国产甲磺酸伊马替尼片治疗慢性粒细胞白血病的临床观察

目的:观察国产甲磺酸伊马替尼片治疗慢性粒细胞白血病(CML)患者的疗效及安全性。方法:选取CML患者16例,其中初诊CML即给予甲磺酸IM治疗者7例,诊断CML超过12个月后再给予甲磺酸IM治疗者9例,所有患者均长期口服甲磺酸伊马替尼片400 mg,qd。治疗后3个月通过检测所有患者血常规、骨髓细胞学、费城染色体(Ph染色体)评估疗效,并观察外周血Bcr-Abl/Abl融合基因突变及不良反应发生情况。结果:治疗后,16例患者均达到完全血液学缓解(CHR);12例患者获得部分细胞遗传学缓解(PCy R),2例患者获得完全细胞遗传学缓解(CCy R),2例患者无细胞遗传学缓解;15例患者Bcr-Abl/Abl转录水平<10%,仅1例>10%。16例患者均未出现难以耐受的不良反应。结论:国产甲磺酸伊马替尼片早期疗效确切,安全性高。     

伊马替尼、尼洛替尼和达沙替尼对慢性粒细胞白血病慢性期患者的临床疗效

目的 观察伊马替尼、尼洛替尼和达沙替尼对慢性粒细胞白血病(CML)慢性期患者治疗的有效性和安全性。方法 123例接受酪氨酸激酶抑制剂治疗的慢性粒细胞白血病慢性期患者分成3组:A组64例接受伊马替尼治疗;B组31例接受尼洛替尼治疗,C组28例接受达沙替尼治疗,对患者临床资料和随访记录进行总结和分析。治疗18个月后,分析患者的完全细胞遗传缓解百分率(CCyR)、完全血液学缓解率(CHR)和主要分子生物学缓解率(MMR)。结果 A组治疗3,6,12,18个月后CCyR、CHR和MMR都呈现出上升趋势。B和C组治疗12,18个月时,CCyR较A组有显著提高(P<0.05);MMR与A组比较差异有显著统计学意义(P<0.01);3组CHR在各时间节点差异无统计学意义(P>0.05)。3组在随访期间的安全性差异无统计学意义(P>0.05)。结论 与伊马替尼相比,尼洛替尼和达沙替尼能更快的在患者体内获得完全细胞遗传学缓解和主要分子生物学缓解,且疗效优于伊马替尼。     

甲磺酸伊马替尼治疗慢性髓系白血病慢性期疗效及不良反应分析

目的 探讨甲磺酸伊马替尼(格列卫)治疗慢性髓系白血病慢性期(CML-CP)的疗效,并对其不良反应进行了初步分析.方法 20例CML-CP患者口服伊马替尼300～800mg/d,监测血常规指标、染色体核型及bcr/abl P210转录本表达,用药期间观察其不良反应.结果 中位随访时间15个月(3～36个月),累积获得的完全血液学缓解(CHR)率为90.0%(18/20例),主要细胞遗传学缓解(MCyR)率80.0%(16/20例),分子生物学缓解(CMoR)率为42.9%(6/14例).不良事件:(1)非血液学毒性,如体表水肿(体液潴留)9/20例,肌肉骨骼疼痛7/20例,关节痛6/20例,头痛3/20例;3个月以后均未发现以上不良反应.(2)血液学不良事件:中性粒细胞减少症13/20例(3个月)、7/18例(6个月)、3/10例(12个月),血小板减少症9/20例(3个月)、5/18例(6个月)、3/10例(12个月),贫血2/20例(3个月)、2/18例(6个月)、0/10例(12个月),SGOT/SGPT升高0/20例,胆红素升高0/20例.结论 甲磺酸伊马替尼治疗可以使CML-CP患者获得极高的血液学缓解率和较高的细胞遗传学缓解率,其不良反应多发生于甲磺酸伊马替尼治疗的早期,与其清除恶性克隆有关.随正常造血的恢复,其治疗相关不良反应发生率明显减少.     

伊马替尼治疗慢性髓细胞白血病慢性期临床疗效观察

目的：分析甲磺酸伊马替尼（IM）治疗慢性髓系白血病（CML）慢性期的临床疗效及影响疗效的因素。方法随访观察74例 CML 慢性期患者,IM中位治疗剂量为400（200～600）mg·d －1,评估其临床疗效,总生存时间和疾病无进展生存时间,并对相关疗效影响因素进行分析。结果中位随访时间为20（6～72）个月,累积达到血液学缓解（CHR）为98．6％,血液学中位缓解时间1（1～3）月;63例（85．1％）达到主要细胞遗传学缓解（MCyR）,中位达 MCyR 时间为9（5～24）个月;53例（71．6％）达完全细胞遗传学缓解（CCyR）,41例（55．4％）达到主要分子生物学缓解（MMR）;6例（8．1％）达到完全分子生物学缓解（CMR）;初治组及复治组应用 IM治疗后 CHR 及 MCyR 差异无统计学意义,但 CCyR 及 MMR 差异均有统计学意义（P ＜0．016）;由 EUTOS 评分区分的低危组与高危组应用 IM治疗后 CHR 差异无统计学意义,但 MCyR、CCyR 及 MMR 差异均有统计学意义（P ＜0．020）;其中初治组与复治组及 EUTOS 评分低危组与高危组 OS 差异无统计学意义,但其 PFS 差异均有统计学意义（P 分别为0．021和0．004）。结论IM用于 CML 慢性期患者治疗可获得极高的血液学缓解率和较高细胞遗传学缓解率,不良反应少,提高了患者生存质量,延长患者的生存时间;在 CML 确诊早期应用可提高疗效,IM治疗前时间大于6个月或EUTOS 评分高危组可影响 IM疗效。     

