The role of mouse tumour models in the discovery and development of anticancer drugs.

Our understanding of cancer biology has increased substantially over the past 30 years. Despite this, and an increasing pharmaceutical company expenditure on research and development, the approval of novel oncology drugs during the past decade continues to be modest. In addition, the attrition of agents during clinical development remains high.

Overview of experimental models of the blood-brain barrier in CNS drug discovery.

The blood-brain barrier (BBB) is a physical and metabolic entity that isolates the brain from the systemic circulation. The barrier consists of tight junctions between endothelial cells that contain egress transporters and catabolic enzymes. To cross the BBB, a drug must possess the appropriate physicochemical properties to achieve a sufficient time-concentration profile in brain interstitial fluid (ISF).

New and emerging immune-targeted drugs for the treatment of multiple sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component that constitutes the most common progressive and disabling neurological condition in young adults. Injectable immunomodulatory medicines such as interferon drugs and glatiramer acetate have dominated the MS market for over the past two decades but this situation is set to change. This is because of: (i) patent expirations, (ii) the introduction of natalizumab, which targets the interaction between leukocytes and the blood-CNS barrier, (iii) the launch of three oral immunomodulatory drugs (fingolimod, dimethyl fumarate and teriflunomide), with another (laquinimod) under regulatory review and (iv) a number of immunomodulatory monoclonal antibodies (alemtuzumab, daclizumab and ocrelizumab) about to enter the market.

Multiple sclerosis and the blood-central nervous system barrier.

The central nervous system (CNS) is isolated from the blood system by a physical barrier that contains efflux transporters and catabolic enzymes. This blood-CNS barrier (BCNSB) plays a pivotal role in the pathophysiology of multiple sclerosis (MS). It binds and anchors activated leukocytes to permit their movement across the BCNSB and into the CNS.

Translational CNS medicines research.

The major imperative of the pharmaceutical industry is to effectively translate insights gained from basic research into new medicines. This task is toughest for CNS disorders. Compared with non-CNS drugs, CNS drugs take longer to get to market and their attrition rate is greater.

The role of the blood brain barrier in neurodegenerative disorders and their treatment.

Neurodegenerative disorders represent a major medical challenge that is set to increase substantially in the decades ahead with the massive increase in the number of people in the world aged 65 or more. Neuroprotective therapeutics have the potential to play a key role in helping manage this growing global burden of long-term neurological care. However, neuropharmaceutical research is associated with significant challenges including: (1) the complexity of the brain (the cause of the majority of neurodegenerative disorders remains unknown); (2) the liability of central nervous system (CNS) drugs to cause CNS side effects (which limits their use); and (3) the requirement of neuropharmaceuticals to cross the blood-brain barrier (BBB).

Neuroprotective therapeutics for Alzheimer's disease: progress and prospects.

The number of people with Alzheimer's disease (AD) has never been greater and is set to increase substantially in the decades ahead as the proportion of the population aged 65 years or more rises sharply. There is therefore an urgent need for safe and effective pharmacotherapy to help combat the corresponding and substantial increase in disease burden. Increased understanding of disease aetiology and pathophysiology, particularly in relation to the loss of vulnerable neurons and the formation of plaques and tangles, has increased hope for medications that can slow (or perhaps even halt) the course of the disease.

Teriflunomide, an inhibitor of dihydroorotate dehydrogenase for the potential oral treatment of multiple sclerosis.

Teriflunomide, being developed as a potential oral treatment for multiple sclerosis (MS) by sanofi-aventis, is the active metabolite of the rheumatoid arthritis drug leflunomide. Both teriflunomide and leflunomide are inhibitors of the mitochondrial enzyme dihydroorotate dehydrogenase, which is critically involved in pyrimidine synthesis. The production of activated T-cells largely depends on de novo pyrimidine synthesis, and thus pyrimidine depletion is thought to result in the inhibition of immune cell proliferation.

Neurochemical changes in a double transgenic mouse model of Alzheimer's disease fed a pro-oxidant diet.

Oxidative stress is implicated in the pathogenesis of Alzheimer's disease (AD) causing neurodegeneration and decreased monoamine neurotransmitters. We investigated the effect of administration of a pro-oxidant diet on the levels of monoamines and metabolites in the brains of wildtype and transgenic mice expressing mutant APP and PS-1 (TASTPM mice). Three-month-old TASTPM and wildtype (C57BL6/J) mice were fed either normal or pro-oxidant diet for 3 months.

Measurement of the pharmacokinetics and pharmacodynamics of neuroactive compounds.

The need to discover and develop safe and effective new medicines is greatest for disorders of the CNS. A core requirement for an effective neurotherapeutic agent is an ability to cross the blood-brain barrier and remain in the brain interstitial fluid (ISF) for a sufficient duration and concentration to evoke the desired therapeutic effect. Measuring the free concentration of a neuroactive compound in brain ISF is therefore an essential step in the critical path towards the development of a CNS medicine.

The role of the blood-CNS barrier in CNS disorders and their treatment.

