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Sample records for antagonist ganirelix prevents

  1. Use of a single bolus of GnRH agonist triptorelin to trigger ovulation after GnRH antagonist ganirelix treatment in women undergoing ovarian stimulation for assisted reproduction, with special reference to the prevention of ovarian hyperstimulation syndrome: preliminary report: short communication.

    Science.gov (United States)

    Itskovitz-Eldor, J; Kol, S; Mannaerts, B

    2000-09-01

    A new treatment option for patients undergoing ovarian stimulation is the gonadotrophin-releasing hormone (GnRH) antagonist protocol, with the possibility to trigger a mid-cycle LH surge using a single bolus of GnRH agonist, reducing the risk of developing ovarian hyperstimulation syndrome (OHSS) in high responders and the chance of cycle cancellation. This report describes the use of 0.2 mg triptorelin (Decapeptyl) to trigger ovulation in eight patients who underwent controlled ovarian hyperstimulation with recombinant FSH (rFSH, Puregon) and concomitant treatment with the GnRH antagonist ganirelix (Orgalutran) for the prevention of premature LH surges. All patients were considered to have an increased risk for developing OHSS (at least 20 follicles > or =11 mm and/or serum oestradiol at least 3000 pg/ml). On the day of triggering the LH surge, the mean number of follicles > or =11 mm was 25.1 +/- 4.5 and the median serum oestradiol concentration was 3675 (range 2980-7670) pg/ml. After GnRH agonist injection, endogenous serum LH and FSH surges were observed with median peak values of 219 and 19 IU/l respectively, measured 4 h after injection. The mean number of oocytes obtained was 23.4 +/- 15.4, of which 83% were mature (metaphase II). None of the patients developed any signs or symptoms of OHSS. So far, four clinical pregnancies have been achieved from the embryos obtained during these cycles, including the first birth following this approach. It is concluded that GnRH agonist effectively triggers an endogenous LH surge for final oocyte maturation after ganirelix treatment in stimulated cycles. Our preliminary results suggest that this regimen may prove effective in triggering ovulation and could be said to prevent OHSS in high responders. The efficacy and safety of such new treatment regimen needs to be established in comparative randomized studies.

  2. Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'

    DEFF Research Database (Denmark)

    Nilsson, Lena; Andersen, A.N.; Lindenberg, Svend

    2010-01-01

    study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5...... before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only...

  3. Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'

    DEFF Research Database (Denmark)

    Nilsson, Lena; Andersen, A.N.; Lindenberg, Svend

    2010-01-01

    before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only...

  4. Ganirelix for luteolysis in poor responder patients undergoing IVF treatment: a Scandinavian multicenter 'extended pilot study'

    DEFF Research Database (Denmark)

    Nilsson, Lena; Andersen, A.N.; Lindenberg, Svend

    2010-01-01

    study in four Scandinavian fertility centers was done including 60 patients. Poor response was defined as when 2000 IU FSH. GnRH antagonist (ganirelix) was given, 0.25 mg s.c. daily, from days 3 to 5...... before expected start of menstruation and continued for 4-7 days. On cycle day 2-3 a starting dose of rFSH (300-400 IU/day) was given. At a leading follicle diameter of 14 mm, ganirelix administration was resumed until final oocyte maturation was induced with 10,000 IU hCG. GnRH antagonist only...... marginally affected the intercycle FSH rise; basal levels of FSH remained similar to those seen after 4 days of antagonist administration. The protocol effectively induced low LH levels and luteolysis, but daily administration of 350 IU rFSH (median) for 11 days only led to the collection of 3 oocytes in 49...

  5. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F

    1992-01-01

    and preventing reinfarction, nevertheless demonstrated pronounced differences between the 3 drugs. Nifedipine had no effect on reinfarction or death. Diltiazem had no overall effect but prevented first reinfarction or cardiac death (cardiac events) in patients without heart failure, and increased cardiac events......Experimental studies have demonstrated that the 3 calcium antagonists nifedipine, diltiazem, and verapamil have a comparable effect in the prevention of myocardial damage during ischaemia. Secondary prevention trials after acute myocardial infarction, which aimed at improving survival...... in patients with heart failure before randomisation. Verapamil prevented first reinfarction or death (major events); the most pronounced effect was found in patients without heart failure before randomisation. Verapamil did not have detrimental effects in patients treated for heart failure before...

  6. Molecular mechanisms of 5-HT(3) and NK(1) receptor antagonists in prevention of emesis.

    Science.gov (United States)

    Rojas, Camilo; Raje, Mithun; Tsukamoto, Takashi; Slusher, Barbara S

    2014-01-05

    Nausea and vomiting are major side effects of chemotherapy and one key reason for non-compliance with cancer treatment. The introduction of 5-HT3 receptor antagonists in the 1990s was a major advance in the prevention of acute emesis, and highlighted the critical role of serotonin in the emetic response. The next major advance in the treatment of chemotherapy induced nausea and vomiting (CINV) occurred in 2003 with the introduction of aprepitant, a tachykinin 1 (NK1) receptor antagonist. Aprepitant not only reduced acute emesis but also helped in the reduction of delayed emesis. Also in 2003, palonosetron, a second generation 5-HT3 receptor antagonist became available. Unlike the first generation 5-HT3 receptor antagonists, palonosetron demonstrated efficacy in preventing both acute and delayed emesis. This review focuses on the mechanism of action of 5-HT3 and NK1 receptor antagonists in acute and delayed CINV prevention. We discuss first, the medicinal chemistry that led to the discovery of these antagonists to underline their common structural features. Second, we discuss their performance in the clinic and what it tells us about the emetic response. Finally, we present recent mechanistic studies that help provide a rationale for efficacy differences between palonosetron and other 5-HT3 receptor antagonists in the clinic. In vitro and in vivo experiments have shown that palonosetron can inhibit substance P-mediated responses, presumably through its unique interactions with the 5-HT3 receptor. The crossroads of acute and delayed emesis seem to include interactions among the 5-HT3 and NK1 receptor signaling pathways and inhibitions of these interactions could lead to improved treatment of CINV. © 2013 Elsevier B.V. All rights reserved.

  7. Structure-Based Design of a Periplasmic Binding Protein Antagonist that Prevents Domain Closure

    Energy Technology Data Exchange (ETDEWEB)

    Borrok, M. Jack; Zhu, Yimin; Forest, Katrina T.; Kiessling, Laura L.; (UW)

    2009-07-31

    Many receptors undergo ligand-induced conformational changes to initiate signal transduction. Periplasmic binding proteins (PBPs) are bacterial receptors that exhibit dramatic conformational changes upon ligand binding. These proteins mediate a wide variety of fundamental processes including transport, chemotaxis, and quorum sensing. Despite the importance of these receptors, no PBP antagonists have been identified and characterized. In this study, we identify 3-O-methyl-D-glucose as an antagonist of glucose/galactose-binding protein and demonstrate that it inhibits glucose chemotaxis in E. coli. Using small-angle X-ray scattering and X-ray crystallography, we show that this antagonist acts as a wedge. It prevents the large-scale domain closure that gives rise to the active signaling state. Guided by these results and the structures of open and closed glucose/galactose-binding protein, we designed and synthesized an antagonist composed of two linked glucose residues. These findings provide a blueprint for the design of new bacterial PBP inhibitors. Given the key role of PBPs in microbial physiology, we anticipate that PBP antagonists will have widespread uses as probes and antimicrobial agents.

  8. 5-HT3 receptor antagonists for the prevention of postoperative shivering: a meta-analysis.

    Science.gov (United States)

    Zhou, Chengmao; Zhu, Yu; Liu, Zhen; Ruan, Lin

    2016-12-01

    Objective We evaluated the efficacy of 5-HT3 receptor antagonists for the prevention of postoperative shivering. Methods We searched PubMed, the Cochrane Library, EMBASE and Web of Knowledge to find randomized controlled trials (RCT) of 5-HT3 receptor antagonists for the prevention of postoperative shivering. Two researchers independently screened studies, extracted data, and assessed quality in accordance with the inclusion and exclusion criteria, and then conducted a meta-analysis using RevMan 5.2. Results Ultimately, 14 RCTs that included 980 patients were included in the analysis. We found that: 1) the incidence of shivering was significantly lower in 5-HT3 groups than placebo groups (relative risk, [RR] = 0.48, 95% confidence interval [CI] 0.40 - 0.58); 2) there was no significant difference in the incidence of shivering between 5-HT3 groups and meperidine groups (RR = 0.89, 95% CI 0.60 - 1.34). Conclusion 5-HT3 receptor antagonists appear to prevent postoperative shivering, with a broadly comparable efficacy to meperidine.

  9. 5-HT3Receptor Antagonists for the Prevention of Perioperative Shivering: A Meta-Analysis.

    Science.gov (United States)

    Wang, Wen; Song, Xiaojing; Wang, Tong; Zhang, Chaobin; Sun, Li

    2017-04-01

    The aim of this meta-analysis was to evaluate the preventive efficacy and safety of 5-HT 3 receptor antagonists (5-HT 3 RAs) on perioperative shivering. Relevant databases were searched to identify eligible randomized, controlled trials through January 2016. Primary outcome was the incidence of perioperative shivering, and secondary outcomes were the incidence of safety-related outcomes including postoperative nausea and vomiting (PONV), bradycardia, and hypotension. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous data. Trial sequential analysis was performed to assess the risk of random errors and calculate the required information size. Sixteen studies with a total of 1126 patients were included in the meta-analysis. Compared with the control group, 5-HT 3 RAs administered intravenously could statistically significantly reduce the incidence of perioperative shivering (RR, 0.44; 95%CI, 0.35 to 0.56; P shivering prevention in the future. © 2016, The American College of Clinical Pharmacology.

  10. CRF Receptor Antagonist Astressin-B Reverses and Prevents Alopecia in CRF Over-Expressing Mice

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    Rivier, Jean; Rivier, Catherine; Craft, Noah; Stenzel-Poore, Mary P.; Taché, Yvette

    2011-01-01

    Corticotropin-releasing factor (CRF) signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE)-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse) injected peripherally once a day for 5 days in 4–9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF2 receptor antagonist, astressin2-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress. PMID:21359208

  11. CRF receptor antagonist astressin-B reverses and prevents alopecia in CRF over-expressing mice.

    Directory of Open Access Journals (Sweden)

    Lixin Wang

    2011-02-01

    Full Text Available Corticotropin-releasing factor (CRF signaling pathways are involved in the stress response, and there is growing evidence supporting hair growth inhibition of murine hair follicle in vivo upon stress exposure. We investigated whether the blockade of CRF receptors influences the development of hair loss in CRF over-expressing (OE-mice that display phenotypes of Cushing's syndrome and chronic stress, including alopecia. The non-selective CRF receptors antagonist, astressin-B (5 µg/mouse injected peripherally once a day for 5 days in 4-9 months old CRF-OE alopecic mice induced pigmentation and hair re-growth that was largely retained for over 4 months. In young CRF-OE mice, astressin-B prevented the development of alopecia that occurred in saline-treated mice. Histological examination indicated that alopecic CRF-OE mice had hair follicle atrophy and that astressin-B revived the hair follicle from the telogen to anagen phase. However, astressin-B did not show any effect on the elevated plasma corticosterone levels and the increased weights of adrenal glands and visceral fat in CRF-OE mice. The selective CRF₂ receptor antagonist, astressin₂-B had moderate effect on pigmentation, but not on hair re-growth. The commercial drug for alopecia, minoxidil only showed partial effect on hair re-growth. These data support the existence of a key molecular switching mechanism triggered by blocking peripheral CRF receptors with an antagonist to reset hair growth in a mouse model of alopecia associated with chronic stress.

  12. APPLICATION OF CALCIUM ANTAGONISTS IN PREVENTION OF CARDIOVASCULAR COMPLICATIONS DURING CARDIAC SURGERY

    Directory of Open Access Journals (Sweden)

    S. V. Nedogoda

    2006-01-01

    Full Text Available Results of randomized clinical trials on the usage of calcium antagonists (CA in order to prevent perioperative complications during aortocoronary bypass procedure and operations on heart valves are analyzed. CA reduced the risk of perioperative myocardial infarctions and episodes of reversible myocardial ischemia. After angioplasty of coronary arteries CA (particularly amlodipine show positive effects on restenosis incidence and reduce about 3 times a number of repeated angioplasty and aortocoronary bypass operations. The use of CA was accompanied by more often need in heart electro stimulation without any subclass differences. It is also registered that nimodipine can strengthen intraoperative blood loss. It is concluded, that CA have significant evident base that allows recommending them to patients undertaken by cardiological surgery.

  13. A prostaglandin E2 receptor antagonist prevents pregnancies during a preclinical contraceptive trial with female macaques.

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    Peluffo, M C; Stanley, J; Braeuer, N; Rotgeri, A; Fritzemeier, K-H; Fuhrmann, U; Buchmann, B; Adevai, T; Murphy, M J; Zelinski, M B; Lindenthal, B; Hennebold, J D; Stouffer, R L

    2014-07-01

    Can administration of a prostaglandin (PG) E2 receptor 2 (PTGER2) antagonist prevent pregnancy in adult female monkeys by blocking periovulatory events in the follicle without altering menstrual cyclicity or general health? This is the first study to demonstrate that a PTGER2 antagonist can serve as an effective non-hormonal contraceptive in primates. The requirement for PGE2 in ovulation and the release of an oocyte surrounded by expanded cumulus cells (cumulus-oocyte expansion; C-OE) was established through the generation of PTGS2 and PTGER2 null-mutant mice. A critical role for PGE2 in primate ovulation is supported by evidence that intrafollicular injection of indomethacin in rhesus monkeys suppressed follicle rupture, whereas co-injection of PGE2 with indomethacin resulted in ovulation. First, controlled ovulation protocols were performed in adult, female rhesus monkeys to analyze the mRNA levels for genes encoding PGE2 synthesis and signaling components in the naturally selected pre-ovulatory follicle at different times after the ovulatory hCG stimulus (0, 12, 24, 36 h pre-ovulation; 36 h post-ovulation, n = 3-4/time point). Second, controlled ovarian stimulation cycles were utilized to obtain multiple cumulus-oocyte complexes (COCs) from rhesus monkeys to evaluate the role of PGE2 in C-OE in vitro (n = 3-4 animals/treatment; ≥3 COCs/animal/treatment). Third, adult cycling female cynomolgus macaques were randomly assigned (n = 10/group) to vehicle (control) or PTGER2 antagonist (BAY06) groups to perform a contraceptive trial. After the first treatment cycle, a male of proven fertility was introduced into each group and they remained housed together for the duration of the 5-month contraceptive trial that was followed by a post-treatment reversibility trial. Quantitative real-time PCR, COC culture and expansion, immunofluorescence/confocal microscopy, enzyme immunoassay, contraceptive trial, ultrasonography, complete blood counts, serum biochemistry tests

  14. Endothelin receptor antagonist prevents parathyroid cell proliferation of low calcium diet-induced hyperparathyroidism in rats.

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    Kanesaka, Y; Tokunaga, H; Iwashita, K; Fujimura, S; Naomi, S; Tomita, K

    2001-01-01

    Secondary hyperparathyroidism, one of the most frequently encountered disorders of the calcium homeostasis, is characterized by an increase in parathyroid epithelial (PT) cell number, which is crucial from a functional viewpoint. However, it is still unknown what factors are involved in PT cell proliferation. Endothelin-1 (ET-1), a vasoconstrictive peptide, has been shown to act as a mitogen in a variety of cell types. Rat PT cells are reported to synthesize ET-1 and possess its receptors. To test the hypothesis that ET-1 plays a role in PT cell proliferation, we used rat test subjects fed a low calcium diet for 8 weeks (low Ca rats). The number of the proliferating PT cells, measured by proliferating cell nuclear antigen immunostaining, was significantly increased, with striking immunoreactivity of ET-1 in the low Ca rats. An endothelin receptor antagonist, bosentan (100 mg/kg.day), prevented any increase in the proliferation of PT cells in the low Ca rats (14.3 +/- 2.7/1000 PT cells with no bosentan; 2.1 +/- 1.3 with bosentan; P hyperparathyroidism.

