Prevalence of Medication Associated with QTc Prolongation Used Among Critically Ill Patients.

Background: Acquired prolonged corrected QT (QTc) interval can lead to life-threatening Torsade de Pointes (TdP) arrhythmia. Multiple risk factors including medications, comorbidities, and electrolyte imbalances contribute significantly to acquired manifestations of the QTc prolongation. Critically ill patients are particularly more vulnerable to TdP due to complex medical conditions, aging, and polypharmacy. Objective: This study aimed to assess the prevalence of TdP-associated medication prescribing, identify risk factors for QTc prolongation and TdP, and determine primary predictors of high TdP medication usage in critically ill patients in Jordan. Methods: We conducted a retrospective cross-sectional analysis of electronic medical records for patients from King Abdullah University Hospital who were admitted to Intensive Care Unit (ICU) between (July 2012-July 2022). We collected data on patients' demographics, clinical characteristics, comorbidities, laboratory results, and prescribed medications. Medications were categorized into three TdP risk levels according to CredibleMeds® assessment tool. Data were analyzed using descriptive statistics and a binary logistic regression model. Results: Of the 13,300 patients (58.2% male, median age 62 years). Prescribing prevalence for medications with known TdP risk was 19%, possible risk (24.7%), conditional risk (21.6%), and confirmed conditional risk (8.3%). Common comorbidities included hypertension (40.9%), diabetes (33.3%), and cancer (15.4%). Drugs with known TdP risk included citalopram, amiodarone, clarithromycin, and ciprofloxacin. A binary regression model revealed that as age increased, the odds of TdP associated medication prescribing decreased (OR = 0.989, p < 0.001), while patients on more than five medications had higher odds (OR = 4.281, p < 0.001). Conclusion: The study identified a notable prevalence of prescribing for medications with QTc prolongation/TdP risk in critically ill patients. Healthcare providers in the ICU should exercise caution to minimize the inadvertent prescription of TdP associated medications especially among older patients and those with polypharmacy.

Preparation of Modified Chitosan-based Nanoparticles for Efficient Delivery of Doxorubicin and/or Cisplatin to Breast Cancer Cells.

PURPOSE: The aim is to develop a novel pH-responsive modified chitosan-based nanoparticles system for active loading of doxorubicin (DOX) and triggered intracellular release. METHODS: Nanoparticles were formed in an aqueous medium via ionic interaction between negatively charged chitosan derivative and positively charged DOX at neutral pH and then transformed in situ into cisplatin (CIS) cross-linked nanoparticles through cross-linking the formed micelles via chelation interaction between the negatively charged polymeric carrier and cisplatin. Nanoparticles were characterized in terms of particle size and zeta potential using DLS and TEM. Drug loading efficiency and encapsulation efficiency were determined based on the physio-chemical proprieties of the polymer and the amount of the cross-linking agent. In vitro release studies were performed using the dialysis method at different pHs. Finally, the cytotoxic effects of these nanoparticles were performed against the MCF-7 BrCA cell line under different pHs. RESULTS: The average particle size of polymer alone and DOX nanoparticles was 277.401 ± 13.50 nm and 290.20 ± 17.43 nm, respectively. The zeta potential was -14.6 ± 1.02 mV and -13.2 ± 0.55 mV, respectively, with a low polydispersity index. Drug loading and encapsulation deficiencies were determined, dependent on the amount of the cross-linking agent. In vitro release studies showed that the release of DOX from these nanoparticles was pH-dependent. Moreover, results showed that the cytotoxicity magnitude of DOX-loaded nanoparticles against MCF-7 BrCA cells was higher compared with free DOX. CONCLUSION: These novel pH-sensitive nanoparticles proved to be a promising Nano-drug delivery for tumor-targeted delivery of DOX.

Crizotinib induced antitumor activity and synergized with chemotherapy and hormonal drugs in breast cancer cells via downregulating MET and estrogen receptor levels.

