scholarly journals Exploring a Safety Signal of Antipsychotic-Associated Pneumonia: A Pharmacovigilance-Pharmacodynamic Study

2020 ◽  
Author(s):  
Dainora Cepaityte ◽  
Spyridon Siafis ◽  
Toine Egberts ◽  
Stefan Leucht ◽  
Dimitrios Kouvelas ◽  
...  
Keyword(s):  
Receptor Occupancy ◽  
Underlying Mechanism ◽  
P Value ◽  
Reporting Odds Ratio ◽  
Safety Signal ◽  
Disproportionality Analysis ◽  
Muscarinic Drugs ◽  
The Relationship ◽  
Safety Signals

Abstract An association between antipsychotic drugs and pneumonia has been demonstrated in several studies; however, the risk for pneumonia caused by specific antipsychotics has not been extensively studied. The underlying mechanism is still unknown, and several receptor mechanisms have been proposed. Therefore, using a combined pharmacovigilance-pharmacodynamic approach, we aimed to investigate safety signals of US Food and Drug Administration (FDA)-approved antipsychotics for reporting pneumonia and the potential receptor mechanisms involved. A disproportionality analysis was performed to detect a signal for reporting “infective-pneumonia” and “pneumonia-aspiration” and antipsychotics using reports submitted between 2004 and 2019 to the FDA adverse events spontaneous reporting system (FAERS) database. Disproportionality was estimated using the crude and the adjusted reporting odds ratio (aROR) and its 95% confidence interval (CI) in a multivariable logistic regression. Linear regressions investigated the relationship between aROR and receptor occupancy, which was estimated using in vitro receptor-binding profiles. Safety signals for reporting infective-pneumonia were identified for clozapine (LL = 95% 3.4, n = 546 [aROR: 4.8]) as well as olanzapine (LL = 95% 1.5, n = 250 [aROR: 2.1]) compared with haloperidol, while aRORs were associated with higher occupancies of muscarinic receptors (beta = .125, P-value = .016), yet other anti-muscarinic drugs were not included as potential confounders. No safety signals for reporting pneumonia-aspiration were detected for individual antipsychotics. Multiple antipsychotic use was associated with both reporting infective-pneumonia (LL 95%: 1.1, n = 369 [aROR:1.2]) and pneumonia-aspiration (LL 95%: 1.7, n = 194 [aROR: 2.0]). Considering the limitations of disproportionality analysis, further pharmacovigilance data and clinical causality assessment are needed to validate this safety signal.

scholarly journals Thaumatin-Like Protein-1 Gene (Bx-tlp-1) Is Associated with the Pathogenicity of Bursaphelenchus xylophilus

2019 ◽  
Vol 109 (11) ◽  
pp. 1949-1956 ◽  
Author(s):  
Fanli Meng ◽  
Yongxia Li ◽  
Xuan Wang ◽  
Yuqian Feng ◽  
Zhenkai Liu ◽  
...  
Keyword(s):  
Severity Index ◽  
Underlying Mechanism ◽  
Bursaphelenchus Xylophilus ◽  
Xylem Cavitation ◽  
Gene Encoding ◽  
Double Stranded Rna ◽  
X Ray ◽  
Pine Trees ◽  
The Relationship

The pine wood nematode Bursaphelenchus xylophilus is a destructive species affecting pine trees worldwide; however, the underlying mechanism leading to pathogenesis remains unclear. In this study, a B. xylophilus gene encoding thaumatin-like protein-1 (Bx-tlp-1) was silenced by RNA interference to clarify the relationship between the Bx-tlp-1 gene and pathogenicity. The in vitro knockdown of Bx-tlp-1 with double-stranded RNA (dsRNA) decreased B. xylophilus reproduction and pathogenicity. Treatments with dsRNA targeting Bx-tlp-1 decreased expression by 90%, with the silencing effect maintained even in the F3 offspring. Pine trees inoculated with B. xylophilus treated with Bx-tlp-1 dsRNA decreased the symptom of wilting, and the disease severity index was 56.7 at 30 days after inoculation. Additionally, analyses of the cavitation of intact pine stem samples by X-ray microtomography revealed that the xylem cavitation area of pine trees inoculated with B. xylophilus treated with Bx-tlp-1 dsRNA was 0.46 mm2 at 30 days after inoculation. Results from this study indicated that the silencing of Bx-tlp-1 has effects on B. xylophilus fitness. The data presented here provide the foundation for future analyses of Bx-tlp-1 functions related to B. xylophilus pathogenicity.

