Treatment of Selective Serotonin Reuptake Inhibitor-Resistant Depression in Adolescents: Predictors and Moderators of Treatment Response

ERIC Educational Resources Information Center

Asarnow, Joan Rosenbaum; Emslie, Graham; Clarke, Greg; Wagner, Karen Dineen; Spirito, Anthony; Vitiello, Benedetto; Iyengar, Satish; Shamseddeen, Wael; Ritz, Louise; Birmaher, Boris; Ryan, Neal; Kennard, Betsy; Mayes, Taryn; DeBar, Lynn; McCracken, James; Strober, Michael; Suddath, Robert; Leonard, Henrietta; Porta, Giovanna; Keller, Martin; Brent, David

2009-01-01

Adolescents who did not improve with Selective Serotonin Reuptake Inhibitor (SSRI) were provided an alternative SSRI plus cognitive-behavioral therapy (CBT). The superiority of the CBT/combined treatment as compared to medication alone is more evident in youths who had more comorbid disorders, no abuse history, and lower hopelessness.

Norepinephrine-deficient mice lack responses to antidepressant drugs, including selective serotonin reuptake inhibitors

PubMed Central

Cryan, John F.; O'Leary, Olivia F.; Jin, Sung-Ha; Friedland, Julie C.; Ouyang, Ming; Hirsch, Bradford R.; Page, Michelle E.; Dalvi, Ashutosh; Thomas, Steven A.; Lucki, Irwin

2004-01-01

Mice unable to synthesize norepinephrine (NE) and epinephrine due to targeted disruption of the dopamine β-hydroxylase gene, Dbh, were used to critically test roles for NE in mediating acute behavioral changes elicited by different classes of antidepressants. To this end, we used the tail suspension test, one of the most widely used paradigms for assessing antidepressant activity and depression-related behaviors in normal and genetically modified mice. Dbh–/– mice failed to respond to the behavioral effects of various antidepressants, including the NE reuptake inhibitors desipramine and reboxetine, the monoamine oxidase inhibitor pargyline, and the atypical antidepressant bupropion, even though they did not differ in baseline immobility from Dbh+/– mice, which have normal levels of NE. Surprisingly, the effects of the selective serotonin reuptake inhibitors (SSRIs) fluoxetine, sertraline, and paroxetine were also absent or severely attenuated in the Dbh–/– mice. In contrast, citalopram (the most selective SSRI) was equally effective at reducing immobility in mice with and without NE. Restoration of NE by using l-threo-3,4-dihydroxyphenylserine reinstated the behavioral effects of both desipramine and paroxetine in Dbh–/– mice, thus demonstrating that the reduced sensitivity to antidepressants is related to NE function, as opposed to developmental abnormalities resulting from chronic NE deficiency. Microdialysis studies demonstrated that the ability of fluoxetine to increase hippocampal serotonin was blocked in Dbh–/– mice, whereas citalopram's effect was only partially attenuated. These data show that NE plays an important role in mediating acute behavioral and neurochemical actions of many antidepressants, including most SSRIs. PMID:15148402

Lamotrigine Augmentation Versus Placebo in Serotonin Reuptake Inhibitors-Resistant Obsessive-Compulsive Disorder: A Randomized Controlled Trial

PubMed Central

Khalkhali, Mohammadrasoul; Zarrabi, Homa; Kafie, Moosa; Heidarzadeh, Abtin

2016-01-01

Objective: Serotonin reuptake inhibitors are frequently used in first-line treatments for patients with obsessive-compulsive disorder. Nevertheless, many of these patients do not respond well to initial therapy. The hypothesis of glutamatergic dysfunction in specific brain regions has been proposed in the pathophysiology of obsessive-compulsive disorder. This study was designed to evaluate the possible efficacy of lamotrigine, a glutamatergic agent in Serotonin reuptake inhibitors-resistant patients with obsessive-compulsive disorder. Method: This study was a 12-week, double blind, randomized, placebo-controlled trial of adjunctive fixed-doses of lamotrigine (100 mg) to Serotonin reuptake inhibitors therapy in obsessive-compulsive disorder. Eligible subjects who had a total Y-BOCS of 21 or above were randomly assigned to receive adjunctive treatment with either lamotrigine (n = 26), or placebo (n = 27). Response to lamotrigine was defined as clinical improvement (>25% decrease in the total Y-BOCS score), which was administered at weeks 0, 8 and 12. Results: At the endpoint (week 12), significant differences were observed in obsession, compulsion, and total Y-BOCS scores comparing lamotrigine to placebo (P = 0.01, 0.005 and 0.007 respectively). The mean reduction in obsession, compulsion and total scores in lamotrigine group was about 4.15, 4.50 and 8.73, respectively. Similarly, the mean reductions in the placebo group were 2.52, 2.56 and 5.07. Effect sizes for efficacy measureswerecalculatedbyCohen’sd, and it was calculated as 0.54 for the total YBOCS. Conclusion: Our findings provide evidence that this augmentation is well tolerated and may be an effective strategy for patients with refractory obsessive-compulsive disorder. PMID:27437007

Design and Synthesis of 4-Heteroaryl 1,2,3,4-Tetrahydroisoquinolines as Triple Reuptake Inhibitors

PubMed Central

2014-01-01

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure–activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13. PMID:25050161

Design and synthesis of 4-heteroaryl 1,2,3,4-tetrahydroisoquinolines as triple reuptake inhibitors.

PubMed

Liu, Shuang; Zha, Congxiang; Nacro, Kassoum; Hu, Min; Cui, Wenge; Yang, Yuh-Lin; Bhatt, Ulhas; Sambandam, Aruna; Isherwood, Matthew; Yet, Larry; Herr, Michael T; Ebeltoft, Sarah; Hassler, Carla; Fleming, Linda; Pechulis, Anthony D; Payen-Fornicola, Anne; Holman, Nicholas; Milanowski, Dennis; Cotterill, Ian; Mozhaev, Vadim; Khmelnitsky, Yuri; Guzzo, Peter R; Sargent, Bruce J; Molino, Bruce F; Olson, Richard; King, Dalton; Lelas, Snjezana; Li, Yu-Wen; Johnson, Kim; Molski, Thaddeus; Orie, Anitra; Ng, Alicia; Haskell, Roy; Clarke, Wendy; Bertekap, Robert; O'Connell, Jonathan; Lodge, Nicholas; Sinz, Michael; Adams, Stephen; Zaczek, Robert; Macor, John E

2014-07-10

A series of 4-bicyclic heteroaryl 1,2,3,4-tetrahydroisoquinoline inhibitors of the serotonin transporter (SERT), norepinephrine transporter (NET), and dopamine transporter (DAT) was discovered. The synthesis and structure-activity relationship (SAR) of these triple reuptake inhibitors (TRIs) will be discussed. Compound 10i (AMR-2), a very potent inhibitor of SERT, NET, and DAT, showed efficacy in the rat forced-swim and mouse tail suspension models with minimum effective doses of 0.3 and 1 mg/kg (po), respectively. At efficacious doses in these assays, 10i exhibited substantial occupancy levels at the three transporters in both rat and mouse brain. The study of the metabolism of 10i revealed the formation of a significant active metabolite, compound 13.

Combinatorial support vector machines approach for virtual screening of selective multi-target serotonin reuptake inhibitors from large compound libraries.

PubMed

Shi, Z; Ma, X H; Qin, C; Jia, J; Jiang, Y Y; Tan, C Y; Chen, Y Z

2012-02-01

Selective multi-target serotonin reuptake inhibitors enhance antidepressant efficacy. Their discovery can be facilitated by multiple methods, including in silico ones. In this study, we developed and tested an in silico method, combinatorial support vector machines (COMBI-SVMs), for virtual screening (VS) multi-target serotonin reuptake inhibitors of seven target pairs (serotonin transporter paired with noradrenaline transporter, H(3) receptor, 5-HT(1A) receptor, 5-HT(1B) receptor, 5-HT(2C) receptor, melanocortin 4 receptor and neurokinin 1 receptor respectively) from large compound libraries. COMBI-SVMs trained with 917-1951 individual target inhibitors correctly identified 22-83.3% (majority >31.1%) of the 6-216 dual inhibitors collected from literature as independent testing sets. COMBI-SVMs showed moderate to good target selectivity in misclassifying as dual inhibitors 2.2-29.8% (majority <15.4%) of the individual target inhibitors of the same target pair and 0.58-7.1% of the other 6 targets outside the target pair. COMBI-SVMs showed low dual inhibitor false hit rates (0.006-0.056%, 0.042-0.21%, 0.2-4%) in screening 17 million PubChem compounds, 168,000 MDDR compounds, and 7-8181 MDDR compounds similar to the dual inhibitors. Compared with similarity searching, k-NN and PNN methods, COMBI-SVM produced comparable dual inhibitor yields, similar target selectivity, and lower false hit rate in screening 168,000 MDDR compounds. The annotated classes of many COMBI-SVMs identified MDDR virtual hits correlate with the reported effects of their predicted targets. COMBI-SVM is potentially useful for searching selective multi-target agents without explicit knowledge of these agents. Copyright © 2011 Elsevier Inc. All rights reserved.

Selective serotonin reuptake inhibitors for premenstrual syndrome and premenstrual dysphoric disorder: a meta-analysis.

PubMed

Shah, Nirav R; Jones, J B; Aperi, Jaclyn; Shemtov, Rachel; Karne, Anita; Borenstein, Jeff

2008-05-01

To systematically review evidence of the treatment benefits of selective serotonin reuptake inhibitors (SSRIs) for symptoms related to severe premenstrual syndrome (PMS) and premenstrual dysphoric disorder. We conducted electronic database searches of MEDLINE, Web of Science, Cochrane Library, Embase, PsycINFO, and Cinahl through March 2007, and hand-searched reference lists and pertinent journals. Studies included in the review were double-blind, randomized, controlled trials comparing an SSRI with placebo that reported a change in a validated score of premenstrual symptomatology. Studies had to report follow-up for any duration longer than one menstrual cycle among premenopausal women who met clinical diagnostic criteria for PMS or premenstrual dysphoric disorder. From 2,132 citations identified, we pooled results from 29 studies (in 19 citations) using random-effects meta-analyses and present results as odds ratios (ORs). Our meta- analysis, which included 2,964 women, demonstrates that SSRIs are effective for treating PMS and premenstrual dysphoric disorder (OR 0.40, 95% confidence interval [CI] 0.31-0.51). Intermittent dosing regimens were found to be less effective (OR 0.55, 95% CI 0.45-0.68) than continuous dosing regimens (OR 0.28, 95% CI 0.18-0.42). No SSRI was demonstrably better than another. The choice of outcome measurement instrument was associated with effect size estimates. The overall effect size is smaller than reported previously. Selective serotonin reuptake inhibitors were found to be effective in treating premenstrual symptoms, with continuous dosing regimens favored for effectiveness.

Rescue Pharmacotherapy With Duloxetine for Selective Serotonin Reuptake Inhibitor Nonresponders in Late-Life Depression: Outcome and Tolerability

PubMed Central

Karp, Jordan F.; Whyte, Ellen M.; Lenze, Eric J.; Dew, Mary A.; Begley, Amy; Miller, Mark D.; Reynolds, Charles F.

2010-01-01

Background Up to 50% of depressed older adults either do not adequately respond to or are unable to tolerate treatment with a serotonin-specific reuptake inhibitor. On the basis of previous experience with serotonin-norepinephrine reuptake inhibitors, we predicted at least a 50% response rate to open-label treatment with duloxetine in subjects who were resistant to treatment with the selective serotonin reuptake inhibitor (SSRI) escitalopram. Method Community-dwelling subjects aged 65 years or older with current nonpsychotic major depressive disorder as established by the Structured Clinical Interview for DSM-IV received escitalopram under protocolized conditions between April 2004 and September 2006. Subjects who failed to meet response criteria or relapsed after achieving an initial response were subsequently switched to open treatment with duloxetine up to 120 mg/day. Side effects were assessed at every visit. Results Subjects (N = 40) switched to duloxetine had a mean (SD) age of 74.4 (7.0) years and a baseline (before escitalopram) 17-item Hamilton Rating Scale for Depression (HAM-D-17) score of 20.0 (3.5) and were predominantly female (65.0%) and white (82.5%). The mean (SD) maximum dose of duloxetine was 93.0 (27.8) mg/day. Subjects received this maximum dose for a median duration of 6.9 weeks. Fifty percent of subjects (N = 20) met criteria for full response, 17.5% (N = 7) were partial responders, and 32.5% (N = 13) did not respond. The median time to response was 12.0 weeks (95% CI = 8.4 to 14.6). Five of the subjects (12.5%) discontinued duloxetine because of intolerable side effects. Discussion These open-label data suggest that duloxetine at doses up to 120 mg/day is a well-tolerated and potentially effective treatment for older adults who fail to respond to an adequate trial of an SSRI. These results are preliminary, and future controlled studies are required to test the efficacy of rescue pharmacotherapy with duloxetine. Trial Registration

Selective serotonin reuptake inhibitor discontinuation: side effects and other factors that influence medication adherence.

PubMed

Goethe, John W; Woolley, Stephen B; Cardoni, Alex A; Woznicki, Brenda A; Piez, Deborah A

2007-10-01

Patients with major depression discontinue taking their antidepressants for many reasons. Although side effects are often cited as the reason for discontinuation, few prospective studies have addressed this question, and none has specifically examined discontinuation in patients with severe depression. Inpatients and outpatients treated with a selective serotonin reuptake inhibitor for major depressive disorder were identified after admission. Three months later, patients were contacted and interviewed to determine antidepressant usage and the side effects experienced, including when these were experienced and their severity. Between October 2001 and April 2003, 406 English- or Spanish-speaking patients aged 18 to 75 years were followed up. One in 4 patients discontinued the index antidepressant. Among specific side effects noted, only "change in weight" and "anxiety" were significant predictors of discontinuation after controlling for confounders. Experiencing 1 or more "extremely" bothersome side effects was associated with more than a doubling of the risk of discontinuation, but the presence of side effects and side effects less severe than "extremely" bothersome were not significant predictors. There were no differences among selective serotonin reuptake inhibitor antidepressants in either the presence/absence of side effects or in the discontinuation rates. The results suggest that the contribution of side effects to antidepressant discontinuation is more complex than previously suggested. Disparate findings from earlier studies may reflect aspects of study design, such as examining populations whose severity of depression varied widely or not controlling for important confounding factors. Future research should separately examine high-risk groups (or control for severity of depression) and carefully rule out other potential contributors to discontinuation.

The Endocannabinoid Reuptake Inhibitor WOBE437 Is Orally Bioavailable and Exerts Indirect Polypharmacological Effects via Different Endocannabinoid Receptors.

PubMed

Reynoso-Moreno, Inés; Chicca, Andrea; Flores-Soto, Mario E; Viveros-Paredes, Juan M; Gertsch, Jürg

2018-01-01

Different anandamide (AEA) transport inhibitors show antinociceptive and antiinflammatory effects in vivo , but due to their concomitant inhibition of fatty acid amide hydrolase (FAAH) and overall poor bioavailability, they cannot be used unequivocally to study the particular role of endocannabinoid (EC) transport in pathophysiological conditions in vivo . Here, the potent and selective endocannabinoid reuptake inhibitor WOBE437, which inhibits AEA and 2-arachidonoylglycerol (2-AG) transport, was tested for its oral bioavailability to the brain. WOBE437 is assumed to locally increase EC levels in tissues in which facilitated EC reuptake intermediates subsequent hydrolysis. Given the marked polypharmacology of ECs, we hypothesized to see differential effects on distinct EC receptors in animal models of acute and chronic pain/inflammation. In C57BL6/J male mice, WOBE437 was orally bioavailable with an estimated t max value of ≤20 min in plasma (C max ∼ 2000 pmol/mL after 50 mg/kg, p.o.) and brain (C max ∼ 500 pmol/g after 50 mg/kg, p.o.). WOBE437 was cleared from the brain after approximately 180 min. In addition, in BALB/c male mice, acute oral administration of WOBE437 (50 mg/kg) exhibited similar brain concentrations after 60 min and inhibited analgesia in the hot plate test in a cannabinoid CB1 receptor-dependent manner, without inducing catalepsy or affecting locomotion. WOBE437 significantly elevated AEA in the somatosensory cortex, while showing dose-dependent biphasic effects on 2-AG levels in plasma but no significant changes in N -acylethanolamines other than AEA in any of the tissues. In order to explore the presumed polypharmacology mediated via elevated EC levels, we tested this EC reuptake inhibitor in complete Freud's adjuvant induced monoarthritis in BALB/c mice as a model of chronic inflammation. Repetitive doses of WOBE437 (10 mg/kg, i.p.) attenuated allodynia and edema via cannabinoid CB2, CB1, and PPARγ receptors. The allodynia inhibition

Understanding the pharmacogenetics of selective serotonin reuptake inhibitors.

PubMed

Fabbri, Chiara; Minarini, Alessandro; Niitsu, Tomihisa; Serretti, Alessandro

2014-08-01

The genetic background of antidepressant response represents a unique opportunity to identify biological markers of treatment outcome. Encouraging results alternating with inconsistent findings made antidepressant pharmacogenetics a stimulating but often discouraging field that requires careful discussion about cumulative evidence and methodological issues. The present review discusses both known and less replicated genes that have been implicated in selective serotonin reuptake inhibitors (SSRIs) efficacy and side effects. Candidate genes studies and genome-wide association studies (GWAS) were collected through MEDLINE database search (articles published till January 2014). Further, GWAS signals localized in promising genetic regions according to candidate gene studies are reported in order to assess the general comparability of results obtained through these two types of pharmacogenetic studies. Finally, a pathway enrichment approach is applied to the top genes (those harboring SNPs with p < 0.0001) outlined by previous GWAS in order to identify possible molecular mechanisms involved in SSRI effect. In order to improve the understanding of SSRI pharmacogenetics, the present review discusses the proposal of moving from the analysis of individual polymorphisms to genes and molecular pathways, and from the separation across different methodological approaches to their combination. Efforts in this direction are justified by the recent evidence of a favorable cost-utility of gene-guided antidepressant treatment.

NO-SSRIs: Nitric Oxide Chimera Drugs Incorporating a Selective Serotonin Reuptake Inhibitor

PubMed Central

2011-01-01

Hybrid nitrate drugs have been reported to provide NO bioactivity to ameliorate side effects or to provide ancillary therapeutic activity. Hybrid nitrate selective serotonin reuptake inhibitors (NO-SSRIs) were prepared to improve the therapeutic profile of this drug class. A synthetic strategy for use of a thiocarbamate linker was developed, which in the case of NO-fluoxetine facilitated hydrolysis to fluoxetine at pH 7.4 within 7 h. In cell culture, NO-SSRIs were weak inhibitors of the serotonin transporter; however, in the forced swimming task (FST) in rats, NO-fluoxetine demonstrated classical antidepressant activity. Comparison of NO-fluoxetine, with fluoxetine, and an NO-chimera nitrate developed for Alzheimer's disease (GT-1061) were made in the step through passive avoidance (STPA) test of learning and memory in rats treated with scopolamine as an amnesic agent. Fluoxetine was inactive, whereas NO-fluoxetine and GT-1061 both restored long-term memory. GT-1061 also produced antidepressant behavior in FST. These data support the potential for NO-SSRIs to overcome the lag in onset of therapeutic action and provide cotherapy of neuropathologies concomitant with depression. PMID:21927645

Treatment of selective mutism: focus on selective serotonin reuptake inhibitors.

PubMed

Kaakeh, Yaman; Stumpf, Janice L

2008-02-01

Abstract Selective mutism is a pediatric psychiatric disorder that occurs when a child consistently fails to speak in specific situations in which speaking is expected, such as at school and social gatherings, but speaks appropriately in other settings. Selective mutism often is diagnosed when a child starts school and does not talk to teachers or peers, but talks to family members at home; the condition is frequently accompanied by anxiety and shyness. Although the underlying etiology of the condition remains unclear, psychotherapy is the preferred initial treatment, with the support of parents and teachers. If the child does not respond to psychotherapy, addition of pharmacologic treatment should be considered, depending on the severity of symptoms and presence of other illnesses. Although data are limited to case reports and trials with small patient populations and short follow-up periods, some patients with selective mutism respond to therapy with selective serotonin reuptake inhibitors (SSRIs). Fluoxetine is the most studied SSRI as treatment for the condition, although further investigation is required to determine the optimal dosage and duration of therapy.

Prenatal exposure to selective serotonin reuptake inhibitors and autistic symptoms in young children: another red herring?

PubMed

Petersen, Irene; Evans, Stephen; Nazareth, Irwin

2014-08-01

In this issue, El Marroun et al suggest an association between prenatal selective serotonin reuptake inhibitor (SSRI) exposure and autistic traits in children, as well as an association with prenatal depressive symptoms. However, SSRIs may be mere markers of severity of underlying illnesses and it may be premature to reach such conclusions about effects of treatment. Studies like this raise concerns as this may fuel further anxiety and guilt among women who are faced with depression in pregnancy and possibly leave some women without treatment. Royal College of Psychiatrists.

A randomised, double-blind study in adults with major depressive disorder with an inadequate response to a single course of selective serotonin reuptake inhibitor or serotonin-noradrenaline reuptake inhibitor treatment switched to vortioxetine or agomelatine.

PubMed

Montgomery, Stuart A; Nielsen, Rebecca Z; Poulsen, Lis H; Häggström, Lars

2014-09-01

This randomised, double-blind, 12-week study compared efficacy and tolerability of flexible-dose treatment with vortioxetine(10-20 mg/day) versus agomelatine (25-50 mg/day) in major depressive disorder patients with inadequate response to selective serotonin reuptake inhibitor (SSRI)/serotonin-noradrenaline reuptake inhibitor (SNRI) monotherapy. Patients were switched directly from SSRI/SNRI to vortioxetine or agomelatine. Primary endpoint was change from baseline to week 8 in the Montgomery-Åsberg Depression Rating Scale (MADRS) total score analysed by mixed model for repeated measurements, using a noninferiority test followed by a superiority test. Secondary endpoints included response and remission rates, anxiety symptoms(Hamilton Anxiety Rating Scale), Clinical Global Impression, overall functioning (Sheehan Disability Scale), health-related quality of life(EuroQol 5 Dimensions), productivity (work limitation questionnaire) and family functioning (Depression and Family Functioning Scale). Primary endpoint noninferiority was established and vortioxetine (n = 252) was superior to agomelatine (n = 241) by 2.2 MADRS points (p<0.01). Vortioxetine was also significantly superior in response and remission rates at weeks 8 and 12; MADRS, Hamilton Anxiety Rating Scale, Clinical Global Impression, Sheehan Disability Scale and EuroQol 5 Dimensions scores at week 4 onwards; work limitation questionnaire at week 8 and Depression and Family Functioning Scale at weeks 8 and 12. Fewer patients withdrew because of adverse events with vortioxetine (5.9% vs 9.5%). Adverse events (incidence ≥5%) were nausea, headache, dizziness and somnolence. Vortioxetine was noninferior and significantly superior to agomelatine in major depressive disorder patients with previous inadequate response to a single course of SSRI/SNRI monotherapy. Vortioxetine was safe and well tolerated.

Selective serotonin reuptake inhibitors and intraoperative blood pressure.

PubMed

van Haelst, Ingrid M M; van Klei, Wilton A; Doodeman, Hieronymus J; Kalkman, Cor J; Egberts, Toine C G

2012-02-01

The influence of selective serotonin reuptake inhibitors (SSRIs) on blood pressure is poorly understood. We hypothesized that if SSRIs have an influence on blood pressure, this might become manifest in changes in intraoperative blood pressure. We aimed to study the association between perioperative use of SSRIs and changes in intraoperative blood pressure by measuring the occurrence of intraoperative hyper- and hypotension. We conducted a retrospective observational follow-up study among patients who underwent elective primary total hip arthroplasty. The index group included users of SSRIs. The reference group included a random sample (ratio 1:3) of nonusers of an antidepressant agent. The outcome was the occurrence of intraoperative hypo- and hypertensive episodes (number, mean and total duration, and area under the curve (AUC)). The outcome was adjusted for confounding factors using regression techniques. The index group included 20 users of an SSRI. The reference group included 60 nonusers. Users of SSRIs showed fewer intraoperative hypotensive episodes, a shorter mean and total duration, and a smaller AUC when compared to the reference group. After adjustment for confounders, SSRI use was associated with a significantly shorter total duration of hypotension: mean difference of -29.4 min (95% confidence interval (CI) -50.4 to -8.3). Two users of an SSRI and two patients in the reference group had a hypertensive episode. Continuation of treatment with SSRIs before surgery was associated with a briefer duration of intraoperative hypotension.

An AOP analysis of selective serotonin reuptake inhibitors (SSRIs) for fish.

PubMed

McDonald, M Danielle

2017-07-01

Pharmaceuticals and personal care products (PPCPs) are found in measureable quantities within the aquatic environment. Selective serotonin reuptake inhibitor (SSRI) antidepressants are one class of pharmaceutical compound that has received a lot of attention. Consistent with most PPCPs, the pharmacokinetics and physiological impacts of SSRI treatment have been well-studied in small mammals and humans and this, combined with the evolutionary conservation of the serotonergic system across vertebrates, allows for the read-across of known SSRI effects in mammals to potential SSRI impacts on aquatic organisms. Using an Adverse Outcome Pathway (AOP) framework, this review examines the similarities and differences between the mammalian and teleost fish SSRI target, the serotonin transporter (SERT; SLC6A4), and the downstream impacts of elevated extracellular serotonin (5-HT; 5-hydroxytryptamine), the consequence of SERT inhibition, on organ systems and physiological processes within teleost fish. This review also intends to reveal potentially understudied endpoints for SSRI toxicity based on what is known to be controlled by 5-HT in fish. Copyright © 2017 Elsevier Inc. All rights reserved.

Sex Differences in Reported Adverse Drug Reactions of Selective Serotonin Reuptake Inhibitors.

PubMed

Ekhart, Corine; van Hunsel, Florence; Scholl, Joep; de Vries, Sieta; van Puijenbroek, Eugene

2018-02-26

Several studies have investigated sex as a risk factor for the occurrence of adverse drug reactions (ADRs) and found that women are more likely to experience ADRs than men. The aim of this explorative study was to investigate whether differences exist in reported ADRs of selective serotonin reuptake inhibitors (SSRIs) for men and women in the database of the Netherlands Pharmacovigilance Centre Lareb. A ratio of reports concerning women and men, corrected for the number of users, was calculated for all the ADRs reported on SSRIs. We found that 16 ADRs were statistically significantly more reported in women than men, and four ADRS were reported more in men than women. ADRs more reported in women than men when using SSRIs were usually dose-related ADRs or commonly occurring ADRs. Differences in the pharmacokinetics of SSRIs between men and women may explain why these reports of dose-related ADRs when using SSRIs concern women more than men.

Triple Reuptake Inhibitors: A Premise and Promise

PubMed Central

Marks, David M.; Patkar, Ashwin A.

2008-01-01

On the horizon there is a new class of psychoactive medications which work by inhibiting the neuronal reuptake of serotonin, norepinephrine, and dopamine. There are multiple potential indications for these drugs. Research suggests that they may have a role in treating depressive disorders, and it is plausible they may have potential efficacy in obesity, addiction, and pain syndromes. The current review describes some of the molecules in development presently and explores the research relevant to possible clinical uses for this class of medications. PMID:20046357

High-mesembrine Sceletium extract (Trimesemine™) is a monoamine releasing agent, rather than only a selective serotonin reuptake inhibitor.

PubMed

Coetzee, Dirk D; López, Víctor; Smith, Carine

2016-01-11

Extracts from and alkaloids contained in plants in the genus Sceletium have been reported to inhibit ligand binding to serotonin transporter. From this, the conclusion was made that Sceletium products act as selective serotonin-reuptake inhibitors. However, other mechanisms which may similarly result in the anxiolytic or anti-depressant effect ascribed to Sceletium, such as monoamine release, have not been investigated. The current study investigated simultaneously and at two consecutive time points, the effect of high-mesembrine Sceletium extract on both monoamine release and serotonin reuptake into both human astrocytes and mouse hippocampal neurons, as well as potential inhibitory effects on relevant enzyme activities. Human astrocytes and mouse hippocampal cells were treated with citalopram or Sceletium extract for 15 and 30min, after which protein expression levels of serotonin transporter (SERT) and vesicular monoamine transporter-2 (VAMT-2) was assessed using fluorescent immunocytochemistry and digital image analysis. Efficacy of inhibition of acetylcholinesterase (AChE) and monoamine oxidate-A (MAO-A) activity were assessed using the Ellman and Olsen methods (and appropriate controls) respectively. We report the first investigation of mechanism of action of Sceletium extract in the context of serotonin transport, release and reuptake in a cellular model. Cell viability was not affected by Sceletium treatment. High-mesembrine Sceletium extract down-regulated SERT expression similarly to citalopram. In addition, VMAT-2 was upregulated significantly in response to Sceletium treatment. The extract showed only relatively mild inhibition of AChE and MAO-A. We conclude that the serotonin reuptake inhibition activity ascribed to the Sceletium plant, is a secondary function to the monoamine-releasing activity of high-mesembrine Sceletium extract (Trimesemine(TM)). Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

The triple monoamine re-uptake inhibitor DOV 216,303 promotes functional recovery after spinal cord contusion injury in mice.

PubMed

Chu, Tak-Ho; Cummins, Karen; Stys, Peter K

2018-05-14

Serotonin, noradrenaline and dopamine are important neuromodulators for locomotion in the spinal cord. Disruption of descending axons after spinal cord injury resulted in reduction of excitatory and neuromodulatory inputs to spinal neurons for locomotion. Receptor agonists or reuptake inhibitors for these neuromodulators have been shown to be beneficial in incomplete spinal cord injury. In this study, we tested a triple re-uptake inhibitor, DOV 216,303, for its ability to affect motor function recovery after spinal cord injury in mice. We impacted C57 mouse spinal cord at the T11 vertebral level and administered vehicle or DOV 216,303 at 10 mg/kg, b.i.d via intraperitoneal injections for 7 days. We monitored motor function with the Basso Mouse Scale for locomotion for 4 weeks. Spinal cords were harvested and histological examinations were performed to assess tissue sparing and lesion severity. Results showed that DOV 216,303-treated mice recovered significantly better than vehicle treated mice starting at 14 days post injury until the end of the survival period. Lesion size of the DOV 216,303 treated mice was also smaller compared to that of vehicle treated mice. This study suggests DOV 216,303 as a potential therapeutic after spinal cord injury warrants further investigation. Copyright © 2018 Elsevier B.V. All rights reserved.

Risk of preeclampsia after gestational exposure to selective serotonin reuptake inhibitors and other antidepressants: A study from The Norwegian Mother and Child Cohort Study.

PubMed

Lupattelli, Angela; Wood, Mollie; Lapane, Kate; Spigset, Olav; Nordeng, Hedvig

2017-10-01

To describe the risk of early- and late-onset preeclampsia across pregnancies exposed to antidepressants and to evaluate the impact of timing and length of gestational exposure to antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), on preeclampsia. The Norwegian Mother and Child Cohort, a prospective population-based study, and the Medical Birth Registry of Norway provided information on antidepressant exposure, depression, and anxiety symptoms in pregnancy, preeclampsia diagnoses, and important covariates. Within a pregnancy cohort of depressed women, we compared the risk of late-onset preeclampsia between SSRI-exposed and nonmedicated pregnancies using marginal structural models (weighted) and modified Poisson regression models. Of the 5887 pregnancies included, 11.1% were exposed at any time before week 34 to SSRIs, 1.3% to serotonin-norepinephrine reuptake inhibitors, 0.4% to tricyclic antidepressants, and 0.5% to other antidepressants. The risks of early- and late-onset preeclampsia by exposure status in pregnancy were 0.3% and 3.6% (nonmedicated), 0.4% and 3.7% (SSRIs), 1.5% and 4.1% (serotonin-norepinephrine reuptake inhibitors), and 7.1% and 10.0% (tricyclic antidepressants). Compared with nonmedicated pregnancies, SSRI-exposed in mid and late gestation had adjusted relative risks for late-onset mild preeclampsia of 0.76 (95% confidence interval, 0.38-1.53) and 1.56 (0.71-3.44) (weighted models), respectively. There was no association between SSRI exposure in pregnancy and severe late-onset preeclampsia. We have provided evidence that SSRI use in early and midpregnancy does not substantially increase the risk of late-onset preeclampsia. © 2017 The Authors. Pharmacoepidemiology & Drug Safety published by John Wiley & Sons Ltd.

Brain Histamine Is Crucial for Selective Serotonin Reuptake Inhibitors‘ Behavioral and Neurochemical Effects

PubMed Central

Munari, Leonardo; Provensi, Gustavo; Passani, Maria Beatrice; Galeotti, Nicoletta; Cassano, Tommaso; Benetti, Fernando; Corradetti, Renato

2015-01-01

Backgound: The neurobiological changes underlying depression resistant to treatments remain poorly understood, and failure to respond to selective serotonin reuptake inhibitors may result from abnormalities of neurotransmitter systems that excite serotonergic neurons, such as histamine. Methods: Using behavioral (tail suspension test) and neurochemical (in vivo microdialysis, Western-blot analysis) approaches, here we report that antidepressant responses to selective serotonin reuptake inhibitors (citalopram or paroxetine) are abolished in mice unable to synthesize histamine due to either targeted disruption of histidine decarboxylase gene (HDC-/-) or injection of alpha-fluoromethylhistidine, a suicide inhibitor of this enzyme. Results: In the tail suspension test, all classes of antidepressants tested reduced the immobility time of controls. Systemic reboxetine or imipramine reduced the immobility time of histamine-deprived mice as well, whereas selective serotonin reuptake inhibitors did not even though their serotonergic system is functional. In in vivo microdialysis experiments, citalopram significantly increased histamine extraneuronal levels in the cortex of freely moving mice, and methysergide, a serotonin 5-HT1/5-HT2 receptor antagonist, abolished this effect, thus suggesting the involvement of endogenous serotonin. CREB phosphorylation, which is implicated in the molecular mechanisms of antidepressant treatment, was abolished in histamine-deficient mice treated with citalopram. The CREB pathway is not impaired in HDC-/- mice, as administration of 8-bromoadenosine 3’, 5’-cyclic monophosphate increased CREB phosphorylation, and in the tail suspension test it significantly reduced the time spent immobile by mice of both genotypes. Conclusions: Our results demonstrate that selective serotonin reuptake inhibitors selectively require the integrity of the brain histamine system to exert their preclinical responses. PMID:25899065

Effects of acute administration of selective serotonin reuptake inhibitors on sympathetic nerve activity

PubMed Central

Tiradentes, R.V.; Pires, J.G.P.; Silva, N.F.; Ramage, A.G.; Santuzzi, C.H.; Futuro, H.A.

2014-01-01

Serotonergic mechanisms have an important function in the central control of circulation. Here, the acute effects of three selective serotonin (5-HT) reuptake inhibitors (SSRIs) on autonomic and cardiorespiratory variables were measured in rats. Although SSRIs require 2-3 weeks to achieve their full antidepressant effects, it has been shown that they cause an immediate inhibition of 5-HT reuptake. Seventy male Wistar rats were anesthetized with urethane and instrumented to record blood pressure, heart rate, renal sympathetic nerve activity (RSNA), and respiratory frequency. At lower doses, the acute cardiovascular effects of fluoxetine, paroxetine and sertraline administered intravenously were insignificant and variable. At middle and higher doses, a general pattern was observed, with significant reductions in sympathetic nerve activity. At 10 min, fluoxetine (3 and 10 mg/kg) reduced RSNA by -33±4.7 and -31±5.4%, respectively, without changes in blood pressure; 3 and 10 mg/kg paroxetine reduced RSNA by -35±5.4 and -31±5.5%, respectively, with an increase in blood pressure +26.3±2.5; 3 mg/kg sertraline reduced RSNA by -59.4±8.6%, without changes in blood pressure. Sympathoinhibition began 5 min after injection and lasted approximately 30 min. For fluoxetine and sertraline, but not paroxetine, there was a reduction in heart rate that was nearly parallel to the sympathoinhibition. The effect of these drugs on the other variables was insignificant. In conclusion, acute peripheral administration of SSRIs caused early autonomic cardiovascular effects, particularly sympathoinhibition, as measured by RSNA. Although a peripheral action cannot be ruled out, such effects are presumably mostly central. PMID:25003632

Do Selective Serotonin Reuptake Inhibitors (SSRIs) Cause Fractures?

PubMed

Warden, Stuart J; Fuchs, Robyn K

2016-10-01

Recent meta-analyses report a 70 % increase in fracture risk in selective serotonin reuptake inhibitor (SSRI) users compared to non-users; however, included studies were observational and limited in their ability to establish causality. Here, we use the Bradford Hill criteria to explore causality between SSRIs and fractures. We found a strong, consistent, and temporal relationship between SSRIs and fractures, which appears to follow a biological gradient. However, specificity and biological plausibility remain concerns. In terms of specificity, the majority of available data have limitations due to either confounding by indication or channeling bias. Self-controlled case series address some of these limitations and provide relatively strong observational evidence for a causal relationship between SSRIs and fracture. In doing so, they suggest that falls contribute to fractures in SSRI users. Whether there are also underlying changes in skeletal properties remains unresolved. Initial studies provide some evidence for skeletal effects of SSRIs; however, the pathways involved need to be established before biological plausibility can be accepted. As the link between SSRIs and fractures is based on observational data and not evidence from prospective trials, there is insufficient evidence to definitively determine a causal relationship and it appears premature to label SSRIs as a secondary cause of osteoporosis. SSRIs appear to contribute to fracture-inducing falls, and addressing any fall risk associated with SSRIs may be an efficient approach to reducing SSRI-related fractures. As fractures stemming from SSRI-induced falls are more likely in individuals with compromised bone health, it is worth considering bone density testing and intervention for those presenting with risk factors for osteoporosis.

Long-term follow-up of hypochondriasis after selective serotonin reuptake inhibitor treatment.

PubMed

Schweitzer, Pernilla J; Zafar, Uzma; Pavlicova, Martina; Fallon, Brian A

2011-06-01

: There is paucity of knowledge on the long-term outcome of hypochondriasis, with even less knowledge about the effect of treatment with a selective serotonin reuptake inhibitor (SSRI). : This prospective follow-up study included 58 patients with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) hypochondriasis who had participated in a trial of SSRI treatment 4 to 16 years earlier (mean ± SD = 8.6 ± 4.5 years). : Information was obtained on 79.3% (n = 46) of the original group. At follow-up, 40% of the patients continued to meet full DSM-IV criteria for hypochondriasis. Persistence of hypochondriasis was individually predicted by longer duration of prior hypochondriasis (P = 0.003), history of childhood physical punishment (P = 0.01), and less usage of SSRIs during the interval period (P = 0.02). Remission status was not significantly predicted by demographic characteristics, baseline hypochondriasis severity, or psychiatric comorbidity. : A substantial proportion of patients with hypochondriasis who receive treatment with SSRIs achieve remission over the long term. Interim SSRI use may be a factor contributing to better prognosis.

Antidepressant-like Effects of LPM580153, A Novel Potent Triple Reuptake Inhibitor.

PubMed

Zhang, Fangxi; Shao, Jing; Tian, Jingwei; Zhong, Yan; Ye, Liang; Meng, Xiangjing; Liu, Qiaofeng; Wang, Hongbo

2016-04-07

The purpose of this study was to characterize a novel compound, 4-[2-(dimethylamino)-1-(1-hydroxycyclohexyl) ethyl] phenyl 3-nitrophenyl ether, designated LPM580153. We used several well-validated animal models of depression to assess the antidepressant-like activity of LPM580153, followed by a neurotransmitter uptake assay and a corticosterone-induced cell injury model to explore its mechanism of action. In mice, LPM580153 reduced immobility time in the tail suspension test, and in rats subjected to chronic unpredictable mild stress it reversed reductions in body weight gain and ameliorated anhedonia. The neurotransmitter uptake assay results demonstrated that LPM580153 inhibited the uptake of serotonin, norepinephrine and dopamine. Furthermore, LPM580153 protected the SH-SY5Y cells against the cytotoxic activity of corticosterone, an action that might be related to the role of LPM580153 in increasing the protein levels of BDNF, p-ERK1/2, p-AKT, p-CREB and p-mTOR. Together, these findings indicate that LPM580153 is a novel triple reuptake inhibitor with robust antidepressant-like effects.

Pilots using selective serotonin reuptake inhibitors compared to other fatally injured pilots.

PubMed

Rogers, Paul; Hileman, Christy; Salazar, Guillermo; Cliburn, Kacey; Paskoff, Lawrence; Hathaway, William; Gildea, Kevin; Tejera Villalaz, Victor Hugo

2017-10-01

Selective Serotonin Reuptake Inhibitors (SSRI) were a disqualifying medication for U.S. civil pilots before April 5, 2010. After this date, a Federal Aviation Administration policy was created that allowed airmen, on select SSRIs, a pathway to hold a valid medical certificate. The purpose of this study was to provide a detailed look at SSRIs in the U.S. pilot population since the inception of this new policy. We examined the toxicology results from fatally injured airmen in addition to outcomes concerning pilots who are participating in the program. This study examined data from the Civil Aerospace Medical Institute's Bioaeronautical Sciences Research Laboratory in conjunction with the Medical Analysis Tracking Registry and the Document Imaging and Workflow System. A count-based regression model quantified the relationships between positive SSRI findings with additional factors of interest. These factors included pilot rating, ethanol, and first generation antihistamines. There were 1484 fatally injured airmen over the six year study period, of which 44-tested positive for an SSRI. First-generation antihistamines were statistically associated with positive findings of SSRIs. Published by Elsevier Ltd.

Selective serotonin reuptake inhibitors: measurement of effect on platelet function.

PubMed

McCloskey, Donna Jo; Postolache, Teodor T; Vittone, Bernard J; Nghiem, Khanh L; Monsale, Jude L; Wesley, Robert A; Rick, Margaret E

2008-03-01

Selective serotonin reuptake inhibitors (SSRIs) reduce platelet serotonin and are associated with increased gastrointestinal bleeding, an effect that is enhanced when taken with NSAIDs or aspirin. The best method to evaluate hemorrhagic events in patients taking SSRIs has not been determined. Platelet aggregation, which is not widely available, shows SSRI inhibition of platelet function; we tested whether a platelet function analyzer could detect SSRI inhibition of platelet function. Two groups of outpatients with mood disorders were recruited; each patient was taking a stable dose of either an SSRI or bupropion for at least 6 weeks. They were tested using the platelet function analyzer-100 (PFA-100; Dade International Inc, Miami, Fla) concomitantly with platelet aggregation. Fifty-eight patients were analyzed. We detected significant differences between the groups using aggregation methods with arachidonic acid (aggregation, P = 0.00001; release, P = 0.009) and collagen (aggregation, P = 0.016; release, P = 0.006). The PFA-100 did not detect differences between the groups or results outside the reference range. The PFA-100 does not detect the inhibitory effects of SSRIs on platelet function, but it can be used to direct evaluation of bleeding in a patient taking an SSRI. Abnormal PFA-100 results suggest additional evaluation for von Willebrand disease, other platelet inhibitory medications, or underlying intrinsic platelet dysfunction.

Fine Motor Differences and Prenatal Serotonin Reuptake Inhibitors Exposure.

PubMed

Partridge, Marie-Claire A E; Salisbury, Amy L; LaGasse, Linda L

2016-08-01

To examine fine motor differences between preschoolers with prenatal exposure to serotonin reuptake inhibitor (SRI) and children of mothers with major depressive disorder. A subset of children (N = 40) from a larger study on the effects of prenatal SRI and untreated major depressive disorder participated in a kinematic task of visual motor and fine motor functions at ages 4-5 years: exposure to SRI (n = 15), untreated major depressive disorder exposure (n = 10), and the control group (n = 15). The task was to reach and secure a peg, then drop it in a small hole near the start position in the light condition with full visibility or in the glow condition in which a phosphorescent peg glows in the dark. Movement-tracking software measured the positioning of the moving hand and fingers. In the glow condition, the group exposed to SRIs had a greater proportion of maximum aperture than the group with major depressive disorder, and the group exposed to SRIs was slower than the group with major depressive disorder to drop the peg into the hole. In the glow condition, the trajectory of the group exposed to SRI was less straight than the group with major depressive disorder, and the group with major depressive disorder had a straighter trajectory than the control group. This study provides evidence that preschool aged children with prenatal SRI exposure have poorer fine motor and visual-motor control compared with those with prenatal untreated major depressive disorder. Copyright © 2016 Elsevier Inc. All rights reserved.

Serotonin and noradrenaline reuptake inhibitors (Snris) for fibromyalgia

PubMed Central

Welsch, Patrick; Üçeyler, Nurcan; Klose, Petra; Walitt, Brian; Häuser, Winfried

2018-01-01

Background Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review. Objectives To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. Search methods For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017. Selection criteria We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults. Data collection and analysis Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events

Investigation of the mechanisms underlying the hypophagic effects of the 5-HT and noradrenaline reuptake inhibitor, sibutramine, in the rat

PubMed Central

Jackson, Helen C; Bearham, M Clair; Hutchins, Lisa J; Mazurkiewicz, Sarah E; Needham, Andrew M; Heal, David J

1997-01-01

Sibutramine is a novel 5-hydroxytryptamine (5-HT) and noradrenaline reuptake inhibitor (serotonin- noradrenaline reuptake inhibitor, SNRI) which is currently being developed as a treatment for obesity. Sibutramine has been shown to decrease food intake in the rat. In this study we have used a variety of monoamine receptor antagonists to examine the pharmacological mechanisms underlying sibutramine-induced hypophagia. Individually-housed male Sprague-Dawley rats were maintained on reversed phase lighting with free access to food and water. Drugs were administered at 09 h 00 min and food intake was monitored over the following 8 h dark period. Sibutramine (10 mg kg−1, p.o.) produced a significant decrease in food intake during the 8 h following drug administration. This hypophagic response was fully antagonized by the α1-adrenoceptor antagonist, prazosin (0.3 and 1 mg kg−1, i.p.), and partially antagonized by the β1-adrenoceptor antagonist, metoprolol (3 and 10 mg kg−1, i.p.) and the 5-HT receptor antagonists, metergoline (non-selective; 0.3 mg kg−1, i.p.); ritanserin (5-HT2A/2C; 0.1 and 0.5 mg kg−1, i.p.) and SB200646 (5-HT2B/2C; 20 and 40 mg kg−1, p.o.). By contrast, the α2-adrenoceptor antagonist, RX821002 (0.3 and 1 mg kg−1, i.p.) and the β2-adrenoceptor antagonist, ICI 118,551 (3 and 10 mg kg−1, i.p.) did not reduce the decrease in food intake induced by sibutramine. These results demonstrate that β1-adrenoceptors, 5-HT2A/2C-receptors and particularly α1-adrenoceptors, are involved in the effects of sibutramine on food intake and are consistent with the hypothesis that sibutramine-induced hypophagia is related to its ability to inhibit the reuptake of both noradrenaline and 5-HT, with the subsequent activation of a variety of noradrenaline and 5-HT receptor systems. PMID:9283694

Effects of selective serotonin reuptake inhibitors on thought-action fusion, metacognitions, and thought suppression in obsessive-compulsive disorder.

PubMed

Besiroglu, Lutfullah; Çetinkaya, Nuralay; Selvi, Yavuz; Atli, Abdullah

2011-01-01

We aimed to assess whether cognitive processes change over time in patients with obsessive-compulsive disorder (OCD) receiving selective serotonin reuptake inhibitors without cognitive behavioral therapy and to investigate the factors associated with probable cognitive changes. During the 16 weeks of the study, 55 patients who met the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, criteria for OCD received open-label treatment with sertraline (100-200 mg/d) or fluoxetine (40-80 mg/d) and were assessed using the Yale-Brown Obsessive-Compulsive Scale, Beck Depression Inventory (BDI), Thought-Action Fusion Scale (TAFS), Metacognitions Questionnaire (MCQ-30), and White Bear Suppression Inventory (WBSI). The Yale-Brown Obsessive-Compulsive Scale (P < .001), BDI (P < .001), TAFS morality (P < .005), MCQ-30 (P < .01), and WBSI (P < .005) scores at follow-up were significantly lower than baseline scores. When we excluded OCD patients with depressive disorder (n = 12), statistical significance in paired comparisons for MCQ and WBSI disappeared. Similarly, when OCD patients with religious obsessions (n = 16) were excluded, paired comparisons for MCQ and TAF morality were not statistically significant. Changes in BDI, TAFS morality, MCQ-30, and WBSI (P < .005) were significantly correlated with changes in severity of obsessions, but not that of compulsions. After controlling for the change in depression severity, significant correlations between changes in obsessive and cognitive scales did not continue to have statistical significance. The BDI changes (P < .05) significantly explained the changes in symptom severity in a linear regression model. Our findings suggest that selective serotonin reuptake inhibitors can change appraisals of obsessive intrusions via their effects on negative emotions. Copyright © 2011 Elsevier Inc. All rights reserved.

Evaluation of the effect of selective serotonin-reuptake inhibitors on lymphocyte subsets in patients with a major depressive disorder.

PubMed

Hernandez, Maria Eugenia; Martinez-Fong, Daniel; Perez-Tapia, Mayra; Estrada-Garcia, Iris; Estrada-Parra, Sergio; Pavón, Lenin

2010-02-01

To date, only the effect of a short-term antidepressant treatment (<12 weeks) on neuroendocrinoimmune alterations in patients with a major depressive disorder has been evaluated. Our objective was to determine the effect of a 52-week long treatment with selective serotonin-reuptake inhibitors on lymphocyte subsets. The participants were thirty-one patients and twenty-two healthy volunteers. The final number of patients (10) resulted from selection and course, as detailed in the enrollment scheme. Methods used to psychiatrically analyze the participants included the Mini-International Neuropsychiatric Interview, Hamilton Depression Scale and Beck Depression Inventory. The peripheral lymphocyte subsets were measured in peripheral blood using flow cytometry. Before treatment, increased counts of natural killer (NK) cells in patients were statistically significant when compared with those of healthy volunteers (312+/-29 versus 158+/-30; cells/mL), but no differences in the populations of T and B cells were found. The patients showed remission of depressive episodes after 20 weeks of treatment along with an increase in NK cell and B cell populations, which remained increased until the end of the study. At the 52nd week of treatment, patients showed an increase in the counts of NK cells (396+/-101 cells/mL) and B cells (268+/-64 cells/mL) compared to healthy volunteers (NK, 159+/-30 cells/mL; B cells, 179+/-37 cells/mL). We conclude that long-term treatment with selective serotonin-reuptake inhibitors not only causes remission of depressive symptoms, but also affects lymphocyte subset populations. The physiopathological consequence of these changes remains to be determined.

Ascorbic Acid Efflux from Human Brain Microvascular Pericytes: Role of Re-uptake

PubMed Central

May, James M.; Qu, Zhi-chao

2015-01-01

Microvascular pericytes take up ascorbic acid on the ascorbate transporter SVCT2. Intracellular ascorbate then protects the cells against apoptosis induced by culture at diabetic glucose concentrations. To investigate whether pericytes might also provide ascorbate to the underlying endothelial cells, we studied ascorbate efflux from human pericytes. When loaded with ascorbate to intracellular concentrations of 0.8–1.0 mM, almost two-thirds of intracellular ascorbate effluxed from the cells over 2 h. This efflux was opposed by ascorbate re-uptake from the medium, since preventing re-uptake by destroying extracellular ascorbate with ascorbate oxidase increased ascorbate loss even further. Ascorbate re-uptake occurred on the SVCT2, since its blockade by replacing medium sodium with choline, by the SVCT2 inhibitor sulfinpyrazone, or by extracellular ascorbate accelerated ascorbate loss from the cells. This was supported by finding that net efflux of radiolabeled ascorbate was increased by unlabeled extracellular ascorbate with a half-maximal effect in the range of the high affinity Km of the SVCT2. Intracellular ascorbate did not inhibit its efflux. To assess the mechanism of ascorbate efflux, known inhibitors of volume-regulated anion channels (VRACs) were tested. These potently inhibited ascorbate transport into cells on the SVCT2, but not its efflux. An exception was the anion transport inhibitor DIDS, which, despite inhibition of ascorbate uptake, also inhibited net efflux at 25–50 µM. These results suggest that ascorbate efflux from vascular pericytes occurs on a DIDS-inhibitable transporter or channel different from VRACs. Further, ascorbate efflux is opposed by re-uptake of ascorbate on the SVCT2, providing a potential regulatory mechanism. PMID:26340060

Contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients on nonsteroidal anti-inflammatory drugs, antiplatelet agents, anticoagulants, corticosteroids and selective serotonin reuptake inhibitors.

PubMed

Venerito, M; Schneider, C; Costanzo, R; Breja, R; Röhl, F-W; Malfertheiner, P

2018-06-01

Nonsteroidal anti-inflammatory drugs, low-dose aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors and corticosteroids increase the risk of gastroduodenal bleeding. To determine in a retrospective cohort study the contribution of Helicobacter pylori infection to the risk of peptic ulcer bleeding in patients taking these drugs. Among patients with peptic ulcer disease diagnosed by endoscopy from 01/2004 to 12/2014 (N = 1719, 60% males, age 65.8 ± 14.5), 56.9% had peptic ulcer bleeding (cases) and 43.1% uncomplicated peptic ulcer disease (controls). Demographics, intake of nonsteroidal anti-inflammatory drugs, aspirin, non-aspirin antiplatelet agents, anticoagulants, selective serotonin reuptake inhibitors, proton pump inhibitors and corticosteroids were documented. H. pylori status was determined by histology, rapid urease test or serology. Adjusted odds ratios (OR) were estimated by logistic regression analysis. Helicobacter pylori infection increased the risk of peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users (OR = 2.91, 95% CI = 1.71-4.98 and OR = 2.23, 95% CI = 1.52-3.28, respectively), but not in patients on anticoagulants, selective serotonin reuptake inhibitor or corticosteroid therapy. H. pylori-positive status substantially increased the risk of peptic ulcer bleeding in patients on non-aspirin antiplatelet agents (OR = 4.37, 95% CI = 1.28-14.99), concomitant aspirin/nonsteroidal anti-inflammatory drug intake (OR = 5.85, 95% CI = 1.68-20.36) and combined antiplatelet therapy (OR = 8.43, 95% CI = 1.09-65.17). After further adjustment for proton pump inhibitor intake, H. pylori infection was still a risk factor for peptic ulcer bleeding in nonsteroidal anti-inflammatory drug and aspirin users. Helicobacter pylori infection increases the risk of peptic ulcer bleeding in peptic ulcer disease patients on nonsteroidal anti-inflammatory drugs, aspirin and non

Effect of selective serotonin reuptake inhibitors on bone mineral density: a systematic review and meta-analysis.

PubMed

Zhou, C; Fang, L; Chen, Y; Zhong, J; Wang, H; Xie, P

2018-02-12

Our work is the first systematic meta-analysis to investigate the effect of selective serotonin reuptake inhibitor (SSRI) medication on bone mineral density. Through meta-analyzed 11 studies, our findings suggested that compared with nonusers, use of SSRIs was significantly associated with lumbar spine BMD reduction, particularly for old people. The use of selective serotonin reuptake inhibitors (SSRIs) has already been associated with bone mass loss. Their effects on bone mineral density (BMD) for the different bone sections have, however, thus been inconsistent. Here, we aim to assess the effects of SSRIs on BMD using a meta-analysis. We searched PubMed, Scopus, ISI Web of Knowledge, the Cochrane Library, and PsycINFO for all English-written studies investigating the effects of SSRIs on BMD and published before November 2017. BMD was compared between non-SSRI users and SSRI users using a random-effect model with standardized mean differences (SMD) and 95% confidence intervals (CIs). Furthermore, subgroup analyses were performed based on study design, age, and sex in order to find the origins of high heterogeneity. Eleven studies met the inclusion criteria and were used for the meta-analysis. Our study demonstrated that the use of SSRIs was significantly associated with lower BMD values (SMD - 0.40; 95% CI - 0.79 to 0.00; p = 0.05) and BMD Z-scores (SMD - 0.28; 95% CI - 0.50 to - 0.05; p = 0.02) of the lumbar spine, but not of the total hip and femoral neck. In addition, SSRI use was associated with a greater bone loss in older people. SSRI use is a risk factor of lower BMD of the lumbar spine, especially for older people. Future studies into the relationship between SSRI use and bone metabolism and bone mass need to be conducted with larger sample sizes for both men and women at different bone sites.

Selective Serotonin Reuptake Inhibitors in Human Pregnancy: To Treat or Not to Treat?

PubMed Central

Diav-Citrin, Orna; Ornoy, Asher

2012-01-01

Selective serotonin reuptake inhibitors (SSRIs) are increasingly prescribed during pregnancy. The purpose of the present paper is to summarize and evaluate the current evidence for the risk/benefit analysis of SSRI use in human pregnancy. The literature has been inconsistent. Although most studies have not shown an increase in the overall risk of major malformations, several studies have suggested that SSRIs may be associated with a small increased risk for cardiovascular malformations. Others have noted associations between SSRIs and specific types of rare major malformations. In some studies, there appears to be a small increased risk for miscarriages, which may be associated with the underlying maternal condition. Neonatal effects have been described in up to 30% of neonates exposed to SSRIs late in pregnancy. Persistent pulmonary hypertension of the newborn has also been described with an absolute risk of <1%. The risk associated with treatment discontinuation, for example, higher frequency of relapse and increased risk of preterm delivery, should also be considered. The overall benefit of treatment seems to outweigh the potential risks. PMID:22190957

Comparison of adjunctive use of aripiprazole with bupropion or selective serotonin reuptake inhibitors/serotonin–norepinephrine reuptake inhibitors: analysis of patients beginning adjunctive treatment in a 52-week, open-label study

PubMed Central

2014-01-01

Background This post hoc analysis assessed the safety, tolerability and effectiveness of long-term treatment with aripiprazole adjunctive to either bupropion or selective serotonin reuptake inhibitors (SSRIs)/serotonin–norepinephrine reuptake inhibitors (SNRIs) in patients with major depressive disorder (MDD). Methods Data from de novo patients (did not participate in 2 previous studies) in a 52-week, open-label safety study of adjunctive aripiprazole after documented inadequate response to 1–4 antidepressant treatments (ADTs; SSRI, SNRI, or bupropion) were analyzed post hoc. Assessments included safety and tolerability, sexual functioning (Massachusetts General Hospital Sexual Functioning Inventory [MGH-SFI]) and Clinical Global Impressions–Severity (CGI-S). Results Forty-seven patients received bupropion plus aripiprazole and 245 received an SSRI/SNRI plus aripiprazole; 19 (40.4%) and 78 (31.8%), respectively, completed 52 weeks of treatment, and 46 and 242, respectively, received ≥1 dose of study medication (safety sample). Median time to discontinuation (any reason) was 184.0 days. Overall, 97.8% of patients in the bupropion group and 93.8% in the SSRI/SNRI group experienced ≥1 adverse event. The most common treatment-emergent adverse events were fatigue (26.1%) and somnolence (21.7%) with bupropion and fatigue (23.6%) and akathisia (23.6%) with an SSRI/SNRI. Mean change in body weight at week 52 (observed cases) was +3.1 kg for bupropion and +2.4 kg for an SSRI/SNRI. Treatment-emergent, potentially clinically relevant abnormalities in fasting glucose occurred in 8.3% of patients with bupropion and 17.4% with an SSRI/SNRI; for abnormalities in fasting total cholesterol, the incidence was 25.0% and 34.7%, respectively. Mean (SE) change from baseline in fasting glucose was 1.4 (1.9) mg/dL with bupropion and 2.7 (1.5) mg/dL with an SSRI/SNRI. Baseline MGH-SFI item scores indicated less severe impairment with bupropion versus an SSRI/SNRI; in both

Atomoxetine, a norepinephrine reuptake inhibitor, reduces seizure-induced respiratory arrest.

PubMed

Zhang, Honghai; Zhao, Haiting; Feng, Hua-Jun

2017-08-01

Sudden unexpected death in epilepsy (SUDEP) is a devastating epilepsy complication, and no effective preventive strategies are currently available for this fatal disorder. Clinical and animal studies of SUDEP demonstrate that seizure-induced respiratory arrest (S-IRA) is the primary event leading to death after generalized seizures in many cases. Enhancing brain levels of serotonin reduces S-IRA in animal models relevant to SUDEP, including the DBA/1 mouse. Given that serotonin in the brain plays an important role in modulating respiration and arousal, these findings suggest that deficits in respiration and/or arousal may contribute to S-IRA. It is well known that norepinephrine is an important neurotransmitter that modulates respiration and arousal in the brain as well. Therefore, we hypothesized that enhancing noradrenergic neurotransmission suppresses S-IRA. To test this hypothesis, we examined the effect of atomoxetine, a norepinephrine reuptake inhibitor (NRI), on S-IRA evoked by either acoustic stimulation or pentylenetetrazole in DBA/1 mice. We report the original observation that atomoxetine specifically suppresses S-IRA without altering the susceptibility to seizures evoked by acoustic stimulation, and atomoxetine also reduces S-IRA evoked by pentylenetetrazole in DBA/1 mice. Our data suggest that the noradrenergic signaling is importantly involved in S-IRA, and that atomoxetine, a medication widely used to treat attention deficit hyperactivity disorder (ADHD), is potentially useful to prevent SUDEP. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of proton pump inhibitors on the serum concentrations of the selective serotonin reuptake inhibitors citalopram, escitalopram, and sertraline.

PubMed

Gjestad, Caroline; Westin, Andreas A; Skogvoll, Eirik; Spigset, Olav

2015-02-01

The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, and sertraline are all metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, and pantoprazole. The aim of the present study was to evaluate the effect of these PPIs on the serum concentrations of citalopram, escitalopram, and sertraline. Serum concentrations from patients treated with citalopram, escitalopram, or sertraline were obtained from a routine therapeutic drug monitoring database, and samples from subjects concomitantly using PPIs were identified. Dose-adjusted SSRI serum concentrations were calculated to compare data from those treated and those not treated with PPIs. Citalopram concentrations were significantly higher in patients treated with omeprazole (+35.3%; P < 0.001), esomeprazole (+32.8%; P < 0.001), and lansoprazole (+14.7%; P = 0.043). Escitalopram concentrations were significantly higher in patients treated with omeprazole (+93.9%; P < 0.001), esomeprazole (+81.8%; P < 0.001), lansoprazole (+20.1%; P = 0.008), and pantoprazole (+21.6%; P = 0.002). Sertraline concentrations were significantly higher in patients treated with esomeprazole (+38.5%; P = 0.0014). The effect of comedication with PPIs on the serum concentration of SSRIs is more pronounced for omeprazole and esomeprazole than for lansoprazole and pantoprazole, and escitalopram is affected to a greater extent than are citalopram and sertraline. When omeprazole or esomeprazole are used in combination with escitalopram, a 50% dose reduction of the latter should be considered.

Effect of Proton Pump Inhibitors on the Serum Concentrations of the Selective Serotonin Reuptake Inhibitors Citalopram, Escitalopram, and Sertraline

PubMed Central

Gjestad, Caroline; Westin, Andreas A.; Skogvoll, Eirik

2015-01-01

Background: The selective serotonin reuptake inhibitors (SSRIs) citalopram, escitalopram, and sertraline are all metabolized by the cytochrome P-450 isoenzyme CYP2C19, which is inhibited by the proton pump inhibitors (PPIs) omeprazole, esomeprazole, lansoprazole, and pantoprazole. The aim of the present study was to evaluate the effect of these PPIs on the serum concentrations of citalopram, escitalopram, and sertraline. Methods: Serum concentrations from patients treated with citalopram, escitalopram, or sertraline were obtained from a routine therapeutic drug monitoring database, and samples from subjects concomitantly using PPIs were identified. Dose-adjusted SSRI serum concentrations were calculated to compare data from those treated and those not treated with PPIs. Results: Citalopram concentrations were significantly higher in patients treated with omeprazole (+35.3%; P < 0.001), esomeprazole (+32.8%; P < 0.001), and lansoprazole (+14.7%; P = 0.043). Escitalopram concentrations were significantly higher in patients treated with omeprazole (+93.9%; P < 0.001), esomeprazole (+81.8%; P < 0.001), lansoprazole (+20.1%; P = 0.008), and pantoprazole (+21.6%; P = 0.002). Sertraline concentrations were significantly higher in patients treated with esomeprazole (+38.5%; P = 0.0014). Conclusions: The effect of comedication with PPIs on the serum concentration of SSRIs is more pronounced for omeprazole and esomeprazole than for lansoprazole and pantoprazole, and escitalopram is affected to a greater extent than are citalopram and sertraline. When omeprazole or esomeprazole are used in combination with escitalopram, a 50% dose reduction of the latter should be considered. PMID:24887634

Nutrition status, bone mass density, and selective serotonin reuptake inhibitors.

PubMed

Kindilien, Shannon; Goldberg, Elle M; Roberts, Melissa H; Gonzales-Pacheco, Diana

2018-05-07

The association between selective serotonin reuptake inhibitor (SSRI) use and bone mass density (BMD) has been debated. Inadequate diet, which may occur in depressed individuals prescribed SSRIs is also associated with decreased BMD. This study seeks to determine if SSRI use in adults is associated with lower than average BMD while controlling for nutrition related variables. Further, it investigates whether there are potential interactions between micronutrients and SSRI use on BMD. Adults, 655 with an SSRI prescription ≥180 days and 12,372 non-users, were identified in the 2005-2014 National Health and Nutrition Examination Survey (NHANES) data. Survey respondents were propensity score matched on propensity to have an SSRI prescription and compared on femoral neck BMD t-scores. A sub-analysis within SSRI users was conducted to calculate the odds ratio (OR) of having a low (osteopenia or osteoporosis) BMD t-score given SSRI exposure and inadequate daily micronutrient intake. Inadequate daily micronutrient intake was common; over half of SSRI users and non-users had inadequate calcium, vitamin d, and potassium. SSRI use was associated with an absolute reduction of 0.11 in BMD t-score. Inadequate daily vitamin D intake was associated with lower BMD t-scores in both SSRI users and non-users. The interaction of SSRI use and inadequate daily intake of zinc was also associated with low BMD (OR: 1.11, 95% CI: 1.01-1.23). Patient health may be improved by nutritional education, referral to a dietician, or by micronutrient monitoring by the prescribing physician. Copyright © 2017. Published by Elsevier Inc.

Selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) for the prevention of tension-type headache in adults.

PubMed

Banzi, Rita; Cusi, Cristina; Randazzo, Concetta; Sterzi, Roberto; Tedesco, Dario; Moja, Lorenzo

2015-05-01

This is an updated version of the Cochrane review published in 2005 on selective serotonin re-uptake inhibitors (SSRIs) for preventing migraine and tension-type headache. The original review has been split in two parts and this review now only regards tension-type headache prevention. Another updated review covers migraine. Tension-type headache is the second most common disorder worldwide and has high social and economic relevance. As serotonin and other neurotransmitters may have a role in pain mechanisms, SSRIs and serotonin-norepinephrine reuptake inhibitors (SNRIs) have been evaluated for the prevention of tension-type headache. To determine the efficacy and tolerability of SSRIs and SNRIs compared to placebo and other active interventions in the prevention of episodic and chronic tension-type headache in adults. For the original review, we searched the Cochrane Central Register of Controlled Trials (CENTRAL 2003, Issue 4), MEDLINE (1966 to January 2004), EMBASE (1994 to May 2003), and Headache Quarterly (1990 to 2003). For this update, we revised the original search strategy to reflect the broader type of intervention (SSRIs and SNRIs). We searched CENTRAL (2014, Issue 10) on the Cochrane Library, MEDLINE (1946 to November 2014), EMBASE (1980 to November 2014), and PsycINFO (1987 to November 2014). We also checked the reference lists of retrieved articles and searched trial registries for ongoing trials. We included randomised controlled trials comparing SSRIs or SNRIs with any type of control intervention in participants 18 years and older, of either sex, with tension-type headache. Two authors independently extracted data (headache frequency, index, intensity, and duration; use of symptomatic/analgesic medication; quality of life; and withdrawals) and assessed the risk of bias of trials. The primary outcome is tension-type headache frequency, measured by the number of headache attacks or the number of days with headache per evaluation period. The original

Upper gastrointestinal bleeding in a patient with depression receiving selective serotonin reuptake inhibitor therapy.

PubMed

Kumar, Deepak; Saaraswat, Tanuj; Sengupta, S N; Mehrotra, Saurabh

2009-02-01

Serotonin plays an important role in the normal clotting phenomenon and is released by platelets. Platelets are dependent on a serotonin transporter for the uptake of serotonin, as they cannot synthesize it themselves. Selective serotonin reuptake inhibitors (SSRIs) block the uptake of serotonin into platelets and can cause problems with clotting leading to bleeding. This case report highlights the occurrence of upper gastrointestinal bleeding in the index case on initiating SSRI therapy for depression and the prompt resolution of the same on its discontinuation on two separate occasions. SSRIs may cause upper gastrointestinal (GI) bleeding. Physicians should be aware of the same and should try to rule out previous episodes of upper GI bleed or the presence of other risk factors which might predispose to it before prescribing SSRIs; they should also warn the patients about this potential side effect. Also, the presence of thalassemia trait in the index patient deserves special attention and needs to be explored to see if it might in any way contribute in potentiating this side effect of SSRIs.

Serotonin reuptake inhibitors in pregnancy and the risk of major malformations: a systematic review.

PubMed

Bellantuono, Cesario; Migliarese, Giovanni; Gentile, Salvatore

2007-04-01

To review studies conducted to establish the risk of major congenital malformations in women exposed to serotonin reuptake inhibitors (SRIs) during the first trimester of pregnancy. A literature search [corrected] was conducted within PsycINFO [corrected] EMBASE, MEDLINE and Cochrane databases from 1966 to October 2006, to identify studies assessing the risk of major malformations in infants whose mother was taking SRIs (SSRIs and SNRIs) during the first trimester of pregnancy. Fifteen studies were selected for the analysis: seven adopted a prospective cohort design and seven a retrospective design, of these one was a case-control study. The reviewed studies suggest that exposure to fluoxetine, sertraline, citalopram and venlafaxine in early pregnancy is not associated with an increased risk of major congenital malformations. For paroxetine, recent data call for caution in prescribing such a drug in early pregnancy. For the other SRIs, the risk remains substantially undetermined, as data are so far scanty. Given this background, large prospective cohort studies are urgently needed to better assess the risk/benefit ratio of SRIs-treatment during pregnancy. Copyright 2007 John Wiley & Sons, Ltd.

Selective serotonin reuptake inhibitor suppression of HIV infectivity and replication.

PubMed

Benton, Tami; Lynch, Kevin; Dubé, Benoit; Gettes, David R; Tustin, Nancy B; Ping Lai, Jian; Metzger, David S; Blume, Joshua; Douglas, Steven D; Evans, Dwight L

2010-11-01

To test the hypothesis that the selective serotonin reuptake inhibitor (SSRI) citalopram would down-regulate human immunodeficiency virus (HIV) infectivity and that the greatest effects would be seen in people with depression. Depression is a risk factor for morbidity and mortality in HIV/acquired immune deficiency syndrome. Serotonin (5-HT) neurotransmission has been implicated in the pathobiology of depression, and pharmacologic therapies for depression target this system. The 5-HT transporter and 5-HT receptors are widely distributed throughout the central nervous and immune systems. Depression has been associated with suppression of natural killer cells and CD8(+) lymphocytes, key regulators of HIV infection. Ex vivo models for acute and chronic HIV infection were used to study the effects of citalopram on HIV viral infection and replication in 48 depressed and nondepressed women. For both the acute and chronic infection models, HIV reverse transcriptase activity was measured in the citalopram treatment condition and the control condition. The SSRI significantly down-regulated the reverse transcriptase response in both the acute and chronic infection models. Specifically, citalopram significantly decreased the acute HIV infectivity of macrophages. Citalopram also significantly decreased HIV viral replication in the latently infected T-cell line and in the latently infected macrophage cell line. There was no difference in down-regulation by depression status. These studies suggest that an SSRI enhances natural killer/CD8 noncytolytic HIV suppression in HIV/acquired immune deficiency syndrome and decreases HIV viral infectivity of macrophages, ex vivo, suggesting the need for in vivo studies to determine a potential role for agents targeting serotonin in the host defense against HIV.

The Effect of Gastric Bypass on the Pharmacokinetics of Serotonin Reuptake Inhibitors

PubMed Central

Hamad, Giselle G.; Helsel, Joseph C.; Perel, James M.; Kozak, Gina M.; McShea, Mary C.; Hughes, Carolyn; Confer, Andrea L.; Sit, Dorothy K.; McCloskey, Carol A.; Wisner, Katherine L.

2013-01-01

Objective Morbidly obese patients frequently present with mood and anxiety disorders, which are often treated with serotonin reuptake inhibitors (SRIs). Having observed that patients treated with SRIs frequently relapse after Rouxen-Y gastric bypass surgery, the authors sought to assess whether SRI bioavailability is reduced postoperatively. Method Twelve gastric bypass candidates treated with an SRI for primary mood or anxiety disorders were studied prospectively. Timed blood samples for SRI plasma levels were drawn for pharmacokinetic studies before surgery and 1, 6, and 12 months afterward. Maximum concentration, time to maximum concentration, and area under the concentration/time curve (AUC) were determined. Results In eight of the 12 patients, AUC values 1 month after surgery dropped to an average of 54% (SD=18) of preoperative levels (range=36%–80%); in six of these patients, AUC values returned to baseline levels (or greater) by 6 months. Four patients had an exacerbation of depressive symptoms, which resolved by 12 months in three of them. Three of the four patients had a reduced AUC level at 1 month and either gained weight or failed to lose weight between 6 and 12 months. Normalization of the AUC was associated with improvement in symptom scores. Conclusions Patients taking SRIs in this study were at risk for reduced drug bioavailability 1 month after Rouxen-Y gastric bypass. The authors recommend close psychiatric monitoring after surgery. PMID:22407114

Selective Serotonin Reuptake Inhibitors for Treating Neurocognitive and Neuropsychiatric Disorders Following Traumatic Brain Injury: An Evaluation of Current Evidence

PubMed Central

Yue, John K.; Burke, John F.; Upadhyayula, Pavan S.; Winkler, Ethan A.; Deng, Hansen; Robinson, Caitlin K.; Pirracchio, Romain; Suen, Catherine G.; Sharma, Sourabh; Ferguson, Adam R.; Ngwenya, Laura B.; Stein, Murray B.; Manley, Geoffrey T.; Tarapore, Phiroz E.

2017-01-01

The prevalence of neuropsychiatric disorders following traumatic brain injury (TBI) is 20%–50%, and disorders of mood and cognition may remain even after recovery of neurologic function is achieved. Selective serotonin reuptake inhibitors (SSRI) block the reuptake of serotonin in presynaptic cells to lead to increased serotonergic activity in the synaptic cleft, constituting first-line treatment for a variety of neurocognitive and neuropsychiatric disorders. This review investigates the utility of SSRIs in treating post-TBI disorders. In total, 37 unique reports were consolidated from the Cochrane Central Register and PubMed (eight randomized-controlled trials (RCTs), nine open-label studies, 11 case reports, nine review articles). SSRIs are associated with improvement of depressive but not cognitive symptoms. Pooled analysis using the Hamilton Depression Rating Scale demonstrate a significant mean decrease of depression severity following sertraline compared to placebo—a result supported by several other RCTs with similar endpoints. Evidence from smaller studies demonstrates mood improvement following SSRI administration with absent or negative effects on cognitive and functional recovery. Notably, studies on SSRI treatment effects for post-traumatic stress disorder after TBI remain absent, and this represents an important direction of future research. Furthermore, placebo-controlled studies with extended follow-up periods and concurrent biomarker, neuroimaging and behavioral data are necessary to delineate the attributable pharmacological effects of SSRIs in the TBI population. PMID:28757598

Selective Serotonin Reuptake Inhibitors for Treating Neurocognitive and Neuropsychiatric Disorders Following Traumatic Brain Injury: An Evaluation of Current Evidence.

PubMed

Yue, John K; Burke, John F; Upadhyayula, Pavan S; Winkler, Ethan A; Deng, Hansen; Robinson, Caitlin K; Pirracchio, Romain; Suen, Catherine G; Sharma, Sourabh; Ferguson, Adam R; Ngwenya, Laura B; Stein, Murray B; Manley, Geoffrey T; Tarapore, Phiroz E

2017-07-25

The prevalence of neuropsychiatric disorders following traumatic brain injury (TBI) is 20%-50%, and disorders of mood and cognition may remain even after recovery of neurologic function is achieved. Selective serotonin reuptake inhibitors (SSRI) block the reuptake of serotonin in presynaptic cells to lead to increased serotonergic activity in the synaptic cleft, constituting first-line treatment for a variety of neurocognitive and neuropsychiatric disorders. This review investigates the utility of SSRIs in treating post-TBI disorders. In total, 37 unique reports were consolidated from the Cochrane Central Register and PubMed (eight randomized-controlled trials (RCTs), nine open-label studies, 11 case reports, nine review articles). SSRIs are associated with improvement of depressive but not cognitive symptoms. Pooled analysis using the Hamilton Depression Rating Scale demonstrate a significant mean decrease of depression severity following sertraline compared to placebo-a result supported by several other RCTs with similar endpoints. Evidence from smaller studies demonstrates mood improvement following SSRI administration with absent or negative effects on cognitive and functional recovery. Notably, studies on SSRI treatment effects for post-traumatic stress disorder after TBI remain absent, and this represents an important direction of future research. Furthermore, placebo-controlled studies with extended follow-up periods and concurrent biomarker, neuroimaging and behavioral data are necessary to delineate the attributable pharmacological effects of SSRIs in the TBI population.

Successful Treatment of Treatment-Resistant Schizophrenia in a 10-Year-Catatonic Patient by Augmentation of Selective Serotonin Reuptake Inhibitors

PubMed Central

Chen, Mei-Jung; Huang, Shiau-Shian; Juang, Kai-Dih; Chan, Chin-Hong

2015-01-01

Abstract Although catatonia is a well defined syndrome, the treatment of chronic catatonia remains an unresolved issue. Here, we report a successful treatment of a 30-year-old patient with treatment-resistant catatonic schizophrenia in 10 years by augmentation of selective serotonin reuptake inhibitors (SSRIs). We present a 30-year-old man with treatment-resistant catatonic schizophrenia who failed to respond to the treatment of benzodiazepines and antipsychotics for 10 years. He markedly improved after taking SSRIs. Now, he does not hold odd postures and begins to talk and show more facial expressions. We postulate that the therapeutic effect is related to the enhancement of 5-HT neurotransmission. SSRIs can be a considerable choice to treat chronic catatonia. PMID:25929916

The safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and breastfeeding: a comprehensive review.

PubMed

Bellantuono, Cesario; Vargas, Marianna; Mandarelli, Gabriele; Nardi, Bernardo; Martini, Maria Giulia

2015-05-01

The present study provides a comprehensive review of the existing literature on the safety of serotonin-noradrenaline reuptake inhibitors (SNRIs) in pregnancy and lactation. Studies published in English, reporting the use of SNRIs in pregnant and/or breastfeeding women, were identified by searching MEDLINE/Pubmed, PsycINFO, and EMBASE. Twenty-nine studies were included in the review. Altogether, the initial evidence coming from the reviewed studies suggests a lack of association between SNRIs and an increased risk of major congenital malformations. Conversely, exposure to SNRIs seems to be significantly associated with an increased risk of some perinatal complications. No neonatal adverse events emerged, so far, in the few studies concerning the safety of SNRIs during breastfeeding. Available data suggest that venlafaxine is relatively safe during pregnancy, in particular as far as major malformations are concerned, whereas considering the small number of studies published, no definitive conclusions can be drawn on its safety during breastfeeding. Because of the few studies so far published, the safety of duloxetine during pregnancy and breastfeeding remains to be well established. Copyright © 2015 John Wiley & Sons, Ltd.

May selective serotonin reuptake inhibitors (SSRIs) provide some benefit for the treatment of schizophrenia?

PubMed

Buoli, Massimiliano; Serati, Marta; Ciappolino, Valentina; Altamura, A Carlo

2016-07-01

The treatment of some psychopathological dimensions of schizophrenia (e.g. negative and depressive symptoms) is still challenging for the modest efficacy of atypical antipsychotics. Among pharmacological alternatives, augmentative Selective Serotonin Reuptake Inhibitors (SSRIs) to antipsychotics are frequently prescribed in clinical practice to improve negative/depressive symptoms of schizophrenia patients; however, the data about the efficacy of these molecules on negative, depressive and obsessive-compulsive symptoms of schizophrenia are contrasting. Research using the main database sources has been conducted to obtain an overview of the use and efficacy of SSRIs in schizophrenia. Data are too scanty to draw definitive recommendations. In a preliminary way, it can be said that available data do not show effectiveness of SSRIs on depressive symptoms of schizophrenia. Regarding negative symptoms, studies are contrasting, but paroxetine appears to be the most effective compound among SSRIs. Despite limited data, SSRIs appear to be useful for the treatment of obsessive-compulsive symptoms of schizophrenia, particularly fluvoxamine. Close clinical and pharmacological monitoring is needed in case of concomitant administration of antipsychotics and antidepressants for potential serious side effects and influence on plasma drug dosages.

Social inequalities in suicide: the role of selective serotonin reuptake inhibitors.

PubMed

Clouston, Sean A P; Rubin, Marcie S; Colen, Cynthia G; Link, Bruce G

2014-10-01

We aimed to examine the relationship between socioeconomic status (SES) and suicide associated with the introduction and diffusion of selective serotonin reuptake inhibitors (SSRIs). Negative binomial regression was used to estimate county-level suicide rates among persons aged 25 years or older using death certificate data collated by the National Center for Health Statistics from 1968 to 2009; SES was measured using the decennial US Census. The National Health and Nutrition Examination Survey and the Medical Expenditure Panel Survey were used to measure SSRI use. Once SSRIs became available in 1988, a 1% increase in SSRI usage was associated with a 0.5% lower suicide rate. Prior to the introduction of SSRIs, SES was not related to suicide. However, with each 1% increase in SSRI use, a 1-standard deviation (SD) higher SES was associated with a 0.6% lower suicide rate. In 2009, persons living in counties with SES 1 SD above the national average were 13.6% less likely to commit suicide than those living in counties with SES 1 SD below the national average--a difference of 1.9/100,000 adults aged ≥25 years. Higher SSRI use was associated with lower suicide rates among US residents aged ≥25 years; however, SES inequalities modified the association between SSRI use and suicide. © The Author 2014. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Enhanced responsiveness to selective serotonin reuptake inhibitors during lactation.

PubMed

Jury, Nicholas J; McCormick, Betsy A; Horseman, Nelson D; Benoit, Stephen C; Gregerson, Karen A

2015-01-01

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence

Enhanced Responsiveness to Selective Serotonin Reuptake Inhibitors during Lactation

PubMed Central

Jury, Nicholas J.; McCormick, Betsy A.; Horseman, Nelson D.; Benoit, Stephen C.; Gregerson, Karen A.

2015-01-01

The physiology of mood regulation in the postpartum is poorly understood despite the fact that postpartum depression (PPD) is a common pathology. Serotonergic mechanisms and their dysfunction are widely presumed to be involved, which has led us to investigate whether lactation induces changes in central or peripheral serotonin (5-HT) systems and related affective behaviors. Brain sections from lactating (day 10 postpartum) and age-matched nulliparous (non-pregnant) C57BL/6J mice were processed for 5-HT immunohistochemistry. The total number of 5-HT immunostained cells and optical density were measured. Lactating mice exhibited lower immunoreactive 5-HT and intensity in the dorsal raphe nucleus when compared with nulliparous controls. Serum 5-HT was quantified from lactating and nulliparous mice using radioimmunoassay. Serum 5-HT concentrations were higher in lactating mice than in nulliparous controls. Affective behavior was assessed in lactating and non-lactating females ten days postpartum, as well as in nulliparous controls using the forced swim test (FST) and marble burying task (MBT). Animals were treated for the preceding five days with a selective serotonin reuptake inhibitor (SSRI, citalopram, 5mg/kg/day) or vehicle. Lactating mice exhibited a lower baseline immobility time during the FST and buried fewer marbles during the MBT as compared to nulliparous controls. Citalopram treatment changed these behaviors in lactating mice with further reductions in immobility during the FST and decreased marble burying. In contrast, the same regimen of citalopram treatment had no effect on these behaviors in either non-lactating postpartum or nulliparous females. Our findings demonstrate changes in both central and peripheral 5-HT systems associated with lactation, independent of pregnancy. They also demonstrate a significant interaction of lactation and responsiveness to SSRI treatment, which has important implications in the treatment of PPD. Although recent evidence

Intracranial haemorrhage and use of selective serotonin reuptake inhibitors

PubMed Central

de Abajo, Francisco J; Jick, Hershel; Derby, Laura; Jick, Susan; Schmitz, Stephen

2000-01-01

Aims In the past few years an increasing number of bleeding disorders have been reported in association with the use of selective serotonin reuptake inhibitors (SSRIs), including serious cases of intracranial haemorrhage, raising concerns about the safety of this class of drugs. The present study was performed to test the hypothesis of an increased risk of intracranial haemorrhage associated with the use of SSRIs. Methods We carried out a case-control study nested in a cohort of antidepressants users with the UK-based General Practice Research Database (GPRD) as the primary source of information. The study cohort encompassed subjects aged between 18 and 79 years who received a first-time prescription for any antidepressant from January, 1990 to October, 1997. Patients with presenting conditions or treatments that could be associated with an increased risk of intracranial haemorrhage were excluded from the cohort. Patients were followed-up until the occurrence of an idiopathic intracranial haemorrhage. Up to four controls per case, matched on age, sex, calendar time and practice were randomly selected from the study cohort. We estimated adjusted odds ratios and 95% confidence intervals of intracranial haemorrhage with current use of SSRIs and other antidepressants as compared with nonuse using conditional logistic regression. Results We identified 65 cases of idiopathic intracranial haemorrhage and 254 matched controls. Current exposure to SSRIs was ascertained in 7 cases (10.8%) and 24 controls (9.7%) resulting in an adjusted OR (95%CI) of 0.8 (0.3,2.3). The estimate for ‘other antidepressants’ was 0.7 (0.3,1.6). The effect measures were not modified by gender or age. No effect related to dose or treatment duration was detected. The risk estimates did not change according to the location of bleeding (intracerebral or subarachnoid). Conclusions Our results are not compatible with a major increased risk of intracranial haemorrhage among users of SSRIs or other

Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on attention and executive functions in patients with major depressive disorder.

