BMC Pharmacology & Toxicology最新文献

{"title":"The association between statin therapy during intensive care unit stay and the incidence of venous thromboembolism: a propensity score-adjusted analysis.","authors":"Shmeylan A Al Harbi,&nbsp;Mohammad Khedr,&nbsp;Hasan M Al-Dorzi,&nbsp;Haytham M Tlayjeh,&nbsp;Asgar H Rishu,&nbsp;Yaseen M Arabi","doi":"10.1186/2050-6511-14-57","DOIUrl":"https://doi.org/10.1186/2050-6511-14-57","url":null,"abstract":"<p><strong>Background: </strong>Studies have shown that statins have pleiotropic effects on inflammation and coagulation; which may affect the risk of developing venous thromboembolism (VTE). The objective of this study was to evaluate the association between statin therapy during intensive care unit (ICU) stay and the incidence of VTE in critically ill patients.</p><p><strong>Methods: </strong>This was a post-hoc analysis of a prospective observational cohort study of patients admitted to the intensive care unit between July 2006 and January 2008 at a tertiary care medical center. The primary endpoint was the incidence of VTE during ICU stay up to 30 days. Secondary endpoint was overall 30-day hospital mortality. Propensity score was used to adjust for clinically and statistically relevant variables.</p><p><strong>Results: </strong>Of the 798 patients included in the original study, 123 patients (15.4%) received statins during their ICU stay. Survival analysis for VTE risk showed that statin therapy was not associated with a reduction of VTE incidence (crude hazard ratio (HR) 0.66, 95% confidence interval (CI) 0.28-1.54, P=0.33 and adjusted HR 0.63, 95% CI 0.25-1.57, P=0.33). Furthermore, survival analysis for hospital mortality showed that statin therapy was not associated with a reduction in hospital mortality (crude HR 1.26, 95% CI 0.95-1.68, P=0.10 and adjusted HR 0.98, 95% CI 0.72-1.36, P=0.94).</p><p><strong>Conclusion: </strong>Our study showed no statistically significant association between statin therapy and VTE risk in critically ill patients. This question needs to be further studied in randomized control trials.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"57"},"PeriodicalIF":2.9,"publicationDate":"2013-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-57","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31846165","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Psychotropic drug use among people with dementia--a six-month follow-up study.","authors":"Maria Gustafsson,&nbsp;Stig Karlsson,&nbsp;Yngve Gustafson,&nbsp;Hugo Lövheim","doi":"10.1186/2050-6511-14-56","DOIUrl":"https://doi.org/10.1186/2050-6511-14-56","url":null,"abstract":"<p><strong>Background: </strong>Psychotropic drugs are widely used among old people with dementia but few studies have described long-term treatment in this group of patients. The purpose of this study was to explore the long-term use of psychotropic drugs in old people with dementia.</p><p><strong>Methods: </strong>Data on psychotropic drug use, functioning in the activities of daily living (ADL), cognitive function and behavioral and psychological symptoms were collected at baseline and six months later, using the Multi-Dimensional Dementia Assessment Scale (MDDAS). The data were collected in 2005-2006. Detailed data about the prescribing of psychotropic drugs were collected from prescription records. This study was conducted in 40 specialized care units in northern Sweden, with a study population of 278 people with dementia.</p><p><strong>Results: </strong>At the start of the study, 229 of the participants (82%) were prescribed at least one psychotropic drug; 150 (54%) used antidepressants, 43 (16%) used anxiolytics, 107 (38%) used hypnotics and sedatives, and 111 (40%) used antipsychotics. Among the baseline users of antidepressants, anxiolytics, hypnotics and sedatives and antipsychotics, 67%, 44%, 57% and 57% respectively, still used the same dose of the same psychotropic drug after six months. Associations were found between behavioral and psychological symptoms and different psychotropic drugs.</p><p><strong>Conclusion: </strong>Psychotropic drug use was high among people with dementia living in specialized care units and in many cases the drugs were used for extended periods. It is very important to monitor the effects and adverse effects of the prescribed drug in this frail group of people.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"56"},"PeriodicalIF":2.9,"publicationDate":"2013-11-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-56","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31837183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dipyrithione induces cell-cycle arrest and apoptosis in four cancer cell lines in vitro and inhibits tumor growth in a mouse model.","authors":"Yumei Fan,&nbsp;Caizhi Liu,&nbsp;Yongmao Huang,&nbsp;Jie Zhang,&nbsp;Linlin Cai,&nbsp;Shengnan Wang,&nbsp;Yongze Zhang,&nbsp;Xianglin Duan,&nbsp;Zhimin Yin","doi":"10.1186/2050-6511-14-54","DOIUrl":"https://doi.org/10.1186/2050-6511-14-54","url":null,"abstract":"<p><strong>Background: </strong>Dipyrithione (PTS2) is widely used as a bactericide and fungicide. Here, we investigated whether PTS2 has broad-spectrum antitumor activity by studying its cytotoxicity and proapoptotic effects in four cancer cell lines.