Showing papers in "Expert Opinion on Investigational Drugs in 2004"

Inhibitors of dipeptidyl peptidase IV: a novel approach for the prevention and treatment of Type 2 diabetes?

Abstract: Inhibitors of the enzyme dipeptidyl peptidase IV (DPP IV) are of increasing interest to both diabetologists and the pharmaceutical industry alike, as they may become established as the next member of the oral antidiabetic class of therapeutic agents, designed to lower blood glucose and, possibly, prevent the progressive impairment of glucose metabolism in patients with impaired glucose tolerance and Type 2 diabetes. DPP IV has become a focus of attention for drug design, as it has a pivotal role in the rapid degradation of at least two of the hormones released during food ingestion, a property that has warranted the design of inhibitor-based drugs. At the molecular level, DPP IV cleaves two amino acids from the N-terminus of the intact, biologically active forms of both so-called incretin hormones, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (formerly known as gastric inhibitory polypeptide), resulting in truncated metabolites, which are largely inactive. Inhibition of the enzyme, therefore, is thought to increase levels of the active forms of both incretin hormones, culminating in an increase in insulin release after a meal, in a fully glucosedependant manner. DPP IV inhibitors combine several features of interest to the drug design process. They can be readily optimised for their target and be designed as low molecular weight, orally active entities compatible with once-daily administration.

Combretastatin A4 phosphate: background and current clinical status

Abstract: Combretastatin A4 phosphate (CA4P) represents the lead compound in a group of novel tubulin depolymerising agents being developed as vascular targeting agents (VTAs). VTAs are drugs that induce rapid and selective vascular dysfunction in tumours. CA4P is a water-soluble prodrug of the cis-stilbene CA4 originally isolated from the tree Combretum caffrum. Preclinical studies have shown that CA4P induces blood flow reductions and subsequent tumour cell death in a variety of preclinical models. Moreover, this activity has been linked to its ability to rapidly alter the morphology of immature endothelial cells by disrupting their tubulin cytoskeleton. Phase I clinical trials have established a maximum tolerated dose in the range 60-68 mg/m2 and in addition have established that significant changes to tumour perfusion can be achieved across a wide range of doses. The dose-limiting toxicities include tumour pain, ataxia and cardiovascular changes. The maximum tolerated dose was independent of schedule, indicating the absence of cumulative toxicity. Although unexpected from preclinical studies, some evidence of clinical response was seen using CA4P as a single modality. Based on the Phase I data, combination studies of CA4P with established therapies are in progress and should determine whether the exciting preclinical data obtained when VTAs are used in combination with cytotoxic chemotherapy, radiation, radioimmunotherapy and even antiangiogenic agents, can be translated into man.

From chemoprevention to chemotherapy: Common targets and common goals

Abstract: Three decades of research have revealed that cancer is easier to prevent than to treat and that consumption of certain fruits and vegetables can reduce the risk of cancer. Whereas chemotherapy is designed to destroy cancer after it appears, chemoprevention involves the abrogation or delay in the onset of cancer. Regardless of whether a chemopreventive or chemotherapeutic approach is taken, cancer is a multifactorial disease that requires modulation of multiple pathways and multiple targets. Various molecular targets of chemoprevention are also relevant to the therapy of cancer. These targets include the activation of apoptosis; suppression of growth factor expression or signalling; downregulation of antiapoptotic proteins; suppression of phosphatidylinositol-3′-kinase/Akt, NF-κB, Janus kinase-signal transducer and activator of transcription and activator protein-1 signalling pathways; and downregulation of angiogenesis through inhibition of vascular endothelial growth factor expression, cyclooxygenase-2, ...

The therapeutic potential of CRF1 antagonists for anxiety

Abstract: Preclinical studies suggest that the brain corticotropin-releasing factor (CRF) systems mediate anxiety-like behavioural and somatic responses through actions at the CRF1 receptor. CRF1 antagonists block the anxiogenic-like effects of CRF and stress in animal models. Cerebrospinal fluid levels of CRF are elevated in some anxiety disorders and normalise with effective treatment, further implicating CRF systems as a therapeutic target. Prototypical CRF1 antagonists are highly lipophilic, non-competitive antagonists of peptide ligands. Modification of the chemotype and the identification of novel pharmacophores are yielding more drug-like structures with increased hydrophilicity at physiological pHs. Newer compounds exhibit improved solubility, pharmacokinetic properties, potency and efficacy. Several clinical candidates have entered Phase I/II trials. However, unmet challenges await resolution during further discovery, clinical development and therapeutic application of CRF1 antagonists.

