scholarly journals An Open-Access Dataset of Thorough QT Studies Results

Data ◽  
2020 ◽  
Vol 5 (1) ◽  
pp. 10
Author(s):  
Barbara Wiśniowska ◽  
Zofia Tylutki ◽  
Sebastian Polak
Keyword(s):  
Study Design ◽  
Data Extraction ◽  
Torsade De Pointes ◽  
Chemical Properties ◽  
Predictive Performance ◽  
Qt Prolongation ◽  
Extensive Literature ◽  
Literature Searches ◽  
Study Results

Along with the current interest in changes of cardiovascular risk assessment strategy and inclusion of in silico modelling into the applicable paradigm, the need for data has increased, both for model generation and testing. Data collection is often time-consuming but an inevitable step in the modelling process, requiring extensive literature searches and other identification of alternative resources providing complementary results. The next step, namely data extraction, can also be challenging. Here we present a collection of thorough QT/QTc (TQT) study results with detailed descriptions of study design, pharmacokinetics, and pharmacodynamic endpoints. The presented dataset provides information that can be further utilized to assess the predictive performance of different preclinical biomarkers for QT prolongation effects with the use of various modelling approaches. As the exposure levels and population description are included, the study design and characteristics of the study population can be recovered precisely in the simulation. Another possible application of the TQT dataset is the analysis of drug characteristic/QT prolongation/TdP (torsade de pointes) relationship after the integration of provided information with other databases and tools. This includes drug cardiac safety classifications (e.g., CredibleMeds), Comprehensive in vitro Proarrhythmia Assay (CiPA) compounds classification, as well as those containing information on physico-chemical properties or absorption, distribution, metabolism, excretion (ADME) data like PubChem or DrugBank.

scholarly journals Lignans of Sesame (Sesamum indicum L.): A Comprehensive Review

Molecules ◽  
2021 ◽  
Vol 26 (4) ◽  
pp. 883
Author(s):  
Mebeaselassie Andargie ◽  
Maria Vinas ◽  
Anna Rathgeb ◽  
Evelyn Möller ◽  
Petr Karlovsky
Keyword(s):  
Biological Activities ◽  
Chemical Properties ◽  
Transformation Products ◽  
Extensive Literature ◽  
Controversial Issues ◽  
Sesame Seeds ◽  
Historical Texts ◽  
Health Promoting ◽  
Processed Products

Major lignans of sesame sesamin and sesamolin are benzodioxol--substituted furofurans. Sesamol, sesaminol, its epimers, and episesamin are transformation products found in processed products. Synthetic routes to all lignans are known but only sesamol is synthesized industrially. Biosynthesis of furofuran lignans begins with the dimerization of coniferyl alcohol, followed by the formation of dioxoles, oxidation, and glycosylation. Most genes of the lignan pathway in sesame have been identified but the inheritance of lignan content is poorly understood. Health-promoting properties make lignans attractive components of functional food. Lignans enhance the efficiency of insecticides and possess antifeedant activity, but their biological function in plants remains hypothetical. In this work, extensive literature including historical texts is reviewed, controversial issues are critically examined, and errors perpetuated in literature are corrected. The following aspects are covered: chemical properties and transformations of lignans; analysis, purification, and total synthesis; occurrence in Seseamum indicum and related plants; biosynthesis and genetics; biological activities; health-promoting properties; and biological functions. Finally, the improvement of lignan content in sesame seeds by breeding and biotechnology and the potential of hairy roots for manufacturing lignans in vitro are outlined.

scholarly journals 684. Cardiac Safety in Adults with Community-Acquired Bacterial Pneumonia (CABP) Treated with Lefamulin (LEF) or Moxifloxacin (MOX): Analysis of Lefamulin Evaluation Against Pneumonia (LEAP) 1 and LEAP 2 Study Results

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S311-S311
Author(s):  
Borje Darpo ◽  
Anita F Das ◽  
Daniel Stein ◽  
Jennifer Schranz ◽  
Steven P Gelone
Keyword(s):  
Torsade De Pointes ◽  
Significant Risk ◽  
Study Drug ◽  
Qt Prolongation ◽  
Drug Discontinuation ◽  
Cardiac Safety ◽  
Study Results ◽  
Minute Interval ◽  
Clinically Significant ◽  
Study Drug Discontinuation

