Current Medicinal Chemistry - Volume 24, Issue 11, 2017

Background: More than 85% of children affected by acute lymphoblastic leukemia (ALL) are successfully treated; however relapse remains a remarkable clinical concern, with 50-60% of relapsing patients facing a fatal outcome. Management of relapsed patients includes standardized intensive risk-adapted regimens based on conventional drugs, and hematopoietic stem cells transplantation for patients with unfavourable features. Biological drugs, in particular the monoclonal antibody epratuzumab and the bi-functional recombinant single chain peptide blinatumomab, have been recently recognized as novel potential agents to be integrated in salvage ALL therapy to further improve rescue outcome. Methods: A systematic search of peer-reviewed scientific literature and clinical trials in public databases has been carried out. Both clinical and pre-clinical studies have been included to summarize recent evidence on epratuzumab and blinatumomab for salvage ALL therapy. Results: Sixty-two papers and 25 clinical trials were included. Although not all patients responded properly to these agents, their use in relapsed and refractory pediatric ALL seems promising. Conclusion: Phase 3 studies have recently begun and more consistent results about epratuzumab and blinatumomab safety and efficacy in comparison to conventional therapies are expected in the next years. Epratuzumab seems safe in the dosing scheme proposed in ALL, but its efficacy over the conventional chemotherapy is still questionable. Blinatumomab has shown promising results in high risk cases such as elder adult patients and conclusive studies on pediatric ALL are needed. Patient inter-individual variability to these agents has not been investigated in depth, but this issue needs to be addressed, in particular for blinatumomab.

It has been over a century since Carlos Chagas discovered the Trypanosoma cruzi (T. cruzi) as the causative agent of Chagas disease (CD), a neglected tropical disease with several socioeconomic, epidemiological and human health repercussions. Currently, there are only two commercialized drugs to treat CD in acute phase, nifurtimox and benznidazol, with several adverse side effects. Thus, new orally available and safe drugs for this parasitic infection are urgently required. One strategy of great importance in new drug discovery programmes is based on the search of molecules enabling to interfere with enzymes involved in T. cruzi metabolism. This review will focus on two of the most promising targets for the therapy of CD: trypanothione reductase (TR) and the iron-containing superoxide dismutase (Fe- SOD), which protect the parasite against oxidative damage by reactive oxygen species. A brief comparison of the function, mechanism of action and the active sites between T. cruzi TR and Fe-SOD with their analogues enzymes in human, glutathione reductase (GR) and the corresponding SODs, will be discussed. This review will also summarize the recent development and structure-activity relationships of novel compounds reported for their ability to selectively inhibit these targets, aiming to define molecular bases in the search for new effective treatment of CD.

This review examines brain sites involved in sexual stimulation. New data on brain activation sites in individuals having erections concomitant with visual erotic stimulation were documented. The activation was chiefly at the midbrain around the cerebral peduncle, and in the pons centering on the tegmentum, they are indicated by blood oxygenation level dependent (BOLD) images captured by functional magnetic resonance imaging (fMRI). The cerebellum and inferior temporal lobe were activated more extensively in individuals viewing pornographic movie with a concomitant erection than those without. Similarly, individuals with erection had activations in the midbrain and pons, while drug addicts had neither erections nor any of these brainstem active sites. From our observation in the new data, we deduced three possible transmitters might be involved in erection: i) cholinergic neurons forming descending pathways and associated with motor activity ii) gamma-aminobutyric acid (GABA), directly or indirectly via decreasing pathways, modulating autonomic vascular responses in the penile vasculature causing the filling of blood iii) GABA decreases to stimulate dopamine increase in ventral tegmentum of the brain, leading to euphoric responses.

Background: Atherosclerosis (AS) is a major cause of death and morbidity in Western world and is strongly connected with atherogenic lipoproteins and inflammation. Bile acids (BA) act as activating signals of endogenous ligands such as Farnesoid-X receptor (FXR). Primary data indicate a potential role of FXR in AS. The therapeutic value of FXR ligands in AS is unknown. Objective: With the present review, we analyzed the efficacy of FXR agonists as a therapeutic modalities against AS. In this aspect, we performed an electronic search through Pub- Med/MEDLINE database by using the key terms: FXR*, Farnesoid X receptor*, atherosclerosis*, bile acids* and agonism*. Conclusion: According to our analysis, the FXR seems to be a promising therapeutic target in the atherosclerosis natural history. FXR agonism could exert protective effects in the development and evolution of AS. However, concomitant side effects such as the reduction of plasma HDL have been reported. Finally, results from undergoing clinical trials with synthetic FXR agonists will shed more light to the precise role of FXR agonism in AS treatment.

Background: Tofacitinib (formerly known as CP-690,550, CP690550, tasocitinib), a novel selective immunosuppressant, is a small molecule classified as Janus kinase inhibitor. The aim of this review article is to present updated data summary on the tofacitinib in the field of dermatology. Method: We undertook a structured search of bibliographic databases for peer-reviewed scientific articles, including review articles, original research articles as well as case report articles based on inclusion/exclusion criteria. Technical reports on tofacitinib from U.S. Food and Drug Administration and European Medical Agency were also included. Results: Forty-three papers were included in this review. We report current data on tofacitinib chemical properties, pharmacology, non-clinical toxicity, as well as efficacy and safety in potential new indications in dermatology: psoriasis, alopecia areata, vitiligo, atopic dermatitis and nail dystrophy associated with alopecia areata. Conclusion: JAK/STAT pathway has an important role in the pathogenesis of psoriasis, alopecia areata, atopic dermatitis, and vitiligo. Despite encouraging efficacy, due to concerns about the overall safety profile of tofacitinib, additional studies will have to determine the adequate risk-to-benefit ratio.