Targeting Syk as a treatment for allergic and autoimmune disorders.

Abstract: Recent advances in our understanding of allergic and autoimmune disorders have begun to translate into novel, effective and safe medicines for these common maladies. Examples include an anti-IgE monoclonal antibody recently approved for severe asthmatics and the TNF-alpha antagonists that have demonstrated their ability to suppress rheumatoid arthritis, Crohn's disease and other chronic inflammatory processes. However, protein therapies are difficult and expensive to develop, manufacture and administer. Clearly, there is also a need for small-molecule inhibitors of novel targets that have safe and effective characteristics. Syk is an intracellular protein tyrosine kinase that was discovered 15 years ago as a key mediator of immunoreceptor signalling in a host of inflammatory cells including B cells, mast cells, macrophages and neutrophils. These immunoreceptors, including Fc receptors and the B-cell receptor, are important for both allergic diseases and antibody-mediated autoimmune diseases and thus pharmacologically interfering with Syk could conceivably treat these disorders. In addition, as Syk is positioned upstream in the cell signalling pathway, therapies targeting Syk may be more advantageous relative to drugs that inhibit a single downstream event. Syk inhibition during an allergic or asthmatic response will block three mast cell functions: the release of preformed mediators such as histamine, the production of lipid mediators such as leukotrienes and prostaglandins and the secretion of cytokines. In contrast, commonly used antihistamines or leukotriene receptor antagonists target only a single mediator of this complex cascade. Despite its expression in platelets and other non-haematopoietic cells, the role of Syk in regulating vascular homeostasis and other housekeeping functions is minimal or masked by redundant Syk-independent pathways. This suggests that targeting Syk would be an optimal approach to effectively treat a multitude of chronic inflammatory diseases without undue toxicity.

The role of growth factors in the pathogenesis of diabetic retinopathy.

Abstract: Diabetic retinopathy (DR) is the most severe of several ocular complications of diabetes. The earliest clinical signs of DR are microaneurysms and haemorrhages. Later signs include dilated, tortuou...

Exploitation of silicon medicinal chemistry in drug discovery.

Abstract: There remains considerable pressure on the pharmaceutical industry to increase productivity and reduce the attrition of drug candidates. Genomics, parallel chemistry and high-throughput biology have not yielded the anticipated benefits, resulting in a renewed focus on validated targets and an aim to generate drugs directed towards such targets, which have a clear advantage. One strategy to identify and develop best-in-class drugs is to apply a high degree of innovation in chemistry and apply this to targets from gene families that have been clinically validated as tractable and drugable. The application of organosilicon medicinal chemistry in the context of privileged structures to aid drug design and development is one such innovative approach that is reviewed in this paper.

Preclinical evaluation of novel antibacterial agents by microbiological and molecular techniques

Abstract: The defining property of an antibacterial agent is its ability to selectively interfere with bacterial growth and/or survival. Consequently, a considerable and crucial part of the preclinical evaluation of any novel antibacterial drug involves judging and characterising its effects on bacteria in vitro. These critical stages in drug development are sometimes made to appear somewhat trivial, sandwiched as they are between the highly demanding antibacterial discovery process and the formidable task of demonstrating safety and efficacy in vivo. However, careful biological evaluation in vitro is key to quantifying and understanding the basis of the antibacterial activity, providing preliminary indications and evaluations of therapeutic potential, assessing the likelihood for the development of bacterial resistance, guiding chemical refinement and assisting subsequent stages of the appraisal of any new antibacterial drug. This review covers concepts in, and strategies for, the in vitro microbiological and mole...

Camptothecins in clinical development.