PubMed

Herrera-Guzmán, Ixchel; Herrera-Abarca, Jorge E; Gudayol-Ferré, Esteve; Herrera-Guzmán, Daniel; Gómez-Carbajal, Lizbeth; Peña-Olvira, Miriam; Villuendas-González, Erwin; Joan, Guàrdia-Olmos

2010-05-30

Several reports suggest that antidepressants may improve cognitive functioning in patients with major depressive disorder (MDD). The present work aims to study the effects of selective serotonin reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments on the performance of working memory, attention and executive functions in patients with MDD. A total of 73 subjects meeting the Diagnostic and Statistical Manual of Mental Disorders version IV (DSM-IV) criteria for MDD, and 37 control subjects were assessed with the Hamilton Depression Rating Scale and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same tests. The depressed subjects showed alterations in attention and cognitive functions when compared to the control group. The administration of both treatments improved working memory, as well as attention and all the executive functions, but the cognitive functions of depressed patients do not improve enough to reach the levels of performance of the control subjects. Our results suggest that both SSRI and SNRI treatments presented the same efficacy in improving attention and the remaining executive functions. Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Major Depressive Disorder in recovery and neuropsychological functioning: effects of selective serotonin reuptake inhibitor and dual inhibitor depression treatments on residual cognitive deficits in patients with Major Depressive Disorder in recovery.

PubMed

Herrera-Guzmán, Ixchel; Gudayol-Ferré, Esteve; Herrera-Abarca, Jorge E; Herrera-Guzmán, Daniel; Montelongo-Pedraza, Pedro; Padrós Blázquez, Ferran; Peró-Cebollero, Maribel; Guàrdia-Olmos, Joan

2010-06-01

Cognitive disturbances in Major Depressive Disorder (MDD) could persist beyond the symptomatic phase of the illness. However, the works addressing this topic did not usually account for the possible impact of medication on the cognitive functions of depressed patients. The present study aims to investigate whether MDD patients in remission treated with selective serotonin reuptake inhibitors (SSRI) or dual serotonergic-noradrenergic reuptake inhibitors (SNRI) show cognitive deficits, to study whether the same patients suffer neuropsychological disturbances when they are unmedicated and in recovery phase, and if the previous pharmacological treatment used to achieve the remission of MDD clinical symptoms had any effect in the profile of these patients' cognitive performance in the recovery phase. Thirty-six subjects with MDD treated with escitalopram and 37 depressed patients with duloxetine were compared both in remission phase and 24 weeks later, when they were unmedicated and in recovery phase. They were also compared, in both moments, to 37 healthy subjects. The control subjects showed a broader better cognitive performance than MDD patients in both measurement moments, but several cognitive functions improved over time. Also, the patients treated with SNRI performed better in memory tests than the SNRI-treated patients in remission phase, and in recovery phase. Our sample size is somewhat small, and we followed our patients only for 6months after treatment. Cognitive functions improve over time in patients with MDD beyond the remission phase, and the antidepressant treatment class used in acute depressive phase could influence his/her memory improvement. Copyright 2009 Elsevier B.V. All rights reserved.

A comparative study of QT prolongation with serotonin reuptake inhibitors.

PubMed

Ojero-Senard, Ana; Benevent, Justine; Bondon-Guitton, Emmanuelle; Durrieu, Geneviève; Chebane, Leila; Araujo, Melanie; Montastruc, Francois; Montastruc, Jean-Louis

2017-10-01

QT interval prolongations were described with citalopram and escitalopram. However, the effects of the other serotonin reuptake inhibitors (SRIs) remained discussed. In order to identify a putative signal with other SRIs, the present study investigates the reports of QT interval prolongation with SRIs in two pharmacovigilance databases (PVDB). Two kinds of investigations were performed: (1) a comparative study in VigiBase®, the WHO PVDB, where notifications of QT prolongation with six SRIs (citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine, sertraline) were selected. Cases with overdose or pregnancy were excluded. The relationship between the "suspected" SRI and occurrence of QT prolongation was assessed by calculating reporting odds ratio (ROR) in a case/non-case design. (2) A descriptive study of QT prolongation reports with citalopram and escitalopram in the French FPVD. In VigiBase®, 855 notifications were identified (mean age 56.2 years, mainly women 73%). Among them, 172 (20.1%) were associated to escitalopram; 299 (35.0%), to citalopram; 186 (21.8%), to fluoxetine; 94 (11.0%), to sertraline; 66 (7.7%), to paroxetine; and 38 (4.4%) to fluvoxamine. A significant ROR value (higher than 1) was only found for citalopram (3.35 CI95% [2.90-3.87]) or escitalopram (2.50 [2.11-2.95]). In the FPVD, eight reports of QT prolongation were found with citalopram and 27 with escitalopram, mainly in women (77.1%) with a mean age of 73.2 years. In 23 cases (66%), SRIs were associated with other suspected drugs, mainly cardiotropic or psychotropic ones. Hypokalemia was associated in six patients. This study, performed in real conditions of life, shows a clear signal of QT prolongation with only two SRIs, citalopram and escitalopram, indicating that QT prolongation is not a SRI class effect.

Effects of selective serotonin reuptake and dual serotonergic-noradrenergic reuptake treatments on memory and mental processing speed in patients with major depressive disorder.

PubMed

Herrera-Guzmán, Ixchel; Gudayol-Ferré, Esteve; Herrera-Guzmán, Daniel; Guàrdia-Olmos, Joan; Hinojosa-Calvo, Erika; Herrera-Abarca, Jorge E

2009-06-01

Patients with major depressive disorder (MDD) usually suffer from altered cognitive functions of episodic memory, working memory, mental processing speed and motor response. Diverse studies suggest that different antidepressant agents may improve cognitive functions in patients with MDD. The aim of this work is to study the effects of serotonergic reuptake inhibitors (SSRIs) and serotonergic-noradrenergic reuptake inhibitors (SNRIs) treatments to improve the performance on memory tasks and mental processing speed in MDD. Seventy-three subjects meeting criteria for major depressive disorder were assessed with the Hamilton depression rating scale and a neuropsychological battery. The subjects were medicated with escitalopram (n=36) or duloxetine (n=37) for 24 weeks. At the end of the trial, the subjects were assessed again with the same neuropsychological battery used prior to the treatment. Both treatments improved importantly the episodic memory and to a lesser extent, working memory, mental processing speed and motor performance. Our results suggest that cognition is partially independent from improvement in clinical symptoms. Both groups achieved remission rates in the HAM-D-17 after 24 weeks of treatment, but SNRI was superior to SSRI at improving episodic and working memory. Our work indicates that the superiority of SNRI over the SSRI at episodic memory improvement is clinically relevant.

The Roles of Maternal Depression, Serotonin Reuptake Inhibitor Treatment, and Concomitant Benzodiazepine Use on Infant Neurobehavioral Functioning Over the First Postnatal Month.

PubMed

Salisbury, Amy L; O'Grady, Kevin E; Battle, Cynthia L; Wisner, Katherine L; Anderson, George M; Stroud, Laura R; Miller-Loncar, Cynthia L; Young, Marion E; Lester, Barry M

2016-02-01

The purpose of this article was to systematically compare the developmental trajectory of neurobehavior over the first postnatal month for infants with prenatal exposure to pharmacologically untreated maternal depression, selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors (collectively: SSRIs), SSRIs with concomitant benzodiazepines (SSRI plus benzodiazepine), and no maternal depression or drug treatment (no exposure). Women (N=184) were assessed at two prenatal time points to determine psychiatric diagnoses, symptom severity, and prenatal medication usage. Infants were examined with a structured neurobehavioral assessment (Neonatal Intensive Care Unit Network Neurobehavioral Scale) at multiple time points across the first postnatal month. SSRI exposure was confirmed in a subset of participants with plasma SSRI levels. General linear-mixed models were used to examine group differences in neurobehavioral scores over time with adjustment for demographic variables and depression severity. Infants in the SSRI and SSRI plus benzodiazepine groups had lower motor scores and more CNS stress signs across the first postnatal month, as well as lower self-regulation and higher arousal at day 14. Infants in the depression group had low arousal throughout the newborn period. Infants in all three clinical groups had a widening gap in scores from the no-exposure group at day 30 in their response to visual and auditory stimuli while asleep and awake. Infants in the SSRI plus benzodiazepine group had the least favorable scores on the Neonatal Intensive Care Unit Network Neurobehavioral Scale. Neonatal adaptation syndrome was not limited to the first 2 weeks postbirth. The profile of neurobehavioral development was different for SSRI exposure than depression alone. Concomitant benzodiazepine use may exacerbate adverse behavioral effects.

Impact of prestroke selective serotonin reuptake inhibitor treatment on stroke severity and mortality.

PubMed

Mortensen, Janne Kaergaard; Larsson, Heidi; Johnsen, Søren Paaske; Andersen, Grethe

2014-07-01

Selective serotonin reuptake inhibitors (SSRIs) have been associated with an increased risk of bleeding but also a possible neuroprotective effect in stroke. We aimed to examine the implications of prestroke SSRI use in hemorrhagic and ischemic stroke. We conducted a registry-based propensity score-matched follow-up study among first-ever patients with hemorrhage and ischemic stroke in Denmark (2003-2012). Multiple conditional logistic regression was used to compute adjusted odds ratios of severe stroke and death within 30 days. Among 1252 hemorrhagic strokes (626 prestroke SSRI users and 626 propensity score-matched nonusers), prestroke SSRI use was associated with an increased risk of the strokes being severe (adjusted propensity score-matched odds ratios, 1.41; confidence interval, 1.08-1.84) and an increased risk of death within 30 days (adjusted propensity score-matched odds ratios, 1.60; confidence interval, 1.17-2.18). Among 8956 patients with ischemic stroke (4478 prestroke SSRI users and 4478 propensity score-matched nonusers), prestroke SSRI use was not associated with the risk of severe stroke or death within 30 days. Prestroke SSRI use is associated with increased stroke severity and mortality in patients with hemorrhagic stroke. Although prestroke depression in itself may increase stroke severity and mortality, this was not found in SSRI users with ischemic stroke. © 2014 American Heart Association, Inc.

Successful treatment of treatment-resistant schizophrenia in a 10-year-catatonic patient by augmentation of selective serotonin reuptake inhibitors: a case report.

PubMed

Chen, Mei-Jung; Huang, Shiau-Shian; Juang, Kai-Dih; Chan, Chin-Hong

2015-05-01

Although catatonia is a well defined syndrome, the treatment of chronic catatonia remains an unresolved issue. Here, we report a successful treatment of a 30-year-old patient with treatment-resistant catatonic schizophrenia in 10 years by augmentation of selective serotonin reuptake inhibitors (SSRIs).We present a 30-year-old man with treatment-resistant catatonic schizophrenia who failed to respond to the treatment of benzodiazepines and antipsychotics for 10 years. He markedly improved after taking SSRIs. Now, he does not hold odd postures and begins to talk and show more facial expressions.We postulate that the therapeutic effect is related to the enhancement of 5-HT neurotransmission. SSRIs can be a considerable choice to treat chronic catatonia.

Risk of mortality with concomitant use of tamoxifen and selective serotonin reuptake inhibitors: multi-database cohort study.

PubMed

Donneyong, Macarius M; Bykov, Katsiaryna; Bosco-Levy, Pauline; Dong, Yaa-Hui; Levin, Raisa; Gagne, Joshua J

2016-09-30

 To compare differences in mortality between women concomitantly treated with tamoxifen and selective serotonin reuptake inhibitors (SSRIs) that are potent inhibitors of the cytochrome-P450 2D6 enzyme (CYP2D6) versus tamoxifen and other SSRIs.  Population based cohort study.  Five US databases covering individuals enrolled in private and public health insurance programs from 1995 to 2013.  Two cohorts of women who started taking tamoxifen. In cohort 1, women started taking an SSRI during tamoxifen treatment. In cohort 2, women were already taking an SSRI when they started taking tamoxifen.  All cause mortality in each cohort in women taking SSRIs that are potent inhibitors of CYP2D6 (paroxetine, fluoxetine) versus other SSRIs. Propensity scores were used to match exposure groups in a variable ratio fashion. Results were measured separately for each cohort and combined hazard ratios calculated from Cox regression models across the two cohorts with random effects meta-analysis.  There were 6067 and 8465 new users of tamoxifen in cohorts 1 and 2, respectively. Mean age was 55. A total of 991 and 1014 deaths occurred in cohorts 1 and 2 during a median follow-up of 2.2 (interquartile range 0.9-4.5) and 2.0 (0.8-3.9) years, respectively. The pooled hazard ratio for death for potent inhibitors (rate 58.6/1000 person years) compared with other SSRIs (rate 57.9/1000 person years) across cohorts 1 and 2 was 0.96 (95% confidence interval 0.88 to 1.06). Results were consistent across sensitivity analyses.  Concomitant use of tamoxifen and potent CYP2D6 inhibiting SSRIs versus other SSRIs was not associated with an increased risk of death. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

[Selective serotonin reuptake inhibitors in the therapy of various types of endogenous depressions].

PubMed

Panteleeva, G P; Abramova, L I; Korenev, A N

2000-01-01

In order to specify differential indications for the use of selective serotonin reuptake inhibitors (SSRI) their therapeutic effect was investigated in apathic-adynamic, melancholic and anxious depressions. Group of 151 patients received monotherapy with one of SSRI-drugs: citalopram--22 patients (mean daily dosage--27.4 mg), paroxetine--47 patients (23 mg), sertraline--19 patients (107 mg), fluvoxamine--28 patients (162 mg), fluoxetine--35 patients (20 mg). The state of the patients was estimated 5 times during 42 days of therapy by clinical estimations and according to Hamilton Depression Scale (HAM-D). Therapeutic effects of the drugs were determined according to the degree of reduction of the total HAM-D scores and they were considered as "significant" (a reduction of the scores by 50% and more), "moderate" (by 21-49%), and "insignificant" (by 1-20%). Positive antidepressive effect, including "significant" was obtained in the case of the use of all the drugs studied. Differential evaluation of the three components of antidepressive activity (thymoleptic, sedative-anxiolytic, and stimulative) according to the degrees and data of expression of drugs' therapeutic effect has allowed to determine indications for the therapy of endogenous depressions by each of SSRI: to recommend cytalopram for the treatment of various types of depressive states mainly, for anxious and apatho-adynamic types; paroxetin--for treatment of melancholic depressions as well as for anxious and apatho-dynamic ones; sertralin++--for depression with anxiety and fobic disorders; fluvoxamine--for melancholic and anxious depression; fluoxetine--for apatho-adynamic depressions.

The selective serotonin reuptake inhibitor, escitalopram, enhances inhibition of prepotent responding and spatial reversal learning

PubMed Central

Brown, Holden D.; Amodeo, Dionisio A.; Sweeney, John A.; Ragozzino, Michael E.

2011-01-01

Previous findings indicate treatment with a selective serotonin reuptake inhibitor (SSRI) facilitates behavioral flexibility when conditions require inhibition of a learned response pattern. The present experiment investigated whether acute treatment with the SSRI, escitalopram, affects behavioral flexibility when conditions require inhibition of a naturally-biased response pattern (elevated conflict test) and/or reversal of a learned response pattern (spatial reversal learning). An additional experiment was carried out to determine whether escitalopram, at doses that affected behavioral flexibility, also reduced anxiety as tested in the elevated plus-maze. In each experiment, Long-Evans rats received an intraperitoneal injection of either saline or escitalopram (0.03, 0.3 or 1.0 mg/kg) 30 minutes prior to behavioral testing. Escitalopram, at all doses tested, enhanced acquisition in the elevated conflict test, but did not affect performance in the elevated plus-maze. Escitalopram (0.3 and 1.0 mg/kg) did not alter acquisition of the spatial discrimination, but facilitated reversal learning. In the elevated conflict and spatial reversal learning test, escitalopram enhanced the ability to maintain the relevant strategy after being initially selected. The present findings suggest that enhancing serotonin transmission with a SSRI facilitates inhibitory processes when conditions require a shift away from either a naturally-biased response pattern or a learned choice pattern. PMID:22219222

Cause or Effect? Selective Serotonin Reuptake Inhibitors and Falls in Older Adults: A Systematic Review

PubMed Central

Gebara, Marie Anne; Lipsey, Kim L.; Karp, Jordan F.; Nash, Maureen C.; Iaboni, Andrea; Lenze, Eric J.

2014-01-01

A 2012 update of the Beers criteria categorizes selective serotonin reuptake inhibitors (SSRIs) as potentially inappropriate medications in all older adults based on fall risk. The application of these recommendations, not only to frail nursing home residents, but also to all older adults, may lead to changes in health policy or clinical practice with harmful consequences. A systematic review of studies on the association between SSRIs and falls in older adults was conducted to examine the evidence for causation. Twenty-six studies met the inclusion criteria. The majority of studies were observational and suggest an association between SSRIs and falls. The direction of the relationship – causation or effect- cannot be discerned from this type of study. Standardized techniques for determining likely causation were then used to see if there was support for the hypothesis that SSRI’s lead to falls. This analysis did not suggest causation was likely. There is no Level 1 evidence that SSRIs cause falls. Therefore, changes in the current treatment guidelines or policies on the use of SSRIs in older adults based on fall risk may not be justified at this time given the lack of an established evidence base. Given its significance to public health, well-designed experimental studies are required to address this question definitively. PMID:25586602

Serotonin and noradrenaline reuptake inhibitors (SNRIs) for fibromyalgia.

PubMed

Welsch, Patrick; Üçeyler, Nurcan; Klose, Petra; Walitt, Brian; Häuser, Winfried

2018-02-28

Fibromyalgia is a clinically defined chronic condition of unknown etiology characterized by chronic widespread pain that often co-exists with sleep disturbances, cognitive dysfunction and fatigue. People with fibromyalgia often report high disability levels and poor quality of life. Drug therapy, for example, with serotonin and noradrenaline reuptake inhibitors (SNRIs), focuses on reducing key symptoms and improving quality of life. This review updates and extends the 2013 version of this systematic review. To assess the efficacy, tolerability and safety of serotonin and noradrenaline reuptake inhibitors (SNRIs) compared with placebo or other active drug(s) in the treatment of fibromyalgia in adults. For this update we searched CENTRAL, MEDLINE, Embase, the US National Institutes of Health and the World Health Organization (WHO) International Clinical Trials Registry Platform for published and ongoing trials and examined the reference lists of reviewed articles, to 8 August 2017. We selected randomized, controlled trials of any formulation of SNRIs against placebo or any other active treatment of fibromyalgia in adults. Three review authors independently extracted data, examined study quality, and assessed risk of bias. For efficacy, we calculated the number needed to treat for an additional beneficial outcome (NNTB) for pain relief of 50% or greater and of 30% or greater, patient's global impression to be much or very much improved, dropout rates due to lack of efficacy, and the standardized mean differences (SMD) for fatigue, sleep problems, health-related quality of life, mean pain intensity, depression, anxiety, disability, sexual function, cognitive disturbances and tenderness. For tolerability we calculated number needed to treat for an additional harmful outcome (NNTH) for withdrawals due to adverse events and for nausea, insomnia and somnolence as specific adverse events. For safety we calculated NNTH for serious adverse events. We undertook meta

Economic impact of therapeutic substitution of a brand selective serotonin reuptake inhibitor with an alternative generic selective serotonin reuptake inhibitor in patients with major depressive disorder.

PubMed

Wu, Eric Q; Yu, Andrew P; Lauzon, Veronique; Ramakrishnan, Karthik; Marynchenko, Maryna; Ben-Hamadi, Rym; Blum, Steven; Erder, M Haim

2011-04-01

To reduce pharmacy costs, managed care organizations encourage therapeutic substitution from brand to a generic product. However, little is known about whether these cost-containment strategies can also potentially lower total expenditures for payers in treatment of major depressive disorder (MDD). To compare economic outcomes of patients with MDD who were switched from a brand selective serotonin reuptake inhibitor (SSRI) to an alternative generic SSRI for nonmedical reasons versus patients who continued on the brand SSRI. Adult MDD patients in the Ingenix Impact Database (2003-2007) were considered "switchers" if they received treatment with a brand SSRI and were later switched to an alternative generic SSRI for nonmedical reasons. Patients who remained on the brand SSRI (nonswitchers) were matched 1:1 with switchers. All-cause, mental health-related, and MDD-related rates of hospitalizations/emergency department (ED) visits and costs over 6 months were compared both descriptively and by using adjusted regression models. A subgroup analysis on patients who were switched from escitalopram (Lexapro) to an alternative generic SSRI was also performed. The study included 4449 matched pairs. Compared with nonswitchers, switchers had higher risk of all-cause, mental health-related, and MDD-related use of hospitalizations/ED visits (OR 1.15, 1.34, and 1.54, respectively; all p < 0.01) and higher risk-adjusted mental health-related and MDD-related medical costs ($219 and $222, respectively; both p < 0.05). Subgroup analysis on escitalopram showed similar results; switchers experienced higher risk of any-cause, mental health-related, and MDD-related use of hospitalizations/ED visits (OR 1.21, 1.41, and 1.53, respectively; all p < 0.01) and higher risk-adjusted MDD-related medical costs ($151; p < 0.05). Compared with patients who continued on their patented SSRIs, patients who switched to a generic SSRI incurred more resource use of hospitalizations/ED visits and higher

Norepinephrine reuptake inhibition promotes mobilization in mice: potential impact to rescue low stem cell yields

PubMed Central

Lucas, Daniel; Bruns, Ingmar; Battista, Michela; Mendez-Ferrer, Simon; Magnon, Claire; Kunisaki, Yuya

2012-01-01

The mechanisms mediating hematopoietic stem and progenitor cell (HSPC) mobilization by G-CSF are complex. We have found previously that G-CSF–enforced mobilization is controlled by peripheral sympathetic nerves via norepinephrine (NE) signaling. In the present study, we show that G-CSF likely alters sympathetic tone directly and that methods to increase adrenergic activity in the BM microenvironment enhance progenitor mobilization. Peripheral sympathetic nerve neurons express the G-CSF receptor and ex vivo stimulation of peripheral sympathetic nerve neurons with G-CSF reduced NE reuptake significantly, suggesting that G-CSF potentiates the sympathetic tone by increasing NE availability. Based on these data, we investigated the NE reuptake inhibitor desipramine in HSPC mobilization. Whereas desipramine did not by itself elicit circulating HSPCs, it increased G-CSF–triggered mobilization efficiency significantly and rescued mobilization in a model mimicking “poor mobilizers.” Therefore, these data suggest that blockade of NE reuptake may be a novel therapeutic target to increase stem cell yield in patients. PMID:22422821

A Mechanism for Intracellular Release of Na+ by Neurotransmitter: Sodium Symporters

PubMed Central

Malinauskaite, Lina; Reinhard, Linda; Lyons, Joseph A.; Yano, Hideaki; Javitch, Jonathan A.

2015-01-01

Neurotransmitter:sodium symporters (NSS) terminate synaptic signal transmission by Na+-dependent reuptake of released neurotransmitters, with key conformational states reported for a bacterial homolog LeuT and an inhibitor-bound Drosophila dopamine transporter. However, a coherent mechanism of Na+-driven transport has not been described. Here, we present two crystal structures of MhsT, a NSS member from Bacillus halodurans, in occluded inward-facing states with bound Na+ ions and L-Trp that provide insight into the cytoplasmic release of Na+. The switch from outward- to inward-oriented states is centered on the partial unwinding of transmembrane helix 5, which is facilitated by a conserved GlyX9Pro motif that opens an intracellular pathway for water to access the Na2 site. Based on our structural and functional findings we propose a mechanism according to which solvation through the TM5 pathway facilitates Na+ release from Na2 and the transition to an inward-open state. PMID:25282149

Selective Serotonin Reuptake Inhibitors (SSRIs) and Markers of Bone Turnover in Men.

PubMed

Williams, Lana J; Berk, Michael; Hodge, Jason M; Kotowicz, Mark A; Stuart, Amanda L; Chandrasekaran, Vinoomika; Cleminson, Jasmine; Pasco, Julie A

2018-02-13

Selective serotonin reuptake inhibitors (SSRIs) have been shown to have a clinically significant impact on bone metabolism. To explore this further, we aimed to determine whether these agents are associated with serum markers of bone turnover utilising a population-based sample of men (n = 1138; 20-96 year) participating in the Geelong Osteoporosis Study. Blood samples were obtained and the bone resorption marker, C-telopeptide (CTx) and formation marker, type 1 procollagen amino-terminal-propeptide (PINP) were measured. Anthropometry and socio-economic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Lifetime mood disorders were assessed using semi-structured clinical interviews. Thirty-seven (3.3%) men reported using SSRIs. Age was an effect modifier in the association between SSRIs and markers of bone turnover. Among younger men (20-60 year; n = 557), adjusted mean CTx and PINP values were 12.4% [16.7 (95% CI 14.6-18.8) vs 19.1 (95% CI 18.7-19.4) pg/ml, p = 0.03] and 13.6% [5.6 (95% CI 4.9-6.3) vs 6.4 (95% CI 6.3-6.6) pg/ml, p = 0.02] lower among SSRI users compared to non-users, respectively. No differences in SSRI use and markers of bone turnover were detected among older men (61-94 year; all p > 0.05). These patterns persisted after further adjustment for activity, alcohol, smoking, SES, depression, bone active medications and other antidepressants. Our data suggest that SSRI use is associated with alterations in bone turnover markers among younger men. The observed decreases in both CTx and PINP are likely to contribute to a low bone turnover state and increased skeletal fragility with this potential imbalance between formation and resorption resulting in subsequent bone loss.

Exploring the Inhibitory Mechanism of Approved Selective Norepinephrine Reuptake Inhibitors and Reboxetine Enantiomers by Molecular Dynamics Study

NASA Astrophysics Data System (ADS)

Zheng, Guoxun; Xue, Weiwei; Wang, Panpan; Yang, Fengyuan; Li, Bo; Li, Xiaofeng; Li, Yinghong; Yao, Xiaojun; Zhu, Feng

2016-05-01

Selective norepinephrine reuptake inhibitors (sNRIs) provide an effective class of approved antipsychotics, whose inhibitory mechanism could facilitate the discovery of privileged scaffolds with enhanced drug efficacy. However, the crystal structure of human norepinephrine transporter (hNET) has not been determined yet and the inhibitory mechanism of sNRIs remains elusive. In this work, multiple computational methods were integrated to explore the inhibitory mechanism of approved sNRIs (atomoxetine, maprotiline, reboxetine and viloxazine), and 3 lines of evidences were provided to verify the calculation results. Consequently, a binding mode defined by interactions between three chemical moieties in sNRIs and eleven residues in hNET was identified as shared by approved sNRIs. In the meantime, binding modes of reboxetine’s enantiomers with hNET were compared. 6 key residues favoring the binding of (S, S)-reboxetine over that of (R, R)-reboxetine were discovered. This is the first study reporting that those 11 residues are the common determinants for the binding of approved sNRIs. The identified binding mode shed light on the inhibitory mechanism of approved sNRIs, which could help identify novel scaffolds with improved drug efficacy.

The economic impact of introducing serotonin-noradrenaline reuptake inhibitors into the Brazilian national drug formulary: cost-effectiveness and budget-impact analyses.

PubMed

Machado, Márcio; Iskedjian, Michael; Ruiz, Inés A; Einarson, Thomas R

2007-01-01

To determine the cost effectiveness, from the Brazilian Ministry of Health viewpoint, of three antidepressant classes for major depressive disorder (MDD), and the budget impact of introducing serotonin-noradrenaline (norepinephrine) reuptake inhibitors (SNRIs) into the current Brazilian national drug formulary, assuming a 6-month treatment duration. An existing decision-tree model was adapted to Brazil, based on local guidelines. Clinical data were obtained from published meta-analyses. Patients included adults aged > or =18 years with MDD, diagnosed using the Diagnostic and Statistical Manual of Mental Disorders, third and fourth editions (DSM-III/IV), with moderate-to-severe disease (Hamilton Depression Rating Scale [HAMD] > or =15 or Montgomery-Asberg Depression Rating Scale [MADRS] > or =18), without co-morbidities or co-medications, receiving > or =6 weeks of treatment with SNRIs, selective serotonin reuptake inhibitors (SSRIs) and/or tricyclic antidepressants (TCAs). Clinical outcome was remission (HAMD < or =7 or MADRS < or =12). Direct costs (drugs, physician visits, hospitalisations) were included. Drug costs were obtained from the 2006 Brazilian National Drug Price List, and hospitalisation and physician costs from the 2006 Healthcare System database. Costs were valued in Brazilian Reais ($Brz), year 2006 values ($Brz1 = $US0.47). Univariate and Monte Carlo sensitivity analyses tested model robustness. Expected costs per patient treated were SNRIs $Brz4848; SSRIs $Brz5466; and TCAs $Brz5046, and overall success rates (primary plus secondary treatment across all decision tree branches) were SNRIs 78.1%; SSRIs 74.0%; and TCAs 76.4%. Average costs/success were SNRIs $Brz6209; SSRIs $Brz7385; and TCAs $Brz6602. SNRIs dominated in incremental cost-effectiveness analyses. Monte Carlo analysis confirmed drug classes' relative positions; however, there was considerable uncertainty. Introducing SNRIs into the formulary could generate average savings of 1% of the

Rapid screening of selective serotonin re-uptake inhibitors in urine samples using solid-phase microextraction gas chromatography-mass spectrometry.

PubMed

Salgado-Petinal, Carmen; Lamas, J Pablo; Garcia-Jares, Carmen; Llompart, Maria; Cela, Rafael

2005-07-01

In this paper a solid-phase microextraction-gas chromatography-mass spectrometry (SPME-GC-MS) method is proposed for a rapid analysis of some frequently prescribed selective serotonin re-uptake inhibitors (SSRI)-venlafaxine, fluvoxamine, mirtazapine, fluoxetine, citalopram, and sertraline-in urine samples. The SPME-based method enables simultaneous determination of the target SSRI after simple in-situ derivatization of some of the target compounds. Calibration curves in water and in urine were validated and statistically compared. This revealed the absence of matrix effect and, in consequence, the possibility of quantifying SSRI in urine samples by external water calibration. Intra-day and inter-day precision was satisfactory for all the target compounds (relative standard deviation, RSD, <14%) and the detection limits achieved were <0.4 ng mL(-1) urine. The time required for the SPME step and for GC analysis (30 min each) enables high throughput. The method was applied to real urine samples from different patients being treated with some of these pharmaceuticals. Some SSRI metabolites were also detected and tentatively identified.

Anhedonia in depressed patients on treatment with selective serotonin reuptake inhibitor anti-depressant--A two-centered study in Malaysia.

PubMed

Yee, Anne; Chin, Soo Cheng; Hashim, Aili Hanim bt; Harbajan Singh, Manveen Kaur A P; Loh, Huai Seng; Sulaiman, Ahmad Hatim; Ng, Chong Guan

2015-01-01

Anhedonia is the reduced ability to experience pleasure. It is a core symptom of depression and is particularly difficult to treat. This study aims to compare the level of anhedonia between depressed patients on anti-depressants and healthy subjects. A total of 111 depressed patients on selective serotonin reuptake inhibitor (SSRI) and 82 healthy subjects were recruited from the outpatient psychiatric services at two major general hospitals in a cross-sectional study. Subjects were assessed using the Mini International Neuropsychiatric Interview 5.0.0 or MINI, Beck's Depression Index (BDI), and Snaith-Hamilton Pleasure Scale (SHAPS). Relevant personal and sociodemographic information were also collected. There was a significant association between educational level and SHAPS-M scores (P < 0.01) among the participants. Most items in the SHAPS scores were significantly different (P < 0.01) in the depressed subjects treated with anti-depressant compared with the healthy subjects, after adjusting the confounding factors, BDI score, and educational level. Anhedonia often persists in depressed patients despite on SSRI anti-depressant treatment.

Compound stimulus presentation and the norepinephrine reuptake inhibitor atomoxetine enhance long-term extinction of cocaine-seeking behavior.

PubMed

Janak, Patricia H; Bowers, M Scott; Corbit, Laura H

2012-03-01

Drug abstinence is frequently compromised when addicted individuals are re-exposed to environmental stimuli previously associated with drug use. Research with human addicts and in animal models has demonstrated that extinction learning (non-reinforced cue-exposure) can reduce the capacity of such stimuli to induce relapse, yet extinction therapies have limited long-term success under real-world conditions (Bouton, 2002; O'Brien, 2008). We hypothesized that enhancing extinction would reduce the later ability of drug-predictive cues to precipitate drug-seeking behavior. We, therefore, tested whether compound stimulus presentation and pharmacological treatments that augment noradrenergic activity (atomoxetine; norepinephrine reuptake inhibitor) during extinction training would facilitate the extinction of drug-seeking behaviors, thus reducing relapse. Rats were trained that the presentation of a discrete cue signaled that a lever press response would result in cocaine reinforcement. Rats were subsequently extinguished and spontaneous recovery of drug-seeking behavior following presentation of previously drug-predictive cues was tested 4 weeks later. We find that compound stimulus presentations or pharmacologically increasing noradrenergic activity during extinction training results in less future recovery of responding, whereas propranolol treatment reduced the benefit seen with compound stimulus presentation. These data may have important implications for understanding the biological basis of extinction learning, as well as for improving the outcome of extinction-based therapies.

Prenatal selective serotonin reuptake inhibitor use and the risk of autism spectrum disorder in children: A systematic review and meta-analysis.

PubMed

Kaplan, Yusuf C; Keskin-Arslan, Elif; Acar, Selin; Sozmen, Kaan

2016-12-01

To determine whether an up-to-date systematic review and meta-analysis of observational studies would support the previously suggested associations regarding prenatal selective serotonin reuptake inhibitor (SSRI) use and the risk for autism spectrum disorders (ASD) in children. PubMed/MEDLINE, Cochrane Central Register of Controlled Trials and Reprotox databases were searched; observational studies with an exposed and unexposed group were included. The meta-analysis of case-control studies demonstrated a significantly increased risk of ASD in the children whose mothers were prenatally exposed to SSRIs during different exposure time windows (except third trimester). The qualitative review of the cohort studies suggested inconsistent findings. The significant association between preconception-only SSRI exposure and ASD in the children and negative/inconsistent findings among cohort studies weaken the significant associations detected in this meta-analysis. We suggest that confounding by indication still cannot be ruled out regarding prenatal SSRI exposure and ASD in children. Copyright © 2016 Elsevier Inc. All rights reserved.

Selective serotonin reuptake inhibitors for fibromyalgia syndrome

PubMed Central

Walitt, Brian; Urrútia, Gerard; Nishishinya, María Betina; Cantrell, Sarah E; Häuser, Winfried

2016-01-01

Background Fibromyalgia is a clinically well-defined chronic condition with a biopsychosocial aetiology. Fibromyalgia is characterized by chronic widespread musculoskeletal pain, sleep problems, cognitive dysfunction, and fatigue. Patients often report high disability levels and poor quality of life. Since there is no specific treatment that alters the pathogenesis of fibromyalgia, drug therapy focuses on pain reduction and improvement of other aversive symptoms. Objectives The objective was to assess the benefits and harms of selective serotonin reuptake inhibitors (SSRIs) in the treatment of fibromyalgia. Search methods We searched the Cochrane Central Register of Controlled Trials (CENTRAL; 2014, Issue 5), MEDLINE (1966 to June 2014), EMBASE (1946 to June 2014), and the reference lists of reviewed articles. Selection criteria We selected all randomized, double-blind trials of SSRIs used for the treatment of fibromyalgia symptoms in adult participants. We considered the following SSRIs in this review: citalopram, fluoxetine, escitalopram, fluvoxamine, paroxetine, and sertraline. Data collection and analysis Three authors extracted the data of all included studies and assessed the risks of bias of the studies. We resolved discrepancies by discussion. Main results The quality of evidence was very low for each outcome. We downgraded the quality of evidence to very low due to concerns about risk of bias and studies with few participants. We included seven placebo-controlled studies, two with citalopram, three with fluoxetine and two with paroxetine, with a median study duration of eight weeks (4 to 16 weeks) and 383 participants, who were pooled together. All studies had one or more sources of potential major bias. There was a small (10%) difference in patients who reported a 30% pain reduction between SSRIs (56/172 (32.6%)) and placebo (39/171 (22.8%)) risk difference (RD) 0.10, 95% confidence interval (CI) 0.01 to 0.20; number needed to treat for an additional

The monoamine reuptake inhibitor BTS 74 398 fails to evoke established dyskinesia but does not synergise with levodopa in MPTP-treated primates.

PubMed

Hansard, Matthew J; Smith, Lance A; Jackson, Michael J; Cheetham, Sharon C; Jenner, Peter

2004-01-01

Long-term treatment of Parkinson's disease (PD) with levodopa (L-dopa) induces dyskinesia that, once established, is provoked by each dose of L-dopa or a dopamine (DA) agonist. In contrast, monoamine reuptake inhibitors may reverse motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated primates without provoking established involuntary movements. We now examine whether the potent monoamine reuptake blocker BTS 74 398 induces established dyskinesia in MPTP-treated common marmosets primed previously with L-dopa and whether co-administration of BTS 74 398 with L-dopa potentiates motor behaviour and dyskinesia induced by acute L-dopa treatment. Administration of BTS 74 398 (2.5, 5.0, or 10.0 mg/kg, p.o.) in MPTP-treated common marmosets increased locomotor activity and reduced motor disability in a dose-related manner but did not provoke involuntary movements. BTS 74 398 (2.5, 5.0, or 10.0 mg/kg p.o.) co-administered with a threshold dose of L-dopa (2.5 mg/kg p.o.) did not evoke a motor response or induce dyskinesia. Similarly, concomitant administration of BTS 74 398 (5.0 mg/kg p.o.) with a submaximal L-dopa dose (12.5 mg/kg p.o.) did not potentiate the motor response produced by L-dopa alone and there was no alteration in the dyskinesia provoked by L-dopa challenge. BTS 74 398 reverses motor abnormalities in MPTP-treated marmosets without evoking established dyskinesia but no additive improvement occurs when administered in combination with L-dopa. The lack of synergy with L-dopa may suggest different sites of drug action. Copyright 2003 Movement Disorder Society

Adherence to Selective Serotonin and Serotonin-Norepinephrine Reuptake Inhibitor Prescriptions Affects Overall Medication Adherence in Older Persons: Evidence From the Italian Nationwide OsMed Health-DB Database.

PubMed

Marengoni, Alessandra; Onder, Graziano; Degli Esposti, Luca; Russo, Pierluigi; Sangiorgi, Diego; Buda, Stefano; Fini, Massimo; Marchionni, Niccolò; Bonassi, Stefano; Mammarella, Federica; Marrocco, Walter; Pozzi, Giuseppe; Palmer, Katie; Monaco, Alessandro; Pecorelli, Sergio; Pani, Luca

2016-12-01

This study aimed to evaluate prevalence of prescription of and adherence to selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs) and whether adherence to these classes of drugs affects overall medication adherence in older persons. In a cross-sectional analysis of administrative data comprehensive of all prescribed drugs reimbursed by the Italian national health care system, new prescriptions of SSRIs and SNRIs to persons aged 65 years or older were analyzed (n = 380,400 in 2011; 395,806 in 2012; 409,741 in 2013, from a total sample of 3,762,299 persons aged 65 years or older) as well as prescriptions of antihypertensives, statins, other psychiatric drugs, antidiabetics, antiplatelets, anticoagulants, drugs for chronic obstructive pulmonary disease, and antiosteoporotics. Adherence was estimated by calculating the proportion of days covered by drugs dispensed during a period of 365 days. Adherence was defined as a proportion of days covered of more than 80%. Prevalence of SSRI and SNRI prescriptions varied from 11.4% in 2011 to 12.1% in 2013. Adherence to SSRI and SNRI prescriptions ranged from 31.2% in persons aged ≥ 95 years in 2011 to 41.8% in persons aged 75-84 years in 2013. Persons adherent to SSRI and SNRI prescriptions were more likely to be adherent to the other medications, after adjustment for age, gender, and number of drugs prescribed. The highest association was found for adherence to psychiatric drugs (OR = 1.9; 95% CI, 1.8-2.0). Adherence to SSRI and SNRI prescriptions is poor in older persons. However, people adherent to these classes of antidepressants are more likely to be adherent to the other medications they are prescribed. Studies are needed to evaluate the reasons for and the potential benefits of increasing adherence to antidepressants on overall adherence. © Copyright 2016 Physicians Postgraduate Press, Inc.

Long-term follow-up study of patients with serotonin reuptake inhibitor-nonresponsive obsessive-compulsive disorder.

PubMed

Reddy, Y C Janardhan; Alur, Adarsha M; Manjunath, Smitha; Kandavel, Thennarasu; Math, Suresh Bada

2010-06-01

There is a paucity of data on the long-term outcome of serotonin reuptake inhibitor (SRI)-nonresponsive obsessive-compulsive disorder (OCD). We report long-term outcome of OCD in subjects who had not responded to at least 2 adequate trials of SRIs. This is a naturalistic follow-up of 36 (72%) of 50 SRI nonresponders with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition OCD, after about 4.5 years. Two had committed suicide (4%), and 12 (24%) could not be traced or refused consent. The study has a catch-up longitudinal design. The primary outcome measure was "remission," measured using the Psychiatric Status Rating Scale. Multiple logistic backward (Wald) regression analysis was used to identify predictors of remission. Of the 36 subjects, 14 were in remission (39%): 4 were in full remission (11%) and 10 were in partial remission (28%). Those who remitted were considered to have good outcome. Not having received cognitive behavior therapy (CBT) in the interval period, poorer quality of life at baseline, shorter duration of follow-up, and later age at onset predicted poor outcome. Study findings suggest that a substantial proportion of OCD patients with proven SRI nonresponse improve over a period, possibly because of continued efforts to treat them. The prognosis of SRI nonresponders need not be viewed pessimistically, and if treated aggressively with both medications and CBT, they may continue to show improvement. There is an urgent need to systematically examine the efficacy of various treatment options, particularly CBT in treating SRI nonresponders.

Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression.

PubMed

Xu, Xiangqing; Wei, Yaqin; Guo, Qiang; Zhao, Song; Liu, Zhiqiang; Xiao, Ting; Liu, Yani; Qiu, Yinli; Hou, Yuanyuan; Zhang, Guisen; Wang, KeWei

2018-06-01

Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3-arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin ( K i = 4.81 nM) and norepinephrine (NE) ( K i = 6.72 nM) transporters and moderate 5-HT 2A antagonist activity (IC 50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT 2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment-resistant depression, and it may warrant further evaluation for clinical development. Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.

A double-blind, placebo-controlled study of edivoxetine as an adjunctive treatment for patients with major depressive disorder who are partial responders to selective serotonin reuptake inhibitor treatment.

PubMed

Ball, Susan; Dellva, Mary Anne; D'Souza, Deborah N; Marangell, Lauren B; Russell, James M; Goldberger, Celine

2014-01-01

This phase 2 study examined the efficacy and tolerability of edivoxetine, a highly selective norepinephrine reuptake inhibitor, as an adjunctive treatment for patients with major depressive disorder (MDD) who have a partial response to selective serotonin reuptake inhibitor (SSRI) treatment. Study design consisted of double-blind, 10-week therapy of adjunctive edivoxetine (6-18 mg once daily) or adjunctive placebo with SSRI. Inclusion/entry criteria included partial response to current SSRI by investigator opinion and a GRID 17-item Hamilton Rating Scale for Depression (HAMD17) total score ≥16. The primary efficacy measure was the Montgomery-Asberg Depression Rating Scale (MADRS). Safety measures included treatment-emergent adverse events (TEAE) and vital signs. For the primary evaluable population (n=63 for adjunctive edivoxetine and n=68 for adjunctive placebo), the treatment groups did not differ significantly on the primary outcome of change from baseline to week 8 in the MADRS total score; the effect size of edivoxetine treatment was 0.26. Significant treatment differences, favoring adjunctive edivoxetine (p≤.05), were shown for improvements in role functioning and the functional impact of fatigue. For the adjunctive edivoxetine randomized group (N=111), the most frequent TEAEs were hyperhidrosis (7.2%), nausea (7.2%), erectile dysfunction (6.3%) and testicular pain (6.3%). Hemodynamic changes were observed in blood pressure and pulse rate between treatment groups. Study was underpowered for an alpha 2-sided 0.05 significance level for the primary outcome. For patients with MDD who had a partial response to SSRIs, adjunctive edivoxetine treatment was not statistically superior to adjunctive placebo on the primary outcome measure. However, pending further study, improved functioning and remission rate suggest a potential role for edivoxetine for patients with depression. Copyright © 2014 Elsevier B.V. All rights reserved.

Are selective serotonin reuptake inhibitors safe for drivers? What is the evidence?

PubMed

Ravera, Silvia; Ramaekers, Johannes G; de Jong-van den Berg, Lolkje T W; de Gier, Johan J

2012-05-01

Selective serotonin reuptake inhibitors (SSRIs) are widely used medications to treat several psychiatric diseases and, above all, depression. They seem to be as effective as older antidepressants but have a different adverse effect profile. Despite their favorable safety profile, little is known about their influence on traffic safety. To conduct a literature review to summarize the current evidence on the role of SSRIs in traffic safety, particularly concerning undesirable effects that could potentially impair fitness to drive, experimental and pharmacoepidemiologic studies on driving impairment, 2 existing categorization systems for driving-impairing medications, and the European legislative procedures for assessing fitness to drive before issuing a driver's license and driving under the influence of medicines. The article search was performed in the following electronic databases: MEDLINE, PsycINFO, ScienceDirect, and SafetyLit. The English-language scientific literature was searched using key words such as SSRIs and psychomotor performance, car crash or traffic accident, and adverse effects. For inclusion in this review, papers had to be full-text articles, refer to possible driving-related adverse effects, and be experimental or pharmacoepidemiologic studies on SSRIs and traffic accident risks. No restrictions concerning publication year were applied. Ten articles were selected as background information on driving-related adverse effects, and 15 articles were selected regarding experimental and pharmacoepidemiologic work. Regarding SSRI adverse effects, the most reported undesirable effects referring to driving impairment were anxiety, agitation, sleep disturbances, headache, increased risk of suicidal behavior, and deliberate self-harm. Regarding the remaining issues addressed in this article, inconsistencies were found between the outcomes of the selected experimental and epidemiologic studies and between the 2 existing categorization systems under

5-HT2C receptors in the BNST are necessary for the enhancement of fear learning by selective serotonin reuptake inhibitors.

PubMed

Pelrine, Eliza; Pasik, Sara Diana; Bayat, Leyla; Goldschmiedt, Debora; Bauer, Elizabeth P

2016-12-01

Selective serotonin reuptake inhibitors (SSRIs) are widely prescribed to treat anxiety and depression, yet they paradoxically increase anxiety during initial treatment. Acute administration of these drugs prior to learning can also enhance Pavlovian cued fear conditioning. This potentiation has been previously reported to depend upon the bed nucleus of the stria terminalis (BNST). Here, using temporary inactivation, we confirmed that the BNST is not necessary for the acquisition of cued or contextual fear memory. Systemic administration of the SSRI citalopram prior to fear conditioning led to an upregulation of the immediate early gene Arc (activity-regulated cytoskeleton-associated protein) in the oval nucleus of the BNST, and a majority of these neurons expressed the 5-HT2C receptor. Finally, local infusions of a 5-HT2C receptor antagonist directly into the oval nucleus of the BNST prevented the fear memory-enhancing effects of citalopram. These findings highlight the ability of the BNST circuitry to be recruited into gating fear and anxiety-like behaviors. Copyright © 2016 Elsevier Inc. All rights reserved.

Neurodevelopment of children prenatally exposed to selective reuptake inhibitor antidepressants: Toronto sibling study.

PubMed

Nulman, Irena; Koren, Gideon; Rovet, Joanne; Barrera, Maru; Streiner, David L; Feldman, Brian M

2015-07-01

The reproductive safety of selective reuptake inhibitor (SRI) antidepressants needs to be established to provide optimal control of maternal depression while protecting the fetus. To define a child's neurodevelopment following prenatal exposure to SRIs and to account for genetic and environmental confounders in a sibling design using the Toronto Motherisk prospective database. Intelligence and behavior of siblings prenatally exposed and unexposed to SRIs were assessed by using the Wechsler Preschool and Primary Scale of Intelligence-Third Edition, Child Behavior Checklist, and Conners Parent Rating Scale-Revised and subsequently compared. Mothers, diagnosed with depression using DSM-IV, were assessed for intelligence quotient (IQ) and for severity of depressive symptoms with the Center for Epidemiologic Studies Depression scale. Prenatal drug doses and durations of exposure, child's age, child's sex, birth order, severity of maternal depression symptoms, and Full Scale IQ, the primary outcome measure, of both the mother and the child were considered in the analyses. Forty-five sibling pairs (ages 3 years to 6 years 11 months, prenatally exposed and unexposed to SRIs) did not differ in their mean ± SD Full Scale IQs (103 ± 13 vs 106 ± 12; P = .30; 95% CI, -7.06 to 2.21) or rates of problematic behaviors. Significant predictor of children's intelligence was maternal IQ (P = .043, β = 0.306). Severity of maternal depression was a significant predictor of Child Behavior Checklist Internalizing (P = .019, β = 0.366), Externalizing (P = .003, β = 0.457), and Total scores (P = .001, β = 0.494). Drug doses and durations of exposure during pregnancy did not predict any outcomes of interest in the exposed siblings. SRI antidepressants were not found to be neurotoxic. Maternal depression may risk the child's future psychopathology. The sibling design in behavioral teratology aids in separating the effects of maternal depression from those of SRIs, providing stronger

Extinction of alcohol seeking is enhanced by compound extinction and the noradrenaline reuptake inhibitor atomoxetine.

PubMed

Leung, Hiu T; Corbit, Laura H

2017-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli provides a means for reducing their impact on relapse. However, the expression of extinction can be disrupted by exposure to the previous reinforcer as well as the simple passage of time. We investigated whether augmentation of prediction error or of noradrenaline neurotransmission by the reuptake inhibitor atomoxetine would enhance long-term extinction of alcohol-seeking behavior. Rats received Pavlovian conditioning of multiple stimuli signaling the delivery of an alcohol reward before individual extinction was given to each of these stimuli. Further extinction was then given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg/kg; Experiment 2). Experiment 3 examined whether the compound stimulus effect relied on noradrenergic activity by testing the effects of the β-adrenergic antagonist propranolol, given prior to compound stimulus trials. Long-term retention of extinction learning was assessed a week later. Compound stimulus presentations enhanced long-term extinction as the stimulus extinguished in compound elicited less responding than a stimulus receiving equal extinction alone when tested a week later. This effect was mimicked by atomoxetine and blocked by propranolol given during extinction training. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Both behavioral and neurobiological processes could be exploited to enhance the outcome of extinction-based treatments for alcohol use disorders. © 2015 Society for the Study of Addiction.

Meta-analysis of selective serotonin reuptake inhibitors in patients with depression and coronary heart disease.

PubMed

Pizzi, Carmine; Rutjes, Anne Wilhelmina Saskia; Costa, Grazia Maria; Fontana, Fiorella; Mezzetti, Andrea; Manzoli, Lamberto

2011-04-01

The occurrence of depression in patients with coronary heart disease (CHD) substantially increases the likelihood of a poorer cardiovascular prognosis. Although antidepressants are generally effective in decreasing depression, their use in patients with CHD is controversial. We carried out a meta-analysis to evaluate the health effects of selective serotonin reuptake inhibitors (SSRIs) versus placebo or no antidepressants in patients with CHD and depression. Observational studies and randomized controlled trials (RCTs) were searched in MEDLINE, EMBASE, PsycINFO, Cochrane Controlled Clinical Trial Register and other trial registries, and references of relevant articles. Primary outcomes were readmission for CHD (including myocardial infarction, unstable angina, and stroke) and all-cause mortality; the secondary outcome was severity of depression symptoms. Seven articles on 6 RCTs involving 2,461 participants were included. One study incorrectly randomized participants, and another was a reanalysis of RCT data. These were considered observational and analyzed separately. When only properly randomized trials were considered (n = 734 patients), patients on SSRIs showed no significant differences in mortality (risk ratio 0.39, 95% confidence interval 0.08 to 2.01) or CHD readmission rates (0.74, 0.44 to 1.23) compared to controls. Conversely, when all studies were included, SSRI use was associated with a significant decrease in CHD readmission (0.63, 0.46 to 0.86) and mortality rates (0.56, 0.35 to 0.88). A significantly greater improvement in depression symptoms was always apparent in patients on SSRIs with all selected indicators. In conclusion, in patients with CHD and depression, SSRI medication decreases depression symptoms and may improve CHD prognosis. Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.

Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study.

PubMed

Molero, Yasmina; Lichtenstein, Paul; Zetterqvist, Johan; Gumpert, Clara Hellner; Fazel, Seena

2015-09-01

Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain. From Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08-1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19-1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25-34 y (HR = 1.20, 95% CI 0.95-1.52, p = 0.125, absolute risk = 1.6%), in those aged 35-44 y (HR = 1.06, 95% CI 0.83-1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84-1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16-1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10-1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07-1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22-1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse (HR = 1.98, 95% CI 1.76-2.21, p < 0.001). With age and

Efficacy of bupropion and the selective serotonin reuptake inhibitors in the treatment of major depressive disorder with high levels of anxiety (anxious depression): a pooled analysis of 10 studies.

PubMed

Papakostas, George I; Stahl, Stephen M; Krishen, Alok; Seifert, Cheryl A; Tucker, Vivian L; Goodale, Elizabeth P; Fava, Maurizio

2008-08-01

The goal of this work was to compare the efficacy of the norepinephrine and dopamine reuptake inhibitor bupropion with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder with high levels of anxiety (anxious depression). Ten double-blind, randomized studies from 1991 through 2006 were combined (N = 2122). Anxious depression was defined as a 17-item Hamilton Rating Scale for Depression (HAM-D-17) anxiety-somatization factor score >or= 7. Among patients with anxious depression (N = 1275), response rates were greater following SSRI than bupropion treatment according to the HAM-D-17 (65.4% vs. 59.4%, p = .03) and the Hamilton Rating Scale for Anxiety (61.5% vs. 54.5%, p = .03). There was also a greater reduction in HAM-D-17 mean +/- SD scores (-14.1 +/- 7.6 vs. -13.2 +/- 7.9, p = .03) and a trend toward statistical significance for a greater reduction in HAM-A mean +/- SD scores (-10.5 +/- 7.4 vs. -9.6 +/- 7.6, p = .05) in favor of SSRI treatment among patients with anxious depression. There was no statistically significant difference in efficacy between bupropion and the SSRIs among patients with moderate/low levels of anxiety. There appears to be a modest advantage for the SSRIs compared to bupropion in the treatment of anxious depression (6% difference in response rates). Using the number-needed-to-treat (NNT) statistic as 1 indicator of clinical significance, nearly 17 patients would need to be treated with an SSRI than with bupropion in order to obtain 1 additional responder. This difference falls well above the limit of NNT = 10, which was suggested by the United Kingdom's National Institute of Clinical Excellence. Nevertheless, the present work is of theoretical interest because it provides preliminary evidence suggesting a central role for serotonin in the regulation of symptoms of negative affect such as anxiety.

Solid-phase microextraction-gas chromatography-mass spectrometry for the analysis of selective serotonin reuptake inhibitors in environmental water.

PubMed

Lamas, J Pablo; Salgado-Petinal, Carmen; García-Jares, Carmen; Llompart, María; Cela, Rafael; Gómez, Mariano

2004-08-13

The continuous contamination of surface waters by pharmaceuticals is of most environmental concern. Selective serotonin reuptake inhibitors (SSRIs) are drugs currently prescribed for the treatment of depressions and other psychiatric disorders and then, they are among the pharmaceuticals that can occur in environmental waters. Solid-phase microextraction (SPME) coupled to gas chromatography-mass spectrometry has been applied to the extraction of five SSRIs--venlafaxine, fluvoxamine, fluoxetine, citalopram and sertraline--from water samples. Some of the analytes were not efficiently extracted as underivatized compounds and so, an in situ acetylation step was introduced in the sample preparation procedure. Different parameters affecting extraction efficiency such as extraction mode, fiber coating and temperature were studied. A mixed-level fractional factorial design was also performed to simultaneously study the influence of other five experimental factors. Finally, a method based on direct SPME at 100 degrees C using polydimethylsiloxane-divinylbenzene fibers is proposed. The performance of the method was evaluated, showing good linearity and precision. The detection limits were in the sub-ng/mL level. Practical applicability was demonstrated through the analysis of real samples. Recoveries obtained for river water and wastewater samples were satisfactory in all cases. An important aspect of the proposed method is that no matrix effects were observed. Two of the target compounds, venlafaxine and citalopram, were detected and quantified in a sewage water sample.

Environmental risk assessment of three selective serotonin reuptake inhibitors in the aquatic environment: a case study including a cocktail scenario.

PubMed

Styrishave, Bjarne; Halling-Sørensen, Bent; Ingerslev, Flemming

2011-01-01

We present an environmental risk assessment of three selective serotonin reuptake inhibitors (SSRIs; citalopram, sertraline, and fluoxetine) in the aquatic environment based on two case scenarios. Abiotic and biotic degradation experiments and sorption estimates were used to predict environmental concentrations of three SSRIs from the wastewater of two psychiatric hospitals, the primary sector, and wastewater entering and leaving wastewater treatment plants (WWTPs). Assuming a sewage treatment retention time of 8 h, abiotic degradation was low, for all three SSRIs inhibitors, ranging between 0 and 2% for hydrolysis and 0 and 6% for photolysis. The biodegradation was also slow, ranging from 0 to 3% within an 8-h period. In untreated sewage, citalopram (CIT) and sertraline (SER) concentrations may be high enough to exert effects on the aquatic biota (CIT: 0.19-10.3 µg/L; SER: 0.14-17.1 µg/L). Removal of the pharmaceuticals is due primarily to sorption in the WWTP. Sertraline was estimated to have the highest concentrations in the sewage effluents, 4.4 and 19.9 ng/L for the two cases, respectively. In treated wastewater, individual SSRI concentrations are probably too low to exert effects on biota. By using concentration addition, a cocktail exposure scenario was estimated. The predicted concentration in the biota calculated from the cocktail effect was 0.05 and 0.16 nmol/g for the two cases, respectively, and SER was found to give the highest contribution to this cocktail effect. The results indicate that the concentrations in the wastewater effluents are one to two orders of magnitude lower than the concentrations likely to cause an effect in the aquatic biota. © 2010 SETAC.

Monoamine reuptake site occupancy of sibutramine: Relationship to antidepressant-like and thermogenic effects in rats.

PubMed

Li, Yu-Wen; Langdon, Shaun; Pieschl, Rick; Strong, Todd; Wright, Robert N; Rohrbach, Kenneth; Lelas, Snjezana; Lodge, Nicholas J

2014-08-15

Sibutramine was formerly marketed as an anti-obesity agent. The current study investigated the relationships between monoamine reuptake site occupancy for sibutramine and both its antidepressant-like efficacy and thermogenic effects. Sibutramine's effects on locomotor activity (LMA) and food intake were also evaluated. Sibutramine occupied monoamine reuptake binding sites with the rank order of potency of NET>SERT>DAT; at 10mg/kg, po, occupancy was 95% NET, 81% SERT and 73% DAT. Sibutramine produced antidepressant-like behavior in the forced swim test; at the lowest effective dose (3mg/kg, po) occupancy was 61%, 90% and 23% at SERT, NET and DAT sites, respectively. Sibutramine also increased body core temperature in a dose- and time-dependent manner; at the lowest effective dose (30mg/kg) SERT, NET and DAT occupancies were respectively 78%, 86% and 59%. A significant decrease in food consumption was observed at 3 and 10mg/kg, po. LMA was increased at ≥10mg/kg, sc. The relationship between efficacy in the FST and occupancy was also determined for citalopram, fluoxetine and reboxetine. Similarly, the relationship between thermogenesis and target occupancy for several single or double/triple reuptake inhibitors was measured and showed that >40-50% DAT binding was required for thermogenesis. Thermogenesis was blocked by the D1 antagonist SCH39166 (3mg/kg, sc). Our findings indicate that the antidepressant-like effect of sibutramine may result from additive or synergistic actions on the three reuptake binding targets. At higher doses, sibutramine produces thermogenesis; DAT inhibition and activation of dopamine D1 receptors are required for this effect. Published by Elsevier B.V.

Five Patients With Burning Mouth Syndrome in Whom an Antidepressant (Serotonin-Noradrenaline Reuptake Inhibitor) Was Not Effective, but Pregabalin Markedly Relieved Pain.

PubMed

Ito, Mikiko; Tokura, Tatsuya; Yoshida, Keizo; Nagashima, Wataru; Kimura, Hiroyuki; Umemura, Eri; Tachibana, Masako; Miyauchi, Tomoya; Kobayashi, Yuka; Arao, Munetaka; Ozaki, Norio; Kurita, Kenichi

2015-01-01

Burning mouth syndrome (BMS) causes idiopathic pain or a burning sensation in clinically normal oral mucosa. Burning mouth syndrome is a chronic disease with an unknown etiology. Burning mouth syndrome is also idiopathic, and a consensus regarding diagnosis/treatment has not been reached yet. Recent studies have supported the suggestion that BMS is a neuropathic pain disorder in which both the peripheral and central nervous systems are involved. Tricyclic antidepressants (nortriptyline and amitriptyline), serotonin-noradrenaline reuptake inhibitors (SNRIs) (duloxetine and milnacipran), and antiepileptic drugs, potential-dependent calcium channel α2δ subunit ligands (gabapentine and pregabalin), are currently recommended as the first-choice drugs for neuropathic pain. In this study, we report 5 patients with BMS in whom there was no response to SNRI (milnacipran or duloxetine), or administration was discontinued because of adverse reactions, but in whom pregabalin therapy markedly reduced or led to the disappearance of pain in a short period. Pregabalin, whose mechanism of action differs from that of SNRIs, may become a treatment option for BMS patients who are not responsive to or are resistant to SNRIs.

Feature extraction using molecular planes for fuzzy relational clustering of a flexible dopamine reuptake inhibitor.

PubMed

Banerjee, Amit; Misra, Milind; Pai, Deepa; Shih, Liang-Yu; Woodley, Rohan; Lu, Xiang-Jun; Srinivasan, A R; Olson, Wilma K; Davé, Rajesh N; Venanzi, Carol A

2007-01-01

Six rigid-body parameters (Shift, Slide, Rise, Tilt, Roll, Twist) are commonly used to describe the relative displacement and orientation of successive base pairs in a nucleic acid structure. The present work adapts this approach to describe the relative displacement and orientation of any two planes in an arbitrary molecule-specifically, planes which contain important pharmacophore elements. Relevant code from the 3DNA software package (Nucleic Acids Res. 2003, 31, 5108-5121) was generalized to treat molecular fragments other than DNA bases as input for the calculation of the corresponding rigid-body (or "planes") parameters. These parameters were used to construct feature vectors for a fuzzy relational clustering study of over 700 conformations of a flexible analogue of the dopamine reuptake inhibitor, GBR 12909. Several cluster validity measures were used to determine the optimal number of clusters. Translational (Shift, Slide, Rise) rather than rotational (Tilt, Roll, Twist) features dominate clustering based on planes that are relatively far apart, whereas both types of features are important to clustering when the pair of planes are close by. This approach was able to classify the data set of molecular conformations into groups and to identify representative conformers for use as template conformers in future Comparative Molecular Field Analysis studies of GBR 12909 analogues. The advantage of using the planes parameters, rather than the combination of atomic coordinates and angles between molecular planes used in our previous fuzzy relational clustering of the same data set (J. Chem. Inf. Model. 2005, 45, 610-623), is that the present clustering results are independent of molecular superposition and the technique is able to identify clusters in the molecule considered as a whole. This approach is easily generalizable to any two planes in any molecule.

Bleeding risk under selective serotonin reuptake inhibitor (SSRI) antidepressants: A meta-analysis of observational studies.

PubMed

Laporte, Silvy; Chapelle, Céline; Caillet, Pascal; Beyens, Marie-Noëlle; Bellet, Florelle; Delavenne, Xavier; Mismetti, Patrick; Bertoletti, Laurent

2017-04-01

Selective serotonin reuptake inhibitors (SSRIs) have been reported to be potentially associated with an increased risk of bleeding. A meta-analysis of observational studies was conducted to quantify this risk. Case-control and cohort studies investigating bleeding risk under SSRI therapy were retrieved by searching the Medline, Pascal, Google Scholar and Scopus databases. Case-control studies were included if they reported bleeding incidents with and without the use of SSRIs and cohort studies were included if they reported the rate of bleeds among SSRI users and non-users. The main outcome was severe bleeding, whatever the site. Only data concerning SSRI belonging to the ATC class N06AB were used. For both case-control and cohort studies, we recorded the adjusted effect estimates and their 95% confidence intervals (CI). Pooled adjusted odds ratio (OR) estimates were computed for case-control and cohort studies using an inverse-variance model. Meta-analysis of the adjusted ORs of 42 observational studies showed a significant association between SSRI use and the risk of bleeding [OR 1.41 (95% CI 1.27-1.57), random effect model, p<0.0001]. The association was found for the 31 case-control studies (1,255,073 patients), with an increased risk of 41% of bleeding [OR 1.41 (95% CI 1.25-1.60)], as well as for the 11 cohort studies including 187,956 patients [OR 1.36 (95% CI 1.12-1.64)]. Subgroup analyses showed that the association remained constant whatever the characteristics of studies. This meta-analysis shows an increased risk of bleeding of at least 36% (from 12% to 64%) based on the high-level of observational studies with SSRIs use. Copyright © 2016 Elsevier Ltd. All rights reserved.

Tramadol: Effects on sexual behavior in male rats are mainly caused by its 5-HT reuptake blocking effects.

PubMed

Olivier, Jocelien D A; Esquivel Franco, Diana C; Oosting, Ronald; Waldinger, Marcel; Sarnyai, Zoltan; Olivier, Berend

2017-04-01

Tramadol is a well-known and effective analgesic. Recently it was shown that tramadol is also effective in human premature ejaculation. The inhibitory effect of tramadol on the ejaculation latency is probably due to its mechanism of action as a μ-opioid receptor agonist and noradrenaline/serotonin (5-HT) reuptake inhibitor. In order to test this speculation, we tested several doses of tramadol in a rat model of male sexual behavior and investigated two types of drugs interfering with the μ-opioid and the 5-HT system. First the μ-opioid receptor agonist properties of tramadol were tested with naloxone, a μ-opioid receptor antagonist. Second, the effects of WAY100,635, a 5-HT 1A receptor antagonist, were tested on the behavioral effects of tramadol. Finally the effects of paroxetine, a selective serotonin reuptake inhibitor, combined with naloxone or WAY100,635 treatment, were compared to the effects of tramadol combined with these drugs. Results showed that naloxone, at a sexually inactive dose, could only partially antagonize the inhibitory effect of tramadol. Moreover, low and behaviorally inactive doses of WAY100,635, strongly decreased sexual behavior when combined with a behaviorally inactive dose of tramadol. Finally we showed that the effects of paroxetine on sexual behavior resembled the effects of tramadol, indicating that tramadol's inhibitory effects on sexual behavior are primarily and mainly caused by its SSRI properties and that its μ-opioid receptor agonistic activity only contributes marginally. These findings support the hypothesis that tramadol exerts inhibition of premature ejaculations in men by its 5-HT reuptake inhibiting properties. Copyright © 2016 Elsevier Ltd. All rights reserved.

Selective Serotonin Reuptake Inhibitors and Violent Crime: A Cohort Study

PubMed Central

Molero, Yasmina; Lichtenstein, Paul; Zetterqvist, Johan; Gumpert, Clara Hellner; Fazel, Seena

2015-01-01

Background Although selective serotonin reuptake inhibitors (SSRIs) are widely prescribed, associations with violence are uncertain. Methods and Findings From Swedish national registers we extracted information on 856,493 individuals who were prescribed SSRIs, and subsequent violent crimes during 2006 through 2009. We used stratified Cox regression analyses to compare the rate of violent crime while individuals were prescribed these medications with the rate in the same individuals while not receiving medication. Adjustments were made for other psychotropic medications. Information on all medications was extracted from the Swedish Prescribed Drug Register, with complete national data on all dispensed medications. Information on violent crime convictions was extracted from the Swedish national crime register. Using within-individual models, there was an overall association between SSRIs and violent crime convictions (hazard ratio [HR] = 1.19, 95% CI 1.08–1.32, p < 0.001, absolute risk = 1.0%). With age stratification, there was a significant association between SSRIs and violent crime convictions for individuals aged 15 to 24 y (HR = 1.43, 95% CI 1.19–1.73, p < 0.001, absolute risk = 3.0%). However, there were no significant associations in those aged 25–34 y (HR = 1.20, 95% CI 0.95–1.52, p = 0.125, absolute risk = 1.6%), in those aged 35–44 y (HR = 1.06, 95% CI 0.83–1.35, p = 0.666, absolute risk = 1.2%), or in those aged 45 y or older (HR = 1.07, 95% CI 0.84–1.35, p = 0.594, absolute risk = 0.3%). Associations in those aged 15 to 24 y were also found for violent crime arrests with preliminary investigations (HR = 1.28, 95% CI 1.16–1.41, p < 0.001), non-violent crime convictions (HR = 1.22, 95% CI 1.10–1.34, p < 0.001), non-violent crime arrests (HR = 1.13, 95% CI 1.07–1.20, p < 0.001), non-fatal injuries from accidents (HR = 1.29, 95% CI 1.22–1.36, p < 0.001), and emergency inpatient or outpatient treatment for alcohol intoxication or misuse

Serotonin reuptake inhibitors and mortality in epilepsy: A linked primary-care cohort study.

PubMed

Josephson, Colin B; Gonzalez-Izquierdo, Arturo; Denaxas, Spiros; Fitzpatrick, Natalie K; Sajobi, Tolulope T; Engbers, Jordan D T; Patten, Scott; Jette, Nathalie; Wiebe, Samuel

2017-11-01

Preliminary evidence suggests that serotonin reuptake inhibitor (SRI) use may increase postictal respiratory drive and prevent death. We sought to determine whether SRIs are associated with improved all-cause and possible seizure-specific mortality in patients with epilepsy. Patients with epilepsy and a random 10:1 sample without epilepsy were extracted from The ClinicAl research using LInked Bespoke studies and Electronic health Records (CALIBER) resource. The hazard ratio (HR) of all-cause and possible seizure-specific mortality, treating SRI use as a time-varying covariate, was determined using the date of a second SRI prescription as exposure and in discrete 6-month periods over the entire duration of follow-up. We used Cox regression and competing risk models with Firth correction to calculate the HR. We controlled for age, sex, depression, comorbidity, (Charlson comorbidity index) and socioeconomic status (Index of Multiple Deprivation). We identified 2,718,952 eligible patients in CALIBER, of whom 16,379 (0.60%) had epilepsy. Median age and follow-up were 44 (interquartile range [IQR] 29-61]) and 6.4 years (IQR 2.4-10.4 years), respectively, and 53% were female. A total of 2,178 patients (13%) had at least two SRI prescriptions. Hazard of all-cause mortality was significantly elevated following a second prescription for an SRI (HR 1.64 95% confidence interval [95% CI] 1.44-1.86; p < 0.001). The HR was similar in 163,778 age, sex, and general practitioner (GP) practice-matched controls without epilepsy. Exposure to an SRI was not associated with seizure-related death (HR 1.08, 95% CI 0.59-1.97; 0.796). There is no evidence in this large population-based cohort that SRIs protect against all-cause mortality or seizure-specific mortality. Rather, SRI use was associated with increased mortality, irrespective of epilepsy, which is probably due to various factors associated with the use of antidepressants. Larger studies with systematically collected clinical

Pharmacokinetic profiles contribute to the differences in behavioral pharmacology of 071031B enantiomers as novel serotonin and norepinephrine reuptake inhibitors.

PubMed

Xue, Rui; Li, Ying; He, Xin-Hua; Jin, Zeng-Liang; Fan, Shi-Yong; Zhang, Ting-Ting; Li, Nuo-Min; Yuan, Li; Zheng, Ai-Ping; Zhong, Bo-Hua; Li, Yun-Feng; Zhang, You-Zhi

2017-03-01

Our previous study indicated that a chiral compound 071031B was a novel serotonin and noradrenaline reuptake inhibitor with superior antidepressant activity compared to duloxetine. The present study aimed to investigate chiral pharmacology differences of 071031B enantiomers, S-071031B and R-071031B, and disclose mechanisms underlying the behavioral differences based on target profiles and pharmacokinetic profiles. In vivo behavioral tests indicated that S-071031B was more potent than R-071031B in two depression models (the forced swimming test in mice and rats) and two pain models (the acetic acid-induced writhing and formalin tests in mice). In vitro assays revealed that both S-071031B and R-071031B showed high affinity for human serotonin transporters and norepinephrine transporters with equal potency, and showed consistently equipotent inhibitory effects on serotonin and norepinephrine uptake. Pharmacokinetic studies demonstrated that oral availability and hepatic metabolism, rather than pH stability, intestinal transport, and plasma binding, contributed to enantiomers' behavioral differences. Based on these findings, it is suggested that S-071031B is a more active enantiomer, and the differential pharmacokinetic profiles, but not target affinity, contribute to differences of S-071031B and R-071031B in behavioral pharmacology. Moreover, current PK-PD study may provide positive exploration for chiral antidepressants development.

Effect of selective serotonin reuptake inhibitors and immunomodulator on cytokines levels: an alternative therapy for patients with major depressive disorder.

PubMed

Hernandez, María Eugenia; Mendieta, Danelia; Pérez-Tapia, Mayra; Bojalil, Rafael; Estrada-Garcia, Iris; Estrada-Parra, Sergio; Pavón, Lenin

2013-01-01

Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator-human dialyzable leukocyte extract (hDLE)-on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1 β , IL-2, and IFN- γ ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone.

An analysis of psychotropic drug sales. Increasing sales of selective serotonin reuptake inhibitors are closely related to number of products.

PubMed

Nielsen, Margrethe; Gøtzsche, Peter

2011-01-01

Prescribing of selective serotonin reuptake inhibitors (SSRIs) has increased dramatically. To compare the sales of benzodiazepines and SSRIs within the primary care sector in Denmark and relate changes in usage to number of indications and products on the market. We used data from various sources to establish the sales curves of psychotropic drugs in the period 1970 to 2007, based on the Anatomic Therapeutic Classification system and Defined Daily Doses. Fluctuations in sales of psychotropic drugs that cannot be explained by disease prevalence were caused by changes in sales of the benzodiazepines and SSRIs. We found a decline in the sales of benzodiazepines after a peak in 1986, likely due to the recognition that they cause dependence. From a low level in 1992, we found that the sales of SSRIs increased almost linearly by a factor of 18, up to 44 DDD per 1000 inhabitants, which was closely related to the number of products on the market that increased by a factor of 16. Sales of antidepressant drugs are mainly determined by market availability of products indicating that marketing pressures are playing an important role. Thus the current level of use of SSRIs may not be evidence-based, which is supported by studies showing that the effect of SSRIs has been overestimated.

Comparison of the neurobiological effects of attribution retraining group therapy with those of selective serotonin reuptake inhibitors

PubMed Central

Wang, C.; Zhang, N.; Zhang, Y.L.; Zhang, J.; Yang, H.; Timothy, T.C.

2013-01-01

The aim of this study was to compare the effectiveness of attribution retraining group therapy (ARGT) with selective serotonin reuptake inhibitors (SSRIs) in the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), and obsessive-compulsive disorder (OCD). Subjects were sequentially recruited and randomized into two groups, one receiving ARGT (n = 63) and the other SSRIs (n = 66) for 8 weeks. Fifty-four ARGT outpatients with MDD (n = 19), GAD (n = 19), and OCD (n = 16) and 55 SSRI outpatients with MDD (n = 19), GAD (n = 19), and OCD (n = 17) completed the study. All subjects were assessed using the Hamilton Depression Scale and Hamilton Anxiety Scale before and after treatment. The 10-item Yale-Brown Obsessive Compulsive Scale was employed only for OCD subjects. Plasma levels of serotonin, norepinephrine, cortisol, and adrenocorticotropic hormone were also measured at baseline and 8 weeks after completion of treatment. Symptom scores were significantly reduced (P < 0.001) in both the ARGT and SSRI groups at the end of treatment. However, MDD, GAD and OCD patients in the ARGT group had significantly lower plasma cortisol concentrations compared to baseline (P < 0.05), whereas MDD and OCD patients receiving SSRIs showed significantly increased plasma levels of serotonin (P < 0.05). These findings suggest that ARGT may modulate plasma cortisol levels and affect the hypothalamus-pituitary-adrenal axis as opposed to SSRIs, which may up-regulate plasma serotonin levels via a different pathway to produce an overall improvement in the clinical condition of the patients. PMID:23558857

Dependence and withdrawal reactions to benzodiazepines and selective serotonin reuptake inhibitors. How did the health authorities react?

PubMed

Nielsen, Margrethe; Hansen, Ebba Holme; Gøtzsche, Peter C

2013-01-01

Our objective was to explore communications from drug agencies about benzodiazepine dependence and selective serotonin reuptake inhibitors (SSRIs) withdrawal reactions over time. Documentary study. We searched the web-sites of the European Medicines Agency and the drug agencies in USA, UK, and Denmark for documents mentioning benzodiazepines or SSRIs. We supplemented with other relevant literature that could contribute to our study. The searches were performed in 2009 in PubMed, Google, BMJ and JAMA. It took many years before the drug regulators acknowledged benzodiazepine dependence and SSRI withdrawal reactions and before the prescribers and the public were informed. Drug regulators relied mainly on the definitions of dependence and withdrawal reactions from the diagnostic psychiatric manuals, which contributed to the idea that SSRIs do not cause dependence, although it is difficult for many patients to stop treatment. In the perspective of a precautionary principle, drug agencies have failed to acknowledge that SSRIs can cause dependence and have minimised the problem with regard to its frequency and severity. In the perspective of a risk management principle, the drug agencies have reacted in concordance with the slowly growing knowledge of adverse drug reactions and have sharpened the information to the prescribers and the public over time. However, solely relying on spontaneous reporting of adverse effects leads to underestimation and delayed information about the problems. Given the experience with the benzodiazepines, we believe the regulatory bodies should have required studies from the manufacturers that could have elucidated the dependence potential of the SSRIs before marketing authorization was granted.

Selective serotonin reuptake inhibitors (SSRIs) for post-partum depression (PPD): a systematic review of randomized clinical trials.

PubMed

De Crescenzo, Franco; Perelli, Federica; Armando, Marco; Vicari, Stefano

2014-01-01

The treatment of postpartum depression with selective serotonin reuptake inhibitors (SSRIs) has been claimed to be both efficacious and well tolerated, but no recent systematic reviews have been conducted. A qualitative systematic review of randomized clinical trials on women with postpartum depression comparing SSRIs to placebo and/or other treatments was performed. A comprehensive literature search of online databases, the bibliographies of published articles and grey literature were conducted. Data on efficacy, acceptability and tolerability were extracted and the quality of the trials was assessed. Six randomised clinical trials, comprising 595 patients, met quality criteria for inclusion in the analysis. Cognitive-behavioural intervention, psychosocial community-based intervention, psychodynamic therapy, cognitive behavioural therapy, a second-generation tricyclic antidepressant and placebo were used as comparisons. All studies demonstrated higher response and remission rates among those treated with SSRIs and greater mean changes on depression scales, although findings were not always statistically significant. Dropout rates were high in three of the trials but similar among treatment and comparison groups. In general, SSRIs were well tolerated and trial quality was good. There are few trials, patients included in the trials were not representative of all patients with postpartum depression, dropout rates in three trials were high, and long-term efficacy and tolerability were assessed in only two trials. SSRIs appear to be efficacious and well tolerated in the treatment of postpartum depression, but the available evidence fails to demonstrate a clear superiority over other treatments. © 2013 Elsevier B.V. All rights reserved.

A metaanalysis of clinical trials comparing moclobemide with selective serotonin reuptake inhibitors for the treatment of major depressive disorder.

PubMed

Papakostas, George I; Fava, Maurizio

2006-10-01

To compare response rates among patients with major depressive disorder (MDD) treated with either moclobemide, an antidepressant thought to simultaneously enhance both noradrenergic and serotonergic neurotransmission, or selective serotonin reuptake inhibitors (SSRIs). Using a random-effects model, we combined 12 trials involving 1207 outpatients with MDD. Patients treated with moclobemide were as likely to experience clinical response as those treated with SSRIs (risk ratio 1.08; 95% confidence interval, 0.92 to 1.26; P = 0.314). Simply pooling response rates for the 2 agents resulted in a 62.1% response rate for moclobemide and a 57.5% response rate for the SSRIs. A metaregression did not reveal a statistically significant relation between the mean moclobemide dosage for each study and the risk ratio for response rates. Further, we found no difference between the 2 treatments in overall discontinuation rates, discontinuation rates due to adverse events, or discontinuation rates due to lack of efficacy. Also, rates of fatigue or somnolence and of insomnia were similar between the 2 treatment groups. However, SSRI treatment was associated with higher rates of nausea, headaches, and treatment-emergent anxiety than was treatment with moclobemide. These results suggest that moclobemide and the SSRIs do differ with respect to their side effect profiles but not in their overall efficacy in the treatment of MDD.

Two-week administration of the combined serotonin-noradrenaline reuptake inhibitor duloxetine augments functioning of mesolimbic incentive processing circuits.

PubMed

Ossewaarde, Lindsey; Verkes, Robbert J; Hermans, Erno J; Kooijman, Sabine C; Urner, Maren; Tendolkar, Indira; van Wingen, Guido A; Fernández, Guillén

2011-09-15

Anhedonia and lack of motivation are core symptoms of major depressive disorder (MDD). Neuroimaging studies in MDD patients have shown reductions in reward-related activity in terminal regions of the mesolimbic dopamine (DA) system, such as the ventral striatum. Monoamines have been implicated in both mesolimbic incentive processing and the mechanism of action of antidepressant drugs. However, not much is known about antidepressant effects on mesolimbic incentive processing in humans, which might be related to the effects on anhedonia. To investigate the short-term effects of antidepressants on reward-related activity in the ventral striatum, we investigated the effect of the combined serotonin-norepinephrine reuptake inhibitor duloxetine. Healthy volunteers underwent functional magnetic resonance imaging in a randomized, double-blind, placebo-controlled, crossover study. After taking duloxetine (60 mg once a day) or placebo for 14 days, participants completed a monetary incentive delay task that activates the ventral striatum during reward anticipation. Our results (n = 19) show enhanced ventral striatal responses after duloxetine administration compared with placebo. Moreover, this increase in ventral striatal activity was positively correlated with duloxetine plasma levels. This is the first study to demonstrate that antidepressants augment neural activity in mesolimbic DA incentive processing circuits in healthy volunteers. These effects are likely caused by the increase in monoamine neurotransmission in the ventral striatum. Our findings suggest that antidepressants may alleviate anhedonia by stimulating incentive processing. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short-term histological outcomes after hypoxic-ischemic brain injury in the neonatal male rat.

PubMed

Toshimitsu, Masatake; Kamei, Yoshimasa; Ichinose, Mari; Seyama, Takahiro; Imada, Shinya; Iriyama, Takayuki; Fujii, Tomoyuki

2018-03-30

Despite the recent progress of perinatal medicine, perinatal hypoxic-ischemic (HI) insult remains an important cause of brain injury in neonates, and is pathologically characterized by neuronal loss and the presence of microglia. Neurotransmitters, such as norepinephrine (NE) and glutamate, are involved in the pathogenesis of hypoxic-ischemic encephalopathy via the interaction between neurons and microglia. Although it is well known that the monoamine neurotransmitter NE acts as an anti-inflammatory agent in the brain under pathological conditions, its effects on perinatal HI insult remains elusive. Atomoxetine, a selective NE reuptake inhibitor, has been used clinically for the treatment of attention-deficit hyperactivity disorder in children. Here, we investigated whether the enhancement of endogenous NE by administration of atomoxetine could protect neonates against HI insult by using the neonatal male rat model. We also examined the involvement of microglia in this process. Unilateral HI brain injury was induced by the combination of left carotid artery dissection followed by ligation and hypoxia (8% O 2 , 2 h) in postnatal day 7 (P7) male rat pups. The pups were randomized into three groups: the atomoxetine treatment immediately after HI insult, the atomoxetine treatment at 3 h after HI insult, or the vehicle treatment group. The pups were euthanized on P8 and P14, and the brain regions including the cortex, striatum, hippocampus, and thalamus were evaluated by immunohistochemistry. HI insult resulted in severe brain damage in the ipsilateral hemisphere at P14. Atomoxetine treatment immediately after HI insult significantly increased NE levels in the ipsilateral hemisphere at 1 h after HI insult and reduced the neuronal damage via the increased phosphorylation of cAMP response element-binding protein (pCREB) in all brain regions examined. In addition, the number of microglia was maintained under atomoxetine treatment compared with that of the vehicle

Prediction of clinical response based on pharmacokinetic/pharmacodynamic models of 5-hydroxytryptamine reuptake inhibitors in mice

PubMed Central

Kreilgaard, M; Smith, D G; Brennum, L T; Sánchez, C

2008-01-01

Background and purpose: Bridging the gap between preclinical research and clinical trials is vital for drug development. Predicting clinically relevant steady-state drug concentrations (Css) in serum from preclinical animal models may facilitate this transition. Here we used a pharmacokinetic/pharmacodynamic (PK/PD) modelling approach to evaluate the predictive validity of 5-hydroxytryptamine (5-HT; serotonin) transporter (SERT) occupancy and 5-hydroxytryptophan (5-HTP)-potentiated behavioral syndrome induced by 5-HT reuptake inhibitor (SRI) antidepressants in mice. Experimental approach: Serum and whole brain drug concentrations, cortical SERT occupancy and 5-HTP-potentiated behavioral syndrome were measured over 6 h after a single subcutaneous injection of escitalopram, paroxetine or sertraline. [3H]2-(2-dimethylaminomethylphenylsulphanyl)-5-methyl-phenylamine ([3H]MADAM) was used to assess SERT occupancy. For PK/PD modelling, an effect-compartment model was applied to collapse the hysteresis and predict the steady-state relationship between drug exposure and PD response. Key results: The predicted Css for escitalopram, paroxetine and sertraline at 80% SERT occupancy in mice are 18 ng mL−1, 18 ng mL−1 and 24 ng mL−1, respectively, with corresponding responses in the 5-HTP behavioral model being between 20–40% of the maximum. Conclusions and implications: Therapeutically effective SERT occupancy for SRIs in depressed patients is approximately 80%, and the corresponding plasma Css are 6–21 ng mL−1, 21-95 ng mL−1 and 20–48 ng mL−1 for escitalopram, paroxetine and sertraline, respectively. Thus, PK/PD modelling using SERT occupancy and 5-HTP-potentiated behavioral syndrome as response markers in mice may be a useful tool to predict clinically relevant plasma Css values. PMID:18552871

Gestational Exposure to Selective Serotonin Reuptake Inhibitors and Offspring Psychiatric Disorders: A National Register-Based Study.

