The roles of cyclic nucleotide phosphodiesterases (PDEs) in steroidogenesis

The second messenger, cAMP, is one of the most important regulatory signals for control of steroidogenesis. This review focuses on current knowledge about regulation of cyclic nucleotides by phosphodiesterases (PDEs) in steroidogenic tissues. The first PDE known to directly regulate steroidogenesis was PDE2, the cGMP-stimulated PDE. PDE2 mediates ANP/cGMP-induced decreases in aldosterone production. Recently, the PDE8 family has been shown to control steroidogenesis in two tissues. Specifically, PDE8A regulates testosterone production by itself and in concert with additional IBMX-sensitive PDEs. PDE8B modulates basal corticosterone synthesis via acute and chronic mechanisms. In addition to cAMP-dependent pathways, cGMP signaling also can promote steroidogenesis, and PDE5 modulates this process. Finally, PDE mutations may lead to several human diseases characterized by abnormal steroid levels.     

PDEs as drug targets for CNS immune disorders

PDEs are important second messenger systems governing a host of cellular functions involved in neural signal transduction in the CNS and inflammatory cell signaling in the immune system. The contributions of PDE family members as novel treatments that target neuroinflammation as a pathophysiological process in the neuropathogenesis of diverse neurological and psychiatric brain disorders with prominent immune system correlates are discussed.     

Recent advances in positron emission tomography (PET) radiotracers for imaging phosphodiesterases

Phosphodiesterases (PDEs) are a family of enzymes that metabolically inactivate the second messengers 3',5'- cyclic adenosine monophosphate (cAMP) and/or 3',5'-cyclic guanosine monophosphate (cGMP). These two messengers regulate the extracellular signal from the plasma membrane G protein-coupled receptors (GPCRs) to the intracellular effector proteins, hence modulating a wide variety of biological processes both in the central nervous system (CNS) and peripheral tissues. Although there are many radiotracers available for positron emission tomography (PET) studies of different receptors, there are just a few tracers available for imaging studies of second messenger systems. The first reported PDE PET ligands were the 11C-labeled versions of the PDE4 inhibitors rolipram and Ro 20-1724, and, to date, PET imaging studies in human subjects have only been reported with [11C]rolipram. As a consequence of the growing interest in identifying selective PDE inhibitors as potential new therapeutic agents, new PET radiotracers for imaging specific PDEs have been described in literature as well. This article highlights these efforts on the design and evaluation of novel PET radioligands for in vivo imaging of PDEs.     

Latest advances in the cannabinoids

The endocannabinoid system has received much attention in recent years as a source of therapeutic targets for a wide range of indications. This review covers advances made in the area of small molecule, non-cannabinoid modulators of the cannabinoid receptors CB₁ and CB₂ since July 2006. Under discussion are patents published in this period that disclose new compounds acting at either of the two confirmed cannabinoid receptors as agonists, antagonists or inverse agonists. The bulk of the material covered is in the area of CB₁ antagonists and inverse agonists; however, there continues to be strong interest in the area of CB₂ agonists, where pain is presently the major indication. New indications for all areas have been claimed as the expression pattern of the receptors continues to be expanded. The discovery of a potential third cannabinoid receptor only increases both the complexity of the field and the potential for providing therapeutic agents.     

Phototriggered structures: Latest advances in biomedical applications

Non-invasive control of the drug molecules accessibility is a key issue in improving diagnostic and therapeutic procedures. Some studies have explored the spatiotemporal control by light as a peripheral stimulus. Phototriggered drug delivery systems (PTDDSs) have received interest in the past decade among biological researchers due to their capability the control drug release. To this end, a wide range of phototrigger molecular structures participated in the DDSs to serve additional efficiency and a high-conversion release of active fragments under light irradiation. Up to now, several categories of PTDDSs have been extended to upgrade the performance of controlled delivery of therapeutic agents based on well-known phototrigger molecular structures like o-nitrobenzyl, coumarinyl, anthracenyl, quinolinyl, o-hydroxycinnamate and hydroxyphenacyl, where either of one endows an exclusive feature and distinct mechanistic approach. This review conveys the design, photochemical properties and essential mechanism of the most important phototriggered structures for the release of single and dual (similar or different) active molecules that have the ability to quickly reason of the large variety of dynamic biological phenomena for biomedical applications like photo-regulated drug release, synergistic outcomes, real-time monitoring, and biocompatibility potential.     

