This review evaluates past and present clinical trials, as well as the current preclinical drug candidates focused on treating Alzheimer's disease (AD), in order to better assess the trends in AD drug discovery in context with specific drug mechanisms. The author begins by presenting a summary of the results of over 160 clinical trials targeted at AD, of which 52% have either failed to meet clinical endpoints or stalled (defined for the purpose of this review as no clinical or publicly mentioned progress for at least 3 years). The author postulates that many of the current clinical approaches fail to sufficiently regulate the amyloid cascade that includes, but is not limited to, the production of soluble β-amyloid precursor protein, β-amyloid and/or amyloid precursor protein intracellular domain and including activation of the tau cascade, ultimately translating to no improvement in cognitive function. To support this argument, the author compares clinical results and peer-reviewed opinions to postulate that appropriately focused multifunctional or dual pathway drugs could make the optimal candidate(s) for further investigations.
In this white paper, Thomson Reuters provides a snapshot of the imaging biomarkers at use in research and development, and the clinic; examines key technical and commercialization challenges; and identifies promising avenues for progress in the field with insight from experts from industry and academia.
Chronic inflammation is increasingly regarded not just as a consequence of a continuous infectious hazard, but also as an integral part of many noninfectious diseases such as autoimmune disorders, diabetes or cardiovascular disease. Thus, it is not surprising that some hormonal systems, like the renin-angiotensin system (RAS), which were originally described in the context of cardiovascular disease have also turned out to be major regulators of the inflammatory response. This review focuses on the role of the RAS in inflammation, with particular emphasis on the role of the angiotensin AT(2) receptor. While the proinflammatory features of the angiotensin AT(1) receptor are well established, most current evidence supports an anti-inflammatory role for AT(2) receptor. However, data on this receptor in inflammation are still rather sparse and are somewhat controversial. This article will discuss the principal mechanisms of AT(2) receptor-coupled interference with proinflammatory pathways as well as data derived from animal models of specific diseases. Finally, it will give a brief outlook into new possibilities in AT(2) receptor research and in the potential utilization of AT(2) receptor stimulation as a novel pharmacological concept in anti-inflammation.
Glutamate is the major excitatory neurotransmitter in the mammalian central nervous system, activating ionotropic (iGlu) and metabotropic (mGlu) glutamate receptors. Targeting iGlu receptors has proven difficult, as these receptors play such a critical role in fast synaptic transmission. In recent years, there has been a switch in the focus of the pharmaceutical industry to target mGlu receptors, as these receptors have a more modulatory role in the brain. Eight subtypes of the G protein-coupled mGlu receptors have been cloned and classified into three groups according to their second messenger association, sequence homology and agonist selectivity. Group I (mGlu(1) and mGlu(5)) receptors are positively coupled to phosphatidylinositol (PO hydrolysis, while group II (mGlu(2) and mGlu(3)) and group III (mGlu(4), mGlu(6), mGlu(7) and mGlu(8)) receptors are negatively coupled to adenylate cyclase and thought to act as presynaptic autoreceptors, regulating glutamate transmission. There has been rapid progress in understanding the biology of mGlu receptors and their function in the central nervous system (CNS), and the field now has highly potent and selective ligands for many of the mGlu receptor subtypes. Pharmacological tools include both orthosteric and allosteric agonists and antagonists. These molecules have been explored across a range of CNS conditions, the findings of which will be discussed briefly in this review. Recently, some of the most promising molecules have progressed into clinical trials (mGlu(2/3) receptor agonists for the treatment of anxiety and schizophrenia and mGlu(5) receptor antagonists for acute migraine and L-DOPA-induced dyskinesia) and achieved proof of concept. These encouraging results suggest mGlu receptors as novel drug targets with application in a range of psychiatric and neurological conditions.
A synthetic cyclic depsipeptide of the kahalalides family with potential antineoplastic activity. PM02734 is a derivative of a natural marine compound extracted from the sacoglossan sea slug, Elysia rufescens. Although the exact mechanism of action has yet to be elucidated, elisidepsin exhibits anti-proliferative activity in a wide variety of cancer types, such as breast, colon, pancreas, lung, and prostate.
Therapeutic vaccines have emerged as a promising alternative in the prevention and treatment of autoimmune diabetes, a progressive autoimmune destruction of insulin-producing beta-cells in the pancreas. Thus, using autoantigens that drive the immune-mediated pathology, diabetes vaccination attempts to induce immune tolerance, thereby delaying or arresting disease progression. The 65-kD isoform of glutamic acid decarboxylase (0,4065) is a major autoantigen in the two autoimmune forms of diabetes: type 1 diabetes and latent adult-onset autoimmune diabetes (LADA). Diamyd(R) is a vaccine candidate containing recombinant human GAD65 (rhGAD65) that has proven to slow down the destruction of insulin-producing beta-cells in preclinical and clinical studies. Phase II clinical studies in children with recent-onset type 1 diabetes and children and adults with LADA have demonstrated the safety of Diamyd(R) and long-term protection of beta-cell function. Currently ongoing phase Ill trials will determine whether Diamyd(R) can preserve residual beta-cell function in young patients with recent-onset type 1 diabetes.
