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Background and Objective The identification and quantification of potential drug–drug interactions is important for avoiding or minimizing the interaction-induced adverse events associated with specific drug combinations. Clinical studies in healthy subjects were performed to evaluate potential pharmacokinetic interactions between vortioxetine (Lu AA21004) and co-administered agents, including fluconazole (cytochrome P450 [CYP] 2C9, CYP2C19 and CYP3A inhibitor), ketoconazole (CYP3A and P-glycoprotein inhibitor), rifampicin (CYP inducer), bupropion (CYP2D6 inhibitor and CYP2B6 substrate), ethinyl estradiol/levonorgestrel (CYP3A substrates) and omeprazole (CYP2C19 substrate and inhibitor). Methods The ratio of central values of the test treatment to the reference treatment for relevant parameters (e.g., area under the plasma concentration–time curve [AUC] and maximum plasma concentration [ C max ]) was used to assess pharmacokinetic interactions. Results Co-administration of vortioxetine had no effect on the AUC or C max of ethinyl estradiol/levonorgestrel or 5′-hydroxyomeprazole, or the AUC of bupropion; the 90 % confidence intervals for these ratios of central values were within 80–125 %. Steady-state AUC and C max of vortioxetine increased when co-administered with bupropion (128 and 114 %, respectively), fluconazole (46 and 15 %, respectively) and ketoconazole (30 and 26 %, respectively), and decreased by 72 and 51 %, respectively, when vortioxetine was co-administered with rifampicin. Concomitant therapy was generally well tolerated; most adverse events were mild or moderate in intensity. Conclusion Dosage adjustment may be required when vortioxetine is co-administered with bupropion or rifampicin.

Purpose We assessed the human in vivo metabolic drug interaction profile of Ginkgo biloba extract EGb 761® with respect to the activities of major cytochrome P450 (CYP) enzymes. Methods A single-center, open-label, randomized, three-fold crossover, cocktail phenotyping design was applied. In random order, the following treatments were administered to 18 healthy men and women for 8 days each: placebo twice daily, EGb 761® 120 mg twice daily, and EGb 761® 240 mg in the morning and placebo in the evening. In the morning of day 8, administration was performed together with the orally administered phenotyping cocktail (enzyme, metric): 150 mg caffeine (CYP1A2, paraxanthine/caffeine plasma ratio 6-h postdose), 125 mg tolbutamide (CYP2C9, plasma concentration 24-h postdose), 20 mg omeprazole (CYP2C19, omeprazole/5-hydroxy omeprazole plasma ratio 3-h postdose), 30 mg dextromethorphan (CYP2D6, dextromethorphan/dextrorphan plasma ratio 3-h postdose), and 2 mg of midazolam (CYP3A, plasma concentration 6-h postdose). Formally, absence of a relevant interaction was assumed if the 90% confidence intervals (CIs) for EGb 761®/placebo ratios of the metrics were within the 0.70–1.43 range. Results EGb 761®/placebo ratios for phenotyping metrics were close to unity for all CYPs. Furthermore, respective CIs were within the specified margins for all ratios except CYP2C19 for EGb 761® 120 mg twice daily (90% CI 0.681–1.122) and for CYP2D6 for EGb 761® 240 mg once daily (90% CI 0.667–1.281). These findings were attributed to the intraindividual variability of the metrics used. All treatments were well tolerated. Conclusion EGb 761® has no relevant effect on the in vivo activity of the major CYP enzymes in humans and therefore has no relevant potential to cause respective metabolic drug–drug interactions.