scholarly journals Comparative study between ECL and ELISA to determine the reliable range of Estradiol in the treatment of infertility

Bionatura ◽  
2020 ◽  
Vol 5 (4) ◽  
pp. 1352-1355
Author(s):  
Ali Sadeghitabar ◽  
Narges Maleki ◽  
Maryam Armand ◽  
Nasiri Reza
Keyword(s):  
Human Subjects ◽  
Pearson Correlation ◽  
Diagnostic Methods ◽  
Enzyme Linked Immunosorbent Assay ◽  
P Value ◽  
Vitro Fertilization ◽  
The Relationship ◽  
Different Levels ◽  
Estradiol Concentration

Estradiol is one factor that can alter the outcome of the treatment of infertile couples following the application of in vitro fertilization techniques. Currently, the estradiol level is measured by two diagnostic methods Enzyme-Linked Immunosorbent Assay (ELISA) and Electrochemiluminescence (ECL). Accordingly, this study determines ELISA and ECL's sensitivity and consistency to measure different levels of estradiol and determine its reliable range and provide this information to laboratories and gynecologists. This study is performed on 250 patients of the Avicenna Fertility Center. The data of the study are analyzed in SPSS18 and MiniTab. Consent was obtained for experimentation with human subjects. Pearson correlation coefficient was used to investigate the relationship between these two methods. The results indicated a strong correlation between the two variables ECL and ELISA ( r= 0.735, P-value<0.001). High numbers indicate that the decrease and increase of one variable are proportional to the other variable's fluctuation. This study shows that the results of estradiol obtained from both ECL and ELISA are similar. In the ELISA method, due to the linear values' limitation, samples with estradiol concentration above the highest standard level should be diluted and the dilution coefficient should then be applied.

Progression of Artificial Caries in Fluorotic and Nonfluorotic Enamel. An in vitro Study

2008 ◽  
Vol 33 (2) ◽  
pp. 127-130 ◽  
Author(s):  
Suma R ◽  
KK Shashibhushan ◽  
ND Shashikiran ◽  
VV Subba Reddy
Keyword(s):  
Dental Caries ◽  
Dental Fluorosis ◽  
Polarized Light ◽  
Public Health Problem ◽  
In Vitro Study ◽  
P Value ◽  
Fluoride Level ◽  
Relationship Of ◽  
The Relationship

Background and objectives: Fluorosis is an important clinical and public health problem in several parts of the world. Although the relationship of fluoride level in drinking water to dental caries and dental fluorosis is known, relationship of fluorosis with the caries is not clear. This study was conducted to evaluate and compare the thickness of enamel and depth of lesion after inducing artificial caries in fluorotic and nonfluorotic teeth. Methods: Study group included 15 fluorosis affected and 15 normal teeth. Artificial caries was induced and teeth were sectioned to 150 microns and observed under polarized light microscope to measure the enamel thickness and depth of lesion in microns. Results: Statistical analyses of the measurements were made using student's unpaired t-test. Thickness of the enamel of nonfluorotic teeth was found to be significantly more when compared with the fluorotic teeth(p-value 0.0404) and depth of lesion was significantly more in fluorotic teeth when compared with the nonfluorotic teeth(p-value 0.0218). Conclusion:Although fluoride is acknowledged as an essential factor in the prevention of dental caries there has to be careful balance in the amount consumed to ensure that fluorosis does not occur.

In Vitro and Clinical Investigation of the Relationship Between CCR5 Receptor Occupancy and Anti-HIV Activity of Aplaviroc

2008 ◽  
Vol 48 (10) ◽  
pp. 1179-1188 ◽  
Author(s):  
James F. Demarest ◽  
Sara S. Sparks ◽  
Kathleen Schell ◽  
Shiro Shibayama ◽  
Charlene B. McDanal ◽  
...  
Keyword(s):  
Clinical Investigation ◽  
Receptor Occupancy ◽  
Ccr5 Receptor ◽  
The Relationship ◽  
Anti Hiv

scholarly journals SAFETY PROFILE OF MIRTAZAPINE: A REAL-WORLD DISPROPORTIONALITY

