西妥昔单抗联合化疗治疗转移性结直肠癌的观察

目的 观察西妥昔单抗联合化疗方案治疗转移性结直肠癌的近期疗效及不良反应.方法 11例经病理组织学确诊的转移性结直肠癌患者,给予西妥昔单抗联合FOLFOX方案治疗,西妥昔单抗首次给予负荷剂量400 mg/m2,每周给予维持剂量为250 mg/m2.结果 全组11例患者中,完全缓解1例,部分缓解5例,稳定2例,进展3例,有效率54.5％ (6/11),疾病控制率为72.7％ (8/11),中位肿瘤进展时间为8.4个月.主要不良反应为痤疮样皮疹(9例)和腹泻(6例).5例合并肝转移患者中经治疗后1例转化为可切除病灶.患者耐受良好,无治疗相关死亡.结论 西妥昔单抗联合FOLFOX方案治疗转移性结直肠癌疗效较好,不良反应多可耐受.     

西妥昔单抗联合化疗治疗转移性结直肠癌的临床观察

目的观察西妥昔单抗与奥沙利铂/5-FU/FA联合治疗转移性结直肠癌的近期疗效及毒性反应。方法对11例转移性结直肠癌(MCRC)患者采用西妥昔单抗与奥沙利铂/5-FU/FA化疗联合方案,应用2周期后评价近期疗效及毒性反应。西妥昔单抗首次推荐剂量为400 mg/m~2,以后每周剂量为250 mg/m~2,奥沙利铂/5-FU/FA化疗剂量采用FOLFOX4方案。结果11例患者均完成西妥昔单抗连续6周用药,奥沙利铂/5-FU/FA化疗2周期(每2周重复1次),无CR病例,2例PR(18.18%),4例SD(36.36%),5例PD(45.45%),疾病控制(PR SD)率54.55%。治疗过程中出现的毒性反应为3～4度的痤疮样皮疹,另外有恶心、呕吐、腹痛和虚弱,2～3度白细胞下降。全组患者无过敏反应。结论西妥昔单抗可提高肿瘤对放化疗的敏感性。采用西妥昔单抗与奥沙利铂联合治疗11例转移性结直肠癌患者,取得初步疗效和安全性观察,且不因联合化疗而增加毒性反应,耐受性良好。     

抗表皮生长因子受体单克隆抗体——西妥昔单抗在结直肠癌治疗中的临床进展

最近,一些临床试验的结果肯定了西妥昔单抗（cetuximab）作为一种表皮生长因子受体（EGFR）单克隆抗体在结直肠肿瘤的治疗作用。本文从转移性结直肠癌治疗的角度综述西妥昔单抗这一EGFR抗体的临床观察结果,回顾分析了多篇近年发表的关于西妥昔单抗在结直肠癌和其它恶性肿瘤临床应用的文献。西妥昔单抗在转移性结直肠肿瘤的无进展生存期的延长上获得了肯定的疗效（3.9月vs2.56月,P〈0.01）。然而,在作为第二线治疗时,西妥昔单抗与依立替康的联合治疗对比依立替康单药治疗并没有使平均生存期得到延长。在副作用方面,痤疮样皮疹的严重程度可以预示肿瘤对西妥昔单抗的应答强弱,外用糖皮质激素和润肤剂可以治疗这一副作用。低镁血症是该药引起的一个比较特殊的副作用,使用静脉补镁是治疗低镁血症的有效方法。     

尼妥珠单抗联合FOLFIRI化疗治疗术后复发转移性结直肠癌的临床观察

目的：观察和评价表皮生长因子受体（EGFR）的单克隆抗体尼妥珠单抗（nimotuzumab）联合FOLFIRI化疗治疗术后复发转移性结直肠癌的近期疗效和不良反应。方法：入组患者为经手术治疗后复发转移性结直肠癌患者17例,应用尼妥珠单抗联合伊立替康＋亚叶酸钙＋氟尿嘧啶两周方案（FOLFIRI）,尼妥珠单抗剂量200mg·m-1,每2周（200mg·m-1）1次维持。治疗4个周期后评价疗效。结果：全组17例完全缓解1例,部分缓解7例,稳定7例,进展2例,总有效率47．1％。不良反应主要是恶心呕吐、骨髓抑制、迟发性腹泻、胆碱能综合征等。结论：尼妥珠单抗联合FOLFIRI化疗治疗术后复发转移性结直肠癌疗效肯定,不良反应可耐受,可供临床安全使用。     

西妥昔单抗联合化疗治疗晚期结直肠癌临床疗效观察

目的 观察西妥昔单抗联合化疗治疗晚期结直肠癌的疗效及毒副反应.方法 25例晚期结直肠癌,给予西妥昔单抗联合化疗治疗.结果 全组有效率56.0%,疾病控制率(DCR)88.0%.中位肿瘤进展时间(TTP)10.5个月.主要毒副反应为痤疮样皮疹.结论 西妥昔单抗联合化疗治疗晚期结直肠癌疗效较好,毒副反应可耐受.     