Abstract Background Preclinical data suggest potential effects of LEF on cardiac interval parameters. We therefore assessed LEF cardiac safety from the LEAP 1/2 trials. Methods In LEAP 1, PORT III–V patients received LEF 150mg IV q12h for 5–7 days or MOX 400mg IV q24h for 7 days, with optional IV-to-oral switch (600mg LEF q12h or 400 mg MOX q24h). In LEAP 2, PORT II–IV patients received oral LEF 600mg q12h for 5 days or oral MOX 400mg q24h for 7 days. Patients with known QT prolongation or on medication with potential to prolong the QT interval were excluded as per MOX label. After 5 minutes of rest in the supine position, triplicate 12-lead ECGs were obtained within a 5-minute interval at Screening in both studies, on Days 1/3 in LEAP 1 (predose and ≤15 minutes after first IV dose), and on Days 1/4 in LEAP 2 (predose and 1–3 hours after first oral dose), and sent to a central ECG reader for adjudication. Results Of 1,282 randomized/treated patients (n = 641/group), 1,274 had baseline (BL) and post-BL ECG data (n = 636 LEF, n = 638 MOX). Consistent with the resolution of infection, ECGs revealed mean reductions of 7–8 beats/minute for both groups in both studies. The largest mean change in QTcF from BL to post-BL was on Day 3 in LEAP 1 (13.6 and 16.4 msec with IV LEF and MOX, respectively) and on Day 4 in LEAP 2 (9.3 and 11.6 msec with oral LEF and MOX, respectively). The proportion of patients meeting potentially important post-BL QTcF values/changes was comparable between treatment groups (table). In the standardized MedDRA query of Torsade de pointes/QT prolongation (broad), the most common treatment-emergent adverse event was ECG QT prolonged (n = 4 LEF, n = 5 MOX). All events were nonserious and mild or moderate in severity. 6 events were considered study drug related (n = 4 LEF, n = 2 MOX). 5 events led to study drug discontinuation (n = 2 LEF, n = 3 MOX). In 2 patients with cardiovascular disease, 1 had ventricular arrhythmia on Day 20 (18 days after last LEF dose) and 1 had cardiac arrest on Day 18 (9 days after last MOX dose); both events were fatal and considered unrelated to study drug by investigator. Conclusion Mild prolongation of the QTcF interval was seen with LEF and MOX, with somewhat smaller effects seen with LEF. Given the small effect, LEF is unlikely to pose a clinically significant risk of ventricular proarrhythmia with appropriate precautions and use. Disclosures All authors: No reported disclosures.

scholarly journals Design and Evaluation of Flurbiprofen Micro-Emulsion Based Gel

2020 ◽  
Vol 11 (4) ◽  
pp. 7293-7300
Author(s):  
Manish Wani ◽  
Akshay Baheti ◽  
Satish Polshettiwar ◽  
Tanaji Nandgude ◽  
Aarti Shastri ◽  
...  
Keyword(s):  
Animal Studies ◽  
Chemical Properties ◽  
Tween 80 ◽  
Skin Penetration ◽  
Oral Route ◽  
Physico Chemical ◽  
Study Results ◽  
Microemulsion Based Gel ◽  
Micro Emulsion

Flurbiprofen via oral route has many side effects. Many inflammatory infections occur locally and close to the body's surface, so topical application of flurbiprofen is advantageous. Still, intact skin acts as a barrier and hampers skin penetration of the drug. Present objective of this work was to reduce the adverse effect of flurbiprofen and increase its bioavailability by formulating Flurbiprofen microemulsion based gel, evaluating it for its Physico-chemical properties and then finally conducting its in-vitro and animal studies to determine its efficiency. Arachis oil was selected as an oil phase as flurbiprofen showed maximum solubility in it. Microemulsion formulations (A1 to A9) were prepared by varying the qty of tween 80 (as a surfactant) and propylene glycol (as co-surfactant). Microemulsions which were found to give satisfactory results w.r.t microemulsion formation (F1 to F5) were converted to microemulsion gel using Carbopol 934 as gel base. The ability of different microemulsions to penetrate flurbiprofen through the skin was in-vitro evaluated. All the formulations were evaluated for their quantity of drug present in the formulation, pH, Viscosity, Spreadability, in vitro diffusion study. Formula F4, which showed good Physico-chemical properties, was subjected to anti-inflammatory study. Results showed that pH, spreadability, viscosity and amount of active ingredient present in formulations were in an acceptable limit. The standard calibration curve for flurbiprofen depicts the linear association between concentration and absorbance. The formulation F4 has the highest % release, 90.54% also showed a higher % inhibition of paw oedema after 4 hrs than marketed formulation.

