Is there a case for MDMA-assisted psychotherapy in the UK?

Much has been written in scientific and popular literature in recent years about the dangers surrounding the recreational use of the drug MDMA/ecstasy.What is little known and understood however is the history of the apparently safe and effective use of MDMA as a therapeutic tool for psychotherapy. In this paper the author explores this history and describes the recent re-emergence of scientific interest in MDMA and other psychedelic drugs. There are currently several new double-blind randomised controlled trials underway re-visiting the subject. By acknowledging the limitations of this new research and emphasising the importance of exercising appropriate but realistic caution, the author asks that the medical profession consider a dispassionate and open-minded debate to examine whether MDMA might have a legitimate place as an adjunct to psychotherapy in modern psychiatric practice.     

Is there a need for emerging drugs for the acute respiratory distress syndrome?

The acute respiratory distress syndrome (ARDS) is a common and devastating syndrome of acute respiratory failure for which little effective pharmacotherapy exists. The authors describe some interventions that show promise as potential therapies for this condition, with particular reference to clinically relevant human models of ARDS. Aspirin, mesenchymal stromal (stem) cells, keratinocyte growth factor, IFN-β and oncostatin M inhibition are discussed.     

Is there a place for duloxetine?

Duloxetine, a combined serotonin and norepinephrine reuptake inhibitor, is licensed in the UK under two brand names for a total of three different indications. It is available as Cymbalta (jointly promoted by Boehringer Ingelheim and Lilly) for the treatment of patients with major depression, or with diabetic peripheral neuropathic pain; and as Yentreve (Lilly) for the treatment of women with "moderate to severe" stress urinary incontinence. Here we consider whether duloxetine has a role in the treatment of patients with any of these conditions.     

Is there a future for renin inhibitors?

Pharmacological interruption of the renin-angiotensin system is possible at three major sites, the angiotensin-converting enzyme (ACE), the AT1 receptor and at the interaction of renin with its substrate, angiotensinogen. Skeggs and his associates in 1957 argued logically but without prognostic accuracy that 'since renin is the initial and rate-limiting substance in the renin-angiotensin system, it would seem that the renin inhibition approach would be the most likely to succeed'. In fact, the development of agents that act at all three levels has enjoyed substantial success, yet renin inhibition, which showed early progress in studies in humans, has languished. Our task in this essay is to review the reasons for the slow evolution of renin inhibition and to discuss the potential of such agents in modern pharmacotherapy. All of the structure-action relationships have involved variation on the original peptide structure. The possibility that alternative approaches based on x-ray crystallography and reconstruction of the structure of the active site would lead to novel agents, appears not to have been explored systematically. This opportunity is all the more attractive because renin is one of the few targets that is actually soluble and amenable to x-ray crystallographic studies. At the moment, it appears that all renin inhibitor development programs have been closed, although hints periodically reappear to indicate that one company or another is pursuing a novel agent. The decision to close programs seems to have reflected not the therapeutic potential of renin inhibitors, but rather the cost of their synthesis, continuing problems with bioavailability and the remarkable success of the competitor class--the AngII antagonists. We believe that the potential of renin inhibition in human therapy has been under estimated and still shows substantial promise.     

Nrf2: a potential therapeutic target for naturally occurring anticancer drugs?

Introduction: Nuclear factor (erythroid-derived-2)-like 2 is one of the most efficient cytoprotective rheostats against exogenous or endogenous oxidative insults. At present, the modulation of the Nrf2 pathway represents an interesting and highly explored strategy in the oncological area.

Area covered: In this review, we present and discuss the different modulation of the Nrf2 pathway by some natural compounds with a well demonstrated anticancer activity, and critically analyze the challenges associated with the development of an Nrf2-based anticancer strategy.

Expert opinion: Many natural compounds with a well-defined anticancer activity are able to modulate this pathway. Both Nrf2 inducers and inhibitors can be useful as anticancer strategy. However, since Nrf2 modulates many networks potentially involved in the detoxification process of anticancer drugs, its activation in cancer cells could lead to chemoresistance. The switch between a beneficial or detrimental role of Nrf2 in cancer cells essentially depends on the tight control of its activity, the specific conditions of tumor microenvironment, and cell type. In line with the paucity of clear data related to the mechanisms underpinning the role of Nrf2 in cancer development and chemoresistance, discovery and development of Nrf2-based strategies is one of the most critical and challenging assignments for fighting cancers.     

Is there a future for direct renin inhibitors?

Importance of the field: The renin-angiotensin-aldosterone system (RAAS) is a key regulator of blood pressure (BP), as well as volume and electrolytes, in both hypertensive and normotensive individuals. Inappropriate activation of the RAAS is important in hypertension-induced cardiovascular disease (CVD) and chronic kidney disease (CKD). Renin is the rate-limiting step in the RAAS cascade, which makes direct renin inhibitors (DRIs) an attractive target for RAAS suppression and treatment of hypertension. Current regimens using either angiotensin-converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB) result in feedback upregulation of renin and aldosterone breakthrough, which contribute to incomplete suppression of the RAAS. Thereby, aliskiren – alone or in combination – might offer a novel therapeutic intervention to improve suppression of the RAAS, with potential to translate to improved CVD and CKD outcomes.

