Disease-modifying therapies in Alzheimer's disease: how far have we come?

Currently, there are no disease-modifying therapies available for Alzheimer's disease (AD). Acetylcholinesterase inhibitors and memantine are licensed for AD and have moderate symptomatic benefits. Epidemiological studies have suggested that NSAIDs, estrogen, HMG-CoA reductase inhibitors (statins) or tocopherol (vitamin E) can prevent AD. However, prospective, randomised studies have not convincingly been able to demonstrate clinical efficacy. Major progress in molecular medicine suggests further drug targets.The metabolism of the amyloid-precursor protein and the aggregation of its Abeta fragment are the focus of current studies. Abeta peptides are produced by the enzymes beta- and gamma-secretase. Inhibition of gamma-secretase has been shown to reduce Abeta production. However, gamma-secretase activity is also involved in other vital physiological pathways. Involvement of gamma-secretase in cell differentiation may preclude complete blockade of gamma-secretase for prolonged times in vivo. Inhibition of beta-secretase seems to be devoid of serious adverse effects according to studies with knockout animals. However, targeting beta-secretase is hampered by the lack of suitable inhibitors to date. Other approaches focus on enzymes that cut inside the Abeta sequence such as alpha-secretase and neprilysin. Stimulation of the expression or activity of alpha-secretase or neprilysin has been shown to enhance Abeta degradation. Furthermore, inhibitors of Abeta aggregation have been described and clinical trials have been initiated. Peroxisome proliferator activated receptor-gamma agonists and selected NSAIDs may be suitable to modulate both Abeta production and inflammatory activation. On the basis of autopsy reports, active immunisation against Abeta in humans seems to have proven its ability to clear amyloid deposits from the brain. However, a first clinical trial with active vaccination against the full length Abeta peptide has been halted because of adverse effects. Further trials with vaccination or passive transfer of antibodies are planned.     

Progress in colorectal cancer chemotherapy: how far have we come, how far to go?

Fluorouracil has been the mainstay of treatment for colorectal cancer (CRC) for almost 40 years. Various schedules and biochemical modulators have been investigated in an attempt to improve the therapeutic efficacy of fluorouracil. To date, fluorouracil plus folinic acid represents the standard therapy in CRC for the adjuvant treatment of patients at high risk for relapse and for the first-line treatment of metastatic disease. To gain clinical acceptance, however, oral fluoropyrimidines must confer at least the same survival advantages associated with the optimal intravenous fluorouracil regimens. Irinotecan and oxaliplatin are 2 other novel agents that have mechanisms of action that are uniquely different from those of fluorouracil, with demonstrated activity in patients with fluorouracil-refractory disease. Recent randomised trials comparing fluorouracil plus folinic acid with combinations of either irinotecan or oxaliplatin and fluorouracil plus folinic acid have shown that response rates are improved and time to progression is increased in patients receiving the combination regimens. These regimens are being rapidly introduced in the adjuvant setting, and the role and acceptance of these combination regimens as first-line therapy needs to be defined. Other novel agents being evaluated in the treatment of patients with advanced CRC include oral edrecolomab (monoclonal antibody 17-1A) and tumour vaccines. Future research is focused on enabling clinicians to individualise treatment strategies in patients with CRC, so as to improve clinical outcomes and reduce drug toxicity.     

ADMET in silico modelling: towards prediction paradise?

Following studies in the late 1990s that indicated that poor pharmacokinetics and toxicity were important causes of costly late-stage failures in drug development, it has become widely appreciated that these areas should be considered as early as possible in the drug discovery process. However, in recent years, combinatorial chemistry and high-throughput screening have significantly increased the number of compounds for which early data on absorption, distribution, metabolism, excretion (ADME) and toxicity (T) are needed, which has in turn driven the development of a variety of medium and high-throughput in vitro ADMET screens. Here, we describe how in silico approaches will further increase our ability to predict and model the most relevant pharmacokinetic, metabolic and toxicity endpoints, thereby accelerating the drug discovery process.     

In silico ADMET tools: the dawn of a new generation?

During the late 1990s, the allure of in silico methods for absorption, distribution, metabolism, excretion and toxicity prediction led to the rapid development of what might be termed first-generation models. However, despite much initial enthusiasm, these largely proved disappointing when applied in real-world settings. Some of the reasons for this disappointment are examined in this perspective. The present status of the field, as second-generation models are beginning to emerge, is surveyed. Finally, the outstanding challenges in the field are delineated and some possible approaches to their resolution suggested.     

