Systematic Review of l-glutamine for Prevention of Vaso-occlusive Pain Crisis in Patients with Sickle Cell Disease

l -glutamine was approved by the U.S. Food and Drug Administration (FDA) for sickle cell disease (SCD) in 2017. A vaso-occlusive crisis (VOC) occurs in persons with SCD and is associated with acute pain episodes. This systematic review summarizes the evidence for l -glutamine in the prevention of VOC and associated pain in patients with SCD. Medline, Embase, and International Pharmaceutical Abstracts were searched for records reporting on l -glutamine use in persons with SCD. Eligibility criteria identified primary reports of investigations conducted in humans who were administered l -glutamine, reported on outcomes related to VOC or associated pain, published in English, and were available as full text. All relevant efficacy, safety, participant demographic data, and study method characteristics were extracted and documented. Risk-of-bias assessments were conducted using the Risk of Bias in Non-Randomized Studies-of Interventions (ROBINS-I) tool and the revised Cochrane risk-of-bias tool for randomized studies. Three studies assessing the effect of exogenous l -glutamine administration in patients with SCD met eligibility criteria: one prospective nonrandomized controlled study and two prospective randomized controlled trials. Rate of VOC and related hospitalizations were reduced in patients receiving l -glutamine, although some conflicting results were noted between studies. l -glutamine was generally well tolerated. Limitations of one or more of the eligible studies included small sample size, nonblinding, and study groups that differed at baseline. l -glutamine has limited high-quality evidence supporting its use. Although l -glutamine is FDA approved for the prevention of frequent episodes of VOC pain, only one randomized controlled trial has strong evidence to support this indication. Based on the results of a systematic review, l -glutamine may be considered for patients unable to receive hydroxyurea or in addition to hydroxyurea for reduction in VOC and associated pain.     

Crizanlizumab for the Prevention of Vaso-Occlusive Pain Crises in Sickle Cell Disease

Objective: To review the efficacy and safety of crizanlizumab (Adakveo) in the prevention of vaso-occlusive pain crises in sickle cell disease. Data Sources: An English-language literature search of PubMed, MEDLINE, and Ovid (1946 to January 2021) was completed using the terms crizanlizumab, SEG101, SelG1, and sickle cell disease. Manufacturer prescribing information, article bibliographies, and data from clinicaltrials.gov were incorporated in the reviewed data. Study Selection/Data Extraction: All studies registered on clinicaltrials.gov were incorporated in the reviewed data. Data Synthesis: Crizanlizumab is the first monoclonal antibody approved for sickle cell disease to reduce the frequency of vaso-occlusive crises. One phase 2 clinical trial and a post hoc analysis of the trial have been published. Relevance to Patient Care and Clinical Practice: Crizanlizumab is a monthly intravenous infusion approved by the Food and Drug Administration for patients with sickle cell disease 16 years of age and older to reduce the frequency of vaso-occlusive crises. Conclusion: Crizanlizumab appears to be an efficacious therapy for patients with sickle cell disease to reduce the frequency of vaso-occlusive crises. Concerns include drug cost and administration. Long-term benefits and risks have not been determined.     

Impact of a Clinical Pharmacy Service on the Management of Patients in a Sickle Cell Disease Outpatient Center

