Pharmacotherapy for end-stage coronary artery disease

Importance of the field: Coronary artery disease remains the leading cause of mortality in the industrialized world. Despite advances in surgical and catheter-based interventions, a select number of patients remain with no options for invasive therapy. The goal of this review is to discuss the current status of pharmacotherapeutic interventions to treat end-stage coronary artery disease.

Areas covered in this review: Literature review on the topic of therapeutic angiogenesis from 1980 to 2009.

What the reader will gain: Insight into current therapeutic strategies employed to manage end-stage coronary artery disease.

Take home message: A promising approach focuses on augmenting the endogenous angiogenic response to chronic myocardial ischemia via the use of growth factors.     

Therapeutic options for HIV-associated lymphomas

Importance of the field: The clinical features and natural history of HIV-associated lymphomas differ greatly from those observed in the general population. The failure to improve outcomes with treatment intensification indicates the need for the introduction of new therapeutic options.

Areas covered in this review: This review summarizes reports from 1995 to the present which focus on the treatment strategies and their prognostic relevance in the setting of HIV-associated lymphomas.

What the reader will gain: The identification of prognostic factors in rare tumors such as HIV-associated lymphomas is going to require the establishment of multi-institutional and cooperative group-supported tissue banks. The rarity of primary effusion lymphomas and plasmablastic lymphomas of the oral cavity type makes large prospective studies difficult and challenges the feasibility of defining therapy specific for a given subpopulation of patients.

Take home message: HIV-associated lymphomas still represent a relevant field of clinical research. Standard methodologies for therapy in this patient population have yet to be established. However, rituximab plus chemotherapy should be offered to the majority of patients with HIV infection and diffuse large B-cell lymphomas; and the feasibility of intensive aggressive chemotherapy regimens has been successfully tested in HIV-associated Burkitt's lymphomas.     

Pixantrone for the treatment of aggressive non-Hodgkin lymphoma

Importance of the field: At present there is no standard treatment for patients with relapsed or refractory aggressive non-Hodgkin's lymphoma who progress following second-line therapy. Anthracyclines are highly active drugs, but their use in this setting is limited by cumulative cardiac toxicity. Pixantrone is a new aza-anthracenedione structurally similar to mitoxantrone and anthracyclines. This compound has been developed to minimize cardiac toxicity without reducing efficacy.

Areas covered in this review: This review summarizes the preclinical and clinical trial data for the use of pixantrone for the treatment of aggressive non-Hodgkin lymphoma.

What the reader will gain: An overview of the mechanism of action of pixantrone, preclinical data, clinical efficacy, safety data and future developments for this compound.

Take home message: Pixantrone has been shown to be superior to other single-agent therapies for the salvage treatment of relapsed/refractory aggressive non-Hodgkin lymphoma. The pixantrone application will be submitted to the regulatory authorities in the USA and in Europe.     

Oligonucleotide delivery in cancer therapy

Importance of the field: Cancer is frequently caused by altered protein expression. Oligonucleotides (ONs) are short synthetic nucleic acid fragments, able to selectively correct protein expression into cells by different mechanisms. However, biological barriers hamper the therapeutic use of ONs without suitable delivery strategies.

Areas covered in this review: This review summarizes the most meaningful non-viral strategies for ON delivery, including the chemical modifications of the ON backbone and non-viral delivery systems.

What the reader will gain: The reader will gain an update of the main strategies for ON delivery in cancer. Advantages and limits of each approach are underlined. Emphasis is given to the delivery strategies that contributed to bringing ONs into clinical trials.

Take home message: In the long story of ONs for cancer therapy, the development of delivery strategies has led, in the last few years, to different opportunities to use the high therapeutic potential of these molecules in humans.     

Therapeutic targeting of EGFR in malignant gliomas

Importance of the field: Despite the improved prognosis for many cancer patients, the survival of those with malignant gliomas (MGs) remains dismal. Even with aggressive intervention, including surgery, chemotherapy and radiotherapy, the overall 2-year survival rate is only 25% in the most optimistic series, and 5-year survival rates are consistently in the low single digits. Therefore, it is evident that novel therapeutic paradigms are necessary to overcome the inherent limitations of conventional treatments. EGFR gene overexpression can be found in 40 – 50% of patients with MGs, whereas its expression is very low in normal brain. Therapeutic targeting of EGFR has indicated clinical success in the treatment of MGs.