MET is a receptor tyrosine kinase known to drive neoplastic transformation and aggressive tumor phenotypes. Crizotinib is an oral multi-targeted tyrosine kinase inhibitor of MET, ALK, RON, and ROS1 kinases. In this study, the anticancer effects of crizotinib on breast cancer cells were investigated in vitro along with the molecular mechanisms associated with these effects. Besides, the antiproliferative effects of crizotinib in combination with chemotherapy, hormonal drugs, and targeted agents were examined. Results showed that crizotinib produced dose-dependent antiproliferative effects in BT-474 and SK-BR-3 breast cancer cells with IC50 values of 1.7 µM and 5.2 µM, respectively. Crizotinib inhibited colony formation of BT-474 cells at low micromolar concentrations (1-5 µM). Immunofluorescence and Western blotting indicated that crizotinib reduced total levels of MET and estrogen receptor (ERα) in BT-474 cells. Also, crizotinib reduced the levels of phosphorylated (active) MET and HER2 in BT-474 cells. The combined treatment of crizotinib with doxorubicin and paclitaxel resulted in synergistic growth inhibition of BT-474 cells with combination index values of 0.46 and 0.35, respectively. Synergy was also observed with the combination of crizotinib with the hormonal drugs 4-hydroxytamoxifen and fulvestrant in BT-474 cells. Alternatively, the combination of crizotinib with lapatinib produced antagonistic antiproliferative effects in both BT-474 and SK-BR-3 cells. Collectively, these findings demonstrate the anticancer effects of crizotinib in breast cancer cells and reveal ERα as a potential therapeutic target of the drug apart from its classical kinase inhibitory activity. Crizotinib could be an appealing option in combination with chemotherapy or hormonal drugs for the management of breast cancer.

Immunomodulatory effect of statins on Regulatory T Lymphocytes in human colorectal cancer is determined by the stage of disease.

Colorectal cancer (CRC) is a public health problem worldwide and in Jordan. Statins are cholesterol lowering agents. Beyond their effects, statins use has been reported to reduced risk of several malignances, including CRC. This study aimed to assess the effect of statins on CRC by studying cellular infiltration of Regulatory T Lymphocytes (Tregs) into CRC tissues and their effect on Transforming growth factor beta 1 (TGF-ß1) level and on angiogenesis. Fourty seven specimens (25 statins users vs. 22 non-users) were used. Immunohistochemistry was performed to study Tregs infiltration using their marker, fork head transcription factor, and angiogenesis using CD31 as a marker. TGF-ß1 levels were measured using ELISA. Results revealed that statins use was associated with more Tregs infiltration, less angiogenesis but no difference in TGF-ß1 content in tumor tissue. When results were further stratified according to stage of disease, more Tregs infiltration was significantly noticed in advanced disease but not in early disease. In addition, more angiogenesis inhibition was noticed in early disease but not in advanced disease. Same stage-dependence wasn't noticed with TGF-ß1 expression. In early disease, reduction of angiogenesis mediated by statins might lead to reduction of tumor aggressiveness. On the other hand, Tregs infiltration into tumor mediated by statins might reduce cancer aggressiveness in advanced disease. These results suggest that statins might be used in the treatment of CRC.

Evaluation of the Effect of Uremic Serum on Hepatic Reductase Functional Expression.

BACKGROUND: The nonrenal clearance of drugs mediated by hepatic reduction is selectively altered by kidney disease. This study evaluated the influence of uremic serum on the expression and activity of reductase enzymes. METHODS: Human hepatocellular carcinoma cells (HepG2) were incubated with 5% pooled serum collected from patients with hemodialysis (pre- and post-dialysis session) or control subjects. The mRNA expression of various aldo-keto (AKR1C) and carbonyl (CBR) reductases were measured. Reductase metabolic activity was assessed in human liver cytosol or HepG2 cells using naltrexone as a substrate. RESULTS: Incubation of cells with pre-dialysis serum resulted in significant upregulation of AKR1C4 (by 63.2%) and CBR1 (by 34.6%) versus control serum. This increase was not observed for AKR1C1 and CBR1 with serum collected post-dialysis. While uremic serum had no effect on reductase activity, some instances with differences in metabolite formation among individual's pre- and post-dialysis samples were observed. CONCLUSION: Although uremic serum can upregulate mRNA expression of several reductases, this effect was not observed at the activity level. Future studies are necessary to improve our understanding of the mechanistic effects of impaired kidney function on drug reduction.

