bluuebunny/crossref_metadata_2025_split huggingface dataset:
Single‐ and multiple‐dose pharmacokinetics and safety of pimodivir, a novel, non‐nucleoside polymerase basic protein 2 subunit inhibitor of the influenza A virus polymerase complex, and interaction with oseltamivir: a Phase 1 open‐label study in healthy volunteers
Authors: Deleu Sofie , Kakuda Thomas N. , Spittaels Kurt , Vercauteren Jurgen J. , Hillewaert Vera , Lwin Amy , Leopold Lorant , Hoetelmans Richard M. W. 
Published: August 2018

AimsThe aim of this study was to evaluate the drug–drug interaction between pimodivir, a novel, non‐nucleoside polymerase basic protein 2 (PB2) subunit inhibitor of the influenza A virus polymerase complex, and oseltamivir, to assess the feasibility of this combination therapy. Furthermore, single‐ and multiple‐dose pharmacokinetics and safety of pimodivir in healthy volunteers were assessed.MethodsIn Part 1 of this open‐label Phase 1 study, healthy volunteers (n = 18) were randomized to one of six cross‐over treatment sequences, each comprising administration of oseltamivir 75 mg or pimodivir 600 mg or combination thereof twice daily on Days 1–4, followed by a single morning dose on Day 5. Between each treatment session, there was a minimum 5‐day washout period. In Part 2, healthy volunteers (n = 16) randomly received pimodivir 600 mg or placebo (3:1) twice daily on Days 1–9, followed by a single morning dose on Day 10. Pharmacokinetics of pimodivir, oseltamivir and oseltamivir carboxylate, and safety were assessed.ResultsIn Part 1, co‐administration of pimodivir with oseltamivir increased the Cmax of pimodivir by 31% (90% CI: 0.92–1.85) with no change in Cmin or AUC12h. Pimodivir had no effect on oseltamivir or oseltamivir carboxylate pharmacokinetics. In Part 2, after single‐ and multiple‐dose administration of pimodivir, there was a 1.2‐ and 1.8‐fold increase in Cmax and AUC12h, respectively, between Day 1 and Day 10. The most frequently reported treatment‐emergent adverse event was diarrhoea (n = 7 each in Part 1 and 2).ConclusionCombination treatment with pimodivir and oseltamivir in healthy volunteers showed no clinically relevant drug–drug interactions. No safety concerns were identified with pimodivir 600 mg twice daily alone or in combination with oseltamivir 75 mg twice daily.
Anticholinergic exposure and cognitive decline in older adults: effect of anticholinergic exposure definitions in a 3‐year analysis of the multidomain Alzheimer preventive trial (MAPT) study
Authors: Andre Laurine , Gallini Adeline , Montastruc François , Coley Nicola , Montastruc Jean‐Louis , Vellas Bruno , Andrieu Sandrine , Gardette Virginie ,   for the MAPT/DSA study group
Published: August 2018

AimThe aim of the present study was to assess the association between anticholinergic (atropinic) burden and cognitive decline in older adults over the course of 3 years.MethodsWe used data from Multidomain Alzheimer Preventive Trial (MAPT) study participants aged ≥70 years and at risk of cognitive decline. Cognitive function was assessed with a composite score [Mini‐Mental State Examination (MMSE) orientation, Free and Cued Selective Reminding Test, Category Naming Test, Digit Symbol Substitution Test] at 12, 24 and 36 months. Participants declining by more than 0.236 points on the composite score (representing the lowest quintile of 1‐year cognitive change) during any 1‐year period were considered to have undergone cognitive decline. Anticholinergic exposure was defined by four methods for each of four anticholinergic scales (Anticholinergic Drug Scale, Anticholinergic Cognitive Burden, Anticholinergic Risk Scale, the Durán list). The association between cognitive decline and time‐varying anticholinergic exposure [primary analysis using the Durán list and maximal anticholinergic score (0, 1 or 3)] was assessed using Cox proportional hazards models. Other cognitive decline definitions were used in sensitivity analyses.ResultsAt baseline, among 1396 patients included, 7.4–23.5% were exposed to anticholinergic agents, depending on the anticholinergic scale used. Sixty‐four per cent of participants experienced cognitive decline during follow‐up. Regardless of the anticholinergic scale/exposure measurement used, no significant association was observed with cognitive decline {primary analysis: compared with non‐anticholinergic agent users, hazard ratio [HR] = 1.14 [95% confidence interval (CI) = 0.95, 1.38] for anticholinergic score = 1; HR = 0.92 [95% CI = 0.65, 1.30] for score = 3}. Results were stable in sensitivity analyses.ConclusionWe found no significant association between anticholinergic exposure and cognitive decline in older adults using anticholinergic scales and definitions of exposure.
Clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcome for acute coronary syndrome patients
Authors: Li Xiaoye , Wang Zi , Wang Qibing , Xu Qing , Lv Qianzhou 
Published: August 2018

