTIR studies suggested the absence of chemical interaction between Tris and CC. TEM revealed formation of irregular oval nanoparticles. SD-1:5 has higher apparent permeability coefficient compared to CC suspension. Furthermore, the pharmacokinetic results proved the ability of the formed nanoparticles to enhance the efficacy of CC compared to drug suspension and marketed product. In conclusion, using of Tris as alkaline esterase activator carrier could be a promising tool to bypass the controversial effect of esterase enzymes that may be a source for inter-individual variations affecting ester prodrug candidates' efficacy.

Imaging-based biomarkers: Changes in the tumor interface of pancreatic ductal adenocarcinoma on computed tomography scans indicate response to cytotoxic therapy.

BACKGROUND: The assessment of pancreatic ductal adenocarcinoma (PDAC) response to therapy remains challenging. The objective of this study was to investigate whether changes in the tumor/parenchyma interface are associated with response. METHODS: Computed tomography (CT) scans before and after therapy were reviewed in 4 cohorts: cohort 1 (99 patients with stage I/II PDAC who received neoadjuvant chemoradiation and surgery); cohort 2 (86 patients with stage IV PDAC who received chemotherapy), cohort 3 (94 patients with stage I/II PDAC who received protocol-based neoadjuvant gemcitabine chemoradiation), and cohort 4 (47 patients with stage I/II PDAC who received neoadjuvant chemoradiation and were prospectively followed in a registry). The tumor/parenchyma interface was visually classified as either a type I response (the interface remained or became well defined) or a type II response (the interface became poorly defined) after therapy. Consensus (cohorts 1-3) and individual (cohort 4) visual scoring was performed. Changes in enhancement at the interface were quantified using a proprietary platform. RESULTS: In cohort 1, type I responders had a greater probability of achieving a complete or near-complete pathologic response (21% vs 0%; P = .01). For cohorts 1, 2, and 3, type I responders had significantly longer disease-free and overall survival, independent of traditional covariates of outcomes and of baseline and normalized cancer antigen 19-9 levels. In cohort 4, 2 senior radiologists achieved a κ value of 0.8, and the interface score was associated with overall survival. The quantitative method revealed high specificity and sensitivity in classifying patients as type I or type II responders (with an area under the receiver operating curve of 0.92 in cohort 1, 0.96 in cohort 2, and 0.89 in cohort 3). CONCLUSIONS: Changes at the PDAC/parenchyma interface may serve as an early predictor of response to therapy. Cancer 2018;124:1701-9. © 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Comparative Pharmaceutical Evaluation of Candesartan and Candesartan Cilexetil: Physicochemical Properties, In Vitro Dissolution and Ex Vivo In Vivo Studies.

The aim of the present work is to answer the question is it possible to replace the ester prodrug candesartan cilexetil (CC) by its active metabolite candesartan (C) to bypass the in vivo variable effect of esterase enzymes. A comparative physicochemical evaluation was conducted through solubility, dissolution, and stability studies; additionally, ex vivo permeation and in vivo studies were assessed. C demonstrated higher solubility over CC at alkaline pH. Moreover, dissolution testing using the pharmacopeial method showed better release profile of C even in the absence of surfactant in the testing medium. Both drugs demonstrated a slight degradation in acidic pH after short-term stability. Instead, shifting to alkaline pH of 6.5 and 7.4 showed superiority of C solution stability compared to CC solution. The ex vivo permeation results demonstrated that the parent compound C has a significant (P < 0.05) enhanced permeation compared to its prodrug from CC, that agreed with in vivo results in which C suspension reached significantly (P < 0.05) higher C max of 1.39 ± 0.59 µg/mL at T max of 0.66 ± 0.11 h, while CC suspension reached C max of 0.47 ± 0.22 µg/mL at T max of 2.00 ± 0.27 h, a lag period of 40 min is needed prior to detection of any absorbed CC in plasma. Those findings are not in agreement with the previously reported rationale on the prodrug formation owing to the poor permeability of the parent compound, suggesting the possibility of marketing the parent drug candesartan for clinical use similarly to azilsartan and its prodrug.

Tumors and Tumorlike Conditions of the Anal Canal and Perianal Region: MR Imaging Findings.