PubMed

Malm, Heli; Brown, Alan S; Gissler, Mika; Gyllenberg, David; Hinkka-Yli-Salomäki, Susanna; McKeague, Ian W; Weissman, Myrna; Wickramaratne, Priya; Artama, Miia; Gingrich, Jay A; Sourander, Andre

2016-05-01

To investigate the impact of gestational exposure to selective serotonin reuptake inhibitors (SSRIs) on offspring neurodevelopment. This is a cohort study using national register data in Finland between the years 1996 and 2010. Pregnant women and their offspring were categorized into 4 groups: SSRI exposed (n = 15,729); exposed to psychiatric disorder, no antidepressants (n = 9,651); exposed to SSRIs only before pregnancy (n = 7,980); and unexposed to antidepressants and psychiatric disorders (n = 31,394). We investigated the cumulative incidence of offspring diagnoses of depression, anxiety, autism spectrum disorder (ASD), and attention-deficit/hyperactivity disorder (ADHD) for the 4 groups from birth to 14 years, adjusting for confounders. The cumulative incidence of depression among offspring exposed prenatally to SSRIs was 8.2% (95% CI = 3.1-13.3%) by age 14.9 years, compared with 1.9% (95% CI = 0.9-2.9%) in the psychiatric disorder, no medication group (adjusted hazard ratio [HR] = 1.78; 95% CI = 1.12-2.82; p = .02) and to 2.8% (95% CI = 1.4-4.3%) in the SSRI discontinued group (HR = 1.84; 95% CI = 1.14-2.97; p = .01). Rates of anxiety, ASD, and ADHD diagnoses were comparable to rates in offspring of mothers with a psychiatric disorder but no medication during pregnancy. Comparing SSRI exposed to unexposed individuals, the HRs were significantly elevated for each outcome. Prenatal SSRI exposure was associated with increased rates of depression diagnoses in early adolescence but not with ASD or ADHD. Until confirmed, these findings must be balanced against the substantial adverse consequences of untreated maternal depression. Copyright © 2016 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Plasma oxytocin changes and anti-obsessive response during serotonin reuptake inhibitor treatment: a placebo controlled study.

PubMed

Humble, Mats B; Uvnäs-Moberg, Kerstin; Engström, Ingemar; Bejerot, Susanne

2013-12-23

The drug treatments of choice for obsessive-compulsive disorder (OCD) are serotonin reuptake inhibitors (SRIs). However, a correlation between the neuropeptide oxytocin in cerebrospinal fluid and the severity of OCD has previously been shown, and oxytocin and serotonin are interconnected within the brain. Few studies have investigated whether SRIs have any effect on oxytocin; thus, our aim was to explore the possibility that oxytocinergic mechanisms contribute to the anti-obsessive effect of SRIs. In a randomized, double-blind trial, comparing SRIs (clomipramine and paroxetine) with placebo in 36 adults with OCD (characterized for subtypes), plasma oxytocin was measured with radioimmunoassay after plasma extraction, at baseline, after 1 week, and after 4 weeks of treatment, and related to baseline severity and clinical response after 12 weeks, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Baseline oxytocin levels correlated positively with baseline Y-BOCS ratings, but only among the future SRI responders. Patients with early onset of OCD had higher baseline oxytocin. During treatment, plasma oxytocin did not differ between SRI and placebo treatment. In SRI responders, plasma oxytocin first decreased and then increased; in non-responders (to SRI as well as to placebo), the reverse was the case. After 4 weeks, treatment responders had attained higher oxytocin levels compared to non-responders. The intra-individual range (i.e., the variability) of plasma oxytocin between measurements was the measure that best differentiated responders from non-responders. This range was higher in responders than non-responders, and lower in patients with autistic traits. SRIs have highly variable effects on plasma oxytocin between individuals. The associations between baseline oxytocin and OCD severity and between oxytocin changes and treatment response support the notions that oxytocin is involved in OCD pathophysiology, and that the anti-obsessive effects of

Serotonin and norepinephrine reuptake inhibitors antidepressant use is related to lower baroreflex sensitivity independently of the severity of depressive symptoms. A community-study of 9213 participants from the Paris Prospective Study III.

PubMed

Empana, Jean-Philippe; Prugger, Christof; Thomas, Frédérique; Perier, Marie-Cécile; Zanoli, Luca; Castiglioni, Paolo; Guibout, Catherine; Causeret, Sophie; Barnes, Caroline; Lemogne, Cédric; Parati, Gianfranco; Laurent, Stéphane; Pannier, Bruno; Boutouyrie, Pierre; Jouven, Xavier

2016-08-01

We assess the respective relationship of high depressive symptoms and antidepressant use (ATD) with baroreflex sensitivity (BRS) in subjects from the community who enrolled the Paris Prospective Study III. Recruitment took place in a large health preventive centre in Paris (France), between May 2008 and June 2012. BRS was investigated by spectral analysis of the spontaneous carotid distension rate and RR intervals using non-invasive high-resolution ultrasound carotid-echotracking. A total score ≥7 on a 13-item standardized questionnaire defined the presence of high depressive symptoms. Information on ATD use was obtained on a face-to-face interview with a medical doctor who checked the most recent medical prescriptions and/or medical package. There were 9213 participants aged 50-75 years (38.6% of women), including 5.6% with high-depressive symptoms and 5.2% on ATD. High depressive symptoms were not associated with low BRS (below the median) even in unadjusted logistic regression analysis (OR = 1.09; 95%CI: 0.91-1.30). Instead, ATD use was related to low BRS in multivariate logistic regression analysis (OR = 1.27; 95% CI: 1.04-1.54). This association remains after adjusting for and matching on propensity score of receiving ATD. A specific association with serotonin and norepinephrine reuptake inhibitors was observed (OR = 1.94; 95% CI: 1.16-3.22). ATD use and serotonin and norepinephrine reuptake inhibitors in particular, but not high depressive symptoms, is associated with low BRS. If confirmed, these results may bring novel insights into the mechanisms linking depressive symptoms and/or ATD use with cardiovascular disease onset. Copyright © 2016 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Selective serotonin reuptake inhibitors and risk of major congenital anomalies for pregnancies in Japan: A nationwide birth cohort study of the Japan Environment and Children's Study.

PubMed

Nishigori, Hidekazu; Obara, Taku; Nishigori, Toshie; Mizuno, Satoshi; Metoki, Hirohito; Hoshiai, Tetsuro; Watanabe, Zen; Sakurai, Kasumi; Ishikuro, Mami; Tatsuta, Nozomi; Nishijima, Ichiko; Fujiwara, Ikuma; Kuriyama, Shinichi; Arima, Takahiro; Nakai, Kunihiko; Yaegashi, Nobuo

2017-05-01

We analyzed data from the Japan Environment and Children's Study (JECS), on the association between selective serotonin reuptake inhibitors (SSRI) use during pregnancy and the risk of developing of major congenital anomalies in Japan. JECS is an ongoing nationwide birth cohort study. The study includes 95 994 single pregnant women and their offspring. Among them, 172 used any SSRI up to the 12 th gestational week. Crude analyses show a significantly increased incidence of upper limb, abdominal, and urogenital abnormalities. In particular, the incidence of microcephaly, hydrencephalus, esophageal atresia, small intestinal atresia, and achondroplasia was significantly higher with than without exposure to these substances. On multivariate analyses, urogenital abnormality was significant (odds ratio 3.227; 95% confidence interval: 1.460-7.134). This Japanese nationwide birth cohort survey clarified that the use of any SSRI until the 12 th gestational week was associated with urogenital abnormality in children. The survey for association with minor classification abnormality needs further examination in Japan. © 2016 Japanese Teratology Society.

Effect of Selective Serotonin Reuptake Inhibitors and Immunomodulator on Cytokines Levels: An Alternative Therapy for Patients with Major Depressive Disorder

PubMed Central

Hernandez, María Eugenia; Mendieta, Danelia; Pérez-Tapia, Mayra; Bojalil, Rafael; Estrada-Parra, Sergio; Pavón, Lenin

2013-01-01

Major depressive disorder (MDD) is a psychiatric illness that presents as a deficit of serotonergic neurotransmission in the central nervous system. MDD patients also experience alterations in cortisol and cytokines levels. Treatment with selective serotonin reuptake inhibitors (SSRIs) is the first-line antidepressant regimen for MDD. The aim of this study was to determine the effect of a combination of SSRIs and an immunomodulator—human dialyzable leukocyte extract (hDLE)—on cortisol and cytokines levels. Patients received SSRIs or SSRIs plus hDLE. The proinflammatory cytokines IL-1β, IL-2, and IFN-γ; anti-inflammatory cytokines IL-13 and IL-10; and 24-h urine cortisol were measured at weeks (W) 0, 5, 20, 36, and 52 of treatment. The reduction in cortisol levels in the SSRI-treated group was 30% until W52, in contrast, the combined treatment induced a 54% decrease at W36. The decline in cortisol in patients who were treated with SSRI plus hDLE correlated with reduction of anti-inflammatory cytokines and increases levels of proinflammatory cytokines at the study conclusion. These results suggest that the immune-stimulating activity of hDLE, in combination with SSRIs, restored the pro- and anti-inflammatory cytokine balance and cortisol levels in depressed patients versus those who were given SSRIs alone. PMID:24348675

Ecstasy use and serotonin syndrome: a neglected danger to adolescents and young adults prescribed selective serotonin reuptake inhibitors.

PubMed

Dobry, Yuriy; Rice, Timothy; Sher, Leo

2013-01-01

At present, there are scarce clinical and basic lab data concerning the risk of acute serotonin toxicity from selective serotonin reuptake inhibitors (SSRIs) and 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) co-administration. The health care community can strongly benefit from efforts to address the high risks associated with serotonin syndrome from this specific drug combination. The aim of this work is to review the risk of serotonin syndrome in adolescents and young adults prescribed with SSRIs and are concurrently using ecstasy. An electronic search of the major behavioral science bibliographic databases (Pubmed, PsycINFO, Medline) was conducted to retrieve peer-reviewed articles, which detail the clinical characteristics, biological mechanisms and social implications of SSRIs, MDMA, and their potential synergism in causing serotonin syndrome in the pediatric and young adult population. Search terms included "serotonin syndrome", "ecstasy", "MDMA", "pediatric", and "SSRI". Additional references were incorporated from the bibliographies of these retrieved articles. MDMA, in combination with the widely-prescribed SSRI antidepressant class, can lead to rapid, synergistic rise of serotonin (5-HT) concentration in the central nervous system, leading to the acute medical emergency known as serotonin syndrome. This review addresses such complication through an exploration of the theoretical mechanisms and clinical manifestations of this life-threatening pharmacological interaction. The increasing incidences of recreational ecstasy use and SSRI pharmacotherapy among multiple psychiatric disorders in the adolescent population have made this an overlooked yet increasingly relevant danger, which poses a threat to public health. This can be curbed through further research, as well as greater health care provision and attention from a regulatory body owing.

Selective serotonin reuptake inhibitor exposure during early pregnancy and the risk of fetal major malformations: focus on paroxetine.

PubMed

Gentile, Salvatore; Bellantuono, Cesario

2009-03-01

To analyze all studies reporting primary data on the rate of fetal malformations after early in utero exposure to paroxetine, investigated either specifically or jointly with other antidepressant medications. Medical literature was identified through searches of MEDLINE/PubMed, TOXNET, EMBASE, and The Cochrane Library (1980 through September 2008). Search terms were pregnancy, antidepressants, SSRIs, paroxetine, and fetal malformations. Additional studies were identified from the reference lists of published articles. Twenty-five articles reporting primary data on the rate of fetal structural malformations following exposure to paroxetine or selective serotonin reuptake inhibitors as a group during the first trimester of pregnancy were electronically or manually selected. Studies on the teratogenic risk of paroxetine show a high degree of heterogeneity. Moreover, research studies performed with the same methodology and thus showing the same level of evidence report conflicting results. Given the inconsistency of the findings and limitations of the methodology of the published studies, the teratogenic potential of paroxetine that has been reported in some studies remains unproven. This relevant safety question is likely to remain unanswered until large, prospective studies are conducted. Such studies should be designed to include a control group of untreated mothers with similar psychiatric diagnosis so as to differentiate effects of drug exposure from impact of underlying mental disorder on the fetus. Moreover, further experimental studies are warranted to definitively assess clinical consequences of the impact on fetal development related to physiologic effects of prenatal paroxetine exposure on different maternal and fetal parameters. ©Copyright 2009 Physicians Postgraduate Press, Inc.

Dosing of Selective Serotonin Reuptake Inhibitors Among Children and Adults Before and After the FDA Black-Box Warning.

PubMed

Bushnell, Greta A; Stürmer, Til; Swanson, Sonja A; White, Alice; Azrael, Deborah; Pate, Virginia; Miller, Matthew

2016-03-01

Prior research evaluated various effects of the 2004 black-box warning by the U.S. Food and Drug Administration (FDA) on the risk of suicidality among children associated with use of antidepressants, but the warning's effect on dosing of antidepressants has not been evaluated. This study estimated whether the initial antidepressant dose prescribed decreased and the proportion of patients who augmented the dose on the second fill increased following the 2004 warning and its 2007 expansion to young adults. The study utilized the LifeLink Health Plan Claims Database. The study cohort consisted of commercially insured children (ages 5-17), young adults (18-24), and adults (25-64) who initiated a selective serotonin reuptake inhibitor (SSRI) (citalopram, fluoxetine, paroxetine, or sertraline) from January 1, 2000, to December 31, 2009. Dose per day was determined by days' supply, strength, and quantity dispensed. Initiation with a low dose and augmentation of >1 mg/day on the second prescription before and after the 2004 warning were considered. Of 51,948 children who initiated an SSRI, 15% initiated with a low dose before the 2004 warning compared with 31% after the warning; there was a smaller change among young adults (6 percentage points) and adults (3 percentage points). The overall increase in dose augmentations among children and young adults was driven by the increase in patients initiating with a low dose. The proportion of commercially insured children initiating an SSRI with a low dose was higher after the 2004 FDA warning on the risk of suicidality among children, suggesting improved prescribing practices surrounding SSRI dosing among children.

A population-based study of the use of selective serotonin reuptake inhibitors before and after introduction of generic equivalents.

PubMed

Bolton, James M; Dahl, Matthew; Sareen, Jitender; Enns, Murray W; Leslie, William D; Collins, David M; Alessi-Severini, Silvia

2012-04-01

Generic drugs are less expensive than their branded equivalents, but receive limited promotion. This study sought to examine how user rates of individual selective serotonin reuptake inhibitors (SSRIs) changed after the introduction of their generic equivalents. Administrative health and census data were used to examine the rates of use of all 6 SSRIs from 1996 to 2009 in the province of Manitoba (population of 1.2 million). The primary outcome measure was a comparison of the rates of use in the pre- and post-generic periods, using generalized estimating equations. Secondary analyses were stratified by specialty of physician prescriber. Escalating rates of use of branded SSRIs in the pre-generic period significantly decreased after generic versions became available (all Ps < 0.001). Incident use of sertraline and paroxetine continued to decrease throughout the post-generic period (1.5% and 1.9% quarterly decreasing rates, respectively). During the years when generic sertraline, fluoxetine, and fluvoxamine were available, their use declined while branded paroxetine and citalopram use continued to increase. Use of branded citalopram, sertraline, and paroxetine prescribed by general practitioners (GPs) increased at rates significantly higher than when prescribed by psychiatrists (all Ps < 0.001). The introduction of cheaper generic alternatives of SSRIs paradoxically resulted in their use diminishing rather than increasing. With the exception of escitalopram, branded SSRIs tended to be preferentially used, compared with available less expensive generic SSRIs. These patterns were more pronounced for prescriptions by GPs.

Inhibition of dopamine and norepinephrine reuptake produces additive effects on energy balance in lean and obese mice.

PubMed

Billes, Sonja K; Cowley, Michael A

2007-04-01

Although originally developed as an antidepressant, long-term bupropion (BUP) treatment was recently shown to cause 5-8% weight loss over placebo in clinical trials with obese adults. BUP's antidepressant properties probably stem from its ability to increase extracellular brain dopamine (DA) and norepinephrine (NE) levels by inhibiting their reuptake, although the mechanism of BUP-induced weight loss is unknown. Consequently, the acute effects of DA and NE reuptake inhibition on energy homeostasis were determined by measuring food intake and body weight in mice following peripheral (intraperitoneal (i.p.)) administration of either BUP, a selective DA (GBR12783), or a selective NE (nisoxetine (NIS)) reuptake inhibitor. BUP, GBR12783, and NIS all dose-dependently decreased acute food intake in fasted lean mice. The ability of BUP to decrease food intake was independent of its ability to cause a temporary increase in locomotor activity. The inhibitory effects of acute GBR12783 and NIS on short-term food intake were additive. Subchronic (via mini-osmotic pump) administration of GBR12783 and NIS produced a transient nonadditive effect on food intake, but produced an additive reduction in body weight (8-10%). Because obesity can affect catecholaminergic signaling, we determined the effects of i.p. BUP, GBR12783, and NIS on short-term food intake in obese mice. Acute BUP, GBR12783, and NIS dose-dependently reduced acute food intake, and the additive effect of GBR12783 and NIS on acute food intake was preserved in obese mice. These results demonstrate that combined DA and NE reuptake inhibition produces additive effects on energy balance in lean and obese mice on both standard and high-fat diet, providing a foundation for further research on the effects of BUP and similar compounds on energy balance in mice.

Perinatal exposure to the selective serotonin reuptake inhibitor citalopram alters spatial learning and memory, anxiety, depression, and startle in Sprague-Dawley rats.

PubMed

Sprowles, Jenna L N; Hufgard, Jillian R; Gutierrez, Arnold; Bailey, Rebecca A; Jablonski, Sarah A; Williams, Michael T; Vorhees, Charles V

2016-11-01

Selective serotonin reuptake inhibitors (SSRIs) block the serotonin (5-HT) reuptake transporter (SERT) and increase synaptic 5-HT. 5-HT is also important in brain development; hence when SSRIs are taken during pregnancy there exists the potential for these drugs to affect CNS ontogeny. Prenatal SSRI exposure has been associated with an increased prevalence of autism spectrum disorder (ASD), and peripheral 5-HT is elevated in some ASD patients. Perinatal SSRI exposure in rodents has been associated with increased depression and anxiety-like behavior, decreased sociability, and impaired learning in the offspring, behaviors often seen in ASD. The present study investigated whether perinatal exposure to citalopram causes persistent neurobehavioral effects. Gravid Sprague-Dawley rats were assigned to two groups and subcutaneously injected twice per day with citalopram (10mg/kg; Cit) or saline (Sal) 6h apart on embryonic day (E)6-21, and then drug was given directly to the pups after delivery from postnatal day (P)1-20. Starting on P60, one male/female from each litter was tested in the Cincinnati water maze (CWM) and open-field before and after MK-801. A second pair from each litter was tested in the Morris water maze (MWM) and open-field before and after (+)-amphetamine. A third pair was tested as follows: elevated zero-maze, open-field, marble burying, prepulse inhibition of acoustic startle, social preference, and forced swim. Cit-exposed rats were impaired in the MWM during acquisition and probe, but not during reversal, shift, or cued trials. Cit-exposed rats also showed increased marble burying, decreased time in the center of the open-field, decreased latency to immobility in forced swim, and increased acoustic startle across prepulse intensities with no effects on CWM. The results are consistent with citalopram inducing several ASD-like effects. The findings add to concerns about use of SSRIs during pregnancy. Further research on different classes of

Systematic Review and Meta-Analysis: Dose-Response Relationship of Selective Serotonin Reuptake Inhibitors in Major Depressive Disorder.

PubMed

Jakubovski, Ewgeni; Varigonda, Anjali L; Freemantle, Nicholas; Taylor, Matthew J; Bloch, Michael H

2016-02-01

Previous studies suggested that the treatment response to selective serotonin reuptake inhibitors (SSRIs) in major depressive disorder follows a flat response curve within the therapeutic dose range. The present study was designed to clarify the relationship between dosage and treatment response in major depressive disorder. The authors searched PubMed for randomized placebo-controlled trials examining the efficacy of SSRIs for treating adults with major depressive disorder. Trials were also required to assess improvement in depression severity at multiple time points. Additional data were collected on treatment response and all-cause and side effect-related discontinuation. All medication doses were transformed into imipramine-equivalent doses. The longitudinal data were analyzed with a mixed-regression model. Endpoint and tolerability analyses were analyzed using meta-regression and stratified subgroup analysis by predefined SSRI dose categories in order to assess the effect of SSRI dosing on the efficacy and tolerability of SSRIs for major depressive disorder. Forty studies involving 10,039 participants were included. Longitudinal modeling (dose-by-time interaction=0.0007, 95% CI=0.0001-0.0013) and endpoint analysis (meta-regression: β=0.00053, 95% CI=0.00018-0.00088, z=2.98) demonstrated a small but statistically significant positive association between SSRI dose and efficacy. Higher doses of SSRIs were associated with an increased likelihood of dropouts due to side effects (meta-regression: β=0.00207, 95% CI=0.00071-0.00342, z=2.98) and decreased likelihood of all-cause dropout (meta-regression: β=-0.00093, 95% CI=-0.00165 to -0.00021, z=-2.54). Higher doses of SSRIs appear slightly more effective in major depressive disorder. This benefit appears to plateau at around 250 mg of imipramine equivalents (50 mg of fluoxetine). The slightly increased benefits of SSRIs at higher doses are somewhat offset by decreased tolerability at high doses.

Inhibition of G-Protein-Activated Inwardly Rectifying K+ Channels by the Selective Norepinephrine Reuptake Inhibitors Atomoxetine and Reboxetine

PubMed Central

Kobayashi, Toru; Washiyama, Kazuo; Ikeda, Kazutaka

2010-01-01

Atomoxetine and reboxetine are commonly used as selective norepinephrine reuptake inhibitors (NRIs) for the treatment of attention-deficit/hyperactivity disorder and depression, respectively. Furthermore, recent studies have suggested that NRIs may be useful for the treatment of several other psychiatric disorders. However, the molecular mechanisms underlying the various effects of NRIs have not yet been sufficiently clarified. G-protein-activated inwardly rectifying K+ (GIRK or Kir3) channels have an important function in regulating neuronal excitability and heart rate, and GIRK channel modulation has been suggested to be a potential treatment for several neuropsychiatric disorders and cardiac arrhythmias. In this study, we investigated the effects of atomoxetine and reboxetine on GIRK channels using the Xenopus oocyte expression assay. In oocytes injected with mRNA for GIRK1/GIRK2, GIRK2, or GIRK1/GIRK4 subunits, extracellular application of atomoxetine or reboxetine reversibly reduced GIRK currents. The inhibitory effects were concentration-dependent, but voltage-independent, and time-independent during each voltage pulse. However, Kir1.1 and Kir2.1 channels were insensitive to atomoxetine and reboxetine. Atomoxetine and reboxetine also inhibited GIRK currents induced by activation of cloned A1 adenosine receptors or by intracellularly applied GTPγS, a nonhydrolyzable GTP analogue. Furthermore, the GIRK currents induced by ethanol were concentration-dependently inhibited by extracellularly applied atomoxetine but not by intracellularly applied atomoxetine. The present results suggest that atomoxetine and reboxetine inhibit brain- and cardiac-type GIRK channels, revealing a novel characteristic of clinically used NRIs. GIRK channel inhibition may contribute to some of the therapeutic effects of NRIs and adverse side effects related to nervous system and heart function. PMID:20393461

Prenatal exposure to selective serotonin reuptake inhibitors and social responsiveness symptoms of autism: population-based study of young children.

PubMed

El Marroun, Hanan; White, Tonya J H; van der Knaap, Noortje J F; Homberg, Judith R; Fernández, Guillén; Schoemaker, Nikita K; Jaddoe, Vincent W V; Hofman, Albert; Verhulst, Frank C; Hudziak, James J; Stricker, Bruno H C; Tiemeier, Henning

2014-08-01

Selective serotonin reuptake inhibitors (SSRIs) are considered safe and are frequently used during pregnancy. However, two case-control studies suggested an association between prenatal SSRI exposure with childhood autism. To prospectively determine whether intra-uterine SSSRI exposure is associated with childhood autistic symptoms in a population-based study. A total of 376 children prenatally exposed to maternal depressive symptoms (no SSRI exposure), 69 children prenatally exposed to SSRIs and 5531 unexposed children were included. Child pervasive developmental and affective problems were assessed by parental report with the Child Behavior Checklist at ages 1.5, 3 and 6. At age 6, we assessed autistic traits using the Social Responsiveness Scale (n = 4264). Prenatal exposure to maternal depressive symptoms without SSRIs was related to both pervasive developmental (odds ratio (OR) = 1.44, 95% CI 1.07-1.93) and affective problems (OR = 1.44, 95% CI 1.15-1.81). Compared with unexposed children, those prenatally exposed to SSRIs also were at higher risk for developing pervasive developmental problems (OR = 1.91, 95% CI 1.13-3.47), but not for affective problems. Children prenatally exposed to SSRIs also had more autistic traits (B = 0.15, 95% CI 0.08-0.22) compared with those exposed to depressive symptoms only. Our results suggest an association between prenatal SSRI exposure and autistic traits in children. Prenatal depressive symptoms without SSRI use were also associated with autistic traits, albeit this was weaker and less specific. Long-term drug safety trials are needed before evidence-based recommendations are possible. Royal College of Psychiatrists.

Aggravation by paroxetine, a selective serotonin reuptake inhibitor, of antral lesions generated by nonsteroidal anti-inflammatory drugs in rats.

PubMed

Takeuchi, Koji; Tanaka, Akiko; Nukui, Kazuo; Kojo, Azusa; Gyenge, Melinda; Amagase, Kikuko

2011-09-01

Recent clinical studies have suggested a risk of adverse gastric reactions from the concomitant use of selective serotonin (5-HT) reuptake inhibitors (SSRIs) with nonsteroidal anti-inflammatory drugs (NSAIDs). We examined the adverse effects of SSRIs on antral lesions produced by indomethacin in rats. Rats fasted for 24 h were refed for 1 h, then administered indomethacin (30 mg/kg s.c.) 1 h after the refeeding and killed 6 h later. Paroxetine (1-10 mg/kg) was given orally 30 min before indomethacin. Indomethacin caused antral lesions in refed rats. Paroxetine dose-dependently aggravated these lesions, despite provoking no damage by itself. Similar results were obtained when other NSAIDs such as diclofenac, flurbiprofen, and loxoprofen were coadministered with paroxetine or when indomethacin was coadministered with other antidepressants such as fluvoxamine and milnacipran, but not imipramine or maprotiline. Exogenous 5-HT also worsened the indomethacin-induced antral damage, whereas the aggravating effect of paroxetine was attenuated by ondansetron, a selective 5-HT(3) antagonist, but not antagonists for other 5-HT receptor subtypes. Indomethacin plus paroxetine had no effect on gastric secretion but significantly decreased mucosal superoxide dismutase (SOD) activity as well as GSH content. The antral damage induced by indomethacin plus paroxetine was significantly prevented by antisecretory (acid or pepsin) agents and mucosal protective agents as well as SOD and allopurinol. These results suggest that SSRIs aggravate NSAID-induced antral lesions, probably via the activation of 5HT(3) receptors, and the mechanism of aggravation may involve the corrosive action of acid/pepsin as well as an impaired antioxidative system.

BIM expression in treatment naïve cancers predicts responsiveness to kinase inhibitors

PubMed Central

Faber, Anthony; Corcoran, Ryan B.; Ebi, Hiromichi; Sequist, Lecia V.; Waltman, Belinda A.; Chung, Euiheon; Incio, Joao; Digumarthy, Subba R.; Pollack, Sarah F.; Song, Youngchul; Muzikansky, Alona; Lifshits, Eugene; Roberge, Sylvie; Coffman, Erik J.; Benes, Cyril; Gómez, Henry; Baselga, Jose; Arteaga, Carlos L.; Rivera, Miguel N.; Dias-Santagata, Dora; Jain, Rakesh K.; Engelman, Jeffrey A.

2011-01-01

Cancers with specific genetic mutations are susceptible to selective kinase inhibitors. However, there is wide spectrum of benefit among cancers harboring the same sensitizing genetic mutations. Herein, we measured apoptotic rates among cell lines sharing the same driver oncogene following treatment with the corresponding kinase inhibitor. There was a wide range of kinase inhibitor-induced apoptosis despite comparable inhibition of the target and associated downstream signaling pathways. Surprisingly, pre-treatment RNA levels of the BH3-only pro-apoptotic BIM strongly predicted the capacity of EGFR, HER2, and PI3K inhibitors to induce apoptosis in EGFR mutant, HER2 amplified, and PIK3CA mutant cancers, respectively, but BIM levels did not predict responsiveness to standard chemotherapies. Furthermore, BIM RNA levels in EGFR mutant lung cancer specimens predicted response and duration of clinical benefit from EGFR inhibitors. These findings suggest assessment of BIM levels in treatment naïve tumor biopsies may indicate the degree of benefit from single-agent kinase inhibitors in multiple oncogene-addiction paradigms. PMID:22145099

Selective serotonin reuptake inhibitors and the risk of hepatocellular carcinoma in hepatitis B virus-infected patients

PubMed Central

Chang, Chia-Ming; Hsieh, Ming-Shun; Yang, Tsung-Chieh; Hsieh, Vivian Chia-Rong; Chiang, Jen-Huai; Huang, Hsien-Hao; How, Chorng-Kuang; Hu, Sung-Yuan; Yen, David Hung-Tsang

2017-01-01

Background This study aimed to investigate the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B virus (HBV) infection. Methods We conducted a population-based cohort study by using claims data from the Taiwan National Health Insurance Research Database (NHIRD). The study cohort comprised 1380 newly diagnosed HBV-infected patients with SSRI use who were frequency matched by age, sex, liver cirrhosis, and index year with HBV-infected patients without SSRI use in the comparison cohort. Each patient case was followed from 2000 to 2012 to identify incident HCC cases. Cox proportional hazards regression was performed to evaluate the association between SSRI use and HCC risk. The further sensitivity analysis used case-control study design. A total of 9070 HCC subjects retrieved from NHIRD, and equal non-HCC subjects were analyzed after matching for age and sex. Results We identified 9 and 24 HCC cases in the study and comparison cohorts during the follow-up period of 7056 and 6845 person-years, respectively. The incidence rate of HCC was 1.28 and 3.51 per 1000 person-years for SSRI and non-SSRI users, respectively. After adjusting for potential confounders, the adjusted hazard ratio (HR) for SSRI use was 0.28 (95% confidence interval [CI], 0.12–0.64; p = 0.0027). For SSRI users with a cumulative defined daily dose (cDDD) of 28–89, 90–364, and ≥365, the adjusted HRs were 0.51, 0.22, and 0.12, respectively, (95% CI, 0.21–1.25, 0.05–0.94, and 0.02–0.90, respectively) compared with non-SSRI users (<28 cDDD). The sensitivity analysis showed that the SSRI presented with a dose-response protective effect for HCC in the multivariate analysis. Conclusion SSRIs use may possibly reduce the risk of HCC in HBV-infected patients in a dose-responsive manner. PMID:29238221

Effects of selective serotonin reuptake inhibitor treatment on plasma oxytocin and cortisol in major depressive disorder.

PubMed

Keating, Charlotte; Dawood, Tye; Barton, David A; Lambert, Gavin W; Tilbrook, Alan J

2013-04-29

Oxytocin is known for its capacity to facilitate social bonding, reduce anxiety and for its actions on the stress hypothalamopituitary adrenal (HPA) axis. Since oxytocin can physiologically suppress activity of the HPA axis, clinical applications of this neuropeptide have been proposed in conditions where the function of the HPA axis is dysregulated. One such condition is major depressive disorder (MDD). Dysregulation of the HPA system is the most prominent endocrine change seen with MDD, and normalizing the HPA axis is one of the major targets of recent treatments. The potential clinical application of oxytocin in MDD requires improved understanding of its relationship to the symptoms and underlying pathophysiology of MDD. Previous research has investigated potential correlations between oxytocin and symptoms of MDD, including a link between oxytocin and treatment related symptom reduction. The outcomes of studies investigating whether antidepressive treatment (pharmacological and non-pharmacological) influences oxytocin concentrations in MDD, have produced conflicting outcomes. These outcomes suggest the need for an investigation of the influence of a single treatment class on oxytocin concentrations, to determine whether there is a relationship between oxytocin, the HPA axis (e.g., oxytocin and cortisol) and MDD. Our objective was to measure oxytocin and cortisol in patients with MDD before and following treatment with selective serotonin reuptake inhibitors, SSRI. We sampled blood from arterial plasma. Patients with MDD were studied at the same time twice; pre- and post- 12 weeks treatment, in an unblinded sequential design (clinicaltrials.govNCT00168493). Results did not reveal differences in oxytocin or cortisol concentrations before relative to following SSRI treatment, and there were no significant relationships between oxytocin and cortisol, or these two physiological variables and psychological symptom scores, before or after treatment. These outcomes

Plasma oxytocin changes and anti-obsessive response during serotonin reuptake inhibitor treatment: a placebo controlled study

PubMed Central

2013-01-01

Background The drug treatments of choice for obsessive-compulsive disorder (OCD) are serotonin reuptake inhibitors (SRIs). However, a correlation between the neuropeptide oxytocin in cerebrospinal fluid and the severity of OCD has previously been shown, and oxytocin and serotonin are interconnected within the brain. Few studies have investigated whether SRIs have any effect on oxytocin; thus, our aim was to explore the possibility that oxytocinergic mechanisms contribute to the anti-obsessive effect of SRIs. Method In a randomized, double-blind trial, comparing SRIs (clomipramine and paroxetine) with placebo in 36 adults with OCD (characterized for subtypes), plasma oxytocin was measured with radioimmunoassay after plasma extraction, at baseline, after 1 week, and after 4 weeks of treatment, and related to baseline severity and clinical response after 12 weeks, as measured by the Yale-Brown Obsessive Compulsive Scale (Y-BOCS). Results Baseline oxytocin levels correlated positively with baseline Y-BOCS ratings, but only among the future SRI responders. Patients with early onset of OCD had higher baseline oxytocin. During treatment, plasma oxytocin did not differ between SRI and placebo treatment. In SRI responders, plasma oxytocin first decreased and then increased; in non-responders (to SRI as well as to placebo), the reverse was the case. After 4 weeks, treatment responders had attained higher oxytocin levels compared to non-responders. The intra-individual range (i.e. the variability) of plasma oxytocin between measurements was the measure that best differentiated responders from non-responders. This range was higher in responders than non-responders, and lower in patients with autistic traits. Conclusions SRIs have highly variable effects on plasma oxytocin between individuals. The associations between baseline oxytocin and OCD severity and between oxytocin changes and treatment response support the notions that oxytocin is involved in OCD pathophysiology

Are antidepressant drugs that combine serotonergic and noradrenergic mechanisms of action more effective than the selective serotonin reuptake inhibitors in treating major depressive disorder? A meta-analysis of studies of newer agents.

PubMed

Papakostas, George I; Thase, Michael E; Fava, Maurizio; Nelson, J Craig; Shelton, Richard C

2007-12-01

Recent studies suggest that the treatment of major depressive disorder (MDD) with newer antidepressant drugs that simultaneously enhance norepinephrine and serotonin neurotransmission might result in higher response and remission rates than the selective serotonin reuptake inhibitors (SSRIs). The goal of our work was to compare response rates among patients with MDD treated with either of these two broad categories of antidepressant drugs. Medline/Pubmed, EMBase, clinical trial registries, program syllabi from major psychiatric meetings held since 1995, and documents from relevant pharmaceutical companies were searched for double-blind, randomized trials comparing a newer serotonergic-noradrenergic antidepressant drug (venlafaxine, duloxetine, milnacipran, mirtazapine, mianserin, or moclobemide) with an SSRI for MDD. Ninety-three trials (n = 17,036) were combined using a random-effects model. Treatment with serotonergic + noradrenergic antidepressant drugs was more likely to result in clinical response than the SSRIs (risk ratio [RR] = 1.059; response rates 63.6% versus 59.3%; p = .003). There was no evidence for heterogeneity among studies combined (p = 1.0). Excluding each individual agent did not significantly alter the pooled RR. With the exception of duloxetine (.985), RRs for response for each individual serotonergic + noradrenergic antidepressant drug were within the 95% confidence interval of the pooled RR (1.019-1.101). Serotonergic-noradrenergic antidepressant drugs seem to have a modest efficacy advantage compared with SSRIs in MDD. With the Number Needed to Treat (NNT) statistic as one indicator of clinical significance, nearly 24 patients would need to be treated with dual-action antidepressant drugs instead of SSRIs in order to obtain one additional responder. This difference falls well below the mark of NNT = 10 suggested by the United Kingdom's National Institute of Clinical Excellence but nonetheless might be of public health relevance given the

Treatment with selective serotonin reuptake inhibitors and mirtapazine results in differential brain activation by visual erotic stimuli in patients with major depressive disorder.

PubMed

Kim, Won; Jin, Bo-Ra; Yang, Wan-Seok; Lee, Kyuong-Uk; Juh, Ra-Hyung; Ahn, Kook-Jin; Chung, Yong-An; Chae, Jeong-Ho

2009-06-01

The objective of this study was to identify patterns of brain activation elicited by erotic visual stimuli in patients treated with either Selective Serotonin Reuptake Inhibitors (SSRIs) or mirtazipine. Nine middle-aged men with major depressive disorder treated with an SSRI and ten middle-aged men with major depressive disorder treated with mirtazapine completed the trial. Ten subjects with no psychiatric illness were included as a control group. We conducted functional brain magnetic resonance imaging (fMRI) while a film alternatively played erotic and non-erotic contents for 14 minutes and 9 seconds. The control group showed activation in the occipitotemporal area, anterior cingulate gyrus, insula, orbitofrontal cortex, and caudate nucleus. For subjects treated with SSRIs, the intensity of activity in these regions was much lower compared to the control group. Intensity of activation in the group treated with mirtazapine was less than the control group but grea-ter than those treated with SSRIs. Using subtraction analysis, the SSRI group showed significantly lower activation than the mirtazapine group in the anterior cingulate gyrus and the caudate nucleus. Our study suggests that the different rates of sexual side effects between the patients in the SSRI-treated group and the mirtazapine-treated group may be due to different effects on brain activation.

Biphasic effects of selective serotonin reuptake inhibitors on anxiety: rapid reversal of escitalopram's anxiogenic effects in the novelty-induced hypophagia test in mice?

PubMed

Koek, Wouter; Mitchell, Nathan C; Daws, Lynette C

2018-06-01

In humans, chronic treatment with selective serotonin reuptake inhibitors (SSRIs) decreases anxiety, unlike acute treatment, which can increase anxiety. Although this biphasic pattern is observed clinically, preclinical demonstrations are rare. In an animal model of antidepressant-induced anxiolytic effects, the novelty-induced hypophagia (NIH) test, a single administration of the SSRI citalopram reportedly elicited anxiogenic-like effects, whereas three administrations over 24 h were sufficient to produce anxiolytic-like effects. Extending these findings, the present study examined the effects of acute and repeated escitalopram in a similar NIH test in a commonly used mouse strain (i.e. C57BL/6J), analyzing results with a method (i.e. survival analysis) that can model the skewed distribution of latencies to consume food and that can deal with censored data (i.e. when consumption does not occur during the test). Saline-treated mice showed robust NIH. Acute escitalopram enhanced NIH, but did so only at a dose (i.e. 32 mg/kg) that similarly enhanced hypophagia in a familiar environment. The effects of escitalopram on NIH did not significantly change after repeated (three times) administration over 24 h. Additional studies are necessary to delineate the conditions under which rapid reversal of SSRI-induced anxiety can be modeled in animals using the NIH test.

Acute and chronic effects of selective serotonin reuptake inhibitor treatment on fear conditioning: implications for underlying fear circuits.

PubMed

Burghardt, N S; Bauer, E P

2013-09-05

Selective serotonin reuptake inhibitors (SSRIs) are widely used for the treatment of a spectrum of anxiety disorders, yet paradoxically they may increase symptoms of anxiety when treatment is first initiated. Despite extensive research over the past 30 years focused on SSRI treatment, the precise mechanisms by which SSRIs exert these opposing acute and chronic effects on anxiety remain unknown. By testing the behavioral effects of SSRI treatment on Pavlovian fear conditioning, a well characterized model of emotional learning, we have the opportunity to identify how SSRIs affect the functioning of specific brain regions, including the amygdala, bed nucleus of the stria terminalis (BNST) and hippocampus. In this review, we first define different stages of learning involved in cued and context fear conditioning and describe the neural circuits underlying these processes. We examine the results of numerous rodent studies investigating how acute SSRI treatment modulates fear learning and relate these effects to the known functions of serotonin in specific brain regions. With these findings, we propose a model by which acute SSRI administration, by altering neural activity in the extended amygdala and hippocampus, enhances both acquisition and expression of cued fear conditioning, but impairs the expression of contextual fear conditioning. Finally, we review the literature examining the effects of chronic SSRI treatment on fear conditioning in rodents and describe how downregulation of N-methyl-d-aspartate (NMDA) receptors in the amygdala and hippocampus may mediate the impairments in fear learning and memory that are reported. While long-term SSRI treatment effectively reduces symptoms of anxiety, their disruptive effects on fear learning should be kept in mind when combining chronic SSRI treatment and learning-based therapies, such as cognitive behavioral therapy. Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.

Pharmacokinetics of paroxetine, a selective serotonin reuptake inhibitor, in Grey parrots (Psittacus erithacus erithacus): influence of pharmaceutical formulation and length of dosing.

PubMed

van Zeeland, Y R A; Schoemaker, N J; Haritova, A; Smit, J W; van Maarseveen, E M; Lumeij, J T; Fink-Gremmels, J

2013-02-01

Paroxetine, a selective serotonin reuptake inhibitor, may be beneficial in the treatment of behavioural disorders in pet birds. The lack of pharmacokinetic data and clinical trials currently limits the use of this drug in clinical avian practice. This paper evaluates the pharmacokinetic properties and potential side effects of single and repeated dosing of paroxetine in Grey parrots (Psittacus erithacus erithacus). Paroxetine pharmacokinetics were studied after single i.v. and single oral dosing, and after repeated oral administration during 1 month. Plasma paroxetine concentrations were determined by liquid chromatography-tandem mass spectrometry. No undesirable side effects were observed during the study. Pharmacokinetic analysis revealed a quick distribution and rapid elimination after i.v. administration. Oral administration of paroxetine HCl dissolved in water resulted in a relatively slow absorption (T(max)=5.9±2.6 h) and a low bioavailability (31±15%). Repeated administration resulted in higher rate of absorption, most likely due to a saturation of the cytochrome P450-mediated first-pass metabolism. This study shows that oral administration of paroxetine HCl (4 mg/kg twice daily) in parrots results in plasma concentrations within the therapeutic range recommended for the treatment of depressions in humans. Further studies are needed to demonstrate the clinical efficacy of this dosage regimen in parrots with behavioural disorders. © 2012 Blackwell Publishing Ltd.

In vitro anti-Candida activity of selective serotonin reuptake inhibitors against fluconazole-resistant strains and their activity against biofilm-forming isolates.

PubMed

Costa Silva, Rose Anny; da Silva, Cecília Rocha; de Andrade Neto, João Batista; da Silva, Anderson Ramos; Campos, Rosana Sousa; Sampaio, Letícia Serpa; do Nascimento, Francisca Bruna Stefany Aires; da Silva Gaspar, Brenda; da Cruz Fonseca, Said Gonçalves; Josino, Maria Aparecida Alexandre; Grangeiro, Thalles Barbosa; Gaspar, Danielle Macedo; de Lucena, David Freitas; de Moraes, Manoel Odorico; Cavalcanti, Bruno Coêlho; Nobre Júnior, Hélio Vitoriano

2017-06-01

Recent research has shown broad antifungal activity of the classic antidepressants selective serotonin reuptake inhibitors (SSRIs). This fact, combined with the increased cross-resistance frequency of the genre Candida regarding the main treatment today, fluconazole, requires the development of novel therapeutic strategies. In that context, this study aimed to assess the antifungal potential of fluoxetine, sertraline, and paroxetine against fluconazole-resistant Candida spp. planktonic cells, as well as to assess the mechanism of action and the viability of biofilms treated with fluoxetine. After 24 h, the fluconazole-resistant Candida spp. strains showed minimum inhibitory concentration (MIC) in the ranges of 20-160 μg/mL for fluoxetine, 10-20 μg/mL for sertraline, and 10-100.8 μg/mL for paroxetine by the broth microdilution method (M27-A3). According to our data by flow cytometry, each of the SSRIs cause fungal death after damaging the plasma and mitochondrial membrane, which activates apoptotic signaling pathways and leads to dose-dependant cell viability loss. Regarding biofilm-forming isolates, the fluoxetine reduce mature biofilm of all the species tested. Therefore, it is concluded that SSRIs are capable of inhibit the growth in vitro of Candida spp., both in planktonic form, as biofilm, inducing cellular death by apoptosis. Copyright © 2017 Elsevier Ltd. All rights reserved.

Infusion of fluoxetine, a serotonin reuptake inhibitor, in the shell region of the nucleus accumbens increases blood glucose concentrations in rats.

PubMed

Diepenbroek, C; Rijnsburger, M; Eggels, L; van Megen, K M; Ackermans, M T; Fliers, E; Kalsbeek, A; Serlie, M J; la Fleur, S E

2017-01-10

The brain is well known to regulate blood glucose, and the hypothalamus and hindbrain, in particular, have been studied extensively to understand the underlying mechanisms. Nuclei in these regions respond to alterations in blood glucose concentrations and can alter glucose liver output or glucose tissue uptake to maintain blood glucose concentrations within strict boundaries. Interestingly, several cortico-limbic regions also respond to alterations in glucose concentrations and have been shown to project to hypothalamic nuclei and glucoregulatory organs. For instance, electrical stimulation of the shell of the nucleus accumbens (sNAc) results in increased circulating concentrations of glucose and glucagon and activation of the lateral hypothalamus (LH). Whether this is caused by the simultaneous increase in serotonin release in the sNAc remains to be determined. To study the effect of sNAc serotonin on systemic glucose metabolism, we implanted bilateral microdialysis probes in the sNAc of male Wistar rats and infused fluoxetine, a serotonin reuptake inhibitor, or vehicle after which blood glucose, endogenous glucose production (EGP) and glucoregulatory hormones were measured. Fluoxetine in the sNAc for 1h significantly increased blood glucose concentrations without an effect on glucoregulatory hormones. This increase was accompanied by a higher EGP in the fluoxetine infused rats compared to the controls. These data provide further evidence for a role of sNAc-serotonin in the regulation of glucose metabolism. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

The effects of prolonged administration of norepinephrine reuptake inhibitors on long-term potentiation in dentate gyrus, and on tests of spatial and object recognition memory in rats.

PubMed

Walling, Susan G; Milway, J Stephen; Ingram, Matthew; Lau, Catherine; Morrison, Gillian; Martin, Gerard M

2016-02-01

Phasic norepinephrine (NE) release events are involved in arousal, novelty detection and in plasticity processes underlying learning and memory in mammalian systems. Although the effects of phasic NE release events on plasticity and memory are prevalently documented, it is less understood what effects chronic NE reuptake inhibition and sustained increases in noradrenergic tone, might have on plasticity and cognitive processes in rodent models of learning and memory. This study investigates the effects of chronic NE reuptake inhibition on hippocampal plasticity and memory in rats. Rats were administered NE reuptake inhibitors (NRIs) desipramine (DMI; 0, 3, or 7.5mg/kg/day) or nortriptyline (NTP; 0, 10 or 20mg/kg/day) in drinking water. Long-term potentiation (LTP; 200 Hz) of the perforant path-dentate gyrus evoked potential was examined in urethane anesthetized rats after 30-32 days of DMI treatment. Short- (4-h) and long-term (24-h) spatial memory was tested in separate rats administered 0 or 7.5mg/kg/day DMI (25-30 days) using a two-trial spatial memory test. Additionally, the effects of chronically administered DMI and NTP were tested in rats using a two-trial, Object Recognition Test (ORT) at 2- and 24-h after 45 and 60 days of drug administration. Rats administered 3 or 7.5mg/kg/day DMI had attenuated LTP of the EPSP slope but not the population spike at the perforant path-dentate gyrus synapse. Short- and long-term memory for objects is differentially disrupted in rats after prolonged administration of DMI and NTP. Rats that were administered 7.5mg/kg/day DMI showed decreased memory for a two-trial spatial task when tested at 4-h. In the novel ORT, rats receiving 0 or 7.5mg/kg/day DMI showed a preference for the arm containing a Novel object when tested at both 2- and 24-h demonstrating both short- and long-term memory retention of the Familiar object. Rats that received either dose of NTP or 3mg/kg/day DMI showed impaired memory at 2-h, however this

Efficacy and Acceptability of Pharmacological Treatments for Depressive Disorders in Primary Care: Systematic Review and Network Meta-Analysis

PubMed Central

Linde, Klaus; Kriston, Levente; Rücker, Gerta; Jamil, Susanne; Schumann, Isabelle; Meissner, Karin; Sigterman, Kirsten; Schneider, Antonius

2015-01-01

PURPOSE The purpose of this study was to investigate whether antidepressants are more effective than placebo in the primary care setting, and whether there are differences between substance classes regarding efficacy and acceptability. METHODS We conducted literature searches in MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and PsycINFO up to December 2013. Randomized trials in depressed adults treated by primary care physicians were included in the review. We performed both conventional pairwise meta-analysis and network meta-analysis combining direct and indirect evidence. Main outcome measures were response and study discontinuation due to adverse effects. RESULTS A total of 66 studies with 15,161 patients met the inclusion criteria. In network meta-analysis, tricyclic and tetracyclic antidepressants (TCAs), selective serotonin reuptake inhibitors (SSRIs), a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine), a low-dose serotonin antagonist and reuptake inhibitor (SARI; trazodone) and hypericum extracts were found to be significantly superior to placebo, with estimated odds ratios between 1.69 and 2.03. There were no statistically significant differences between these drug classes. Reversible inhibitors of monoaminoxidase A (rMAO-As) and hypericum extracts were associated with significantly fewer dropouts because of adverse effects compared with TCAs, SSRIs, the SNRI, a noradrenaline reuptake inhibitor (NRI), and noradrenergic and specific serotonergic antidepressant agents (NaSSAs). CONCLUSIONS Compared with other drugs, TCAs and SSRIs have the most solid evidence base for being effective in the primary care setting, but the effect size compared with placebo is relatively small. Further agents (hypericum, rMAO-As, SNRI, NRI, NaSSAs, SARI) showed some positive results, but limitations of the currently available evidence makes a clear recommendation on their place in clinical practice difficult. PMID:25583895

Treatment with Selective Serotonin Reuptake Inhibitors and Mirtapazine Results in Differential Brain Activation by Visual Erotic Stimuli in Patients with Major Depressive Disorder

PubMed Central

Kim, Won; Jin, Bo-Ra; Yang, Wan-Seok; Lee, Kyuong-Uk; Juh, Ra-Hyung; Ahn, Kook-Jin; Chung, Yong-An

2009-01-01

Objective The objective of this study was to identify patterns of brain activation elicited by erotic visual stimuli in patients treated with either Selective Serotonin Reuptake Inhibitors (SSRIs) or mirtazipine. Methods Nine middle-aged men with major depressive disorder treated with an SSRI and ten middle-aged men with major depressive disorder treated with mirtazapine completed the trial. Ten subjects with no psychiatric illness were included as a control group. We conducted functional brain magnetic resonance imaging (fMRI) while a film alternatively played erotic and non-erotic contents for 14 minutes and 9 seconds. Results The control group showed activation in the occipitotemporal area, anterior cingulate gyrus, insula, orbitofrontal cortex, and caudate nucleus. For subjects treated with SSRIs, the intensity of activity in these regions was much lower compared to the control group. Intensity of activation in the group treated with mirtazapine was less than the control group but grea-ter than those treated with SSRIs. Using subtraction analysis, the SSRI group showed significantly lower activation than the mirtazapine group in the anterior cingulate gyrus and the caudate nucleus. Conclusion Our study suggests that the different rates of sexual side effects between the patients in the SSRI-treated group and the mirtazapine-treated group may be due to different effects on brain activation. PMID:20046380

Health resource use and costs of vilazodone and other selective serotonin re-uptake inhibitors in treating major depressive disorder.

PubMed

Zhou, Zheng-Yi; Sun, Shawn; Chopra, Pooja; Zhong, Yichen; Totev, Todor; Signorovitch, James

2015-01-01

Selective serotonin re-uptake inhibitors (SSRIs) are widely prescribed antidepressants. This claims database study compared healthcare resource use and costs among patients with major depressive disorder (MDD) treated with vilazodone vs other SSRIs. Adults with an MDD diagnosis and ≥ 1 prescription fill for vilazodone, citalopram, escitalopram, fluoxetine, paroxetine, or sertraline were identified from administrative claims data (2010-2012). Patients who concomitantly used adjunctive medication, either a second-generation antidepressant or antipsychotic, were excluded. All-cause and MDD-related healthcare resource use and costs (in 2012 USD) were compared between patients treated with vilazodone vs other SSRIs over a 6-month follow-up period using unadjusted and multivariable analyses. The study cohort included 49 861 patients (mean age = 44.0 years; 70% female). Compared with the vilazodone cohort (n = 3527), patients in the citalopram (n = 12 187), escitalopram (n = 8275), fluoxetine (n = 10 142), paroxetine (n = 3146), and sertraline (n = 12 584) cohorts had significantly more all-cause inpatient hospital visits, longer hospital stays and more frequent emergency department visits, following the index date, after adjusting for baseline characteristics. All-cause medical service costs (inpatient + outpatient + emergency department visits) were significantly higher across all other SSRI cohorts vs vilazodone by $758-$1165 (p < 0.05). Similarly, all-cause total costs, were significantly or numerically (non-significantly) higher across all SSRI cohorts vs vilazodone by $351-$780. The was no clinical measurement of disease severity, partial coverage of the Medicare-eligible population, and short follow-up. MDD treatment with vilazodone was associated with significantly lower rates of inpatient and emergency services, and with significantly lower all-cause medical service costs and numerically (non-significantly) lower total costs to payers than with the other SSRIs

Real-world outcomes in patients with depression treated with duloxetine or a selective serotonin reuptake inhibitor in East Asia.

PubMed

Hong, Jihyung; Novick, Diego; Montgomery, William; Moneta, Maria Victoria; Dueñas, Héctor; Peng, Xiaomei; Haro, Josep Maria

2016-03-01

This study compared treatment outcomes in patients with major depressive disorder treated with either duloxetine with a daily dose of ≤60 mg or a selective serotonin reuptake inhibitor (SSRI) as monotherapy for up to 6 months in a naturalistic setting in East Asia. In addition, this study examined the impact of painful physical symptoms (PPS) on the effects of these treatments. This post-hoc analysis of data from a 6-month prospective observational study involving 1,549 major depressive disorder patients without sexual dysfunction focused on a subgroup of patients from East Asia (n = 587). Depression severity was measured using the Clinical Global Impression of Severity and the 16-item Quick Inventory of Depressive Symptomatology Self-Report (QIDS-SR16 ), whereas quality of life (QoL) was measured using EuroQoL instruments. PPS were rated using the modified Somatic Symptom Inventory. Multiple regression analyses were performed to compare the treatment outcomes. Duloxetine-treated patients had higher odds of achieving remission (odds ratio = 2.578, P < 0.001) and response (odds ratio = 2.704, P < 0.001) during follow-up, compared with SSRI-treated patients. They also had lower levels of disease severity and higher levels of QoL during follow-up. A similar pattern was observed in each subgroup of patients with and without PPS at baseline, but the effects of duloxetine relative to SSRIs were in general greater in patients with PPS. Patients treated with duloxetine had better treatment outcomes in terms of remission, response, depressive symptoms, and QoL, compared with SSRIs. Treatment with duloxetine may have additional advantages for patients with concurrent PPS. © 2015 Wiley Publishing Asia Pty Ltd.

Pharmacokinetics and pharmacodynamics of edivoxetine (LY2216684), a norepinephrine reuptake inhibitor, in pediatric patients with attention-deficit/hyperactivity disorder.

PubMed

Kielbasa, William; Quinlan, Tonya; Jin, Ling; Xu, Wen; Lachno, D Richard; Dean, Robert A; Allen, Albert J

2012-08-01

Edivoxetine (LY2216684) is a selective and potent norepinephrine reuptake inhibitor (NERI). The pharmacokinetics (PK) and pharmacodynamics (PD) of edivoxetine were assessed in children and adolescent patients with attention-deficit/hyperactivity disorder (ADHD) following single and once-daily oral doses of edivoxetine. During a phase 1 open-label safety, tolerability, and PK study, pediatric patients were administered edivoxetine at target doses of 0.05, 0.1, 0.2 and 0.3 mg/kg, and blood samples were collected to determine plasma concentrations of edivoxetine for PK assessments and plasma 3,4-dihydroxyphenylglycol (DHPG) concentrations for PD assessments. Edivoxetine plasma concentrations were measured using liquid chromatography with tandem mass spectrometric detection, and DHPG was measured using liquid chromatography with electrochemical detection. Edivoxetine PK was comparable between children and adolescents. The time to maximum concentration (t(max)) of edivoxetine was ∼2 hours, which was followed by a mono-exponential decline in plasma concentrations with a terminal elimination half-life (t(1/2)) of ∼6 hours. Dose-dependent increases in area under the edivoxetine plasma concentration versus time curve from zero to infinity (AUC(0-∞)) and maximum plasma concentration (C(max)) were observed, and there was no discernable difference in the apparent clearance (CL/F) or the apparent volume of distribution at steady state (V(ss)/F) across the dose range. In adolescents, edivoxetine caused a maximum decrease in plasma DHPG concentrations from baseline of ∼28%, most notably within 8 hours of edivoxetine administration. This initial study in pediatric patients with ADHD provides new information on the PK profile of edivoxetine, and exposures that decrease plasma DHPG consistent with the mechanism of action of a NERI. The PK and PD data inform edivoxetine pharmacology and can be used to develop comprehensive population PK and/or PK-PD models to guide dosing

Pharmacokinetics and tolerability of DA-8031, a novel selective serotonin reuptake inhibitor for premature ejaculation in healthy male subjects.

PubMed

Shin, Dongseong; Lee, SeungHwan; Yi, Sojeong; Yoon, Seo Hyun; Cho, Joo-Youn; Bahng, Mi Young; Jang, In-Jin; Yu, Kyung-Sang

2017-01-01

DA-8031 is a selective serotonin reuptake inhibitor under development for the treatment of premature ejaculation. This is the first-in-human study aimed at evaluating the pharmacokinetics and tolerability of DA-8031 and its metabolites (M1, M2, M4, and M5) in the plasma and urine after administration of a single oral dose in healthy male subjects. A dose block-randomized, double-blind, placebo-controlled, single ascending dose study was conducted. Subjects received either placebo or a single dose of DA-8031 at 5, 10, 20, 40, 60, 80, or 120 mg. DA-8031 and its four metabolites were analyzed in the plasma and urine for pharmacokinetic evaluation. The effect of genetic polymorphisms of cytochrome-P450 (CYP) enzymes on the pharmacokinetics of DA-8031 was evaluated. After a single dose, plasma DA-8031 reached the maximum concentration at a median of 2-3 h and was eliminated with terminal elimination half-life of 17.9-28.7 h. The mean renal clearance was 3.7-5.6 L/h. Dose-proportional pharmacokinetics was observed over the dose range of 20-80 mg. Among the metabolites, M4 had the greatest plasma concentration, followed by M5 and M1. Subjects with CYP2D6 intermediate metabolizer had significantly greater dose-normalized C max and AUC 0- t of DA-8031 as well as smaller metabolic ratios than those subjects with CYP2D6 extensive metabolizer. The most common adverse events were nausea, dizziness, and headache, and no serious adverse events were reported. In conclusion, the systemic exposure of DA-8031 was increased proportionally to the dose within 20-80 mg. Genetic polymorphisms of CYP2D6 had an effect on the systemic exposure of DA-8031. DA-8031 was well tolerated after single doses of 80 mg or less.

Effect of spinal monoaminergic neuronal system dysfunction on pain threshold in rats, and the analgesic effect of serotonin and norepinephrine reuptake inhibitors.

PubMed

Tamano, Ryuta; Ishida, Mitsuhiro; Asaki, Toshiyuki; Hasegawa, Minoru; Shinohara, Shunji

2016-02-26

Dysfunction in the central serotonin (5-HT) and norepinephrine (NE) systems cause depression and pain. Descending spinal pain modulatory pathways are important in the analgesic mechanisms of antidepressants, particularly serotonin and norepinephrine reuptake inhibitors (SNRIs). While many non-clinical studies have demonstrated the roles of central monoaminergic systems in pain, there is little evidence to illuminate the direct contribution of spinal descending pain modulatory systems independently of depressive-like behavior. To examine the effects of dysfunction of spinal monoaminergic systems on pain sensitivity, we established a rat chronic pain model by administering lumbar-intrathecal reserpine to minimize its influence on brain. Lumbar-intrathecal reserpine evoked persistent mechanical hypersensitivity and corresponding reductions in spinal 5-HT and NE concentrations (from 767.2 to 241.6ng/g and from 455.9 to 41.7ng/g, respectively after reserpine 30nmol). Lumbar-intrathecal reserpine did not deplete brain monoamines or bring about depressive-like behavior in the forced swim test. Spinal monoamines depletion-induced pain sensitivity was ameliorated by lumbar-intrathecal administration of the SNRIs (duloxetine and milnacipran) in dose-dependent manners. These suggest that increased pain sensitivity could be induced by dysfunction solely of the descending pain modulatory system, regardless of depressive-like behavior, and lumbar-intrathecal administration of SNRIs could ameliorate the pain sensitivity which might be mediated by affecting the descending pain modulatory system in the spinal cord, not via their antidepressant effects. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Mice lacking the serotonin 5-HT2B receptor as an animal model of resistance to selective serotonin reuptake inhibitors antidepressants.

PubMed

Diaz, Silvina Laura; Narboux-Nême, Nicolas; Boutourlinsky, Katia; Doly, Stéphane; Maroteaux, Luc

2016-02-01

Depressive disorders are among the most prevalent neuropsychiatric dysfunctions worldwide, with high rates of resistance to antidepressant treatment. Genetic factors clearly contribute to the manifestation of depression as well as to the response to antidepressants. Transgenic mouse models appear as seminal tools to disentangle this complex disorder. Here, we analyzed new key aspects of the phenotype of knock-out mice for the gene encoding the serotonin 2B receptor (Htr(2B)(-/-)), including basal phenotype, ability to develop a depressive-like phenotype upon chronic isolation, and effect of chronic exposure to fluoxetine on chronically stressed Htr(2B)(-/-) mice. We find, here, that Htr(2B)(-/-) mice display an antidepressant-like phenotype, which includes reduced latency to feed in the novelty suppressed feeding test, basal increase in hippocampal BDNF levels, no change in TrkB and p75 protein levels, and an increased preference for sucrose consumption compared to wild type (Htr(2B)(+/+)) mice. Nevertheless, we show that these mice can develop depressive-like behaviors when socially isolated during four weeks. Selective serotonin reuptake inhibitors (SSRI) have been previously shown to be ineffective in non-stressed Htr(2B)(-/-) mice. We evaluated, here, the effects of the SSRI fluoxetine in chronically stressed Htr(2B)(-/-) mice and similarly no behavioral or plastic effect was induced by this antidepressant. All together, these results highlight the suitability to study resistance to SSRI antidepressants of this mouse model displaying panoply of conditions among which behavioral, neurotrophic and plastic causative factors can be analyzed. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

The Relationship Between Plasma Cytokine Levels and Response to Selective Serotonin Reuptake Inhibitor Treatment in Children and Adolescents with Depression and/or Anxiety Disorders.

PubMed

Amitai, Maya; Taler, Michal; Carmel, Miri; Michaelovsky, Elena; Eilat, Tamar; Yablonski, Maya; Orpaz, Naama; Chen, Alon; Apter, Alan; Weizman, Abraham; Fennig, Silvana

2016-10-01

In adults there is growing evidence that antidepressant (AD) treatment results in a decline in inflammatory cytokines. This is the first report, to our knowledge, of the relationship between response to selective serotonin reuptake inhibitor (SSRI) treatment for anxiety and/or depression and cytokine levels in children and adolescents. Forty-one patients who met Diagnostic and Statistical Manual for Mental Disorders, 4th ed. (DSM-IV) criteria for major depressive disorder (MDD) or anxiety disorders participated in study. Their ages ranged from 9 to 18 (14.12 ± 2.30) years. The patients were treated with fluoxetine for 8 weeks. Plasma concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, and IL-1β were measured by enzyme linked immunosorbent assays (ELISA) before and after fluoxetine treatment. Clinical response was measured with several scales, including the Children's Depression Rating Scale-Revised (CDRS-R), the Beck Depression Inventory (BDI), and the Screen for Child Anxiety Related Emotional Disorders (SCARED) Results: The overall response rate was 56%. Antidepressant treatment significantly reduced TNF-α levels (p = 0.037), with no significant changes in the levels of IL-6 and IL-1β. All three proinflammatory cytokines were significantly (p < 0.05) higher in SSRI-refractory than in SSRI-responsive patients. Higher levels of TNF-α, IL-6, and IL-1β might predict nonresponse to fluoxetine treatment in children.

Demonstration of clomipramine and venlafaxine occupation at serotonin reuptake sites in man in vivo.

PubMed

Malizia, A L; Melichar, J M; Brown, D J; Gunn, R N; Reynolds, A; Jones, T; Nutt, D J

1997-01-01

We describe the use of 11CRTI-55 and the Multiple Objects Coincidences Counter (MOCC) to detect in-vivo binding to peripheral serotonin reuptake sites (left chest comprising platelet and lung serotonin reuptake sites) in man. Displacement and preloading experiments with clomipramine and venlafaxine in two healthy volunteers demonstrated that 11CRTI-55 binding is decreased in a dose-dependent fashion by both these drugs which bind to the serotonin transporter. In addition parallel data from the total head curve (representing 11CRTI-55 binding to central serotonin and dopamine (DA) reuptake sites) suggest that prior blockade of the serotonin transporter may be a useful strategy to maximize radioactive counts in the head when measuring the DA transporter. The MOCC is likely to be useful to determine sequential indices of relative serotonin reuptake blockade in patients on treatment.

Neuronal NOS inhibitor 1-(2-trifluoromethylphenyl)-imidazole augment the effects of antidepressants acting via serotonergic system in the forced swimming test in rats.

PubMed

Ulak, Güner; Mutlu, Oguz; Akar, Füruzan Yildiz; Komsuoğlu, F Ipek; Tanyeri, Pelin; Erden, B Faruk

2008-10-01

Treatment-resistant depression has necessitated new therapeutic strategies in augmenting the therapeutic actions of currently existing antidepressant drugs. The aim of this study was to investigate the possibility of synergistic interaction between 1-(2-trifluoromethylphenyl)-imidazole (TRIM), a novel neuronal nitric oxide synthase (nNOS) inhibitor and conventional antidepressants of different classes in the forced swimming test (FST) in rats. TRIM decreased the immobility time at 50 mg/kg doses in the FST in rats. Treatment with a behaviourally subeffective dose of TRIM (20 mg/kg) augmented the behavioural effect of tricyclic antidepressant imipramine, selective serotonin re-uptake inhibitor (SSRI) citalopram and fluoxetine or selective serotonin reuptake enhancer tianeptine but failed to augment the antidepressant effect of reboxetine, a noradrenaline re-uptake inhibitor, in this test. Therefore inhibition of NOS augments the effects of antidepressants acting on serotonergic system in the FST. Neither TRIM (10-50 mg/kg) nor other drug treatments affected the locomotor activity of animals. These findings are in agreement with the view that antidepressant effects or augmentation of these effects in the FST may be explained with inhibition of NOS activity and this may be a new approach in offering greater therapeutic efficacy of antidepressants acting via serotonergic system.

Assessment of functional outcomes by Sheehan Disability Scale in patients with major depressive disorder treated with duloxetine versus selective serotonin reuptake inhibitors.

PubMed

Sheehan, David V; Mancini, Michele; Wang, Jianing; Berggren, Lovisa; Cao, Haijun; Dueñas, Héctor José; Yue, Li

2016-01-01

We compared functional impairment outcomes assessed with Sheehan Disability Scale (SDS) after treatment with duloxetine versus selective serotonin reuptake inhibitors (SSRIs) in patients with major depressive disorder. Data were pooled from four randomized studies comparing treatment with duloxetine and SSRIs (three double blind and one open label). Analysis of covariance, with last-observation-carried-forward approach for missing data, explored treatment differences between duloxetine and SSRIs on SDS changes during 8 to 12 weeks of acute treatment for the intent-to-treat population. Logistic regression analysis examined the predictive capacity of baseline patient characteristics for remission in functional impairment (SDS total score ≤ 6 and SDS item scores ≤ 2) at endpoint. Included were 2193 patients (duloxetine n = 1029; SSRIs n = 835; placebo n = 329). Treatment with duloxetine and SSRIs resulted in significantly (p < 0.01) greater improvements in the SDS total score versus treatment with placebo. Higher SDS (p < 0.0001) or 17-item Hamilton Depression Rating Scale baseline scores (p < 0.01) predicted lower probability of functional improvement after treatment with duloxetine or SSRIs. Female gender (p ≤ 0.05) predicted higher probability of functional improvement after treatment with duloxetine or SSRIs. Treatment with SSRIs and duloxetine improved functional impairment in patients with major depressive disorder. Higher SDS or 17-item Hamilton Depression Rating Scale baseline scores predicted less probability of SDS improvement; female gender predicted better improvement in functional impairment at endpoint. © 2015 The Authors. Human Psychopharmacology: Clinical and Experimental published by John Wiley & Sons, Ltd.

Ascorbic acid efflux and re-uptake in endothelial cells: maintenance of intracellular ascorbate.

PubMed

May, James M; Qu, Zhi-chao

2009-05-01

Entry of vitamin C or ascorbate into most tissues requires its movement across the endothelial cell barrier of vessels. If trans-cellular ascorbate movement occurs, then it should be evident as ascorbate efflux from endothelial cells. Cultured EA.926 endothelial cells that had been loaded to about 3.5 mM intracellular ascorbate lost 70-80% of ascorbate to the medium over several hours at 37 degrees C via a non-saturable process that was insensitive to anion transport inhibitors and thiol reagents. Oxidation of this extracellular ascorbate by ascorbate oxidase or ferricyanide enhanced apparent ascorbate efflux, suggesting that efflux of the vitamin was countered in part by its re-uptake on ascorbate transporters. Although basal ascorbate efflux was not calcium-dependent, increased entry of calcium into the cells enhanced ascorbate release. These results support the hypothesis that ascorbate efflux reflects trans-endothelial cell ascorbate movement out of the blood vessel.

Association of brain-derived neurotrophic factor valine to methionine polymorphism with sexual dysfunction following selective serotonin reuptake inhibitor treatment in female patients with major depressive disorder.

PubMed

Nazree, Nur Elia; Mohamed, Zahurin; Reynolds, Gavin P; Mohd Zain, Shamsul; Masiran, Ruziana; Sidi, Hatta; Chong, Lu Ann; Hway, Anne Yee; Adlan, Aida Syarinaz; Zainal, Nor Zuraida

2016-12-01

The occurrence of female sexual dysfunction (FSD) in patients with major depressive disorder (MDD) receiving selective serotonin reuptake inhibitors (SSRIs) treatment gives negative impacts on patients' quality of life and causes treatment discontinuation. We aimed to investigate whether genetic polymorphism of identified candidate gene is associated with FSD in our study population. This is a cross-sectional study. A total of 95 female patients with MDD who met the criteria of the study were recruited and were specifically assessed on the sexual function by trained psychiatrists. Patients' DNA was genotyped for BDNF Val66Met polymorphism using real-time polymerase chain reaction. The prevalence of FSD in this study is 31.6%. In the FSD group, patients with problematic marriage were significantly more frequent compared with patients who did not have problematic marriage (P = 0.009). Significant association was detected in the lubrication domain with BDNF Val66Met polymorphism (P = 0.030) using additive genetic model, with even stronger association when using the recessive model (P = 0.013). This study suggested that there was no significant association between BDNF Val66Met with FSD. However, this polymorphism is significantly associated with lubrication disorder in patients treated with SSRIs. © 2015 Wiley Publishing Asia Pty Ltd.

Association of the Polygenic Scores for Personality Traits and Response to Selective Serotonin Reuptake Inhibitors in Patients with Major Depressive Disorder

PubMed Central

Amare, Azmeraw T.; Schubert, Klaus Oliver; Tekola-Ayele, Fasil; Hsu, Yi-Hsiang; Sangkuhl, Katrin; Jenkins, Gregory; Whaley, Ryan M.; Barman, Poulami; Batzler, Anthony; Altman, Russ B.; Arolt, Volker; Brockmöller, Jürgen; Chen, Chia-Hui; Domschke, Katharina; Hall-Flavin, Daniel K.; Hong, Chen-Jee; Illi, Ari; Ji, Yuan; Kampman, Olli; Kinoshita, Toshihiko; Leinonen, Esa; Liou, Ying-Jay; Mushiroda, Taisei; Nonen, Shinpei; Skime, Michelle K.; Wang, Liewei; Kato, Masaki; Liu, Yu-Li; Praphanphoj, Verayuth; Stingl, Julia C.; Bobo, William V.; Tsai, Shih-Jen; Kubo, Michiaki; Klein, Teri E.; Weinshilboum, Richard M.; Biernacka, Joanna M.; Baune, Bernhard T.

2018-01-01

Studies reported a strong genetic correlation between the Big Five personality traits and major depressive disorder (MDD). Moreover, personality traits are thought to be associated with response to antidepressants treatment that might partly be mediated by genetic factors. In this study, we examined whether polygenic scores (PGSs) derived from the Big Five personality traits predict treatment response and remission in patients with MDD who were prescribed selective serotonin reuptake inhibitors (SSRIs). In addition, we performed meta-analyses of genome-wide association studies (GWASs) on these traits to identify genetic variants underpinning the cross-trait polygenic association. The PGS analysis was performed using data from two cohorts: the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS, n = 529) and the International SSRI Pharmacogenomics Consortium (ISPC, n = 865). The cross-trait GWAS meta-analyses were conducted by combining GWAS summary statistics on SSRIs treatment outcome and on the personality traits. The results showed that the PGS for openness and neuroticism were associated with SSRIs treatment outcomes at p < 0.05 across PT thresholds in both cohorts. A significant association was also found between the PGS for conscientiousness and SSRIs treatment response in the PGRN-AMPS sample. In the cross-trait GWAS meta-analyses, we identified eight loci associated with (a) SSRIs response and conscientiousness near YEATS4 gene and (b) SSRI remission and neuroticism eight loci near PRAG1, MSRA, XKR6, ELAVL2, PLXNC1, PLEKHM1, and BRUNOL4 genes. An assessment of a polygenic load for personality traits may assist in conjunction with clinical data to predict whether MDD patients might respond favorably to SSRIs. PMID:29559929

Treatment of depression in patients with temporal lobe epilepsy: A pilot study of cognitive behavioral therapy vs. selective serotonin reuptake inhibitors.

PubMed

Orjuela-Rojas, Juan Manuel; Martínez-Juárez, Iris E; Ruiz-Chow, Angel; Crail-Melendez, Daniel

2015-10-01

There is a high prevalence of depression in patients with epilepsy, which negatively impacts their quality of life (QOL) and seizure control. Currently, the first-line of treatment for depression in patients with epilepsy is based on selective serotonin reuptake inhibitors (SSRIs). The main objective of this pilot study was to compare cognitive behavioral therapy (CBT) versus SSRIs for the treatment of major depressive disorder (MDD) in patients with temporal lobe epilepsy (TLE). Seven patients who received group CBT were compared with eight patients treated with SSRIs. All were diagnosed with MDD and TLE. Patients were assessed at baseline before treatment and at six and 12weeks during treatment with the Quality of Life in Epilepsy Scale of 31 items (QOLIE 31), the Beck Depression Inventory (BDI), and the Hospital Anxiety and Depression Scale (HADS). Seizure records were also taken on a monthly basis. After 12weeks of treatment, both groups showed improved QOL and reduced severity of depression symptoms. There were no statistically significant group differences in the final scores for the BDI (p=0.40) and QOLIE 31 (p=0.72), although the effect size on QOL was higher for the group receiving CBT. In conclusion, the present study suggests that both CBT and SSRIs may improve MDD and QOL in patients with TLE. We found no significant outcome differences between both treatment modalities. These findings support further study using a double-blind controlled design to demonstrate the efficacy of CBT and SSRIs in the treatment of MDD and QOL in patients with TLE. Copyright © 2015 Elsevier Inc. All rights reserved.

A neurobiological perspective on attachment problems in sexual offenders and the role of selective serotonin re-uptake inhibitors in the treatment of such problems.

PubMed

Beech, Anthony R; Mitchell, Ian J

2005-02-01

This paper describes what is currently known about attachment from the development, social-cognitive and biological literatures and outlines the impact on organisms given adverse development experiences that can have an effect upon attachment formation in childhood across these three literatures. We then describe the effects that 'insecure' attachment styles arising in childhood can affect brain chemistry and brain function and subsequently adult social/romantic relationships. In the paper, we note that a number of sexual offenders report adverse childhood experiences and that they possess attachment styles that, taken together, make it likely that they will either seek out intimate attachments in ways where they will have sex with children, perhaps confusing sex with intimacy or in aggressive ways as particularly happens with men who sexually assault adult women. The last section of the paper describes chemical treatment for sexual offenders, focusing on the use of selective serotonin re-uptake inhibitors (SSRIs). We note evidence for the role of SSRIs in promoting more social/affiliative behaviors and speculate on the effects that SSRIs have in the treatment of sexual offenders by targeting areas of the social brain. Here, we would argue that it would be useful to carry out treatment where there is a combination of SSRI treatment (to promote more prosocial feelings and behaviors) in conjunction with therapy that typically addresses thoughts and behaviors, i.e., cognitive-behavioral therapy/schema-focused therapy.

5-HT has contrasting effects in the frontal cortex, but not the hypothalamus, on changes in noradrenaline efflux induced by the monoamine releasing-agent, d-amphetamine, and the reuptake inhibitor, BTS 54 354.

PubMed

Géranton, Sandrine M; Heal, David J; Stanford, S Clare

2004-03-01

There is extensive evidence for functional interactions between central noradrenergic and serotonergic neurones. Here, dual-probe microdialysis was used in freely-moving rats to compare the effects of 5-HT on noradrenergic transmission in the rat frontal cortex and hypothalamus. We studied the effects of the 5-HT synthesis inhibitor, para-chlorophenylalanine (pCPA; which depleted 5-HT stores in both the frontal cortex and the hypothalamus), on spontaneous efflux of noradrenaline and on the noradrenergic responses to d-amphetamine, and the monoamine reuptake inhibitor, BTS 54 354. pCPA pretreatment alone did not affect spontaneous noradrenaline efflux in either brain region, whether or not alpha2-autoreceptors were inactivated by administration of the alpha2-antagonist, atipamezole (1 mg/kg i.p). However, in the frontal cortex, pCPA pretreatment augmented the amplitude of, and prolonged, the noradrenergic response to local infusion of d-amphetamine (10 microM). In contrast, pCPA abolished the increase in cortical noradrenaline efflux induced by local infusion of BTS 54 354 (50 microM). In the hypothalamus, pCPA did not affect the amplitude of the response to either of these agents but did prolong the effects of d-amphetamine on noradrenaline efflux. These findings suggest that serotonergic transmission has complex effects on the noradrenergic response to drugs that increase noradrenergic transmission in the frontal cortex, but has less influence in the hypothalamus.

Ascorbic Acid Efflux and Re-uptake in Endothelial Cells: Maintenance of Intracellular Ascorbate

PubMed Central

May, James M.; Qu, Zhi-chao

2013-01-01

Entry of vitamin C or ascorbate into most tissues requires its movement across the endothelial cell barrier of vessels. If trans-cellular ascorbate movement occurs, then it should be evident as ascorbate efflux from endothelial cells. Cultured EA.926 endothelial cells that had been loaded to about 3.5 mM intracellular ascorbate lost 70–80% of ascorbate to the medium over several hours at 37 °C via a non-saturable process that was insensitive to anion transport inhibitors and thiol reagents. Oxidation of this extracellular ascorbate by ascorbate oxidase or ferricyanide enhanced apparent ascorbate efflux, suggesting that efflux of the vitamin was countered in part by its re-uptake on ascorbate transporters. Although basal ascorbate efflux was not calcium-dependent, increased entry of calcium into the cells enhanced ascorbate release. These results support the hypothesis that ascorbate efflux reflects trans-endothelial cell ascorbate movement out of the blood vessel. PMID:19148707

Gastrointestinal bleeding risk of selective serotonin reuptake inhibitors by level of kidney function: a population-based cohort study.

PubMed

Iwagami, Masao; Tomlinson, Laurie A; Mansfield, Kathryn E; Douglas, Ian J; Smeeth, Liam; Nitsch, Dorothea

2018-06-04

To estimate the risk of gastrointestinal (GI) bleeding associated with serotonin reuptake inhibitors (SSRIs) by level of kidney function. We conducted a cohort study using the Clinical Practice Research Datalink linked to Hospital Episode Statistics. We identified patients with chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73m 2 for ≥3 months), and a comparison group of patients without it. Patients with CKD were further classified as stage 3a (eGFR 45-59 mL/min/1.73m 2 ), 3b (30-44 mL/min/1.73m 2 ), and 4/5 (<30 mL/min/1.73m 2 ). We excluded prevalent SSRI users at cohort entry. Exposure was time-dependent SSRI prescription and outcome was first hospitalisation for GI bleeding. We estimated adjusted rate ratio (aRR) and rate difference (aRD) of GI bleeding comparing periods with and without SSRI prescription at each level of kidney function. The aRRs and aRDs were: (i) no CKD (N=202,121) aRR: 1.66 (95%CI 1.37-2.01), aRD: 2.0/1000 person-years (5.5 versus 3.5/1000 person-years in period with and without SSRIs); (ii) CKD stage 3a (N=153,316) aRR: 1.86 (1.62-2.15), aRD: 4.2/1000 person-years (8.3 versus 4.1/1000 person-years); (iii) CKD stage 3b (N=46,482) aRR: 1.61 (1.27-2.04), aRD: 4.8/1000 person-years (9.9 versus 5.1/1000 person-years); and (iv) CKD stage 4/5 (N=11,197) aRR: 1.84 (1.14-2.96), aRD: 7.9/1000 person-years (15.3 versus 7.4/1000 person-years). While there was no evidence of increase in the aRR (p-trend=0.922), there was strong evidence that the aRD increased as kidney function deteriorated (p-trend=0.001). While the relative risk was constant, the excess risk of GI bleeding associated with SSRIs markedly increased among patients with decreased kidney function. This article is protected by copyright. All rights reserved.

Heterogeneities in Axonal Structure and Transporter Distribution Lower Dopamine Reuptake Efficiency

PubMed Central

Block, Ethan R.; Bartol, Tom M.; Sorkin, Alexander

2018-01-01

Abstract Efficient clearance of dopamine (DA) from the synapse is key to regulating dopaminergic signaling. This role is fulfilled by DA transporters (DATs). Recent advances in the structural characterization of DAT from Drosophila (dDAT) and in high-resolution imaging of DA neurons and the distribution of DATs in living cells now permit us to gain a mechanistic understanding of DA reuptake events in silico. Using electron microscopy images and immunofluorescence of transgenic knock-in mouse brains that express hemagglutinin-tagged DAT in DA neurons, we reconstructed a realistic environment for MCell simulations of DA reuptake, wherein the identity, population and kinetics of homology-modeled human DAT (hDAT) substates were derived from molecular simulations. The complex morphology of axon terminals near active zones was observed to give rise to large variations in DA reuptake efficiency, and thereby in extracellular DA density. Comparison of the effect of different firing patterns showed that phasic firing would increase the probability of reaching local DA levels sufficiently high to activate low-affinity DA receptors, mainly owing to high DA levels transiently attained during the burst phase. The experimentally observed nonuniform surface distribution of DATs emerged as a major modulator of DA signaling: reuptake was slower, and the peaks/width of transient DA levels were sharper/wider under nonuniform distribution of DATs, compared with uniform. Overall, the study highlights the importance of accurate descriptions of extrasynaptic morphology, DAT distribution, and conformational kinetics for quantitative evaluation of dopaminergic transmission and for providing deeper understanding of the mechanisms that regulate DA transmission. PMID:29430519

Danish physicians' preferences for prescribing escitalopram over citalopram and sertraline to treatment-naïve patients: a national, register-based study.