AbstractAcute coronary syndrome (ACS) has become a vital disease with high mortality worldwide. A combined antiplatelet therapy (aspirin and a P2Y12 antagonist) is commonly used to prevent re‐infarction in ACS patients who have undergone percutaneous coronary intervention (PCI). Clopidogrel, a P2Y12 antagonist, plays an important role in the inhibition of platelet aggregation (IPA). However, it is a pro‐drug requiring biotransformation by cytochrome P450 (CYP450). The aim of this study is to unravel the effect of clopidogrel‐associated genetic variants on inhibition of platelet activity and clinical outcomes in ACS patients. In our study, a total of 196 patients with metabolic gene polymorphism of clopidogrel were enrolled, and their antiplatelet effect as well as their cardiovascular events were collected. Approximately 2 mL of venous blood samples were used for genotype detection and another 4 mL were collected for platelet reactivity with thrombelastography. The primary clinical end‐point was defined as a combination of cardiovascular mortality and revascularization for targeted vascular lesion. Based on the results of IPA, the prevalence of high on‐treatment platelet reactivity (HPR) was 17.3% and the majority of patients (82.7%) obtained normal on‐treatment platelet reactivity (NPR). The HPR group had significantly higher body mass index (BMI) and lower arachidonic acid (AA) induced IPA (P < 0.05). Therapy including Glycoprotein (GP) IIb/IIIa antagonist increased IPA (P < 0.05). ADP‐induced IPA effect was lower with the presence of CYP2C19*2, *3 and paraoxonase (PON)1 Q192R loss‐of‐function (LOF) alleles, respectively (P < 0.05). Multivariate logistic regression analysis demonstrated that aspirin resistance (AA‐induced IPA < 50%) had a greater risk of the occurrence of major adverse cardiovascular events (MACE) (OR = 3.817; 95% CI: 1.672‐8.700; P = 0.002). CYP2C19*2 LOF alleles were associated with high risk of MACE in 1‐year post PCI operations (OR = 2.571; 95% CI: 1.143‐5.780; P = 0.030). For the ACS patients, the presence of CYP2C19*2 and PON1 Q192R LOF alleles were the major drivers of HPR.
An observational, multicentre study of cabazitaxel in patients with metastatic castration‐resistant prostate cancer previously treated with docetaxel (CAPRISTANA)
Authors: Carles Joan , Pichler Angelika , Korunkova Hana , Tomova Antoaneta , Ghosn Marwan , El Karak Fadi , Makdessi Joseph , Koroleva Irina , Barnes Gisoo , Bury Denise , Özatilgan Ayse , Hitier Simon , Katolicka Jana 
Published: August 2018

