Evaluation of SAMe-TT2R2 score and other clinical factors influencing the quality of anticoagulation therapy in non-valvular atrial fibrillation: a nationwide study in Spain

Objective: To assess the major clinical factors affecting the quality of anticoagulation and evaluate the predictive value of the SAMe-TT₂R₂ score to identify patients who will achieve a high average time in therapeutic range (T.T.R.) with vitamin K antagonist (V.K.A.) treatment. Research design and methods: This observational, cross-sectional, retrospective and nationwide multicenter study included 1524 patients from the primary care setting with non-valvular atrial fibrillation receiving V.K.A. (≥12 months). We performed a bivariate analysis to identify factors individually associated with the T.T.R. and a multiple regression analysis to identify the independent predictive factors. For the validation of the SAMe-TT₂R₂ score, the receiver operating characteristic (R.O.C.) curve was calculated and the Hosmer–Lemeshow test was used to test calibration. Results: A total of 94.8% of patients received acenocumarol (4.8% warfarin). A progressive decrease in mean T.T.R. was found when the SAMe-TT₂R₂ score increased from 0 points (72.1?±?17.1%) to 4 points (64.1?±?23.2%), p?<?0.001. Other risk scores (CHADS₂ and CHA₂DS₂-VASc, HAS-BLED) were also associated with the mean T.T.R. We found a significant association between low T.T.R. and the following clinical factors: female sex, three or more comorbidities, amiodarone treatment, dietary habits, bleeding history and the intake of ≥7 tablets per day besides V.K.A. (p?<?0.01). Regarding SAMe-TT₂R₂ score validation, the R.O.C. curve showed significant capability, although not high, of discriminating good anticoagulation control (T.T.R. ≥65%) with an area under the curve of 0.562 (95% C.I. 0.533–0.592, p?<?0.001) which increased, remaining modest, to 0.594 (95% C.I. 0.564–0.624, p?<?0.001) when the factors not included in SAMe-TT₂R₂ score were added. Conclusion: In this cohort, the SAMe-TT₂R₂ score had a significant, although modest, ability to assess the likelihood of good international normalized ration (I.N.R.) control, and its predictive value might slightly improve by adding other simple clinical factors. Further research is needed to refine the predictive scales.     

A rapid evidence assessment of bleed-related healthcare resource utilization in publications reporting the use of direct oral anticoagulants for non-valvular atrial fibrillation

Objective: Non-valvular atrial fibrillation (NVAF), a common cardiac arrhythmia, is associated with high morbidity and carries a substantial economic burden. Historically, vitamin K antagonists (VKAs; e.g. warfarin) have been used for therapy of NVAF, but recently several direct oral anticoagulants (DOACs) have been approved for prevention of stroke in patients with NVAF. This review summarizes the real-world evidence (RWE) for healthcare resource utilization (HRU) in patients receiving oral anticoagulants (VKAs and/or DOACs) for therapy of NVAF.

Methods: A PRISMA-compliant literature search assessed Medline^® and Embase^® databases from 1 January 2011 to 4 May 2017, and the National Health Service Economic Evaluation Database from 1 January 2011 to 31 December 2015. Publications were included if they reported observational data from real-world use of one or more anticoagulant therapies. Outcomes of interest included hospitalizations, length of stay (LOS), mortality and costs.

Results: Twenty-eight publications were included. Apixaban and dabigatran were associated with fewer bleed-related hospitalizations than warfarin. Bleed-related LOS were generally longer for warfarin than for DOACs. Bleed-related treatment costs were lower for patients receiving apixaban or receiving dabigatran than patients receiving rivaroxaban or receiving warfarin. Bleed-related mortality in patients receiving oral anticoagulation for treatment of NVAF were low across all DOACs and warfarin.

Conclusions: The limited available evidence for HRU burden among patients receiving oral anticoagulation for NVAF suggests that DOACs (particularly apixaban and dabigatran) offer some degree of benefit in terms of HRU outcomes, compared with warfarin. Further work is required to understand HRU outcomes in patients receiving DOACs.     

