Effectiveness and Safety of Apatinib Plus Chemotherapy as Neoadjuvant Treatment for Locally Advanced Gastric Cancer: A Nonrandomized Controlled Trial.

Importance: Apatinib is a novel treatment option for chemotherapy-refractory advanced gastric cancer (GC), but it has not been evaluated in patients with locally advanced GC. Objective: To investigate the effectiveness and safety of apatinib combined with S-1 plus oxaliplatin (SOX) as a neoadjuvant treatment for locally advanced GC. Design, Setting, and Participants: This multicenter, prospective, single-group, open-label, phase 2 nonrandomized controlled trial was conducted in 10 centers in southern China. Patients with M0 and either clinical T2 to T4 or N+ disease were enrolled between July 1, 2017, and June 30, 2019. Statistical analysis was performed from December 1, 2019, to January 31, 2020. Interventions: Eligible patients received apatinib (500 mg orally once daily on days 1 to 21 and discontinued in the last cycle) plus SOX (S-1: 40-60 mg orally twice daily on days 1 to 14; oxaliplatin: 130 mg/m2 intravenously on day 1) every 3 weeks for 2 to 5 cycles. A D2 gastrectomy was performed 2 to 4 weeks after the last cycle. Main Outcomes and Measures: The primary end point was R0 resection rate. Secondary end points were the response rate, toxic effects, and surgical outcome. Results: A total of 48 patients (mean [SD] age, 63.2 [8.2] years; 37 men [77.1%]) were enrolled in this study. Forty patients underwent surgery (38 had gastrectomy, and 2 had exploratory laparotomy), with an R0 resection rate of 75.0% (95% CI, 60.4%-86.4%). The radiologic response rate was 75.0%, and T downstaging was observed in 16 of 44 patients (36.4%). The pathological response rate was 54.2% (95% CI, 39.2%-68.6%); moreover, this rate was significantly higher in patients who achieved a radiologic response compared with those who did not (12 [80.0%] vs 1 [20.0%]; P = .03) and in those who had an Eastern Cooperative Oncology Group Performance Status score of 0 (20 [76.9%] vs 10 [45.5%]; P = .03) or had tumors located in the upper one-third of the stomach (16 [61.5%] vs 7 [31.8%]; P = .04). Patients who achieved a pathological response (vs those who did not) had significantly less blood loss (median [range]: 60 [10-200] mL vs 80 [20-300] mL; P = .04) and significantly more lymph nodes harvested (median [range]: 40 [24-67] vs 32 [19-51]; P = .04) during surgery. Postoperative complications were observed in 7 of 38 patients (18.4%). Grade 3 toxic effects occurred in 16 of 48 patients (33.3%), and no grade 4 toxic effects or preoperative deaths were observed. Conclusions and Relevance: This nonrandomized controlled trial found that apatinib combined with SOX was effective and had an acceptable safety profile as a neoadjuvant treatment for locally advanced GC. A large-scale randomized clinical trial may be needed to confirm the findings. Trial Registration: ClinicalTrials.gov Identifier: NCT03192735.

Therapeutic effects of regorafenib after sorafenib monotherapy with advanced hepatocellular carcinoma including Child-Pugh classification B: A retrospective observational study.

