Current Medicinal Chemistry (v.23, #21)

Meet Our Editorial Board Member by Werner Sieghart (2189-2189).

Update on Therapeutic Approaches for Rheumatoid Arthritis by Eugénia Nogueira, Andreia Gomes, Ana Preto, Artur Cavaco-Paulo (2190-2203).
Rheumatoid arthritis is a common chronic inflammatory and destructive arthropathy that consumes considerable personal, social and economic costs. It consists of a syndrome of pain, stiffness and symmetrical inflammation of the synovial membrane (synovitis) of freely moveable joints such as the knee (diarthrodial joints). Although the etiology of rheumatoid arthritis is unclear, the disease is characterized by inflammation of the synovial lining of diarthrodial joints, high synovial proliferation and an influx of inflammatory cells, macrophages and lymphocytes through angiogenic blood vessels. Diseasemodifying antirheumatic drugs slow disease progression and can induce disease remission in some patients. Methotrexate is the first line therapy, but if patients become intolerant to this drug, biologic agents should be used. The development of biological substances for the treatment of rheumatic conditions has been accompanied by ongoing health economic discussions regarding the implementation of these highly effective, but accordingly, highly priced drugs are the standard treatment guidelines of rheumatic diseases. In this way, more efficient strategies have to be identified. Despite numerous reviews in rheumatoid arthritis in the last years, this area is in constant development and updates are an urgent need to incorporate new advances in rheumatoid arthritis research. This review highlights the immunopathogenesis rationale for the current therapeutic strategies in rheumatoid arthritis.

Current Trends on Antipsychotics: Focus on Asenapine by Donatella Marazziti, Armando Piccinni, Stefano Baroni, Francesco Mungai, Silvio Presta, Federico Mucci, Liliana Dell';Osso (2204-2216).
Over the years, both first- (FGAs) and second-generation antipsychotics (SGAs), continue to gain increasing evidence of being effective in the treatment of psychotic symptoms. Currently, they represent the first-line treatment of schizophrenia and bipolar disorder, although they are widely used in psychotic depression and other clinical conditions, such as agitation and/or behavioural disturbances. Despite representing an indispensable tool for the treatment of severe psychotic disorders, they are widely known to have a number of unwanted side effects that the clinician must be aware of, and handle carefully to provide the patient the best available treatment in the short and long-term. However, even with respect to the long-term use of some of the most effective SGAs, it is imperative for clinicians not to overlook the risk linked to the onset of potentially severe metabolic side effects such as weight gain, dyslipidaemia, insulinresistance and type II diabetes.
Asenapine is one of the newest SGAs licenced in Europe for the treatment of manic episodes and in the US for schizophrenia. It belongs to the same class of clozapine, olanzapine and quetiapine, sharing with them a rather complex pharmacological binding profile. In fact, asenapine shows a high affinity for the serotonin (5HT) receptor of the type 2A (5HT2A) and to a lesser extent for the dopamine receptor of the type 2 (D2), similar to other SGAs. Asenapine behaves also as an antagonist at the level of 5HT2C, H1 and ?2-receptors. Asenapine has been reported to be effective either in monotherapy or in combination with mood stabilers (lithium and valproate) in the treatment of manic or mixed episodes, with a lower propensity to induce, or being followed by, depressive symptoms, when compared to other SGAs. These unique properties may explain the increasing interest towards the use of this drug in mixed states, besides schizophrenia and acute mania.
The aim of this paper was at reviewing current data on pharmacological properties and clinical use of asenapine, as well as on possible future indication of this SGA.

To date, two kinds of Granulocyte Colony-Stimulating Factors (G-CSF) have been approved for autologous peripheral blood hematopoietic stem cell (PBSCs) mobilization and posttransplant hematologic recovery after high-dose chemotherapy: filgrastim (originator and biosimilar) and lenograstim. Biosimilar filgrastim has been approved on the basis of comparable efficacy and safety in clinical studies where it has been used as chemotherapy-induced febrile neutropenia prophylaxis, but no specific pre-registration studies have been published in the transplant setting. Hence, there is still general skepticism about the role of biosimilar G-CSFs in this setting of patients. This review of biochemical, pre-clinical and clinical data suggests significant comparability of biosimilar filgrastim with both originator filgrastim and lenograstim in autologous PBSCs mobilization and post-autograft hematologic recovery.