Despite the fact that the threat of a new influenza pandemic has been hovering over us for quite some time, the truth is that the weapons currently licensed for fighting the swine-derived H1N1 virus are not quite up to the current needs. Although considerable effort has been put into developing new vaccines and antivirals, the available agents are basically the same ones as 10 years ago. In this review, we consider novel prophylactic and therapeutic alternatives, which luckily are being proposed by experts in the field. The better understanding and basic knowledge of influenza viruses, including their high variability and potential for antigenic drift, has prompted the development of new antivirals and more efficacious vaccines that hold promise for the near future.
The pursuit of personalized medicine requires the development of biomarkers to predict disease course, monitor disease evolution, stratify patient subgroups by disease activity and to predict and monitor response to therapies. Multiple sclerosis (MS) is a common neurological disease in young adults with an unpredictable course that may be associated with significant disability, diminishing the patient's quality of life. Currently, disease prognosis is based on clinical information (relapse rate and disability scales) and diagnostic tests (brain MRI or the presence of oligoclonal bands in the cerebrospinal fluid). However, the ability of neurologists to make an accurate prognosis is very limited based on such information, a situation perceived by patients as one of their biggest concerns. Although many recent studies have identified different molecules and imaging techniques associated with the course of MS, in most cases the diagnostic accuracy of such technologies has not been properly assessed. This shortcoming is partly due to the failure to validate such biomarkers, which impedes their application in clinical practice. However, the recent validation of anti-aquaporin-4 antibodies for Devic's disease and the development of optic coherent tomography for MS, are examples of the benefits that the development of MS biomarkers can offer. Indeed, it may currently be necessary to redress the bias in research towards clinical validation rather than discovery in order to promote translational research and improve patient's quality of life.
Regulatory agencies are the gateway between the pharma/biotech industry and patients and can serve as stimulators of new drug development. This article highlights several means of doing so implemented thus far, many with already impressive histories, such as orphan drug legislation, and others of a more experimental nature, such as the FDA's priority review voucher program. These initiatives represent different approaches to finding treatments for rare and widespread but neglected diseases, as well as speeding the development process for pharmaceutical and biological agents more generally. Commercial incentives, streamlined regulatory processing, exploratory trial designs, research assistance and cash infusions are all means of promoting drug development being explored in the United States, Europe and beyond. In some cases, such as fast track designation and priority review vouchers, regulatory agencies have turned their own processes into incentives, offering advantageous alternative routes to product approval, like a faster lane on the highway for vehicles carrying multiple passengers. In 2009, regulatory agencies and the governments they represent also had to confront two tremendous challenges: the global recession and the H1N1 influenza virus pandemic. These tests have been met with increased funding in the former case and coordinated efforts to develop, approve and stockpile H1N1 vaccines in the latter.
There is a constant need for discovering novel sources of compounds with antimicrobial properties, and recent studies support that symbiotic associations involving chemically mediated interactions may be a prominent source of novel compound discovery. Here I review a particularly promising natural system involving such interactions, the multipartite fungus-growing ant symbiosis. This includes a review of the ancient symbiosis involving intricate interactions between at least six symbionts, a review of the efforts that have been made in examining host-symbiont and symbiont-symbiont interactions, as well as the efforts made in identifying and characterizing chemical compounds mediating these interactions. Finally, I outline the prospects for future natural product discoveries from the system, touching on how advances in chemical analyses and whole-genome sequencing techniques will facilitate the process of natural product discovery of biomedical interest.
Multiple sclerosis (MS) is a chronic demyelinating autoimmune disease of the central nervous system. Different therapeutic options are available, but all require parenteral application and some expose patients to potentially lethal adverse effects. The response to treatment remains variable and often incomplete. Thus, the search for novel therapeutic agents is ongoing and relevant. The chimeric compound quinpramine-generated from its precursor substances imipramine and quinacrine-has recently demonstrated clinical efficacy in experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Mechanistic considerations and recent experimental data suggest that intracellular redistribution of antigen-presenting molecules and cholesterol-rich membrane domains may account for the clinical efficacy of this drug. This article summarizes available treatment options in MS and explains why the candidate compound quinpramine may transfer from bench to bedside in the near future.