The therapeutic effect of regorafenib was previously demonstrated in patients with advanced hepatocellular carcinoma (HCC) and Child-Pugh classification A (CP-A) whose disease progressed during sorafenib treatment in a phase III trial. However, treatment options are limited for patients with advanced HCC other than CP-A. In this study, we aimed to evaluate the therapeutic effect of regorafenib on advanced HCC patients including those with Child-Pugh classification B (CP-B).We retrospectively analyzed the medical records of 21 patients with advanced HCC who were treated with regorafenib after sorafenib monotherapy at our hospital from July 2017 to April 2018 and were followed up until September 2019. Patients were classified according to liver function and adverse events experienced during sorafenib treatment and were started on regorafenib with a pre-defined reduced starting dose along with a dose reduction and schedule change based on the judgement of the attending physician.At regorafenib initiation, 13 and 8 patients were classified as CP-A and CP-B, respectively. In all patients with CP-B, the starting dose of regorafenib was reduced, and the pre-defined starting-dose sets were applied to 17 (81%) patients. The median duration of regorafenib treatment in patients with CP-A and CP-B were 4.1 months and 2.0 months, respectively, with no significant difference. The median overall survival from regorafenib initiation (OS-r) and sorafenib initiation (OS-s) was 13.2 months and 30.9 months, respectively. In subgroup analysis, OS-r was 16.3 months in patients with CP-A and 10.1 months with CP-B with no significant difference (P = .44), whereas OS-r was 16.3 months in patients with modified albumin-bilirubin Grade 1/2a and 13.2 months in patients with Grade 2b, with no significant difference. There was no clear difference in the incidence rate of ≥grade 3 adverse events between CP-A and CP-B. OS-r and OS-s were significantly correlated.Even patients with impaired liver function achieved the desired therapeutic effects by safely reducing the starting dose of regorafenib according to both impaired liver function and adverse events during pretreatment. Regorafenib may be considered to be an effective treatment after sorafenib monotherapy in patients with impaired liver function.

Efficacy of Palbociclib and Endocrine Treatment in Heavily Pretreated Hormone Receptor-positive/HER2-negative Advanced Breast Cancer: Retrospective Multicenter Trial

Background: The synthesis of CDK4/6 inhibitors with endocrine treatment in two series of treatment has been widely accepted as the standard for patients with estrogen receptor-positive metastatic breast cancer. In spite of this, the activity of CDK4/6 inhibitors in patients with metastatic breast cancer who have progressed despite receiving multiple lines of treatment is not well understood. Aims: To report the activity and safety of a CDK4/6 inhibitor (palbociclib) in patients in whom at least three lines of treatment for ER+ metastatic breast cancer had failed. Study Design: Multicenter retrospective observational cohort study. Methods: In this retrospective observational cohort study, we included 43 patients who received palbociclib after at least three lines of systemic treatment for ER+/HER2− metastatic breast cancer. Results: The median progression-free survival in our population was 7 months (25th-75th percentile, 4-10), and the median overall survival was 11 months (25th-75th percentile, 6-19). Although there were some adverse events, palbociclib was generally well tolerated, so dose reduction was needed for only six patients (14%). Conclusion: The efficacy of palbociclib among heavily treated hormone receptor-positive/HER2− patients with advanced breast cancer was acceptable in terms of clinical benefit, and it was generally well tolerated among this population.

Identification, Characterization and HPLC Quantification of Process-Related Impurities in Bepotastine Besilate Bulk Drug.

Bepotastine besilate (here after referred to as BTST), chemically known as ({d(S)4[4[(4chlorophenyl) (2pyridyl) methoxy] piperidino} butyric acid monobenzene sulphonate), is a second-generation antihistamine drug. To the best of our knowledge, no studies concerning the isolation or identification of process-related impurities have been reported so far. The current study reports the development and validation of a stability-indicating RP-HPLC method for the separation and identification of 5 potential impurities in bepotastine besilate. In this experiment, the structures of 3 process-related impurities were found to be new compounds. They were characterized and confirmed by NMR and MS spectroscopy analyses. These 3 new compounds were proposed to be (S)-4-[(phenyl)-2-pyridinylmethoxy]-1-piperidinebutanoic acid,(Imp-A); 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy]-1- piperidinebutyric acid, N-oxide (Imp-B) and (S)-4-[(4- chlorophenyl)-2-pyridinylmethoxy]-1-piperidylethane (Imp-C). In addition, an efficient optimized chromatographic method was performed on a Shimadzu Inertsil C8-3 column (150 mm×4.6 mm, 3 µm) to separate and quantify these 5 impurities. It was using 15 mmol ammonium formate buffer in water (pH adjusted to 3.8 with formic acid) and acetonitrile as the mobile phase in gradient mode. The method was developed to separate and quantify these 5 impurities obtained in the range of 0.05-0.75 µg/mL. It was validated and proven to be selective, accurate and precise and suitable. It is the first publication of identification and characterization data of the 3 new compounds. It is also the first effective HPLC method for separation and quantification of all of process-related impurities in bepotastine besilate.

Comparison of the Therapeutic Efficacies of Topical Rivoceranib and Topical Bevacizumab in a Murine Model of Corneal Neovascularization.

