Physiologically Based Pharmacokinetic Modeling: Methodology, Applications, and Limitations with a Focus on Its Role in Pediatric Drug Development

The concept of physiologically based pharmacokinetic (PBPK) modeling was introduced years ago, but it has not been practiced significantly. However, interest in and implementation of this modeling technique have grown, as evidenced by the increased number of publications in this field. This paper demonstrates briefly the methodology, applications, and limitations of PBPK modeling with special attention given to discuss the use of PBPK models in pediatric drug development and some examples described in detail. Although PBPK models do have some limitations, the potential benefit from PBPK modeling technique is huge. PBPK models can be applied to investigate drug pharmacokinetics under different physiological and pathological conditions or in different age groups, to support decision-making during drug discovery, to provide, perhaps most important, data that can save time and resources, especially in early drug development phases and in pediatric clinical trials, and potentially to help clinical trials become more “confirmatory” rather than “exploratory”

Efficacy and tolerability of sulforaphane in the therapeutic management of cancers: a systematic review of randomized controlled trials

ObjectivesThis paper presents a systematic review aimed at assessing the therapeutic potential of sulforaphane (SFN) in the treatment of diverse cancer types.MethodsFollowing Cochrane guidelines for systematic reviews, we conducted an exhaustive search of electronic databases up to May 12, 2023, encompassing PubMed, Cochrane, Embase, Web of Science, Google Scholar, Natural Medicines, ProQuest, ClinicalTrials.gov, and ICTRP. Studies were included if they were human-based RCTs involving cancer patients where SFN was the primary experimental treatment. The Cochrane Risk of Bias tool for RCTs (RoB2) was used for quality assessment.ResultsEight studies investigating the efficacy and safety of SFN in prostate cancer (PCa), breast cancer, pancreatic cancer, and melanoma were identified and included in the review. The dosing regimens were variable and inconsistent across the studies. SFN treatment led to statistically significant alterations in several vital genes and histological biomarkers across the studies. However, it did not impact some other key genes. Although not statistically significant, SFN improved overall survival in pancreatic cancer patients. The results on prostate-specific antigen (PSA) were inconsistent in PCa. None of the studies reported significant differences between SFN and comparative controls in terms of adverse events.ConclusionSFN has emerged as a promising and safe therapeutic agent for diverse cancer types. Nevertheless, the high levels of methodological and clinical heterogeneity across the included studies precluded the possibility of conducting meta-analyses. Further robust clinical investigations to conclusively ascertain the chemotherapeutic potential of SFN in the management of various cancer forms are needed.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022323788, identifier CRD42022323788

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Delirium incidence, predictors and outcomes in the intensive care unit: A prospective cohort study

Aim: The aim of this study was to investigate the incidence, predictors, and outcomes of delirium in intensive care units. Background: Delirium is a common complication in intensive care units. In developing countries, it can be misdiagnosed or unrecognised. Design: Prospective cohort study reported according to the strengthening the reporting of observational studies in epidemiology criteria. Methods: We included patients who were conscious, \u3e18 years old, and admitted to the intensive care units for at least 8 h between December 2019 and February 2020. Patients with a Richmond score of −4 or −5, mental disability, receptive aphasia and/or visual or auditory impairment were excluded from the study. Delirium was assessed using the Confusion Assessment Method for the ICU (CAM-ICU), whereas the functional outcome was assessed by the Katz Activity of Daily Living Index. Results: This study included 111 patients with a delirium incidence of 31.5%. The severity of illness was the only significant predictor of delirium. Patients with delirium had longer intensive care unit and in-hospital stays in contrast to those without delirium. Delirium was associated with in-hospital and 4-month mortality but not the activities of daily living. Conclusions: Delirium is associated with increased length of stay and mortality. Further investigation to determine whether delirium management can improve outcomes is warranted

Design, Synthesis and Biological Evaluation of Novel Chalcone Analogs as Potential Therapeutic Agents for Castration-Resistant Prostate Cancer

Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormone targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, termed as castration-resistant prostate cancer (CRPC), which currently lacks curative therapeutic options and is associated with poor prognosis. Therefore, the development of alternative treatments for PCa is urgently needed. Chalcones, also known as 1,3-diphenyl-2-propen-1-ones, are among the highly attractive scaffolds being investigated for their antitumor activities. Three series of 18 cyclic (tetralone-based) and two acyclic chalcone analogs, in which ring B was either substituted with nitrogen mustard or replaced by pyrrole or pyridine heterocyclic rings, were designed, synthesized and evaluated as potential therapies for CRPC. Compounds were synthesized by Claisen-Schmidt condensation reaction, purified using column-chromatography or recrystallization, and characterized by 1H-NMR, 13C-NMR and LC-MS. The compounds' in-vitro cytotoxicity was evaluated against three prostate cancer cell lines (PC3, DU145, and LNCaP). Among the tested compounds, OH14, OH19 and OH22 showed potent antiproliferative activities at low micromolar levels with IC50 values ranging between 4.4 and 10 M against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule OH19 revealed that it significantly induced apoptosis through upregulation of Bax and downregulation of BCL-2. In addition, OH19 potently inhibited colony formation and reduced cell migration of androgen independent PCa cell lines (PC3 and DU145). Mechanistically, the anticancer activity of OH19 was associated with attenuation in the phosphorylation of Akt and ERK. Furthermore, OH19 inhibited blood vessel formation in the chick chorioallantoic membrane (CAM) model as compared to control. These results indicate that OH19 could serve a potential promising lead molecule for the treatment of CRPC and thus, further in-vitro and in-vivo testing is warrante

Targeting triple negative breast cancer heterogeneity with chalcones: a molecular insight.

Triple negative breast cancers (TNBCs) are aggressive heterogeneous cancers with not yet determined conventional targeted medication. Therefore, identification of new alternatives or improved treatment options to combat this deadly disease is highly needed. On the other hand, various derived products with chalcone scaffold were historically considered excellent candidates for the development of anticancer drugs. Chalcones unique chemical structure and their substantial biological activities in cancer cells make them an extremely attractive target for the treatment of several human carcinomas including TNBCs. This review highlights the promising therapeutic role of chalcones in TNBC management

Development of Novel Chalcone Analogs as Potential Multi-Targeted Therapies for Castration-Resistant Prostate Cancer

Prostate cancer (PCa) is the second most frequently diagnosed malignancy, as well as a leading cause of cancer-related mortality in men globally. Despite the initial response to hormonal targeted therapy, the majority of patients ultimately progress to a lethal form of the disease, castration-resistant prostate cancer (CRPC). Therefore, the objective of this study was to discover and develop novel treatment modalities for CRPC. Chalcones are among the highly attractive scaffolds being investigated for their antitumor activities. A library of 26 chalcone analogs were designed, synthesized and evaluated as potential therapies for CRPC. The design was guided by in-silico ADMET prediction in which analogs with favorable drug-likeness properties were prioritized. The new compounds were synthesized, purified and characterized by extensive structural elucidation studies. The compounds in vitro cytotoxicity was evaluated against two androgen receptor (AR)-negative prostate cancer cell lines (PC3 and DU145). Among the tested compounds, pyridine containing analogs (13, 15 and 16) showed potent antiproliferative activities with IC50 values ranging between 4.32-6.47 µM against PC3 and DU145 cell lines. Detailed biological studies of the lead molecule 16 revealed that it can significantly induce apoptosis through upregulation of Bax and downregulation of Bcl-2. In addition, compound 16 potently inhibited colony formation and reduced cell migration of AR-negative PCa cell lines (PC3 and DU145). The molecular pathway analysis showed that the anticancer activity of compound 16 is associated with blocking of ERK1/2 and Akt activities. Furthermore, compound 16 inhibited angiogenesis in the chick chorioallantoic membrane (CAM) model as compared to control. Structure-activity relationship study revealed that the cytotoxicity could dramatically improve via changing the methoxylation pattern by more than 2-folds (IC50 << 2.5 μM). These results indicate that pyridine-based chalcones could serve as promising lead molecules for the treatment of CRPC; thus, further in vitro and in vivo studies are warranted