  15. Prevention of chemotherapy-induced nausea: the role of neurokinin-1 (NK1) receptor antagonists.

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    Bošnjak, Snežana M; Gralla, Richard J; Schwartzberg, Lee

    2017-05-01

    Chemotherapy-induced nausea (CIN) has a significant negative impact on the quality of life of cancer patients. The use of 5-hydroxytryptamine-3 (5-HT 3 ) receptor antagonists (RAs) has reduced the risk of vomiting, but (except for palonosetron) their effect on nausea, especially delayed nausea, is limited. This article reviews the role of NK 1 RAs when combined with 5-HT 3 RA-dexamethasone in CIN prophylaxis. Aprepitant has not shown consistent superiority over a two-drug (ondansetron-dexamethasone) combination in nausea control after cisplatin- or anthracycline-cyclophosphamide (AC)-based highly emetogenic chemotherapy (HEC). Recently, dexamethasone and dexamethasone-metoclopramide were demonstrated to be non-inferior to aprepitant and aprepitant-dexamethasone, respectively, for the control of delayed nausea after HEC (AC/cisplatin), and are now recognized in the guidelines. The potential impact of the new NK 1 RAs rolapitant and netupitant (oral fixed combination with palonosetron, as NEPA) in CIN prophylaxis is discussed. While the clinical significance of the effect on nausea of the rolapitant-granisetron-dexamethasone combination after cisplatin is not conclusive, rolapitant addition showed no improvement in nausea prophylaxis after AC or moderately emetogenic chemotherapy (MEC). NEPA was superior to palonosetron in the control of nausea after HEC (AC/cisplatin). Moreover, the efficacy of NEPA in nausea control was maintained over multiple cycles of HEC/MEC. Recently, NK 1 RAs have been challenged by olanzapine, with olanzapine showing superior efficacy in nausea prevention after HEC. Fixed antiemetic combinations (such as NEPA) or new antiemetics with a long half-life that may be given once per chemotherapy cycle (rolapitant or NEPA) may improve patient compliance with antiemetic treatment.

  16. Risk of tuberculosis in patients treated with tumor necrosis factor antagonists due to incomplete prevention of reactivation of latent infection.

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    Gómez-Reino, Juan J; Carmona, Loreto; Angel Descalzo, Miguel

    2007-06-15

    To evaluate the causes of new cases of active tuberculosis (ATB) in patients treated with tumor necrosis factor (TNF) antagonists included in the national registry BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) after the dissemination of recommendations to prevent reactivation of latent tuberculosis infection (LTBI). Incidence rate of ATB per 100,000 patient-years and 95% confidence intervals (95% CIs) were calculated in patients entering BIOBADASER after March 2002 and were stratified by compliance with recommendations (complete or incomplete). ATB rates in BIOBADASER were compared with the background rate and the rate in the rheumatoid arthritis cohort EMECAR (Estudio de la Morbilidad y Expresión Clínica de la Artritis Reumatoide) not treated with TNF antagonists. In addition, rates of ATB among patients treated with adalimumab, etanercept, and infliximab were estimated and compared only for treatments started after September 2003, when all 3 drugs became fully available. Following March 2002, a total of 5,198 patients treated with a TNF antagonist were registered in BIOBADASER. Fifteen ATB cases were noted (rate 172 per 100,000 patient-years, 95% CI 103-285). Recommendations were fully followed in 2,655 treatments. The probability of developing ATB was 7 times higher when recommendations were not followed (incidence rate ratio 7.09, 95% CI 1.60-64.69). Two-step tuberculosis skin test for LTBI was the major failure in complying with recommendations. New cases of ATB still occur in patients treated with all available TNF antagonists due to lack of compliance with recommendations to prevent reactivation of LTBI. Continuous evaluation of recommendations is required to improve clinical practice.

  17. Casopitant: a novel NK1-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting

    Directory of Open Access Journals (Sweden)

    Christina Ruhlmann

    2009-05-01

    Full Text Available Christina Ruhlmann, Jørn HerrstedtOdense University Hospital, Department of Oncology, Odense, DenmarkAbstract: Chemotherapy-induced nausea and vomiting (CINV are among the most feared and distressing symptoms experienced by patients with cancer. The knowledge of the pathogenesis and neuropharmacology of CINV has expanded enormously over the last decades, the most significant discoveries being the role of 5-hydroxytryptamine (5-HT3- and neurokinin (NK1 receptors in the emetic reflex arch. This has led to the development of two new classes of antiemetics acting as highly selective antagonists at one of these receptors. These drugs have had a huge impact in the protection from chemotherapy-induced vomiting, whereas the effect on nausea seems to be limited. The first NK1 receptor antagonist, aprepitant, became clinically available in 2003, and casopitant, the second in this class of antiemetics, has now completed phase III trials. This review delineates the properties and clinical use of casopitant in the prevention of CINV.Keywords: casopitant, GW679769, NK1 receptor antagonist, chemotherapy, emesis

  18. A selective, non-peptide CRF receptor 1 antagonist prevents sodium lactate-induced acute panic-like responses.

    Science.gov (United States)

    Shekhar, Anantha; Johnson, Philip L; Fitz, Stephanie D; Nakazato, Atsuro; Chaki, Shigeyuki; Steckler, Thomas; Schmidt, Mark

    2011-04-01

    Corticotropin releasing factor (CRF) is implicated in a variety of stress-related disorders such as depression and anxiety, and blocking CRF receptors is a putative strategy for treating such disorders. Using a well-studied animal model of panic, we tested the efficacy of JNJ19567470/CRA5626, a selective, non-peptidergic CRF type 1 receptor (CRF1) antagonist (3, 10 and 40 mg/kg intraperitoneal injection), in preventing the sodium lactate (NaLac)-induced panic-like behavioural and cardiovascular responses. Adult male rats with chronic reduction of GABA levels (by inhibition of GABA synthesis with l-allyglycine, a glutamic acid decarboxylase inhibitor) in the dorsomedial/perifornical hypothalamus are highly anxious and exhibit physiological and behavioural responses to intravenous NaLac infusions similar to patients with panic disorder. These 'panic-prone' rats pre-treated with vehicle injections displayed NaLac-induced increases in autonomic responses (i.e. tachycardia and hypertensive responses), anxiety-like behaviour in the social interaction test, and flight-like increases in locomotor activity. However, systemically injecting such panic-prone rats with the highest dose of CRF1 receptor antagonist prior to NaLac infusions blocked all NaLac-induced behaviour and cardiovascular responses. These data suggest that selective CRF1 receptor antagonists could be a novel target for developing anti-panic drugs that are as effective as benzodiazepines in acute treatment of a panic attack without the deleterious side-effects (e.g. sedation and cognitive impairment) associated with benzodiazepines.

  19. Phase III trial of casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of nausea and vomiting in patients receiving moderately emetogenic chemotherapy

    DEFF Research Database (Denmark)

    Herrstedt, Jørn; Apornwirat, Wichit; Shaharyar, Ahmed

    2009-01-01

    PURPOSE: The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemo...

  20. Clinical evaluation of leukotriene receptor antagonists in preventing common cold-like symptoms in bronchial asthma patients.

    Science.gov (United States)

    Horiguchi, Takahiko; Ohira, Daisuke; Kobayashi, Kashin; Hirose, Masahiro; Miyazaki, Junichi; Kondo, Rieko; Tachikawa, Soichi

    2007-09-01

    We investigated the possibility of preventing common cold-like symptoms as a previously unknown benefit of leukotriene receptor antagonists (LTRAs). A total of 279 adult patients with bronchial asthma referred to our hospital between June and December 2004 were retrospectively analyzed. Patients were divided into LTRA treated and untreated groups. Frequency of acute exacerbations and number of visits to emergency rooms and of hospital admissions were analyzed as indicators of frequency of infections and asthma exacerbation over the previous 12 months. Irrespective of inhaled corticosteroid (ICS) use, frequency of infections was significantly lower in the LTRA treated group (0.3 +/- 0.7 times/year) than in the LTRA untreated group (1.6 +/- 4.2 times/year) (P cold-like symptoms. Frequency of acute exacerbations and number of hospital admissions were significantly lower in the LTRA treated versus LTRA untreated group (0.4 +/- 0.8 versus 2.7 +/- 4.3 times/year and 0.0 +/- 0.2 versus 0.4 +/- 0.7 times/year, respectively; both P cold-like symptoms than those not receiving LTRAs. LTRAs play an important role in reducing the incidence of common cold-like symptoms among asthma patients and in suppressing exacerbation of asthma symptoms possibly associated with these symptoms.

  1. Non-analgesic effects of opioids: management of opioid-induced constipation by peripheral opioid receptor antagonists: prevention or withdrawal?

    Science.gov (United States)

    Holzer, Peter

    2012-01-01

    The therapeutic action of opioid analgesics is compromised by peripheral adverse effects among which opioid-induced constipation (OIC) is the most disabling, with a prevalence reported to vary between 15 and 90 %. Although OIC is usually treated with laxatives, there is insufficient clinical evidence that laxatives are efficacious in this indication. In contrast, there is ample evidence from double- blind, randomized and placebo-controlled trials that peripheral opioid receptor antagonists (PORAs) counteract OIC. This specific treatment modality is currently based on subcutaneous methylnaltrexone for the interruption of OIC in patients with advanced illness, and a fixed combination of oral prolonged-release naloxone with prolonged-release oxycodone for the prevention of OIC in the treatment of non-cancer and cancer pain. Both drugs counteract OIC while the analgesic effect of opioids remains unabated. The clinical studies show that more than 50 % of the patients with constipation under opioid therapy may benefit from the use of PORAs, while PORA-resistant patients are likely to suffer from non-opioid-induced constipation, the prevalence of which increases with age. While the addition of naloxone to oxycodone seems to act by preventing OIC, the intermittent dosing of methylnaltrexone every other day seems to stimulate defaecation by provoking an intestinal withdrawal response. The availability of PORAs provides a novel opportunity to specifically control OIC and other peripheral adverse effects of opioid analgesics (e.g., urinary retention and pruritus). The continuous dosing of a PORA has the advantage of few adverse effects, while intermittent dosing of a PORA can be associated with abdominal cramp-like pain.

  2. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist.

    Science.gov (United States)

    Hoffman, Hal M; Rosengren, Sanna; Boyle, David L; Cho, Jae Y; Nayar, Jyothi; Mueller, James L; Anderson, Justin P; Wanderer, Alan A; Firestein, Gary S

    Familial cold autoinflammatory syndrome (FCAS) is an autosomal dominant disorder characterised by recurrent episodes of rash, arthralgia, and fever after cold exposure. The genetic basis of this disease has been elucidated. Cryopyrin, the protein that is altered in FCAS, is one of the adaptor proteins that activate caspase 1, resulting in release of interleukin 1. An experimental cold challenge protocol was developed to study the acute inflammatory mechanisms occurring after a general cold exposure in FCAS patients and to investigate the effects of pretreatment with an antagonist of interleukin 1 receptor (IL-1Ra). ELISA, real-time PCR, and immunohistochemistry were used to measure cytokine responses. After cold challenge, untreated patients with FCAS developed rash, fever, and arthralgias within 1-4 h. Significant increases in serum concentrations of interleukin 6 and white-blood-cell counts were seen 4-8 h after cold challenge. Serum concentrations of interleukin 1 and cytokine mRNA in peripheral-blood leucocytes were not raised, but amounts of interleukin 1 protein and mRNA were high in affected skin. IL-1Ra administered before cold challenge blocked symptoms and increases in white-blood-cell counts and serum interleukin 6. The ability of IL-1Ra to prevent the clinical features and haematological and biochemical changes in patients with FCAS indicates a central role for interleukin 1beta in this disorder. Involvement of cryopyrin in activation of caspase 1 and NF-kappaB signalling suggests that it might have a role in many chronic inflammatory diseases. These findings support a new therapy for a disorder with no previously known acceptable treatment. They also offer insights into the role of interleukin 1beta in more common inflammatory diseases.

  3. Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep.

    Science.gov (United States)

    Padmanabhan, Vasantha; Veiga-Lopez, Almudena; Herkimer, Carol; Abi Salloum, Bachir; Moeller, Jacob; Beckett, Evan; Sreedharan, Rohit

    2015-07-01

    Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insulin sensitizer, rosiglitazone; 5) prenatal T and postnatal flutamide; 6) prenatal T and postnatal rosiglitazone; and 7) prenatal T and postnatal metformin. Prenatal treatments spanned 30-90 days of gestation and postnatal treatments began at approximately 8 weeks of age and continued throughout. Blood samples were taken twice weekly, beginning at approximately 12 weeks of age to time puberty. Two-hour samples after the synchronization with prostaglandin F2α were taken for 120 hours to characterize LH surge dynamics at 7 and 19 months of age. Prenatal T females entered puberty earlier than controls, and all interventions prevented this advancement. Prenatal T reduced the percentage of animals having LH surge, and females that presented LH surge exhibited delayed timing and dampened amplitude of the LH surge. Prenatal androgen antagonist, but not other interventions, restored LH surges without normalizing the timing of the surge. Normalization of pubertal timing with prenatal/postnatal androgen antagonist and insulin sensitizer interventions suggests that pubertal advancement is programmed by androgenic actions of T involving insulin as a mediary. Restoration of LH surges by cotreatment with androgen antagonist supports androgenic programming at the organizational level.

  4. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation.

    Science.gov (United States)

    Bruins Slot, Karsten Mh; Berge, Eivind

    2018-03-06

    Factor Xa inhibitors and vitamin K antagonists (VKAs) are now recommended in treatment guidelines for preventing stroke and systemic embolic events in people with atrial fibrillation (AF). This is an update of a Cochrane review previously published in 2013. To assess the effectiveness and safety of treatment with factor Xa inhibitors versus VKAs for preventing cerebral or systemic embolic events in people with AF. We searched the trials registers of the Cochrane Stroke Group and the Cochrane Heart Group (September 2016), the Cochrane Central Register of Controlled Trials (CENTRAL) (August 2017), MEDLINE (1950 to April 2017), and Embase (1980 to April 2017). We also contacted pharmaceutical companies, authors and sponsors of relevant published trials. We used outcome data from marketing authorisation applications of apixaban, edoxaban and rivaroxaban that were submitted to regulatory authorities in Europe and the USA. We included randomised controlled trials (RCTs) that directly compared the effects of long-term treatment (lasting more than four weeks) with factor Xa inhibitors versus VKAs for preventing cerebral and systemic embolism in people with AF. The primary efficacy outcome was the composite endpoint of all strokes and systemic embolic events. Two review authors independently extracted data, and assessed the quality of the trials and the risk of bias. We calculated a weighted estimate of the typical treatment effect across trials using the odds ratio (OR) with 95% confidence interval (CI) by means of a fixed-effect model. In case of moderate or high heterogeneity of treatment effects, we used a random-effects model to compare the overall treatment effects. We also performed a pre-specified sensitivity analysis excluding any open-label studies. We included data from 67,688 participants randomised into 13 RCTs. The included trials directly compared dose-adjusted warfarin with either apixaban, betrixaban, darexaban, edoxaban, idraparinux, idrabiotaparinux, or

  5. Study of Positive and Negative Consequences of Using GnRH Antagonist in Intrauterine Insemination Cycles

    Directory of Open Access Journals (Sweden)

    Maryam Bagheri

    2009-01-01

    Full Text Available Background: To assess the usefulness of premature luteinization hormone (LH surge preventionin an intrauterine insemination (IUI cycle by GnRH antagonist administration.Materials and Methods: Sixty patients with unexplained or mild male infertility or minimalto mild endometriosis were enrolled in this prospective randomized controlled trial. There weretwenty patients in group A (with GnRH antagonist and 40 patients in group B (without GnRHantagonist.In all of the participants, clomiphene citrate and human menopausal gonadotropin (CC+HMG wereused for ovarian stimulation. When at least one follicle with ≥ 16 mm diameter was seen, LH surgewas checked by a urinary LH kit. In patients with negative results, human chorionic gonadotropinwas continued in both groups, but in group A 0.25 mg Ganirelix SQ was administered for two days,,then in both groups human chorionic gonadotropin (HCG was injected on the third day and IUIwas done 36-40 hours later. Ongoing pregnancy was the primary outcome.Results: Baseline characters and clinical parameters were similar in both groups with the exceptionof ≥14 mm follicles which were higher in group A (p value= 0.003. The pregnancy rate in bothgroups was not significantly different, although it was higher in group B (10% in group A and 15%in group B.Conclusion: At least in CC+HMG stimulated cycles for IUI, the occurrence of premature LHsurge could have a useful rule and GnRH antagonist administration could be an inappropriateintervention.

  6. Effect of a low dose combined oral contraceptive pill on the hormonal profile and cycle outcome following COS with a GnRH antagonist protocol in women over 35 years old.

    Science.gov (United States)

    Bakas, Panagiotis; Hassiakos, Dimitrios; Grigoriadis, Charalampos; Vlahos, Nikolaos F; Liapis, Angelos; Creatsas, George

    2014-11-01

    This prospective study examines if pre-treatment with two different doses of an oral contraceptive pill (OCP) modifies significantly the hormonal profile and/or the IVF/ICSI outcome following COS with a GnRH antagonist protocol. Infertile patients were allocated to receive either OCP containing 0.03 mg of ethinylestradiol and 3 mg of drospirenone, or OCP containing 0.02 mg of ethinylestradiol and 3 mg of drospirenone prior to initiation of controlled ovarian stimulation (COS) with recombinant gonadotropins on a variable multi-dose antagonist protocol (Ganirelix), while the control group underwent COS without OCP pretreatment. Lower dose OCP was associated with recovery of FSH on day 3 instead of day 5, but the synchronization of the follicular cohort, the number of retrieved oocytes and the clinical pregnancy rate were similar to higher dose OCP.