ObjectivesTo obtain routine clinical practice data on cabazitaxel usage patterns for patients with metastatic castration‐resistant prostate cancer (mCRPC) and to describe physician‐assessed cabazitaxel effectiveness, health‐related quality of life (HRQoL) and safety.Patients and MethodsCAPRISTANA was an international, observational cohort study examining cabazitaxel use for the treatment of patients with mCRPC. Effectiveness was assessed by overall survival (OS), progression‐free survival (PFS), time to treatment failure (TTF) and disease control rate. HRQoL was assessed using the Functional Assessment of Cancer Therapy‐Prostate questionnaire (FACT‐P) and the three‐level European Quality of Life questionnaire (EQ‐5D‐3L). Safety was assessed by adverse event (AE) reporting.ResultsA total of 189 patients were treated across 54 centres between April 2012 and June 2016. At baseline, 58.7% had ≥1 comorbidity, 93.7% had an Eastern Cooperative Oncology Group performance status ≤1, and 60.1% had a Gleason score at diagnosis of ≥8. Patients received a median of 6 cabazitaxel cycles; 84.7% received cabazitaxel as second‐line therapy. The median OS, PFS and TTF were 13.2, 5.6 and 4.4 months, respectively. Cabazitaxel led to disease control in 52.9% of patients. HRQoL was maintained (40.3%) or improved (32.2%) in 72.5% of patients based on total FACT‐P scores. Interestingly, 53.6% of patients reported pain improvement and a further 21.2% maintained pain control based on FACT‐P prostate cancer‐specific pain scores. The most common treatment‐related grade ≥3 AEs were neutropenia (7.9%) and anaemia (2.1%).ConclusionPatients in CAPRISTANA treated with cabazitaxel had similar disease outcomes and safety profiles compared with large phase III clinical trials. Most patients had maintained or improved HRQoL scores; >70% of patients had maintained or improved pain control.
Effect of positioning on ureteric stone retropulsion: ‘gravity works’
Authors: Patel Roshan M. , Walia Arman S. , Grohs Evan , Okhunov Zhamshid , Landman Jaime , Clayman Ralph V. 
Published: August 2018

ObjectiveTo evaluate the potential impact of alterations in ‘patient’ position on laser‐induced ureteric stone retropulsion in an in vitro model.Materials and MethodsA ceramic (phantom) stone was placed in a water‐filled clear polymer tube and subjected to continuous laser energy until the stone had retropulsed a distance of 10 cm. The trial was stopped after 60 s if the stone had not reached 10 cm. The time and total energy needed to cause 10 cm of retropulsion were recorded at incline angles of 0°, 10°, 20°, and 40°; 10 trials at each angle were completed. The study was then repeated with pure calcium phosphate brushite stones.ResultsRetropulsion decreased with increasing incline angle of the saline‐filled clear polymer tube. At 0° of incline the phantom stone reached a distance of 10 cm after 7.4 s. At 10°, 20° and 40°, the phantom stone migrated a mean maximum distance of 3.1, 1.2 and 0.7 cm, respectively, and the trial was stopped after 60 s. For the calcium phosphate stone, at 0° and 10° of incline, the stone reached 10 cm after 6.9 and 42.8 s, respectively (P < 0.05). At 20° and 40°, the calcium phosphate stone moved a mean maximum distance of 2.4 and 1 cm, and the trial was stopped after 60 s.ConclusionAlterations in the angle of inclination reduced stone retropulsion during ureteroscopic lithotripsy in an in vitro model to <1 cm. Increasing the incline angle of a patient may effectively preclude retropulsion when performing laser lithotripsy of ureteric stones.
Inhibition of hyperpolarization‐activated cyclic nucleotide‐gated channels by β‐blocker carvedilol
Authors: Cao Ying , Chen Shujun , Liang Yemei , Wu Ting , Pang Jianxin , Liu Shuwen , Zhou Pingzheng 
Published: August 2018

