Selective serotonin reuptake inhibitor antidepressant use in first trimester pregnancy and risk of specific congenital anomalies: a European register-based study

Evidence of an association between early pregnancy exposure to selective serotonin reuptake inhibitors (SSRI) and congenital heart defects (CHD) has contributed to recommendations to weigh benefits and risks carefully. The objective of this study was to determine the specificity of association between first trimester exposure to SSRIs and specific CHD and other congenital anomalies (CA) associated with SSRI exposure in the literature (signals). A population-based case-malformed control study was conducted in 12 EUROCAT CA registries covering 2.1 million births 1995-2009 including livebirths, fetal deaths from 20 weeks gestation and terminations of pregnancy for fetal anomaly. Babies/fetuses with specific CHD (n = 12,876) and non-CHD signal CA (n = 13,024), were compared with malformed controls whose diagnosed CA have not been associated with SSRI in the literature (n = 17,083). SSRI exposure in first trimester pregnancy was associated with CHD overall (OR adjusted for registry 1.41, 95% CI 1.07-1.86, fluoxetine adjOR 1.43 95% CI 0.85-2.40, paroxetine adjOR 1.53, 95% CI 0.91-2.58) and with severe CHD (adjOR 1.56, 95% CI 1.02-2.39), particularly Tetralogy of Fallot (adjOR 3.16, 95% CI 1.52-6.58) and Ebstein's anomaly (adjOR 8.23, 95% CI 2.92-23.16). Significant associations with SSRI exposure were also found for ano-rectal atresia/stenosis (adjOR 2.46, 95% CI 1.06-5.68), gastroschisis (adjOR 2.42, 95% CI 1.10-5.29), renal dysplasia (adjOR 3.01, 95% CI 1.61-5.61), and clubfoot (adjOR 2.41, 95% CI 1.59-3.65). These data support a teratogenic effect of SSRIs specific to certain anomalies, but cannot exclude confounding by indication or associated factors.

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials.
Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules.
Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (>6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma.
Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly.

Study of the effect of novel CDK9 inhibitor on in vitro-induced hypertrophy in human stem-cells-derived cardiomyocytes

This is an abstract of a presented talk at the European Biotechnology Conference held in Latvia during 05–07 May 2016

A decrease in dkk1, a Wnt inhibitor, contributes to placental and fetal lipid accumulation in an obesity-prone rat model

Placenta, as the sole transport mechanism between mother and fetus, links the maternal physical state and the immediate and life-long outcomes of the offspring. The present study examined the mechanisms behind the effect of maternal obesity on placental lipid accumulation and metabolism. Pregnant Obese Prone (OP) and Obese Resistant (OR) rat strains were fed a control diet throughout gestation. Placentas were collected on gestational d21 for analysis and frozen placental sections were analyzed for fat accumulation as well as β-Catenin and Dkk1 localization. Additionally, DKK1 was overexpressed in JEG3 trophoblast cells, followed by treatment with NEFA and Oil Red O stain quantification and mRNA analysis to determine the relationship between placental DKK1 and lipid accumulation. Maternal plasma and placental NEFA and TG were elevated in OP dams, and offspring of OP dams were smaller than OR. Placental Dkk1 mRNA content was 4-fold lower in OP placentas, and there was a significant increase in β-Catenin accumulation as well as mRNA content of fat transport and TG synthesis enzymes, including Ppar-delta, Fatp1, Fat/Cd36, Lipin1, and Lipin3. There was significant lipid accumulation within the decidual zones in OP but not OR placentas, and the thickness of the decidual and junctional zones was significantly smaller in OP than OR placentas. Overexpression of DKK1 in JEG3 cells decreased lipid accumulation and the mRNA content of PPAR-Delta, FATP1, FAT/CD36, LIPIN1, and LIPIN3. Our results indicate that Dkk1 may be regulating placental lipid metabolism through Wnt-mediated mechanisms. Additionally, recent studies have suggested that maternal obesity may also program early development of non-alcoholic fatty liver disease (NAFLD), rates of which have correlated with the increase in the obesity epidemic. In the current study, livers of OP offspring had significantly increased TG content (P<0.05) and lipid accumulation when compared to offspring of OR dams. Additionally, hepatic Dkk1 mRNA content was significantly decreased in OP livers when compared to OR (P<0.05), and treating H4IIECR rat hepatocyte cells with NEFA showed that Dkk1 mRNA was also decreased in NEFA-treated cells (P<0.05) that also had lipid accumulation. Chromatin Immunoprecipitation (ChIP) analysis of the Dkk1 promoter in fetal livers showed a pattern of histone modifications associated with decreased gene transcription in OP offspring, which agrees with our gene expression data. These results demonstrate that the hepatic Dkk1 gene is epigenetically regulated via histone modification in neonatal offspring in the current model of gestational obesity, and future studies will be needed to determine whether these changes contribute to excessive hepatic lipid accumulation in offspring of obese dams.

