The second Lilly Prize Lecture, University of Newcastle, July 1977. beta-Adrenergic receptor blockade in hypertension, past, present and future.

All beta-adrenoceptor blocking drugs that have been described share the common property of being competitive inhibitors. They differ in their associated properties, the presence or absence of cardioselectivity, membrane stabilizing activity, and partial agonist activity. Recently some beta-adrenoceptor blocking drugs have been reported which also possess alpha-adrenoceptor blocking activity. The associated properties have been used as a basis for classifying beta-adrenoceptor blocking drugs (Fitzgerald, 1969, 1972). The presence or absence of cardioselectivity is most useful for dividing beta-adrenoceptor blocking drugs. The non-selective drugs (Division I) can be further divided according to the presence or absence of intrinsic sympathomimetic activity (ISA) and membrane stabilizing activity (Fitzgerald's groups I-IV). Group I possess both membrane activity and ISA, e.g. alprenolol, oxprenolol, group II just membrane action, e.g. propanolol, group III ISA but no membrane action, e.g. pindolol. Fitzgerald placed pindolol in group I but should be placed in group III as it possesses a high degree of beta-adrenoceptor blocking potency in relation to its membrane activity (Prichard, 1974). Finally drugs in group IV have neither ISA nor membrane action, e.g. sotalol, timolol. The cardioselective drugs (Division II) can be similarly sub-divided into groups I-IV according to the presence or absence of ISA or membrane action (Fitzgerald grouped all these together as group V). Lastly there are new beta-adrenergic receptor blocking drugs which in addition have alpha- adrenergic receptor blocking properties (Division III).     

铂类抗肿瘤药物的研究现状

自从顺铂作为第一代抗肿瘤药物被开发利用以来，人们一直在寻找广谱、高活性、低毒性和无交叉耐药性的铂类抗肿瘤药物，合成和筛选出各种铂络合物。分别介绍根据不同设计思路合成的四价铂络合物、具有活性配体的铂络合物、生物载体为配体的靶向铂络合物、反式铂络合物和具有立体位阻效应的铂络合物及其抗肿瘤活性，综述当前铂类抗肿瘤药物的研究现状。     

Novel agents for the treatment of resistant Gram-positive infections

Bacteria have proved themselves able to develop resistance to every antibiotic used clinically. Traditional agents used for treatment of serious infections caused by Gram-positive species have recently been supplemented with the introduction of linezolid, quinupristin-dalfopristin, several new quinolones and telithromycin. However, resistance to many of these agents has already been reported and, although each currently retains activity against the vast majority of clinical isolates of its target species, their long-term efficacy is uncertain. We must look to develop other compounds to replace and hopefully improve upon existing anti-Gram-positive agents. Daptomycin (a lipopeptide), oritavancin and dalbavancin (both second-generation glycopeptides) and ramoplanin (a glycolipodepsipeptide) are among the agents in advanced stages of development and, at present, many seem likely to proceed to licensing. In addition, it is encouraging that many agents active against novel bacterial targets have been discovered and are in earlier stages of development. In the next two decades, we should be optimistic that a regular flow of new anti-Gram-positive agents will enable us to offset the constant spectre of bacterial resistance.     

Novel agents for the treatment of resistant Gram-positive infections

Bacteria have proved themselves able to develop resistance to every antibiotic used clinically. Traditional agents used for treatment of serious infections caused by Gram-positive species have recently been supplemented with the introduction of linezolid, quinupristin-dalfopristin, several new quinolones and telithromycin. However, resistance to many of these agents has already been reported and, although each currently retains activity against the vast majority of clinical isolates of its target species, their long-term efficacy is uncertain. We must look to develop other compounds to replace and hopefully improve upon existing anti-Gram-positive agents. Daptomycin (a lipopeptide), oritavancin and dalbavancin (both second-generation glycopeptides) and ramoplanin (a glycolipodepsipeptide) are among the agents in advanced stages of development and, at present, many seem likely to proceed to licensing. In addition, it is encouraging that many agents active against novel bacterial targets have been discovered and are in earlier stages of development. In the next two decades, we should be optimistic that a regular flow of new anti-Gram-positive agents will enable us to offset the constant spectre of bacterial resistance.     

