多聚N-（2-羟丙基）甲基丙烯酰胺-抗肿瘤药物偶合物的组成和应用研究进展

多聚N-（2-羟丙基）甲基丙烯酰胺（HPMA）-抗肿瘤药物偶合物可通过靶向分子及肿瘤细胞的增强渗透和滞留效应实现药物的靶向治疗,显著减少传统药物全身毒副作用,以其独特的优势成为目前抗肿瘤药物的研究热点之一。本文对多聚HPMA-抗肿瘤药物偶合物的组成及近几年来的临床前和临床应用研究现状和前景进行综述。     

多聚N-（2-羟丙基）甲基丙烯酰胺-抗肿瘤药物偶合物的研究进展

大分子聚合物-抗肿瘤药物偶合物能利用增强渗透和滞留效应将抗肿瘤药物-偶合物选择性投放于肿瘤组织,从而提高抗肿瘤药物在肿瘤组织的浓度,减少药物的系统毒性。多聚N-（2-羟丙基）甲基丙烯酰胺（HPMA）作为大分子载体具有许多优点,如生物相容性、非免疫原性等,因此多聚HPMA-抗肿瘤药物偶合物成为当前大分子靶向抗肿瘤药物研究的热点之一。目前进入临床的偶合物有6种,还有许多处于临床前研究。本文综述多聚HPMA-抗肿瘤药物偶合物研究的进展。     

抗体导向药物的研究——Ⅰ.以多聚谷氨酸为中介载体的抗体药物偶合物的制备

本文以多聚-L-谷氨酸(PLGA)为中介载体,将抗肿瘤药物丝裂霉素C、柔红霉素及阿霉素分别与抗胃癌单克隆抗体MGb_2偶联,研制抗体导向偶合物。为了避免多聚物的形成,我们采用了一种反应选择性的交联策略。首先于PLGA分子中引入一定数目的保护性巯基,制备PLGA衍生物(Ⅰ);在碳二亚胺作用下,丝裂霉素C、柔红霉素或阿霉素与(Ⅰ)缩合,得药物-PLGA缩合物(Ⅱ);然后以二硫苏糖醇还原脱保护,即得巯基化的药物-PLGA缩合物(Ⅲ);相应地,制备马来酰亚胺取代的抗体衍生物(Ⅳ);最后,(Ⅲ)分子中的巯基与(Ⅳ)分子中的马来酰亚胺基的双键进行反应,形成以硫醚键交联的抗体导向偶合物R-NH-PLGA-S-MGb_2(Ⅴ_(1～3))。     

以氨基酸为连接子的吉西他滨-聚谷氨酸偶合物设计、合成及评价

目的设计、合成抗肿瘤药物吉西他滨与聚谷氨酸的偶合物,通过调节连接子的结构以控制药物的释放,提高抗肿瘤药物的疗效。方法首先合成吉西他滨3′-或5′-的氨基酸酯衍生物,然后在DCC作用下,氨基酸的氨基与聚谷氨酸分子中的羧基缩合,得到以氨基酸为连接子的吉西他滨-聚谷氨酸偶合物;用紫外法测定偶合物载药量;用HPLC法测定偶合物在水溶液或血浆中的稳定性。结果与结论共合成目标化合物11个,载药量为25%~30%。稳定性试验结果表明,偶合物在水溶性或血浆中能够稳定地释放游离药物,氨基酸类型及连接位置可影响药物的释放速率,偶合物PG-Ala-3′-Gem的释放速率最快,4h释放50%的药物,而PG-Val-3′-Gem和PG-Ala-5′-Gem在48h分别释放30.3%和43.5%;偶合物在血浆中的释放速率略快于水溶液中的释放速率。     