The physical barrier between blood and the CNS (the blood-brain barrier, the blood-spinal cord barrier and the blood-CSF barrier) protects the CNS from both toxic and pathogenic agents in the blood. It is now clear that disruption of the blood-CNS barrier plays a key role in a number of CNS disorders, particularly those associated with neurodegeneration. Such disruption is inevitably accompanied by inflammatory change, as immune cells and immune mediators gain access to the brain or spinal cord.

Pharmacotherapy for multiple sclerosis: progress and prospects.

Multiple sclerosis (MS) is a neurodegenerative disease with a major inflammatory component, and constitutes the most common progressive and disabling neurological condition in young adults. Currently available therapies predominantly include biological agents (beta-interferon and a mAb to a cell adhesion molecule [integrin] on lymphocytes that is involved in the adhesion of lymphocytes to the blood-brain barrier) that attenuate the neuroinflammatory response; however, the ability of these agents to modify the disease course of MS is only modest at best. Because of the inadequacy of current treatment options, there is a need for the development of more effective disease-modifying therapies (eg, sodium channel blockers), along with new drugs to treat specific symptoms of MS, such as fatigue.

Neurodegenerative disorders and their treatment.

This Society for Medicines Research symposium was held on June 6, 2007, at the Eli Lilly Research Centre in Windlesham, Surrey, United Kingdom. The meeting, organized by Eric Karran and Alan Palmer, reviewed the progress made, and the challenges still to be overcome, in discovering safe and effective therapies for the most common chronic neurodegenerative diseases: Alzheimer's disease, Parkinson's disease and multiple sclerosis. Progress in establishing effective pharmacotherapy for acute neurodegenerative disorders (stroke and traumatic brain injury) was also reviewed.

Society for Medicines Research: 40th anniversary symposium.

The recent symposium of the Society for Medicines Research (SMR), held on December 11, 2006, in Westminster, UK, celebrated the 40th anniversary of the formation of the SMR. The meeting began with an overview of future strategies for medicines research and its funding in Europe. This session was followed by the 2006 SMR Award lecture, which was given by Dr.

Drug metabolism and pharmacokinetics, the blood-brain barrier, and central nervous system drug discovery.

The worldwide market for therapies for CNS disorders is worth more than 50 billion dollars and is set to grow substantially in the years ahead. This is because: 1) the incidence of many CNS disorders (e.g.

Therapeutic strategies for tissue regeneration.

Tissue regeneration represents an emerging approach to the development of new medicines. It has even been described as the major therapeutic approach of the 21st century. Realization of this promise depends on overcoming a number of significant challenges.

CNS drug discovery: challenges and solutions.

The worldwide market for therapies for central nervous system (CNS) disorders was valued at around US dollars 50 billion in 2001, and is set to grow sharply in the years ahead. This is because of a marked increase in the number of people aged over 65 (the "baby boomer" effect), which will lead to increased demand for more safe and effective medicines for CNS disorders. This one-day Society for Medicines Research symposium, held September 23, 2004, in London, United Kingdom, was organized by Dr.

The pivotal role of drug metabolism and pharmacokinetics in the discovery and development of new medicines.

An appropriate drug metabolism and pharmacokinetic (DMPK) profile remains a major hurdle to reducing risk and improving productivity in pharmaceutical R&D, accounting for approximately 40% of all drug failures. For orally administered drugs, failure is often attributable to low intestinal absorption and/or high clearance, causing poor and variable bioavailability. Additional reasons for failure include drug-drug interactions and the presence of active metabolites.

Pharmacotherapy for neuropathic pain: progress and prospects.

Neuropathic pain, a persistent chronic pain resulting from damage to the central or peripheral pain signaling pathway, has become an area of intense research activity--largely because it represents a disorder with high unmet medical need. It is not a single disease entity, but rather includes a range of heterogeneous conditions that differ in etiology, location and initiating cause. Despite this diversity, the clinical presentation is frequently surprisingly similar, which suggests a common biological basis.

Cholinergic therapies for Alzheimer's disease: progress and prospects.

Cholinomimetic drugs are now available to treat the cognitive impairments associated with Alzheimer's disease (AD), although evidence indicates that the effects of acetylcholinesterase (AChE) inhibitors on measures of cognitive function may be secondary to an action on attentional mechanisms. There is also convincing evidence suggesting that cholinomimetic drugs (e.g.

Characterisation of the actions of group I metabotropic glutamate receptor subtype selective ligands on excitatory amino acid release and sodium-dependent re-uptake in rat cerebrocortical minislices.

In this study we have tested the effects of a wide range of metabotropic glutamate receptor ligands on (i) depolarisation-evoked efflux of pre-accumulated d-[3H]aspartic acid (d-[3H]asp) from rapidly superfused rat cerebrocortical minislices, and (ii) Na+-dependent uptake of d-[3H]asp into cerebrocortical tissue. Transient elevations in extracellular K+ produced concentration-dependent increases in d-[3H]asp efflux. A submaximally effective concentration (50 mm) was used in all subsequent experiments.