美法仑-甘草次酸复合物的合成及其体外抗肿瘤活性研究

目的设计合成美法仑–甘草次酸复合物,并对其体内外抗肿瘤活性进行研究。方法以美法仑和18α-甘草次酸为原料,通过酯化、氧化、酰化和缩合反应制备目标化合物3a和3b,结构经元素分析、MS、1H-NMR确证,并采用MTT法对其体外抗肿瘤活性进行研究,同时考察了其对正常大鼠肝细胞BRL和小鼠成纤维细胞L929的细胞毒性。结果目标化合物3a、3b的体外抗肿瘤活性明显优于母体药物18α-甘草次酸和美法仑,且对正常细胞的毒性小于氮芥类药物美法仑。结论美法仑–甘草次酸复合物3a和3b抗肿瘤活性良好,具有开发成抗肿瘤候选药物的前景。     

美法仑衍生物的合成及其抗肿瘤活性研究

目的以苦参碱和18α-甘草次酸作为载体对美法仑进行结构拼合,并对其体内外抗肿瘤活性进行研究。方法以槐果碱和美法仑为原料,经过加成、酰化反应合成了美法仑衍生物2;以18α-甘草次酸和美法仑为原料,经酯化和酰化反应合成了美法仑衍生物5,目标化合物的结构经元素分析、MS、1H-NMR确证,并采用MTT法对其进行体外抗肿瘤活性研究,对体外活性较为显著的化合物2进行小鼠体内试验。结果目标化合物2和5的合成总收率分别为21.3%、18.1%。目标化合物2的体外抗肿瘤活性明显高于化合物5、18α-甘草次酸、苦参碱和美法仑。体内活性试验中,目标化合物2给药剂量为6、9μmol/kg时对Hep A肿瘤的抑瘤率分别为52.00%、62.12%,而6μmol/kg美法仑的抑制率为39.93%,化合物2的抑瘤效果优于美法仑,尤以高剂量效果最为明显。结论化合物2表现出体外、体内较高的抗肿瘤活性,值得进一步研究。     

甘草次酸-苦参碱复合物的合成及其抗肿瘤活性研究

目的：设计合成甘草次酸–苦参碱复合物,并对其体外抗肿瘤活性进行研究。方法以槐果碱、18α-甘草次酸和18β-甘草次酸为原料,经过加成、氧化、酯化缩合等反应合成目标化合物甘草次酸–苦参碱复合物,并采用MTT法对其进行体外抗肿瘤活性研究。结果设计并合成了目标产物甘草次酸–苦参碱复合物,利用MS和1H-NMR确证了结构;体外活性实验中,甘草次酸–苦参碱复合物的抗肿瘤活性明显高于甘草次酸及苦参碱,并优于对照药美法仑。结论甘草次酸–苦参碱复合物具有良好的抗肿瘤活性,尤其对肝癌细胞生长产生较好的抑制作用,值得进一步进行研究。     

新型酯类苦参碱衍生物的合成与体外抗肿瘤活性

目的:合成苦参碱衍生物并研究其体外抗肿瘤活性。方法:以槐果碱为原料,设计合成了12个酯类衍生物,采用MTT法测试所合成化合物的体外抗肿瘤活性。结果:目标化合物结构经元素分析、1H-NMR和MS确证。体外抗肿瘤结果显示,化合物3 l的活性优于参照药物美法仑,3 f～k的活性弱于美法仑但优于苦参碱,3a～e没有生物活性。结论:苯环和氮芥基团的引入可使苦参碱抗肿瘤活性增强。     

头孢妥仑匹酯片微生物限度检查方法的研究

目的:建立头孢妥仑匹酯片的微生物限度检查方法。方法:按《中国药典》2015版四部通则1105和1106,对头孢妥仑匹酯片进行微生物限度方法学适用性试验。结果:头孢妥仑匹酯片具有较强的抗菌活性,以pH 7.0无菌氯化钠-蛋白胨缓冲液(含0.1%卵磷脂以及0.7%聚山梨酯80)为稀释液,将供试品稀释成1∶20的供试液,静置沉淀,并采用薄膜过滤法和中和法结合(200 mL稀释,冲洗量每膜800 mL),加入头孢菌素酶,可消除其抑菌活性。结论:采用薄膜过滤法和中和法相结合,并在培养基中加入中和剂的方法可用于头孢妥仑匹酯片的微生物限度检查。     

