Optimizing Emergency Medical Service Structures Using a Rule-Based Discrete Event Simulation-A Practitioner's Point of View.

Many studies in research deal with optimizing emergency medical services (EMS) on both the operational and the strategic level. It is the purpose of this method-oriented article to explain the major features of "rule-based discrete event simulation" (rule-based DES), which we developed independently in Germany and Switzerland. Our rule-based DES addresses questions concerning the location and relocation of ambulances, dispatching and routing policies, and EMS interplay with other players in prehospital care. We highlight three typical use cases from a practitioner's perspective and go into different countries' peculiarities. We show how research results are applied to EMS and healthcare organizations to simulate and optimize specific regions in Germany and Switzerland with their strong federal structures. The rule-based DES serves as basis for decision support to improve regional emergency services' efficiency without increasing cost. Finally, all simulation-based methods suggest normative solutions and optimize EMS' performance within given healthcare system structures. We argue that interactions between EMS, emergency departments, and public healthcare agencies are crucial to further improving effectiveness, efficiency, and quality.

Are predictive biomarkers of toxicity worth having? An economic model.

In this paper we model the cost-benefit of excluding populations at risk through predictive toxicity biomarkers and diagnostics. False positives/ negatives inherent in predictive markers and the frequency and nature of adverse events determine whether biomarkers are beneficial and economically viable. We present a model that takes these and other factors into account using data largely in line with real world cases.

Will biomedical innovation change the future of healthcare?

Healthcare costs in all industrial nations have increased and payors are starting to look at new ways to contain costs and at new funding models. The business model of pharmaceutical companies is also undergoing rapid changes - potentially disruptive new modalities, such as RNAi, therapeutic vaccines, and cell therapy are emerging, R&D costs have increased year on year, pressures on drug pricing and the efficacy and safety of medicines are mounting. Change is therefore inevitable and already ongoing in healthcare systems and pharmaceutical companies alike. This paper presents several major forces which could drive different future scenarios including: R&D costs, the source of payments for medicines and the emergence of new modalities.

Small, non-peptide C5a receptor antagonists: part 1.

The optimisation of a series of amides for C5a receptor binding and functional activity, and physicochemical properties is described. The initial hit, 1 (IC(50) 1 microM), was discovered during high throughput screening, from which highly potent C5a receptor antagonists (e.g.14, IC(50) 5 nM) were developed.

Small, non-peptide C5a receptor antagonists: part 2.

Starting from 2, several highly potent C5a receptor antagonists were synthesised through alpha-amide substitution. Attempts to increase the polarity of these compounds through the introduction of basic centres or incorporation into weakly basic heterocycles is described.

Pharmaceutical R&D in the spotlight: why is there still unmet medical need?

Huge amounts of money and knowledge have been poured into biomedical research for decades. Yet, in some disease areas next to no progress has been made in providing medical treatment. Importantly, it is not only neglected diseases where unmet medical need remains, but many diseases of 'rich' countries are also affected. Occasionally, new therapies exacerbate the medical need gap, such as in cancer. Our paper discusses some of the reasons why this might be and why all of society needs to find solutions to address unmet medical need.

Communicating the risks and benefits of medicines.

Pharmaceutical innovation, together with rising education, sanitation and wealth, prolonged life expectancy in industrialised countries throughout the 20th century. At the turn of the 21st century, with many, formerly common, lethal diseases confined to the developing world, the benefits of medical intervention are taken for granted in industrialized countries, and the expectations of safety have risen considerably. The perception and tolerance of risk has changed largely in the absence of immediate, population-wide health threats. Here, we review selected examples of drug withdrawals and adverse drug effects, and their impact on public perception. We analyse the role of major players, such as the media, patients, prescribers, regulators and pharmaceutical companies, and what actions are needed to better describe and communicate the risks and benefits of medicines to the public.

R&D technology investments: misguided and expensive or a better way to discover medicines?

The pharmaceutical industry is in crisis owing to spiralling costs and a lack of new product launches. It is said that expensive investments in technology have not paid off. But is this really true? In this review, we explore some of the recent medicines that were, or are being, brought to market, and we discuss how they were discovered and what difference new technologies have made during the discovery of these medicines.

Drug withdrawals and the lessons within.

Drug withdrawals over recent decades have triggered changes in the way that drug targets and screening programs are researched and designed. In the cases having the greatest impact, the reason for withdrawal was the reversible interaction of a drug or its metabolite with a single receptor, ion channel or enzyme (primary or secondary pharmacology). Once this interaction is identified, screens can be established and validated. When the mechanism is complex (eg, organ toxicity), however, such screens are difficult to implement and usually examine only the initial step, leading to considerable problems in extrapolation and risk definition. This review classifies drugs withdrawn from the US market over the last 25 years by their reasons for withdrawal, and examines how drug discovery programs have been modified in response to these events.

Keynote review: Is declining innovation in the pharmaceutical industry a myth?

Increasing the rate of innovation is a requirement to achieve much-needed advances in patient care, as well as to secure the future of the pharmaceutical industry. Currently, there is a perception in the external environment that pharmaceutical R&D is no longer innovative, fails to bring new drugs to market or, at best, produces a rising number of 'me-too' drugs with no advantage over existing treatments. In addition, the cost to discover and develop new medicines (i.e. cost per launch) has risen dramatically in recent years. The quoted development cost per medicine is a reality, and is not disputed here. However, data are provided that demonstrate that with regard to innovation rates, the current perception is wrong - although there have been, and continue to be, fluctuations in drug launches, there has been a steady increase in the number of new chemical entities launched, both in absolute numbers of FDA-approved medicines and in the proportion of priority reviews.