Background and Objectives: Corneal neovasculariziation (CNV) is a serious vision-threatening complication; however, all therapeutics have their clinical limitations. The aim of this study is to investigate the efficacy of topical rivoceranib compared with topical bevacizumab in a murine model of corneal neovascularization (CNV). Materials and Methods: Murine CNV was induced by means of total de-epithelization and alkali burn. Mice were divided into five groups according to topical treatment: untreated control, phosphate-buffered saline (PBS), 0.1% and 0.5% rivoceranib, and 0.5% bevacizumab. CNV area and index were measured 7 and 14 days after treatment. After corneal tissues were excised at day 14, the blood and lymphatic vessels were quantified by cluster of differentiation 31 (CD31) and lymphatic vessel endothelial hyaluronan receptor 1 (LYVE1) immunofluorescence, respectively. Results: After 14 days, treatment groups with 0.1% and 0.5% rivoceranib and 0.5% bevacizumab showed a decrease in CNV area and index compared with the untreated and PBS groups (all p < 0.01). Blood and lymphatic vascularization significantly decreased in the 0.5% rivoceranib and 0.5% bevacizumab groups, as measured by CD31 and LYVE1 immunofluorescence. There was no significant difference of vascularization between the 0.5% rivoceranib and bevacizumab groups. Conclusions: Topical application of rivoceranib could effectively decrease CNV equivalent to topical bevacizumab in a murine model.

Extended-duration betrixaban versus shorter-duration enoxaparin for venous thromboembolism prophylaxis in critically ill medical patients: an APEX trial substudy.

PURPOSE: To assess the efficacy and safety of betrixaban for venous thromboembolism (VTE) prophylaxis among critically ill patients. METHODS: The APEX trial randomized 7513 acutely ill hospitalized patients to betrixaban for 35-42 days or enoxaparin for 10 ± 4 days. Among those, 703 critically ill patients admitted to the intensive care unit were included in the analysis, and 547 patients who had no severe renal insufficiency or P-glycoprotein inhibitor use were included in the full-dose stratum. The risk of VTE, bleeding, net clinical benefit (composite of VTE and major bleeding), and mortality was compared at 35-42 days and at 77 days. RESULTS: At 35-42 days, extended betrixaban reduced the risk of VTE (4.27% vs 7.95%, P = 0.042) without causing excess major bleeding (1.14% vs 3.13%, P = 0.07). Both VTE (3.32% vs 8.33%, P = 0.013) and major bleeding (0.00% vs 3.26%, P = 0.003) were decreased in the full-dose stratum. Patients who received betrixaban had more non-major bleeding than enoxaparin (overall population: 2.56% vs 0.28%, P = 0.011; full-dose stratum: 3.32% vs 0.36%, P = 0.010). Mortality was similar at the end of study (overall population: 13.39% vs 16.19%, P = 0.30; full-dose stratum: 13.65% vs 16.30%, P = 0.39). CONCLUSIONS: Compared with shorter-duration enoxaparin, critically ill medical patients who received extended-duration betrixaban had fewer VTE without more major bleeding events. The benefit of betrixaban was driven by preventing asymptomatic thrombosis and offset by an elevated risk of non-major bleeding. The APEX trial did not stratify by intensive care unit admission and the present study included a highly selected population of critically ill patients. These hypothesis-generating findings need to be validated in future studies. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov . Unique identifier: NCT01583218.

A Review on the New and Old Anticoagulants.

Anticoagulants serve as the primary strategy for the prevention and treatment of both arterial and venous thromboembolism. Anticoagulants disrupt coagulation by interfering at various points in the coagulation cascade. This class of medications does not lyse clots that already exist; rather, it prevents thrombus formation and prevents or slows the extension of an existing clot. For decades, the standard therapy for patients requiring oral anticoagulation was warfarin. However, due to some of the shortcomings of warfarin, including the need for continuous routine monitoring, longtime onset and offset of anticoagulation effect, major food and drug interactions, and high incidence of bleeding, newer agents, termed direct oral anticoagulants, or DOACs were developed. This article will provide a review of clinically important information regarding the most commonly used anticoagulants and their reversal agents.

