Proteomics: state of the art and its application in cardiovascular research

The cellular and molecular mechanisms underlying cardiovascular dysfunctions are widely unknown. Basically, pathological changes in the cardiovascular system arise from protein alterations. Proteomics comprises a set of tools for the large-scale study of gene expression at the protein level thereby allowing for the identification of protein alterations responsible for the development and the pathological outcome of diseases including those of the cardiovascular system. In principle these alterations include those of suitable candidates for drug targets and disease biomarkers as well as therapeutic proteins/peptides. Since gene therapy depends on the function of a therapeutic protein encoded by a "therapeutic" gene proteomic analyses also provide the basis for the design and application of gene therapies. Proteomic technologies allow to identify not only proteins but also the nature of their posttranslational modifications thus enabling the elucidation of signal transduction pathways and their deregulation under pathological conditions. The linkage of information about proteome changes with functional consequences lead to the development of functional proteomic studies. Functional proteomic analyses will particularly help to better understand the relations between proteome changes and cardiovascular dysfunctions. The storage and administration of experimental data obtained by the application of proteomic analyses is supported by species- and tissue-specific protein databases and specific software. Publications in this field are reviewed in this paper.     

Clinical characteristics and prognosis of infections caused by OXA-48 carbapenemase-producing Enterobacteriaceae in patients treated with ceftazidime-avibactam

Background

Ceftazidime-avibactam has in vitro activity against Gram-negative bacilli that produce Class A, C and some D β-lactamases, and has been successfully used in the treatment of infections caused by cephalosporin and carbapenem-resistant Enterobacteriaceae. However, actual experience in the treatment of OXA-48 carbapenemase-producing Enterobacteriaceae (CPE) is limited.

Centralized intravenous additive services (CIVAS): the state of the art in 2010

In hospitals, the major part of the drugs is administered by intravenous way and the majority of the reconstitution of injectable drugs are carried out right before the administration to the patient by the nursing staff. The risks and errors related to the preparation and the administration of the injectable drugs are numerous. The standardization then the centralization of the preparations and reconstitution by the hospital pharmacy make it possible to reduce these various risks and errors. In addition to the preparation of the mixtures of parenteral nutrition as well as doses of anticancer chemotherapy, many other treatments can be taken in charge, such as antibiotics, antiemetics and pain treatments. Consequent equipment is necessary but the realization of these treatments proves non-overdrawn insofar as a certain quantity of production is reached. The reconstitution of the intravenous treatments by a centralized intravenous admixture service guarantees the chemical stability and the microbiological quality of the ready-to-use injectable drugs and contributes to the quality and the total management of the care of the patient.     

Dengue vaccines: state of the art

Importance of the field: Dengue is a significant public health problem transcending geographical boundaries to place nearly 50% of the global population at risk. A vaccine to prevent dengue is an unmet need that should be addressed urgently.

Areas covered in the review: A brief introduction to dengue and a detailed review of the classical and modern approaches being undertaken currently to develop dengue vaccines described in recent patent literature, highlighting the inherent hurdles and challenges.

What the reader will gain: An understanding of the approaches being deployed to develop multiple viral and non-viral vaccine candidates and an appreciation of the complexity of developing dengue vaccines.

Take home message: Live viral vaccines, which have advanced to clinical trials, have revealed new challenges, emphasizing the need to pursue non-viral alternatives simultaneously.     

Antisense oligonucleotides: the state of the art

The use of antisense oligonucleotides as therapeutic agents has generated considerable enthusiasm in the research and medical community. Antisense oligonucleotides as therapeutic agents were proposed as far back as in the 1970s when the antisense strategy was initially developed. Nonetheless, it has taken almost a quarter of a century for this potential to be realized. The principle of antisense technology is the sequence-specific binding of an antisense oligonucleotide to target mRNA, resulting in the prevention of gene translation. The specificity of hybridization by Watson-Crick base pairing make antisense oligonucleotides attractive as tools for targeted validation and functionalization, and as therapeutics to selectively modulate the expression of genes involved in the pathogenesis of diseases. The last few years have seen a rapid increase in the number of antisense molecules progressing past Phase I, II and III clinical trials. This review outlines the basic concept of the antisense technology, its development and recent potential therapeutic applications.     

