Postoperative ileus: mechanisms and future directions for research

Postoperative ileus (POI) is an abnormal pattern of gastrointestinal motility characterized by nausea, vomiting, abdominal distension and/or delayed passage of flatus or stool, which may occur following surgery. Postoperative ileus slows recovery, increases the risk of developing postoperative complications and confers a significant financial load on healthcare institutions. The aim of the present review is to provide a succinct overview of the clinical features and pathophysiological mechanisms of POI, with final comment on selected directions for future research.Terminology used when describing POI is inconsistent, with little differentiation made between the obligatory period of gut dysfunction seen after surgery (‘normal POI’) and the more clinically and pathologically significant entity of a ‘prolonged POI’. Both normal and prolonged POI represent a fundamentally similar pathophysiological phenomenon. The aetiology of POI is postulated to be multifactorial, with principal mediators being inflammatory cell activation, autonomic dysfunction (both primarily and as part of the surgical stress response), agonism at gut opioid receptors, modulation of gastrointestinal hormone activity and electrolyte derangements. A final common pathway for these effectors is impaired contractility and motility and gut wall oedema. There are many potential directions for future research. In particular, there remains scope to accurately characterize the gastrointestinal dysfunction that underscores an ileus, development of an accurate risk stratification tool will facilitate early implementation of preventive measures and clinical appraisal of novel therapeutic strategies that target individual pathways in the pathogenesis of ileus warrant further investigation.     

Wound healing: future directions

Over the years, numerous attempts have been made to accelerate the wound healing response, with varying degrees of success. This review covers the different phases of repair and attempts to highlight potential therapies, including modulation of re-epithelialization, granulation tissue formation and angiogenesis. Of the plethora of factors involved in these processes, three stand out as future candidates for development. Keratinocyte growth factor is undoubtedly a target for re-epithelialization, transforming growth factor-beta for matrix deposition and vascular endothelial growth factor is a prime target for angiogenesis. Particular emphasis is placed on angiogenesis as this offers perhaps the most intriguing line of therapy.     

Drug-induced phospholipidosis: issues and future directions

Numerous drugs containing a cationic amphiphilic structure are capable of inducing phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. There is an abundance of data providing an understanding of potential mechanisms for the induction of phospholipidosis; however, the process is likely to be complex and may differ from one drug to another. The functional consequences of the presence of this condition on cellular or tissue function are not well understood. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, additional studies to examine this question are needed. Until this issue is resolved, concerns about phospholipidosis will continue to exist at regulatory agencies. Procedures for the screening of potential phospholipogenic candidate compounds are available. In contrast, a clear need exists for the identification of valid biomarkers to assess the development of phospholipidosis in preclinical and clinical studies.     

Drug-induced phospholipidosis: issues and future directions

Numerous drugs containing a cationic amphiphilic structure are capable of inducing phospholipidosis in cells under conditions of in vivo administration or ex vivo incubation. The principal characteristics of this condition include the reversible accumulation of polar phospholipids in association with the development of unicentric or multicentric lamellated bodies within cells. There is an abundance of data providing an understanding of potential mechanisms for the induction of phospholipidosis; however, the process is likely to be complex and may differ from one drug to another. The functional consequences of the presence of this condition on cellular or tissue function are not well understood. The general consensus is that the condition is an adaptive response rather than a toxicological manifestation; however, additional studies to examine this question are needed. Until this issue is resolved, concerns about phospholipidosis will continue to exist at regulatory agencies. Procedures for the screening of potential phospholipogenic candidate compounds are available. In contrast, a clear need exists for the identification of valid biomarkers to assess the development of phospholipidosis in preclinical and clinical studies.     

Reproductive toxicology: current and future directions.

