Hepatic encephalopathy:Lessons from preclinical studies

Hepatic encephalopathy(HE) is a major complication that is closely related to the progression of end-stage liver disease.Metabolic changes in advanced liver failure can promote cognition impairment,attention deficits and motor dysfunction that may result in coma and death.HE can be subdivided according to the type of hepatic injury,namely,type A,which results from acute liver failure,type B,which is associated with a portosystemic shunting without intrinsic liver disease,and type C,which is due to chronic liver disease.Several studies have investigated the pathogenesis of the disease,and most of the mechanisms have been explored using animal models.This article aimed to review the use of preclinical models to investigate HE.The most used animal species are rats and mice.Experimental models of type A HE include surgical procedures and the administration of hepatotoxic medications,whereas models of types B and C HE are generally surgically induced lesions in liver tissue,which evolve to hepatic cirrhosis.Preclinical models have allowed the comprehension of the pathways related to HE.     

Pharmacological intervention studies using mouse models of the inflammatory bowel diseases: translating preclinical data into new drug therapies

Most therapeutic agents used in clinical practice today were originally developed and tested in animal models so that drug toxicity and safety, dose-responses, and efficacy could be determined. Retrospective analyses of preclinical intervention studies using animal models of different diseases demonstrate that only a small percentage of the interventions reporting promising effects translate to clinical efficacy. The failure to translate therapeutic efficacy from bench to bedside may be due, in part, to shortcomings in the design of the clinical studies; however, it is becoming clear that much of the problem resides within the preclinical studies. One potential strategy for improving our ability to identify new therapeutics that may have a reasonable chance of success in clinical trials is to identify the most immunologically-relevant mouse models of IBD and pharmacologic strategies that most closely mimic the clinical situation. This review presents a critical evaluation of the different mouse models and pharmacological approaches that may be used in intervention studies as well as discuss emerging issues related to study design and data interpretation of preclinical studies.     

Novel therapies in myeloma

PURPOSE OF REVIEW: Several novel therapies have been licensed for the treatment of myeloma in recent years. We summarize some of the trials leading to their approval and the current evidence for their clinical use. A number of promising agents undergoing phase I/II trial evaluation are also discussed. RECENT FINDINGS: The immunomodulatory drugs, thalidomide and lenalidomide, and the proteasome inhibitor, bortezomib, have been shown to be effective agents, both alone and as part of combination regimens, for the treatment of myeloma. Studies are now focusing on the optimal sequencing of these drugs throughout the disease course, with a view to maximizing antitumor efficacy and minimizing overlapping toxicities. New protocols are increasingly based on preclinical evidence of synergy. The incorporation of these agents into transplant-based treatment protocols has improved outcomes. Other examples of novel agents undergoing assessment at present include arsenic trioxide, hsp90 inhibitors and histone deacetylase inhibitors. Future developments are likely to include individualized treatment plans based on patient-specific parameters including cytogenetic analysis and gene expression profiling. SUMMARY: Thalidomide, lenalidomide and bortezomib can now be considered as standard options both as first-line agents and beyond for the treatment of myeloma, with respective combinations also emerging as valid choices for all stages of the disease.     

Novel therapies in melanoma

The incidence of cutaneous melanoma is on the rise worldwide despite increasing awareness and vigilance towards prevention by the lay public and health professionals. Melanoma is easily curable by surgical excision when detected early, but it is nearly incurable when discovered in its later stages owing to resistance to treatment. Unfortunately, treatment options traditionally used in melanoma have not shown a survival benefit. However, as the understanding of tumor biology and metastatic growth evolves, new therapeutic options for metastatic melanoma have shown impressive survival benefit. The blockade of cytotoxic T-lymphocyte antigen 4 (CTLA-4) by use of the monoclonal antibody, ipilimumab (Yervoy?, Bristol-Myers Squibb), produces favorable antitumor immune system responses and was recently approved by the US FDA for use in patients with advanced melanoma. In addition, targeting components of the MAPK pathway have also demonstrated survival advantage in patients with BRAF-mutated melanoma and vemurafenib (Zelboraf?, Plexxikon/Roche) was approved by the FDA in August 2011 for the first-line treatment of both metastatic and unresectable melanomas for patients whose tumors have V600E mutations in the BRAF gene.     