Oral delivery of G protein-coupled receptor modulators: an explanation for the observed class difference.

G protein-coupled receptors (GPCRs) represent important targets for drug intervention. However, analysis of GPCR modulator drugs exhibits an important class difference, with many drugs available against aminergic GPCR targets, but relatively few against non-aminergic targets. The reason for this is that commonly drugs mimic the physicochemistry of the receptor ligand. Aminergic ligands generally exhibit physicochemical properties (molecular weight, lipophilicity and hydrogen bonding potential) that are consistent with extensive oral absorption. In contrast, non-aminergic ligands generally exhibit physicochemical properties that are at odds with oral delivery. Thus, combining required potency versus the receptor, with oral delivery potential is a significant challenge, and drug discovery becomes a question of finding the exceptional compound that lies at the edge of ADME space.

Is pharmaceutical R&D just a game of chance or can strategy make a difference?

The pharmaceutical industry is currently experiencing turbulent, yet exciting times. Despite widely expressed negative sentiments regarding productivity there are now signs that innovation could yet win the day and bring a fresh wave of breakthrough drugs. Nowhere is this truer than for oncology, which previously was dominated by cytotoxic drugs. Today, however, this field shows exciting progress with the emergence of kinase inhibitors, as well as various antibody-based mechanistic approaches. Similarly, new drug mechanisms have transformed HIV therapy. Are these chance events, or have they come about through strategy? Here, we argue that a complex interplay of chance and strategy is at work in pharmaceutical R&D, separated in time by 10 years or more.

Do drug metabolism and pharmacokinetic departments make any contribution to drug discovery?

The alignment of drug metabolism and pharmacokinetic departments with drug discovery has not produced a radical improvement in the pharmacokinetic properties of new chemical entities. The reason for this is complex, reflecting in part the difficulty of combining potency, selectivity, water solubility, metabolic stability and membrane permeability into a single molecule. This combination becomes increasingly problematic as the drug targets become more distant from aminergic seven-transmembrane-spanning receptors (7-TMs). The leads available for aminergic 7-TMs, like the natural agonists, are invariably small molecular weight, water soluble and potent. Even moving to 7-TMs for which the agonist is a peptide invariably produces lead matter that is less drug-like (higher molecular weight and lipophilic). The role of drug metabolism departments, therefore, has been to guide chemistry to obtaining adequate, rather than optimal, pharmacokinetic properties for these 'difficult' drug targets. A consistent belief of many researchers is that a high value is placed on optimal, rather than adequate, pharmacokinetic properties. One measure of value is market sales, and when these are examined no clear pattern emerges. Part of the success of amlodipine in the calcium channel antagonist sector must be due to its excellent pharmacokinetic profile, but the best-selling drugs among the angiotensin antagonists and beta-blockers have a much greater market share than other agents with better pharmacokinetic properties. Clearly, many other factors are important in the successful launch of a medicine, some reflected in the manner the compound is developed and the subsequent structure of the labelling. Overall, therefore the presence of drug metabolism in drug discovery has probably contributed most by allowing 'difficult' drug targets to be prosecuted, rather than by guiding medicinal chemists to optimal pharmacokinetics. These 'difficult' target candidates become successful drugs when skilfully developed. There is no doubt that skilful development relies heavily on drug metabolism and pharmacokinetic departments, in this case those with a clinical rather than a preclinical orientation.

Discovery, innovation and the cyclical nature of the pharmaceutical business.

Unlike many recent articles, which paint the future of the pharmaceutical industry in gloomy colours, this article provides an optimistic outlook. It explores the foundations on which the pharmaceutical industry has based its outstanding successes. Case studies of important drug classes underpin the arguments made and provide the basis for the authors' argument that recent technological breakthroughs and the unravelling of the human genome will provide a new wave of high quality targets (substrate) on which the industry can build. The article suggests that in a conducive environment that understands the benefits that pharmaceuticals provide to healthcare, those players who can base their innovation on a sufficient scale and from a large capital base will reshape the industry.

AUD4, a new amplifiable element from Streptomyces lividans.

After transformation of the Streptomyces lividans chloramphenicol-sensitive, arginine-auxotrophic mutant strain AJ100 with a derivative of plasmid SCP2, some of the regenerated protoplasts contained an 8.2 kb DNA sequence amplified to several hundred copies per chromosome. The corresponding non-amplified sequence, called AUD4, was isolated from a lambda phage genomic library of S. lividans 1326. Two cytosine residues were the only directly repeated nucleotides at the ends of the element, indicating that AUD4 is a class I amplifiable sequence. The element mapped in the AseI-D fragment of the S. lividans chromosome, where other class I amplifications have been described. The complete element was sequenced and 10 ORFs were identified. Some of the deduced proteins are highly conserved in other organisms but a putative function could be attributed to only a few of them. Duplication of AUD4 by integration of an Escherichia coli plasmid carrying various parts of AUD4 and a thiostrepton-resistance gene in S. lividans AJ100, ZX7 or TK64 induced amplification of the integrated plasmid, AUD4 or both at high frequency.