抗抑郁药物的研究进展

目的:对临床上使用的及临床试验中的抗抑郁药物进行分析和总结,拟为今后新型抗抑郁药物的研发提供参考。方法:通过查阅近年的文献,将抗抑郁药物按照机制进行归纳和整理。结果:从第一代的三环类、单胺氧化酶抑制剂类抗抑郁药物,到第二代的基于单胺类神经递质及相应受体所研发的药物,之前的研发集中在调节单胺类神经递质的摄取和释放方面。而随着氯胺酮等快速起效的抗抑郁药物的发现,新的靶点,比如谷氨酸神经递质及相关通路成为研究的热点。结论:抗抑郁药物的发展仍会遵循着单胺类的策略,但是靶向谷氨酸神经递质系统的药物及联合用药是新的发展趋势。     

阴离子多聚物类杀微生物剂的研究进展

目的:概括阴离子多聚物作为Ⅰ型人类免疫缺陷病毒(HIV-1)感染抑制剂的兴衰历程,为未来更合理使用此类化合物以及杀微生物剂的研发提供参考。方法:查阅国内外文献,进行全面综合、整理和归纳,对阴离子多聚物类化合物作为抗病毒药物的应用进行综述。结果:阴离子多聚物类候选杀微生物剂临床失败的原因有:受试者对药物的依从性差;阴离子多聚物抑制R5型的HIV-1效果差,而R5型的HIV-1是性传播的最主要的型别;低浓度的阴离子多聚物能增加HIV-1感染的几率;阴离子多聚物能破坏阴道上皮细胞和阴道黏膜的保护作用等。这些分析都集中于药物本身,但临床前试验结果与临床结果之间存在较大的差距,预示着临床前的试验还有某些方面亟待完善,其中药物的安全性、有效性、药物在体内的停留时间及浓度、精液的活动等是研究热点。研究表明,阴离子多聚物能与精液来源的病毒增强子结合,并促进淀粉样纤维的形成,这有可能是阴离子多聚物临床失败的原因之一。结论:杀微生物剂的临床前研究尚有一些亟待完善的地方,未来开发阴离子多聚物类化合物需要谨慎对待,并从中吸取经验教训。     

聚合物-抗癌药偶合物的研究进展

治疗癌症较为理想的方法之一就是抗癌药物可以选择性地杀死快速增生的肿瘤细胞而对正常组织和细胞没有损伤。但当前所用的抗癌药物-主要是小分子药物能够快速地穿过细胞膜而渗透分散全身各处,针对肿瘤组织的作用有限,它们在杀死肿瘤细胞的同时也杀死了正常增生的细胞(如骨髓细胞和小肠内皮细胞),此外水溶性较差、体内的不稳定性和剂量限制性毒性等也限制了这些药物的应用。因此,发展新型抗癌药物传递系统是当前一项刻不容缓的任务。如果选择抗癌药物与聚合物,特别是亲水性的聚合物偶合,形成聚合物-药物偶合物的传递系统可以改善难溶性药物的…     

壳聚糖-巯基醋酸偶合物的巯基含量与体外黏附性关系研究

目的考察壳聚糖-巯基醋酸偶合物的巯基含量与体外黏附性的关系。方法制备了不同巯基含量的壳聚糖-巯基醋酸偶合物，分别对其溶胀性和制成测试片与黏膜分离时的瞬间拆分力进行测定，记录最大拆分力，并计算出总黏附功。结果壳聚糖-巯基醋酸偶合物的体外黏附性与巯基含量呈正相关，随着偶合物中巯基含量的增加，偶合物的黏附性呈非线性增加，增加的速度越来越小。结论高巯基含量的壳聚糖-巯基醋酸偶合物黏附性远强于壳聚糖。     

