Investigation of Solid Dosage Form Components Interaction Using Orthogonal Techniques- Discovery of New Forms of Sodium Stearyl Fumarate

Physical or chemical interactions between drug product (DP) components can occur during manufacturing and/or upon storage; and may alter DP shelf life and performance. In this work a new Powder X-ray Diffraction (PXRD) peak was observed in DP under accelerated storage conditions. Due to the complex drug product matrix (including API, polymer, fillers, super disintegrant and lubricant), it was challenging to pinpoint the component(s) responsible for the new peak. In addition to PXRD, other orthogonal techniques including Differential Scanning Calorimetry (DSC), thermogravimetric analysis (TGA), dynamic vapor sorption (DVS), Solid State Nuclear Magnetic Resonance (SSNMR) and Infrared (IR) spectroscopy were employed in this investigation to understand the root cause mechanistically. Specifically, multi nuclei SSNMR (¹H, ²³Na, ¹³C) was instrumental in delineating the components of the matrix. We identified the root cause to be an acid base reaction occurring in the DP, whereby sodium ion in sodium stearyl fumarate (SSF) is replaced by proton leading to SSF form conversion. We also identified commercially available SSF to be a hydrate that can dehydrate to an anhydrous form upon heating. In general, the same techniques can be used to investigate interactions of any multi component solid dosage forms.     

喘可治注射液联合布地奈德福莫特罗治疗慢性阻塞性肺疾病的疗效观察

摘 要 目的： 观察喘可治注射液联合布地奈德福莫特罗治疗慢性阻塞性肺疾病(COPD) 的疗效。方法: 120例COPD患者随机分为2组,观察组予布地奈德福莫特罗吸入同时肌注喘可治注射液,对照组单纯给予布地奈德福莫特罗吸入。治疗28 d,比较两组FEV₁%预计值、FEV₁ /FVC、6 min 步行距离(6MWD)等肺功能指标变化和急性加重次数,同时观察治疗期间两组药物不良反应的发生情况。结果: 治疗后2组肺功能和 6 MWD均较前改善;观察组比对照组FEV1%预计值改善更明显[（59.7±12.1) %和(49.8±11.3)%,P<0.05],至少有1次急性加重的患者数明显减少( 35%和62%,P＜0.01) ,并且两组的药品不良反应发生率差异无统计学意义。结论:喘可治注射液联合布地奈德福莫特罗比单用布地奈德福莫特罗能更好地改善COPD患者的肺功能,减少急性加重次数,不会增加药品的不良反应发生率。     

Asociación Mexicana de Hepatología A.C. Guía Clínica de Hepatitis B

Hepatitis B virus (HBV) infection continues to be a worldwide public health problem. In Mexico, at least three million adults are estimated to have acquired hepatitis B (total hepatitis B core antibody [anti-HBc]-positive), and of those, 300,000 active carriers (hepatitis B surface antigen [HBsAg]-positive) could require treatment. Because HBV is preventable through vaccination, its universal application should be emphasized. HBV infection is a major risk factor for developing hepatocellular carcinoma. Semi-annual liver ultrasound and serum alpha-fetoprotein testing favor early detection of that cancer and should be carried out in all patients with chronic HBV infection, regardless of the presence of advanced fibrosis or cirrhosis. Currently, nucleoside/nucleotide analogues that have a high barrier to resistance are the first-line therapies.     

Effectiveness of Delayed-release Dimethyl Fumarate on Clinical and Patient-reported Outcomes in Patients With Relapsing Multiple Sclerosis Switching From Glatiramer Acetate: RESPOND,a Prospective Observational Study

Purpose

The goal of this study was to evaluate clinical outcomes and patient-reported outcomes (PROs) over 12 months in patients with relapsing multiple sclerosis (RMS) who switched from glatiramer acetate (GA) to delayed-release dimethyl fumarate (DMF) 240 mg BID after suboptimal response to GA in real-world clinical practice.