Latest advances towards the discovery of 5-HT(7) receptor ligands

The 5-HT(7)receptor (5-HT(7)R), characterized in 1993, is the most recently described member of the serotonin family. Since its discovery, 5-HT(7)R has been the subject of extensive research due to its widespread distribution in the brain, suggestive of multiple central roles. The focus of this review is to illustrate the literature concerning developments of the last few years (2007-2010) towards the discovery of novel and selective 5-HT(7)R ligands, agonists, antagonist and inverse agonists.     

Latest advances in cannabinoid receptor agonists

Background: Since the discovery of cannabinoid receptors and their endogenous ligands in early 1990s, the endocannabinoid system has been shown to play a vital role in several pathophysiological processes. It has been targeted for the treatment of several diseases including neurodegenerative diseases (Parkinson's disease, Alzheimer's disease, Huntington's disease and MS), cancer, obesity, inflammatory bowel disease, neuropathic and inflammatory pain. The last decade has witnessed remarkable advances in the development of cannabinergic ligands displaying high selectivity and potency towards two subtypes of cannabinoid receptors, namely CB1 and CB2. Objective: In this review, we highlight the latest advances made in the development of cannabinoid agonists and summarize recently disclosed, novel chemical scaffolds as CB-selective agonists in patents that appeared during January 2008 – June 2009. Methods: Data presented here are obtained through the search of PubMed for research articles and reviews, and the website of European patents (http://ep.espacenet.com), SciFinder Scholar? and US patents (www.uspto.gov). Conclusions: Our analysis reveals prolific patenting activity mainly in the CB2 selective agonist area. Limiting the BBB penetrability, thereby, leading to peripherally restricted CB1/CB2 agonists and enhancing CB2-selectivity emerge as likely prerequisites for avoidance of adverse central CB1 mediated side effects.     

Recent advances in the drug discovery of metabotropic glutamate receptor 4 (mGluR4) activators for the treatment of CNS and non-CNS disorders

INTRODUCTION: The metabotropic glutamate receptor type 4 (mGluR4) plays a pivotal role in a plethora of therapeutic areas, as recently demonstrated in preclinical validation studies with several chemical classes of compounds in rodent models of central nervous system (CNS) and peripheral disorders. Activation of mGluR4 with orthosteric agonists, allosteric agonists or pure positive allosteric modulators (PAM) has been postulated to be of broad therapeutic use. AREAS COVERED: The authors address past and current drug discovery efforts, insights and achievements in the field toward the identification of therapeutically promising and emerging class of mGluR4 activators, over the 2005 - 2011 period. Chemical structures, properties and in vivo pharmacological results discussed in the present review were retrieved from public literature including PubMed searches, Thomson Pharma and SciFinder databases searches, conferences, proceedings and posters. EXPERT OPINION: Developing a subtype-selective, orally bioavailable brain penetrant mGluR4 orthosteric agonist remains challenging. Lack of subtype selectivity and low brain penetration has been a common limitation of the first generation of mGluR4 agonist and potentiators. However, significant progress has recently been made with the identification of several double- to single-digit nanomolar mGluR4 PAM having reasonable pharmacokinetic properties, oral bioavailability and brain penetration. The use of such compounds in research has led to advancement in understanding the central role of mGluR4 in multiple neurodegenerative and neuroinflammatory disorders, such as Parkinson's disease and multiple sclerosis. Our understanding of the potential application of mGluR4 as therapeutic target is expected to grow as these compounds advance into preclinical and clinical development.     

