铂类抗癌药物的发展历程

铂类抗癌药物是当今肿瘤化疗的基石。本文简要介绍已经上市的几个铂类抗癌药物的研发历史。     

铂类抗肿瘤药物的研发进展及市场情况

近年来,铂类抗肿瘤药物的临床研究进展较快,其抗肿瘤谱广,抗肿瘤活性增强,不良反应降低,已成为目前有关抗肿瘤药物研发的重要领域。新的铂类抗肿瘤药物将从那些在临床研究中显示出低毒性、抗肿瘤谱广、与现有药物无交叉耐药性的化合物中产生。本文就其作用机制、国内外上市开发现状、国内外销售情况及国内研究开发进展等进行综述。     

奈达铂与其他铂类制剂药物不良反应的临床比较研究

目的 调查分析奈达铂和其它铂类制剂药物不良反应(Adverse Drug Reaction,ADR)发生情况,为临床选用铂类制剂和预防铂类制剂ADR提供参考.方法 随机抽取2009年1月～2010年12月间使用铂类制剂病例共224例,其中使用奈达铂112例,其它铂类制剂(包括顺铂、卡铂、奥沙利铂,按4∶2∶4抽取)112例为对照组,采用回顾性分析方法进行统计.结果 奈达铂和其它铂类制剂组ADR发生率分别为62.5％,66.07％,无明显统计学意义,其中骨髓抑制奈达铂发生率高于其他铂类制剂,有统计学意义(P＜0.05),肝肾功能损害发生率明显低于其他铂类制剂(P＜0.05).约95％ADR能治愈；约65％ADR为严重级；ADR男女发生率分别为61.81％、38.19％,有统计学意义,ADR发生年龄主要为58- 72岁患者.结论 奈达铂发生骨髓抑制高于其他铂类制剂,而对肝肾功能损害比其他铂类制剂低.     

铂类抗肿瘤药物的应用现状及合理性探析

目的 研究铂类抗肿瘤药物实际应用现状与应用合理性分布情况。方法 在本院药学部抗肿瘤药物应用记录表中选出13 400份铂类抗肿瘤药物处方,选定时间为2021年1月至2022年1月,比较铂类抗肿瘤药物的处方使用量、销售金额、用药期间不良反应发生率与不合理用药行为占比率。结果 13 400份铂类抗肿瘤药物处方中奥沙利铂处方占比率60.07%,奈达铂20.90%,顺铂11.19%,卡铂7.88%;销售金额奥沙利铂最高,卡铂药物每日规定剂量最多为200 mg/m²;其中150例奈达铂药物使用者不良反应率33.33%,奥沙利铂3.33%,不良反应率数据有统计学意义(P <0.05)。4种常用铂类药物不合理用药率均低于1%。结论 铂类抗肿瘤药物实际应用中奥沙利铂、奈达铂、顺铂与卡铂药物的使用量较大,奥沙利铂销售总金额最高,奈达铂易出现不良反应,需在药物应用环节严控用药合理性,加强不良反应监督,充分展现药效。     

顺铂注射液有关物质的检测

本文采用《中国药典》1990年版顺铂项下的方法检测顺铂注射液有关物质，结果满意，各物质的Rf值分别为：顺铂0．62，反铂0．81，三氯氨铂0.92，水合铂0．0。杂质的最小检出限：反铂、三氯氨铂为0.1μg，水合铂为0．05μg。方法分离度好，灵敏度高，能满足顺铂注射液质量检测的要求。     

新铂类药物双环铂与顺铂、卡铂体内毒性的比较研究

目的:比较新铂类药物双环铂与顺铂、卡铂的体内毒性.方法:大鼠重复静脉注射双环铂、顺铂与卡铂,分别于给药结束以及恢复期末收集标本,进行血液学、血尿生化指标及病理切片的检测.结果:与溶剂对照组比较,重复静脉注射后,双环铂的高剂量组(13.89 mg·kg-1)全血网织红细胞以及红细胞明显降低(P＜0.01),骨髓切片示有核细胞显著减少;恢复期末网织红细胞和骨髓切片基本恢复至正常,而红细胞仍维持较低水平(P＜0.05).而双环铂各组尿酶、血尿素氮和肌苷以及肾脏病理切片在给药结束和恢复期均未见明显改变.结论:双环铂对SD大鼠的肾毒性明显低于顺铂,其骨髓抑制作用与卡铂相近,暗示肾毒性可能不会成为限制双环铂临床应用的主要毒副反应,临床应用需密切观察其对造血组织的损伤.     

