全反式维甲酸对血管平滑肌细胞增殖和转化生长因子-β mRNA表达的影响

目的：研究全反式维甲酸对血管平滑肌细胞增殖，ＤＮＡ合成和转化生长因子－β（ＴＧＦ－β）基因表达的影响。方法：采用血管平滑肌细胞培养，细胞计数，３Ｈ－ＴｄＲ参入，斑点杂交和图像分析方法。结果：全反式维甲酸（Ａ－ＴＲＡ，０．０１，０．１，１μｍｏｌ·Ｌ－１）明显抑制胎牛血清（ＦＣＳ）促进的血管平滑肌细胞增殖和ＤＮＡ合成，其最大抑制率分别是２２．４％和８７．１％；全反式维甲酸明显抑制ＦＣＳ促进的血管平滑肌细胞ＴＧＦ－βｍＲＮＡ表达。结论：ＡＴＲＡ具有抗血管平滑肌细胞增殖作用，其机制与抑制ＴＧＦ－β基因表达有关。     

维甲酸综合征1例

维甲酸综合征１例唐茂勤，张云清，张修明（重庆市潼南县人民医院内科，潼南６３２６６０）关键词维生素Ａ酸类；维甲酸；急性早幼粒细胞性白血病维甲酸综合征（ｒｅｔｉｎｏｉｃａｃｉｄｓｙｎｄｒｏｍｅ，ＲＡＳ）是全反式维甲酸（ａｌ－ｔｒａｎｓ－ｒｅｔｉｎｏｉｃａ...     

全反式维甲酸对人胃癌细胞株增殖的影响

研究全反式维甲酸对三株分化程度不同的人胃癌细胞增殖的影响，发现该药对人胃癌细胞株（ＭＫＮ－２８，ＳＧＣ－７９０１）的体外增殖和裸鼠体内移植瘤的生长都有选择性抑制作用，并有不影响细胞活力的特点。而对低分化癌细胞株则无明显作用。进一步研究发现全反式维甲酸可使敏感的胃癌细胞株的３Ｈ－ＴｄＲ掺入值降低，胃癌细胞大多积滞于Ｇ１／Ｇ０期，而Ｇ２／Ｍ期细胞比例相应下降，提示该药对胃癌细胞的ＤＮＡ合成和增殖周期有影响。     

全反式维甲酸对胃癌BGC-823细胞增值和凋亡的影响及其机制研究

目的探讨全反式维甲酸（a11．transretinoicacid,ATRA）对体外培养的胃癌BGC-823细胞增殖和细胞凋亡的影响。方法不同浓度全反式维甲酸处理培养的胃癌BGC-823细胞后,采用MTT法检测细胞的增殖活性,采用TUNEL法检测细胞凋亡情况,采用RT．PCR检测细胞Survivin基因mRNA的变化。结果全反式维甲酸对胃癌BGC-823细胞的生长具有明显的抑制作用,其作用表现为剂量依赖性和时间依赖性（P〈0．05）。TUNEL检测显示：以5Ixmol／L的全反式维甲酸对BGC-823细胞处理0、24、48、72h后细胞凋亡率逐渐增加（P〈0．05）,呈时间依赖性。RT-PCR检测显示BGC-823细胞Survivin基因的mRNA表达呈时间依赖性下调。结论全反式维甲酸对胃癌BGC-823细胞株具有明显的增殖抑制和诱导凋亡作用,其作用机制可能与下调Survivin基因表达有关。     

三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病29例

目的观察三氧化二砷（As2O3）联合全反式维甲酸（ATRA）治疗急性早幼粒细胞白血病（APL）的疗效及毒副反应。方法患者使用三氧化二砷联合全反式维甲酸双诱导治疗,对高白细胞患者加用单一化疗药物高三尖衫酯碱（H）或柔红霉素（DNR）,合并弥漫性血管内凝血（DIC）患者予以输注血浆／纤维蛋白原。结果29例患者中26例完全缓解,完全缓解（CR）率89．66％;3例死于颅内出血。结论三氧化二砷联合全反式维甲酸治疗急性早幼粒细胞白血病的疗效确切,患者耐受性较好。     