Tumors and tumorlike conditions of the anus and perianal region originate from the anal canal and anal margin or result from direct extension of tumors from adjacent organs. The anatomy of the anal canal is complex, and its different histologic characteristics can lead to diverse pathologic conditions. The anal canal extends from the anorectal junction to the anal verge. The World Health Organization classification of anal canal tumors includes (a) anal intraepithelial neoplasia, the precursor of squamous cell carcinoma (SCC), and (b) invasive tumors. Invasive tumors are further classified on the basis of cell type as epithelial tumors (SCC, adenocarcinoma, mucinous adenocarcinoma, small cell carcinoma, and undifferentiated carcinoma), nonepithelial tumors, carcinoid tumors, melanoma, and secondary tumors (direct spread from rectal, cervical, or prostate carcinoma). The anal margin, or perianal skin, lies outside the anal verge and encompasses a radius of 5 cm from the anal verge. Tumors in the anal margin are classified according to the World Health Organization classification of skin tumors. Anal margin tumors include SCC, anal intraepithelial neoplasia, also known as Bowen disease, adenocarcinoma and its precursor Paget disease, basal cell carcinoma, and verrucous carcinoma (Buschke-Löwenstein tumor), which is a rare variant of SCC. Imaging plays an important role in the evaluation, staging, and follow-up of patients with anal and perianal tumors. However, because of the overlap in imaging features among these diverse entities, a definitive diagnosis is best established at histopathologic examination. Nevertheless, familiarity with the pathogenesis, imaging features, and treatment of these tumors can aid radiologic diagnosis and guide appropriate patient treatment. (©)RSNA, 2016.

Evaluating the effect of NPO status on mucosal coating during double contrast barium esophagrams.

INTRODUCTION: Current guidelines for double contrast barium esophagography studies (BAS) suggest that patients should be nil per os (NPO) prior to completing BAS for optimal esophageal coating, although the time required varies between practices and institutions. It is believed that consumption of food or water disrupts the ability for thick barium contrast to properly coat the esophageal mucosa. Exams that are rescheduled for this reason can lead to delays in care, without substantial evidence that NPO status truly affects esophageal mucosal coating for these exams with current barium mixtures. OBJECTIVE: The study aims to identify the necessity, or lack thereof, of standard NPO protocol in patients undergoing BAS, in effort to prevent unnecessary procedural delay. MATERIALS AND METHODS: This study is an IRB-approved HIPAA-compliant study of 370 consecutive adult patients (115 male/255 female, mean age 55) who underwent BAS at our institution from January to June of 2022. Patients were divided into two groups: < 4 h NPO (n = 334), and ≥ 4 h NPO (n = 36). Four abdominal radiologists blinded to NPO interval independently reviewed a random sample of approximately 92 patients (91-94) and graded esophageal coating on a 4-point-scale with 1 being insufficient coating and 4 being optimal coating. RESULTS: No significant statistical difference in mean esophageal coating score was found between the ≥ 4 h NPO cohort (3.04 ± SD 0.78) and the < 4 h NPO cohort (2.97 ± SD 0.70; P = 0.54). Subset analysis of patients who were NPO for < 2 h (n = 9) also showed no significant difference in mean esophageal coating score (3.11 ± SD 0.6; P = 0.92), compared to the standard ≥ 4 NPO status. CONCLUSION: Non-adherence to standard NPO protocol prior to BAS studies did not result in a significant difference in esophageal coating when compared to traditional preprocedural fasting of 4 or more hours.

3D-Printed Microfluidics Potential in Combating Future and Current Pandemics (COVID-19).

Coronavirus disease (COVID-19) emerged in China in December 2019. In March 2020, the WHO declared it a pandemic leading to worldwide lockdowns and travel restrictions. By May, it infected 4,789,205 and killed 318,789 people. This led to severe shortages in the medical sector besides devastating socio-economic effects. Many technologies such as artificial intelligence (AI), virtual reality (VR), microfluidics, 3D printing, and 3D scanning can step into contain the virus and hinder its extensive spread. This article aims to explore the potentials of 3D printing and microfluidic in accelerating the diagnosis and monitoring of the disease and fulfilling the shortages of personal protective equipment (PPE) and medical equipment. It highlights the main applications of 3D printers and microfluidics in providing PPE (masks, respirators, face shields, goggles, and isolation chambers/hoods), supportive care (respiratory equipment) and diagnostic supplies (sampling swabs & lab-on-chip) to ease the COVID-19 pressures. Also, the cost of such technology and regulation considerations are addressed. We conclude that 3D printing provided reusable and low-cost solutions to mitigate the shortages. However, safety, sterility, and compatibility with environmental protection standards need to be guaranteed through standardization and assessment by regulatory bodies. Finally, lessons learned from this pandemic can also help the world prepare for upcoming outbreaks.

