How can high-throughput screening deliver drugs to treat atherosclerosis?

Importance of the field: Atherosclerosis is a progressive disease that is characterized by the accumulation of lipid-rich plaques within the artery walls. Despite the past 3 decades witnessing the most significant advances in the pharmacotherapy of atherosclerosis with statins, atherosclerosis is still one of the leading causes of mortality in industrialized and developing nations. The applications of high-throughput screening (HTS) have retrieved hits and lead compounds which may be further developed to new promising therapeutics to achieve more effective reductions in the risk of cardiovascular morbidity and mortality.

Areas covered in this review: The review provides a summary of potential drug targets other than HMG-CoA reductase (primary target of statins) and their application in biochemical or cell-based HTS assays used by pharmaceutical companies and academic laboratories for anti-atherosclerotic drug discovery.

What the reader will gain: The reader will gain an overview of the HTS strategies currently used in the development of anti-atherosclerotic agents. The reader is also provided with some abortive examples in anti-atherosclerotic drug discovery as well as the associated limitations and challenges of the process that HTS delivers new drugs to treat atherosclerosis.

Take home message: HTS can assist in the efficient discovery of new drugs towards the potential targets involved in the progress of atherosclerosis.     

Whither high-throughput screening?

‘…today’s HTS will become the fulcrum that fully leverages genomics in drug discovery’     

Developing drugs to treat osteoporosis: lessons learned?

Background: Selective estrogen-receptor modulators (SERMs) are drugs that act as estrogen receptor agonists or antagonists depending on the target tissue. Theoretically this class of agents would be an ideal substitute for hormone replacement therapy (HRT), if their effects on the skeleton matched those of estrogen while their actions on other tissues were either neutral or beneficial. Objective: To evaluate a Phase III trial of a new SERM, arzoxefine, for prevention of osteoporosis in younger postmenopausal women. Methods/results: Arzoxifene induced modest but significant increases in bone mineral density versus a control group during 2 years of therapy, with minor adverse events. However, fracture efficacy and other patient-specific outcomes were not evaluated. Conclusion: Despite a positive study of surrogate end points (bone density and biochemical markers of bone turnover), arzoxifene was withdrawn from further FDA evaluation, principally because of long-term side effects and lack of non-vertebral fracture efficacy in the companion Phase III fracture study. Each SERM has a unique profile on bone and other tissues. Regulatory approval of this class of agents may remain problematic for the immediate future.     

Prediabetes: to treat or not to treat?

The incidence of diabetes is continuously increasing worldwide. Pre-diabetes (defined as impaired glucose tolerance, impaired fasting glucose or both) represents an intermediate state, which often progresses to overt diabetes within a few years. In addition, pre-diabetes may be associated with increased risk of microvascular and macrovascular complications. Thus, reverting a pre-diabetic state as well as preventing the development of diabetes represents enormous challenge for the clinician. Lifestyle modification in pre-diabetic individuals was found particularly effective in the prevention of diabetes. However, compliance to lifestyle modification measures can be a crucial problem in the everyday clinical practice, especially in developing countries. During the last decade many studies support the use of anti-diabetic treatment schemes in pre-diabetic subjects to be advantageous. The American Diabetes Prevention Program (DPP) as well as other minor studies and meta-analyses has convincingly demonstrated the efficacy of metformin in this patient group. In addition, results of the 10 year DPP follow up have recently been published, demonstrating the long term safety and sustainability of metformin treatment benefits in this population. In contrast to metformin, the evidence from the use of other anti-diabetic agents (thiazolidinediones, a-glucosidase inhibitors, incretin mimetics) in pre-diabetic individuals is rather inadequate and prospective data is further needed. Furthermore, large scale studies with hard clinical endpoints are needed to delineate the effect of pre-diabetes treatment on macro- and microvascular complications. In conclusion, several strategies of patient management, mainly lifestyle modification and pharmacological interventions can prevent diabetes development in subjects diagnosed with pre-diabetes or even revert pre-diabetic state. However, whether this biochemical improvement can be translated into actual clinical benefit remains to be established.     

Development of drugs for Epstein–Barr virus using high-throughput in silico virtual screening

Importance of the field: Epstein–Barr virus (EBV) is a ubiquitous human herpesvirus that is causally associated with endemic forms of Burkitt's lymphoma, nasopharyngeal carcinoma and lymphoproliferative disease in immunosuppressed individuals. On a global scale, EBV infects > 90% of the adult population and is responsible for ～ 1% of all human cancers. To date, there is no efficacious drug or therapy for the treatment of EBV infection and EBV-related diseases.