CARs and other T cell therapies for MM: The clinical experience

Harnessing the endogenous immune system to eliminate malignant cells has long been an intriguing approach. After considerable success in the treatment of B-cell acute lymphoblastic leukemia, chimeric antigen receptor (CAR)-modified T cells have entered early clinical evaluation in the field of multiple myeloma (MM). The choice of suitable non-CD19 target antigens is challenging and a variety of myeloma-associated surface molecules have been under preclinical investigation. Most recent clinical protocols have focused on targeting B-cell maturation antigen (BCMA), and early results are promising. The trials differ in receptor constructs, patient selection, dosing strategies and conditioning chemotherapy and will thus pave the way to eventually define the optimal parameters. Other sources for autologous T-cell therapy of MM include affinity-enhanced T-cell receptor-modified cells and marrow infiltrating lymphocytes. In summary, adoptive T-cell transfer for the treatment of MM is still in its infancy, but if early response rates indicate durability, will be a paradigm changing therapeutic modality for the treatment of MM.     

Novel therapies in monoclonal gammopathies

Multiple myeloma (MM) is a plasma cell malignancy with an incidence of approximately 20 000 cases per year. Over the past decade, the advent of novel therapies has resulted in a positive shift in survival for patients with advanced MM. Over the last decade progress has been made in the understanding of the mechanisms involved in myeloma cell proliferation, trafficking and survival. Through this understanding, molecular therapeutic targets have been identified and treatment programs which incorporate these concepts are beginning to appear. The current review does not intend to be a comprehensive compendium of available treatments rather to highlight the most exciting avenues of research in myeloma therapeutics. Novel immunomodulating drugs, proteasome inhibitors and monoclonal antibodies will be highlighted.     

Novel therapies in lupus nephritis

Renal disease continues to cause major morbidity and some mortality for around 30-40% of patients with systemic lupus erythematosus (SLE). Although the combinations of prednisolone and azathioprine or prednisolone and cyclophosphamide have been beneficial to many patients with SLE, they are not always effective and have significant side effects. It is very encouraging that new immunosuppressive drugs such as mycophenolate mofetil and more targeted therapies e.g., anti-CD20 are coming rapidly to larger scale clinical trials. The treatment of lupus nephritis is set to change quite rapidly in the next decade. In this review we highlight the likely major therapeutic advances.     

5-Aza-2'-deoxycytidine: preclinical studies in mice

5-Aza-2'-deoxycytidine administered to normal mice repeatedly on daily schedule affects mainly the number of blood leukocytes and bone marrow myeloid cells. Using the cell-free extract from mouse spleen phosphorylated intermediates of 5-aza-2'-deoxycytidine-3H have been isolated and kinetics of their formation both in vitro and in vivo in mouse spleen cells have been studied. The administration of the drug affects the synthesis of DNA in mouse spleen resulting in its initial depression followed later by the enhancement of thymidine uptake.     

Novel melatonin-based therapies: potential advances in the treatment of major depression

Major depression is one of the leading causes of premature death and disability. Although available drugs are effective, they also have substantial limitations. Recent advances in our understanding of the fundamental links between chronobiology and major mood disorders, as well as the development of new drugs that target the circadian system, have led to a renewed focus on this area. In this review, we summarise the associations between disrupted chronobiology and major depression and outline new antidepressant treatment strategies that target the circadian system. In particular, we highlight agomelatine, a melatonin-receptor agonist and selective serotonergic receptor subtype (ie, 5-HT(2C)) antagonist that has chronobiotic, antidepressant, and anxiolytic effects. In the short-term, agomelatine has similar antidepressant efficacy to venlafaxine, fluoxetine, and sertraline and, in the longer term, fewer patients on agomelatine relapse (23·9%) than do those receiving placebo (50·0%). Patients with depression treated with agomelatine report improved sleep quality and reduced waking after sleep onset. As agomelatine does not raise serotonin levels, it has less potential for the common gastrointestinal, sexual, or metabolic side-effects that characterise many other antidepressant compounds.     

Interleukin-2 in bone marrow transplantation: preclinical studies.