  7. Development of a peptidomimetic antagonist of neuropeptide FF receptors for the prevention of opioid-induced hyperalgesia.

    Science.gov (United States)

    Bihel, Frédéric; Humbert, Jean-Paul; Schneider, Séverine; Bertin, Isabelle; Wagner, Patrick; Schmitt, Martine; Laboureyras, Emilie; Petit-Demoulière, Benoît; Schneider, Elodie; Mollereau, Catherine; Simonnet, Guy; Simonin, Frédéric; Bourguignon, Jean-Jacques

    2015-03-18

    Through the development of a new class of unnatural ornithine derivatives as bioisosteres of arginine, we have designed an orally active peptidomimetic antagonist of neuropeptide FF receptors (NPFFR). Systemic low-dose administration of this compound to rats blocked opioid-induced hyperalgesia, without any apparent side-effects. Interestingly, we also observed that this compound potentiated opioid-induced analgesia. This unnatural ornithine derivative provides a novel therapeutic approach for both improving analgesia and reducing hyperalgesia induced by opioids in patients being treated for chronic pain.

  8. Radiation-induced glomerular thrombus formation and nephropathy are not prevented by the ADP receptor antagonist clopidogrel

    International Nuclear Information System (INIS)

    Poele, Johannes A.M. te; Kleef, Ellen M. van; Wal, Anja F. van der; Dewit, Luc G.H.; Stewart, Fiona A.

    2001-01-01

    Purpose: To assess the effects of kidney irradiation on glomerular adenosine diphosphatase (ADPase) activity and intraglomerular microthrombus formation, and their correlation to the development of renal functional impairment. Methods and Materials: C3H/HenAf-nu + mice were given single-dose or fractionated kidney irradiations. Glomerular ADPase activity was measured using a cerium-based histochemical method. Microthrombus formation within the glomeruli was assessed by a semiquantitative immunohistochemical analysis of fibrinogen/fibrin deposits. Renal function was assessed by the [ 51 Cr]EDTA retention assay. Results: The ADPase activity was significantly reduced, to approximately 50% of pretreatment value, 4-40 weeks after 10-16 Gy single-dose irradiation and at 44 weeks after 20x2 Gy. No dose-effect relationship was found. An approximately fourfold increase in glomerular fibrinogen/fibrin staining was observed at 1 year after irradiation. This increase was not influenced by treating the mice with daily, oral clopidogrel, a platelet ADP receptor antagonist, which reduced platelet aggregation by more than 75%. Radiation-induced impairment of glomerular filtration was also not affected by the clopidogrel treatment. Conclusion: These data indicate that irradiation significantly reduced glomerular ADPase activity, which correlated with an increased glomerular fibrinogen/fibrin deposition. We were not able to reduce these prothrombotic changes, nor to protect against radiation nephropathy, by pharmacological intervention with an ADP-receptor antagonist

  9. I.c.v. administration of the nonsteroidal glucocorticoid receptor antagonist, CP-472555, prevents exacerbated hypoglycemia during repeated insulin administration.

    Science.gov (United States)

    Kale, A Y; Paranjape, S A; Briski, K P

    2006-06-30

    Hypoglycemia elicits an integrated array of CNS-mediated counterregulatory responses, including activation of the hypothalamic-pituitary-adrenal axis. The role of antecedent adrenocortical hypersecretion in impaired glucose counterregulation remains controversial. The present studies utilized the selective, nonsteroidal glucocorticoid receptor antagonist, CP-472555, as a pharmacological tool to investigate the hypothesis that hypoglycemic hypercorticosteronemia modulates CNS efferent autonomic and neuroendocrine motor responses to recurring insulin-induced hypoglycemia via glucocorticoid receptor-dependent mechanisms. Groups of adult male rats were injected s.c. with either one or four doses of the intermediate-acting insulin, Humulin neutral protamine Hagedorn (NPH), on as many days, while controls were injected with diluent alone. Animals injected with four doses of insulin were pretreated by i.c.v. administration of graded doses of the glucocorticoid receptor antagonist or vehicle alone prior to the first three doses of insulin. Repeated daily injection of NPH exacerbated hypoglycemia, attenuated patterns of glucagon and epinephrine secretion, and diminished neuronal transcriptional activation in discrete CNS metabolic loci, including the lateral hypothalamic area, dorsomedial hypothalamic nucleus, paraventricular hypothalamic nucleus, and nucleus of the solitary tract. While i.c.v. delivery of 25 or 100 ng doses of CP-472555 did not alter any of these parameters, animals treated with 500 ng exhibited circulating glucose, glucagon, and epinephrine levels that were similar to those in rats injected with one dose of insulin, as well as a reversal of recurring insulin-induced hypoglycemia-associated reductions in Fos immunolabeling in the lateral hypothalamic area, dorsomedial hypothalamic nucleus, and paraventricular hypothalamic nucleus. These results provide unique pharmacological evidence that antecedent activation of central glucocorticoid receptor is required

  10. The M1 Muscarinic Receptor Antagonist VU0255035 Delays the Development of Status Epilepticus after Organophosphate Exposure and Prevents Hyperexcitability in the Basolateral Amygdala

    Science.gov (United States)

    Miller, Steven L.; Aroniadou-Anderjaska, Vassiliki; Pidoplichko, Volodymyr I.; Figueiredo, Taiza H.; Apland, James P.; Krishnan, Jishnu K. S.

    2017-01-01

    Exposure to organophosphorus toxins induces seizures that progress to status epilepticus (SE), which can cause brain damage or death. Seizures are generated by hyperstimulation of muscarinic receptors, subsequent to inhibition of acetylcholinesterase; this is followed by glutamatergic hyperactivity, which sustains and reinforces seizure activity. It has been unclear which muscarinic receptor subtypes are involved in seizure initiation and the development of SE in the early phases after exposure. Here, we show that pretreatment of rats with the selective M1 receptor antagonist, VU0255035 [N-(3-oxo-3-(4-(pyridine-4-yl)piperazin-1-yl)propyl)-benzo[c][1,2,5]thiadiazole-4 sulfonamide], significantly suppressed seizure severity and prevented the development of SE for about 40 minutes after exposure to paraoxon or soman, suggesting an important role of the M1 receptor in the early phases of seizure generation. In addition, in in vitro brain slices of the basolateral amygdala (a brain region that plays a key role in seizure initiation after nerve agent exposure), VU0255035 blocked the effects produced by bath application of paraoxon—namely, a brief barrage of spontaneous inhibitory postsynaptic currents, followed by a significant increase in the ratio of the total charge transferred by spontaneous excitatory postsynaptic currents over that of the inhibitory postsynaptic currents. Furthermore, paraoxon enhanced the hyperpolarization-activated cation current Ih in basolateral amygdala principal cells, which could be one of the mechanisms underlying the increased glutamatergic activity, an effect that was also blocked in the presence of VU0255035. Thus, selective M1 antagonists may be an efficacious pretreatment in contexts in which there is risk for exposure to organophosphates, as these antagonists will delay the development of SE long enough for medical assistance to arrive. PMID:27799295

  11. Prevention of Spinal Anesthesia-Induced Hypotension During Cesarean Delivery by 5-Hydroxytryptamine-3 Receptor Antagonists: A Systematic Review and Meta-analysis and Meta-regression.

    Science.gov (United States)

    Heesen, Michael; Klimek, Markus; Hoeks, Sanne E; Rossaint, Rolf

    2016-10-01

    Hypotension remains a frequent complication of spinal anesthesia, increasing the risk of nausea and vomiting, altered mental status, and aspiration. The aim of this systematic review and meta-analysis was to determine whether 5-hydroxytryptamine3 (5-HT3) receptor antagonists, administered before the initiation of spinal anesthesia, mitigate hypotension. After a systematic literature search in various databases, randomized placebo-controlled double-blind trials studying the preventive effect of 5-HT3 receptor antagonists were included. A random-effects model was applied, risk ratio (RR, binary variables) or weighted mean difference (continuous variables) with 95% confidence intervals (CIs) were calculated. The primary outcome was the incidence of hypotension. Seventeen trials (8 obstetric, 9 non-obstetric) reporting on 1604 patients were identified. Ondansetron in doses from 2 to 12 mg was studied in 12 trials. Prophylactic 5-HT3 administration significantly reduced the risk of hypotension in the combined analysis of 17 trials, RR 0.54 (95% CI 0.36-0.81, I = 79%). In obstetric trials, the RR was 0.52, 95% CI 0.30-0.88, I = 87% (number needed to treat 4). In non-obstetric studies, the 95% CIs were wide and included a clinically relevant reduction in the risk of hypotension (RR 0.50, 95% CI 0.22-1.16; I = 66%). Contour-enhanced funnel plots confirmed publication bias. Meta-regression showed a significant ondansetron dose response in non-obstetric patients (β = -0.355, P = .04). In the combined and in the obstetric-only analysis, the risk of bradycardia was significantly reduced as was the use of phenylephrine equivalents. 5-HT3 antagonists are effective in reducing the incidence of hypotension and bradycardia; the effects are moderate and are only significant in the subgroup of patients undergoing cesarean delivery. The effects in the non-obstetric population are not significant.

  12. Histamine-2 Receptor Antagonist Cannot Prevent Recurrent Peptic Ulcers in Patients With Atherosclerotic Diseases Who Receive Platelet ADP Receptor Antagonist Monotherapy: A Randomized-Controlled, Double-Blind, and Double-Dummy Trial.

    Science.gov (United States)

    Hsu, Ping-I; Wu, Deng-Chyang; Tsay, Feng-Woei; Cheng, Jin-Shiung; Liu, Chun-Peng; Lai, Kwok-Hung; Chen, Wen-Chi; Wang, Huay-Min; Tsai, Tzung-Jiun; Tsai, Kuo-Wang; Kao, Sung-Shuo

    2017-02-01

    Proton pump inhibitor can effectively prevent recurrent peptic ulcers among atherosclerotic patients receiving clopidogrel monotherapy. However, the interaction between proton pump inhibitors and clopidogrel has raised concerns over the safety of combined use of the two medicines in clinical practice. The aims of this randomized-controlled, double-blind and double-dummy trial were to investigate the efficacy of histamine-2 receptor antagonist (H2RA) in the prevention of recurrent peptic ulcer in patients undergoing thienopyridine monotherapy. From January 2012 to 2016, long-termed thienopyridine users with a peptic ulcer history who did not have peptic ulcers at initial endoscopy were randomly assigned to receive either famotidine (40 mg, before bedtime) or placebo (before bedtime) for 6 months. Follow-up endoscopy was performed at the end of the 6th month and whenever dyspepsia, hematemesis, or melena occurred. The cumulative incidence of recurrent peptic ulcer during the 6-month period was 7.0% in famotidine group (n=114) and 11.4% in the placebo group (n=114). The two patient groups had comparable cumulative incidence of peptic ulcer (difference, 4.4%; 95% confidence interval (CI), -11.7 to 2.9%; P=0.239). Additionally, there was no difference in the cumulative incidence of ulcer bleeding (2.6% vs. 1.8%; difference, 0.8%; 95% CI, -0.6 to 2.4%, P=1.000) between famotidine and placebo groups. However, the former had a lower incidence of gastroduodenal erosion than the latter (21.1% vs. 36.8%; difference, 15.7%; 95% CI, -27.3 to -4.1%; P=0.013). Famotidine cannot decrease the incidence of peptic ulcer or ulcer bleeding in thienopyridine users with atherosclerotic disease and a history of peptic ulcer.

  13. Selective A2A receptor antagonist prevents microglia-mediated neuroinflammation and protects retinal ganglion cells from high intraocular pressure-induced transient ischemic injury.

    Science.gov (United States)

    Madeira, Maria H; Boia, Raquel; Elvas, Filipe; Martins, Tiago; Cunha, Rodrigo A; Ambrósio, António Francisco; Santiago, Ana Raquel

    2016-03-01

    Glaucoma is a leading cause of vision loss and blindness worldwide, characterized by chronic and progressive neuronal loss. Reactive microglial cells have been recognized as a neuropathologic feature, contributing to local inflammation and retinal neurodegeneration. In a recent in vitro work (organotypic cultures), we demonstrated that blockade of adenosine A2A receptor (A2AR) prevents the neuroinflammatory response and affords protection to retinal ganglion cells (RGCs) against exposure to elevated hydrostatic pressure (EHP), to mimic elevated intraocular pressure (IOP), the main risk factor for glaucoma development. Herein, we investigated whether a selective A2AR antagonist (SCH 58261) could modulate retinal microglia reactivity and their inflammatory response. Furthermore, we took advantage of the high IOP-induced transient ischemia (ischemia-reperfusion, I-R) animal model to evaluate the protective role of A2AR blockade in the control of retinal neuroinflammation and neurodegeneration. Primary microglial cell cultures were challenged either with lipopolysaccharide or with EHP, in the presence or absence of A2AR antagonist SCH 58261 (50 nM). In addition, I-R injury was induced in adult Wistar rats after intravitreal administration of SCH 58261 (100 nM, 5 μL). Our results showed that SCH 58261 attenuated microglia reactivity and the increased expression and release of proinflammatory cytokines. Moreover, intravitreal administration of SCH 58261 prevented I-R-induced cell death and RGC loss, by controlling microglial-mediated neuroinflammatory response. These results prompt the proposal that A2AR blockade may have great potential in the management of retinal neurodegenerative diseases characterized by microglia reactivity and RGC death, such as glaucoma and ischemic diseases. Copyright © 2016 Elsevier Inc. All rights reserved.

  14. Prevention of alcohol-heightened aggression by CRF-R1 antagonists in mice: critical role for DRN-PFC serotonin pathway.

    Science.gov (United States)

    Quadros, Isabel M; Hwa, Lara S; Shimamoto, Akiko; Carlson, Julia; DeBold, Joseph F; Miczek, Klaus A

    2014-11-01

    Alcohol can escalate aggressive behavior in a significant subgroup of rodents, humans, and nonhuman primates. The present study investigated whether blockade of corticotropin-releasing factor receptor type 1 (CRF-R1) could prevent the emergence of alcohol-heightened aggression in mice. The serotonin (5-HT) pathway from the dorsal raphe nucleus (DRN) to the medial prefrontal cortex (mPFC) by CRF-R1 was investigated as a possible target for the prevention of alcohol-heightened aggressive behavior. Male CFW mice that reliably exhibited aggressive behaviors after consuming 1 g/kg of alcohol received systemic or intra-DRN administration of CRF-R1 antagonists, CP-154,526 or MTIP, before a confrontation with a male conspecific. Blockade of DRN CRF-R1 receptors with both antagonists significantly reduced only alcohol-heightened aggression, whereas systemic administration reduced both alcohol-heightened and species-typical aggression. Next, a 5-HT1A agonist, 8-OH-DPAT, was coadministered with CP-154,526 into the DRN to temporarily disrupt 5-HT activity. This manipulation abolished the antiaggressive effects of intra-DRN CP-154,526. In the mPFC, in vivo microdialysis revealed that extracellular 5-HT levels were increased in mice that consumed alcohol and were then injected with CP-154,526, both systemically or intra-DRN. Neither alcohol nor CP-154,526 alone affected 5-HT release in the mPFC. The present results suggest the DRN as a critical site for CRF-R1 to modulate alcohol-heightened aggression via action on the serotonergic DRN-PFC pathway.

  15. The CRF₁ receptor antagonist SSR125543 prevents stress-induced long-lasting sleep disturbances in a mouse model of PTSD: comparison with paroxetine and d-cycloserine.

    Science.gov (United States)

    Philbert, Julie; Beeské, Sandra; Belzung, Catherine; Griebel, Guy

    2015-02-15

    The selective CRF₁ (corticotropin releasing factor type 1) receptor antagonist SSR125543 has been previously shown to attenuate the long-term behavioral and electrophysiological effects produced by traumatic stress exposure in mice. Sleep disturbances are one of the most commonly reported symptoms by people with post-traumatic stress disorder (PTSD). The present study aims at investigating whether SSR125543 (10 mg/kg/day/i.p. for 2 weeks) is able to attenuate sleep/wakefulness impairment induced by traumatic stress exposure in a model of PTSD in mice using electroencephalographic (EEG) analysis. Effects of SSR125543 were compared to those of the 5-HT reuptake inhibitor, paroxetine (10 mg/kg/day/i.p.), and the partial N-methyl-d-aspartate (NMDA) receptor agonist, d-cycloserine (10 mg/kg/day/i.p.), two compounds which have demonstrated clinical efficacy against PTSD. Baseline EEG recording was performed in the home cage for 6h prior to the application of two electric foot-shocks of 1.5 mA. Drugs were administered from day 1 post-stress to the day preceding the second EEG recording session, performed 14 days later. Results showed that at day 14 post-stress, shocked mice displayed sleep fragmentation as shown by an increase in the occurrence of both non-rapid eye movement (NREM) sleep and wakefulness bouts. The duration of wakefulness, NREM and REM sleep were not significantly affected. The stress-induced effects were prevented by repeated administration of SSR125543, paroxetine and D-cycloserine. These findings confirm further that the CRF₁ receptor antagonist SSR125543 is able to attenuate the deleterious effects of traumatic stress exposure. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Use of vitamin K antagonists for secondary stroke prevention depends on the treating healthcare provider in Germany - results from the German AFNET registry.