The emerging increase of antibiotic resistance constitutes an important risk to human health. Two million patients acquire nosocomial infections in U.S. hospitals each year. Of these infections, 60% involve resistant bacteria. In the last decade, only a few new antibiotics with new mechanisms of action were approved by the FDA, but additional costs for preventing the spread of bacteria, side effects and resistance may limit their long-term usefulness. Therefore, the number of therapeutic options is limited and necessitates exploration of novel antibacterial agents/approaches to treat hospital- and community-acquired infections. The challenge in antibacterial research is to find appropriate structurally novel antibacterial agents inhibiting bacterial targets. The XF drug series, having a dicationic porphyrin structure, which is distinct from all other known antibiotic classes, are rapidly active against a broad range of bacteria. Another new strategy is called photodynamic inactivation of bacteria (PDIB), which utilizes visible light in combination with photosensitizing molecules to efficiently kill bacteria via reactive oxygen species. The XF drugs act additionally as photosensitizers to inactivate bacteria upon light activation. This review summarizes the efficacy of the XF series and describes it as a new class of antibacterial agents or as new photosensitizers.
Staphylococcus causes a large number of animal and human diseases and has been considered as a major health concern. With the emergence of resistant strains of staphylococcus, like methicillin-resistant Staphylococcus aureus and vancomycin-resistant Staphylococcus aureus, the search for novel antibacterial targets has intensified. FtsZ, a bacterial cytoskeleton protein, is involved in cell division. FtsZ assembles into protofilaments in a GTP-dependent manner, and forms a dynamic Z-ring at the mid-cell position. The assembly dynamics of FtsZ in the Z-ring are regulated by the combined actions of several FtsZ-associated proteins. Furthermore, the interaction of FtsZ with accessory proteins is essential for their recruitment to the Zring. A disruption of this interaction perturbs the Z-ring formation. FtsZ inhibitors like PC-190723 have been suggested to inhibit the Staphylococcus cell division by perturbing the assembly and stability of FtsZ polymers. In this review, we discuss the assembly dynamics of Z-ring and its role in cell division. In addition, we highlight recent advances suggesting the potential of FtsZ as a drug target for antistaphylococcal therapy.
Angiogenesis is crucial for the growth of cancer. As such, it has become an established target to fight cancer. Metronomic chemotherapy-the chronic administration of chemotherapy at relatively low, minimally toxic doses on a frequent schedule of administration, at close regular intervals, with no prolonged drug-free breaks-is a potential approach to control advanced cancer disease. It is thought to work primarily through antiangiogenic mechanisms and has the property to kill resistant cancer cells and/or to inhibit tumor growth while significantly reducing undesirable toxic side effects. Here, we will discuss potential mechanisms of action of metronomic chemotherapy and briefly review the data regarding the clinical experience with this kind of anticancer treatment. Based on recent insights in the various mechanisms of action, we will try to predict the potential new developments of metronomic chemotherapy in oncology.
Although cocaine is illegal in most countries of the world, addiction is common and increasing in many populations, and the effectiveness of current treatment options for those afflicted has been very limited. The availability of an anti-cocaine vaccine could offer help to those who wish to quit their addiction. A number of vaccines differing in their chemical nature have been developed, and one has advanced into clinical trials. This review will discuss the successes and limitations of the various vaccines and the results of clinical trials of the vaccine using succinyl norcocaine conjugated to cholera toxin B. This latter vaccine shows considerable promise for those individuals whose antibody response is adequate..
Chronic lymphocytic leukemia (CLL) represents 22-30% of all leukemia cases, thus being the most commonly diagnosed form of adult leukemia in the Western world. On a cellular level, the disease progresses due to the prolonged survival of B-cell CLL cells arrested in the G, stage of the cell cycle. The current standard treatment for CLL is a combination regimen containing purine analogues and monoclonal antibodies. Although response rates to such regimens in previously untreated patients are high, patients with CLL invariably experience relapse and often acquire high-risk chromosomal abnormalities. Therefore, the search for novel avenues in CLL treatment is warranted. In this manuscript, we will describe theoretical premises and some preliminary data making the case for inhibitors of the potassium currents as possible proapoptotic agents that warrant investigation as a potential pharmacologic target in CLL.
Epidemiological studies have begun to suggest obesity is a risk factor for chronic migraine, although no causal relationship has been established and risk factors for progression from episodic to chronic migraine remain unknown. The neuropeptide calcitonin gene-related peptide (CGRP) plays a important role in the pathophysiology of migraine. Here, the potential role of CGRP as a molecular link between obesity and migraine is reviewed. A mechanistic association is supported by several lines of evidence: 1) common markers are elevated in obesity and migraine, 2) adipose tissue secretes proinflammatory cytokines and adipocytokines that have been implicated in migraine pathophysiology and 3) elevated levels of CGRP have been found in plasma of obese individuals. We propose that CGRP released from trigeminal neurons may represent a biological link between obesity and migraine. Enhanced trigeminal CGRP production in obese susceptible individuals may lower the threshold necessary to trigger migraine attacks, leading to more frequent episodes and eventually to chronic migraine.
Liver transplantation as a treatment for transthyretin amyloidosis (ATTR) was introduced 20 years ago and is currently the only available treatment for the disease. Although the procedure has been ...