PubMed

Poulsen, Karen Killerup; Glintborg, Dorte; Moreno, Søren Ilsøe; Thirstrup, Steffen; Aagaard, Lise; Andersen, Stig Ejdrup

2013-05-01

To investigate whether general practitioners, hospital physicians and specialized practitioners in psychiatry have similar preferences for initiating treatment with expensive serotonin-specific reuptake inhibitors (SSRIs). All first-time prescriptions for the SSRIs escitalopram, citalopram and sertraline reported to the Danish National Register of Medicinal Product Statistics from April 1, 2009 until March 31, 2010 were analysed with regard to treatment naivety and type of prescriber. A prescription was considered as first time if the patient had not received a prescription for the same drug within the last 2 years. Patients who had not received a prescription for an antidepressant within 6 months prior to the date of redemption were classified as treatment-naïve. We included 82,702 first-time prescriptions, 65,313 (79 %) of which were for treatment-naïve patients. Of the treatment-naïve patients, 19 % were initially prescribed escitalopram. Hospital physicians prescribed escitalopram to 34 % of their treatment-naïve patients, while practitioners specialized in psychiatry prescribed it to 25 %, and general practitioners prescribed it to 17 %. General practitioners, however, were responsible for initiating 87 % of all treatment-naïve patients. The most expensive SSRI, escitalopram, is prescribed as first choice to one in five patients receiving their first antidepressant of escitalopram, citalopram or sertraline. General practitioners made the bulk of all first-time SSRI prescriptions to treatment-naïve patients.

Cephradine as corrosion inhibitor for copper in 0.9% NaCl solution

NASA Astrophysics Data System (ADS)

Tasić, Žaklina Z.; Petrović Mihajlović, Marija B.; Radovanović, Milan B.; Simonović, Ana T.; Antonijević, Milan M.

2018-05-01

The effect of (6R,7R)-7-[[(2R)-2-amino-2-cyclohexa-1,4-dien-1-ylacetyl]amino]-3-methyl-8-oxo-5-thia-1-azobicyclo[4.2.0]oct-2-ene-2-carboxylic acid (cephradine) on corrosion behavior of copper in 0.9% NaCl solution was investigated. The electrochemical methods including the open circuit potential measurements, potentiodynamic polarization and electrochemical impedance spectroscopy measurements, scanning electron microscopy with energy dispersive X-ray spectroscopy and quantum chemical calculations were used for this investigation. According to the results obtained by potentiodynamic polarization, cephradine acts as mixed type inhibitor. Also, the results obtained by electrochemical impedance spectroscopy indicate that cephradine provides good copper protection in 0.9% NaCl solution. The inhibition efficiency of cephradine increases with increasing its concentration. The scanning electron microscopy with energy dispersive X-ray spectroscopy confirms that a protective layer is formed on the copper surface due to the adsorption of cephradine on the active sites on the copper surface. Adsorption of cephradine in 0.9% NaCl solution follows the Langmuir adsorption isotherm. Quantum chemical calculations are in agreement with results obtained by electrochemical measurements.

Identification of the binding sites for ubiquinone and inhibitors in the Na+-pumping NADH-ubiquinone oxidoreductase from Vibrio cholerae by photoaffinity labeling

PubMed Central

Ito, Takeshi; Ninokura, Satoshi; Kitazumi, Yuki; Mezic, Katherine G.; Cress, Brady F.; Koffas, Mattheos A. G.; Morgan, Joel E.; Barquera, Blanca; Miyoshi, Hideto

2017-01-01

The Na+-pumping NADH-quinone oxidoreductase (Na+-NQR) is the first enzyme of the respiratory chain and the main ion transporter in many marine and pathogenic bacteria, including Vibrio cholerae. The V. cholerae Na+-NQR has been extensively studied, but its binding sites for ubiquinone and inhibitors remain controversial. Here, using a photoreactive ubiquinone PUQ-3 as well as two aurachin-type inhibitors [125I]PAD-1 and [125I]PAD-2 and photoaffinity labeling experiments on the isolated enzyme, we demonstrate that the ubiquinone ring binds to the NqrA subunit in the regions Leu-32–Met-39 and Phe-131–Lys-138, encompassing the rear wall of a predicted ubiquinone-binding cavity. The quinolone ring and alkyl side chain of aurachin bound to the NqrB subunit in the regions Arg-43–Lys-54 and Trp-23–Gly-89, respectively. These results indicate that the binding sites for ubiquinone and aurachin-type inhibitors are in close proximity but do not overlap one another. Unexpectedly, although the inhibitory effects of PAD-1 and PAD-2 were almost completely abolished by certain mutations in NqrB (i.e. G140A and E144C), the binding reactivities of [125I]PAD-1 and [125I]PAD-2 to the mutated enzymes were unchanged compared with those of the wild-type enzyme. We also found that photoaffinity labeling by [125I]PAD-1 and [125I]PAD-2, rather than being competitively suppressed in the presence of other inhibitors, is enhanced under some experimental conditions. To explain these apparently paradoxical results, we propose models for the catalytic reaction of Na+-NQR and its interactions with inhibitors on the basis of the biochemical and biophysical results reported here and in previous work. PMID:28298441

Synergistic Activity between Two Antifungal Proteins, the Plant Defensin NaD1 and the Bovine Pancreatic Trypsin Inhibitor

PubMed Central

Dawson, Charlotte S.; McKenna, James A.; Quimbar, Pedro; Hayes, Brigitte M. E.; van der Weerden, Nicole L.

2017-01-01

ABSTRACT Defensins are a large family of small, cationic, cysteine-rich proteins that are part of the defense arsenal that plants use for protection against potentially damaging fungal infections. The plant defensin NaD1 from Nicotiana alata is a potent antifungal protein that inhibits growth and kills a variety of fungal pathogens that affect both plant and animal (human) hosts. Some serine protease inhibitors have also been reported to be antifungal molecules, while others have no inhibitory activity against fungi. Here we describe the synergistic activity of the plant defensin NaD1 with a selection of serine protease inhibitors against the plant pathogens Fusarium graminearum and Colletotrichum graminicola and the animal pathogen Candida albicans. The synergistic activity was not related to the protease inhibitory activity of these molecules but may arise from activation of fungal stress response pathways. The bovine pancreatic trypsin inhibitor (BPTI) displayed the most synergy with NaD1. BPTI also acted synergistically with several other antifungal molecules. The observation that NaD1 acts synergistically with protease inhibitors provides the foundation for the design of transgenic plants with improved resistance to fungal disease. It also supports the possibility of naturally occurring accessory factors that function to enhance the activity of innate immunity peptides in biological systems. IMPORTANCE This work describes the increased activity of a natural antifungal peptide in the presence of another antifungal peptide from a different family. This is termed antifungal synergy. Synergy is important for decreasing the amount of antifungal molecule needed to control the disease. Traditionally, naturally occurring antifungal molecules are assayed in isolation. Identification of synergistic interactions between antifungal peptides means that their activities in a complex biological system are likely to be different from what we observe when examining them

The relationship between adverse events during selective serotonin reuptake inhibitor treatment for major depressive disorder and nonremission in the suicide assessment methodology study.

PubMed

Daly, Ella J; Trivedi, Madhukar H; Fava, Maurizio; Shelton, Richard; Wisniewski, Stephen R; Morris, David W; Stegman, Diane; Preskorn, Sheldon H; Rush, A John

2011-02-01

Little is known about the association between antidepressant treatment-emergent adverse events and symptom nonremission in major depressive disorder. The objective of the current analysis was to determine whether particular baseline symptoms or treatment-emergent symptoms (adverse events) during the first 2 weeks are associated with nonremission after 8 weeks of treatment with a selective serotonin reuptake inhibitor (SSRI).Outpatients clinically diagnosed with nonpsychotic major depressive disorder were recruited from 6 primary and 9 psychiatric care sites. Participants (n = 206) were treated with an SSRI antidepressant (citalopram [20-40 mg/d], escitalopram [10-20 mg/d], fluoxetine [20-40 mg/d], paroxetine [20-40 mg/d], paroxetine CR [25-37.5 mg/d], or sertraline [50-150 mg/d]) for 8 weeks. Remission was defined as having a score of 5 or less on the 16-item Quick Inventory of Depressive Symptomatology-Clinician-Rated at week 8, or using last observation carried forward. Adverse events were identified using the 55-item Systematic Assessment for Treatment Emergent Events-Systematic Inquiry completed by participants at baseline and week 2.Findings indicated that the emergence of adverse events of weakness/fatigue, strange feeling, and trouble catching breath/hyperventilation at week 2 were independently associated with lack of remission even after controlling for the potential confounders of baseline depressive severity, anxious symptoms, antidepressant medication, chronic depression, race, burden of general medical comorbidity, and time in study. Hearing/seeing things appeared to have a protective effect. In conclusion, during SSRI treatment, the adverse events of weakness/fatigue, feeling strange, and trouble catching breath/hyperventilation are associated with nonremission, possibly due to lower adherence, early attrition, difficulty increasing the dose, and reduced efficacy.

Effect of Time-Dependent Selective Serotonin Reuptake Inhibitor Antidepressants During Pregnancy on Behavioral, Emotional, and Social Development in Preschool-Aged Children.

PubMed

Lupattelli, Angela; Wood, Mollie; Ystrom, Eivind; Skurtveit, Svetlana; Handal, Marte; Nordeng, Hedvig

2018-03-01

To evaluate the effect of prenatal exposure to selective serotonin reuptake inhibitors (SSRIs) on children's behavioral, emotional, and social development by age 5 years, and over time since age 1.5 years. The prospective Norwegian Mother and Child Cohort Study was linked to the Medical Birth Registry of Norway. We included women who reported depressive/anxiety disorders before and/or during pregnancy. Children born to women who used SSRIs in early (weeks 0-16), mid- (weeks 17-28), or late (> week 29) pregnancy were compared to those who were unexposed. Children's internalizing and externalizing behaviors (Child Behavior Checklist) and temperament traits (Emotionality, Activity and Shyness Temperament Questionnaire) were measured at 1.5, 3, and 5 years. Mean scores were calculated and standardized. General linear marginal structural models were fitted to account for time-varying exposure and confounders, and censoring; 3-level growth-curve models were used. A total of 8,359 mother-child dyads were included, and 4,128 children had complete outcome data at age 5 years. Children exposed to SSRIs in late pregnancy had an increased risk of anxious/depressed behaviors by age 5 years compared with unexposed children (adjusted β = 0.50, 95% CI = 0.04, 0.96). Such risk was not evident for earlier timings of exposure. There was no evidence for a substantial prenatal SSRI effect on externalizing, social, and emotional problems. These findings suggest no substantial increased risk for externalizing, emotional, or social problems in preschool-aged children following prenatal SSRI exposure. Although the role of chance and potential unmeasured confounding cannot be ruled out, late-pregnancy SSRI exposure was associated with greater anxious/depressed behaviors in the offspring. Copyright © 2017 American Academy of Child and Adolescent Psychiatry. Published by Elsevier Inc. All rights reserved.

Effects of nominally selective inhibitors of the kinases PI3K, SGK1 and PKB on the insulin-dependent control of epithelial Na+ absorption.

PubMed

Mansley, Morag K; Wilson, Stuart M

2010-10-01

Insulin-induced Na(+) retention in the distal nephron may contribute to the development of oedema/hypertension in patients with type 2 diabetes. This response to insulin is usually attributed to phosphatidylinositol-3-kinase (PI3K)/serum and glucocorticoid-inducible kinase 1 (SGK1) but a role for protein kinase B (PKB) has been proposed. The present study therefore aimed to clarify the way in which insulin can evoke Na(+) retention. We examined the effects of nominally selective inhibitors of PI3K (wortmannin, PI103, GDC-0941), SGK1 (GSK650394A) and PKB (Akti-1/2) on Na(+) transport in hormone-deprived and insulin-stimulated cortical collecting duct (mpkCCD) cells, while PI3K, SGK1 and PKB activities were assayed by monitoring the phosphorylation of endogenous proteins. Wortmannin substantially inhibited basal Na(+) transport whereas PI103 and GDC-0941 had only very small effects. However, these PI3K inhibitors all abolished insulin-induced Na(+) absorption and inactivated PI3K, SGK1 and PKB fully. GSK650394A and Akti-1/2 also inhibited insulin-evoked Na(+) absorption and while GSK650394A inhibited SGK1 without affecting PKB, Akti-1/2 inactivated both kinases. While studies undertaken using PI103 and GDC-0941 show that hormone-deprived cells can absorb Na(+) independently of PI3K, PI3K seems to be essential for insulin induced Na(+) transport. Akti-1/2 does not act as a selective inhibitor of PKB and data obtained using this compound must therefore be treated with caution. GSK650394A, on the other hand, selectively inhibits SGK1 and the finding that GSK650394A suppressed insulin-induced Na(+) absorption suggests that this response is dependent upon signalling via PI3K/SGK1.

Importance of the Extracellular Loop 4 in the Human Serotonin Transporter for Inhibitor Binding and Substrate Translocation*

PubMed Central

Rannversson, Hafsteinn; Wilson, Pamela; Kristensen, Kristina Birch; Sinning, Steffen; Kristensen, Anders Skov; Strømgaard, Kristian; Andersen, Jacob

2015-01-01

The serotonin transporter (SERT) terminates serotonergic neurotransmission by performing reuptake of released serotonin, and SERT is the primary target for antidepressants. SERT mediates the reuptake of serotonin through an alternating access mechanism, implying that a central substrate site is connected to both sides of the membrane by permeation pathways, of which only one is accessible at a time. The coordinated conformational changes in SERT associated with substrate translocation are not fully understood. Here, we have identified a Leu to Glu mutation at position 406 (L406E) in the extracellular loop 4 (EL4) of human SERT, which induced a remarkable gain-of-potency (up to >40-fold) for a range of SERT inhibitors. The effects were highly specific for L406E relative to six other mutations in the same position, including the closely related L406D mutation, showing that the effects induced by L406E are not simply charge-related effects. Leu406 is located >10 Å from the central inhibitor binding site indicating that the mutation affects inhibitor binding in an indirect manner. We found that L406E decreased accessibility to a residue in the cytoplasmic pathway. The shift in equilibrium to favor a more outward-facing conformation of SERT can explain the reduced turnover rate and increased association rate of inhibitor binding we found for L406E. Together, our findings show that EL4 allosterically can modulate inhibitor binding within the central binding site, and substantiates that EL4 has an important role in controlling the conformational equilibrium of human SERT. PMID:25903124

Rate of improvement during and across three treatments for panic disorder with or without agoraphobia: cognitive behavioral therapy, selective serotonin reuptake inhibitor or both combined.

PubMed

Van Apeldoorn, Franske J; Van Hout, Wiljo J P J; Timmerman, Marieke E; Mersch, Peter Paul A; den Boer, Johan A

2013-09-05

Existing literature on panic disorder (PD) yields no data regarding the differential rates of improvement during Cognitive Behavioral Therapy (CBT), Selective Serotonin Reuptake Inhibitor (SSRI) or both combined (CBT+SSRI). Patients were randomized to CBT, SSRI or CBT+SSRI which each lasted one year including three months of medication taper. Participating patients kept record of the frequency of panic attacks throughout the full year of treatment. Rate of improvement on panic frequency and the relationship between rate of improvement and baseline agoraphobia (AG) were examined. A significant decline in frequency of panic attacks was observed for each treatment modality. SSRI and CBT+SSRI were associated with a significant faster rate of improvement as compared to CBT. Gains were maintained after tapering medication. For patients with moderate or severe AG, CBT+SSRI was associated with a more rapid improvement on panic frequency as compared to patients receiving either mono-treatment. Frequency of panic attacks was not assessed beyond the full year of treatment. Second, only one process variable was used. Patients with PD respond well to each treatment as indicated by a significant decline in panic attacks. CBT is associated with a slower rate of improvement as compared to SSRI and CBT+SSRI. Discontinuation of SSRI treatment does not result in a revival of frequency of panic attacks. Our data suggest that for patients without or with only mild AG, SSRI-only will suffice. For patients with moderate or severe AG, the combined CBT+SSRI treatment is recommended. Copyright © 2013 Elsevier B.V. All rights reserved.

Novel selective and potent 5-HT reuptake inhibitors with 5-HT1D antagonist activity: chemistry and pharmacological evaluation of a series of thienopyran derivatives.

PubMed

Torrado, Alicia; Lamas, Carlos; Agejas, Javier; Jiménez, Alma; Diaz, Nuria; Gilmore, Jeremy; Boot, John; Findlay, Jeremy; Hayhurst, Lorna; Wallace, Louise; Broadmore, Richard; Tomlinson, Rosemarie

2004-10-15

A series of compounds combining the naphthylpiperazine and thienopyran scaffolds has been prepared and evaluated for 5-HT reuptake inhibition with 5-HT1D antagonist activity. The design of these compounds has been based on the 'overlapping type' strategy where two pharmacophores are linked in a single molecule. The resultant dual pharmacological profile has the potential to deliver a more efficient treatment for depression.

Normal Bone Microstructure and Density But Worse Physical Function in Older Women Treated with Selective Serotonin Reuptake Inhibitors, a Cross-Sectional Population-Based Study.

PubMed

Larsson, Berit; Mellström, Dan; Johansson, Lisa; Nilsson, Anna G; Lorentzon, Mattias; Sundh, Daniel

2018-05-05

Depression in the elderly is today often treated with selective serotonin reuptake inhibitors (SSRIs) because of their favorable adverse effect profile. However, treatment with SSRIs is associated with increased risk of fractures. Whether this increased risk depends on reduced bone strength or increased fall risk due to reduced physical function is not certain. The aim was therefore to investigate if treatment with SSRIs is associated with impaired bone microstructure, bone density, or physical function in older women. From an ongoing population-based study, 1057 women (77.7 ± 1.5 years) were included. Validated questionnaires were used to assess information regarding medical history, medications, smoking, mental and physical health, and physical activity. Physical function was measured using clinically used tests: timed up and go, walking speed, grip strength, chair stand test, and one leg standing. Bone mineral density (BMD) was measured at the hip and spine with dual-energy X-ray absorptiometry (Hologic Discovery A). Bone geometry and microstructure were measured at the ultradistal and distal (14%) site of radius and tibia using high-resolution peripheral quantitative computed tomography (HR-pQCT; XtremeCT). Treatment with SSRIs was associated with higher BMD at the femoral neck, total hip, and lumbar spine, whereas no associations were found for any HR-pQCT-derived measurements. The use of SSRIs was associated with lower grip strength, walking speed, and fewer chair stand rises. These associations were valid also after adjustments for known risk factors for falls. Treatment with SSRIs was, independently of covariates, associated with worse physical function without any signs of inferior bone geometry and microstructure.

In utero exposure to venlafaxine, a serotonin-norepinephrine reuptake inhibitor, increases cardiac anomalies and alters placental and heart serotonin signaling in the rat.

PubMed

Laurent, Laetitia; Huang, Chunwei; Ernest, Sheila R; Berard, Anick; Vaillancourt, Cathy; Hales, Barbara F

2016-12-01

Human studies are inconsistent with respect to an association between treatment with selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRI/SNRIs) and an increase in the incidence of congenital heart defects. Here we tested the hypothesis that in utero exposure to venlafaxine, a highly prescribed SNRI, increases the incidence of fetal heart defects and alters placental and fetal heart serotonin signaling in the rat. Timed-pregnant Sprague Dawley rats were gavaged daily with venlafaxine hydrochloride (0, 3, 10, 30, or 100 mg/kg/day) from gestation day 8 to 20. On gestation day 21, fetuses were examined for external and internal malformations; placentas and fetal hearts were collected for the analysis of gene expression. Venlafaxine had no effect on the number of live fetuses, fetal body weights, or external morphology in the absence of maternal toxicity. However, venlafaxine significantly increased the placental index (fetal body/placental weight ratio) and the incidence of fetal cardiac anomalies. Venlafaxine exposure decreased placental expression of the serotonin transporter (SERT/Slc6a4) at the transcript and protein levels. In contrast, venlafaxine increased SERT expression in the hearts of female, but not male, fetuses. Expression of the serotonin 2B receptor (5-HT 2B /Htr2b) and of fibroblast growth factor 8 was induced in fetal hearts. In utero venlafaxine exposure altered the placental index and induced fetal cardiac anomalies in rats. We propose that the increased incidence of cardiac anomalies is mediated through alterations in serotonin signaling in the placenta and fetal heart. Birth Defects Research (Part A), 2016. © 2016 Wiley Periodicals, Inc. Birth Defects Research (Part A) 106:1044-1055, 2016. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Repeated administration of the monoamine reuptake inhibitor BTS 74 398 induces ipsilateral circling in the 6-hydroxydopamine lesioned rat without sensitizing motor behaviours.

PubMed

Lane, E L; Cheetham, S C; Jenner, P

2005-01-01

BTS 74 398 (1-[1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone monocitrate) is a monoamine reuptake inhibitor that reverses motor deficits in MPTP-treated (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) common marmosets without provoking established dyskinesia. However, it is not known whether BTS 74 398 primes the basal ganglia for dyskinesia induction. In this study, the ability of BTS 74 398 to sensitize 6-hydroxydopamine (6-OHDA)-lesioned rats for the production of abnormal motor behaviours and the induction of striatal DeltaFosB were determined in comparison with l-3,4-dihydroxyphenylalanine methyl ester (L-dopa). Acute administration of BTS 74 398 induced a dose-dependent ipsilateral circling response in unilaterally 6-OHDA-lesioned rats whereas L-dopa produced dose-dependent contraversive rotation. The ipsilateral circling response to BTS 74 398 did not alter during 21 days of administration. In contrast, L-dopa treatment for 21 days caused a marked increase in rotational response. Repeated administration of both L-dopa and BTS 74 398 increased general motor activity and stereotypic behaviour. In L-dopa-treated rats, orolingual, locomotive, forelimb and axial abnormal movements developed whereas BTS 74 398 produced only locomotion with a side bias but no other abnormal movements. Sensitization of circling responses and the development of abnormal movements in 6-OHDA-lesioned rats have been associated with the potential of dopaminergic drugs to induce dyskinesia. Furthermore, striatal DeltaFosB immunoreactivity, shown to correlate with dyskinesia induction, was increased by L-dopa but was unaffected by repeated BTS 74 398 administration. The lack of such changes following repeated BTS 74 398 treatment suggests that it may be an effective antiparkinsonian therapy that is unlikely to produce involuntary movements.

Six-Month Follow-Up of a Randomized Controlled Trial Augmenting Serotonin Reuptake Inhibitor Treatment With Exposure and Ritual Prevention for Obsessive-Compulsive Disorder

PubMed Central

Foa, Edna B.; Simpson, Helen Blair; Liebowitz, Michael R.; Powers, Mark B.; Rosenfield, David; Cahill, Shawn P.; Campeas, Raphael; Franklin, Martin; Hahn, Chang-Gyu; Hembree, Elizabeth A.; Huppert, Jonathan D.; Schmidt, Andrew B.; Vermes, Donna; Williams, Monnica T.

2014-01-01

Objective This article describes the long-term effects of augmenting serotonin reuptake inhibitors (SRIs) with exposure and ritual prevention or stress management training in patients with DSM-IV obsessive-compulsive disorder (OCD). Method Between November 2000 and November 2006, 111 OCD patients from 2 academic outpatient centers with partial SRI response were randomized to the addition of exposure and ritual prevention or stress management training, delivered twice weekly for 8 weeks (acute phase); 108 began treatment. Responders (38 of 52 in the exposure and ritual prevention condition, 11 of 52 in the stress management training condition) entered a 24-week maintenance phase. The Yale-Brown Obsessive Compulsive Scale (YBOCS) was the primary outcome measure. Results After 24 weeks, patients randomized to and receiving exposure and ritual prevention versus stress management training had significantly better outcomes (mean YBOCS scores of 14.69 and 21.37, respectively; t = 2.88, P = .005), higher response rates (decrease in YBOCS scores ≥ 25%: 40.7% vs 9.3%, Fisher exact test P < .001), and higher rates of excellent response (YBOCS score ≤ 12: 24.1% vs 5.6%, Fisher exact test P = .01). During the maintenance phase, the slope of change in YBOCS scores was not significant in either condition (all P values ≥ .55), with no difference between exposure and ritual prevention and stress management training (P > .74). Better outcome was associated with baseline variables: lower YBOCS scores, higher quality of life, fewer comorbid Axis I diagnoses, and male sex. Conclusions Augmenting SRIs with exposure and ritual prevention versus stress management training leads to better outcome after acute treatment and 24 weeks later. Maintenance outcome, however, was primarily a function of OCD severity at entrance. Greater improvement during the acute phase influences how well patients maintain their gains, regardless of treatment condition. PMID:23759449

Phenotypic Drug Susceptibility Assay for Influenza Virus Neuraminidase Inhibitors

PubMed Central

McSharry, James J.; McDonough, Ann C.; Olson, Betty A.; Drusano, George L.

2004-01-01

A flow cytometric (fluorescence-activated cell sorter [FACS]) assay was developed for analysis of the drug susceptibilities of wild-type and drug-resistant influenza A and B virus laboratory strains and clinical isolates for the neuraminidase (NA) inhibitors oseltamivir carboxylate, zanamivir, and peramivir. The drug susceptibilities of wild-type influenza viruses and those with mutations in the hemagglutinin (HA) and/or NA genes rendering them resistant to one or more of the NA inhibitors were easily determined with the FACS assay. The drug concentrations that reduced the number of virus-infected cells or the number of PFU by 50% as determined by the FACS assay were similar to those obtained with the more time-consuming and labor-intensive virus yield reduction assay. The NA inhibition (NAI) assay confirmed the resistance patterns demonstrated by the FACS and virus yield assays for drug-resistant influenza viruses with mutations in the NA gene. However, only the FACS and virus yield assays detected NA inhibitor-resistant influenza viruses with mutations in the HA gene but not in the NA gene. The FACS assay is more rapid and less labor-intensive than the virus yield assay and just as quantitative. The FACS assay determines the drug susceptibilities of influenza viruses with mutations in either the HA or NA genes, making the assay more broadly useful than the NAI assay for measuring the in vitro susceptibilities of influenza viruses for NA inhibitors. However, since only viruses with mutations in the NA gene that lead to resistance to the NA inhibitors correlate with clinical resistance, this in vitro assay should not be used in the clinical setting to determine resistance to NA inhibitors. The assay may be useful for determining the in vivo susceptibilities of other compounds effective against influenza A and B viruses. PMID:14715540

Characterization of noradrenaline release in the locus coeruleus of freely moving awake rats by in vivo microdialysis.

PubMed

Fernández-Pastor, Begoña; Mateo, Yolanda; Gómez-Urquijo, Sonia; Javier Meana, J

2005-07-01

The origin and regulation of noradrenaline (NA) in the locus coeruleus (LC) is unknown. The neurochemical features of NA overflow (nerve impulse dependence, neurotransmitter synthesis, vesicle storage, reuptake, alpha2-adrenoceptor-mediated regulation) were characterized in the LC. Brain microdialysis was performed in awake rats. Dialysates were analyzed for NA. NA in the LC decreased via local infusion of Ca2+-free medium (-42+/-5%) or the sodium channel blocker tetrodotoxine (TTX) (-47+/-8%) but increased (333+/-40%) via KCl-induced depolarization. The tyrosine hydroxylase (TH) inhibitor alpha-methyl-p-tyrosine (250 mg kg(-1), i.p.) and the vesicle depletory drug reserpine (5 mg kg(-1), i.p.) decreased NA. Therefore, extracellular NA in the LC satisfies the criteria for an impulse flow-dependent vesicular exocytosis of neuronal origin. Local perfusion of the alpha2-adrenoceptor agonist clonidine (0.1-100 microM) decreased NA (E(max)=-79+/-5%) in the LC, whereas the opposite effect (E(max)=268+/-53%) was observed with the alpha2A-adrenoceptor antagonist BRL44408 (0.1-100 microM). This suggests a tonic modulation of NA release through local alpha2A-adrenoceptors. The selective NA reuptake inhibitor desipramine (DMI) (0.1-100 microM) administered into the LC increased NA in the LC (E(max)=223+/-40%) and simultaneously decreased NA in the cingulate cortex, confirming the modulation exerted by NA in the LC on firing activity of noradrenergic cells and on the subsequent NA release in noradrenergic terminals. Synaptic processes underlying NA release in the LC are similar to those in noradrenergic terminal areas. NA in the LC could represent local somatodendritic release, but also the presence of neurotransmitter release from collateral axon terminals.

Chronic treatment with fluoxetine modulates vascular adrenergic responses by inhibition of pre- and post-synaptic mechanisms.

PubMed

Pereira, Camila A; Rodrigues, Fernanda L; Ruginsk, Silvia G; Zanotto, Camila Z; Rodrigues, José A; Duarte, Diego A; Costa-Neto, Claudio M; Resstel, Leonardo B; Carneiro, Fernando S; Tostes, Rita C

2017-04-05

Fluoxetine, a serotonin reuptake inhibitor (SSRI), has other effects in addition to blocking serotonin reuptake, including changes in the vasomotor tone. Whereas many studies focused on the acute effects of fluoxetine in the vasculature, its chronic effects are still limited. In the present study, we tested the hypothesis that chronic fluoxetine treatment modulates adrenergic vascular responses by interfering with post- and pre-synaptic mechanisms. Wistar rats were treated with vehicle (water) or chronic fluoxetine (10mg/kg/day) for 21 days. Blood pressure (BP) and heart rate were measured. Vascular reactivity was evaluated in perfused mesenteric arterial beds (MAB) and in mesenteric resistance arteries. Protein expression by western blot analysis or immunohistochemistry, β-arrestin recruitment by BRET and calcium influx by FLIPR assay. Fluoxetine treatment decreased phenylephrine (PE)-induced, but not electrical-field stimulation (EFS)-induced vasoconstriction. Fluoxetine-treated rats exhibited increased KCl-induced vasoconstriction, which was abolished by prazosin. Desipramine, an inhibitor of norepinephrine (NA) reuptake, increased EFS-induced vasoconstrictor response in vehicle-treated, but not in fluoxetine-treated rats. Chronic treatment did not alter vascular expression of α 1 adrenoceptor, phosphorylation of PKCα or ERK 1/2 and RhoA. On the other hand, vascular contractions to calcium (Ca 2+ ) as well as Ca 2+ influx in mesenteric arteries were increased, while intracellular Ca 2+ storage was decreased by the chronic treatment with fluoxetine. In vitro, fluoxetine decreased vascular contractions to PE, EFS and Ca 2+ , but did not change β-arrestin activity. In conclusion, chronic treatment with fluoxetine decreases sympathetic-mediated vascular responses by mechanisms that involve inhibition of NA release/reuptake and decreased Ca 2+ stores. Copyright © 2017 Elsevier B.V. All rights reserved.

Rapid Onset of the Effects of Combined Selective Serotonin Reuptake Inhibitors and Electroacupuncture on Primary Depression: A Meta-Analysis.

PubMed

Zhang, Yue; Qu, Shan-shan; Zhang, Ji-ping; Sun, Ya-ling; Liu, Wei-lu; Xie, Ling; Huang, Yong; Chen, Jun-qi

2016-01-01

To evaluate the efficacy and safety of combined selective serotonin reuptake inhibitors (SSRIs) and electroacupuncture therapies for the early treatment of primary depression. Randomized controlled trials (RCTs) were analyzed to compare therapy combining SSRIs and electroacupuncture to SSRI therapy alone. The RCTs were identified by searching, among others, PubMed, the Cochrane Library, the Chinese National Knowledge Infrastructure, the Chongqing VIP database for Chinese Technical Periodicals, WANFANG DATA, and the Chinese Biological Medical Literature Database. Scores from Self-Rated Depression Scale (SDS), the Hamilton Depression Scale (HAMD), the Side Effect Rating Scale (SERS), and the Treatment Emergent Symptom Scale (TESS) were analyzed and coded by two independent investigators and used to evaluate the safety and efficacy of treatment. Statistical analyses were performed using RevMan 5.2 software. Six RCTs were analyzed. The meta-analysis revealed that the combined therapy of SSRIs and electroacupuncture were associated with superior scores on the HAMD, SDS, and SERS measures compared with SSRIs alone after 1-4 weeks of treatment: HAMD scores, mean difference (MD)(1 week), 2.32 (95% confidence interval [CI](1 week), 1.47-3.16, p(1 week)<0.00001); MD(2 weeks), 2.65 (95% CI(2 weeks), 1.81- 3.50, p(2 weeks)<0.00001); MD(4 weeks), 2.70 (95% CI(4 weeks), 1.90-3.51, p(4 weeks)<0.00001); SDS scores: MD(1 week), 3.13 (95% CI(1 week), 1.22-5.03, p(1 week) = 0.001); MD(2 weeks), 4.05 (95% CI(2 weeks), 0.22-7.87, p(2 weeks) = 0.04); MD(4 weeks), 5.02 (95% CI(4 weeks), 1.61-8.43, p(4 weeks) = 0.004); SERS scores: MD(2 weeks), 2.20 (95% CI(2 weeks), 1.43-2.96, p(2 weeks)<0.00001); MD(4 weeks), 2.12 (95% CI(4 weeks), 1.42-2.83, p(4 weeks)<0.00001). However, two of the aforementioned outcomes were rated as medium quality because of heterogeneity, as assessed using the Grading of Recommendations Assessment, Development and Evaluation system. The available

Ionization pattern obtained in electrospray ionization or atmospheric pressure chemical ionization interfaces for authorized antidepressants in Romania

NASA Astrophysics Data System (ADS)

Grecu, Iulia; Ionicǎ, Mihai; Vlǎdescu, Marian; Truţǎ, Elena; Sultan, Carmen; Viscol, Oana; Horhotǎ, Luminiţa; Radu, Simona

2016-12-01

Antidepressants were found in 1950. In the 1990s there was a new generation of antidepressants. They act on the level of certain neurotransmitters extrasinpatic by its growth. After their mode of action antidepressants may be: SSRIs (Selective Serotonin Reuptake Inhibitors); (Serotonin-Norepinephrine Reuptake Inhibitors); SARIs (Serotonin Antagonist Reuptake Inhibitors); NRIs (Norepinephrine Reuptake Inhibitors); NDRIs (Norepinephrine-Dopamine Reuptake Inhibitors) NDRAs (Norepinephrine-Dopamine Releasing Agents); TCAs (Tricyclic Antidepressants); TeCAs (Tetracyclic Antidepressants); MAOIs (Monoamine Oxidase Inhibitors); agonist receptor 5-HT1A (5- hydroxytryptamine); antagonist receptor 5-HT2; SSREs (Selective Serotonin Reuptake Enhancers) and Sigma agonist receptor. To determine the presence of antidepressants in biological products, it has been used a system HPLC-MS (High Performance Liquid Chromatography - Mass Spectrometry) Varian 12001. The system is equipped with APCI (Atmospheric Pressure Chemical Ionization) or ESI (ElectroSpray Ionization) interface. To find antidepressants in unknown samples is necessary to recognize them after mass spectrum. Because the mass spectrum it is dependent on obtaining private parameters work of HPLC-MS system, and control interfaces, the mass spectra library was filled with the mass spectra of all approved antidepressants in Romania. The paper shows the mass spectra obtained in the HPLCMS system.

Risk of autism spectrum disorder in offspring following paternal use of selective serotonin reuptake inhibitors before conception: a population-based cohort study

PubMed Central

Yang, Fen; Chen, Jianping; Miao, Mao-Hua; Yuan, Wei; Li, Lin; Liang, Hong; Ehrenstein, Vera; Li, Jiong

2017-01-01

Objective The present study aimed to examine the association between paternal selective serotonin reuptake inhibitor (SSRI) use before conception and the risk of autism spectrum disorder (ASD) in offspring. Design A population-based cohort study. Methods We conducted a cohort study of 669 922 children born from 1998 to 2008, with follow-up throughout 2013. Based on Danish national registers, we linked information on paternal use of SSRIs, ASD diagnosed in children and a range of potential confounders. The children whose fathers used SSRIs during the last 3 months prior to conception were identified as the exposed. Cox regression model was used to estimate the HR for ASD in children. Results Compared with unexposed children, the exposed had a 1.62-fold higher risk of ASD (95% CI 1.33 to 1.96) and the risk attenuated after adjusting for potential confounders, especially fathers’ psychiatric conditions (HR=1.43, 95% CI 1.18 to 1.74). When extending the exposure window to 1 year before conception, the increased risk persisted in children of fathers using SSRIs only from the last year until the last 3 months prior to conception (HR=1.54, 95% CI 1.21 to 1.94) but not in children of fathers using SSRIs only during the last 3 months prior to conception (HR=1.17, 95% CI 0.75 to 1.82). We also performed stratified analyses according to paternal history of affective disorders and observed no increased ASD risk among children whose father had affective disorders. Besides, the sibling analysis showed that the ASD risk did not increase among exposed children compared with their unexposed siblings. Conclusions The mildly increased risk of ASD in the offspring associated with paternal SSRI use before conception may be attributable to paternal underlying psychiatric indications related to SSRI use or other unmeasured confounding factors. PMID:29275337

Antenatal exposure to the selective serotonin reuptake inhibitor fluoxetine leads to postnatal metabolic and endocrine changes associated with type 2 diabetes in Wistar rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

De Long, Nicole E.; Barry, Eric J.; Pinelli, Christopher

Hypothesis: 10–15% of women take antidepressant medications during pregnancy. A recent clinical study reported that the use of selective serotonin reuptake inhibitor antidepressants during pregnancy is linked with an increased risk of postnatal obesity. While obesity is often associated with fatty liver, dyslipidemia and inflammation, to date, the effects of perinatal exposure to SSRIs on these outcomes are unknown. Methods: Female nulliparous Wistar rats were given vehicle (N = 15) or fluoxetine hydrochloride (FLX 10 mg/kg/d; N = 15) orally for 2 weeks prior to mating until weaning. We assessed glucometabolic changes and hepatic pathophysiology in the offspring. Results: Fluoxetinemore » exposed offspring demonstrated altered glucose homeostasis without any alterations to beta cell mass. FLX-exposed offspring had a significant increase in the number of offspring with mild to moderate NASH and dyslipidemia. There was also increased inflammation of the liver in FLX-exposed offspring; males had significant elevations in TNFα, IL6 and monocyte chemoattractant protein 1 (MCP1), while female offspring had higher expression of TNFα, and increased macrophage infiltration (MCP1). Limitations: This is an animal study. Further research examining the metabolic outcomes of children exposed to antidepressants in utero are required, given the increase in childhood obesity and psychiatric medication use during pregnancy. Conclusion: These data demonstrate that fetal and neonatal exposure to FLX results in evidence of increased adiposity, fatty liver and abnormal glycemic control. Since these are all hallmarks of the metabolic syndrome, this raises concerns regarding the long term metabolic sequelae of fetal exposure to SSRIs in human populations. - Highlights: • Antenatal exposure to fluoxetine results in postnatal adiposity in the offspring. • Offspring exposed to fluoxetine have abnormal glycemic control in adulthood. • Maternal exposure to fluoxetine causes fatty

5-HT1A and 5-HT7 receptor crosstalk in the regulation of emotional memory: implications for effects of selective serotonin reuptake inhibitors.

PubMed

Eriksson, Therese M; Holst, Sarah; Stan, Tiberiu L; Hager, Torben; Sjögren, Benita; Ogren, Sven Öve; Svenningsson, Per; Stiedl, Oliver

2012-11-01

This study utilized pharmacological manipulations to analyze the role of direct and indirect activation of 5-HT(7) receptors (5-HT(7)Rs) in passive avoidance learning by assessing emotional memory in male C57BL/6J mice. Additionally, 5-HT(7)R binding affinity and 5-HT(7)R-mediated protein phosphorylation of downstream signaling targets were determined. Elevation of 5-HT by the selective serotonin reuptake inhibitor (SSRI) fluoxetine had no effect by itself, but facilitated emotional memory performance when combined with the 5-HT(1A)R antagonist NAD-299. This facilitation was blocked by the selective 5-HT(7)R antagonist SB269970, revealing excitatory effects of the SSRI via 5-HT(7)Rs. The enhanced memory retention by NAD-299 was blocked by SB269970, indicating that reduced activation of 5-HT(1A)Rs results in enhanced 5-HT stimulation of 5-HT(7)Rs. The putative 5-HT(7)R agonists LP-44 when administered systemically and AS19 when administered both systemically and into the dorsal hippocampus failed to facilitate memory. This finding is consistent with the low efficacy of LP-44 and AS19 to stimulate protein phosphorylation of 5-HT(7)R-activated signaling cascades. In contrast, increasing doses of the dual 5-HT(1A)R/5-HT(7)R agonist 8-OH-DPAT impaired memory, while co-administration with NAD-299 facilitated of emotional memory in a dose-dependent manner. This facilitation was blocked by SB269970 indicating 5-HT(7)R activation by 8-OH-DPAT. Dorsohippocampal infusion of 8-OH-DPAT impaired passive avoidance retention through hippocampal 5-HT(1A)R activation, while 5-HT(7)Rs appear to facilitate memory processes in a broader cortico-limbic network and not the hippocampus alone. Copyright © 2012 Elsevier Ltd. All rights reserved.

Central dopaminergic neurotransmission plays an important role in thermoregulation and performance during endurance exercise.

PubMed

Zheng, Xinyan; Hasegawa, Hiroshi

2016-10-01

Dopamine (DA) has been widely investigated for its potential role in determining exercise performance. It was originally thought that DA's ergogenic effect was by mediating psychological responses. Recently, some studies have also suggested that DA may regulate physiological responses, such as thermoregulation. Hyperthermia has been demonstrated as an important limiting factor during endurance exercise. DA is prominent in the thermoregulatory centre, and changes in DA concentration have been shown to affect core temperature regulation during exercise. Some studies have proposed that DA or DA/noradrenaline (NA) reuptake inhibitors can improve exercise performance, despite hyperthermia during exercise in the heat. DA/NA reuptake inhibitors also increase catecholamine release in the thermoregulatory centre. Intracerebroventricularly injected DA has been shown to improve exercise performance through inhibiting hyperthermia-induced fatigue, even at normal ambient temperatures. Further, caffeine has been reported to increase DA release in the thermoregulatory centre and improves endurance exercise performance despite increased core body temperature. Taken together, DA has been shown to have ergogenic effects and increase heat storage and hyperthermia tolerance. The mechanisms underlying these effects seem to involve limiting/overriding the inhibitory signals from the central nervous system that result in cessation of exercise due to hyperthermia.

NaStEP: a proteinase inhibitor essential to self-incompatibility and a positive regulator of HT-B stability in Nicotiana alata pollen tubes.

PubMed

Jiménez-Durán, Karina; McClure, Bruce; García-Campusano, Florencia; Rodríguez-Sotres, Rogelio; Cisneros, Jesús; Busot, Grethel; Cruz-García, Felipe

2013-01-01

In Solanaceae, the self-incompatibility S-RNase and S-locus F-box interactions define self-pollen recognition and rejection in an S-specific manner. This interaction triggers a cascade of events involving other gene products unlinked to the S-locus that are crucial to the self-incompatibility response. To date, two essential pistil-modifier genes, 120K and High Top-Band (HT-B), have been identified in Nicotiana species. However, biochemistry and genetics indicate that additional modifier genes are required. We recently reported a Kunitz-type proteinase inhibitor, named NaStEP (for Nicotiana alata Stigma-Expressed Protein), that is highly expressed in the stigmas of self-incompatible Nicotiana species. Here, we report the proteinase inhibitor activity of NaStEP. NaStEP is taken up by both compatible and incompatible pollen tubes, but its suppression in Nicotiana spp. transgenic plants disrupts S-specific pollen rejection; therefore, NaStEP is a novel pistil-modifier gene. Furthermore, HT-B levels within the pollen tubes are reduced when NaStEP-suppressed pistils are pollinated with either compatible or incompatible pollen. In wild-type self-incompatible N. alata, in contrast, HT-B degradation occurs preferentially in compatible pollinations. Taken together, these data show that the presence of NaStEP is required for the stability of HT-B inside pollen tubes during the rejection response, but the underlying mechanism is currently unknown.

Inhibition of neuraminidase by Ganoderma triterpenoids and implications for neuraminidase inhibitor design

PubMed Central

Zhu, Qinchang; Bang, Tran Hai; Ohnuki, Koichiro; Sawai, Takashi; Sawai, Ken; Shimizu, Kuniyoshi

2015-01-01

Neuraminidase (NA) inhibitors are the dominant antiviral drugs for treating influenza in the clinic. Increasing prevalence of drug resistance makes the discovery of new NA inhibitors a high priority. Thirty-one triterpenoids from the medicinal mushroom Ganoderma lingzhi were analyzed in an in vitro NA inhibition assay, leading to the discovery of ganoderic acid T-Q and TR as two inhibitors of H5N1 and H1N1 NAs. Structure-activity relationship studies revealed that the corresponding triterpenoid structure is a potential scaffold for the design of NA inhibitors. Using these triterpenoids as probes we found, through further in silico docking and interaction analysis, that interactions with the amino-acid residues Arg292 and/or Glu119 of NA are critical for the inhibition of H5N1 and H1N1. These findings should prove valuable for the design and development of NA inhibitors. PMID:26307417

Anxiety and depression with neurogenesis defects in exchange protein directly activated by cAMP 2-deficient mice are ameliorated by a selective serotonin reuptake inhibitor, Prozac

PubMed Central

Zhou, L; Ma, S L; Yeung, P K K; Wong, Y H; Tsim, K W K; So, K F; Lam, L C W; Chung, S K

2016-01-01

Intracellular cAMP and serotonin are important modulators of anxiety and depression. Fluoxetine, a selective serotonin reuptake inhibitor (SSRI) also known as Prozac, is widely used against depression, potentially by activating cAMP response element-binding protein (CREB) and increasing brain-derived neurotrophic factor (BDNF) through protein kinase A (PKA). However, the role of Epac1 and Epac2 (Rap guanine nucleotide exchange factors, RAPGEF3 and RAPGEF4, respectively) as potential downstream targets of SSRI/cAMP in mood regulations is not yet clear. Here, we investigated the phenotypes of Epac1 (Epac1−/−) or Epac2 (Epac2−/−) knockout mice by comparing them with their wild-type counterparts. Surprisingly, Epac2−/− mice exhibited a wide range of mood disorders, including anxiety and depression with learning and memory deficits in contextual and cued fear-conditioning tests without affecting Epac1 expression or PKA activity. Interestingly, rs17746510, one of the three single-nucleotide polymorphisms (SNPs) in RAPGEF4 associated with cognitive decline in Chinese Alzheimer's disease (AD) patients, was significantly correlated with apathy and mood disturbance, whereas no significant association was observed between RAPGEF3 SNPs and the risk of AD or neuropsychiatric inventory scores. To further determine the detailed role of Epac2 in SSRI/serotonin/cAMP-involved mood disorders, we treated Epac2−/− mice with a SSRI, Prozac. The alteration in open field behavior and impaired hippocampal cell proliferation in Epac2−/− mice were alleviated by Prozac. Taken together, Epac2 gene polymorphism is a putative risk factor for mood disorders in AD patients in part by affecting the hippocampal neurogenesis. PMID:27598965

The effects of the adjunctive bupropion on male sexual dysfunction induced by a selective serotonin reuptake inhibitor: a double-blind placebo-controlled and randomized study.

PubMed

Safarinejad, Mohammad Reza

2010-09-01

To determine the safety and efficacy of adjunctive bupropion sustained-release (SR) on male sexual dysfunction (SD) induced by a selective serotonin reuptake inhibitor (SSRI), as SD is a common side-effect of SSRIs and the most effective treatments have yet to be determined. The randomized sample consisted of 234 euthymic men who were receiving some type of SSRI. The men were randomly assigned to bupropion SR (150 mg twice daily, 117) or placebo (twice daily, 117) for 12 weeks. Efficacy was evaluated using the Clinical Global Impression-Sexual Function (CGI-SF; the primary outcome measure), the International Index of Erectile Function (IIEF), Arizona Sexual Experience Scale (ASEX), and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) (secondary outcome measures). Participants were followed biweekly during study period. After 12 weeks of treatment, the mean (sd) scores for CGI-SF were significantly lower, i.e. better, in patients on bupropion SR, at 2.4 (1.2), than in the placebo group, at 3.9 (1.1) (P= 0.01). Men who received bupropion had a significant increase in the total IIEF score (54.4% vs 1.2%; P= 0.003), and in the five different domains of the IIEF. Total ASEX scores were significantly lower, i.e. better, among men who received bupropion than placebo, at 15.5 (4.3) vs 21.5 (4.7) (P= 0.002). The EDITS scores were 67.4 (10.2) for the bupropion and 36.3 (11.7) for the placebo group (P= 0.001). The ASEX score and CGI-SF score were correlated (P= 0.003). In linear regression analyses the CGI-SF score was not affected significantly by the duration of SD, type of SSRI used and age. Bupropion is an effective treatment for male SD induced by SSRIs. These results provide empirical support for conducting a further study of bupropion.

Individual-based versus aggregate meta-analysis in multi-database studies of pregnancy outcomes: the Nordic example of selective serotonin reuptake inhibitors and venlafaxine in pregnancy.

PubMed

Selmer, Randi; Haglund, Bengt; Furu, Kari; Andersen, Morten; Nørgaard, Mette; Zoëga, Helga; Kieler, Helle

2016-10-01

Compare analyses of a pooled data set on the individual level with aggregate meta-analysis in a multi-database study. We reanalysed data on 2.3 million births in a Nordic register based cohort study. We compared estimated odds ratios (OR) for the effect of selective serotonin reuptake inhibitors (SSRI) and venlafaxine use in pregnancy on any cardiovascular birth defect and the rare outcome right ventricular outflow tract obstructions (RVOTO). Common covariates included maternal age, calendar year, birth order, maternal diabetes, and co-medication. Additional covariates were added in analyses with country-optimized adjustment. Country adjusted OR (95%CI) for any cardiovascular birth defect in the individual-based pooled analysis was 1.27 (1.17-1.39), 1.17 (1.07-1.27) adjusted for common covariates and 1.15 (1.05-1.26) adjusted for all covariates. In fixed effects meta-analyses pooled OR was 1.29 (1.19-1.41) based on crude country specific ORs, 1.19 (1.09-1.29) adjusted for common covariates, and 1.16 (1.06-1.27) for country-optimized adjustment. In a random effects model the adjusted OR was 1.07 (0.87-1.32). For RVOTO, OR was 1.48 (1.15-1.89) adjusted for all covariates in the pooled data set, and 1.53 (1.19-1.96) after country-optimized adjustment. Country-specific adjusted analyses at the substance level were not possible for RVOTO. Results of fixed effects meta-analysis and individual-based analyses of a pooled dataset were similar in this study on the association of SSRI/venlafaxine and cardiovascular birth defects. Country-optimized adjustment attenuated the estimates more than adjustment for common covariates only. When data are sparse pooled data on the individual level are needed for adjusted analyses. Copyright © 2016 John Wiley & Sons, Ltd. Copyright © 2016 John Wiley & Sons, Ltd.

Pollination in Nicotiana alata stimulates synthesis and transfer to the stigmatic surface of NaStEP, a vacuolar Kunitz proteinase inhibitor homologue

PubMed Central

Busot, Grethel Yanet; McClure, Bruce; Ibarra-Sánchez, Claudia Patricia; Jiménez-Durán, Karina; Vázquez-Santana, Sonia; Cruz-García, Felipe

2008-01-01

After landing on a wet stigma, pollen grains hydrate and germination generally occurs. However, there is no certainty of the pollen tube growth through the style to reach the ovary. The pistil is a gatekeeper that evolved in many species to recognize and reject the self-pollen, avoiding endogamy and encouraging cross-pollination. However, recognition is a complex process, and specific factors are needed. Here the isolation and characterization of a stigma-specific protein from N. alata, NaStEP (N. alata Stigma Expressed Protein), that is homologous to Kunitz-type proteinase inhibitors, are reported. Activity gel assays showed that NaStEP is not a functional serine proteinase inhibitor. Immunohistochemical and protein blot analyses revealed that NaStEP is detectable in stigmas of self-incompatible (SI) species N. alata, N. forgetiana, and N. bonariensis, but not in self-compatible (SC) species N. tabacum, N. plumbaginifolia, N. benthamiana, N. longiflora, and N. glauca. NaStEP contains the vacuolar targeting sequence NPIVL, and immunocytochemistry experiments showed vacuolar localization in unpollinated stigmas. After self-pollination or pollination with pollen from the SC species N. tabacum or N. plumbaginifolia, NaStEP was also found in the stigmatic exudate. The synthesis and presence in the stigmatic exudate of this protein was strongly induced in N. alata following incompatible pollination with N. tabacum pollen. The transfer of NaStEP to the stigmatic exudate was accompanied by perforation of the stigmatic cell wall, which appeared to release the vacuolar contents to the apoplastic space. The increase in NaStEP synthesis after pollination and its presence in the stigmatic exudates suggest that this protein may play a role in the early pollen–stigma interactions that regulate pollen tube growth in Nicotiana. PMID:18689443

Pollination in Nicotiana alata stimulates synthesis and transfer to the stigmatic surface of NaStEP, a vacuolar Kunitz proteinase inhibitor homologue.

PubMed

Busot, Grethel Yanet; McClure, Bruce; Ibarra-Sánchez, Claudia Patricia; Jiménez-Durán, Karina; Vázquez-Santana, Sonia; Cruz-García, Felipe

2008-01-01

After landing on a wet stigma, pollen grains hydrate and germination generally occurs. However, there is no certainty of the pollen tube growth through the style to reach the ovary. The pistil is a gatekeeper that evolved in many species to recognize and reject the self-pollen, avoiding endogamy and encouraging cross-pollination. However, recognition is a complex process, and specific factors are needed. Here the isolation and characterization of a stigma-specific protein from N. alata, NaStEP (N. alata Stigma Expressed Protein), that is homologous to Kunitz-type proteinase inhibitors, are reported. Activity gel assays showed that NaStEP is not a functional serine proteinase inhibitor. Immunohistochemical and protein blot analyses revealed that NaStEP is detectable in stigmas of self-incompatible (SI) species N. alata, N. forgetiana, and N. bonariensis, but not in self-compatible (SC) species N. tabacum, N. plumbaginifolia, N. benthamiana, N. longiflora, and N. glauca. NaStEP contains the vacuolar targeting sequence NPIVL, and immunocytochemistry experiments showed vacuolar localization in unpollinated stigmas. After self-pollination or pollination with pollen from the SC species N. tabacum or N. plumbaginifolia, NaStEP was also found in the stigmatic exudate. The synthesis and presence in the stigmatic exudate of this protein was strongly induced in N. alata following incompatible pollination with N. tabacum pollen. The transfer of NaStEP to the stigmatic exudate was accompanied by perforation of the stigmatic cell wall, which appeared to release the vacuolar contents to the apoplastic space. The increase in NaStEP synthesis after pollination and its presence in the stigmatic exudates suggest that this protein may play a role in the early pollen-stigma interactions that regulate pollen tube growth in Nicotiana.

Acute effects of Sceletium tortuosum (Zembrin), a dual 5-HT reuptake and PDE4 inhibitor, in the human amygdala and its connection to the hypothalamus.

PubMed

Terburg, David; Syal, Supriya; Rosenberger, Lisa A; Heany, Sarah; Phillips, Nicole; Gericke, Nigel; Stein, Dan J; van Honk, Jack

2013-12-01

The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form. Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin. Follow-up connectivity analysis on the emotion-matching task showed that amygdala-hypothalamus coupling was also reduced. These results demonstrate, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity.

Acute Effects of Sceletium tortuosum (Zembrin), a Dual 5-HT Reuptake and PDE4 Inhibitor, in the Human Amygdala and its Connection to the Hypothalamus

PubMed Central

Terburg, David; Syal, Supriya; Rosenberger, Lisa A; Heany, Sarah; Phillips, Nicole; Gericke, Nigel; Stein, Dan J; van Honk, Jack

2013-01-01

The South African endemic plant Sceletium tortuosum has a long history of traditional use as a masticatory and medicine by San and Khoikhoi people and subsequently by European colonial farmers as a psychotropic in tincture form. Over the past decade, the plant has attracted increasing attention for its possible applications in promoting a sense of wellbeing and relieving stress in healthy individuals and for treating clinical anxiety and depression. The pharmacological actions of a standardized extract of the plant (Zembrin) have been reported to be dual PDE4 inhibition and 5-HT reuptake inhibition, a combination that has been argued to offer potential therapeutic advantages. Here we tested the acute effects of Zembrin administration in a pharmaco-fMRI study focused on anxiety-related activity in the amygdala and its connected neurocircuitry. In a double-blind, placebo-controlled, cross-over design, 16 healthy participants were scanned during performance in a perceptual-load and an emotion-matching task. Amygdala reactivity to fearful faces under low perceptual load conditions was attenuated after a single 25 mg dose of Zembrin. Follow-up connectivity analysis on the emotion-matching task showed that amygdala–hypothalamus coupling was also reduced. These results demonstrate, for the first time, the attenuating effects of S. tortuosum on the threat circuitry of the human brain and provide supporting evidence that the dual 5-HT reuptake inhibition and PDE4 inhibition of this extract might have anxiolytic potential by attenuating subcortical threat responsivity. PMID:23903032

Inhibitors of Fatty Acid Amide Hydrolase and Monoacylglycerol Lipase: New Targets for Future Antidepressants.

PubMed

Ogawa, Shintaro; Kunugi, Hiroshi

2015-01-01

Cannabis and analogs of Δ⁹-tetrahydrocannabinol have been used for therapeutic purposes, but their therapeutic use remains limited because of various adverse effects. Endogenous cannabinoids have been discovered, and dysregulation of endocannabinoid signaling is implicated in the pathophysiology of major depressive disorder (MDD). Recently, endocannabinoid hydrolytic enzymes such as fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) have become new therapeutic targets in the treatment of MDD. Several FAAH or MAGL inhibitors are reported to have no cannabimimetic side effects and, therefore, are new potential therapeutic options for patients with MDD who are resistant to first-line antidepressants (selective serotonin and serotonin-norepinephrine reuptake inhibitors). In this review, we focus on the possible relationships between MDD and the endocannabinoid system as well as the inhibitors' therapeutic potential. MAGL inhibitors may reduce inflammatory responses through activation of cannabinoid receptor type 2. In the hypothalamic-pituitary-adrenal axis, repeated FAAH inhibitor administration may be beneficial for reducing circulating glucocorticoid levels. Both FAAH and MAGL inhibitors may contribute to dopaminergic system regulation. Recently, several new inhibitors have been developed with strong potency and selectivity. FAAH inhibitor, MAGL inhibitor, or dual blocker use would be promising new treatments for MDD. Further pre-clinical studies and clinical trials using these inhibitors are warranted.

Simultaneous quantification of selective serotonin reuptake inhibitors and metabolites in human plasma by liquid chromatography-electrospray mass spectrometry for therapeutic drug monitoring.

PubMed

Ansermot, Nicolas; Brawand-Amey, Marlyse; Eap, Chin B

2012-02-15

A simple and sensitive liquid chromatography-electrospray ionization mass spectrometry method was developed for the simultaneous quantification in human plasma of all selective serotonin reuptake inhibitors (citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline) and their main active metabolites (desmethyl-citalopram and norfluoxetine). A stable isotope-labeled internal standard was used for each analyte to compensate for the global method variability, including extraction and ionization variations. After sample (250μl) pre-treatment with acetonitrile (500μl) to precipitate proteins, a fast solid-phase extraction procedure was performed using mixed mode Oasis MCX 96-well plate. Chromatographic separation was achieved in less than 9.0min on a XBridge C18 column (2.1×100mm; 3.5μm) using a gradient of ammonium acetate (pH 8.1; 50mM) and acetonitrile as mobile phase at a flow rate of 0.3ml/min. The method was fully validated according to Société Française des Sciences et Techniques Pharmaceutiques protocols and the latest Food and Drug Administration guidelines. Six point calibration curves were used to cover a large concentration range of 1-500ng/ml for citalopram, desmethyl-citalopram, paroxetine and sertraline, 1-1000ng/ml for fluoxetine and fluvoxamine, and 2-1000ng/ml for norfluoxetine. Good quantitative performances were achieved in terms of trueness (84.2-109.6%), repeatability (0.9-14.6%) and intermediate precision (1.8-18.0%) in the entire assay range including the lower limit of quantification. Internal standard-normalized matrix effects were lower than 13%. The accuracy profiles (total error) were mainly included in the acceptance limits of ±30% for biological samples. The method was successfully applied for routine therapeutic drug monitoring of more than 1600 patient plasma samples over 9 months. The β-expectation tolerance intervals determined during the validation phase were coherent with the results of quality control samples analyzed

Effects of selective serotonin reuptake inhibition on neural activity related to risky decisions and monetary rewards in healthy males.

PubMed

Macoveanu, Julian; Fisher, Patrick M; Haahr, Mette E; Frokjaer, Vibe G; Knudsen, Gitte M; Siebner, Hartwig R

2014-10-01

Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are commonly prescribed antidepressant drugs targeting the dysfunctional serotonin (5-HT) system, yet little is known about the functional effects of prolonged serotonin reuptake inhibition in healthy individuals. Here we used functional MRI (fMRI) to investigate how a three-week fluoxetine intervention influences neural activity related to risk taking and reward processing. Employing a double-blinded parallel-group design, 29 healthy young males were randomly assigned to receive 3 weeks of a daily dose of 40 mg fluoxetine or placebo. Participants underwent task-related fMRI prior to and after the three-week intervention while performing a card gambling task. The task required participants to choose between two decks of cards. Choices were associated with different risk levels and potential reward magnitudes. Relative to placebo, the SSRI intervention did not alter individual risk-choice preferences, but modified neural activity during decision-making and reward processing: During the choice phase, SSRI reduced the neural response to increasing risk in lateral orbitofrontal cortex, a key structure for value-based decision-making. During the outcome phase, a midbrain region showed an independent decrease in the responsiveness to rewarding outcomes. This midbrain cluster included the raphe nuclei from which serotonergic modulatory projections originate to both cortical and subcortical regions. The findings corroborate the involvement of the normally functioning 5HT-system in decision-making under risk and processing of monetary rewards. The data suggest that prolonged SSRI treatment might reduce emotional engagement by reducing the impact of risk during decision-making or the impact of reward during outcome evaluation. Copyright © 2014 Elsevier Inc. All rights reserved.

Modulation of appetite and feeding behavior of the larval mosquito Aedes aegypti by the serotonin-selective reuptake inhibitor paroxetine: shifts between distinct feeding modes and the influence of feeding status.

PubMed

Kinney, Michael P; Panting, Nicholas D; Clark, Thomas M

2014-03-15

The effects of the serotonin-selective reuptake inhibitor paroxetine (2×10(-5) mol l(-1)) on behavior of the larval mosquito Aedes aegypti are described. Four discrete behavioral states dominate larval behavior: wriggling, two distinct types of feeding, and quiescence. Feeding behaviors consist of foraging along the bottom of the container (substrate browsing), and stationary filter feeding while suspended from the surface film. Fed larvae respond to paroxetine with increased wriggling, and reductions in both feeding behaviors. In contrast, food-deprived larvae treated with paroxetine show no change in the proportion of time spent wriggling or feeding, but shift from stationary filter feeding to substrate browsing. Thus, actions of paroxetine in fed larvae are consistent with suppression of appetite and stimulation of wriggling, whereas paroxetine causes food-deprived larvae to switch from one feeding behavior to another. Further analysis of unfed larvae revealed that paroxetine decreased the power stroke frequency during wriggling locomotion, but had no effect on the swimming velocity during either wriggling or substrate browsing. These data suggest that: (1) serotonergic pathways may trigger shifts between distinct behaviors by actions on higher level (brain) integrating centers where behaviors such as feeding and locomotion are coordinated; (2) these centers in fed and food-deprived larvae respond differently to serotonergic stimulation suggesting sensory feedback from feeding status; and (3) serotonergic pathways also modulate central pattern generators of the nerve cord where the bursts of action potentials originate that drive the rhythmic muscle contractions of wriggling.

The cannabinoid transporter inhibitor OMDM-2 reduces social interaction: Further evidence for transporter-mediated endocannabinoid release.

PubMed

Seillier, Alexandre; Giuffrida, Andrea

2018-03-01

Experimental evidence suggests that the transport of endocannabinoids might work bi-directionally. Accordingly, it is possible that pharmacological blockade of the latter affects not only the re-uptake, but also the release of endocannabinoids, thus preventing them from stimulating CB 1 receptors. We used biochemical, pharmacological, and behavioral approaches to investigate the effects of the transporter inhibitor OMDM-2 on social interaction, a behavioral assay that requires activation of CB 1 receptors. The underlying mechanisms of OMDM-2 were compared with those of the Fatty Acid Amide Hydrolase (FAAH) inhibitor URB597. Systemic administration of OMDM-2 reduced social interaction, but in contrast to URB597-induced social deficit, this effect was not reversed by the TRPV1 antagonist capsazepine. The CB 1 antagonist AM251, which did not affect URB597-induced social withdrawal, exacerbated OMDM-2 effect. In addition, the potent CB 1 agonist CP55,940 reversed OMDM-2-, but not URB597-, induced social withdrawal. Blockade of CB 1 receptor by AM251 reduced social interaction and the cholecystokinin CCK2 antagonist LY225910 reversed this effect. Similarly, OMDM-2-induced social withdrawal was reversed by LY225910, whereas URB597 effect was not. Elevation of endocannabinoid levels by URB597 or JZL184, an inhibitor of 2-AG degradation, failed to reverse OMDM-2-induced social withdrawal, and did not show additive effects on cannabinoid measurements when co-administered with OMDM-2. Taken together, these findings indicate that OMDM-2 impaired social interaction in a manner that is consistent with reduced activation of presynaptic CB 1 receptors. As cannabinoid reuptake inhibitors may impair endocannabinoid release, caution should be taken when using these drugs to enhance endocannabinoid tone in vivo. Copyright © 2017 Elsevier Ltd. All rights reserved.

When Medication Is Prescribed

MedlinePlus

... or combination of medications for the patient. Selective serotonin reuptake inhibitors (SSRIs): citalopram (brand name: Celexa) escitalopram ( ... brand names: Paxil, Pexeva) sertraline (brand name: Zoloft) Serotonin and norepinephrine reuptake inhibitors (SNRIs): venlafaxine (brand name: ...

Selective Serotonin Reuptake Inhibitor (SSRI) Antidepressants in Pregnancy and Congenital Anomalies: Analysis of Linked Databases in Wales, Norway and Funen, Denmark

PubMed Central

Morris, Joan K.; Davies, Gareth I.; Tucker, David; Thayer, Daniel S.; Luteijn, Johannes M.; Morgan, Margery; Garne, Ester; Hansen, Anne V.; Klungsøyr, Kari; Engeland, Anders; Boyle, Breidge; Dolk, Helen

2016-01-01

Background Hypothesised associations between in utero exposure to selective serotonin reuptake inhibitors (SSRIs) and congenital anomalies, particularly congenital heart defects (CHD), remain controversial. We investigated the putative teratogenicity of SSRI prescription in the 91 days either side of first day of last menstrual period (LMP). Methods and Findings Three population-based EUROCAT congenital anomaly registries- Norway (2004–2010), Wales (2000–2010) and Funen, Denmark (2000–2010)—were linked to the electronic healthcare databases holding prospectively collected prescription information for all pregnancies in the timeframes available. We included 519,117 deliveries, including foetuses terminated for congenital anomalies, with data covering pregnancy and the preceding quarter, including 462,641 with data covering pregnancy and one year either side. For SSRI exposures 91 days either side of LMP, separately and together, odds ratios with 95% confidence intervals (ORs, 95%CI) for all major anomalies were estimated. We also explored: pausing or discontinuing SSRIs preconception, confounding, high dose regimens, and, in Wales, diagnosis of depression. Results were combined in meta-analyses. SSRI prescription 91 days either side of LMP was associated with increased prevalence of severe congenital heart defects (CHD) (as defined by EUROCAT guide 1.3, 2005) (34/12,962 [0.26%] vs. 865/506,155 [0.17%] OR 1.50, 1.06–2.11), and the composite adverse outcome of 'anomaly or stillbirth' (473/12962, 3.65% vs. 15829/506,155, 3.13%, OR 1.13, 1.03–1.24). The increased prevalence of all major anomalies combined did not reach statistical significance (3.09% [400/12,962] vs. 2.67% [13,536/506,155] OR 1.09, 0.99–1.21). Adjusting for socio-economic status left ORs largely unchanged. The prevalence of anomalies and severe CHD was reduced when SSRI prescriptions were stopped or paused preconception, and increased when >1 prescription was recorded, but differences were

Selective Serotonin Reuptake Inhibitors (SSRIs)

MedlinePlus

... dangerous reactions when combined with certain medications or herbal supplements. Serotonin syndrome. Rarely, an antidepressant can cause high ... antidepressants, certain pain or headache medications, and the herbal supplement St. John's wort. Signs and symptoms of serotonin ...

Contribution of Neuraminidase of Influenza Viruses to the Sensitivity to Sera Inhibitors and Reassortment Efficiency

PubMed Central

Kiseleva, Irina; Larionova, Natalie; Fedorova, Ekaterina; Bazhenova, Ekaterina; Dubrovina, Irina; Isakova-Sivak, Irina; Rudenko, Larisa

2014-01-01

Live attenuated influenza vaccine (LAIV) represent reassortant viruses with hemagglutinin (HA) and neuraminidase (NA) gene segments inherited from circulating wild-type (WT) parental influenza viruses recommended for inclusion into seasonal vaccine formulation, and the 6 internal protein-encoding gene segments from cold-adapted attenuated master donor viruses (genome composition 6:2). In this study, we describe the obstacles in developing LAIV strains while taking into account the phenotypic peculiarities of WT viruses used for reassortment. Genomic composition analysis of 849 seasonal LAIV reassortants revealed that over 80% of reassortants based on inhibitor-resistant WT viruses inherited WT NA, compared to 26% of LAIV reassortants based on inhibitor-sensitive WT viruses. In addition, the highest percentage of LAIV genotype reassortants was achieved when WT parental viruses were resistant to non-specific serum inhibitors. We demonstrate that NA may play a role in influenza virus sensitivity to non-specific serum inhibitors. Replacing NA of inhibitor-sensitive WT virus with the NA of inhibitor-resistant master donor virus significantly decreased the sensitivity of the resulting reassortant virus to serum heat-stable inhibitors. PMID:25132869

A serine palmitoyltransferase inhibitor blocks hepatitis C virus replication in human hepatocytes.

PubMed

Katsume, Asao; Tokunaga, Yuko; Hirata, Yuichi; Munakata, Tsubasa; Saito, Makoto; Hayashi, Hitohisa; Okamoto, Koichi; Ohmori, Yusuke; Kusanagi, Isamu; Fujiwara, Shinya; Tsukuda, Takuo; Aoki, Yuko; Klumpp, Klaus; Tsukiyama-Kohara, Kyoko; El-Gohary, Ahmed; Sudoh, Masayuki; Kohara, Michinori

2013-10-01

Host cell lipid rafts form a scaffold required for replication of hepatitis C virus (HCV). Serine palmitoyltransferases (SPTs) produce sphingolipids, which are essential components of the lipid rafts that associate with HCV nonstructural proteins. Prevention of the de novo synthesis of sphingolipids by an SPT inhibitor disrupts the HCV replication complex and thereby inhibits HCV replication. We investigated the ability of the SPT inhibitor NA808 to prevent HCV replication in cells and mice. We tested the ability of NA808 to inhibit SPT's enzymatic activity in FLR3-1 replicon cells. We used a replicon system to select for HCV variants that became resistant to NA808 at concentrations 4- to 6-fold the 50% inhibitory concentration, after 14 rounds of cell passage. We assessed the ability of NA808 or telaprevir to inhibit replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in mice with humanized livers (transplanted with human hepatocytes). NA808 was injected intravenously, with or without pegylated interferon alfa-2a and HCV polymerase and/or protease inhibitors. NA808 prevented HCV replication via noncompetitive inhibition of SPT; no resistance mutations developed. NA808 prevented replication of all HCV genotypes tested in mice with humanized livers. Intravenous NA808 significantly reduced viral load in the mice and had synergistic effects with pegylated interferon alfa-2a and HCV polymerase and protease inhibitors. The SPT inhibitor NA808 prevents replication of HCV genotypes 1a, 1b, 2a, 3a, and 4a in cultured hepatocytes and in mice with humanized livers. It might be developed for treatment of HCV infection or used in combination with pegylated interferon alfa-2a or HCV polymerase or protease inhibitors. Copyright © 2013 AGA Institute. Published by Elsevier Inc. All rights reserved.

Na+/H+ exchanger 3 inhibitor diminishes hepcidin-enhanced duodenal calcium transport in hemizygous β-globin knockout thalassemic mice.

PubMed

Charoenphandhu, Narattaphol; Kraidith, Kamonshanok; Lertsuwan, Kornkamon; Sripong, Chanakarn; Suntornsaratoon, Panan; Svasti, Saovaros; Krishnamra, Nateetip; Wongdee, Kannikar

2017-03-01

Recent investigation has shown that the liver-derived iron-regulating hormone, hepcidin, can potentiate intestinal calcium absorption in hemizygous β-globin knockout thalassemic (BKO) mice. Since the upregulation of Fe 2+ and H + cotransporter, divalent metal transporter (DMT)-1, has been shown to correlate with thalassemia-induced intestinal calcium absorption impairment, the inhibition of the apical Na + /H + exchanger (NHE)-3 that is essential for cytoplasmic pH regulation and transepithelial sodium absorption was hypothesized to negatively affect hepcidin action. Herein, the positive effect of hepcidin on the duodenal calcium transport was evaluated using Ussing chamber technique. The results showed that BKO mice had lower absorptive surface area and duodenal calcium transport than wild-type mice. Besides, paracellular transport of zinc in BKO mice was compromised. Hepcidin administration completely restored calcium transport. Since this hepcidin action was totally abolished by inhibitors of the basolateral calcium transporters, Na + /Ca 2+ exchanger (NCX1) and plasma membrane Ca 2+ -ATPase (PMCA 1b ), the enhanced calcium flux potentially occurred through the transcellular pathway rather than paracellular pathway. Interestingly, the selective NHE3 inhibitor, 100 nM tenapanor, markedly inhibited hepcidin-enhanced calcium transport. Accordingly, hepcidin is one of the promising therapeutic agents for calcium malabsorption in β-thalassemia. It mainly stimulates the transcellular calcium transport across the duodenal epithelium in an NHE3-dependent manner.

NaStEP: A Proteinase Inhibitor Essential to Self-Incompatibility and a Positive Regulator of HT-B Stability in Nicotiana alata Pollen Tubes1[W][OA

PubMed Central

Jiménez-Durán, Karina; McClure, Bruce; García-Campusano, Florencia; Rodríguez-Sotres, Rogelio; Cisneros, Jesús; Busot, Grethel; Cruz-García, Felipe

2013-01-01

In Solanaceae, the self-incompatibility S-RNase and S-locus F-box interactions define self-pollen recognition and rejection in an S-specific manner. This interaction triggers a cascade of events involving other gene products unlinked to the S-locus that are crucial to the self-incompatibility response. To date, two essential pistil-modifier genes, 120K and High Top-Band (HT-B), have been identified in Nicotiana species. However, biochemistry and genetics indicate that additional modifier genes are required. We recently reported a Kunitz-type proteinase inhibitor, named NaStEP (for Nicotiana alata Stigma-Expressed Protein), that is highly expressed in the stigmas of self-incompatible Nicotiana species. Here, we report the proteinase inhibitor activity of NaStEP. NaStEP is taken up by both compatible and incompatible pollen tubes, but its suppression in Nicotiana spp. transgenic plants disrupts S-specific pollen rejection; therefore, NaStEP is a novel pistil-modifier gene. Furthermore, HT-B levels within the pollen tubes are reduced when NaStEP-suppressed pistils are pollinated with either compatible or incompatible pollen. In wild-type self-incompatible N. alata, in contrast, HT-B degradation occurs preferentially in compatible pollinations. Taken together, these data show that the presence of NaStEP is required for the stability of HT-B inside pollen tubes during the rejection response, but the underlying mechanism is currently unknown. PMID:23150644

The transdermal delivery system of monoamine oxidase inhibitors.

PubMed

VanDenBerg, Chad M

2012-01-01

Monoamine oxidase inhibitors (MAOIs) were once widely used as effective treatments for major depressive disorder, particularly for patients with atypical or treatment-resistant depression. Today, MAOIs have largely been replaced by newer antidepressants because of concerns over potential serious side effects due to their mechanism of action. Monoamine oxidase (MAO) is an enzyme that metabolizes serotonin, norepinephrine, and dopamine, the neurotransmitters that are most associated with depression; inhibiting MAO, therefore, makes more of these neurotransmitters available for synaptic action. However, MAO also metabolizes tyramine, a trace amine found in some foods that acts as a sympathomimetic. Allowing excess tyramine to accumulate via MAO inhibition can result in hypertensive crisis due to the release of norepinephrine; therefore, patients taking an MAOI have had to follow dietary restrictions to avoid tyramine-rich foods. Hypertensive crisis may also be precipitated by using MAOIs in conjunction with other drugs that have vasoconstrictive properties, that act as sympathomimetics, or that inhibit the reuptake of norepinephrine. Serotonin syndrome is another serious adverse effect that can potentially occur when using an MAOI with another drug that inhibits the reuptake of serotonin. In this article, the mechanism of action of MAOIs is reviewed, along with that of a newer MAOI formulation that lessens the need for dietary restrictions and has a greater safety and tolerability profile than the older oral formulations. © Copyright 2012 Physicians Postgraduate Press, Inc.

The effects of gestational stress and Selective Serotonin reuptake inhibitor antidepressant treatment on structural plasticity in the postpartum brain--A translational model for postpartum depression.

PubMed

Haim, Achikam; Albin-Brooks, Christopher; Sherer, Morgan; Mills, Emily; Leuner, Benedetta

2016-01-01

This article is part of a Special Issue "Parental Care". Postpartum depression (PPD) is a common complication following childbirth experienced by one in every five new mothers. Although the neural basis of PPD remains unknown, previous research in rats has shown that gestational stress, a risk factor for PPD, induces depressive-like behavior during the postpartum period. Moreover, the effect of gestational stress on postpartum mood is accompanied by structural modifications within the nucleus accumbens (NAc) and the medial prefrontal cortex (mPFC)-limbic regions that have been linked to PPD. Mothers diagnosed with PPD are often prescribed selective serotonin reuptake inhibitor (SSRI) antidepressant medications and yet little is known about their effects in models of PPD. Thus, here we investigated whether postpartum administration of Citalopram, an SSRI commonly used to treat PPD, would ameliorate the behavioral and morphological consequences of gestational stress. In addition, we examined the effects of gestational stress and postpartum administration of Citalopram on structural plasticity within the basolateral amygdala (BLA) which together with the mPFC and NAc forms a circuit that is sensitive to stress and is involved in mood regulation. Our results show that postpartum rats treated with Citalopram do not exhibit gestational stress-induced depressive-like behavior in the forced swim test. In addition, Citalopram was effective in reversing gestational stress-induced structural alterations in the postpartum NAc shell and mPFC. We also found that gestational stress increased spine density within the postpartum BLA, an effect which was not reversed by Citalopram treatment. Overall, these data highlight the usefulness of gestational stress as a valid and informative translational model for PPD. Furthermore, they suggest that structural alterations in the mPFC-NAc pathway may underlie stress-induced depressive-like behavior during the postpartum period and provide

Nicergoline enhances glutamate re-uptake and protects against brain damage in rat global brain ischemia.

PubMed

Asai, S; Zhao, H; Yamashita, A; Jike, T; Kunimatsu, T; Nagata, T; Kohno, T; Ishikawa, K

1999-11-03

Whereas a 2-3 degrees C decrease in intraischemic brain temperature can be neuroprotective, mild brain hyperthermia significantly worsens outcome. Our previous study suggested that an ischemic injury mechanism which is sensitive to temperature may not actually increase the extracellular glutamate concentration ([Glu](e)) during the intraischemic period, but rather impairs the Glu re-uptake system, which has been suggested to be involved in the reversed uptake of Glu. We speculated that enhancing Glu re-uptake, pharmacologically or hypothermically, may shorten exposure to high [Glu](e) in the postischemic period and thereby decrease its deleterious excitotoxic effect on neuronal cells. In the present study, rats treated with nicergoline (32 mg/kg, i.p.), an ergot alkaloid derivative, showed minimal inhibition of the [Glu](e) elevation which characteristically occurs during the 10-min intraischemic period, while Glu re-uptake was dramatically improved in the postischemic period, when severe transient global ischemia was caused by mild hyperthermia. Moreover, the nicergoline (32 mg/kg, i.p.) treated rats showed reduced cell death morphologically and clearly had a far lower mortality. The present study suggests that the development of therapeutic strategies aimed at inhibition or prevention of the reversed uptake of glutamate release during ischemia, i.e., activation of the glutamate uptake mechanism, is a promising approach to reduce neural damage occurring in response to brain ischemia.

Fluorescence-based Neuraminidase Inhibition Assay to Assess the Susceptibility of Influenza Viruses to The Neuraminidase Inhibitor Class of Antivirals.

PubMed

Leang, Sook-Kwan; Hurt, Aeron C

2017-04-15

The neuraminidase (NA) inhibitors are the only class of antivirals approved for the treatment and prophylaxis of influenza that are effective against currently circulating strains. In addition to their use in treating seasonal influenza, the NA inhibitors have been stockpiled by a number of countries for use in the event of a pandemic. It is therefore important to monitor the susceptibility of circulating influenza viruses to this class of antivirals. There are different types of assays that can be used to assess the susceptibility of influenza viruses to the NA inhibitors, but the enzyme inhibition assays using either a fluorescent substrate or a chemiluminescent substrate are the most widely used and recommended. This protocol describes the use of a fluorescence-based assay to assess influenza virus susceptibility to NA inhibitors. The assay is based on the NA enzyme cleaving the 2'-(4-Methylumbelliferyl)-α-D-N-acetylneuraminic acid (MUNANA) substrate to release the fluorescent product 4-methylumbelliferone (4-MU). Therefore, the inhibitory effect of an NA inhibitor on the influenza virus NA is determined based on the concentration of the NA inhibitor that is required to reduce 50% of the NA activity, given as an IC50 value.

Treatment with Medications Affecting Dopaminergic and Serotonergic Mechanisms: Effects on Fluency and Anxiety in Persons Who Stutter

ERIC Educational Resources Information Center

Stager, Sheila V.; Calis, Karim; Grothe, Dale; Bloch, Meir; Berensen, Nannette M.; Smith, Paul J.; Braun, Allen

2005-01-01

Medications with dopamine antagonist properties, such as haloperidol, and those with serotonin reuptake inhibitor properties, such as clomipramine, have been shown to improve fluency. To examine the degree to which each of these two pharmacological mechanisms might independently affect fluency, a selective serotonin reuptake inhibitor, paroxetine,…

Low doses of cyclic AMP-phosphodiesterase inhibitors rapidly evoke opioid receptor-mediated thermal hyperalgesia in naïve mice which is converted to prominent analgesia by cotreatment with ultra-low-dose naltrexone.

PubMed

Crain, Stanley M; Shen, Ke-Fei

2008-09-22

Systemic (s.c.) injection in naïve mice of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors, e.g. 3-isobutyl-1-methylxanthine [(IBMX) or caffeine, 10 mg/kg] or the more specific cAMP-PDE inhibitor, rolipram (1 mug/kg), rapidly evokes thermal hyperalgesia (lasting >5 h). These effects appear to be mediated by enhanced excitatory opioid receptor signaling, as occurs during withdrawal in opioid-dependent mice. Cotreatment of these mice with ultra-low-dose naltrexone (NTX, 0.1 ng/kg-1 pg/kg, s.c.) results in prominent opioid analgesia (lasting >4 h) even when the dose of rolipram is reduced to 1 pg/kg. Cotreatment of these cAMP-PDE inhibitors in naïve mice with an ultra-low-dose (0.1 ng/kg) of the kappa-opioid receptor antagonist, nor-binaltorphimine (nor-BNI) or the mu-opioid receptor antagonist, beta-funaltrexamine (beta-FNA) also results in opioid analgesia. These excitatory effects of cAMP-PDE inhibitors in naïve mice may be mediated by enhanced release of small amounts of endogenous bimodally-acting (excitatory/inhibitory) opioid agonists by neurons in nociceptive networks. Ultra-low-dose NTX, nor-BNI or beta-FNA selectively antagonizes high-efficacy excitatory (hyperalgesic) Gs-coupled opioid receptor-mediated signaling in naïve mice and results in rapid conversion to inhibitory (analgesic) Gi/Go-coupled opioid receptor-mediated signaling which normally requires activation by much higher doses of opioid agonists. Cotreatment with a low subanalgesic dose of kelatorphan, an inhibitor of multiple endogenous opioid peptide-degrading enzymes, stabilizes endogenous opioid agonists released by cAMP-PDE inhibitors, resulting in conversion of the hyperalgesia to analgesia without requiring selective blockade of excitatory opioid receptor signaling. The present study provides a novel pharmacologic paradigm that may facilitate development of valuable non-narcotic clinical analgesics utilizing cotreatment with ultra-low-dose rolipram plus ultra-low-dose NTX or related

Risk of upper gastrointestinal bleeding with selective serotonin reuptake inhibitors with or without concurrent nonsteroidal anti-inflammatory use: a systematic review and meta-analysis.

