Statins and dilated cardiomyopathy: do we have enough data?

INTRODUCTION: Dilated cardiomyopathy (DCM) is a multifactorial disease in which there is enlargement and systolic dysfunction of one or both ventricles. The exhaustion of compensatory mechanisms leads to the symptoms of congestive heart failure (CHF). Despite treatment, CHF is a progressive disease with high morbidity and mortality, suggesting that important pathogenic mechanisms remain active and unmodified by currently available treatment. AREAS COVERED: Several lines of evidence suggest that inflammation plays a role in the development and progression of CHF, influencing heart contractility and hypertrophy, promoting apoptosis and contributing to myocardial remodeling. More general immunomodulating treatments, such as statins, have shown promising results in patients with cardiomyopathies. MEDLINE (1966 - May 2010), EMBASE and SCOPUS (1965 - May 2010) and DARE (1966 - May 2010) were searched, in addition to abstracts from national and international cardiovascular meetings. The main data search terms were: dilated cardiomyopathy, dyslipidemia, heart failure, left ventricle dysfunction and statins. EXPERT OPINION: Inhibition of inflammation, alleviating endothelial damage and reducing endothelial dysfunction might comprise part of the underlying mechanisms leading to the improvement of left ventricular function and exercise tolerance in patients with DCM. Candidates for statin therapy with DCM should be in New York Heart Association class II or III and should have normal or increased levels of lipids.     

Angiotensin II receptor antagonists: where do we stand?

Losartan, the first angiotensin II receptor antagonist was introduced in 1994. Since then, five other antagonists have been launched for the management of hypertension. In recent years, numerous studies have demonstrated that angiotensin II antagonists are as effective as other antihypertensive agents but with a better tolerability profile. The challenge with these agents is now to demonstrate their potential benefits on morbidity and mortality, and several very large clinical trials are therefore running in hypertension, congestive heart failure and diabetic nephropathy. In addition, research is focusing intensively on defining the role of angiotensin AT2 receptors, and the potential benefits of combining ACE inhibitors and angiotensin II antagonists.     

In vivo opioid receptor heteromerization: where do we stand?

Opioid receptors are highly homologous GPCRs that modulate brain function at all levels of neural integration, including autonomous, sensory, emotional and cognitive processing. Opioid receptors functionally interact in vivo, but the underlying mechanisms involving direct receptor–receptor interactions, affecting signalling pathways or engaging different neuronal circuits, remain unsolved. Heteromer formation through direct physical interaction between two opioid receptors or between an opioid receptor and a non-opioid one has been postulated and can be characterized by specific ligand binding, receptor signalling and trafficking properties. However, despite numerous studies in heterologous systems, evidence for physical proximity in vivo is only available for a limited number of opioid heteromers, and their physiopathological implication remains largely unknown mostly due to the lack of appropriate tools. Nonetheless, data collected so far using endogenous receptors point to a crucial role for opioid heteromers as a molecular entity that could underlie human pathologies such as alcoholism, acute or chronic pain as well as psychiatric disorders. Opioid heteromers therefore stand as new therapeutic targets for the drug discovery field.

LINKED ARTICLES

This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2     

How do we choose between atypical antipsychotics? The advantages of amisulpride

Clinician choice of an atypical antipsychotic may depend on a number of factors such as perceived efficacy, tolerability and cost. It is also important that the choice of treatment takes into consideration the previous response to treatment, experience of side-effects and personal clinical characteristics. The receptor-affinity profiles of the atypical antipsychotics differ; with the exception of amisulpride, a selective D2/D3 antagonist, all the atypical antipsychotics exhibit a greater affinity for the serotonin-2A receptors than dopamine receptors. However, there is no evidence that the variation in receptor affinities is relevant to efficacy. Indeed, the crucial factor may be fast dissociation from low affinity for the D2 receptor. Tolerability also varies between the atypical antipsychotics and the side-effect profile may be related to the receptor-affinity profile of the individual drugs. Extrapyramidal side-effects are generally less of a problem with most atypical drugs than with conventional drugs, but weight gain, loss of glycaemic control, sedation and hyperprolactinaemia remain problematic in some patients. Amisulpride is effective for the treatment of both positive and negative symptoms, and is well tolerated with regard to weight gain, glucose tolerance and sedation. In two clinical trials, the AMIRIS and SOLIANOL studies, amisulpride demonstrated clear advantages over some other atypical antipsychotics with respect to negative symptoms, depressive symptoms and weight gain.     