Abstract: Following the realisation that DNA topoisomerase I is a useful therapeutic target to be exploited for the design of potential inhibitors, topoisomerase I inhibitors now represent an established class of effective agents. In spite of intense efforts in the field, only camptothecins have a clinical relevance. Several options in chemical manipulation of natural camptothecin have been explored to overcome the major drawbacks of the drug, which include water insolubility, lactone instability, reversibility of the drug-target interaction and drug resistance. Several analogues are currently in clinical development, including water soluble camptothecins, lipophilic camptothecins and polymer-bound camptothecins. The therapeutic advantages of novel camptothecins over the two analogues (topotecan and irinotecan) approved for clinical use remain to be defined. This article is an overview of the relevant features of the analogues that are undergoing clinical development.

Histone deacetylase inhibitors in clinical development.

Abstract: In addition to a variety of other novel agents, interest in histone deacetylase inhibitors (HDACIs) as antineoplastic drugs has recently accelerated and increasing numbers of these compounds have entered clinical trials in humans. HDACIs represent a prototype of molecularly targeted agents that perturb signal transduction, cell cycle-regulatory and survival-related pathways. Newer generation HDACIs have been introduced into the clinical arena that are considerably more potent on a molar basis than their predecessors and are beginning to show early evidence of activity, particularly in hematopoietic malignancies. In addition, there is an increasing appreciation of the fact that HDACIs may act through mechanisms other than induction of histone acetylation and, as in the case of other molecularly-targeted agents, it is conceivable that the ultimate role of HDACIs in cancer therapy will be as modulators of apoptosis induced by other cytotoxic agents. One particularly promising strategy involves attempts to combine HDACIs with other novel agents to promote tumour cell differentiation or apoptosis. The present review focuses on recent insights into the mechanisms by which HDACIs exert their anticancer effects, either alone or in combination with other compounds, as well as attempts to translate these findings into the clinic.

Diquafosol tetrasodium: a novel dry eye therapy

Abstract: The ophthalmic formulation of diquafosol tetrasodium (INS365), a P2Y2 receptor agonist, is targeted to treat dry eye disease through rehydration of the ocular surface. Existing pharmacological therapies for dry eye disease are limited, therefore, approval of this medication is anticipated. This review summarises key findings during development and in clinical trials including clinical effectiveness and safety. The relevance of P2Y2 receptor technology to dry eye disease and the disease process is discussed.

Peroxisome proliferator-activated receptor-γ: therapeutic target for diseases beyond diabetes: quo vadis?

Abstract: The discovery that the insulin-sensitising thiazolidinediones (TZDs), specific peroxisome proliferator-activated receptor-γ (PPARγ) agonists, have antiproliferative, anti-inflammatory and immunomodulatory effects has led to the evaluation of their potential use in the treatment of diabetic complications and inflammatory, proliferative diseases in non-insulin-resistant, euglycaemic individuals. Apart from improving insulin resistance, plasma lipids and systemic inflammatory markers, ameliorating atherosclerosis and preventing coronary artery restenosis in diabetic subjects, currently approved TZDs have been shown to improve psoriasis and ulcerative colitis in euglycaemic human subjects. These data imply that the activation of PPAR-γ may improve cardiovascular risk factors and cardiovascular outcomes in both insulin-resistant diabetic and non-diabetic individuals. Through their immunomodulatory and anti-inflammatory actions, TZDs and other PPAR-γ agonists may prove to be effective in treating diseases unrel...

Recent developments in transient receptor potential vanilloid receptor 1 agonist-based therapies.

Abstract: Capsaicin and other naturally occurring pungent molecules have been used for centuries as topical analgesics and rubefactants to treat a variety of chronically painful conditions. Recently, instillations of high-concentration capsaicin and resiniferatoxin solutions have been found to be useful for the management of persistent bladder pain or overactive bladder. However, only within the last 7 years has it been appreciated that the selective action of these compounds on a subset of sensory nerve fibres is mediated by agonist activity at a ligand-gated ion channel called the transient receptor potential vanilloid receptor 1 (TRPV1). Accordingly, this discovery has fueled intensive research and drug development efforts, mainly in a search for novel analgesic or anti-inflammatory therapies. Two different, but non-mutually exclusive, strategies are being pursued: optimisation of TRPV1 agonist-based therapies, which can functionally inactivate nociceptive nerve fibres, and identification of receptor antagonists, which would prevent nociceptive fibres from being activated by ongoing inflammatory stimuli. Available information on TRPV1 agonists in development and their biological rationale will be summarised in this review.

