Identification of cytochrome P450 enzymes involved in the metabolism of 4′-methoxy-α-pyrrolidinopropiophenone (MOPPP), a designer drug,in human liver microsomes

1. The metabolism of 4′-methoxy-α-pyrrolidinopropiophenone (MOPPP), a novel designer drug, to its demethylated major metabolite 4′-hydroxy-pyrrolidinopropio-phenone (HO-PPP) was studied in pooled human liver microsomes (HLM) and in cDNA-expressed human hepatic cytochrome P450 (CYP) enzymes.

2. CYP2C19 catalysed the demethylation with apparent K_m and V_max values of 373.4 ± 45.1?μM and 6.0 ± 0.3?pmol?min^?1?pmol^?1 CYP, respectively (mean ± SD). Both CYP2D6 and HLM exhibited clear biphasic profiles with apparent K_m,1 values of 1.3 ± 0.4 and 22.0 ± 6.5?μM, respectively, and V_max,1 values of 1.1 ± 0.1 pmol?min^?1?pmol^?1 CYP and 169.1 ± 20.5?pmol?min^?1?mg^?1 protein, respectively.

3. Percentages of intrinsic clearances of MOPPP by particular CYPs were calculated using the relative activity factor (RAF) approach with (S)-mephenytoin-4′-hydroxylation or bufuralol-1′-hydroxylation as index reactions for CYP2C19 or CYP2D6, respectively.

4. MOPPP, HO-PPP and the standard 3′,4′-methylenedioxy-pyrrolidinopropio-phenone (MDPPP) were separated and analysed by liquid chromatography–mass spectrometry in the selected-ion monitoring (SIM) mode.

5. The CYP2D6 specific chemical inhibitor quinidine (3?μM) significantly (?p<0.0001) inhibited HO-PPP formation by 91.8 ± 0.5% (mean ± SEM) in incubation mixtures with HLM and 2?μM MOPPP.

6. It can be concluded from the data obtained from kinetic and inhibition studies that polymorphically expressed CYP2D6 is the enzyme mainly responsible for MOPPP demethylation.     

HPLC-柱后生物活性检测在线联用技术在天然活性成分筛选中的应用

HPLC由于分离度和灵敏度高,其在柱后与生物活性检测联用形成的天然活性成分筛选技术,具有操作简单、耗费低、灵敏度和专属性高等优点,已用于天然产物中抗氧化剂、乙酰胆碱酯酶（AChE）抑制剂、磷酸二酯酶（PDE）抑制剂、血管紧张素转移酶（ACE）抑制剂、细胞色素P450抑制剂等的筛选。综述了HPLC-柱后生物活性检测在线联用技术在天然活性成分筛选研究中的应用,同时对其优点和不足进行了总结。     

梭果黄芪不同极性部位抗疲劳和免疫调节研究

目的：考察梭果黄芪不同极性部位对小鼠抗疲劳作用和免疫调节作用的影响。方法：分别采用小鼠负重力竭游泳实验,碳粒廓清指数、免疫器官重量法以及小鼠腹腔巨噬细胞吞噬鸡红细胞实验观测梭果黄芪不同极性部位对小鼠抗疲劳和免疫调节的影响。结果：①梭果黄芪乙酸乙酯部位对小鼠运动所致疲劳具有抗疲劳作用,能显著增加小鼠游泳时间t=（16.28±4.28）min（P〈0.05）。②乙酸乙酯部位、水部位能增加小鼠血清溶血术抗体的生成,其OD值分别为0.9851±0.1232、1.0527±0.1950（P〈0.05）。③梭果黄芪各部位对小鼠巨噬细胞吞噬功能有一定影响作用,但在吞噬指数和廓清指数上无显著性影响;乙酸乙酯部位、正丁醇部位、水部位能显著增加胸腺器官的重量,胸腺指数分别为（3.1960±0.4820）、（3.5550±0.8259）、（2.6960±1.0834）mg/g（P〈0.05）。结论：梭果黄芪乙酸乙酯部位能明显提高正常小鼠机体的抗疲劳能力,乙酸乙酯部位和水部位能明显增加小鼠血清溶血术抗体的生成,各部位对小鼠巨噬细胞吞噬功能有一定影响作用。     