</p><p><strong>Methods: </strong>We used MTT assays and trypan blue staining to test the viability of cancer cell lines. Hoechst 33258 and DAPI staining were used to observe cell apoptosis. Cell-cycle percentages were analyzed by flow cytometry. Apoptosis was assayed using caspase-3 and poly (ADP-ribose) polymerase (PARP) combined with Western blotting. Student's t-test was used for statistical analysis.</p><p><strong>Results: </strong>PTS2 inhibited proliferation in four cancer cell lines in a dose-dependent manner. Treated cells showed shrinkage, irregular fragments, condensed and dispersed blue fluorescent particles compared with control cells. PTS2 induced cycle-arrest and death. Cleavage of caspase-9, caspase-3, and PARP were detected in PTS2-treated cells. Antitumor activity of PTS2 was more effective against widely used cancer drugs and its precursor.</p><p><strong>Conclusions: </strong>PTS2 appears to have novel cytotoxicity and potent broad-spectrum antitumor activity, which suggests its potential as the basis of an anticancer drug.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"54"},"PeriodicalIF":2.9,"publicationDate":"2013-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-54","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31818637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Physiological and pharmacokinetic effects of oral 1,3-dimethylamylamine administration in men.","authors":"Brian K Schilling,&nbsp;Kelley G Hammond,&nbsp;Richard J Bloomer,&nbsp;Chaela S Presley,&nbsp;Charles R Yates","doi":"10.1186/2050-6511-14-52","DOIUrl":"https://doi.org/10.1186/2050-6511-14-52","url":null,"abstract":"<p><strong>Background: </strong>1,3-dimethylamylamine (DMAA) has been a component of dietary supplements and is also used within \"party pills,\" often in conjunction with alcohol and other drugs. Ingestion of higher than recommended doses results in untoward effects including cerebral hemorrhage. To our knowledge, no studies have been conducted to determine both the pharmacokinetic profile and physiologic responses of DMAA.</p><p><strong>Methods: </strong>Eight men reported to the lab in the morning following an overnight fast and received a single 25 mg oral dose of DMAA. Blood samples were collected before and through 24 hours post-DMAA ingestion and analyzed for plasma DMAA concentration using high-performance liquid chromatography-mass spectrometry. Resting heart rate, blood pressure, and body temperature was also measured.</p><p><strong>Results: </strong>One subject was excluded from the data analysis due to abnormal DMAA levels. Analysis of the remaining seven participants showed DMAA had an oral clearance of 20.02 ± 5 L∙hr⁻¹, an oral volume of distribution of 236 ± 38 L, and terminal half-life of 8.45 ± 1.9 hr. Lag time, the delay in appearance of DMAA in the circulation following extravascular administration, varied among participants but averaged approximately 8 minutes (0.14 ± 0.13 hr). The peak DMAA concentration for all subjects was observed within 3-5 hours following ingestion and was very similar across subjects, with a mean of ~70 ng∙mL⁻¹. Heart rate, blood pressure, and body temperature were largely unaffected by DMAA treatment.</p><p><strong>Conclusions: </strong>These are the first data to characterize the oral pharmacokinetic profile of DMAA. These findings indicate a consistent pattern of increase across subjects with regards to peak DMAA concentration, with peak values approximately 15-30 times lower than those reported in case studies linking DMAA intake with adverse events. Finally, a single 25 mg dose of DMAA does not meaningfully impact resting heart rate, blood pressure, or body temperature.</p><p><strong>Trial registration: </strong>NCT01765933.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"52"},"PeriodicalIF":2.9,"publicationDate":"2013-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-52","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31778628","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics and biodistribution of the cyclin-dependent kinase inhibitor -CR8- in mice.","authors":"Hatem Sallam,&nbsp;Ibrahim El-Serafi,&nbsp;Laurent Meijer,&nbsp;Moustapha Hassan","doi":"10.1186/2050-6511-14-50","DOIUrl":"https://doi.org/10.1186/2050-6511-14-50","url":null,"abstract":"<p><strong>Background: </strong>CR8 is a second generation inhibitor of cyclin-dependent kinases derived from roscovitine. CR8 was shown to be 50-100 fold more potent than roscovitine in inducing apoptosis in different tumor cell lines. In the present investigation, we have established an analytical method for the quantification of CR8 in biological samples and evaluated its bioavailability, biodistribution and pharmacokinetics in mice.</p><p><strong>Methods: </strong>A liquid chromatography method utilizing UV-detection was used for the determination of CR8. CR8 was administered either orally (100 mg/kg) or i.v. (50 mg/kg) and the animals were sacrificed at different time points. Blood samples and organs were collected, after which the pharmacokinetic parameters were calculated for plasma and organs.