Current Medicinal Chemistry - Volume 13, Issue 21, 2006

This paper reviews the recent advances and the key strategies in capillary electrophoresis (CE) with electrochemical detection (ECD) for separating and detecting a variety of bioactive constituents in traditional Chinese medicines (TCMs). The subjects covered include the separation modes for the CE analysis of the constituents in TCMs, the CE-ECD system, the sample preparations of TCMs, the ECD of TCMs, the applications of CE-ECD in the determination of various bioactive constituents in Chinese medicinal materials and their preparations, the identification and differentiation of TCMs by CE-ECD, and future prospects. It is expected that CE-ECD will become a powerful tool in the herbal medicinal fields and will lead to the creation of truly routine devices for TCM analysis..

Endotoxin tolerance is a well known phenomenon, described both in vivo and in vitro, in which repeated exposure to endotoxin results in a diminished response, usually characterised as a reduction in proinflammatory cytokine release. The mechanisms responsible for endotoxin tolerance have become clear in recent years as our understanding of the pathways through which endotoxin mediates its effects has increased. The principal cell surface receptor for the lipopolysaccharide (LPS) component of endotoxin is Toll-Like Receptor 4 (TLR-4), a member of a highly conserved family of receptors specific for highly conserved bacterial and viral components which play key roles in the early inflammatory response to pathogens. As our understanding of the part played by TLR-4 signalling in endotoxin has increased, so it has become clear that response tolerance occurs to other TLR ligands in addition to LPS/endotoxin. Clinically, endotoxin/TLR response tolerance is thought to play an important part in susceptibility to reinfection in patients treated for severe sepsis. Whilst this may have developed as a protective evolutionary mechanism to prevent death caused by overwhelming cytokine release in sepsis, in the modern era of antibiotics, vasopressors and organ support, undoing this downregulation or 're-booting' the immune system may be a useful therapeutic target in the postseptic patient. This should, however, be approached with caution as it is possible that endotoxin/TLR response tolerance is also a physiological regulatory mechanism in areas normally exposed to bacterial-derived TLRligands such as the gut and liver.

In the last decade, there has been a rapid proliferation of new technologies that are capable of identifying an increasing spectrum of autoantibodies and other biomarkers in autoimmune diseases. These newer diagnostic technologies include line immunoassays, addressable laser bead immunoassays, microarrays in microfluidics platforms and nanobarcode particles. Multiplexed bead assays are a particularly robust platform because they are adaptable to the detection of a variety of disease specific biomarkers, such as autoantibodies, cytokines, adipokines, drugs, oligonucleotides and single nucleotide polymorphisms, Although many laboratories have adopted a variety of these diagnostic platforms to improve turn around times and meet budget constraints, there is an urgent need to ensure that the rapid adoption of new technologies is attended by an appropriate balance of assay sensitivity and specificity.

The roles of metals in the development and inhibition of cancer have a complex character and have risen many questions because of their essential and toxic effects on human health. Question of whether trace metal concentrations in tissues are increased or decreased in cancerous patients in comparison with noncancerous patients has not been answered yet, due to the fact that the data known in this field is rare and have contradictory results. Although Zn and Cu concentrations in serum and tissues of cancerous patients have been extensively studied, the precise role of these metals in carcinogenesis is not clearly understood. On the other hand, the comprehensive review on trace metal concentrations in cancerous and non-cancerous tissues is uncommon. The differences in literature on the increases or decreases in trace metal concentrations of cancerous tissues in comparison with non-cancerous tissues may be attributed to a few reasons such as the tissue basis-dry or wet weight, different sensitivities and basis of analysis methods that affect the accuracy, and the difficulties in taking of the sample representing the cancerous or non-cancerous area. In this study, the data published up to now have been reviewed. Comparison of results was done according to tissue and cancer types and trace metal species. The probable causes of differences in literature data were discussed. Especially, the published studies in recent years needed such a review.