聚乙二醇化多聚β肽抗肝癌转移的体内外实验研究

目的：观察多聚β肽及其聚乙二醇（PEG）修饰物对肝癌细胞株侵袭黏附能力和对裸鼠移植人肝癌早期切除术后转移复发的影响。方法：以MTT法测量多聚β肽和其PEG修饰物对肝癌细胞与纤连蛋白（FN）黏附的影响。以细胞侵袭实验观察多聚β肽及其PEG修饰物对肝癌细胞侵袭能力的影响。以LCI-D20裸鼠人肝癌转移模型为材料，观察多聚β肽及其PEG修饰物对早期肝癌切除术后转移复发的影响。结果：β2、β2-PEG、β3和β3-PEG对SMMC-7721细胞与FN黏附抑制率分别为31．3％、39．2％、45．7％和57．1％，侵袭抑制率分别为33．6％、35．9％、38．3％和41．2％；对HCCLM6细胞与FN的黏附抑制率分别为48．7％、60．9％、63．4％和79．3％，侵袭抑制率分别为36．8％、46．6％、45．6％和50．8％。多聚β肽及其PEG修饰物组切缘复发肿瘤重量和肺转移灶个数显著低于对照组（P％0．05）。结论：多聚β肽及其PEG修饰物能抑制肿瘤细胞的黏附和侵袭能力，亦能防治裸鼠移植人肝癌早期切除术后的转移和复发。     

药物分子设计的策略：苗头和先导物的品质决定新药的成败

苗头化合物-先导物-候选药物是创制新药的三个重要里程碑，其中候选药物的确定是新药创制的关键环节，将创制过程分成研究和开发两个阶段，并且开发阶段所有环节都取决于候选药物的化学结构，所以决定了临床前和临床研究的命运。候选药物质量的高低又受制于先导化合物的类药性和苗头化合物的品质，苗头化合物演化成先导物是将新药的研究植根于有研发前景的结构上，先导物的优化是将活性化合物转化成候选药物的过程，是在药效、药代、安全性和物化性质等多维空间中的优化操作。本文结合实例讨论了发现苗头、确定先导物、先导物优化和确定候选药物的策略原则。     

Peptide–drug conjugates (PDCs): a novel trend of research and development on targeted therapy,hype or hope?

Peptide–drug conjugates (PDCs) are the next generation of targeted therapeutics drug after antibody–drug conjugates (ADCs), with the core benefits of enhanced cellular permeability and improved drug selectivity. Two drugs are now approved for market by US Food and Drug Administration (FDA), and in the last two years, the pharmaceutical companies have been developing PDCs as targeted therapeutic candidates for cancer, coronavirus disease 2019 (COVID-19), metabolic diseases, and so on. The therapeutic benefits of PDCs are significant, but poor stability, low bioactivity, long research and development time, and slow clinical development process as therapeutic agents of PDC, how can we design PDCs more effectively and what is the future direction of PDCs? This review summarises the components and functions of PDCs for therapeutic, from drug target screening and PDC design improvement strategies to clinical applications to improve the permeability, targeting, and stability of the various components of PDCs. This holds great promise for the future of PDCs, such as bicyclic peptide?toxin coupling or supramolecular nanostructures for peptide-conjugated drugs. The mode of drug delivery is determined according to the PDC design and current clinical trials are summarised. The way is shown for future PDC development.     

Exploiting EPR in polymer drug conjugate delivery for tumor targeting

Treatment of tumor tissue without affecting normal cells has always been formidable task for drug delivery scientists and this task is effectively executed by polymer drug conjugate (PDC) delivery. The novelty of this concept lies in the utilization of a physical mechanism called enhanced permeability and retention (EPR) for targeting tumors. EPR is a physiological phenomenon that is customary for fast growing tumor and solves the problem of targeting the miscreant tissue. PDCs offer added advantages of reduced deleterious effects of anticancer drugs and augmentation of its formulation capability (e.g. Solubility). There are now at least eleven PDCs that have entered phase I/II/III clinical trial as anticancer drugs. PDCs once entered into the tumor tissue, taking advantage of EPR, are endocytosed into the cell either by simple or receptor mediated endocytosis. Various polymeric carriers have been used with hydrolyzable linker arm for conjugation with bioactive moiety. The hydrolyzable linkages of PDC are broken down by acid hydrolyses of lysosomes and releases the drug. High concentrations of the chemotherapeutic agent are maintained near the nucleus, the target site. Passive targeting by PDCs is due to the physiological event of EPR, which is becoming one of the major thrust areas for targeting solid tumors.     