Current status and future of antifungal therapy for systemic mycoses

Since the 1950s there has been an increase in the incidence of invasive fungal disease. The first successful systemically administered antifungal drug, amphotericin B, was introduced in the 1950s and, until very recently, was considered the best therapeutic drug for severe mycoses. The development of new antifungals to treat systemic disease has been slow compared to that of antibacterial compounds, with the introduction of only a single new class of drugs over the past 20 years. This review discusses the antifungal drugs that are clinically in use and summarizes interesting new applications and patents from the US Patent and Trademark Office.     

Pharmacoeconomics of treatment with the newer anti-Gram-positive agents

The unmet medical need of emerging resistance among Gram-positive pathogens, such as methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and penicillin-resistant Streptococcus pneumoniae, has driven industry towards the identification and development of novel anti-Gram-positive agents. Among the newer agents are improved quinolones, a lipopeptide, an oxazolidinone and novel glycopeptides. Scientific distinctions between these drugs, which impact on the placement, usage and, ultimately, the pharmacoeconomics of several of these new agents, may lead to further consideration despite poor initial observations of minimal improvement. Key differences in the characteristics of these drugs (i.e., spectrum, activity, resistance emergence, efficacy, target, safety) provide a basis for an emerging pharmacoeconomic-based distinction between these newer anti-Gram-positive agents.     

DNA intercalators in cancer therapy: organic and inorganic drugs and their spectroscopic tools of analysis

Since the discovery of the DNA intercalation process by Lerman in 1961 thousands of organic, inorganic octahedral (particularly ruthenium(II) and rhodium(III)) and square-planar (particularly platinum(II)) compounds have been developed as potential anticancer agents and diagnostic agents. The design and synthesis of new drugs is focused on bis-intercalators which have two intercalating groups linked via a variety of ligands, and synergistic drugs, which combine the anticancer properties of intercalation with other functionalities, such as covalent binding or boron-cages (for radiation therapy). Advances in spectroscopic techniques mean that the process of DNA intercalation can be examined in far greater detail than ever before, yielding important information on structure-activity relationships. In this review we examine the history and development of DNA intercalators as anticancer agents and advances in the analysis of DNA-drug interactions.     

Cardiovascular drugs

Since the category of cardiovascular drugs comprises a considerable number of pharmacotherapeutic groups, an overview of future developments must necessarily be limited to those areas in which innovations are most likely to occur. Further extension of our knowledge of thrombolytic therapy may eventually lead to new choices of primary drugs. In the area of antiarrhythmic therapy, the clinical use of a number of drugs has been hampered by the pro-arrhythmogenic actions of these agents. The development of new class III anti-arrhythmics will continue, probably giving rise to new therapeutic options. In the vascular area a new group of drugs, the renin inhibitors, is likely to emerge for the treatment of hypertension. Moreover, exciting discoveries in vascular pharmacology should eventually translate into new pharmacotherapeutic approaches. Finally, the large-scale availability of blood fractions (coagulation factors) prepared by recombinant technology may help solve current shortages of products derived from donated blood.     

Cardiovascular drugs

Since the category of cardiovascular drugs comprises a considerable number of pharmacotherapeutic groups, an overview of future developments must necessarily be limited to those areas in which innovations are most likely to occur. Further extension of our knowledge of thrombolytic therapy may eventually lead to new choices of primary drugs. In the area of antiarrhythmic therapy, the clinical use of a number of drugs has been hampered by the pro-arrhythmogenic actions of these agents. The development of new class III anti-arrhythmics will continue, probably giving rise to new therapeutic options. In the vascular area a new group of drugs, the renin inhibitors, is likely to emerge for the treatment of hypertension. Moreover, exciting discoveries in vascular pharmacology should eventually translate into new pharmacotherapeutic approaches. Finally, the large-scale availability of blood fractions (coagulation factors) prepared by recombinant technology may help solve current shortages of products derived from donated blood.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1987). I. Susceptibility distribution