PubMed

Anglin, Rebecca; Yuan, Yuhong; Moayyedi, Paul; Tse, Frances; Armstrong, David; Leontiadis, Grigorios I

2014-06-01

There is emerging concern that selective serotonin reuptake inhibitors (SSRIs) may be associated with an increased risk of upper gastrointestinal (GI) bleeding, and that this risk may be further increased by concurrent use of nonsteroidal anti-inflammatory (NSAID) medications. Previous reviews of a relatively small number of studies have reported a substantial risk of upper GI bleeding with SSRIs; however, more recent studies have produced variable results. The objective of this study was to obtain a more precise estimate of the risk of upper GI bleeding with SSRIs, with or without concurrent NSAID use. MEDLINE, EMBASE, PsycINFO, the Cochrane central register of controlled trials (through April 2013), and US and European conference proceedings were searched. Controlled trials, cohort, case-control, and cross-sectional studies that reported the incidence of upper GI bleeding in adults on SSRIs with or without concurrent NSAID use, compared with placebo or no treatment were included. Data were extracted independently by two authors. Dichotomous data were pooled to obtain odds ratio (OR) of the risk of upper GI bleeding with SSRIs +/- NSAID, with a 95% confidence interval (CI). The main outcome and measure of the study was the risk of upper GI bleeding with SSRIs compared with placebo or no treatment. Fifteen case-control studies (including 393,268 participants) and four cohort studies were included in the analysis. There was an increased risk of upper GI bleeding with SSRI medications in the case-control studies (OR=1.66, 95% CI=1.44,1.92) and cohort studies (OR=1.68, 95% CI=1.13,2.50). The number needed to harm for upper GI bleeding with SSRI treatment in a low-risk population was 3,177, and in a high-risk population it was 881. The risk of upper GI bleeding was further increased with the use of both SSRI and NSAID medications (OR=4.25, 95% CI=2.82,6.42). SSRI medications are associated with a modest increase in the risk of upper GI bleeding, which is lower than has

Maternal and infant genetic variants, maternal periconceptional use of selective serotonin reuptake inhibitors, and risk of congenital heart defects in offspring: population based study.

PubMed

Nembhard, Wendy N; Tang, Xinyu; Hu, Zhuopei; MacLeod, Stewart; Stowe, Zachary; Webber, Daniel

2017-03-06

Objective  To evaluate whether the association between maternal periconceptional use of selective serotonin reuptake inhibitors (SSRIs) and increased risk of congenital heart defects in offspring is modified by maternal or infant genetic variants in folate, homocysteine, or transsulfuration pathways. Design  Population based study. DNA from mothers, fathers, and infants was genotyped with an Illumina GoldenGate custom single nucleotide polymorphism panel. A hybrid design based on a log linear model was used to calculate relative risks and Bayesian false discovery probabilities (BFDP) to identify polymorphisms associated with congenital heart defects modified by SSRI use. Data sources  Data from the US National Birth Defects Prevention Study on 1180 liveborn infants with congenital heart defects and 1644 controls, born 1997-2008. Main outcome measures  Cases included infants with selected congenital heart defects and control infants had no major defects. SSRI use was obtained from telephone interviews with mothers. Results  For women who reported taking SSRIs periconceptionally, maternal SHMT1 (rs9909104) GG and AGgenotypes were associated with a 5.9 and 2.4 increased risk of select congenital heart defects in offspring, respectively, versus the AA genotype (BFDP=0.69). Compared with the AA genotype, BHMT (rs492842 and rs542852) GG and AG genotypes were associated with twice the riskof congenital heart defects (BFDP=0.74 and 0.79, respectively). MGST1 (rs2075237) CC and ACgenotypes were associated with an increased risk compared with the GG genotype (8.0 and 2.8, respectively; BFDP=0.79). Single nucleotide polymorphism in infant genes in the folate (MTHFS rs12438477), homocysteine (TRDMT1 rs6602178 and GNMT rs11752813) and transsulfuration (GSTP1 rs7941395 and MGST1 rs7294985) pathways were also associated with an increased risk of congenital heart defects. Conclusions  Common maternal or infant genetic variants in folate, homocysteine, or transsulfuration

Intensive Family-Based Cognitive-Behavioral Therapy for Pediatric Obsessive-Compulsive Disorder: Applications for Treatment of Medication Partial- or Nonresponders

ERIC Educational Resources Information Center

Marien, Wendi E.; Storch, Eric A.; Geffken, Gary R.; Murphy, Tanya K.

2009-01-01

Serotonin reuptake inhibitor medications and cognitive-behavioral therapy (CBT) are both effective treatments for pediatric obsessive-compulsive disorder (OCD). Despite recommendations that youth with OCD be treated with CBT alone or together with serotonin reuptake inhibitor medication, many youth are treated with medication alone or with non-CBT…

Inhibitor effects of sodium benzoate on corrosion resistance of Al6061-B4C composites in NaCl and H3BO3 solutions

NASA Astrophysics Data System (ADS)

Rafi-ud-din; Shafqat, Q. A.; Shahzad, M.; Ahmad, Ejaz; Asghar, Z.; Rafiq, Nouman; Qureshi, A. H.; Syed, Waqar adil; asim Pasha, Riffat

2016-12-01

Sodium benzoate (SB) is used for the first time to inhibit the corrosion of Al6061-B4C composites in H3BO3 and NaCl solutions. Al6061100-x -x wt% B4C (x = 0, 5, and 10) composites are manufactured by a powder metallurgy route. The corrosion inhibition efficiency of SB is investigated as a function of the volume fractions of B4C particles by using potentiodynamic polarization and electrochemical impedance techniques. Without the use of an inhibitor, an increase of the B4C particles in the composite decreases the corrosion resistance of Al6061-B4C composites. It is found that SB is an efficient corrosion inhibitor for Al6061-B4C composites in both investigated solutions. The corrosion inhibition efficiency of SB increases with an increase in B4C content. Since SB is an adsorption type inhibitor, it is envisaged that an extremely thin layer of molecules adsorbs onto the surface and suppresses the oxidation and reduction. It is found that the inhibitor effect of SB is more pronounced in a H3BO3 environment than in NaCl solution. Further, the mechanism of corrosion inhibition by SB is illustrated by using optical and scanning electron microscopy of corroded samples. It is found that the adsorption of benzoate ions on the Al surface and its bonding with Al3+ ions forms a hydrophobic layer on top of the exposed Al surface, which enhances the protection against dissolved boride ions.

Molecular dynamics of conformation-specific dopamine transporter-inhibitor complexes.

PubMed

Jean, Bernandie; Surratt, Christopher K; Madura, Jeffry D

2017-09-01

The recreational psychostimulant cocaine inhibits dopamine reuptake from the synapse, resulting in excessive stimulation of postsynaptic dopamine receptors in brain areas associated with reward and addiction. Cocaine binds to and stabilizes the outward- (extracellular-) facing conformation of the dopamine transporter (DAT) protein, while the low abuse potential DAT inhibitor benztropine prefers the inward- (cytoplasmic-) facing conformation. A correlation has been previously postulated between psychostimulant abuse potential and preference for the outward-facing DAT conformation. The 3β-aryltropane cocaine analogs LX10 and LX11, however, differ only in stereochemistry and share a preference for the outward-facing DAT, yet are reported to vary widely in abuse potential in an animal model. In search of the molecular basis for DAT conformation preference, complexes of cocaine, benztropine, LX10 or LX11 bound to each DAT conformation were subjected to 100ns of all-atom molecular dynamics simulation. Results were consistent with previous findings from cysteine accessibility assays used to assess an inhibitor's DAT conformation preference. The respective 2β- and 2α-substituted phenyltropanes of LX10 and LX11 interacted with hydrophobic regions of the DAT S1 binding site that were inaccessible to cocaine. Solvent accessibility measurements also revealed subtle differences in inhibitor positioning within a given DAT conformation. This work serves to advance our understanding of the conformational selectivity of DAT inhibitors and suggests that MD may be useful in antipsychostimulant therapeutic design. Copyright © 2017 Elsevier Inc. All rights reserved.

[Panic disorder: clinical phenomena and treatment options].

PubMed

Sivolap, Yu P

2017-01-01

Panic disorder is a common mental disease with high psychiatric comorbidity. It is considered that a combination of genetic predisposition and a special psychic vulnerability plays a key role in the occurrence of panic disorder. Clinically proven efficacy in the treatment of panic disorder have benzodiazepines, tricyclic antidepressants, monoamine oxidase inhibitors, selective serotonin reuptake inhibitors and selective serotonin and norepinephrine reuptake inhibitors; antidepressants from other pharmaceutical groups are also used. Selective serotonin reuptake inhibitors are the first line medicines in the treatment of panic disorder. Atypical antipsychotics may be used for the therapy augmentation in addition to first line drugs. Psychotherapy is used along with medications, and a combination of pharmacotherapy and cognitive behavioral therapy is the best method of treatment.

Distinct Neural-Functional Effects of Treatments With Selective Serotonin Reuptake Inhibitors, Electroconvulsive Therapy, and Transcranial Magnetic Stimulation and Their Relations to Regional Brain Function in Major Depression: A Meta-analysis.

PubMed

Chau, David T; Fogelman, Phoebe; Nordanskog, Pia; Drevets, Wayne C; Hamilton, J Paul

2017-05-01

Functional neuroimaging studies have examined the neural substrates of treatments for major depressive disorder (MDD). Low sample size and methodological heterogeneity, however, undermine the generalizability of findings from individual studies. We conducted a meta-analysis to identify reliable neural changes resulting from different modes of treatment for MDD and compared them with each other and with reliable neural functional abnormalities observed in depressed versus control samples. We conducted a meta-analysis of studies reporting changes in brain activity (e.g., as indexed by positron emission tomography) following treatments with selective serotonin reuptake inhibitors (SSRIs), electroconvulsive therapy (ECT), or transcranial magnetic stimulation. Additionally, we examined the statistical reliability of overlap among thresholded meta-analytic SSRI, ECT, and transcranial magnetic stimulation maps as well as a map of abnormal neural function in MDD. Our meta-analysis revealed that 1) SSRIs decrease activity in the anterior insula, 2) ECT decreases activity in central nodes of the default mode network, 3) transcranial magnetic stimulation does not result in reliable neural changes, and 4) regional effects of these modes of treatment do not significantly overlap with each other or with regions showing reliable functional abnormality in MDD. SSRIs and ECT produce neurally distinct effects relative to each other and to the functional abnormalities implicated in depression. These treatments therefore may exert antidepressant effects by diminishing neural functions not implicated in depression but that nonetheless impact mood. We discuss how the distinct neural changes resulting from SSRIs and ECT can account for both treatment effects and side effects from these therapies as well as how to individualize these treatments. Copyright © 2017 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Female sexual dysfunction in patients with major depressive disorder (MDD) treated with selective serotonin reuptake inhibitor (SSRI) and its association with serotonin 2A-1438 G/A single nucleotide polymorphisms.

PubMed

Masiran, Ruziana; Sidi, Hatta; Mohamed, Zahurin; Mohd Nazree, Nur Elia; Nik Jaafar, Nik Ruzyanei; Midin, Marhani; Das, Srijit; Mohamed Saini, Suriati

2014-04-01

Selective serotonin reuptake inhibitors (SSRIs) are known for their sexual side effects. Different SSRIs may affect different areas of sexual function at different rates. The study aimed to determine the prevalence of female sexual dysfunction (FSD), its clinical correlates, and association with 5HT2A (rs6311) single nucleotide polymorphisms (SNPs) in patients with major depressive disorder (MDD) who were on SSRI therapy. This was a cross-sectional study on 95 female outpatients with MDD treated with SSRI. The patients were in remission as determined by Montgomery-Asberg Depression Rating Scale. Genomic DNA was isolated from buccal swabs and samples were processed using a real time polymerase chain reaction. The presence or absence of FSD as measured by the Malay Version of Female Sexual Function Index and 5HT2A-1438 G/A (rs6311) SNP. The overall prevalence of FSD was 32.6%. After controlling for age, number of children, education level, total monthly income, SSRI types, and SSRI dosing, being employed significantly enhanced FSD by 4.5 times (odds ratio [OR] = 4.51; 95% confidence interval [CI] 1.00, 20.30; P = 0.05). Those having marital problems were 6.7 times more likely to have FSD (OR = 6.67; 95% CI 1.57, 28.34). 5HT2A-1438 G/A (rs6311) SNP was not significantly associated with FSD. There was no significant association between FSD and the 5HT2A (rs6311) SNP in patients with MDD on SSRI therapy. Employment status and marital state were significantly associated with FSD among these patients. © 2014 International Society for Sexual Medicine.

DOR activation inhibits anoxic/ischemic Na+ influx through Na+ channels via PKC mechanisms in the cortex.

PubMed

Chao, Dongman; He, Xiaozhou; Yang, Yilin; Bazzy-Asaad, Alia; Lazarus, Lawrence H; Balboni, Gianfranco; Kim, Dong H; Xia, Ying

2012-08-01

Activation of delta-opioid receptors (DOR) is neuroprotective against hypoxic/ischemic injury in the cortex, which is at least partially related to its action against hypoxic/ischemic disruption of ionic homeostasis that triggers neuronal injury. Na(+) influx through TTX-sensitive voltage-gated Na(+) channels may be a main mechanism for hypoxia-induced disruption of K(+) homeostasis, with DOR activation attenuating the disruption of ionic homeostasis by targeting voltage-gated Na(+) channels. In the present study we examined the role of DOR in the regulation of Na(+) influx in anoxia and simulated ischemia (oxygen-glucose deprivation) as well as the effect of DOR activation on the Na(+) influx induced by a Na(+) channel opener without anoxic/ischemic stress and explored a potential PKC mechanism underlying the DOR action. We directly measured extracellular Na(+) activity in mouse cortical slices with Na(+) selective electrodes and found that (1) anoxia-induced Na(+) influx occurred mainly through TTX-sensitive Na(+) channels; (2) DOR activation inhibited the anoxia/ischemia-induced Na(+) influx; (3) veratridine, a Na(+) channel opener, enhanced the anoxia-induced Na(+) influx; this could be attenuated by DOR activation; (4) DOR activation did not reduce the anoxia-induced Na(+) influx in the presence of chelerythrine, a broad-spectrum PKC blocker; and (5) DOR effects were blocked by PKCβII peptide inhibitor, and PKCθ pseudosubstrate inhibitor, respectively. We conclude that DOR activation inhibits anoxia-induced Na(+) influx through Na(+) channels via PKC (especially PKCβII and PKCθ isoforms) dependent mechanisms in the cortex. Copyright © 2012 Elsevier Inc. All rights reserved.

Comparison between the analysis of the loudness dependency of the auditory N1/P2 component with LORETA and dipole source analysis in the prediction of treatment response to the selective serotonin reuptake inhibitor citalopram in major depression.

PubMed

Mulert, C; Juckel, G; Augustin, H; Hegerl, U

2002-10-01

The loudness dependency of the auditory evoked potentials (LDAEP) is used as an indicator of the central serotonergic system and predicts clinical response to serotonin agonists. So far, LDAEP has been typically investigated with dipole source analysis, because with this method the primary and secondary auditory cortex (with a high versus low serotonergic innervation) can be separated at least in parts. We have developed a new analysis procedure that uses an MRI probabilistic map of the primary auditory cortex in Talairach space and analyzed the current density in this region of interest with low resolution electromagnetic tomography (LORETA). LORETA is a tomographic localization method that calculates the current density distribution in Talairach space. In a group of patients with major depression (n=15), this new method can predict the response to an selective serotonin reuptake inhibitor (citalopram) at least to the same degree than the traditional dipole source analysis method (P=0.019 vs. P=0.028). The correlation of the improvement in the Hamilton Scale is significant with the LORETA-LDAEP-values (0.56; P=0.031) but not with the dipole source analysis LDAEP-values (0.43; P=0.11). The new tomographic LDAEP analysis is a promising tool in the analysis of the central serotonergic system.

Comparison of the Efficacy and Safety of Aripiprazole Versus Bupropion Augmentation in Patients With Major Depressive Disorder Unresponsive to Selective Serotonin Reuptake Inhibitors: A Randomized, Prospective, Open-Label Study.

PubMed

Cheon, Eun-Jin; Lee, Kwang-Hun; Park, Young-Woo; Lee, Jong-Hun; Koo, Bon-Hoon; Lee, Seung-Jae; Sung, Hyung-Mo

2017-04-01

The purpose of this study was to compare the efficacy and safety of aripiprazole versus bupropion augmentation in patients with major depressive disorder (MDD) unresponsive to selective serotonin reuptake inhibitors (SSRIs). This is the first randomized, prospective, open-label, direct comparison study between aripiprazole and bupropion augmentation. Participants had at least moderately severe depressive symptoms after 4 weeks or more of SSRI treatment. A total of 103 patients were randomized to either aripiprazole (n = 56) or bupropion (n = 47) augmentation for 6 weeks. Concomitant use of psychotropic agents was prohibited. Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, Iowa Fatigue Scale, Drug-Induced Extrapyramidal Symptoms Scale, Psychotropic-Related Sexual Dysfunction Questionnaire scores were obtained at baseline and after 1, 2, 4, and 6 weeks of treatment. Overall, both treatments significantly improved depressive symptoms without causing serious adverse events. There were no significant differences in the Montgomery Asberg Depression Rating Scale, 17-item Hamilton Depression Rating scale, and Iowa Fatigue Scale scores, and response rates. However, significant differences in remission rates between the 2 groups were evident at week 6 (55.4% vs 34.0%, respectively; P = 0.031), favoring aripiprazole over bupropion. There were no significant differences in adverse sexual events, extrapyramidal symptoms, or akathisia between the 2 groups. The present study suggests that aripiprazole augmentation is at least comparable to bupropion augmentation in combination with SSRI in terms of efficacy and tolerability in patients with MDD. Both aripiprazole and bupropion could help reduce sexual dysfunction and fatigue in patients with MDD. Aripiprazole and bupropion may offer effective and safe augmentation strategies in patients with MDD who are unresponsive to SSRIs. Double-blinded trials are warranted to confirm the present findings.

3,4-Dihydro-2H-benzoxazinones are 5-HT(1A) receptor antagonists with potent 5-HT reuptake inhibitory activity.

PubMed

Atkinson, Peter J; Bromidge, Steven M; Duxon, Mark S; Gaster, Laramie M; Hadley, Michael S; Hammond, Beverley; Johnson, Christopher N; Middlemiss, Derek N; North, Stephanie E; Price, Gary W; Rami, Harshad K; Riley, Graham J; Scott, Claire M; Shaw, Tracey E; Starr, Kathryn R; Stemp, Geoffrey; Thewlis, Kevin M; Thomas, David R; Thompson, Mervyn; Vong, Antonio K K; Watson, Jeannette M

2005-02-01

Starting from a high throughput screening hit, a series of 3,4-dihydro-2H-benzoxazinones has been identified with both high affinity for the 5-HT(1A) receptor and potent 5-HT reuptake inhibitory activity. The 5-(2-methyl)quinolinyloxy derivative combined high 5-HT(1A/1B/1D) receptor affinities with low intrinsic activity and potent inhibition of the 5-HT reuptake site (pK(i)8.2). This compound also had good oral bioavailability and brain penetration in the rat.

Selective serotonin reuptake inhibitors versus placebo in patients with major depressive disorder. A systematic review with meta-analysis and Trial Sequential Analysis.

PubMed

Jakobsen, Janus Christian; Katakam, Kiran Kumar; Schou, Anne; Hellmuth, Signe Gade; Stallknecht, Sandra Elkjær; Leth-Møller, Katja; Iversen, Maria; Banke, Marianne Bjørnø; Petersen, Iggiannguaq Juhl; Klingenberg, Sarah Louise; Krogh, Jesper; Ebert, Sebastian Elgaard; Timm, Anne; Lindschou, Jane; Gluud, Christian

2017-02-08

The evidence on selective serotonin reuptake inhibitors (SSRIs) for major depressive disorder is unclear. Our objective was to conduct a systematic review assessing the effects of SSRIs versus placebo, 'active' placebo, or no intervention in adult participants with major depressive disorder. We searched for eligible randomised clinical trials in The Cochrane Library's CENTRAL, PubMed, EMBASE, PsycLIT, PsycINFO, Science Citation Index Expanded, clinical trial registers of Europe and USA, websites of pharmaceutical companies, the U.S. Food and Drug Administration (FDA), and the European Medicines Agency until January 2016. All data were extracted by at least two independent investigators. We used Cochrane systematic review methodology, Trial Sequential Analysis, and calculation of Bayes factor. An eight-step procedure was followed to assess if thresholds for statistical and clinical significance were crossed. Primary outcomes were reduction of depressive symptoms, remission, and adverse events. Secondary outcomes were suicides, suicide attempts, suicide ideation, and quality of life. A total of 131 randomised placebo-controlled trials enrolling a total of 27,422 participants were included. None of the trials used 'active' placebo or no intervention as control intervention. All trials had high risk of bias. SSRIs significantly reduced the Hamilton Depression Rating Scale (HDRS) at end of treatment (mean difference -1.94 HDRS points; 95% CI -2.50 to -1.37; P < 0.00001; 49 trials; Trial Sequential Analysis-adjusted CI -2.70 to -1.18); Bayes factor below predefined threshold (2.01*10 -23 ). The effect estimate, however, was below our predefined threshold for clinical significance of 3 HDRS points. SSRIs significantly decreased the risk of no remission (RR 0.88; 95% CI 0.84 to 0.91; P < 0.00001; 34 trials; Trial Sequential Analysis adjusted CI 0.83 to 0.92); Bayes factor (1426.81) did not confirm the effect). SSRIs significantly increased the risks of serious

Effect of Zr Inhibitor on Corrosion of Haynes 230 and NS-163 Alloys in Flinak

NASA Astrophysics Data System (ADS)

Peng, Yuxiang; Reddy, Ramana G.

The intrinsic corrosion behavior of Haynes 230 and NS-163 alloys after adding corrosion inhibitor Zr to LiF-NaF-KF (FLiNaK) salts was evaluated. Thermodynamic modeling studies were performed to investigate the compatibility of Haynes alloys for solar thermal energy storage applications in the molten salts. Equilibrium conditions were considered for predicting the corrosion products and weight loss of salts at higher temperatures (700 - 1000°C). Weight loss of FLiNaK salt after corrosion with or without inhibitor is less than 5%, indicating no significant change in compositions of FLiNaK even with Zr inhibitor. Furthermore, to compare with experimental data, modeling calculation with known amount of trace impurities (Ni2+, Fe3+ and so on) added to the molten salts, shows similar trend and corrosion product with and without Zr inhibitor.

The Na+/H+ exchange inhibitor cariporide is washed out of the myocardium by crystalloid cardioplegia.

PubMed

Bechtel, J F M; Eichler, W; Toerber, K; Weidtmann, B; Hernandez, M; Klotz, K F; Sievers, H H; Bartels, C

2006-08-01

Inhibition of the Na (+)/H (+) exchanger (NHE) is cardioprotective, but dosage and timing of NHE-inhibitors are critical for their efficacy. We studied the effect of a new dosing regime of the NHE-inhibitor cariporide on myocardial function and damage after cardioplegic arrest (CPA) and determined its myocardial and serum concentrations. 3 pigs received a bolus of 180 mg cariporide intravenously (i. v.) and were sacrificed shortly thereafter to allow measurement of the myocardial concentrations of cariporide. Subsequently, 10 pigs were randomized to receive either i. v. cariporide (bolus followed by an infusion of 40 mg/h) or placebo. Cardiopulmonary bypass was initiated, and the heart was arrested for 60 minutes by infusion of St. Thomas Hospital solution. Left ventricular (LV) function was studied using microsonometry. Myocardial damage was assessed by troponin T. Serum concentrations of cariporide were measured throughout the study, and myocardial concentrations were measured before the end of CPA and 180 minutes thereafter. Cariporide was present in all myocardial specimens (median: 1.4 ng/mg) studied previously. In the main study, LV function or myocardial damage did not differ significantly between the groups at any time point. Stable serum cariporide concentrations were achieved (3.4 +/- 0.5 microg/ml). Cariporide was detectable in only one of the myocardial biopsies obtained before the end of CPA, but 180 minutes thereafter, the myocardial cariporide concentration was 2.5 +/- 0.3 ng/mg. We observed no effect of i. v. cariporide on LV function or myocardial damage after cardioplegic arrest. Our data suggest that cariporide is washed out of the myocardium by repeated application of crystalloid cardioplegia. Thus, the mode of delivery also appears to be critical for cardioprotection with NHE-inhibitors.

Biaryls as potent, tunable dual neurokinin 1 receptor antagonists and serotonin transporter inhibitors.

PubMed

Degnan, Andrew P; Tora, George O; Han, Ying; Rajamani, Ramkumar; Bertekap, Robert; Krause, Rudolph; Davis, Carl D; Hu, Joanna; Morgan, Daniel; Taylor, Sarah J; Krause, Kelly; Li, Yu-Wen; Mattson, Gail; Cunningham, Melissa A; Taber, Matthew T; Lodge, Nicholas J; Bronson, Joanne J; Gillman, Kevin W; Macor, John E

2015-08-01

Depression is a serious illness that affects millions of patients. Current treatments are associated with a number of undesirable side effects. Neurokinin 1 receptor (NK1R) antagonists have recently been shown to potentiate the antidepressant effects of serotonin-selective reuptake inhibitors (SSRIs) in a number of animal models. Herein we describe the optimization of a biaryl chemotype to provide a series of potent dual NK1R antagonists/serotonin transporter (SERT) inhibitors. Through the choice of appropriate substituents, the SERT/NK1R ratio could be tuned to afford a range of target selectivity profiles. This effort culminated in the identification of an analog that demonstrated oral bioavailability, favorable brain uptake, and efficacy in the gerbil foot tap model. Ex vivo occupancy studies with compound 58 demonstrated the ability to maintain NK1 receptor saturation (>88% occupancy) while titrating the desired level of SERT occupancy (11-84%) via dose selection. Copyright © 2015 Elsevier Ltd. All rights reserved.

The steroidal Na+/K+ ATPase inhibitor 3-[(R)-3-pyrrolidinyl]oxime derivative (3-R-POD) induces potent pro-apoptotic responses in colonic tumor cells.

PubMed

Alkahtani, Saad Hussin

2014-06-01

Recently, potent anticancer actions of the steroidal Na(+)/K(+) ATPase inhibitor 3-[(R)-3-pyrrolidinyl]oxime derivative 3 (3-R-POD) have been reported for multiple cell lines, including prostate and lung cancer cells. In the present study, the anticancer action of 3-R-POD was addressed in colonic tumor cells. Treatment of Caco2 colonic tumor cells with increasing concentrations of 3-R-POD induced potent, dose-dependent inhibition of cell growth as measured by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. In addition, the APOpercentage apoptosis assay revealed significant pro-apoptotic responses, suggesting that the anticancer activity of this steroidal Na(+)/K(+) ATPase inhibitor in colonic tumors takes places mainly through the induction of strong pro-apoptotic effects. Focussing on the molecular mechanism that may regulate these interactions, 3-R-POD was shown to induce significant early actin re-organization and late Protein Kinase B (AKT) de-phosphorylation. Finally, the 3-R-POD-induced inhibition of cell growth and early actin reorganization in colonic cancer cells remained unchanged when cells were pre-treated with pertussis toxin, thus excluding possible interactions of this inhibitor with G-coupled receptors. These results indicate that 3-R-POD induces potent pro-apoptotic responses in colonic tumor cells governed by actin re-organization and inhibition of AKT pro-survival signaling. Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

Serotonin and Norepinephrine Reuptake Inhibitors (SNRIs)

MedlinePlus

... addition to depression. SNRIs ease depression by impacting chemical messengers (neurotransmitters) used to communicate between brain cells. Like most antidepressants, SNRIs work by ultimately effecting changes in brain chemistry and communication in brain nerve cell circuitry known ...

Paroxetine Is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial Contractility

DOE Office of Scientific and Technical Information (OSTI.GOV)

Thal, David M.; Homan, Kristoff T.; Chen, Jun

2012-08-10

G protein-coupled receptor kinase 2 (GRK2) is a well-established therapeutic target for the treatment of heart failure. In this paper we identify the selective serotonin reuptake inhibitor (SSRI) paroxetine as a selective inhibitor of GRK2 activity both in vitro and in living cells. In the crystal structure of the GRK2·paroxetine–Gβγ complex, paroxetine binds in the active site of GRK2 and stabilizes the kinase domain in a novel conformation in which a unique regulatory loop forms part of the ligand binding site. Isolated cardiomyocytes show increased isoproterenol-induced shortening and contraction amplitude in the presence of paroxetine, and pretreatment of mice withmore » paroxetine before isoproterenol significantly increases left ventricular inotropic reserve in vivo with no significant effect on heart rate. Neither is observed in the presence of the SSRI fluoxetine. Our structural and functional results validate a widely available drug as a selective chemical probe for GRK2 and represent a starting point for the rational design of more potent and specific GRK2 inhibitors.« less

Discovery of Indazoles as Potent, Orally Active Dual Neurokinin 1 Receptor Antagonists and Serotonin Transporter Inhibitors for the Treatment of Depression.

PubMed

Degnan, Andrew P; Tora, George O; Huang, Hong; Conlon, David A; Davis, Carl D; Hanumegowda, Umesh M; Hou, Xiaoping; Hsiao, Yi; Hu, Joanna; Krause, Rudolph; Li, Yu-Wen; Newton, Amy E; Pieschl, Rick L; Raybon, Joseph; Rosner, Thorsten; Sun, Jung-Hui; Taber, Matthew T; Taylor, Sarah J; Wong, Michael K; Zhang, Huiping; Lodge, Nicholas J; Bronson, Joanne J; Macor, John E; Gillman, Kevin W

2016-12-21

Combination studies of neurokinin 1 (NK1) receptor antagonists and serotonin-selective reuptake inhibitors (SSRIs) have shown promise in preclinical models of depression. Such a combination may offer important advantages over the current standard of care. Herein we describe the discovery and optimization of an indazole-based chemotype to provide a series of potent dual NK1 receptor antagonists/serotonin transporter (SERT) inhibitors to overcome issues of ion channel blockade. This effort culminated in the identification of compound 9, an analogue that demonstrated favorable oral bioavailability, excellent brain uptake, and robust in vivo efficacy in a validated depression model. Over the course of this work, a novel heterocycle-directed asymmetric hydrogenation was developed to facilitate installation of the key stereogenic center.

Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.

PubMed

Moyer, Bryan D; Murray, Justin K; Ligutti, Joseph; Andrews, Kristin; Favreau, Philippe; Jordan, John B; Lee, Josie H; Liu, Dong; Long, Jason; Sham, Kelvin; Shi, Licheng; Stöcklin, Reto; Wu, Bin; Yin, Ruoyuan; Yu, Violeta; Zou, Anruo; Biswas, Kaustav; Miranda, Les P

2018-01-01

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.

Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V

PubMed Central

Murray, Justin K.; Ligutti, Joseph; Andrews, Kristin; Favreau, Philippe; Jordan, John B.; Lee, Josie H.; Liu, Dong; Long, Jason; Sham, Kelvin; Shi, Licheng; Stöcklin, Reto; Wu, Bin; Yin, Ruoyuan; Yu, Violeta; Zou, Anruo; Biswas, Kaustav; Miranda, Les P.

2018-01-01

Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C

Effect of mirtazapine versus selective serotonin reuptake inhibitors on benzodiazepine use in patients with major depressive disorder: a pragmatic, multicenter, open-label, randomized, active-controlled, 24-week trial.

PubMed

Hashimoto, Tasuku; Shiina, Akihiro; Hasegawa, Tadashi; Kimura, Hiroshi; Oda, Yasunori; Niitsu, Tomihisa; Ishikawa, Masatomo; Tachibana, Masumi; Muneoka, Katsumasa; Matsuki, Satoshi; Nakazato, Michiko; Iyo, Masaomi

2016-01-01

This study aimed to evaluate whether selecting mirtazapine as the first choice for current depressive episode instead of selective serotonin reuptake inhibitors (SSRIs) reduces benzodiazepine use in patients with major depressive disorder (MDD). We concurrently examined the relationship between clinical responses and serum mature brain-derived neurotrophic factor (BDNF) and its precursor, proBDNF. We conducted an open-label randomized trial in routine psychiatric practice settings. Seventy-seven MDD outpatients were randomly assigned to the mirtazapine or predetermined SSRIs groups, and investigators arbitrarily selected sertraline or paroxetine. The primary outcome was the proportion of benzodiazepine users at weeks 6, 12, and 24 between the groups. We defined patients showing a ≥50 % reduction in Hamilton depression rating scale (HDRS) scores from baseline as responders. Blood samples were collected at baseline, weeks 6, 12, and 24. Sixty-five patients prescribed benzodiazepines from prescription day 1 were analyzed for the primary outcome. The percentage of benzodiazepine users was significantly lower in the mirtazapine than in the SSRIs group at weeks 6, 12, and 24 (21.4 vs. 81.8 %; 11.1 vs. 85.7 %, both P  < 0.001; and 12.5 vs. 81.8 %, P  = 0.0011, respectively). No between-group difference was observed in HDRS score changes. Serum proBDNF levels were significantly decreased ( χ 2  = 8.5, df  = 3, P  = 0.036) and serum mature BDNF levels were temporarily significantly decreased ( F  = 3.5, df  = 2.4, P  = 0.027) in the responders of both groups at week 24. This study demonstrated mirtazapine as the first-choice antidepressant for current depressive episodes may reduce benzodiazepine use in patients with MDD. Trial registration UMIN000004144. Registered 2nd September 2010. The date of enrolment of the first participant to the trial was 24th August 2010. This study was retrospectively registered 9 days after the first participant was

Can we really accelerate and enhance the selective serotonin reuptake inhibitor antidepressant effect? A randomized clinical trial and a meta-analysis of pindolol in nonresistant depression.

PubMed

Portella, Maria J; de Diego-Adeliño, Javier; Ballesteros, Javier; Puigdemont, Dolors; Oller, Sílvia; Santos, Borja; Álvarez, Enric; Artigas, Francesc; Pérez, Víctor

2011-07-01

Since depression entails not only dramatic personal disruption but also a huge amount of medical and socioeconomic burden, slowness of antidepressant action and difficulties to attain remission are entangled issues to be solved. Given the controversial previous findings with enhancing strategies such as pindolol, we examined whether the speed of selective serotonin reuptake inhibitor (SSRI) action can be truly accelerated with optimized pindolol dosage. Additionally, we aimed at elucidating whether pindolol benefits emerge, particularly in a population with nonresistant depression. Thirty outpatients with major depressive disorder (DSM-IV criteria) recruited between December 2002 and November 2005 were randomly assigned to receive citalopram + pindolol (5 mg tid) or citalopram + placebo for 6 weeks in a double-blind randomized clinical trial. A meta-analysis of randomized controlled trials of pindolol augmentation in patients with nonresistant depression was also performed. Outcome criteria were based on the 17-item Hamilton Depression Rating Scale. For the meta-analysis, efficacy was assessed by the number of treatment responders at 2 weeks and 4-6 weeks. Clinical trial outcomes: Repeated-measures analysis of variance showed a significant group-by-time interaction (P = .01). Cumulative percentage showed a trend for sustained response (odds ratio [OR] = 2.09; 95% CI, 0.914-4.780; P = .08) and a well-defined increased likelihood of sustaining remission (OR = 5.00; 95% CI, 1.191-20.989; P = .03) in pindolol receivers. Median survival time until first response was 65% less in the pindolol group (22 days vs 30 days; P = .03). The negative binomial regression model yielded different rates of response per person-day for pindolol and placebo groups (7.6% vs 4.7%, respectively; P = .03). Meta-analysis: Outcome favored pindolol at 2 weeks' time (relative risk [RR] = 1.68; 95% CI, 1.18-2.39; P = .004) and also at 4-6 weeks' time (RR = 1.11; 95% CI, 1.02-1.20; P = .02

Priming with BTCP, a dopamine reuptake blocker, reinstates cocaine-seeking and enhances cocaine cue-induced reinstatement.

PubMed

Martin-Fardon, Rémi; Lorentz, Christina U; Stuempfig, Nathan D; Weiss, Friedbert

2005-09-01

N-[1-(2-benzo[b]thiophenyl)cyclohexyl]piperidine (BTCP), a potent dopamine reuptake inhibitor, substitutes for the reinforcing effects of cocaine and meets other criteria for possible agonist pharmacotherapeutic potential. The purpose of this study was to determine (1) whether BTCP modifies reinstatement of cocaine-seeking elicited by cocaine-related environmental stimuli and (2) whether this compound produces priming effects. Male Wistar rats were trained to associate discriminative stimuli (S(D)) with cocaine availability (0.25 mg/infusion) versus non-reward and then were subjected to repeated extinction sessions during which the reinforcer and S(D) were withheld. Subsequent presentation of the cocaine S(D) produced recovery of cocaine-seeking. BTCP (2.5-30 mg/kg; i.p.) did not attenuate the conditioned reinstatement induced by the cocaine S(D) but, rather, potentiated this effect at 10 mg/kg. To test whether BTCP, by itself, exerts priming effects, different groups of rats were trained to self-administer cocaine (0.25 mg/infusion) for 2 weeks. After a 2-week extinction period, BTCP (5, 10 and 20 mg/kg, i.p.) reinstated cocaine-seeking, showing that BTCP not only increases cocaine-seeking induced by cocaine-related stimuli but also produces priming effects following abstinence. The results suggest that, in cocaine abstinent rats, BTCP produces cocaine-like effects.

QSAR analyses on avian influenza virus neuraminidase inhibitors using CoMFA, CoMSIA, and HQSAR

NASA Astrophysics Data System (ADS)

Zheng, Mingyue; Yu, Kunqian; Liu, Hong; Luo, Xiaomin; Chen, Kaixian; Zhu, Weiliang; Jiang, Hualiang

2006-09-01

The recent wide spreading of the H5N1 avian influenza virus (AIV) in Asia, Europe and Africa and its ability to cause fatal infections in human has raised serious concerns about a pending global flu pandemic. Neuraminidase (NA) inhibitors are currently the only option for treatment or prophylaxis in humans infected with this strain. However, drugs currently on the market often meet with rapidly emerging resistant mutants and only have limited application as inadequate supply of synthetic material. To dig out helpful information for designing potent inhibitors with novel structures against the NA, we used automated docking, CoMFA, CoMSIA, and HQSAR methods to investigate the quantitative structure-activity relationship for 126 NA inhibitors (NIs) with great structural diversities and wide range of bioactivities against influenza A virus. Based on the binding conformations discovered via molecular docking into the crystal structure of NA, CoMFA and CoMSIA models were successfully built with the cross-validated q 2 of 0.813 and 0.771, respectively. HQSAR was also carried out as a complementary study in that HQSAR technique does not require 3D information of these compounds and could provide a detailed molecular fragment contribution to the inhibitory activity. These models also show clearly how steric, electrostatic, hydrophobicity, and individual fragments affect the potency of NA inhibitors. In addition, CoMFA and CoMSIA field distributions are found to be in well agreement with the structural characteristics of the corresponding binding sites. Therefore, the final 3D-QSAR models and the information of the inhibitor-enzyme interaction should be useful in developing novel potent NA inhibitors.

Monoamine reuptake inhibition and mood-enhancing potential of a specified oregano extract.

PubMed

Mechan, Annis O; Fowler, Ann; Seifert, Nicole; Rieger, Henry; Wöhrle, Tina; Etheve, Stéphane; Wyss, Adrian; Schüler, Göde; Colletto, Biagio; Kilpert, Claus; Aston, James; Elliott, J Martin; Goralczyk, Regina; Mohajeri, M Hasan

2011-04-01

A healthy, balanced diet is essential for both physical and mental well-being. Such a diet must include an adequate intake of micronutrients, essential fatty acids, amino acids and antioxidants. The monoamine neurotransmitters, serotonin, dopamine and noradrenaline, are derived from dietary amino acids and are involved in the modulation of mood, anxiety, cognition, sleep regulation and appetite. The capacity of nutritional interventions to elevate brain monoamine concentrations and, as a consequence, with the potential for mood enhancement, has not been extensively evaluated. The present study investigated an extract from oregano leaves, with a specified range of active constituents, identified via an unbiased, high-throughput screening programme. The oregano extract was demonstrated to inhibit the reuptake and degradation of the monoamine neurotransmitters in a dose-dependent manner, and microdialysis experiments in rats revealed an elevation of extracellular serotonin levels in the brain. Furthermore, following administration of oregano extract, behavioural responses were observed in mice that parallel the beneficial effects exhibited by monoamine-enhancing compounds when used in human subjects. In conclusion, these data show that an extract prepared from leaves of oregano, a major constituent of the Mediterranean diet, is brain-active, with moderate triple reuptake inhibitory activity, and exhibits positive behavioural effects in animal models. We postulate that such an extract may be effective in enhancing mental well-being in humans.

Environmental Exposures, Genetic Polymorphisms and p53 Mutational Spectra in a Case-Control Study of Breast Cancer.

DTIC Science & Technology

1998-01-01

Further, preliminary clinical data suggest that serotonin reuptake inhibitors , such as fluoxetinc hydrochloride, may promote smoking cessation (15,16...benefits of serotonin reuptake inhibitors in smoking cessation (16) suggested that this gene may be a plausible candidate for predisposition to... used for random selection of women under age 65; women age 65 and over were randomly selected from the listing of the Health Care Finance

Differences in the effects of Na+-H+ exchange inhibitors on cardiac function and apoptosis in guinea-pig ischemia-reperfused hearts.

PubMed

Hotta, Yoshihiro; Nishimaki, Haruaki; Takeo, Tomohiro; Itoh, Gen; Yajima, Michio; Otsuka-Murakami, Hidetsugu; Ishikawa, Naohisa; Kawai, Norio; Huang, Lei; Yamada, Kazuto; Yamamoto, Setsuko; Matsui, Kazuki; Ohashi, Naohito

2004-10-25

The protective effects of the Na+-H+ exchange (NHE) inhibitors SM-198110 (2-[[(aminoiminomethyl) amino] carbonyl]-4-chloro-1H-indole-1-propanesulfonic acid monohydrate) and SM-197378 (N-(aminoiminomethyl)-1-methyl-7-(sulfooxy)-4-(trifluoromethyl)-1H-indole-2-carboxamide monohydrate) were investigated in perfused Langendorff guinea-pig hearts subjected to ischemia (40 min) and reperfusion (40 min). The recovery of left ventricular developed pressure (LVDP) from ischemia by reperfusion was 39.0% in the control, while in the hearts pretreated with SM-198110 or SM-197378 (10(-7) M), it was about 100%. The ATP level, monitored simultaneously by (31)P-nuclear magnetic resonance spectrometry, was already higher than the control value at the end of the ischemic period, and the elevation in Na+ or Ca2+ fluorometric signals induced during ischemia was suppressed. In post-treated hearts, the LVDP recovery rate was significantly higher with SM-198110 than with SM-197378. By in vitro electron paramagnetic resonance spectrometry, SM-197378 was found to directly quench the active oxygen radical, whereas SM-198110 had no effect. Numbers of apoptotic cardiomyocytes after ischemia (1 h) followed by reperfusion (5 h) were significantly lower in SM-197378-treated than in SM-198110-treated hearts, consistent with the level of activity of caspase-3. These results suggest that the antioxidant effects of NHE inhibitors have an important role in apoptosis during ischemia-reperfusion, but apoptosis is not a major manifestation of cardiac function during postischemic recovery, and that NHE-sensitive mechanisms of reperfusion injury promote both necrotic and apoptotic processes death.

Progress of small molecular inhibitors in the development of anti-influenza virus agents

PubMed Central

Wu, Xiaoai; Wu, Xiuli; Sun, Qizheng; Zhang, Chunhui; Yang, Shengyong; Li, Lin; Jia, Zhiyun

2017-01-01

The influenza pandemic is a major threat to human health, and highly aggressive strains such as H1N1, H5N1 and H7N9 have emphasized the need for therapeutic strategies to combat these pathogens. Influenza anti-viral agents, especially active small molecular inhibitors play important roles in controlling pandemics while vaccines are developed. Currently, only a few drugs, which function as influenza neuraminidase (NA) inhibitors and M2 ion channel protein inhibitors, are approved in clinical. However, the acquired resistance against current anti-influenza drugs and the emerging mutations of influenza virus itself remain the major challenging unmet medical needs for influenza treatment. It is highly desirable to identify novel anti-influenza agents. This paper reviews the progress of small molecular inhibitors act as antiviral agents, which include hemagglutinin (HA) inhibitors, RNA-dependent RNA polymerase (RdRp) inhibitors, NA inhibitors and M2 ion channel protein inhibitors etc. Moreover, we also summarize new, recently reported potential targets and discuss strategies for the development of new anti-influenza virus drugs. PMID:28382157

A randomized trial of cognitive-behavioral therapy or selective serotonin reuptake inhibitor or both combined for panic disorder with or without agoraphobia: treatment results through 1-year follow-up.

PubMed

van Apeldoorn, Franske J; Timmerman, Marieke E; Mersch, Peter Paul A; van Hout, Wiljo J P J; Visser, Sako; van Dyck, Richard; den Boer, Johan A

2010-05-01

To establish the long-term effectiveness of 3 treatments for DSM-IV panic disorder with or without agoraphobia: cognitive-behavioral therapy (CBT), pharmacotherapy using a selective serotonin reuptake inhibitor (SSRI), or the combination of both (CBT + SSRI). As a secondary objective, the relationship between treatment outcome and 7 predictor variables was investigated. Patients were enrolled between April 2001 and September 2003 and were randomly assigned to treatment. Academic and nonacademic clinical sites participated. Each treatment modality lasted 1 year. Pharmacotherapists were free to choose between 5 SSRIs currently marketed in The Netherlands. Outcome was assessed after 9 months of treatment (posttest 1), after discontinuation of treatment (posttest 2), and 6 and 12 months after treatment discontinuation (follow-up 1 and follow-up 2). In the sample (N = 150), 48% did not suffer from agoraphobia or suffered from only mild agoraphobia, while 52% suffered from moderate or severe agoraphobia. Patients in each treatment group improved significantly from pretest to posttest 1 on the primary outcome measures of level of anxiety (P < .001), degree of coping (P < .001), and remitter status (P < .001), as well as on the secondary outcome measures of depressive symptomatology (P < .001), and from pretest to posttest 2 for health-related quality of life (P < .001). Gains were preserved from posttest 2 throughout the follow-up period. Some superiority of CBT + SSRI and SSRI as compared with CBT was observed at posttest 1. However, at both follow-ups, differences between treatment modalities proved nonsignificant. Client satisfaction appeared to be high at treatment endpoint, while patients receiving CBT + SSRI appeared slightly (P < .05) more satisfied than those receiving CBT only. No fall-off in gains was observed for either treatment modality after treatment discontinuation. SSRIs were associated with adverse events. Gains produced by CBT were slower to emerge than

Effect of soothing-liver and nourishing-heart acupuncture on early selective serotonin reuptake inhibitor treatment onset for depressive disorder and related indicators of neuroimmunology: a randomized controlled clinical trial.

PubMed

Liu, Yi; Feng, Hui; Mo, Yali; Gao, Jingfang; Mao, Hongjing; Song, Mingfen; Wang, Shengdong; Yin, Yan; Liu, Wenjuan

2015-10-01

To observe the effect of soothing-liver and nourishing-heart acupuncture on selective serotonin reuptake inhibitor (SSRIs) treatment effect onset in patients with depressive disorder and related indicators of neuroimmunology. Overall, 126 patients with depressive disorder were randomly divided into a medicine and acupuncture-medicine group using a random number table. Patients were treated for 6 consecutive weeks. The two groups were evaluated by the Montgomery-Asberg Depression Rating Scale (MADRS) and Side Effects Rating Scale (SERS) to assess the effect of the soothing-liver and nourishing-heart acupuncture method on early onset of SSRI treatment effect. Changes in serum 5-hydroxytryptamine (5-HT) and inflammatory cytokines before and after treatment were recorded and compared between the medicine group and the acupuncture-medicine group. The acupuncture-medicine group had significantly lower MADRS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). The acupuncture group had significantly lower SERS scores at weeks 1, 2, 4, and 6 after treatment compared with the medicine group (P < 0.01). At 6 weeks after treatment, serum 5-HT in the acupuncture-medicine group was significantly higher compared with the medicine group (P < 0.01). Interleukin-6 (IL-6) in the acupuncture-medicine group was significantly lower than that in the medicine group (P < 0.01), whereas there was no significant difference in IL-1β between the groups (P > 0.05). Anti-inflammatory cytokines IL-4 and IL-10 were significantly higher in the acupuncture-medicine group compared with the medicine group (P < 0.01, P < 0.05, respectively). The soothing-liver and nourishing-heart acupuncture method can effectively accelerate the onset of SSRI effects when treating depressive disorder and can significantly reduce the adverse reactions of SSRIs. Moreover, acupuncture can enhance serum 5-HT and regulate the balance of pro-inflammatory cytokines and anti

Protein Phosphatase 1 Inhibitor-1 Deficiency Reduces Phosphorylation of Renal NaCl Cotransporter and Causes Arterial Hypotension

PubMed Central

Picard, Nicolas; Trompf, Katja; Yang, Chao-Ling; Miller, R. Lance; Carrel, Monique; Loffing-Cueni, Dominique; Fenton, Robert A.; Ellison, David H.

2014-01-01

The thiazide-sensitive NaCl cotransporter (NCC) of the renal distal convoluted tubule (DCT) controls ion homeostasis and arterial BP. Loss-of-function mutations of NCC cause renal salt wasting with arterial hypotension (Gitelman syndrome). Conversely, mutations in the NCC-regulating WNK kinases or kelch-like 3 protein cause familial hyperkalemic hypertension. Here, we performed automated sorting of mouse DCTs and microarray analysis for comprehensive identification of novel DCT-enriched gene products, which may potentially regulate DCT and NCC function. This approach identified protein phosphatase 1 inhibitor-1 (I-1) as a DCT-enriched transcript, and immunohistochemistry revealed I-1 expression in mouse and human DCTs and thick ascending limbs. In heterologous expression systems, coexpression of NCC with I-1 increased thiazide-dependent Na+ uptake, whereas RNAi-mediated knockdown of endogenous I-1 reduced NCC phosphorylation. Likewise, levels of phosphorylated NCC decreased by approximately 50% in I-1 (I-1−/−) knockout mice without changes in total NCC expression. The abundance and phosphorylation of other renal sodium-transporting proteins, including NaPi-IIa, NKCC2, and ENaC, did not change, although the abundance of pendrin increased in these mice. The abundance, phosphorylation, and subcellular localization of SPAK were similar in wild-type (WT) and I-1−/− mice. Compared with WT mice, I-1−/− mice exhibited significantly lower arterial BP but did not display other metabolic features of NCC dysregulation. Thus, I-1 is a DCT-enriched gene product that controls arterial BP, possibly through regulation of NCC activity. PMID:24231659

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a.

PubMed

Deuis, Jennifer R; Dekan, Zoltan; Wingerd, Joshua S; Smith, Jennifer J; Munasinghe, Nehan R; Bhola, Rebecca F; Imlach, Wendy L; Herzig, Volker; Armstrong, David A; Rosengren, K Johan; Bosmans, Frank; Waxman, Stephen G; Dib-Hajj, Sulayman D; Escoubas, Pierre; Minett, Michael S; Christie, Macdonald J; King, Glenn F; Alewood, Paul F; Lewis, Richard J; Wood, John N; Vetter, Irina

2017-01-20

Human genetic studies have implicated the voltage-gated sodium channel Na V 1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits Na V 1.7 (IC 50 0.9 nM) with at least 40-1000-fold selectivity over all other Na V subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by Na V 1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective Na V 1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective Na V 1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted Na V 1.7 inhibitors can only produce analgesia when administered in combination with an opioid.

Pharmacological characterisation of the highly NaV1.7 selective spider venom peptide Pn3a

PubMed Central

Deuis, Jennifer R.; Dekan, Zoltan; Wingerd, Joshua S.; Smith, Jennifer J.; Munasinghe, Nehan R.; Bhola, Rebecca F.; Imlach, Wendy L.; Herzig, Volker; Armstrong, David A.; Rosengren, K. Johan; Bosmans, Frank; Waxman, Stephen G.; Dib-Hajj, Sulayman D.; Escoubas, Pierre; Minett, Michael S.; Christie, Macdonald J.; King, Glenn F.; Alewood, Paul F.; Lewis, Richard J.; Wood, John N.; Vetter, Irina

2017-01-01

Human genetic studies have implicated the voltage-gated sodium channel NaV1.7 as a therapeutic target for the treatment of pain. A novel peptide, μ-theraphotoxin-Pn3a, isolated from venom of the tarantula Pamphobeteus nigricolor, potently inhibits NaV1.7 (IC50 0.9 nM) with at least 40–1000-fold selectivity over all other NaV subtypes. Despite on-target activity in small-diameter dorsal root ganglia, spinal slices, and in a mouse model of pain induced by NaV1.7 activation, Pn3a alone displayed no analgesic activity in formalin-, carrageenan- or FCA-induced pain in rodents when administered systemically. A broad lack of analgesic activity was also found for the selective NaV1.7 inhibitors PF-04856264 and phlotoxin 1. However, when administered with subtherapeutic doses of opioids or the enkephalinase inhibitor thiorphan, these subtype-selective NaV1.7 inhibitors produced profound analgesia. Our results suggest that in these inflammatory models, acute administration of peripherally restricted NaV1.7 inhibitors can only produce analgesia when administered in combination with an opioid. PMID:28106092

Desvenlafaxine in major depressive disorder: an evidence-based review of its place in therapy

PubMed Central

Lieberman, Daniel Z; Massey, Suena H

2010-01-01

Introduction: Desvenlafaxine, the active metabolite of venlafaxine, is a serotonin norepinephrine reuptake inhibitor (SNRI) recently approved for the treatment of major depressive disorder. It is one of only three medications in this class available in the United States. Aims: The objective of this article is to review the published evidence for the safety and efficacy of desvenlafaxine, and to compare it to other antidepressants to delineate its role in the treatment of depression. Evidence review: At the recommended dose of 50 mg per day the rate of response and remission was similar to other SNRIs, as was the adverse effect profile. The rate of discontinuation was no greater than placebo, and a discontinuation syndrome was not observed at this dose. Higher doses were not associated with greater efficacy, but they did lead to more side effects, and the use of a taper prior to discontinuation. The most common side effects reported were insomnia, somnolence, dizziness, and nausea. Some subjects experienced clinically significant blood pressure elevation. Place in therapy: Like duloxetine, desvenlafaxine inhibits the reuptake of both norepinephrine and serotonin at the starting dose. Dual reuptake inhibitors have been shown to have small but statistically significantly greater rates of response and remission compared to selective serotonin reuptake inhibitors, and they have also shown early promise in the treatment of neuropathic pain. Desvenlafaxine may prove to be a valuable treatment option by expanding the limited number of available dual reuptake inhibitors. PMID:20694066

Na+/H+ exchanger 3 inhibitor diminishes the amino-acid-enhanced transepithelial calcium transport across the rat duodenum.

PubMed

Thammayon, Nithipak; Wongdee, Kannikar; Lertsuwan, Kornkamon; Suntornsaratoon, Panan; Thongbunchoo, Jirawan; Krishnamra, Nateetip; Charoenphandhu, Narattaphol

2017-04-01

Na + /H + exchanger (NHE)-3 is important for intestinal absorption of nutrients and minerals, including calcium. The previous investigations have shown that the intestinal calcium absorption is also dependent on luminal nutrients, but whether aliphatic amino acids and glucose, which are abundant in the luminal fluid during a meal, similarly enhance calcium transport remains elusive. Herein, we used the in vitro Ussing chamber technique to determine epithelial electrical parameters, i.e., potential difference (PD), short-circuit current (Isc), and transepithelial resistance, as well as 45 Ca flux in the rat duodenum directly exposed on the mucosal side to glucose or various amino acids. We found that mucosal glucose exposure led to the enhanced calcium transport, PD, and Isc, all of which were insensitive to NHE3 inhibitor (100 nM tenapanor). In the absence of mucosal glucose, several amino acids (12 mM in the mucosal side), i.e., alanine, isoleucine, leucine, proline, and hydroxyproline, markedly increased the duodenal calcium transport. An inhibitor for NHE3 exposure on the mucosal side completely abolished proline- and leucine-enhanced calcium transport, but not transepithelial transport of both amino acids themselves. In conclusion, glucose and certain amino acids in the mucosal side were potent stimulators of the duodenal calcium absorption, but only amino-acid-enhanced calcium transport was NHE3-dependent.

Common mechanisms of inhibition for the Na+/glucose (hSGLT1) and Na+/Cl−/GABA (hGAT1) cotransporters

PubMed Central

Hirayama, Bruce A; Díez-Sampedro, Ana; Wright, Ernest M

2001-01-01

Electrophysiological methods were used to investigate the interaction of inhibitors with the human Na+/glucose (hSGLT1) and Na+/Cl−/GABA (hGAT1) cotransporters. Inhibitor constants were estimated from both inhibition of substrate-dependent current and inhibitor-induced changes in cotransporter conformation. The competitive, non-transported inhibitors are substrate derivatives with inhibition constants from 200 nM (phlorizin) to 17 mM (esculin) for hSGLT1, and 300 nM (SKF89976A) to 10 mM (baclofen) for hGAT1. At least for hSGLT1, values determined using either method were proportional over 5-orders of magnitude. Correlation of inhibition to structure of the inhibitors resulted in a pharmacophore for glycoside binding to hSGLT1: the aglycone is coplanar with the pyranose ring, and binds to a hydrophobic/aromatic surface of at least 7×12Å. Important hydrogen bond interactions occur at five positions bordering this surface. In both hSGLT1 and hGAT1 the data suggests that there is a large, hydrophobic inhibitor binding site ∼8Å from the substrate binding site. This suggests an architectural similarity between hSGLT1 and hGAT1. There is also structural similarity between non-competitive and competitive inhibitors, e.g., phloretin is the aglycone of phlorizin (hSGLT1) and nortriptyline resembles SKF89976A without nipecotic acid (hGAT1). Our studies establish that measurement of the effect of inhibitors on presteady state currents is a valid non-radioactive method for the determination of inhibitor binding constants. Furthermore, analysis of the presteady state currents provide novel insights into partial reactions of the transport cycle and mode of action of the inhibitors. PMID:11588102

Analysis of Aprotinin, a Protease Inhibitor, Action on the Trafficking of Epithelial Na+ Channels (ENaC) in Renal Epithelial Cells Using a Mathematical Model.

PubMed

Sasamoto, Kouhei; Marunaka, Rie; Niisato, Naomi; Sun, Hongxin; Taruno, Akiyuki; Pezzotti, Giuseppe; Yamamoto, Toshiro; Kanamura, Narisato; Zhu, Wenliang; Nishio, Kyosuke; Inui, Toshio; Eaton, Douglas C; Marunaka, Yoshinori

2017-01-01

Epithelial Na+ channels (ENaC) play a crucial role in control of blood pressure by regulating renal Na+ reabsorption. Intracellular trafficking of ENaC is one of the key regulators of ENaC function, but a quantitative description of intracellular recycling of endogenously expressed ENaC is unavailable. We attempt here to provide a model for intracellular recycling after applying a protease inhibitor under hypotonic conditions. We simulated the ENaC-mediated Na+ transport in renal epithelial A6 cells measured as short-circuit currents using a four-state mathematical ENaC trafficking model. We developed a four-state mathematical model of ENaC trafficking in the cytosol of renal epithelial cells that consists of: an insertion state of ENaC that can be trafficked to the apical membrane state (insertion rate); an apical membrane state of ENaC conducting Na+ across the apical membrane; a recycling state containing ENaC that are retrieved from the apical membrane state (endocytotic rate) and then to the insertion state (recycling rate) communicating with the apical membrane state or to a degradation state (degradation rate). We studied the effect of aprotinin (a protease inhibitor) blocking protease-induced cleavage of the extracellular loop of γ ENaC subunit on the rates of intracellular ENaC trafficking using the above-defined four-state mathematical model of ENaC trafficking and the recycling number relative to ENaC staying in the apical membrane. We found that aprotinin significantly reduced the insertion rate of ENaC to the apical membrane by 40%, the recycling rate of ENaC by 81%, the cumulative time of an individual ENaC staying in the apical membrane by 32%, the cumulative life-time after the first endocytosis of ENaC by 25%, and the cumulative Na+ absorption by 31%. The most interesting result of the present study is that cleavage of ENaC affects the intracellular ENaC trafficking rate and determines the residency time of ENaC, indicating that more active

New Pyrazolopyrimidine Inhibitors of Protein Kinase D as Potent Anticancer Agents for Prostate Cancer Cells

PubMed Central

Tandon, Manuj; Johnson, James; Li, Zhihong; Xu, Shuping; Wipf, Peter; Wang, Qiming Jane

2013-01-01

The emergence of protein kinase D (PKD) as a potential therapeutic target for several diseases including cancer has triggered the search for potent, selective, and cell-permeable small molecule inhibitors. In this study, we describe the identification, in vitro characterization, structure-activity analysis, and biological evaluation of a novel PKD inhibitory scaffold exemplified by 1-naphthyl PP1 (1-NA-PP1). 1-NA-PP1 and IKK-16 were identified as pan-PKD inhibitors in a small-scale targeted kinase inhibitor library assay. Both screening hits inhibited PKD isoforms at about 100 nM and were ATP-competitive inhibitors. Analysis of several related kinases indicated that 1-NA-PP1 was highly selective for PKD as compared to IKK-16. SAR analysis showed that 1-NA-PP1 was considerably more potent and showed distinct substituent effects at the pyrazolopyrimidine core. 1-NA-PP1 was cell-active, and potently blocked prostate cancer cell proliferation by inducing G2/M arrest. It also potently blocked the migration and invasion of prostate cancer cells, demonstrating promising anticancer activities on multiple fronts. Overexpression of PKD1 or PKD3 almost completely reversed the growth arrest and the inhibition of tumor cell invasion caused by 1-NA-PP1, indicating that its anti-proliferative and anti-invasive activities were mediated through the inhibition of PKD. Interestingly, a 12-fold increase in sensitivity to 1-NA-PP1 could be achieved by engineering a gatekeeper mutation in the active site of PKD1, suggesting that 1-NA-PP1 could be paired with the analog-sensitive PKD1M659G for dissecting PKD-specific functions and signaling pathways in various biological systems. PMID:24086585

Short-term use of serotonin reuptake inhibitors and risk of upper gastrointestinal bleeding.

PubMed

Wang, Yen-Po; Chen, Yung-Tai; Tsai, Chia-Fen; Li, Szu-Yuan; Luo, Jiing-Chyuan; Wang, Shuu-Jiun; Tang, Chao-Hsiun; Liu, Chia-Jen; Lin, Han-Chieh; Lee, Fa-Yauh; Chang, Full-Young; Lu, Ching-Liang

2014-01-01

The association between selective serotonin receptor inhibitors (SSRIs) and risk of upper gastrointestinal bleeding remains controversial. Previous studies have generally evaluated the issue for approximately 3 months, even though the SSRI-mediated inhibition of platelet serotonin concentrations occurs within 7-14 days. The authors explored the risk of upper gastrointestinal bleeding after short-term SSRI exposure by a case-crossover design. The records of psychiatric inpatients with upper gastrointestinal bleeding were retrieved from the Taiwan National Health Insurance Database (1998-2009). Rates of antidepressant use were compared for case and control periods with time windows of 7, 14, and 28 days. The adjusted self-matched odds ratios from a conditional logistic regression model were used to determine the association between SSRI use and upper gastrointestinal bleeding. A total of 5,377 patients with upper gastrointestinal bleeding were enrolled. The adjusted odds ratio for the risk of upper gastrointestinal bleeding after SSRI exposure was 1.67 (95% CI=1.23-2.26) for the 7-day window, 1.84 (95% CI=1.42-2.40) for the 14-day window, and 1.67 (95% CI=1.34-2.08) for the 28-day window. SSRIs with high and intermediate, but not low, affinity for serotonin transporter were associated with upper gastrointestinal bleeding. An elevated risk of upper gastrointestinal bleeding after SSRI exposure was seen in male but not female patients. Short-term SSRI use (7-28 days) is significantly associated with upper gastrointestinal bleeding. Gender differences may exist in the relationship between SSRI use and upper gastrointestinal bleeding. Physicians should carefully monitor signs of upper gastrointestinal bleeding even after short-term exposure to SSRIs, as is done with nonsteroidal anti-inflammatory drugs and aspirin.

Neutralizing inhibitors in the airways of naïve ferrets do not play a major role in modulating the virulence of H3 subtype influenza A viruses.

PubMed

Job, Emma R; Pizzolla, Angela; Nebl, Thomas; Short, Kirsty R; Deng, Yi-Mo; Carolan, Louise; Laurie, Karen L; Brooks, Andrew G; Reading, Patrick C

2016-07-01

Many insights regarding the pathogenesis of human influenza A virus (IAV) infections have come from studies in mice and ferrets. Surfactant protein (SP)-D is the major neutralizing inhibitor of IAV in mouse airway fluids and SP-D-resistant IAV mutants show enhanced virus replication and virulence in mice. Herein, we demonstrate that sialylated glycoproteins, rather than SP-D, represent the major neutralizing inhibitors against H3 subtype viruses in airway fluids from naïve ferrets. Moreover, while resistance to neutralizing inhibitors is a critical factor in modulating virus replication and disease in the mouse model, it does not appear to be so in the ferret model, as H3 mutants resistant to either SP-D or sialylated glycoproteins in ferret airway fluids did not show enhanced virulence in ferrets. These data have important implications for our understanding of pathogenesis and immunity to human IAV infections in these two widely used animal models of infection. Copyright © 2016. Published by Elsevier Inc.

A Network Meta-Analysis Comparing Effects of Various Antidepressant Classes on the Digit Symbol Substitution Test (DSST) as a Measure of Cognitive Dysfunction in Patients with Major Depressive Disorder.

PubMed

Baune, Bernhard T; Brignone, Mélanie; Larsen, Klaus Groes

2018-02-01

Major depressive disorder is a common condition that often includes cognitive dysfunction. A systematic literature review of studies and a network meta-analysis were carried out to assess the relative effect of antidepressants on cognitive dysfunction in major depressive disorder. MEDLINE, Embase, Cochrane, CDSR, and PsychINFO databases; clinical trial registries; and relevant conference abstracts were searched for randomized controlled trials assessing the effects of antidepressants/placebo on cognition. A network meta-analysis comparing antidepressants was conducted using a random effects model. The database search retrieved 11337 citations, of which 72 randomized controlled trials from 103 publications met the inclusion criteria. The review identified 86 cognitive tests assessing the effect of antidepressants on cognitive functioning. However, the Digit Symbol Substitution Test, which targets multiple domains of cognition and is recognized as being sensitive to change, was the only test that was used across 12 of the included randomized controlled trials and that allowed the construction of a stable network suitable for the network meta-analysis. The interventions assessed included selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors, and other non-selective serotonin reuptake inhibitors/serotonin-norepinephrine reuptake inhibitors. The network meta-analysis using the Digit Symbol Substitution Test showed that vortioxetine was the only antidepressant that improved cognitive dysfunction on the Digit Symbol Substitution Test vs placebo {standardized mean difference: 0.325 (95% CI = 0.120; 0.529, P=.009}. Compared with other antidepressants, vortioxetine was statistically more efficacious on the Digit Symbol Substitution Test vs escitalopram, nortriptyline, and the selective serotonin reuptake inhibitor and tricyclic antidepressant classes. This study highlighted the large variability in measures used to assess cognitive functioning

Serotonergic mediation of the effects of fluoxetine, but not desipramine, in the rat forced swimming test.

PubMed

Page, M E; Detke, M J; Dalvi, A; Kirby, L G; Lucki, I

1999-11-01

The forced swimming test (FST) is a behavioral test in rodents that predicts the clinical efficacy of many types of antidepressant treatments. Recently, a behavior sampling technique was developed that scores individual response categories, including swimming, climbing and immobility. Although all antidepressant drugs reduce immobility in the FST, at least two distinct active behavioral patterns are produced by pharmacologically selective antidepressant drugs. Serotonin-selective reuptake inhibitors increase swimming behavior, while drugs acting primarily to increase extracellular levels of norepinephrine or dopamine increase climbing behavior. Distinct patterns of active behaviors in the FST may be mediated by distinct neurotransmitters, but this has not been shown directly. The present study examined the role of serotonin in mediating active behaviors in the forced swimming test after treatment with two antidepressant drugs, the selective serotonin reuptake inhibitor, fluoxetine and the selective norepinephrine reuptake inhibitor, desipramine. Endogenous serotonin was depleted by administering para-cholorophenylalanine (PCPA, 150 mg/kg, IP.) to rats 72 h and 48 h prior to the swim test. Fluoxetine (10 mg/kg, SC) or desipramine (10 mg/kg, SC) was given three times over a 24-h period prior to the FST. Behavioral responses, including immobility, swimming and climbing, were counted during the 5-min test. Pretreatment with PCPA blocked fluoxetine-induced reduction in immobility and increase in swimming behavior during the FST. In contrast, PCPA pretreatment did not interfere with the ability of desipramine to reduce immobility and increase climbing behavior. Depletion of serotonin prevented the behavioral effects of the selective serotonin reuptake inhibitor fluoxetine in the rat FST. Furthermore, depletion of serotonin had no impact on the behavioral effects induced by the selective norepinephrine reuptake inhibitor, desipramine. The effects of antidepressant drugs

The differential effects of chronic imipramine or citalopram administration on physiological and behavioral outcomes in naïve mice.

PubMed

Strekalova, Tatyana; Anthony, Daniel C; Dolgov, Oleg; Anokhin, Konstantin; Kubatiev, Aslan; Steinbusch, Harry M W; Schroeter, Careen

2013-05-15

Tricyclics and selective serotonin reuptake inhibitors (SSRIs) are probably the most widely employed reference antidepressants in animal studies on depression. Using imipramine and citalopram, we sought to assess which drug would be more appropriate as pharmacological reference in paradigms of depression in C57BL6N mice by measuring their effect on liquid consumption, home cage activity, body weight and long-term memory in naïve animals treated with each compound at generally used dose of 15 mg/kg/day. Continuous logging of home cage movement, weekly monitoring of vertical activity in a novel cage, and body weight was recorded during four-week treatment period and for four weeks after discontinuation of the antidepressant; sucrose preference was evaluated at weekly intervals during drug administration. A novel object recognition memory test was performed in mice treated the antidepressants for two weeks. Compared to control, imipramine-treated mice displayed increased sucrose and water intake, as well as enhanced home-cage and novelty exploration activities, and reduced body weight. Imipramine also impaired learning in the object recognition task, but citalopram diminished object exploration sufficiently to invalidate the test. Citalopram-treated animals demonstrated no changes in a sucrose test and had elevated body mass. Thus basic physiological and behavioral outcomes in naïve mice were significantly altered by the chronic administration of imipramine and, to a lesser extent, citalopram. As altered variables are crucial for the evaluation of antidepressant-like effects in mice, our data suggest that, at commonly used doses, both drugs must be applied in mouse models of depression with caution. Copyright © 2013 Elsevier B.V. All rights reserved.

Sodium glucose co-transporter 2 (SGLT2) inhibitors: new among antidiabetic drugs.

PubMed

Opie, L H

2014-08-01

Type 2 diabetes is characterized by decreased insulin secretion and sensitivity. The available oral anti-diabetic drugs act on many different molecular sites. The most used of oral anti-diabetic agents is metformin that activates glucose transport vesicles to the cell surface. Others are: the sulphonylureas; agents acting on the incretin system; GLP-1 agonists; dipetidylpeptidase-4 inhibitors; meglinitide analogues; and the thiazolidinediones. Despite these many drugs acting by different mechanisms, glycaemic control often remains elusive. None of these drugs have a primary renal mechanism of action on the kidneys, where almost all glucose excreted is normally reabsorbed. That is where the inhibitors of glucose reuptake (sodium-glucose cotransporter 2, SGLT2) have a unique site of action. Promotion of urinary loss of glucose by SGLT2 inhibitors embodies a new principle of control in type 2 diabetes that has several advantages with some urogenital side-effects, both of which are evaluated in this review. Specific approvals include use as monotherapy, when diet and exercise alone do not provide adequate glycaemic control in patients for whom the use of metformin is considered inappropriate due to intolerance or contraindications, or as add-on therapy with other anti-hyperglycaemic medicinal products including insulin, when these together with diet and exercise, do not provide adequate glycemic control. The basic mechanisms are improved β-cell function and insulin sensitivity. When compared with sulphonylureas or other oral antidiabetic agents, SGLT2 inhibitors provide greater HbA1c reduction. Urogenital side-effects related to the enhanced glycosuria can be troublesome, yet seldom lead to discontinuation. On this background, studies are analysed that compare SGLT2 inhibitors with other oral antidiabetic agents. Their unique mode of action, unloading the excess glycaemic load, contrasts with other oral agents that all act to counter the effects of diabetic

Enhancement of corrosion resistance of carbon steel by Dioscorea Hispida starch in NaCl

NASA Astrophysics Data System (ADS)

Zulhusni, M. D. M.; Othman, N. K.; Lazim, Azwan Mat

2015-09-01

Starch is a one of the most abundant natural product in the world and has the potential as corrosion inhibitor replacing harmful synthetic chemical based corrosion inhibitor. This research was aimed to examines the potential of starch extracted from local Malaysian wild yam (Dioscorea hispida), as corrosion inhibitor to carbon steel in NaCl media replicating sea water. By using gravimetric test and analysis, in which the carbon steel specimens were immersed in NaCl media for 24, 48 and 60 hours with the starch as corrosion inhibitor. the corrosion rate (mmpy) and inhibition efficiencies (%) was calculated. The results obtained showed decrease in corrosion rate as higher concentration of starch was employed. The inhibition efficiencies also shows an increasing manner up to 95.97 % as the concentration of the inhibitor increased.

ROMK inhibitor actions in the nephron probed with diuretics

PubMed Central

Kharade, Sujay V.; Flores, Daniel; Lindsley, Craig W.; Satlin, Lisa M.

2015-01-01

Diuretics acting on specific nephron segments to inhibit Na+ reabsorption have been used clinically for decades; however, drug interactions, tolerance, and derangements in serum K+ complicate their use to achieve target blood pressure. ROMK is an attractive diuretic target, in part, because its inhibition is postulated to indirectly inhibit the bumetanide-sensitive Na+-K+-2Cl− cotransporter (NKCC2) and the amiloride- and benzamil-sensitive epithelial Na+ channel (ENaC). The development of small-molecule ROMK inhibitors has created opportunities for exploring the physiological responses to ROMK inhibition. The present study evaluated how inhibition of ROMK alone or in combination with NKCC2, ENaC, or the hydrochlorothiazide (HCTZ) target NCC alter fluid and electrolyte transport in the nephron. The ROMK inhibitor VU591 failed to induce diuresis when administered orally to rats. However, another ROMK inhibitor, termed compound A, induced a robust natriuretic diuresis without kaliuresis. Compound A produced additive effects on urine output and Na+ excretion when combined with HCTZ, amiloride, or benzamil, but not when coadministered with bumetanide, suggesting that the major diuretic target site is the thick ascending limb (TAL). Interestingly, compound A inhibited the kaliuretic response induced by bumetanide and HCTZ, an effect we attribute to inhibition of ROMK-mediated K+ secretion in the TAL and CD. Compound A had no effect on heterologously expressed flow-sensitive large-conductance Ca2+-activated K+ channels (Slo1/β1). In conclusion, compound A represents an important new pharmacological tool for investigating the renal consequences of ROMK inhibition and therapeutic potential of ROMK as a diuretic target. PMID:26661652

Development of Heat Shock Protein (Hsp90) Inhibitors To Combat Resistance to Tyrosine Kinase Inhibitors through Hsp90-Kinase Interactions.

PubMed

Wang, Meining; Shen, Aijun; Zhang, Chi; Song, Zilan; Ai, Jing; Liu, Hongchun; Sun, Liping; Ding, Jian; Geng, Meiyu; Zhang, Ao

2016-06-23

Heat shock protein 90 (Hsp90) is a ubiquitous chaperone of all of the oncogenic tyrosine kinases. Many Hsp90 inhibitors, alone or in combination, have shown significant antitumor efficacy against the kinase-positive naïve and mutant models. However, clinical trials of these inhibitors are unsuccessful due to insufficient clinical benefits and nonoptimal safety profiles. Recently, much progress has been reported on the Hsp90-cochaperone-client complex, which will undoubtedly assist in the understanding of the interactions between Hsp90 and its clients. Meanwhile, Hsp90 inhibitors have shown promise against patients' resistance caused by early generation tyrosine kinase inhibitors (TKIs), and at least 13 Hsp90 inhibitors are being reevaluated in the clinic. In this regard, the objectives of the current perspective are to summarize the structure and function of the Hsp90-cochaperone-client complex, to analyze the structural and functional insights into the Hsp90-client interactions to address several existing unresolved problems with Hsp90 inhibitors, and to highlight the preclinical and clinical studies of Hsp90 inhibitors as an effective treatment against resistance to tyrosine kinase inhibitors.

Discovery of Dihydrobenzoxazepinone (GS-6615) Late Sodium Current Inhibitor (Late INai), a Phase II Agent with Demonstrated Preclinical Anti-Ischemic and Antiarrhythmic Properties.

PubMed

Zablocki, Jeff A; Elzein, Elfatih; Li, Xiaofen; Koltun, Dmitry O; Parkhill, Eric Q; Kobayashi, Tetsuya; Martinez, Ruben; Corkey, Britton; Jiang, Haibo; Perry, Thao; Kalla, Rao; Notte, Gregory T; Saunders, Oliver; Graupe, Michael; Lu, Yafan; Venkataramani, Chandru; Guerrero, Juan; Perry, Jason; Osier, Mark; Strickley, Robert; Liu, Gongxin; Wang, Wei-Qun; Hu, Lufei; Li, Xiao-Jun; El-Bizri, Nesrine; Hirakawa, Ryoko; Kahlig, Kris; Xie, Cheng; Li, Cindy Hong; Dhalla, Arvinder K; Rajamani, Sridharan; Mollova, Nevena; Soohoo, Daniel; Lepist, Eve-Irene; Murray, Bernard; Rhodes, Gerry; Belardinelli, Luiz; Desai, Manoj C

2016-10-03

Late sodium current (late I Na ) is enhanced during ischemia by reactive oxygen species (ROS) modifying the Na v 1.5 channel, resulting in incomplete inactivation. Compound 4 (GS-6615, eleclazine) a novel, potent, and selective inhibitor of late I Na , is currently in clinical development for treatment of long QT-3 syndrome (LQT-3), hypertrophic cardiomyopathy (HCM), and ventricular tachycardia-ventricular fibrillation (VT-VF). We will describe structure-activity relationship (SAR) leading to the discovery of 4 that is vastly improved from the first generation late I Na inhibitor 1 (ranolazine). Compound 4 was 42 times more potent than 1 in reducing ischemic burden in vivo (S-T segment elevation, 15 min left anteriorior descending, LAD, occlusion in rabbits) with EC 50 values of 190 and 8000 nM, respectively. Compound 4 represents a new class of potent late I Na inhibitors that will be useful in delineating the role of inhibitors of this current in the treatment of patients.

The effect of sibutramine, a serotonin-norepinephrine reuptake inhibitor, on platelets and fibrin networks of male Sprague-Dawley rats: a descriptive study.

PubMed

van der Schoor, Ciska; Oberholzer, Hester Magdalena; Bester, Megan Jean; van Rooy, Mia-Jeanne

2014-12-01

Sibutramine is used in the treatment of obesity due to its ability to influence feelings of hunger and satiety by inhibiting the re-uptake of serotonin and noradrenalin in the central nervous system (CNS). Sibutramine use has been associated with numerous adverse events in particular cardiovascular complications possibly due to the formation of thrombi. This ultrastructural descriptive study investigated the effect of sibutramine on blood coagulation, specifically the effect on morphology of platelets and fibrin networks using scanning electron microscopy. Male Sprague-Dawley rats treated with either a recommended therapeutic dose [low dosage 1.32 mg/kg] or a toxicological higher dose [high dosage 13.2 mg/kg] of sibutramine for 28 days were used and compared to control animals. Blood samples were collected and plasma smears were prepared for platelet evaluation. Following the addition of thrombin to the plasma samples, the morphology of the fibrin clots was evaluated. Platelet evaluation by scanning electron microscopy revealed morphology typical of a prothrombotic state with a characteristic excessive platelet activation in both low-dose (LD) and high-dose (HD) rats. The fibrin clots of sibutramine-treated rats, LD and HD revealed fused thick fibers with thin fibers forming a net-like structure over the thick fibers which differ considerably from the organized structure of the control animals. It can be concluded that sibutramine alters the ultrastructure of platelets and fibrin networks creating a prothrombotic state.

ROMK inhibitor actions in the nephron probed with diuretics.

PubMed

Kharade, Sujay V; Flores, Daniel; Lindsley, Craig W; Satlin, Lisa M; Denton, Jerod S

2016-04-15

Diuretics acting on specific nephron segments to inhibit Na + reabsorption have been used clinically for decades; however, drug interactions, tolerance, and derangements in serum K + complicate their use to achieve target blood pressure. ROMK is an attractive diuretic target, in part, because its inhibition is postulated to indirectly inhibit the bumetanide-sensitive Na + -K + -2Cl - cotransporter (NKCC2) and the amiloride- and benzamil-sensitive epithelial Na + channel (ENaC). The development of small-molecule ROMK inhibitors has created opportunities for exploring the physiological responses to ROMK inhibition. The present study evaluated how inhibition of ROMK alone or in combination with NKCC2, ENaC, or the hydrochlorothiazide (HCTZ) target NCC alter fluid and electrolyte transport in the nephron. The ROMK inhibitor VU591 failed to induce diuresis when administered orally to rats. However, another ROMK inhibitor, termed compound A, induced a robust natriuretic diuresis without kaliuresis. Compound A produced additive effects on urine output and Na + excretion when combined with HCTZ, amiloride, or benzamil, but not when coadministered with bumetanide, suggesting that the major diuretic target site is the thick ascending limb (TAL). Interestingly, compound A inhibited the kaliuretic response induced by bumetanide and HCTZ, an effect we attribute to inhibition of ROMK-mediated K + secretion in the TAL and CD. Compound A had no effect on heterologously expressed flow-sensitive large-conductance Ca 2+ -activated K + channels (Slo1/β1). In conclusion, compound A represents an important new pharmacological tool for investigating the renal consequences of ROMK inhibition and therapeutic potential of ROMK as a diuretic target. Copyright © 2016 the American Physiological Society.

Maternal Antidepressant Use During Pregnancy and the Risk of Attention-Deficit/Hyperactivity Disorder in Children: A Systematic Review of the Current Literature.

PubMed

Uguz, Faruk

2018-06-01

This study reviewed the current literature examining the potential relationship between use of antidepressants during pregnancy and attention-deficit/hyperactivity disorder (ADHD) in children. PubMed was searched for English language reports between January 1, 1995, and July 31, 2017, by using combinations of the key words pregnancy, antidepressants, selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), children, offspring, and ADHD. Studies that reported association between ADHD in children and use of antidepressant in pregnant women were included in the review. A total of 7 relevant studies that met the review criteria were examined. The studies reported that compared with nonusers adjusted risks of ADHD in children were 1.2 to 1.6 for the use of any antidepressant, 0.91 to 1.66 for selective serotonin reuptake inhibitors, 1.1 to 1.4 for selective serotonin-norepinephrine reuptake inhibitors, and 1.1 to 1.8 for tricyclic antidepressants. There was some scientific evidences suggesting a connection between antidepressant use during all trimesters of pregnancy and increased risk of ADHD in children. In addition, the study results suggest that underlying maternal anxiety or depressive disorders may also contribute to increased risk of ADHD. Although some studies have suggested a moderately increased risk of ADHD in children with maternal antidepressant use during pregnancy, based on limitations and results of the studies, this review concluded that there is no strong evidence to suggest a causal link.

Locking the 150-cavity open: in silico design and verification of influenza neuraminidase inhibitors.

PubMed

Han, Nanyu; Mu, Yuguang

2013-01-01

Neuraminidase (NA) of influenza is a key target for virus infection control and the recently discovered open 150-cavity in group-1 NA provides new opportunity for novel inhibitors design. In this study, we used a combination of theoretical methods including fragment docking, molecular linking and molecular dynamics simulations to design ligands that specifically target at the 150-cavity. Through in silico screening of a fragment compound library on the open 150-cavity of NA, a few best scored fragment compounds were selected to link with Zanamivir, one NA-targeting drug. The resultant new ligands may bind both the active site and the 150-cavity of NA simultaneously. Extensive molecular dynamics simulations in explicit solvent were applied to validate the binding between NA and the designed ligands. Moreover, two control systems, a positive control using Zanamivir and a negative control using a low-affinity ligand 3-(p-tolyl) allyl-Neu5Ac2en (ETT, abbreviation reported in the PDB) found in a recent experimental work, were employed to calibrate the simulation method. During the simulations, ETT was observed to detach from NA, on the contrary, both Zanamivir and our designed ligand bind NA firmly. Our study provides a prospective way to design novel inhibitors for controlling the spread of influenza virus.

Application of response surface methodology method in designing corrosion inhibitor

NASA Astrophysics Data System (ADS)

Asmara, Y. P.; Athirah; Siregar, J. P.; Kurniawan, T.; Bachtiar, D.

2017-10-01

In oil and gas pipelines and offshore structure, inhibitors have been considered to be the first choice to reduce corrosion rate. There are many corrosion inhibitor compositions available in the market. To produce the best corrosion inhibitor requires many experimental data which is not efficient. These experiments used response surface methodology (RSM) to select corrosion inhibitor compositions. The experiments investigated effects of corrosion inhibition on corrosion rate of low carbon steel in 3% NaCl solution with different concentrations of selected main inhibitor compositions which are ethyl acetate (EA), ethylene glycol (EG) and sodium benzoate (SB). Corrosion rate were calculated using linear polarization resistance (LPR). All of the experiments were set in natural conditions at pH 7. MINITAB® version 15 was used for data analysis. It is shown that a quadratic model is a representative model can predict best corrosion inhibitor composition comprehensibly.