Effects of different gelling agents on the different stages of rice regeneration in two rice cultivars.

Plant tissue culture technology offers a solution for meeting the increasing commercial demand on economically important plants such as rice, a widespread dietary staple. However, significant genotype-specific morphogenetic responses constitute a considerable on rice regeneration in plant biotechnology contexts. Aside from genotype dependency, the components of the nutrient media including gelling agents have an important impact on regeneration efficiency. The current study explores the effect of different gelling agents on various stages of rice regeneration in two Egyptian rice cultivars-Sakha104 and Giza178. Media solidified with varying concentrations of a variety of gelling agents (agar, bacto agar, gelrite and phytagel) were tested for their impact on the frequency of callus induction, shoot regeneration and rooting. The results indicated gellan gum (gelrite and phytagel) was superior to agar products (agar and bacto agar) for callus induction. By contrast, no significant differences were found between different gelling agents for shoot regeneration. Gellan gum and media solidified with bacto agar were found to lead to significantly higher root regeneration than agar. The Sakha104 cultivar showed better responses than Giza 178 for callus induction and similar performance to the Giza 178 cultivar for root regeneration irrespective of the gelling agent. This work provides insights into the impact of different gelling agents on the morphogenetic response of two rice cultivars and can be used to help maximize the frequency of rice regeneration.

Pancreatic Ductal Adenocarcinoma: Interface Enhancement Gradient Measured on Dual-Energy CT Images Improves Prognostic Evaluation.

Purpose: To investigate the prognostic value of differential enhancement on baseline dual-energy CT images in patients with treatment-naive pancreatic ductal adenocarcinoma (PDAC), with a focus on tumor-host interface characterization. Materials and Methods: This was a retrospective, institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study of 158 consecutive adult patients (mean age, 68 years; age range, 40.9-88.9 years; 50% women) with histopathologically proven, treatment-naive PDAC, who had undergone multiphasic pancreatic dual-energy CT from December 2011 to March 2017. Regions of interest in tumor core, tumor border, pancreas border with tumor, nontumoral pancreas, and aorta were recorded on pancreatic parenchymal phase (PPP) dual-energy CT 70-keV, 52-keV, and iodine material density (MD) images, plus portal venous phase (PVP) conventional CT images. Enhancement gradient (delta) across the tumor-pancreas interface was calculated. Delta was evaluated combining the dual-energy CT values with the PVP values and as individual predictors. Receiver operating characteristic analysis with logistic regression was used to determine the optimal cut point for each dual-energy CT delta to predict disease outcome based on highest Youden index. Survival curves were generated using Kaplan-Meier method, and comparison between two independent groups (high and low delta) was evaluated with log-rank test. Clinical outcomes included overall survival and distant metastasis-free survival. Three independent blinded radiologists visually scored tumor conspicuity (subjective delta score) on a 1-5 scale, and agreement was evaluated with κ statistic. Results: Ninety-three patients had advanced stage (50 locally advanced and 43 metastatic) and 65 had lower stage (48 resectable and 17 borderline resectable) tumors. Patients with high delta tumors (≥ 40 HU) on either 70-keV PPP images or conventional PVP images had significantly shorter overall survival compared with those with low delta tumors (< 40 HU) in both early stage PDAC (13.5 months vs 23.3 months; hazard ratio [HR], 1.87; 95% confidence interval [CI]: 1.01, 3.5; P = .04) and advanced stage PDAC (10.8 months vs 18.0 months; HR, 2.1; 95% CI: 1.28, 3.6; P = .003). Qualitative visual scoring of tumor conspicuity also showed shorter overall survival in patients with more conspicuous tumors. Highest interreader agreement for subjective delta score was 0.73 and 0.60 using iodine MD and 52-keV images, respectively. Conclusion: Increased quantitative and qualitative border conspicuity (high delta) is associated with shorter survival in patients with PDAC. Agreement on the subjective qualitative characterization of PDAC borders is best achieved using iodine MD and lower-energy simulated monoenergetic images at pancreatic protocol dual-energy CT.Keywords: Abdomen/GI, CT, CT-Dual Energy, CT-Quantitative, PancreasSupplemental material is available for this article.© RSNA, 2020.

