Leptin-based immune intervention: current status and future directions

Current understanding of the role of leptin has expanded from its narrow association with obesity to a variety of effects on different biological processes including immune function. More specifically, leptin links nutritional status and energy balance to regulation of pro-inflammatory T-helper 1 immune responses. This has prompted several studies of targeted intervention with leptin antagonists in rodents to suppress onset and/or progression of chronic inflammation and autoimmunity. This review presents current preclinical evidence and potential applications for leptin-based immune approaches aimed at improving therapy for chronic and autoimmune conditions.     

The enantiomer debate: current status and future directions

Psychopharmacology, and the treatment of depression in particular, is one area where there is currently an increasing awareness of chiral drug phenomena. It is now generally agreed that the pharmacological and pharmacokinetic properties of chiral drugs and their enantiomers should be assessed early on in the drug development process. However, issues surrounding the potential advantages and disadvantages of enantiomeric drugs, compared with racemates, continue to be debated. This article highlights some of the key issues raised during one such debate, the aim of which was to address the hypothesis that each enantiomeric drug should be considered on its own merit. The idea is considered both in general terms and specifically in the context of clinical psychiatry, with an emphasis on the treatment of depression. An update on recent developments in enantiomeric antidepressant therapy is also provided. Copyright 2001 John Wiley & Sons, Ltd.     

Biomaterial-based scaffolds – current status and future directions

Introduction: Biomaterial-based scaffold formulations (three-dimensional Porous matrix, nano-fibre mesh, hydrogels and microspheres) are the major components that are used to deliver the bioactive molecules into the body organs through different routes for an effective treatment of various diseases.

Areas covered: Various fabrication techniques such as freeze-drying, polymerisation, spray drying, gas foaming, supercritical fluid technology, etc., are successfully used for fabrication of scaffold formulations. Due to their unique characteristics, these formulations are widely used against various diseases such as tuberculosis, bone defects, cartilage repair, skin diseases, cardiovascular diseases, periodontal diseases, wound dressing, etc.

Expert opinion: The study of biomaterial-based scaffold formulations is exhilarating with novel approaches to drug/cell/gene delivery being developed all the time. At present, there is a huge extent of research being performed worldwide on all aspects of tissue engineering/drug or gene delivery. In the future, the main focus will be on the development of more patient compliant, sustained and controlled delivery systems against various diseases by modification of polymers, manufacturing technologies as well as carrier systems.     

Telomerase inhibitors in cancer therapy: current status and future directions

The ends of chromosomes (telomeres) are subject to progressive shortening in normal somatic cells, leading ultimately to irreversible growth arrest. In contrast, telomeres in all cancer cells are stabilized in length and effectively immortalized by the enzyme telomerase, which catalyzes the synthesis of telomeric DNA repeats. Several strategies have been devised for the inhibition of telomerase in the hope that this will result in anticancer effects. The principal approaches of catalytic inhibitors, antisense to the template, and folding of the DNA substrate, are reviewed and critically evaluated for their potential in anticancer therapy.     

Pharmacological treatments for methamphetamine addiction: current status and future directions

Introduction: Methamphetamine (MA) abuse remains a global health challenge despite intense research interest in the development of pharmacological treatments. This review provides a summary of clinical trials and human studies on the pharmacotherapy of methamphetamine use disorder (MUD).

Areas covered: We summarize published clinical trials that tested candidate medications for MUD and also conducted PubMed and Google Scholar searches to identify recently completed clinical trials using the keywords ‘methamphetamine’ ‘addiction’ ‘pharmacotherapy’ and ‘clinical trial.’ To determine the status of ongoing clinical trials targeting MUD, we also searched the ClinicalTrials.gov online database. We conclude this review with a discussion of current research gaps and future directions.

Expert commentary: Clinical trials examining the potential for pharmacotherapies of MUD have largely been negative. Future studies need to address several limitations to reduce the possibility of Type II errors: small sample sizes, high dropout rates or multiple comorbidities. Additionally, new treatment targets, such as MA-induced disruptions in cognition and in the neuroimmune system, merit trials with agents that selectively modulate these processes.     

