Medical treatment and neuroprotection in traumatic brain injury

The goal of this article is to give an overview about the established current treatment concepts of traumatic brain injury, as well as an outlook on possible future developments in pharmacological neuroprotection. Modern medical treatment modalities of traumatic brain injury (TBI), including the preclinical management of severely head-injured patients, are reviewed. Since an increased intracranial pressure represents the most common complication of severe traumatic brain injury, frequently associated with the development of secondary brain damage, special emphasis was given to an updated treatment algorithm for this important condition. New insight into the pathophysiology of severe traumatic brain injury, especially the realization that brain damage develops sequentially, initiated several new treatment approaches aiming at the interruption of pathophysiological mechanisms leading to secondary brain injury. A high number of pharmacological substances have been tested for their ability to ameliorate secondary damage after TBI, or are currently under clinical trial. Although no drug has achieved this goal so far, the most promising of these therapeutical approaches, glutamate receptor antagonists, calcium channel antagonists, free radical scavengers, and cyclosporin A will be discussed in this review. Although a "magical bullet" for the treatment of traumatic brain injury has not been developed yet, several of the currently investigated neuroprotective strategies seem to be encouraging. A promising future approach might be to evaluate treatment strategies that combine several pharmacological agents, and possibly other treatment modalities, such as mild hypothermia, "tailored" according to the special pathology of patient subgroups, or even to every single patient in order to achieve an improvement in outcome after TBI.     

The role of adhesive proteins in the hematogenous spread of cancer

The understanding of the mechanisms that control metastasis and invasion are critical for the identification of new targets for drug development. In this review we focused on two major pathways that mediate hematogenous cancer spread: the hemostatic system and cell adhesive interactions that lead to tumor invasion and angiogenesis. We describe the contribution of platelets and a number of adhesive proteins as well as their receptors that have recently been shown to play a role in metastasis. In addition, enzymes and their inhibitors that modulate cellular adhesive interactions are described. We hope that this summary will stimulate researchers in this area to focus their efforts on molecules that have recently been discovered. These molecules will not only lead to the fuller understanding of the "soil and seed" hypothesis proposed more than 100 years ago but also provide new therapeutic approaches for the treatment of metastatic disease.     

Nanomedicine(s) under the microscope

Depending on the context, nanotechnologies developed as nanomedicines (nanosized therapeutics and imaging agents) are presented as either a remarkable technological revolution already capable of delivering new diagnostics, treatments for unmanageable diseases, and opportunities for tissue repair or highly dangerous nanoparticles, nanorobots, or nanoelectronic devices that will wreak havoc in the body. The truth lies firmly between these two extremes. Rational design of "nanomedicines" began almost half a century ago, and >40 products have completed the complex journey from lab to routine clinical use. Here we critically review both nanomedicines in clinical use and emerging nanosized drugs, drug delivery systems, imaging agents, and theranostics with unique properties that promise much for the future. Key factors relevant to the design of practical nanomedicines and the regulatory mechanisms designed to ensure safe and timely realization of healthcare benefits are discussed.     

Commentary to "Linear and Nonlinear System Approaches in Pharmacokinetics. How much do they have to offer? I. General considerations"

The review by Veng-Pedersen will hopefully stimulate workers in the field to consider systems techniques more thoroughly. As these techniques are well developed in the engineering fields, students should be encouraged to take relevant courses. In this reviewer's opinion, understanding systems theory will allow pharmacokineticists to "cut through the fat" in the derivation of relationships between kinetic phenomena. However, it should be recognized that the system approaches described in Veng-Pedersen's review probably do not by themselves solve the major problems of response approximation and prediction.     

Clinical development landscape in GIST: from novel agents that target accessory pathways to revisiting non-targeted therapies

Introduction: Activating mutations in the genes encoding the tyrosine receptor kinases KIT and platelet-derived growth factor receptor occur in 85%–90% of patients with gastrointestinal stromal tumors (GIST). Although imatinib and other tyrosine kinase inhibitors have revolutionized the treatment of GIST, most patients progress within a few years.

Areas covered: Monoclonal antibodies and small-molecule inhibitors targeting specific signaling pathways or proteins associated with resistance to existing treatments are being explored as alternative treatment approaches for GIST. Other alternative approaches include inhibiting more general regulators of protein folding, chromatin packaging, and cell-cycle regulation; nontargeted approaches are also being evaluated in select patient populations. This review summarizes preclinical and clinical data from agents using these accessory pathways.