In silico structural prediction of human steroid 5α-reductase type II

Steroid 5α-reductase type II is a membrane-associated enzyme in an oxidoreductase family. This enzyme, which is found in male sexual organs, plays the important biological actions toward steroid metabolism. Overexpression of 5α-reductase type II has affected the balance between testosterone and dihydrotestosterone, which implicates the androgenic disorders, including prostate cancer, hirsutism, and androgenic alopecia. Lack of single-crystal X-ray structures of 5α-reductase has hindered mechanistic understanding and delayed the discovery and development of an effective inhibitor. Herein, we illustrated a comparative structure of 5α-reductase type II that derived from the homology modeling, employing a membrane-bound protein, isoprenylcysteine carboxyl methyltransferase as a homologous template. A catalytic pocket and the transmembrane site were identified. The resulting in silico structure was validated via Ramachandran plot and confirmed by docking studies of 30 known 5α-reductase type I and type II inhibitors, including finasteride and dutasteride. The comparative docking study of the derived in silico 5α-reductase type II and 5β-reductase, a reported surrogate enzyme, was conducted. Our homology model approximately fitted to the membrane-associated character and showed the reasonable docking results, which depicted the well-defined comparative three-dimensional structure applicable for steroid reductase drug design.     

The failure of torcetrapib: what have we learned?

The failure of the cholesterol ester transfer protein (CETP) inhibitor, torcetrapib, has led to questions regarding whether the molecule itself or the mechanism of CETP inhibition was responsible for the adverse cardiovascular outcomes. Given the association with increases in blood pressure and plasma aldosterone levels, torcetrapib has been postulated to have adverse 'off-target' effects. In this issue of British Journal of Pharmacology, Forrest and co-workers have elegantly investigated these effects, demonstrating two salient points -- (1) the pressor effect of torcetrapib is independent of CETP inhibition and (2) although associated with hyperaldosteronism, the pressor effect is likely not mediated by hyperaldosteronism. Anacetrapib, by contrast, did not demonstrate any pressor or off-target effects. Despite these findings, it remains to be proven whether the adverse cardiovascular outcomes from torcetrapib were indeed related to the pressor effects and whether CETP inhibition by other agents will result in beneficial clinical outcomes. Yet, the studies of Forrest and co-workers do bring us closer to unravelling the reasons behind the failure of torcetrapib.     

Investigational cannabinoids in seizure disorders,what have we learned thus far?

Introduction:The anticonvulsant activity of cannabinoids attracted much attention in the last decade. Cannabinoids that are currently investigated with the intention of making them drugs for the treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin, and Δ9-tetrahydrocannabinolic acid.

Areas covered:In this review, the authors look at the results of preclinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR, and SCINDEX databases.

Expert opinion: Preclinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While the results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy-resistant seizures associated with Dravet syndrome and in patients with Lennox–Gastaut syndrome who have drop seizures. However, the full therapeutic potential of cannabinoids in treatment-resistant epilepsy needs to be investigated in the near future.     

Genetic insights into sepsis: what have we learned and how will it help?

Sepsis and septic shock, are complex disorders that are a major cause of mortality in the intensive care unit. In spite of major advances in our understanding of the pathophysiology of sepsis, accurate prediction of susceptibility to sepsis, multi-organ dysfunction, and death, even in the setting of a seemingly similar burden of infection, continues to challenge critical care clinicians. Evidence from family-based studies and recent gene-association studies suggest that a significant portion of the apparent variability in susceptibility is due to genetic factors. Common sequence variations in genes coding for innate immune effectors, inflammatory mediators, and modulators of coagulation have received particular attention. This review will summarize and integrate the results of studies testing for associations between sequence variations in genes from these functional classes and susceptibility to sepsis and related clinical outcomes. The important insights on sepsis pathophysiology provided by these studies will be discussed along with the relevance of these findings to the design of future diagnostic approaches and therapeutic trials.     

Antiepileptogenic agents: how close are we?