Areas covered in this review: Herein, we present the current state of knowledge of DRIs in the preclinical and clinical realm and their antihypertensive efficacy in relation to cardiovascular and renal risk. Recent clinical trials (2007 – 2009) support the efficacy of aliskiren, and studies suggest the potential for improved CVD and CKD outcomes.

What the reader will gain: An understanding of the mechanism of action of DRIs and a perspective of recent clinical trials.

Take home message: The DRI aliskiren is an effective antihypertensive agent that preliminary data suggests has a beneficial effect in CVD and CKD. Combination of aliskiren with an ACEi or ARB may be better tolerated than the ACEi–ARB combination. Future work is needed to further quantify aliskiren's impact on hard CVD and CKD end points.     

Is there a best strategy for drug discovery?

The Society for Medicines Research held a meeting on March 18, 2003, at the National Heart & Lung Institute in London, United Kingdom, to discuss strategies for drug discovery. The meeting began with a history of the origins of drug discovery. Discussions also covered the best strategies for drug discovery, including combinatorial chemistry and high-throughput screening, and ways to meet the challenge of the so-called "innovation gap," among other topics. Speakers included a Nobel Laureate and discoverer of two of the most significant drug classes of the 20th century, and the greatest drug generator of all time. Various companies and institutions were also represented in the talks.     

Is there heterogeneity among syndromes of substance use disorder for illicit drugs?

The use of DSM criteria to evaluate liability to substance use disorders (SUDs) and to identify SUD phenotypes may not provide the sensitivity required to identify genes associated with vulnerability to SUDs. The purpose of this study is to evaluate a number of basic aspects of substance use that may be more proximal than full SUDs to risk genes, some of which may thus have greater potential utility as phenotypes in subsequent molecular genetic analyses. In this paper we present results from the first stage of our planned analyses, focusing on how individual symptoms of abuse and dependence may be used to create alternate phenotypes for SUDs. Specifically, we used factor analysis and biometrical modeling on each symptom of illicit substance abuse and dependence within different types of substances, and compared and contrasted factor patterns and heritabilities across the different substances. These analyses were carried out using a population-based sample of 3372 male-male twin pairs from the Vietnam Era Twin Registry who participated in the Harvard Twin Study of Substance Abuse. We obtained extensive data from these participants on substance use and SUDs via telephone interview in 1992, including data on the illicit substances: opiates, cocaine, cannabis, sedatives, stimulants, and psychedelics. The results indicate that: A) although a one-factor model assuming a single underlying liability for abuse and dependence symptoms and behaviors can be rejected for most substances, there is no uniform support for a two-factor model differentiating between abuse versus dependence; B) patterns of symptoms or behaviors reported by substance users vary across substances; C) not all symptoms or behaviors contribute equally to the presentation of an SUD; and D) the heritability of symptoms or behaviors of substance users varies both within and between substances. These results represent important first steps in facilitating the search for SUD-risk genes in subsequent high-throughput molecular genetic analyses by providing alternate phenotypes that may have both optimal validity and increased heritability.     

Is there scope for improving the cost-effective prescribing of nonsteroidal anti-inflammatory drugs?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely throughout the world to relieve the symptoms of musculoskeletal disorders, in particular osteoarthritis and rheumatoid arthritis. These drugs have significant adverse effects, including gastrointestinal ulceration and the associated complications of perforation and bleeding. The relative toxicity of competing forms of branded and generic NSAIDs varies considerably. Their acquisition cost also varies considerably, sometimes with relatively more toxic drugs being more expensive. Thus, it may be possible to reduce both adverse effects and pharmaceutical expenditures associated with NSAIDs, if doctors' prescribing behaviour can be changed. A tentative exploration of alternative patterns of NSAID use demonstrates that it may be possible to reduce expenditures on NSAIDs in the UK to below the 1994 level, and reduce adverse events. If prescribing of NSAIDs was reduced by 25%, average dosage reduced by 10% and patients switched to less toxic NSAIDs, up to 86 million pounds sterling could be saved per year in the UK, the number of serious adverse events per year reduced by 189 (from a baseline figure of around 500) and the annual number of gastrointestinal complications reduced by 127 (from a baseline figure of around 315). Such results may be achieved without reductions in the quality of life of patients using these drugs. The available clinical and economic information about NSAIDs is limited, and the publication of numerous poor quality studies has corrupted the knowledge base. Despite these problems, there appears to be enough evidence to indicate that expenditure on NSAIDs could be considerably reduced and significant adverse effects could be avoided if general practitioners were persuaded to change their prescribing behaviour. Inefficient and inappropriate prescribing of these often beneficial, but sometimes dangerous, drugs appears to be wasting scarce UK National Health Service resources and harming patients.