Background and PurposeCarvedilol is a clinically effective β‐blocker broadly used for treating congestive heart failure (CHF), and several clinical trials have demonstrated that it shows a favourable effect compared with other β‐blockers in patients with CHF. The mechanism underlying this beneficial effect of carvedilol compared to other β‐blockers is not clearly understood. In addition to β‐blockers, inhibitors of hyperpolarization‐activated cyclic nucleotide (HCN)‐gated channels, which play a critical role in spontaneous rhythmic activity in the heart, have also been proposed to be suitable drugs for reducing heart rate and, therefore, beneficial for treating CHF. In the present study, we investigated the effect of carvedilol on HCN channels.Experimental ApproachWhole‐cell patch‐clamp recordings were used to assess the effect of carvedilol on currents from wild‐type and mutant HCN1, HCN2 and HCN4 channels expressed in CHO cells.Key ResultsCarvedilol was the only β‐blocker tested that showed inhibitory effects on the major sinoatrial HCN channel isoform HCN4. Carvedilol inhibited HCN4 in a concentration‐dependent manner with an EC50 of 4.4 μM. In addition, carvedilol also inhibited HCN1 and HCN2 channels. Carvedilol blocked HCN channels by decelerating the rate of channel activation and increasing that of deactivation, and shifted the voltage‐dependence of activation leftwards. Our data also showed that carvedilol, unlike other inhibitors of this channel (ivabradine and ZD7288), is not an ‘open‐channel’ inhibitor of HCN4.Conclusions and ImplicationsCarvedilol is a negative gating modulator of HCN channels. It represents a novel structure for future drug design of HCN channel inhibitors.
Stable isotope constraints on the fluid source of hydrothermal breccia pipes in the Tankwa Karoo depocentre, South Africa: Breakdown of authigenic minerals during sill intrusion
Authors: Harris Chris , Buthelezi Nonkululeko , Kahle Beth , Kahle Richard , Ramahala Kathlego , Smith George 
Published: August 2018

AbstractThe Karoo Basin covers much of South Africa and is an area of prospective shale gas exploration, with the Whitehill Formation the target shale unit. However, the sedimentary succession, including the Whitehill, has been intruded by a series of sills and dykes associated with the Karoo Large Igneous Province (~183 Ma), which are expected to have modified the thermal history of the basin dramatically. Here, we investigate a secondary effect of these intrusions: a series of hydrothermal vent complexes, or breccia pipes, focusing on using O, H, and C isotopes to constrain the origin and evolution of fluids produced during the intrusion of basaltic sills. A cluster of breccia pipes have been eroded down to the level of the Ecca Group at Luiperdskop on the western edge of the Karoo basin; a small isolated pipe of similar appearance crops out 13 km to the east. The Luiperdskop pipes are underlain by a Karoo dolerite sill that is assumed to provide the heat driving fluidization. The pipes consist of fine‐grained matrix and about 8% clasts, on average, of mostly sedimentary material; occasional large rafts of quartzite and dolerite are also present. The presence of clasts apparently from the Dwyka Group is consistent with the depth of formation of the pipes being at, or near, the base of the Karoo Supergroup, between 400 and 850 m below present surface. The presence of chlorite as the dominant hydrous mineral is consistent with an emplacement temperature between 300 and 350°C. The major and trace element, and O‐ and H‐isotope composition of the Tankwa breccias is homogenous, consistent with them being derived from the same source. The δ18O values (vsVSMOW) of the breccias are relatively uniform (7.1‰–8.7‰), and are similar to that of the country rock shale, and both are lower than expected for shale. The water content of the breccia is between 2.7 and 3.1 wt.% and the δD values range from −109‰ to −144‰. Calcite in vesicles has δ13C and δ18O (VSMOW) values of −4.2‰ and 24.0‰, respectively. The low δD value of the breccia rocks does not appear to be due to the presence of methane in the fluid. Instead, it is proposed that low δD and δ18O values are the result of the fluid being derived from the breakdown of clay minerals that formed and were deposited at a time of cold climate at ~290 Ma.
TRIM44 promotes human esophageal cancer progression via the AKT/mTOR pathway
Authors: Xiong Dian , Jin Chun , Ye Xudong , Qiu Baiquan , Jianjun Xu , Zhu Shuqiang , Xiang Long , Wu Haibo , Yongbing Wu 
Published: August 2018