比索洛尔治疗原发性高血压的疗效及对心功能的影响

目的：研究比索洛尔治疗原发性高血压的临床疗效及对左心功能的影响。方法选择2012—2013年湖州市七里亭新村社区卫生服务站收治的150例原发性高血压患者,分为比索洛尔组83例和氯沙坦组67例。患者治疗前后行心脏彩超检查,记录治疗前后的每搏输出量（SV）、心排血量（CO）、左心室射血分数（LVEF）、左心室缩短分数（LVFS）及左室舒张早期血流峰值（E 峰）速度、舒张晚期血流峰值（A 峰）速度,计算 E 峰/ A 峰比值（E/ A）。结果比索洛尔组总有效率为94.0%,高于氯沙坦组的85.1%,差异有统计学意义（P ＜0.05）。治疗后比索洛尔组 E/ A 值高于氯沙坦组,差异有统计学意义（P ＜0.05）。结论比索洛尔治疗原发性高血压的疗效确切,可有效改善左心室的舒张功能。     

比索洛尔对心力衰竭患者心功能及血淋巴细胞内游离钙浓度的影响

目的 :研究心力衰竭患者心功能与血淋巴细胞内游离钙浓度的关系及比索洛尔对二者的影响。方法 :应用超声心动图及荧光分光光度计分别测定 40例心力衰竭患者和 15例健康人的左室舒缩功能和血淋巴细胞内游离钙浓度 （[Ca2 +]i） ,心衰患者中 2 5例在强心、利尿、扩血管等治疗基础上加用比索洛尔 5 mg/ d,另 15例患者仅常规治疗。 3周后重复各项检查。结果 :1心衰患者血淋巴细胞内 [Ca2 +]i 显著高于正常对照组。 2比索洛尔治疗 3周后 ,心功能改善 ,血淋巴细胞内 [Ca2 +]i 明显降低 （P<0 .0 1）。3心功能改善程度与 [Ca2 +]i 降幅呈正相关 （r=0 .6 8,P<0 .0 1）。结论 :比索洛尔与心力衰竭常规治疗联合应用 ,能明显改善患者心功能 ,其机制可能与抑制交感神经过亢活性 ,逆转心肌细胞内 Ca2 +超载有关     

比索洛尔治疗原发性高血压180例报告

目的：观察比索洛尔对轻中度高血压的降压疗效及其安全性。方法：采用自身对照开放试验方法。180例原发性高血压（EH）病人，服安慰剂1周后，口服比索洛尔5～20mg（80％病人服5～10mg）共6周，不服其它降血压药。结果：服药6周后血压为18．6±1．77／11．3±1．05kPa，收缩压下降4.0kPa，舒张压下降2．4kPa，有效31．1％，显效67．2％，总有效率98．3％；36例冠心病人中19例心绞痛及心肌缺血好转改善率为52．7％。出现不良反应20例（11．1％），但症状轻，不需停药。治疗前后血生化及肝肾功能无改变。结论：比索洛尔对轻中度EH病人具有降压作用，对合并冠心病者兼有抗缺血效应，不良反应少，耐受性好。     

Aclidinium bromide and formoterol fumarate for the maintenance treatment of chronic obstructive pulmonary disease

ABSTRACT

Introduction: Treatment options for COPD have evolved rapidly in the last decade and inhaled bronchodilators have largely supplanted the use of oral bronchodilators because of their increased efficacy and excellent safety with topical delivery to the lung. Recently added to the therapeutic armamentarium are fixed-dose combinations (FDC) of two long acting bronchodilators. LAMAs (long acting muscarinic antagonists) and LABAs (long acting beta agonists) are the main classes available and use different pathways to effectively produce bronchial smooth muscle relaxation.

Areas covered: The most recent inhaled FDC LAMA/LABA to come to market is Aclidinium Bromide and Formoterol Fumarate. We searched databases of PubMed, Cochrane Library, and manufacturers’ websites and retrieved all the randomized-controlled trials (RCTs) conducted with these drugs up to September 2019.

Expert opinion: It is likely that FDCs will become the core of our COPD pharmacotherapy for all but the mildest COPD patients. These individual drugs have excellent efficacy and safety records for the maintenance treatment of COPD. Studies have demonstrated that twice daily treatment with aclidinium/formoterol resulted in significant improvement in lung function and an improved exercise tolerance when compared to placebo. Adverse effects are within the range of what is seen with other LAMA/LABA combinations.     