丙泊酚长期镇静对大鼠认知功能及海马高级糖基化终末产物受体表达的影响

目的观察丙泊酚长期镇静对大鼠认知功能及海马高级糖基化终末产物受体（RAGE）蛋白表达的影响及认知功能改变与海马RAGE蛋白表达有无关联,为临床提供依据。方法选取成年雄性Wistar大鼠28只,随机分为对照组和丙泊酚组,各14只。预实验找出使大鼠反正反射消失的剂量,丙泊酚腹腔注射30mg／kg,尾静脉穿刺留置静脉导管。在尾静脉再给予丙泊酚组镇静作用的基本剂量即36～72mg/（h·kg）,每日连续输注8h,连续给药5d,对照组给予生理盐水。于完全停药后1d应用Morris水迷宫对两组大鼠开始连续5d的行为学观察,记录逃逸潜伏期和空间探索时间。米次大鼠水迷宫测试lh后,取大鼠海马,用酶联免疫吸附试验（EUSA）法测定RAGE蛋白的表达。结果①定位航行实验结果：与对照组比较,丙泊酚组第1～4日逃逸潜伏期延长（P〈0．05）;②空间探索实验结果：与对照组比较,丙泊酚组空间探索时间缩短、穿越平台次数减少,两组比较的差异均有统计学意义（F=7．04,22．33,P〈0．05）;③ELISA法测定RAGE蛋白结果：与对照组比较,丙泊酚组海马RAGE蛋白表达显著上调（F=5．247,P：0．007）。结论①丙泊酚长期镇静可损害成年大鼠的空间学习记忆能力,可导致成年大鼠认知功能降低,可能与其上调海马RAGE表达有关。     

Synthesis and Biological Evaluation of Novel Bromophenol Derivatives as Carbonic Anhydrase Inhibitors

Here, we provide an alternative synthesis of the natural bromophenol 3,4‐dibromo‐5‐(2,3‐dibromo‐4,5‐dihydroxybenzyl)‐6‐(ethoxymethyl)benzene‐1,2‐diol ( 3 ) and the first synthesis of (4,5‐dihydroxy‐2‐methylphenyl)(3,4‐dihydroxyphenyl)methanone ( 18 ) and its brominated derivatives 19 – 21 . The compounds were characterized and tested against the two most studied members of the pH regulatory enzyme family, carbonic anhydrase (CA). The inhibitory potencies of the novel compounds and two natural bromophenols 2 , 3 were analyzed at the human isoforms hCA I and hCA II as targets and the K_I values were calculated. The K_I values of the novel compounds were measured in the range of 13.7–32.7 µM for the hCA I isozyme and 0.65–1.26 µM for the hCA II isozyme. The structurally related compound 14 was also tested in order to understand the structure–activity relationship, and the clinically used sulfonamide acetazolamide (AZA) was tested for comparison reasons. All of the compounds exhibited competitive inhibition with 4‐nitrophenylacetate as substrate. The compounds showed strong inhibitory activity against hCA I, being more effective as compared to the clinically used AZA (K_I: 36.2 µM), but rather less activity against hCA II.     

不同手术时机对急性重症胰腺炎的综合影响比较

目的:探讨外科不同手术时机对急性重症胰腺炎(SAP)治疗结果的影响。方法:选择进行治疗的急性重症胰腺炎患者64例为研究对象,根据手术时间分为早期手术组(22例)、延期手术组(23例)和非手术组(19例),就三组患者治疗前后血液淀粉酶、尿液淀粉酶、病死率、治愈率、并发症情况进行统计比较。结果:早期手术组、延期手术组和非手术组的并发症发生率分别为22.73%(5/22),65.22%(15/23),42.11%(8/19);病死率分别为13.64%(3/22),17.39%(4/23),21.05%(4/19);治疗后早期手术组淀粉酶平均水平最低,其次为非手术组,延期手术组平均水平最高。多个参数显示早期手术组对患者病情治疗效果优于延期治疗和非手术治疗。结论:治疗急性重症胰腺炎时应注重个体化治疗,选择合适的手术时机和治疗方式有助于提升疗效。     

Dual Characteristics of Skin Care Creams Evaluated by Two In-Vivo Human Experimental Models

The use of skin care creams is a well documented protection measure to reduce the risk of barrier damage and contact dermatitis from exogenous contact with skin irritants. Before choosing a skin care cream two aspects should be considered: a) Is the product able to reduce irritant reactions caused by the irritant, and b) is the product well tolerated, also on damaged skin. Both aspects can be evaluated by experimental models in human volunteers. We used two standard experimental designs to compare six commercially available skin care products: a) the chamber scarification test, designed to assess the irritancy potential, and b) the repeated short-time occlusive irritation test (ROIT), developed to evaluate the efficacy of skin care creams. The results showed that a high score in the chamber scarification test for skin irritation was not necessarily correlated to the products' ability to impede sodium lauryl sulfate (SLS)-induced irritant skin reactions. Three products were shown to both have a low irritancy potential and be capable of reducing skin barrier damage induced by SLS, and one product had both an irritant potential on scarified skin and also a modest capability to reduce skin irritation induced by SLS. The use of both test methods, chamber scarification and ROIT, gives valuable information on skin compatibility and efficacy of skin care creams. The clinical relevance of the test results can only be determined by comparing products with high and low scores in both tests in controlled clinical experiments with subjects at risk of developing irritant contact dermatitis.     