Expert opinion: As we learn more about GIST biology, it is becoming clear that treatment strategies will become more personalized, as reflected by the fact that several trials are enrolling specific subpopulations of patients with GIST. Going forward, researchers should evaluate these new drugs alone or in combination with other types of drugs to better meet patient needs.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. β-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

Targeting Technologies—The Expanding Patent Literature

Abstract

Progress in the development of drug targeting technologies is advancing at an ever-increasing rate as we hurtle toward the new millennium. Examination of just the past three years of the drug delivery technology patent literature suggests that what was previously thought impossible may now be a reality. As one goes through this literature, the breadth and ingenuity of many of these approaches are obvious. As in the inaugural article, I have grouped information gathered from this search into areas of mucosal targeting, organ and/or tissue targeting, tumor targeting and focal delivery. The patent applications described in this article represent a sampling of the work in these areas, with particular attention being paid to a few of the more novel or intriguing claims.

The patent literature provides unique insights into the direction(s) taken by industrial and academic scientists in their efforts to provide better and more effective targeted drug delivery systems. The need for novel and innovative delivery designs continues to grow with the discovery of new potential therapeutics which will only realize a clinical benefit if delivered selectively to a site of action by a targeting technology. The ingenuity and creativity of those attempting to meet these challenges with novel targeting technologies is rather striking. In general, though, the pharmaceutical industry, has been slow to incorporate many of these less traditional approaches in designing formulations and products. The rationale behind this conservative approach is probably multifaceted but most likely based to a large degree on the perceived comfort level of regulatory agencies with these novel targeting technologies. Since many of the potential new drug entities in the pipeline of pharmaceutical companies will require targeting technologies, it will be interesting to see how open the industry, as a whole, will be to utilize some of these novel delivery approaches and make the effort to convince regulatory agencies of their safe and effective application.     

New anti-inflammatory therapies and targets for asthma and chronic obstructive pulmonary disease

Asthma and chronic obstructive pulmonary disease (COPD) are diseases of the airways with an underlying inflammatory component. The prevalence and healthcare burden of asthma and COPD is still rising and is predicted to continue to rise in the foreseeable future. Beta-agonists and corticosteroids form the basis of the therapies available to treat asthma. However, the treatments available for COPD, corticosteroids and anticholinergics, reduce the number and severity of exacerbations, but have a limited effect on slowing the progression of the disease. The inflammatory processes underlying the pathology of asthma have received a great deal of attention and more recently, those underlying COPD have begun to be elucidated. This has resulted in the identification of new targets that will allow the development of novel approaches by the pharmaceutical industry, which will be able to focus its efforts in an attempt to provide new and improved therapies to treat these debilitating diseases. The resultant therapies should impinge on the underlying development of these diseases rather than providing symptomatic relief or palliative treatment alone. This review will outline new targets and novel approaches currently under investigation, which may provide opportunities for novel anti-inflammatory therapeutic interventions that slow or halt disease progression in asthma and COPD.     

Cell-based therapy for liver diseases

Although liver transplantation has become standard therapy in the treatment of patients with liver failure, several problems should be considered in the management of these patients. Other approaches have been proposed, in particular cellular-based procedures. Isolated hepatocytes may be used instead of whole organ transplantation or integrated within the bioartificial devices, in order to replace the missing synthetic and metabolic liver functions. Moreover patient's own hepatocytes may be ex vivo genetically modified to provide the function of a mutant gene. However, new cell sources alternative to adult hepatocytes are actually under investigation, on the basis of recent advances in the field of liver repopulation. Xenogenic primary cells, human hepatoma cells, immortalized hepatocytes and stem cells have been testing in several experiments, even if up to now none of them represent a "gold-standard" for cell-based treatment of liver diseases. In the next future, it is possible that different clinical situations will require different therapeutic approaches, that will be finally defined from the concomitant advances in the development of artificial devices and liver cell biology.     