Two new dammarane-type triterpene saponins from red American ginseng

Two new dammarane-type triterpene saponins were isolated from the red American ginseng. The new saponins were named as pseudoginsenoside G₁ (1) and pseudoginsenoside G₂ (2). Their structures were elucidated by the combined analysis of NMR and mass spectrometry as 3-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl]-dammar-12-one-20S,24R-epoxy-3β,25-diol (pseudoginsenoside G₁) (1) and 3-O-[β-d-glucopyranosyl-(1 → 2)-β-d-glucopyranosyl]-dammar-12-one-20S,24S-epoxy-3β,25-diol (pseudoginsenoside G₂) (2).     

Stroke risk reduction outweighed bleeding risk increase from vitamin K antagonist treatment among nonvalvular atrial fibrillation patients with high stroke risk and low bleeding risk

Objective: Warfarin is widely used for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF). We compared the rates of stroke and major bleeding in NVAF patients with a high stroke risk and low bleeding risk profile during warfarin treated (W+) and warfarin untreated (W?) periods.

Method: Insurance claims from six commercial, Medicaid or Medicare databases were analyzed from 2000 to 2014. NVAF patients treated with warfarin, with a CHADS₂/CHA₂DS₂-VASc score ≥2, and an ATRIA score ≤3 at baseline were identified. Incidence rate ratios (IRRs) of stroke and major bleeding were calculated for W?+?versus W? episodes of person-time, as well as for first 30 days versus beyond 30 days of W?+?episodes.

Results: Among 316,145 patients, anticoagulant prophylaxis with warfarin significantly reduced stroke risk, with IRRs ranging from 0.48 (95% CI: 0.46–0.51) to 0.80 (95% CI: 0.70–0.91), and increased major bleeding risk, with IRRs ranging from 1.13 (95% CI: 1.10–1.15) to 1.95 (95% CI: 1.10–3.45). Stroke and major bleeding rates were higher during the first 30 days of W?+?than beyond.

Conclusion: In NVAF patients at high risk for stroke and low risk for bleeding, our data confirm the effectiveness of anticoagulation for stroke prevention. The decrease in stroke risk of anticoagulation may outweigh the risk of major bleeding events, particularly among elderly patients. Potential risks of warfarin during initiation warrant attention, especially among patients who stop and start therapy repeatedly.     

Four new diarylheptanoids from Rhizoma Zingiberis

Four new diarylheptanoids, (1S, 3R, 5R, 6R)-1, 5-epoxy-3, 6 dihydroxy-1-(4-hydroxy-3, 5-dimethoxyphenyl)-7-(4-hydroxy-3-methoxyphenyl) heptane (1), (1R, 3R, 5S)-1, 5-epoxy-3-acetoxy-1-(4, 5-dihydroxy-3-methoxyphenyl)-7-(3, 4- hydroxyphenyl) heptane (2), (3R, 5S, 6R, 7S)-3, 6-epoxy-7-hydroxyl-1-(4-hydroxyphenyl)-7-(3-methoxy-4-hydroxyphenyl) heptane (3), (E)-3-keto-1-(3-methoxy-4-hydroxyphenyl)-7-(4, 5-dihydroxy-3-methoxyphenyl)-4- heptene (4), were isolated from Rhizoma Zingiberis, and their structures were determined based on HR-ESI-MS and extensive spectroscopic techniques (UV, IR, 1D-NMR and 2D-NMR). Compounds 1–4 exhibited no cytotoxicity against HepG2 cell lines.

     

Treating short bowel syndrome with pharmacotherapy

ABSTRACT

Introduction

Short bowel syndrome (SBS) has traditionally been regarded as a rapidly fatal medical catastrophe. The advent of pharmacological options directly targeting disease pathophysiology justified this review.     

A pharmacological profile of intravenous amisulpride for the treatment of postoperative nausea and vomiting

ABSTRACT

Introduction

The issue of postoperative nausea and vomiting (PONV) remains important in surgical practice, contributing to patient distress, slower recovery, and increased use of healthcare resources. Many surgical patients report it to be a worse problem than the pain. New antiemetics of different classes are still needed to help manage PONV effectively, especially the treatment of established PONV after the failure of common prophylactic antiemetics such as 5-HT₃-antagonists and corticosteroids. Intravenous amisulpride, a drug with a long history of safe use in oral form as an antipsychotic, has recently been approved in the US (trade name: Barhemsys) as an intravenous antiemetic for the prevention and treatment of PONV.     