Aberrant expression of TRIM‐containing protein 44 (TRIM44) acts as a promoter in multiple cancers. Here, we investigated the biological functions and clinical significance of TRIM44 in human esophageal cancer (HEC). TRIM44 expression was significantly higher in HEC tissues than corresponding normal tissues at both the mRNA (2.42 ± 0.52 vs 0.99 ± 0.25) and protein (1.01 ± 0.27 vs 0.30 ± 0.13) levels. Patients with high TRIM44 expression showed poor differentiation (P = 1.39 × 10−5), advanced TNM stage (P = 3.87 × 10−4) and, most importantly, significantly poorer prognosis (P = 2.80 × 10−5). TRIM44 played a crucial role in epithelial mesenchymal transition (EMT). A significant correlation was observed between TRIM44 and Ki67 expression. We demonstrated that TRIM44 markedly enhanced HEC cell proliferation, migration, and invasion. Additionally, TRIM44 was involved in the AKT/mTOR signaling pathway and its downstream targets, such as STAT3 phosphorylation. Thus, elevated TRIM44 expression promotes HEC development by EMT via the AKT/mTOR pathway, and TRIM44 may be a novel prognostic indicator for HEC patients after curative resection.
Combined inhibition of MEK and PI3K pathways overcomes acquired resistance to EGFR‐TKIs in non‐small cell lung cancer
Authors: Sato Hiroki , Yamamoto Hiromasa , Sakaguchi Masakiyo , Shien Kazuhiko , Tomida Shuta , Shien Tadahiko , Ikeda Hirokuni , Hatono Minami , Torigoe Hidejiro , Namba Kei , Yoshioka Takahiro , Kurihara Eisuke , Ogoshi Yusuke , Takahashi Yuta , Soh Junichi , Toyooka Shinichi 
Published: August 2018

Compensatory activation of the signal transduction pathways is one of the major obstacles for the targeted therapy of non‐small cell lung cancer (NSCLC). Herein, we present the therapeutic strategy of combined targeted therapy against the MEK and phosphoinositide‐3 kinase (PI3K) pathways for acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in NSCLC. We investigated the efficacy of combined trametinib plus taselisib therapy using experimentally established EGFR‐TKI‐resistant NSCLC cell lines. The results showed that the feedback loop between MEK/ERK and PI3K/AKT pathways had developed in several resistant cell lines, which caused the resistance to single‐agent treatment with either inhibitor alone. Meanwhile, the combined therapy successfully regulated the compensatory activation of the key intracellular signals and synergistically inhibited the cell growth of those cells in vitro and in vivo. The resistance mechanisms for which the dual kinase inhibitor therapy proved effective included (MET) mesenchymal‐epithelial transition factor amplification, induction of epithelial‐to‐mesenchymal transition (EMT) and EGFR T790M mutation. In further analysis, the combination therapy induced the phosphorylation of p38 MAPK signaling, leading to the activation of apoptosis cascade. Additionally, long‐term treatment with the combination therapy induced the conversion from EMT to mesenchymal‐to‐epithelial transition in the resistant cell line harboring EMT features, restoring the sensitivity to EGFR‐TKI. In conclusion, our results indicate that the combined therapy using MEK and PI3K inhibitors is a potent therapeutic strategy for NSCLC with the acquired resistance to EGFR‐TKIs.
Quantitative assessment of changes in anterior segment morphology after argon laser peripheral iridoplasty: findings from the EARL study group
Authors: Lim Dawn K , Chan Hwei W , Zheng Ce , Aquino Maria C , Wong Wan Ling , Ritch Robert , Chew Paul TK 
Published: August 2018