Ambulatory care clinical pharmacy services have expanded beyond primary care settings, but literature supporting the benefits of clinical pharmacy involvement with patients who have rare diseases such as sickle cell disease (SCD) is lacking. Hydroxyurea is the only agent approved by the U.S. Food and Drug Administration for the treatment of SCD; full benefit in controlling pain episodes and other complications is achieved through monitored escalation to a maximum tolerated dose. The primary objective of this analysis was to evaluate the impact of a newly implemented clinical pharmacy service on the management of patients with SCD. We performed a retrospective cross‐sectional analysis of 385 adults with SCD who received care between January 1, 2014, and December 31, 2014, at a single Sickle Cell Outpatient Center that implemented a clinical pharmacy service in August 2013. Data were collected on hydroxyurea dose escalation, immunization completion rates, and health maintenance metrics (screening for nephropathy with microalbuminuria testing, retinopathy with annual retinal examinations, and pulmonary hypertension with echocardiography). The impact of the clinical pharmacy service on quality measurements was evaluated by using univariate and multivariate analyses. The number of pharmacist encounters, defined as a clinic visit when a clinical pharmacist interacted with a patient as documented in the medical records, was associated with an improved hydroxyurea dose escalation rate (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.07–2.05, p=0.02). Immunization rates for the 23‐valent pneumococcal polysaccharide vaccine, the 13‐valent pneumococcal conjugate vaccine, and influenza vaccine were 66%, 47%, and 62%, respectively. The number of pharmacist encounters was associated with improved immunization completion rates (OR 1.38, 95% CI 1.17–1.62, p<0.001). Improved screening for microalbuminuria (OR 2.14, 95% CI 1.60–2.86, p<0.001) and sickle cell retinopathy (OR 1.16, 95% CI 1.00–1.35, p=0.05) were also associated with the number of pharmacist encounters. A new clinical pharmacy service implemented in managing a rare disease, SCD, was associated with an improved hydroxyurea dose escalation rate, immunization completion rates, and health maintenance metrics.     

聚乙二醇修饰牛血红蛋白作为红细胞代用品的条件优化和产物检测

目的:考察不同条件下单甲氧基聚乙二醇琥珀酰亚胺酯(SC-mPEG)与牛血红蛋白(BHB)的反应产率,以建立分析(SC-mPEG-BHB)混合物的方法。方法:综合运用十二烷基硫酸钠聚丙烯酰胺凝胶电泳(SDS-PAGE)、凝胶渗透色谱(GPC)、毛细管电泳(CE)、三硝基苯磺酸(TNBS)等方法对产物进行分析。根据不同因素对SC-mPEG修饰BHB反应的影响,确定了SC-mPEG与BHB反应的最佳体系。结果:确定的最佳分析条件为SC-mPEG与BHB最佳配比60∶1,在4℃、pH9的缓冲溶液体系反应2h。结论:本文可为后续的红细胞代用品的研究奠定基础。     

Senicapoc (ICA-17043): a potential therapy for the prevention and treatment of hemolysis-associated complications in sickle cell anemia

Sickle cell disease (SCD) is characterized by hemolytic as well as vaso-occlusive complications. The development of treatments for this inherited disease is based on an understanding of its pathophysiology. Polymerization of sickle hemoglobin is dependent on several independent factors, including the intracellular hemoglobin concentration. The hydration state (and intracellular hemoglobin concentration) of the sickle erythrocyte depends on the loss of solute and osmotically obliged water through specific pathways. Senicapoc (also known as ICA-17043) is a potent blocker of the Gardos channel, a calcium-activated potassium channel of intermediate conductance, in the red blood cell. Preclinical studies and studies in transgenic models of SCD show that inhibition of potassium efflux through the Gardos channel is associated with an increased hemoglobin level, decreased dense cells and decreased hemolysis. Senicapoc is well tolerated when administered to SCD patients and produces dose-dependent increases in hemoglobin and decreases in markers of hemolysis. Despite the lack of a reduction in the frequency of pain episodes, the increasing recognition that hemolysis contributes to the development of several SCD-related complications suggests that by decreasing hemolysis, senicapoc may yet prove to be beneficial in this disease.     

镰状细胞病患儿疼痛危象药物治疗进展

血管阻塞性危象（VOC）又称镰状细胞疼痛危象,是镰状细胞病（SCD）的标志性并发症,临床表现复杂,通常伴有急性疼痛。不能有效控制、反复发作的疼痛是患儿入院的主要原因,因此,安全有效地进行疼痛预防及控制至关重要,药物治疗是最主要方式之一。本文整理归纳国内外SCD患儿VOC治疗的有限资料,从儿童VOC疼痛成因、疼痛评估及药物治疗三个方面进行综述,其中,药物治疗部分包括非阿片类药物、阿片类药物、辅助镇痛药物治疗以及预防疼痛危象药物治疗。SCD患儿疼痛危象的治疗与预防中应注重多模式镇痛的应用,基于患儿个体特征慎重选择镇痛方案,减少阿片类药物使用剂量,避免不良反应的发生,从而提升镇痛效果,改善患儿生活质量。     

奥希替尼治疗晚期非小细胞肺癌的药物经济学系统评价

目的:系统评价奥希替尼治疗晚期非小细胞肺癌(NSCLC)的经济性,为临床应用及卫生和医保决策者提供参考.方法:计算机检索PubMed、Embase、Cochrane图书馆、Health Technology Assessment、中国知网、万方数据、维普网和中国生物医学文献数据库等数据库,查询自建库至2020年4月公开...     