Brachytherapy: state of the art and possible improvements

Cancer often remains an incurable disease, despite significant progresses in diagnosis and treatment that have been made. Specifically, the use of nuclear medicine in oncology is greatly contributing to both imaging and therapy aspects. Targeted therapies are a major field of interest since it increases efficiency and reduces side effects. Brachytherapy is among the most valuable of recent developments for treating localized tumours resulting in improvements in improved quality of life. This is primarily because it irradiates cancerous cells most exclusively while barely effecting healthy tissue. The use of radiochemicals implies specific management for production, transport and handling that have limited the development of this technique. This review article describes brachytherapy and their latest developments. Furthermore, alternative activation methods for the production of radioisotopes and a novel delivery system for targeted multi-therapy by using PLA-ferrite nanospheres are described.     

Nanoparticles and liposomes: a state of the art

The loading of drugs into ultrafine host vesicles or colloidal capsules in the nanometer size range is an acknowledged technique for the optimization of controlled drug delivery. The main purpose will always be to design inert auxiliary accompanying materials; to use body-friendly and biodegradable excipients; and to miniaturize the drug carrier system dramatically in order to get good stability, excellent absorption, quantitative tissular transfer and, therefore, the expected pharmacodynamic activity. Furthermore, side effects and foreign body irritation should be avoided and a good local and systemic tolerance during and after medication should be a condition sine qua non. The actual state of the art is shown with 4 practical application examples, namely: a cellular uptake by endocytosis and a specific lysosomotropic cell transfer with cell tracer-loaded nanoparticles; the strong immunosuppressive stimulation of nanocapsules--as new adjuvants--when loaded with viral or other antigens; the better blood-brain barrier transfer of an antiparkinson drug when covalently bound to special liposomes; and the use of minivesicles for controlled site-specific anticancer drug release (tumor targeting). In the future, we must find a possibility to deliver the correct dose of the drug precisely to the diseased target organs, tissues or cells of destination, without flooding the organism with massive drug doses. One technologic answer could be the minicarrier concept with specific pathfinders and aspecific pretargeters that serve as switchmen to guide the drug-loaded carrier to the organs, with precise spot landing.     

Glucocorticoids and the cardiovascular system: state of the art

Glucocorticoids (GC) are drugs commonly used, by approximately 1% of the total adult population as anti-inflammatory and immunosuppressive therapies for asthma, inflammatory bowel disease, dermatological, ophthalmic, neurological, and rheumatic autoimmune diseases. Supporting evidence exists of GC use in both immune mediated and non-immune mediated heart disease. The molecular mechanisms by which GC induces immune-modulation and direct cardioprotection, are complex and not fully understood. We review herein, the current knowledge of GC use in various immune-mediated or non-immune mediated cardiovascular conditions. GC have been investigated in autoimmune, inflammatory and idiopathic heart diseases such as atrio-ventricular conduction abnormalities, rheumatic fever, myocarditis, dilated cardiomyopathy, Churg-Strauss syndrome, Kawasaki disease and sarcoidosis. GC therapy has been studied in non-autoimmune and non-inflammatory indications such as acute myocardial infarction, angina, postpericardiotomy syndrome and other pericardial diseases, endocarditis and cardiac amyloidosis, as well as in invasive cardiology, coronary interventions, and cardiopulmonary-bypass surgery. Despite GC's role as natural, physiologic regulators of the immune system, cardiovascular adverse outcomes may occur. Some of the well-known side effects of GC therapy involve bone, metabolic, and cardiovascular systems and include osteoporosis, fractures, dyslipidemia, diabetes, obesity, and hypertension.     