Areas covered in this review: In this review, we discuss the existing anti-EBV inhibitors and those under development. We discuss the value of different molecular targets, including EBV lytic DNA replication enzymes as well as proteins that are expressed exclusively during latent infection, such as EBV nuclear antigen 1 (EBNA-1) and latent membrane protein 1. As the atomic structure of the EBNA-1 DNA binding domain has been described, it is an attractive target for in silico methods of drug design and small molecule screening. We discuss the use of computational methods that can greatly facilitate the development of novel inhibitors and how in silico screening methods can be applied to target proteins with known structures, such as EBNA-1, to treat EBV infection and disease.

What the reader will gain: The reader is familiarized with the problems in targeting of EBV for inhibition by small molecules and how computational methods can greatly facilitate this process.

Take home message: Despite the impressive efficacy of nucleoside analogs for the treatment of herpesvirus lytic infection, there remain few effective treatments for latent infections. As EBV latent infection persists within and contributes to the formation of EBV-associated cancers, targeting EBV latent proteins is an unmet medical need. High-throughput in silico screening can accelerate the process of drug discovery for novel and selective agents that inhibit EBV latent infection and associated disease.     

Do British commercial mountaineering expeditions carry drugs to treat high altitude illnesses?

High altitude commercial expeditions are increasingly popular. As high altitude illnesses are common on ascent to altitude, this study aimed to ascertain whether medications for these conditions were carried by commercial operators who run high altitude expeditions. Despite recommendations, it appears that drugs to treat high altitude illnesses are not routinely carried by commercial operators.     

What can independent research for mesothelioma achieve to treat this orphan disease?

Introduction: Malignant pleural mesothelioma (MPM) is a rare neoplasm with a poor prognosis, as current therapies are ineffective. Despite the increased understanding of the molecular biology of mesothelioma, there is still a lack of drugs that dramatically enhance patient survival.

Area Covered: This review discusses recent and complete clinical trials supported by the NIH, other U.S. Federal agencies, universities and organizations found on clinicaltrials.gov. Firstly, chemotherapy-based trials are described, followed by immunotherapy and multitargeted therapy. Then we introduce drug repositioning and the use of drug docking as tools to find new interesting molecules. Finally, we highlight potential molecular pathways that may play a role in mesothelioma biology and therapy.

Expert Opinion: Numerous biases are present in the clinical trials due to a restricted number of cases, inappropriate endpoints and inaccurate stratification of patients which delay the finding of a treatment for MPM. The most crucial issue of independent research for MPM is the lack of more substantive funding to translate these findings to the clinical setting. However, this approach is not necessarily scientific given the low mutational load of mesothelioma relative to other cancers, and therefore patients need a more solid rationale to have a good chance of successful treatment     

From screening criteria to colorectal cancer screening: what can New Zealand learn from other countries?

New Zealand is currently exploring how population-based colorectal cancer (CRC) screening will be implemented. The United Kingdom (UK), Australia, France, Italy, Spain, Finland, Denmark, the Netherlands, and Switzerland have conducted or are currently conducting pilot/feasibility studies. The UK, Australia, Finland, Canada, France and Italy are all in the early stages of implementing population-based CRC screening programmes. Most of these countries have lower CRC mortality rates than New Zealand. New Zealand is in a good position to learn from this overseas experience. Some of the key areas that will require careful consideration include; the best use of a population register to identify and invite eligible participants; the type of screening test to be used; ensuring adequate colonoscopy capacity; efficient and effective information systems; the management of high-risk groups; and how to ensure that all population groups benefit from screening.     

Dyslipidaemia in the elderly: to treat or not to treat?

Introduction: The elderly population (i.e. aged ≥ 65 years) is increasing worldwide. Ageing is associated with a higher incidence and prevalence of cardiovascular disease (CVD).

Areas covered: The prevalence of CVD risk factors including type 2 diabetes mellitus, hypertension and dyslipidaemia also increases with advancing age, contributing to the higher absolute CVD risk observed in the elderly. The present narrative review comments on the associations of dyslipidaemia with CVD as well as the effects of lifestyle measures and lipid-lowering drugs on lipids and CVD risk with a special focus on the elderly population. Individual treatment goals and therapeutic options according to current guidelines are also reviewed. Finally, we discuss special characteristics of the elderly that may influence the efficacy and safety of drug therapy and should be considered before selection of hypolipidaemic pharmacotherapy.