Screening of stabilizers for LC-MS/MS analysis of clevidipine and its primary metabolite in dog whole blood.

BACKGROUND: Clevidipine is an ester-containing antihypertensive agent that undergoes rapid hydrolysis in blood. A reliable stabilizer cocktail containing citric acid and ascorbic acid was established and the LC-MS/MS method was validated for simultaneous determination of clevidipine and its major metabolite in beagle dog whole blood. RESULTS: The stabilizer could nearly completely inhibit the esterase activity. Both analytes were extracted from whole blood by toluene and detected by MS/MS in positive ESI mode. The linearity range was 0.1-100.0 ng/ml for clevidipine and 1.0-1000.0 ng/ml for the primary metabolite. CONCLUSION: The stabilizer cocktail was able to effectively suppress the activity of esterase in blood. The method was successfully applied to a PK study of clevidipine in beagle dogs.

Nicotelline: a proposed biomarker and environmental tracer for particulate matter derived from tobacco smoke.

Particulate matter (PM) derived from tobacco smoke contains numerous toxic substances. Since the PM and gas phase of tobacco smoke may distribute differently in the environment and substances in them may have different human bioavailability, multiple tracers and biomarkers for tobacco smoke constituents are desirable. Nicotelline is a relatively nonvolatile alkaloid present in tobacco smoke, and therefore, it has the potential to be a suitable tracer and biomarker for tobacco smoke-derived PM. We describe experiments demonstrating that nicotelline is present almost entirely in the PM, in both freshly generated cigarette smoke and aged cigarette smoke. An excellent correlation between the mass of nicotelline and the mass of the PM in aged cigarette smoke was found. We also describe experiments suggesting that the main source of nicotelline in tobacco smoke is dehydrogenation of another little-studied tobacco alkaloid, anatalline, during the burning process. We show that nicotelline metabolites can be measured in the urine of smokers and that nicotelline can be measured in house dust from homes of smokers and nonsmokers. We conclude that nicotelline should be useful as a tracer and biomarker for PM derived from tobacco smoke.

Proposed cutoff for identifying adult smokeless tobacco users with urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol: an aggregated analysis of NHANES 2007-2010 data.

INTRODUCTION: NNAL [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanonol] is a valid biomarker of tobacco use. However; no study has assessed its use in distinguishing current smokeless tobacco (SLT) users from nonusers. Therefore, this study used aggregated data from the 2007-2008 and 2009-2010 waves of the National Health and Nutrition Examination Survey to determine an optimal threshold for identifying SLT users with NNAL. METHODS: Optimal urinary total NNAL concentrations for discriminating SLT-only users from nonusers of any tobacco were determined using receiver operating characteristic analysis. Percentage agreement between self-reported SLT use status and NNAL levels was calculated overall and by sociodemographic characteristics. All analyses were weighted and performed with Stata, Version 11, and MedCalc for Windows, Version 9.5.0.0. RESULTS: In total, 264 individuals reported exclusively using SLT (and no other combustible tobacco product) within the past 5 days, whereas 14,824 were self-reported nonusers of any combustible or smokeless tobacco product. The optimal NNAL cutoff point was 34.0 pg/ml, which was associated with a high sensitivity (95.2%), specificity (93.4%), and overall correct classification rate (93.5%). The area under the curve was 98.3% and the corresponding Youden's Index was 88.7%. There was high agreement between the proposed NNAL cutoff point and self-reported SLT-only use (95.6%) and self-reported SLT nonuse (93.9%). CONCLUSION: The proposed cutoff point of 34.0 pg/ml had high sensitivity and specificity and may be used by clinicians and researchers to verify or detect recent SLT use. This study also indicated that self-reported SLT use among adults is a reliable measure and has high agreement with biochemical assessment.

Oral and topical pharmacokinetic studies of a novel TRPV1 antagonist, PAC-14028 in rats and minipigs using liquid chromatography/tandem mass spectrometric method.