西妥昔单抗在结直肠癌中的研究与应用

结直肠癌在我国发病呈明显的上升趋势,由于其难以早期发现,患者在接受治疗时往往已经是中晚期,传统的化疗药物不能取得满意的疗效,并且毒副作用明显,患者难以耐受。分子靶向治疗药物以其低毒高效的特点在临床肿瘤治疗中发展迅速,为肿瘤患者个体化治疗开辟了新的道路。表皮生长因子受体(EGFR)在结直肠癌中高表达,它是一种跨膜酪氨酸激酶(TKs)受体,与肿瘤细胞耐药及患者预后密切相关,针对表皮生长因子受体的靶向治疗药物——西妥昔单抗的研发成功为临床结直肠癌的治疗带来了新希望。西妥昔单抗(Cetuximab)是一种嵌合型单克隆抗体,可与肿瘤细胞上的靶向表皮生长因子受体(EGFR)特异性结合,提高肿瘤对化疗的敏感性。本文将就西妥昔单抗在结直肠癌治疗中的作用进行阐述。     

新型抗肿瘤药物西妥昔单抗

西妥昔单抗(cetuximab,又名IMC-C225,Erbitux)是目前临床上最为先进的抗EGFR人/鼠嵌合单克隆抗体,它选择性地与表皮生长因子受体(EGFR)结合,在临床前试验中显示对多种肿瘤细胞株具有抗瘤活性.已被证实它对头颈部癌,非小细胞肺癌和结肠癌等多种肿瘤有效.西妥昔单抗最早在瑞士批准用于对伊立替康(irinotecan)标准疗法不再响应的结肠癌患者,2004年2月初被FDA批准上市,与伊立替康联用治疗EGFR阳性,含伊立替康方案治疗失败的转移性结直肠癌及单药用于不能耐受伊立替康的EGFR阳性晚期结直肠癌.     

西妥昔单抗联合替吉奥治疗老年转移性结直肠癌的临床观察

目的 探讨西妥昔单抗联合替吉奥治疗老年转移性结直肠癌的疗效及安全性.方法 收集一线解救化学治疗(化疗)不能耐受及拒绝一线化疗方案的32例老年患者的临床资料.按K-Ras基因表型分为联合用药组(16例),对照组(16例).联合用药组患者采用西妥昔单抗联合替吉奥方案治疗,西妥昔单抗首次剂量为400mg/m2,以后每周剂量为250mg/m2,每周1次.替吉奥根据体表面积来确定初始剂量,体表面积＜1.25 m2,40mg;体表面积1.25～1.5 m2,50mg;体表面积＞1.5m2,60mg.用法:2次/d,早饭后和晚饭后分别口服1次,连续服用14d,停药7d,3周为1个周期;对照组根据体表面积服用相应剂量的西妥昔单抗.至少给予2个周期治疗.观察疗效及不良反应.结果 联合用药组完全缓解3例(18.75％),部分缓解4例(25.00％),病情稳定5例(31.25％),病情进展4例(25.00％),有效率43.75％ (7/16),疾病控制率75.00％(12/16).对照组完全缓解3例(18.75％),部分缓解3例(18.75％),病情稳定3例(18.75％),病情进展7例(43.75％),有效率37.50％ (6/16),疾病控制率56.25％(9/16).联合用药组的疾病控制率均优于对照组,差异均有统计学意义(P＜0.05);2组有效率比较,差异无统计学意义(P＞0.05).联合用药组和对照组常见的不良反应为色素沉着、皮疹,其发生率分别为87.50％ (14/16)和56.25％(9/16),恶心呕吐的发生率分别为62.50％(10/16)和56.25％(9/16).2组不良反应发生率差异无统计学意义(P＞0.05).结论 西妥昔单抗联合替吉奥治疗老年转移性结直肠癌较对照组更有效,不良反应可耐受.     