Identification, purification and partial characterization of low molecular weight protein inhibitor of Na⁺/K⁺-ATPase from pulmonary artery smooth muscle cells.

PubMed

Rahaman, Sayed Modinur; Dey, Kuntal; Das, Partha; Roy, Soumitra; Chakraborti, Tapati; Chakraborti, Sajal

2014-08-01

We have identified a novel endogenous low mol wt. (15.6 kDa) protein inhibitor of Na(+)/K(+)-ATPase in cytosolic fraction of bovine pulmonary artery smooth muscle cells. The inhibitor showed different affinities toward the α₂β₁ and α₁β₁ isozymes of Na(+)/K(+)-ATPase, where α₂ is more sensitive than α₁. The inhibitor interacted reversibly to the E1 site of the enzyme and blocked the phosphorylated intermediate formation. Circular dichroism study suggests that the inhibitor causes an alteration in the confirmation of the enzyme.

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy.

PubMed

Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

2015-01-01

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naοve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naοve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe.

An open-label, multicenter, randomized, crossover study comparing sildenafil citrate and tadalafil for treating erectile dysfunction in Chinese men naïve to phosphodiesterase 5 inhibitor therapy

PubMed Central

Bai, Wen-Jun; Li, Hong-Jun; Dai, Yu-Tian; He, Xue-You; Huang, Yi-Ran; Liu, Ji-Hong; Sorsaburu, Sebastian; Ji, Chen; Jin, Jian-Jun; Wang, Xiao-Feng

2015-01-01

The study was to compare treatment preference, efficacy, and tolerability of sildenafil citrate (sildenafil) and tadalafil for treating erectile dysfunction (ED) in Chinese men naïve to phosphodiesterase 5 (PDE5) inhibitor therapies. This multicenter, randomized, open-label, crossover study evaluated whether Chinese men with ED preferred 20-mg tadalafil or 100-mg sildenafil. After a 4 weeks baseline assessment, 383 eligible patients were randomized to sequential 20-mg tadalafil per 100-mg sildenafil or vice versa for 8 weeks respectively and then chose which treatment they preferred to take during the 8 weeks extension. Primary efficacy was measured by Question 1 of the PDE5 Inhibitor Treatment Preference Questionnaire (PITPQ). Secondary efficacy was analyzed by PITPQ Question 2, the International Index of Erectile Function (IIEF) erectile function (EF) domain, sexual encounter profile (SEP) Questions 2 and 3, and the Drug Attributes Questionnaire. Three hundred and fifty men (91%) completed the randomized treatment phase. Two hundred and forty-two per 350 (69.1%) patients preferred 20-mg tadalafil, and 108/350 (30.9%) preferred 100-mg sildenafil (P < 0.001) as their treatment in the 8 weeks extension. Ninety-two per 242 (38%) patients strongly preferred tadalafil and 37/108 (34.3%) strongly the preferred sildenafil. The SEP2 (penetration), SEP3 (successful intercourse), and IIEF-EF domain scores were improved in both tadalafil and sildenafil treatment groups. For patients who preferred tadalafil, getting an erection long after taking the medication was the most reported reason for tadalafil preference. The only treatment-emergent adverse event reported by > 2% of men was headache. After tadalafil and sildenafil treatments, more Chinese men with ED naïve to PDE5 inhibitor preferred tadalafil. Both sildenafil and tadalafil treatments were effective and safe. PMID:25370206

LeuT-Desipramine Structure Reveals How Antidepressants Block Neurotransmitter Reuptake

DOE Office of Scientific and Technical Information (OSTI.GOV)

Zhou,Z.; Zhen, J.; Karpowich, N.

2007-01-01

Tricyclic antidepressants exert their pharmacological effect -- inhibiting the reuptake of serotonin, norepinephrine, and dopamine -- by directly blocking neurotransmitter transporters (SERT, NET, and DAT, respectively) in the presynaptic membrane. The drug-binding site and the mechanism of this inhibition are poorly understood. We determined the crystal structure at 2.9 angstroms of the bacterial leucine transporter (LeuT), a homolog of SERT, NET, and DAT, in complex with leucine and the antidepressant desipramine. Desipramine binds at the inner end of the extracellular cavity of the transporter and is held in place by a hairpin loop and by a salt bridge. This bindingmore » site is separated from the leucine-binding site by the extracellular gate of the transporter. By directly locking the gate, desipramine prevents conformational changes and blocks substrate transport. Mutagenesis experiments on human SERT and DAT indicate that both the desipramine-binding site and its inhibition mechanism are probably conserved in the human neurotransmitter transporters.« less

Influence of lorcainide on microsomal Na+, K(+)-ATPase in guinea-pig isolated heart preparations.

PubMed Central

Almotrefi, A. A.; Dzimiri, N.

1991-01-01

1. The effects of lorcainide on the myocardial Mg2(+)-dependent, Na+ and K(+)-activated adenosine triphosphatase (Na+, K(+)-ATPase) were compared in guinea-pig heart preparations with those of ouabain, a specific inhibitor of the enzyme activity. 2. Both ouabain and lorcainide inhibited the microsomal Na+, K(+)-ATPase activity in a concentration-dependent fashion. Their inhibitory effective ranges were 0.05-100 microM and 0.15-125 microM, respectively, and the concentrations for half maximal inhibition (IC50 values) were 2.1 +/- 0.3 and 33.5 +/- 7.3 microM, respectively. 3. In a second series of experiments, the combined effects of the two drugs on the enzyme activity were studied. In these experiments, lorcainide produced a concentration-dependent potentiation of the inhibitory effects of ouabain on Na+, K(+)-ATPase activity. 4. The present study demonstrates that lorcainide is a potent inhibitor of myocardial Na+, K(+)-ATPase. PMID:1849773

A role for serotonin in the antidepressant activity of NG-Nitro-L-arginine, in the rat forced swimming test.

PubMed

Gigliucci, Valentina; Buckley, Kathleen Niamh; Nunan, John; O'Shea, Karen; Harkin, Andrew

2010-02-01

The present study determined regional serotonin (5-HT) synthesis and metabolism changes associated with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine (L-NA) and the influence of 5-HT receptor blockade in the antidepressant-like actions of L-NA in the forced swimming test (FST). Regional effects of L-NA (5,10 and 20mg/kg i.p.) on tryptophan hydroxylase (TPH) activity, the rate limiting enzyme for 5-HT synthesis, were determined by measuring accumulation of the transient intermediate 5-hydoxytryptophan (5-HTP) following in vivo administration of the amino acid decarboxylase inhibitor, NSD 1015 (100mg/kg). L-NA (5-20mg/kg) dose dependently increased 5-HTP accumulation, particularly in the amygdaloid cortex, following exposure to the FST. L-NA also provoked an increase in regional brain 5-HIAA concentrations and in the 5-HIAA:5-HT metabolism ratio. Co-treatment with NSD-1015 failed to consistently modify the antidepressant-like effects of L-NA in the FST. Sub-active doses of L-NA (1mg/kg) and the 5-HT re-uptake inhibitor fluoxetine (2.5mg/kg) acted synergistically to increase swimming in the test. Co-treatment with the non-selective 5-HT receptor antagonist metergoline (1, 2 and 4mg/kg), attenuated the L-NA (20mg/kg)-induced reduction in immobility and increase in swimming behaviours. Metergoline alone however provoked an increase in immobility and reduction in swimming behaviours in the test. A similar response was obtained following co-treatment with the preferential 5-HT(2A) receptor antagonist ketanserin (5mg/kg) and the 5-HT(2C) receptor antagonist RO-430440 (5mg/kg). Co-treatment with the 5-HT(1A) receptor antagonist WAY 100635 (0.3mg/kg) or the 5-HT(1B) receptor antagonist GR 127935 (4mg/kg) failed to influence the antidepressant-like activity of L-NA. Taken together these data provide further support for a role for 5-HT in the antidepressant-like properties of NOS inhibitors. Copyright 2009 Elsevier Inc. All rights reserved.

Predicting DPP-IV inhibitors with machine learning approaches

NASA Astrophysics Data System (ADS)

Cai, Jie; Li, Chanjuan; Liu, Zhihong; Du, Jiewen; Ye, Jiming; Gu, Qiong; Xu, Jun

2017-04-01

Dipeptidyl peptidase IV (DPP-IV) is a promising Type 2 diabetes mellitus (T2DM) drug target. DPP-IV inhibitors prolong the action of glucagon-like peptide-1 (GLP-1) and gastric inhibitory peptide (GIP), improve glucose homeostasis without weight gain, edema, and hypoglycemia. However, the marketed DPP-IV inhibitors have adverse effects such as nasopharyngitis, headache, nausea, hypersensitivity, skin reactions and pancreatitis. Therefore, it is still expected for novel DPP-IV inhibitors with minimal adverse effects. The scaffolds of existing DPP-IV inhibitors are structurally diversified. This makes it difficult to build virtual screening models based upon the known DPP-IV inhibitor libraries using conventional QSAR approaches. In this paper, we report a new strategy to predict DPP-IV inhibitors with machine learning approaches involving naïve Bayesian (NB) and recursive partitioning (RP) methods. We built 247 machine learning models based on 1307 known DPP-IV inhibitors with optimized molecular properties and topological fingerprints as descriptors. The overall predictive accuracies of the optimized models were greater than 80%. An external test set, composed of 65 recently reported compounds, was employed to validate the optimized models. The results demonstrated that both NB and RP models have a good predictive ability based on different combinations of descriptors. Twenty "good" and twenty "bad" structural fragments for DPP-IV inhibitors can also be derived from these models for inspiring the new DPP-IV inhibitor scaffold design.

Effect of fluid flow, pH and tobacco extracts concentration as organic inhibitors to corrosion characteristics of AISI 1045 steel in 3.5% NaCl environment containing CO2 gas

NASA Astrophysics Data System (ADS)

Kurniawan, Budi Agung; Pratiwi, Vania Mitha; Ahmadi, Nafi'ul Fikri

2018-04-01

Corrosion become major problem in most industries. In the oil and gas company, corrosion occurs because of reaction between steel and chemical species inside crude oil. Crude oil or nature gas provide corrosive species, such as CO2, O2, H2S and so on. Fluid containing CO2 gas causes CO2 corrosion which attack steel as well as other corrosion phenomena. This CO2 corrosion commonly called as sweet environment and produce FeCO3 as corrosion products. Fluid flow factor in pipelines during the oil and gas transportation might increase the rate of corrosion itself. Inhibitor commonly use used as corrosion protection because its simplicity in usage. Nowadays, organic inhibitor become main issue in corrosion protection because of biodegradable, low cost, and environmental friendly. This research tried to use tobacco leaf extract as organic inhibitor to control corrosion in CO2 environment. The electrolyte solution used was 3.5% NaCl at pH 4 and pH 7. Weight loss test results showed that the lowest corrosion rate was reach at 132.5 ppm inhibitor, pH 7 and rotational speed of 150 rpm with corrosion rate of 0.091 mm/y. While at pH 4, the lowest corrosion rate was found at rotational speed of 150 rpm with inhibitor concentration of 265 ppm and corrosion rate of 0.327 mm/y. FTIR results indicate the presence of nicotine functional groups on the steel surface. However, based on corrosion rate, it is believed that corrosion occurs, and FeCO3 was soluble in electrolyte. Tobacco leaf extract inhibitors worked by a physisorption mechanism, where tobacco inhibitors formed thin layer on the steel surface.

The effects of compound stimulus extinction and inhibition of noradrenaline reuptake on the renewal of alcohol seeking

PubMed Central

Furlong, T M; Pan, M J; Corbit, L H

2015-01-01

Alcohol-related stimuli can trigger relapse of alcohol-seeking behaviors even after extended periods of abstinence. Extinction of such stimuli can reduce their impact on relapse; however, the expression of extinction can be disrupted when testing occurs outside the context where extinction learning took place, an effect termed renewal. Behavioral and pharmacological methods have recently been shown to augment extinction learning; yet, it is not known whether the improved expression of extinction following these treatments remains context-dependent. Here we examined whether two methods, compound–stimulus extinction and treatment with the noradrenaline reuptake inhibitor atomoxetine, would reduce the vulnerability of extinction to a change in context. Following alcohol self-administration, responding was extinguished in a distinct context. After initial extinction, further extinction was given to a target stimulus presented in compound with another alcohol-predictive stimulus intended to augment prediction error (Experiment 1) or after a systemic injection of atomoxetine (1.0 mg kg−1; Experiment 2). A stimulus extinguished as part of a compound elicited less responding than a stimulus receiving equal extinction alone regardless of whether animals were tested in the training or extinction context; however, reliable renewal was not observed in this paradigm. Importantly, atomoxetine enhanced extinction relative to controls even in the presence of a reliable renewal effect. Thus, extinction of alcohol-seeking behavior can be improved by extinguishing multiple alcohol-predictive stimuli or enhancing noradrenaline neurotransmission during extinction training. Importantly, both methods improve extinction even when the context is changed between extinction training and test, and thus could be utilized to enhance the outcome of extinction-based treatments for alcohol-use disorders. PMID:26327688

The analgesic agent tapentadol inhibits calcitonin gene-related peptide release from isolated rat brainstem via a serotonergic mechanism.

PubMed

Greco, Maria Cristina; Navarra, Pierluigi; Tringali, Giuseppe

2016-01-15

In this study we tested the hypothesis that tapentadol inhibits GGRP release from the rat brainstem through a mechanism mediated by the inhibition of NA reuptake; as a second alternative hypothesis, we investigated whether tapentadol inhibits GGRP release via the inhibition of 5-HT reuptake. Rat brainstems were explanted and incubated in short-term experiments. CGRP released in the incubation medium was taken as a marker of CGRP release from the central terminals of trigeminal neurons within the brainstem. CGRP levels were measured by radioimmunoassay under basal conditions or in the presence of tapentadol; NA, 5-HT, clonidine, yohimbine and ondansetron were used as pharmacological tools to investigate the action mechanism of tapentadol. The α2-antagonist yohimbine failed to counteract the effects of tapentadol. Moreover, neither NA nor the α2-agonist clonidine per se inhibited K(+)-stimulated CGRP release, thereby indicating that the effects of tapentadol are nor mediated through the block of NA reuptake. Further experiments showed that 5-HT and tramadol, which inhibits both NA and 5-HT reuptake, significantly reduced K(+)-stimulated CGRP release. Moreover, the 5-HT3 antagonist ondansetron was able to counteract the effects of tapentadol in this system. This study provided pharmacological evidence that tapentadol inhibits stimulated CGRP release from the rat brainstem in vitro through a mechanism involving an increase in 5-HT levels in the system and the subsequent activation of 5-HT3 receptors. Copyright © 2015 Elsevier Inc. All rights reserved.

Psychopharmacological strategies in the management of posttraumatic stress disorder (PTSD): what have we learned?

PubMed

Bernardy, Nancy C; Friedman, Matthew J

2015-04-01

There have been significant advancements in the pharmacologic management of posttraumatic stress disorder (PTSD) in the past two decades. Multisite randomized clinical trials (RCTs) have noted the efficacy of selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNR Is) for PTSD treatment. Unfortunately, there have been no new medications approved to treat PTSD in the past 10 years. Although there have been exciting new findings in our knowledge of the neurobiology of PTSD, clinical trials testing new medications have lagged. This review summarizes recent research that builds on the unique pathophysiology of PTSD and suggests ways to move the field forward.

Design, synthesis, and structure-activity relationships of 3,4-dihydropyridopyrimidin-2(1H)-one derivatives as a novel class of sodium/calcium exchanger inhibitor.

PubMed

Hasegawa, Hirohiko; Muraoka, Masami; Ohmori, Mikiko; Matsui, Kazuki; Kojima, Atsuyuki

2005-10-01

Design, synthesis, and structure-activity relationships for 3,4-dihydropyridopyrimidin-2(1H)-one derivatives, which are aza-3,4-dihydro-2(1H)-quinazolinone derivatives, as the sodium/calcium (Na+/Ca2+) exchanger inhibitors are discussed. These studies based on 3,4-dihydro-2(1H)-quinazolinone derivatives led to the discovery of a structurally novel and potent Na+/Ca2+ exchanger inhibitor, 3,4-dihydropyridopyrimidin-2(1H)-one derivative (26), with an IC30 value of 0.02 microM. Compound 26 directly inhibited the Na+-dependent Ca2+ influx via the Na+/Ca2+ exchanger after Na+-free treatment in cardiomyocytes.

The Role of Na+/K+-ATPase during Chick Skeletal Myogenesis

PubMed Central

Oliveira, Taissa Neustadt; Possidonio, Ana Claudia; Soares, Carolina Pontes; Ayres, Rodrigo; Costa, Manoel Luis; Quintas, Luis Eduardo Menezes; Mermelstein, Cláudia

2015-01-01

The formation of a vertebrate skeletal muscle fiber involves a series of sequential and interdependent events that occurs during embryogenesis. One of these events is myoblast fusion which has been widely studied, yet not completely understood. It was previously shown that during myoblast fusion there is an increase in the expression of Na+/K+-ATPase. This fact prompted us to search for a role of the enzyme during chick in vitro skeletal myogenesis. Chick myogenic cells were treated with the Na+/K+-ATPase inhibitor ouabain in four different concentrations (0.01-10 μM) and analyzed. Our results show that 0.01, 0.1 and 1 μM ouabain did not induce changes in cell viability, whereas 10 μM induced a 45% decrease. We also observed a reduction in the number and thickness of multinucleated myotubes and a decrease in the number of myoblasts after 10 μM ouabain treatment. We tested the involvement of MEK-ERK and p38 signaling pathways in the ouabain-induced effects during myogenesis, since both pathways have been associated with Na+/K+-ATPase. The MEK-ERK inhibitor U0126 alone did not alter cell viability and did not change ouabain effect. The p38 inhibitor SB202190 alone or together with 10 μM ouabain did not alter cell viability. Our results show that the 10 μM ouabain effects in myofiber formation do not involve the MEK-ERK or the p38 signaling pathways, and therefore are probably related to the pump activity function of the Na+/K+-ATPase. PMID:25775465

The role of Na+/K+-ATPase during chick skeletal myogenesis.

PubMed

Oliveira, Taissa Neustadt; Possidonio, Ana Claudia; Soares, Carolina Pontes; Ayres, Rodrigo; Costa, Manoel Luis; Quintas, Luis Eduardo Menezes; Mermelstein, Cláudia

2015-01-01

The formation of a vertebrate skeletal muscle fiber involves a series of sequential and interdependent events that occurs during embryogenesis. One of these events is myoblast fusion which has been widely studied, yet not completely understood. It was previously shown that during myoblast fusion there is an increase in the expression of Na+/K+-ATPase. This fact prompted us to search for a role of the enzyme during chick in vitro skeletal myogenesis. Chick myogenic cells were treated with the Na+/K+-ATPase inhibitor ouabain in four different concentrations (0.01-10 μM) and analyzed. Our results show that 0.01, 0.1 and 1 μM ouabain did not induce changes in cell viability, whereas 10 μM induced a 45% decrease. We also observed a reduction in the number and thickness of multinucleated myotubes and a decrease in the number of myoblasts after 10 μM ouabain treatment. We tested the involvement of MEK-ERK and p38 signaling pathways in the ouabain-induced effects during myogenesis, since both pathways have been associated with Na+/K+-ATPase. The MEK-ERK inhibitor U0126 alone did not alter cell viability and did not change ouabain effect. The p38 inhibitor SB202190 alone or together with 10 μM ouabain did not alter cell viability. Our results show that the 10 μM ouabain effects in myofiber formation do not involve the MEK-ERK or the p38 signaling pathways, and therefore are probably related to the pump activity function of the Na+/K+-ATPase.

Improved preclinical cardiovascular therapeutic indices with long-term inhibition of norepinephrine reuptake using reboxetine

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fossa, Anthony A., E-mail: anthony.fossa@icardiac.com; Wisialowski, Todd A.; Cremers, Thomas

2012-11-01

Norepinephrine reuptake inhibitors (NRIs) acutely increase norepinephrine (NE) levels, but therapeutic antidepressant activity is only observed after weeks of treatment because central NE levels progressively increase during continued drug exposure. Similarly, while NRIs acutely increase blood pressure (BP) and heart rate (HR) due to enhanced sympathetic neurotransmission, chronic treatment changes the responsiveness of the central noradrenergic system and suppresses these effects via autonomic regulation. To better understand the relationship between NE increases and cardiovascular safety, we investigated acute and chronic effects of the NRI reboxetine on central NE release and on BP and HR and electrical alternans, a measure ofmore » arrhythmia liability, in guinea pigs. NE release was assessed by microdialysis in medial prefrontal cortex (mPFC) and hypothalamic paraventricular nucleus (PVN); BP and HR were measured by telemetry. Animals were treated for 28 days with 15 mg/kg/day of reboxetine or vehicle via an osmotic minipump and then challenged with acute intravenous doses of reboxetine. Animals chronically treated with reboxetine had 2-fold higher extracellular basal NE levels in mPFC and PVN compared to basal levels after chronic vehicle treatment. BP was significantly increased after the first day of treatment, and gradually returned to vehicle levels by day 21. These data indicate that chronic NRI treatment may lead to an increase in central NE levels and a concomitant reduction in BP based on exposure–response curves compared to vehicle treatment, suggesting a larger separation between preclinical estimates of efficacy vs. safety compared to acute NRI treatment. -- Highlights: ► Acute RBX produces blood pressure increases acutely that decrease with chronic RBX ► Chronic RBX increases brain NE levels, a preclinical surrogate of improved efficacy ► Short-term screening of NRI often underestimates the chronic therapeutic index ► Chronic

Selective serotonin reuptake inhibition modulates response inhibition in Parkinson’s disease

PubMed Central

Ye, Zheng; Altena, Ellemarije; Nombela, Cristina; Housden, Charlotte R.; Maxwell, Helen; Rittman, Timothy; Huddleston, Chelan; Rae, Charlotte L.; Regenthal, Ralf; Sahakian, Barbara J.; Barker, Roger A.; Robbins, Trevor W.

2014-01-01

Impulsivity is common in Parkinson’s disease even in the absence of impulse control disorders. It is likely to be multifactorial, including a dopaminergic ‘overdose’ and structural changes in the frontostriatal circuits for motor control. In addition, we proposed that changes in serotonergic projections to the forebrain also contribute to response inhibition in Parkinson’s disease, based on preclinical animal and human studies. We therefore examined whether the selective serotonin reuptake inhibitor citalopram improves response inhibition, in terms of both behaviour and the efficiency of underlying neural mechanisms. This multimodal magnetic resonance imaging study used a double-blind randomized placebo-controlled crossover design with an integrated Stop-Signal and NoGo paradigm. Twenty-one patients with idiopathic Parkinson’s disease (46–76 years old, 11 male, Hoehn and Yahr stage 1.5–3) received 30 mg citalopram or placebo in addition to their usual dopaminergic medication in two separate sessions. Twenty matched healthy control subjects (54–74 years old, 12 male) were tested without medication. The effects of disease and drug on behavioural performance and regional brain activity were analysed using general linear models. In addition, anatomical connectivity was examined using diffusion tensor imaging and tract-based spatial statistics. We confirmed that Parkinson’s disease caused impairment in response inhibition, with longer Stop-Signal Reaction Time and more NoGo errors under placebo compared with controls, without affecting Go reaction times. This was associated with less stop-specific activation in the right inferior frontal cortex, but no significant difference in NoGo-related activation. Although there was no beneficial main effect of citalopram, it reduced Stop-Signal Reaction Time and NoGo errors, and enhanced inferior frontal activation, in patients with relatively more severe disease (higher Unified Parkinson’s Disease Rating Scale

Identification of Chemical Inhibitors of β-Catenin-Driven Liver Tumorigenesis in Zebrafish

PubMed Central

Evason, Kimberley J.; Francisco, Macrina T.; Juric, Vladislava; Balakrishnan, Sanjeev; Lopez Pazmino, Maria del Pilar; Gordan, John D.; Kakar, Sanjay; Spitsbergen, Jan; Goga, Andrei; Stainier, Didier Y. R.

2015-01-01

Hepatocellular carcinoma (HCC) is one of the most lethal human cancers. The search for targeted treatments has been hampered by the lack of relevant animal models for the genetically diverse subsets of HCC, including the 20-40% of HCCs that are defined by activating mutations in the gene encoding β-catenin. To address this chemotherapeutic challenge, we created and characterized transgenic zebrafish expressing hepatocyte-specific activated β-catenin. By 2 months post fertilization (mpf), 33% of transgenic zebrafish developed HCC in their livers, and 78% and 80% of transgenic zebrafish showed HCC at 6 and 12 mpf, respectively. As expected for a malignant process, transgenic zebrafish showed significantly decreased mean adult survival compared to non-transgenic control siblings. Using this novel transgenic model, we screened for druggable pathways that mediate β-catenin-induced liver growth and identified two c-Jun N-terminal kinase (JNK) inhibitors and two antidepressants (one tricyclic antidepressant, amitriptyline, and one selective serotonin reuptake inhibitor) that suppressed this phenotype. We further found that activated β-catenin was associated with JNK pathway hyperactivation in zebrafish and in human HCC. In zebrafish larvae, JNK inhibition decreased liver size specifically in the presence of activated β-catenin. The β-catenin-specific growth-inhibitory effect of targeting JNK was conserved in human liver cancer cells. Our other class of hits, antidepressants, has been used in patient treatment for decades, raising the exciting possibility that these drugs could potentially be repurposed for cancer treatment. In support of this proposal, we found that amitriptyline decreased tumor burden in a mouse HCC model. Our studies implicate JNK inhibitors and antidepressants as potential therapeutics for β-catenin-induced liver tumors. PMID:26134322

Increased brain serotonin turnover in panic disorder patients in the absence of a panic attack: reduction by a selective serotonin reuptake inhibitor.

PubMed

Esler, Murray; Lambert, Elisabeth; Alvarenga, Marlies; Socratous, Florentia; Richards, Jeff; Barton, David; Pier, Ciaran; Brenchley, Celia; Dawood, Tye; Hastings, Jacqueline; Guo, Ling; Haikerwal, Deepak; Kaye, David; Jennings, Garry; Kalff, Victor; Kelly, Michael; Wiesner, Glen; Lambert, Gavin

2007-08-01

serotonin turnover most likely derived not from impaired serotonin reuptake, but from increased firing in serotonergic midbrain raphe neurons projecting to both subcortical brain regions and the cerebral cortex.

Reduced levels of skeletal muscle Na+K+ -ATPase in McArdle disease

NASA Technical Reports Server (NTRS)

Haller, R. G.; Clausen, T.; Vissing, J.; Blomqvist, C. G. (Principal Investigator)

1998-01-01

We evaluated the hypothesis that impaired sarcolemmal function associated with exaggerated potassium release, impaired potassium uptake, or both may contribute to exertional fatigue and abnormal circulatory responses to exercise in McArdle disease (MD). The cellular mechanism of exertional fatigue and muscle injury in MD is unknown but likely involves impaired function of the ATPases that couple ATP hydrolysis to cellular work, including the muscle sodium potassium pump (Na+K+-ATPase). However, the concentration of muscle Na+K+ pumps in MD is not known, and no studies have related exercise increases in blood potassium concentrations to muscle Na+K+ pump levels. We measured muscle Na+K+ pumps (3H-ouabain binding) and plasma K+ in response to 20 minutes of cycle exercise in six patients with MD and in six sex-, age-, and weight-matched sedentary individuals. MD patients had lower levels of 3H-ouabain binding (231 +/- 18 pmol/g w.w., mean +/- SD, range, 210 to 251) than control subjects (317 +/- 37, range, 266 to 371, p < 0.0004), higher peak increases in plasma potassium in response to 45 +/- 7 W cycle exercise (MD, 1.00 +/- 0.15 mmol/L; control subjects, 0.48 +/- 0.09; p < 0.0001), and mean exercise heart rate responses to exercise that were 45 +/- 12 bpm greater than control subjects. Our results indicate that Na+K+ pump levels are low in MD patients compared with healthy subjects and identify a limitation of potassium reuptake that could result in sarcolemmal failure during peak rates of membrane activation and may promote exaggerated potassium-activated circulatory responses to submaximal exercise. The mechanism of the low Na+K+ pump concentrations in MD is unknown but may relate to deconditioning or to disruption of a close functional relationship between membrane ion transport and glycolysis.

A randomised controlled trial of cognitive behaviour therapy in adolescents with major depression treated by selective serotonin reuptake inhibitors. The ADAPT trial.

PubMed

Goodyer, I M; Dubicka, B; Wilkinson, P; Kelvin, R; Roberts, C; Byford, S; Breen, S; Ford, C; Barrett, B; Leech, A; Rothwell, J; White, L; Harrington, R

2008-05-01

To determine if, in the short term, depressed adolescents attending routine NHS Child and Adolescent Mental Health Services (CAMHS), and receiving ongoing active clinical care, treatment with selective serotonin reuptake inhibitors (SSRIs) plus cognitive behaviour therapy (CBT) compared with SSRI alone, results in better healthcare outcomes. A pragmatic randomised controlled trial (RCT) was conducted on depressed adolescents attending CAMHS who had not responded to a psychosocial brief initial intervention (BII) prior to randomisation. Six English CAMHS participated in the study. A total of 208 patients aged between 11 and 17 years were recruited and randomised. All participants received active routine clinical care in a CAMHS outpatient setting and an SSRI and half were offered CBT. The duration of the trial was a 12-week treatment phase, followed by a 16-week maintenance phase. Follow-up assessments were at 6, 12 and 28 weeks. The primary outcome measure was the Health of the Nation Outcome Scales for Children and Adolescents (HoNOSCA). Secondary outcome measures were self-report depressive symptoms, interviewer-rated depressive signs and symptoms, interviewer-rated psychosocial impairment and clinical global impression of response to treatment. Information on resource use was collected in interview at baseline and at the 12- and 28-week follow-up assessments using the Child and Adolescent Service Use Schedule (CA-SUS). Of the 208 patients randomised, 200 (96%) completed the trial to the primary end-point at 12 weeks. By the 28-week follow-up, 174 (84%) participants were re-evaluated. Overall, 193 (93%) participants had been assessed at one or more time points. Clinical characteristics indicated that the trial was conducted on a severely depressed group. There was significant recovery at all time points in both arms. The findings demonstrated no difference in treatment effectiveness for SSRI + CBT over SSRI only for the primary or secondary outcome measures at

Phytoextraction of Cadmium and Zinc By Sedum plumbizincicola Using Different Nitrogen Fertilizers, a Nitrification Inhibitor and a Urease Inhibitor.

PubMed

Arnamwong, Suteera; Wu, Longhua; Hu, Pengjie; Yuan, Cheng; Thiravetyan, Paitip; Luo, Yongming; Christie, Peter

2015-01-01

Cadmium (Cd) and zinc (Zn) phytoavailability and their phytoextraction by Sedum plumbizincicola using different nitrogen fertilizers, nitrification inhibitor (dicyandiamide, DCD) and urease inhibitor (N-(n-Butyl) thiophosphoric triamide, NBPT) were investigated in pot experiments where the soil was contaminated with 0.99 mg kg(-1) of Cd and 241 mg kg(-1) Zn. The soil solution pH varied between 7.30 and 8.25 during plant growth which was little affected by the type of N fertilizer. The (NH4)2SO4+DCD treatment produced higher NH4+-N concentrations in soil solution than the (NH4)2SO4 and NaNO3 treatment which indicated that DCD addition inhibited the nitrification process. Shoot Cd and Zn concentrations across all treatments showed ranges of 52.9-88.3 and 2691-4276 mg kg(-1), respectively. The (NH4)2SO4+DCD treatment produced slightly higher but not significant Cd and Zn concentrations in the xylem sap than the NaNO3 treatment. Plant shoots grown with NaNO3 had higher Cd concentrations than (NH4)2SO4+DCD treatment at 24.0 and 15.4 mg kg(-1), respectively. N fertilizer application had no significant effect on shoot dry biomass. Total Cd uptake in the urea+DCD treatment was higher than in the control, urea+NBPT, urea+NBPT+DCD, or urea treatments, by about 17.5, 23.3, 10.7, and 25.1%, respectively.

Antidepressant Use Is Associated With an Increased Risk of Developing Microbleeds.

PubMed

Akoudad, Saloua; Aarts, Nikkie; Noordam, Raymond; Ikram, M Arfan; Tiemeier, Henning; Hofman, Albert; Stricker, Bruno H; Vernooij, Meike W; Visser, Loes E

2016-01-01

Serotonin-specific antidepressants may increase the risk of adverse bleeding events. In a previous cross-sectional study, we did not observe an association between antidepressant use and presence of subclinical cerebral bleedings. In this study, we investigated longitudinally whether antidepressant use is associated with an increased risk of new subclinical cerebral microbleeds. In total, 2559 participants aged ≥45 years of the population-based Rotterdam Study, all without microbleeds at baseline, underwent baseline and repeat brain magnetic resonance imaging between 2005 and 2013 (mean time interval, 3.9 years; SD, 0.5) to determine the incidence of microbleeds. Antidepressant use (yes versus no) was assessed between baseline and follow-up scan. In additional analyses, antidepressants were classified as low, intermediate, or high affinity for the serotonin transporter, and alternatively as selective serotonin reuptake inhibitors or non-selective serotonin reuptake inhibitors. We used multivariable logistic regression models to investigate the association of antidepressants with incident microbleeds. Antidepressant use was associated with a higher cerebral microbleed incidence (odds ratio, 2.22; 95% confidence interval, 1.31-3.76) than nonuse. When stratified by affinity for the serotonin transporter, intermediate serotonin affinity antidepressant use was associated with an increased risk of developing microbleeds (odds ratio, 3.07; 95% confidence interval, 1.53-6.17). Finally, selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor use were both associated with increased microbleed incidence. Antidepressant use was associated with an increased risk of developing microbleeds. Our results may support findings from previous clinical studies about increased intracranial and extracranial bleeding risk in antidepressant users. © 2015 American Heart Association, Inc.

Antidepressants and Youth: Healing or Harmful?

PubMed Central

Markowitz, Sara; Cuellar, Alison

2007-01-01

A series of drug innovations that began in 1987, including the introduction of several Selective Serotonin Reuptake Inhibitors (SSRIs) has led to a tremendous growth in the use of antidepressants in the United States. This growth, however, has been accompanied by a growing concern about the risks of prescribing antidepressants, particularly to children. Indeed, research linking the use of antidepressant drugs to an increased risk of suicidal behaviors in youth motivated the U.S. Food and Drug Administration to direct antidepressant drug manufacturers to include warning labels about the potential dangers. This paper examines the relationship between antidepressants and suicide among youth in the USA. Using state-level data on youth suicides and age-specific prescriptions for antidepressants, we find no relationships between suicides for adolescents ages 15 to 19 and prescriptions for Selective Serotonin Reuptake Inhibitors/Serotonin-Norepinephrine Reuptake Inhibitors or tricyclic and tetracyclic antidepressants. In contrast, we find that newer generation antidepressants are associated with lower numbers of suicides for this age group. For younger children, ages 10 to 14 we find no relationship with suicides for any type of antidepressant. PMID:17374550

SSRI antidepressants potentiate methylphenidate (Ritalin)-induced gene regulation in the adolescent striatum

PubMed Central

Van Waes, Vincent; Beverley, Joel; Marinelli, Michela; Steiner, Heinz

2010-01-01

The psychostimulant methylphenidate (Ritalin) is used in conjunction with selective serotonin reuptake inhibitors (SSRIs) in the treatment of medical conditions such as attention-deficit hyperactivity disorder with anxiety/depression comorbidity and major depression. Co-exposure also occurs in patients on SSRIs that use psychostimulant “cognitive enhancers”. Methylphenidate is a dopamine/norepinephrine reuptake inhibitor that produces altered gene expression in the forebrain; these effects partly mimic gene regulation by cocaine (dopamine/norepinephrine/serotonin reuptake inhibitor). We investigated whether the addition of SSRIs (fluoxetine or citalopram; 5 mg/kg) modified gene regulation by methylphenidate (2–5 mg/kg) in the striatum and cortex of adolescent rats. Our results show that SSRIs potentiate methylphenidate-induced expression of the transcription factors zif 268 and c-fos in the striatum, rendering these molecular changes more cocaine-like. Present throughout most of the striatum, this potentiation was most robust in its sensorimotor parts. The methylphenidate + SSRI combination also enhanced behavioral stereotypies, consistent with dysfunction in sensorimotor striatal circuits. In so far as such gene regulation is implicated in psychostimulant addiction, our findings suggest that SSRIs may enhance the addiction liability of methylphenidate. PMID:20704593

Cytochemical localization of Na+, K+-ATPase in the rat hepatocyte.

PubMed Central

Blitzer, B L; Boyer, J L

1978-01-01

The enzyme Na+,5+-ATPase was cytochemically localized in the rat hepatocyte by a modification of the Ernst potassium-dependent nitrophenyl phosphatase technique. Measurement of nitrophenol release from 50-micrometer liver slices confirmed the presence of ouabain-inhibitable nitrophenyl phosphatase activity that increased over the 30-min incubation period. Electron micrographs demonstrated that sinusoidal and lateral membrane reaction product deposition was K+-dependent, Mg++-dependent, inhibited by ouabain but not by alkaline phosphatase inhibitors, and was localized to the cytoplasmic side of the membrane. In contrast, canalicular reaction product was K+-independent, Mg++-dependent, inhibited by alkaline phosphatase inhibitors but not by ouabain, and was localized to the luminal side of the membrane. These findings indicate that Na+,K+-ATPase is localized to the sinusoidal and lateral portions of the rat hepatocyte plasma membrane and is not detectable on the bile canaliculus where alkaline phosphatase is confined. This basolateral localization of Na+,K+-ATPase is similar to that found in epithelia where secretion is also directed across the apical membrane. Images PMID:213446

[Mirtazapine versus other antidepressive agents for depression].

PubMed

Knud Larsen, Jens

2012-11-12

A Cochrane analysis compared efficacy and side effects of mirtazapine with other antidepressants. After six weeks of treatment no reliable difference of efficacy between mirtazapine, selective serotonin reuptake inhibitors (SSRI), noradrenaline reuptake inhibitors or tricyclic antidepressants was found. The side effects like increased sleep and weight gain were compared by treatment with mirtazapine and treatment with SSRI antidepressants. The very fact of the sleep effect and the fast onset of action have probably increased the effect size compared with SSRI antidepressants. The results of the Cochrane analysis cannot for certain be generalized to inpatients, as other studies have found tricyclic antidepressants to be especially effective.

Postictal ventricular tachycardia after electroconvulsive therapy treatment associated with a lithium-duloxetine combination.

PubMed

Heinz, Boeker; Lorenzo, Perniola; Markus, Risch; Holger, Himmighoffen; Beatrix, Roemer; Erich, Seifritz; Alain, Borgeat

2013-09-01

This report addresses the dilemma of continuing lithium prophylaxis and antidepressant therapy in view of cardiovascular adverse effects under electroconvulsive therapy (ECT) in patients with a long history of recurrent affective disorders. A severely depressed 48-year-old woman who had been treated with lithium for 18 years developed a ventricular tachycardia during ECT. Possible interaction with succinylcholine was taken into account, and rocuronium was used as an alternative muscle relaxant. Electroconvulsive therapy was continued without adverse effects after reduction of lithium and withdrawal from duloxetine. Systemic studies on cardiac adverse effects of serotonin and norepinephrine reuptake inhibitors and serotonin and norepinephrine reuptake inhibitor-lithium combinations during ECT are needed.

Chemical probes to potently and selectively inhibit endocannabinoid cellular reuptake.

PubMed

Chicca, Andrea; Nicolussi, Simon; Bartholomäus, Ruben; Blunder, Martina; Aparisi Rey, Alejandro; Petrucci, Vanessa; Reynoso-Moreno, Ines Del Carmen; Viveros-Paredes, Juan Manuel; Dalghi Gens, Marianela; Lutz, Beat; Schiöth, Helgi B; Soeberdt, Michael; Abels, Christoph; Charles, Roch-Philippe; Altmann, Karl-Heinz; Gertsch, Jürg

2017-06-20

The extracellular effects of the endocannabinoids anandamide and 2-arachidonoyl glycerol are terminated by enzymatic hydrolysis after crossing cellular membranes by facilitated diffusion. The lack of potent and selective inhibitors for endocannabinoid transport has prevented the molecular characterization of this process, thus hindering its biochemical investigation and pharmacological exploitation. Here, we report the design, chemical synthesis, and biological profiling of natural product-derived N -substituted 2,4-dodecadienamides as a selective endocannabinoid uptake inhibitor. The highly potent (IC 50 = 10 nM) inhibitor N -(3,4-dimethoxyphenyl)ethyl amide (WOBE437) exerted pronounced cannabinoid receptor-dependent anxiolytic, antiinflammatory, and analgesic effects in mice by increasing endocannabinoid levels. A tailored WOBE437-derived diazirine-containing photoaffinity probe (RX-055) irreversibly blocked membrane transport of both endocannabinoids, providing mechanistic insights into this complex process. Moreover, RX-055 exerted site-specific anxiolytic effects on in situ photoactivation in the brain. This study describes suitable inhibitors to target endocannabinoid membrane trafficking and uncovers an alternative endocannabinoid pharmacology.

Modeling the Binding of Neurotransmitter Transporter Inhibitors with Molecular Dynamics and Free Energy Calculations

NASA Astrophysics Data System (ADS)

Jean, Bernandie

The monoamine transporter (MAT) proteins responsible for the reuptake of the neurotransmitter substrates, dopamine, serotonin, and norepinephrine, are drug targets for the treatment of psychiatric disorders including depression, anxiety, and attention deficit hyperactivity disorder. Small molecules that inhibit these proteins can serve as useful therapeutic agents. However, some dopamine transporter (DAT) inhibitors, such as cocaine and methamphetamine, are highly addictive and abusable. Efforts have been made to develop small molecules that will inhibit the transporters and elucidate specific binding site interactions. This work provides knowledge of molecular interactions associated with MAT inhibitors by offering an atomistic perspective that can guide designs of new pharmacotherapeutics with enhanced activity. The work described herein evaluates intermolecular interactions using computational methods to reveal the mechanistic detail of inhibitors binding in the DAT. Because cocaine recognizes the extracellular-facing or outward-facing (OF) DAT conformation and benztropine recognizes the intracellular-facing or inward-facing (IF) conformation, it was postulated that behaviorally "typical" (abusable, locomotor psychostimulant) inhibitors stabilize the OF DAT and "atypical" (little or no abuse potential) inhibitors favor IF DAT. Indeed, behaviorally-atypical cocaine analogs have now been shown to prefer the OF DAT conformation. Specifically, the binding interactions of two cocaine analogs, LX10 and LX11, were studied in the OF DAT using molecular dynamics simulations. LX11 was able to interact with residues of transmembrane helix 8 and bind in a fashion that allowed for hydration of the primary binding site (S1) from the intracellular space, thus impacting the intracellular interaction network capable of regulating conformational transitions in DAT. Additionally, a novel serotonin transporter (SERT) inhibitor previously discovered through virtual screening at the

Histone deacetylases inhibitors effects on Cryptococcus neoformans major virulence phenotypes

PubMed Central

Brandão, Fabiana AS; Derengowski, Lorena S; Albuquerque, Patrícia; Nicola, André M; Silva-Pereira, Ildinete; Poças-Fonseca, Marcio J

2015-01-01

Cryptococcus neoformans undergoes phenotypical changes during host infection in order to promote persistence and survival. Studies have demonstrated that such adaptations require alterations in gene transcription networks by distinct mechanisms. Drugs such as the histone deacetylases inhibitors (HDACi) Sodium Butyrate (NaBut) and Trichostatin A (TSA) can alter the chromatin conformation and have been used to modulate epigenetic states in the treatment of diseases such as cancer. In this work, we have studied the effect of NaBut and TSA on the expression of C. neoformans major virulence phenotypes and on the survival rate of an animal model infected with drugs-treated yeasts. Both drugs affected fungal growth at 37°C more intensely than at 30°C; nonetheless, drugs did not affect cell viability at the concentrations we studied. HDACi also provoked the reduction of the fungal capsule expansion. Phospholipases enzyme activity decreased; mating process and melanin synthesis were also affected by both inhibitors. NaBut led to an increase in the population of cells in G2/M. Treated yeast cells, which were washed in order to remove the drugs from the culture medium prior to the inoculation in the Galleria mellonela infection model, did not cause significant difference at the host survival curve when compared to non-treated cells. Overall, NaBut effects on the impairment of C. neoformans main virulence factors were more intense and stable than the TSA effects. PMID:26103530

Involvement of the strychnine-sensitive glycine receptor in the anxiolytic effects of GlyT1 inhibitors on maternal separation-induced ultrasonic vocalization in rat pups.

PubMed

Komatsu, Hiroko; Furuya, Yoshiaki; Sawada, Kohei; Asada, Takashi

2015-01-05

Several studies have shown that glycine transporter 1 (GlyT1) inhibitors have anxiolytic actions. There are two types of glycine receptor: the strychnine-sensitive glycine receptor (GlyA) and the strychnine-insensitive glycine receptor (GlyB); however, which receptor is the main contributor to the anxiolytic actions of GlyT1 inhibitors is yet to be determined. Here, we clarified which glycine receptor is the main contributor to the anxiolytic effects of GlyT1 inhibitors by using maternal separation-induced ultrasonic vocalization (USV) by rat pups as an index of anxiety. We confirmed that administration of the benzodiazepine diazepam or the selective serotonin reuptake inhibitor escitaloplam, which are both clinically proven anxiolytics, or the GlyT1 inhibitor SSR504734 (2-chloro-N-[(S)-phenyl[(2S)-piperidin-2-yl] methyl]-3-trifluoromethyl benzamide), decreases USV in rat pups. In addition, we showed that another GlyT1 inhibitor, ALX5407 ((R)-N-[3-(4'-fluorophenyl)-3(4'-phenylphenoxy)propyl]sarcosine) also decreases USV in rat pups. SSR504734- or ALX5407-induced decreases in USV were dose-dependently reversed by administration of the GlyA antagonist strychnine, whereas the diazepam- or escitalopram-induced decreases in USV were not. Furthermore, GlyT1-induced decreases in USV were not reversed by administration of the GlyB antagonist L-687,414. Together, these results suggest that GlyA activation is the main contributor to the anxiolytic actions of GlyT1 inhibitors and that the anxiolytic actions of diazepam and escitalopram cannot be attributed to GlyA activation. Our findings provide new insights into the importance of the activation of GlyA in the anxiolytic effects of GlyT1 inhibitors. Copyright © 2014 Elsevier B.V. All rights reserved.

Electrogenic Na+/Ca2+ Exchange

PubMed Central

Danaceau, Jonathan P.; Lucero, Mary T.

2000-01-01

Olfactory receptor neurons (ORNs) from the squid, Lolliguncula brevis, respond to the odors l-glutamate or dopamine with increases in internal Ca2+ concentrations ([Ca2+]i). To directly asses the effects of increasing [Ca2+]i in perforated-patched squid ORNs, we applied 10 mM caffeine to release Ca2+ from internal stores. We observed an inward current response to caffeine. Monovalent cation replacement of Na+ from the external bath solution completely and selectively inhibited the caffeine-induced response, and ruled out the possibility of a Ca2+-dependent nonselective cation current. The strict dependence on internal Ca2+ and external Na+ indicated that the inward current was due to an electrogenic Na+/Ca2+ exchanger. Block of the caffeine-induced current by an inhibitor of Na+/Ca2+ exchange (50–100 μM 2′,4′-dichlorobenzamil) and reversibility of the exchanger current, further confirmed its presence. We tested whether Na+/Ca2+ exchange contributed to odor responses by applying the aquatic odor l-glutamate in the presence and absence of 2′,4′-dichlorobenzamil. We found that electrogenic Na+/Ca2+ exchange was responsible for ∼26% of the total current associated with glutamate-induced odor responses. Although Na+/Ca2+ exchangers are known to be present in ORNs from numerous species, this is the first work to demonstrate amplifying contributions of the exchanger current to odor transduction. PMID:10828249

Characteristics of injury and recovery of net NO3- transport of barley seedlings from treatments of NaCl

NASA Technical Reports Server (NTRS)

Klobus, G.; Ward, M. R.; Huffaker, R. C.

1988-01-01

The nature of the injury and recovery of nitrate uptake (net uptake) from NaCl stress in young barley (Hordeum vulgare L, var CM 72) seedlings was investigated. Nitrate uptake was inhibited rapidly by NaCl, within 1 minute after exposure to 200 millimolar NaCl. The duration of exposure to saline conditions determined the time of recovery of NO3- uptake from NaCl stress. Recovery was dependent on the presence of NO3- and was inhibited by cycloheximide, 6-methylpurine, and cerulenin, respective inhibitors of protein, RNA, and sterol/fatty acid synthesis. These inhibitors also prevented the induction of the NO3- uptake system in uninduced seedlings. Uninduced seedlings exhibited endogenous NO3- transport activity that appeared to be constitutive. This constitutive activity was also inhibited by NaCl. Recovery of constitutive NO3- uptake did not require the presence of NO3-.

Na[superscript +] binding to meizothrombin desF1

DOE Office of Scientific and Technical Information (OSTI.GOV)

Papaconstantinou, M.E.; Gandhi, P.S.; Chen, Z.

2009-06-10

Meizothrombin is the physiologically active intermediate generated by a single cleavage of prothrombin at R320 to separate the A and B chains. Recent evidence has suggested that meizothrombin, like thrombin, is a Na{sup +}-activated enzyme. In this study we present the first X-ray crystal structure of human meizothrombin desF1 solved in the presence of the active site inhibitor PPACK at 2.1 {angstrom} resolution. The structure reveals a Na{sup +} binding site whose architecture is practically identical to that of human thrombin. Stopped-flow measurements of Na{sup +} binding to meizothrombin desF1 document a slow phase of fluorescence change with a kmore » obs decreasing hyperbolically with increasing [Na{sup +}], consistent with the existence of three conformations in equilibrium, E*, E and E:Na{sup +}, as for human thrombin. Evidence that meizothrombin exists in multiple conformations provides valuable new information for studies of the mechanism of prothrombin activation.« less

Potential New H1N1 Neuraminidase Inhibitors from Ferulic Acid and Vanillin: Molecular Modelling, Synthesis and in Vitro Assay

NASA Astrophysics Data System (ADS)

Hariono, Maywan; Abdullah, Nurshariza; Damodaran, K. V.; Kamarulzaman, Ezatul E.; Mohamed, Nornisah; Hassan, Sharifah Syed; Shamsuddin, Shaharum; Wahab, Habibah A.

2016-12-01

We report the computational and experimental efforts in the design and synthesis of novel neuraminidase (NA) inhibitors from ferulic acid and vanillin. Two proposed ferulic acid analogues, MY7 and MY8 were predicted to inhibit H1N1 NA using molecular docking. From these two analogues, we designed, synthesised and evaluated the biological activities of a series of ferulic acid and vanillin derivatives. The enzymatic H1N1 NA inhibition assay showed MY21 (a vanillin derivative) has the lowest IC50 of 50 μM. In contrast, the virus inhibition assay showed MY15, a ferulic acid derivative has the best activity with the EC50 of ~0.95 μM. Modelling studies further suggest that these predicted activities might be due to the interactions with conserved and essential residues of NA with ΔGbind values comparable to those of oseltamivir and zanamivir, the two commercial NA inhibitors.

Bruxism and oral parafunctional hyperactivity in social phobia outpatients.

PubMed

Hermesh, H; Schapir, L; Marom, S; Skopski, R; Barnea, E; Weizman, A; Winocur, E

2015-02-01

Anxiety and selective serotonin reuptake inhibitors (SSRIs) are considered aggravating factors for bruxism. We examined the influence of anxiety, depression and SSRI on bruxism in social phobia (SP). Twenty-three drug naïve, 17 SSRI-treated SP patients and 33 healthy controls underwent a psychiatric assessment and completed Leibowitz Social Anxiety Scale and Beck Depression Inventory. Oral parafunctional activity (PF) was evaluated by TM-dental examination and by a questionnaire. Drug- naïve and SSRI-treated SP patients did not differ on demographic and clinical measures. Awake bruxism, 'JAW PLAY' and at least one PF were more prevalent in SP than in controls. Severity of SP predicted the presence of PF. SP, but not depression, was associated with higher risk of oral PF and awake bruxism. Chronic SSRI treatment of SP did not affect sleep and awake bruxism. Dental and anxiety screening may improve the prognosis psychiatric and dental patients. Effective treatment of SP may mitigate bruxism. © 2014 John Wiley & Sons Ltd.

Impact of Treatments for Depression on Comorbid Anxiety, Attentional, and Behavioral Symptoms in Adolescents With Selective Serotonin Reuptake Inhibitor–Resistant Depression

PubMed Central

Hilton, Robert C.; Rengasamy, Manivel; Mansoor, Brandon; He, Jiayan; Mayes, Taryn; Emslie, Graham J.; Porta, Giovanna; Clarke, Greg N.; Wagner, Karen Dineen; Birmaher, Boris; Keller, Martin B.; Ryan, Neal; Shamseddeen, Wael; Asarnow, Joan Rosenbaum; Brent, David A.

2013-01-01

Objective To assess the relative efficacy of antidepressant medication, alone and in combination with cognitive behavioral therapy (CBT), on comorbid symptoms of anxiety, attention, and disruptive behavior disorders in participants in the Treatment of Resistant Depression in Adolescents (TORDIA) trial. Method Adolescents with selective serotonin reuptake inhibitor (SSRI)–resistant depression (N = 334) were randomly assigned to a medication switch alone (to another SSRI or to venlafaxine) or to a medication switch plus CBT. Anxiety, attention-deficit/hyperactivity disorder (ADHD), and disruptive behavior disorder (DBD) symptoms were assessed by psychiatric interview and self-report at regular intervals between baseline and 24 weeks. The differential effects of medication and of CBT, and the impact of remission on the course of comorbid symptoms and diagnoses, were assessed using generalized linear mixed models. Results Remission was associated with a greater reduction in scalar measures of anxiety, ADHD, and DBDs, and a greater decrease in the rate of diagnosed anxiety disorders. The correlations between the changes in symptoms of depression on the CDRS-R and anxiety, ADHD, and oppositional symptoms were modest, ranging from r = 0.12 to r = 0.28. There were no significant differential treatment effects on diagnoses, or corresponding symptoms. Conclusion The achievement of remission had a beneficial effect on anxiety, ADHD, and DBD symptoms, regardless of the type of treatment received. There were no differential effects of medication or CBT on outcome, except for a nonsignificant trend that those adolescents treated with SSRIs showed a greater decrease in rates of comorbid DBDs relative to those treated with venlafaxine. PMID:23622849

Mechanism of the Association between Na+ Binding and Conformations at the Intracellular Gate in Neurotransmitter:Sodium Symporters*

PubMed Central

Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; Gotfryd, Kamil; Khelashvili, George; Gether, Ulrik; Loland, Claus J.; Javitch, Jonathan A.; Noskov, Sergei; Weinstein, Harel; Shi, Lei

2015-01-01

Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na+-dependent reuptake of released neurotransmitters. Previous studies suggested that Na+-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. We describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT, two different perturbations disrupting Na+ binding and transport (i.e. replacing Na+ with Li+ or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na+ cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na+ dependence. Thus, the detailed AIN generated from our method is shown to connect Na+ binding with global conformational changes that are critical for the transport mechanism. That the AIN between the Na+ binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function. PMID:25869126

Mechanism of the association between Na + binding and conformations at the intracellular gate in neurotransmitter:sodium symporters

DOE PAGES

Stolzenberg, Sebastian; Quick, Matthias; Zhao, Chunfeng; ...

2015-04-13

Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by Na +-dependent reuptake of released neurotransmitters. Previous studies suggested that Na +-binding reconfigures dynamically coupled structural elements in an allosteric interaction network (AIN) responsible for function-related conformational changes, but the intramolecular pathway of this mechanism has remained uncharted. Here we describe a new approach for the modeling and analysis of intramolecular dynamics in the bacterial NSS homolog LeuT. From microsecond-scale molecular dynamics simulations and cognate experimental verifications in both LeuT and human dopamine transporter (hDAT), we apply the novel method to identify the composition and the dynamic properties of their conserved AIN. In LeuT,more » two different perturbations disrupting Na+ binding and transport ( i.e. replacing Na + with Li + or the Y268A mutation at the intracellular gate) affect the AIN in strikingly similar ways. In contrast, other mutations that affect the intracellular gate (i.e. R5A and D369A) do not significantly impair Na + cooperativity and transport. Our analysis shows these perturbations to have much lesser effects on the AIN, underscoring the sensitivity of this novel method to the mechanistic nature of the perturbation. Notably, this set of observations holds as well for hDAT, where the aligned Y335A, R60A, and D436A mutations also produce different impacts on Na + dependence. Furthermore, the detailed AIN generated from our method is shown to connect Na + binding with global conformational changes that are critical for the transport mechanism. Lastly, that the AIN between the Na + binding sites and the intracellular gate in bacterial LeuT resembles that in eukaryotic hDAT highlights the conservation of allosteric pathways underlying NSS function.« less

Synthesis and evaluation of poly(Sodium 2-Acrylamido-2-Methylpropane Sulfonate-co-Styrene)/magnetite nanoparticle composites as corrosion inhibitors for steel.

PubMed

El-Mahdy, Gamal A; Atta, Ayman M; Al-Lohedan, Hamad A

2014-01-30

Self-stabilized magnetic polymeric composite nanoparticles of coated poly-(sodium 2-acrylamido-2-methylpropane sulfonate-co-styrene)/magnetite (PAMPS-Na-co-St/Fe3O4) were prepared by emulsifier-free miniemulsion polymerization using styrene (St) as a monomer, 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na) as an ionic comonomer, N,N-methylenebisacrylamide (MBA) as crosslinker, hexadecane (HD) as a hydrophobic solvent, and 2,2-azodiisobutyronitrile (AIBN) as an initiator in the presence of hydrophobic oleic acid coated magnetite particles. Hydrophobic oleic acid coated magnetite particles with an average size of about 7-10 nm were prepared with the new modified water-based magnetite ferrofluid, synthesized by a chemical modified coprecipitation method. The morphology and the particle size distributions of the crosslinked PAMPS-Na-co-St/Fe3O4 composite were observed and analyzed by transmission electron microscopy (TEM). The average Fe3O4 content of PAMPS-Na-co-St/Fe3O4 was determined by thermogravimetric analysis (TGA). The inhibitory action of PAMPS-Na-co-St/Fe3O4 towards steel corrosion in 1 M HCl solutions has been investigated by polarization and electrochemical impedance spectroscopy (EIS) methods. Polarization measurements indicate that PAMPS-Na-co-St/Fe3O4 acts as a mixed type-inhibitor and the inhibition efficiency increases with inhibitor concentration. The results of potentiodynamic polarization and EIS measurements clearly showed that the inhibition mechanism involves blocking of the steel surface by inhibitor molecules via adsorption.

A comparative review of escitalopram, paroxetine, and sertraline: are they all alike?

PubMed Central

Reines, Elin H.; Montgomery, Stuart A.

2014-01-01

It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter. PMID:24424469

A comparative review of escitalopram, paroxetine, and sertraline: Are they all alike?

PubMed

Sanchez, Connie; Reines, Elin H; Montgomery, Stuart A

2014-07-01

It is known that newer antidepressants, such as the selective serotonin reuptake inhibitors (SSRIs), provide advantages in tolerability over antidepressants such as the tricyclics. However, even within the SSRI class, differences in efficacy or tolerability exist between the individual drugs. Among the three most widely prescribed SSRIs are paroxetine, sertraline, and escitalopram. Escitalopram is commonly referred to as an SSRI, but also has well-documented allosteric properties, and thus can be further classed as an allosteric serotonin reuptake inhibitor. All three antidepressants are efficacious compared with placebo, but there is evidence that escitalopram is more effective than a range of other antidepressants. There are no direct data to regard either paroxetine or sertraline as a superior antidepressant. Escitalopram is superior compared with paroxetine, which has a less favorable tolerability profile. Paroxetine is associated with cholinergic muscarinic antagonism and potent inhibition of CYP2D6, and sertraline has moderate drug interaction issues in comparison with escitalopram. Overall, as an allosteric serotonin reuptake inhibitor that is somewhat different from classical SSRIs, escitalopram is the first choice judged by combined efficacy and tolerability, and nonclinical data have offered possible mechanisms through which escitalopram could be more efficacious, based on its interaction with orthosteric and allosteric binding sites at the serotonin transporter.

Control of serotonin transporter phosphorylation by conformational state

PubMed Central

Zhang, Yuan-Wei; Turk, Benjamin E.

2016-01-01

Serotonin transporter (SERT) is responsible for reuptake and recycling of 5-hydroxytryptamine (5-HT; serotonin) after its exocytotic release during neurotransmission. Mutations in human SERT are associated with psychiatric disorders and autism. Some of these mutations affect the regulation of SERT activity by cGMP-dependent phosphorylation. Here we provide direct evidence that this phosphorylation occurs at Thr276, predicted to lie near the cytoplasmic end of transmembrane helix 5 (TM5). Using membranes from HeLa cells expressing SERT and intact rat basophilic leukemia cells, we show that agents such as Na+ and cocaine that stabilize outward-open conformations of SERT decreased phosphorylation and agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increased phosphorylation. The opposing effects of the inhibitors cocaine and ibogaine were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na+ and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively, as measured by the accessibility of cysteine residues in the extracellular and cytoplasmic permeation pathways, respectively. The results are consistent with a mechanism of SERT regulation that is activated by the transport of 5-HT, which increases the level of inward-open SERT and may lead to unwinding of the TM5 helix to allow phosphorylation. PMID:27140629

Control of serotonin transporter phosphorylation by conformational state.

PubMed

Zhang, Yuan-Wei; Turk, Benjamin E; Rudnick, Gary

2016-05-17

Serotonin transporter (SERT) is responsible for reuptake and recycling of 5-hydroxytryptamine (5-HT; serotonin) after its exocytotic release during neurotransmission. Mutations in human SERT are associated with psychiatric disorders and autism. Some of these mutations affect the regulation of SERT activity by cGMP-dependent phosphorylation. Here we provide direct evidence that this phosphorylation occurs at Thr276, predicted to lie near the cytoplasmic end of transmembrane helix 5 (TM5). Using membranes from HeLa cells expressing SERT and intact rat basophilic leukemia cells, we show that agents such as Na(+) and cocaine that stabilize outward-open conformations of SERT decreased phosphorylation and agents that stabilize inward-open conformations (e.g., 5-HT, ibogaine) increased phosphorylation. The opposing effects of the inhibitors cocaine and ibogaine were each reversed by an excess of the other inhibitor. Inhibition of phosphorylation by Na(+) and stimulation by ibogaine occurred at concentrations that induced outward opening and inward opening, respectively, as measured by the accessibility of cysteine residues in the extracellular and cytoplasmic permeation pathways, respectively. The results are consistent with a mechanism of SERT regulation that is activated by the transport of 5-HT, which increases the level of inward-open SERT and may lead to unwinding of the TM5 helix to allow phosphorylation.

IMPACT OF SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) DURING PREGNANCY AND LACTATION: A FOCUS ON SHORT AND LONG-TERM VASCULAR EFFECTS.

PubMed

Zullino, S; Simoncini, T

2018-05-24

SSRIs are the first choice for the treatment of mood disorders during pregnancy and lactation. Despite the known side effects, the benefits/risks balance suggests their use. Hypertensive disorders of pregnancy (HDP) and Intrauterine growth restriction (IUGR) are the main vascular effects of these drugs, with mechanisms that involves endothelial dysfunction in feto-placental system. These data are supported by animal models, even if preliminary findings are not yet adequately supported by molecular and clinical data. SSRIs. applications and mode of action. Nowadays selective serotonin reuptake inhibitors (SSRIs) are among the most used antidepressants in the treatment of major depressive and anxiety disorders. This class of drugs is also widely prescribed for panic disorders, obsessive-compulsive disorder (OCD), eating disorders and post-traumatic stress disorder (PTSD). The exact mechanism of action of SSRIs is unknown. However SSRIs are believed to increase the extracellular levels of the neurotransmitterserotonin by limiting its reuptake into the presynaptic cell, increasing the levels in the synaptic cleft available to bind the postsynaptic receptor. They have varying degrees of selectivity for the other monoamine transporters, with pure SSRIs having only weak affinity for the norepinephrine and dopamine transporters [1]. SSRIs during pregnancy and lactation: use and benefits/risk balance. Approximately 10-20% of women experience depression and/or anxiety during the perinatal period. Moreover an increasing number of patients needs to continue a previous psychiatric treatment during and after pregnancy. Data from the Slone Epidemiology Center Birth Defect Study [2] underlines an increased use of antidepressants from 1 to 7% in the last thirty years. SSRIs, and in particular sertraline and fluoxetine, are considered the gold standard to manage maternal mood disorders during pregnancy and in the post-partum [3-7]. They have replaced tricyclic antidepressants as the

Atypical dopamine transporter inhibitors R-modafinil and JHW 007 differentially affect D2 autoreceptor neurotransmission and the firing rate of midbrain dopamine neurons.

PubMed

Avelar, Alicia J; Cao, Jianjing; Newman, Amy Hauck; Beckstead, Michael J

2017-09-01

Abuse of psychostimulants like cocaine that inhibit dopamine (DA) reuptake through the dopamine transporter (DAT) represents a major public health issue, however FDA-approved pharmacotherapies have yet to be developed. Recently a class of ligands termed "atypical DAT inhibitors" has gained attention due to their range of effectiveness in increasing extracellular DA levels without demonstrating significant abuse liability. These compounds not only hold promise as therapeutic agents to treat stimulant use disorders but also as experimental tools to improve our understanding of DAT function. Here we used patch clamp electrophysiology in mouse brain slices to explore the effects of two atypical DAT inhibitors (R-modafinil and JHW 007) on the physiology of single DA neurons in the substantia nigra and ventral tegmental area. Despite their commonalities of being DAT inhibitors that lack cocaine-like behavioral profiles, these compounds exhibited surprisingly divergent cellular effects. Similar to cocaine, R-modafinil slowed DA neuron firing in a D2 receptor-dependent manner and rapidly enhanced the amplitude and duration of D2 receptor-mediated currents in the midbrain. In contrast, JHW 007 exhibited little effect on firing, slow DAT blockade, and an unexpected inhibition of D2 receptor-mediated currents that may be due to direct D2 receptor antagonism. Furthermore, pretreatment with JHW 007 blunted the cellular effects of cocaine, suggesting that it may be valuable to investigate similar DAT inhibitors as potential therapeutic agents. Further exploration of these and other atypical DAT inhibitors may reveal important cellular effects of compounds that will have potential as pharmacotherapies for treating cocaine use disorders. Copyright © 2017 Elsevier Ltd. All rights reserved.

Comparison of treatment adherence between selective serotonin reuptake inhibitors and moclobemide in patients with social anxiety disorder.

PubMed

Lim, Se-Won; Kwon, Yong-Seok; Ha, Juwon; Yoon, Hyeng-Geun; Bae, Seung-Min; Shin, Dong-Won; Shin, Young-Chul; Oh, Kang-Seob

2012-03-01

With respect to the pharmacotherapy of social anxiety disorder (SAD), it has been suggested that treatment duration is an important factor that can significantly predict responses. The present study aimed to compare the treatment adherence of SAD patients who were taking either SSRIs or reversible inhibitors of MAO-A (moclobemide) by measuring treatment duration and all-cause discontinuation rates of pharmacotherapy in a natural clinical setting. We retrospectively analysed the data of 172 patients diagnosed with SAD. Depending on their medication, we divided the patients into two groups, SSRI (n=54) or moclobemide (n=118). The expected number of all-cause discontinuation every 2 weeks after starting treatment was calculated by life table survival methods. A multi-variable Cox proportional hazard regression was used to analyze the potential influence of explanatory variables. Treatment duration was significantly longer in the SSRI group [46.41±56.96, median=12.0 (weeks)] than in the moclobemide group [25.53±34.74, median=12.0 (weeks), Z=2.352, p=0.019]. Overall, all-cause discontinuation rates were significantly lower with SSRIs (81%) than moclobemide (96%, χ²=4.532, p=0.033). The SSRI group had a longer treatment duration and lower all-cause discontinuation rate than moclobemide. Further, only the type of medication had a significant effect on all-cause discontinuation rates and therefore, we could predict better treatment adherence with the SSRIs in the treatment of SAD.

Identification of NaK-ATPase inhibitors in human plasma as nonesterified fatty acids and lysophospholipids.

PubMed

Kelly, R A; O'Hara, D S; Mitch, W E; Smith, T W

1986-09-05

Elevated plasma levels of factors with cardiac glycoside-like activity have been implicated in the response to volume expansion in animals and in the pathogenesis of certain human diseases. We recently described four fractions (IR1, EI1, EI2, EI3) from normal human plasma that inhibit NaK-ATPase, displace ouabain from the enzyme, and exhibit digoxin-like immunoreactivity (Kelly, R. A., O'Hara, D. S., Canessa, M. L., Mitch, W. E., and Smith, T. W. (1985) J. Biol. Chem. 260, 11396-11405). In this report, we identify the active component of these plasma fractions as long-chain nonesterified fatty acids (NEFA) and lysophospholipids. These lipids were present in fractions EI1, EI2, and EI3 in quantities sufficient to account for all of the NaK-ATPase inhibitory activity. The digoxin-like immunoreactivity in fraction IR1 could be attributed to hydrocortisone and other endogenous steroids. To explore the nature of the lipid-NaK-ATPase interactions, we examined the effects of various ATP or sodium concentrations on the NaK-ATPase activity measured in the presence of NEFA. Varying sodium did not affect the inhibition of NaK-ATPase by linoleic acid. At less than 0.15 mM ATP, linoleic acid stimulated NaK-ATPase, but at higher ATP concentrations, the enzyme was progressively inhibited. In summary, NEFA and lysophospholipids, at levels similar to those occurring in human plasma, may account for all of the NaK-ATPase inhibitory activity observed in human plasma fractions. These lipids probably do not directly regulate NaK-ATPase in vivo under normal physiologic conditions, but may alter the sodium pump in disease states characterized by abnormalities in lipid metabolism or plasma protein binding.

Treatment of anxiety and depression: medicinal plants in retrospect.

PubMed

Fajemiroye, James O; da Silva, Dayane M; de Oliveira, Danillo R; Costa, Elson A

2016-06-01

Anxiety and depression are complex heterogeneous psychiatric disorders and leading causes of disability worldwide. This review summarizes reports on the fundamentals, prevalence, diagnosis, neurobiology, advancement in treatment of these diseases and preclinical assessment of botanicals. This review was conducted through bibliographic investigation of scientific journals, books, electronic sources, unpublished theses and electronic medium such as ScienceDirect and PubMed. A number of the first-line drugs (benzodiazepine, azapirone, antidepressant tricyclics, monoamine oxidase inhibitors, serotonin selective reuptake inhibitors, noradrenaline reuptake inhibitors, serotonin and noradrenaline reuptake inhibitors, etc.) for the treatment of these psychiatric disorders are products of serendipitous discoveries. Inspite of the numerous classes of drugs that are available for the treatment of anxiety and depression, full remission has remained elusive. The emerging clinical cases have shown increasing interests among health practitioners and patients in phytomedicine. The development of anxiolytic and antidepressant drugs of plant origin takes advantage of multidisciplinary approach including but not limited to ethnopharmacological survey (careful investigation of folkloric application of medicinal plant), phytochemical and pharmacological studies. The selection of a suitable plant for a pharmacological study is a basic and very important step. Relevant clues to achieving this step include traditional use, chemical composition, toxicity, randomized selection or a combination of several criteria. Medicinal plants have been and continue to be a rich source of biomolecule with therapeutic values for the treatment of anxiety and depression. © 2016 Société Française de Pharmacologie et de Thérapeutique.

Seizures during antidepressant treatment in psychiatric inpatients--results from the transnational pharmacovigilance project "Arzneimittelsicherheit in der Psychiatrie" (AMSP) 1993-2008.

PubMed

Köster, M; Grohmann, R; Engel, R R; Nitsche, M A; Rüther, E; Degner, D

2013-11-01

There is little clinical data available about seizure rates in psychiatric inpatients, and there are no studies with reference data to the frequencies of antidepressant (AD) use for this important clinical population. This study investigates seizure rates during AD treatment in psychiatric inpatient settings, drawn from the transnational pharmacovigilance programme Arzneimittelsicherheit in der Psychiatrie (AMSP) in relation to the known frequencies of ADs used in the participating clinics. Comparisons are made to former publications and their limitations. Seventy-seven cases were identified with grand mal seizures (GMS) during AD treatment between 1993 and 2008, with a total number of 142,090 inpatients under surveillance treated with ADs in the participating hospitals. The calculated overall rate of reported seizures of patients during AD treatment in this collective is 0.05 % for ADs imputed alone or in combination with other psychotropic drug groups and 0.02 % when only ADs were given and held responsible for GMS. The patients receiving tri- or tetracyclic ADs (TCAs) had a 2-fold risk to develop a seizure as compared to the overall average rate in this sample. In 11 cases, there was only one AD imputed--the majority of these cases (9/11) were TCA. Monotherapy with selective serotonin reuptake inhibitors (SSRI) or dual serotonin and noradrenaline reuptake inhibitors (SNRI) were never imputed alone in this sample. The results of the study favour the assumption that SSRIs, noradrenergic and specific serotonergic antidepressants (NaSSA) and dual SNRI might be more appropriate than TCAs for the treatment of psychiatric patients with an enhanced seizure risk.

Carbon monoxide induces cardiac arrhythmia via induction of the late Na+ current.

PubMed

Dallas, Mark L; Yang, Zhaokang; Boyle, John P; Boycott, Hannah E; Scragg, Jason L; Milligan, Carol J; Elies, Jacobo; Duke, Adrian; Thireau, Jérôme; Reboul, Cyril; Richard, Sylvain; Bernus, Olivier; Steele, Derek S; Peers, Chris

2012-10-01

Clinical reports describe life-threatening cardiac arrhythmias after environmental exposure to carbon monoxide (CO) or accidental CO poisoning. Numerous case studies describe disruption of repolarization and prolongation of the QT interval, yet the mechanisms underlying CO-induced arrhythmias are unknown. To understand the cellular basis of CO-induced arrhythmias and to identify an effective therapeutic approach. Patch-clamp electrophysiology and confocal Ca(2+) and nitric oxide (NO) imaging in isolated ventricular myocytes was performed together with protein S-nitrosylation to investigate the effects of CO at the cellular and molecular levels, whereas telemetry was used to investigate effects of CO on electrocardiogram recordings in vivo. CO increased the sustained (late) component of the inward Na(+) current, resulting in prolongation of the action potential and the associated intracellular Ca(2+) transient. In more than 50% of myocytes these changes progressed to early after-depolarization-like arrhythmias. CO elevated NO levels in myocytes and caused S-nitrosylation of the Na(+) channel, Na(v)1.5. All proarrhythmic effects of CO were abolished by the NO synthase inhibitor l-NAME, and reversed by ranolazine, an inhibitor of the late Na(+) current. Ranolazine also corrected QT variability and arrhythmias induced by CO in vivo, as monitored by telemetry. Our data indicate that the proarrhythmic effects of CO arise from activation of NO synthase, leading to NO-mediated nitrosylation of Na(V)1.5 and to induction of the late Na(+) current. We also show that the antianginal drug ranolazine can abolish CO-induced early after-depolarizations, highlighting a novel approach to the treatment of CO-induced arrhythmias.

Urinary Proteolytic Activation of Renal Epithelial Na+ Channels in Chronic Heart Failure.

PubMed

Zheng, Hong; Liu, Xuefei; Sharma, Neeru M; Li, Yulong; Pliquett, Rainer U; Patel, Kaushik P

2016-01-01

One of the key mechanisms involved in renal Na(+) retention in chronic heart failure (CHF) is activation of epithelial Na(+) channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC, resulting in renal Na(+) retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared with sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06, and plasmin 3.57 versus sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch clamp was conducted in cultured renal collecting duct M-1 cells to record Na(+) currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na(+) inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ≈2-folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid, which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na(+) retention commonly observed in CHF. © 2015 American Heart Association, Inc.

Urinary proteolytic activation of renal epithelial Na+ channels in chronic heart failure

PubMed Central

Zheng, Hong; Liu, Xuefei; Sharma, Neeru M.; Li, Yulong; Pliquett, Rainer U; Patel, Kaushik P.

2015-01-01

One of the key mechanisms involved in renal Na+ retention in chronic heart failure (CHF) is activation of epithelial Na+ channels (ENaC) in collecting tubules. Proteolytic cleavage has an important role in activating ENaC. We hypothesized that enhanced levels of proteases in renal tubular fluid activate ENaC resulting in renal Na+ retention in rats with CHF. CHF was produced by left coronary artery ligation in rats. By immunoblotting, we found that several urinary serine proteases were significantly increased in CHF rats compared to sham rats (fold increases: furin 6.7, prostasin 23.6, plasminogen 2.06 and plasmin 3.57 vs. sham). Similar increases were observed in urinary samples from patients with CHF. Whole-cell patch-clamp was conducted in cultured renal collecting duct M-1 cells to record Na+ currents. Protease-rich urine (from rats and patients with CHF) significantly increased the Na+ inward current in M-1 cells. Two weeks of protease inhibitor treatment significantly abrogated the enhanced diuretic and natriuretic responses to ENaC inhibitor benzamil in rats with CHF. Increased podocyte lesions were observed in the kidneys of rats with CHF by transmission electron microscopy. Consistent with these results, podocyte damage markers desmin and podocin expressions were also increased in rats with CHF (increased ~2 folds). These findings suggest that podocyte damage may lead to increased proteases in the tubular fluid which in turn contributes to the enhanced renal ENaC activity, providing a novel mechanistic insight for Na+ retention commonly observed in CHF. PMID:26628676

Ouabain-induced internalization and lysosomal degradation of the Na+/K+-ATPase.

PubMed

Cherniavsky-Lev, Marina; Golani, Ofra; Karlish, Steven J D; Garty, Haim

2014-01-10

Internalization of the Na(+)/K(+)-ATPase (the Na(+) pump) has been studied in the human lung carcinoma cell line H1299 that expresses YFP-tagged α1 from its normal genomic localization. Both real-time imaging and surface biotinylation have demonstrated internalization of α1 induced by ≥100 nm ouabain which occurs in a time scale of hours. Unlike previous studies in other systems, the ouabain-induced internalization was insensitive to Src or PI3K inhibitors. Accumulation of α1 in the cells could be augmented by inhibition of lysosomal degradation but not by proteosomal inhibitors. In agreement, the internalized α1 could be colocalized with the lysosomal marker LAMP1 but not with Golgi or nuclear markers. In principle, internalization could be triggered by a conformational change of the ouabain-bound Na(+)/K(+)-ATPase molecule or more generally by the disruption of cation homeostasis (Na(+), K(+), Ca(2+)) due to the partial inhibition of active Na(+) and K(+) transport. Overexpression of ouabain-insensitive rat α1 failed to inhibit internalization of human α1 expressed in the same cells. In addition, incubating cells in a K(+)-free medium did not induce internalization of the pump or affect the response to ouabain. Thus, internalization is not the result of changes in the cellular cation balance but is likely to be triggered by a conformational change of the protein itself. In physiological conditions, internalization may serve to eliminate pumps that have been blocked by endogenous ouabain or other cardiac glycosides. This mechanism may be required due to the very slow dissociation of the ouabain·Na(+)/K(+)-ATPase complex.

Hepatitis C virus protease inhibitor-resistance mutations: our experience and review.

PubMed

Wu, Shuang; Kanda, Tatsuo; Nakamoto, Shingo; Imazeki, Fumio; Yokosuka, Osamu

2013-12-21

Direct-acting antiviral agents (DAAs) for hepatitis C virus (HCV) infection are one of the major advances in its medical treatment. The HCV protease inhibitors boceprevir and telaprevir were the first approved DAAs in the United States, Europe, and Japan. When combined with peginterferon plus ribavirin, these agents increase sustained virologic response rates to 70%-80% in treatment-naïve patients and previous-treatment relapsers with chronic HCV genotype 1 infection. Without peginterferon plus ribavirin, DAA mono-therapies increased DAA-resistance mutations. Several new DAAs for HCV are now in clinical development and are likely to be approved in the near future. However, it has been reported that the use of these drugs also led to the emergence of DAA-resistance mutations in certain cases. Furthermore, these mutations exhibit cross-resistance to multiple drugs. The prevalence of DAA-resistance mutations in HCV-infected patients who were not treated with DAAs is unknown, and it is as yet uncertain whether such variants are sensitive to DAAs. We performed a population sequence analysis to assess the frequency of such variants in the sera of HCV genotype 1-infected patients not treated with HCV protease inhibitors. Here, we reviewed the literature on resistance variants of HCV protease inhibitors in treatment naïve patients with chronic HCV genotype 1, as well as our experience.

Safety of Flibanserin in Women Treated With Antidepressants: A Randomized, Placebo-Controlled Study.

PubMed

Clayton, Anita H; Croft, Harry A; Yuan, James; Brown, Louise; Kissling, Robert

2018-01-01

Depression is often associated with sexual dysfunction, and pharmacologic treatment for hypoactive sexual desire disorder can be considered in women receiving treatment for depression. To evaluate the safety of flibanserin in women treated for depression with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors. In this double-blinded, randomized, placebo-controlled trial, women with remitted or mild depression treated with selective serotonin reuptake inhibitors or serotonin and norepinephrine reuptake inhibitors who were not postmenopausal and were experiencing symptoms of hypoactive sexual desire disorder (ie, decreased sexual desire and related distress) received flibanserin 50 mg at bedtime (qhs) for 2 weeks and up-titrated to 100 mg qhs, flibanserin 100 mg qhs for the entire treatment period, or placebo for up to 12 weeks. Safety assessment included adverse events and symptoms of depression and anxiety. 73 patients were randomly assigned to flibanserin (both dose groups combined) and 38 to placebo. The sponsor terminated the study early at discontinuation of the development of flibanserin. Treatment duration was at least 8 weeks for 84.9% and 94.7% of patients in the flibanserin and placebo groups, respectively. The most common adverse events (incidence ≥ 2% in the flibanserin group and higher than that in the placebo group) included dry mouth (5.5% for flibanserin vs 2.6% for placebo), insomnia (5.5% vs 2.6%), back pain (4.1% vs 2.6%), and dizziness (4.1% vs 0.0%). There were no serious adverse events and no instances of suicidal ideation or behavior. The proportions of patients with symptom worsening in the flibanserin and placebo groups, respectively, were 6.9% and 21.6% for depression and 1.4% and 2.7% for anxiety. Remission of depression at study end point, as measured by the Quick Inventory of Depressive Symptomatology-Self Report, was experienced by 19.4% of flibanserin-treated patients and 10.8% of patients

Natural Gas Evolution in a Gas Hydrate Melt: Effect of Thermodynamic Hydrate Inhibitors.

PubMed

Sujith, K S; Ramachandran, C N

2017-01-12

Natural gas extraction from gas hydrate sediments by injection of hydrate inhibitors involves the decomposition of hydrates. The evolution of dissolved gas from the hydrate melt is an important step in the extraction process. Using classical molecular dynamics simulations, we study the evolution of dissolved methane from its hydrate melt in the presence of two thermodynamic hydrate inhibitors, NaCl and CH 3 OH. An increase in the concentration of hydrate inhibitors is found to promote the nucleation of methane nanobubbles in the hydrate melt. Whereas NaCl promotes bubble formation by enhancing the hydrophobic interaction between aqueous CH 4 molecules, CH 3 OH molecules assist bubble formation by stabilizing CH 4 bubble nuclei formed in the solution. The CH 3 OH molecules accumulate around the nuclei leading to a decrease in the surface tension at their interface with water. The nanobubbles formed are found to be highly dynamic with frequent exchange of CH 4 molecules between the bubble and the surrounding liquid. A quantitative analysis of the dynamic behavior of the bubble is performed by introducing a unit step function whose value depends on the location of CH 4 molecules with respect to the bubble. It is observed that an increase in the concentration of thermodynamic hydrate inhibitors reduces the exchange process, making the bubble less dynamic. It is also found that for a given concentration of the inhibitor, larger bubbles are less dynamic compared to smaller ones. The dependence of the dynamic nature of nanobubbles on bubble size and inhibitor concentration is correlated with the solubility of CH 4 and the Laplace pressure within the bubble. The effect of CO 2 on the formation of nanobubble in the CH 4 -CO 2 mixed gas hydrate melt in the presence of inhibitors is also examined. The simulations show that the presence of CO 2 molecules significantly reduces the induction time for methane nanobubble nucleation. The role of CO 2 in the early nucleation of

Hot flushes in women with breast cancer: state of the art and future perspectives.

PubMed

Barba, Maddalena; Pizzuti, Laura; Sergi, Domenico; Maugeri-Saccà, Marcello; Vincenzoni, Cristina; Conti, Francesca; Tomao, Federica; Vizza, Enrico; Di Lauro, Luigi; Di Filippo, Franco; Carpano, Silvia; Mariani, Luciano; Vici, Patrizia

2014-02-01

Although not life-threatening, vasomotor symptoms might have a detrimental effect on quality of life and represent a major determinant of poor therapeutic compliance in breast cancer patients. Limitations of hormonal therapies have fostered the use of non-estrogenic pharmacological agents, which mainly include centrally acting compounds, antidepressant drugs, serotonin-norepinephrine reuptake inhibitors and serotonin reuptake inhibitors. Integrating therapeutic tools have recently come from a wide range of heterogeneous approaches varying from phytoestrogens use to ganglion block. We herein critically review the most updated evidence on the available treatment options for management of vasomotor symptoms. The need for a patient-oriented approach following systematic evaluation of the presence and degree of vasomotor disturbances is also discussed and future perspectives in therapeutics are summarized.

The difference in the effect of glutamate and NO synthase inhibitor on free calcium concentration and Na+, K+-ATPase activity in synaptosomes from various brain regions.