赛特铂抗肿瘤作用的临床前观察

目的观察赛特铂临床前抗肿瘤作用.方法体外观察赛特铂对人卵巢癌细胞A2780,肺腺癌细胞A549,结肠癌细胞HCT8,乳腺癌细胞MCF7和前列腺癌细胞DU145等10株人肿瘤细胞的细胞毒作用.体内观察赛特铂对人卵巢癌A2780,小鼠肉瘤S180和小鼠肝癌HepS的生长抑制作用.结果赛特铂的体外体内作用强度与对照药顺铂相当.对10种肿瘤细胞的半数抑制浓度IC50为0.51～3.29μmol·L-1,平均IC50为(1.44±0.32)μmo1·L-1;体内口服给药明显抑制裸鼠人卵巢癌A2780,小鼠肉瘤S180和小鼠肝癌HepS的生长,抑制率分别为61.3%,57.9%和50.6%.结论赛特铂的体外细胞毒和体内口服抗小鼠肿瘤生长抑制作用均与顺铂相仿.     

吉西他滨联合铂类治疗卵巢癌的研究进展

吉西他滨(gemcitabine,GEM)是嘧啶类抗肿瘤药物,已广泛用于实体瘤的治疗,在卵巢癌治疗中,吉西他滨单药或铂类联合方案,是晚期复发转移卵巢癌的标准方案之一.另有临床研究显示,吉西他滨与铂类联用可作为卵巢癌的一线治疗方案.本文简要介绍了吉西他滨联合铂类治疗卵巢癌的相关信息.     

Protective effect of resveratrol against 6-hydroxydopamine-induced impairment of renal<Emphasis Type="Italic"> p</Emphasis>-aminohippurate transport

In the present study, the effects of resveratrol on 6-hydroxydopamine (6-OHDA)-induced p-aminohippurate (PAH) transport impairment were investigated in vitro using rat renal cortical slices. Cisplatin and cephaloridine (CPH), known nephrotoxins, were used as positive controls. In one series of experiments, renal cortical slices were incubated in a cisplatin-containing medium or a cisplatin-free medium. In another series of experiments, renal cortical slices were incubated in a CPH-containing medium, in a CPH- and probenecid-containing medium, or in a CPH-free medium. Subsequently, for each series of experiments kidney slices were incubated in a media containing PAH or tetraethylammonium. In a further series of experiments, renal cortical slices were incubated in a 6-OHDA-containing medium and in a 6-OHDA-free medium. In another series of experiments, renal cortical slices were incubated in a medium containing 50 µM 6-OHDA, in a 6-OHDA- and resveratrol-containing medium or in a 6-OHDA- and resveratrol-free medium. Subsequently, for each series of experiments kidney slices were incubated in media containing PAH. The results of this study in which slices were incubated in 6-OHDA-containing media indicate that 6-OHDA induced a time- and concentration-dependent decrease in PAH accumulation by renal cortical slices. Resveratrol inhibited the 6-OHDA-induced time-dependent decrease of PAH accumulation in a concentration-dependent manner. Therefore, 6-OHDA causes functional injuries of renal proximal tubule cell membrane, thus leading to impairment of transport processes across the cell membrane and to nephrotoxicity. Resveratrol has a nephroprotective effect.     