Knowledge and Awareness of Colorectal Cancer Early Warning Signs and Risk Factors among University Students in Jordan.

In the present study, we aimed to assess the level of awareness regarding CRC warning signs and risk factors among undergraduate students. A cross-sectional survey using standardized questionnaire developed by the Cancer Research Center in the UK was carried out in three different public universities in Jordan including Jordan University of Science and Technology, Yarmouk University, and AL al-Bayt University over a 5-month period. Volunteers were asked about their knowledge regarding CRC symptoms, risk factors, and their behaviors regarding seeking medical advice. Findings revealed that response rate was 80.1%. Vast majority of responders were female (70.9%) and 18.2% of them were studying medical-related specialties. Regarding CRC symptoms, 14.3% of responders experienced poor knowledge, 52.9% have fair knowledge, and 32.8% have good knowledge. Abdominal pain was the most recognized warning signs where 70.8% of responders could recall it. In addition, risk factors awareness was lower than warning signs awareness. About 36.1% of responders have poor knowledge, 47.4% had fair knowledge, and 16.5% had good knowledge. Unhealthy diet was the most recognized risk factor where 32.3% of responders could recall it. Moreover, females were more aware regarding CRC symptoms. Similar findings were obtained for participants who were aged 20 years or more and for those who had previous experience of cancer. Students who were studying medical-related specialties were more aware of both CRC symptoms and risk factors than those who studying other specialties. Furthermore, regarding time to seek medical attention we found that 60.6% of volunteers would seek medical advice within 1 week of noticing CRC symptoms and 12% would seek it within 2 weeks. The mean duration for seeking medical advice was found to be 1.9 weeks. University students' awareness level of CRC is poor, and therefore, extended attention should be attempted to enhance the awareness of CRC via continuous education programs, lectures, or campaigns to encourage the early detection CRC.

A mini-review of c-Met as a potential therapeutic target in melanoma.

Melanoma is the third highest rated cancer in prevalence. Surgery, radiotherapy and targeted/biological therapies in addition to chemotherapy are available options for management of this cancer. Met is an appealing target for management of this type of cancer, since it targets many cancer vital processors, such as angiogenesis, cell growth, scattering and differentiation. In this review, we provide an overview about pathway abnormalities associated with melanoma. We also provide a summary about the events involved in Met signaling and related signaling molecules. We also show the evidence of the importance of Met signaling pathway as a target in cancer management. We also summarize clinical evidence about the use of Met signaling in management of cancer and summarize available trials related to targeting Met in other cancers.

Changes in the expression and protein level of matrix metalloproteinases after exposure to waterpipe tobacco smoke.

Waterpipe smoking has become a worldwide epidemic with health consequences that only now are beginning to be understood fully. Because waterpipe use involves inhaling a large volume of toxicant-laden smoke that can cause inflammation, some health consequences may include inflammation-mediated lung injury. Excess matrix metalloproteinase expression is a key step in the etiology of toxicant exposure-driven inflammation and injury. In this study, changes in the level and mRNA of major matrix metalloproteinases (MMP-1, -9, and -12) in the lungs of mice following exposure to waterpipe smoke were investigated. Balb/c mice were exposed to waterpipe smoke for one hour daily, over a period of 2 or 8 weeks. Control mice were exposed to fresh air only. ELISA and real-time PCR techniques were used to determine the protein and mRNA levels of MMP-1, -9, and -12 in the lungs. Our findings showed that MMP-1, -9, and -12 levels in the lung significantly increased after both 2 (p < 0.05) and 8 weeks (p < 0.01) exposures. Similarly, RT-PCR findings showed that mRNA of those proteinases significantly increased following 2 (p < 0.01) and 8 weeks (p < 0.001) exposures. In conclusion, waterpipe smoking is associated strongly with lung injury as measured by elevation in the expression of MMPs in the lung tissue.