During the 20th century, there has been an increased risk from environmental by-products that may be harmful to reproductive function in humans. Therefore, as the 21st century begins, it is appropriate to evaluate future directions within the field of reproductive toxicology. This commentary identifies several approaches and developing technologies that would help research continue in a meaningful direction. Four areas for development are suggested, and selected examples of research involved in those areas are discussed: (1) Translational applications: workplace exposures thought to cause infertility in men (1,2-dibromo-3-chloropropane, DBCP) and menstrual disturbances in women (2-bromopropane, 2BP) are given as examples of human effects that have prompted animal studies. (2) Exposure paradigms: extrapolating dosing in animals to exposures in humans becomes complex. Two examples of surprising findings using lower doses are cited: ovotoxicity caused by polycyclic aromatic hydrocarbons (PAHs), and disrupted sexual differentiation caused by the fungicide vinclozolin. (3) Gender differences: predicting variable risk between women and men requires investigation of the effects of reproductive toxicants in both genders. The phthalates provide a good example for this comparison. Whereas di-(2-ethylhexyl)phthalate (DEHP) is a reproductive toxicant working by similar mechanisms in males and females, di-n-butyl phthalate (DBP) produces developmental effects in males and reproductive tract effects in females. (4) Endocrine disruptors: recent research has identified environmental chemicals that disrupt reproductive processes by altering the actions of endogenous steroid hormones. The endocrine disruptor issue is discussed in terms of evaluation of the actual risk these chemicals may pose in humans.     

Human vaginal mucosa as a model of buccal mucosa for in vitro permeability studies: an overview

The buccal cavity is attractive for noninvasive, controlled transmucosal delivery of both local and systemic therapeutically active compounds. Administering drugs via this route is advantageous due to the rich vasculature of the oral mucosa, and the absence of gastrointestinal and "first-pass" hepatic degradation. Moreover, the barrier properties of the oral mucosa against noxious substances and its role in disease require further investigation. However, the scarcity of sizeable specimens of human oral mucosa for in vitro experimental studies has hampered research on this tissue. For this reason we developed a model in which human vaginal mucosa is used as a substitute for buccal mucosa. In this article the quality and predictive value of the human vaginal/buccal in vitro model with respect to a number of drugs and other chemical compounds differing widely in molecular size and lipophilicity, including water, arecoline, arecaidine, benzo[a]pyrene, 17beta-estradiol, sumatriptan, vasopressin and dextrans, are reviewed. In addition some applications of the model for investigating the effect of areca nut extract on epithelial barrier properties, temperature effects on water and 17beta-estradiol flux rates, and cyclosporin diffusion through mucosal membranes are described. The permeability characteristics of vaginal mucosa, as a model of buccal mucosa, are compared with those of other human tissue, including mucosae from the small intestine and colon.     

口腔颊粘膜给药系统及其质量评价

介绍了口腔颊粘膜给药系统,并对其制剂的粘附力、粘附时间、膨胀率、均匀度和有效性等质量评价方面进行了综述。作为新型给药系统,颊粘膜给药系统的成熟与发展还需要在质量评价等方面进行深入研究。     

Emerging interventions for PTSD: future directions for clinical care and research

Efficacious therapeutic approaches for treating Posttraumatic Stress Disorder (PTSD) are needed given the significant psychosocial and physical impairment associated with the disorder (e.g., Hidalgo and Davidson, 2000; Jaycox and Foa, 1999; Stein et al., 2000). Although variations of cognitive behavioral therapy (CBT) effectively treat PTSD, non-response rates and dropout rates remain relatively high (Bradley et al., 2005; Schottenbauer et al., 2008). Thus, treatment outcome research is needed to improve the effectiveness of existing protocols, particularly within specific populations, develop new approaches for treating individuals who cannot access or do not benefit from traditional treatments, and evaluate the types of treatment that may be effective for particular individuals. The present review provides an overview of emerging treatment approaches for PTSD that attempt to address these remaining issues in the treatment outcome literature. This article is part of a Special Issue entitled 'Post-Traumatic Stress Disorder'.     

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality.

Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients.

Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.     

Psoriatic arthritis: current therapy and future directions

Introduction: Psoriatic arthritis (PsA) once regarded as an auto-inflammatory arthritis that involves the skin is proving to be more complex with a different driver of disease process compared to rheumatoid arthritis. As growing differences emerge between PsA and rheumatoid arthritis so have the experiences and responses to therapeutics used in both disease processes.

Areas covered: This review highlights articles of interest in the past 10 years in the OVID and PubMed database and focuses on major concepts regarding current disease-modifying anti-rheumatic drugs in PsA as well as newer target agents.