PAC-14028 ((E)-N-((R)-1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl)-3-(2-propyl-6-trifluoromethyl-pyridine-3-yl)-acrylamide) is a novel and potent transient receptor potential vanilloid type I (TRPV1) antagonist. We developed and validated a rapid, sensitive and selective liquid chromatography/tandem mass spectrometric method for determination of PAC-14028 in rat and minipig plasma. After protein precipitation PAC-14028 and internal standard (methylated analog, PAC-14026) were separated on a Symmetry C(18) column (4.6 mm × 75 mm, 3.5 µm) with an isocratic mobile phase, acetonitrile: water (8:2, v/v) containing 0.2% formic acid and monitored by electrospray positive ionization with multiple reaction monitoring mode (PAC-14028, 492→156; IS, 506→156, m/z). The calibration curve was linear over the range of 1.0-500 ng/ml (r(2)>0.999) and lower limit of quantitation (LLOQ) was 1 ng/ml. The precision and accuracy were within ± 15% and the stability was acceptable during bench-top, auto-sampler, 3 freeze-thaw cycles and 4-week storage in a freezer at -80°C. This method was successfully applied to the intravenous, oral and topical pharmacokinetic studies of PAC-14028 in rats and minipigs, which showed comparable pharmacokinetic parameters (T1/2, 2.1h and 3.8h; F%, 52.7% and 64.2% for rats and minipigs, respectively). Percutaneous absorption of PAC-14028 was negligible after topical application (F% 0.2-1.7%).

Chemical standards in ion mobility spectrometry.

In ion mobility spectrometry (IMS), reduced mobility values (K(0)) are used as a qualitative measure of gas phase ions, and are reported in the literature as absolute values. Unfortunately, these values do not always match with those collected in the field. One reason for this discrepancy is that the buffer gas may be contaminated with moisture or other volatile compounds. In this study, the effect of moisture and organic contaminants in the buffer gas on the mobility of IMS standards and analytes was investigated for the first time using IMS directly coupled to mass spectrometry. 2,4-Dimethylpyridine, 2,6-di-tert-butylpyridine (DTBP), and tetrabutylammonium, tetrapropylammonium, tetraethylammonium, and tetramethylammonium chlorides were used as chemical standards. In general, the mobility of IMS standard product ions was not affected by small amounts of contamination while the mobilities of many analytes were affected. In the presence of contaminants in the buffer gas, the mobility of analyte ions is often decreased by forming ion-molecule clusters with the contaminant. To ensure the measurement of accurate reduced mobility values, two IMS standards are required: an instrument and a mobility standard. An instrument standard is not affected by contaminants in the buffer gas, and provides an accurate measurement of the instrumental parameters, such as voltage, drift length, pressure, and temperature. The mobility standard behaves like an analyte ion in that the compound's mobility is affected by low levels of contamination in the buffer gas. Prudent use of both of these standards can lead to improved measurement of accurate reduced mobility values.

Results of an international comparison of 57Co.

As part of a Cooperative Research Project (CRP) aimed at improving the state of radioactivity measurement in nuclear medicine, the International Atomic Energy Agency (IAEA) organized a comparison of (57)Co solutions among the participants of the project. The comparison solutions were prepared from a single master stock solution and distributed to the participating laboratories, who measured the activity concentration of the solution using either the laboratory's radionuclide activity calibrator or primary standardization methods. A total of 9 sets of results were received, with 5 laboratories reporting results of primary measurements, one reporting results of secondary measurements calibrated against primary standards, and three laboratories reporting values based on measurements in commercial re-entrant ionization chambers using manufacturer-recommended calibration figures. Most of the laboratories reporting primary standardizations also provided results from secondary standardizations. The Comparison Reference Value was calculated from the mean of the five primary standardizations and was found to be 35.54 MBq g(-1), with a standard deviation of the mean of 0.17 MBq g(-1). Degrees of equivalence were calculated for each reporting laboratory and demonstrated that equivalence to within about 4% could be achieved, even in the case of those laboratories that used instruments calibrated by third parties.

Unboosted atazanavir plus co-formulated lamivudine/abacavir as a ritonavir-sparing simplification strategy in routine clinical practice.