外周动脉闭塞性疾病的抗血小板与抗凝治疗进展

目的:探讨外周动脉闭塞性疾病抗血小板与抗凝治疗及进展。方法:查询近几年国内外关于外周动脉闭塞性疾病抗血小板和抗凝药物治疗文献并进行分析。结果和结论:抗血小板治疗有助于降低外周动脉闭塞性疾病患者心脑血管事件发生率,并通过提高血管重建术后的通畅率,改善患者的预后。抗凝药物在外周动脉闭塞性疾病患者的治疗中仍应占有一席之地,尤其是在某些特定情况下。抗凝和抗血小板药物合理的联用可能为外周动脉闭塞性疾病患者的药物治疗提供新的思路。     

Latest advances and research in lung cancer

Lung cancer is the biggest killer worldwide among all cancers. In the United States, one third of male and one quarter of female cancer deaths are from lung cancer. In spite of continued research efforts, 5-year survival remains low, at around 15% in the United States and about 10% in Europe. The majority (85%) of cases of lung cancer in men are related to cigarette smoking, and while the proportion of tobacco related cases in women is lower (47%), female deaths from lung cancer are nevertheless catching up with male rates around the world. The 11th World Conference of the International Society for Lung Cancer was held July 3-6, 2005, in Barcelona, Spain, and brought together more than 5,000 delegates to discuss the latest developments and research in the field.     

Animal models of CNS disorders

There is intense interest in the development and application of animal models of CNS disorders to explore pathology and molecular mechanisms, identify potential biomarkers, and to assess the therapeutic utility, estimate safety margins and establish pharmacodynamic and pharmacokinetic parameters of new chemical entities (NCEs). This is a daunting undertaking, due to the complex and heterogeneous nature of these disorders, the subjective and sometimes contradictory nature of the clinical endpoints and the paucity of information regarding underlying molecular mechanisms. Historically, these models have been invaluable in the discovery of therapeutics for a range of disorders including anxiety, depression, schizophrenia, and Parkinson's disease. Recently, however, they have been increasingly criticized in the wake of numerous clinical trial failures of NCEs with promising preclinical profiles. These failures have resulted from a number of factors including inherent limitations of the models, over-interpretation of preclinical results and the complex nature of clinical trials for CNS disorders. This review discusses the rationale, strengths, weaknesses and predictive validity of the most commonly used models for psychiatric, neurodegenerative and neurological disorders as well as critical factors that affect the variability and reproducibility of these models. It also addresses how progress in molecular genetics and the development of transgenic animals has fundamentally changed the approach to neurodegenerative disorder research. To date, transgenic animal models\have not been the panacea for drug discovery that many had hoped for. However continual refinement of these models is leading to steady progress with the promise of eventual therapeutic breakthroughs.     

Latest advances and research in stroke treatment 2007

The 32nd International Stroke Conference, held February 7-9, 2007, in San Francisco, California, U.S.A., was an excellent forum to bring together advances in stroke treatment. Very challenging new steps in the process of developing drugs for stroke from basic science to clinical trials, such as testing the in vitro efficacy in human tissue of a candidate drug, or its in vivo PET distribution in ischemic brain, were proposed. This report focuses on new therapeutic stroke targets addressed in the meeting, together with the trends in neurovascular research presented at the oral and poster sessions. Some of the results obtained by researchers in several stroke fields such as thrombolysis, new drugs or devices and nonpharmacological approaches for stroke treatment tested in humans will also be covered. From the basic research, promising strategies found in new drugs and targets, and endothelial progenitor cells, cellular therapies and angiogenesis will be discussed. Also covered in this review are a selection of advances introduced in secondary prevention and in cerebral hemorrhage.     