    Science.gov (United States)

    Haeusler, Karl Georg; Gerth, Andrea; Limbourg, Tobias; Tebbe, Ulrich; Oeff, Michael; Wegscheider, Karl; Treszl, András; Ravens, Ursula; Meinertz, Thomas; Kirchhof, Paulus; Breithardt, Günter; Steinbeck, Gerhard; Nabauer, Michael

    2015-08-05

    Anticoagulation using vitamin K antagonists (VKAs) significantly reduces the risk of recurrent stroke in stroke patients with atrial fibrillation (AF) and is recommended by guidelines. The German Competence NETwork on Atrial Fibrillation established a nationwide prospective registry including 9,574 AF patients, providing the opportunity to analyse AF management according to German healthcare providers. On enrolment, 896 (9.4 %) patients reported a prior ischaemic stroke or transient ischaemic attack. Stroke patients were significantly older, more likely to be female, had a higher rate of cardiovascular risk factors, and more frequently received anticoagulation (almost exclusively VKA) than patients without prior stroke history. Following enrolment, 76.4 % of all stroke patients without VKA contraindications received anticoagulation, which inversely associated with age (OR 0.95 per year; 95 % CI 0.92-0.97). General practitioners/internists (OR 0.40; 95 % CI 0.21-0.77) and physicians working in regional hospitals (OR 0.47; 95 % CI 0.29-0.77) prescribed anticoagulation for secondary stroke prevention less frequently than physicians working at university hospitals (reference) and office-based cardiologists (OR 1.40; 95 % CI 0.76-2.60). The impact of the treating healthcare provider was less evident in registry patients without prior stroke. In the AFNET registry, anticoagulation for secondary stroke prevention was prescribed in roughly three-quarters of AF patients, a significantly higher rate than in primary prevention. We identified two factors associated with withholding oral anticoagulation in stroke survivors, namely higher age and-most prominently-treatment by a general practitioner/internist or physicians working at regional hospitals.

  17. The AT1 Receptor Antagonist, L-158,809, Prevents or Ameliorates Fractionated Whole-Brain Irradiation-Induced Cognitive Impairment

    International Nuclear Information System (INIS)

    Robbins, Mike E.; Payne, Valerie B.S.; Tommasi, Ellen B.S.; Diz, Debra I.; Hsu, Fang-Chi; Brown, William R.; Wheeler, Kenneth T.; Olson, John; Zhao Weiling

    2009-01-01

    Purpose: We hypothesized that administration of the angiotensin type 1 (AT1) receptor antagonist, L-158,809, to young adult male rats would prevent or ameliorate fractionated whole-brain irradiation (WBI)-induced cognitive impairment. Materials and Methods: Groups of 80 young adult male Fischer 344 x Brown Norway (F344xBN) rats, 12-14 weeks old, received either: (1) fractionated WBI; 40 Gy of γ rays in 4 weeks, 2 fractions/week, (2) sham-irradiation; (3) WBI plus L-158,809 (20 mg/L drinking water) starting 3 days prior, during, and for 14, 28, or 54 weeks postirradiation; and (4) sham-irradiation plus L-158,809 for 14, 28, or 54 weeks postirradiation. An additional group of rats (n = 20) received L-158,809 before, during, and for 5 weeks postirradiation, after which they received normal drinking water up to 28 weeks postirradiation. Results: Administration of L-158,809 before, during, and for 28 or 54 weeks after fractionated WBI prevented or ameliorated the radiation-induced cognitive impairment observed 26 and 52 weeks postirradiation. Moreover, giving L-158,809 before, during, and for only 5 weeks postirradiation ameliorated the significant cognitive impairment observed 26 weeks postirradiation. These radiation-induced cognitive impairments occurred without any changes in brain metabolites or gross histologic changes assessed at 28 and 54 weeks postirradiation, respectively. Conclusions: Administering L-158,809 before, during, and after fractionated WBI can prevent or ameliorate the chronic, progressive, cognitive impairment observed in rats at 26 and 52 weeks postirradiation. These findings offer the promise of improving the quality of life for brain tumor patients

  18. GABAB antagonists

    DEFF Research Database (Denmark)

    Frydenvang, Karla Andrea; Hansen, J J; Krogsgaard-Larsen, P

    1994-01-01

    chromatographic techniques. The absolute stereochemistry of (-)-(R)-phaclofen was established by X-ray crystallographic analysis. (-)-(R)-Phaclofen was shown to inhibit the binding of [3H]-(R)-baclofen to GABAB receptor sites on rat cerebellar membranes (IC50 = 76 +/- 13 microM), whereas (+)-(S......)-baclofen and the antagonist (-)-(R)-phaclofen suggests that these ligands interact with the GABAB receptor sites in a similar manner. Thus, it may be concluded that the different pharmacological effects of these compounds essentially result from the different spatial and proteolytic properties of their acid groups....

  19. Investigating racial disparities in use of NK1 receptor antagonists to prevent chemotherapy-induced nausea and vomiting among women with breast cancer.

    Science.gov (United States)

    Check, Devon K; Reeder-Hayes, Katherine E; Basch, Ethan M; Zullig, Leah L; Weinberger, Morris; Dusetzina, Stacie B

    2016-04-01

    Chemotherapy-induced nausea and vomiting (CINV) is a major concern for cancer patients and, if uncontrolled, can seriously compromise quality of life (QOL) and other treatment outcomes. Because of the expense of antiemetic medications used to prevent CINV (particularly oral medications filled through Medicare Part D), disparities in their use may exist. We used 2006-2012 SEER-Medicare data to evaluate the use of neurokinin-1 receptor antagonists (NK1s), a potent class of antiemetics, among black and white women initiating highly emetogenic chemotherapy for the treatment of early-stage breast cancer. We used modified Poisson regression to assess the relationship between race and (1) any NK1 use, (2) oral NK1 (aprepitant) use, and (3) intravenous NK1 (fosaprepitant) use. We report adjusted risk ratios (aRR) and 95 % confidence intervals (CI). The study included 1130 women. We observed racial disparities in use of any NK1 (aRR: 0.68, 95 % CI 0.51-0.91) and in use of oral aprepitant specifically (aRR: 0.54, 95 % CI 0.35-0.83). We did not observe disparities in intravenous fosaprepitant use. After controlling for variables related to socioeconomic status, disparities in NK1 and aprepitant use were reduced but not eliminated. We found racial disparities in women's use of oral NK1s for the prevention of CINV. These disparities may be partly explained by racial differences in socioeconomic status, which may translate into differential ability to afford the medication.

  20. The V2 receptor antagonist tolvaptan raises cytosolic calcium and prevents AQP2 trafficking and function: an in vitro and in vivo assessment.

    Science.gov (United States)

    Tamma, Grazia; Di Mise, Annarita; Ranieri, Marianna; Geller, Ari; Tamma, Roberto; Zallone, Alberta; Valenti, Giovanna

    2017-09-01

    Tolvaptan, a selective vasopressin V2 receptor antagonist, is a new generation diuretic. Its clinical efficacy is in principle due to impaired vasopressin-regulated water reabsorption via aquaporin-2 (AQP2). Nevertheless, no direct in vitro evidence that tolvaptan prevents AQP2-mediated water transport, nor that this pathway is targeted in vivo in patients with syndrome of inappropriate antidiuresis (SIAD) has been provided. The effects of tolvaptan on the vasopressin-cAMP/PKA signalling cascade were investigated in MDCK cells expressing endogenous V2R and in mouse kidney. In MDCK, tolvaptan prevented dDAVP-induced increase in ser256-AQP2 and osmotic water permeability. A similar effect on ser256-AQP2 was found in V1aR -/- mice, thus confirming the V2R selectively. Of note, calcium calibration in MDCK showed that tolvaptan per se caused calcium mobilization from the endoplasmic reticulum resulting in a significant increase in basal intracellular calcium. This effect was only observed in cells expressing the V2R, indicating that it requires the tolvaptan-V2R interaction. Consistent with this finding, tolvaptan partially reduced the increase in ser256-AQP2 and the water permeability in response to forskolin, a direct activator of adenylyl cyclase (AC), suggesting that the increase in intracellular calcium is associated with an inhibition of the calcium-inhibitable AC type VI. Furthermore, tolvaptan treatment reduced AQP2 excretion in two SIAD patients and normalized plasma sodium concentration. These data represent the first detailed demonstration of the central role of AQP2 blockade in the aquaretic effect of tolvaptan and underscore a novel effect in raising intracellular calcium that can be of significant clinical relevance. © 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.

  1. PF-03882845, a non-steroidal mineralocorticoid receptor antagonist, prevents renal injury with reduced risk of hyperkalemia in an animal model of nephropathy

    Directory of Open Access Journals (Sweden)

    Stephen eOrena

    2013-10-01

    Full Text Available The mineralocorticoid receptor (MR antagonists PF 03882845 and eplerenone were evaluated for renal protection against aldosterone mediated renal disease in uninephrectomized Sprague Dawley (SD rats maintained on a high salt diet and receiving aldosterone by osmotic mini pump for 27 days. Serum K+ and the urinary albumin to creatinine ratio (UACR were assessed following 14 and 27 days of treatment. Aldosterone induced renal fibrosis as evidenced by increases in UACR, collagen IV staining in kidney cortex, and expression of pro fibrotic genes relative to sham operated controls not receiving aldosterone. While both PF 03882845 and eplerenone elevated serum K+ levels with similar potencies, PF 03882845 was more potent than eplerenone in suppressing the rise in UACR. PF 03882845 prevented the increase in collagen IV staining at 5, 15 and 50 mg/kg BID while eplerenone was effective only at the highest dose tested (450 mg/kg BID. All doses of PF 03882845 suppressed aldosterone induced increases in collagen IV, transforming growth factor 1 (Tgf 1, interleukin 6 (Il-6, intermolecular adhesion molecule 1 (Icam-1 and osteopontin gene expression in kidney while eplerenone was only effective at the highest dose. The therapeutic index (TI, calculated as the ratio of the EC50 for increasing serum K+ to the EC50 for UACR lowering, was 83.8 for PF 03882845 and 1.47 for eplerenone. Thus the TI of PF 03882845 against hyperkalemia was 57 fold superior to that of eplerenone indicating that PF 03882845 may present significantly less risk for hyperkalemia compared to eplerenone.

  2. Dalteparin or vitamin K antagonists to prevent recurrent venous thromboembolism in cancer patients: a patient-level economic analysis for France and Austria.

    Science.gov (United States)

    Dranitsaris, George; Shane, Lesley G; Galanaud, Jean-Philippe; Stemer, Gunar; Debourdeau, Philippe; Woodruff, Seth

    2017-07-01

    International guidelines recommend extended duration secondary prophylaxis in cancer patients who develop primary venous thromboembolism (VTE). Agent selection is guided in part by one large randomized trial (i.e., CLOT; Lee et al., N Engl J Med 349:146-53, 2003) which demonstrated that dalteparin reduced the relative risk of recurrence by 52% compared with oral vitamin K antagonists (VKA; HR = 0.48, 95% CI, 0.30 to 0.77). In a subgroup analysis from that same trial, patients with renal impairment also derived benefit with dalteparin (VTE rates = 3% vs. 17%; p = 0.011). To measure the economic value of secondary VTE prophylaxis with dalteparin, a patient-level pharmacoeconomic analysis was conducted from the Austrian and French healthcare system perspectives. Chapter 1 Healthcare resource use collected during the CLOT trial was extracted and converted into direct cost estimates. Incremental cost differences between the dalteparin and VKA groups were then combined with health state utilities to measure the cost per quality-adjusted life year (QALY) gained. The dalteparin group had significantly higher costs than the VKA group in both countries (Austria: dalteparin = €2687 vs. VKA = €2012; France: dalteparin = €2053 vs. VKA = €1352: p Austria and France, respectively. The analyses in patients with renal impairment suggested an even better economic profile, with the cost per QALY gained being less than €4000 in both countries. Secondary prophylaxis with dalteparin is a cost-effective alternative to VKA for the prevention of recurrent VTE in patients with cancer.

  3. Calcium antagonists for aneurysmal subarachnoid haemorrhage

    NARCIS (Netherlands)

    Dorhout Mees, S. M.; Rinkel, G. J. E.; Feigin, V. L.; Algra, A.; van den Bergh, W. M.; Vermeulen, M.; van Gijn, J.

    2007-01-01

    BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has been incompletely elucidated, but vasospasm probably is a contributing factor. Experimental studies have suggested that calcium antagonists can prevent or reverse

  4. Random-start GnRH antagonist for emergency fertility preservation: a self-controlled trial

    Directory of Open Access Journals (Sweden)

    Checa MA

    2015-02-01

    Full Text Available Miguel A Checa,1,2 Mario Brassesco,2 Margalida Sastre,1 Manuel Gómez,2 Julio Herrero,3 Laura Marque,3 Arturo Brassesco,2 Juan José Espinós3 1Department of Obstetrics and Gynecology, Parc de Salut Mar, Universitat Autònoma de Barcelona, 2Centro de Infertilidad y Reproducción Humana (CIRH, 3Centro de Reproducción Asistida Sagrada Familia, Clínica Sagrada Familia, Barcelona, Spain Abstract: The aim of this study is to evaluate the feasibility and safety of random-start controlled ovarian hyperstimulation (COH for emergency fertility preservation, regardless of the phase of the menstrual cycle. A self-controlled pilot clinical trial (NCT01385332 was performed in an acute-care teaching hospital and in two private reproductive centers in Barcelona, Spain. Eleven egg donors participated in the study. Two random-start gonadotropin-releasing hormone (GnRH antagonist protocols were assessed in which ganirelix was initiated on either day 10 (protocol B or on day 20 (protocol C of the menstrual cycle and was continued until estradiol levels were below 60 pg/dL. These protocols were compared with a standard protocol (protocol A. The main outcome of interest was the number of metaphase 2 oocytes retrieved. Results from this study show that the number of mature oocytes retrieved was comparable across the different protocols (14.3±4.6 in the standard protocol versus 13.0±9.1 and 13.2±5.2 in protocols B and C, respectively; values expressed as mean ± standard deviation. The mean number of days needed for a GnRH antagonist to lower estradiol levels, as well as the ongoing pregnancy rates, were also similar when protocols B (stimulation in follicular phase and C (stimulation on luteal phase were compared with protocol A (standard stimulation. GnRH antagonists can be effectively used for random-start controlled ovarian hyperstimulation with an ovarian response similar to that of standard protocols, and the antagonists appear suitable for emergency

  5. Developmental Programming: Prenatal and Postnatal Androgen Antagonist and Insulin Sensitizer Interventions Prevent Advancement of Puberty and Improve LH Surge Dynamics in Prenatal Testosterone-Treated Sheep

    OpenAIRE

    Padmanabhan, Vasantha; Veiga-Lopez, Almudena; Herkimer, Carol; Abi Salloum, Bachir; Moeller, Jacob; Beckett, Evan; Sreedharan, Rohit

    2015-01-01

    Prenatal T excess induces maternal hyperinsulinemia, early puberty, and reproductive/metabolic defects in the female similar to those seen in women with polycystic ovary syndrome. This study addressed the organizational/activational role of androgens and insulin in programming pubertal advancement and periovulatory LH surge defects. Treatment groups included the following: 1) control; 2) prenatal T; 3) prenatal T plus prenatal androgen antagonist, flutamide; 4) prenatal T plus prenatal insuli...

  6. The angiotensin II AT1 receptor antagonist irbesartan prevents thromboxane A2-induced vasoconstriction in the rat hind-limb vascular bed in vivo.