Antagonism of 5-methoxy-N,N-dimethyltryptamine-induced changes in postdecapitation convulsions in rats by repeated treatment with drugs enhancing 5-hydroxytryptamine neurotransmission

Repeated administration of drugs that increase tryptaminergic neurotransmission antagonized the increase in latency to onset and the duration of postdecapitation convulsions (PDCs) induced by an acute 5-methoxy-N,N-dimethyltryptamine (5-MeODMT) injection; Zimelidine (2 X 5 mg kg-1), fluoxetine (2 X 5 mg kg-1), amiflamine (2 X 2.5 mg kg-1) and alpha-ethyltryptamine (2 X 2.5 mg kg-1) administered orally over 10 days caused a substantial blockade of the increase in latency to onset and duration of PDCs following 5-MeODMT, whereas alaproclate (2 X 5 mg kg-1), clorgyline (1 X 1 mg kg-1) and pargyline (2 X 2.5 mg kg-1) caused a lesser blockade. Repeated 5-MeODMT (3 X 2 mg kg-1) administration blocked the acute effects of 5-MeODMT (2 and 4 mg kg-1) upon PDCs completely. These findings indicate down-regulation of the 5-hydroxytryptamine receptors which mediate the action of 5-MeODMT on the PDCs and offer a simple model system for studying 5-HT receptor sensitivity changes at the spinal level.     

Introduction of "clinical pharmacognosy"--integration between pharmacognosy and clinical pharmacy

In Japanese hospitals or pharmacies, crude drugs and natural products are used as the components of kampo medicine and dietary supplements. Clinical pharmacy can provide information such as the efficacy, adverse action, or interactions of crude drugs or natural products as well as chemical drugs. However, it is very difficult for a clinical pharmacist without a knowledge of pharmacognosy to offer full information, because crude drugs and natural products have very different pharmaceutical characteristics from chemical drugs containing a single compound. Drug information provided by such a pharmacist is sometimes ridiculous and may be misleading by suggesting the unusefulness of crude drugs. Therefore, in order to use crude drugs and kampo medicine effectively and safely, it is necessary to integrate the clinical pharmacy and pharmacognosy as "clinical pharmacognosy". Clinical pharmacognosy would also be capable of handling kampo medicine, a Japanese traditional medicine. Since basic pharmacognosy is a modern pharmaceutical science, pharmacognosists are limited in their understanding of a kampo formula and its clinical usefulness solely with a knowledge of that field. I suggest here that clinical pharmacognosy would better adopt the knowledge of traditional Chinese medicine that includes a theory of traditional pharmacology of the crude drugs used in kampo medicine.     

Reverse water-in-fluorocarbon emulsions for use in pressurized metered-dose inhalers containing hydrofluoroalkane propellants

Pulmonary administration of drugs has demonstrated numerous advantages in the treatment of pulmonary diseases due to direct targeting to the respiratory tract. It enables avoiding the first pass effect, reduces the amount of drugs administered, targets drugs to specific sites and reduces their side effects. Reverse water-in-fluorocarbon (FC) emulsions are potential drug delivery systems for pulmonary administration using pressurized metered-dose inhalers (pMDI). The external phase of these emulsions consists of perfluorooctyl bromide (PFOB, perflubron), whereas their internal phase contains the drugs solubilized or dispersed in water. These emulsions are stabilized by a perfluoroalkylated dimorpholinophosphate (F8H11DMP), i.e. a fluorinated surfactant. This study demonstrates the possibility of delivering a reverse fluorocarbon emulsion via the pulmonary route using a CFC-free pMDI. Two hydrofluoroalkanes (HFAs) (Solkane(R) 134a and Solkane(R) 227) were used as propellants, and various solution (or emulsion)/propellant ratios (1/3, 1/2, 2/3, 1/1, 3/2, 3/1 v/v) were investigated. The insolubility of water (with or without the fluorinated surfactant F8H11DMP) in both HFA 227 and HFA 134a was demonstrated. PFOB and the reverse emulsion were totally soluble or dispersible in all proportions in both propellants. This study demonstrated also that the reverse FC emulsion can be successfully used to deliver caffeine in a homogeneous and reproducible way. The mean diameter of the emulsion water droplets in the pressured canister was investigated immediately after packaging and after 1 week of storage at room temperature. Best results were obtained with emulsion/propellant ratios comprised between 2/3 and 3/2, and with HFA 227 as propellant.     