The effect of the proton pump inhibitor pantoprazole on the biology of Campylobacter jejuni

Campylobacter is a major cause of acute bacterial gastroenteritis worldwide, with the highest number of infections being attributed to Campylobacter jejuni. C. jejuni is a Gram negative, spiral, motile bacterium that belongs to the campylobacterales order and is related to both Helicobacter spp. and Wolinella sp.. It has long been established that proton pump inhibitors (PPIs) and other benzimidazole derivatives display anti-Helicobacter activity in vitro. PPIs have in the past been shown to affect Helicobacter pylori growth, survival, motility, morphology, adhesion/invasion potential and susceptibility to conventional antibiotics. PPIs are highly effective drugs that are well tolerated, safe for prolonged daily use and are therefore in high demand. Both the PPIs omeprazole and lansoprazole featured in the top ten drugs prescribed in England in 2014. In 2014 Campylobacter was also the most commonly diagnosed gastrointestinal infection in Scotland, in England and Wales and also in Europe. It has previously been generally accepted that patients who are being treated with PPIs are more susceptible to enteric infections such as Campylobacter than people not taking PPIs. The effect of PPI exposure on H. pylori has been investigated rigorously in the past. A single previous study has hinted that PPIs may also be capable of affecting the related organism C. jejuni,but investigations have been extremely limited in comparison to those investigating the effect of PPIs on H. pylori. This study has investigated the in vitro effects of direct contact with PPIs on the biology ofC. jejuni. Exposure to the PPI pantoprazole was found to affect C. jejuni growth/survival, motility, morphology, biofilm formation, invasion potential and susceptibility to some conventional antibiotics. Microarray studies showed that the cmeA and Cj0561c genes were significantly up-regulated in response to pantoprazole exposure and a CmeABC deficient mutant was found to be significantly more susceptible to killing by pantoprazole than was the parent strain. Proteomic analysis indicated that the oxidative stress response of C. jejuni was induced following exposure to sub-lethal concentrations of pantoprazole. C. jejuni gene expression was assessed using qRT-PCR and the genes encoding for thiol peroxidase and GroEL co-chaperonin (both involved in the C. jejuni oxidative stress response) were found to be around four times higher in response to exposure to sub-lethal concentrations of pantoprazole. Experiments using the oxidative stress inhibitors thiourea (a hydroxyl radical quencher) and bipyridyl (a ferrous iron chelator) showed that killing by pantoprazole was not mediated by hydroxyl radical production.

The biofilm inhibitor Carolacton inhibits planktonic growth of virulent pneumococci via a conserved target

New antibacterial compounds, preferentially exploiting novel cellular targets, are urgently needed to fight the increasing resistance of pathogens against conventional antibiotics. Here we demonstrate that Carolacton, a myxobacterial secondary metabolite previously shown to damage Streptococcus mutans biofilms, inhibits planktonic growth of Streptococcus pneumoniae TIGR4 and multidrug-resistant clinical isolates of serotype 19A at nanomolar concentrations. A Carolacton diastereomer is inactive in both streptococci, indicating a highly specific interaction with a conserved cellular target. S. mutans requires the eukaryotic-like serine/threonine protein kinase PknB and the cysteine metabolism regulator CysR for susceptibility to Carolacton, whereas their homologues are not needed in S. pneumoniae, suggesting a specific function for S. mutans biofilms only. A bactericidal effect of Carolacton was observed for S. pneumoniae TIGR4, with a reduction of cell numbers by 3 log units. The clinical pneumonia isolate Sp49 showed immediate growth arrest and cell lysis, suggesting a bacteriolytic effect of Carolacton. Carolacton treatment caused a reduction in membrane potential, but not membrane integrity, and transcriptome analysis revealed compensatory reactions of the cell. Our data show that Carolacton might have potential for treating pneumococcal infections.

Resistance of an epoxy coating with an organic inhibitor to cathodic disbondment in sea water

In this study, the effect of anti-corrosion inhibitor addition to epoxy coating, on the disbanding rate was evaluated. First to determination of mechanism, the bare steel substrates were immersed in the 3.5% NaCl solution and the solution containing 1 mM anti corrosion. The Electrochemical Impedance Spectroscopy was performed after 5 and 24 hour. The results indicated a lower corrosion rate in the presence of inhibitor. During the time, charge transfer resistance, was decreased for the substrates immersed in NaCl solution, and increased for the substrates immersed in NaCl solution containing 1 mM anti corrosion. This result can be related to more stability of corrosion products in presence of anti-corrosion and film formation. The coated substrates, with four different concentration of anticorrosion in coating, were protected under -1.2 voltage in the 3.5% NaCl solution. After 12 and 24 hour, the EIS test and disbanding area measurement, were evaluate. The lower disbanding rate, more charge transfer resistance and less double layer capacitance for the coating containing 0.75w% inhibitor, were observed. The result of Pull-off test after 1 day immersion in 3.5% NaCl solution, showed more wet adhesion for the coating containing 0.75w% inhibitor. The images of FE-SEM electron microscope and surface analyses EDX on the coated substrate after disbanding and the bare substrate immersed in 3.5w% NaCl containing 1 mM inhibitor, were proved the formation of stabilized film.