The rabbit syndrome: state of the art

INTRODUCTION: The rabbit syndrome (RS) is a rare movement disorder generally associated with prolonged use of antipsychotics and characterized by inwilling, rhythmic, fast and fine movements of oral and masticatory muscles along the vertical axis of the mouth. PREVALENCE: The prevalence of RS ranges between 1.5% and 4.4%; middle and elderly ages, the female gender, as well as past brain injuries are considered risk factors for its development. PATHOPHYSIOLOGY: Although a dysbalance of the cholinergic and dopaminergic neurotransmission in the basal ganglia seems to be involved in the pathophysiology of RS, its precise mechanisms need to be clarified as yet. RELATIONSHIPS WITH ANTIPSYCHOTICS: Fifty cases of RS have been published up-to-now: 34 and 10 occurred during treatments with typical and atypical antipsychotics, respectively, while 6 seemed unrelated to these drugs. DIFFERENTIAL DIAGNOSIS: The differential diagnosis between RS and tardive dyskinesias involving the mouth may be based mainly on the evidence that in these last conditions the movements of the mouth are less regular and slower and involve the tongue. Treatment strategy: The available data suggest that RS responds favourably to anticholinergic drugs and to the change of the antipsychotic.     

Sublingual specific immunotherapy: state of the art

Sublingual immunotherapy (SLIT) was first attempted more than a century ago. After a long parenthesis probably related to the lack of impressive clinical results, the advances on allergen quantification and characterization, together with the improvements in the recombination techniques have renewed the interest in this therapy during the past decade. There are currently enough high quality clinical trials on its efficacy in the management of respiratory allergies (asthma and rhinoconjunctivitis) to conclude that SLIT could be an effective tool for the management of those diseases. This effectiveness has been shown both in children and in adults. However, while there are some clues related to the mechanism of action of SLIT, there is still much to know about it. In addition, more studies comparing the effectiveness of SLIT vs the standard subcutaneous immunotherapy (SCIT) are needed to definitely establish the role of SLIT in the treatment of allergic diseases. SLIT has proven a very safe therapy as compared to SCIT, a fact which adds a very important advantage to the sublingual route.     

Engineering endomorphin drugs: state of the art

INTRODUCTION: Although endomorphins-1 (EM-1; H-Tyr-Pro-Phe-Trp-NH(2)) and -2 (EM-2; H-Tyr-Pro-Phe-Phe-NH(2)) are primarily considered agonists for the μ-opioid receptor (MOR), systematic alterations to specific residues provided antagonists and ligands with mixed μ/δ-opioid properties, suitable for application to health-related topics. While the application of endomorphins as antinociceptive agents and numerous biological endpoints were experimentally delineated in laboratory animals and in vitro, clinical use is currently absent. However, structural alterations provide enhanced stability; formation of MOR antagonists or mixed and dual μ/δ-acting ligands could find considerable therapeutic potential. AREAS COVERED: This review attempts to succinctly provide insight on the development and bioactivity of endomorphin analogues during the past decade. Rational design approaches will focus on the engineering of endomorphin agonists, antagonists and mixed ligands for their application as a multi-target ligand. EXPERT OPINION: Aside from alleviating pain, EM analogues open new horizons in the treatment of medical syndromes involving neural reward mechanisms and extraneural regulation effects on homeostasis. Highly selective MOR antagonists may be promising to reduce inflammation, attenuate addiction to drugs and excess consumption of high-caloric food, ameliorate alcoholism, affect the immune system and combat opioid bowel dysfunction.     

Diagnosis and treatment of rosacea: state of the art

Rosacea is a common disorder that is both under recognized and undertreated. Prevalence figures indicate that it may be present in 1 of every 10 adults in a primary care waiting room. Untreated, patients with rosacea can suffer significant emotional, workplace, and social impairments. While rosacea has been recognized since ancient times, only recently have investigators begun to identify the pathophysiologic elements responsible for the characteristic erythema, flushing, dysesthesias, and papulopustular manifestations of the disease. Although the etiology of rosacea is unclear, inflammation appears to be a central element. Experimental evidence suggests that abnormalities of the skin's innate and adaptive immune responses may play pivotal roles. Once recognized, effective topical and systemic therapies can be prescribed to lessen the impact of the disease on the patient's life. Although initially administered in an empiric fashion, it now seems clear that the role of antibiotics in patients with rosacea depends upon their anti-inflammatory rather than their antimicrobial properties. Consequently, practitioners have the opportunity to practice good antibiotic stewardship when treating the disease, particularly with systemic therapies. Therapy with subantimicrobial dosing and with topical treatments can modulate the inflammation of rosacea without exerting antibiotic pressure responsible for the emergence of antibiotic resistance.     