The diesters of benzene-1,2-dicarboxylic (phthalic) acid, commonly known as phthalates, are a family of industrial compounds, primarily used as plasticizers in enormous quantities for a variety of industrial uses in the formulation of plastics. Di-(2-ethylhexyl) phthalate (DEHP) is the most commonly used plasticizer. These plasticizers are not covalently bound to the polymer and leach out into the environment, thus becoming ubiquitous environmental contaminants. Cumulating evidence points out on the adverse effects of phthalate exposure during intrauterine life. Recently, it has been documented that in utero phthalate exposure is associated with a shorter duration of pregnancy. Phthalates induce and activate a subset of peroxisome proliferator-activated receptors (PPARs) and have an intrinsic pro-inflammatory activity, while some natural PPAR agonists induce cyclooxygenase (COX)-2 expression. To this regard, COX-2 is thought to be overexpressed in chorioamnionitis (CA), a fetal systemic inflammatory response syndrome and a leading cause of preterm birth. An adequate maternal dietary intake of essential fatty acids, well known antiinflammatory agents, is indispensable to fetal development. Recently, it has been shown that phthalates alter the placental essential fatty acids (EFAs) homeostasis so potentially leading to abnormal fetal development. Likewise, a possible down-regulation of COX-2 by omega-3 fatty acids has been suggested. As a consequence, maternal supplementation with omega 3 during pregnancy could counteract the adverse effects of phthalates exposure in the human fetus. Here, we analyze the existing evidence on the link between antenatal phthalate exposure and abnormal fetal development, as well as on possible therapeutic tools to fight the adverse effect of this exposure.

The therapeutical use of drugs involves the application of dosage forms, serving as carrier systems together with several excipients to deliver the active ingredient to the site of action. Drug delivery technology combines an understanding of medicinal chemistry and pharmacology with the skill of formulation, aiming the preparation of improved pharmaceuticals. The recently introduced Biopharmaceutical Classification System provides guidance for dosage form design, taking the molecular and physico-chemical properties of drugs into consideration through their solubility and permeability characteristics. Pharmaceutical excipients used for oral dosage form have been traditionally assumed as being inert. However, recent experience and new results have shown that they can interact with the active drug ingredient, affecting its dissolution, absorption and bioavailability. Classification of the excipients is based on their role in the pharmaceutical formulation and on their interactions influencing drug delivery, based on their chemical and physico-chemical properties. The main classes are the antioxidants, coating materials, emulgents, taste- and smell-improvers, ointment bases, conserving agents, consistency-improvers and disintegrating materials. Some of the excipients may serve multiple purposes; for example, methylcellulose is a coating material, is applied in the preparation of suspensions, to increase viscosity, as a disintegrating agent or binder in tablets. The aim of this paper is to review the drug-excipients with respect to their chemistry, importance and interactions altering the pharmacokinetics of the drug substances. Emphasis will be given to two major classes of excipients: the antioxidants and disintegrants (substances facilitating disintegration of the drug tablets in the gastro-intestinal tract). Details will be given on the mechanisms through which they can alter drug effectiveness and tolerance, and control their application. Examples and references will be given for their analysis.

The increase in diagnostic imaging procedures that require infusion of intravenous radiographic contrast has led to a parallel increase in the incidence of contrast-induced nephropathy (CIN). Since CIN accounts for a significant increase of hospital-acquired renal failure, length of stay and mortality, several additive strategies to prevent CIN are presently advocated, including N-acetylcysteine (NAC), sodium bicarbonate, theophylline or fenoldopam, and peri-procedural hemofiltration/hemodialysis. As only one (nonrandomized) study has been performed in the intensive care setting, at present it is hard to give firm recommendations on preventive measures for CIN in intensive care patients. Indeed, future studies are needed to determine the true role of the above-mentioned preventive measures in critically ill patients at risk for CIN. Since NAC has only few side-effects, we presently advise NAC as an additive preventive measure in the intensive care setting. Theophylline or sodium bicarbonate hydration are viable options, either in conjunction NAC or as alternatives.

Millions of people in the developing world are affected by diseases caused by the kinetoplastid parasites: the leishmaniases, African trypanosomiasis, and Chagas disease. In many cases the drugs employed for treatment are toxic, marginally effective, given by injection, and/or compromised by the development of resistance. Since safe, effective, and affordable chemotherapeutic agents for leishmaniasis and trypanosomiasis are clearly needed, the identification of new antikinetoplastid drug candidates should be an urgent priority. Numerous plant-derived natural products from different structural classes have been investigated as antileishmanial and antitrypanosomal candidates, including various alkaloids, terpenoids, flavonoids, and quinonoids. This review outlines the antikinetoplastid activities of plant-derived natural products reported in the literature and also provides an overview of mechanistic studies that have been conducted with these compounds. Given the activities of these agents and their diverse range of effects on parasite biology, natural products are a potentially rich source of drug candidates and leads against leishmaniasis and trypanosomiasis.