2021 ◽  
Vol 10 (2) ◽  
pp. 20-24
Author(s):  
Chenthamarai.G ◽  
Lakshmi Prasanna.T.
Keyword(s):  
Adverse Events ◽  
Reporting System ◽  
Proportional Reporting Ratio ◽  
Antidepressant Drug ◽  
Severe Depression ◽  
Epidemiological Studies ◽  
Reporting Odds Ratio ◽  
Disproportionality Analysis ◽  
Post Marketing Surveillance ◽  
Safety Signals

Introduction: Mirtazapine is an antidepressant drug that produces both noradrenergic and serotonergic activity. It is effective in treating of mild to severe depression. Proper evidence pointing to the safety of Mirtazapine is not established. The need for post-marketing surveillance (PMS) is considered most essential. This study was aimed to generate signal for unreported adverse drug reactions for Mirtazapine.  Materials and Methods: Our study retrospectively analyzed the AEs reported entered in the Adverse Events Reporting System (FAERS) databases in the last 10-years during the period of Jan 2011 to June 2020. Disproportionality analysis was done using Reporting Odds Ratio, Proportional Reporting Ratio, and Information Component with 95% confidence interval. Results: A disproportionality analysis was done for 41 adverse events, out of these, signal for 11 adverse events was found. ROR values 10.17 being the highest for abulia and 2.22 being the lowest for homicidal Ideation. The PRR value was 10.17 being the highest for abulia and 2.22 being the lowest for homicidal ideation. The IC025 value was 1.87 for abulia and 0.27 for homicidal Ideation. Conclusion: The present study using the Adverse Events Reporting System (FAERS) databases maintained by the FDA suggested new safety signals for Mirtazapine. Still more cohort and epidemiological studies are recommended to validate these results. Keywords: Mirtazapine, Disproportionality analysis, Safety Signals.

scholarly journals Knockdown of Lncrna PVT1 Enhances Radiosensitivity in Non-Small Cell Lung Cancer by Sponging Mir-195

2017 ◽  
Vol 42 (6) ◽  
pp. 2453-2466 ◽  
Author(s):  
Dapeng Wu ◽  
Yong Li ◽  
Huixiang Zhang ◽  
Xigang Hu
Keyword(s):  
Lung Cancer ◽  
Colony Formation ◽  
Underlying Mechanism ◽  
Tumor Xenograft ◽  
Luciferase Reporter ◽  
Nsclc Patients ◽  
The Relationship ◽  
Variant Translocation

Background/Aims: Plasmacytoma variant translocation 1 (PVT1) exerts an oncogenic role in many tumors, including lung cancer. However, the roles of PVT1 in regulating radiosensitivity of NSCLC and its underlying mechanism are still unclear. Methods: Expression levels of PVT1 and miR-195 in NSCLC tissues and cells were examined by qRT-PCR. Effects of PVT1 and miR-195 on cell proliferation, apoptosis and colony formation abilities were assessed by MTT assay, flow cytometry and colony formation assay. Luciferase reporter assay was performed to confirm the relationship between PVT1 and miR-195. Tumor xenograft experiments were conducted to observe the effect of PVT1 on radiosensitivity of NSCLC in vivo. Results: PVT1 was negatively correlated with miR-195 expression in NSCLC tissues and associated with poor prognosis of NSCLC patients. Expression of PVT1 and miR-195 varied inversely after irradiation in NSCLC cells. PVT1 knockdown or miR-195 overexpression enhanced radiosensitivity of NSCLC in vitro by inhibiting proliferation and inducing apoptosis. PVT1 directly interacted with miR-195 and regulated its expression. Moreover, PVT1 knockdown improved radiosensitivity of NSCLC cells in vitro and in vivo by sponging miR-195. Conclusion: Knockdown of PVT1 enhances radiosensitivity of NSCLC by sponging miR-195, providing a novel therapeutic target to improve radiotherapy efficiency in NSCLC.

scholarly journals HOXA13, Negatively Regulated by miR-139-5p, Decreases the Sensitivity of Gastric Cancer to 5-Fluorouracil Possibly by Targeting ABCC4