Expert commentary: There may be a greater CVD benefit in older patients following drug therapy compared with younger ones. Treatment goals and therapeutic options should be individualized according to current guidelines. Specific characteristics that may influence the efficacy and safety of drug therapy in the elderly should be considered in relation to dyslipidaemia treatment.     

How can we bring high drug doses to the lung?

In the last decades, dry powder inhalation has become a very attractive option for pulmonary drug delivery to treat lung diseases like cystic fibroses and lung infections. In contrast to the traditional pulmonary application of drugs for asthma and chronic obstructive pulmonary disease, these therapies require higher lung doses to be administered. The developments and improvements toward high dose powder pulmonary drug delivery are summarized and discussed in this chapter. These include the invention and improvement of novel inhaler devices as well as the further development of formulation principles and new powder engineering methods. The implementation of these strategies is subsequently described for some prototypes and formulations in research and development stage as well as for already marketed dry powder products. Finally, possible adverse effects that can occur after inhalation of high powder doses are shortly addressed.     

How well tolerated are lipid-lowering drugs?

It has been clearly established that lipid-lowering treatments [such as 3-hydroxyl-3-methylglutamyl coenzyme A reductase inhibitors ('statins') or fibrates] can reduce cardiovascular events, and with one of the statins even total mortality, in high-risk populations. Intervention studies have not included the very old, but it is generally assumed that this patient group would benefit from these treatments to an extent similar to younger patients. Worries about the associations seen in observational studies between low cholesterol levels and cancer, cerebral haemorrhage or mood and behaviour change have been largely overcome by findings from the latest large drug intervention trials, which do not show any increase in these conditions with statin or fibrate treatments. The common adverse effects associated with these drugs are relatively mild and often transient in nature. Potentially more serious adverse effects, which are more clearly related to drug treatment and are probably dose-dependent, include elevations in hepatic transaminase levels and myopathy; however, these effects are uncommon and generally resolve rapidly when treatment is stopped. The risk of myopathy with fibrate treatment is increased in patients with renal impairment, and the risk of myopathy with statin treatment increases with co-administration of drugs that inhibit statin metabolism or transport. Other adverse effects are related to specific drugs, for example, clofibrate is associated with an increased risk of gallstones. Studies in elderly patients have not shown an increased risk of adverse effects with lipid-lowering drugs compared with younger patients, but in clinical practice there may be some increased risk, particularly with regards to drug interactions. Therefore, lipid-lowering drugs should be administered with extra caution to elderly patients.     

Colloidal carriers and blood–brain barrier (BBB) translocation: A way to deliver drugs to the brain?

The major problem in drug delivery to the brain is the presence of the blood-brain barrier (BBB) which limits drug penetration even if in certain pathological situations the BBB is partly disrupted. Therefore, various strategies have been proposed to improve the delivery of drugs to this tissue. This review presents the status of the BBB in healthy patients and in pathologies like neurodegenerative, cerebrovascular and inflammatory diseases. The second part of this article aims to review the invasive and non-invasive strategies developed to circumvent the BBB and deliver drugs into the brain. The use of nanotechnologies (liposomes, nanoparticles) is especially discussed in the ultimate part of the review evidencing their potentiality as non-invasive technique in the brain delivery of drugs with the possibility to target specific brain tissue thanks to ligand linked to carrier surface.     

How much do Manhattan-arrestees spend on drugs?

INTRODUCTION: Information about individuals' drug expenses can indicate much about the size of drug markets, the financial burden of use, drug-related crime, and potential challenges for treatment. Most often, expenses have been estimated holistically by asking respondents to report how much they spent. In 2000, the Arrestee Drug Abuse Monitoring (ADAM) program introduced an advanced questionnaire using a series of highly specific questions like, "how much cash did you pay for crack that last time you bought it?" METHODS: This paper describes a procedure for estimating arrestees' drug expenses with the new ADAM questionnaire, discusses pitfalls in interpretation, presents findings for 2979 ADAM-Manhattan respondents interviewed 2000-2002, examines covariates of drug expense, and compares the 2000-2002 findings with those obtained from 2256 respondents interviewed 1998-1999 with the previous questionnaire. RESULTS: Among 2000-2002 arrestees, median drug expense in the past 30 days varied widely with frequency of use and drug-user type. Infrequent marijuana-only users spent as little as $5, daily marijuana-only users spent about $600. Arrestees that used both heroin and cocaine spent over $1000. Estimates with the 1998-1999 data were about half as large. DISCUSSION: ADAM's new drug market questions may greatly advance the quality of estimates of drug expenses. However, further research is needed to better establish the estimator's accuracy.