Targeted therapy in acute myeloid leukaemia: current status and future directions

Background: The limit of acceptable toxicity for standard chemotherapeutic drugs used in acute myeloid leukaemia (AML) therapy has been reached. New therapeutic strategies are therefore needed. Objective: This review summarizes development in new strategies, and gives an overview of the clinical status on new drugs for non-promyelocytic AML in adults. Methods: Information was principally gathered from the databases ClinicalTrials.gov and PubMed.gov. Results/conclusion: The major improvements in AML treatment during the last two decades has not been the introduction of new therapeutic agents, but rather the more optimal use of well-known drugs (e.g., high-dose cytarabine therapy, the use of ATRA in maintenance therapy of acute promyelocytic leukaemia) and improvement in the diagnosis and treatment of potentially life-threatening complications in patients treated with allogeneic stem cell transplantation. However, further investigations based on specific targeted therapy and stratification of patients according to knowledge of the individual disease and health status will probably be necessary in future studies of new targeted therapy.     

HER family inhibitors in pancreatic cancer: current status and future directions

Pancreatic cancer is characterized by multiple genetic abnormalities that can be used as targets for specific therapeutics. The HER family consists of four transmembrane growth factor receptors. Targeting HER1 with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib demonstrated a survival advantage for patients with advanced pancreatic cancer. Multiple other agents that target members of the HER family are under investigation. These include reversible and irreversible, single and pan HER tyrosine kinase inhibitors. Chimeric, humanized and fully human monoclonal antibodies that target specific HER receptors are also being studied. These agents are also radiation sensitizers. This article reviews clinical trials of HER family inhibitors in pancreatic cancer, discusses the role of these agents in the management of patients and outlines future directions for pancreatic cancer management.     

HER family inhibitors in pancreatic cancer: current status and future directions

Pancreatic cancer is characterized by multiple genetic abnormalities that can be used as targets for specific therapeutics. The HER family consists of four transmembrane growth factor receptors. Targeting HER1 with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib demonstrated a survival advantage for patients with advanced pancreatic cancer. Multiple other agents that target members of the HER family are under investigation. These include reversible and irreversible, single and pan HER tyrosine kinase inhibitors. Chimeric, humanized and fully human monoclonal antibodies that target specific HER receptors are also being studied. These agents are also radiation sensitizers. This article reviews clinical trials of HER family inhibitors in pancreatic cancer, discusses the role of these agents in the management of patients and outlines future directions for pancreatic cancer management.     

Antivascular agents for non-small-cell lung cancer: current status and future directions

Background: Despite improvements in surgery and chemo(radio)therapy which have allowed for modest advances in the treatment of patients with non-small-cell lung cancer (NSCLC), survival remains poor and further improvements are needed. Attention over recent years has focused, therefore, on targeted therapies, with notable success in the development of antivascular drugs. Objective: To summarize the current knowledge on antivascular therapy in patients with NSCLC. Method: Review of randomized controlled trials exploring treatment of NSCLC patients with antivascular drugs. Results/conclusion: Bevacizumab, a humanized monoclonal antibody against the vascular endothelial growth factor (VEGF), when added to cytotoxic chemotherapy, was the first treatment to prolong the overall survival of patients with advanced NSCLC beyond 12 months, a significant breakthrough in the management of advanced NSCLC. Small-molecule tyrosine kinase inhibitors and alternative antivascular strategies such as VEGF-trap and vascular disrupting agents are also being investigated and have shown promise in clinical trials. This review summarizes the most recent and important findings in antivascular agents in NSCLC.     

Endothelin receptor antagonists in heart failure: current status and future directions

Experimental evidence suggests that endothelin substantially contributes to left ventricular remodelling and progression of heart failure. Plasma endothelin (ET)-1 levels are increased in patients with heart failure, independent of the aetiology, and correlate with the severity of the disease. Furthermore, tissue endothelin levels and endothelin receptors are upregulated in myocardium from animals and humans with heart failure. In several experimental models of left ventricular remodelling and/or heart failure, treatment with nonselective ET-A and -B as well as selective ET-A antagonists exerted beneficial cardiovascular effects. In patients with heart failure, short-term studies of treatment with endothelin antagonists demonstrated an improvement of haemodynamic parameters; however, long-term treatment with these drugs did not significantly improve combined morbidity/mortality endpoints. Furthermore, in the recently completed Endothelin-A Receptor Antagonist Trial in Heart Failure (EARTH) trial in patients with chronic heart failure, the selective ET-A receptor antagonist darusentan did not significantly affect left ventricular remodelling as assessed by cardiac magnetic resonance imaging. Potential reasons for the lack of beneficial effects of long-term treatment with ET antagonists in patients with heart failure include the following. Firstly, adverse effects on left ventricular healing have been observed when endothelin antagonist therapy was introduced early after myocardial infarction in rats. Secondly, the role of the ET-B receptor in the pathophysiology of heart failure and remodelling processes has not been clearly defined. Finally, for the detection of improvement in left ventricular remodelling, a study needs to be conducted in patients with recent myocardial infarction and signs of heart failure.     