2021 ◽  
Vol 11 ◽  
Author(s):  
Zhengqian Chen ◽  
Zhiwei Qin ◽  
Lei Li ◽  
Qi Wo ◽  
Xia Chen
Keyword(s):  
Gastric Cancer ◽  
Underlying Mechanism ◽  
Cell Counting ◽  
Luciferase Reporter ◽  
Sequencing Analysis ◽  
Kaplan Meier ◽  
The Relationship ◽  
Kaplan Meier Plotter

PurposeChemoresistance remains a major challenge in the therapy of gastric cancer (GC). The homeobox (HOX) gene family has gained attention in carcinogenesis and chemoresistance. Here, this study aimed to explore the mechanism of HOXA13 in GC chemoresistance.MethodsQuantitative real-time PCR (qRT-PCR) and Western blot were used to evaluate the expression of HOXA13 in GC tissues. The Kaplan–Meier plotter database was mined for prognosis analysis of GC patients with different HOXA13 expression receiving 5-Fluorouracil (5-FU) therapy. The effects of HOXA13 on sensitivity of GC cells to 5-FU were investigated by Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2’-deoxyuridine (EdU) incorporation, flow cytometry and experiment in vivo. RNA-Sequencing analysis was performed to explore the underlying mechanism of HOXA13-mediated 5-FU resistance in GC. Chromatin immunoprecipitation (ChIP) and rescue experiments were applied to determine the relationship between HOXA13 and ABCC4. Luciferase reporter assay was performed to assess interaction of miR-139-5p and HOXA13.ResultsHOXA13 was upregulated in GC and its high expression was associated with poor prognosis of GC patients with 5-FU treatment. Overexpression of HOXA13 impaired the inhibitory effects of 5-FU on GC cells proliferation in vitro and vivo, and knockdown of HOXA13 exacerbated 5-FU-induced GC cells apoptosis. Mechanistically, HOXA13, directly targeted by miR-139-5p in GC, might upregulate ABCC4 expression, thereby accentuating 5-FU resistance of GC cells.ConclusionOur study suggests that HOXA13 attenuates 5-FU sensitivity of GC possibly by upregulating ABCC4. Thus, targeting HOXA13 would provide a novel prospective into the potential therapeutic strategy for reversing chemoresistance.

scholarly journals Machine Learning for Detection of Safety Signals From Spontaneous Reporting System Data: Example of Nivolumab and Docetaxel

2021 ◽  
Vol 11 ◽  
Author(s):  
Ji-Hwan Bae ◽  
Yeon-Hee Baek ◽  
Jeong-Eun Lee ◽  
Inmyung Song ◽  
Jee-Hyong Lee ◽  
...  
Keyword(s):  
Machine Learning ◽  
Spontaneous Reporting ◽  
Learning Algorithms ◽  
Predictive Performance ◽  
Machine Learning Algorithms ◽  
Gradient Boosting ◽  
Reporting Odds Ratio ◽  
Disproportionality Analysis ◽  
Analysis Methods ◽  
Safety Signals

Introduction: Various methods have been implemented to detect adverse drug reaction (ADR) signals. However, the applicability of machine learning methods has not yet been fully evaluated.Objective: To evaluate the feasibility of machine learning algorithms in detecting ADR signals of nivolumab and docetaxel, new and old anticancer agents.Methods: We conducted a safety surveillance study of nivolumab and docetaxel using the Korea national spontaneous reporting database from 2009 to 2018. We constructed a novel input dataset for each study drug comprised of known ADRs that were listed in the drug labels and unknown ADRs. Given the known ADRs, we trained machine learning algorithms and evaluated predictive performance in generating safety signals of machine learning algorithms (gradient boosting machine [GBM] and random forest [RF]) compared with traditional disproportionality analysis methods (reporting odds ratio [ROR] and information component [IC]) by using the area under the curve (AUC). Each method then was implemented to detect new safety signals from the unknown ADR datasets.Results: Of all methods implemented, GBM achieved the best average predictive performance (AUC: 0.97 and 0.93 for nivolumab and docetaxel). The AUC achieved by each method was 0.95 and 0.92 (RF), 0.55 and 0.51 (ROR), and 0.49 and 0.48 (IC) for respective drug. GBM detected additional 24 and nine signals for nivolumab and 82 and 76 for docetaxel compared to ROR and IC, respectively, from the unknown ADR datasets.Conclusion: Machine learning algorithm based on GBM performed better and detected more new ADR signals than traditional disproportionality analysis methods.