冠脉宁联合常规治疗对冠心病的系统评价

目的系统评价冠脉宁联合常规治疗对冠心病的疗效。方法计算机检索Cochrane图书馆（2013年第2期）、EMBase、PubMed、中国期刊全文数据库（CNKI）、中国生物医学文献数据库（CBM）、中文科技期刊全文数据库（vIP）（各数据库检索时间均从创建至2013年3月）关于冠脉宁联合常规治疗对冠心病的随机对照试验。2名数据员按纳入与排除标准独立筛选试验,并对纳入研究的方法学质量进行评价,提取资料,用RevMan 5．14软件对数据进行Meta分析。结果共纳入6篇RCT,包括725例患者。Meta分析结果显示,与对照组相比,冠脉宁组临床有效率优于常规治疗组[RR=5．87,95％CI（3．45,9．99）,P〈0．00001];冠脉宁组心电图改善率优于常规治疗组[RR=2,95％CI（1．33,3．02）,P〈0．00001],差异均有统计学意义。结论基于现有临床证据,冠脉宁联合常规治疗对冠心病有效,安全性好。但由于纳入研究数量较少,研究质量不统一,本结论尚需要更多大样本、高质量临床随机对照试验予以证实。     

ACEI和ARB联合治疗原发性高血压的系统评价

目的:对血管紧张素转换酶抑制剂(ACEI)和血管紧张素受体拮抗药(ARB)联合治疗原发性高血压的有效性和安全性进行系统评价。方法:计算机检索Cochrane临床对照试验数据库、PubMed、Embase、中国生物医学文献数据库、中国期刊全文数据库,纳入ACEI和ARB联合治疗原发性高血压的随机或半随机对照的临床试验,对纳入的临床研究进行质量评价和Meta分析。结果:共纳入28篇文献,其中英文文献12篇。文献质量评价Jadad评分4～7分的为6篇,其余22篇低于4分,纳入试验的方法学质量较低。Meta分析结果显示:与单用ACEI治疗比较,联合治疗可降低血压3.54/2.07mmHg,降低24h动态血压2.14/1.00mmHg;与单用ARB治疗比较,联合治疗可降低血压3.10/3.35mmHg,降低24h动态血压3.11/2.30mmHg。与ACEI/ARB单用治疗相比,联合治疗降低左心室质量指数13.17/15.69g·m-2,对于射血分数、心率、尿素氮、肌酐、不良反应发生率等的影响差异无统计学意义。结论:联合治疗较单药治疗能一定程度上降低血压,但作用有限。纳入研究质量较低且缺乏以临床事件为终点的试验研究,目前尚无足够的证据证明联合用药比单药治疗更有效、更安全。有必要开展更多高质量、大样本、长期随访的随机对照试验,以提供更可靠的证据。     

In Vitro Evaluation of the Plasma and Blood Compatibility of a Parenteral Formulation for Ditekiren,a Novel Renin Inhibitor Pseudopeptide

Ditekiren (U-71038; Boc-Pro-Phe-N-MeHis-Leu-[CHOHCH₂]-Val-Ile-aminomethyl)pyridine) is a potent renin inhibitor peptide and was formulated for clinical intravenous administration in acidified dextrose. This formulation of ditekiren was evaluated in vitro with human and monkey plasma as to its potential for forming a precipitate either of drug or of plasma proteins. Analysis by centrifugation showed that no drug precipitation occurred in plasma from either species at concentrations 25 times higher than anticipated in clinical studies. Results obtained by turbidimetry indicated that formulated ditekiren did not cause aggregation of human platelets or flocculation of proteins at concentrations approaching the solubility limit of the drug in plasma. Ditekiren or vehicle also caused no detectable lysis of red cells at concentrations representing 10 times the maximum clinical level. Therefore, ditekiren solutions as formulated are judged completely compatible with blood and plasma upon clinical intravenous administration.     