    Science.gov (United States)

    Fukuhara, M; Neves, L A; Li, P; Diz, D I; Ferrario, C M; Brosnihan, K B

    2001-03-01

    We studied the vasoconstrictor effects of the thromboxane A2 (TxA2) analogue U46619 in the perfused hind limb of rats under constant flow before and after intravenous injection of irbesartan, an angiotensin II AT1 receptor antagonist, to test whether irbesartan interacts in vivo with the thromboxane A2/prostaglandin endoperoxidase H2 (TxA2/PGH2) receptor. Male Sprague-Dawley rats (n = 15, body weight 350-420 g) were anesthetized with thiobutabarbital sodium (Inactin, 100 mg/kg intraperitoneally). Regional vascular responses to U46619 (0.5 and 1.0 microg) were investigated in the rat hind quarter under conditions of controlled flow before and after administration of irbesartan (10 mg/kg, intravenously). In addition, to test the specificity of the effect of irbesartan on U46619, phenylephrine (0.5, 1.0 microg) and another AT1 receptor antagonist, candesartan CV11974 (0.3 mg/kg, intravenously) were used. The dose-dependent increases in hind-limb perfusion pressure produced by U46619 were significantly attenuated by prior injection of irbesartan, at a dose that blocked the angiotensin II (Ang II) pressor responses. The specificity for the response was shown with the demonstrations that the increase in vascular resistance produced by phenylephrine was unchanged by irbesartan and, furthermore, that the increase in vascular resistance produced by U46619 was unchanged by another AT1 receptor antagonist, candesartan. This study demonstrates that irbesartan interacts at the TxA2/PGH2 receptor in the rat's hind limb in vivo, to modify changes in local regional vascular resistance. The dual antagonistic actions of irbesartan, acting at both AT1 and TxA2 receptors in blood vessels, may overall enhance its therapeutic profile in the treatment of hypertension.

  7. Peripherally Administered Y2-Receptor Antagonist BIIE0246 Prevents Diet-Induced Obesity in Mice With Excess Neuropeptide Y, but Enhances Obesity in Control Mice.

    Science.gov (United States)

    Ailanen, Liisa; Vähätalo, Laura H; Salomäki-Myftari, Henriikka; Mäkelä, Satu; Orpana, Wendy; Ruohonen, Suvi T; Savontaus, Eriika

    2018-01-01

    Neuropeptide Y (NPY) plays an important role in the regulation of energy homeostasis in the level of central and sympathetic nervous systems (SNSs). Genetic silencing of peripheral Y 2 -receptors have anti-obesity effects, but it is not known whether pharmacological blocking of peripheral Y 2 -receptors would similarly benefit energy homeostasis. The effects of a peripherally administered Y 2 -receptor antagonist were studied in healthy and energy-rich conditions with or without excess NPY. Genetically obese mice overexpressing NPY in brain noradrenergic nerves and SNS (OE-NPY DβH ) represented the situation of elevated NPY levels, while wildtype (WT) mice represented the normal NPY levels. Specific Y 2 -receptor antagonist, BIIE0246, was administered (1.3 mg/kg/day, i.p.) for 2 or 4.5 weeks to OE-NPY DβH and WT mice feeding on chow or Western diet. Treatment with Y 2 -receptor antagonist increased body weight gain in both genotypes on chow diet and caused metabolic disturbances (e.g., hyperinsulinemia and hypercholesterolemia), especially in WT mice. During energy surplus (i.e., on Western diet), blocking of Y 2 -receptors induced obesity in WT mice, whereas OE-NPY DβH mice showed reduced fat mass gain, hepatic glycogen and serum cholesterol levels relative to body adiposity. Thus, it can be concluded that with normal NPY levels, peripheral Y 2 -receptor antagonist has no potential for treating obesity, but oppositely may even induce metabolic disorders. However, when energy-rich diet is combined with elevated NPY levels, e.g., stress combined with an unhealthy diet, Y 2 -receptor antagonism has beneficial effects on metabolic status.

  8. The N-Methyl-d-Aspartate Receptor Antagonist MK-801 Prevents Thallium-Induced Behavioral and Biochemical Alterations in the Rat Brain.

    Science.gov (United States)

    Osorio-Rico, Laura; Villeda-Hernández, Juana; Santamaría, Abel; Königsberg, Mina; Galván-Arzate, Sonia

    2015-01-01

    Thallium (Tl(+)) is a toxic heavy metal capable of increasing oxidative damage and disrupting antioxidant defense systems. Thallium invades the brain cells through potassium channels, increasing neuronal excitability, although until now the possible role of glutamatergic transmission in this event has not been investigated. Here, we explored the possible involvement of a glutamatergic component in the Tl(+)-induced toxicity through the N-methyl-d-aspartate (NMDA) receptor antagonist dizocilpine (MK-801) in rats. The effects of MK-801 (1 mg/kg, intraperitoneally [ip]) on early (24 hours) motor alterations, lipid peroxidation, reduced glutathione (GSH) levels, and GSH peroxidase activity induced by Tl(+) acetate (32 mg/kg, ip) were evaluated in adult rats. MK-801 attenuated the Tl(+)-induced hyperactivity and lipid peroxidation in the rat striatum, hippocampus and midbrain, and produced mild effects on other end points. Our findings suggest that glutamatergic transmission via NMDA receptors might be involved in the Tl(+)-induced altered regional brain redox activity and motor performance in rats. © The Author(s) 2015.

  9. Presymptomatically applied AMPA receptor antagonist prevents calcium increase in vulnerable type of motor axon terminals of mice modeling amyotrophic lateral sclerosis.

    Science.gov (United States)

    Patai, Roland; Paizs, Melinda; Tortarolo, Massimo; Bendotti, Caterina; Obál, Izabella; Engelhardt, József I; Siklós, László

    2017-07-01

    Increased intracellular calcium (Ca), which might be the consequence of an excess influx through Ca-permeable α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, plays a crucial role in degeneration of motor neurons. Previously we demonstrated that the presymptomatic application of AMPA receptor antagonist, talampanel, could reduce Ca elevation in spinal motor neurons of mice carrying the G93A mutation of superoxide dismutase 1 (SOD1), modeling amyotrophic lateral sclerosis (ALS). It remained to be examined whether the remote, functionally semi-autonomous motor axon terminals could be rescued from the Ca overload, or if the terminals, where the degeneration possibly starts, already experience intractable changes at early time points. Thus using electron microscopic techniques, we measured the Ca level of motor axon terminals in the interosseus muscle of the SOD1 mutant animals, which are prototypes of vulnerable nerve endings in ALS. In line with the results obtained in the perikarya, talampanel treatment could reduce Ca increase evoked by the presence of mutant SOD1 in the axon terminals if the treatment was started presymptomatically but not at an early symptomatic stage. We also tested the Ca level in the cell bodies and axon terminals of the oculomotor neurons, which are resistant to the disease. Neither Ca increase, nor talampanel effect could be demonstrated at either time point. This is consistent with the observations that oculomotor neurons contain increased level of Ca buffer, which could reduce excess Ca load, and they also express glutamate receptor subunit type 2, which renders AMPA receptors impermeable to Ca. Copyright © 2017. Published by Elsevier B.V.

  10. Prevention of drug priming- and cue-induced reinstatement of MDMA-seeking behaviors by the CB1 cannabinoid receptor antagonist AM251.

    Science.gov (United States)

    Nawata, Yoko; Kitaichi, Kiyoyuki; Yamamoto, Tsuneyuki

    2016-03-01

    3,4-Methylenedioxymethamphetamine (MDMA), a methamphetamine (METH) derivative, exhibits METH-like actions at monoamine transporters and positive reinforcing effects in rodents and primates. The purposes of the present study were to determine whether cross-reinstatement would be observed between MDMA and METH and if the cannabinoid receptor, a receptor known to play critical roles in the brain reward system, could modulate MDMA craving. Rats were trained to press a lever for intravenous MDMA (0.3mg/infusion) or METH (0.02mg/infusion) infusions under a fixed ratio 1 schedule paired with drug-associated cues (light and tone). Following drug self-administration acquisition training, rats underwent extinction training (an infusion of saline). Reinstatement tests were performed once the extinction criteria were achieved. In MDMA-trained rats, the MDMA-priming injection (3.2mg/kg, i.p.) or re-exposure to MDMA-associated cues reinstated MDMA-seeking behavior. Additionally, a priming injection of METH (1.0mg/kg, i.p.) also reinstated MDMA-seeking behavior. In contrast, none of the MDMA doses reinstated METH-seeking behavior in the METH-trained rats. The CB1 cannabinoid receptor antagonist AM251 markedly attenuated the MDMA-seeking behaviors induced by MDMA-priming injection or re-exposure to MDMA-associated cues in a dose-dependent manner. These findings show that MDMA has obvious addictive potential for reinstating drug-seeking behavior and that METH can be an effective stimulus for reinstating MDMA-seeking behaviors. Furthermore, based on the attenuating effect of AM251 in the reinstatement of MDMA-seeking behaviors, drugs that suppress CB1 receptors may be used in treatment of MDMA dependence. Copyright © 2016. Published by Elsevier Ireland Ltd.

  11. Calcium gluconate infusion is as effective as the vascular endothelial growth factor antagonist cabergoline for the prevention of ovarian hyperstimulation syndrome.

    Science.gov (United States)

    Naredi, Nikita; Karunakaran, Sandeep

    2013-10-01

    Ovarian hyperstimulation syndrome (OHSS) is an iatrogenic and potentially life-threatening disease process, which may occur in healthy young women undergoing controlled ovarian hyperstimulation for assisted reproduction. As the treatment is largely empirical, prevention forms the mainstay of management. The present study was aimed to evaluate the effectiveness of intravenous (IV) calcium gluconate infusion in comparison to the dopamine agonist cabergoline (Cb2) in preventing OHSS in high risk patients undergoing assisted reproductive technique cycles. It was a comparative study wherein the 202 high risk patients undergoing in vitro-fertilization over a period of 18 months after meeting the strict inclusion and the exclusion criteria, were randomly divided into two groups (98 subjects in Group I and 104 in Group II). Women in Group I were administered IV calcium gluconate while the remaining 104 received the dopamine agonist Cb2. The 104 patients belonging to Group II were started Cb2 0.5 mg/day from the day of ovulation trigger and continued until the next 8 days while the 98 high risk patients from Group I were infused with 10 ml of 10% calcium gluconate solution in 200 ml physiologic saline within 30 min of ovum pick up and continued thereafter on day 1, day 2 and day 3. The occurrence of OHSS was seen in only nine patients (in the calcium infusion group, when compared with 16 patients (9.2% vs. 15.4%) who were administered Cb2, but it was not statistically significant. However, only one had severe OHSS in Group I, whereas two women were diagnosed as severe OHSS belonging to the Cb2 arm. Our results document that calcium infusion can effectively prevent severe OHSS and decreases OHSS occurrence rates when used for high-risk patients, but does not suggest its superiority over Cb2. With comparable success rates, either of them can be employed as a preventive strategy for OHSS.

  12. Comparison of proton pump inhibitor and histamine-2 receptor antagonist in the prevention of recurrent peptic ulcers/erosions in long-term low-dose aspirin users: a retrospective cohort study.

    Science.gov (United States)

    Chen, Wen-Chi; Li, Yun-Da; Chiang, Po-Hung; Tsay, Feng-Woei; Chan, Hoi-Hung; Tsai, Wei-Lun; Tsai, Tzung-Jiun; Wang, E-Ming; Cheng, Jin-Shiung; Lai, Kwok-Hung

    2014-01-01

    Proton pump inhibitor and histamine-2 receptor antagonist can prevent aspirin-related ulcers/erosions but few studies compare the efficacy of these two agents. Aims. We evaluated the efficacy of omeprazole and famotidine in preventing recurrent ulcers/erosions in low-dose aspirin users. The 24-week clinical outcomes of the patients using low-dose aspirin for cardiovascular protection with a history of ulcers/erosions and cotherapy of omeprazole or famotidine were retrospectively reviewed. The incidence of gastrointestinal symptoms, recurrent ulcers/erosions, erosive esophagitis, gastrointestinal bleeding, and thromboembolic events was analyzed. A total of 104 patients (famotidine group, 49 patients; omeprazole group, 55 patients) were evaluated. Famotidine group had more gastrointestinal symptoms episodes than omeprazole group (46.9% versus 23.6%, P=0.01). Fifteen famotidine group patients and 5 omeprazole group patients had recurrent ulcers/erosions (30.6% versus 9.1%, P=0.005). Lanza scale was significantly lower in omeprazole group than in famotidine group (1.2±0.7 versus 1.7±1.1, P=0.008). Only 1 famotidine group patient had ulcer bleeding. The incidences of erosive esophagitis and thromboembolic events were comparable between both groups. Omeprazole was superior to famotidine with less gastrointestinal symptoms and recurrent ulcers/erosions in patients using 24-week low-dose aspirin. The risk of erosive esophagitis, gastrointestinal bleeding, and thromboembolic events was similar between both groups.

  13. Calcium antagonists for aneurysmal subarachnoid haemorrhage

    NARCIS (Netherlands)

    Rinkel, G. J. E.; Feigin, V. L.; Algra, A.; van den Bergh, W. M.; Vermeulen, M.; van Gijn, J.

    2005-01-01

    BACKGROUND: Secondary ischaemia is a frequent cause of poor outcome in patients with subarachnoid haemorrhage (SAH). Its pathogenesis has not been elucidated yet, but may be related to vasospasm. Experimental studies have indicated that calcium antagonists can prevent or reverse vasospasm and have

  14. A novel 5HT3 antagonist 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide) prevents diabetes-induced depressive phenotypes in mice: Modulation of serotonergic system.

    Science.gov (United States)

    Gupta, Deepali; Thangaraj, Devadoss; Radhakrishnan, Mahesh

    2016-01-15

    Despite the presence of a multitudinous pharmacotherapy, diabetes-induced depressive disorder remains undertreated. Evidence suggests that brain serotonergic deficits are associated with depressive-like behavior in diabetes and that 5HT3 receptor (5HT3R) antagonists have serotonergic facilitatory effects. This study examined the effects of a novel 5HT3R antagonist, 4i (N-(3-chloro-2-methylphenyl)quinoxalin-2-carboxamide), in diabetes-induced depressive phenotypes. Experimentally, (1) to evaluate the effects of 4i, mice with 8-weeks of diabetes (induced by streptozotocin, 200mg/kg, i.p.) were treated with vehicle, 4i (0.5 and 1mg/kg/day, i.p.), fluoxetine (10mg/kg/day, i.p.) for 4-weeks and subjected to neurobehavioral assays, followed by biochemical estimation of serotonin levels in midbrain, prefrontal-cortex and cerebellum. (2) To evaluate the role of 5HT3R in the postulated effect of 4i, diabetic mice were given 4i (1mg/kg/day, i.p.) after 1h of 1-(m-chlorophenyl)-biguanide (mCPBG, a 5HT3R agonist, 10mg/kg/day, i.p.) treatment and subjected to the same protocol. The results showed that diabetic mice exhibited a significant behavioral deficit, including depression-like behavior in forced swim test, anxiety-like in open field test and sociability deficits in social interaction test, along with a significant decrease in serotonin level in these brain regions. 4i (1mg/kg), similar to fluoxetine, prevented these behavioral abnormalities and normalized brain serotonin levels. 4i (0.5mg/kg) ameliorated only diabetes-induced depressive-like behavior and serotonin deficits, but not anxiety-like effects. mCPBG blunted 4i-mediated behavioral response and increase in brain serotonin levels. Altogether, this study suggests that 4i prevents diabetes-induced depressive phenotypes in mice, which may involve antagonism of 5HT3Rs and increase in serotonin levels in discrete brain regions. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Comparison of Proton Pump Inhibitor and Histamine-2 Receptor Antagonist in the Prevention of Recurrent Peptic Ulcers/Erosions in Long-Term Low-Dose Aspirin Users: A Retrospective Cohort Study

    Directory of Open Access Journals (Sweden)

    Wen-Chi Chen

    2014-01-01

    Full Text Available Background. Proton pump inhibitor and histamine-2 receptor antagonist can prevent aspirin-related ulcers/erosions but few studies compare the efficacy of these two agents. Aims. We evaluated the efficacy of omeprazole and famotidine in preventing recurrent ulcers/erosions in low-dose aspirin users. Methods. The 24-week clinical outcomes of the patients using low-dose aspirin for cardiovascular protection with a history of ulcers/erosions and cotherapy of omeprazole or famotidine were retrospectively reviewed. The incidence of gastrointestinal symptoms, recurrent ulcers/erosions, erosive esophagitis, gastrointestinal bleeding, and thromboembolic events was analyzed. Results. A total of 104 patients (famotidine group, 49 patients; omeprazole group, 55 patients were evaluated. Famotidine group had more gastrointestinal symptoms episodes than omeprazole group (46.9% versus 23.6%, P=0.01. Fifteen famotidine group patients and 5 omeprazole group patients had recurrent ulcers/erosions (30.6% versus 9.1%, P=0.005. Lanza scale was significantly lower in omeprazole group than in famotidine group (1.2±0.7 versus 1.7±1.1, P=0.008. Only 1 famotidine group patient had ulcer bleeding. The incidences of erosive esophagitis and thromboembolic events were comparable between both groups. Conclusions. Omeprazole was superior to famotidine with less gastrointestinal symptoms and recurrent ulcers/erosions in patients using 24-week low-dose aspirin. The risk of erosive esophagitis, gastrointestinal bleeding, and thromboembolic events was similar between both groups.