Recent advances in protein tyrosine phosphatase 1B inhibitors

Abstract: Type 2 diabetes and obesity are characterised by insulin and leptin resistance. Studies suggest that these may be due to defects in the insulin and leptin signalling pathways. Over the last decade, a considerable body of evidence has been amassed indicating that protein tyrosine phosphatase 1B (PTP1B) is involved in the downregulation of insulin and leptin signalling. Consequently, compounds that inhibit PTP1B have potential as therapeutics for treating Type 2 diabetes and obesity. This review covers recent advances in PTP1B inhibitors with an emphasis on recent attempts to create potent, selective and cell-permeable small-molecule inhibitors.

Therapeutic potential of melanin-concentrating hormone-1 receptor antagonists for the treatment of obesity

Abstract: The compelling genetic and pharmacological evidence implicating melanin-concentrating hormone-1 receptor (MCH-1R) signalling in the regulation of food intake and energy expenditure has generated a great deal of interest by pharmaceutical companies for the discovery of MCH-1R antagonists, evidenced by the increased number of patents describing MCH-1R antagonists for the treatment of obesity and metabolic syndrome. The structural diversity of small molecular weight drug-like MCH-1R antagonists produced and preclinical studies showing hypophagia and weight loss with small molecular weight and peptidal antagonists in rodents is encouraging and suggests that the identification of clinical candidates will be forthcoming.

Lipopeptides, focusing on daptomycin, for the treatment of Gram-positive infections.

Abstract: The increasing incidence of serious infections caused by antibiotic-resistant Gram-positive bacteria has led to the development of new spectrum-specific agents. One such agent is Cubicin (daptomycin for injection), the first member of a new class of antibacterials called cyclic lipopeptides. Daptomycin has rapid, concentration-dependent bactericidal activity against most clinically significant Gram-positive pathogens, including vancomycin-resistant enterococci, methicillin-resistant Staphylococcus aureus, and vancomycin-intermediate and -resistant S. aureus. This cyclic lipopeptide has a unique mechanism of action and exhibits a relatively prolonged concentration-dependent postantibiotic effect in vitro. In September 2003 the US FDA approved daptomycin for the treatment of complicated skin and skin-structure infections. With its once-daily dosing, excellent safety profile and low potential for resistance, daptomycin is a welcome new addition to the armamentarium against Gram-positive infections.

The therapeutic potential of agents targeting the type I insulin-like growth factor receptor.

Abstract: The type I insulin-like growth factor receptor (IGF-1R) is a receptor tyrosine kinase that mediates insulin-like growth factor I (IGF-1) and IGF-2 signalling. Increased expression levels and/or enhanced activity of IGF-1R have been observed in many types of cancer. It is well documented that IGF-1R plays important roles in the proliferation, transformation, motility and metastasis of cancer cells. Therefore, IGF-1R has surfaced as an attractive target for cancer therapy. There are several aspects of this receptor that need to be considered when thinking about inhibitory strategies. In this review, several points relevant to targeting IGF-1R will be discussed, including the signalling pathways downstream of the receptor, the potential role for the insulin receptor in regulating IGF action and multiple cancer phenotypes regulated by this receptor. In addition, there are several strategies that could be used to inhibit IGF action. Inhibition of receptor function by lowering protein expression, decreasing kinase activity by small-molecule inhibitors, disrupting receptor function by monoclonal antibody blockade and neutralising circulating ligand all represent potential therapeutic strategies. As these strategies move forward to clinical trial, several important considerations need to be incorporated into the clinical trial design.

Recent advances in natriuretic peptides in congestive heart failure

Abstract: Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are secreted by the heart and play important roles in the compensation of congestive heart failure with their vasodilating, natriuretic, antiproliferative, lusitropic and neurohumoral-modulating properties. Based on these beneficial properties, exogenous BNP was developed as a new treatment for congestive heart failure and approved in the US for acute decompensated heart failure. New therapeutic strategies for heart failure that are currently being investigated include chronic subcutaneous BNP administration and intermittent BNP infusions. Furthermore, strategies combining exogenous BNP with an inhibitor of the BNP-degrading enzyme neutral endopeptidase could contribute to maximising the actions of BNP and reduce the amount of exogenous BNP needed.