AbstractImportanceArgon laser peripheral iridoplasty (ALPI) could be effective in widening residual angle closure following laser peripheral iridotomy (LPI).BackgroundWe investigated changes in angle parameters following ALPI and its safety profile in this study.DesignRetrospective, observational case series.ParticipantsThe records from a single centre, of 36 patients (60 eyes) who underwent ALPI, for residual angle closure following LPI, were reviewed.MethodsWe analysed anterior chamber parameters in anterior segment optical coherence tomography (ASOCT) images using customized software pre‐ and post‐ALPI. Paired t‐test was used to compare changes.Main Outcome MeasuresASOCT parameters analysed included angle opening distance (AOD 500 and 750), trabecular iris surface area (TISA 500 and 750), anterior chamber width (ACW), anterior chamber volume (ACV), angle recess area (ARA), anterior chamber area (ACA), anterior chamber depth (ACD) and lens vault (LV).ResultsThere was a mean increase in AOD 500 (0.05 vs. 0.16 mm, P < 0.001), AOD 750 (0.15 vs. 0.27 mm, P < 0.001), TISA 500 (0.010 vs. 0.038 mm2, P < 0.001), TISA 750 (0.039 vs. 0.102 mm2, P < 0.001), ACV (89.76 vs. 102.25 mm3, P = 0.01), ARA 500 (0.015 vs. 0.033 mm2, P < 0.001) and ARA 750 (0.044 vs. 0.088 mm2, P < 0.001). There was no significant change in ACW, ACD, ACA and LV. Mean intraocular pressure (IOP) decreased post‐ALPI (17.2 vs. 15.7 mmHg, P = 0.002). The mean follow‐up duration was 2.1 years (range 0.5–5 years).Conclusions and RelevanceALPI results in changes to the angle morphology and lowered IOP in eyes with residual angle closure. Our findings suggest a possible role for ALPI in eyes with residual angle closure following peripheral iridotomy.
Once‐daily, prolonged‐release tacrolimus vs twice‐daily, immediate‐release tacrolimus in de novo living‐donor liver transplantation: A Phase 4, randomized, open‐label, comparative, single‐center study
Authors: Shin Min‐Ho , Song Gi‐Won , Lee Sung‐Gyu , Hwang Shin , Kim Ki‐Hun , Ahn Chul‐Soo , Moon Deok‐Bog , Ha Tae‐Yong , Jung Dong‐Hwan , Park Gil‐Chun , Yun Young‐In , Kim Wan‐Jun , Kang Woo‐Hyoung , Kim Seok‐Hwan , Jiang Hongsi , Lee Sungmin , Tak Eun‐Young 
Published: August 2018

AbstractRandomized, open‐label, comparative, single‐center, Phase 4, 24‐week study comparing pharmacokinetics (PK), safety, and efficacy of once‐daily, prolonged‐release tacrolimus (PR‐T) with twice‐daily, immediate‐release tacrolimus (IR‐T) in adult de novo living‐donor liver transplant (LDLT) recipients in Korea. All patients received intravenous tacrolimus from Day 0 (transplantation) for 4 days and were randomized (1:1) to receive oral PR‐T or IR‐T from Day 5. PK profiles were taken on Days 6 and 21. Primary endpoint: area under the concentration‐time curve over 24 hour (AUC0‐24). Predefined similarity interval for confidence intervals of ratios: 80%‐125%. Secondary endpoints included: tacrolimus concentration at 24 hour (C24), patient/graft survival, biopsy‐confirmed acute rejection (BCAR), treatment‐emergent adverse events (TEAEs). One‐hundred patients were included (PR‐T, n = 50; IR‐T, n = 50). Compared with IR‐T, 40% and 66% higher mean PR‐T daily doses resulted in similar AUC0‐24 between formulations on Day 6 (PR‐T:IR‐T ratio of means 96.8%), and numerically higher AUC0‐24 with PR‐T on Day 21 (128.8%), respectively. Linear relationship was similar between AUC0‐24 and C24, and formulations. No graft loss/deaths, incidence of BCAR and TEAEs similar between formulations. Higher PR‐T vs IR‐T doses were required to achieve comparable systemic exposure in Korean de novo LDLT recipients. PR‐T was efficacious; no new safety signals were detected.