蛋白激酶C抑制药enzastaurin对吉非替尼耐药的人非小细胞肺癌细胞株生长的影响

目的：观察新型靶向制剂enzastaurin单独或联合吉非替尼对耐药人非小细胞肺癌细胞株的影响,设计合理的治疗药物组合。方法：CCK8法检测细胞增殖,Chou-Talalay联用指数法判定联合用药效果,流式细胞仪检测细胞周期变化。结果：单药吉非替尼及enzastaurin作用NCI-H460耐药肺癌细胞72 h的半数抑制浓度（IC50）分别为6.99μmol·L-1（95%CI 3.55~13.79μmol·L-1）,7.25μmol·L-1（95%CI 4.77~1.02μmol·L-1）。两药联合应用对肺癌细胞的抑制作用增强（P 〈0.05）,同时给药组抑制效果更显著（P〈0.01）。同时给药组、序贯给药组（先用吉非替尼）和序贯给药组（先用enzastaurin）吉非替尼对H460细胞的IC50值分别为0.006μmol·L-1（95%CI 0.002~0.020μmol·L-1）,0.02μmol·L-1（95%CI 0.011~0.037μmol·L-1）,0.085μmol·L-1（95%CI 0.042~0.170μmol·L-1）。联合指数法显示在吉非替尼浓度0.05μmol·L-1以上时,同时给药组联合指数均〈1。细胞周期分布实验结果显示同时给药组可显著提高G0/G1期细胞比例（P〈0.05）,阻滞细胞于G1期。结论：蛋白激酶C抑制药enzastaurin与EGFR抑制药吉非替尼联用具有较好的协同作用,两药联合应用可能是出现吉非替尼耐药的非小细胞肺癌后续治疗的一个新选择。     

维奥欣治疗脑血管疾病的临床循证研究

目的系统评价维奥欣(薯蓣皂苷)治疗脑血管疾病的疗效及安全性。方法搜集维奥欣治疗脑血管疾病随机对照试验的文献,由两名研究者独立选择试验、评价质量、提取数据,并交叉核对。使用RevMan 5.0软件进行Meta分析。结果共纳入9个RCT,844例脑血管疾病患者。结果显示维奥欣组与对照组总有效率比较为[84.9%vs62.4%,OR=5.41,95%CI(3.92,5.01),P<0.01];同时维奥欣可降低TC、TG、LDL-c水平,升高HDL-c水平,并具有统计学差异(P<0.05),其亦可改善全血高切,低切年度,红细胞比容,血浆年度及纤维蛋白原(P<0.05),并具有统计学差异,治疗过程仅有个别病例轻微胃肠功能不适。结论薯蓣皂苷片可显著改善脑血管患者症状,血脂代谢,改善血液流变学指标,治疗过程无明显不良反应。但由于纳入研究的方法质量和可能存在发表偏倚,有待进一步开展大样本、高质量、多中心的随机双盲对照试验来证实。     

Discovery of DS79932728: A Potent,Orally Available G9a/GLP Inhibitor for Treating β-Thalassemia and Sickle Cell Disease

Therapeutic reactivation of the γ-globin genes for fetal hemoglobin (HbF) production is an attractive strategy for treating β-thalassemia and sickle cell disease. It was reported that genetic knockdown of the histone lysine methyltransferase EHMT2/1 (G9a/GLP) is sufficient to induce HbF production. The aim of the present work was to acquire a G9a/GLP inhibitor that induces HbF production sufficiently. It was revealed that tetrahydroazepine has versatility as a side chain in various skeletons. We ultimately obtained a promising aminoindole derivative (DS79932728), a potent and orally bioavailable G9a/GLP inhibitor that was found to induce γ-globin production in a phlebotomized cynomolgus monkey model. This work could facilitate the development of effective new approaches for treating β-thalassemia and sickle cell disease.     