Pharmacotherapy for smoking cessation in schizophrenia: a systematic review

ABSTRACT

Introduction

Rates of tobacco smoking are high in people with schizophrenia with greater difficulty of quitting smoking compared to the general population, which also relate to the increased cardiovascular and cancer risks in this co-occurring disorder. Therefore, effective smoking cessation pharmacotherapies addressing tobacco co-morbidity are imperative.     

华法林快速抗凝方案在脑梗死合并房颤患者中的应用价值

目的 探索华法林快速抗凝方案在中国急性脑梗死合并非瓣膜病性心房颤动患者中的应用价值。方法 2013年1月-2016年2月间急性脑梗死合并非瓣膜病性房颤患者101例,采用前瞻性开放研究,将其分为快速抗凝组和常规抗凝组。快速抗凝组的华法林初始剂量为3~4.5 mg,随后按流程每日调整剂量至INR稳定达标;常规抗凝组的初始剂量为1~3 mg,随后根据对患者的风险与获益评估调整华法林剂量。主要终点是比较2组间的INR稳定达标率、达标时间和安全性。结果 至1周、2周和1月时,快速抗凝组INR稳定达标率均显著高于常规抗凝组（48.2% vs 4.4%,P=0.000;91.1% vs 40.0%,P=0.000;96.4% vs 48.9%,P=0.000）、INR稳定达标时间分别为（8.3±2.9） d和（13.2±4.5） d（P=0.000）。随访至1年,快速抗凝组的INR稳定达标率为54.5%（30/55）,而常规抗凝组仅为31.8%（14/44）,2组具有显著性差异（P<0.05）。在安全性方面,快速抗凝组与常规抗凝组2周内INR ≥ 4的患者比例分别为5.4%（3/56）和6.7%（3/45）。结论 华法林快速抗凝治疗比常规抗凝不仅更安全有效,而且显著增加了患者的依从性,值得借鉴。     

Population Pharmacokinetic Model of N-acetylmannosamine (ManNAc) and N-acetylneuraminic acid (Neu5Ac) in Subjects with GNE Myopathy

BackgroundGNE myopathy is a rare genetic muscle disease resulting from deficiency in an enzyme critical for the biosynthesis of N-acetylneuraminic acid (Neu5Ac, sialic acid). The uncharged Neu5Ac precursor, N-acetylmannosamine (ManNAc), is under development as an orphan drug for treating GNE myopathy.MethodsA semi-mechanistic population pharmacokinetic model was developed to simultaneously characterize plasma ManNAc and its metabolite Neu5Ac following oral administration of ManNAc to subjects with GNE myopathy. Plasma ManNAc and Neu5Ac pharmacokinetic data were obtained from two clinical studies (ClinicalTrials.gov identifiers {"type":"clinical-trial","attrs":{"text":"NCT01634750","term_id":"NCT01634750"}}NCT01634750, {"type":"clinical-trial","attrs":{"text":"NCT02346461","term_id":"NCT02346461"}}NCT02346461) and were simultaneously modeled using NONMEM.ResultsManNAc and Neu5Ac plasma concentrations were obtained from 34 subjects with GNE myopathy (16 male, 18 female, median age 39.5 years). The model parameter estimates included oral absorption rate (k_a) = 0.256 h⁻¹, relative bioavailability relationship with dose (F-Dose) slope = −0.405 (where F = 1 for 6-g dose), apparent clearance (CL_M/F) = 631 L/h, volume of distribution (V_M/F) = 506 L, Neu5Ac elimination rate constant (k_out) = 0.283 h⁻¹, initial ManNAc to Neu5Ac conversion (SLP₀) = 0.000619 (ng/mL)⁻¹ and at steady-state (SLP_SS) = 0.00334 (ng/mL)⁻¹, with a rate-constant of increase (k_inc) = 0.0287 h⁻¹. Goodness-of-fit plots demonstrated an acceptable and unbiased fit to the plasma ManNAc and Neu5Ac concentration data. Visual predictive checks demonstrated reasonable agreement between the 5th, 50th, and 95th percentiles of the observed and simulated data.ConclusionsThis population pharmacokinetic model can be used to evaluate ManNAc dosing regimens and to calculate Neu5Ac production and exposure following oral administration of ManNAc in subjects with GNE myopathy.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40268-021-00343-6.     