Mitogen-activated protein kinases (MAPKs) are implicated in regulating plant growth, development, and response to the environment. However, the underlying mechanisms are unknown because of the lack of information about their substrates. Using a conditional gain-of-function transgenic system, we demonstrated that the activation of SIPK, a tobacco (Nicotiana tabacum) stress-responsive MAPK, induces the biosynthesis of ethylene. Here, we report that MPK6, the Arabidopsis thaliana ortholog of tobacco SIPK, is required for ethylene induction in this transgenic system. Furthermore, we found that selected isoforms of 1-aminocyclopropane-1-carboxylic acid synthase (ACS), the rate-limiting enzyme of ethylene biosynthesis, are substrates of MPK6. Phosphorylation of ACS2 and ACS6 by MPK6 leads to the accumulation of ACS protein and, thus, elevated levels of cellular ACS activity and ethylene production. Expression of ACS6DDD, a gain-of-function ACS6 mutant that mimics the phosphorylated form of ACS6, confers constitutive ethylene production and ethylene-induced phenotypes. Increasing numbers of stress stimuli have been shown to activate Arabidopsis MPK6 or its orthologs in other plant species. The identification of the first plant MAPK substrate in this report reveals one mechanism by which MPK6/SIPK regulates plant stress responses. Equally important, this study uncovers a signaling pathway that modulates the biosynthesis of ethylene, an important plant hormone, in plants under stress.

Purpose Midostaurin (PKC412), a multitargeted tyrosine kinase inhibitor that targets FMS-related tyrosine kinase 3 and KIT, is in clinical trials for the treatment for acute myeloid leukemia and advanced systemic mastocytosis. In vitro studies showed that midostaurin is predominantly metabolized by cytochrome P450 3A4 (CYP3A4) and that midostaurin inhibits and/or induces the same enzyme. Here, we address the clinical relevance of CYP3A4-related drug–drug interactions with midostaurin as either a “victim” or “perpetrator.” Methods Three phase I studies in healthy volunteers evaluated the effects of a CYP3A4 inhibitor (ketoconazole 400 mg daily for 10 days) or CYP3A4 inducer (rifampicin 600 mg daily for 14 days) on concentrations of midostaurin and its metabolites following a single 50-mg dose of midostaurin and the effects of midostaurin as a single dose (100 mg) and multiple doses (50 mg twice daily) on midazolam (a sensitive CYP3A4 probe) concentration. The plasma concentrations of midostaurin and its 2 active metabolites, CGP62221 and CGP52421, were determined using a sensitive liquid chromatography/tandem mass spectrometry method. Results Inhibition of CYP3A4 by ketoconazole increased midostaurin exposure more than tenfold, and induction of CYP3A4 by rifampicin decreased midostaurin exposure by more than tenfold. Midostaurin did not appreciably affect the concentrations of midazolam or its metabolite, 1′-hydroxymidazolam, at single or multiple doses. Conclusion The pharmacokinetics of midostaurin and its metabolites was affected substantially by ketoconazole and rifampicin, suggesting that midostaurin is a sensitive CYP3A4 substrate. Midostaurin did not appear to inhibit or induce CYP3A4 in vivo.

Global cerebral ischemia arises in patients who have a variety of clinical conditions including cardiac arrest, shock and asphyxia. In spite of advances in understanding of the brain ischemia and stroke etiology, therapeutic approaches to improve ischemic injury still remain limited. It has been established that metformin can attenuate cell death in cerebral ischemia. One of the main functions of metformin is proposed to be conducted via AMP-activated protein kinase (AMPK)-dependent pathway in the experimental cerebral ischemia model. It is also established that metformin can suppress inflammation and activate Nuclear factor erythroid 2-related factor (Nrf2) pathways in neurons. In the current study, the role of metformin in regulating inflammatory and antioxidant pathways in the global cerebral ischemia was investigated. Our results indicated that pretreatment of rats by metformin attenuated cellular levels of nuclear factor-κB, Tumor Necrosis Factor alpha and Cyclooxygenase-2 which are considered as three important proteins involved in the inflammation pathway. Pretreatment by metformin increased the level of Nrf2 and heme oxygenase-1 in the hippocampus of ischemic rats compared with untreated ischemic group. Moreover, pretreatment by metformin enhanced the level of glutathione and catalase activities compared with them in ischemic group. Such protective changes detected by metformin pretreatment were reversed by injecting compound c, an AMPK inhibitor. These findings suggested that metformin might protect cells through modulating inflammatory and antioxidant pathways via induction of AMPK. However, more experimental and clinical trial studies regarding neuroprotective potential of metformin and the involved mechanisms, especially in the context of cerebral ischemic injuries, are necessary.