Latest advances in the development of dry powder inhalers

The current market for dry powder inhalers (DPIs) has over 20 devices in present use and at least another 30 under development. Clinicians recognize that DPIs are a suitable alternative to pressurized metered dose inhalers (pMDIs) for some patients but the relative performance of devices is often unclear. The problem is compounded by the need to reformulate pMDIs with new propellants, introducing further products to the market with associated variations in performance. This article reviews the DPIs currently available, the driving forces governing new designs, and the claimed advantages of DPIs in the development pipeline.     

Recent advances in biotransformation of CNS and cardiovascular agents

Compound biotransformation is a very important research area for drug discovery and development. In this review, publications from the metabolism studies of ten compounds, seven CNS and three cardiovascular agents, from the Johnson & Johnson Corp. were reviewed. The seven CNS compounds are: three antipsychotic agents, mazapertine (arypiperazine analog), RWJ-46344 (arypiperidine analog) and risperidone (aryisoxazole-piperidine analog), one antidepressant, etoperidone (arypiperazine analog), one anxiolytic agent, fenobam (aryimidazole urea analog), one muscle relaxant, xilobam (pyrrolidinylidene urea analog), and one antiepileptic agent, topiramate (fructopyranose sulfamate analog). The three cardiovascular agents are: two arylalkylamine calcium channel blockers, bepridil and RWJ-26240, and one thioindolaminidine antianginal agent, RWJ-34130. Other antipsychotic and antidepressant agents with similar analogs (ziprasidone, trazodone and nefazodone) as well as other similar analogs of calcium channel blockers (verapamil) are discussed. In this article, excretion and metabolism (in vitro, in vivo) of compounds are reviewed from the CNS agents to the cardiovascular agents, including structures of parent compounds, their metabolites, metabolic pathways, and methods for the isolation, profiling, quantification and structural identification of unchanged compounds and metabolites. Pharmacological activities of parent compounds and their metabolites are also briefly discussed.     

Understanding the role of inflammatory-related pathways in the pathophysiology and treatment of psychiatric disorders: evidence from human peripheral studies and CNS studies

Many lines of evidence now support the hypothesis that inflammation-related pathways are involved in the pathophysiology of psychiatric disorders. Much of the data underpinning this hypothesis has come from the study of inflammation-related proteins in blood of individuals with mood disorders and schizophrenia. Significantly, recent data have emerged to suggest that changes in inflammation-related pathways are present in the CNS of subjects with psychiatric disorders. It is therefore timely to overview how such data, plus data on the role of inflammation-related proteins in CNS function, is contributing to understanding the pathophysiology of mood disorders and schizophrenia. In addition, it has been suggested that antidepressants, mood stabilizers and antipsychotic drugs act on inflammation-related pathways and therefore measuring levels of inflammation-related proteins in blood may be useful in monitoring treatment responsiveness. Despite these important neuropsychopharmacological discoveries, there is no clear understanding as to how inflammatory-related pathways can precipitate the onset of psychiatric symptoms. This review will focus on data suggesting that acute-reactive proteins and cytokines are affected by the pathophysiology of mood disorders and schizophrenia, that levels of blood inflammation-related proteins before and after treatment might be useful in the diagnosis of psychiatric disorders or measuring responsiveness to drug treatment. Finally, it will be postulated how changes in these proteins affect CNS function to cause psychiatric disorders.     

Ginkgo biloba extract (EGb 761) and CNS functions: basic studies and clinical applications

