Current Medicinal Chemistry - Volume 21, Issue 7, 2014

This review was designed as a handbook of metabolomic markers of high significance for a wide range of human diseases. This is the first report to collate results from recent studies in a format that allows ready identification of key metabolites by cross-comparisons of results from one disease to another. All the data presented in this work were obtained by previous research carried out exclusively during clinical trials in humans. Also, discussion of the pathophysiological pathways linked to the markers described is provided. The clinical assays focused on non-targeted or targeted metabolomics and metabolite profiling (focused assays which only refer to a limited array of known biomarkers, applying discriminatory and bioinformatic tools to them) as well as predictive modelling based on clinical trials. The data also highlight pathways and biological compounds that are disrupted at early stages of the diseases, in order to help elucidate target compounds and the pathophysiology of the considered diseases for early prognosis and diagnosis using noninvasive samples (saliva, sputum, serum, plasma, blood, urine, tissue, faecal water or faeces). In the tables, the candidate metabolites for biomarkers of diagnosis, or the biomarkers themselves, are detailed, indicating the type of sample in which they were detected and their up- or down-regulation (if calculated). The metabolites derived from each study have been filtered carefully, according to the analytical platform, and biostatistical discriminant analyses developed. Among the pool of data provided, those reaching a level of significance of p=0.05-0.0001, according to the Bonferroni correction, Steel- Dwass t- or Wilcoxon matched pair tests, are shown.

The synthesis of recombinant human erythropoietin has marked a turning point in the treatment of anaemia secondary to chronic kidney disease. However, the potentially fatal cardio- and cerebrovascular complications of the intake of high-doses of ESAs (erythropoiesis-stimulating agents), such as those observed in athletes who resort to doping, reason out the ever-prevalent debate concerning the balance between the risks and benefits of ESA administration for therapeutic purposes. Hence, there is still a discussion as to what values haemoglobin should ideally be maintained at. Additional concerns arise in cancer patients due to the ability of erythropoietin to act as an angiogenic and, in general, as a cell growth factor, because this might favour the progression of neoplastic disease. We summarized the prominent points of the latest guidelines on the management of anaemia in nephropathic patients, also identifying the possible risks that may result from the tendency to aim at too low haemoglobin levels.

Graphene, a truly two-dimensional (2D) and fully π-conjugated honeycomb network, exhibits many unique physical and chemical properties that are interesting in a wide range of areas. Since its discovery in 2004, graphene has been extensively studied in many different fields including nano-electronics, composite materials, energy research, catalysis and so on. Based on the fascinating action of members in the carbon family, notably zero dimensional (0D) fullerenes and one dimensional (1D) carbon nanotubes (CNTs) in biomedical areas, increasing number of reports have explored the potential of graphene for different biomedical and biotechnical applications since 2008. This manuscript aims to provide a summary of current research progress of graphene-based carbon materials in biosensing, drug (gene) delivery and tissue engineering, and discusses the opportunities and challenges in this rapidly growing field.

Opportunistic fungi are the most important pathogens in modern world. They are responsible for severe infections in majority of immunocompromised patients. These microorganisms are commonly present in our environment which is natural reservoir of new, resistant species. For this reason mycoses are mainly chronic or long-lasting diseases. Our arsenal of antifungal drugs is growing but still insufficient for emerging resistant pathogens. An alternative for novel chemical entity drugs is the multidrug approach. This exploiting the drugs being currently on market applying simultaneously for better efficacy or to eradicate resistance. Synergy is the term that describes the phenomenon of increased potency of two or more drugs administered in combination. In the last decades it gains more interest and numbers of synergy claimed reports is growing exponentially. However these have rather low impact on clinical trials or practical use of antimycotics. In present review we wish to discuss current status of synergy between antifungal drugs. Both theoretical point of view and practical applicability in clinical terms are covered. There are serious differences between the assumptions, methods and interpretations of the results and sometimes even obvious mistakes in the procedure that was applied or in the outcomes discussed. On the other hands the specificity of fungal infections introduce dozens of factors affecting the observed results. Shift form in vitro studies to clinical trials reveals further difficulties. Hopefully multi-drug approach seems to be effective even if no strong synergy is displayed.