</p><p><strong>Results: </strong>CR8 was eluted at 5 minutes in the high performance liquid chromatography system used. The LLOQ detection was 0.10 μg/ml and linearity was observed within the 0.10-10 μg/ml range (r² > 0.998). The accuracy and precision were >86%, while the recovery from plasma was >95%. CR8 was stable for 2 months at room temperature in both solution and plasma. CR8 pharmacokinetics was fitted to a two-compartment open model after oral administration and to a one compartment model after i.v. injection. The elimination half-life was about 3 hours. Organ exposure to CR8 (expressed as % AUC organ vs. AUC plasma) was highest in liver (205%), adipose tissue (188%) and kidney (150%) and low in bone marrow (30%) and brain (15%) as compared to plasma. The oral bioavailability of CR8 was found to be essentially 100%.</p><p><strong>Conclusions: </strong>We have developed a rapid and simple method for the analysis of CR8. CR8 pharmacokinetics pattern showed 100% bioavailability, long half-life and limited distribution to brain and bone marrow, which may allow systemic exposure higher than the IC₅₀ reported for cell death in tumor cell lines. CR8 displays favorable pharmacological properties and is therefore a good candidate for future clinical studies.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"50"},"PeriodicalIF":2.9,"publicationDate":"2013-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-50","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31769747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Translational toxicology: a developmental focus for integrated research strategies.","authors":"Claude Hughes, Michael Waters, David Allen, Iyabo Obasanjo","doi":"10.1186/2050-6511-14-51","DOIUrl":"10.1186/2050-6511-14-51","url":null,"abstract":"<p><strong>Background: </strong>Given that toxicology studies the potential adverse effects of environmental exposures on various forms of life and that clinical toxicology typically focuses on human health effects, what can and should the relatively new term of \"translational toxicology\" be taken to mean?</p><p><strong>Discussion: </strong>Our assertion is that the core concept of translational toxicology must incorporate existing principles of toxicology and epidemiology, but be driven by the aim of developing safe and effective interventions beyond simple reduction or avoidance of exposure to prevent, mitigate or reverse adverse human health effects of exposures.The field of toxicology has now reached a point where advances in multiple areas of biomedical research and information technologies empower us to make fundamental transitions in directly impacting human health. Translational toxicology must encompass four action elements as follows: 1) Assessing human exposures in critical windows across the lifespan; 2) Defining modes of action and relevance of data from animal models; 3) Use of mathematical models to develop plausible predictions as the basis for: 4) Protective and restorative human health interventions. The discussion focuses on the critical window of in-utero development.</p><p><strong>Summary: </strong>Exposure assessment, basic toxicology and development of certain categories of mathematical models are not new areas of research; however overtly integrating these in order to conceive, assess and validate effective interventions to mitigate or reverse adverse effects of environmental exposures is our novel opportunity. This is what we should do in translational toxicology so that we have a portfolio of interventional options to improve human health that include both minimizing exposures and specific preventative/restorative/mitigative therapeutics.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"51"},"PeriodicalIF":2.9,"publicationDate":"2013-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-51","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31769435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The current status and trend of clinical pharmacology in developing countries.","authors":"Andrew Walubo","doi":"10.1186/2050-6511-14-49","DOIUrl":"https://doi.org/10.1186/2050-6511-14-49","url":null,"abstract":"<p><strong>Background: </strong>Several international forums for promoting clinical pharmacology in developing countries have been held since 1980, and several clinical pharmacology programmes targeting developing countries were instituted such that the status of clinical pharmacology in developing countries is not where it was 50 years ago. Therefore, a survey and an appraisal of the literature on the current status of clinical pharmacology in developing countries were undertaken with a hope that it would enable development of appropriate strategies for further promotion of clinical pharmacology in these countries.