国内对头孢克肟的临床研究与评价

头孢克肟是第1种第3代口服头孢菌素类抗生素,由日本藤泽制药株式会社于1987年研制成功并首先在日本上市应用于临床,1989年在美国上市。1999年已在80多个国家得到广泛的临床使用。头孢克肟的制剂剂型的研究已发展有胶囊剂、颗粒剂、混悬剂、片剂(普通片剂、咀嚼片、分散片)等。笔者综述了国产头孢克肟与日本产头孢克肟在胶囊剂、颗粒剂、混悬剂、片剂(普通片剂、咀嚼片、分散片)等的药动学比较,以及头孢克肟与头孢泊肟、头孢克洛、头孢呋辛、头孢美他酯、头孢噻肟、头孢地尼、头孢特仑、头孢妥仑匹酯等体外抗菌活性及临床药效学比较。     

一种新型的HA载药系统药物释放度的测定

目的:设计一种新型的透明质酸(HA)靶向载药系统,为开发治疗卵巢癌的美法仑靶向制剂奠定基础。方法:用活化的聚乙二醇对HA进行修饰后作为载体,与抗肿瘤药美法仑键合形成前药,再自组装成纳米胶束给药系统,并用高效液相法(HPLC)测定药物在模拟人体环境条件下的释药情况。结果:pH值会显著影响药物的累计释放量,P0.05;取样量对给药体系的累计释放量没有显著性影响,P0.05。结论:pH影响透明质酸酶的活性,所以会对药物的释放度带来影响。而取样量的对释放度没有显著性影响。     

头孢他美的体内外抗菌活性

测定头孢他美对临床分离菌株 (包括革兰氏阳性菌、革兰氏阴性菌 )的体内、体外抗菌活性 ,同时测定了头孢他美对产 β-内酰胺酶菌株的最低抑菌浓度及它对 β-内酰胺酶的稳定性。并与头孢噻肟、头孢哌酮、头孢呋辛、头孢曲松等 4个头孢菌素做了比较。结果表明头孢他美具有和它们相似的抗菌活性 ,而且具有很强的β-内酰胺酶稳定性。     

苦参碱-美法仑复合物MAT-MEL的合成及其体内外抗肿瘤活性的研究

目的 制备苦参碱-美法仑复合物(MAT-MEL),测定其抗肿瘤活性.方法 以槐果碱和美法仑为原料,利用拼合原理制备MAT-MEL;采用MTT法在体外测定复合物对人乳腺癌MCF-7细胞、人肝癌SMMC-7721细胞及小鼠骨肉瘤S180细胞的生长抑制作用;采用S180小鼠移植肿瘤模型评价复合物的体内抗肿瘤活性.结果 MAT-MEL的收率为61％,其结构通过核磁、质谱和元素分析得到确证;对3种细胞株的IC50分别为116.7±27.8、56.3±19.5、1.9±1.0 nmol· mL-1;3、6、9 μmol·kg-1的复合物对小鼠S180的抑瘤率分别为49.56％、54.58％、77.18％.结论 MAT-MEL具有显著的抗肿瘤活性.     

盐酸头孢他美酯中间体的合成

目的：通过设计出最佳工艺条件,提高产品质量．收率。方法：通过对头孢母核7-氨基-3-甲基-3-头孢烯-4-羧酸(7-ADCA)上7号位置上氨基侧链的改造,得到具有药用活性物质盐酸头孢他美酯的重要中间体——头孢他美酸。结果：经溶媒法析结晶并养晶后,将湿品减压干燥,得到质量、收率较好的头孢他美酸。结论：该工艺是合成盐酸头孢他美酯的重要中间体——头孢他美酸的较佳工艺,适合工业化规模生产。     

Synergistic combination of menogarol and melphalan and other two drug combinations

Summary Menogarol is a new anthracycline undergoing phase I clinical trial. We report here the lethality after 2 hr exposure to 2 drug combinations of menogarol and several antitumor agents. A new statistical procedure was used to identify synergistic combinations. Most of these combinations were additive, except for menogarol plus melphalan, which was synergistic. Adriamycin plus melphalan was also synergistic. The menogarol-melphalan combination was studied in detail with regard to the effect of dose and drug-schedule, lethality for exponential and plateau phase cells and effect on cell cycle progression. Although the combination was synergistic for exponential cells it was additive for plateau phase cells. The combination exerted a synergistic effect in inhibiting progression of cells through the cell cycle. After 2 hr menogarol exposure cells were blocked in G₂ for about 12 hr following which the block was reversed. This reversal was inhibited when menogarol was combined with melphalan. The uptake of menogarol or melphalan was not changed in the presence of the other drug.     

