Mesenchymal stem cells: a new trend for cell therapy

Mesenchymal stem cells (MSCs), the major stem cells for cell therapy, have been used in the clinic for approximately 10 years. From animal models to clinical trials, MSCs have afforded promise in the treatment of numerous diseases, mainly tissue injury and immune disorders. In this review, we summarize the recent opinions on methods, timing and cell sources for MSC administration in clinical applications, and provide an overview of mechanisms that are significant in MSC-mediated therapies. Although MSCs for cell therapy have been shown to be safe and effective, there are still challenges that need to be tackled before their wide application in the clinic.     

The cancer stem cell paradigm: a new understanding of tumor development and treatment

Importance of the field: Cancer is the second leading cause of death in the United States, and therefore remains a central focus of modern medical research. Accumulating evidence supports a ‘cancer stem cell’ (CSC) model – where cancer growth and/or recurrence is driven by a small subset of tumor cells that exhibit properties similar to stem cells. This model may provide a conceptual framework for developing more effective cancer therapies that target cells propelling cancer growth.

Areas covered in this review: We review evidence supporting the CSC model and associated implications for understanding cancer biology and developing novel therapeutic strategies. Current controversies and unanswered questions of the CSC model are also discussed.

What the reader will gain: This review aims to describe how the CSC model is key to developing novel treatments and discusses associated shortcomings and unanswered questions.

Take home message: A fresh look at cancer biology and treatment is needed for many incurable cancers to improve clinical prognosis for patients. The CSC model posits a hierarchy in cancer where only a subset of cells drive malignancy, and if features of this model are correct, has implications for development of novel and hopefully more successful approaches to cancer therapy.     

Small molecule glucokinase activators as glucose lowering agents: a new paradigm for diabetes therapy

Glucokinase (GK) is a molecular sensor that regulates glucose induced insulin secretion in pancreatic beta-cells and glucose homeostasis in the liver via catalysis of glucose to glucose-6-phosphate. The recent discovery and development of small molecule glucokinase activators represents a potentially important development for the management of type 2 diabetes. Since the discovery of the first orally active small molecule GK activator RO0281675, a number of research groups have reported the identification of potent activators. In this review, the biological significance of GK in whole body glucose homeostasis is briefly described coupled with the recent progress regarding the identification of novel small molecule GK activators.     

Anti-angiogenic therapy as a cancer treatment paradigm

The inhibition of angiogenesis is an emerging therapeutic strategy for cancer treatment. In contrast to conventional therapies, anti-angiogenic therapies primarily target tumor-associated endothelial cells which serve as a lifeline for tumor growth, progression and metastasis. By blocking the supply of essential nutrients and the removal of metabolites, anti-angiogenic therapies aim to delay both primary and metastastic tumor growth while overcoming the inherent cytotoxicities of classical chemotherapies. Indeed, tumor-related angiogenesis is a multi-step process initiated by a cascade of proangiogenic factors secreted from both the tumor and host tissues. These intricate processes involve a close interaction of tumor and associated endothelial cells as well as an intimate communication between proliferating endothelial cells, stromal cells and extracellular matrix components. Inhibition of these proangiogenic mechanisms has become a major challenge for the development of anti-cancer treatment modalities. In this regard, anti-angiogenic therapies embody a potentially powerful adjunct to traditional cancer therapies. In this review, we provide an overview of traditional anti-cancer drugs and discuss the fundamentals of anti-angiogenic therapies. While presenting the salient features of the anti-angiogenic agents targeting the individual phases of angiogenesis, we highlight the potential for specific agent development as novel anti-angiogenic therapeutics. Finally, we present and summarize emerging angiogenesis inhibitors.     

Multiple-pulse drug delivery systems: setting a new paradigm for infectious disease therapy

Background: Pulsatile drug delivery of actives based on the body's biological rhythms came into sight as a novel and emerging concept in the field of drug delivery. The concept of late has given birth to another field of research worth exploring: multiple-pulse drug delivery. Objective: Delivering a drug in multiple pulses has been applied to antibiotics for effective and patient compliant drug delivery. Delivering antibiotics in divided pulses results in better annihilation of microbes, as it prevents them going into a resistant/dormant stage and developing biological tolerance. The concept appears to have potential, and on 16 March 2009 MiddleBrook^? Pharmaceuticals, Inc. will launch the first of such once-daily product based on their proprietary pulsatile drug delivery technology, PULSYS^?. Methods: This review focuses on the rationale, possible strategies and technologies employed for multiple-pulse delivery, as well as current status and future trends. Conclusion: The concept is in its infancy and promises great potential in the fight against microbial resistance; many approved formulations based on similar approaches with new and improved therapeutic paradigms are anticipated in the near future.     

