Endothelial atypical cannabinoid receptor: do we have enough evidence?

Cannabinoids and their synthetic analogues affect a broad range of physiological functions, including cardiovascular variables. Although direct evidence is still missing, the relaxation of a vast range of vascular beds induced by cannabinoids is believed to involve a still unidentified non-CB₁, non-CB₂ G_i/o protein-coupled receptor located on endothelial cells, the so called endothelial cannabinoid receptor (eCB receptor). Evidence for the presence of an eCB receptor comes mainly from vascular relaxation studies, which commonly employ pertussis toxin as an indicator for GPCR-mediated signalling. In addition, a pharmacological approach is widely used to attribute the relaxation to eCB receptors. Recent findings have indicated a number of GPCR-independent targets for both agonists and antagonists of the presumed eCB receptor, warranting further investigations and cautious interpretation of the vascular relaxation studies. This review will provide a brief historical overview on the proposed novel eCB receptor, drawing attention to the discrepancies between the studies on the pharmacological profile of the eCB receptor and highlighting the G_i/o protein-independent actions of the eCB receptor inhibitors widely used as selective compounds. As the eCB receptor represents an attractive pharmacological target for a number of cardiovascular abnormalities, defining its molecular identity and the extent of its regulation of vascular function will have important implications for drug discovery. This review highlights the need to re-evaluate this subject in a thoughtful and rigorous fashion. More studies are needed to differentiate G_i/o protein-dependent endothelial cannabinoid signalling from that involving the classical CB₁ and CB₂ receptors as well as its relevance for pathophysiological conditions.Table of Links

Psychopharmacological treatment of schizophrenia: What do we have,and what could we get?

Antipsychotic drugs for the treatment of schizophrenia arrived in the clinic in the fifties of the previous century and have since been the most effective treatment for patients with this devastating disorder. In spite of the more than half a century of clinical experience, and the introduction of a large number of chemical divers antipsychotic drugs, several recent large, multi-center studies have shown that, although novel (second generation) antipsychotics seem to be tolerated somewhat better (especially in relation to neurological side effects), their therapeutic potential is comparable to that of first generation antipsychotics. Hence there is still an urgent need for better pharmacological tools to treat schizophrenic patients. The current paper reviews the benefits and shortcomings of the currently available drugs, and gives an outlook towards the drugs and targets that are currently being pursued in clinical trials. Given the uncertainty of the drug discovery process and the relatively poor predictive validity of the currently available animal models, it is, at present, impossible to predict which of these drugs will ultimately become available for treating schizophrenic patients.     

Challenges to environmental toxicology and epidemiology: where do we stand and which way do we go?

Modern toxicology investigates a wide array of both old and new health hazards. Priority setting is needed to select agents for research from the plethora of exposure circumstances. The changing societies and a growing fraction of the aged have to be taken into consideration. A precise exposure assessment is of importance for risk estimation and regulation. Toxicology contributes to the exploration of pathomechanisms to specify the exposure metrics for risk estimation. Combined effects of co-existing agents are not yet sufficiently understood. Animal experiments allow a separate administration of agents which can not be disentangled by epidemiological means, but their value is limited for low exposure levels in many of today's settings. As an experimental science, toxicology has to keep pace with the rapidly growing knowledge about the language of the genome and the changing paradigms in cancer development. During the pioneer era of assembling a working draft of the human genome, toxicogenomics has been developed. Gene and pathway complexity have to be considered when investigating gene-environment interactions. For a best conduct of studies, modern toxicology needs a close liaison with many other disciplines like epidemiology and bioinformatics.     

Beta-blockers in chronic heart failure: what have we learned? What do we still need to know?

Current heart failure guidelines mandate the use of beta-blockers in patients with symptomatic systolic heart failure. In the past 12-18 months, there have been several reported advances in our understanding of beta-blocker therapy for heart failure. Despite these advances, there remain several unanswered questions with regard to beta-blockers. These involve, firstly, clarifying the underlying mechanisms of action of beta-blockers; secondly, further analysing patients with systolic heart failure who are not well-studied in major clinical trials (e.g. the elderly); thirdly, investigating unexplored indications for beta-blockers in heart failure; and finally, directly examining the clinical relevance of pharmacological differences among agents. The impact of genetic polymorphisms on the response to beta-blocker therapy, as well as interaction of these agents with future heart failure therapies, requires extensive investigation.     

