Baicalein and U0126 suppress bladder cancer proliferation via MAPK signaling pathway

Purpose: To investigate baicalein and 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene (U0126)effects on human bladder cell line T24 proliferation and related mechanisms.Methods: Twenty micromoles of baicalein or 10 μM U0126 were incubated with T24 cells. Cell viability was tested by CCK8 assay. Cell cycle was evaluated by flow cytometry while cell apoptosis was detected by Annexin V/PI and TUNEL assay. MAPK signaling pathway was evaluated by real time polymerase chain reaction (RT-PCR) and western blot.Results: Baicalein and U0126 suppressed bladder cancer cell T24 proliferation by blocking cell cycle in G0~G1 phase. TUNEL and Annexin V/PI detection showed both baicalein and U0126 induced T24 cell apoptosis. Baicalein and U0126 significantly down-regulated MAPK signaling pathway related molecule activity in both mRNA and protein levels (p < 0.05).Conclusion: Baicalein and U0126 restrain bladder cancer cell proliferation and promote cell apoptosis by affecting MAPK signaling pathway. Thus, they have  potentials for use in the treatment of bladder cancer.Keywords: Bladder cancer, Baicalein, 1,4-diamino-2,3-dicyano-1,4-bis[2-aminophenylthio] butadiene, MAPK signal pathway, Apoptosi

Noncompliance with guidelines on proton pump inhibitor prescription as gastroprotection in hospitalized surgical patients who are prescribed NSAIDs

Background and aims As NSAIDs can cause serious upper gastrointestinal harm, guidelines have been established for the prescribing of proton pump inhibitors (PPIs) in high-risk patients using NSAIDs. Studies examining guideline compliance in surgical patients are scarce. Therefore, a retrospective cross-sectional database study was carried out aimed at determining the proportion of noncompliance with the Dutch guideline and determining the association of several factors with this noncompliance. Materials and methods Hospital admissions of patients on surgical wards of Erasmus University Medical Center between 1 January 2013 and 1 August 2014 were included in which an NSAID was newly prescribed. Preadmission PPI use was excluded. The main outcome was the proportion of noncompliance with the guideline. As a secondary outcome, the association of several potential risk factors with noncompliance was assessed. The proportion of guideline noncompliance was calculated as the percentage of all included surgical ward admissions. For the secondary analysis, univariate and multivariable logistic regression analyses were carried out. R