Discovery and Development of LX7101, a Dual LIM-Kinase and ROCK Inhibitor for the Treatment of Glaucoma

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Hematological parameters in tench Tinca tinca after short term exposure to lead

Alterations in the hematological parameters of Tinca tinca were studied after exposure to lead at different concentrations and durations of exposure. Dose of 75/24 (ppm/h) did not cause significant change in any blood parameter. The 300/48 dose caused a significant increase in hematocrit (Hct), mean corpuscular volume (MCV) and mean corpuscular hemoglobin (MCH) and a significant decrease in red blood cell (RBC) count and mean corpuscular hemoglobin concentration (MCHC). The 30/24 dose caused a significant increase in Hct and RBC count only. The 30/96 dose caused a significant increase in Hct and a significant decrease in MCHC only. The 30/504 dose caused a significant decrease in RBC count and a significant increase in MCV and MCH. The 75/96 dose caused a significant increase in Hct and a significant decrease in MCH and MCHC. The 75/504 dose caused a significant decrease in Hct, hemoglobin (Hb) and RBC count, and a significant increase in MCV and MCH. These alterations were attributed to direct or feedback responses of structural damage to RBC membranes resulting in hemolysis and impairment in hemoglobin synthesis, stress related release of RBCs from the spleen and hypoxia, induced by exposure to lead.     

Spirituality,Intoxication and Addiction: Six Forms of Relationship

The paper considers six connections between spirituality and intoxication or addiction. They are: intoxication as a means of communication with a spiritual world; intoxication as destroying spirituality; shared use and intoxication as creating and validating community; spirituality and religion as a means of collective sobering-up; spirituality in individual sobering up; and abstinence as a spiritual practice, a witness, or a badge of membership in a spiritual community. Intoxication can either enhance or impede spirituality, both at individual and collective levels. Spirituality is often important in sobering up, both individually and collectively, and abstinence is a part of spiritual or religious practice in some traditions. But a full account must acknowledge the diversity in the interactions of spirituality and intoxication or addiction.     

Development of a method for clinical medication review by a pharmacist in general practice

Medication review of patients on long-term treatment in general practice in the UK has been reported to be inadequate. Proposals followed suggesting that pharmacists could use their expertise to lead such a medication review in conjunction with the general practitioner. This paper describes the concept of clinical medication review by a pharmacist based in general practice. We describe the development of a method for a structured and systematic process for undertaking such a review in clinics conducted by a pharmacist. The method was developed for a nationally funded study in the UK. We provide a definition of clinical medication review and suggests a structure for the process through data gathering, evaluation and implementation.     

Quantitative decision-making in randomized Phase II studies with a time-to-event endpoint

One of the most critical decision points in clinical development is Go/No-Go decision-making after a proof-of-concept study. Traditional decision-making relies on a formal hypothesis testing with control of type I and type II error rates, which is limited by assessing the strength of efficacy evidence in a small isolated trial. In this article, we propose a quantitative Bayesian/frequentist decision framework for Go/No-Go criteria and sample size evaluation in Phase II randomized studies with a time-to-event endpoint. By taking the uncertainty of treatment effect into consideration, we propose an integrated quantitative approach for a program when both the Phase II and Phase III trials share a common endpoint while allowing a discount of the observed Phase II data. Our results confirm the argument that an increase in the sample size of a Phase II trial will result in greater increase in the probability of success of a Phase III trial than increasing the Phase III trial sample size by equal amount. We illustrate the steps in quantitative decision-making with a real example of a randomized Phase II study in metastatic pancreatic cancer.     

Synthesis of 3- or 4-phenyl-1,8-naphthyridine derivatives and evaluation of antimycobacterial and antimicrobial activity

A series of 3- or 4-phenyl-1,8-naphthyridine derivatives variously substituted in the positions 2, 6 and 7 were synthesized and evaluated for in vitro evaluation for their antimycobacterial activity as part of a TAACF TB screening program under the direction of the US National Institute of Health, NIAID division. Several compounds showed an interesting activity when tested at a concentration of 6.25 microg/ml against Mycobacterium tuberculosis H(37)Rv and in particular compounds 2a, 4a,d, 8a,d and 8i, exhibit a % inhibition from 91 to 99. Among these, compounds 2a, 8a and 8d appeared to have a good activity with minimum inhibitory concentrations (MICs) of 6.25 microg/ml. On the basis of the biological results, the most effective substituent in position 2 or 7 seems to be the piperidinyl group. The introduction of a morpholinyl group either in position 2 or 7 of the heterocycle ring caused a decrease in activity. The 1,8-naphthyridine derivatives were also tested in vitro for their antimicrobial activity against Staphylococcus aureus as Gram-positive bacteria and Escherichia coli as Gram-negative bacteria.     