Epilepsy is a common neurological condition, affecting about 4% of individuals over their lifetime. Epilepsy can be idiopathic, secondary to an underlying genetic abnormality or unknown causes, or acquired. Known potential causes account for about one third of epilepsy. Control of epilepsy has primarily focused on suppressing seizure activity after epilepsy has developed. An intriguing possibility is to control acquired epilepsy by preventing epileptogenesis, the process by which the brain becomes epileptic. Many laboratory models simulate human epilepsy as well as provide a system for studying epileptogenesis. The kindling model involves repeated application of subconvulsive electrical stimulation to the brain, leading to spontaneous seizures. Other models include the cortical or systemic injection of various chemicals. These models suggest that many antiepileptic drugs, from phenobarbital and valproate (valproic acid) to levetiracetam and tiagabine, have antiepileptogenic potential. Some promising other possibilities include N-methyl-D-aspartate (NMDA) or alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) antagonists as well as the neurotrophins and their receptors. Phenobarbital, phenytoin, valproate, carbamazepine and, to a very limited extent, diazepam have been evaluated in clinical trials to test whether they actually prevent epileptogenesis in humans. Results have been very disappointing. Meta-analyses of 12 different drug-condition combinations show none with significantly lower unprovoked seizure rates among those receiving the active drug. In 4 of the 12, the observed rate was actually slightly higher among treated individuals. None of the newer drugs have been evaluated in antiepileptogenesis trials. Until some drugs demonstrate a clear antiepileptogenic effect in clinical trials, the best course to reduce the incidence of epilepsy is primary prevention of the risk-increasing events--for example, wearing helmets, using seat belts, or decreasing the risk of stroke by reducing smoking.     

Safe use of long-acting β-agonists: what have we learnt?

INTRODUCTION: Long-acting β-agonists (LABAs) added to inhaled corticosteroids (ICS) reduce symptoms, improve lung function and enhance overall asthma control. However, several studies have indicated an increased risk of asthma mortality and asthma-related serious adverse events and the FDA recently mandated restrictions to the use of LABAs in asthma. AREAS COVERED: This review highlights the clinical studies on which safety analyses pertaining to salmeterol and formoterol have been based and then focuses on recent meta-analyses of safety outcomes with and without consideration of concomitant ICS. EXPERT OPINION: The phenomenon of masking of inflammation by LABA if ICS dose is insufficient underscores the potential for confounding in determining real safety risks. Under-treatment with ICS and differential dosing of ICS in many trials are major factors driving the LABA safety concern. The FDA meta-analysis, when stratified for mandatory ICS use, found no significant increase in the composite outcome of asthma mortality, intubations and hospitalizations. Add-on therapy with LABA is effective and safe if the dose of ICS is adequate to treat airway inflammation. LABA and ICS given in a single device will negate the possibility of LABA monotherapy which is contraindicated. The FDA has recommended that LABAs be withdrawn when control is achieved with combination therapy but recent evidence suggests this may result in loss of symptom control.     

Practical considerations for conducting ecotoxicity test methods with manufactured nanomaterials: what have we learnt so far?

This review paper reports the consensus of a technical workshop hosted by the European network, NanoImpactNet (NIN). The workshop aimed to review the collective experience of working at the bench with manufactured nanomaterials (MNMs), and to recommend modifications to existing experimental methods and OECD protocols. Current procedures for cleaning glassware are appropriate for most MNMs, although interference with electrodes may occur. Maintaining exposure is more difficult with MNMs compared to conventional chemicals. A metal salt control is recommended for experiments with metallic MNMs that may release free metal ions. Dispersing agents should be avoided, but if they must be used, then natural or synthetic dispersing agents are possible, and dispersion controls essential. Time constraints and technology gaps indicate that full characterisation of test media during ecotoxicity tests is currently not practical. Details of electron microscopy, dark-field microscopy, a range of spectroscopic methods (EDX, XRD, XANES, EXAFS), light scattering techniques (DLS, SLS) and chromatography are discussed. The development of user-friendly software to predict particle behaviour in test media according to DLVO theory is in progress, and simple optical methods are available to estimate the settling behaviour of suspensions during experiments. However, for soil matrices such simple approaches may not be applicable. Alternatively, a Critical Body Residue approach may be taken in which body concentrations in organisms are related to effects, and toxicity thresholds derived. For microbial assays, the cell wall is a formidable barrier to MNMs and end points that rely on the test substance penetrating the cell may be insensitive. Instead assays based on the cell envelope should be developed for MNMs. In algal growth tests, the abiotic factors that promote particle aggregation in the media (e.g. ionic strength) are also important in providing nutrients, and manipulation of the media to control the dispersion may also inhibit growth. Controls to quantify shading effects, and precise details of lighting regimes, shaking or mixing should be reported in algal tests. Photosynthesis may be more sensitive than traditional growth end points for algae and plants. Tests with invertebrates should consider non-chemical toxicity from particle adherence to the organisms. The use of semi-static exposure methods with fish can reduce the logistical issues of waste water disposal and facilitate aspects of animal husbandry relevant to MMNs. There are concerns that the existing bioaccumulation tests are conceptually flawed for MNMs and that new test(s) are required. In vitro testing strategies, as exemplified by genotoxicity assays, can be modified for MNMs, but the risk of false negatives in some assays is highlighted. In conclusion, most protocols will require some modifications and recommendations are made to aid the researcher at the bench.     

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.