Beta-lactams in the new millennium. Part-I: monobactams and carbapenems

Beta-lactam ring-containing compounds such as penicillins, ampicillin, amoxicillin, cephalosporins and carbapenem are among the most famous antibiotics. This article reviews the recent developments in the study of such compounds. The introductory paragraph, which highlights the significance of the subject and cites most of the leading references of the previous century, is followed by an overview of beta-lactams and some novel methodologies for the synthesis of bi-, tri- and polycyclic derivatives. The rest of the sections deal with design, synthesis and biological activity of monobactams and carbapenems. Many of them have potential antibacterial activity, even against some resistant strains, and enzyme inhibitory activity.     

Preparing for the new millennium

Since being introduced to the field of drug discovery at Zeneca Pharmaceuticals in 1991, it has become apparent to me that a blizzard of revolutionary novel approaches has swept through the pharmaceutical industry. Now, the discovery process has become completely transformed and the race to develop commercially successful drugs is now taking place in a very different realm. Rapid advances in automation, combinatorial chemistry, high-throughput screening (HTS), genomics, proteomics and bioinformatics appear to be principally responsible for driving such a rapidly evolving discovery process. In these exciting times for pharmaceutical R&D, it is a delight for me to take over the Editor's reins of Drug Discovery Today.     

Goals for transplantation in the new millennium

Presentations at the XVIII International Congress of the Transplantation Society covered all key organ-specific and subspecialty areas of transplantation. Highlights were sessions under the auspices of two new sections of the Society, the International Xenotransplantation Association and the Section on Transplant Infectious Disease.     

Online genomics facilities in the new millennium

The review begins by providing a brief typology of biological databases on the Internet, illustrated by examples of the most influential resources of each kind. We then take an insider look at one typical on-line genomic resource -- the yeast genome database hosted at the Munich Information Center for Protein Sequences (MIPS) -- and explain how and why it has evolved from a basic sequence repository to a multidomain knowledge base. The role of community efforts in curating and annotating genome data is discussed. The crucial role of data integration and interoperability in developing next-generation genomic facilities is underscored.     

Critical review of the role of HTS in drug discovery

'A wise use of lead discovery tactics will distinguish successful drug discovery engines.'     

Antidepressants for the new millennium.

Despite a remarkable structural diversity, most conventional antidepressants may be viewed as 'monoamine based', increasing the synaptic availability of serotonin, norepinephrine, and/or dopamine. Both preclinical and recent clinical studies indicate that compounds which reduce transmission at N-methyl-D-aspartate (NMDA) receptors are antidepressant. Moreover, chronic administration of antidepressants to mice alters both the mRNA levels encoding N-methyl-D-aspartate receptor subunits and radioligand binding to these receptors within circumscribed areas of the central nervous system. It is hypothesized that these two different treatment strategies converge to produce an identical functional endpoint: a region-specific dampening of NMDA receptor function. The pathways leading to this convergence provide a rudimentary framework for discovering novel antidepressants.     

Genomics and proteomics: the new millennium of drug discovery and development

One of the most pressing issues facing the pharmaceutical and biotechnology industry is the tremendous dropout rate of lead drug candidates. Over the last two decades, several new genomic technologies have been developed in hopes of addressing the issues of target identification and lead candidate optimization. Gene expression microarray is one of these technologies and this review describes the four main formats, which are currently available: (a) cDNA; (b) oligonucleotide; (c) electrokinetic; and (d) fiberoptic. Many of these formats have been developed with the goal of screening large numbers of genes. Recently, a high-throughput array format has been developed where a large number of samples can be assayed using arrays in parallel. In addition, focusing on gene expression may be only one avenue in preventing lead candidate failure. Proteomics or the study of protein expression may also play a role. Two-dimensional polyacrylamide gel electrophoresis (2-DE) coupled with mass spectroscopy has been the most widely accepted format to study protein expression. However, protein microarrays are now being developed and modified to a high-throughput screening format. Examples of several gene and protein expression studies as they apply to drug discovery and development are reviewed. These studies often result in large data sets. Examples of how several statistical methods (principal components analysis [PCA], clustering methods, Shannon entropy, etc.) have been applied to these data sets are also described. These newer genomic and proteomic technologies and their analysis and visualization methods have the potential to make the drug discovery and development process less costly and more efficient by aiding to select better target and lead candidates.     

Cancer treatments for the new millennium

The SMR Symposium Cancer Treatments for the New Millennium was held on March 9, 2006, at the National Heart and Lung Institute, Imperial College London. The conference program brought together an international line-up of speakers representing academia, biotech and large pharma to discuss the development status of a number of new innovative treatments for the treatment or prevention of cancer. Presentations also focused on how new technologies are being applied to the design of the next generation of cancer drugs and the fundamental biological challenges that must be addressed in attempting to discover effective new treatments.     

Safety pharmacology: an essential interface of pharmacology and toxicology in the non-clinical assessment of new pharmaceuticals

Safety pharmacology studies are defined as the studies that investigate the potential undesirable pharmacodynamic effects of a substance on physiological functions in relation to exposure. In consequence, these studies are an integral part of the non-clinical safety assessment of new pharmaceuticals, in association with toxicological studies. A retrospective shows the evolution of the discipline in these last years. Safety pharmacology studies are of special interest, and some drawbacks and pitfalls must be considered (i.e. invasive methods, difficulties related to GLP (good laboratory practices) requirements, choice of a strategy). In the future, some priority should be given to education, promotion of scientific activities, reinforcement of the links between pharmacologists and toxicologists and implementation of relevant guidelines.     