The association between suicide and the socio-economic characteristics of geographical areas: a systematic review

2005 ◽  
Vol 36 (2) ◽  
pp. 145-157 ◽  
Author(s):  
DAVID H. REHKOPF ◽  
STEPHEN L. BUKA
Keyword(s):  
Systematic Review ◽  
Study Design ◽  
Extensive Literature ◽  
Median Income ◽  
High Poverty ◽  
Suicide Rates ◽  
Study Results ◽  
Study Characteristics ◽  
Measurement Strategies ◽  
Economic Measure

Background. Despite an extensive literature, there have been widely divergent findings regarding the direction of the association between area socio-economic characteristics and area suicide rates, with high-quality studies finding either a direct relation (higher rates of suicide in higher socio-economic areas), an inverse relation (lower rates of suicide in higher socio-economic areas) or no association.Method. We performed a systematic review of the literature dating from 1897 to 2004 and identified 86 publications with 221 separate analyses that met our inclusion criteria. We examined the percent of direct, inverse and null findings stratified by key study characteristics including size of aggregated area, socio-economic measure used, region of study, control variables and study design.Results. Analyses at the community level are significantly more likely to demonstrate lower rates of suicide among higher socio-economic areas than studies using larger areas of aggregation. Measures of area poverty and deprivation are most likely to be inversely associated with suicide rates and median income is least likely to be inversely associated with suicide rates. Analyses using measures of unemployment and education and occupation were equally likely to demonstrate inverse associations. Study results did not vary significantly by gender or by study design.Conclusions. The heterogeneity of associations is mostly accounted for by study design features that have largely been neglected in this literature. Enhanced attention to size of region and measurement strategies provide a clearer picture of how suicide rates vary by region. Resources for suicide prevention should be targeted to high poverty/deprivation and high unemployment areas.

Autologous transplantation of mesenchymal stem cells into the portal vein of the miniature pig; a preliminary experiment for NOTES approach

2019 ◽  
Vol 98 (9) ◽  
pp. 350-355
Keyword(s):  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Cell Therapy ◽  
Portal Vein ◽  
Liver Parenchyma ◽  
Miniature Pig ◽  
Hepatic Diseases ◽  
Study Results

Introduction: There is evidence that mesenchymal stem cells (MSCs) could trans-differentiate into the liver cells in vitro and in vivo and thus may be used as an unfailing source for stem cell therapy of liver disease. Combination of MSCs (with or without their differentiation in vitro) and minimally invasive procedures as laparoscopy or Natural Orifice Transluminal Endoscopic Surgery (NOTES) represents a chance for many patients waiting for liver transplantation in vain. Methods: Over 30 millions of autologous MSCs at passage 3 were transplanted via the portal vein in an eight months old miniature pig. The deposition of transplanted cells in liver parenchyma was evaluated histologically and the trans-differential potential of CM-DiI labeled cells was assessed by expression of pig albumin using immunofluorescence. Results: Three weeks after transplantation we detected the labeled cells (solitary, small clusters) in all 10 samples (2 samples from each lobe) but no diffuse distribution in the samples. The localization of CM-DiI+ cells was predominantly observed around the portal triads. We also detected the localization of albumin signal in CM-DiI labeled cells. Conclusion: The study results showed that the autologous MSCs (without additional hepatic differentiation in vitro) transplantation through the portal vein led to successful infiltration of intact miniature pig liver parenchyma with detectable in vivo trans-differentiation. NOTES as well as other newly developed surgical approaches in combination with cell therapy seem to be very promising for the treatment of hepatic diseases in near future.

Development and Ex-vivo Evaluation of Topiramate Mucoadhesive Nanoparticles for Intranasal Delivery

2020 ◽  
Vol 13 (6) ◽  
pp. 5250-5255
Author(s):  
Ashwin Kumar Tulasi ◽  
Anil Goud Kandhula ◽  
Ravi Krishna Velupula
Keyword(s):  
Particle Size ◽  
Nasal Mucosa ◽  
Intranasal Administration ◽  
Ex Vivo ◽  
Chemical Properties ◽  
Brain Targeting ◽  
Oral Tablet ◽  
Promising Alternative ◽  
Ex Vivo Permeation