Areas covered in this review: The purpose of this review is to discuss the current status of several EGFR-targeted therapies in MGs patients and address the efficacy of these drugs as monotherapy or in combination with other drugs and/or treatments. We also emphasize the lessons learned and the future perspectives in the development of EGFR-targeted therapies for MGs.

What the reader will gain: A more comprehensive understanding of the molecular, structural and biological characteristics of EGFR and the mechanisms of action of EGFR-targeted antagonists will most likely contribute to the successful use of strategies of EGFR-targeted therapy in the clinic.

Take home message: Therapeutic targeting of EGFR include anti-EGFR mAbs, small-molecule EGFR tyrosine kinase inhibitors, peptide vaccination therapy and other therapeutic strategies. Each EGFR antagonist has its own advantages and limitations in terms of BBB crossing, ease of delivery, combination therapies and potential toxicity. Therefore, a multiple approach combining different agents that target EGFR signaling at multiple levels seems to have potential as future therapeutics for MGs, once the technical and safety issues unique to each of the approaches are overcome.     

Therapeutic targeting of miRNAs in neuroblastoma

Importance of the field: Neuroblastomas arise from precursor cells of the sympathetic nervous system and are noted for highly heterogeneous clinical behavior. These tumors currently account for ～ 15% of all childhood cancer related deaths in spite of intensive multimodal chemotherapy and are a major problem in pediatric oncology. The identification of novel therapeutic targets is urgently required to reduce patient morbidity.

Areas covered in this review: The purpose of this article is to review and synthesize all of the rapidly expanding evidence for the contribution of microRNAs (miRNAs) in neuroblastoma aggressive disease pathogenesis, along with the prospect of using small RNAs as therapeutics.

What the reader will gain: The reader will obtain insight on the miRNAs that are dysregulated in neuroblastoma along with potential therapeutic strategies and the most promising targets.

Take home message: A number of miRNAs which are associated with aggressive disease pathogenesis in neuroblastoma patients have been demonstrated to contribute in major ways to cell proliferation rates, apoptosis, differentiation, invasiveness and tumor growth in vitro and in vivo. Directly or indirectly interfering with the function of these miRNAs may prove to be an important and novel form of therapy.     

Risk-adapted strategies for the treatment of Hodgkin lymphoma

Introduction: Over the past several decades, Hodgkin lymphoma (HL) has become a highly treatable lymphoid malignancy with excellent response rates and long-term disease-free survival. Late-toxicities, however, continue to be an area of significant concern. Recent studies have evaluated novel approaches to limit long-term toxicity without adversely impacting short-term survival. While early or interim PET scan has been correlated with PFS and OS in HL, the modification of therapy based on interim PET (response-adapted therapy) has been evaluated in retrospective and prospective cohorts. This paper will review evidence for the role of response-adapted therapy in HL.

Areas covered: Data from completed and ongoing retrospective and prospective cohorts of HL patients were reviewed utilizing pubmed and clinicaltrials.org and pertinent studies culled to compile this review article.

Expert opinion: While response-adapted therapy represents a promising area of research which may ultimately become standard-of-care, current data does not unequivocally endorse this approach, which should be used with caution outside of a clinical trial.     

Efficacy and safety of drugs for ulcerative colitis

Importance of the field: Ulcerative colitis (UC) is a chronic inflammatory disorder of the colon that carries considerable burden and morbidity for patients and presents a constant challenge in management for gastroenterologists. Continued advances in medical therapies provide a range of treatment options for patients, but with this is the need to balance the potential benefits of a particular medication with its side effect profile in both the short and the long term.

Areas covered in this review: This article will review the current drugs used in the treatment of UC, including 5-amninosalicylates, antibiotics, steroids, immunomodulators and biologics, with particular attention to their indications, efficacy and toxicity profile.

What the reader will gain: The reader will gain a comprehensive understanding of the various medical therapies used in the treatment of UC with focus on efficacy and toxicity profiles, allowing providers to choose appropriate medical therapies for their patients.

Take home message: The particular agent used depends upon the extent and severity of disease, with mild-to-moderate disease treated with conventional therapy including 5-amninosalicylates. Steroids are used in the short term to bring active disease into remission, and the more aggressive immunomodulators and biologics are reserved for more severe disease given their toxicity profiles.     