Парнапарин в хирургии, сосудистой хирургии и в смежных дисциплинах

Aliterature review is dedicated to the use of Parnaparin in various surgical specialties. Prevention and treatment of thromboembolic complications is the major indication for the use of Parnaparin. In the review, the authors dwell on comparative studies of the efficacy oflow molecular weight heparins and unfractionated heparin. They also discuss in detail pharmacokinetics and pharmacodynamics of Parnaparin, its structure and effect on hemostasis components. Due tolack of direct comparative studies of variouslow molecular weight heparins, the authors provide reviews based on the network meta-analysis, which allowed them to identify the advantages of a specificlow molecular weight heparin by indirect comparison.There are few direct comparative studies of variouslow molecular weight heparins in theliterature, which does not allow for an objective assessment of their advantages and disadvantages. The authors do not only provideliterature data on direct comparative studies, but also show data on indirect comparisons (network meta-analysis). They analysed the efficacy of Parnaparin and otherlow molecular weight heparins for the prevention of thromboembolic complications, treatment of deep vein thrombosis and post-thrombophlebitic syndrome. The issues of the efficacy of Parnaparin in chronic arterial insufficiency and use in acute coronary syndrome are highlighted separately. The final part of the review is concerned with a promising, butlittle-known area of prophylaxis of restenosis and prevention of atherosclerosis progression. Experimental studies have allowed us to state that Parnaparin is one of the most effectivelow molecular weight heparins as far as thromboembolic complications are concerned. Parnaparin significantly reduces frequency of DVT events and, at the same time, decreases major bleeding risk as compared with unfractionated heparin. No dose adjustment is required in obese patients. Dose adjustments are based not on body weight but on risk factors for thrombosis, and obesity is only one of them to be considered to choose a dose. Amonglow molecular weight heparins, Parnaparin is one of the most potent drugs that reduces the proliferative and migratory capacity of smooth muscle cells; however, further research is needed to assess the prospects of using Parnaparin for the prevention of restenosis.Обзор литературы посвящен использованию парнапарина в различных специальностях хирургического профиля. Основным показанием для применения парнапарина является его использование для профилактики и лечения тромбоэмболических осложнений. В обзоре авторы подробно останавливаются на сравнительных исследованиях эффективности низкомолекулярных гепаринов и нефракционированного гепарина. Подробно обсуждается фармакокинетика и фармакодинамика парнапарина, его структура и влияние на звенья гемостаза. При недостатке данных прямых сравнительных исследований различных низкомолекулярных гепаринов авторы приводят данные сетевого метаанализа, позволяющего путем косвенного сравнения выявить преимущества конкретного низкомолекулярного гепарина. Анализируется эффективность парнапарина и других низкомолекулярных гепаринов для профилактики тромбоэмболических осложнений, лечения тромбоза глубоких вен и посттромбофлебитического синдрома. Отдельно освещены вопросы эффективности парнапарина при хронической артериальной недостаточности и использования при остром коронарном синдроме. Заключительная часть обзора посвящена перспективному, но малоизученному направлению профилактики рестенозов и предупреждению прогрессирования атеросклероза. Проведенные экспериментальные исследования позволяют утверждать, что парнапарин является одним из наиболее эффективных низкомолекулярных гепаринов в плане профилактики тромбоэмболических осложнений. Парнапарин в сравнении с нефракционированным гепарином достоверно значимо снижает частоту тромбоза глубоких вен и одновременно понижает шанс больших кровотечений. Коррекция дозы осуществляется не по массе тела, а по факторам риска тромбоза, и ожирение является лишь одним из них, учитываемым при выборе дозы. Среди низкомолекулярных гепаринов парнапарин - один из наиболее сильных препаратов, снижающих пролиферативную и миграционную способность гладко-мышечных клеток, однако для оценки перспективности применения парнапарина в профилактике рестенозов необходимы дополнительные исследования

Association between oral fluoroquinolones and seizures: A self-controlled case series study.

OBJECTIVES: The aim of this study was to investigate the association and to estimate the crude absolute risk of seizure among patients exposed to fluoroquinolones (FQs) in Hong Kong and the United Kingdom. METHODS: A self-controlled case series study was conducted. Data were collected from the Hong Kong Clinical Data Analysis and Reporting System database and the Clinical Practice Research Datalink. Patients who were prescribed any oral FQ and had an incident seizure diagnosis from 2001 to 2013 were included. The risk windows were defined as pre-FQ start, FQ-exposed, and post-FQ completion. Incidence rate ratios were estimated in all risk windows and compared with baseline periods. A post hoc subgroup analysis was conducted to examine the effect of patients with a history of seizure. RESULTS: An increased incidence rate ratio was found in the pre-FQ start periods and no association was found in the post-FQ completion periods in both databases. The crude absolute risk of an incident seizure in 10,000 oral FQ prescriptions was 0.72 (95% confidence interval 0.47-1.10) in the Clinical Data Analysis and Reporting System and 0.40 (95% confidence interval 0.30-0.54) in the Clinical Practice Research Datalink. The rate ratio during treatment was not higher than pre-FQ start periods among patients with a history of seizure, therefore the results did not raise serious concerns. CONCLUSIONS: This study does not support a causal association between the use of oral FQs and the subsequent occurrence of seizure. An increased risk before the FQ exposure period suggests that the clinical indication for which FQ was prescribed may have contributed to the development of seizure rather than the drug itself

Cardiac safety of second-generation H1 -antihistamines when updosed in chronic spontaneous urticaria