At the cellular level, cadmium (Cd) induces both damaging and repair processes in which the cellular redox status plays a crucial role. Being not redox-active, Cd is unable to generate reactive oxygen species (ROS) directly, but Cd-induced oxidative stress is a common phenomenon observed in multiple studies. The current review gives an overview on Cd-induced ROS production and anti-oxidative defense in organisms under different Cd regimes. Moreover, the Cd-induced oxidative challenge is discussed with a focus on damage and signaling as downstream responses. Gathering these data, it was clear that oxidative stress related responses are affected during Cd stress, but the apparent discrepancies observed in between the different studies points towards the necessity to increase our knowledge on the spatial and temporal ROS signature under Cd stress. This information is essential in order to reveal the exact role of Cd-induced oxidative stress in the modulation of downstream responses under a diverse array of conditions.

The abnormal accumulation of methylglyoxal (MG) leading to increased glycation of protein and DNA has emerged as an important metabolic stress, dicarbonyl stress, linked to aging, and disease. Increased MG glycation produces inactivation and misfolding of proteins, cell dysfunction, activation of the unfolded protein response, and related low-grade inflammation. Glycation of DNA and the spliceosome contribute to an antiproliferative and apoptotic response of high, cytotoxic levels of MG. Glyoxalase 1 (Glo1) of the glyoxalase system has a major role in the metabolism of MG. Small molecule inducers of Glo1, Glo1 inducers, have been developed to alleviate dicarbonyl stress as a prospective treatment for the prevention and early-stage reversal of type 2 diabetes and prevention of vascular complications of diabetes. The first clinical trial with the Glo1 inducer, trans-resveratrol and hesperetin combination (tRES-HESP)—a randomized, double-blind, placebo-controlled crossover phase 2A study for correction of insulin resistance in overweight and obese subjects, was completed successfully. tRES-HESP corrected insulin resistance, improved dysglycemia, and low-grade inflammation. Cell permeable Glo1 inhibitor prodrugs have been developed to induce severe dicarbonyl stress as a prospective treatment for cancer—particularly for high Glo1 expressing-related multidrug-resistant tumors. The prototype Glo1 inhibitor is prodrug S-p-bromobenzylglutathione cyclopentyl diester (BBGD). It has antitumor activity in vitro and in tumor-bearing mice in vivo. In the National Cancer Institute human tumor cell line screen, BBGD was most active against the glioblastoma SNB-19 cell line. Recently, potent antitumor activity was found in glioblastoma multiforme tumor-bearing mice. High Glo1 expression is a negative survival factor in chemotherapy of breast cancer where adjunct therapy with a Glo1 inhibitor may improve treatment outcomes. BBGD has not yet been evaluated clinically. Glycation by MG now appears to be a pathogenic process that may be pharmacologically manipulated for therapeutic outcomes of potentially important clinical impact.

Levels of endogenous abscisic acid (ABA) are changed dynamically in response to environmental conditions. The ABA 8'-hydroxylase is a key enzyme in ABA catabolism and is encoded by CYP707A genes. In this study, we examined physiological roles of Arabidopsis (Arabidopsis thaliana) CYP707As in the plant's response to changes in humidity. The cyp707a1 and cyp707a3 mutants displayed lower stomatal conductance under turgid conditions (relative humidity 60%) than the wild type. When wild-type plants were transferred to high-humidity conditions (relative humidity 90%), CYP707A1 and CYP707A3 transcript levels increased, followed by the reduction of ABA levels. The cyp707a3 mutant exhibited high ABA levels even after transferring to high-humidity conditions, whereas, under similar conditions, the cyp707a1 mutant exhibited low ABA levels comparable to the wild type. Analysis of spatial expression patterns by using transgenic plants harboring a promoter::β-glucuronidase gene indicated that high-humidity-induced expression of CYP707A1 and CYP707A3 occurred primarily in guard cells and vascular tissues, respectively. Furthermore, stomatal closure of the cyp707a1 mutant, but not cyp707a3 mutant, was ABA hypersensitive when epidermal peel was treated with exogenous ABA, suggesting that CYP707A1 is essential for ABA catabolism inside the guard cells. These results implicate that CYP707A3 reduces the amount of mobile ABA in vascular tissues in response to high humidity, whereas CYP707A1 inactivates local ABA pools inside the guard cells. Taken together, ABA catabolism in both vascular tissues and guard cells participates in the systemic ABA action that controls stomatal movement in response to high humidity.