金艾康合并化学药物治疗肿瘤临床疗效观察

目的：探讨金艾康（汉防己甲素片）合用化学药物治疗肿瘤的临床增效作用。方法：通过比较治疗组与对照组（金艾康合并化学药物者为治疗组,单用化学药物者为对照组,每组各为３０例）的总缓解率与毒副反应来评价金艾康对化疗药物的增效作用。结果：治疗组与对照组的总缓解率分别为８０％与６６．７％,其中部分毒副反应如消化道反应与肢端订木症状等治疗组明显低于对照组。结论：金艾康具有对化学药物治疗肿瘤增效作用,其作用机理可     

The pharmacology of DMP696 and DMP904, non-peptidergic CRF1 receptor antagonists

CRF(1) antagonists DMP696 and DMP904 were designed as drug development candidates for the treatment of anxiety and depression. Both compounds display nanomolar affinity for human CRF(1) receptors, and exhibit >1000-fold selectivity for CRF(1) over CRF(2) receptors and over a broad panel of other proteins. DMP696 and DMP904 block CRF-stimulated adenylyl cyclase activity in cortical homogenates and cell-lines expressing CRF(1) receptors. Both compounds inhibit CRF-stimulated ACTH release from rat pituitary corticotropes. Binding and functional studies indicate that DMP696 and DMP904 behave as noncompetitive full antagonists. DMP696 and DMP904 exhibit anxiolytic-like efficacy in several rat anxiety models. In the defensive withdrawal test, both compounds reduce exit latency with lowest effective doses of 3 and 1 mg/kg, respectively. The anxiolytic-like effect is maintained over 14 days of repeated dosing. In the context of a novel environment used in this test, DMP696 and DMP904 reverse mild stress-induced increases in plasma CORT secretion but at doses 3-4-fold greater than those required for anxiolyticlike efficacy. DMP696 and DMP904 are ineffective in three depression models including the learned helplessness paradigm at doses up to 30 mg/kg. At lowest anxiolytic-like doses, DMP696 and DMP904 occupy >50% CRF(1) receptors in the brain. The in vivo IC(50) values (plasma concentrations required for occupying 50% CRF(1) receptors) estimated based upon free, but not total, plasma concentrations are an excellent correlation with the in vitro IC(50) values. Neither compound produces sedation, ataxia, chlordiazepoxide-like subjective effects or adverse effects on cognition at doses 10-fold higher than anxiolytic-like doses. Neither compound produces physiologically significant changes in cardiovascular, respiratory, gastrointestinal or renal functions at anxiolytic-like doses. DMP696 and DMP904 have favorable pharmacokinetic profiles with good oral bioavailabilities. The overall pharmacological properties suggest that both compounds may be effective anxiolytics with low behavioral side effect liabilities.     

The anxiolytic CRF<Subscript>1</Subscript> antagonist DMP696 fails to function as a discriminative stimulus and does not substitute for chlordiazepoxide in rats

Rationale. Compounds with a mechanism of action different from benzodiazepines may retain the anxiolytic effects of benzodiazepines with fewer side effects. CRF₁ antagonists have anxiolytic-like effects but may have different discriminative stimulus (DS) effects compared with benzodiazepines. Objective. The present study evaluated the similarity of DS effects of a CRF₁ antagonist DMP696 to the benzodiazepine chlordiazepoxide and the ability of DMP696 to produce DS effects on its own using drug discrimination procedures, as well as its anxiolytic-like effects after acute or chronic administration. Methods. Rats were trained to discriminate chlordiazepoxide (5.0 mg/kg, IP, 30 min prior to session) from vehicle under a fixed-ratio 10 schedule of food reinforcement and drug- or vehicle-lever selection following administration of DMP696 was determined. The effects of DMP696 on latency to exit a dark chamber (defensive withdrawal model of anxiety) were used as an index of anxiolytic-like activity. Results. In chlordiazepoxide-trained rats, DMP696 (1.0–100 mg/kg, PO) resulted in most of the animals selecting the vehicle lever, as did another anxiolytic, the 5-HT_1A partial agonist buspirone (0.3–10 mg/kg, IP). DMP696 reduced exit latency in defensive withdrawal at 10 mg/kg administered either acutely or chronically for 14 days. Thus, the doses of DMP696 studied in drug discrimination were up to 10-fold higher than those active in the anxiety model. In addition, DMP696 (10–60 mg/kg, PO) could not be established as a DS under the conditions used in this study. In a subsequent study, chlordiazepoxide was established as a DS in these same animals. Conclusions. Lack of substitution of DMP696 for the chlordiazepoxide DS in rats and its inability to acquire DS properties suggest that the DS effects of DMP696 differ from those of benzodiazepines. Electronic Publication     