Cancer metastasis therapeutic targets and drug discovery: emerging small-molecule protein kinase inhibitors.

Abstract: Cancer metastasis is a significant problem and a tremendous challenge to drug discovery relative to identifying key therapeutic targets as well as developing breakthrough medicines. Recent progress in unravelling the complex molecular circuitry of cancer metastasis, including receptors, intracellular proteins and genes, is highlighted. Furthermore, recent advances in drug discovery to provide novel proof-of-concept ligands, in vivo effective lead compounds and promising clinical candidates, are summarised. Such drug discovery efforts illustrate the integration of functional genomics, cell biology, structural biology, drug design, molecular/cellular screening and chemical diversity (e.g., small molecules, peptides/peptidomimetics, natural products, antisense, vaccines and antibodies). Promising therapeutic targets for cancer metastasis have been identified, including Src, focal adhesion kinase, the integrin receptor, the vascular endothelial growth factor receptor, the epidermal growth factor receptor, Her-2/neu, c-Met, Ras/Rac GTPases, Raf kinase, farnesyl diphosphate synthase (i.e., amino-bisphosphonate therapeutic target) and matrix metalloproteases within the context of their implicated functional roles in cancer growth, invasion, angiogenesis and survival at secondary sites. Clinical and preclinical drug discovery is described and emerging small-molecule inhibitors of protein kinases are highlighted.

Perspectives on cognitive domains, H3 receptor ligands and neurological disease

Abstract: Histamine H3 receptor agonists and antagonists have been evaluated in numerous in vitro and in vivo animal models to better understand how H3 receptors modulate neurotransmitter function in the central nervous system. Likewise, behavioural models have explored the hypothesis that changes in neurotransmitter release could enhance cognitive function in human diseases. This review examines the reported effects of H3 receptor ligands and how they influence cognitive behaviour. These data are interpreted on the basis of different cognitive domains that are relevant to neuropsychiatric diseases. Because of the diversity of H3 receptors, their function and their influence on neurotransmitter systems, considerable promise exists for H3 ligands to treat diseases in which aspects of learning and memory are impaired. However, because of the complexities of the histaminergic system and H3 receptors and the lack of clinical data so far, proof of principle for use in human disease remains to be established.

Metal-protein attenuating compounds and Alzheimer's disease.

Abstract: Since the description of the amyloid plaque in the pathology of Alzheimer’s disease, one of the main focuses of research has been the role of the amyloid precursor protein metabolite amyloid-β, which is the constituent protein of plaque. Affecting the production, aggregation or clearance of this protein may well have a modifying effect on disease progression. Although available therapies for Alzheimer’s disease may interact with amyloid-β in vivo, no conspicuous disease-modifying effect has been demonstrated in clinical trials with these drugs. Drugs whose primary target is not the rectification of the neurotransmitter deficits associated with Alzheimer’s disease but rather the life cycle of amyloid-β are currently being developed with varying degrees of success. Of these drugs, the metal-protein attenuating compounds have currently the most encouraging clinical data supporting their use. Clioquinol is an example from this class, which has recently shown encouraging efficacy from early clinical evaluation...

Cataract formation and prevention

Abstract: Cataract, a leading cause of blindness worldwide, is a multifactorial eye disease. In developing countries the incidence of cataract among young generations is not uncommon due to malnutrition, excess exposure to ultraviolet radiation and so on. In developed countries, age-related cataract affecting the population over 65 years of age is a major concern. Oxidative stress was suggested to inflict damage to the lens and induce opacification, and a variety of antioxidant nutrients were tested for the prevention or delay of cataract development. Although promising results were obtained in animal studies of various antioxidants, epidemiological studies on human populations do not seem to support their protective effects unequivocally. It is unlikely that age-related cataract in man, similar to the ageing process itself, will be prevented or delayed by therapeutic drugs in the foreseeable future. At present, keeping a health-conscious life style (i.e., no smoking) may be the most effective and least expensive s...

Recent advances in the development of multifactorial therapies for the treatment of traumatic brain injury.

