Aline Guerra Manssour Fraga

Synthesis and pharmacological evaluation of novel heterotricyclic acylhydrazone derivatives, designed as PAF antagonists ☆

This paper describes the synthesis and the antiplatelet properties of new heterotricyclic N-acylhydrazone derivatives (7a-e), structurally analogous to known hetrazepinic PAF antagonists, exploring molecular hybridization as a tool for molecular designing. The synthetic route employed to access compounds (7a-e) used, as starting material, the previously described methyl 3-hydroxy-8-methyl-6-phenyl-6H-pyrazolo[3,4-b]thieno[2, 3-d]pyridine-2-carboxylate derivative. The results from inhibitory effects of these novel acylhydrazone derivatives (7a-e) upon PAF-induced platelet aggregation, indicated that all compounds present a significant antithrombotic profile.

Activation of GPER ameliorates experimental pulmonary hypertension in male rats.

Rationale: Pulmonary hypertension (PH) is characterized by pulmonary vascular remodeling that leads to pulmonary congestion, uncompensated right‐ventricle (RV) failure, and premature death. Preclinical studies have demonstrated that the G protein‐coupled estrogen receptor (GPER) is cardioprotective in male rats and that its activation elicits vascular relaxation in rats of either sex. Objectives: To study the effects of GPER on the cardiopulmonary system by the administration of its selective agonist G1 in male rats with monocrotaline (MCT)‐induced PH. Methods: Rats received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Experimental groups were as follows: control, MCT + vehicle, and MCT + G1 (400 &mgr;g/kg/day subcutaneous). Animals (n = 5 per group) were treated with vehicle or G1 for 14 days after disease onset. Measurements and Main Results: Activation of GPER attenuated exercise intolerance and reduced RV overload in PH rats. Rats with PH exhibited echocardiographic alterations, such as reduced pulmonary flow, RV hypertrophy, and left‐ventricle dysfunction, by the end of protocol. G1 treatment reversed these PH‐related abnormalities of cardiopulmonary function and structure, in part by promoting pulmonary endothelial nitric oxide synthesis, Ca2 + handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. Conclusions: G1 was effective to reverse PH‐induced RV dysfunction and exercise intolerance in male rats, a finding that have important implications for ongoing clinical evaluation of new cardioprotective and vasodilator drugs for the treatment of the disease. Graphical Abstract GPER activation by G1 reverses pulmonary hypertension in male rats by promoting pulmonary endothelial nitric oxide synthesis, Ca2+ handling regulation and reduction of inflammation in cardiomyocytes, and a decrease of collagen deposition by acting in pulmonary and cardiac fibroblasts. Figure. No caption available.

Rational use of antioxidants in solid oral pharmaceutical preparations

Antioxidants are currently used as efficient excipients that delay or inhibit the oxidation process of molecules. Excipients are often associated with adverse reactions. Stability studies can guide the search for solutions that minimize or delay the processes of degradation. The ability to predict oxidation reactions in different drugs is important. Methods: This study was conducted to assess the rational use of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite (SMB), propyl gallate (PG) and cysteine (CYS) in tablet formulations of simvastatin and ketoconazole. These antioxidants were evaluated according to stability parameters and the relationship between efficiency of the antioxidant and chemical structure of the drugs. Results were compared with DPPH tests and computational simulations. BHT was most efficient regarding simvastatin stability, and the most effective BHT concentrations for maintaining stability were 0.5 and 0.1%. In relation to ketoconazole, SMB was most efficient for maintaining content and dissolution profile. The evaluation by DPPH showed that the largest percentage of absorbance reduction was observed for PG, while SMB proved most efficient and had lower consumption of DPPH. The same pattern was observed, albeit with lower efficiency, for the other lipophilic antioxidants such as BHT and BHA. The results of the molecular modeling study demonstrated that electronic properties obtained were correlated with antioxidant activity in solution, being useful for the rational development of liquid pharmaceutical formulations but not for solid oral formulations. This study demonstrated the importance of considering stability parameters and molecular modeling to elucidate the chemical phenomena involved in antioxidant activity, being useful for the rational use of antioxidants in the development of pharmaceutical formulations.

CYP1A2-mediated biotransformation of cardioactive 2-thienylidene-3,4-methylenedioxybenzoylhydrazine (LASSBio-294) by rat liver microsomes and human recombinant CYP enzymes

We describe herein the metabolic fate of cardioactive 1,3-benzodioxolyl N-acylhydrazone prototype LASSBio-294 (4) and the structural identification of its major phase I metabolite from rat liver microsomal assays. Our results confirmed the hard-metabolic character of N-acylhydrazone (NAH) framework of LASSBio-294 (4). The development of a reproducible analytical methodology for the major metabolite by using HPLC-MS and the comparison with an authentic synthetic sample, allowed us to identify 2-thienylidene 3,4-dihydroxybenzoylhydrazine derivative (7), formed by oxidative scission of methylenedioxy bridge of LASSBio-294, as the main metabolite formed by action of CYP1A2 isoform. The identification of this isoform in the LASSBio-294 in the clearance of LASSBio-294 (4) oxidation was performed by the use of selective CYP inhibitors or human recombinant CYP enzymes.