</p><p><strong>Methods: </strong>First, nine determinants (or enabling factors) for running a successful clinical pharmacology programme were identified, i.e., disease burden, drug situation, economic growth, clinical pharmacology activities, recognition, human capital, government support, international collaboration, and support for traditional/alternative medicines. These factors were then evaluated with regard to their current status in the developing countries that responded to an electronic questionnaire, and their historical perspective, using the literature appraisal. From these, a projected trend was constructed with recommendations on the way forward.</p><p><strong>Results: </strong>Clinical pharmacology services, research and teaching in developing countries have improved over the past 50 years with over 90% of countries having the appropriate policies for regulation and rational use of medicines in place. Unfortunately, policy implementation remains a challenge, owing to a worsening disease burden and drug situation, versus fewer clinical pharmacologists and other competing priorities for the national budgets. This has led to a preference for training 'a physician clinical pharmacologist' in programmes emphasizing local relevancy and for a shorter time, and the training of other professionals in therapeutics for endemic diseases (task shifting), as the most promising strategies of ensuring rational use of medicines.</p><p><strong>Conclusion: </strong>Clinical pharmacology in developing countries is advancing in a different way to that in the developed world and continuing support for these efforts will go a long way in promoting improved health for all.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"49"},"PeriodicalIF":2.9,"publicationDate":"2013-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-49","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31765418","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The favorable kinetics and balance of nebivolol-stimulated nitric oxide and peroxynitrite release in human endothelial cells.","authors":"R Preston Mason,&nbsp;Robert F Jacob,&nbsp;J Jose Corbalan,&nbsp;Damian Szczesny,&nbsp;Kinga Matysiak,&nbsp;Tadeusz Malinski","doi":"10.1186/2050-6511-14-48","DOIUrl":"https://doi.org/10.1186/2050-6511-14-48","url":null,"abstract":"<p><strong>Background: </strong>Nebivolol is a third-generation beta-blocker used to treat hypertension. The vasodilation properties of nebivolol have been attributed to nitric oxide (NO) release. However, the kinetics and mechanism of nebivolol-stimulated bioavailable NO are not fully understood.</p><p><strong>Methods: </strong>Using amperometric NO and peroxynitrite (ONOO⁻) nanosensors, β₃-receptor (agonist: L-755,507; antagonists: SR59230A and L-748,337), ATP efflux (the mechanosensitive ATP channel blocker, gadolinium) and P2Y-receptor (agonists: ATP and 2-MeSATP; antagonist: suramin) modulators, superoxide dismutase and a NADPH oxidase inhibitor (VAS2870), we evaluated the kinetics and balance of NO and ONOO⁻ stimulated by nebivolol in human umbilical vein endothelial cells (HUVECs). NO and ONOO⁻ were measured with nanosensors (diameter ~ 300 nm) placed 5 ± 2 μm from the cell membrane and ATP levels were determined with a bioluminescent method. The kinetics and balance of nebivolol-stimulated NO and ONOO⁻ were compared with those of ATP, 2-MeSATP, and L-755,507.</p><p><strong>Results: </strong>Nebivolol stimulates endothelial NO release through β₃-receptor and ATP-dependent, P2Y-receptor activation with relatively slow kinetics (75 ± 5 nM/s) as compared to the kinetics of ATP (194 ± 10 nM/s), L-755,507 (108 ± 6 nM/s), and 2-MeSATP (105 ± 5 nM/s). The balance between cytoprotective NO and cytotoxic ONOO- was expressed as the ratio of [NO]/[ONOO⁻] concentrations. This ratio for nebivolol was 1.80 ± 0.10 and significantly higher than that for ATP (0.80 ± 0.08), L-755,507 (1.08 ± 0.08), and 2-MeSATP (1.09 ± 0.09). Nebivolol induced ATP release in a concentration-dependent manner.</p><p><strong>Conclusion: </strong>The two major pathways (ATP efflux/P2Y receptors and β₃ receptors) and several steps of nebivolol-induced NO and ONOO⁻ stimulation are mainly responsible for the slow kinetics of NO release and low ONOO⁻. The net effect of this slow kinetics of NO is reflected by a favorable high ratio of [NO]/[ONOO⁻] which may explain the beneficial effects of nebivolol in the treatment of endothelial dysfunction, hypertension, heart failure, and angiogenesis.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"48"},"PeriodicalIF":2.9,"publicationDate":"2013-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-48","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31764670","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Raltegravir does not revert efflux activity of MDR1-P-glycoprotein in human MDR cells.","authors":"Maria Luisa Dupuis,&nbsp;Alessandro Ascione,&nbsp;Lucia Palmisano,&nbsp;Stefano Vella,&nbsp;Maurizio Cianfriglia","doi":"10.1186/2050-6511-14-47","DOIUrl":"https://doi.org/10.1186/2050-6511-14-47","url":null,"abstract":"<p><strong>Background: </strong>Raltegravir (Isentress®)(RALT) has demonstrated excellent efficacy in both treatment-experienced and naïve patients with HIV-1 infection, and is the first strand transfer integrase inhibitor to be approved for use in HIV infected adults worldwide. Since the in vivo efficacy of this class of antiviral drugs depends on their access to intracellular sites where HIV-1 replicates, we analyzed the biological effects induced by RALT on human MDR cell systems expressing multidrug transporter MDR1-P-glycoprotein (MDR1-Pgp).