Background d-chiroinositol (DCI) is a inositolphosphoglycan (IPG) involved in several cellular functions that control the glucose metabolism. DCI functions as second messenger in the insulin signaling pathway and it is considered an insulin sensitizer since deficiency in tissue availability of DCI were shown to cause insulin resistance (IR). Polycystic ovary syndrome (PCOS) is a pathological condition that is often accompanied with insulin resistance. DCI can positively affects several aspect of PCOS etiology decreasing the total and free testosterone, lowering blood pressure, improving the glucose metabolism and increasing the ovulation frequency. The purpose of this study was to evaluate the effects of DCI and insulin combined with gonadotrophins namely follicle-stimulating hormone (FSH) and luteinizing hormone (LH) on key steroidogenic enzymes genes regulation, cytochrome P450 family 19 subfamily A member 1 ( CYP19A1 ) and cytochrome P450 side-chain cleavage ( P450scc ) in primary cultures of human granulosa cells (hGCs). We also investigated whether DCI, being an insulin-sensitizer would be able to counteract the expected stimulator activity of insulin on human granulosa cells (hGCs). Methods The study was conducted on primary cultures of hGCs. Gene expression was evaluated by RT-qPCR method. Statistical analysis was performed applying student t -test, as appropriate ( P  < 0.05) set for statistical significance. Results DCI is able to reduce the gene expression of CYP19A1 , P450scc and insulin-like growth factor 1 receptor ( IGF-1R ) in dose–response manner. The presence of DCI impaired the increased expression of steroidogenic enzyme genes generated by the insulin treatment in gonadotrophin-stimulated hGCs. Conclusions Insulin acts as co-gonadotrophin increasing the expression of steroidogenic enzymes genes in gonadotrophin-stimulated granulosa cells. DCI is an insulin-sensitizer that counteracts this action by reducing the expression of the genes CYP19A1 , P450scc and IGF-1R. The ability of DCI to modulate in vitro ovarian activity of insulin could in part explain its beneficial effect when used as treatment for conditions associated to insulin resistance.

Motor neuron disease (MND) is a progressive neurodegenerative disease with no effective treatment. One of the principal pathological hallmarks is the deposition of TAR DNA binding protein 43 (TDP-43) in cytoplasmic inclusions. TDP-43 aggregation occurs in both familial and sporadic MND; however, the mechanism of endogenous TDP-43 aggregation in disease is incompletely understood. This study focused on the induction of cytoplasmic accumulation of endogenous TDP-43 in the motor neuronal cell line NSC-34. The endoplasmic reticulum (ER) stressor tunicamycin induced casein kinase 1 (CK1)-dependent cytoplasmic accumulation of endogenous TDP-43 in differentiated NSC-34 cells, as seen by immunocytochemistry. Immunoblotting showed that induction of ER stress had no effect on abundance of TDP-43 or phosphorylated TDP-43 in the NP-40/RIPA soluble fraction. However, there were significant increases in abundance of TDP-43 and phosphorylated TDP-43 in the NP-40/RIPA-insoluble, urea-soluble fraction, including high molecular weight species. In all cases, these increases were lowered by CK1 inhibition. Thus ER stress signalling, as induced by tunicamycin, causes CK1-dependent phosphorylation of TDP-43 and its consequent cytosolic accumulation.