国内人群应用孟鲁司特钠治疗慢性阻塞性肺疾病的系统评价

摘 要 目的: 系统评价国内人群应用孟鲁司特钠治疗慢性阻塞性肺疾病有效性及安全性。方法: 计算机检索中国生物医学、文献数据库（CBM）、中国知网全文数据库（CNKI）、维普中文期刊数据库（VIP）、万方数据库等数据库,收集孟鲁司特钠治疗慢性阻塞性肺疾病的随机对照试验。系统筛选文献、提取资料及评价质量后,对同质研究采用RevMan 5.0软件进行Meta 分析。结果:共纳入6项研究,418 例患者。Meta分析结果显示,孟鲁司特钠在提高FEV1/FVC方面优于对照组,两组间比较差异有统计学意义［MD=3.39,95%CI(2.00,4.79),P＜0.000 01］;孟鲁司特钠能更好的改善FEV1%［MD=7.06,95%CI（5.21,8.91),P＜0.000 01］及提高PaO2［MD=4.32,95%CI(2.77,5.86),P＜0.000 01］。结论:孟鲁司特钠治疗慢性阻塞性肺疾病疗效较为确切,但纳入研究较少、研究质量较低,结果还有待高质量、大样本的随机双盲对照试验加以验证。     

左旋肉碱治疗非酒精性脂肪肝的系统评价

目的 对左旋肉碱治疗非酒精性脂肪肝的有效性及安全性进行评价.方法 系统检索相关文献,根据纳入标准筛选后对纳入的研究进行评价和Meta分析.结果 总有效率、总胆固醇降低量、甘油三酯降低量等指标,左旋肉碱单用组的结果差异无统计学意义,联合用药组的结果差异具有统计学意义.丙氨酸氨基转移酶降低量、天门冬酸氨基转移酶降低量等指标,单用组及联合用药组的结果差异均具有统计学意义.两组不良反应发生率的差异无统计学意义.结论 左旋肉碱治疗非酒精性脂肪肝安全有效,但需联合其他阳性药物才能更好地发挥作用.     

醒脑静治疗急性脑出血的系统评价

目的：评价醒脑静治疗急性脑出血的疗效及安全性。方法：检索Cochrane图书馆、中国生物医学文献光盘数据库（1978—2008年）、中国期刊网全文专题数据库（1979—2008年）、中国科技期刊数据库（1989～2008年）和万方电子期刊数据库（1989—2008年）等文献数据库,收集醒脑静治疗急性脑出血的随机对照研究。对符合纳入标准的临床研究进行Meta分析。结果：共纳入28篇随机对照研究。与基础治疗组相比,加用醒脑静组可明显降低急性脑出血患者治疗期间病死率（P〈0．01）;在近期疗效上,醒脑静可明显提高急性脑出血患者的临床治疗有效率（P〈0．01）;治疗前后神经功能缺损评分醒脑静组明显低于基础治疗组（P〈0．01）;醒脑静组对促进意识恢复、降低体温及治疗前后水肿大小的研究均优于基础治疗组（P〈0．01）;对促进血肿的吸收和短期内日常生活能力评价的研究和基础治疗组相比无明显差异（P〉0．05）。结论：醒脑静可降低脑出血患者的病死率,在改善神经功能缺损、促进意识恢复、降低体温、消除脑水肿等方面也优于对照组,并未见明显不良反应发生,但由于目前的临床研究质量较低,尚需进行严格的、多中心的随机双盲对照研究加以证实。     

A Systematic Review Comparing Cognitive-Behavioral Therapy and Contingency Management for Cocaine Dependence

The main objective of this review was to compare the effectiveness of cognitive-behavioral therapy and contingency management for cocaine dependence. Contingency management alone reliably reduced cocaine use during active treatment in all cited trials, whereas the positive effect of cognitive-behavioral therapy emerged after treatment in 3 of 5 trials. Synergistic effects of the combination of contingency management plus cognitive-behavioral therapy are shown in 2 trials, but another 3 trials found no additive effects. Positive, rapid, and enduring effects on cocaine use are reliably seen with contingency management interventions, whereas measurable effects of cognitive-behavioral therapy emerge after treatment and are not as reliable as effects with contingency management.     