  16. Prevention

    Science.gov (United States)

    ... Error processing SSI file About Heart Disease & Stroke Prevention Heart disease and stroke are an epidemic in ... secondhand smoke. Barriers to Effective Heart Disease & Stroke Prevention Many people with key risk factors for heart ...

  17. Prevention

    Science.gov (United States)

    ... Contact Aging & Health A to Z Find a Geriatrics Healthcare Professional Medications & Older Adults Making Your Wishes ... Prevention Hearing Loss Heart Attack High Blood Pressure Nutrition Osteoporosis Shingles Skin Cancer Related News Quitting Smoking, ...

  18. Evaluation of the effects of gonadotropin-releasing hormone antagonist (GnRH-ant) and agonist (GnRH-a) in the prevention of postoperative adhesion formation in a rat model with immunohistochemical analysis.

    Science.gov (United States)

    Tamay, Asli Goker; Guvenal, Tevfik; Micili, Serap Cilaker; Yildirim, Yasemin; Ozogul, Candan; Koyuncu, Faik Mumtaz; Koltan, Semra Oruc

    2011-11-01

    To investigate the effects of GnRH antagonist (GnRH-ant) and agonist (GnRH-a) in the prevention of postoperative pelvic adhesions by a visual scoring system and immunohistochemical methods in a rat uterine horn model. Controlled experimental animal study. Animal laboratory at an academic research environment. Twenty-one Wistar albino rats. Rats were randomized into three groups. One week before the operation the rats received either GnRH-ant or GnRH-a or saline solution; they then underwent surgical laparotomy, and both uterine horns were traumatized by a scalpel. Three weeks later, all rats were sacrificed and extension and severity of the adhesions in each group were scored by a visual scoring system. Adhesion tissues were evaluated immunohistochemically for vitronectin and u-PAR. Scores of extend and severity of adhesions and staining of vitronectin and u-PAR. The extent of adhesion scores were 1.85 ± 0.86, 0.78 ± 1.05, and 0.42 ± 0.64, and the severity of adhesion scores were 1.71 ± 0.91, 0.57 ± 0.85, 0.50 ± 0.75 for control, GnRH-ant, and GnRH-a groups, respectively. The extent and severity of adhesions were significantly lower in both GnRH-ant and GnRH-a groups when compared with the control group. Adhesion extent scores in the GnRH-a group were lower than in the GnRH-ant group, but this difference was not significant. vitronectin and u-PAR staining were significantly greater in both the GnRH-ant and GnRH-a groups than in the control group. GnRH-ant as well as GnRH-a reduced postoperative adhesion formation in a rat model. This finding was supported immunohistochemically by vitronectin and u-PAR staining. Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

  19. Prevention

    DEFF Research Database (Denmark)

    Halken, S; Høst, A

    2001-01-01

    , breastfeeding should be encouraged for 4-6 months. In high-risk infants a documented extensively hydrolysed formula is recommended if exclusive breastfeeding is not possible for the first 4 months of life. There is no evidence for preventive dietary intervention neither during pregnancy nor lactation...... populations. These theories remain to be documented in proper, controlled and prospective studies. Breastfeeding and the late introduction of solid foods (>4 months) is associated with a reduced risk of food allergy, atopic dermatitis, and recurrent wheezing and asthma in early childhood. In all infants....... Preventive dietary restrictions after the age of 4-6 months are not scientifically documented....

  20. Naloxone : actions of an antagonist

    NARCIS (Netherlands)

    Dorp, Eveline Louise Arianna van

    2009-01-01

    The opioid antagonist naloxone has a special place in pharmacology – it has no intrinsic action of its own, but it is able to save lives in the case of life threatening side-effects caused by other drugs. Naloxone is an antagonist for all opioid receptors, but most specifically for the μ-opioid

  1. Opioid antagonists for alcohol dependence.

    Science.gov (United States)

    Rösner, Susanne; Hackl-Herrwerth, Andrea; Leucht, Stefan; Vecchi, Simona; Srisurapanont, Manit; Soyka, Michael

    2010-12-08

    Alcohol dependence belongs to the globally leading health risk factors. Therapeutic success of psychosocial programs for relapse prevention is moderate and could be increased by an adjuvant treatment with the opioid antagonists naltrexone and nalmefene. To determine the effectiveness and tolerability of opioid antagonists in the treatment of alcohol dependence. We searched the Cochrane Drugs and Alcohol Group (CDAG) Specialized Register, PubMed, EMBASE and CINAHL in January 2010 and inquired manufacturers and researchers for unpublished trials. All double-blind randomised controlled trials (RCTs) which compare the effects of naltrexone or nalmefene with placebo or active control on drinking-related outcomes. Two authors independently extracted outcome data. Trial quality was assessed by one author and cross-checked by a second author. Based on a total of 50 RCTs with 7793 patients, naltrexone reduced the risk of heavy drinking to 83% of the risk in the placebo group RR 0.83 (95% CI 0.76 to 0.90) and decreased drinking days by about 4%, MD -3.89 (95% CI -5.75 to -2.04). Significant effects were also demonstrated for the secondary outcomes of the review including heavy drinking days, MD - 3.25 (95% CI -5.51 to -0.99), consumed amount of alcohol, MD - 10.83 (95% CI -19.69 to -1.97) and gamma-glutamyltransferase, MD - 10.37 (95% CI -18.99 to -1.75), while effects on return to any drinking, RR 0.96 (95 CI 0.92 to 1.00) missed statistical significance. Side effects of naltrexone were mainly gastrointestinal problems (e.g. nausea: RD 0.10; 95% CI 0.07 to 0.13) and sedative effects (e.g. daytime sleepiness: RD 0.09; 95% CI 0.05 to 0.14). Based on a limited study sample, effects of injectable naltrexone and nalmefene missed statistical significance. Effects of industry-sponsored studies, RR 0.90 (95% CI 0.78 to 1.05) did not significantly differ from those of non-profit funded trials, RR 0.84 (95% CI 0.77 to 0.91) and the linear regression test did not indicate publication

  2. Studies on antagonistic marine streptomycetes

    Digital Repository Service at National Institute of Oceanography (India)

    Chandramohan, D.; Nair, S.

    Sixty nine strains of Streptomyces sp. isolated from the sediments of Andaman and Nicobar islands (Bay of Bengal) were screened for their antagonistic property against a number of test cultures (Vibrio sp., Klebsiella sp., Escherichia coli, Shigella...

  3. Endothelin receptor antagonists influence cardiovascular morphology in uremic rats.

    Science.gov (United States)

    Nabokov, A V; Amann, K; Wessels, S; Münter, K; Wagner, J; Ritz, E

    1999-02-01

    In is generally held that renal failure results in blood pressure (BP)-independent structural changes of the myocardium and the vasculature. The contribution, if any, of endothelin (ET) to these changes has been unknown. We morphometrically studied random samples of the left ventricle myocardium and small intramyocardial arteries in subtotally (5/6) nephrectomized (SNx) male Sprague-Dawley rats treated with either the selective ETA receptor antagonist BMS182874 (30 mg/kg/day) or the nonselective ETA/ETB receptor antagonist Ro46-2005 (30 mg/kg/day) in comparison with either sham-operated rats, untreated SNx, or SNx rats treated with the angiotensin-converting enzyme inhibitor trandolapril (0.1 mg/kg/day). Eight weeks later, systolic BP was lower in trandolapril-treated SNx compared with untreated SNx animals. No decrease in BP was seen following either ET receptor antagonist at the dose used. A significantly increased volume density of the myocardial interstitium was found in untreated SNx rats as compared with sham-operated controls. Such interstitial expansion was prevented by trandolapril and either ET receptor antagonist. SNx caused a substantial increase in the wall thickness of small intramyocardial arteries. The increase was prevented by trandolapril or BMS182874 treatment. The arteriolar wall:lumen ratio was significantly lower in all treated groups when compared with untreated SNx. In contrast, only trandolapril, but not the ET receptor antagonists, attenuated thickening of the aortic media in SNx animals. The ETA-selective and ETA/ETB-nonselective receptor antagonists appear to prevent development of myocardial fibrosis and structural changes of small intramyocardial arteries in experimental chronic renal failure. This effect is independent of systemic BP.

  4. Clinical pharmacology of calcium antagonists as antihypertensive and anti-anginal drugs

    NARCIS (Netherlands)

    van Zwieten, P. A.

    1996-01-01

    USE OF CALCIUM ANTAGONISTS: These drugs are prescribed for antihypertensive activity in patients with essential hypertension, perioperative hypertension associated with thoracic surgery, angina pectoris and for secondary prevention after acute coronary syndromes (myocardial infarction, unstable

  5. First Irish birth following IVF therapy using antagonist protocol.

    LENUS (Irish Health Repository)

    Mocanu, E V

    2012-02-01

    BACKGROUND: During in vitro fertilization (IVF), the prevention of a premature LH surge was traditionally achieved using a gonadotrophin releasing hormone agonist (GnRH-a), and more recently, a GnRH antagonist. AIMS: We report a case of a 37 year old treated using the GnRH antagonist in a second completed cycle of IVF. METHODS: IVF was performed for primary infertility of 5-year duration due to frozen pelvis secondary to endometriosis. RESULTS: Following controlled ovarian hyperstimulation, oocyte recovery and fertilization, cleavage and transfer of two zygotes, a pregnancy established. A twin gestation was diagnosed at 7-weeks scan and pregnancy ended with the delivery of twin girls by emergency caesarean section. CONCLUSION: This is a first report of a delivery following IVF using the antagonist protocol in Ireland. Such therapy is patient friendly and its use should be introduced on a larger scale in clinical practice.

  6. Olanzapine-Based Triple Regimens Versus Neurokinin-1 Receptor Antagonist-Based Triple Regimens in Preventing Chemotherapy-Induced Nausea and Vomiting Associated with Highly Emetogenic Chemotherapy: A Network Meta-Analysis.

    Science.gov (United States)

    Zhang, Zhonghan; Zhang, Yaxiong; Chen, Gang; Hong, Shaodong; Yang, Yunpeng; Fang, Wenfeng; Luo, Fan; Chen, Xi; Ma, Yuxiang; Zhao, Yuanyuan; Zhan, Jianhua; Xue, Cong; Hou, Xue; Zhou, Ting; Ma, Shuxiang; Gao, Fangfang; Huang, Yan; Chen, Likun; Zhou, Ningning; Zhao, Hongyun; Zhang, Li

    2018-01-12

    The current antiemetic prophylaxis for patients treated with highly emetogenic chemotherapy (HEC) included the olanzapine-based triplet and neurokinin-1 receptor antagonists (NK-1RAs)-based triplet. However, which one shows better antiemetic effect remained unclear. We systematically reviewed 43 trials, involving 16,609 patients with HEC, which compared the following antiemetics at therapeutic dose range for the treatment of chemotherapy-induced nausea and vomiting: olanzapine, aprepitant, casopitant, fosaprepitant, netupitant, and rolapitant. The main outcomes were the proportion of patients who achieved no nausea, complete response (CR), and drug-related adverse events. A Bayesian network meta-analysis was performed. Olanzapine-based triple regimens showed significantly better no-nausea rate in overall phase and delayed phase than aprepitant-based triplet (odds ratios 3.18, 3.00, respectively), casopitant-based triplet (3.78, 4.12, respectively), fosaprepitant-based triplet (3.08, 4.10, respectively), rolapitant-based triplet (3.45, 3.20, respectively), and conventional duplex regimens (4.66, 4.38, respectively). CRs of olanzapine-based triplet were roughly equal to different NK-1RAs-based triplet but better than the conventional duplet. Moreover, no significant drug-related adverse events were observed in olanzapine-based triple regimens when compared with NK-1RAs-based triple regimens and duplex regimens. Additionally, the costs of olanzapine-based regimens were obviously much lower than the NK-1RA-based regimens. Olanzapine-based triplet stood out in terms of nausea control and drug price but represented no significant difference of CRs in comparison with NK-1RAs-based triplet. Olanzapine-based triple regimens should be an optional antiemetic choice for patients with HEC, especially those suffering from delayed phase nausea. According to the results of this study, olanzapine-based triple antiemetic regimens were superior in both overall and delayed

  7. Impact of Aldosterone Antagonists on Sudden Cardiac Death Prevention in Heart Failure and Post-Myocardial Infarction Patients: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

    Directory of Open Access Journals (Sweden)

    Hai-Ha Le

    Full Text Available Sudden cardiac death (SCD is a severe burden of modern medicine. Aldosterone antagonist is publicized as effective in reducing mortality in patients with heart failure (HF or post myocardial infarction (MI. Our study aimed to assess the efficacy of AAs on mortality including SCD, hospitalization admission and several common adverse effects.We searched Embase, PubMed, Web of Science, Cochrane library and clinicaltrial.gov for randomized controlled trials (RCTs assigning AAs in patients with HF or post MI through May 2015. The comparator included standard medication or placebo, or both. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA guidelines were followed. Event rates were compared using a random effects model. Prospective RCTs of AAs with durations of at least 8 weeks were selected if they included at least one of the following outcomes: SCD, all-cause/cardiovascular mortality, all-cause/cardiovascular hospitalization and common side effects (hyperkalemia, renal function degradation and gynecomastia.Data from 19,333 patients enrolled in 25 trials were included. In patients with HF, this treatment significantly reduced the risk of SCD by 19% (RR 0.81; 95% CI, 0.67-0.98; p = 0.03; all-cause mortality by 19% (RR 0.81; 95% CI, 0.74-0.88, p<0.00001 and cardiovascular death by 21% (RR 0.79; 95% CI, 0.70-0.89, p<0.00001. In patients with post-MI, the matching reduced risks were 20% (RR 0.80; 95% CI, 0.66-0.98; p = 0.03, 15% (RR 0.85; 95% CI, 0.76-0.95, p = 0.003 and 17% (RR 0.83; 95% CI, 0.74-0.94, p = 0.003, respectively. Concerning both subgroups, the relative risks respectively decreased by 19% (RR 0.81; 95% CI, 0.71-0.92; p = 0.002 for SCD, 18% (RR 0.82; 95% CI, 0.77-0.88, p < 0.0001 for all-cause mortality and 20% (RR 0.80; 95% CI, 0.74-0.87, p < 0.0001 for cardiovascular mortality in patients treated with AAs. As well, hospitalizations were significantly reduced, while common adverse effects were significantly

  8. Excitatory amino acid receptor antagonists

    DEFF Research Database (Denmark)

    Johansen, T N; Frydenvang, Karla Andrea; Ebert, B

    1997-01-01

    We have previously shown that (RS)-2-amino-2-(5-tert-butyl-3-hydroxyisoxazol-4-yl)acetic acid (ATAA) is an antagonist at N-methyl-D-aspartic acid (NMDA) and (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA) receptors. We have now resolved ATAA via diastereomeric salt formation...

  9. ANTAGONISTIC POTENTIAL OF FLUORESCENT Pseudomonas ...

    African Journals Online (AJOL)

    Prof. Adipala Ekwamu

    This study focused on the antagonistic potential of fluorescent Pseudomonas in vitro, and its inoculation effect on growth performance of Lycopersicon esculentum in Fusarium oxysporum and Rhizoctonia solani infested soil. Biochemical characteristics of fluorescent Pseudomonas showed that all ten isolates were positive ...

  10. Antinociception and prevention of hyperalgesia by intrathecal administration of Ro 25-6981, a highly selective antagonist of the 2B subunit of N-methyl-D-aspartate receptor.

    Science.gov (United States)

    Jiang, Ming; Zhang, Wei; Ma, Zhengliang; Gu, Xiaoping

    2013-11-01

    NR2B subunits (NMDA receptor 2B subunit) play an important role in generation of pain and forming central sensitization of pain. Ro 25-6981, a highly selective NR2B antagonist, gained much attention in recent years. In this study, we used a rat model of incisional pain to investigate effects of postoperative analgesia and changes of postoperative hyperalgesia induced by remifentanil through the pretreatment of intrathecal administration with Ro 25-6981. The behavioral changes of rats have been evaluated by the paw withdrawal mechanical threshold and paw withdrawal thermal latency after intrathecal injection of Ro 25-6981. The expression of NR2B with tyrosine phosphorylation in the spinal dorsal horn was analyzed by Western blotting. Intrathecal injection of Ro 25-6981 significantly enhanced the paw withdrawal mechanical threshold and paw withdrawal thermal latency after the operation. Significant change has been observed after intrathecal injection of 800.0 μg of Ro 25-6981 and at 2h after operation in the oblique pull test degree and BBB rating score. Pretreatment of Ro 25-6981 decreased the high level expression of NR2B with tyrosine phosphorylation in spinal dorsal horn of the rat model after the operation. Intrathecal injection of Ro 25-6981 had significant analgesic effects on incision pain in rats and effectively attenuated postoperative hyperalgesia induced by remifentanil. © 2013.