Trends in early drug safety

Successful introduction of a new drug to the market is not only an extremely costly and complicated process, but also fraught with a substantial risk of failure. The number of new drugs launched each year from 1990 to 2000 has stayed relatively constant, while the cost of pharmaceutical research and development has risen by almost 2.5-fold over the same period. What is not revealed by these figures is that the chance of success for a drug candidate passing through the various hurdles in pharmaceutical development is at best 1 in 10 and has barely changed despite advancing technology in other areas of research and development. While we expect high failure rates in drug discovery, it is of substantial concern that most candidates in development on which large investments have already been made are probably not going to make any return. A major stumbling block is the absorption, distribution, metabolism, excretion and toxicology profile of drug candidates. These issues were discussed at the Society for Medicines Research symposium held September 18, 2003, in London, United Kingdom. Recent SMR symposia have focused on the ADME and pharmacokinetic aspects of drug discovery and development. Indeed, it is now uncommon for drug discovery projects not to address these issues early in their lifetimes. Although it is less common to address drug safety early in a project, it is being utilized more frequently to help select the best clinical candidates for further development. This meeting report summarizes some of the key aspects of early drug safety issues facing the drug discoverer today. Classical approaches to toxicology, p450-mediated safety, cardiovascular safety, "omics" approaches and their impact upon clinical safety will be discussed.     

Polymer implants for intratumoral drug delivery and cancer therapy

To address the need for minimally invasive treatment of unresectable tumors, intratumoral polymer implants have been developed to release a variety of chemotherapeutic agents for the locoregional therapy of cancer. These implants, also termed "polymer millirods," were designed to provide optimal drug release kinetics to improve drug delivery efficiency and antitumor efficacy when treating unresectable tumors. Modeling of drug transport properties in different tissue environments has provided theoretical insights on rational implant design, and several imaging techniques have been established to monitor the local drug concentrations surrounding these implants both ex vivo and in vivo. Preliminary antitumor efficacy and drug distribution studies in a rabbit liver tumor model have shown that these implants can restrict tumor growth in small animal tumors (diameter < 1 cm). In the future, new approaches, such as three-dimensional (3-D) drug distribution modeling and the use of multiple drug-releasing implants, will be used to extend the efficacy of these implants in treating larger tumors more similar to intractable human tumors.     

Novel preparative regimens in hematopoietic stem cell transplantation

Hematopoietic stem cell transplantation is an established treatment modality for malignant and non-malignant diseases. Prior to the infusion of allogeneic or autologous cells, patients usually receive radiation or chemotherapy. This "preparative" or 'conditioning' regimen provides treatment for the underlying disease and is expected to impair the recipient's immune system and allow engraftment. The last decade witnessed a significant reduction in treatment-related mortality, in great part a result of less toxic preparative regimens and improvements in supportive care. Another important trend has been the incorporation of newer drugs to 'classic' conditioning regimens, as illustrated by the addition of rituximab to BEAM and other combinations. It is expected that this trend will continue leading to increased cure rates by incorporation of targeted therapies to hematopoietic transplant. The next decade will likely witness further integration of new preparative regimens with graft engineering, and pharmacologic, cellular and immunologic post transplant interventions. The design of creative clinical trials that will allow the critical evaluation of the role of these new approaches in transplantation will also be a major challenge to the transplant community in the years to come. In this article, we review newer transplant conditioning regimens and discuss their indications and future directions in this rapidly changing landscape.     

Analyzing data from open enrollment groups: current considerations and future directions

Difficulties in modeling turnover in treatment-group membership have been cited as one of the major impediments to ecological validity of substance abuse and alcoholism treatment research. In this review, our primary foci are on (a) the discussion of approaches that draw on state-of-the-science analytic methods for modeling open-enrollment group data and (b) highlighting emerging issues that are critical to this relatively new area of methodological research (e.g., quantifying membership change, modeling "holiday" effects, and modeling membership change among group members and leaders). Continuing refinement of new modeling tools to address these analytic complexities may ultimately lead to the development of more federally funded open-enrollment trials. These developments may also facilitate the building of a "community-friendly" treatment research portfolio for funding agencies that support substance abuse and alcoholism treatment research.     