Anti-estrogens in the treatment of breast cancer: current status and future directions

For many years, the non-steroidal estrogen receptor (ER) blocker tamoxifen has been the drug of choice for the treatment of hormone-responsive breast cancer. However, deleterious effects on other tissues such as the endometrium and the frequent occurrence of relapse due to tamoxifen resistance have led to the search for alternative drugs that exhibit more favorable tissue-specific ER effects. Alongside these selective ER modulators, a new generation of aromatase inhibitors, which act by limiting the supply of local estrogen to the breast tumor, has emerged to challenge tamoxifen for supremacy. Together with other novel therapies under investigation, it can be hoped that such drugs may, alone or in combination, lead to better breast cancer treatment.     

Drug discrimination by humans compared to nonhumans: current status and future directions

In drug discrimination (DD) procedures, behavior is differentially reinforced depending on the presence or absence of specific drug stimuli. The DD paradigm has been widely adopted by behavioral pharmacologists because of its specificity of stimulus control, concordance with drug action at cellular levels and its use as a preclinical model of subject-rated effects in humans. With the successful extension of DD to humans, a comparison of human and nonhuman DD will help place each in the context of the other. Twenty-eight studies of DD in humans are reviewed, including studies of amphetamine, opioid, benzodiazepine, caffeine, nicotine, marijuana and ethanol discriminative stimuli. Comparison of procedures between studies in humans and nonhumans reveals a common tradition, except the use of instructions appears to facilitate greatly DD acquisition in humans. Findings were qualitatively similar between humans and nonhumans. Potency relationships were quantitatively similar between humans and most, but not all, other species. Areas of human DD needing additional empirical evaluation include the influence of instructions, the effects of training dose and the effects of antagonists. Additionally, antihistamines, barbiturates, nicotine and marijuana are under-represented in human DD.     

Tivozanib: current status and future directions in the treatment of solid tumors

Introduction: Tivozanib is a novel tyrosine kinase inhibitor (TKI) which inhibits vascular endothelial growth factor (VEGF) receptors-1, -2, and -3 at nanomolar concentrations.

Areas covered: A comprehensive MEDLINE and American Society of Clinical Oncology abstract search was performed to gather all relevant clinical and translational data related to tivozanib. We discuss pre-clinical studies associated with tivozanib, and the results of a Phase I assessment in advanced solid tumors. We highlight combination studies with tivozanib, including pairings of tivozanib with cytotoxic therapy in patients with colorectal cancer and breast cancer. A randomized discontinuation Phase II study and a randomized Phase III study assessing the activity of tivozanib in metastatic renal cell carcinoma (mRCC) are described in detail.

Expert opinion: Tivozanib will face the challenge of entering an already crowded therapeutic space in mRCC—emerging combination studies and biomarker assessments may distinguish this agent among other VEGF-TKIs. The current review will outline the development pathway of tivozanib to date, and offer lessons learned and future opportunities.     

Monoclonal antibody-based targeted therapy in breast cancer: current status and future directions

The recent development of monoclonal antibodies targeting growth factor receptors in cancer treatment represents a milestone for both researchers and physicians. Advances in the understanding of key molecular pathways for tumour growth and survival have facilitated the development of these targeted therapies, in particular in breast cancer. This review focuses on the three most important recombinant humanised monoclonal antibodies that have shown activity in women with breast cancer: trastuzumab, pertuzumab and bevacizumab. Trastuzumab, an anti-erbB2 (human epidermal growth factor receptor) monoclonal antibody, is currently routinely used in both the metastatic and adjuvant settings for patients with erbB2-positive tumours. Pertuzumab, a monoclonal antibody binding to a different epitope on erbB2 than trastuzumab, is under early clinical evaluation. This drug has been developed for breast cancer patients, whether overexpressing erbB2 or not. Bevacizumab, a monoclonal antibody directed against vascular endothelial growth factor-A, is being evaluated in the metastatic setting for its antiangiogenic properties, and is showing promising results.