An update on benzofuran inhibitors: a patent review

ABSTRACT

Introduction: Benzofuran is a fundamental unit in numerous bioactive heterocycles. They have attracted chemists and medical researchers due to their broad range of biological activity, where some of them possess unique anticancer, antitubercular, antidiabetic, anti-Alzheimer and anti-inflammatory properties. The benzofuran nucleus is present in a huge number of bioactive natural and synthetic compounds. Benzofuran derivatives have potent applications in pharmaceuticals, agriculture, and polymers. The recent developments considering the biological activities of benzofuran compounds are reported. They have a vital role as pronounced inhibitors against a number of diseases, viruses, fungus, microbes, and enzymes.

Areas covered: This review covers the recent developments of biological activities of benzofurans during the period 2014–2019. The covered areas here comprised antimicrobial, anti-inflammatory, antitumor, antitubercular, antidiabetic, anti-Alzheimer, antioxidant, antiviral, vasorelaxant, anti-osteoporotic and enzyme inhibitory activities.

Expert opinion: In addition to the already commercialized 34 benzofurans-based drugs in the market, this chapter outlines several potent benzofuran derivatives that may be useful as potential pro-drugs. It is also focused on providing details of SAR and the effect of certain functional groups on the activity of the benzofuran compounds. The presence of -OH, -OMe, sulfonamide, or halogen contributed greatly to increasing the therapeutic activities comparing with reference drugs.     

Biosimilars lining up to compete with Herceptin – opportunity knocks

Trastuzumab is a monoclonal antibody developed by Genentech as a treatment for breast cancer and gastric cancer when the cancer cells overexpress HER2, a membrane-bound receptor activated by epidermal growth factor. Now marketed by Roche under the trade name Herceptin, trastuzumab has been readily adopted as treatment for some of the most invasive types of breast cancer. The cost for Herceptin is over $50,000 for a full course of treatment. With the development of regulatory pathways for biosimilar products, and the imminent expiry of patents covering Herceptin, several companies have developed biosimilar trastuzumab products. As biosimilar manufacturers look for opportunities to market biosimilar trastuzumab products, Roche has positioned itself to protect its market by developing additional anti-HER2 products complementary to Herceptin. The advent of competition from biosimilars should bring some opportunity for cost savings for patients, as well as incentive for continued advancement in development of better treatments to fight breast cancer.     

Novel approaches in the treatment of lupus nephritis

In systemic lupus erythematosus hyperactive helper T-cells drive polyclonal B-cell activation and secretion of pathogenic auto-antibodies. The auto-antibodies form immune complexes with their respective auto-antigens, which in turn deposit in sites such as the kidney and initiate a destructive inflammatory reaction. Lupus nephritis can be managed successfully in the majority of cases; however, the most widely used immunosuppressive therapies, notably corticosteroids and cyclophosphamide are non-specific and are associated with substantial toxicities. Novel treatments for lupus nephritis have to be at least as effective and less toxic than existing therapies. The ultimate aim is to develop treatments that target specific steps in the disease process. Novel therapeutic strategies in the short-term more likely will focus on refining regimens of drugs that are already in use (mycophenolate mofetil, adenosine analogues) and combinations of existing chemotherapeutic agents, as well as attempts to achieve immunological reconstitution using immunoablative chemotherapy with or without haematopoietic stem cell rescue. Several new agents targeting specific steps in the pathogenesis of lupus are in various phases of clinical development. Interrupting the interactions between T-lymphocytes and other cells by blocking co-stimulatory molecules, such as CD40 ligand or CTLA4-Ig, may interfere with the early steps of pathogenesis. Blocking IL-10 may decrease auto-antibody production and help normalise T-cell function. Treating patients with DNase or interfering with the complement cascade by blocking C5, or neutralising pathogenic antibodies by administering specific binding peptides or inducing specific anti-idiotype antibodies may prevent immune complex formation and/or deposition.