Topiramate is a second-generation antiepileptic drug used in partial, generalized seizures as an oral tablet. Oral route of administration is most convenient but shows delayed absorption. Moreover, in emergency cases, parenteral administration is not possible as it requires medical assistance. Hence, the present study was aimed to develop topiramate mucoadhesive nanoparticles for intranasal administration using ionotropic gelation method. The developed nanoparticles were evaluated for physico-chemical properties like particle size, zeta potential, surface morphology, drug content, entrapment efficiency, in vitro drug release, mucoadhesive strength, and ex vivo permeation studies in excised porcine nasal mucosa. Optimized nanoparticle formulation (T9) was composed oil mucoadhesive agent (Chitosan 1% w/w), cross linking polymer (TPP) and topiramate 275mg, 100mg and 4% respectively. It showed particle size of 350nm, high encapsulation efficacy and strong mucoadhesive strength. In vitro drug diffusion of optimized formulation showed 95.12% release of drug after 180min. Ex-vivo permeation of drug across nasal mucosa was   88.05 % after 180min. Nasocilial toxicity studies showed optimized formulation did not damage the nasal mucosa. Thus, the intranasal administration of topiramate using chitosan can be a promising alternative for brain targeting and the treatment of epilepsy.

Novel Swellable/Expandable Gastroretentive Floating Films of Gliclazide Folded in Capsule Shell for the Effective Management of Diabetes Mellitus: Formulation Development, Optimization and In vitro Evaluation

2020 ◽  
Vol 15 ◽  
Author(s):  
Diksha Sharma ◽  
Deepak Sharma
Keyword(s):  
Diabetes Mellitus ◽  
Drug Absorption ◽  
Gastric Fluid ◽  
Stability Study ◽  
Gastric Retention ◽  
Effective Management ◽  
In Vitro Evaluation ◽  
Capsule Shell ◽  
Study Results

Background: Gliclazide (GLZ) belongs to the second-generation of sulphonylureas, is a drug of choice for the management of type II DM. It belongs to BCS Class II. The major site of drug absorption for GLZ is the stomach; it displayed variation in the drug absorption rate and bioavailability due to the shorter gastric retention time. Floating mechanism performance gets affected when the gastric fluid level not sufficiently higher, which ultimately obstructs the floating behavior, which is the major limitation of reported formulations. This limitation can get over by folded the film into the capsule shell that dissolved in gastric fluid and film swell/expands to dimensions higher than pylorus sphincter (12mm), thus prevents its evacuation. Objective: To explore the floating mechanism in the designing of films along with a tendency to expand by swelling and unfolding by utilizing a mixture of hydrophilic and hydrophobic polymer to achieve the controlled drug delivery and prolonged gastric retention of drug. Methods: The gastroretentive floating films were formulated by the solvent casting technique using 32 full factorial design and subjected to in vitro evaluation parameters, drug-excipient compatibility, X-ray diffraction and accelerated stability study. Results: The pre-formulation study established the purity and identification of drug. FTIR study confirmed no drug excipient interaction. F3, F6, and F9 were optimized based on in vitro floating characteristics, swelling/expanding ability, and unfolding time study. All developed formulations were unfolded within 14-22 min after capsule disintegration. The F3 was selected as final formulation as its ability to control the release of drug for 24 hrs followed by Zero-order kinetics having super case 2 transport. XRD confirmed the amorphousness of drug within formulation. The stability study results revealed that formulation was quite stable at extreme storage condition. Conclusion: The developed novel formulation has a good potential for the effective management and treatment of Diabetes Mellitus.

Alkaloids as Anticancer Agents: A Review of Chinese Patents in Recent 5 Years

2020 ◽  
Vol 15 (1) ◽  
pp. 2-13 ◽  
Author(s):  
Hongyu Tao ◽  
Ling Zuo ◽  
Huanli Xu ◽  
Cong Li ◽  
Gan Qiao ◽  
...  
Keyword(s):  
Anticancer Activity ◽  
Anticancer Agents ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Cdk Inhibitors ◽  
Comprehensive Overview ◽  
P53 Expression ◽  
Study Results

Background: In recent years, many novel alkaloids with anticancer activity have been found in China, and some of them are promising for developing as anticancer agents. Objective: This review aims to provide a comprehensive overview of the information about alkaloid anticancer agents disclosed in Chinese patents, and discusses their potential to be developed as anticancer drugs used clinically. Methods: Anticancer alkaloids disclosed in Chinese patents in recent 5 years were presented according to their mode of actions. Their study results published on PubMed, and SciDirect databases were presented. Results: More than one hundred anticancer alkaloids were disclosed in Chinese patents and their mode of action referred to arresting cell cycle, inhibiting protein kinases, affecting DNA synthesis and p53 expression, etc. Conclusion: Many newly found alkaloids displayed potent anticancer activity both in vitro and in vivo, and some of the anticancer alkaloids acted as protein kinase inhibitors or CDK inhibitors possess the potential for developing as novel anticancer agents.