Nutraceuticals' Novel Formulations: The Good, the Bad, the Unknown and Patents Involved.

Traditional nutraceuticals and cosmeceuticals hold pragmatic nature with respect to their definitions, claims, purposes and marketing strategies. Their definitions are not well established worldwide. They also have different regulatory definitions and registration regulatory processes in different parts of the world. Global prevalence of nutraceuticals and cosmeceuticals is noticeably high with large market share with minimal regulation compared to traditional drugs. The global market is flooded with nutraceuticals and cosmeceuticals claiming to be of natural origin and sold with a therapeutic claim by major online retail stores such as Amazon and eBay. Apart from the traditional formulations, many manufacturers and researchers use novel formulation technologies in nutraceutical and cosmeceutical formulations for different reasons and objectives. Manufacturers tend to differentiate their products with novel formulations to increase market appeal and sales. On the other hand, researchers use novel strategies to enhance nutraceuticals and cosmeceuticals activity and safety. The objective of this review is to assess the current patents and research adopting novel formulation strategies in nutraceuticals and cosmeceuticals. Patents and research papers investigating nutraceutical and cosmeceutical novel formulations were surveyed for the past 15 years. Various nanosystems and advanced biotechnology systems have been introduced to improve the therapeutic efficacy, safety and market appeal of nutraceuticals and cosmeceuticals, including liposomes, polymeric micelles, quantum dots, nanoparticles, and dendrimers. This review provides an overview of nutraceuticals and cosmeceuticals current technologies, highlighting their pros, cons, misconceptions, regulatory definitions and market. This review also aims in separating the science from fiction in the nutraceuticals and cosmeceuticals development, research and marketing.

Integrated continuous manufacturing in pharmaceutical industry: current evolutionary steps toward revolutionary future.

Continuous manufacturing (CM) has the potential to provide pharmaceutical products with better quality, improved yield and with reduced cost and time. Moreover, ease of scale-up, small manufacturing footprint and on-line/in-line monitoring and control of the process are other merits for CM. Regulating authorities are supporting the adoption of CM by pharmaceutical manufacturers through issuing proper guidelines. However, implementation of this technology in pharmaceutical industry is encountered by a number of challenges regarding the process development and quality assurance. This article provides a background on the implementation of CM in pharmaceutical industry, literature survey of the most recent state-of-the-art technologies and critically discussing the encountered challenges and its future prospective in pharmaceutical industry.

Antimicrobial Effects of Egyptian Local Chicory, Cichorium endivia subsp. pumilum.

The discovery of novel and more efficient antimicrobial agents from natural sources like plants is one of the most important ways through which the growing threat of antibiotic-resistant pathogens can be overcome. Herein, we report the potential antimicrobial activity of Cichorium endivia L. subsp. pumilum. Different concentrations of various solvent extracts prepared from several parts of chicory were tested for their antimicrobial effect against a panel of microorganisms. The antimicrobial activity was analyzed using the well diffusion method, where zones of inhibition were used as indicators of antimicrobial activity. The results indicated the superiority of seed extracts over both leaf and root extracts. Methanol extracts showed higher activity compared with chloroform and water extracts. Increased solvent extract concentration was accompanied by a parallel increase in the diameter of the inhibition zone. Gram-positive bacteria were found to be more sensitive than Gram-negative bacteria and fungi. On a whole, the highest observed inhibition zones (21.3 ± 0.6 and 20.1 ± 0.4 mm) were recorded with the methanolic extract of chicory seeds against S. aureus and B. cereus, respectively. These results offer insights into the antimicrobial potency of this Egyptian local plant and provide a basis for further phytochemical and pharmacological research.

A Visually Apparent and Quantifiable CT Imaging Feature Identifies Biophysical Subtypes of Pancreatic Ductal Adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. EXPERIMENTAL DESIGN: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. RESULTS: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. CONCLUSIONS: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.

Incidental Suspicious Regional Lymph Nodes on Breast Sonography: Is Sampling Necessary?