</p><p><strong>Methods: </strong>Our study about RALT was performed by using a set of consolidated methodologies suitable for evaluating the MDR1-Pgp substrate nature of chemical and biological agents, namely: i) assay of drug efflux function; ii) analysis of MDR reversing capability by using cell proliferation assays; iii) monoclonal antibody UIC2 (mAb) shift test, as a sensitive assay to analyze conformational transition associated with MDR1-Pgp function; and iv) induction of MDR1-Pgp expression in MDR cell variant subjected to RALT exposure.</p><p><strong>Results: </strong>Functional assays demonstrated that the presence of RALT does not remarkably interfere with the efflux mechanism of CEM-VBL100 and HL60 MDR cells. Accordingly, cell proliferation assays clearly indicated that RALT does not revert MDR phenotype in human MDR1-Pgp expressing cells. Furthermore, exposure of CEM-VBL10 cells to RALT does not induce MDR1-Pgp functional conformation intercepted by monoclonal antibody (mAb) UIC2 binding; nor does exposure to RALT increase the expression of this drug transporter in MDR1-Pgp expressing cells.</p><p><strong>Conclusions: </strong>No evidence of RALT interaction with human MDR1-Pgp was observed in the in vitro MDR cell systems used in the present investigation, this incorporating all sets of studies recommended by the FDA guidelines. Taken in aggregate, these data suggest that RALT may express its curative potential in all sites were HIV-1 penetrates, including the MDR1-Pgp protected blood/tissue barrier. Moreover RALT, evading MDR1-Pgp drug efflux function, would not interfere with pharmacokinetic profiles of co-administered MDR1-Pgp substrate antiretroviral drugs.</p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"47"},"PeriodicalIF":2.9,"publicationDate":"2013-09-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-47","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31747604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessing the translatability of in vivo cardiotoxicity mechanisms to in vitro models using causal reasoning.","authors":"Ahmed E Enayetallah,&nbsp;Dinesh Puppala,&nbsp;Daniel Ziemek,&nbsp;James E Fischer,&nbsp;Sheila Kantesaria,&nbsp;Mathew T Pletcher","doi":"10.1186/2050-6511-14-46","DOIUrl":"https://doi.org/10.1186/2050-6511-14-46","url":null,"abstract":"<p><p>Drug-induced cardiac toxicity has been implicated in 31% of drug withdrawals in the USA. The fact that the risk for cardiac-related adverse events goes undetected in preclinical studies for so many drugs underscores the need for better, more predictive in vitro safety screens to be deployed early in the drug discovery process. Unfortunately, many questions remain about the ability to accurately translate findings from simple cellular systems to the mechanisms that drive toxicity in the complex in vivo environment. In this study, we analyzed translatability of cardiotoxic effects for a diverse set of drugs from rodents to two different cell systems (rat heart tissue-derived cells (H9C2) and primary rat cardiomyocytes (RCM)) based on their transcriptional response. To unravel the altered pathway, we applied a novel computational systems biology approach, the Causal Reasoning Engine (CRE), to infer upstream molecular events causing the observed gene expression changes. By cross-referencing the cardiotoxicity annotations with the pathway analysis, we found evidence of mechanistic convergence towards common molecular mechanisms regardless of the cardiotoxic phenotype. We also experimentally verified two specific molecular hypotheses that translated well from in vivo to in vitro (Kruppel-like factor 4, KLF4 and Transforming growth factor beta 1, TGFB1) supporting the validity of the predictions of the computational pathway analysis. In conclusion, this work demonstrates the use of a novel systems biology approach to predict mechanisms of toxicity such as KLF4 and TGFB1 that translate from in vivo to in vitro. We also show that more complex in vitro models such as primary rat cardiomyocytes may not offer any advantage over simpler models such as immortalized H9C2 cells in terms of translatability to in vivo effects if we consider the right endpoints for the model. Further assessment and validation of the generated molecular hypotheses would greatly enhance our ability to design predictive in vitro cardiotoxicity assays. </p>","PeriodicalId":48846,"journal":{"name":"BMC Pharmacology & Toxicology","volume":"14 ","pages":"46"},"PeriodicalIF":2.9,"publicationDate":"2013-09-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1186/2050-6511-14-46","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"31712190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}