Abstract: Traumatic brain injury (TBI) is one of the leading causes of death and disability in the industrialised world and remains a major health problem with serious socioeconomic consequences. So far, despite encouraging preclinical results, almost all neuroprotection trials have failed to show any significant efficacy in the treatment of clinical TBI. This may be due, in part, to the fact that most of the therapies investigated have targeted an individual injury factor. It is now recognised that TBI is a very heterogeneous type of injury that varies widely in its aetiology, clinical presentation, severity and pathophysiology. The pathophysiological sequelae of TBI are mediated by an interaction of acute and delayed molecular, biochemical and physiological events that are both complex and multifaceted. Accordingly, a successful TBI treatment may have to simultaneously attenuate many injury factors. Recent efforts in experimental TBI have, therefore, focused on the development of neuropharmacotherapies that target multiple injury factors and thus improve the likelihood of a successful outcome. This review will focus on three such novel compounds that are currently being assessed in clinical trials; progesterone, dexanabinol and dexamethasone, and provide an update on the progress of both magnesium and cyclosporin A.

American Heart Association scientific sessions.

Abstract: The Annual Scientific Sessions of the American Heart Association is the leading scientific conference in the cardiovascular field, both for basic and clinical research in cardiology and related disclipines. This report covers the outcome of major clinical trials that were presented in the ‘late-breaking’ clinical trial sessions. The Valsartan in Acute Myocardial Infarction Trial (VALIANT) investigated the angiotensin receptor blocker valsartan, the angiotensin-converting enzyme inhibitor captopril, and their combination in 14,703 survivors of an acute myocardial infarction with a reduced left ventricular ejection fraction on clinical outcome. The study demonstrated that valsartan and captopril where equally effective, whereas the combination was associated with an increased risk of side effects without further benefit. VALIANT is a landmark trial because it was the first large study that compared the combination of an angiotensin receptor blocker with an angiotensin-converting enzyme inhibitor in the sett...

Gallium nitrate for the treatment of non-Hodgkin's lymphoma.

Abstract: Mortality from non-Hodgkin's lymphoma (NHL) is high, thus defining the need for additional therapeutic agents for this disease. Gallium nitrate is a metal compound that is presently approved for the treatment of hypercalcaemia associated with malignancy. In clinical trials first conducted over two decades ago, this drug was found to have antineoplastic activity in NHL. However, its development as an antineoplastic agent for the treatment of NHL was never rigorously pursued. Gallium has unique mechanisms of action that include its binding to transferrin in the circulation and targeting transferrin receptors present on lymphoma cells. As it shares chemical properties with iron, gallium can disrupt critical steps in iron homeostasis that are essential for tumour cell viability and growth and can inhibit the iron-dependent activity of ribonucleotide reductase. The drug may also target other cellular processes unrelated to iron. Phase I/II studies have shown that gallium nitrate displays the most efficacy and lowest toxicity in NHL when administered as a continuous intravenous infusion, producing response rates of 43% in patients with relapsed or refractory NHL. It does not suppress the white blood cells or platelets and does not share cross-resistance with other chemotherapeutic drugs. These characteristics make it particularly attractive for the treatment of myelosuppressed patients and for incorporation into combination therapy. Multi-institutional Phase II clinical trials are in progress to evaluate gallium nitrate as a single agent or in combination. These studies will help define its role in the current treatment of NHL.

Sarpogrelate: cardiovascular and renal clinical potential

Abstract: Sarpogrelate is a selective 5-hydroxytryptamine receptor subtype 2A (5-HT2A) antagonist. It is metabolised to racemic M-1 and both enantiomers of M-1 are also antagonists of 5-HT2A receptors. Sarpogrelate inhibits responses to 5-HT mediated by 5-HT2A receptors such as platelet aggregation, vasoconstriction and vascular smooth muscle proliferation. There is no information available on the pharmacokinetics of sarpogrelate. Sarpogrelate is efficacious in animal models of thrombosis, coronary artery spasm, atherosclerosis, restenosis, peripheral vascular disease, pulmonary hypertension, ischaemic heart disease, myocardial infarction, diabetes and kidney disease. Small clinical trials indicate that sarpogrelate may be beneficial in the treatment of coronary artery disease, angina, restenosis, heart valve prostheses surgery, diabetes mellitus, Raynaud's phenomenon, systemic sclerosis and Buerger's disease. Larger, randomised, double-blind, placebo-controlled clinical trials of sarpogrelate in intermittent claudication, coronary artery disease, restenosis and diabetes should be considered.