NK-1 receptor antagonists: a new paradigm in pharmacological therapy

The neuropeptide substance P (SP) shows a widespread distribution in both the central and peripheral nervous systems and it is known that after binding to the neurokinin-1 (NK-1) receptors, SP regulates many biological functions in the central nervous system such as emotional behaviour, stress, depression, anxiety, emesis, migraine, alcohol addiction and neurodegeneration. SP has been also implicated in pain, inflammation, hepatotoxicity and in virus proliferation, and it plays an important role in cancer (e.g., tumour cell proliferation, angiogenesis, and the migration of tumour cells for invasion and metastasis). By contrast, it is known that after binding to NK-1 receptors, NK-1 receptor antagonists specifically inhibit the above-mentioned biological functions mediated by SP. Thus, these antagonists exert an anxyolitic, antidepressant, antiemetic, antimigraine, antialcohol addiction or neuroprotector effect in the central nervous system, and they play a role in analgesic, antiinflammatory, hepatoprotector processes and in antivirus proliferation. Regarding cancer, NK-1 receptor antagonists exert an antitumour action (inducing tumour cell death by apoptosis), and induce antiangiogenesis and inhibit the migration of tumour cells. It is also known that NK-1 receptors have a widespread distribution and that they are overexpressed in tumour cells. Thus, NK-1 receptor antagonists are molecularly targeted agents. In general, current drugs have a single therapeutic effect, although less commonly they may exert several. However, the data reported above indicate that NK-1 receptor antagonists are promising drugs, exerting many therapeutic effects (the action of such antagonists is dose-dependent and, depending on the concentration, has more positive effects). In this review, we update the multiple therapeutic effects exerted by NK-1 receptor antagonists.     

A new paradigm for managing dyslipidemia with combination therapy: laropiprant + niacin + simvastatin

Importance of the field: Despite effective lowering of low-density lipoprotein cholesterol (LDL-C) with statin for prevention of cardiovascular adverse events, residual risk remains high due to low high-density lipoprotein cholesterol (HDL-C) levels in patients with mixed dyslipidemia. As a result, alternative treatment options to raise HDL-C are being investigated intensively. Currently, niacin is the most potent lipid lowering agent for raising HDL-C levels together with lowering of triglyceride and LDL-C. Previous clinical studies have demonstrated that niacin therapy significantly reduces the risk of cardiovascular events in high risk subjects. However, the clinical use of niacin is limited by its major adverse effect, cutaneous flushing. Although the use of extended-release (ER) formulation can reduce flushing, the tolerability and compliance of niacin remains suboptimal. A selective antagonist of prostaglandin D Type 1 receptor, laropiprant, has been investigated in a number of clinical studies and shown to be effective in reducing niacin-induced flushing. Despite the potential of laropiprant in reducing niacin-induced flushing, the long-term clinical efficacy and potential off-target side effects are not well studied.

Areas covered in this reviews: In this article, the pharmacological properties, clinical efficacy and future perspective of this combination therapy of simvastatin/ER niacin/laropiprant are reviewed.

What the reader will gain: Readers will understand both the mechanism and clinical effects of the combination therapy of simvastatin/ER niacin/laropiprant.

Take home message: The triple combination therapy of simvastatin/ER niacin/laropiprant may reduce flushing side effects and facilitate a more comprehensive treatment for patients with mixed dyslipidemia.     

Dendrimer disassembly as a new paradigm for the application of dendritic structures

We present an overview of an entirely new concept in nanotechnology, dendrimer disassembly. Dendrimer disassembly is a process that relies on a single triggering event to initiate multiple cleavages throughout a dendritic structure that result in release of individual dendrimer subunits or larger dendrimer fragments. The potential of this process lies in (1) the nature of dendrimers as covalent assemblages of active species, and using the chemistry of disassembly to release these species into a system; and (2) the role of dendritic components of a system in influencing solubility, energy harvesting, or insulating capabilities, etc., and using the chemistry of disassembly to reverse those contributions to a system. This is a powerful construct, in that dendrimers and dendritic structures can be made up of a wide variety of subunits, compatibilized with many different environments, and incorporated into countless systems. We anticipate that dendritic materials with disassembly capabilities will (a) be useful for traditional polymer degradation technologies and (b) have potential applications in nanotechnology, biomedicine, sensors, etc.     