  11. Clinical Development of Histamine H4Receptor Antagonists.

    Science.gov (United States)

    Thurmond, Robin L; Venable, Jennifer; Savall, Brad; La, David; Snook, Sandra; Dunford, Paul J; Edwards, James P

    2017-01-01

    The discovery of the histamine H 4 receptor (H 4 R) provided a new avenue for the exploration of the physiological role of histamine, as well as providing a new drug target for the development of novel antihistamines. The first step in this process was the identification of selective antagonists to help unravel the pharmacology of the H 4 R relative to other histamine receptors. The discovery of the selective H 4 R antagonist JNJ 7777120 was vital for showing a role for the H 4 R in inflammation and pruritus. While this compound has been very successful as a tool for understanding the function of the receptor, it has drawbacks, including a short in vivo half-life and hypoadrenocorticism toxicity in rats and dogs, that prevented advancing it into clinical studies. Further research let to the discovery of JNJ 39758979, which, similar to JNJ 7777120, was a potent and selective H 4 R antagonist and showed anti-inflammatory and anti-pruritic activity preclinically. JNJ 39758979 advanced into human clinical studies and showed efficacy in reducing experimental pruritus and in patients with atopic dermatitis. However, development of this compound was terminated due to the occurrence of drug-induced agranulocytosis. This was overcome by developing another H 4 R antagonist with a different chemical structure, toreforant, that does not appear to have this side effect. Toreforant has been tested in clinical studies in patients with rheumatoid arthritis, asthma, or psoriasis. In conclusions there have been many H 4 R antagonists reported in the literature, but only a few have been studied in humans underscoring the difficulty in finding ligands with all of the properties necessary for testing in the clinic. Nevertheless, the clinical data to date suggests that H 4 R antagonists can be beneficial in treating atopic dermatitis and pruritus.

  12. Risk of major bleeding and stroke associated with the use of vitamin K antagonists, nonvitamin K antagonist oral anticoagulants and aspirin in patients with atrial fibrillation: a cohort study

    NARCIS (Netherlands)

    Gieling, E.M.; Ham, H.A. van den; Onzenoort, H. van; Bos, J.; Kramers, C.; Boer, A. de; Vries, F de; Burden, A.M.

    2017-01-01

    AIMS: Nonvitamin K antagonist oral anticoagulants (NOACs) are now available for the prevention of stroke in patients with atrial fibrillation (AF) as an alternative to vitamin K antagonists (VKA) and aspirin. The comparative effectiveness and safety in daily practice of these different drug classes

  13. Indications for the use of parenteral H2-receptor antagonists.

    Science.gov (United States)

    Thompson, J C; Walker, J P

    1984-11-19

    Development of acute mucosal ulceration is a complex series of catabolic interactions. Hospitalized patients with duodenal or gastric ulcer, pathologic gastric hypersecretory states (such as Zollinger-Ellison syndrome), gastric outlet obstruction, esophagitis, severe gastritis or duodenitis, sepsis, trauma (particularly head injury or burns), and some patients receiving high-dose corticosteroids are at risk of developing acute stress ulcers. Treatment should be initiated as soon as the patient is identified as being at risk, because measures designed to prevent bleeding or perforation are more effective than those designed to stop bleeding once it supervenes and the cascade of multiple organ failure commences. The presence of acid will trigger the onset of this condition; however, ulceration will not occur if the intraluminal pH can be maintained above 5 by periodic antacid treatment or by H2-receptor blockade. The dosing regimen of antacid or of H2-receptor antagonist should not be fixed, but should be sufficient to keep the gastric pH higher than 5. Antagonists administered via a nasogastric tube are the first line of defense, but 30 to 50 percent of the most ill patients will also be treated parenterally with H2-receptor antagonists. Parenteral H2-receptor blockade therapy is indicated in these patients when the risk of acute or continued ulceration of esophageal, gastric, or duodenal mucosa is high and the oral administration of medication is either not possible or the response to such therapy is unreliable. Parenteral H2-receptor antagonists are rarely administered alone.

  14. Smac mimetics as IAP antagonists.

    Science.gov (United States)

    Fulda, Simone

    2015-03-01

    As the Inhibitor of Apoptosis (IAP) proteins are expressed at high levels in human cancers, they represent promising targets for therapeutic intervention. Small-molecule inhibitors of IAP proteins mimicking the endogenous IAP antagonist Smac, called Smac mimetics, neutralize IAP proteins and thereby promote the induction of cell death. Smac mimetics have been shown in preclinical models of human cancer to directly trigger cancer cell death or to sensitize for cancer cell death induced by a variety of cytotoxic stimuli. Smac mimetics are currently undergoing clinical evaluation in phase I/II trials, demonstrating that therapeutic targeting of IAP proteins has reached the clinical stage. Copyright © 2015 Elsevier Ltd. All rights reserved.

  15. Use of Vitamins K antagonists in non-valvular atrial fibrillation ...

    African Journals Online (AJOL)

    Introduction: atrial fibrillation is the commonest cardiac rythm disorder. Thromboembolic accidents are common complications that should be prevented by anticoagulant treatment. The aim of our study is to assess the use of vitamins K antagonists in the prevention of thromboembolic risk in atrial fibrillation. Methods: it was a ...

  16. Synthetic peptide antagonists of glucagon

    International Nuclear Information System (INIS)

    Unson, C.G.; Andreu, D.; Gurzenda, E.M.; Merrifield, R.B.

    1987-01-01

    Several glucagon analogs were synthesized in an effort to find derivatives that would bind with high affinity to the glucagon receptor of rat liver membranes but would not activate membrane-bound adenylate cyclase and, therefore, would serve as antagonists of the hormone. Measurements on a series of glucagon/secretin hybrids indicated that replacement of Asp 9 in glucagon by Glu 9 , found in secretin, was the important sequence difference in the N terminus of the two hormones. Further deletion of His 1 and introduction of a C-terminal amide resulted in des-His 1 -[Glu 9 ]glucagon amide, which had a 40% binding affinity relative to that of native glucagon but caused no detectable adenylate cyclase activation in the rat liver membrane. This antagonist completely inhibited the effect of a concentration of glucagon that alone gave a full agonist response. It had an inhibition index of 12. The pA 2 was 7.2. An attempt was made to relate conformation with receptor binding. The peptides were synthesized by solid-phase methods and purified to homogeneity by reverse-phase high-performance liquid chromatography on C 18 -silica columns

  17. High ovarian response does not jeopardize ongoing pregnancy rates and increases cumulative pregnancy rates in a GnRH-antagonist protocol.

    Science.gov (United States)

    Fatemi, Human M; Doody, Kevin; Griesinger, Georg; Witjes, Han; Mannaerts, Bernadette

    2013-02-01

    Is the ovarian response to controlled ovarian stimulation (COS) related to the ongoing pregnancy rate when taking into account the main covariates affecting the probabilities of pregnancy following fresh embryo transfer? In patients treated with corifollitropin alfa or daily recombinant FSH (rFSH) in a GnRH-antagonist protocol, a high ovarian response did not compromise ongoing pregnancy rates and increased cumulative pregnancy rates following fresh and frozen-thawed embryo transfer. A strong association between the number of oocytes and pregnancy rates has been described but this is the first comprehensive analysis assessing important confounders that might affect pregnancy rates. In a large, prospective, double-blind, randomized trial (Engage; n = 1506), patients were treated with either a single dose of 150 μg corifollitropin alfa or daily 200 IU rFSH for the first 7 days of COS in a GnRH-antagonist (ganirelix) protocol. In this retrospective analysis, patients were categorized into five groups according to the number of oocytes retrieved (0-5, 6-9, 10-13, 14-18 and >18 oocytes). The number of good-quality embryos obtained and transferred, as well as the ongoing pregnancy rates, live birth rates and cumulative ongoing pregnancy rates per started cycle by group were evaluated. Univariate analysis was performed to identify factors that predict the chance of ongoing pregnancy. Logistic regression analysis on the dependent variables ongoing pregnancy and cumulative ongoing pregnancy, respectively, including oocyte category as an independent factor in the model, was performed by treatment group (corifollitropin alfa and rFSH) and overall. The likelihood of ongoing pregnancy and cumulative ongoing pregnancy was then evaluated taking into account ovarian response as well as other identified significant predictors of success. In total, 1506 patients had been randomized in a ratio of 1:1 to either of the treatment groups. Patients were aged ≤ 36 years and had a body

  18. The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

    Directory of Open Access Journals (Sweden)

    Mallory Batty

    2016-08-01

    Full Text Available This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa. Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers.

  19. New antagonist agents of neuropeptide y receptors

    Directory of Open Access Journals (Sweden)

    Ignacio Aldana

    2000-12-01

    Full Text Available In the CNS, NPY has been implicated in obesity and feeding, endocrine function and metabolism. Potent and selective rNPY antagonists will be able to probe the merits of this approach for the treatment of obesity. We report the synthesis and preliminary evaluation of some hydrazide derivatives as antagonists of rNPY.

  20. S179D prolactin: antagonistic agony!

    Science.gov (United States)

    Walker, Ameae M

    2007-09-30

    The aims of this review are three-fold: first, to collate what is known about the production and activities of phosphorylated prolactin (PRL), the latter largely, but not exclusively, as illustrated through the use of the molecular mimic, S179D PRL; second, to apply this and related knowledge to produce an updated model of prolactin-receptor interactions that may apply to other members of this cytokine super-family; and third, to promote a shift in the current paradigm for the development of clinically important growth antagonists. This third aim explains the title since, based on results with S179D PRL, it is proposed that agents which signal to antagonistic ends may be better therapeutics than pure antagonists-hence antagonistic agony. Since S179D PRL is not a pure antagonist, we have proposed the term selective prolactin receptor modulator (SPeRM) for this and like molecules.

  1. [Extracorporeal life support in calcium antagonist intoxication].

    Science.gov (United States)

    Groot, M W; Grewal, S; Meeder, H J; van Thiel, R J; den Uil, C A

    2017-01-01

    Intoxication with calcium antagonists is associated with poor outcome. Even mild calcium antagonist overdose may be fatal. A 51-year-old woman and a 51-year-old man came to the Accident and Emergency Department in severe shock after they had taken a calcium antagonist overdose. After extensive medicinal therapy had failed, they both needed extracorporeal life support (ECLS) as a bridge to recovery. In severe calcium antagonist overdose, the combination of vasoplegia and cardiac failure leads to refractory shock. ECLS temporarily supports the circulation and maintains organ perfusion. In this way ECLS functions as a bridge to recovery and may possibly save lives. Timely consultation with and referral to an ECLS centre is recommended in patients with calcium antagonist overdose.

  2. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology.

    Science.gov (United States)

    Al-Inany, Hesham G; Youssef, Mohamed A; Ayeleke, Reuben Olugbenga; Brown, Julie; Lam, Wai Sun; Broekmans, Frank J

    2016-04-29

    Gonadotrophin-releasing hormone (GnRH) antagonists can be used to prevent a luteinizing hormone (LH) surge during controlled ovarian hyperstimulation (COH) without the hypo-oestrogenic side-effects, flare-up, or long down-regulation period associated with agonists. The antagonists directly and rapidly inhibit gonadotrophin release within several hours through competitive binding to pituitary GnRH receptors. This property allows their use at any time during the follicular phase. Several different regimens have been described including multiple-dose fixed (0.25 mg daily from day six to seven of stimulation), multiple-dose flexible (0.25 mg daily when leading follicle is 14 to 15 mm), and single-dose (single administration of 3 mg on day 7 to 8 of stimulation) protocols, with or without the addition of an oral contraceptive pill. Further, women receiving antagonists have been shown to have a lower incidence of ovarian hyperstimulation syndrome (OHSS). Assuming comparable clinical outcomes for the antagonist and agonist protocols, these benefits would justify a change from the standard long agonist protocol to antagonist regimens. This is an update of a Cochrane review first published in 2001, and previously updated in 2006 and 2011. To evaluate the effectiveness and safety of gonadotrophin-releasing hormone (GnRH) antagonists compared with the standard long protocol of GnRH agonists for controlled ovarian hyperstimulation in assisted conception cycles. We searched the Cochrane Menstrual Disorders and Subfertility Group Trials Register (searched from inception to May 2015), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, inception to 28 April 2015), Ovid MEDLINE (1966 to 28 April 2015), EMBASE (1980 to 28 April 2015), PsycINFO (1806 to 28 April 2015), CINAHL (to 28 April 2015) and trial registers to 28 April 2015, and handsearched bibliographies of relevant publications and reviews, and abstracts of major scientific meetings, for

  3. PXR antagonists and implication in drug metabolism

    Science.gov (United States)

    Mani, Sridhar; Dou, Wei; Redinbo, Matthew R.

    2013-01-01

    Adopted orphan nuclear receptor (NR), pregnane X receptor (PXR), plays a central role in the regulation of xeno- and endobiotic metabolism. Since the discovery of the functional role of PXR in 1998, there is evolving evidence for the role of PXR agonists in abrogating metabolic pathophysiology (e.g., cholestasis, hypercholesterolemia, and inflammation). However, more recently, it is clear that PXR is also an important mediator of adverse xeno- (e.g., enhances acetaminophen toxicity) and endobiotic (e.g., hepatic steatosis) metabolic phenotypes. Moreover, in cancer therapeutics, PXR activation can induce drug resistance, and there is growing evidence for tissue-specific enhancement of the malignant phenotype. Thus, in these instances, there may be a role for PXR antagonists. However, as opposed to the discovery efforts for PXR agonists, there are only a few antagonists described. The mode of action of these antagonists (e.g., sulforaphane) remains less clear. Our laboratory efforts have focused on this question. Since the original discovery of azoles analogs as PXR antagonists, we have preliminarily defined an important PXR antagonist pharmacophore and developed less-toxic PXR antagonists. In this review, we describe our published and unpublished findings on recent structure-function studies involving the azole chemical scaffold. Further work in the future is needed to fully define potent, more-selective PXR antagonists that may be useful in clinical application. PMID:23330542

  4. Prevention of Stimulant Induced Euphoria with an Opioid Receptor Antagonist

    Science.gov (United States)

    2017-02-28

    Aviat Space Environ Med, 2005. 76(1): p. 39- 45. 8. Westcott, K.J., Modafinil, sleep deprivation , and cognitive function in military and medical settings...51. 6. Caldwell, J.A., et al., Modafinil’s effects on simulator performance and mood in pilots during 37 h without sleep . Aviat Space Environ Med, 2004...75(9): p. 777-84. 7. McLellan, T.M., et al., Caffeine maintains vigilance and marksmanship in simulated urban operations with sleep deprivation

  5. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

    Krall, Jacob; Balle, Thomas; Krogsgaard-Larsen, Niels

    2015-01-01

    to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists and describes the development of potent antagonists from partial agonists originally derived from the potent GABAAR agonist muscimol. In this process, several heterocyclic aromatic systems have been used in combination with structural models in order to map the orthosteric binding site...... and to reveal structural details to be used for obtaining potency and subtype selectivity. The challenges connected to functional characterization of orthosteric GABAAR partial agonists and antagonists, especially with regard to GABAAR stoichiometry and alternative binding sites are discussed. GABAAR...

  6. Antagonist wear by polished zirconia crowns.

    Science.gov (United States)

    Hartkamp, Oliver; Lohbauer, Ulrich; Reich, Sven

    The aim of this in vivo study was to measure antagonist wear caused by polished monolithic posterior zirconia crowns over a 24-month period using the intraoral digital impression (IDI) technique. Thirteen zirconia crowns were placed in nine patients. The crowns and adjacent teeth were captured using an intraoral scanner (Lava C.O.S.). The corresponding antagonist teeth and the respective neighboring teeth were also scanned. Scanning was performed immediately after the restoration (baseline) as well as 12 and 24 months after crown placement. Geomagic Qualify software was used to superimpose the follow-up data sets onto the corresponding baseline data set, identify wear sites, and measure maximum vertical height loss in each individual wear site. Overall antagonist wear was then determined as the mean of wear rates measured in all of the individual antagonist units. In addition, wear rates in enamel and ceramic antagonists were analyzed as part of the scope of this study. The maximum mean wear with standard deviation (SD) in the overall sample with a total of nine patients, 13 antagonist units, and 98 evaluable wear sites was 86 ± 23 µm at 12 months, and 103 ± 39 µm at 24 months. The maximum mean wear in the enamel antagonist subgroup was 87 ± 41 µm at 12 months, and 115 ± 71 µm at 24 months; and in the ceramic antagonist subgroup 107 ± 22 µm at 12 months, and 120 ± 27 µm at 24 months. The wear rates determined in this study are comparable to those of existing studies. The IDI technique of wear analysis can be carried out in a practical manner and produces useful results.

  7. Clinical impact and course of major bleeding with edoxaban versus vitamin K antagonists

    NARCIS (Netherlands)

    Brekelmans, Marjolein P. A.; Bleker, Suzanne M.; Bauersachs, Rupert; Boda, Zoltan; Büller, Harry R.; Choi, Youngsook; Gallus, Alex; Grosso, Michael A.; Middeldorp, Saskia; Oh, Doyeun; Raskob, Gary; Schwocho, Lee; Cohen, Alexander T.