DMP 504, a novel hydrogel bile acid sequestrant: II. Lipid-lowering pharmacology in the hamster

DMP 504 is a novel hydrogel bile acid sequestrant in development for the treatment of moderate hypercholesterolemia. The drug is a condensation polymer synthesized from 1,10-dibromodecane and 1,6-diaminohexane. In vitro binding studies demonstrate that DMP 504 is superior to cholestyramine (CS) with respect to equilibrium binding capacity and affinity for bile acids. The goals of the research reported herein were to assess the in vivo hypolipidemic activity of DMP 504, to elucidate the mechanism of action of DMP 504, and to determine the potency of DMP 504 relative to CS in hamsters. Six dose groups each of DMP 504 and CS were included in the study, along with an untreated control group. The DMP 504 doses ranged from 20–1,000 mg/kg/day for 14 days; CS doses ranged from 50–2,000 mg/kg/day for 14 days. There were 48 animals per dose group; drugs were administered in the feed. At the midpoints of the dose-response curves, DMP 504 was superior to CS with respect to increasing the output of fecal bile acids (7-fold) and sterols (3-fold), increasing the activity of hepatic cholesterol 7α-hydroxylase activity (C7αOH) (6-fold), and decreasing the circulating levels of total serum cholesterol (6-fold), non-HDL cholesterol (6-fold), and HDL cholesterol (4-fold). Neither DMP 504 nor CS had significant effects on serum triglycerides or apo-B. In summary, DMP 504 is a new bile acid sequestrant that is mechanistically similar to CS, but is, on average, 6-fold more potent. Drug Dev. Res. 41:65–75, 1997. © 1997 Wiley-Liss, Inc.     

Enantiomeric separations of illicit drugs and controlled substances using cyclofructan‐based (LARIHC) and cyclobond I 2000 RSP HPLC chiral stationary phases

Recently a novel class of chiral stationary phases (CSPs) based on cyclofructan (CF) has been developed. Cyclofructans are cyclic oligosaccharides that possess a crown ether core and pendent fructofuranose moieties. Herein, we evaluate the applicability of these novel CSPs for the enantiomeric separation of chiral illicit drugs and controlled substances directly without any derivatization. A set of 20 racemic compounds were used to evaluate these columns including 8 primary amines, 5 secondary amines, and 7 tertiary amines. Of the new cyclofructan‐based LARIHC columns, 14 enantiomeric separations were obtained including 7 baseline and 7 partial separations. The LARIHC CF6‐P column proved to be the most useful in separating illicit drugs and controlled substances accounting for 11 of the 14 optimized separations. The polar organic mode containing small amounts of methanol in acetonitrile was the most useful solvent system for the LARIHC CF6‐P CSP. Furthermore, the LARIHC CF7‐DMP CSP proved to be valuable for the separation of the tested chiral drugs resulting in four of the optimized enantiomeric separations, whereas the CF6‐RN did not yield any optimum separations. The broad selectivity of the LARIHC CF7‐DMP CSP is evident as it separated primary, secondary and tertiary amine containing chiral drugs. The compounds that were partially or un‐separated using the cyclofructan based columns were screened with a Cyclobond I 2000 RSP column. This CSP provided three baseline and six partial separations. Copyright © 2013 John Wiley & Sons, Ltd.