Study of Nutraceuticals and Phytochemicals for the Management of Alzheimer's Disease: A Review

Background Alzheimer''s disease (AD) affects several people worldwide and has devastating impacts on society with a limited number of approaches for its pharmacological treatment. The main causes of AD are not clear yet. However, the formation of senile plaques, neurofibrillary tangles, hyper-phosphorylation of tau protein, and disruption of redox homeostasis may cause AD. These causes have a positive correlation with oxidative stress, producing reactive ions, which are responsible for altering the physiological condition of the body.Conclusion Ongoing research recommended the use of phytochemicals as acetylcholinesterase inhibitors to hinder the onset and progression of AD. The natural compound structures, including lignans, flavonoids, tannins, polyphenols, triterpenes, sterols, and alkaloids have anti-inflammatory, antioxidant, and anti-amyloidogenic properties. The purpose of this article is to provide a brief introduction to AD along with the use of natural compounds as new therapeutic approaches for its management.     

Medical Technology: A Systematic Review on Medical Devices Utilized for Epilepsy Prediction and Management

Background: Epilepsy is a devastating neurological disorder that affects nearly 70 million people worldwide. Epilepsy causes uncontrollable, unprovoked and unpredictable seizures that reduce the quality of life of those afflicted, with 1-9 epileptic patient deaths per 1000 patients occurring annually due to sudden unexpected death in epilepsy (SUDEP). Predicting the onset of seizures and managing them may help patients from harming themselves and may improve their well-being. For a long time, electroencephalography (EEG) devices have been the mainstay for seizure detection and monitoring. This systematic review aimed to elucidate and critically evaluate the latest advancements in medical devices, besides EEG, that have been proposed for the management and prediction of epileptic seizures. A literature search was performed on three databases, PubMed, Scopus and EMBASE.Methods: Following title/abstract screening by two independent reviewers, 27 articles were selected for critical analysis in this review.Results: These articles revealed ambulatory, non-invasive and wearable medical devices, such as the in-ear EEG devices; the accelerometer-based devices and the subcutaneous implanted EEG devices might be more acceptable than traditional EEG systems. In addition, extracerebral signal-based devices may be more efficient than EEG-based systems, especially when combined with an intervention trigger. Although further studies may still be required to improve and validate these proposed systems before commercialization, these findings may give hope to epileptic patients, particularly those with refractory epilepsy, to predict and manage their seizures.Conclusion: The use of medical devices for epilepsy may improve patients'' independence and quality of life and possibly prevent sudden unexpected death in epilepsy (SUDEP).     

Colchicine for Secondary Cardiovascular Prevention: A Systematic Review

Despite advancements in medical and interventional therapy, patients with cardiovascular disease (CVD) continue to have residual risk for recurrent cardiovascular events. Colchicine has a unique antiinflammatory mechanism that has generated interest in its potential use as a secondary cardiovascular preventive therapy. The objective of this systematic review was to evaluate the evidence for long-term (6 months or more) colchicine therapy in patients with established CVD. A search of Medline and Embase from inception to February 2020 was performed. Included were randomized controlled trials (RCTs) or propensity score-matched observational studies that compared colchicine (at any dose) with placebo or no treatment. Outcomes of interest included any major adverse cardiovascular event, cardiovascular hospitalization, coronary artery restenosis, cardiovascular death, or all-cause death. Five RCTs were included. The dose of colchicine ranged from 0.5 mg/day to 0.6 mg twice/day, and follow-up ranged from ~6–36 months. Two trials (one double blind and one single blind) showed a reduction in composite outcomes of major adverse cardiovascular events. One study failed to demonstrate a benefit with colchicine in restenosis or recurrent ischemia after angioplasty; however, it was conducted before the routine use of modern percutaneous coronary intervention and medical therapies. In contrast, a more recent trial found that colchicine reduced the rate of in-stent restenosis in patients who received a bare metal stent. Finally, one trial in patients with heart failure with reduced ejection fraction did not observe a benefit in death or heart failure hospitalization with colchicine despite a reduction in inflammatory markers. No trial demonstrated a reduction in cardiovascular or all-cause death, and most trials showed an increase in the rate of diarrhea with colchicine. Overall, colchicine has demonstrated promising results for the secondary prevention of CVD; however, further studies are required to confirm these findings before colchicine can be routinely recommended in practice.