Galanin receptor subtypes 1 and 2 as therapeutic targets in head and neck squamous cell carcinoma

Importance of the field: Despite advances in the therapeutic approaches for head and neck squamous cell carcinoma (HNSCC) at some sites, no substantial improvement in treatment efficacy and survival has occurred over the past several decades. Recent application of molecular biology has focused on the importance of galanin and its receptors as potential therapeutic targets for HNSCC.

Areas covered in this review: Our aim is to examine galanin receptor 1 (GALR1) and galanin receptor 2 (GALR2) as HNSCC therapeutic targets and explore opportunities and strategies for making use of GALR1 and GALR2 signaling.

What the reader will gain: This review provides recent data about galanin receptor signaling and function in various cell types, especially HNSCC. Signaling through GALR1 induces cell cycle arrest and suppresses proliferation in HNSCC. Similar to GALR1, GALR2 not only induces cell cycle arrest but also apoptosis, which was not observed with GALR1.

Take home messages: GALR1 and GALR2 act as tumor suppressors in HNSCC, in a p53-independent manner. The current data suggest that GALR1 and GALR2 are potentially significant therapeutic targets and prognostic factors in HNSCC.     

Challenges and advances in the development of inhalable drug formulations for cystic fibrosis lung disease

Introduction: Cystic fibrosis (CF) is a multisystem genetic disorder, which usually results in significant respiratory dysfunction. At present there is no cure for CF, but advances in pharmacotherapy have gradually increased the life expectancy of CF patients. As many drugs used in the therapy of CF are delivered by inhalation, the demand for effective and convenient inhalational CF drug formulations will grow as CF patients live longer. Knowledge of the current limitations in inhalational CF drug delivery is critical in identifying new opportunities and designing rational delivery strategies.

Areas covered: This review discusses current and emerging therapeutic agents for CF therapy, selected physiological challenges to effective inhalational medication delivery, and various approaches to overcoming these challenges. The reader will find an integrated view of the known inhalational drug delivery challenges and the rationales for recent investigational inhalational drug formulations.

Expert opinion: An ideal drug/gene delivery system to CF airways should overcome the tenacious sputum, which presents physical, chemical and biological barriers to effective transport of therapeutic agents to the targets and various cellular challenges.     

The development of the tumor vascular-disrupting agent ASA404 (vadimezan,DMXAA): current status and future opportunities

Importance of the field: Targeting tumor vasculature with antiangiogenic agents improves outcomes achieved with chemotherapy in some cancers, but toxicity limits their applicability. Tumor vascular-disrupting agents (tumor-VDAs) induce an acute collapse in tumor vascular supply; ASA404 (vadimezan, 5,6-dimethylxanthenone-4-acetic acid [DMXAA]) is the tumor-VDA most advanced in clinical development. Recent randomized trials of ASA404 in combination with chemotherapy suggested a survival advantage in NSCLC comparable to that achieved with bevacizumab, but with little additional toxicity. Phase III trials in advanced NSCLC have completed accrual, and a review of this exciting agent is timely.

Areas covered in this review: This review focuses on the development of ASA404 to date, its mechanisms of action, the current body of clinical research and potential avenues for therapeutic use. It includes all completed clinical trials since it entered clinical testing in 1995 through to 2009.

What the reader will gain: This review will help the reader to understand why ASA404 is unique among tumor-VDAs; the clinical trial methodology required to evaluate such agents; and its remarkable potential clinical utility.

Take home message: ASA404 is a tumor-VDA that offers considerable potential to improve outcomes in cancer patients in combination with existing treatments.     

Liposomes,a promising strategy for clinical application of platinum derivatives

Introduction: Liposomes represent a versatile system for drug delivery in various pathologies. Platinum derivatives have been demonstrated to have therapeutic efficacy against several solid tumors. But their use is limited due to their side effects. Since liposomal formulations are known to reduce the toxicity of some conventional chemotherapeutic drugs, the encapsulation of platinum derivatives in these systems may be useful in reducing toxicity and maintaining an adequate therapeutic response.

Areas covered: This review describes the strategies applied to platinum derivatives in order to improve their therapeutic activity, while reducing the incidence of side effects. It also reviews the results found in the literature for the different platinum-drugs liposomal formulations and their current status.