Thrombin is a key enzyme of blood coagulation system which has multiple functions including pro- and anticoagulant, platelet aggregating and inflammatory activities. Unsurprisingly, this enzyme has been a target for anticoagulant drug development for decades. Among the most interesting direct thrombin inhibitors with intravenous administration route are the following ones: 1) hirudins, proteins with bivalent binding mode to the thrombin, 2) bivalirudin, the peptide with bivalent binding mode to the thrombin, 3) argatroban, the chemical that binds to the thrombin active site, and 4) G-quadruplex DNA aptamers, structured oligonucleotides with an affinity to protein-binding site of the thrombin. Efficiency of all these inhibitors has been studied in vivo in preclinical and clinical trials, as well as in vitro with various tests, allowing to compare them thoroughly.
In the review three levels of comparison were used to highlight the features of each inhibitor: 1) thrombin inhibition constants as a characteristic of inhibitor potency in simple enzymatic system; 2) inhibition of fibrin fiber formation and thrombin generation in coagulation cascade as a characteristic of anticoagulant potency in human blood plasma; and 3) therapeutic doses used and therapeutic profiles obtained after intravenous administration into animals and humans. The data clearly demonstrate weak and strong aspects of thrombin binding aptamers providing a solid background for further novel anticoagulant development.

Human Tuberculosis. III. Current and Prospective Approaches in Anti-Tubercular Therapy by Giampietro Sgaragli, Maria Frosini, Simona Saponara, Federico Corelli (2245-2274).
Ineffectively treated tuberculosis (TB) is associated with substantial morbidity and mortality. Cure of TB patients is hampered by the development of multidrug resistance in M. tuberculosis and the need of long-term treatment. The diarylquinoline derivative bedaquiline was approved in December 2012 under the accelerated-approval regulations of FDA as part of a combination therapy for treating adults with pulmonary MDR-TB for whom effective cures are not otherwise available. The bicyclic nitroimidazoles delamanid and its companion pretomanid inhibit mycolic acid synthesis via an unknown mechanism. In November 2013, delamanid received conditional approval by the European Medicines Agency for MDR-TB treatment. Use of both drugs, however, is limited owing to toxicity issues. If the aim to reduce treatment duration is pursued in order to limit costs and improve patient adherence, it is mandatory to demonstrate their noninferiority with fewer months of therapy. In three phase III clinical trials the efficacy of the most recent fluoroquinolones, gatifloxacin and moxifloxacin, has been investigated in a four-month treatment regimen of drug-susceptible TB. In all three studies, after two months the culture conversion rates of observed sputum indicated that fluoroquinolone-based therapies were likely to be superior. However, this feature did not reliably predict sterilizing activity or a risk of relapse. In other words, the shortened treatments were not noninferior to standard treatments. To counteract mycobacterial survival strategies and reduce the timelength of treatment with anti-TB drugs, other novel and powerful agents, as well as tuberculosis vaccines, are under intense clinical investigation for safety and efficacy assessment.

Pompe Disease and Autophagy: Partners in Crime, or Cause and Consequence? by M. Rodríguez-Arribas, J. M. Bravo-San Pedro, R. Gómez-Sánchez, S. M.S. Yakhine-Diop, G. Martínez-Chacón, E. Uribe-Carretero, D. C.J. Pinheiro De Castro, I. Casado-Naranjo, A. López de Munaín, M. Niso-Santano, J. M. Fuentes, R. A. González-Polo (2275-2285).
Pompe disease or glycogen storage disease type II (OMIM: 232300) is a lysosomal storage disorder resulting from a partial or total lack of acid alphaglucosidase, which may produce muscle weakness, gait abnormalities, or even death by respiratory failure. In the last decade, autophagy has been proposed as a mechanism involved in the severity of symptoms related to this disorder and as a potential therapeutic target to alleviate disease progression. This review summarizes the relationship between autophagy and Pompe disease, including what information has been recently discovered and what remains unclear.