Integrative pharmacology and drug discovery--is the tide finally turning?

In vivo animal experiments are essential (and a regulatory requirement) to demonstrate the potential efficacy, safety and pharmacodynamic/pharmacokinetic profile of candidate drugs. However, the number of pharmacologists (and other bioscientists) with integrative (in vivo) pharmacology skills has been in decline for a number of years, as have the opportunities for students to learn such skills. This article reviews some recent initiatives that are underway to rebuild this essential skills base in the United Kingdom and the United States. Partnerships between industry and national funders of research and education have proved to be a particularly effective approach to support this strategically important area of biological science.     

Squalamine: a polyvalent drug of the future?

The purpose of this mini-review is to summarize and highlight the different advances in our understanding of the antimicrobial and antiangiogenic activity of squalamine, a cationic steroid isolated in 1993 from the dogfish shark Squalus Acanthias. Indeed, squalamine has shown to be useful for the treatment of important diseases such as cancers (lung, ovarian, brain and others), age-related macular degeneration (AMD) and the control of body weight in man. All these results led to a question: could we consider squalamine as a polyvalent drug of the future?     

Physiology and pharmacology of alcohol: the imidazobenzodiazepine alcohol antagonist site on subtypes of GABAA receptors as an opportunity for drug development?

Alcohol (ethanol, EtOH) has pleiotropic actions and induces a number of acute and long-term effects due to direct actions on alcohol targets, and effects of alcohol metabolites and metabolism. Many detrimental health consequences are due to EtOH metabolism and metabolites, in particular acetaldehyde, whose high reactivity leads to nonspecific chemical modifications of proteins and nucleic acids. Like acetaldehyde, alcohol has been widely considered a nonspecific drug, despite rather persuasive evidence implicating inhibitory GABA(A) receptors (GABA(A)Rs) in acute alcohol actions, for example, a GABA(A)R ligand, the imidazobenzodiazepine Ro15-4513 antagonizes many low-to-moderate dose alcohol actions in mammals. It was therefore rather surprising that abundant types of synaptic GABA(A)Rs are generally not responsive to relevant low concentrations of EtOH. In contrast, delta-subunit-containing GABA(A)Rs and extrasynaptic tonic GABA currents mediated by these receptors are sensitive to alcohol concentrations that are reached in blood and tissues during low-to-moderate alcohol consumption. We recently showed that low-dose alcohol enhancement on highly alcohol-sensitive GABA(A)R subtypes is antagonized by Ro15-4513 in an apparently competitive manner, providing a molecular explanation for behavioural Ro15-4513 alcohol antagonism. The identification of a Ro15-4513/EtOH binding site on unique GABA(A)R subtypes opens the possibility to characterize this alcohol site(s) and screen for compounds that modulate the function of EtOH/Ro15-4513-sensitive GABA(A)Rs. The utility of such drugs might range from novel alcohol antagonists that might be useful in the emergency room, to drugs for the treatment of alcoholism, as well as alcohol-mimetic drugs to harness acute positive effects of alcohol.     

Lipoic acid - the drug of the future?

Numerous experimental and clinical studies proved efficiency of treatment with lipoic acid-containing drugs in diseases, in which pro- and antioxidant balance is disrupted (diabetes, neurodegenerative diseases, acquired immune deficiency syndrome (AIDS), tumors, etc.). Efficiency of lipoate has been attributed to unique antioxidant properties of lipoate/dihydrolipoate system, its reactive oxygen species (ROS) scavenging ability and significant effect on the tissue concentrations of reduced forms of other antioxidants, including one of the most powerful, glutathione (thus lipoate is called an antioxidant of antioxidants). Moreover, analysis of literature data suggests participation of lipoic acid in processes of cell growth and differentiation. This fact can be crucial to clinical practice, however, this problem requires further studies.     

Methotrexate: a drug of the future in ulcerative colitis?

Ulcerative colitis (UC) is a chronic inflammatory bowel disease that is thought to affect 1780000 patients in USA and Europe. Its incidence is increasing rapidly in Asia. Drugs with proven clinical activity that are currently used in UC patients include salicylates, steroids, azathioprine and infliximab. None of them is active in every patient and all carry significant side effects. There is a need for other active drugs in UC. Low dose methotrexate has been used for decades in psoriasis, rheumatoid arthritis and Crohn's disease. In these diseases, it is an active, well tolerated and cheap drug. In UC there have been several open series, most of which are retrospective. Overall, these studies have shown promising results, with response rates of 50 to 72 %. There have been two randomized clinical trials of methotrexate vs placebo in UC. Both were negative but methotrexate was prescribed orally at suboptimal doses. So far, there is no evidence for the efficacy of methotrexate in UC. Therefore, there is a need for clinical trials with methotrexate using adequate dosage and the parenteral route. Two multicenter randomized trials of methotrexate 25 mg/week parenterally vs placebo are either ongoing (METEOR, the European trial) or being built up (MERIT, the US trial). These trials should determine if methotrexate is a valuable therapeutic option in UC.     