Since 1979, Ikemoto et al. have been retrospectively surveying the sensitivity of major species of bacteria isolated from patients with urinary tract infections to various antibacterial agents and antibiotics. Their findings for the past year are reported below. A total of 825 clinical strains of bacteria was investigated. Of this total, Gram-positive bacteria accounted for 28.0% (231 strains) and Gram-negative bacteria for 72.0% (594 strains). Taxonomically, Escherichia coli accounted for 34.7% (286 strains), Enterococcus faecalis for 14.3% (118), Pseudomonas aeruginosa for 11.0% (91), Klebsiella pneumoniae for 7.8% (64), and coagulase-negative staphylococci for 7.3% (60). Sensitivity spectra of these major bacteria to various drugs were as follows. 1. E. faecalis was sensitive to parenteral imipenem (IPM) and ampicillin and oral vancomycin. It was also sensitive to ofloxacin (OFLX) and ciprofloxacin (CPFX), which are new quinolones. Some strains were only slightly sensitive to second and third generation cephems cefmenoxime (CMX) and cefuzonam (CZON) aminoglycosides amikacin (AMK) and arbekacin (HBK), and erythromycin which is a macrolide. 2. Staphylococcus aureus was sensitive to dicloxacillin (MDIPC) which is a penicillin drug, cefotiam (CTM) which is a cephem, IPM, minocycline (MINO), and HBK. A fairly large number of strains were only slightly sensitive to cefazolin (CEZ), OFLX and CPFX. 3. Coagulase-negative staphylococci were sensitive to MDIPC which is a penicillin derivative, cephems CTM and CZON, IPM, HBK, clindamycin (CLDM) and MINO. Some strains, however, were only slightly sensitive to a majority of these drugs. 4. E. coli was sensitive to CTM, CMX, latamoxef (LMOX), ceftazidime (CAZ), CZON, and flomoxef (FMOX), all of which are second or third generation cephems. It was also sensitive to IPM, a carbapenem, carumonam (CRMN), a monobactam, and new quinolones, OFLX and CPFX. 5. K. pneumoniae was sensitive to cephems, viz. CTM, CAZ, CZON, FMOX and cefixime, CRMN which is a monobactam, IPM, a carbapenem and new quinolones, OFLX and CPFX. Some strains were only slightly sensitive to CTM, cefmetazole cefoperazone (CPZ), and FMOX. 6. Citrobacter freundii was sensitive to CRMN which is a monobactam, and new quinolones, OFLX and CPFX. Many strains were only slightly sensitive to cephems, viz. CEZ, CTM, CPZ and CAZ. 7. Enterobacter cloacae was sensitive to gentamicin and AMK which are aminoglycosides, but showed a bimodal pattern of sensitivity to CPZ, CAZ and CZON, all of which are cephems, and to quinolones, OFLX and CPFX.(ABSTRACT TRUNCATED AT 400 WORDS)     

The future prospects of oxazolidinones

The high rates of antimicrobial resistance seen among many Gram-positive pathogens means that there is an ongoing need for new antibacterial drugs. Currently, several pharmaceutical companies are investigating compounds belonging to a new class of anti-Gram-positive agents, the oxazolidinones, one member of which, linezolid, is licensed for clinical use. Interest in oxazolidinones is being stimulated by the results of recent trials demonstrating the excellent clinical efficacy of linezolid in a range of infections. Linezolid is also a relatively safe drug, the main toxicity issue relating to development of thrombocytopenia in some patients receiving prolonged courses. With regard to new oxazolidinones, there is particular interest in analogs that, in early laboratory evaluation, show enhanced activity against the respiratory pathogens Haemophilus influenzae and Moraxella catarrhalis. The future potential of the oxazolidinones will depend on the antibacterial spectra, pharmacokinetic properties and toxicity profiles of new compounds, and the degree to which their clinical use may be affected by the emergence of oxazolidinone-resistant pathogens.     

Comparative studies on activities of antimicrobial agents against causative organisms isolated from urinary tract infections (1987). III. Secular changes in susceptibility