甲磺酸伊马替尼(格列卫)治疗晚期慢性粒细胞性白血病的临床疗效观察

目的:探讨甲磺酸伊马替尼(格列卫)治疗晚期慢性粒细胞白血病的临床疗效及不良反应情况。方法:对我院近年来应用甲磺酸伊马替尼治疗的29例晚期慢性粒细胞白血病患者的临床资料进行回顾性分析,并记录治疗过程中各时间点血常规、骨髓细胞形态学检查、细胞遗传学检查情况,对临床疗效及不良反应进行评价。结果:急变期CML患者血液学缓解率为28.6%,完全细胞遗传学缓解率为0,均明显低于加速期CML患者的73.3%和26.7%,差异均有统计学意义。治疗过程中血液学不良反应主要以白细胞,血小板减少多主,非血液学不良反应可有恶心、呕吐、水肿、骨骼肌酸痛、乏力、头昏、头痛、皮疹等。结论:甲磺酸伊马替尼治疗慢性粒细胞白血病加速期急变期患者疗效好,不良反应少,可耐受且加速期疗效优于急变期。     

达沙替尼治疗伊马替尼耐药的 BCR／ABL阳性白血病

目的评价达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病的疗效和安全性。方法对9例伊马替尼耐药的慢性髓系白血病（CML）或Ph阳性急性淋巴细胞白血病（Ph＋ALL）患者,给予达沙替尼100～140 mg·d-1口服治疗,评估疗效和耐受情况。结果 9例伊马替尼耐药的BCR/ABL阳性白血病,2例CML-CP患者均获得CHR,1例达CCyR;5例CML-BC患者中4例获得CHR和PCyR,1例NR;2例Ph＋ALL患者中1例检测到E255V突变,采用达沙替尼治疗达CHR和PCyR,1例诱导缓解时,同时行VDP方案化疗,继发严重感染死亡。结论达沙替尼治疗伊马替尼耐药的BCR/ABL阳性白血病患者可获得血液学甚至细胞遗传学缓解,且耐受性好。     

甲磺酸伊马替尼治疗慢性粒细胞白血病进展期疗效观察

目的：观察甲磺酸伊马替尼治疗慢性粒细胞白血病（CML）进展期的临床疗效。方法将41例 CML进展期患者随机分为观察组21例和对照组20例。观察组给予甲磺酸伊马替尼,对照组给予常规化疗,比较2组临床疗效和不良反应发生情况。结果观察组总有效率为80.95%高于对照组的20.00%,差异有统计学意义（P ﹤0.05）。结论与传统的常规化疗相比,甲磺酸伊马替尼对 CML 进展期患者近期疗效明显,不良反应可耐受。     

伊马替尼治疗Ph阳性进展期慢性粒细胞白血病

目的:观察伊马替尼治疗Ph阳性进展期慢性粒细胞白血病(CML)的疗效和耐药情况,研究改善伊马替尼耐药的方法。方法:32例Ph阳性进展期CML病人,其中加速期12例,急变期20例,每日口服伊马替尼600或800mg,持续3～9mo。结果:CML加速期病人血液学完全缓解率和总有效率分别为42%和83%,主要细胞遗传学缓解率25%,持续完全血液学缓解病例占25%。CML急变期各类型病人血液学完全缓解率和总有效率分别为20%和55%,主要细胞遗传学缓解率15%,持续完全血液学缓解病例占10%。CML急变期原发耐药和继发耐药分别为45%和20%,联合化疗与暂停伊马替尼对继发耐药可暂时改善其耐药性,但药物有效时间明显缩短。结论:伊马替尼对初治或复治的CML加速期和急变期病人均有效,可作为非移植CML治疗的标准一线方案,伊马替尼治疗CML急变期的原发耐药和继发耐药率较高,联合化疗和暂停伊马替尼可暂时改善其耐药性。     

伊马替尼治疗儿童慢性粒细胞白血病发生急淋变2例报告及文献复习

目的探讨伊马替尼治疗儿童慢性粒细胞白血病(CML)过程中发生急淋变的治疗经验。方法 纳入安徽省肿瘤医院2015年8月及2016年6月收住的2例儿童CML口服伊马替尼治疗过程中发生急淋变病人,统计达到血液学反应(CHR)时间、定期复查骨髓细胞学及融合基因、染色体。确定儿童CML急淋变后予以“达沙替尼+改良VDLP” 方案化疗,骨髓缓解后积极行异基因造血干细胞移植(HSCT)。结果 2例病人分别于口服伊马替尼后第18天及第33天达到CHR,1年后Ph染色体均未转阴,且发生急淋变。确定儿童CML急淋变后予以“达沙替尼+改良VDLP” 方案化疗,骨髓均得到缓解,2例HSCT均顺利完成。结论 伊马替尼治疗儿童CML过程中发生急淋变后,予以改用达沙替尼及改良VDLP方案化疗,并予以HSCT,患儿预后良好。     

伊马替尼治疗慢性粒细胞性白血病的临床应用意义探究

目的:探究伊马替尼治疗慢性粒细胞性白血病的临床应用价值.方法:选取我院2014年9月~2015年12月收治的30例慢性粒细胞性白血病患者,通过伊马替尼治疗.结果:治疗后,完全血液学缓解CHR、部分血液学缓解PHR、未缓解NR分别为90%、6.67%、3.33%;完全遗传学缓解CCR、部分遗传学缓解PCR、未缓解NR分别为83.33%、10%、6.67%.随访6个月,复发率3.33%(1/30).结论:慢性粒细胞性白血病,经伊马替尼治疗,临床疗效显著,但应结合病情变化、耐受情况,适当调整药物的剂量,以便充分发挥伊马替尼的药效,提高临床效果.     

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.

     

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.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.     

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.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.