Nuclear receptors: the controlling force in drug metabolism of the liver?

The body is in a constant battle to achieve homeostasis; indeed, the robustness with which it can respond to moves away from homeostasis is a vital part in the survival of the organism as a whole. There thus exists a need for a network of sensors that are able to capture, interpret, and respond to alterations in chemical levels that move the body away from homeostasis and this applies to both endogenous and exogenous chemicals. With respect to external chemicals (xenobiotics), this xenosensing is often carried out through specific interactions with cellular receptors. The phenomenon of ‘xenosensing’ has attracted much interest of late, whereby xenobiotics interact with receptors resulting in the activation of a battery of genes mediating oxidative drug metabolism, conjugation, and transport, thereby enhancing the elimination of the xenobiotic by the organism. However, this beneficial response is counterbalanced by the increasingly recognized role of nuclear receptors in mediating drug–drug interactions via enzyme induction or the production of toxicity through interaction with endogenous pathways. This review will focus on the role of nuclear receptors in mediating these effects, and how such knowledge will contribute to a mechanism-based risk assessment for xenobiotics.     

Tumour endoproteases: the cutting edge of cancer drug delivery?

Despite progression in anticancer drug development and improvements in the clinical utilization of therapies, current treatment regimes are still dependent upon the use of systemic antiproliferative cytotoxic agents. Although these agents are unquestionably potent, their efficacy is limited by toxicity towards 'normal' cells and a lack of tumour selective targeting, resulting in a therapeutic index which is modest at best. Consequently, the development of more tumour selective cancer treatments, with better discrimination between tumour and normal cells is unequivocally an important goal for cancer drug discovery. One such strategy is to exploit the tumour phenotype as a mechanism for tumour-selective delivery of potent therapeutics. An exciting approach in this area is to develop anticancer therapeutics as prodrugs, which are non-toxic until activated by enzymes localized specifically in the tumour. Enzymes suitable for tumour-activated prodrug development must have increased activity in the tumour relative to non-diseased tissue and an ability to activate the prodrug to its active form. One class of enzyme satisfying these criteria are the tumour endoproteases, particularly the serine- and metallo-proteases. These proteolytic enzymes are essential for tumour angiogenesis, invasion and metastasis, the major defining features of malignancy. This review describes the concept behind development of tumour-endoprotease activated prodrugs and discusses the various studies to date that have demonstrated the huge potential of this approach for improvement of cancer therapy.     

Benzylpiperazine: a drug of abuse?

N-benzylpiperazine (BZP) is the active ingredient in recreational 'party' or 'p.e.p.' pills, which are used to provide a stimulant, euphoric effect akin to that of methylenedioxymethamphetamine (MDMA, 'ecstasy'). BZP predominantly affects dopamine neurotransmission in a similar fashion to known 'drugs of abuse', such as methamphetamine and cocaine, which strongly suggests BZP has abuse liability. BZP is illegal in many countries including the United States of America and Australia, yet it remains legal in the United Kingdom, Canada and New Zealand. There has been little research, to date, on the neurological consequences of high dose or chronic exposure of BZP. Here we provide a comprehensive review of the information currently available on BZP and suggest a need for further research into the mechanisms of action, long-term effects and potentially addictive properties of BZP.     

In vitro screening of drug metabolism during drug development: can we trust the predictions?

Due to the importance of drug metabolism for drug action, side effects, interactions and interindividual differences, in vitro assays of drug metabolism are widely employed during drug development. Validation of the in vitro systems is still in a rather elementary stage, but some tentative conclusions about their performance for predicting various important in vivo characteristics of drugs can be attempted. So far, prediction of drug-drug interactions on the basis of in vitro screens has been advanced to a relatively reliable level. Prediction of other important characteristics, such as metabolic stability and consequent half-life and dosage schedule, or induction potential, is less reliable. Although metabolite profiles and participating enzymes are predicted quite accurately with advanced analytical techniques, an important problem here is the lack of reliable methods to detect reactive metabolites or products, which may be of significance regarding toxicity.