Sensitivity spectra of major species of bacteria (namely Escherichia coli, Klebsiella spp., Proteus spp., Citrobacter spp., Enterobacter spp., Serratia marcescens and Pseudomonas aeruginosa) which were among the clinical isolates mentioned in the first and second reports to various antibacterial and antibiotic agents and time courses of the spectra are reported below. 1. E. coli was sensitive to cefmenoxime (CMX), latamoxef (LMOX), ceftazidime (CAZ), cefzonam (CZON) and flomoxef (FMOX) which are third generation cephems, carumonam (CRMN) which is a monobactam, imipenem (IPM) which is a carbapenem, ofloxacin (OFLX) and ciprofloxacin (CPFX) which are new quinolones. Compared to the preceding 5-year period, sensitivities to most drugs have increased. 2. Klebsiella spp. were sensitive to CMX, CZON and FMOX which are third generation cephem antibiotics, CRMN which is a monobactam and gentamicin (GM) and arbekacin (HBK) which are aminoglycosides. Compared to the preceding 5-year period, the sensitivity on the whole has increased slightly. 3. Proteus spp. were sensitive to CMX, LMOX, CAZ and CZON which are third generation cephems, CRMN, a monobactam and OFLX and CPFX which are new quinolones. Compared to the preceding 5-year period, increased sensitivities, particularly to parenteral cephems, were found. 4. Citrobacter spp. were sensitive to CPFX which is a new quinolone antibiotic and CRMN, a monobactam. Compared to the preceding 5-year period, the sensitivity as a whole increased but there were still strains against which cefotiam, cefmetazole and, cefoperazone (CPZ) showed high MIC values. 5. Enterobacter spp. were sensitive to OFLX and CPFX, which are new quinolones, IPM, a carbapenem, and GM and HBK which are aminoglycosides. Compared to other bacteria, bacteria of this group were less sensitive to CPZ, CAZ, CZON, and FMOX which are third generation cephems. Compared to the preceding 5-year period, slight increases in sensitivity were found in cases of simple urinary tract infections. 6. S. marcescens as a whole was not very sensitive to antibiotics tested. Compared to the preceding 5-year period, sensitivities to CRMN and minocycline improved slightly. 7. P. aeruginosa was not very sensitive to any drug, as other bacteria were. Compared to the preceding 5-year period, sensitivities to new quinolones OFLX and CPFX and carbapenem IPM decreased slightly.     

含氮姜黄素衍生物的合成及抗肿瘤活性研究

目的 合成具有新结构骨架的含氮姜黄素类抗肿瘤化合物并考察目标化合物的体外抗肿瘤活性.方法 以姜黄素和查耳酮为先导物,利用药效团和骨架迁越原理,设计并合成一系列含碱基的姜黄素类似物.选取人肺癌细胞(A-549)和人胃癌细胞(SGC-7901)对所合成的新化合物进行体外抗肿瘤活性筛选.并且用Discovery Studio...     

Three‐Dimensional Pharmacology,a Subject Ranging from Ignorance to Overstatements

Abstract: Stereoselectivity has been known to play a role in drug action for 100 years or more. Nevertheless, chiral drugs have been developed and used as racemates, neglecting the fact that they comprise mixtures of two or more compounds which may have quite different pharmacological properties. A very limited access to pure enantiomers in the past has been responsible for this unsatisfactory state of affairs. During the last 20 years, significant achievements have made it possible to perform stereoselective synthesis and analysis. Today, novel chiral drugs are as a rule developed as single enantiomers. Yet, studies of old racaemic drugs are still designed, performed and published without mention of the fact that two or more compounds are involved. In recent years, a number of old racaemic drugs have been re‐evaluated and re‐introduced into the clinical area as the pure, active enantiomer (the eutomer). While in principle correct, the clinical benefit of this shift from a well established racaemate to a pure enantiomer often seems to be limited and sometimes exaggerated. Racaemic drugs with a deleterious enantiomer that does not contribute to the therapeutic effect (the distomer), may have been sorted out in the safety evaluation process. However, in the future any pharmacological study of racaemic drugs must include the pure enantiomers. This will generate new, valuable information on stereoselectivity in drug action and interaction.     

Erythropoiesis‐stimulating agents: development,detection and dangers

Epoetin alfa, the first member of the family of erythropoiesis stimulating agents (ESAs), was introduced to the market in 1989. Since then development has progressed to epoetins of the third generation. Currently drugs that use alternative approaches to stimulate erythropoiesis are under development. Uptake of all available ESAs into doping has occurred rapidly after their introduction. A multitude of dangers to health are associated with the illicit use of these substances. Different approaches to detect ESAs in doping control have been developed to comply with the very diverse nature of the compounds used. Future developments in the field of ESA require the development of new techniques in doping analysis. This review gives an overview of the development of ESA and its detection methods as well as future developments. [Correction made here after initial online publication] Copyright © 2009 John Wiley & Sons, Ltd.     

Comparative studies of antimicrobial agents against causative organisms isolated from urinary tract infections (1982). III. Secular changes in susceptibility

In vitro susceptibilities have been investigated against several species isolated from patients with simple and complicated urinary tract infections (UTI) during 1980-1982. Antimicrobial activities of the third generation cephems against E. coli isolated from patients with complicated UTI were found to decrease slightly in 1982. And those against Klebsiella spp. isolated from patients with simple and complicated UTI were also found to decrease similarly. Against P. mirabilis, all the drugs tested have showed relatively potent activities and slight changes in the susceptibility. The marked decrease of susceptibility against Citrobacter spp. isolated from UTI have been found even in the third generation cephems. Especially, Citrobacter spp. exhibited a greater degree of resistant to CZX and CPZ. Strains of P. aeruginosa were on the whole susceptible to the drugs tested, CFS, GM, TOB and AMK, inhibiting 50-80% of the strains tested at 1.56 micrograms/ml. CTX, CZX and CMX seemed most effective against S. marcescens among the third generation cephems, inhibiting 50-90% of the strains tested at 3.13 micrograms/ml.     