Associação entre o proteassoma e o inibidor de protease BTCI : caracterização fisico-química e efeitos moleculares em células de câncer de mama (MCF-7)

Dissertação (mestrado)—Universidade de Brasília, Instituto de Ciências Biológicas, Departamento de Biologia Celular, Pós-Graduação em Biologia Molecular, 2010.

Quercetin as an inhibitor of snake venom secretory phospholipase A2

As polyphenolic compounds isolated from plants extracts, flavonoids have been applied to various pharmaceutical uses in recent decades due to their anti-inflammatory, cancer preventive, and cardiovascular protective activities. In this study, we evaluated the effects of the flavonoid quercetin on Crotalus durissus terrificus secretory phospholipase A2 (sPLA2), an important protein involved in the release of arachidonic acid from phospholipid membranes. The protein was chemically modified by treatment with quercetin, which resulted in modifications in the secondary structure as evidenced through circular dichroism. In addition, quercetin was able to inhibit the enzymatic activity and some pharmacological activities of sPLA2, including its antibacterial activity, its ability to induce platelet aggregation, and its myotoxicity by approximately 40%, but was not able to reduce the inflammatory and neurotoxic activities of sPLA2. These results suggest the existence of two pharmacological sites in the protein, one that is correlated with the enzymatic site and another that is distinct from it. We also performed molecular docking to better understand the possible interactions between quercetin and sPLA2. Our docking data showed the existence of hydrogen-bonded, polar interactions and hydrophobic interactions, suggesting that other flavonoids with similar structures could bind to sPLA2. Further research is warranted to investigate the potential use of flavonoids as sPLA2 inhibitors. (C) 2010 Elsevier B.V. All rights reserved.

A novel method to determine new potent angiotensin inhibitor, azilsartan, in human plasma via micelle-enhanced spectrofluorimetry using cremophor RH 40

Purpose: To develop a micelle-enhanced spectrofluorimetric method for the assay of azilsartan (AZL) in bulk form and spiked human plasma without the need for derivatization procedure. Method: The proposed method was based on studying the fluorescence behavior of AZL in Cremophor RH 40 (Cr RH 40) micellar system. The fluorescence intensity was measured at 371 nm after excitation at 264 nm. The proposed procedure was validated according to International Council on Harmonization (ICH) guidelines. Results: In aqueous solution, the fluorescence intensity of AZL was greatly enhanced by more than 3- fold in the presence of Cr RH 40. The fluorescence –concentration plot was linear over the range of 10 – 500 ng.mL-1, with a limit of detection of 3.287 ngmL-1. The proposed method was successfully applied to the determination of AZL in pure powder form and spiked human plasma. The mean recovery of AZL in spiked human plasma using the proposed method was 90.54 ± 1.17 %. Conclusion: The suggested method is highly sensitive and simple, and can easily be applied for the quantification of AZL in pure powder form as well as in biological fluids such as plasma.

Clinical Studies on conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor in second-line treatment of non-small cell lung cancer

Purpose: To study the effect of conformal radiotherapy combined with epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) in the second-line treatment of non-small cell lung cancer (NSCLC). Methods: A total of 316 patients attending Shanghai Pulmonary Hospital affiliated to Tongji University, were divided into two groups: 106 patients were treated with conformal radiotherapy combined with EGFR-TKI (gefitinib, 250 mg/day; or erlotinib, 150 mg/day), while 210 patients were treated with EGFRTKI alone. Some factors, including adverse reactions (AR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), and one-year and two-year survival rate, were evaluated. Results: No obvious difference was observed in AR between the two groups (p > 0.05). In the combination therapy group, complete response (CR) was 5 cases, partial response (PR) 43 cases, and stable disease (SD) 47 cases, progressive disease (PD) was 11 cases, response rate (RR) was 45.3 %, and DCR 89.6 %. Median PFS in the combination therapy group and targeted therapy group was 6.5 and 5.0 months, respectively. On the other hand, median OS in the combination therapy group and targeted group was 14.1 and 12.6 months, respectively. One-year survival rate of the combination therapy group and EGFR-TKI group was 60.3 and 50.0 %, respectively, while the two-year survival rate was 26.3 and 19.0 %, respectively. Conclusion: Conformal radiotherapy combined with EGFR-TKI can be used as an effective second-line treatment for NSCLC.