Suspicious regional lymph nodes may be incidentally identified on breast ultrasound examinations in patients who present for sonographic evaluation without a known or a suspected breast malignancy, and there is a paucity of data on whether biopsy should be performed. This study aims to characterize incidental sonographically detected suspicious regional lymph nodes and determine whether tissue sampling or follow-up imaging is required. A total of 40,773 consecutive breast ultrasounds were reviewed. Overall, 7 women with nonpalpable, incidental, suspicious axillary or supraclavicular lymph nodes in an otherwise unremarkable breast and without history of malignancy or systemic disease were identified. In all, 5 women with 6 nodes underwent ultrasound-guided fine needle aspiration and 2 women with 3 nodes were recommended follow-up ultrasound. Follow-up imaging, cytology, and all-cause clinical data were reviewed to evaluate outcomes. All 6 biopsied lymph nodes (mean = 1.5cm) were benign on cytology. Follow-up imaging was available for 3 nodes (mean = 2.6 years), with all-cause follow-up for all nodes of 2.2 years. In the follow-up group, 3 lymph nodes (mean = 1.6cm) were monitored (mean = 4.3 years) with all-cause follow-up of 4.7 years. No new cancers, growth, or suspicious features were found in these nodes during follow-up for either group of women. In conclusion, women without history of prior malignancy or systemic disease with incidentally detected, nonpalpable, suspicious regional lymph nodes with an otherwise normal breast ultrasound examination underwent fine needle aspiration or were recommended short-term follow-up ultrasound. No indeterminate features or malignancies were observed at the time of tissue sampling or developed over several years of follow-up. Avoiding sampling of these nodes would reduce patient morbidity and health care costs.

Leukemia cell proliferation and death in chronic lymphocytic leukemia patients on therapy with the BTK inhibitor ibrutinib.

BACKGROUND. Ibrutinib is an effective targeted therapy for patients with chronic lymphocytic leukemia (CLL) that inhibits Bruton's tyrosine kinase (BTK), a kinase involved in B cell receptor signaling. METHODS. We used stable isotopic labeling with deuterated water (2H2O) to measure directly the effects of ibrutinib on leukemia cell proliferation and death in 30 patients with CLL. RESULTS. The measured average CLL cell proliferation ("birth") rate before ibrutinib therapy was 0.39% of the clone per day (range 0.17%-1.04%); this decreased to 0.05% per day (range 0%-0.36%) with treatment. Death rates of blood CLL cells increased from 0.18% per day (average, range 0%-0.7%) prior to treatment to 1.5% per day (range 0%-3.0%) during ibrutinib therapy, and they were even higher in tissue compartments. CONCLUSIONS. This study provides the first direct in vivo measurements to our knowledge of ibrutinib's antileukemia actions, demonstrating profound and immediate inhibition of CLL cell proliferation and promotion of high rates of CLL cell death. TRIAL REGISTRATION. This trial was registered at clinicaltrials.gov (NCT01752426). FUNDING. This study was supported by a Cancer Center Support Grant (National Cancer Institute grant P30 CA016672), an NIH grant (CA081554) from the National Cancer Institute, MD Anderson's Moon Shots Program in CLL, and Pharmacyclics, an AbbVie company.

Toward stratification of patients with pancreatic cancer: Past lessons from traditional approaches and future applications with physical biomarkers.

Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate and outcomes have not improved substantially for decades. Significant attention has focused on the biological drivers of the disease, and preclinical work has pointed to multiple biomarker candidates and therapeutic avenues. However, translation of these promising biomarkers and treatment strategies to patients has not been overwhelmingly successful. New strategies to account for the significant heterogeneity of the disease are needed so that rational treatments can be administered. Here, we focus on how physical sciences-based approaches may play a role in stratifying patients for clinical trials, and how this view of PDAC may reinvigorate treatment strategies that have been abandoned after "failing" to fulfill their potential in unselected patient populations. By complementing biological approaches, the development of physical biomarkers of PDAC may help deliver on the promise of personalized medicine for this devastating disease.

Imaging genomics of Glioblastoma: state of the art bridge between genomics and neuroradiology.

Glioblastoma (GBM) is the most common and most aggressive primary malignant tumor of the central nervous system. Recently, researchers concluded that the "one-size-fits-all" approach for treatment of GBM is no longer valid and research should be directed toward more personalized and patient-tailored treatment protocols. Identification of the molecular and genomic pathways underlying GBM is essential for achieving this personalized and targeted therapeutic approach. Imaging genomics represents a new era as a noninvasive surrogate for genomic and molecular profile identification. This article discusses the basics of imaging genomics of GBM, its role in treatment decision-making, and its future potential in noninvasive genomic identification.