Expert opinion: The design of liposomes to achieve effectiveness in antitumor treatment is a goal for platinum derivatives. Liposomes can change the pharmacokinetic parameters of these encapsulated drugs, reducing their side effects. However, few liposomal formulations have demonstrated a significant advantage in therapeutic terms. Lipoplatin, a cisplatin formulation in Phase III, combines a reduction in the toxicity associated with an antitumor activity similar to the free drug. Thermosensitive or targeted liposomes for tumor therapy are also included in this review. Few articles about this strategy applied to platinum drugs can be found in the literature.     

Towards a targeted multi-drug delivery approach to improve therapeutic efficacy in breast cancer

Importance of the field: Significant improvements in breast cancer treatments have resulted in a significant decrease in mortality. However, current breast cancer therapies, for example, chemotherapy, often result in high toxicity and nonspecific side effects. Other treatments, such as hormonal and antiangiogenic therapies, often have low treatment efficacy if used alone. In addition, acquired drug resistance decreases further the treatment efficacy of these therapies. Intra-tumor heterogeneity of the tumor tissue may be a major reason for the low treatment efficacy and the development of chemoresistance. Therefore, targeted multi-drug therapy is a valuable option for addressing the multiple mechanisms that may be responsible for reduced efficacy of current therapies.

Areas covered in this review: In this article, different classes of drugs for treating breast cancer, the possible reasons for the drug resistance in breast cancer, as well as different targeted drug delivery systems are summarized. The current targeting strategies used in cancer treatment are discussed.

What the reader will gain: This article considers the current state of breast cancer therapy and the possible future directions in targeted multi-drug delivery for treating breast cancer.

Take home message: A better understanding of tumor biology and physiological responses to nanoparticles, as well as advanced nanoparticle design, are needed to improve the therapeutic outcomes for treating breast cancer using nanoparticle-based targeted drug delivery systems. Moreover, selective delivery of multi-drugs to tumor tissue using targeted drug delivery systems may reduce systemic toxicity further, overcome drug resistances, and improve therapeutic efficacy in treating breast cancer.     

Polymeric colloidal particulate systems: intelligent tools for intracellular targeting of antileishmanial cargos

Introduction: Targeted cargo delivery systems can overcome drawbacks associated with antileishmanials delivery, by defeating challenges of physiological barriers. Various colloidal particulate systems have been developed in the past; few of them even achieved success in the market, but still are limited in some ways.

Areas covered: This review is focused on the pathobiology of leishmaniasis, interactions of particulate systems with biological environment, targeting strategies along with current conventional and vaccine therapies with special emphasis on polymeric nanotechnology for effective antileishmanial cargo delivery.

Expert opinion: The problems concerned with limited accessibility of chemotherapeutic cargos in conventional modes to Leishmania-harboring macrophages, their toxicity, and resistant parasitic strain development can be sorted out through target-specific delivery of cargos. Vaccination is another therapeutic approach employing antigen alone or adjuvant combinations delivered by means of a carrier, and can provide preventive measures against human leishmaniasis (HL). Therefore, there is an urgent need of designing site-specific antileishmanial cargo carriers for safe and effective management of HL. Among various colloidal carriers, polymeric particulate systems hold tremendous potential as an effective delivery tool by providing control over spatial and temporal distribution of cargos after systemic or localized administration along with enhancing their stability profile at a comparatively cost-effective price leading to improved chances of commercial applicability.     

Medical management of polymyalgia rheumatica

Importance of the field: Polymyalgia rheumatica (PMR) is a relatively frequent condition in individuals older than 50 who originate from Western countries. Corticosteroids constitute the cornerstone therapy in the management of patients with PMR.

Areas covered in this review: This review summarizes the current literature on clinical clues for the diagnosis of PMR, conditions mimicking PMR, relapses in the setting of PMR and the main therapeutic strategies.

What the reader will gain: With this information, the reader receives an overview on the current available data on clinical diagnosis and treatment options in PMR.

Take-home messages: An initial dose of prednisone of 10 – 20 mg/day yields clinical improvement in the majority of patients with PMR. This is generally achieved within 7 days of the onset of this therapy. Conditions different from isolated PMR should be considered in atypical cases or when a good response to 20 mg/day of prednisone is not achieved. Relapses of PMR are not uncommon when the dose of prednisone is equal to or below than 5 mg/day. Methotrexate is the most commonly used corticosteroid sparing agent. Osteoporosis prophylaxis is also recommended.     