Knowledge level and attitude towards complementary and alternative treatment methods among medical students: a cross-sectional survey study in Turkey

Abstract

Objective

People often use complementary and alternative medicine (CAM) methods in Turkey, but reliability of the application of these methods is controversial. Considering the role of medical students (i.e. physician candidates) in sustainable health, their perspectives on CAM methods are important. This report explores the level of knowledge, experience, and preferences for the use of CAM methods among medical school students.     

Minor dammarane saponins from the hongshen extract of Shenmai injection

A new dammarane-type triterpenoid saponin, (20R)-ginsenoside ST₂ (1), along with five known saponins was isolated from the hongshen extract of Shenmai injection. The structure of 1 was elucidated to be (20R)-dammar-23(E)-ene-3β,6α,12β,20,25-pentol 6-O-β-d-glucopyranoside by means of spectroscopic methods.     

Pyridostigmine bromide and its relation to Gulf War illness

Abstract

Pyridostigmine bromide acts as a reversible cholinesterase inhibitor that is used at relatively high doses in treatment of Myasthenia gravis and in low dose regimens as prophylaxis against nerve agents poisoning during the Gulf War. The manifestation of late nonspecific symptoms commonly called Gulf War illness has led to the discussion about the role of pyridostigmine bromide in the pathogenesis of this illness. In our study, we described plasma absorption profile of pyridostigmine bromide after p.o. administration in rats; subsequently, changes in blood biochemical and oxidative stress markers were measured. Pyridostigmine bromide was applied p.o. at the dose of 5.82?mg/kg b.w. according to the previously published recommendations. The absorption of pyridostigmine was relatively fast; the C_max in plasma was 110.20?±?15.12?ng/ml at T_max of 197.12?±?17.14?min. The bioavailability expressed as AUC_total was 44,348?±?7608?min ng/ml. The prolongation of pyridostigmine in circulation is in agreement with relatively long half-life that was 179.00?±?28.54?min. Several blood biochemical markers were altered, including glucose, creatinine, creatine kinase, alanine aminotransferase, aspartate aminotransferase, interleukin-6, triglycerides, and cholesterol. However, the changes could be considered as mild. Thiobarbituric acid reactive substances and ferric reducing ability of plasma indicate suppression of basal metabolism. The results of blood biochemical and oxidative stress markers imply that long-term use might possibly change the basal metabolism and cause cellular damage with inflammatory changes.     

Comparisons of acute inflammatory responses of nose-only inhalation and intratracheal instillation of ammonia in rats

Objective: To establish a rat model with respiratory and pulmonary responses caused by inhalation exposure to non-lethal concentrations of ammonia (NH₃) that can be used for evaluation of new medical countermeasure strategies for NH₃-induced acute lung injury (ALI). This is of great value since no specific antidotes of NH₃-induced injuries exist and medical management relies on supportive and symptomatically relieving efforts.

Methods: Female Sprague-Dawley rats (8–9?weeks old, 213g?±?2g) were exposed to NH₃ using two different exposure regimens; nose-only inhalation or intratracheal instillation. The experiment was terminated 5?h, 24?h, 14 and 28?days post-exposure.

Results: Nose-only inhalation of NH₃ (9000–15 000?ppm) resulted in increased salivation and labored breathing directly post-exposure. Exposure did not increase inflammatory cells in bronchoalveolar lavage fluid but exposure to 12 000?ppm NH₃ during 15?min reduced body weight and induced coagulation abnormalities by increasing serum fibrinogen levels. All animals were relatively recovered by 24?h. Intratracheal instillation of NH₃ (1%) caused early symptoms of ALI including airway hyperresponsiveness, neutrophilic lung inflammation and altered levels of coagulation factors (increased fibrinogen and PAI-1) and early biomarkers of ALI (IL-18, MMP-9, TGFβ) which was followed by increased deposition of newly produced collagen 14?days later. Histopathology analysis at 5?h revealed epithelial desquamation and that most lesions were healed after 14?days.