OBJECTIVE: To assess the effectiveness and safety of antiretroviral therapy with unboosted atazanavir (400 mg once daily) plus co-formulated abacavir/lamivudine as a treatment simplification strategy in HIV-infected patients with sustained viral suppression in routine clinical practice. METHODS: We performed a retrospective study including patients who were switched to unboosted atazanavir plus abacavir/lamivudine and whose HIV-1 RNA was <50 copies/mL. The primary endpoint was the percentage of subjects who maintained viral suppression after 48 weeks of follow-up. Secondary endpoints included the percentage of subjects who maintained viral suppression after 96 weeks of follow-up, the incidence of adverse events, changes in CD4+ T-cell count and in lipid profile, and the percentage of patients with subtherapeutic atazanavir trough concentrations during follow-up. RESULTS: Forty-six patients were included. None had a prior history of resistance to protease inhibitors or to lamivudine or abacavir. The percentage of patients with viral suppression at Week 48 was 73.9% when all the included patients were considered (full dataset analysis) and 85.0% when only subjects on treatment were considered. There was a continuous immune recovery and an improvement in lipid profile during follow-up. Two thirds of the patients had subtherapeutic atazanavir trough concentrations in plasma in at least one determination during follow-up. CONCLUSION: Antiretroviral therapy with unboosted atazanavir plus abacavir/lamivudine is safe and effective in the long term as a treatment simplification strategy in HIV-infected patients with sustained virological suppression in routine clinical practice.

Quantification of tenatoprazole in rat plasma by HPLC: validation and its application to pharmacokinetic studies.

A simple, reliable HPLC method with UV detection (295 nm) in rat plasma was developed and validated for quantification of tenatoprazole, a novel proton pump inhibitor, which is in clinical trials. Following a single-step liquid-liquid extraction, the analyte and internal standard were separated using an isocratic mobile phase on a reverse phase C(18) column. The lower limit of quantitation was 20 ng/mL, with a relative standard deviation of less than 10%. A linear dynamic range of 20-6000 ng/mL was established. This HPLC method was validated with between-batch and within-batch precision of 2.9-6.3 and 1.4-5.8%, respectively. The between-batch and within-batch accuracy was 95.1-104.1 and 92.4-101.0%, respectively. This validated method is simple and repeatable enough to be used in pharmacokinetic studies.

Prevention of premature discontinuation of dual antiplatelet therapy in patients with coronary artery stents: a science advisory from the American Heart Association, American College of Cardiology, Society for Cardiovascular Angiography and Interventions, American College of Surgeons, and American Dental Association, with representation from the American College of Physicians.

Dual antiplatelet therapy with aspirin and a thienopyridine has been shown to reduce cardiac events after coronary stenting. However, many patients and healthcare providers prematurely discontinue dual antiplatelet therapy, which greatly increases the risk of stent thrombosis, myocardial infarction, and death. This advisory stresses the importance of 12 months of dual antiplatelet therapy after placement of a drug-eluting stent and educating the patient and healthcare providers about hazards of premature discontinuation. It also recommends postponing elective surgery for 1 year, and if surgery cannot be deferred, considering the continuation of aspirin during the perioperative period in high-risk patients with drug-eluting stents.

Integration of atazanavir into an existing liquid chromatography UV method for protease inhibitors: validation and application.

Atazanavir (ATV) is a widely used human immunodeficiency virus (HIV)-1 protease inhibitor (PI) that, like other approved PIs, has been considered as a candidate for therapeutic drug monitoring (TDM). To provide ATV assay results that can be applied to patient management through TDM, the assay would need to perform in a manner consistent with Clinical Laboratory Improvement Amendments (CLIA) standards. To quantitate ATV concentrations in human plasma, the authors added ATV to a previously published reversed-phase high-performance liquid chromatography (HPLC) method from their laboratory. Detection was effected with use of a photodiode-array detector (PDA) collecting spectra at 248 nm. This method allows for detection of ATV to a lower limit of quantitation of 0.05 microg/mL, with an intra-assay coefficient of variation (CV%) of 8.9% or less over 5 days of testing and an interassay CV% ranging from 1.4 to 6.4%. The assay has met passing requirements for interlaboratory proficiency testing for 2 years nationally and internationally, with accuracy within +/-15% over all test samples. During 2 years, more than 100 batches of analyses have been performed and have proved the method is rugged, specific, and accurate. This assay method is currently used in the authors' clinical research program in TDM.