Hormonal regulation of Cyp4a isoforms in mouse liver and kidney

Abstract

1. Mouse Cyp4a subfamily, including Cyp4a10, Cyp4a12a, Cyp4a12b and Cyp4a14, demonstrate a gender- and strain-specific expression in liver and kidney. In C57BL/6 mouse liver and kidney, Cyp4a12a and 4a12b are male-predominant, whereas Cyp4a14 is female-predominant. Cyp4a10 is female-predominant in liver, but shows no gender difference in kidney.

2. The present study was aimed to determine whether sex hormones and/or growth hormone (GH) secretion patterns are responsible for the gender-specific Cyp4a expression in C57BL/6 mice. Gonadectomized mice, GH-releasing hormone receptor-deficient little (lit/lit) mice and hypophysectomized mice were used with replacement of sex hormones or GH in male or female secretion patterns. Both androgens and male-pattern GH regulated the gender-divergent Cyp4a10, 4a12a and 4a12b in liver, whereas androgens played an exclusive role in regulating Cyp4a10 and 4a12a in kidney. In contrast, Cyp4a12b was increased by male-pattern GH but not androgens in kidney.

3. The female-predominant Cyp4a14 in liver and kidney was due to a combined effect of male-pattern GH and androgens. In addition, estrogens played a minor role in regulation of Cyp4a isoforms through an indirect pathway.

4. In conclusion, gender-divergent Cyp4a mRNA expression in liver is caused by male-pattern GH secretion pattern and androgens, whereas in kidney, Cyp4a mRNA expression is primarily regulated by androgens.     

Cyp1a1(-/-) male mice: protection against high-dose TCDD-induced lethality and wasting syndrome, and resistance to intrahepatocyte lipid accumulation and uroporphyria

To study liver toxicity and uroporphyrin (URO) accumulation and urinary excretion, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), a potent ligand for the aryl hydrocarbon receptor (AHR), is often used as the prototype. In this study, we asked the question how important is the role of CYP1A1 in causing TCDD toxicity. Using a single large intraperitoneal dose of TCDD (200 microg/kg) and following the response over an 8-week period, we found this dose: (a) was lethal in less than 4 weeks to Cyp1a1(+/+) males but not to Cyp1a1(-/-) males or to females of either genotype; (b) caused a wasting syndrome in Cyp1a1(+/+) but not Cyp1a1(-/-) mice; (c) resulted in thymic atrophy, regardless of gender or genotype; (d) decreased spleen size and caused leukocytopenia in males but not females of either genotype; (e) caused hepatocyte hypertrophy in Cyp1a1(+/+) more so than in Cyp1a1(-/-) mice; (f) increased intrahepatocyte lipids and total liver fat content in Cyp1a1(+/+) more than Cyp1a1(-/-) males and females; and (g) caused uroporphyria in Cyp1a1(+/+) males much more than Cyp1a1(+/+) females, or in Cyp1a1(-/-) mice. Contrary to Cyp1a2(-/-) knockout mice that exhibited 15 times less accumulation of TCDD in liver than Cyp1a1/1a2(+/+) wild-type mice, Cyp1a1(-/-) mice did not show this altered TCDD distribution-indicating that CYP1A2 but not CYP1A1 is the major hepatic TCDD-binding "sink". Our data demonstrate that CYP1A1 contributes to high-dose TCDD-induced toxicity, uroporphyria, and lethality.     

Kinetics and Mechanism of Zinc Ion-Mediated Degradation of Cephalosporins in Tromethamine Solution

Earlier studies of the hydrolysis and aminolysis of penicillin, in the presence of zinc ion and tromethamine (Tris), revealed a very rapid catalysis mediated by a ternary complex in which the metal ion brought the reactants into close proximity in a suitable configuration for reaction. In the present work similar studies with a group of cephalosporins show not only much slower rates of reaction but a different mechanism in which the zinc ion–tromethamine complex functions as a nucleophile in a bimolecular reaction. Evidence for the differences in mechanism includes not only the different dependence of rate upon tromethamine concentration, but comparable rates of reaction of methyl esters of a penicillin and a cephalosporin and the reaction products observed by high-performance liquid chromatography.