Glufosfamide as a new oxazaphosphorine anticancer agent

Glufosfamide (β-D-glucose-isophosphoramide mustard, D-19575) belongs to the oxazaphosphorine class. Glufosfamide is a novel glucose conjugate of ifosfamide in which isophosphoramide mustard, the alkylating metabolite of ifosfamide, is glycosidically linked to the β-D-glucose molecule. Glufosfamide represents an attractive new agent for cancer therapy. Its mode of action on normal and pathological cells is still under experimental and clinical investigations. An assessment of the anticancer potential of glufosfamide is of key importance in therapy. The researchers reviewed the current knowledge available on glufosfamide tested in the preclinical studies/clinical trials, based on a collection of the original papers and conference abstracts published and relevant articles searched in the SCOPUS and MEDLINE database and websites.     

Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent

Fondaparinux (Arixtra^®, Sanofi-Synthélabo/Organon) is the first of a new class of antithrombotic agents distinct from low molecular weight heparins (LMWHs) and heparin. It is a chemically synthetic pentasaccharide mimicking the site of heparin that binds to antithrombin III (AT). It exhibits only factor (F) Xa (FXa) inhibitor activity via binding to AT, which in turn inhibits thrombin generation. In contrast to heparin and LMWH, plasma anti-Xa activity corresponds directly to levels of fondaparinux. It does not release tissue factor pathway inhibitor (TFPI). There is nearly complete bioavailability by the sc. route, rapid onset of action, a prolonged half-life in both iv. and sc. (14 - 20 h) dosing regimens and no metabolism preceding renal excretion. Phase IIb clinical studies have identified a dose of 2.5 mg once-daily for prophylaxis of venous thrombosis. Four Phase III studies (n > 7000) have demonstrated a combined 50% relative risk reduction of venous thromboembolic events in orthopaedic surgery patients in comparison to the LMWH, enoxaparin. Haemmorrhagic complications for fondaparinux were either comparable to or higher than those for LMWH. The activated partial thromboplastin time (aPTT) is not affected by fondaparinux. At present, laboratory monitoring is not recommended. Clinical trials for treatment of established thrombosis, coronary syndromes and adjunct to thrombolytic therapy are in progress.     

Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent

Fondaparinux (Arixtra, Sanofi-Synthélabo/Organon) is the first of a new class of antithrombotic agents distinct from low molecular weight heparins (LMWHs) and heparin. It is a chemically synthetic pentasaccharide mimicking the site of heparin that binds to antithrombin III (AT). It exhibits only factor (F) Xa (FXa) inhibitor activity via binding to AT, which in turn inhibits thrombin generation. In contrast to heparin and LMWH, plasma anti-Xa activity corresponds directly to levels of fondaparinux. It does not release tissue factor pathway inhibitor (TFPI). There is nearly complete bioavailability by the sc. route, rapid onset of action, a prolonged half-life in both iv. and sc. (14 - 20 h) dosing regimens and no metabolism preceding renal excretion. Phase IIb clinical studies have identified a dose of 2.5 mg once-daily for prophylaxis of venous thrombosis. Four Phase III studies (n > 7000) have demonstrated a combined 50% relative risk reduction of venous thromboembolic events in orthopaedic surgery patients in comparison to the LMWH, enoxaparin. Haemmorrhagic complications for fondaparinux were either comparable to or higher than those for LMWH. The activated partial thromboplastin time (aPTT) is not affected by fondaparinux. At present, laboratory monitoring is not recommended. Clinical trials for treatment of established thrombosis, coronary syndromes and adjunct to thrombolytic therapy are in progress.     

Basal cell carcinoma: a paradigm for targeted therapies

Introduction: Basal cell carcinoma (BCC) is the most frequent cancer with increasing incidence over the last decades. Standard of care is surgical excision, upon which complete tumour clearance is achieved in most cases. However, a small subgroup of patients will have remnants of disease post-excision and require further treatment options. Over 90% of all BCCs carry a mutation in PTCH 1 or SMO, two conducting proteins of the Hedgehog pathway (Hh). Therefore, inhibition of the Hh pathway is a promising option for systemic first-line therapy. Vismodegib was the first developed of these small molecules, which was approved by the FDA in January 2012.

Areas covered: The authors review current treatment modalities for BCC and discuss current developments in pharmacological therapy. The current literature including meta-analyses, the Cochrane database and registered as well as completed randomized controlled trials.

Expert opinion: Hh inhibitors are a new promising treatment option for patients with advanced or metastatic BCC. Phase I and II clinical trials with the Hh inhibitor, vismodegib, showed a significant reduction in tumour size and appearance of new tumours with relatively good tolerability. Nevertheless, further investigation on new molecules and the effectiveness of an intermittent dosing regimen is necessary.