Among the numerous endogenous promoters of angiogenesis, vascular endothelia growth factor (VEGF) plays a leading role in angiogenesis, which has huge impact on proliferation, survival, migration and permeability of tumor cells. VEGF signal system also becomes remarkable anticancer targets, including VEGF, vascular endothelia growth factor receptor (VEGFR), and VEGF downstream signal pathways. So far, there has been many clinical or approved anticancer drugs that directly or indireactly interfere with VEGF signal system applied in the treatment of various tumors and other diseases associated with pathological angiogenesis. Various kinds of antiangiogenic agents which inhibit VEGF and VEGFR have been developed and discovered gradually, including antibodies, ribozymes and small molecule inhibitors. Meanwhile, the investigation into antiangiogenic agents which block certain signal proteins of VEGF downstream signal pathways attracts the attention of medicinal chemists and enriches the application of antiangiogenic agents. This review will interpret the mysterious VEGF signal system from its molecular structure and probe to the mechanism of the combination of VEGF and its receptors. Furthermore, the detail of VEGF signal pathways will be introduced comprehensively and methodically. In addition, some up-to-date clinical or approved anticancer agents will be clearly tabulated. The binding modes of different kinase inhibitors will be used to explain the SAR of the small molecule inhibitors. Finally, in order to make the readers master VEGF signal system completely, some novel targets and inhibitors which block the downstream signal pathways of VEGF are plainly stated.

Synthetic heterocyclic compounds have remarkable potential activity against diseases; thioamides, benzimidazoles, quinolones and derivatives with carboxylic acid and esters moieties have shown excellent activity against Mycobacterium tuberculosis. We reviewed antituberculosis activities of above compounds with reference to half maximal inhibitory concentration, minimum inhibitory concentration and structural-activity relationship which clearly indicate that electron- withdrawing groups are the main inducers of antimycobacterium activity. Comparison between clinically used drugs and new synthetic derivatives showed recent advances made in the last decade.

Gardasil® is a quadrivalent human papillomavirus (HPV) protein-based vaccine containing genotype-specific L1 capsid proteins of HPV-16, HPV-18, HPV-6 and HPV-11 in the form of virus-like-particles (VLPs) as the active ingredient. The VLPs are produced by a DNA recombinant technology. It is uncertain if the residual HPV L1 gene DNA fragments in the vaccine products are considered contaminants or excipients of the Gardasil® vaccine. Because naked viral DNA fragments, if present in the vaccine, may bind to the insoluble amorphous aluminum hydroxyphosphate sulfate (AAHS) adjuvant which may help deliver the foreign DNA into macrophages, causing unintended pathophysiologic effects, experiments were undertaken to develop tests for HPV L1 gene DNA fragments in the final products of Gardasil® by polymerase chain reaction (PCR) and direct DNA sequencing. The results showed that while the HPV-11 and HPV-18 L1 gene DNA fragments in Gardasil® were readily amplified by the common GP6/MY11 degenerate consensus primers, the HPV-16 L1 gene DNA may need specially designed non-degenerate PCR primers for amplification at different regions of the L1 gene and different stringency conditions for detection. These variable melting profiles of HPV DNA in the insoluble fraction of the Gardasil® vaccine suggest that the HPV DNA fragments are firmly bound to the aluminum AAHS adjuvant. All methods developed for detecting residual HPV DNA in the vaccine Gardasil® for quality assurance must take into consideration the variable melting profiles of the DNA to avoid false negative results.

We examined a large number of sudden infant death syndrome victims in order to point out a possible causal relationship between a previous hexavalent vaccination and the sudden infant death. We selected 110 cases submitted to in-depth histological examination of the autonomic nervous system and provided with detailed clinical and environmental information. In 13 cases (11.8%) the death occurred in temporal association with administration of the hexavalent vaccine (from 1 to 7 days). In none of these victims congenital developmental alterations of the main nervous structures regulating the vital functions were observed. Only the hypoplasia of the arcuate nucleus was present in 5 cases. In one case in particular an acquired hyperacute encephalitis of the tractus solitarii nucleus was diagnosed in the brainstem. This study does not prove a causal relationship between the hexavalent vaccination and SIDS. However, we hypothesize that vaccine components could have a direct role in sparking off a lethal outcome in vulnerable babies. In conclusion, we sustain the need that deaths occurring in a short space of time after hexavalent vaccination are appropriately investigated and submitted to a post-mortem examination particularly of the autonomic nervous system by an expert pathologist to objectively evaluate the possible causative role of the vaccine in SIDS.