Human inter-individual DNA sequence variation in candidate genes, drug targets, the importance of haplotypes and pharmacogenomics

The identification of genes predisposing to human diseases is of paramount importance for understanding the molecular basis of the disease and individually different drug response, and will establish new routes to diagnosis and therapeutic advances of immense medical benefit. A key step common to all strategies for disease gene identification is the systematic analysis of candidate gene sequences to identify specific sequence variations associated with disease or any other phenotype of pharmaceutical relevance. In this article, current concepts and approaches to haplotype-based candidate gene analysis are reviewed. Moreover, a comprehensive summary of recent studies and data on the amount, nature, pattern and structure of genetic variation in candidate genes is given. These data demonstrate altogether remarkable gene sequence and haplotype diversity. Numerous individually different forms of a gene may exist. This presents challenges to the traditional views of the concept of "a" gene with far-reaching implications on the functional analysis of candidate gene variation, on the establishment of "sequence"-"structure"-"function" and complex haplotype/genotype-phenotype relationships, on the identification, evaluation and prioritization of drug targets and the concept of a "personalized medicine" in general. Moreover, present and future approaches to the identification of candidate and disease genes will be addressed. These include whole genome-based approaches such as integrative genomics as well as functional genomics-based approaches to analyze and model complex biological and medical processes. The analysis of whole complex systems in particular will provide the basis to make "maximally informed" guesses on candidate genes and address complex variability patterns in genes as well as complex genotype-phenotype relationships comprehensively at an advanced level.     

Platforms for the identification of GPCR targets, and of orthosteric and allosteric modulators

Areas covered in this review: The review provides a summary of old and new approaches for GPCR target identification and for the screening of molecules acting on GPCR targets. The new findings in the field are presented as well as an opinion about how these developments may help GPCR drug discovery. Importance in the field: GPCRs have been the most useful family of proteins in terms of targets for drug discovery. The expectations for GPCR target identification and discovery of new drugs acting on 'old' or 'new' GPCR targets are very high. Given the fact that the pace at which new 'GPCR drugs' appear in the market is decreasing and since the new developments in the field are not being translated into drug discovery there is a need to review the field from a critical perspective. Take home message: To overcome the limitation of the old approaches used in GPCR target identification and drugs discovery new approaches are required. In particular successful approaches in GPCR drug discovery should take into account that the real GPCR targets for a given disease are not GPCR monomers but GPCR heteromers. What the reader will gain: The reader will gain an overview of the strategies currently used and their pros and cons. The reader will also understand that new strategies may help in accelerating the access of GPCR into the market, and also notice that successful strategies should take advantage of the new findings in the field of GPCRs.     

Functional genomics and depression research. Beyond the monoamine hypothesis.

Although antidepressants have been used clinically for more than 50 years, no consensus has been reached concerning their precise molecular mechanism of action. Functional genomics is a powerful tool that can be used to identify genes affected by antidepressants or by other effective therapeutic manipulations. Using this tool we have previously identified more than 300 cDNA fragments as antidepressant related genes and from these, original cDNA microarrays were developed. Some of these candidate genes may encode common functional molecules induced by chronic antidepressant treatment. Defining the roles of these genes in drug-induced neural plasticity is likely to transform the course of research on the biological basis of depression. Such detailed knowledge will have profound effects on the diagnosis, prevention, and treatment of depression. Novel biological approaches beyond the "monoamine hypothesis" are expected to evoke paradigm shifts in the future of depression research.     

Insomnia

The launch of eszopiclone by Sepracor Inc in April 2005 in the US has marked the long-anticipated advent of a new generation of hypnotics that promise safer treatment for chronic insomnia. Over the coming years more compounds are expected to be launched, offering improved daytime well being and fewer side effects compared with their predecessors that were launched in the early 1990s. This article examines the factors that will drive the uptake of the new insomnia drugs by the public, describes potential barriers to adoption of these drugs and provides ideas for future treatment approaches that may offer better targeting and management of possible underlying conditions rather than merely controlling a symptom.     

Glyco-nanomaterials: translating insights from the "sugar-code" to biomedical applications

Over the past decade, diagnostics and therapeutics have changed gradually towards the use of more specific and targeted approaches. The most profound impact has been in the nanotechnology sectors, where an explosion in directing biomolecules to specific biomarkers has illustrated great potentials not only in detection but also in targeted therapy. Increased knowledge of the diseases at the molecular level catalyzed a shift towards identifying new biological indicators. In particular, carbohydrate-mediated molecular recognitions using nano-vehicles are likely to increasingly affect medicine opening a new area of biomedical applications. This article provides an overview of the recent progress made in recruiting the "sugar code" functionalized on various nano-platforms to decipher cellular information for both in vitro and in vivo applications. Today's glyco-technologies are enabling better detection with great therapeutic potentials. Tomorrow they are likely to bring a full understanding of the "cell-glyconanomaterial bio-conversation" where major biomedical problems will be overcome translating insights from the "glyco-nanoworld" into clinical practice.