亚砷酸联合全反式维甲酸治疗急性早幼粒细胞白血病的临床分析

目的探讨亚砷酸联合全反式维甲酸治疗急性早幼粒细胞白血病的临床效果。方法将本院2008年1月～2013年9月收治的64例急性早幼粒细胞白血病患者随机分为4组,每组各16例。联合组给予亚砷酸和全反式维甲酸进行双诱导治疗,亚砷酸组给予亚砷酸治疗,维甲酸组给予全反式维甲酸治疗,化疗组给予常规化疗治疗。结果联合组、亚砷酸组的所有患者（100％）完全缓解,无死亡病例,维甲酸组13例（81．2％）患者达到完全缓解,1例死亡,化疗组仅6例（37．5％）完全缓解,2例死亡,前3组的完全缓解率均显著高于化疗组（P〈0.05）;联合组患者用药至完全缓解的时间明显短于亚砷酸组、维甲酸组（P〈0.05）;联合组患者凝血指标恢复正常所用的时间短于亚砷酸组、维甲酸组（P〈0.05）;肝功能损伤情况：联合组最严重,亚砷酸组次之,维甲酸组较轻,化疗组最轻（P〈0.05）,化疗组的胃肠道反应、皮肤损伤情况较严重,受影响患者明显多于其他3组（P〈0.05）。结论亚砷酸联合维甲酸治疗急性早幼粒细胞白血病短期效果显著,完全缓解率高,并可缩短患者的完全缓解时间。     

HPLC-MS/MS法测定NB4细胞培养液中的全反式维甲酸

目的 建立HPLC-MS/MS法测定NB4细胞培养液中全反式维甲酸的浓度。方法 采用ACQUITY UPLCTM BEH C₁₈（50 mm×2.1 mm,1.7 μm）色谱柱,以布洛芬为内标,流动相为乙腈-水（含0.1%乙酸）,体积流量为0.2 mL/min,梯度洗脱方式分离全反式维甲酸,同时采用ESI源负离子检测方式,定量分析时的离子反应分别为m/z 299.2→m/z 255.2（全反式维甲酸）和m/z 205.4→m/z 161.3（内标布洛芬）。结果 全反式维甲酸在2.55~255 ng/mL线性关系良好,定量限为2.55 ng/mL,日内精密度RSD ≤ 10.3%,日间精密度RSD ≤ 12.9%。结论 建立的HPLC-MS/MS法可用于测定NB4细胞含维甲酸的培养液中全反式维甲酸的浓度,以及在加入维甲酸代谢阻断剂时全反式维甲酸浓度的变化。     

小剂量全反式维甲酸治疗纯红细胞再生障碍性贫血疗效观察

本文报告用小剂量全反式维甲酸（ＬＤ－ＡＴＲＡ）治疗纯红细胞再生障碍性贫血（ＰＲＣＡ）４例，取得２例缓解，１例明显进步的疗效，认为该法是用量小，见效快，副作用轻，无产生高白细胞综合征之虑，ＬＤ－ＡＴＲＡ治疗ＰＲＣＡ的机理可能是促使停滞在原始红系祖细胞向成熟阶段分化起上作用。     

全反式维甲酸治疗急性早幼粒细胞白血病25例长期随访报告

通过对全反式维甲酸治疗的急性早幼粒细胞白血病２５例长期随访，发现采用全反式维甲酸与化疗交替持续治疗者，１年存活率９４％，２年存活率７６．５％，３年为７０．６％，３０个月后呈平坦期，最长１生存期已超过６年，单用全反式维甲酸持续治疗者，１年存活率５０％，２年存活率３７．５％，认为维持治疗时间为３年为宜，复发者的治疗以联合化疗为主，单用维甲酸效果不佳，同时认为重体力劳动和强烈精神刺激可能是导致复发的诱因     

全反式维甲酸综合征的再认识

全反式维甲酸（ATRA）综合征简称为维甲酸综合征（retinoic acidsyndrome，RAS），是维甲酸诱导治疗急性早幼粒细胞白血病（APL）时发生的最严重并发症。熟悉RAS的诊治及预防等方面有着重要的临床意义。     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

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Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.