Conclusions: This study demonstrates that intratracheal instillation can reproduce several early hallmarks of ALI. Our findings therefore support that the intratracheal instillation exposure regimen can be used for new medical countermeasure strategies for NH₃-induced ALI.     

Modeling the impact of real-world adherence to once-daily (QD) versus twice-daily (BID) non-vitamin K antagonist oral anticoagulants on stroke and major bleeding events among non-valvular atrial fibrillation patients

Objectives: To estimate the real-world (RW) impact of adherence to once-daily (QD: rivaroxaban and edoxaban) and twice-daily (BID: apixaban and dabigatran) non-vitamin K antagonist (NOACs) on the risk of stroke and major bleeding (MB) among non-valvular atrial fibrillation (NVAF) patients.

Methods: First, claims from the Optum Clinformatics Data Mart database (July 2012–December 2016) were analyzed. Adult NVAF patients with ≥2 NOAC dispensings (index date) were included. The relationship between NOAC adherence (proportion of days covered ≥80%) and stroke/MB 1-year post-index was evaluated using adjusted Cox proportional hazards models. Second, the natural logarithm of hazard ratios (HRs) was multiplied to a literature-derived mean adherence difference between QD and BID NOACs yielding stroke and MB rates. Third, these rates were multiplied by 1-year Kaplan-Meier rates of stroke and MB which yielded the number of strokes prevented and MBs caused. Annual cost savings were evaluated using literature-based stroke ($81,414/patient) and MB ($63,905/patient) cost estimates.

Results: In total, 54,280 patients were included. HRs for adherent vs non-adherent patients were 0.67 (p?<?.001) for stroke and 1.09 (p?=?.179) for MB. The claims-derived 1-year Kaplan-Meier rates were 3.0% and 3.4% for strokes and MBs, respectively. For 100,000?AF patients, 64 strokes were prevented (p?<?.001), and a non-significant number of MBs (n?=?15, p?<?.191) were caused by QD vs BID NOACs annually, which leads to cost savings estimated at $58 million for QD NOACs.

Conclusion: QD NOACs prevented a significant number of strokes and caused no significant increase in MBs compared to BID NOACs, which leads to significant net cost savings for NVAF patients in the US.     

Triterpenoids from Walsura trichostemon

Bioactivity guided separation of Walsura trichostemon stem methanolic extract led to the isolation of four new dammarane (1–4) and two new apotirucallane triterpenoids (5–6), together with one limonoid (7), 11,25-dideacetyltrichostemonate, 12β, 20S, 24R-trihydroxydammar-25-en-3-one and 12β, 20S, 25-trihydroxydammar-23-en-3-one. Compounds 1–7 showed in vitro inhibitory activity on the proliferation of A549, human lung adenocarcinoma cell line.

     

Bioactive megastigmane glucosides and monoterpenes from Lyonia ovalifolia

Three new megastigmane glucosides (1–3) and two new monoterpenes (4–5), together with 14 related known compounds (6–19) were isolated from the twigs and leaves of Lyonia ovalifolia. The structures of the new compounds were determined by extensive MS, NMR, CD experiments and chemical methods. Compounds 2, 6, and 18 displayed potent antiviral activity against Coxsackie B3, with IC₅₀ values between 6.4 and 14.6 µM. Additionally, compounds 6, 10, and 11 exhibited noteworthy anti-inflammatory activities, with inhibition rates ranging from 54.55% to 83.33% under the concentration of 10^?5 M.     

Two novel dammarane-type compounds from the leaves and stems of Panax quinquefolium L.

Two new dammarane-type compounds were isolated from the leaves and stems of Panax quinquefolium L. The new compounds were named as pseudo-ginsenoside RT₆ (1) and pseudoginsengenin R₁ (2). The structures of the new compounds were elucidated by the combined analysis of NMR and HR-ESI-MS as (20S,24R)-6-O-β-d-glucopyranosyl-dammar-3-one-20,24-epoxy-6α,12β,25-triol (1) and (20S,24R)-dammar-3-one-20,24-epoxy-6α,12β,25-triol (2).