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.     

Will the new CB1 cannabinoid receptor antagonist SR-147778 have advantages over rimonabant?

Obesity and alcoholism are two common modern-day diseases. The cannabinoid CB1 receptor antagonist rimonabant is in Phase III clinical trial for the treatment of obesity with preliminary results showing that it decreases appetite and body weight. Animal studies have shown that rimonabant is effective in the treatment of alcoholism. SR-147778 is a new potent and selective CB1 receptor antagonist. In animals, SR-147778 has been shown to inhibit CB1 receptor-mediated hypothermia, analgesia and slowing of gastro-intestinal transit. In rats trained to drink sucrose, the oral administration of SR-147778 3 mg/kg, before the presentation of sucrose, decreased the consumption of sucrose. SR-147778 3mg/kg also reduced spontaneous feeding in rats deprived of food and also in non-deprived rats. In Sardinian alcohol--preferring (sP) rats, in the alcohol-naive state, SR-147778 slowed the development of a preference for alcohol. In alcohol-experienced sP rats SR-147778 (2.5, 5 and 10 mg/kg p.o.) reduced the alcohol intake. When alcohol-experienced sP rats are deprived of alcohol for 15 days, there is a large intake of alcohol on reintroduction of alcohol, and this response was almost abolished by treatment with SR-147778. From the preclinical studies published to date, there is no obvious major point of difference between rimonabant and SR-147778, and both are promising agents for the treatmentof obesity and alcoholism.     

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.     

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.     

GPR55: a new member of the cannabinoid receptor clan?

In this issue of the British Journal of Pharmacology, Ryberg et al. present convincing in vitro evidence that the orphan GPCR, GPR55, is a cannabinoid receptor. GPR55 was activated by a range of plant, synthetic and endogenous cannabinoids and blocked by the non-psychoactive phytocannabinoid, cannabidiol. Their experiments have revealed several differences between the pharmacology of GPR55 and the established cannabinoid CB1 and CB2 receptors. For example, the CB1 receptor antagonist, AM251, activated GPR55 and the main psychoactive constituent of cannabis, Delta9-tetrahydrocannabinol, displayed greater efficacy at GPR55 than at CB1 or CB2 receptors. They also compared the distribution of GPR55 and CB1 mRNA in mouse and report that GPR55 couples to Galpha13, that it is activated by virodhamine, palmitoylethanolamide and oleoylethanolamide, and that virodhamine displays relatively high efficacy as a GPR55 agonist. Still to be identified are the main roles played by GPR55 in health and disease and any potential therapeutic benefits of activating or blocking this receptor.     

CB2 cannabinoid receptor agonists: pain relief without psychoactive effects?

Cannabinoid receptor agonists significantly diminish pain responses in animal models; however, they exhibit only modest analgesic effects in humans. The relative lack of efficacy in man may be because of the dose limitations imposed by psychoactive side effects. Cannabinoid agonists that selectively target CB(2) (peripheral) cannabinoid receptors should be free of psychoactive effects, perhaps allowing for more effective dosing. CB(2) receptor activation inhibits acute, inflammatory and neuropathic pain responses in animal models. In preclinical studies, CB(2) receptor agonists do not produce central nervous system effects. Therefore, they show promise for the treatment of acute and chronic pain without psychoactive effects.