Drug-resistant tuberculosis: what do we do now?

Drug-resistant tuberculosis (TB) represents a threat to TB control programmes. Erratic and inappropriate use of currently available medications, HIV-TB co-infection, and concern about transmission of drug-resistant strains in the general population all contribute to a worrying picture. What do we do now? In the last few years, there has been considerable progress in the understanding of mechanisms of action and resistance to antituberculosis agents, and in establishing the value of directly observed therapy in preventing treatment failure. However, a limited effort has been devoted to the development of new active compounds or of rapid diagnostic tests, and their relevance to global tuberculosis control has been questioned.     

Designing drugs that overcome antibacterial resistance: where do we stand and what should we do?

Introduction: In recent years, infections caused by multidrug-resistant bacterial pathogens have become a huge issue to public healthcare systems. Indeed, the misuse of antibiotics has led to, over the past 30 years, the emergence of a number of resistant bacterial strains including Staphylococcus aureus, Neisseria gonorrhoeae, Escherichia coli and Mycobacterium tuberculosis. Unfortunately, efforts to produce new antibiotics have not been sufficient to cope with the emergence of these new antibiotic-resistant (AR) strains.

Areas covered: There is an urgent need to invent and employ unconventional strategies for antimicrobial drug development to tackle the rising global threats imposed by the spread of antimicrobial resistance. Herein, the authors discuss these novel design strategies and provide their expert perspective on the subject.

Expert opinion: To deal with the growing threat of AR, it is important to cut down the use of antibiotics to the very minimum to diminish the risk of unknown drug-resistant bacteria and increase antibacterial vaccination programs. Furthermore, it is important to develop new classes of antibiotics that can deal with multidrug-resistant bacterial pathogens.     

Measles in travelers: are we aware enough?

Measles is still an important public health concern in most developing countries. Nonimmune or single-dose vaccinees traveling to high-endemic countries should be advised on the risk of acquiring the infection. We describe two cases of imported measles in Spanish travelers.     

PPAR and immune system--what do we know?

Peroxisome proliferator-activated receptors (PPARs) belong to the nuclear steroid receptor superfamily. Originally, the receptors were identified as critical controllers for several key enzymes that catalyze the oxidation of fatty acids. PPARs consist of three members: PPAR-alpha, PPAR-beta/delta, and PPAR-gamma. Among them, PPAR-gamma is essential for controlling thermogenesis and adipocyte differentiation. The ligands for PPAR-gamma include 15-deoxy-delta(12,14)-prostaglandin J2 (15d-PGJ2)--a metabolite from the prostaglandin synthesis pathway, and "glitazones"--drugs utilized in the treatment of patients with diabetes. The precursors for prostaglandins are fatty acids consumed from diet and these precursors have long been postulated to have a regulatory role in immune functions. Emerging evidence indicates that PPAR-gamma and its ligands are indeed important for the modulation of immune and inflammatory reactions. In this review, we will spotlight the molecular mechanisms of receptor/ligand function and how they may regulate immune and inflammatory reactions. We also propose that PPAR-gamma and its endogenous ligands are participating factors for Type 1/Type 2 T and NK cell differentiation and development. Deciphering the mechanism of action of PPAR-gamma and its ligands may lead to a new therapeutic regiment for treatment of diseases involving dysfunction of the immune system.     

A civil action and statistical assessments of the spatial pattern of disease: do we have a cluster?

A reported "cluster" of excess childhood leukemia cases and possible environmental causes in Woburn, Massachusetts, formed a key motivation for the events described in the popular book and motion picture A Civil Action. Although statistical methods to assess spatial clustering existed prior to the events in Woburn, increasing interest in environmental risk factors and recent developments in geographical information systems and data availability prompt increased attention to such methods and their application to public health data. In this article, we review statistical and epidemiological concepts involved in the analysis of disease clusters. We discuss data issues, outline some methodological approaches, and illustrate ideas using data regarding leukemia incidence in upstate New York for the years 1978-1982.