PubMed

Avrova, N F; Shestak, K I; Zakharova, I O; Sokolova, T V; Leont'ev, V G

1999-09-01

The significant increase of free calcium concentration ([Ca2+]i) was found in rat cerebral cortex synaptosomes and hippocampal crude synaptosomal fraction after their exposure to glutamate. But no change of [Ca2+]i was revealed in cerebellar synaptosomes, the slight increase of [Ca2+]i in striatal synaptosomes was not significant. The presence of Ng-nitro-L-arginine methyl ester (L-NAME) in the incubation medium practically prevented the increase of [Ca2+]i initiated by glutamate in cerebral cortex synaptosomes, but not in hippocampal ones. The significant diminution of [Ca2+]i in the presence of this inhibitor was shown in striatal synaptosomes exposed to glutamate. Na+,K+-ATPase activity is significantly lower in cerebral cortex, striatal and hippocampal synaptosomes exposed to glutamate. L-NAME prevented the inactivation of this enzyme by glutamate. In cerebellar synaptosomes the tendency to the decrease of enzymatic activity in the presence of L-NAME was on the contrary noticed. Thus, the data obtained provide evidence of the protective effect of NO synthase inhibitor in brain cortex and striatal synaptosomes, but not in cerebellar synaptosomes. Synaptosomes appear to be an adequate model to study the regional differences in the mechanism of toxic effect of excitatory amino acids.

The effects of tianeptine or paroxetine on 35% CO2 provoked panic in panic disorder.

PubMed

Schruers, Koen; Griez, Eric

2004-12-01

Antidepressants that inhibit the reuptake of serotonin (5-HT) are particularly effective in the treatment of panic disorder. Evidence suggests that increased 5-HT availability is important for the anti-panic effect of serotonergic drugs and in maintaining the response to selective serotonin reuptake inhibitors (SSRIs). Tianeptine is an antidepressant with 5-HT reuptake enhancing properties (i.e. the opposite pharmacological profile to that of SSRIs). Therefore, no effect would be expected in panic disorder. The aim of the present study was to compare the effect of tianeptine with that of paroxetine, a selective 5-HT reuptake inhibitor with demonstrated efficacy in panic disorder, on the vulnerability to a laboratory panic challenge in panic disorder patients. Twenty panic disorder patients were treated with either tianeptine or paroxetine for a period of 6 weeks, in a randomized, double-blind, separate group design. The reaction to a 35% CO(2) panic challenge was assessed at baseline and after treatment. Improvement on several clinical scales was also monitored. Tianeptine, as well as paroxetine, showed a significant reduction in vulnerability to the 35% CO(2) panic challenge. In spite of their opposite influence on 5-HT uptake, both tianeptine and paroxetine appeared to reduce the reaction to the panic challenge. These results raise questions about the necessity of 5-HT uptake for the therapeutic efficacy of anti-panic drugs.

In silico prediction of multiple-category classification model for cytochrome P450 inhibitors and non-inhibitors using machine-learning method.

PubMed

Lee, J H; Basith, S; Cui, M; Kim, B; Choi, S

2017-10-01

The cytochrome P450 (CYP) enzyme superfamily is involved in phase I metabolism which chemically modifies a variety of substrates via oxidative reactions to make them more water-soluble and easier to eliminate. Inhibition of these enzymes leads to undesirable effects, including toxic drug accumulations and adverse drug-drug interactions. Hence, it is necessary to develop in silico models that can predict the inhibition potential of compounds for different CYP isoforms. This study focused on five major CYP isoforms, including CYP1A2, 2C9, 2C19, 2D6 and 3A4, that are responsible for more than 90% of the metabolism of clinical drugs. The main aim of this study is to develop a multiple-category classification model (MCM) for the major CYP isoforms using a Laplacian-modified naïve Bayesian method. The dataset composed of more than 4500 compounds was collected from the PubChem Bioassay database. VolSurf+ descriptors and FCFP_8 fingerprint were used as input features to build classification models. The results demonstrated that the developed MCM using Laplacian-modified naïve Bayesian method was successful in classifying inhibitors and non-inhibitors for each CYP isoform. Moreover, the accuracy, sensitivity and specificity values for both training and test sets were above 80% and also yielded satisfactory area under the receiver operating characteristic curve and Matthews correlation coefficient values.

Intracellular pH regulatory mechanism in human atrial myocardium: functional evidence for Na(+)/H(+) exchanger and Na(+)/HCO(3)(-) symporter.

PubMed

Loh, Shih-Hurng; Chen, Wei-Hwa; Chiang, Cheng-Hsien; Tsai, Chien-Sung; Lee, Guo-Chen; Jin, Jong-Shiaw; Cheng, Tzu-Hurng; Chen, Jin-Jer

2002-01-01

Intracellular pH (pH(i)) exerts considerable influence on cardiac contractility and rhythm. Over the last few years, extensive progress has been made in understanding the system that controls pH(i) in animal cardiomyocytes. In addition to the housekeeping Na(+)-H(+) exchanger (NHE), the Na(+)-HCO(3)(-) symporter (NHS) has been demonstrated in animal cardiomyocytes as another acid extruder. However, whether the NHE and NHS functions exist in human atrial cardiomyocytes remains unclear. We therefore investigated the mechanism of pH(i) recovery from intracellular acidosis (induced by NH(4)Cl prepulse) using intracellular 2',7'-bis(2-carboxethyl)-5(6)-carboxy-fluorescein fluorescence in human atrial myocardium. In HEPES (nominally HCO(3)(-)-free) Tyrode solution, pH(i) recovery from induced intracellular acidosis could be blocked completely by 30 microM 3-methylsulfonyl-4-piperidinobenzoyl, guanidine hydrochloride (HOE 694), a specific NHE inhibitor, or by removing extracellular Na(+). In 3% CO(2)-HCO(3)(-) Tyrode solution, HOE 694 only slowed the pH(i) recovery, while addition of HOE 694 together with 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (an NHS inhibitor) or removal of extracellular Na(+) inhibited the acid extrusion entirely. Therefore, in the present study, we provided evidence that two acid extruders involved in acid extrusion in human atrial myocytes, one which is HCO(3)(-) independent and one which is HCO(3)(-) dependent, are mostly likely NHE and NHS, respectively. When we checked the percentage of contribution of these two carriers to pH(i) recovery following induced acidosis, we found that the activity of NHE increased steeply in the acid direction, while that of NHS did not change. Our present data indicate for the first time that two acid extruders, NHE and NHS, exist functionally and pH(i) dependently in human atrial cardiomyocytes. Copyright 2002 National Science Council, ROC and S. Karger AG, Basel

Antagonism of Lidocaine Inhibition by Open-Channel Blockers That Generate Resurgent Na Current

PubMed Central

Bant, Jason S.; Aman, Teresa K.; Raman, Indira M.

2013-01-01

Na channels that generate resurgent current express an intracellular endogenous open-channel blocking protein, whose rapid binding upon depolarization and unbinding upon repolarization minimizes fast and slow inactivation. Na channels also bind exogenous compounds, such as lidocaine, which functionally stabilize inactivation. Like the endogenous blocking protein, these use-dependent inhibitors bind most effectively at depolarized potentials, raising the question of how lidocaine-like compounds affect neurons with resurgent Na current. We therefore recorded lidocaine inhibition of voltage-clamped, tetrodotoxin-sensitive Na currents in mouse Purkinje neurons, which express a native blocking protein, and in mouse hippocampal CA3 pyramidal neurons with and without a peptide from the cytoplasmic tail of NaVβ4 (the β4 peptide), which mimics endogenous open-channel block. To control channel states during drug exposure, lidocaine was applied with rapid-solution exchange techniques during steps to specific voltages. Inhibition of Na currents by lidocaine was diminished by either the β4 peptide or the native blocking protein. In peptide-free CA3 cells, prolonging channel opening with a site-3 toxin, anemone toxin II, reduced lidocaine inhibition; this effect was largely occluded by open-channel blockers, suggesting that lidocaine binding is favored by inactivation but prevented by open-channel block. In constant 100 μM lidocaine, current-clamped Purkinje cells continued to fire spontaneously. Similarly, the β4 peptide reduced lidocaine-dependent suppression of spiking in CA3 neurons in slices. Thus, the open-channel blocking protein responsible for resurgent current acts as a natural antagonist of lidocaine. Neurons with resurgent current may therefore be less susceptible to use-dependent Na channel inhibitors used as local anesthetic, antiarrhythmic, and anticonvulsant drugs. PMID:23486968

Escitalopram: a review of its use in the management of major depressive disorder.

PubMed

Murdoch, David; Keam, Susan J

2005-01-01

Escitalopram (Cipralex, Lexapro), the active S-enantiomer of the racemic selective serotonin reuptake inhibitor (SSRI) citalopram (RS-citalopram), is a highly selective inhibitor of the serotonin transporter protein. It possesses a rapid onset of antidepressant activity, and is an effective and generally well tolerated treatment for moderate-to-severe major depressive disorder (MDD). Pooled analyses from an extensive clinical trial database suggest that escitalopram is consistently more effective than citalopram in moderate-to-severe MDD. Preliminary studies suggest that escitalopram is as effective as other SSRIs and the extended-release (XR) formulation of the serotonin/noradrenaline (norepinephrine) reuptake inhibitor venlafaxine, and may have cost-effectiveness and cost-utility advantages. However, additional longer-term, comparative studies evaluating specific efficacy, tolerability, health-related quality of life and economic indices would be helpful in definitively positioning escitalopram relative to these other agents in the treatment of MDD. Nevertheless, available clinical and pharmacoeconomic data indicate that escitalopram is an effective first-line option in the management of patients with MDD.

Double-blind, placebo-controlled pilot study of adjunctive quetiapine SR in the treatment of PMS/PMDD.

PubMed

Jackson, Christine; Pearson, Brenda; Girdler, Susan; Johnson, Jacqueline; Hamer, Robert M; Killenberg, Susan; Meltzer-Brody, Samantha

2015-11-01

Premenstrual dysphoric disorder (PMDD), a more severe form of premenstrual syndrome (PMS), afflicts 5-8% of reproductive age women and results in significant functional impairment. We conducted a double-blind, placebo-controlled trial of adjunctive quetiapine in patients with PMS/PMDD who had inadequate response to selective serotonin reuptake inhibitor/serotonin-norepinephrine reuptake inhibitor therapy for their symptoms. A PMS/PMDD diagnosis was confirmed by 2-month prospective diagnostic assessment of PMS/PMDD using the Prospective Record of the Impact and Severity of Premenstrual Symptoms (PRISM) calendar. Women were randomized equally to receive quetiapine sustained-release (SR) or placebo (25-mg starting dose) during the luteal phase for 3 months. Outcome variables included the Hamilton Depression and Anxiety Scales, Clinical Global Impression Scale, and PRISM. Twenty women were enrolled in the treatment phase. Although the study was underpowered, greater reductions in luteal phase mood ratings were observed in the quetiapine group on the 17-item Hamilton Depression Rating Scale, Clinical Global Impression improvement rating, and PRISM daily score. The quetiapine group showed most improvement in symptoms of mood lability, anxiety, and irritability. This small double-blind study suggests that adjunctive treatment with quetiapine SR may be a useful addition to selective serotonin reuptake inhibitor therapy in women with PMS/PMDD by reducing symptoms and improving quality of life. Copyright © 2015 John Wiley & Sons, Ltd.

The safety of escitalopram during pregnancy and breastfeeding: a comprehensive review.

PubMed

Bellantuono, Cesario; Bozzi, Francesca; Orsolini, Laura; Catena-Dell'Osso, Mario

2012-11-01

Escitalopram (ESC) is considered one of the most effective selective serotonin reuptake inhibitors for the treatment of major depression. However, little is known on its potential risk of inducing major malformations (MMs) and perinatal complications (PCs). Hence, aim of the present study is to provide a comprehensive review of the available literature on the safety profile of ESC during pregnancy and breastfeeding. MEDLINE and PubMed databases were searched for English language articles by using the following keywords: escitalopram, selective serotonin reuptake inhibitors, major malformations, perinatal complications, pregnancy, and breastfeeding. Although some cases of MMs have been reported after maternal exposure to ESC during early pregnancy, the rate of these adverse events is substantially in the range of those reported in unexposed women. On the contrary, exposure to ESC seems to be significantly associated with some PCs. No adverse effects have been reported in the few studies evaluating its safety during breastfeeding. The available data seem to support the notion that ESC might be considered safe during pregnancy, in particular as far as MMs is concerned. However, similar to other selective serotonin reuptake inhibitors, it could be associated with an increased risk of PCs. Given the paucity of the studies published so far, no definitive conclusions can be drawn on its safety profile during breastfeeding. Copyright © 2012 John Wiley & Sons, Ltd.

Antidepressant Prescription Pattern in the Presence of Medical Co-morbidity: REAP-AD 2013 Study.

PubMed

Grover, S; Avasthi, A; Tripathi, A; Tanra, A J; Chee, K Y; He, Y L; Chiu, H Fk; Kuga, H; Lee, M S; Chong, M Y; Udormatn, P; Kanba, S; Yang, S Y; Si, T M; Sim, K; Tan, C H; Shen, W W; Xiang, Y T; Sartorius, N; Shinfuku, N

2015-09-01

To evaluate the prescription pattern of antidepressants in patients with medical co-morbidity from major psychiatric centres in Asia. The Research on Asian Psychotropic Prescription Pattern for Antidepressants (REAP-AD 2013) collected data from 42 psychiatric centres in 10 Asian countries and regions. Antidepressant prescriptions of 2320 patients with various psychiatric disorders were evaluated. Of these, 370 patients who had specified medical co-morbidities formed the study cohort. Escitalopram (20%) and mirtazapine (20%) were the most commonly prescribed antidepressants in patients with medical co-morbidity followed by sertraline (16%), trazodone (15%), and paroxetine (12%). Overall, more than half (52%; 247/476) of prescriptions comprised selective serotonin reuptake inhibitors. Slightly less than two-thirds (63%; n = 233) of patients received at least 1 selective serotonin reuptake inhibitor. In addition, 79% of patients were prescribed only 1 antidepressant. The mean number of antidepressants used per patient was 1.25 (standard deviation, 0.56). There were subtle differences in the most preferred antidepressant across medical illnesses such as diabetes mellitus, liver dysfunction, acid peptic disease, and cerebrovascular disease. Differences were also seen in prescription patterns across different countries. Although selective serotonin reuptake inhibitors formed the bulk of antidepressant prescriptions in the presence of medical co-morbidity, mirtazapine was also commonly used in the presence of medical co-morbidities. Specified medical morbidities do influence the selection of antidepressants.

Systemic modulation of serotonergic synapses via reuptake blockade or 5HT1A receptor antagonism does not alter perithreshold taste sensitivity in rats.

PubMed

Mathes, Clare M; Spector, Alan C

2014-09-01

Systemic blockade of serotonin (5HT) reuptake with paroxetine has been shown to increase sensitivity to sucrose and quinine in humans. Here, using a 2-response operant taste detection task, we measured the effect of paroxetine and the 5HT1A receptor antagonist WAY100635 on the ability of rats to discriminate sucrose, NaCl, and citric acid from water. After establishing individual psychometric functions, 5 concentrations of each taste stimulus were chosen to represent the dynamic portion of the concentration-response curve, and the performance of the rats to these stimuli was assessed after vehicle, paroxetine (7mg/kg intraperitoneally), and WAY100635 (0.3mg/kg subcutaneously; 1mg/kg intravenously) administration. Although, at times, overall performance across concentrations dropped, at most, 5% from vehicle to drug conditions, no differences relative to vehicle were seen on the parameters of the psychometric function (asymptote, slope, or EC50) after drug administration. In contrast to findings in humans, our results suggest that modulation of 5HT activity has little impact on sucrose detectability at perithreshold concentrations in rats, at least at the doses used in this task. In the rat model, the purported paracrine/neurocrine action of serotonin in the taste bud may work in a manner that does not impact overt taste detection behavior. © The Author 2014. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin.

PubMed

Lakshmanan, Aparna; Scarberry, Daniel; Green, Jill A; Zhang, Xiaoli; Selmi-Ruby, Samia; Jhiang, Sissy M

2015-10-13

Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na+/I- Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAFV600E or RET/PTC3 oncogene. Our data showed that (1) PI3K inhibitor GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-β, a cytokine secreted in the invasive fronts of thyroid cancers; (3) RAIU reduction by TGF-β was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-β, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAFV600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events.

Modulation of thyroidal radioiodide uptake by oncological pipeline inhibitors and Apigenin

PubMed Central

Lakshmanan, Aparna; Scarberry, Daniel; Green, Jill A.; Zhang, Xiaoli; Selmi-Ruby, Samia; Jhiang, Sissy M.

2015-01-01

Targeted radioiodine therapy for thyroid cancer is based on selective stimulation of Na+/I− Symporter (NIS)-mediated radioactive iodide uptake (RAIU) in thyroid cells by thyrotropin. Patients with advanced thyroid cancer do not benefit from radioiodine therapy due to reduced or absent NIS expression. To identify inhibitors that can be readily translated into clinical care, we examined oncological pipeline inhibitors targeting Akt, MEK, PI3K, Hsp90 or BRAF in their ability to increase RAIU in thyroid cells expressing BRAFV600E or RET/PTC3 oncogene. Our data showed that (1) PI3K inhibitor GDC-0941 outperformed other inhibitors in RAIU increase mainly by decreasing iodide efflux rate to a great extent; (2) RAIU increase by all inhibitors was extensively reduced by TGF-β, a cytokine secreted in the invasive fronts of thyroid cancers; (3) RAIU reduction by TGF-β was mainly mediated by NIS reduction and could be reversed by Apigenin, a plant-derived flavonoid; and (4) In the presence of TGF-β, GDC-0941 with Apigenin co-treatment had the highest RAIU level in both BRAFV600E expressing cells and RET/PTC3 expressing cells. Taken together, Apigenin may serve as a dietary supplement along with small molecule inhibitors to improve radioiodine therapeutic efficacy on invasive tumor margins thereby minimizing future metastatic events. PMID:26397139

Measuring inhibition of monoamine reuptake transporters by new psychoactive substances (NPS) in real-time using a high-throughput, fluorescence-based assay.

PubMed

Zwartsen, Anne; Verboven, Anouk H A; van Kleef, Regina G D M; Wijnolts, Fiona M J; Westerink, Remco H S; Hondebrink, Laura

2017-12-01

The prevalence and use of new psychoactive substances (NPS) is increasing and currently over 600 NPS exist. Many illicit drugs and NPS increase brain monoamine levels by inhibition and/or reversal of monoamine reuptake transporters (DAT, NET and SERT). This is often investigated using labor-intensive, radiometric endpoint measurements. We investigated the applicability of a novel and innovative assay that is based on a fluorescent monoamine mimicking substrate. DAT, NET or SERT-expressing human embryonic kidney (HEK293) cells were exposed to common drugs (cocaine, dl-amphetamine or MDMA), NPS (4-fluoroamphetamine, PMMA, α-PVP, 5-APB, 2C-B, 25B-NBOMe, 25I-NBOMe or methoxetamine) or the antidepressant fluoxetine. We demonstrate that this fluorescent microplate reader-based assay detects inhibition of different transporters by various drugs and discriminates between drugs. Most IC 50 values were in line with previous results from radiometric assays and within estimated human brain concentrations. However, phenethylamines showed higher IC 50 values on hSERT, possibly due to experimental differences. Compared to radiometric assays, this high-throughput fluorescent assay is uncomplicated, can measure at physiological conditions, requires no specific facilities and allows for kinetic measurements, enabling detection of transient effects. This assay is therefore a good alternative for radiometric assays to investigate effects of illicit drugs and NPS on monoamine reuptake transporters. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

TS-071 is a novel, potent and selective renal sodium-glucose cotransporter 2 (SGLT2) inhibitor with anti-hyperglycaemic activity.

PubMed

Yamamoto, K; Uchida, S; Kitano, K; Fukuhara, N; Okumura-Kitajima, L; Gunji, E; Kozakai, A; Tomoike, H; Kojima, N; Asami, J; Toyoda, H; Arai, M; Takahashi, T; Takahashi, K

2011-09-01

The renal sodium-glucose cotransporter 2 (SGLT2) plays an important role in the reuptake of filtered glucose in the proximal tubule and therefore may be an attractive target for the treatment of diabetes mellitus. This study characterizes the pharmacological profile of TS-071 ((1S)-1,5-anhydro-1-[5-(4-ethoxybenzyl)-2-methoxy-4-methylphenyl]-1-thio-D-glucitol hydrate), a novel SGLT2 inhibitor in vitro and in vivo. Inhibition of glucose uptake by TS-071 was studied in CHO-K1 cells stably expressing either human SGLT1 or SGLT2. Single oral dosing studies were performed in rats, mice and dogs to assess the abilities of TS-071 to increase urinary glucose excretion and to lower plasma glucose levels. TS-071 inhibited SGLT2 activity in a concentration-dependent manner and was a potent and highly selective inhibitor of SGLT2. Orally administered TS-071 increased urinary glucose excretion in Zucker fatty rats and beagle dogs at doses of 0.3 and 0.03 mg·kg(-1) respectively. TS-071 improved glucose tolerance in Zucker fatty rats without stimulating insulin secretion and reduced hyperglycaemia in streptozotocin (STZ)-induced diabetic rats and db/db mice at a dose of 0.3 mg·kg(-1). These data indicate that TS-071 is a potent and selective SGLT2 inhibitor that improves glucose levels in rodent models of type 1 and 2 diabetes and may be useful for the treatment for diabetes mellitus. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.

Toxicity evaluation of convection-enhanced delivery of small-molecule kinase inhibitors in naïve mouse brainstem.

PubMed

Zhou, Zhiping; Ho, Sharon L; Singh, Ranjodh; Pisapia, David J; Souweidane, Mark M

2015-04-01

Diffuse intrinsic pontine gliomas (DIPGs) are inoperable and lethal high-grade gliomas lacking definitive therapy. Platelet-derived growth factor receptor (PDGFR) and its downstream signaling molecules are the most commonly overexpressed oncogenes in DIPG. This study tested the effective concentration of PDGFR pathway inhibitors in cell culture and then toxicity of these small-molecule kinase inhibitors delivered to the mouse brainstem via convection-enhanced delivery (CED) for potential clinical application. Effective concentrations of small-molecule kinase inhibitors were first established in cell culture from a mouse brainstem glioma model. Sixteen mice underwent CED, a local drug delivery technique, of saline or of single and multidrug combinations of dasatinib (2 M), everolimus (20 M), and perifosine (0.63 mM) in the pons. Animals were kept alive for 3 days following the completion of infusion. No animals displayed any immediate or delayed neurological deficits postoperatively. Histological analysis revealed edema, microgliosis, acute inflammation, and/or axonal injury in the experimental animals consistent with mild acute drug toxicity. Brainstem CED of small-molecule kinase inhibitors in the mouse did not cause serious acute toxicities. Future studies will be necessary to evaluate longer-term safety to prepare for potential clinical application.

Characterization of neuraminidase inhibitor-resistant influenza A(H1N1)pdm09 viruses isolated in four seasons during pandemic and post-pandemic periods in Japan.

PubMed

Takashita, Emi; Fujisaki, Seiichiro; Kishida, Noriko; Xu, Hong; Imai, Masaki; Tashiro, Masato; Odagiri, Takato

2013-11-01

Japan has the highest frequency of neuraminidase (NA) inhibitor use against influenza in the world. Therefore, Japan could be at high risk of the emergence and spread of NA inhibitor-resistant viruses. The aim of this study was to monitor the emergence of NA inhibitor-resistant viruses and the possibility of human-to-human transmission during four influenza seasons in Japan. To monitor antiviral-resistant A(H1N1)pdm09 viruses, we examined viruses isolated in four seasons from the 2008-2009 season through the 2011-2012 season in Japan by allelic discrimination, NA gene sequencing, and NA inhibitor susceptibility. We found that 157 (1·3%) of 12 026 A(H1N1)pdm09 isolates possessed an H275Y substitution in the NA protein that confers about 400- and 140-fold decreased susceptibility to oseltamivir and peramivir, respectively, compared with 275H wild-type viruses. The detection rate of resistant viruses increased from 1·0% during the pandemic period to 2·0% during the post-pandemic period. The highest detection rate of the resistant viruses was found in patients who were 0-9 years old. Furthermore, among the cases with resistant viruses, the percentage of no known exposure to antiviral drugs increased from 16% during the pandemic period to 44% during the post-pandemic period, implying that suspected human-to-human transmission of the resistant viruses gradually increased in the post-pandemic period. A(H1N1)pdm09 viruses resistant to oseltamivir and peramivir were sporadically detected in Japan, but they did not spread throughout the community. No viruses resistant to zanamivir and laninamivir were detected. © 2013 John Wiley & Sons Ltd.

Effect of wine inhibitors on free pineapple stem bromelain activity in a model wine system.

PubMed

Esti, Marco; Benucci, Ilaria; Liburdi, Katia; Garzillo, Anna Maria Vittoria

2011-04-13

The influence of potential inhibitors, naturally present in wine, on the activity of stem bromelain was investigated in order to evaluate the applicability of this enzyme for protein stabilization in white wine. Bromelain proteolytic activity was tested against a synthetic substrate (Bz-Phe-Val-Arg-pNA) in a model wine system after adding ethanol, sulfur dioxide (SO(2)), skin, seed, and gallic and ellagic tannins at the average range of their concentration in wine. All the inhibitors of stem bromelain activity tested turned out to be reversible. Ethanol was a competitive inhibitor with a rather limited effect. Gallic and ellagic tannins have no inhibitory effect on stem bromelain activity, while both seed and skin tannins were uncompetitive inhibitors. The strongest inhibition effect was revealed for sulfur dioxide, which was a mixed-type inhibitor for the enzyme activity. This study provides useful information relative to a future biotechnological application of stem bromelain in winemaking.

The use of morinda citrifolia as a green corrosion inhibitor for low carbon steel in 3.5% NaCl solution

NASA Astrophysics Data System (ADS)

Kusumastuti, Rahayu; Pramana, Rakhmad Indra; Soedarsono, Johny W.

2017-03-01

The effect and mechanism of green corrosion inhibitor of Morinda Citrifolia (Noni) toward low carbon steel material has been researched. The general background is to develop the cheap and eco-friendly corrosion inhibitor based on components taken from tropical plants that grow +in Indonesia. This research aims to determine the effectiveness of the use of the extracts of noni as green corrosion inhibitor of carbon steel material in aggressive environment. The medium applied for this experiment is 3.5% natrium chloride solution. The variation of the concentration and immersion time duration has been applied as the experimental parameters. All the work was done at room temperature. The corrosion rate was measured by electrochemical polarization method with CMS 600-Gamry instruments and weight loss. The adsorption of inhibitor into the metal surface, which induced bonding formation after immersion was observed by using FTIR method. Inhibition mechanism was observed by polarization curves and fitted by the Langmuir adsorption models. The experimental results show that the higher concentration of inhibitor increasing the inhibition effect. The optimum inhibition is obtained at 3 ppm noni fruit extract, after immersion for about 288 hours. The corrosion rates obtained was 1.385 mpy, with the inhibitor efficiency of 76.92%. The monolayer film is formed coating the surface material as a result of mixed type corrosion inhibitor behavior of Noni. It can be concluded that this green inhibitor is effective to be used for low carbon steel material.

Codeine

MedlinePlus

... with other medications, to reduce coughing. Codeine will help relieve symptoms but will not treat the cause ... granisetron (Kytril), ondansetron (Zofran, Zuplenz), or palonosetron (Aloxi); selective serotonin-reuptake inhibitors such as citalopram (Celexa), escitalopram ( ...

Pathological yawning in a patient with anxiety and chronic disease anaemia.

PubMed

Taskapilioglu, O; Akkaya, C; Sarandol, A; Kirli, S

2009-03-01

Yawning, frequent in daily life, is accepted as a complex arousal reflex. Excessive yawning may be due to neurological, psychiatric, infectious, gastrointestinal or metabolic diseases. This reflex has also been associated with different selective serotonin reuptake inhibitors. We report a female patient, with excessive yawning, who was on selective serotonin reuptake inhibitor treatment with the diagnosis of generalised anxiety disorder. She was then found to have endometrial carcinoma. Her complaints of palpitation, shortness of breath and loss of energy might be explained by a psychiatric disease and/or anaemia. Previous anaemic periods and partial response of her psychiatric symptoms during last 3 years alerted us to think about an organic cause. Investigations for chronic disease anaemia resulted in diagnosis of endometrial carcinoma. This case is a good example showing misdiagnosis caused by medical stigmatisation.

Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John's wort: an [11C]-harmine PET study.

PubMed

Sacher, Julia; Houle, Sylvain; Parkes, Jun; Rusjan, Pablo; Sagrati, Sandra; Wilson, Alan A; Meyer, Jeffrey H

2011-11-01

Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John's wort, an herb purported to have MAO-A inhibitor properties. Participants underwent 2 [(11)C]-harmine positron emission tomography scans. Healthy controls completed a test-retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John's wort for 6 weeks at the assigned dose. We measured MAO-A VT, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus. We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A VT decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F1,15 = 71.08-130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John's wort did not significantly alter MAO-A VT. The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%-78%, and we can estimate with 95% certainty that the occupancy of St. John's wort is less than 5%. For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John's wort should not be classified as an MAO-A inhibitor. The magnitude of MAO-A blockade during moclobemide

Inhibition of the sodium-translocating NADH-ubiquinone oxidoreductase [Na+-NQR] decreases cholera toxin production in Vibrio cholerae O1 at the late exponential growth phase

PubMed Central

Minato, Yusuke; Fassio, Sara R.; Reddekopp, Rylan L.; Häse, Claudia C.

2014-01-01

Two virulence factors produced by Vibrio cholerae, cholera toxin (CT) and toxin-corregulated pilus (TCP), are indispensable for cholera infection. ToxT is the central regulatory protein involved in activation of CT and TCP expression. We previously reported that lack of a respiration-linked sodium-translocating NADH–ubiquinone oxidoreductase (Na+-NQR) significantly increases toxT transcription. In this study, we further characterized this link and found that Na+-NQR affects toxT expression only at the early-log growth phase, whereas lack of Na+-NQR decreases CT production after the mid-log growth phase. Such decreased CT production was independent of toxT and ctxB transcription. Supplementing a respiratory substrate, L-lactate, into the growth media restored CT production in the nqrA-F mutant, suggesting that decreased CT production in the Na+-NQR mutant is dependent on electron transport chain (ETC) activity. This notion was supported by the observations that two chemical inhibitors, a Na+-NQR specific inhibitor 2-n-Heptyl-4-hydroxyquinoline N-oxide (HQNO) and a succinate dehydrogenase (SDH) inhibitor, thenoyltrifluoroacetone (TTFA), strongly inhibited CT production in both classical and El Tor biotype strains of V. cholerae. Accordingly, we propose the main respiratory enzyme of V. cholerae, as a potential drug target to treat cholera because human mitochondria do not contain Na+-NQR orthologs. PMID:24361395

Granisetron

MedlinePlus

... 5-HT3 receptor antagonists. It works by blocking serotonin, a natural substance in the body that causes ... Eldepryl, Emsam, Zelapar), and tranylcypromine (Parnate); phenobarbital; selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram ( ...

Analysis of citalopram and desmethylcitalopram in postmortem fluids and tissues using liquid chromatography-mass spectrometry.

DOT National Transportation Integrated Search

2011-10-01

"Citalopram is a selective serotonin reuptake inhibitor that is a commonly prescribed drug for the treatment of : depression, obsessive-compulsive disorder, panic disorder, anxiety disorder, and post-traumatic stress disorder. : While the use of cita...

Molecular fMRI of Serotonin Transport.

PubMed

Hai, Aviad; Cai, Lili X; Lee, Taekwan; Lelyveld, Victor S; Jasanoff, Alan

2016-11-23

Reuptake of neurotransmitters from the brain interstitium shapes chemical signaling processes and is disrupted in several pathologies. Serotonin reuptake in particular is important for mood regulation and is inhibited by first-line drugs for treatment of depression. Here we introduce a molecular-level fMRI technique for micron-scale mapping of serotonin transport in live animals. Intracranial injection of an MRI-detectable serotonin sensor complexed with serotonin, together with serial imaging and compartmental analysis, permits neurotransmitter transport to be quantified as serotonin dissociates from the probe. Application of this strategy to much of the striatum and surrounding areas reveals widespread nonsaturating serotonin removal with maximal rates in the lateral septum. The serotonin reuptake inhibitor fluoxetine selectively suppresses serotonin removal in septal subregions, whereas both fluoxetine and a dopamine transporter blocker depress reuptake in striatum. These results highlight promiscuous pharmacological influences on the serotonergic system and demonstrate the utility of molecular fMRI for characterization of neurochemical dynamics. Copyright © 2016 Elsevier Inc. All rights reserved.

In silico study of carvone derivatives as potential neuraminidase inhibitors.

PubMed

Jusoh, Noorakmar; Zainal, Hasanuddin; Abdul Hamid, Azzmer Azzar; Bunnori, Noraslinda M; Abd Halim, Khairul Bariyyah; Abd Hamid, Shafida

2018-03-15

Recent outbreaks of highly pathogenic influenza strains have highlighted the need to develop new anti-influenza drugs. Here, we report an in silico study of carvone derivatives to analyze their binding modes with neuraminidase (NA) active sites. Two proposed carvone analogues, CV(A) and CV(B), with 36 designed ligands were predicted to inhibit NA (PDB ID: 3TI6) using molecular docking. The design is based on structural resemblance with the commercial inhibitor, oseltamivir (OTV), ligand polarity, and amino acid residues in the NA active sites. Docking simulations revealed that ligand A18 has the lowest energy binding (∆G bind ) value of -8.30 kcal mol -1 , comparable to OTV with ∆G bind of -8.72 kcal mol -1 . A18 formed seven hydrogen bonds (H-bonds) at residues Arg292, Arg371, Asp151, Trp178, Glu227, and Tyr406, while eight H-bonds were formed by OTV with amino acids Arg118, Arg292, Arg371, Glu119, Asp151, and Arg152. Molecular dynamics (MD) simulation was conducted to compare the stability between ligand A18 and OTV with NA. Our simulation study showed that the A18-NA complex is as stable as the OTV-NA complex during the MD simulation of 50 ns through the analysis of RMSD, RMSF, total energy, hydrogen bonding, and MM/PBSA free energy calculations.

Is sibutramine more than a slim hope?

PubMed

2001-12-01

Sibutramine (Reductil-Abbott Laboratories), an orally active monoamine re-uptake inhibitor, is marketed in the UK for treating overweight adults. The company claims that it "helps obese patients control their eating". Is the drug worth prescribing?

The R292K Mutation That Confers Resistance to Neuraminidase Inhibitors Leads to Competitive Fitness Loss of A/Shanghai/1/2013 (H7N9) Influenza Virus in Ferrets

PubMed Central

Yen, Hui-Ling; Zhou, Jie; Choy, Ka-Tim; Sia, Sin Fun; Teng, Ooiean; Ng, Iris H.; Fang, Vicky J.; Hu, Yunwen; Wang, Wei; Cowling, Benjamin J.; Nicholls, John M.; Guan, Yi; Peiris, Joseph Sriyal Malik

2014-01-01

Background Neuraminidase (NA) inhibitors are the only licensed therapeutic option for human zoonotic H7N9 infections. An NA-R292K mutation that confers broad-spectrum resistance to NA inhibitors has been documented in H7N9 patients after treatment. Methods We evaluated the transmission potential of a human influenza A H7N9 isolate with a NA-R292K mutation in the ferret model followed by genotyping assay to monitor its competitive fitness in vivo. Results Plaque-purified A/Shanghai/1/2013 wild-type and NA-R292K viruses transmitted at comparable efficiency to direct or respiratory droplet contact ferrets. In ferrets inoculated with the plaque-purified A/Shanghai/1/2013 NA-R292K virus with dominant K292 (94%), the resistant K292 genotype was outgrown by the wild-type R292 genotype during the course of infection. Transmission of the resistant K292 genotype was detected in 3/4 direct contact and 3/4 respiratory droplet contact ferrets at early time points but was gradually replaced by the wild-type genotype. In the respiratory tissues of inoculated or infected ferrets, the wild-type R292 genotype dominated in the nasal turbinate, whereas the resistant K292 genotype was more frequently detected in the lungs. Conclusions The NA inhibitor-resistant H7N9 virus with the NA-R292K mutation may transmit among ferrets but showed compromised fitness in vivo while in competition with the wild-type virus. PMID:24951824

Monoamine oxidase A inhibitor occupancy during treatment of major depressive episodes with moclobemide or St. John’s wort: an [11C]-harmine PET study

PubMed Central

Sacher, Julia; Houle, Sylvain; Parkes, Jun; Rusjan, Pablo; Sagrati, Sandra; Wilson, Alan A.; Meyer, Jeffrey H.

2011-01-01

Background Monoamine oxidase A (MAO-A) inhibitor antidepressants raise levels of multiple monoamines, whereas the selective serotonin reuptake inhibitors (SSRIs) only raise extracellular serotonin. Despite this advantage of MAO-A inhibitors, there is much less frequent development of MAO inhibitors compared with SSRIs. We sought to measure brain MAO-A occupancy after 6 weeks of treatment in depressed patients with a clinically effective dose of a selective MAO-A inhibitor and measure MAO-A occupancy after repeated administration of St. John’s wort, an herb purported to have MAO-A inhibitor properties. Methods Participants underwent 2 [11C]-harmine positron emission tomography scans. Healthy controls completed a test–retest condition, and depressed patients were scanned before and after repeated administration of moclobemide or St. John’s wort for 6 weeks at the assigned dose. We measured MAO-A VT, an index of MAO-A density, in the prefrontal, anterior cingulate and anterior temporal cortices, putamen, thalamus, midbrain and hippocampus. Results We included 23 participants (10 controls and 13 patients with major depressive disorder [MDD]) in our study. Monoamine oxidase A VT decreased significantly throughout all regions after moclobemide treatment in patients with MDD compared with controls (repeated-measures analysis of variance, F1,15 = 71.08–130.06, p < 0.001 for all regions, mean occupancy 74% [standard deviation 6%]). Treatment with St. John’s wort did not significantly alter MAO-A VT. Limitations The occupancy estimates are limited by the sample size of each treatment group; hence, our estimate for the overall moclobemide occupancy of 74% has a 95% confidence interval of 70%–78%, and we can estimate with 95% certainty that the occupancy of St. John’s wort is less than 5%. Conclusion For new MAO-A inhibitors, about 74% occupancy at steady-state dosing is desirable. Consistent with this, St. John’s wort should not be classified as an MAO

Na+-dependent and Na+-independent betaine transport across the apical membrane of rat renal epithelium.

PubMed

Cano, Mercedes; Calonge, María L; Ilundáin, Anunciación A

2015-10-01

The low renal excretion of betaine indicates that the kidney efficiently reabsorbs the betaine filtered by the glomeruli but the mechanisms involved in such a process have been scarcely investigated. We have detected concentrative and non-concentrative betaine transport activity in brush-border membrane vesicles (BBMV) from rat renal cortex and medulla. The concentrative system is the Sodium/Imino-acid Transporter 1 (SIT1) because it is Na+- and Cl--dependent, electrogenic and is inhibited by an anti-SIT1 antibody. Its apparent affinity constant for betaine, Kt, is 1.1±0.5 mM and its maximal transport velocity, Vmax, 0.5±0.1 nmol betaine/mg protein/s. Inhibitors of the Na+/Cl-/betaine uptake are L-proline (75%) and cold betaine, L-carnitine and choline (40-60%). Neither creatine, TEA, taurine, β-alanine, GABA nor glycine significantly inhibited Na+/Cl-/betaine uptake. The non-concentrative betaine transport system is Na+- and H+-independent, electroneutral, with a Kt for betaine of 47±7 μM and a Vmax of 7.8±1 pmol betaine/mg protein/s. Its transport activity is nearly abolished by betaine, followed by L-carnitine (70-80%) and proline (40-50%), but a difference from the Na+/Cl-/betaine transport is that it is inhibited by TEA (approx. 50%) and unaffected by choline. The underlying carrier functions as an antiporter linking betaine entry into the BBMV with the efflux of either L-carnitine or betaine, an exchange unaffected by the anti-SIT1 antibody. As far as we know this is the first work reporting that betaine crosses the apical membrane of rat renal epithelium by SIT1 and by a Na+- and H+-independent transport system. Copyright © 2015 Elsevier B.V. All rights reserved.

Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model.

PubMed

Song, Yafeng; Stål, Per S; Yu, Ji-Guo; Lorentzon, Ronny; Backman, Clas; Forsgren, Sture

2014-04-11

We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins. Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA). A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group. The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of the SP system. Endogenously produced

17β-Estradiol augments antidepressant efficacy of escitalopram in ovariectomized rats: Neuroprotective and serotonin reuptake transporter modulatory effects.

PubMed

Ibrahim, Weam W; Safar, Marwa M; Khattab, Mahmoud M; Agha, Azza M

2016-12-01

The prevalence or recurrence of depression is seriously increased in women during the transition to and after menopause. The chronic hypo-estrogenic state of menopause may reduce the response to antidepressants; however the influence of estrogen therapy on their efficacy is still controversial. This study aimed at investigating the effects of combining escitalopram with 17β-estradiol on depression and cognitive impairment induced by ovariectomy, an experimental model of human menopause. Young adult female Wistar rats were subjected to either sham operation or ovariectomy. Ovariectomized animals were treated chronically with escitalopram (10mg/kg/day, i.p) alone or with four doses of 17β-estradiol (40μg/kg, s.c) given prior to the behavioral tests. Co-administration of 17β-estradiol improved escitalopram-induced antidepressant effect in forced swimming test verified as more prominent decrease in the immobility time without opposing its memory enhancing effect in Morris water maze. 17β-estradiol augmented the modulatory effects of escitalopram on the hippocampal levels of brain-derived neurotrophic factor and serotonin reuptake transporter as well as tumor necrosis factor-alpha without altering its effects on the gene expressions of serotonin receptor 1A, estrogen receptors alpha and beta, or acetylcholinestearase content. This combined therapy afforded synergistic protective effects on the brain histopathological architecture, particularly, the hippocampus. The antidepressant effect of 17β-estradiol was abolished by pretreatment with estrogen receptor antagonist, tamoxifen (10mg/kg, p.o). In conclusion, 17β-estradiol-induced antidepressant effect was confined to intracellular estrogen receptors activation. Moreover, 17β-estradiol enhanced escitalopram's efficiency in ameliorating menopausal-like depression, via exerting synergistic neuroprotective and serotonin reuptake transporter modulatory effects, without impeding escitalopram-mediated cognitive

Sibutramine, a serotonin-norepinephrine reuptake inhibitor, causes fibrosis in rats.

PubMed

Oberholzer, Hester Magdalena; van der Schoor, Ciska; Bester, Megan Jean

2015-07-01

Sibutramine hydrochloride monohydrate is a weight loss agent indicated for the treatment of obesity. Although it has been banned from most markets, studies are still relevant as it is often a hidden ingredient in herbal and over the counter slimming products. Sibutramine induces liver fibrosis with steatosis in female Sprague-Dawley rats fed a high-energy diet without significant weight gain. In this study, using the same animal model, the effect of Sibutramine on lung morphology was investigated using histological evaluation of the terminal bronchiole and transmission electron microscopy evaluation of the respiratory tissue. From these results Sibutramine was found to induce lung fibrosis in Sprague-Dawley rats as increased collagen synthesis, mast cell accumulation and aggregates of Bronchus Associated Lymphoid Tissue (BALT) in the terminal bronchiole as well as increased collagen deposition in the respiratory tissue was seen. Copyright © 2015 Elsevier B.V. All rights reserved.

Porphyrins as Corrosion Inhibitors for N80 Steel in 3.5% NaCl Solution: Electrochemical, Quantum Chemical, QSAR and Monte Carlo Simulations Studies.

PubMed

Singh, Ambrish; Lin, Yuanhua; Quraishi, Mumtaz A; Olasunkanmi, Lukman O; Fayemi, Omolola E; Sasikumar, Yesudass; Ramaganthan, Baskar; Bahadur, Indra; Obot, Ime B; Adekunle, Abolanle S; Kabanda, Mwadham M; Ebenso, Eno E

2015-08-18

The inhibition of the corrosion of N80 steel in 3.5 wt. % NaCl solution saturated with CO2 by four porphyrins, namely 5,10,15,20-tetrakis(4-hydroxyphenyl)-21H,23H-porphyrin (HPTB), 5,10,15,20-tetra(4-pyridyl)-21H,23H-porphyrin (T4PP), 4,4',4″,4‴-(porphyrin-5,10,15,20-tetrayl)tetrakis(benzoic acid) (THP) and 5,10,15,20-tetraphenyl-21H,23H-porphyrin (TPP) was studied using electrochemical impedance spectroscopy (EIS), potentiodynamic polarization, scanning electrochemical microscopy (SECM) and scanning electron microscopy (SEM) techniques. The results showed that the inhibition efficiency, η% increases with increasing concentration of the inhibitors. The EIS results revealed that the N80 steel surface with adsorbed porphyrins exhibited non-ideal capacitive behaviour with reduced charge transfer activity. Potentiodynamic polarization measurements indicated that the studied porphyrins acted as mixed type inhibitors. The SECM results confirmed the adsorption of the porphyrins on N80 steel thereby forming a relatively insulated surface. The SEM also confirmed the formation of protective films of the porphyrins on N80 steel surface thereby protecting the surface from direct acid attack. Quantum chemical calculations, quantitative structure activity relationship (QSAR) were also carried out on the studied porphyrins and the results showed that the corrosion inhibition performances of the porphyrins could be related to their EHOMO, ELUMO, ω, and μ values. Monte Carlo simulation studies showed that THP has the highest adsorption energy, while T4PP has the least adsorption energy in agreement with the values of σ from quantum chemical calculations.

A Computational Model for Docking of Noncompetitive Neuraminidase Inhibitors and Probing their Binding Interactions with Neuraminidase of Influenza Virus H5N1.

PubMed

Chintakrindi, Anand S; Martis, Elvis A F; Gohil, Devanshi J; Kothari, Sweta T; Chowdhary, Abhay S; Coutinho, Evans C; Kanyalkar, Meena A

2016-01-01

With cases of emergence of drug resistance to the current competitive inhibitors of neuraminidase (NA) such as oseltamivir and zanamavir, there is a present need for an alternative approach in the treatment of avian influenza. With this in view, some flavones and chalcones were designed based on quercetin, the most active naturally occurring noncompetitive inhibitor. We attempt to understand the binding of quercetin to H5N1-NA, and synthetic analogs of quercetin namely flavones and its precursors the chalcones using computational tools. Molecular docking was done using Libdock. Molecular dynamics (MD) simulations were performed using Amber14. We synthesized the two compounds; their structures were confirmed by infrared spectroscopy, 1H-NMR, and mass spectrometry. These molecules were then tested for H5N1-NA inhibition and kinetics of inhibition. Molecular docking studies yielded two compounds i.e., 4'-methoxyflavone and 2'-hydroxy-4-methoxychalcone, as promising leads which identified them as binders of the 150-cavity of NA. Furthermore, MD simulation studies revealed that quercetin and the two compounds bind and hold the 150 loop in its open conformation, which ultimately perturbs the binding of sialic acid in the catalytic site. Estimation of the free energy of binding by MM-PBSA portrays quercetin as more potent than chalcone and flavone. These molecules were then determined as non-competitive inhibitors from the Lineweaver-Burk plots rendered from the enzyme kinetic studies. We conclude that non-competitive type of inhibition, as shown in this study, can serve as an effective method to block NA and evade the currently seen drug resistance.

Mutations in the Na+/Citrate Cotransporter NaCT (SLC13A5) in Pediatric Patients with Epilepsy and Developmental Delay

PubMed Central

Klotz, Jenna; Porter, Brenda E; Colas, Claire; Schlessinger, Avner; Pajor, Ana M

2016-01-01

Mutations in the SLC13A5 gene that codes for the Na+/citrate cotransporter, NaCT, are associated with early onset epilepsy, developmental delay and tooth dysplasia in children. In this study, we identify additional SLC13A5 mutations in nine epilepsy patients from six families. To better characterize the syndrome, families with affected children answered questions about the scope of illness and the treatment strategies. Currently, there are no effective treatments, but some antiepileptic drugs targeting the γ-aminobutyric acid system reduce seizure frequency. Acetazolamide, a carbonic anhydrase inhibitor and atypical antiseizure medication, decreases seizures in four patients. In contrast to previous reports, the ketogenic diet and fasting resulted in worsening of symptoms. The effects of the mutations on NaCT transport function and protein expression were examined by transient transfections of COS-7 cells. There was no transport activity from any of the mutant transporters, although some of the mutant transporter proteins were present on the plasma membrane. The structural model of NaCT suggests that these mutations can affect helix packing or substrate binding. We tested various treatments, including chemical chaperones and low temperatures, but none improved transport function in the NaCT mutants. Interestingly, coexpression of NaCT and the mutants results in decreased protein expression and activity of the wild-type transporter, indicating functional interaction. In conclusion, this study has identified additional SLC13A5 mutations in patients with chronic epilepsy starting in the neonatal period, with the mutations producing inactive Na+/citrate transporters. PMID:27261973

A novel pathogenic mechanism of highly pathogenic avian influenza H5N1 viruses involves hemagglutinin mediated resistance to serum innate inhibitors.

PubMed

Panaampon, Jutatip; Ngaosuwankul, Nathamon; Suptawiwat, Ornpreya; Noisumdaeng, Pirom; Sangsiriwut, Kantima; Siridechadilok, Bunpote; Lerdsamran, Hatairat; Auewarakul, Prasert; Pooruk, Phisanu; Puthavathana, Pilaipan

2012-01-01

In this study, the effect of innate serum inhibitors on influenza virus infection was addressed. Seasonal influenza A(H1N1) and A(H3N2), 2009 pandemic A(H1N1) (H1N1pdm) and highly pathogenic avian influenza (HPAI) A(H5N1) viruses were tested with guinea pig sera negative for antibodies against all of these viruses as evaluated by hemagglutination-inhibition and microneutralization assays. In the presence of serum inhibitors, the infection by each virus was inhibited differently as measured by the amount of viral nucleoprotein produced in Madin-Darby canine kidney cells. The serum inhibitors inhibited seasonal influenza A(H3N2) virus the most, while the effect was less in seasonal influenza A(H1N1) and H1N1pdm viruses. The suppression by serum inhibitors could be reduced by heat inactivation or treatment with receptor destroying enzyme. In contrast, all H5N1 strains tested were resistant to serum inhibitors. To determine which structure (hemagglutinin (HA) and/or neuraminidase (NA)) on the virus particles that provided the resistance, reverse genetics (rg) was applied to construct chimeric recombinant viruses from A/Puerto Rico/8/1934(H1N1) (PR8) plasmid vectors. rgPR8-H5 HA and rgPR8-H5 HANA were resistant to serum inhibitors while rgPR8-H5 NA and PR8 A(H1N1) parental viruses were sensitive, suggesting that HA of HPAI H5N1 viruses bestowed viral resistance to serum inhibition. These results suggested that the ability to resist serum inhibition might enable the viremic H5N1 viruses to disseminate to distal end organs. The present study also analyzed for correlation between susceptibility to serum inhibitors and number of glycosylation sites present on the globular heads of HA and NA. H3N2 viruses, the subtype with highest susceptibility to serum inhibitors, harbored the highest number of glycosylation sites on the HA globular head. However, this positive correlation cannot be drawn for the other influenza subtypes.

In silico prediction of ROCK II inhibitors by different classification approaches.

PubMed

Cai, Chuipu; Wu, Qihui; Luo, Yunxia; Ma, Huili; Shen, Jiangang; Zhang, Yongbin; Yang, Lei; Chen, Yunbo; Wen, Zehuai; Wang, Qi

2017-11-01

ROCK II is an important pharmacological target linked to central nervous system disorders such as Alzheimer's disease. The purpose of this research is to generate ROCK II inhibitor prediction models by machine learning approaches. Firstly, four sets of descriptors were calculated with MOE 2010 and PaDEL-Descriptor, and optimized by F-score and linear forward selection methods. In addition, four classification algorithms were used to initially build 16 classifiers with k-nearest neighbors [Formula: see text], naïve Bayes, Random forest, and support vector machine. Furthermore, three sets of structural fingerprint descriptors were introduced to enhance the predictive capacity of classifiers, which were assessed with fivefold cross-validation, test set validation and external test set validation. The best two models, MFK + MACCS and MLR + SubFP, have both MCC values of 0.925 for external test set. After that, a privileged substructure analysis was performed to reveal common chemical features of ROCK II inhibitors. Finally, binding modes were analyzed to identify relationships between molecular descriptors and activity, while main interactions were revealed by comparing the docking interaction of the most potent and the weakest ROCK II inhibitors. To the best of our knowledge, this is the first report on ROCK II inhibitors utilizing machine learning approaches that provides a new method for discovering novel ROCK II inhibitors.

Contribution of the amiloride-sensitive component and the Na+/H+ exchanger to renal responsiveness to vasoconstrictors.

PubMed

Vargas, Pablo; Wangensteen, Rosemary; Rodríguez-Gómez, Isabel; Perez-Abud, Rocío; Osuna, Antonio; Quesada, Andrés; Vargas, Félix

2011-01-01

This study analyzed the role of the amiloride-sensitive component and the participation of the Na(+)/H(+) exchanger in renal responsiveness to vasoconstrictors in the isolated perfused rat kidney. The renal responses to vasoconstrictors (angiotensin II, phenylephrine, vasopressin and KCl) were studied under baseline conditions and after the administration of amiloride (10 and 100 μmol/l) or the specific Na(+)/H(+) exchange inhibitor ethylisopropylamiloride (EIPA, 10 μmol/l). The effects of amiloride and EIPA on renal responsiveness to vasoconstrictors were also analyzed in endothelium-denuded preparations. Amiloride reduced renal responsiveness to all vasoconstrictors in a dose-related manner, whereas EIPA did not affect the renal pressor response to KCl. The inhibitory effects of amiloride and EIPA on renal responsiveness to vasoconstrictors persisted after endothelium removal. These results indicate that the amiloride-sensitive component and the Na(+)/H(+) exchanger play an important role in responsiveness to the main endogenous vasoconstrictors in the renal vasculature. These results also suggest that amiloride might be useful as an inhibitor of renal vasoconstriction, even in diseases with endothelial dysfunction. Copyright © 2011 S. Karger AG, Basel.

Ranolazine vs phenytoin: greater effect of ranolazine on the transient Na(+) current than on the persistent Na(+) current in central neurons.

PubMed

Terragni, Benedetta; Scalmani, Paolo; Colombo, Elisa; Franceschetti, Silvana; Mantegazza, Massimo

2016-11-01

Voltage-gated Na(+) channels (NaV) are involved in pathologies and are important targets of drugs (NaV-blockers), e.g. some anti-epileptic drugs (AEDs). Besides the fast inactivating transient Na(+) current (INaT), they generate a slowly inactivating "persistent" current (INaP). Ranolazine, a NaV-blocker approved for treatment of angina pectoris, is considered a preferential inhibitor of INaP and has been proposed as a novel AED. Although it is thought that classic NaV-blockers used as AEDs target mainly INaT, they can also reduce INaP. It is important to disclose specific features of novel NaV-blockers, which could be necessary for their effect as AEDs in drug resistant patients. We have compared the action of ranolazine and of the classic AED phenytoin in transfected cells expressing the neuronal NaV1.1 Na(+) channel and in neurons of neocortical slices. Our results show that the relative block of INaT versus INaP of ranolazine and phenytoin is variable and depends on Na(+) current activation conditions. Strikingly, ranolazine blocks with less efficacy INaP and more efficacy INaT than phenytoin in conditions mimicking pathological states (i.e. high frequency firing and long lasting depolarizations). The effects are consistent with binding of ranolazine to both open/pre-open and inactivated states; larger INaT block at high stimulation frequencies is caused by the induction of a slow inactivated state. Thus, contrary than expected, ranolazine is not a better INaP blocker than phenytoin in central neurons, and phenytoin is not a better INaT blocker than ranolazine. Nevertheless, they show a complementary action and could differentially target specific pathological dysfunctions. Copyright © 2016 Elsevier Ltd. All rights reserved.

Silica-Immobilized Enzyme Reactors (Postprint)

DTIC Science & Technology

2007-09-01

mode of action of drugs such as aspirin and ibuprofen .[61] Serotonin reuptake inhibitors and monoamine oxidase inhibitors can function as...immobilizing PGA onto chromatography supports and using the enantiomeric selectivity of the enzyme to resolve racemic mixtures.[100] Immobilization onto...column. J. Chroma- togr. B. Biomed. Sci. Appl. 2001, 753, 375–383. 37. Jadaud, P.; Wainer, I.W. The stereochemical resolution of the enantiomers of

A Case of Treatment- resistant Depression and Body Dysmorphic Disorder: The Role of Electroconvulsive Therapy Revisited.

PubMed

Mahato, Ram S; San Gabriel, Maria Chona P; Longshore, Carrol T; Schnur, David B

2016-01-01

Body dysmorphic disorder is a common, often disabling condition, and is frequently comorbid with major depressive disorder. Selective serotonin reuptake inhibitors constitute first line set of somatic interventions but the management of refractory patients remains challenging. Electroconvulsive therapy, an often highly beneficial treatment for medication resistant-depression, is not considered an effective therapeutic alternative for treatment refractory body dysmorphic disorder. Here we present a 50-year-old woman with body dysmorphic disorder and comorbid major depressive disorder who remained incapacitated and suicidal despite several trials with selective serotonin reuptake inhibitors and antipsychotic medication. Depressive and dysmorphic symptoms appeared to resolve with electroconvulsive therapy, and remission was sustained for two months. Electroconvulsive therapy has an important place in the management of treatment- resistant depression associated with body dysmorphic disorder, and, in select cases, may be effective for dysmorphic symptoms as well.

New perspectives in the treatment of body dysmorphic disorder

PubMed Central

Hong, Kevin; Nezgovorova, Vera; Hollander, Eric

2018-01-01

Body dysmorphic disorder (BDD) is a disabling illness with a high worldwide prevalence. Patients demonstrate a debilitating preoccupation with one or more perceived defects, often marked by poor insight or delusional convictions. Multiple studies have suggested that selective serotonin reuptake inhibitors and various cognitive behavioral therapy modalities are effective first-line treatments in decreasing BDD severity, relieving depressive symptoms, restoring insight, and increasing quality of life. Selective serotonin reuptake inhibitors have also recently been shown to be effective for relapse prevention. This review provides a comprehensive summary of the current understanding of BDD, including its clinical features, epidemiology, genetics, and current treatment modalities. Additional research is needed to fully elucidate the relationship between BDD and comorbid illnesses such as obsessive–compulsive-related disorders and depression and to develop therapies for refractory patients and those who have contraindications for pharmacological intervention. PMID:29636904

A meta-analysis to determine the effect of pharmacological and non-pharmacological treatments on fibromyalgia symptoms comprising OMERACT-10 response criteria.

PubMed

Papadopoulou, Despoina; Fassoulaki, Argyro; Tsoulas, Christos; Siafaka, Ioanna; Vadalouca, Athina

2016-03-01

Fibromyalgia is characterized by widespread pain, sleep problems, fatigue, functional impairment, psychological distress, and cognitive dysfunction. The objective of this meta-analysis is to synthesize the available data on the effectiveness of pharmacological and non-pharmacological interventions across all domains included in the Outcome Measures in Rheumatology Clinical Trials (OMERACT-10) fibromyalgia response definitions, and to examine response based on these definitions. We searched Cochrane, PubMed, Scopus, and the reference lists of articles for randomized controlled trials of any drug formulation or non-pharmacological intervention used for fibromyalgia treatment. We extracted efficacy data regarding pain, sleep, physical function, fatigue, anxiety, depression, and cognition. The available data were insufficient to draw definite conclusions regarding response. Indirect evidence indicates that it may be expected with the use of serotonin noradrenaline reuptake inhibitors (SNRIs), noradrenaline reuptake inhibitors (NRIs), and multidisciplinary treatment.

Cellular localization of Na(+), K(+)-ATPase in the mammalian vestibular system

NASA Technical Reports Server (NTRS)

Kerr, T. P.

1984-01-01

Two different, but complementary, procedures for cellular localization of Na+, K+-ATPase in the guinea pig vestibular system were employed. One of these techniques, devised by Stirling, depends upon the well documented ability of the specific inhibitor ouabain to bind selectively to Na+,K+-ATPase, blocking catalytic activity. Microdisected vestibular tissues are incubated with tritium-labelled (3H-) ouabain, and regions with a high concentration of Na+,K+-ATPase are subsequently identified by light microscope autoradiography. A second method, originated by Ernst, detects inorganic phosphate released from an artificial substrate (nitrophenyl phosphate) by catalytic activity of the enzyme. In the presence of strontium ion, phosphate is precipitated near regions of high activity, then converted to a product which may finally be visualized in the electron microscope. This cytochemical enzymatic reaction is inhibited by ouabain.

Analgesic and anti-inflammatory effects of A-286501, a novel orally active adenosine kinase inhibitor.

PubMed

Jarvis, Michael F; Yu, Haixia; McGaraughty, Steve; Wismer, Carol T; Mikusa, Joe; Zhu, Chang; Chu, Katharine; Kohlhaas, Kathy; Cowart, Marlon; Lee, Chih Hung; Stewart, Andrew O; Cox, Bryan F; Polakowski, James; Kowaluk, Elizabeth A

2002-03-01

Adenosine (ADO) is an inhibitory neuromodulator that can increase nociceptive thresholds in response to noxious stimulation. Inhibition of the ADO-metabolizing enzyme, adenosine kinase (AK) increases extracellular ADO concentrations at sites of tissue trauma and AK inhibitors may have therapeutic potential as analgesic and anti-inflammatory agents. N7-((1'R,2'S,3'R,4'S)-2',3'-dihydroxy-4'-amino-cyclopentyl)-4-amino-5-bromo-pyrrolo[2,3-a]pyrimidine (A-286501) is a novel and potent (IC50=0.47 nM) carbocyclic nucleoside AK inhibitor that has no significant activity (IC50 >100 microM) at other sites of ADO interaction (A1, A2A, A3 receptors, ADO transporter, and ADO deaminase) or other (IC50 value >10 microM) neurotransmitter and peptide receptors, ion channel proteins, neurotransmitter reuptake sites and enzymes, including cyclooxygenases-1 and -2. A-286501 showed equivalent potency to inhibit AK from several mammalian species and kinetic studies revealed that A-286501 was a reversible and competitive inhibitor with respect to ADO and non-competitive with respect to MgATP2-. A-286501 was orally effective to reduce nociception in animal models of acute (thermal), inflammatory (formalin and carrageenan), and neuropathic (L5/L6 nerve ligation and streptozotocin-induced diabetic) pain. A-286501 was particularly potent (ED50=1 micromol/kg, p.o.) to reduce carrageenan-induced inflammatory thermal hyperalgesia as compared to its analgesic actions in other pain models (acute and neuropathic) and its ability to alter hemodynamic function and motor performance. A-286501 was also effective to reduce carrageenan-induced paw edema and myeloperoxidase activity, a measure of neutrophil influx (ED50=10 micromol/kg, p.o.), in the injured paw. The anti-nociceptive effects of A-286501 in the L5/L6 nerve injury model of neuropathic pain (ED50=20 micromol/kg, p.o.) were not blocked by the opioid antagonist naloxone, but were blocked by the ADO receptor antagonist, theophylline. Following

Endogenous flow-induced superoxide stimulates Na/H exchange activity via PKC in thick ascending limbs

PubMed Central

Garvin, Jeffrey L.

2014-01-01

Luminal flow stimulates Na reabsorption along the nephron and activates protein kinase C (PKC) which enhances endogenous superoxide (O2−) production by thick ascending limbs (TALs). Exogenously-added O2− augments TAL Na reabsorption, a process also dependent on PKC. Luminal Na/H exchange (NHE) mediates NaHCO3 reabsorption. However, whether flow-stimulated, endogenously-produced O2− enhances luminal NHE activity and the signaling pathway involved are unclear. We hypothesized that flow-induced production of endogenous O2− stimulates luminal NHE activity via PKC in TALs. Intracellular pH recovery was measured as an indicator of NHE activity in isolated, perfused rat TALs. Increasing luminal flow from 5 to 20 nl/min enhanced total NHE activity from 0.104 ± 0.031 to 0.167 ± 0.036 pH U/min, 81%. The O2− scavenger tempol decreased total NHE activity by 0.066 ± 0.011 pH U/min at 20 nl/min but had no significant effect at 5 nl/min. With the NHE inhibitor EIPA in the bath to block basolateral NHE, tempol reduced flow-enhanced luminal NHE activity by 0.029 ± 0.010 pH U/min, 30%. When experiments were repeated with staurosporine, a nonselective PKC inhibitor, tempol had no effect. Because PKC could mediate both induction of O2− by flow and the effect of O2− on luminal NHE activity, we used hypoxanthine/xanthine oxidase to elevate O2−. Hypoxanthine/xanthine oxidase increased luminal NHE activity by 0.099 ± 0.020 pH U/min, 137%. Staurosporine and the PKCα/β1-specific inhibitor Gö6976 blunted this effect. We conclude that flow-induced O2− stimulates luminal NHE activity in TALs via PKCα/β1. This accounts for part of flow-stimulated bicarbonate reabsorption by TALs. PMID:25080525

The R292K mutation that confers resistance to neuraminidase inhibitors leads to competitive fitness loss of A/Shanghai/1/2013 (H7N9) influenza virus in ferrets.

PubMed

Yen, Hui-Ling; Zhou, Jie; Choy, Ka-Tim; Sia, Sin Fun; Teng, Ooiean; Ng, Iris H; Fang, Vicky J; Hu, Yunwen; Wang, Wei; Cowling, Benjamin J; Nicholls, John M; Guan, Yi; Peiris, Joseph Sriyal Malik

2014-12-15

Neuraminidase (NA) inhibitors are the only licensed therapeutic option for human zoonotic H7N9 infections. An NA-R292K mutation that confers broad-spectrum resistance to NA inhibitors has been documented in H7N9 patients after treatment. We evaluated the transmission potential of a human influenza A H7N9 isolate with a NA-R292K mutation in the ferret model followed by genotyping assay to monitor its competitive fitness in vivo. Plaque-purified A/Shanghai/1/2013 wild-type and NA-R292K viruses transmitted at comparable efficiency to direct or respiratory droplet contact ferrets. In ferrets inoculated with the plaque-purified A/Shanghai/1/2013 NA-R292K virus with dominant K292 (94%), the resistant K292 genotype was outgrown by the wild-type R292 genotype during the course of infection. Transmission of the resistant K292 genotype was detected in 3/4 direct contact and 3/4 respiratory droplet contact ferrets at early time points but was gradually replaced by the wild-type genotype. In the respiratory tissues of inoculated or infected ferrets, the wild-type R292 genotype dominated in the nasal turbinate, whereas the resistant K292 genotype was more frequently detected in the lungs. The NA inhibitor-resistant H7N9 virus with the NA-R292K mutation may transmit among ferrets but showed compromised fitness in vivo while in competition with the wild-type virus. © The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The effect of functionalized polycarboxylate structures as corrosion inhibitors in a simulated concrete pore solution

NASA Astrophysics Data System (ADS)

Fazayel, A. S.; Khorasani, M.; Sarabi, A. A.

2018-05-01

In this study, the effects of polycarboxylate derivatives with different comonomers and functional groups on the control or reduction of corrosion in steel specimens were evaluated through electrochemical impedance spectroscopy (EIS) and potentiodynamic analysis. A highly alkaline contaminated concrete pore solution (CPS) containing chlorides was used to simulate the pitting corrosion, and according to the results, the mechanism of inhibitive action was determined. Both the inhibition efficiency and pitting corrosion inhibition of methacrylate-copolymers were in the order of poly methacrylate-co acrylamide > poly methacrylate-co-2-acrylamido-2 methylpropane sulfonic acid > poly methacrylate-co-hydroxyethyl methacrylate. In addition, the corrosion potential of steel specimens in all studied concentrations of NaCl with different concentrations of polymethacrylate-co acrylamide (as the best inhibitor in this study) in saturated Ca(OH)2 solution showed almost an identical trend. Polymethacrylic acid-co-acrylamide showed a 92.35% inhibitor efficiency in the saturated Ca(OH)2 solution containing 1.8 wt.% chlorides and could effectively reduce the corrosion rate. Even at 3.5 wt.% of NaCl, this inhibitor could remarkably reduce the destructive effect of chloride ion attacks on the steel surface and passive film. The inhibition effect of these polymeric inhibitors seemed to be due to the formation of a barrier layer on the metal surface, approved by the well-known adsorption mechanism of organic molecules at the metal/solution interface. The results of SEM, EDS and AFM investigations were also in agreement with the outcomes of electrochemical studies.

BSC-1 growth inhibitor transforms a mitogenic stimulus into a hypertrophic stimulus for renal proximal tubular cells: relationship to Na/sup +//H/sup +/ antiport activity

DOE Office of Scientific and Technical Information (OSTI.GOV)

Fine, L.G.; Holley, R.W.; Nasri, H.

Renal hypertrophy is characterized by an increase in cell size and protein content with minimal hyperplasia. The mechanisms of control of this pattern of cell growth have not been determined. The present studies examined whether the growth inhibitor elaborated by BSC-1 kidney epilethal cells (GI), which has nearly identical biological properties to transforming growth factor ..beta.. (TGF-..beta..), could transform a mitogenic stimulus into a hypertrophic stimulus for rabbit renal proximal tubular cells in primary culture. Insulin plus hydrocortisone increased the amount of protein per cell, cell volume, and (/sup 3/H)thymidine incorporation at 24 and 48 hr in these cells. Whenmore » added together with insulin plus hydrocortisone, GI/TGF-..beta.. inhibited the stimulatory effect of these mitogens on (/sup 3/H)thymidine incorporation but did not block the increase in protein per cell and cell volume - i.e., the cells underwent hypertrophy. The fact that this pattern persisted for 48 hr indicated that GI/TGF-..beta.. exerted a prolonged inhibitory effect on mitogenic-stimulated DNA synthesis rather than delaying its onset. Amiloride-sensitive Na/sup +/ uptake using /sup 22/Na/sup +/ as a tracer, correlated with protein per cell and cell volume rather than with DNA synthesis. These studies indicate that the control of cell size may be regulated by autocrine mechanisms mediated by the elaboration of growth inhibitory factors that alter the pattern of the growth response to mitogens.« less

Discovery of a Highly Selective NAMPT Inhibitor That Demonstrates Robust Efficacy and Improved Retinal Toxicity with Nicotinic Acid Coadministration.

PubMed

Zhao, Genshi; Green, Colin F; Hui, Yu-Hua; Prieto, Lourdes; Shepard, Robert; Dong, Sucai; Wang, Tao; Tan, Bo; Gong, Xueqian; Kays, Lisa; Johnson, Robert L; Wu, Wenjuan; Bhattachar, Shobha; Del Prado, Miriam; Gillig, James R; Fernandez, Maria-Carmen; Roth, Ken D; Buchanan, Sean; Kuo, Ming-Shang; Geeganage, Sandaruwan; Burkholder, Timothy P

2017-12-01

NAMPT, an enzyme essential for NAD + biosynthesis, has been extensively studied as an anticancer target for developing potential novel therapeutics. Several NAMPT inhibitors have been discovered, some of which have been subjected to clinical investigations. Yet, the on-target hematological and retinal toxicities have hampered their clinical development. In this study, we report the discovery of a unique NAMPT inhibitor, LSN3154567. This molecule is highly selective and has a potent and broad spectrum of anticancer activity. Its inhibitory activity can be rescued with nicotinic acid (NA) against the cell lines proficient, but not those deficient in NAPRT1, essential for converting NA to NAD + LSN3154567 also exhibits robust efficacy in multiple tumor models deficient in NAPRT1. Importantly, this molecule when coadministered with NA does not cause observable retinal and hematological toxicities in the rodents, yet still retains robust efficacy. Thus, LSN3154567 has the potential to be further developed clinically into a novel cancer therapeutic. Mol Cancer Ther; 16(12); 2677-88. ©2017 AACR . ©2017 American Association for Cancer Research.

The role of transmembrane segment 5 (TM5) in Na2 release and the conformational transition of neurotransmitter:sodium symporters toward the inward-open state

PubMed Central

Stolzenberg, Sebastian; Li, Zheng; Quick, Matthias; Malinauskaite, Lina; Nissen, Poul; Weinstein, Harel; Javitch, Jonathan A.; Shi, Lei

2017-01-01

Neurotransmitter:sodium symporters (NSSs) terminate neurotransmission by the reuptake of released neurotransmitters. This active accumulation of substrate against its concentration gradient is driven by the transmembrane Na+ gradient and requires that the transporter traverses several conformational states. LeuT, a prokaryotic NSS homolog, has been crystallized in outward-open, outward-occluded, and inward-open states. Two crystal structures of another prokaryotic NSS homolog, the multihydrophobic amino acid transporter (MhsT) from Bacillus halodurans, have been resolved in novel inward-occluded states, with the extracellular vestibule closed and the intracellular portion of transmembrane segment 5 (TM5i) in either an unwound or a helical conformation. We have investigated the potential involvement of TM5i in binding and unbinding of Na2, i.e. the Na+ bound in the Na2 site, by carrying out comparative molecular dynamics simulations of the models derived from the two MhsT structures. We find that the helical TM5i conformation is associated with a higher propensity for Na2 release, which leads to the repositioning of the N terminus and transition to an inward-open state. By using comparative interaction network analysis, we also identify allosteric pathways connecting TM5i and the Na2 binding site to the extracellular and intracellular regions. Based on our combined computational and mutagenesis studies of MhsT and LeuT, we propose that TM5i plays a key role in Na2 binding and release associated with the conformational transition toward the inward-open state, a role that is likely to be shared across the NSS family. PMID:28320858

Reevaluating Antidepressant Selection in Patients With Bruxism and Temporomandibular Joint Disorder.

PubMed

Rajan, Royce; Sun, Ye-Ming

2017-05-01

Temporomandibular joint disorder (TMD) is a broad pain disorder that refers to several conditions affecting the temporomandibular joint of the jaw and the muscles of mastication. As with most pain disorders, a high prevalence of depression and anxiety is associated with TMD. Research has shown that selective serotonin reuptake inhibitors (SSRIs), the first-line drug therapy for major depressive disorder, may not be suitable for TMD patients because SSRIs can induce teeth-grinding, otherwise known as bruxism. This is problematic because bruxism is believed to further exacerbate TMD. Therefore, the purpose of this literature review is to better understand the mechanism of SSRI-induced bruxism, as well as discuss alternative antidepressant options for treating depression and anxiety in patients with bruxism and TMD. Alternative classes of antidepressants reviewed include serotonin-norepinephrine reuptake inhibitors, tricyclic antidepressants, atypical antidepressants, and monoamine oxidase inhibitors. Findings indicate that dopamine agonists and buspirone are currently the most effective medications to treat the side effects of SSRI-induced bruxism, but results regarding the effectiveness of specific antidepressants that avoid bruxism altogether remain inconclusive.

The glycine reuptake inhibitor org 25935 interacts with basal and ethanol-induced dopamine release in rat nucleus accumbens.

PubMed

Lidö, Helga Höifödt; Stomberg, Rosita; Fagerberg, Anne; Ericson, Mia; Söderpalm, Bo

2009-07-01

The mesolimbic dopamine (DA) projection from the ventral tegmental area to nucleus accumbens (nAc), a central part of the reward system, is activated by ethanol (EtOH) and other drugs of abuse. We have previously demonstrated that the glycine receptor in the nAc and its amino acid agonists may be implicated in the DA activation and reinforcing properties of EtOH. We have also reported that the glycine transporter 1 inhibitor, Org 25935, produces a robust and dose-dependent decrease in EtOH consumption in Wistar rats. The present study explores the interaction between EtOH and Org 25935 with respect to DA levels in the rat nAc. The effects of Org 25935 (6 mg/kg, i.p.) and/or EtOH (2.5 g/kg, i.p.) on accumbal DA levels were examined by means of in vivo microdialysis (coupled to HPLC-ED) in freely moving male Wistar rats. The effect of Org 25935 on accumbal glycine output was also investigated. Systemic Org 25935 increased DA output in a subpopulation of rats (52% in Experiment 1 and 38% in Experiment 2). In Experiment 2, EtOH produced a significant increase in DA levels in vehicles (35%) and in Org 25935 nonresponders (19%), whereas EtOH did not further increase the DA level in rats responding to Org 25935 (2%). The same dose of Org 25935 increased glycine levels by 87% in nAc. This study demonstrates that Org 25935, probably via increased glycine levels, (i) counteracts EtOH-induced increases of accumbal DA levels and (ii) increases basal DA levels in a subpopulation of rats. The results are in line with previous findings and it is suggested that the effects observed involve interference with accumbal GlyRs and are related to the alcohol consumption modulating effect of Org 25935.

Substituted 2-benzothiazolamines as sodium flux inhibitors: quantitative structure-activity relationships and anticonvulsant activity.

PubMed

Hays, S J; Rice, M J; Ortwine, D F; Johnson, G; Schwarz, R D; Boyd, D K; Copeland, L F; Vartanian, M G; Boxer, P A

1994-10-01

Thirty-two aryl-substituted 2-benzothiazolamines have been tested for their ability to modulate sodium flux in rat cortical slices. A QSAR analysis, applied to these derivatives, showed a trend toward increasing potency as sodium flux inhibitors with increasing lipophilicity, decreasing size, and increasing electron withdrawal of the benzo ring substituents. Additionally, 4- or 5-substitution of the benzo ring was found to decrease potency. The combination of increased lipophilicity, small size, and electron withdrawal severely limited which groups were tolerated on the benzo ring, thus suggesting that the optimal substitution patterns have been prepared within this series. Nine of these compounds were potent inhibitors of veratridine-induced sodium flux (NaFl). These nine compounds also proved to be anticonvulsant in the maximal electroshock (MES) assay. Fourteen additional 2-benzothiazolamines demonstrated activity in the MES screen, yet exhibited no activity in the NaFl assay. These derivatives may be interacting at the sodium channel in a manner not discernible by the flux paradigm, or they may be acting by an alternative mechanism in vivo.

Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases.

PubMed

Healy, David; Le Noury, Joanna; Mangin, Derelie

2018-05-01

To investigate clinical reports of post-SSRI sexual dysfunction (PSSD), post-finasteride syndrome (PFS) and enduring sexual dysfunction following isotretinoin. Data from RxISK.org, a global adverse event reporting website, have been used to establish the clinical features, demographic details and clinical trajectories of syndromes of persistent sexual difficulties following three superficially different treatment modalities.RESULTSWe report on 300 cases of enduring sexual dysfunction from 37 countries following 14 different drugs comprised of serotonin reuptake inhibiting antidepressants, 5α-reductase inhibitors and isotretinoin. While reports of certain issues were unique to the antidepressants, such as the onset of premature ejaculation and persistent genital arousal disorder (PGAD), there was also a significant overlap in symptom profile between the drug groups, with common features including genital anaesthesia, pleasureless or weak orgasm, loss of libido and impotence. Secondary consequences included relationship breakdown and impaired quality of life.CONCLUSIONSThese data point to a legacy syndrome or syndromes comprising a range of disturbances to sexual function. More detailed studies will require developments in coding systems that recognise the condition(s). Further exploration of these tardive sexual syndromes may yield greater understanding of tardive syndromes in general.

Enduring sexual dysfunction after treatment with antidepressants, 5α-reductase inhibitors and isotretinoin: 300 cases

PubMed Central

Healy, David; Le Noury, Joanna; Mangin, Derelie

2018-01-01

OBJECTIVE: To investigate clinical reports of post-SSRI sexual dysfunction (PSSD), post-finasteride syndrome (PFS) and enduring sexual dysfunction following isotretinoin. METHODS: Data from RxISK.org, a global adverse event reporting website, have been used to establish the clinical features, demographic details and clinical trajectories of syndromes of persistent sexual difficulties following three superficially different treatment modalities. RESULTS We report on 300 cases of enduring sexual dysfunction from 37 countries following 14 different drugs comprised of serotonin reuptake inhibiting antidepressants, 5α-reductase inhibitors and isotretinoin. While reports of certain issues were unique to the antidepressants, such as the onset of premature ejaculation and persistent genital arousal disorder (PGAD), there was also a significant overlap in symptom profile between the drug groups, with common features including genital anaesthesia, pleasureless or weak orgasm, loss of libido and impotence. Secondary consequences included relationship breakdown and impaired quality of life. CONCLUSIONS These data point to a legacy syndrome or syndromes comprising a range of disturbances to sexual function. More detailed studies will require developments in coding systems that recognise the condition(s). Further exploration of these tardive sexual syndromes may yield greater understanding of tardive syndromes in general. PMID:29733030

Urea inhibits NaK2Cl cotransport in human erythrocytes.

PubMed Central

Lim, J; Gasson, C; Kaji, D M

1995-01-01

We examined the effect of urea on NaK2Cl cotransport in human erythrocytes. In erythrocytes from nine normal subjects, the addition of 45 mM urea, a concentration commonly encountered in uremic subjects, inhibited NaK2Cl cotransport by 33 +/- 7%. Urea inhibited NaK2Cl cotransport reversibly, and in a concentration-dependent fashion with half-maximal inhibition at 63 +/- 10 mM. Acute cell shrinkage increased, and acute cell swelling decreased NaK2Cl cotransport in human erythrocytes. Okadaic acid (OA), a specific inhibitor of protein phosphatase 1 and 2A, increased NaK2Cl cotransport by nearly 80%, suggesting an important role for these phosphatases in the regulation of NaK2Cl cotransport. Urea inhibited bumetanide-sensitive K influx even when protein phosphatases were inhibited with OA, suggesting that urea acted by inhibiting a kinase. In cells subjected to shrinking and OA pretreatment, maneuvers expected to increase the net phosphorylation, urea inhibited cotransport only minimally, suggesting that urea acted by causing a net dephosphorylation of the cotransport protein, or some key regulatory protein. The finding that concentrations of urea found in uremic subjects inhibited NaK2Cl cotransport, a widespread transport pathway with important physiological functions, suggests that urea is not only a marker for accumulation of other uremic toxins, but may be a significant uremic toxin itself. PMID:7593597

Hemispheric Specialization for Emotional Word Processing Is a Function of SSRI Responsiveness

ERIC Educational Resources Information Center

Walsh, Amy; McDowall, John; Grimshaw, Gina M.

2010-01-01

Vulnerability to depression and non-response to Selective Serotonin Reuptake Inhibitors (SSRIs) are associated with specific neurophysiological characteristics including greater right hemisphere (RH) relative to left hemisphere (LH) activity. The present study investigated the relationship between hemispheric specialization and processing of…

[Antidepressant and tolerance: Determinants and management of major side effects].

PubMed

David, D J; Gourion, D

2016-12-01

Antidepressant therapy aims to reach remission of depressive symptoms while reducing the complications and risks of relapse. Even though they have proven their efficacy, it takes several weeks for antidepressants to demonstrate full effectiveness, and adverse effects occur more quickly or (quicker) which can be a source of poor compliance. This latest aspect often leads to dose reduction and/or change of molecule that have the effect of delaying remission. This review attempts to present, from the pharmacological properties of the major classes of antidepressants (monoamine oxidase inhibitor [MAOI], tricyclic antidepressants [TCA], selective serotonin reuptake inhibitor [SSRI] and serotonin and noradrenaline reuptake inhibitor [SNRI]), to the pharmacological mechanisms involved in adverse effects by focusing on sexual dysfunction, nausea/vomiting, and weight changes and sleep disruption. If the activation of dopamine D 1/2  or norepinephrine receptors through the autonomic nervous system controls and facilitates sexual desire, increasing serotoninergic transmission through 5-HT 1B/2A/2C receptors activation inhibits this process. The pharmacological properties of drugs inducing nausea/vomiting activate opiate receptors μ, increase dopaminergic and serotoninergic transmission activating the dopamine D 2  and serotonin 5-HT 3  receptors, respectively. Among the causes responsible for weight gain under antidepressant therapy, monoamine neurotransmission still plays an important role. The blockade of serotonin 5-HT 2C or histamine H 1  receptors is directly responsible for weight gain. Finally, the activation of 5-HT 1A/1B/3/7 serotoninergique receptors modulates wakefulness, raid eyes movement or sleep duration. In conclusion, if antidepressant activity of SERT or MAO inhibitors is an indirect consequence of postsynaptic 5-HT, DA, NA receptor activation, it is also responsible for side effects, causes of poor compliance and hence therapeutic failures. Finally, we

The effect of nitric oxide synthase inhibitors nitro-L-arginine and 7-nitroindazole on spatial learning and motor functions in Lurcher mutant and wild type mice.

PubMed

Markvartová, V; Vozeh, F

2008-01-01

Nitric oxide (NO) is an intercellular messenger that, among other things, plays an important role in the nervous system as a gaseous neurotransmitter, modulating long-term potentiation (LTP) induction of synaptic transmission. LTP has been suggested to be the basis of memory formation. On the other hand NO also participates in excitotoxic processes which play an important role in many neuropathological states. The aim of this work was to observe the effect of two NO synthase (NOS) inhibitors (N omega-Nitro-L-arginine, NA; 7-nitroindazole, NI) on spontaneous behaviour, spatial learning and motor functions in Lurcher (+/Lc) and wild type (+/+) mice, derived from the B6CBA strain. Heterozygous Lurcher mutant mice represent a natural model of the olivocerebellar degeneration. They suffer from postnatal, practically total, extinction of cerebellar Purkinje cells (due to the excitotoxic apoptosis) and a partial decrease of granule cells and inferior olive neurons (ION) because of the lost target of their axons. +/+ animals are healthy littermates of +/Lc. NA is a nonselective NOS inhibitor which influences, except neuronal (n), also endothelial (e) NOS with an impact on blood pressure, NI is a selective nNOS inhibitor without any circulatory effect. The adult animals of both types (+/Lc; +/+) were influenced by acute administration of both inhibitors (25 mg/kg i.p. 30 min. before experiments) and newborns only by both acute and long-term administration of NI (1 month, starting from postnatal day 2, P2). Control solutions - saline or solvents of both NA and NI inhibitors--diluted 1M HCl and dimethyl sulfoxide (DMSO) respectively, were given at a relevant volume in the same way. The effect of both inhibitors and control solutions on motor functions was tested using four standard procedures (horizontal wire, slanting ladder, rotating cylinder, foot-bridge); in newborns at the age of 14 days. Spatial learning ability was examined in five-day long procedure in the Morris

Association of Panic Disorder, Generalized Anxiety Disorder, and Benzodiazepine Treatment During Pregnancy With Risk of Adverse Birth Outcomes.