Strategies for the biological evaluation of gold anticancer agents

Since the introduction of the monomeric orally bioavailable anti-arthritic gold compound auranofin in 1985, and the success of the platinum-based anti-cancer drugs, there has been a great deal of interest in the use of gold compounds for cancer therapy. However this early promise has not materialized into an approved drug in spite of extensive and innovative efforts in gold chemistry. Therefore, in the light of this lack of success, the strategies for the biological evaluation of potential gold-based anti-cancer drugs are discussed. It is proposed that the biological testing strategy should be multi-faceted incorporating an understanding of the molecular properties of the compounds under investigation related to their behaviour in a biological environment, an evaluation of their comparative in vitro potency against tumor cells, ascertaining the biochemical mechanism of action and target identification to aid in medicinal chemistry design, evaluation of in vivo activity in relevant tumor models, and an understanding of their toxicological and pharmacokinetic properties. This strategy will be exemplified with work on Au(III) cyclometallated complexes in which an integrated approach to the search for new metal-based anticancer drugs was adopted, incorporating in vitro screening, in vivo human tumor xenograft models, and mechanistic studies. The importance of mechanistic studies which have led to the identification of new molecular targets for gold drugs, and in vivo evaluation are emphasized.     

Cancer chemotherapy and heterocyclic compounds

The search for pharmacological approaches to neoplastic disease has made some impressive gains started after 1940 when the antileukemic activity of nitrogen mustard was discovered during world war II. It is generally accepted that neoplastic transformation is related to genes alteration or oncogene activation, so the progress in the development of the new drugs for treatment of malignant diseases has been rapid, both in revealing pathobiology of the diseases and discovery of new drugs. In addition attempts have been made to define optimal combinations, treatment strategies and patient support measures. Cancer chemotherapy is now of established value and a highly specialized field. Among the modifications to the family of antitumor compounds, heterocyclic organic compounds have been extensively applied by many groups in order to modify the reactivity profile. Pyrrole, pyrimidine, indole, quinoline and purine are few classes of heterocycles which showed interesting cytotoxicity profiles. The updated material related to these modifications has been rationalized and ordered, in order to offer an overview of the argument.     

灯盏花中新的酚酸类化合物的结构及活性研究

目的研究中药灯盏花［Erigeron breviscapus (Vant.)Hand-Mazz］的心血管活性成分。方法用各种色谱技术进行分离,用IR,UV,MS,¹HNMR,¹³CNMR,2DNMR光谱鉴定他们的结构。以乳酸脱氢酶(LDH)释放量为指标测定BCMEC(bovinecerebralmicrovascularendothelialcell)损伤,比色法测定药物体外抗氧化和抗活性氧能力。结果从灯盏花中分离得到2个化合物,分别鉴定化合物的结构为：1-O-甲基-3,5-O-双咖啡酰基奎宁酸甲酯(III)和5-O-咖啡酰基奎宁酸丁酯(IV)。结论化合物III,IV为新的酚酸类化合物,化合物III对LPC引起的BCMEC损伤有明显的保护作用。     

Chemistry and pharmacology of pyran derivatives. 16. Derivatives of 2-(dialkylamino)-7-methoxychromone with antiallergic activity

Since 2-(diethylamino)-7-methoxychromone (III a) showed remarkable activity in the rat PCA test, some modifications to its structure were made. For instance new substituents such as chlorine or nitro group were introduced into the molecule and the diethylamino group modified. Thus, 2-(ethylamino)-7-methoxychromone (IX) was prepared by treating 3-methoxyphenol with N-ethylethoxycarbonylacetamide in the presence of phosphorus oxychloride. In this case a small amount of 4-chloro-7-methoxycoumarin was also isolated from the reaction mixture. Moreover compounds (XIV), (XV), (XVII) structurally related to sodium cromoglycate were prepared. The pharmacological screening of some compounds showed a useful antiallergic activity.