Hypertensive nephropathy: prevention and treatment recommendations

Importance of the field: A worldwide epidemic of chronic kidney disease (CKD) exists; hypertensive nephropathy is second only to diabetes as a leading cause of progressive CKD. Due to the increasing morbidity and mortality and escalating costs associated with end-stage renal disease (ESRD), novel therapeutic strategies are needed urgently to maximally reduce albuminuria, control blood pressure, and delay progression of hypertensive nephropathy to ESRD. In particular, rational use of renin–angiotensin–aldosterone (RAAS) blockers and achieving blood pressure targets are crucial to reduce cardiovascular and renal outcomes.

Areas covered in this review: We discuss the pathophysiology of hypertensive nephropathy and review current research evidence in support of i) albuminuria reduction as a key factor to maximally slow CKD progression, ii) the blood pressure (BP) goal of < 130 mmHg, and iii) strategies for prevention and optimal treatment of hypertensive nephropathy.

What will the reader gain: Insight into the complexity of treating patients with hypertensive nephropathy and the effective strategies required for reducing albuminuria, achieving BP goals and delaying progression of hypertensive nephropathy.

Take home message: Patients with hypertensive proteinuric nephropathy need aggressive BP-lowering with multiple agents that should include RAAS blockers, calcium antagonists and diuretics to maximally slow progression to ESRD.     

Emerging medical treatment for angina pectoris

Importance of the field: Despite improved mortality and morbidity in the treatment of coronary artery disease, a significant proportion of patients will continue to experience recurrent angina pectoris.

Areas covered in this review: Anti-anginal therapy has long been dominated by the use of β-blockers, Ca²⁺ channel blockers and nitrates. Most recently, ranolazine was introduced as a new anti-anginal class. This review article presents current and novel anti-anginal strategies under development. A discussion of their molecular mechanisms that may complement traditional therapies is presented. Medline and PubMed scientific search tools were primarily used to identify relevant literature dating from 1970 to 2008.

What the reader will gain: This review provides a summary of both traditional and emerging therapeutic approaches to angina pectoris management. A discussion on the mechanism of action and clinical efficacy of ranolazine, trimetazidine, nicorandil, ivabradine, fasudil and growth factor gene therapy as anti-anginal agents is provided.

Take home message: The need for multiple approaches cannot be over-emphasized. Availability of various modalities would strongly enhance the ability to meet the needs of a heterogeneous patient population. Patients with recurrent angina pectoris most likely will require multi-drug regimen where different mechanisms may complement each other and result in a more efficacious strategy.     

Voriconazole therapeutic drug monitoring: focus on safety

Importance of the field: Voriconazole has been widely used for the treatment of invasive fungal diseases, particularly invasive aspergillosis. Drug–drug interactions are, however, the main drawback associated with voriconazole use, since this drug suffers from extensive hepatic metabolism.

Areas covered in this review: This article reviews the current literature on voriconazole therapeutic drug monitoring, with a special focus on drug safety.

What the reader will gain: An update on voriconazole metabolism, drug interactions, toxicity and the relation of these with voriconazole drug concentrations.

Take home message: Therapy with voriconazole may be better guided by measuring voriconazole concentrations in the plasma.     

A review of in vitro and in vivo models of oesophageal and gastric cancer

Importance of the field: Oesophageal and gastric cancers are leading causes of cancer-related mortality. In the era of targeted therapy and individualized treatment strategies, novel treatments for upper-gastrointestinal cancers are only just emerging compared to significant advances in other solid tumour types such as colorectal, breast and lung cancers. Clinical trials are investigating the value of established targeted agents for the treatment of oesophageal and gastric malignancies; however none are used in routine clinical practice.

Areas covered in this review: In this review we have looked at current in vitro and in vivo models of oesophageal and gastric cancers which may improve our understanding of the biology of these tumours and lead to the development of new preventative, diagnostic and therapeutic approaches.

What the reader will gain: We discuss the limitations of our current models and the challenges associated with research into these cancers.

Take home message: The lack of appropriate models for drug development in oesophageal and gastric cancers has hindered the progress of targeted therapy in this field.