NF-κB Signaling Pathway Inhibitors as Anticancer Drug Candidates

Cancer incidence represents an important public health problem worldwide. Nuclear factor kappa B (NF- κB) transcription factor plays a pivotal role in the regulation of genes that control various responses in eukaryotic cells, including proliferation and survival, cytoskeletal remodeling, cellular adhesion and apoptosis. Extensive studies have demonstrated the contribution of NF-κB transcription in the promotion and progression of several hematological malignancies and solid tumors, in which NF-κB constitutive activation and/or overexpression are common clinical features. Moreover, triggering the NF-κB pathway is already considered one of the important mechanisms of resistance development to chemotherapy and radiotherapy, indicating that the inhibition of this signaling cascade is a promising approach to enhancing efficacy and preventing acquired resistance in cancer treatment. In this review, research efforts dedicated to the identification of novel NF-κB signaling pathway inhibitors as promising anticancer drug candidates are described.

Cardioprotection Induced by Activation of GPER in Ovariectomized Rats With Pulmonary Hypertension

Pulmonary hypertension (PH) is a disease of women (female-to-male ratio 4:1), and is associated with cardiac and skeletal muscle dysfunction. Herein, the activation of a new estrogen receptor (GPER) by the agonist G1 was evaluated in oophorectomized rats with monocrotaline (MCT)-induced PH. Depletion of estrogen was induced by bilateral oophorectomy (OVX) in Wistar rats. Experimental groups included SHAM or OVX rats that received a single intraperitoneal injection of MCT (60 mg/kg) for PH induction. Animals received s.c. injection of either vehicle or G1, a GPER agonist, (400 µg/kg/day) for 14 days after the onset of disease. Rats with PH exhibited exercise intolerance and cardiopulmonary alterations, including reduced pulmonary artery flow, biventricular remodeling, and left ventricular systolic and diastolic dysfunction. The magnitude of these PH-induced changes was significantly greater in OVX versus SHAM rats. G1 treatment reversed both cardiac and skeletal muscle functional aberrations caused by PH in OVX rats. G1 reversed PH-related cardiopulmonary dysfunction and exercise intolerance in female rats, a finding that may have important implications for the ongoing clinical evaluation of new drugs for the treatment of the disease in females after the loss of endogenous estrogens.

Sulfate-Reducing Bacteria: Biofilm Formation and Corrosive Activity in Endodontic Files

Aim This study describes the biofilm formation and the corrosive capacity of sulfate-reducing bacteria (SRB) on the metallic structure of used endodontic files. Methods Sulfate-reducing bacteria (SRB) (Desulfovibrio desulfuricans oral and Desulfovibrio fairfieldensis or D. desulfuricans environmental) were inoculated into the culture media (Postgate C culture medium or modified Postgate E culture medium). The biocorrosive potential of these bacteria will be an important component of a biopharmaceutical under development called BACCOR. Afterwards, four used endodontic files (UEFs) were separately inoculated into a specific culture media for 445 days at 30°C in an incubator. The four UEFs were placed in a scanning electron microscope (SEM) and analyzed by the energy-dispersive X-ray spectrometry (EDS). Results The confocal laser scanning microscopic images indicate the presence of biofilm in the four samples. The SEM and SEM-EDS revealed the presence of rough, irregular structures adhering along the metallic surface of the used endodontic files, suggesting a mature calcified biofilm with a high concentration of Ca, P, C, and S. Conclusion The formation of SRB biofilms on used endodontic files shows characteristics that may contribute to the biocorrosion of these files, and the results may also provide complementary data for a biopharmaceutical, which is still under development to assist in the removal of fractured endodontic files inside root channels.

Leishmaniasis: History, Evolution of Treatment and the Need for New Drugs

Leishmaniasis is defined as a cluster of infectious diseases caused by protozoan parasites of the genus Leishmania. It is recognized worldwide as a major health problem, showing high endemicity in developing countries. The present review details this complex group of neglected diseases, with important clinical spectrum and large epidemiological diversity, and discusses the evolution of leishmaniasis treatment and the urgent need for less toxic, more specific and effective drugs against these parasites. Finally, the value of natural products and synthetic derivatives as rich sources of antileishmanial drug candidates is demonstrated, indicating a promising approach for the development of novel therapeutic alternatives.

Femoral osteochondrosis mimicking chronic arthritis

Osteochondrosis or osteochondritis are alterations characterized by failure in sub-chondral ossification and affects the immature skeleton of children and teenagers. It may affects any epiphysis, apophysis or short bone with similar radiological and anatomopathological characteristics. It has no defined etiology, although there are some risk factors as constitutional predisposing, trauma and ischemia. Femoral osteochondrosis is usually unilateral and can be misdiagnosed as juvenile idiopathic arthritis (JIA). The authors report two patients with bilateral femoral condyle osteochondrosis that were treated as JIA.

Preparation and scale up of extended-release tablets of bromopride

Reproducibility of the tablet manufacturing process and control of its pharmaceutics properties depends on the optimization of formulation aspects and process parameters. Computer simulation such as Design of Experiments (DOE) can be used to scale up the production of this formulation, in particular for obtaining sustained-release tablets. Bromopride formulations are marketed in the form of extended-release pellets, which makes the product more expensive and difficult to manufacture. The aim of this study was to formulate new bromopride sustained release formulations as tablets, and to develop mathematical models to standardize the scale up of this formulation, controlling weight and hardness of the tablets during manufacture according to the USP 34th edition. DOE studies were conducted using Minitab(tm) software. Different excipient combinations were evaluated in order to produce bromopride sustained-release matrix tablets. In the scale-up study, data were collected and variations in tableting machine parameters were measured. Data were processed by Minitab(tm) software, generating mathematical equations used for prediction of powder compaction behavior, according to the settings of the tableting machine suitable for scale-up purposes. Bromopride matrix tablets with appropriate characteristics for sustained release were developed. The scale-up of the formulation with the most suitable sustained release profile was established by using mathematical models, indicating that the formulation can be a substitute for the pellets currently marketed.