Expert opinion: Presently, it is agreed upon that use of tumor necrosis factor inhibitors (TNFi) has greatly changed our ability to manage varying aspects of disease in PsA. However, there remain many unanswered questions in which research in PsA is mirroring RA work, these include: i) the need for outcome measures that are more specific to PsA, ii) the concept of early and treat to target, iii) the role of highly sensitive imaging, and iv) efficacy of combination therapy and further targets in those unable to tolerate or fail TNFi.     

Cutaneous leishmaniasis: therapeutic strategies and future directions

Cutaneous leishmaniasis is a major tropical infection caused by vector-borne protozoa of the Leishmania species. Disease presentation, clinical course, prognosis and response to therapy is species- and geographic region-dependent. A wide variety of treatment modalities exist for the diverse spectrum of clinical disease. Traditional antileishmanial systemic agents such as antimonials, pentamidine and amphotericin are limited by toxic side effects, parenteral route of administration and emerging drug resistance. Newer agents such as oral miltefosine have shown efficacy and tolerability. However, use of systemic pharmacotherapies remains limited by their relative high cost in developing countries and despite advances in basic scientific research, there has been little progress in new drug development for what remains a neglected disease afflicting 12 million of the world's poorest population. This article examines the merits of existing and emerging therapies and reasons for variation in therapy response.     

Haemophilia B: current pharmacotherapy and future directions

Introduction: Hemophilia B is a rare hereditary hemorrhagic disorder characterized by deficiency of the clotting factor IX (FIX). Hemophilia B patients experience mild to severe bleeding complications according to the degree of FIX defect. Nowadays, the most challenging complication of individuals with hemophilia B is the development of alloantibodies, which render the standard replacement therapy with FIX concentrates ineffective, exposing them to a significantly increased morbidity and mortality. Areas covered: This review summarizes the most important events leading to the development of the current FIX products available for the treatment of hemophilia B patients. In addition, it focuses on the more recent advances in the production of new FIX molecules aimed at improving the clinical management of such patients. Expert opinion: Although the availability of plasma-derived FIX concentrates has greatly improved the clinical management of hemophilia B patients, the introduction of FIX products using recombinant DNA technology has represented the most significant therapeutic progress in hemophilia B therapy, ensuring an advanced level of safety. The development of rFIX products with extended half lives will further improve the therapeutic armamentarium for hemophilia B patients.     

Polycythemia vera: current pharmacotherapy and future directions

Introduction: In the past, management of polycythemia vera (PV) was built upon a cornerstone of control over erythrocytosis, through therapeutic phlebotomy, as well as the use of low-dose aspirin. Historically, selected patients were managed with additional cytoreductive therapies to decrease the risk of vascular events, with the recognition that these therapies likely did not impede progression.

Areas covered: Recent clinical trials have demonstrated, in a randomized fashion, that optimal control of the hematocrit to target levels < 45% are important for decreasing the risk of vascular events. We are identifying that our historical set of cytoreductive agents, such as hydroxyurea, may be replaced in the future. The first candidate is pegylated interferon alpha-2a, which is demonstrating the ability to control vascular events and control extended hematopoiesis, while potentially having impact on fibrotic progression and Janus kinase 2 (JAK2) V1617F mutant allele burden. Ruxolitinib, as well as other JAK2 inhibitors in development, are demonstrating that this class of agents is making a very meaningful impact on the risk of vascular events in PV, controlling expanded hematopoiesis, as well as helping with symptomatic burden.

Expert opinion: Future goals include attaining a better understanding of the specific roles of JAK inhibitor therapy and whether their use in combination with standard therapies offers greater efficacy than single agents alone.     

Tailored communications for smoking cessation: past successes and future directions

Tailored communications are one of the most promising approaches to smoking cessation interventions for entire populations. Assessments based on the Transtheoretical Model are processed by computer-based expert systems that generate feedback reports tailored to each individual to accelerate their progress through the stages of change for smoking cessation. Seven studies are reviewed that range from a more traditional clinical trial to trials on entire populations of smokers to population trials designed to change multiple behaviours, including smoking. A series of three tailored communications was found to produce long-term point prevalence abstinence rates within the narrow range of 22-26% abstinence. This same range of abstinence was found even when two or three other behaviours (e.g. diet and sun protection) were treated in the population. These results point to a future in which health behaviour risk interventions will be assessed not solely by their efficacy but by their population impact.