Effect of Pegylated Interferon Plus Tenofovir Combination on Higher Hepatitis B Surface Antigen Loss in Treatment-naive Patients With Hepatitis B e Antigen -positive Chronic Hepatitis B: A Real-world Experience

PurposeThe loss of serum hepatitis B surface antigen (HBsAg) in patients with chronic hepatitis B (CHB) is considered an ideal clinical outcome but rarely achieved with current standard of care. We evaluated the effectiveness in inducing HBsAg seroclearance in a real-world clinical cohort of Chinese patients with CHB treated with a combination of pegylated interferon (Peg-IFN) with tenofovir disoproxil fumarate (TDF) or monotherapy with each agent.MethodsA total of 330 patients with CHB were assigned to receive Peg-IFN plus TDF for 48 weeks (Peg-IFN plus TDF group), Peg-IFN alone for 48 weeks (Peg-IFN group), or TDF alone for 144 weeks (TDF group). The primary end point was the percentages of patients who achieved HBsAg seroclearance at week 72. Differences from the baseline characteristics and treatment data were compared using the χ² test for categorical variables or 1-way ANOVA for continuous variables. A Kaplan–Meier test was performed to compare the HBsAg loss among the 3 groups. Discrimination of responders versus nonresponders was quantified using AUC curves. Optimal cut-offs were selected based on Youden's J statistic defined as J = sensitivity + specificity-1.FindingsAt week 72, the Kaplan–Meier cumulative HBsAg loss was 11.5% in the Peg-IFN plus TDF group, 5.7% in the Peg-IFN group, and 0% in the TDF group. The percentage of patients with HBsAg loss was comparable in the Peg-IFN plus TDF and Peg-IFN groups (P = 0.143), but both were significantly higher than that in the TDF group (P = 0.000 and P = 0.010). In addition, a significantly higher percentage of patients in the combination group and Peg-IFN group had serum HBsAg of <100 IU/mL compared with the TDF group (32.7% vs 23.6% vs 9.2%; P < 0.001) but no significant differences in the percentages of patients with HBsAg <1000 IU/mL, the undetectable serum HBV DNA and hepatitis B e antigen seroconversion. Our model predicted serum HBsAg loss at week 72 (AUC = 0.846) if the HBsAg level was reduced by > 1.5 log₁₀ IU/mL from baseline at treatment week 24, an optimal timepoint for prediction of HBsAg loss in this cohort.ImplicationsA 48-week course of Peg-IFN and TDF combination therapy led to profound reduction in serum HBsAg level, resulting in a significantly higher rate of HBsAg loss compared with TDF monotherapy. Patients with steep HBsAg decline >1.5 log₁₀ IU/mL at week 24 well signaled a higher probability of achieving HBsAg loss at week 72.     

G蛋白β3亚单位C825T基因多态性与富马酸比索洛尔降压疗效的相关性

 目的 探讨G蛋白β₃亚单位C825T基因多态性与富马酸比索洛尔降压疗效的相关性。方法 选择2018-10至2020-10在解放军总医院第一医学中心心内科住院或门诊就诊的轻、中度原发性高血压患者,均口服5 mg/d比索洛尔,进行GNβ₃-C825T基因型测定,依据基因型分为3组:CC组、CT组、TT组,每组150例,在3组受试者治疗7 d,1、3、6个月后进行随访,测定患者的富马酸比索洛尔药物代谢血药浓度;治疗前、治疗7 d,1、3、6个月后进行24 h动态血压监测,比较患者静息状态下收缩压及舒张压(SBP、DBP),24 h收缩压均数(24 h SBP)、24 h舒张压均数(24 h DBP)、白天收缩压均数(d SBP)、白天舒张压均数(d DBP)、夜间收缩压均数(n SBP)、夜间舒张压均数(n DBP)的组间差异;进行24 h动态心电图监测,比较24 h平均心率、窦性心律震荡水平。结果 治疗7 d,随访1、3、6个月TT组富马酸比索洛尔血药浓度均高于CC组及CT组,差异均有统计学意义(P＜0.05),CC组与CT组无统计学差异,3组组内不同时间血药浓度变化均无统计学差异;应用富马酸比索洛尔后,3组患者血压均有下降趋势,其中TT组降压效果＞CT组＞CC组,3组间血压下降水平有统计学差异(P＜0.05);治疗7 d后,动态心电图显示:3组患者心率有下降趋势,TT组＞CT组＞CC组,其中TT组与CT组、CC组比较有统计学差异(P＜0.05),CT组与CC组心率下降无统计学差异;TT组窦性心律震荡水平优于CT组、CC组。结论 G蛋白β₃亚单位C825T基因多态性与富马酸比索洛尔降压疗效之间具有相关性。