The effects of EGb 761 on the CNS underlie one of its major therapeutic indications; i.e., individuals suffering from deteriorating cerebral mechanisms related to age-associated impairments of memory, attention and other cognitive functions. EGb 761 is currently used as symptomatic treatment for cerebral insufficiency that occurs during normal ageing or which may be due to degenerative dementia, vascular dementia or mixed forms of both, and for neurosensory disturbances. Depressive symptoms of patients with Alzheimer's disease (AD) and aged non-Alzheimer patients may also respond to treatment with EGb 761 since this extract has an "anti-stress" effect. Basic and clinical studies, conducted both in vitro and in vivo, support these beneficial neuroprotective effects of EGb 761. EGb 761 has several major actions; it enhances cognition, improves blood rheology and tissue metabolism, and opposes the detrimental effects of ischaemia. Several mechanisms of action are useful in explaining how EGb 761 benefits patients with AD and other age-related, neurodegenerative disorders. In animals, EGb 761 possesses antioxidant and free radical-scavenging activities, it reverses age-related losses in brain alpha 1-adrenergic, 5-HT1A and muscarinic receptors, protects against ischaemic neuronal death, preserves the function of the hippocampal mossy fiber system, increases hippocampal high-affinity choline uptake, inhibits the down-regulation of hippocampal glucocorticoid receptors, enhances neuronal plasticity, and counteracts the cognitive deficits that follow stress or traumatic brain injury. Identified chemical constituents of EGb 761 have been associated with certain actions. Both flavonoid and ginkgolide constituents are involved in the free radical-scavenging and antioxidant effects of EGb 761 which decrease tissue levels of reactive oxygen species (ROS) and inhibit membrane lipid peroxidation. Regarding EGb 761-induced regulation of cerebral glucose utilization, bilobalide increases the respiratory control ratio of mitochondria by protecting against uncoupling of oxidative phosphorylation, thereby increasing ATP levels, a result that is supported by the finding that bilobalide increases the expression of the mitochondrial DNA-encoded COX III subunit of cytochrome oxidase. With regard to its "anti-stress" effect, EGb 761 acts via its ginkgolide constituents to decrease the expression of the peripheral benzodiazepine receptor (PBR) of the adrenal cortex.     

Psychopharmacological advances in eating disorders

Introduction: Anorexia nervosa (AN), bulimia nervosa (BN) and binge eating disorder (BED) are the primary eating disorders (EDs). The only psychopharmacological treatment options for EDs with approval in some countries include fluoxetine for BN and lisdexamfetamine for BED. Given the high comorbidity and genetic correlations with other psychiatric disorders, it seems possible that novel medications for these conditions might also be effective in EDs.

Areas covered: The current scientific literature has increased our understanding of how medication could be beneficial for patients with EDs on a molecular, functional and behavioral level. On the basis of theoretical considerations about neurotransmitters, hormones and neural circuits, possible drug targets for the treatment of EDs may include signal molecules and receptors of the self-regulatory system such as serotonin, norepinephrine and glutamate, the hedonic system including opioids, cannabinoids and dopamine and the hypothalamic homeostatic system including histamine, ghrelin, leptin, insulin, and glucagon-like peptide-1.

Expert commentary: The latest research points to an involvement of both the immune and the metabolic systems in the pathophysiology of EDs and highlights the importance of the microbiome. Therefore, the next few years may unveil drug targets for EDs not just inside and outside of the brain, but possibly even outside of the human body.     

Latest advances in cannabinoid receptor antagonists and inverse agonists

This review covers the progress made in the field of CB₁ and CB₂ cannabinoid receptor antagonists and inverse agonists since 2004. The high therapeutic potential of these compounds is reflected by the great number of patents filed during the last 3 years. Although the vast majority of the patents are related to CB₁ due to the known therapeutic potential of CB₁ antagonists, several compounds acting at CB₂ have also been disclosed. Obesity, metabolic syndrome and smoking cessation are CB₁ antagonists indications supported by the recent clinical trials results.     

Latest advances from basic and clinical research in hematology

New treatments in hematological malignancies were a focal point of sessions and presentations at the 42nd Annual Meeting of the American Society of Hematology, held December 15, 2000, in San Francisco, California, U.S.A. The meeting also provided discussion on pathogen inactivation in blood banking, stem cell transplantation in leukemia as well as nonmalignant diseases, the reparative potential of stem cells, a new oral antithrombotic therapy and a new class of highly selective factor Xa inhibitors.