Antiprotozoal compounds: state of the art and new developments

Protozoa can cause severe diseases, including malaria, leishmaniasis, Chagas disease, sleeping sickness and amoebiasis, all being responsible for morbidity and mortality particularly in tropical countries. To date there are no protective vaccines against any of these diseases, and many of the available drugs are old or elicit serious adverse reactions. Moreover, parasite resistance to existing drugs has become a serious problem. Owing to lack of financial returns, research in this field is of limited interest to pharmaceutical companies and largely depends on funding by public authorities. This article aims to provide a concise overview of the state-of-the-art treatment for the most important tropical protozoal infections as well as new approaches.     

Nitric oxide: state of the art in drug design

Since the great discovery of Furchgott, Ignarro and Murad in the late 90's, nitric oxide (NO) is considered one of the most versatile endogenous molecules, which is involved in important signaling biochemistry pathways of the human body. Thus, it is directly related to pathological processes and its over- or low-production is able to cause damage in systems that are involved. By using certain functional groups present in molecules that already have potential therapeutic value, hybrid compounds, by means of inclusion of NO-donors (e.g., ester nitrates, furoxans, benzofuroxans, NONOates, S-nitrosothiols, metal complexes), can be generated that have a NO release benefit along with maintaining the activity of the native drug. This approach has proved to be useful in many spheres of Medicinal Chemistry, such as cardiovascular, inflammatory, bacterial, fungal, viral, parasitic, ocular diseases and cancer. Potent and selective nitric oxide synthase inhibitors are being designed, mainly through enzyme structure based process, however, due to high homology between the isoforms, these studies have proved to be very difficult. The objective of the research is to achieve a balance between the release of therapeutic amounts of NO, especially in specific site of action, and maintaining the native drug activity. The search for new and effective NO-donor hybrid drugs, as well as selective nitric oxide synthase inhibitors, is an important focus in modern drug design in order to manipulate biochemical pathways involving NO that influence many dysfunctions of the human organism.     

Solid Lipid Nanoparticles (SLN) and Nanostructured Lipid Carriers (NLC) for pulmonary application: A review of the state of the art

Drug delivery by inhalation is a noninvasive means of administration that has following advantages for local treatment for airway diseases: reaching the epithelium directly, circumventing first pass metabolism and avoiding systemic toxicity. Moreover, from the physiological point of view, the lung provides advantages for systemic delivery of drugs including its large surface area, a thin alveolar epithelium and extensive vasculature which allow rapid and effective drug absorption. Therefore, pulmonary application is considered frequently for both, the local and the systemic delivery of drugs. Lipid nanoparticles – Solid Lipid Nanoparticles and Nanostructured Lipid Carriers – are nanosized carrier systems in which solid particles consisting of a lipid matrix are stabilized by surfactants in an aqueous phase. Advantages of lipid nanoparticles for the pulmonary application are the possibility of a deep lung deposition as they can be incorporated into respirables carriers due to their small size, prolonged release and low toxicity. This paper will give an overview of the existing literature about lipid nanoparticles for pulmonary application. Moreover, it will provide the reader with some background information for pulmonary drug delivery, i.e., anatomy and physiology of the respiratory system, formulation requirements, application forms, clearance from the lung, pharmacological benefits and nanotoxicity.     

Nanotechnology advances in brain tumors: the state of the art

Primary malignant central nervous system (CNS) tumors only represent about 2% of all cancers. However, they are very often associated with high morbidity and mortality. Despite current standard-of-care therapy, such as surgery, irradiation, and chemotherapy, neither cure nor any toxic therapy against malignant CNS tumors has been developed so far. Nanotechnology may alter this situation. It offers a new promise for cancer diagnosis and treatment. This emerging technology, by developing and manufacturing materials using atomic and molecular elements, can provide a platform for the combination of diagnostics, therapeutics and delivery to the tumor, with subsequent monitoring of the response. This review focuses on recent developments in cancer nanotechnology with particular attention to nanoparticle systems, important tools for the improvement of drug delivery in brain tumor. The latest advances in both the research sector and in recent patents for cancer imaging and therapy are discussed.