The NK₁ receptor antagonist aprepitant does not alter the pharmacokinetics of high-dose melphalan chemotherapy in patients with multiple myeloma

AIMS

The objective of this investigation was to assess the effect of aprepitant on the pharmacokinetics of high-dose melphalan used as conditioning therapy before blood stem cell transplantation in multiple myeloma.

METHODS

Aprepitant (125 mg) or placebo was administered 1 h before melphalan therapy (1 h infusion of 100 mg m⁻²). Eleven plasma samples were obtained over 8 h and melphalan was quantified using an LC/MS/MS method. Standard pharmacokinetic parameters were calculated and nonparametric testing was applied to assess the differences between aprepitant and placebo treatment.

RESULTS

Twenty patients received placebo and 10 patients aprepitant treatment. There were no differences observed for C_max at the end of melphalan infusion (placebo 3431 ± 608 ng ml⁻¹vs. aprepitant 3269 ± 660 ng ml⁻¹). In addition, AUC and terminal elimination half-life were not changed by aprepitant. Total clearance of melphalan was 304 ± 58 ml min⁻¹ m⁻² (placebo) which was not influenced by aprepitant (288 ± 78 ml min⁻¹ m⁻²).

CONCLUSIONS

The administration of the NK₁ receptor antagonist aprepitant 1 h before a high-dose chemotherapy does not influence the exposure and the elimination of melphalan. Therefore, oral administration of 125 mg aprepitant 1 h before melphalan infusion does not alter the disposition of intravenously administered melphalan.     

Preparation and biodistribution of [125I]Melphalan: a potential radioligand for diagnostic and therapeutic applications

This paper addresses the development of a new radiopharmaceutical for cancer imaging and therapy. The optimization of the labeling conditions of thymidine analogue, melphalan, with¹²⁵I is described. High radiochemical yield 96.8% was obtained by reacting 0.2 mg melphalan with ¹²⁵I in the presence of choloramin‐T as oxidizing agent in 0.5 M phosphate buffer, pH 7, at 70°C for 15 min. Preliminary in vivo study was done in non‐tumor bearing mice. The results revealed that this new tracer,¹²⁵I‐melphalan, has a high affinity to be localized in the tumor site for a long period, which indicates the specificity of this tracer to the tumor cells. The labeled compound was cleared quickly from most of the body organs. These findings suggest that ¹²⁵I‐melphalan allows imaging and treatment of cancer. ¹²⁵I‐melphalan meets most of the requirements necessary to be used as a successful diagnostic and therapeutic agent: it is a low‐molecular‐weight molecule that diffuses readily in the tissues, and dose not induce an antibody response. Copyright © 2009 John Wiley & Sons, Ltd.     

The pharmacokinetics of melphalan during intermittent therapy of multiple myeloma

Summary During intermittent melphalan-prednisone therapy the area under the plasma concentration-time curve of melphalan increased by an average of 45% after oral or intravenous administration of the drug in myeloma patients during the initial three courses at six-week intervals.The rise in melphalan plasma concentrations could not be referred to an alteration in melphalan elimination, metabolism, erythrocyte/plasma partition ratio, or protein binding.A possible explanation could be that covalent binding sites of melphalan were successively saturated during intermittent treatment, resulting in higher drug concentrations during successive courses of therapy.     

Population pharmacokinetics of melphalan in paediatric blood or marrow transplant recipients

AIM: To develop a population pharmacokinetic model for melphalan in children with malignant diseases and to evaluate limited sampling strategies for melphalan. METHODS: Melphalan concentration data following a single intravenous dose were collected from 59 children with malignant diseases aged between 0.3 and 18 years. The data were split into two sets: the model development dataset (39 children, 571 concentration observations) and the model validation dataset (20 children, 277 concentration observations). Population pharmacokinetic modelling was performed with the NONMEM software. Stepwise multiple linear regression was used to develop a limited sampling model for melphalan. RESULTS: A two-compartment model was fitted to the concentration-vs.-time data. The following covariate population pharmacokinetic models were obtained: (i) Clearance (l h(-1)) = 0.34.WT - 3.17.CPT + 0.0377.GFR, where WT = weight (kg), CPT = prior carboplatin therapy (0 = no, 1 = yes), and GFR = glomerular filtration rate (ml min(-1) 1.73 m(-2)); (ii) Volume of distribution (l) = 1.12 + 0.178.WT. Interpatient variability (coefficient of variation) was 27.3% for clearance and 33.8% for volume of distribution. There was insignificant bias and imprecision between observed and model-predicted melphalan concentrations in the validation dataset. A three-sample limited sampling model was developed which adequately predicted the area under the concentration-time curve (AUC) in the development and validation datasets. CONCLUSIONS: A population pharmacokinetic model for melphalan has been developed and validated and may now be used in conjunction with pharmacodynamic data to develop safe and effective dosing guidelines in children with malignant diseases.     