PubMed

Yonkers, Kimberly Ann; Gilstad-Hayden, Kathryn; Forray, Ariadna; Lipkind, Heather S

2017-11-01

Registry data show that maternal panic disorder, or anxiety disorders in general, increase the risk for adverse pregnancy outcomes. However, diagnoses from registries may be imprecise and may not consider potential confounding factors, such as treatment with medication and maternal substance use. To determine whether panic disorder or generalized anxiety disorder (GAD) in pregnancy, or medications used to treat these conditions, are associated with adverse maternal or neonatal pregnancy outcomes. This cohort study conducted between July 1, 2005, and July 14, 2009, recruited women at 137 obstetric practices in Connecticut and Massachusetts before 17 weeks of pregnancy and reassessed them at 28 (±4) weeks of pregnancy and 8 (±4) weeks postpartum. Psychiatric diagnoses were determined by answers to the World Mental Health Composite International Diagnostic Interview. Assessments also gathered information on treatment with medications and confounding factors, such as substance use, previous adverse birth outcomes, and demographic factors. Panic disorder, GAD, or use of benzodiazepines or serotonin reuptake inhibitors. Among mothers: preterm birth, cesarean delivery, and hypertensive diseases of pregnancy. Among neonates: low birth weight, use of minor respiratory interventions, and use of ventilatory support. Of the 2654 women in the final analysis (mean [SD] age, 31.0 [5.7] years), most were non-Hispanic white (1957 [73.7%]), 98 had panic disorder, 252 had GAD, 67 were treated with a benzodiazepine, and 293 were treated with a serotonin reuptake inhibitor during pregnancy. In adjusted models, neither panic disorder nor GAD was associated with maternal or neonatal complications of interest. Most medication exposures occurred early in pregnancy. Maternal benzodiazepine use was associated with cesarean delivery (odds ratio [OR], 2.45; 95% CI, 1.36-4.40), low birth weight (OR, 3.41; 95% CI, 1.61-7.26), and use of ventilatory support for the newborn (OR, 2.85; 95% CI, 1

α-Amylase inhibitor activity of endophytic bacteria isolated from Annona muricata L

NASA Astrophysics Data System (ADS)

Pujiyanto, Sri; Resdiani, Merysa; Raharja, Budi; Siti Ferniah, Rejeki

2018-05-01

α-amylase (α-1,4-glucan-4-glucohydrolase, EC 3.2.1.1) is an enzyme that catalyzes the degradation of starch into its monomers. Most people use medicinal plants for keeping normal level of blood glucose, for example, the Annona muricata. The objectives of this study are to obtain endophytic bacteria from the plant, knowing the activity of the α-amylase inhibitor of selected isolates. Endophytic bacteria are isolated from the roots, stems, and leaves of the plant have been sterilized surface and grown in NA medium. A total of 11 isolates were found to produce α-amylase inhibitor compounds. The isolates obtained were tested for their α-amylase inhibitor activity, and isolates with the highest activity tested further. Isolate DS21 show the best activity with 72,22% inhibition. The experimental design used in this research is Completely Randomized Design (RAL). The best isolates treated by a variety of carbon sources, and the best carbon source treated with various pH. The data obtained were analyzed usingAnalysis of Variance (ANOVA). The results of statistical tests show the treatment of starch and lactose has a significant effect on the production of α-amylase inhibitors (P <0.05) and the pH 5 and 6,0 significantly affected the production of α-amylase inhibitors (P <0.05).

Localized CO2 corrosion of carbon steel with different microstructures in brine solutions with an imidazoline-based inhibitor

NASA Astrophysics Data System (ADS)

Zhang, Huan-huan; Pang, Xiaolu; Gao, Kewei

2018-06-01

CO2 corrosion behavior of carbon steel with different microstructures (H steel: coarse laminar pearlite; T steel: globular and shot rod shaped pearlite) was analyzed in 3 wt.% NaCl solution at 60 °C with imidazoline-based inhibitor by electrochemical and weight loss methods. Electrochemical measurements showed that, compared to H steel, the inhibitor film adsorbed on T steel had a higher pitting corrosion resistance and the inhibition efficiency for T steel was larger at each concentration of inhibitor. Weight loss results exhibited that both steels suffered general corrosion in absence of inhibitor; however, localized corrosion was observed on the samples with insufficient concentration of inhibitor. H steel suffered more severe localized corrosion than T steel, it was related to that H steel had a higher density of dislocations in the pearlite area and the larger driving force for galvanic corrosion. The localized corrosion on H steel mainly distributed on the laminar pearlite area.

Effect of ENaC Modulators on Rat Neural Responses to NaCl

PubMed Central

Mummalaneni, Shobha; Qian, Jie; Phan, Tam-Hao T.; Rhyu, Mee-Ra; Heck, Gerard L.; DeSimone, John A.; Lyall, Vijay

2014-01-01

The effects of small molecule ENaC activators N,N,N-trimethyl-2-((4-methyl-2-((4-methyl-1H-indol-3-yl)thio)pentanoyl)oxy)ethanaminium iodide (Compound 1) and N-(2-hydroxyethyl)-4-methyl-2-((4-methyl-1H-indol-3-yl)thio)pentanamide (Compound 2), were tested on the benzamil (Bz)-sensitive NaCl chorda tympani (CT) taste nerve response under open-circuit conditions and under ±60 mV applied lingual voltage-clamp, and compared with the effects of known physiological activators (8-CPT-cAMP, BAPTA-AM, and alkaline pH), and an inhibitor (ionomycin+Ca2+) of ENaC. The NaCl CT response was enhanced at −60 mV and suppressed at +60 mV. In every case the CT response (r) versus voltage (V) curve was linear. All ENaC activators increased the open-circuit response (ro) and the voltage sensitivity (κ, negative of the slope of the r versus V curve) and ionomycin+Ca2+ decreased ro and κ to zero. Compound 1 and Compound 2 expressed a sigmoidal-saturating function of concentration (0.25–1 mM) with a half-maximal response concentration (k) of 0.49 and 1.05 mM, respectively. Following treatment with 1 mM Compound 1, 8-CPT-cAMP, BAPTA-AM and pH 10.3, the Bz-sensitive NaCl CT response to 100 mM NaCl was enhanced and was equivalent to the Bz-sensitive CT response to 300 mM NaCl. Plots of κ versus ro in the absence and presence of the activators or the inhibitor were linear, suggesting that changes in the affinity of Na+ for ENaC under different conditions are fully compensated by changes in the apical membrane potential difference, and that the observed changes in the Bz-sensitive NaCl CT response arise exclusively from changes in the maximum CT response (rm). The results further suggest that the agonists enhance and ionomycin+Ca2+ decreases ENaC function by increasing or decreasing the rate of release of Na+ from its ENaC binding site to the receptor cell cytosol, respectively. Irrespective of agonist type, the Bz-sensitive NaCl CT response demonstrated a maximum response enhancement

Inhibitory effects of α-Na8SiW11CoO40 on tyrosinase and its application in controlling browning of fresh-cut apples.

PubMed

Chen, Bing-Nian; Xing, Rui; Wang, Fang; Zheng, A-Ping; Wang, Li

2015-12-01

α-Na8SiW11CoO40 was synthesized and characterized. The inhibitory effects of α-Na8SiW11CoO40 on the activity of mushroom tyrosinase and the effects of α-Na8SiW11CoO40 on the browning of fresh-cut apples were studied. The Native-PAGE result showed that α-Na8SiW11CoO40 had a significant inhibitory effect on tyrosinase. Kinetic analyses showed that α-Na8SiW11CoO40 was an irreversible and competitive inhibitor. The inhibitor concentration leading to a 50% reduction in activity (IC50) was estimated to be 0.239 mM. Additionally, the results also showed that α-Na8SiW11CoO40 treatment could significantly decrease the browning process of apple slices and inhibit the polyphenol oxidase (PPO) activity. Moreover, application of α-Na8SiW11CoO40 resulted in higher peroxidase activity and promoted high amounts of phenolic compounds and ascorbic acid. This study may provide a promising method for the use of polyoxometalates to inhibit tyrosinase activity and control the browning of fresh-cut apples. Copyright © 2015 Elsevier Ltd. All rights reserved.

Short-term effects of cardiac steroids on intracellular membrane traffic in neuronal NT2 cells.

PubMed

Rosen, H; Glukmann, V; Feldmann, T; Fridman, E; Lichtstein, D

2006-12-30

Cardiac steroids (CS) are specific inhibitors of Na+, K+-ATPase activity. Although the presence of CS-like compounds in animal tissues has been established, their physiological role is not clear. In a previous study we showed that in pulse-chase membrane-labeling experiments, long term (hours) interaction of CS at physiological concentrations (nM) with Na+, K+-ATPase, caused changes in endocytosed membrane traffic in human NT2 cells. This was associated with the accumulation of large vesicles adjacent to the nucleus. For this sequence of events to function in the physiological setting, however, CS would be expected to modify membrane traffic upon short term (min) exposure and membrane labeling. We now demonstrate that CS affects membrane traffic also following a short exposure. This was reflected by the CS-induced accumulation of FM1-43 and transferrin in the cells, as well as by changes in their colocalization with Na+, K+-ATPase. We also show that the CS-induced changes in membrane traffic following up to 2 hrs exposure are reversible, whereas longer treatment induces irreversible effects. Based on these observations, we propose that endogenous CS-like compounds are physiological regulators of the recycling of endocytosed membrane proteins and cargo in neuronal cells, and may affect basic mechanisms such as neurotransmitter release and reuptake.

Inhibitors of endopeptidase and angiotensin-converting enzyme lead to an amplification of the morphological changes and an upregulation of the substance P system in a muscle overuse model

PubMed Central

2014-01-01

Background We have previously observed, in studies on an experimental overuse model, that the tachykinin system may be involved in the processes of muscle inflammation (myositis) and other muscle tissue alterations. To further evaluate the significance of tachykinins in these processes, we have used inhibitors of neutral endopeptidase (NEP) and angiotensin-converting enzyme (ACE), substances which are known to terminate the activity of various endogenously produced substances, including tachykinins. Methods Injections of inhibitors of NEP and ACE, as well as the tachykinin substance P (SP), were given locally outside the tendon of the triceps surae muscle of rabbits subjected to marked overuse of this muscle. A control group was given NaCl injections. Evaluations were made at 1 week, a timepoint of overuse when only mild inflammation and limited changes in the muscle structure are noted in animals not treated with inhibitors. Both the soleus and gastrocnemius muscles were examined morphologically and with immunohistochemistry and enzyme immunoassay (EIA). Results A pronounced inflammation (myositis) and changes in the muscle fiber morphology, including muscle fiber necrosis, occurred in the overused muscles of animals given NEP and ACE inhibitors. The morphological changes were clearly more prominent than for animals subjected to overuse and NaCl injections (NaCl group). A marked SP-like expression, as well as a marked expression of the neurokinin-1 receptor (NK-1R) was found in the affected muscle tissue in response to injections of NEP and ACE inhibitors. The concentration of SP in the muscles was also higher than that for the NaCl group. Conclusions The observations show that the local injections of NEP and ACE inhibitors led to marked SP-like and NK-1R immunoreactions, increased SP concentrations, and an amplification of the morphological changes in the tissue. The injections of the inhibitors thus led to a more marked myositis process and an upregulation of

ProTx-II, a selective inhibitor of NaV1.7 sodium channels, blocks action potential propagation in nociceptors.

PubMed

Schmalhofer, William A; Calhoun, Jeffrey; Burrows, Rachel; Bailey, Timothy; Kohler, Martin G; Weinglass, Adam B; Kaczorowski, Gregory J; Garcia, Maria L; Koltzenburg, Martin; Priest, Birgit T

2008-11-01

Voltage-gated sodium (Na(V)1) channels play a critical role in modulating the excitability of sensory neurons, and human genetic evidence points to Na(V)1.7 as an essential contributor to pain signaling. Human loss-of-function mutations in SCN9A, the gene encoding Na(V)1.7, cause channelopathy-associated indifference to pain (CIP), whereas gain-of-function mutations are associated with two inherited painful neuropathies. Although the human genetic data make Na(V)1.7 an attractive target for the development of analgesics, pharmacological proof-of-concept in experimental pain models requires Na(V)1.7-selective channel blockers. Here, we show that the tarantula venom peptide ProTx-II selectively interacts with Na(V)1.7 channels, inhibiting Na(V)1.7 with an IC(50) value of 0.3 nM, compared with IC(50) values of 30 to 150 nM for other heterologously expressed Na(V)1 subtypes. This subtype selectivity was abolished by a point mutation in DIIS3. It is interesting that application of ProTx-II to desheathed cutaneous nerves completely blocked the C-fiber compound action potential at concentrations that had little effect on Abeta-fiber conduction. ProTx-II application had little effect on action potential propagation of the intact nerve, which may explain why ProTx-II was not efficacious in rodent models of acute and inflammatory pain. Mono-iodo-ProTx-II ((125)I-ProTx-II) binds with high affinity (K(d) = 0.3 nM) to recombinant hNa(V)1.7 channels. Binding of (125)I-ProTx-II is insensitive to the presence of other well characterized Na(V)1 channel modulators, suggesting that ProTx-II binds to a novel site, which may be more conducive to conferring subtype selectivity than the site occupied by traditional local anesthetics and anticonvulsants. Thus, the (125)I-ProTx-II binding assay, described here, offers a new tool in the search for novel Na(V)1.7-selective blockers.

Effects of Combined CCR5/Integrase Inhibitors-Based Regimen on Mucosal Immunity in HIV-Infected Patients Naïve to Antiretroviral Therapy: A Pilot Randomized Trial.

PubMed

Serrano-Villar, Sergio; Sainz, Talia; Ma, Zhong-Min; Utay, Netanya S; Chun, Tae-Wook; Wook-Chun, Tae; Mann, Surinder; Kashuba, Angela D; Siewe, Basile; Albanese, Anthony; Troia-Cancio, Paolo; Sinclair, Elizabeth; Somasunderam, Anoma; Yotter, Tammy; Deeks, Steven G; Landay, Alan; Pollard, Richard B; Miller, Christopher J; Moreno, Santiago; Asmuth, David M

2016-01-01

Whether initiation of antiretroviral therapy (ART) regimens aimed at achieving greater concentrations within gut associated lymphoid tissue (GALT) impacts the level of mucosal immune reconstitution, inflammatory markers and the viral reservoir remains unknown. We included 12 HIV- controls and 32 ART-naïve HIV patients who were randomized to efavirenz, maraviroc or maraviroc+raltegravir, each with fixed-dose tenofovir disoproxil fumarate/emtricitabine. Rectal and duodenal biopsies were obtained at baseline and at 9 months of ART. We performed a comprehensive assay of T-cell subsets by flow cytometry, T-cell density in intestinal biopsies, plasma and tissue concentrations of antiretroviral drugs by high-performance liquid chromatography/mass spectroscopy, and plasma interleukin-6 (IL-6), lipoteichoic acid (LTA), soluble CD14 (sCD14) and zonulin-1 each measured by ELISA. Total cell-associated HIV DNA was measured in PBMC and rectal and duodenal mononuclear cells. Twenty-six HIV-infected patients completed the follow-up. In the duodenum, the quadruple regimen resulted in greater CD8+ T-cell density decline, greater normalization of mucosal CCR5+CD4+ T-cells and increase of the naïve/memory CD8+ T-cell ratio, and a greater decline of sCD14 levels and duodenal HIV DNA levels (P = 0.004 and P = 0.067, respectively), with no changes in HIV RNA in plasma or tissue. Maraviroc showed the highest drug distribution to the gut tissue, and duodenal concentrations correlated well with other T-cell markers in duodenum, i.e., the CD4/CD8 ratio, %CD4+ and %CD8+ HLA-DR+CD38+ T-cells. Maraviroc use elicited greater activation of the mucosal naïve CD8+ T-cell subset, ameliorated the distribution of the CD8+ T-cell maturational subsets and induced higher improvement of zonulin-1 levels. These data suggest that combined CCR5 and integrase inhibitor based combination therapy in ART treatment naïve patients might more effectively reconstitute duodenal immunity, decrease inflammatory

Development and Psychometric Evaluation of the Treatment-Emergent Activation and Suicidality Assessment Profile

ERIC Educational Resources Information Center

Reid, Jeannette M.; Storch, Eric A.; Murphy, Tanya K.; Bodzin, Danielle; Mutch, P. Jane; Lehmkuhl, Heather; Aman, Michael; Goodman, Wayne K.

2010-01-01

Although effective in treating a range of childhood psychiatric conditions, selective serotonin reuptake inhibitors (SSRI) have been implicated in the induction of an "activation syndrome" (characterized by symptoms of irritability, restlessness, emotional labiality, etc.) that may represent an intermediary state change that fosters…

Neonatal intraventricular haemorrhage associated with maternal use of paroxetine

PubMed Central

Duijvestijn, Yvonne C M; Kalmeijer, Mathijs D; Passier, Anneke L M; Dahlem, Peter; Smiers, Frans

2003-01-01

Selective serotonin reuptake inhibitors (SSRIs) have been reported to inhibit serotonin uptake into platelets, resulting in decreased platelet function. We report a case of a large intraventricular haemorrhage in a 6-h-old boy, whose mother used paroxetine during pregnancy. PMID:14651736

WE-FG-202-05: Quantification of Bone Flare On [F-18] NaF PET/CT in Metastatic Prostate Cancer

DOE Office of Scientific and Technical Information (OSTI.GOV)

Weisman, A; Harmon, S; Perk, T

Purpose: Bone flare has been observed on Tc-99m bone scans during early assessment in metastatic Castration-Resistant Prostate Cancer (mCRPC) patients receiving select androgen-signaling pathway (AR) targeted treatments, including CYP17-inhibitor Abiraterone. This study investigates the appearance and potential clinical impact of bone flare in mCRPC patients receiving CYP17-inhibitors using {sup 18}F-NaF PET/CT. Methods: Twenty-three mCRPC patients being treated with CYP17-inhibitors received NaF PET/CT scans at baseline, week 6, and week 12 of treatment. Individual lesions were identified using a SUV>15 threshold within skeletal regions and articulated bone registration was used to track lesions between scans. Standard SUV metrics were extracted globallymore » for each patient (pSUV) and for each individual lesion (iSUV). Differences in metrics across time-points were compared using Wilcoxon signed-rank tests. Cox proportional hazard regression analyses were conducted between global metrics and progression-free survival (PFS). Results: Nineteen patients (83%) showed increasing NaF PET global metrics at week 6, with pSUV{sub total} reflecting consensus change across other global metrics with median increase +33% (range +2 to 205%). Of these patients, 14 showed subsequent decrease in pSUV{sub total}, with a median of −17% (range −76 to −1%), indicating flare phenomenon. Increasing pSUV{sub mean} at week 6 correlated with extended clinical PFS (HR = 0.58, p=0.02). New lesions did not account for the initial increase in global NaF metrics. Lesion-level analysis reveals 316 lesions in the 14 patients exhibiting global flare. On average, 75% (sd: 22%) of lesions follow global trends with iSUV{sub total} increasing at week 6 and 65% (sd: 17%) showing iSUV{sub total} decrease at week 12. Conclusion: Bone flare was detected on NaF PET/CT in the first 6 weeks of treatment for mCRPC patients receiving CYP17-inhibitors, subsiding by week 12. Characterization provided

[Social phobia].

PubMed

Bandelow, B; Wedekind, D

2014-05-01

With a lifetime prevalence of 13% social phobia (social anxiety disorder) is a common and serious condition that should not be played down because of the burden associated with the disorder, an increased suicide rate and the frequent comorbidity with substance abuse disorders. Social phobia is characterized by the excessive and unrealistic fear of being scrutinized or criticized by others. The disorder often begins in adolescence.Symptoms of social phobia can be effectively treated with evidence-based treatment, including cognitive behavior therapy (CBT) and psychopharmacological medications. In the present paper, treatment recommendations are given, which are based on a systematic review of all available randomized trials for the treatment of social phobia. Among psychological therapies, variants of CBT have been proven to be effective in controlled studies. Selective serotonin reuptake inhibitors (SSRIs) and the selective serotonin norepinephrine reuptake inhibitor (SNRI) venlafaxine are among the drugs of first choice.

Compulsive masturbation in infantile autism treated by mirtazapine.

PubMed

Albertini, Giorgio; Polito, Emilena; Sarà, Marco; Di Gennaro, Giancarlo; Onorati, Paolo

2006-05-01

This case report describes a child with a severe autistic syndrome worsened by hypersexual behavior consisting of compulsive masturbatory activity. Selective serotonin reuptake inhibitors have been reported to be beneficial in reducing hypersexual behaviors. A treatment with mirtazapine improved the entire clinical autistic picture with the disappearance of masturbation. This result suggests that selective serotonin reuptake inhibitors could be useful and promising tools in the treatment of hypersexual behaviors in children with autistic disorders. Moreover, the general, and in some ways unexpected, improvement of the social interaction, communication, and imagination, the dramatic reduction of aloof mannerisms, stereotypes, aggressiveness, and inappropriate emotional response to frustrations, as well as the first appearance of the pragmatic use of language and a strong impetus to emotional development disclosed a new spectrum of possible applications of these drugs, and mirtazapine in particular, suggesting the need for new and more extensive studies on the pharmacotherapy of autism.

The effect of inhibitor sodium nitrate on pitting corrosion of dissimilar material weldment joint of stainless steel AISI 304 and mild steel SS 400

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hilca, B. R., E-mail: bangkithilca@yahoo.com; Triyono, E-mail: triyonomesin@uns.ac.id

This study experimentally evaluated the effect of Sodium Nitrate inhibitor (NaNO{sub 3}) of 0.1%, 0.3%, and 0.5% on NaCl 3.5% toward pitting corrosion of dissimilar metal welding joint between stainless steel AISI 304 and mild steel SS 400. Electrochemical corrosion was tested using potentiodynamic polarization. Further the Scanning Electron Microscope (SEM) conducted to analyze the specimen. Chemical composition analysis used Energy Dispersive X-ray Spectrometry (EDS). The highest efficiency of sodium nitrate for ER 308 attained 63.8% and 64.89%for ER 309L. The specimen surface which observed through SEM showed decrease of pitting corrosion respectively with the addition of sodium nitrate contentmore » as inhibitor.« less

Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents.

PubMed

Paterson, Neil E; Fedolak, Allison; Olivier, Berend; Hanania, Taleen; Ghavami, Afshin; Caldarone, Barbara

2010-06-01

The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil. Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors. Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the mu-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion. Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo. Copyright 2010 Elsevier Inc. All rights reserved.

Unique Determinants of Neuraminidase Inhibitor Resistance among N3, N7, and N9 Avian Influenza Viruses.

PubMed

Song, Min-Suk; Marathe, Bindumadhav M; Kumar, Gyanendra; Wong, Sook-San; Rubrum, Adam; Zanin, Mark; Choi, Young-Ki; Webster, Robert G; Govorkova, Elena A; Webby, Richard J

2015-11-01

Human infections with avian influenza viruses are a serious public health concern. The neuraminidase (NA) inhibitors (NAIs) are the frontline anti-influenza drugs and are the major option for treatment of newly emerging influenza. Therefore, it is essential to identify the molecular markers of NAI resistance among specific NA subtypes of avian influenza viruses to help guide clinical management. NAI-resistant substitutions in NA subtypes other than N1 and N2 have been poorly studied. Here, we identified NA amino acid substitutions associated with NAI resistance among influenza viruses of N3, N7, and N9 subtypes which have been associated with zoonotic transmission. We applied random mutagenesis and generated recombinant influenza viruses carrying single or double NA substitution(s) with seven internal genes from A/Puerto Rico/8/1934 (H1N1) virus. In a fluorescence-based NA inhibition assay, we identified three categories of NA substitutions associated with reduced inhibition by NAIs (oseltamivir, zanamivir, and peramivir): (i) novel subtype-specific substitutions in or near the enzyme catalytic site (R152W, A246T, and D293N, N2 numbering), (ii) subtype-independent substitutions (E119G/V and/or D and R292K), and (iii) substitutions previously reported in other subtypes (Q136K, I222M, and E276D). Our data show that although some markers of resistance are present across NA subtypes, other subtype-specific markers can only be determined empirically. The number of humans infected with avian influenza viruses is increasing, raising concerns of the emergence of avian influenza viruses resistant to neuraminidase (NA) inhibitors (NAIs). Since most studies have focused on NAI-resistance in human influenza viruses, we investigated the molecular changes in NA that could confer NAI resistance in avian viruses grown in immortalized monolayer cells, especially those of the N3, N7, and N9 subtypes, which have caused human infections. We identified not only numerous NAI

Propolis as a green corrosion inhibitor for bronze in weakly acidic solution

NASA Astrophysics Data System (ADS)

Varvara, Simona; Bostan, Roxana; Bobis, Otilia; Găină, Luiza; Popa, Florin; Mena, Vicente; Souto, Ricardo M.

2017-12-01

In the present work, the inhibitive action of natural propolis on bronze corrosion in a weakly acidic solution containing Na2SO4 and NaHCO3 at pH 5 was evaluated using multiscale electrochemical techniques, namely potentiodynamic polarization, electrochemical impedance spectroscopy and scanning vibrating electrode technique measurements. The major constituents of propolis were identified by HPLC. Surface characterization was performed by SEM-EDX and AFM analysis. Experiments were performed as a function of the propolis concentration and immersion time in the corrosive electrolyte. The obtained results showed that propolis presents good anticorrosive properties on bronze, acting as a mixed-type inhibitor, but its protective effectiveness is time-dependent. The highest inhibiting efficiency of 98.9% was obtained in the presence of 100 ppm propolis, after about 12 h of exposure to inhibitor-containing electrolyte through the stabilization of Cu2O on the bronze surface. The inhibitive properties of propolis on bronze corrosion are likely due to the adsorption of its main constituents (flavonoids and phenolic compounds), through the oxygen atoms in their functional groups and aromatic rings, which have been evidenced by FT-IR spectra. The adsorption of propolis on bronze was found to follow Langmuir adsorption isotherm.

Bupropion Administration Increases Resting-State Functional Connectivity in Dorso-Medial Prefrontal Cortex.

PubMed

Rzepa, Ewelina; Dean, Zola; McCabe, Ciara

2017-06-01

Patients on the selective serotonergic reuptake inhibitors like citalopram report emotional blunting. We showed previously that citalopram reduces resting-state functional connectivity in healthy volunteers in a number of brain regions, including the dorso-medial prefrontal cortex, which may be related to its clinical effects. Bupropion is a dopaminergic and noradrenergic reuptake inhibitor and is not reported to cause emotional blunting. However, how bupropion affects resting-state functional connectivity in healthy controls remains unknown. Using a within-subjects, repeated-measures, double-blind, crossover design, we examined 17 healthy volunteers (9 female, 8 male). Volunteers received 7 days of bupropion (150 mg/d) and 7 days of placebo treatment and underwent resting-state functional Magnetic Resonance Imaging. We selected seed regions in the salience network (amygdala and pregenual anterior cingulate cortex) and the central executive network (dorsal medial prefrontal cortex). Mood and anhedonia measures were also recorded and examined in relation to resting-state functional connectivity. Relative to placebo, bupropion increased resting-state functional connectivity in healthy volunteers between the dorsal medial prefrontal cortex seed region and the posterior cingulate cortex and the precuneus cortex, key parts of the default mode network. These results are opposite to that which we found with 7 days treatment of citalopram in healthy volunteers. These results reflect a different mechanism of action of bupropion compared with selective serotonergic reuptake inhibitors. These results help explain the apparent lack of emotional blunting caused by bupropion in depressed patients. © The Author 2017. Published by Oxford University Press on behalf of CINP.

Acute and Chronic Noradrenergic Effects on Cortical Excitability in Healthy Humans

PubMed Central

Kuo, Hsiao-I; Paulus, Walter; Batsikadze, Giorgi; Jamil, Asif; Kuo, Min-Fang

2017-01-01

Abstract Background Noradrenaline is a major neuromodulator in the central nervous system, and it is involved in the pathophysiology of diverse neuropsychiatric diseases. Previous transcranial magnetic stimulation studies suggested that acute application of selective noradrenaline reuptake inhibitors enhances cortical excitability in the human brain. However, other, such like clinical effects, usually require prolonged noradrenaline reuptake inhibitor treatment, which might go along with different physiological effects. Methods The purpose of this study was to investigate the acute and chronic effects of the selective noradrenaline reuptake inhibitor reboxetine on cortical excitability in healthy humans in a double-blind, placebo-controlled, randomized crossover study. Sixteen subjects were assessed with different transcranial magnetic stimulation measurements: motor thresholds, input-output curve, short-latency intracortical inhibition and intracortical facilitation, I-wave facilitation, and short-interval afferent inhibition before and after placebo or reboxetine (8 mg) single-dose administration. Afterwards, the same subjects took reboxetine (8 mg/d) consecutively for 21 days. During this period (subjects underwent 2 experimental sessions with identical transcranial magnetic stimulation measures under placebo or reboxetine), transcranial magnetic stimulation measurements were assessed before and after drug intake. Results Both single-dose and chronic administration of reboxetine increased cortical excitability; increased the slope of the input-output curve, intracortical facilitation, and I-wave facilitation; but decreased short-latency intracortical inhibition and short-interval afferent inhibition. Moreover, chronic reboxetine showed a larger enhancement of intracortical facilitation and I-wave facilitation compared with single-dose application. Conclusions The results show physiological mechanisms of noradrenergic enhancement possibly underlying the

The pump, the exchanger, and the holy spirit: origins and 40-year evolution of ideas about the ouabain-Na+ pump endocrine system.

PubMed

Blaustein, Mordecai P

2018-01-01

Two prescient 1953 publications set the stage for the elucidation of a novel endocrine system: Schatzmann's report that cardiotonic steroids (CTSs) are all Na + pump inhibitors, and Szent-Gyorgi's suggestion that there is an endogenous "missing screw" in heart failure that CTSs like digoxin may replace. In 1977 I postulated that an endogenous Na + pump inhibitor acts as a natriuretic hormone and simultaneously elevates blood pressure (BP) in salt-dependent hypertension. This hypothesis was based on the idea that excess renal salt retention promoted the secretion of a CTS-like hormone that inhibits renal Na + pumps and salt reabsorption. The hormone also inhibits arterial Na + pumps, elevates myocyte Na + and promotes Na/Ca exchanger-mediated Ca 2+ gain. This enhances vasoconstriction and arterial tone-the hallmark of hypertension. Here I describe how those ideas led to the discovery that the CTS-like hormone is endogenous ouabain (EO), a key factor in the pathogenesis of hypertension and heart failure. Seminal observations that underlie the still-emerging picture of the EO-Na + pump endocrine system in the physiology and pathophysiology of multiple organ systems are summarized. Milestones include: 1) cloning the Na + pump isoforms and physiological studies of mutated pumps in mice; 2) discovery that Na + pumps are also EO-triggered signaling molecules; 3) demonstration that ouabain, but not digoxin, is hypertensinogenic; 4) elucidation of EO's roles in kidney development and cardiovascular and renal physiology and pathophysiology; 5) discovery of "brain ouabain", a component of a novel hypothalamic neuromodulatory pathway; and 6) finding that EO and its brain receptors modulate behavior and learning.

NO Metabolites Levels in Human Red Blood Cells are Affected by Palytoxin, an Inhibitor of Na(+)/K(+)-ATPase Pump.

PubMed

Carelli-Alinovi, Cristiana; Tellone, Ester; Russo, Anna Maria; Ficarra, Silvana; Pirolli, Davide; Galtieri, Antonio; Giardina, Bruno; Misiti, Francesco

2014-01-01

Palytoxin (PTX), a marine toxin, represents an increasing hazard for human health. Despite its high toxicity for biological systems, the mechanisms triggered by PTX, are not well understood. The high affinity of PTX for erythrocyte Na(+)/K(+)-ATPase pump is largely known, and it indicates PTX as a sensitive tool to characterize the signal transducer role for Na(+)/K(+)-ATPase pump. Previously, it has been reported that in red blood cells (RBC), probably via a signal transduction generated by the formation of a PTX-Na(+)/K(+)-ATPase complex, PTX alters band 3 functions and glucose metabolism. The present study addresses the question of which other signaling pathways are regulated by Na(+)/K(+)-ATPase in RBC. Here it has been evidenced that PTX following its interaction with Na(+)/K(+)-ATPase pump, alters RBC morphology and this event is correlated to decreases by 30% in nitrites and nitrates levels, known as markers of plasma membrane eNOS activity. Orthovanadate (OV), an antagonist of PTX binding to Na(+)/K(+)-ATPase pump, was able to reverse the effects elicited by PTX. Finally, current investigation firstly suggests that Na(+)/K(+)-ATPase pump, following its interaction with PTX, triggers a signal transduction involved in NO metabolism regulation.

Study of caffeine as corrosion inhibitors of carbon steel in chloride solution containing hydrogen sulfide using electrochemical impedance spectroscopy (EIS)

NASA Astrophysics Data System (ADS)

Solehudin, Agus; Berman, Ega Taqwali; Nurdin, Isdiriayani

2015-09-01

The corrosion behaviour of steel surface in the absence and presence of caffeine in 3.5% NaCl solution containing dissolved H2S gas is studied using electrochemical impedance spectroscopy (EIS). The experimental results of carbon steel corrosion in 3.5% NaCl solution containing 500 mg/l H2S at different caffeine concentrations showed that corrosion rate of carbon steel decreases with increasing of caffeine concentrations from 0 to 0,1 mmol/l. Whereas, the corrosion rate increase with increasing of caffeine concentrations from 1 to 10 mmol/l. It is clear that no inhibition efficiency increases with increasing inhibitor concentration. The optimum value of inhibition efficiency was 90% at a caffeine concentration of 0.1 mmol/l. This suggests that caffeine's performance as a corrosion inhibitor is more effective at a concentration of 0.1 mmol/l.

Characterization of digitalis-like factors in human plasma. Interactions with NaK-ATPase and cross-reactivity with cardiac glycoside-specific antibodies.

PubMed

Kelly, R A; O'Hara, D S; Canessa, M L; Mitch, W E; Smith, T W

1985-09-25

Much of the evidence for a physiologically important endogenous inhibitor of the sodium pump has been either contradictory or indirect. We have identified three discrete fractions in desalted deproteinized plasma from normal humans that resemble the digitalis glycosides in that they: are of low molecular weight; are resistant to acid and enzymatic proteolysis; inhibit NaK-ATPase activity; inhibit Na+ pump activity in human erythrocytes; displace [3H]ouabain bound to the enzyme; and cross-react with high-affinity polyclonal and monoclonal digoxin-specific antibodies but not with anti-ouabain or anti-digitoxin antibodies. An additional fraction cross-reacted with digoxin-specific antibodies but had no detectable activity against NaK-ATPase. The three inhibitory fractions differed from cardiac glycosides in that their concentration-effect curves in a NaK-ATPase inhibition and [3H]ouabain radioreceptor assays were steeper than unlabeled ouabain. This suggests that these inhibitors are not simple competitive ligands for binding to NaK-ATPase. In the presence of sodium, no fraction required ATP for binding to NaK-ATPase, and in the presence of potassium, only one fraction had the reduced affinity for the enzyme that is characteristic of cardiac glycosides. Unlike digitalis, all three NaK-ATPase inhibitory fractions stimulated the activity of skeletal muscle sarcoplasmic reticulum Ca-ATPase. The presence of at least three fractions in human plasma that inhibit NaK-ATPase and cross-react to a variable degree with different digoxin-specific antibody populations could explain much of the conflicting evidence for the existence of endogenous digitalis-like compounds in plasma.

Na+/Ca2+ exchange and regulation of cytoplasmic concentration of calcium in rat cerebellar neurons treated with glutamate.

PubMed

Storozhevykh, T P; Sorokina, E G; Vabnitz, A V; Senilova, Ya E; Tukhbatova, G R; Pinelis, V G

2007-07-01

In the present work, the forward and/or reversed Na+/Ca2+ exchange in cerebellar granular cells was suppressed by substitution of Na+o by Li+ before, during, and after exposure to glutamate for varied time and also using the inhibitor KB-R7943 of the reversed exchange. After glutamate challenge for 1 min, Na+o/Li+ substitution did not influence the recovery of low [Ca2+]i in a calcium-free medium. A 1-h incubation with 100 microM glutamate induced in the neurons a biphasic and irreversible [Ca2+]i rise (delayed calcium deregulation (DCD)), enhancement of [Na+]i, and decrease in the mitochondrial potential. If Na+o had been substituted by Li+ before the application of glutamate, i.e. the exchange reversal was suppressed during the exposure to glutamate, the number of cells with DCD was nearly fourfold lowered. However, addition of the Na+/K+-ATPase inhibitor ouabain (0.5 mM) not preventing the exchange reversal also decreased DCD in the presence of glutamate. Both exposures decreased the glutamate-caused loss of intracellular ATP. Glucose deprivation partially abolished protective effects of the Na+o/Li+ substitution and ouabain. KB-R7943 (10 microM) increased 7.4-fold the number of cells with the [Ca2+]i decreased to the basal level after the exposure to glutamate. Thus, reversal of the Na+/Ca2+ exchange reinforced the glutamate-caused perturbations of calcium homeostasis in the neurons and slowed the recovery of the decreased [Ca2+]i in the post-glutamate period. However, for development of DCD, in addition to the exchange reversal, other factors are required, in particular a decrease in the intracellular concentration of ATP.

Super-Hydrophobic Green Corrosion Inhibitor On Carbon Steel

NASA Astrophysics Data System (ADS)

Hassan, H.; Ismail, A.; Ahmad, S.; Soon, C. F.

2017-06-01

There are many examples of organic coatings used for corrosion protection. In particular, hydrophobic and super-hydrophobic coatings are shown to give good protection because of their enhanced ability to slow down transport of water and ions through the coating. The purpose of this research is to develop water repellent coating to avoid direct contact between metal and environment corrosive and mitigate corrosion attack at pipeline system. This water repellent characteristic on super-hydrophobic coating was coated by electrodeposition method. Wettability of carbon steel with super-hydrophobic coating (cerium chloride and myristic acid) and oxidized surface was investigated through contact angle and inhibitor performance test. The inhibitor performance was studied in 25% tannin acid corrosion test at 30°C and 3.5% sodium chloride (NaCl). The water contact angle test was determined by placing a 4-μL water droplet of distilled water. It shows that the wettability of contact angle super-hydrophobic with an angle of 151.60° at zero minute can be classified as super-hydrophobic characteristic. By added tannin acid as inhibitor the corrosion protection on carbon steel becomes more consistent. This reveals that the ability of the coating to withstand with the corrosion attack in the seawater at different period of immersions. The results elucidate that the weight loss increased as the time of exposure increased. However, the corrosion rates for uncoated carbon steel is high compared to coated carbon steel. As a conclusion, from both samples it can be seen that the coated carbon steel has less corrosion rated compared to uncoated carbon steel and addition of inhibitor to the seawater provides more protection to resist corrosion attack on carbon steel.

Pharmacotherapy and Children with Autism Spectrum Disorder: A Tutorial for Speech-Language Pathologists

ERIC Educational Resources Information Center

Self, Trisha L.; Hale, LaDonna S.; Crumrine, Daiquirie

2010-01-01

Purpose: The purpose of this tutorial is to provide speech-language pathologists (SLPs) with general information regarding the most commonly prescribed medications for children with autism spectrum disorder (ASD; e.g., central nervous system stimulants, noradrenergic reuptake inhibitors, alpha-2 adrenergic agonists, antipsychotics,…

Psychotherapy, Pharmacotherapy, and Their Combination for Adolescents with Major Depressive Disorder: A Meta-Analysis

ERIC Educational Resources Information Center

Singh, Nikita; Reece, John

2014-01-01

This meta-analysis aims to inform clinical practice of treatment strategies for adolescents with major depressive disorder (MDD). The efficacy of three empirically validated treatments was compared to determine the most effective treatment. These were: cognitive-behavioural therapy (CBT), selective serotonin reuptake inhibitor (SSRI)…

A Randomized Effectiveness Trial of Brief Cognitive-Behavioral Therapy for Depressed Adolescents Receiving Antidepressant Medication

ERIC Educational Resources Information Center

Clarke, Gregory; DeBar, Lynn; Lynch, Frances; Powell, James; Gale, John; O'Connor, Elizabeth; Ludman, Evette; Bush, Terry; Lin, Elizabeth H. B.; Von Korff, Michael; Hertert, Stephanie

2005-01-01

Objective: To test a collaborative-care, cognitive-behavioral therapy (CBT) program adjunctive to selective serotonin reuptake inhibitor (SSRI) treatment in HMO pediatric primary care. Method: A randomized effectiveness trial comparing a treatment-as-usual (TAU) control condition consisting primarily of SSRI medication delivered outside the…

Jak2 and Ca2+/calmodulin are key intermediates for bradykinin B2 receptor-mediated activation of Na+/H+ exchange in KNRK and CHO cells.

PubMed

Lefler, David; Mukhin, Yurii V; Pettus, Tobiah; Leeb-Lundberg, L M Fredrik; Garnovskaya, Maria N; Raymond, John R

2003-04-01

Na(+)/H(+) exchangers are ubiquitous in mammalian cells, carrying out key functions, such as cell volume defense, acid-base homeostasis, and regulation of the cytoskeleton. We used two screening technologies (FLIPR and microphysiometry) to characterize the signal transduction pathway used by the bradykinin B(2) receptor to activate Na(+)/H(+) exchange in two cell lines, KNRK and CHO. In both cell types, B(2) receptor activation resulted in rapid increases in the rate of proton extrusion that were sodium-dependent and could be blocked by the Na(+)/H(+) exchange inhibitors EIPA and MIA or by replacing extracellular sodium with TMA. Activation of Na(+)/H(+) exchange by bradykinin was concentration-dependent and could be blocked by the selective B(2) receptor antagonist HOE140, but not by the B(1) receptor antagonist des-Arg10-HOE140. Inhibitors of Jak2 tyrosine kinase (genistein and AG490) and of CAM (W-7 and calmidazolium) attenuated bradykinin-induced activation of Na(+)/H(+) exchange. Bradykinin induced formation of a complex between CAM and Jak2, supporting a regulatory role for Jak2 and CAM in the activation of Na(+)/H(+) exchange in KNRK and CHO cells. We propose that this pathway (B(2) receptor --> Jak2 --> CAM --> Na(+)/H(+) exchanger) is a fundamental regulator of Na(+)/H(+) exchange activity.

HDAC inhibitors TSA and sodium butyrate enhanced the human IL-5 expression by altering histone acetylation status at its promoter region.

PubMed

Han, Songyan; Lu, Jun; Zhang, Yu; Cheng, Cao; Li, Lin; Han, Liping; Huang, Baiqu

2007-02-15

The expression of IL-5 correlated tightly with the maturation and differentiation of eosinophils, and is considered as a cytokine responsible for allergic inflammation. We report here that inhibition of HDAC activity by Trichostatin A (TSA) and sodium butyrate (NaBu), the two specific HDAC inhibitors, resulted in the elevation of both endogenous and exogenous activity of IL-5 promoter. We demonstrated that both the mRNA expression and protein production of IL-5 were stimulated by TSA and NaBu treatments. ChIP assays showed that treatments of TSA and NaBu caused hyperacetylation of histones H3 and H4 on IL-5 promoter in Jurkat cells, which consequently promoted the exogenous luciferase activity driven by this promoter. Moreover, site-directed mutagenesis studies showed that the binding sites for transcription factors NFAT, GATA3 and YY1 on IL-5 promoter were critical for the effects of TSA and NaBu, suggesting that the transcriptional activation of IL-5 gene by these inhibitors was achieved by affecting HDAC function on IL-5 promoter via transcription factors. These data will contribute to elucidating the unique mechanism of IL-5 transcriptional control and to the therapy of allergic disorders related to IL-5.

Discovering Anti-platelet Drug Combinations with an Integrated Model of Activator-Inhibitor Relationships, Activator-Activator Synergies and Inhibitor-Inhibitor Synergies

PubMed Central

Lombardi, Federica; Golla, Kalyan; Fitzpatrick, Darren J.; Casey, Fergal P.; Moran, Niamh; Shields, Denis C.

2015-01-01

Identifying effective therapeutic drug combinations that modulate complex signaling pathways in platelets is central to the advancement of effective anti-thrombotic therapies. However, there is no systems model of the platelet that predicts responses to different inhibitor combinations. We developed an approach which goes beyond current inhibitor-inhibitor combination screening to efficiently consider other signaling aspects that may give insights into the behaviour of the platelet as a system. We investigated combinations of platelet inhibitors and activators. We evaluated three distinct strands of information, namely: activator-inhibitor combination screens (testing a panel of inhibitors against a panel of activators); inhibitor-inhibitor synergy screens; and activator-activator synergy screens. We demonstrated how these analyses may be efficiently performed, both experimentally and computationally, to identify particular combinations of most interest. Robust tests of activator-activator synergy and of inhibitor-inhibitor synergy required combinations to show significant excesses over the double doses of each component. Modeling identified multiple effects of an inhibitor of the P2Y12 ADP receptor, and complementarity between inhibitor-inhibitor synergy effects and activator-inhibitor combination effects. This approach accelerates the mapping of combination effects of compounds to develop combinations that may be therapeutically beneficial. We integrated the three information sources into a unified model that predicted the benefits of a triple drug combination targeting ADP, thromboxane and thrombin signaling. PMID:25875950

Monoamine uptake inhibitors block alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation.

PubMed

Long, Cheng; Chen, Mei-Fang; Sarwinski, Susan J; Chen, Po-Yi; Si, Minliang; Hoffer, Barry J; Evans, M Steven; Lee, Tony J F

2006-07-01

We have proposed that activation of cerebral perivascular sympathetic alpha7-nicotinic acetylcholine receptors (alpha7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced alpha7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced alpha7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03-0.1 microM) but inhibited at higher concentrations (0.3-10 microM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1-30 mM)-evoked inward currents were reversibly blocked by 1-30 microM mecamylamine, 1-30 microM methyllycaconitine, 10-300 nM alpha-bungarotoxin, and 0.1-10 microM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional alpha7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In alpha7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by alpha-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the alpha7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on alpha7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.

Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation.

PubMed

Llewellyn-Jones, C G; Lomas, D A; Stockley, R A

1994-06-01

Neutrophil elastase is able to degrade connective tissue matrices and is thought to be involved in the pathogenesis of destructive lung diseases. The ability of recombinant secretory leucoprotease inhibitor (rSLPI) to inhibit neutrophil mediated degradation of fibronectin in vitro is demonstrated and its efficacy compared with native alpha-1-proteinase inhibitor (n alpha 1-PI), recombinant alpha-1-proteinase inhibitor (r alpha 1-PI), and the chemical elastase inhibitor ICI 200,355. When preincubated with neutrophils both rSLPI and r alpha 1-PI were effective inhibitors of fibronectin degradation although n alpha 1-PI and ICI 200,355 were less effective. Recombinant SLPI was the most effective inhibitor when the cells were allowed to adhere to fibronectin before the addition of the inhibitors. Preincubation of rSLPI (0.1 mumol/l) with the fibronectin plate resulted in almost total inhibition of fibronectin degradation (reduced to 3.3 (SE 0.9)% of control). Pretreating the fibronectin plate with 1 mumol/l rSLPI, r alpha 1-PI and ICI 200,355 followed by thorough washing before the addition of cells resulted in no inhibition of fibronectin degradation with r alpha 1-PI and the ICI inhibitor, but rSLPI retained its inhibitory effect. This effect could be reduced by adding rSLPI in high pH buffer or 2 mol/1 NaCl. It is postulated that rSLPI binds to fibronectin to form a protective layer which prevents its degradation by neutrophil elastase. It may prove to be the most useful therapeutic agent in the prevention of neutrophil mediated lung damage.

A role for the serotonin reuptake transporter in the brain and intestinal features of autism spectrum disorders and developmental antidepressant exposure.

PubMed

Margolis, Kara Gross

2017-10-01

Many disease conditions considered CNS-predominant harbor significant intestinal comorbidities. Serotonin (5-HT) and the serotonin reuptake transporter (SERT) have increasingly been shown to play important roles in both brain and intestinal development and long-term function. 5-HT and SERT may thus modulate critical functions in the development and perpetuation of brain-gut axis disease. We discuss the potential roles of 5-HT and SERT in the brain and intestinal manifestations of autism spectrum disorders and developmental antidepressant exposure. The potential therapeutic value of 5-HT 4 modulation in the subsequent treatment of these conditions is also addressed. Copyright © 2017 Elsevier B.V. All rights reserved.

Prevalence of antiretroviral drug resistance and resistance-associated mutations in antiretroviral therapy-naïve HIV-infected individuals from 40 United States cities.

PubMed

Ross, Lisa; Lim, Michael L; Liao, Qiming; Wine, Brian; Rodriguez, Allan E; Weinberg, Winkler; Shaefer, Mark

2007-01-01

Transmission of drug-resistant HIV strains to antiretroviral therapy (ART)-naïve subjects can negatively impact therapy response. As treatment strategies and utilization of antiretroviral drugs evolve, patterns of transmitted mutations may shift. Paired genotypic and phenotypic susceptibility data were retrospectively analyzed for 317 ART-naïve, HIV-infected subjects from 40 small and major metropolitan cities in the Northeastern, Midwestern, Southern, Southwestern, and Northwestern United States during 2003. Using current (January 2007) PhenoSense cutoffs, HIV-from 8% of subjects had reduced susceptibility to > or = 1 drug. By class, < 1% had reduced susceptibility to protease inhibitors (PIs), and 1% had reduced susceptibility to nucleoside reverse transcriptase inhibitors (NRTIs); reduced susceptibility to > or = 1 non-nucleoside reverse transcriptase inhibitor (NNRTIs) was seen in 7% of subjects, with 4% of all subjects having reduced susceptibility to all NNRTIs. IAS-USA-defined NRTI, NNRTI, and/or major PI HIV-drug resistance-associated mutations were detected for 0% of the subjects. HIV risk factors included homosexual contact (74%), heterosexual contact (28%), and injectable drug use/transfusion/other (7%). Reduced susceptibility to > or = 1 drug was significantly higher (p = .034) for white subjects than African Americans and Hispanics/others. The high prevalence of drug resistance in these ART-naïve subjects suggests that transmitted resistance is occurring widely within the United States. HIV genotyping and/or phenotyping for antiretroviral-naïve patients seeking treatment should be considered, especially if the therapy will include an NNRTI.

The secretion of alkali metal ions by the perfused cat pancreas as influenced by the composition and osmolality of the external environment and by inhibitors of metabolism and Na+, K+-ATPase activity

PubMed Central

Case, R. M.; Scratcherd, T.

1974-01-01

1. The secretion of sodium, potassium and lithium has been studied in the isolated cat pancreas, perfused with bicarbonate buffered saline solutions of varying composition and osmolality, and stimulated maximally with secretin. 2. Under isosmolal conditions, when perfusate sodium chloride was replaced by sucrose, sodium secretion and potassium secretion were directly related to perfusate sodium concentration, [Na]p. 3. When osmolality was varied by increasing or decreasing perfusate sodium chloride concentration, the secretion of sodium and of potassium were maximal at [Na]p of about 120 and 80 mM respectively. 4. At a given [Na]p, sodium secretion was greater under hypo-osmolal conditions than under isosmolal conditions. 5. When potassium concentration was varied over the range 0-130 mM under isosmolal conditions, by adjusting perfusate NaCl concentration, the secretion of potassium and of sodium were maximal at [K]p of about 50 and 10 mM respectively. Water flux was maximal at a [K]p of 10-15 mM. The concentration of potassium in the secretion was almost identical with that in the perfusate over the whole concentration range. 6. Replacement of perfusate sodium by lithium reduced the volume of secretion, though a small secretion was maintained even in the complete absence of sodium. The concentration of lithium in the secretion was generally slightly greater than that in the perfusate. 7. Omission of potassium from the perfusate reduced secretion by about 65%. Rubidium was a complete substitute for potassium; caesium was not. 8. Energy for secretion is derived largely from oxidative phosphorylation. Secretion was reduced by more than 90% under anaerobic conditions and in the presence of dinitrophenol or cyanide. Removal of glucose from the perfusate reduced secretion by more than 50% within 30 min; lactate was a complete substitute for glucose. 9. Ouabain, ethacrinic acid and frusimide, known inhibitors of Na+, K+-ATPase activity, all inhibited pancreatic

Decreased Family Accommodation Associated with Improved Therapy Outcome in Pediatric Obsessive-Compulsive Disorder

ERIC Educational Resources Information Center

Merlo, Lisa J.; Lehmkuhl, Heather D.; Geffken, Gary R.; Storch, Eric A.

2009-01-01

Pediatric obsessive-compulsive disorder (OCD) is a chronic, disabling condition that affects both patients and their families. Despite the identification of efficacious treatments (e.g., cognitive-behavioral therapy and selective serotonin reuptake inhibitor medications), not all patients respond fully. The purpose of the present study was to…

Role of the Na+/H+ antiporter in rat proximal tubule bicarbonate absorption.

PubMed Central

Preisig, P A; Ives, H E; Cragoe, E J; Alpern, R J; Rector, F C

1987-01-01

Amiloride and the more potent amiloride analog, 5-(N-t-butyl) amiloride (t-butylamiloride), were used to examine the role of the Na+/H+ antiporter in bicarbonate absorption in the in vivo microperfused rat proximal convoluted tubule. Bicarbonate absorption was inhibited 29, 46, and 47% by 0.9 mM or 4.3 mM amiloride, or 1 mM t-butylamiloride, respectively. Sensitivity of the Na+/H+ antiporter to these compounds in vivo was examined using fluorescent measurements of intracellular pH with (2', 7')-bis(carboxyethyl)-(5,6)-carboxyfluorescein (BCECF). Amiloride and t-butylamiloride were shown to be as potent against the antiporter in vivo as in brush border membrane vesicles. A model of proximal tubule bicarbonate absorption was used to correct for changes in the luminal profiles for pH and inhibitor concentration, and for changes in luminal flow rate in the various series. We conclude that the majority of apical membrane proton secretion involved in transepithelial bicarbonate absorption is mediated by the Na+-dependent, amiloride-sensitive Na+H+ antiporter. However, a second mechanism of proton secretion contributes significantly to bicarbonate absorption. This mechanism is Na+-independent and amiloride-insensitive. PMID:2888788

An investigation of the effect of migratory type corrosion inhibitor on mechanical properties of zeolite-based novel geopolymers

NASA Astrophysics Data System (ADS)

Auqui, Nestor Ulloa; Baykara, Haci; Rigail, Andres; Cornejo, Mauricio H.; Villalba, Jose Luis

2017-10-01

The effects of migratory type corrosion inhibitor and curing time on the thermal stability and mechanical properties of Ecuadorian natural zeolite-based geopolymers were evaluated. Geopolymer samples were prepared by alkali activation of the natural zeolite by 8 M NaOH solution and calcium hydroxide Ca(OH)2 1-3 wt%, with an activator/binder ratio of 0.6. The geopolymer samples cured for 24 h at 40 °C and then for 6 days more at room temperature showed the compressive strength values in a range of 3-5,5 MPa. Mineralogical analysis of natural zeolite obtained by XRD is as follows: Mordenite (∼67%), quartz (∼27%) and amorphous (∼6%). SEM-EDS micrographs analysis of geopolymers revealed the presence of Na and Ca which proves the incorporation of the activators, NaOH and Ca(OH)2. The compressive strength values obtained indicate that the use of alkali activation of natural zeolites is an effective method for the synthesis of geopolymers. The mechanical properties of geopolymers were slightly but not adversely affected by the addition of the migratory corrosion inhibitor, MCI-2005 NS. These results will be used in future research on geopolymer concrete with embedded reinforcing steel.

New advances in the treatment of generalized anxiety disorder: the multimodal antidepressant vortioxetine.

PubMed

Orsolini, Laura; Tomasetti, Carmine; Valchera, Alessandro; Iasevoli, Felice; Buonaguro, Elisabetta Filomena; Vellante, Federica; Fornaro, Michele; Fiengo, Annastasia; Mazza, Monica; Vecchiotti, Roberta; Perna, Giampaolo; de Bartolomeis, Andrea; Martinotti, Giovanni; Di Giannantonio, Massimo; De Berardis, Domenico

2016-05-01

Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, exaggerated worry and tension, mainly comorbid with Major Depressive Disorder (MDD). Currently, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recommended as first-line treatment of GAD. However, some patients may not respond to the treatment or discontinue due to adverse effects. Vortioxetine (VRX) is a multimodal antidepressant with a unique mechanism of action, by acting as 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, partial agonist at the 5-HT1A and 5-HT1B receptors and inhibitor at the 5-HT transporter. Preliminary clinical trials showed contrasting findings in terms of improvement of the anxiety symptomatology and/or cognitive impairment. Here, we aim to systematically review the evidence currently available on the efficacy, safety and tolerability of VRX in the treatment of GAD. The generalizability of results on the efficacy of VRX in patients with anxiety symptomatology and GAD is limited due to few and contrasting RCTs so far available. Only two studies, of which one prevention relapse trial, reported a significant improvement in anxiety symptomatology compared to three with negative findings.

Antidepressants in Parkinson's disease. Recommendations by the movement disorder study group of the Neurological Association of Madrid.

PubMed

Peña, E; Mata, M; López-Manzanares, L; Kurtis, M; Eimil, M; Martínez-Castrillo, J C; Navas, I; Posada, I J; Prieto, C; Ruíz-Huete, C; Vela, L; Venegas, B

2016-03-19

Although antidepressants are widely used in Parkinson's disease (PD), few well-designed studies to support their efficacy have been conducted. These clinical guidelines are based on a review of the literature and the results of an AMN movement disorder study group survey. Evidence suggests that nortriptyline, venlafaxine, paroxetine, and citalopram may be useful in treating depression in PD, although studies on paroxetine and citalopram yield conflicting results. In clinical practice, however, selective serotonin reuptake inhibitors are usually considered the treatment of choice. Duloxetine may be an alternative to venlafaxine, although the evidence for this is less, and venlafaxine plus mirtazapine may be useful in drug-resistant cases. Furthermore, citalopram may be indicated for the treatment of anxiety, atomoxetine for hypersomnia, trazodone and mirtazapine for insomnia and psychosis, and bupropion for apathy. In general, antidepressants are well tolerated in PD. However, clinicians should consider the anticholinergic effect of tricyclic antidepressants, the impact of serotonin-norepinephrine reuptake inhibitors on blood pressure, the extrapyramidal effects of antidepressants, and any potential interactions between monoamine oxidase B inhibitors and other antidepressants. Copyright © 2016 Sociedad Española de Neurología. Published by Elsevier España, S.L.U. All rights reserved.

The serotonergic system and anxiety.

PubMed

Gordon, Joshua A; Hen, Rene

2004-01-01

The wide use of serotonin reuptake inhibitors and serotonin receptor agonists in anxiety disorders has suggested a key role for the modulatory neurotransmitter in anxiety. However, serotonin's specific role is still uncertain. This article reviews the literature concerning how and where serotonergic agents modulate anxiety. Varying and sometimes conflicting data from human and animal studies argue for both anxiolytic and anxiogenic roles for serotonin, depending on the specific disorder, structure, or behavioral task studied. However, recent data from molecular genetic studies in the mouse point toward two important roles for the serotonin 1A receptor. In development, serotonin acts through this receptor to promote development of the circuitry necessary for normal anxiety-like behaviors. In adulthood, serotonin reuptake inhibitors act through the same receptor to stimulate neurogenesis and reduce anxiety-like behaviors. These studies highlight that the complex serotonin system likely plays various roles in the regulation of anxiety both during development and in adulthood.

Nurse Practitioners' Education, Awareness, and Therapeutic Approaches for the Management of Fibromyalgia.

PubMed

Hughes, Linda; Adair, Jean; Feng, Feng; Maciejewski, Stephanie; Sharma, Harsha

2016-01-01

In the United States, fibromyalgia affects 2%-5% of the adult population, rendering it the most common chronic, widespread pain condition. The American College of Rheumatology has published diagnostic criteria for fibromyalgia, with the latest version in 2010. The purpose of this study was to evaluate nurse practitioners' education and awareness of fibromyalgia and to evaluate nurse practitioners' practices for the management of fibromyalgia. Sixty-six nurse practitioners voluntarily completed an online survey regarding their education, diagnosis, and treatment options for patients with fibromyalgia. The majority of participants reported that they always or occasionally had difficulty diagnosing fibromyalgia and worried about labeling their patients as having fibromyalgia. The most commonly used agents were nonsteroidal anti-inflammatory drugs (70%), serotonin norepinephrine reuptake inhibitors (61%), selective serotonin reuptake inhibitors (51%), and muscle relaxants (44%). Nondrug therapies included exercise (88%), cognitive behavior therapy (58%), and nutrition (56%). Further education is needed for nurse practitioners to increase confidence in diagnosing and managing fibromyalgia.

Escitalopram prolonged fear induced by simulated public speaking and released hypothalamic-pituitary-adrenal axis activation.

PubMed

Garcia-Leal, C; Del-Ben, C M; Leal, F M; Graeff, F G; Guimarães, F S

2010-05-01

Simulated public speaking (SPS) test is sensitive to drugs that interfere with serotonin-mediated neurotransmission and is supposed to recruit neural systems involved in panic disorder. The study was aimed at evaluating the effects of escitalopram, the most selective serotonin-selective reuptake inhibitor available, in SPS. Healthy males received, in a double-blind, randomized design, placebo (n = 12), 10 (n = 17) or 20 (n = 14) mg of escitalopram 2 hours before the test. Behavioural, autonomic and neuroendocrine measures were assessed. Both doses of escitalopram did not produce any effect before or during the speech but prolonged the fear induced by SPS. The test itself did not significantly change cortisol and prolactin levels but under the higher dose of escitalopram, cortisol and prolactin increased immediately after SPS. This fear-enhancing effect of escitalopram agrees with previously reported results with less selective serotonin reuptake inhibitors and the receptor antagonist ritanserin, indicating that serotonin inhibits the fear of speaking in public.

Oxytocin and social functioning

PubMed Central

Jones, Candace; Barrera, Ingrid; Brothers, Shaun; Ring, Robert; Wahlestedt, Claes

2017-01-01

Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed. PMID:28867943

Oxytocin and social functioning.

PubMed

Jones, Candace; Barrera, Ingrid; Brothers, Shaun; Ring, Robert; Wahlestedt, Claes

2017-06-01

Social anxiety is a form of anxiety characterized by continuous fear of one or more social or performance situations. Although multiple treatment modalities (cognitive behavioral therapy, selective serotonin reuptake inhibitors/selective norepinephrine reuptake inhibitors, benzodiazepines) exist for social anxiety, they are effective for only 60% to 70% of patients. Thus, researchers have looked for other candidates for social anxiety treatment. Our review focuses on the peptide oxytocin as a potential therapeutic option for individuals with social anxiety. Animal research both in nonprimates and primates supports oxytocin's role in facilitation of prosocial behaviors and its anxiolytic effects. Human studies indicate significant associations between social anxiety and oxytocin receptor gene alleles, as well as social anxiety and oxytocin plasma levels. In addition, intranasal administration of oxytocin in humans has favorable effects on social anxiety symptomology. Other disorders, including autism, schizophrenia, and anorexia, have components of social anxiety in their pathophysiology. The therapeutic role of oxytocin for social dysfunction in these disorders is discussed.

[Antidepressive agents and suicidal tendencies].

PubMed

Gründer, G; Veselinović, T; Paulzen, M

2014-09-01

In the last 2 years the discussions on the question whether antidepressants, especially selective serotonin reuptake inhibitors (SSRIs) can lead to suicidality, aggression and violence, flared up again. The available data on the problem, which has been discussed since the introduction of this substance group in the late 1980s, is presented in this article. A systematic literature search showed that a scientific consensus exists that the benefits of antidepressant pharmacotherapy in general, and of treatment with SSRIs and selective serotonin/norepinephrine reuptake inhibitors (SSNRIs) in particular, outweigh the risks of their use. This also applies to the treatment of children, adolescents and young adults. The agitation occasionally occurring at the beginning of treatment, which can be experienced as aversive in susceptible patients, can intensify or even trigger suicidal thoughts or impulses. This has to be paid particular attention to especially at the beginning of treatment. It is recommended that the indications for antidepressant pharmacotherapy of children, adolescents and young adults are assessed by a specialist.

Levomilnacipran (F2695), a norepinephrine-preferring SNRI: profile in vitro and in models of depression and anxiety.

PubMed

Auclair, A L; Martel, J C; Assié, M B; Bardin, L; Heusler, P; Cussac, D; Marien, M; Newman-Tancredi, A; O'Connor, J A; Depoortère, R

2013-07-01

Levomilnacipran (LVM; F2695) is the more active enantiomer of the serotonin/norepinephrine (5-HT/NE) reuptake inhibitor (SNRI) milnacipran and is currently under development for the treatment of major depressive disorder. LVM was benchmarked against two other SNRIs, duloxetine and venlafaxine, in biochemical, neurochemical and pharmacological assays. LVM exhibited high affinity for human NE (Ki = 92.2 nM) and 5-HT (11.2 nM) transporters, and potently inhibited NE (IC50 = 10.5 nM) and 5-HT (19.0 nM) reuptake (human transporter) in vitro. LVM had 2-fold greater potency for norepinephrine relative to serotonin reuptake inhibition (i.e. NE/5-HT potency ratio: 0.6) and 17 and 27 times higher selectivity for NE reuptake inhibition compared with venlafaxine and duloxetine, respectively. LVM did not exhibit affinity for 23 off-target receptors. LVM (i.p.) increased cortical extracellular levels of 5-HT, and NE (minimal effective doses: MEDs = 20 and 10 mg/kg, respectively). In anti-depressive/anti-stress models, i.p. LVM diminished immobility time in the mouse forced swim (MED = 20 mg/kg) and tail suspension (MED = 2.5 mg/kg) tests, and reduced shock-induced ultrasonic vocalizations in rats (MED = 5 mg/kg). Duloxetine and venlafaxine were less potent (MEDs ≥ 10 mg/kg). At doses active in these three therapeutically-relevant models, LVM (i.p.) did not significantly affect spontaneous locomotor activity. In summary, LVM is a potent, selective inhibitor of NE and 5-HT transporters with preferential activity at the former. It is efficacious in models of anti-depressive/anti-stress activity, with minimal potential for locomotor side effects. Copyright © 2013 Elsevier Ltd. All rights reserved.

The neuropharmacology of ADHD drugs in vivo: insights on efficacy and safety.

PubMed

Heal, D J; Cheetham, S C; Smith, S L

2009-12-01

Results from in vivo techniques, especially intracerebral microdialysis in freely-moving rats, have provided insights into potential mechanisms responsible for the efficacy and safety of catecholaminergic drugs for ADHD treatment. The drugs reviewed come from distinct pharmacological classes: psychostimulant releasing agents, eg d-amphetamine; psychostimulant reuptake inhibitors, eg dl-threo-methylphenidate (dl-MPH), and non-stimulant reuptake inhibitors, eg atomoxetine. Psychostimulants, which currently deliver the best efficacy in treating ADHD, exhibit the following characteristics on extraneuronal catecholamine concentrations in rodent brain in vivo: 1) They enhance the efflux and function of both noradrenaline and dopamine in the central nervous system. 2) The increase of dopamine efflux that they produce is not limited to cortical regions. 3) They have a rapid onset of action with no ceiling on drug effect. d-Amphetamine has a mechanism independent of neuronal firing rate, displacing intraneuronal stores of catecholamines, delaying their reuptake and inhibiting catabolism by monoamine oxidase. dl-MPH has an enigmatic, extraneuronal action that is neuronal firing rate-dependent and reuptake transporter-mediated, yet paradoxically, almost as powerful as that of d-amphetamine. In safety terms, these powerful catecholaminergic effects also make the psychostimulants liable for abuse. Since efficacy and safety derive from the same pharmacological mechanisms, it has not yet been possible to separate these two components. However, the development of once-daily psychostimulant formulations and a prodrug, lisdexamfetamine, has improved patient compliance and markedly reduced scope for their diversion/abuse. This review will discuss the in vivo pharmacological profiles of approved catecholaminergic drugs for treatment of ADHD and implications for their clinical efficacy and abuse liability.

Effects of histone deacetylase inhibitor sodium butyrate on heroin seeking behavior in the nucleus accumbens in rats.

PubMed

Chen, Wei-Sheng; Xu, Wen-Jin; Zhu, Hua-Qiang; Gao, Lei; Lai, Miao-Jun; Zhang, Fu-Qiang; Zhou, Wen-Hua; Liu, Hui-Fen

2016-12-01

Histone acetylation and other modifications of the chromatin are important regulators of gene expression and may contribute to drug-induced behaviors and neuroplasticity. Inhibition of histone deacetylases (HDAC) activity results in the change of some drug-induced behaviors，however, relatively little is known about the effects of HDAC inhibitors on heroin-seeking behavior. In the present study, male rats were trained to self-administer heroin under a FR1 schedule for consecutive 14 days, followed by 14 daily 2h extinction session in the operant chamber. After training, the heroin priming (250μg/kg) was introduced for the reinstatement of heroin-seeking behavior. Pretreatment with sodium butyrate (NaB) (200 or 400mg/kg, i.p.), an inhibitor of HDAC, failed to affect heroin self-administration. Additionally，systemic administration of NaB (400mg/kg, i.p.)increased significantly the reinstatement of heroin-seeking induced by heroin priming when NaB administered 12h, but not 6h before the reinstatement test. The same effect was observed after the intracerebroventricular injection of NaB (5μL, 100μg/μL). Moreover, the levels of histone H3 acetylation at lysine 18（H3K18）and H4 acetylation at lysine 5 or lysine 8（H4K5 or H4K8）in the accumbens nucleus core and shell were remarkably increased during the reinstatement and were further strengthened after intracerebroventricular injection of NaB. These results demonstrated that activation of histone acetylation may be involved in the heroin-seeking behavior, and identifying these epigenetic changes will be critical in proposing a novel pharmacological strategy for treating heroin addiction. Copyright © 2016. Published by Elsevier B.V.

Development and validation of stability indicating method for the quantitative determination of venlafaxine hydrochloride in extended release formulation using high performance liquid chromatography

PubMed Central

Kaur, Jaspreet; Srinivasan, K. K.; Joseph, Alex; Gupta, Abhishek; Singh, Yogendra; Srinivas, Kona S.; Jain, Garima

2010-01-01

Objective: Venlafaxine,hydrochloride is a structurally novel phenethyl bicyclic antidepressant, and is usually categorized as a serotonin–norepinephrine reuptake inhibitor (SNRI) but it has been referred to as a serotonin–norepinephrine–dopamine reuptake inhibitor. It inhibits the reuptake of dopamine. Venlafaxine HCL is widely prescribed in the form of sustained release formulations. In the current article we are reporting the development and validation of a fast and simple stability indicating, isocratic high performance liquid chromatographic (HPLC) method for the determination of venlafaxine hydrochloride in sustained release formulations. Materials and Methods: The quantitative determination of venlafaxine hydrochloride was performed on a Kromasil C18 analytical column (250 × 4.6 mm i.d., 5 μm particle size) with 0.01 M phosphate buffer (pH 4.5): methanol (40: 60) as a mobile phase, at a flow rate of 1.0 ml/min. For HPLC methods, UV detection was made at 225 nm. Results: During method validation, parameters such as precision, linearity, accuracy, stability, limit of quantification and detection and specificity were evaluated, which remained within acceptable limits. Conclusions: The method has been successfully applied for the quantification and dissolution profiling of Venlafaxine HCL in sustained release formulation. The method presents a simple and reliable solution for the routine quantitative analysis of Venlafaxine HCL. PMID:21814426

A Naturalistic Study of Referred Children and Adolescents with Obsessive-Compulsive Disorder.

ERIC Educational Resources Information Center

Masi, Gabriele; Millepiedi, Stefania; Mucci, Maria; Bertini, Nicoletta; Milantoni, Luca; Arcangeli, Francesca

2005-01-01

Objective: To report on clinical features, comorbidity, and response to pharmacotherapy in children and adolescents with obsessive-compulsive disorder (OCD) naturalistically followed and treated with serotonin reuptake inhibitors (SRIs). Method: A consecutive series of 94 patients (65 males, 29 females, age 13.6 [+ or -] 2.8 years), referred in…

The Bi-Directional Relationship between Parent-Child Conflict and Treatment Outcome in Treatment-Resistant Adolescent Depression

ERIC Educational Resources Information Center

Rengasamy, Manivel; Mansoor, Brandon M.; Hilton, Robert; Porta, Giovanna; He, Jiayan; Emslie, Graham J.; Mayes, Taryn; Clarke, Gregory N.; Wagner, Karen Dineen; Keller, Martin B.; Ryan, Neal D.; Birmaher, Boris; Shamseddeen, Wael; Asarnow, Joan Rosenbaum; Brent, David A.

2013-01-01

Objective: To examine the bidirectional relationship between parent-child discord and treatment outcome for adolescent treatment-resistant depression. Method: Depressed youth who had not responded to an adequate course of a selective serotonin reuptake inhibitor (SSRI) were randomized to either a switch to another SSRI or venlafaxine, with or…

The Effects of Response Interruption and Redirection and Sertraline on Vocal Stereotypy

ERIC Educational Resources Information Center

Miguel, Caio F.; Clark, Kathy; Tereshko, Lisa; Ahearn, William H.

2009-01-01

Although response interruption and redirection (RIRD) has been shown to be successful in reducing vocal stereotypy, recent reports have suggested that selective serotonin reuptake inhibitors (SSRIs) may also reduce these behaviors. The purpose of the current investigation was to examine the effects of RIRD with and without sertraline on…

Improvement with Duloxetine in an Adult ADHD Patient

ERIC Educational Resources Information Center

Tourjman, Smadar Valerie; Bilodeau, Mathieu

2009-01-01

Introduction: Attention-deficit/hyperactivity disorder (ADHD) is a common and disabling disorder among adults and is treated with stimulant and non stimulant medication. Objective: To report the case of a patient with ADHD showing good clinical response to duloxetine, a selective serotonin and norepinephrine reuptake inhibitor (SSNRI). Case…

Citalopram Intervention for Hostility: Results of a Randomized Clinical Trial

ERIC Educational Resources Information Center

Kamarck, Thomas W.; Haskett, Roger F.; Muldoon, Matthew; Flory, Janine D.; Anderson, Barbara; Bies, Robert; Pollock, Bruce; Manuck, Stephen B.

2009-01-01

Hostility is associated with an increased risk for cardiovascular disease (CVD). Because central serotonin may modulate aggression, we might expect selective serotonin reuptake inhibitors (SSRIs) to be effective in reducing hostility. Such effects have never been examined in individuals scoring high on hostility who are otherwise free from major…

A Pilot Randomized Controlled Trial of Combined Trauma-Focused CBT and Sertraline for Childhood PTSD Symptoms

ERIC Educational Resources Information Center

Cohen, Judith A.; Mannarino, Anthony P.; Perel, James M.; Staron, Virginia

2007-01-01

Objective: To examine the potential benefits of adding a selective serotonin reuptake inhibitor, sertraline, versus placebo, to trauma-focused cognitive-behavioral therapy (TF-CBT) for improving posttraumatic stress disorder and related psychological symptoms in children who have experienced sexual abuse. Method: Twenty-four 10- to 17-year-old…

A Double-Blind, Randomized, Placebo-Controlled Trial of Escitalopram in the Treatment of Pediatric Depression

ERIC Educational Resources Information Center

Wagner, Karen Dineen; Jonas, Jeffrey; Findling, Robert L.; Ventura, Daniel; Saikali, Khalil

2006-01-01

Objective: Escitalopram is a selective serotonin reuptake inhibitor antidepressant indicated for use in adults. This trial examined the efficacy and safety of escitalopram in pediatric depression. Method: Patients (6-17 years old) with major depressive disorder were randomized to receive 8 weeks of double-blind flexibly dosed treatment with…

Na+ channel regulation by Ca2+/calmodulin and Ca2+/calmodulin-dependent protein kinase II in guinea-pig ventricular myocytes†

PubMed Central

Aiba, Takeshi; Hesketh, Geoffrey G.; Liu, Ting; Carlisle, Rachael; Villa-Abrille, Maria Celeste; O'Rourke, Brian; Akar, Fadi G.; Tomaselli, Gordon F.

2010-01-01

Aims Calmodulin (CaM) regulates Na+ channel gating through binding to an IQ-like motif in the C-terminus. Ca2+/CaM-dependent protein kinase II (CaMKII) regulates Ca2+ handling, and chronic overactivity of CaMKII is associated with left ventricular hypertrophy and dysfunction and lethal arrhythmias. However, the acute effects of Ca2+/CaM and CaMKII on cardiac Na+ channels are not fully understood. Methods and results Purified NaV1.5–glutathione-S-transferase fusion peptides were phosphorylated in vitro by CaMKII predominantly on the I–II linker. Whole-cell voltage-clamp was used to measure Na+ current (INa) in isolated guinea-pig ventricular myocytes in the absence or presence of CaM or CaMKII in the pipette solution. CaMKII shifted the voltage dependence of Na+ channel availability by ≈+5 mV, hastened recovery from inactivation, decreased entry into intermediate or slow inactivation, and increased persistent (late) current, but did not change INa decay. These CaMKII-induced changes of Na+ channel gating were completely abolished by a specific CaMKII inhibitor, autocamtide-2-related inhibitory peptide (AIP). Ca2+/CaM alone reproduced the CaMKII-induced changes of INa availability and the fraction of channels undergoing slow inactivation, but did not alter recovery from inactivation or the magnitude of the late current. Furthermore, the CaM-induced changes were also completely abolished by AIP. On the other hand, cAMP-dependent protein kinase A inhibitors did not abolish the CaM/CaMKII-induced alterations of INa function. Conclusion Ca2+/CaM and CaMKII have distinct effects on the inactivation phenotype of cardiac Na+ channels. The differences are consistent with CaM-independent effects of CaMKII on cardiac Na+ channel gating. PMID:19797425

Potential role of recombinant secretory leucoprotease inhibitor in the prevention of neutrophil mediated matrix degradation.

PubMed Central

Llewellyn-Jones, C. G.; Lomas, D. A.; Stockley, R. A.

1994-01-01

BACKGROUND--Neutrophil elastase is able to degrade connective tissue matrices and is thought to be involved in the pathogenesis of destructive lung diseases. METHODS--The ability of recombinant secretory leucoprotease inhibitor (rSLPI) to inhibit neutrophil mediated degradation of fibronectin in vitro is demonstrated and its efficacy compared with native alpha-1-proteinase inhibitor (n alpha 1-PI), recombinant alpha-1-proteinase inhibitor (r alpha 1-PI), and the chemical elastase inhibitor ICI 200,355. RESULTS--When preincubated with neutrophils both rSLPI and r alpha 1-PI were effective inhibitors of fibronectin degradation although n alpha 1-PI and ICI 200,355 were less effective. Recombinant SLPI was the most effective inhibitor when the cells were allowed to adhere to fibronectin before the addition of the inhibitors. Preincubation of rSLPI (0.1 mumol/l) with the fibronectin plate resulted in almost total inhibition of fibronectin degradation (reduced to 3.3 (SE 0.9)% of control). Pretreating the fibronectin plate with 1 mumol/l rSLPI, r alpha 1-PI and ICI 200,355 followed by thorough washing before the addition of cells resulted in no inhibition of fibronectin degradation with r alpha 1-PI and the ICI inhibitor, but rSLPI retained its inhibitory effect. This effect could be reduced by adding rSLPI in high pH buffer or 2 mol/1 NaCl. CONCLUSIONS--It is postulated that rSLPI binds to fibronectin to form a protective layer which prevents its degradation by neutrophil elastase. It may prove to be the most useful therapeutic agent in the prevention of neutrophil mediated lung damage. Images PMID:7912452

Fetzima (levomilnacipran), a drug for major depressive disorder as a dual inhibitor for human serotonin transporters and beta-site amyloid precursor protein cleaving enzyme-1.

PubMed

Rizvi, Syed Mohd Danish; Shaikh, Sibhghatulla; Khan, Mahiuddin; Biswas, Deboshree; Hameed, Nida; Shakil, Shazi

2014-01-01

Pharmacological management of Major Depressive Disorder includes the use of serotonin reuptake inhibitors which targets serotonin transporters (SERT) to increase the synaptic concentrations of serotonin. Beta-site amyloid precursor protein cleaving enzyme-1 (BACE-1) is responsible for amyloid β plaque formation. Hence it is an interesting target for Alzheimer's disease (AD) therapy. This study describes molecular interactions of a new Food and Drug Administration approved antidepressant drug named 'Fetzima' with BACE-1 and SERT. Fetzima is chemically known as levomilnacipran. The study has explored a possible link between the treatment of Depression and AD. 'Autodock 4.2' was used for docking study. The free energy of binding (ΔG) values for 'levomilnacipran-SERT' interaction and 'levomilnacipran-BACE1' interaction were found to be -7.47 and -8.25 kcal/mol, respectively. Levomilnacipran was found to interact with S438, known to be the most important amino acid residue of serotonin binding site of SERT during 'levomilnacipran-SERT' interaction. In the case of 'levomilnacipran-BACE1' interaction, levomilnacipran interacted with two very crucial aspartic acid residues of BACE-1, namely, D32 and D228. These residues are accountable for the cleavage of amyloid precursor protein and the subsequent formation of amyloid β plaques in AD brain. Hence, Fetzima (levomilnacipran) might act as a potent dual inhibitor of SERT and BACE-1 and expected to form the basis of a future dual therapy against depression and AD. It is an established fact that development of AD is associated with Major Depressive Disorder. Therefore, the design of new BACE-1 inhibitors based on antidepressant drug scaffolds would be particularly beneficial.

Treatment of esophageal motility disorders based on the chicago classification.

PubMed

Maradey-Romero, Carla; Gabbard, Scott; Fass, Ronnie

2014-12-01

The Chicago Classification divides esophageal motor disorders based on the recorded value of the integrated relaxation pressure (IRP). The first group includes those with an elevated mean IRP that is associated with peristaltic abnormalities such as achalasia and esophagogastric junction outflow obstruction. The second group includes those with a normal mean IRP that is associated with esophageal hypermotility disorders such as distal esophageal spasm, hypercontractile esophagus (jackhammer esophagus), and hypertensive peristalsis (nutcracker esophagus). The third group includes those with a normal mean IRP that is associated with esophageal hypomotility peristaltic abnormalities such as absent peristalsis, weak peristalsis with small or large breaks, and frequent failed peristalsis. The therapeutic options vary greatly between the different groups of esophageal motor disorders. In achalasia patients, potential treatment strategies comprise medical therapy (calcium channel blockers, nitrates, and phosphodiesterase 5 inhibitors), endoscopic procedures (botulinum toxin A injection, pneumatic dilation, or peroral endoscopic myotomy) or surgery (Heller myotomy). Patients with a normal IRP and esophageal hypermotility disorder are candidates for medical therapy (nitrates, calcium channel blockers, phosphodiesterase 5 inhibitors, cimetropium/ipratropium bromide, proton pump inhibitors, benzodiazepines, tricyclic antidepressants, trazodone, selective serotonin reuptake inhibitors, and serotonin-norepinephrine reuptake inhibitors), endoscopic procedures (botulinum toxin A injection and peroral endoscopic myotomy), or surgery (Heller myotomy). Lastly, in patients with a normal IRP and esophageal hypomotility disorder, treatment is primarily focused on controlling the presence of gastroesophageal reflux with proton pump inhibitors and lifestyle modifications (soft and liquid diet and eating in the upright position) to address patient's dysphagia.

[Antidepressant prescription patterns in patients affiliated with the General Social Security Health System of Colombia].

PubMed

Machado-Alba, Jorge E; Morales Plaza, Cristhian David; Solarte Gómez, Mónica Johanna

2011-11-01

Determine patterns of antidepressive drug prescription in a group of patients affiliated with the General Social Security Health System in Colombia. Observational descriptive study of 9 881 patients, of both sexes and older than 5 years of age, medicated with antidepressants and continuously treated from August to October 2009. The patients include residents from 56 Colombian cities. A database was designed based on the consumption of medicines obtained from the company that distributes them to the patients. The average age was 59.1 ± 16.1 years; 73.7% of the participants were women. Of the total number of patients, 83.3% were treated with monotherapy and 16.7% with two or more antidepressants. The order of the prescription of the medicines was: selective serotonin reuptake inhibitors, 47.0%; atypical, 37.8%; tricyclical, 31.8%; selective serotonin reuptake inhibitors and norepinephrine, 1.8%; and selective norepinephrine reuptake inhibitors, 0.03%. The combinations most used were fluoxetine + trazodone (n = 1 029); amitriptyline + fluoxetine (n = 265); amitriptyline + trazodone (n = 122); fluoxetine + imipramine (n = 106); and imipramine + trazodone (n = 71). The most prescribed co-medications were anti-hypertensives (52.3%); thyroid hormones (23.3%); anti-inflammatories (19.6%); anti-epileptics (15.4%); anti-diabetics (13.8%); anti-anxiety and hypnotics (12.4%); antipsychotics (7.4%); anti-Parkinsons (4.3%); and anti-neoplastics (2.2%). The practice of prescribing medicines with a high therapeutic value predominates, mainly for antidepressive monotherapy. Most of the antidepressants are prescribed at dosages lower than those recommended. There is a need to design educational strategies to correct some prescription practices and to conduct research.