西妥昔单抗联合NK-DC在肿瘤治疗中的研究进展

目的西妥昔单抗作为一种EGFR的单克隆抗体已广泛应用于结直肠癌、头颈部肿瘤等癌症的治疗中。最近的研究证明其对肿瘤免疫起着重要的作用,尤其是对NK和DC细胞的影响,及对NK介导的ADCC作用。本文总结了西妥昔单抗的抗肿瘤作用,及其对NK-DC的抗肿瘤作用的影响,以便未来对肿瘤过继性免疫治疗提供方案。     

比较单用FOLFIRI化疗方案及其与西妥昔单抗联用治疗晚期结肠癌的疗效

目的 比较西妥昔单抗联合FOLFIRI化疗方案(伊利替康+亚叶酸钙+5-氟尿嘧啶)与单用FOLFIR1化疗方案一线治疗晚期结肠癌的临床疗效.方法34例经组织病理学证实的晚期结肠癌患者入选治疗组.治疗组:西妥昔单抗先于化疗药物前使用,两者相隔1h以上.首次静滴西妥昔单抗400 mg·m-2,持续静滴120 min,以后每周250 mg·m-2,持续静滴60 min,共用6～12次.对照组33例,单用FOLFIRI方案进行化疗,比较2组近期疗效和安全性.结果 临床有效率2组分别为52.9％和39.3％,联合化疗方案明显优于单用化疗方案(P＜0.05).患者出现的不良反应有腹泻、骨髓抑制、恶心呕吐、肝肾功能损害、皮疹等,但2组差异无统计学意义;治疗组患者典型毒副反应是痤疮样皮疹,发生率是86.2％,2组比较有显著性差异.结论 西妥昔单抗联合FOLFIRI化疗方案治疗晚期结肠癌近期疗效显著.较单用FOLFIRI,不良反应无明显增加,患者可以耐受.     

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.

     

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.     

2-(Acetoxyphenyl)-(Z)-styryl sulfides as cyclooxygenase inhibitors

2-(Acetoxyphenyl)-(Z)-styryl sulfides are described as selective cyclooxygenase-2 (COX-2) inhibitors, useful for treating inflammation and COX-2-mediated disorders including neoplasia. 2-(Acetoxyphenyl)-(Z)-styryl sulfide is claimed to be the most potent COX inhibitor in the series with a COX-2 selectivity ratio of 33. This compound is also claimed to be superior to celecoxib (Celebrex^®, Pfizer) in inhibiting cell growth of colorectal carcinoma cells. In this evaluation, the COX inhibitory activity of this compound is compared to that previously disclosed for diarylheterocycles and 2-(acetoxyphenyl)alkyl sulfides. The validity of the DLD-1 cell line in the growth inhibition studies is questioned based on recent literature reports indicating the lack of COX-2 expression in this cell line.     

Sleep-disordered breathing with chronic opioid use

Chronic opioid use for pain relief or as substitution therapy for illicit drug abuse is prevalent in our societies. In the US, retail distribution of methadone and oxycodone has increased by 824 and 660%, respectively, between 1997 and 2003. μ-Opioids depress respiration and deaths related to illicit and non illicit chronic opioid use are not uncommon. Since 2001 there has been an emerging literature that suggests that chronic opioid use is related to central sleep apnoea of both periodic and non-periodic breathing types, and occurs in ～ 30% of these subjects. The clinical significance of these sleep-related abnormalities are unknown. This review addresses the present knowledge of control of ventilation mechanisms during wakefulness and sleep, the effects of opioids on ventilatory control mechanisms, the sleep-disordered breathing found with chronic opioid use and a discussion regarding the future research directions in this area.     

Drug targets for cognitive enhancement in neuropsychiatric disorders

The investigation of novel drug targets for treating cognitive impairments associated with neurological and psychiatric disorders remains a primary focus of study in central nervous system (CNS) research. Many promising new therapies are progressing through preclinical and clinical development, and offer the potential of improved treatment options for neurodegenerative diseases such as Alzheimer's disease (AD) as well as other disorders that have not been particularly well treated to date like the cognitive impairments associated with schizophrenia (CIAS). Among targets under investigation, cholinergic receptors have received much attention with several nicotinic agonists (α7 and α4β2) actively in clinical trials for the treatment of AD, CIAS and attention deficit hyperactivity disorder (ADHD). Both glutamatergic and serotonergic (5-HT) agonists and antagonists have profound effects on neurotransmission and improve cognitive function in preclinical experiments with animals; some of these compounds are now in proof-of-concept studies in humans. Several histamine H3 receptor antagonists are in clinical development not only for cognitive enhancement, but also for the treatment of narcolepsy and cognitive deficits due to sleep deprivation because of their expression in brain sleep centers. Compounds that dampen inhibitory tone (e.g., GABA_A α5 inverse agonists) or elevate excitatory tone (e.g., glycine transporter inhibitors) offer novel approaches for treating diseases such as schizophrenia, AD and Down syndrome. In addition to cell surface receptors, intracellular drug targets such as the phosphodiesterases (PDEs) are known to impact signaling pathways that affect long-term memory formation and working memory. Overall, there is a genuine need to treat cognitive deficits associated with many neuropsychiatric conditions as well as an increasingly aging population.