scholarly journals On the relationship between inhibition and receptor occupancy by nondepolarizing neuromuscular blocking drugs

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Hikaru Hoshino ◽  
Eiko Furutani
Keyword(s):  
Receptor Binding ◽  
Receptor Occupancy ◽  
Neuromuscular Blocking ◽  
In Vitro Experiments ◽  
Binding Model ◽  
Neuromuscular Blocking Drugs ◽  
The Relationship ◽  
Nondepolarizing Neuromuscular Blocking Drugs

Abstract Background Nondepolarizing neuromuscular blocking drugs (NDNBs) are clinically used to produce muscle relaxation during general anesthesia. To better understand clinical properties of NDNBs, comparative in vitro pharmacologic studies have been performed. In these studies, a receptor binding model, which relies on the assumption that the inhibition, i.e., the effect of an NDNB, is proportional to the receptor occupancy by the drug, has been effectively used to describe obtained experimental data. However, it has not been studied in literature under which conditions the above assumption can be justified nor the assumption still holds in vivo. The purpose of this study is to explore the in vivo relationship between the inhibition and the receptor occupancy by an NDNB and to draw implications on how in vitro experimental results can be used to discuss the in vivo properties of NDNBs. Methods An ordinary differential equation model is employed to simulate physiologic processes of the activation of receptors by acetylcholine (ACh) as well as inhibition by an NDNB. With this model, the degree of inhibition is quantified by the fractional amount of receptors that are not activated by ACh due to the presence of an NDNB. The results are visualized by plotting the fractional amounts of the activated receptors as a function of the receptor occupancy. Results Numerical investigations reflecting in vivo conditions show that the degree of inhibition is not proportional to the receptor occupancy, i.e., there is a nonlinear relationship between the inhibition and the receptor occupancy. However, under a setting of high concentration of ACh reflecting a typical situation of in vitro experiments, the relationship between the inhibition and the receptor occupancy becomes linear, suggesting the validity of the receptor binding model. Also, it is found that the extent of nonlinearity depends on the selectivity of NDNBs for the two binding sites of the receptors. Conclusions While the receptor binding model may be effective for estimating affinity of an NDNB through in vitro experiments, these models do not directly describe in vivo properties of NDNBs, because the nonlinearity between the inhibition and the receptor occupancy causes the modulation of the resultant concentration-effect relationships of NDNBs.

scholarly journals Embryo aggregation regulates in vitro stress conditions to promote developmental competence in pigs

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e8143 ◽  
Author(s):  
Pil-Soo Jeong ◽  
Seung-Bin Yoon ◽  
Mun-Hyeong Lee ◽  
Hee-Chang Son ◽  
Hwal-Yong Lee ◽  
...  
Keyword(s):  
Large Scale ◽  
Formation Rate ◽  
Underlying Mechanism ◽  
Stress Conditions ◽  
Developmental Competence ◽  
Scale Production ◽  
Cell Stage ◽  
Beneficial Effects ◽  
The Relationship

Embryo aggregation is a useful method to produce blastocysts with high developmental competence to generate more offspring in various mammals, but the underlying mechanism(s) regarding the beneficial effects are largely unknown. In this study, we investigated the effects of embryo aggregation using 4-cell stage embryos in in vitro developmental competence and the relationship of stress conditions in porcine early embryogenesis. We conducted aggregation using the well of the well system and confirmed that aggregation using two or three embryos was useful for obtaining blastocysts. Aggregated embryos significantly improved developmental competence, including blastocyst formation rate, blastomere number, ICM/TE ratio, and cellular survival rate, compared to non-aggregated embryos. Investigation into the relationship between embryo aggregation and stress conditions revealed that mitochondrial function increased, and oxidative and endoplasmic reticulum (ER)-stress decreased compared to 1X (non-aggregated embryos) blastocysts. In addition, 3X (three-embryo aggregated) blastocysts increased the expression of pluripotency, anti-apoptosis, and implantation related genes, and decreased expression of pro-apoptosis related genes. Therefore, these findings indicate that embryo aggregation regulates in vitro stress conditions to increase developmental competence and contributes to the in vitro production of high-quality embryos and the large-scale production of transgenic and chimeric pigs.

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