Chronopharmacology: a new perspective in pharmacology

Vital signs and several constituents of the serum and urine exhibit a circadian rhythm, and the same is true for the onset of several diseases. The rhythmic changes in the blood volume, functions of the liver and kidney, etc., have implications for drug availability, and the circadian changes should be taken into account in pharmacokinetic studies. These changes are the subject of chronopharmacokinetics. In addition to the circadian rhythm in changes in drug absorption, elimination and bioavailability, a rhythm of the intensity of drug effects and side-effects may also be observed: this is the domain of chronopharmacodynamics. Several examples demonstrate that chronopharmacokinetic and chronopharmacodynamic results support the view that the temporal organization of the organism is an important variable influencing the action of drugs.     

Mechanisms of antimicrobial resistance: their clinical relevance in the new millennium

Antimicrobials show selective toxicity. Suitable targets for antimicrobials to act at include the bacterial cell wall, bacterial protein and folic acid synthesis, nucleic acid metabolism in bacteria and the bacterial cell membrane. Acquired antimicrobial resistance generally can be ascribed to one of five mechanisms. These are production of drug-inactivating enzymes, modification of an existing target, acquisition of a target by-pass system, reduced cell permeability and drug removal from the cell. Introduction of a new antimicrobial into clinical practice is usually followed by the rapid emergence of resistant strains of bacteria in some species that were initially susceptible. This has reduced the long-term therapeutic value of many antimicrobials. It used to be thought that antibacterial resistance was mainly a hospital problem but now it is also a major problem in the community. Organisms in which resistance is a particular problem in the community include members of the Enterobacteriaceae, including Salmonella spp. and Shigella spp., Mycobacterium tuberculosis, Streptococcus pneumoniae, Haemophilus influenzae and Neisseria gonorrhoeae. Multi-resistant Gram-negative rods, methicillin-resistant Staphylococcus aureus and vancomycin-resistant enterococci are major causes of concern in the hospital setting. Prevalence of antibacterial resistance depends both on acquisition and spread. Decreasing inappropriate usage of antimicrobials should lessen the rate of acquisition, and spread can be minimised by sensible infection control measures.     

Ethical issues for bioscientists in the new millennium

The scientific understanding of biological processes is developing extremely fast, providing opportunities for changing people's lives in many ways-through health care, food and the environment. The speed with which these changes are occurring means that even bioscientists can only keep up with their own narrow field of science. It is not surprising that members of the public are frightened about the rapidity and impact of the changes arising from the biological revolution. These concerns are often expressed in ethical terms. Decision making about the direction of research and its application is becoming more transparent. This means that bioscientists will have to engage in the debate about their work with members of the public, including those who are opposed to it, in order to create acceptance of their work and its products. At the moment, bioscientists are often ill equipped to enter this debate because of their lack of training in ethics and lack of understanding of the impact of ethics on their work. A better understanding of bioethics will be necessary for entering this debate with vigour. A comprehensive ethical analysis is outside the scope of this text. Some of the principal arguments about the ethics of two aspects of bioscience research-genetically modified crops and the use of experimental animals-will be discussed to illustrate a few of the issues that derive from ethical analyses. I hope that this will encourage toxicologists to take a greater interest in bioethics.     

The role of aminosalicylates at the beginning of the new millennium in the treatment of chronic inflammatory bowel disease

Objective: To discuss the pharmacological properties of aminosalicylates and their potential value in the treatment of chronic inflammatory bowel disease (IBD). Methods: A review of clinical studies on the pharmacokinetics and mode of action of aminosalicylates is provided. In addition, the clinical efficacy and safety of aminosalicylates in the treatment of IBD, according to several recent meta-analyses, is summarised. Results: Whereas aminosalicylates represent drugs of first choice in the acute treatment of ulcerative colitis and also for maintaining those patients in remission, their value for patients with Crohn's disease, either for achieving or maintaining remission, is at best modest. There is a large variability in the clinical results, especially in Crohn's disease, which is probably due to the variable extent and severity of IBD, different instruments in the evaluation of therapeutic outcome, and also at least partly caused by the different preparations and dosages of aminosalicylates used, as well as the high variation in drug disposition and topical availability of the active drug. The popular use of aminosalicylates is most likely due to the low incidence of side effects and the good overall safety records of mesalazine (mesalamine). Conclusions: Apparently, the full therapeutic potential of aminosalicylates has not yet been evaluated (e.g. upper dosage range, combination therapy, responding subgroups). Consequently, the imperfect treatment might be improved in the new millennium by novel insights in the complex mode of action of mesalazine as well as in the etiopathogenesis of IBD. Received: 1 February 2000 / Accepted in revised form: 26 April 2000     

Biological importance of imidazole nucleus in the new millennium

Imidazole nucleus is a constituent of many bioactive heterocyclic compounds that are of wide interest because of their diverse biological and clinical applications. This created interest in researchers to synthesize variety of imidazole derivatives and to screen them for their various biological activities viz. anti-cancer, anti-viral, antiHIV, anti-protozoal, anti-mycobacterial, anti-inflammatory, analgesic, anxiolytic, as well anti-diabetic activities.