Concentration profile for the dissolution of drug tablets undergoing simultaneous degradation

An empirical approach to the concentration-time history of a dissolving drug has resulted in a cube-root equation in which the characteristic constant of the equation embodies the important physical variables of the system. This expression has been used to study the dissolution of a drug that degrades simultaneously in the test solution. An alternative representation of the dissolution process is first-order kinetics. These two approaches are compared by fitting the experimental data of the dissolution of digoxin and melphalan tablets in various media, and a new method for the proper analysis of data for the dissolution of tablets that simultaneously degrade in the test solution is presented.This work was supported by Grant CA-17094 from the National Cancer Institute, and a donation by Burroughs Wellcome Company, Research Triangle Park, North Carolina.     

Cytotoxic effects of glutathione synthesis inhibition by L-buthionine-(SR)-sulfoximine on human and murine tumor cells

The glutathione (GSH) synthesis inhibitor, buthionine sulfoximine (BSO) was tested for cytotoxicity and thiol depletion in murine and human tumor cells in vitro, and for its antitumor activity and toxicity in vivo. The cell lines used in these studies included murine L-1210 leukemia, human RPMI 8226 myeloma, MCF-7 breast cancer and WiDr colon carcinoma. Soft agar colony forming assays showed that BSO was most effective at reducing tumor colony formation when exposed continuously to cells in vitro. Drug concentrations which inhibited colony formation to 50% of control levels ranged from 2.0–6.2 mM (for 1 hour exposures), 2–100 mM for 24 hour exposures and 0.4–1.40 M (for continuous BSO exposures). Human myeloma cells proved most sensitive to BSO. In vitro cytotoxicity correlated with depletion of intracellular nonprotein sulfhydryls to 10% of control values in both L-1210 and 8226 cells. This was routinely achieved with prolonged exposures to mM BSO concentrations for > 24 hours. Normal mice tolerated high BSO doses (up to 5.0 g/kg) without evidence of acute toxicity. BSO was not active against L-1210 leukemia-bearing DBA/2 mice. When tested in vivo against MOPC-315 plasmacytoma-bearing BALB/c mice, BSO was not active at doses up to 4.0 g/kg. In contrast, the bifunctional alkylating agent melphalan (L-PAM) was active against MOPC-315 and this activity was enhanced by a 24 hour pretreatment of mice with 50 mg/kg of L-BSO. This BSO dose was shown to significantly reduce sulfhydryl levels in the liver (50% of control) and kidney (20% of control) but not in the bone marrow (100% of control). The enhancement by BSO was most significant only for the lower doses of L-PAM tested. These results suggest that BSO may not have direct antitumor activity, but that it can enhance cytotoxicity from a classic alkylating agent in vivo. Due to its low toxicity, BSO should be tested in combination with either anticancer agents which are dependent on (GSH) for detoxification and potential drug resistance.     

Strain differences influence timing and magnitude of both acute and late inflammatory reactions after intratracheal instillation of an alkylating agent in rats

The acute pulmonary responses after exposure to sulfur and nitrogen mustards are well documented whereas the late pulmonary effects are not. With a novel focus on the immune system this paper investigate whether late phase pulmonary effects developed in rats exposed to the nitrogen mustard melphalan are linked to the acute responses and whether the reactions are genetically regulated. The DA rat strain was used to establish a lung exposure model. Five other inbred rat strains (PVG, PVG.1AV1, LEW, WF and F344) were compared within the model at selected time points. All rat strains displayed a biphasic pattern of leukocyte infiltration in the lungs, dominated by neutrophils 2 days after exposure and a second peak dominated by macrophages 29 days after exposure. The number of macrophages was higher in the DA rat compared with the other strains. The infiltration of lymphocytes in the lungs varied in both time of appearance and magnitude between strains. The quantity of collagen deposition in the lungs varied between strains at day 90; LEW and WF displayed high collagen content which coincided with an increased level of cytotoxic T cells. LEW further displayed an increased number of T helper cells and natural killer (NK) T cells in the lungs. The results in this study suggest there is a link between the development of lung fibrosis and high cytotoxic cell responses and that there is a genetic influence, as there are variations in acute and late adverse reactions between rat strains in both timing and magnitude. Copyright © 2013 John Wiley & Sons, Ltd.