The potential role of non-steroidal anti-inflammatory drugs in treating Alzheimer’s disease

Abstract: Epidemiological studies suggest that long-term use of non-steroidal anti-inflammatory drugs (NSAIDs) may protect against Alzheimer's disease (AD). Despite encouraging evidence, all large, long-term, placebo-controlled clinical trials aimed at reducing inflammation in the brain of AD patients produced negative results. More recently it has been shown that some NSAIDs decrease the production of amyloid-beta(1-42) (Abeta42), the major component of senile plaques of the AD brain, and counteract the progression of Abeta42 pathology in transgenic mouse models of AD. The proposed mechanism for this activity is an allosteric modulation of gamma-secretase activity, the enzyme responsible for the formation of amyloid-beta. The inhibition of Abeta42 production is independent from the anti-cyclooxygenase (COX) activity and is related to the chemical structure of the compounds, with some NSAIDs being active (ibuprofen, sulindac, flurbiprofen, indomethacin, diclofenac) and others not (naproxen, aspirin, celecoxib). This could explain the negative results of the large AD trials carried out so far, as they were conducted with compounds (naproxen, hydroxychloroquine, dapsone, prednisone, rofecoxib and celecoxib) that are not able to decrease Abeta42 production. Unfortunately, the use of these NSAIDs in AD is hampered by a significant gastrointestinal toxicity associated with COX inhibition. Thus, new NSAID analogues are being developed with potent and selective inhibitory activity on Abeta42 but with either lack of COX inhibitory activity or reduced gastrointestinal toxicity potential.

Selective activators of thyroid hormone receptors.

Abstract: An excess of thyroid hormone (TH) leads to a mix of deleterious (increased heart rate, muscle wasting and osteoporosis) and beneficial effects (reduced serum cholesterol and lipoprotein A and weight loss). All of these actions are mediated by nuclear thyroid hormone receptors (TRs), however, genetic evidence suggests that different TR isoforms do not contribute equally to individual TH effects. Thus, TR isoform selective activators could mimic the beneficial aspects of TH excess while avoiding the harmful effects. This article reviews new selective TR activators, their mechanism of action (they work by targeting the TR-beta isoform) and their actions in animal models. It is clear that these compounds represent a promising new avenue for the treatment of lipid disorders and obesity.

Cationic antimicrobial peptides - an update.

Abstract: Cationic antimicrobial peptides play a very important role in nature as a first line of defence against attack and damage. However, their application to the clinic has not been very encouraging to date. There are indications that the barriers to their success may now be eroding with companies developing peptides to be more stable, cost effective and targeted to specific indications. These include systemic infectious disease, acne, vaginitis, wound infection and inflammation. In addition, the use of such peptides as modulators of innate immunity in the treatment of infectious disease and inflammation has added a further dimension to the field.

The therapeutic potential of glycine transporter-1 inhibitors.

Abstract: While current antipsychotic medications are often efficacious for the positive symptoms of schizophrenia, there remains a critical need for compounds with improved tolerability and efficacy for the negative symptoms and cognitive dysfunction associated with this disease. There is a growing body of evidence suggesting that the potentiation of N -methyl-D-aspartate (NMDA) receptor function may be a useful approach for the treatment of schizophrenia. One proposed strategy for this potentiation is to increase synaptic levels of the neurotransmitter glycine by blocking the glycine transporter-1. Since glycine acts as a required co-agonist for the NMDA receptor complex; this approach allows an increase in the effectiveness of normal glutamatergic signalling at the NMDA receptor complex. Recent preclinical research, focused on the development and testing of novel glycine transporter-1 inhibitors, suggests that this approach may be feasible. Converging clinical evidence suggesting therapeutic efficacy following the potentiation of glycinergic activity further supports this approach. Clinical studies with novel glycine re-uptake inhibitors will provide critical information regarding the therapeutic utility and tolerability of this treatment for schizophrenia and other disorders associated with NMDA receptor hypofunction.