The symptoms of chronic urticaria, be it chronic spontaneous urticaria (CSU) or chronic inducible urticaria (CindU), are mediated primarily by the actions of histamine on H1 receptors located on endothelial cells (the weal) and on sensory nerves (neurogenic flare and pruritus). Thus, second-generation H1 antihistamines (sgAHs) are the primary treatment of these conditions. However, many patients are poorly responsive to licensed doses of antihistamines. In these patients, the current EAACI/GA2 LEN/EDF/WAO guideline for urticaria suggests updosing of sgAHs up to fourfold. However, such updosing is off-label and the responsibility resides with the prescribing physician. Therefore, the safety of the drug when used above its licensed dose is of paramount importance. An important aspect of safety is potential cardiotoxicity. This problem was initially identified some 20 years ago with cardiotoxic deaths occurring with astemizole and terfenadine, two early sgAHs. In this review, we discuss the mechanisms and assessments of potential cardiotoxicity of H1 antihistamines when updosed to four times their licensed dose. In particular, we have focused on the potential of H1 antihistamines to block hERG (human Ether-a-go-go-Related Gene) voltage-gated K+ channels, also known as Kv11.1 channels according to the IUPHAR classification. Blockade of these channels causes QT prolongation leading to torsade de pointes that may possibly degenerate into ventricular fibrillation and sudden death. We considered in detail bilastine, cetirizine, levocetirizine, ebastine, fexofenadine, loratadine, desloratadine, mizolastine and rupatadine and concluded that all these drugs have an excellent safety profile with no evidence of cardiotoxicity even when updosed up to four times their standard licensed dose, provided that the prescribers carefully consider and rule out potential risk factors for cardiotoxicity, such as the presence of inherited long QT syndrome, older age, cardiovascular disorders, hypokalemia and hypomagnesemia, or the use of drugs that either have direct QT prolonging effects or inhibit sgAH metabolism

Potential adverse effects of long term use of Proton Pump Inhibitors

Proton-Pump Inhibitors (PPIs) have changed the therapy of numerous upper gastrointestinal tract disorders; but their use is not without risk of adverse effects. Recent studies suggest more serious adverse events with chronic use of PPIs. Because of these risks, clinicians should reassess individual patient’s needs for chronic PPI therapy

Proton pump inhibitors and serum magnesium levels in patients with Torsades de Pointes

Background: Torsades de pointes (TdP) is a life-threatening ventricular tachycardia occurring in long QT-syndrome patients. It usually develops when multiple QT-prolonging factors are concomitantly present, more frequently drugs and electrolyte imbalances. Since proton-pump inhibitors (PPIs)-associated hypomagnesemia is an increasingly recognized adverse event, PPIs were recently included in the list of drugs with conditional risk of TdP, despite only few cases of TdP in PPI users have been reported so far. Objectives: Aim of the present study is to evaluate whether PPI-induced hypomagnesemia actually has a significant clinical impact on the risk of TdP in the general population. Methods: Forty-eight unselected patients who experienced TdP were consecutively enrolled (2008-2017). Shortly after the first TdP episode, in those patients who did not receive magnesium sulfate and/or potassium or calcium replacement therapy, serum electrolytes were measured and their relationship with PPI usage analyzed. Results: Many patients (28/48, 58%) were under current PPI treatment when TdP occurred. Among TdP patients in whom serum electrolyte determinations were obtained before replacement therapy (27/48), those taking PPIs had significantly lower serum magnesium levels than those who did not. Hypomagnesemia occurred in ~40% of patients receiving PPIs (6/14), in all cases after an extended treatment (> 2 weeks). In patients taking PPIs the mean QT-prolonging risk factor number was significantly higher than in those who did not, a difference which was mainly driven by lower magnesium levels. Conclusions: In unselected TdP patients, PPI-induced hypomagnesemia was common and significantly contributed to their cumulative arrhythmic risk. By providing clinical support to current recommendations, our data confirm that more awareness is needed when a PPI is prescribed, specifically as regards the risk of life-threatening arrhythmias