In-vitro and in-vivo evaluation of antidiabetic activity of Withania coagulans extract

2019 ◽  
Vol 09 ◽  
Author(s):  
Tejas Patel ◽  
B.N. Suhagia
Keyword(s):  
Blood Glucose ◽  
Acute Toxicity ◽  
Aqueous Extract ◽  
Pancreatic Beta Cell ◽  
Toxicity Study ◽  
Acute Toxicity Study ◽  
Withania Coagulans ◽  
Study Results

Background: Diabetes mellitus is major issue to public health as its prevalence is rising day by day. Synthetic agents available for the diabetic treatment are expensive or produce undesirable side effect on chronic use and some of them are not suitable during pregnancy. Herbal medicines accepted widely due to side effects and low cost. Objective: The aim of present study was to evaluate the activity of Withania coagulans extract using In-vitro and In-vivo model. Methods: Different three types of Withania coagulans extract were prepared using aqueous (W1), Alcohol (W2) and hydro-alcoholic (50:50) mixture (W3). In-vitro Anti-diabetic activity of the all three extracts evaluated using RINm5F Pancreatic beta cells.Further, n-vivo anti-diabetic evaluation performed by administering 50 mg/kg (p.o) aqueous extract for 7 days in Streptozotocin (STZ)-induced mice. Body weight of the animals was also determined to perform acute toxicity study. Results: The results of in –vitro cell based study indicated that among all three extract, aqueous extract (W1) of Withania coagulans showed potential increase in inulin release. The EC50 of the W1 (249.6 µg/L) which is compared with standard (Glibenclamide) EC50. From the results of In-vitro study, W1 subjected for acute toxicity study and the acute toxicity study results indicated LD50 of 50mg/kg. Diabetic rats treated with W1 extract at oral dose of 50 mg/kg for 7 days showed 34.17% reduction in blood glucose in comparison to untreated diabetic (STZ-induced) rats. Blood glucose levels of Standard treated (Glibenclamide) and control untreated. Conclusion: In conclusion, results of pancreatic beta cell based study showed increase in insulin release by administration of extract. Further aqueous extract (W1) was potentially reduced blood glucose level in STZ induced diabetic mice.

scholarly journals Drug interactions: a review of the unseen danger of experimental COVID-19 therapies

2020 ◽  
Vol 75 (12) ◽  
pp. 3417-3424 ◽  
Author(s):  
Catherine Hodge ◽  
Fiona Marra ◽  
Catia Marzolini ◽  
Alison Boyle ◽  
Sara Gibbons ◽  
...  
Keyword(s):  
Drug Interactions ◽  
Herbal Medicines ◽  
Qt Prolongation ◽  
Critically Ill Patient ◽  
Experimental Drugs ◽  
Mesh Terms ◽  
Experimental Therapies ◽  
Clinically Significant ◽  
Novel Coronavirus

Abstract As global health services respond to the coronavirus pandemic, many prescribers are turning to experimental drugs. This review aims to assess the risk of drug–drug interactions in the severely ill COVID-19 patient. Experimental therapies were identified by searching ClinicalTrials.gov for ‘COVID-19’, ‘2019-nCoV’, ‘2019 novel coronavirus’ and ‘SARS-CoV-2’. The last search was performed on 30 June 2020. Herbal medicines, blood-derived products and in vitro studies were excluded. We identified comorbidities by searching PubMed for the MeSH terms ‘COVID-19’, ‘Comorbidity’ and ‘Epidemiological Factors’. Potential drug–drug interactions were evaluated according to known pharmacokinetics, overlapping toxicities and QT risk. Drug–drug interactions were graded GREEN and YELLOW: no clinically significant interaction; AMBER: caution; RED: serious risk. A total of 2378 records were retrieved from ClinicalTrials.gov, which yielded 249 drugs that met inclusion criteria. Thirteen primary compounds were screened against 512 comedications. A full database of these interactions is available at www.covid19-druginteractions.org. Experimental therapies for COVID-19 present a risk of drug–drug interactions, with lopinavir/ritonavir (10% RED, 41% AMBER; mainly a perpetrator of pharmacokinetic interactions but also risk of QT prolongation particularly when given with concomitant drugs that can prolong QT), chloroquine and hydroxychloroquine (both 7% RED and 27% AMBER, victims of some interactions due to metabolic profile but also perpetrators of QT prolongation) posing the greatest risk. With management, these risks can be mitigated. We have published a drug–drug interaction resource to facilitate medication review for the critically ill patient.

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