Interleukin-2 (IL-2) promotes the generation and proliferation of killer cells in the peripheral blood and bone marrow (BM) both in vitro and in vivo. When employed in a syngeneic bone marrow transplantation (BMT) setting and followed by IL-2 therapy, murine BM cells activated with IL-2 in vitro (ABM) demonstrate potent graft-versus-leukemia (GVL) and anticytomegalovirus effects. ABM cells retain the capacity to reconstitute the hemopoietic system both in normal and leukemic mice. This therapy does not cause graft-versus-host disease (GVHD). Human ABM cells carry out purging of leukemia without loss of progenitor cell activity in vitro. The purging ability of ABM can be augmented by interleukin-1, interferon, and tumor necrosis factor. IL-2 therapy stimulates the veto suppressor cell activity of T cell-depleted BM, and has reduced GVHD and permitted engraftment of mismatched allogeneic BM in murine models. Future studies should determine the optimum treatment schedules with IL-2 for improving the GVL effect in autologous BMT, and for abolishing GVHD in allogeneic BMT settings.     

Therapeutic vaccination in chronic hepatitis B: preclinical studies in the woodchuck model

Summary.  Interferon-α and nucleoside analogues are available for the treatment of chronic hepatitis B virus (HBV) infection but do not lead to a satisfactory result. New findings about the immunological control of HBV during acute infection suggest the pivotal role of T-cell mediated immune responses. Several preclinical and clinical trials were undertaken to explore the possibility of stimulating specific immune responses in chronically infected animals and patients by vaccination. However, vaccination with commercially available HBV vaccines in patients and immunization in woodchucks with core or surface proteins of woodchuck hepatitis virus (WHV) did not result in effective control of HBV and WHV infection, suggesting that new formulations of therapeutic vaccines are needed. Some new approaches combining antiviral treatments with nucleoside analogues, DNA vaccines and protein vaccines were tested in the woodchuck model. It could be shown that therapeutic vaccinations are able to stimulate specific B- and T-cell responses and to achieve transient suppression of viral replication. These results suggest the great potential of therapeutic vaccination in combination with antivirals to reach an effective and sustained control of HBV infection.     

Novel endoscopic bariatric therapies: A glimpse into the future

The management of obesity generally consists of lifestyle interventions, which are often inadequate, or invasive surgery, that carries a high cost and strict eligibility requirements. The recent rise of endoscopic bariatric interventions has the potential to provide a minimally invasive, cost-effective, and reversible option for patients. Although a few of these therapies have already gained Food and Drug Administration (FDA) approval, many more are in various stages of development and clinical trials. These methods use a wide array of techniques, including reducing gastric capacity, limiting absorption, duodenal mucosal resurfacing, and creating intestinal diversion. This review focuses on these newer, nonFood and Drug Administration approved approaches, which have the potential to drastically change the landscape of bariatric interventional options in the near-term future.     

Developing idiotype vaccines for lymphoma: from preclinical studies to phase III clinical trials

Therapeutic vaccines for B-cell non-Hodgkin lymphoma (NHL) using the clonal tumour immunoglobulin idiotype (Id) have been under development for more than three decades. A major obstacle for rapid progress in the field has been that the Id vaccine is patient-specific and required the generation of a custom-made product. The manufacturing issues were recently overcome by advances in hybridoma and recombinant DNA technology which facilitated the completion of several phase I and II clinical trials. The strong immunogenicity and apparent clinical benefit observed on the early phase studies led to the initiation of three randomized phase III clinical trials that are also nearing completion. This review will focus on the development of Id vaccines before and after the introduction of rituximab for the treatment of B-cell NHL and also discuss potential strategies to enhance the efficacy of active immunotherapy in the future.     

Nuclear magnetic resonance: preclinical and clinical studies in tumor detection

Nuclear magnetic resonance has been applied extensively to biochemical problems over the las decade. In vitro NMR relaxation data has shown significant differences between normal and malignant tissue and in the case of breast tissue, between tumors and fibrocystic disease. In vivo, whole body NMR imaging has developed rapidly and has been used in detecting various tumors, particularly in the abdomen. To date, no harmful effects of NMR scanning have been found. NMR scanning is likely to become a major imaging technique with significant applications, particularly in the detection of malignancies.