    2016-01-01

    Edoxaban is a once-daily direct oral anticoagulant (DOAC). The Hokusai-VTE study revealed that, after initial treatment with heparin, edoxaban was non-inferior to and safer than vitamin K antagonists (VKA) in the prevention of recurrent deep-vein thrombosis and pulmonary embolism. This is the first

  8. Pharmacoeconomics of angiotensin II antagonists in type 2 diabetic patients with nephropathy - Implications for decision making

    NARCIS (Netherlands)

    Boersma, C; Atthobari, J; Gansevoort, RT; de Jong-Van den Berg, LTW; de Jong, PE; de Zeeuw, D; Annemans, LJP; Postma, MJ

    2006-01-01

    Angiotensin II receptor antagonists (angiotensin II receptor blockers; ARBs) are a class of antihypertensive drugs that are generally considered comparable to ACE inhibitors in the prevention of heart and kidney failure. However, these two classes of agents do interfere in different stages of the

  9. Coronary dilation with nitrocompounds and calcium antagonists.

    Science.gov (United States)

    Jost, S; Rafflenbeul, W; Lichtlen, P R

    1990-01-01

    The vasodilatory effects of nitrocompounds and calcium antagonists on epicardial coronary arteries represent substantial antianginal mechanisms in the presence of coronary vasospasm or eccentric coronary stenoses. With high doses of nitrocompounds, angiographically normal coronary segments can be dilated by an average of approx. 30%, some coronary stenoses even by up to 100%, usually without severe reduction of blood pressure. With calcium antagonists, a similar extent of dilation of normal coronary arteries and eccentric stenoses can be obtained. Our own group demonstrated an average dilation of normal coronary arteries of about 20% after intravenous administration of dihydropyridine calcium antagonists; however, the average systolic blood pressure dropped below 100 mmHg after these compounds. Hence, although in isolated human coronary arteries high concentrations of calcium antagonists were shown to induce a considerably greater vasodilation than nitrocompounds, the early drop in blood pressure prohibits a higher dosage of calcium antagonists in vivo. In the presence of coronary artery disease, particularly when associated with coronary vasospasm, a combination of the two groups of compounds might be recommendable, since an addition of the effects of coronary vasomotor tone is likely. Furthermore, the antianginal effects of a reduction of preload and afterload are complementary.

  10. Bitter melon: antagonist to cancer.

    Science.gov (United States)

    Nerurkar, Pratibha; Ray, Ratna B

    2010-06-01

    The incidence of cancer is increasing worldwide, in spite of substantial progress in the development of anti-cancer therapies. One approach to control cancer could be its prevention by diet, which inhibits one or more neoplastic events and reduces cancer risk. Dietary compounds offer great potential in the fight against cancer by inhibiting the carcinogenesis process through the regulation of cell homeostasis and cell-death machineries. For centuries, Ayurveda (Indian traditional medicine) has recommended the use of bitter melon (Momordica charantia) as a functional food to prevent and treat diabetes and associated complications. It is noteworthy to mention that bitter melon extract has no-to-low side effects in animals as well as in humans. The anti-tumor activity of bitter melon has recently begun to emerge. This review focuses on recent advancements in cancer chemopreventive and anti-cancer efficacy of bitter melon and its active constituents. Several groups of investigators have reported that treatment of bitter-melon-related products in a number of cancer cell lines induces cell cycle arrest and apoptosis without affecting normal cell growth. Therefore, the effect of bitter melon should be beneficial for health, and use of the non-modified dietary product is cost effective.

  11. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

    De Mey, Jo G R; Compeer, Matthijs G; Lemkens, Pieter

    2011-01-01

    . In resistance arteries, the long-lasting contractile effects can only be partly and reversibly relaxed by low-molecular-weight ET(A) antagonists (ERAs). However, the neuropeptide calcitonin-gene-related peptide selectively terminates binding of ET1 to ET(A). We propose that ET1 binds polyvalently to ET......(A) and that ERAs and the physiological antagonist allosterically reduce ET(A) functions. Combining the two-state model and the two-domain model of GPCR function and considering receptor activation beyond agonist binding might lead to better anti-endothelinergic drugs. Future studies could lead to compounds...

  12. Maintenance therapy with oxytocin antagonists for inhibiting preterm birth after threatened preterm labour.

    Science.gov (United States)

    Papatsonis, Dimitri N M; Flenady, Vicki; Liley, Helen G

    2013-10-13

    In some women, an episode of preterm labour settles and does not result in immediate preterm birth. Subsequent treatment with tocolytic agents such as oxytocin receptor antagonists may then have the potential to prevent the recurrence of preterm labour, prolonging gestation, and preventing the adverse consequences of prematurity for the infant. To assess the effects of maintenance therapy with oxytocin antagonists administered by any route after an episode of preterm labour in order to delay or prevent preterm birth. We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 July 2013), sought ongoing and unpublished trials by contacting experts in the field and searched the reference lists of relevant articles. Randomised controlled trials comparing oxytocin antagonists with any alternative tocolytic agent, placebo or no treatment, used for maintenance therapy after an episode of preterm labour. We used the standard methods of The Cochrane Collaboration and the Cochrane Pregnancy and Childbirth Group. Two review authors independently undertook evaluation of methodological quality and extracted trial data. This review includes one trial of 513 women. When compared with placebo, atosiban did not reduce preterm birth before 37 weeks (risk ratio (RR) 0.89; 95% confidence intervals (CI) 0.71 to 1.12), 32 weeks (RR 0.85; 95% CI 0.47 to 1.55), or 28 weeks (RR 0.75; 95% CI 0.28 to 2.01). No difference was shown in neonatal morbidity, or perinatal mortality. There is insufficient evidence to support the use of oxytocin receptor antagonists to inhibit preterm birth after a period of threatened or actual preterm labour. Any future trials using oxytocin antagonists or other drugs as maintenance therapy for preventing preterm birth should examine a variety of important infant outcome measures, including reduction of neonatal morbidity and mortality, and long-term infant follow-up. Future research should also focus on the pathophysiological pathways that

  13. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I.; Sester, M.; Gomez-Reino, J.J.

    2010-01-01

    Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased...... a history of bacille Calmette-Guerin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...... and an interferon-gamma release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy...

  14. The risk of tuberculosis related to tumour necrosis factor antagonist therapies: a TBNET consensus statement

    DEFF Research Database (Denmark)

    Solovic, I; Sester, M; Gomez-Reino, J J

    2010-01-01

    Anti-tumour necrosis factor (TNF) monoclonal antibodies or soluble TNF receptors have become an invaluable treatment against chronic inflammatory diseases, such as rheumatoid arthritis, inflammatory bowel disease and psoriasis. Individuals who are treated with TNF antagonists are at an increased...... of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...... and an interferon-¿ release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy as it significantly...

  15. 5-HT2B Receptor Antagonists Inhibit Fibrosis and Protect from RV Heart Failure

    Directory of Open Access Journals (Sweden)

    Wiebke Janssen

    2015-01-01

    Full Text Available Objective. The serotonin (5-HT pathway was shown to play a role in pulmonary hypertension (PH, but its functions in right ventricular failure (RVF remain poorly understood. The aim of the current study was to investigate the effects of Terguride (5-HT2A and 2B receptor antagonist or SB204741 (5-HT2B receptor antagonist on right heart function and structure upon pulmonary artery banding (PAB in mice. Methods. Seven days after PAB, mice were treated for 14 days with Terguride (0.2 mg/kg bid or SB204741 (5 mg/kg day. Right heart function and remodeling were assessed by right heart catheterization, magnetic resonance imaging (MRI, and histomorphometric methods. Total secreted collagen content was determined in mouse cardiac fibroblasts isolated from RV tissues. Results. Chronic treatment with Terguride or SB204741 reduced right ventricular fibrosis and showed improved heart function in mice after PAB. Moreover, 5-HT2B receptor antagonists diminished TGF-beta1 induced collagen synthesis of RV cardiac fibroblasts in vitro. Conclusion. 5-HT2B receptor antagonists reduce collagen deposition, thereby inhibiting right ventricular fibrosis. Chronic treatment prevented the development and progression of pressure overload-induced RVF in mice. Thus, 5-HT2B receptor antagonists represent a valuable novel therapeutic approach for RVF.

  16. CRTH2 antagonists in asthma: current perspectives

    Directory of Open Access Journals (Sweden)

    Singh D

    2017-12-01

    Full Text Available Dave Singh, Arjun Ravi, Thomas Southworth Division of Infection, Immunity and Respiratory Medicine, The Medicines Evaluation Unit, Manchester Academic Health Science Centre, Manchester University NHS Foundation Trust, The University of Manchester, Manchester, UK Abstract: Chemoattractant receptor-homologous molecule expressed on TH2 cells (CRTH2 binds to prostaglandin D2. CRTH2 is expressed on various cell types including eosinophils, mast cells, and basophils. CRTH2 and prostaglandin D2 are involved in allergic inflammation and eosinophil activation. Orally administered CRTH2 antagonists are in clinical development for the treatment of asthma. The biology and clinical trial data indicate that CRTH2 antagonists should be targeted toward eosinophilic asthma. This article reviews the clinical evidence for CRTH2 involvement in asthma pathophysiology and clinical trials of CRTH2 antagonists in asthma. CRTH2 antagonists could provide a practical alternative to biological treatments for patients with severe asthma. Future perspectives for this class of drug are considered, including the selection of the subgroup of patients most likely to show a meaningful treatment response. Keywords: CRTH2, clinical trial, eosinophilic asthma, prostaglandin D2

  17. Carbon adaptation influence the antagonistic ability of ...

    African Journals Online (AJOL)

    Influences of carbon adaptation on antagonistic activities of three Pseudomonas aeruginosa strains V4, V7 and V10 against Fusarium oxysporum f. sp. melonis were determined in this study. Results from this study showed that the P. aeruginosa strains and their adapted strains significantly inhibited the growth of mycelium ...

  18. Antagonistic properties of microogranisms associated with cassava ...

    African Journals Online (AJOL)

    The antagonistic properties of indigenous microflora from cassava starch, flour and grated cassava were investigated using the conventional streak, novel ring and well diffusion methods. Antagonism was measured by zone of inhibition between the fungal plug and bacterial streak/ring. Bacillus species were more effective ...

  19. Antagonist-Elicited Cannabis Withdrawal in Humans

    Science.gov (United States)

    Gorelick, David A.; Goodwin, Robert S.; Schwilke, Eugene; Schwope, David M.; Darwin, William D.; Kelly, Deanna L.; McMahon, Robert P.; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A.

    2013-01-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ9-tetrahydrocannabinol (THC) dosages (40–120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0–8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses. PMID:21869692

  20. Antagonist-elicited cannabis withdrawal in humans.

    Science.gov (United States)

    Gorelick, David A; Goodwin, Robert S; Schwilke, Eugene; Schwope, David M; Darwin, William D; Kelly, Deanna L; McMahon, Robert P; Liu, Fang; Ortemann-Renon, Catherine; Bonnet, Denis; Huestis, Marilyn A

    2011-10-01

    Cannabinoid CB1 receptor antagonists have potential therapeutic benefits, but antagonist-elicited cannabis withdrawal has not been reported in humans. Ten male daily cannabis smokers received 8 days of increasingly frequent 20-mg oral Δ⁹-tetrahydrocannabinol (THC) dosages (40-120 mg/d) around-the-clock to standardize cannabis dependence while residing on a closed research unit. On the ninth day, double-blind placebo or 20- (suggested therapeutic dose) or 40-mg oral rimonabant, a CB1-cannabinoid receptor antagonist, was administered. Cannabis withdrawal signs and symptoms were assessed before and for 23.5 hours after rimonabant. Rimonabant, THC, and 11-hydroxy-THC plasma concentrations were quantified by mass spectrometry. The first 6 subjects received 20-mg rimonabant (1 placebo); the remaining 4 subjects received 40-mg rimonabant (1 placebo). Fourteen subjects enrolled; 10 completed before premature termination because of withdrawal of rimonabant from clinical development. Three of 5 subjects in the 20-mg group, 1 of 3 in the 40-mg group, and none of 2 in the placebo group met the prespecified withdrawal criterion of 150% increase or higher in at least 3 visual analog scales for cannabis withdrawal symptoms within 3 hours of rimonabant dosing. There were no significant associations between visual analog scale, heart rate, or blood pressure changes and peak rimonabant plasma concentration, area-under-the-rimonabant-concentration-by-time curve (0-8 hours), or peak rimonabant/THC or rimonabant/(THC + 11-hydroxy-THC) plasma concentration ratios. In summary, prespecified criteria for antagonist-elicited cannabis withdrawal were not observed at the 20- or 40-mg rimonabant doses. These data do not preclude antagonist-elicited withdrawal at higher rimonabant doses.

  1. Combining elements from two antagonists of formyl peptide receptor 2 generates more potent peptidomimetic antagonists

    DEFF Research Database (Denmark)

    Skovbakke, Sarah Line; Holdfeldt, Andre; Nielsen, Christina

    2017-01-01

    Structural optimization of a peptidomimetic antagonist of formyl peptide receptor 2 (FPR2) was explored by an approach involving combination of elements from the two most potent FPR2 antagonists described: a Rhodamine B-conjugated 10-residue gelsonin-derived peptide (i.e., PBP10, Rh......B-QRLFQVKGRR-OH) and the palmitoylated α-peptide/β-peptoid hybrid Pam-(Lys-βNspe)6-NH2. This generated an array of hybrid compounds from which a new subclass of receptor-selective antagonists was identified. The most potent representatives displayed activity in the low nanomolar range. The resulting stable and potent FPR2-selective...... antagonists (i.e., RhB-(Lys-βNphe)n-NH2; n = 4–6) are expected to become valuable tools in further elucidation of the physiological role of FPR2 in health and disease....

  2. Similarities and differences between calcium antagonists: pharmacological aspects

    NARCIS (Netherlands)

    van Zwieten, P. A.; Pfaffendorf, M.

    1993-01-01

    Characteristics of three different calcium antagonist groups: Most important calcium antagonists used to treat cardiovascular disease belong to one of three main groups, phenylalkylamines, dihydropyridines and benzothiazepines. The best known drug in each group is verapamil, nifedipine and

  3. Protective effects of calcium antagonists in different organs and tissues

    NARCIS (Netherlands)

    van Zwieten, P. A.

    1993-01-01

    The therapeutic efficacy of calcium antagonists in ischemic disorders of various tissues is attributed to vasodilator and antivasoconstrictor activities. A direct, energy-conserving, antiischemic effect of certain calcium antagonists has been claimed repeatedly by basic scientists. The clinical

  4. A novel antagonist of CRTH2 blocks eosinophil release from bone marrow, chemotaxis and respiratory burst

    DEFF Research Database (Denmark)

    Royer, J F; Schratl, P; Lorenz, S

    2007-01-01

    developed small molecule antagonist of CRTH2, Cay10471, on eosinophil function with respect to recruitment, respiratory burst and degranulation. METHODS: Chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils were determined using microBoyden chambers. Eosinophil release...... from bone marrow was investigated in the in situ perfused guinea pig hind limb preparation. Respiratory burst and degranulation were measured by flow cytometry. RESULTS: Cay10471 bound with high affinity to recombinant human and guinea pig CRTH2, but not DP, receptors. The antagonist prevented the PGD......(2)-induced release of eosinophils from guinea pig bone marrow, and inhibited the chemotaxis of guinea pig bone marrow eosinophils and human peripheral blood eosinophils. Pretreatment with PGD(2) primed eosinophils for chemotaxis towards eotaxin, and this effect was prevented by Cay10471. In contrast...

  5. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    2010-01-01

    Full Text Available In species across taxa, offspring have means to influence parental investment (PI. PI thus evolves as an interacting phenotype and indirect genetic effects may strongly affect the co-evolutionary dynamics of offspring and parental behaviors. Evolutionary theory focused on explaining how exaggerated offspring solicitation can be understood as resolution of parent-offspring conflict, but the evolutionary origin and diversification of different forms of family interactions remains unclear.In contrast to previous theory that largely uses a static approach to predict how "offspring individuals" and "parental individuals" should interact given conflict over PI, we present a dynamic theoretical framework of antagonistic selection on the PI individuals obtain/take as offspring and the PI they provide as parents to maximize individual lifetime reproductive success; we analyze a deterministic and a stochastic version of this dynamic framework. We show that a zone for equivalent co-adaptation outcomes exists in which stable levels of PI can evolve and be maintained despite fast strategy transitions and ongoing co-evolutionary dynamics. Under antagonistic co-adaptation, cost-free solicitation can evolve as an adaptation to emerging preferences in parents.We show that antagonistic selection across the offspring and parental life-stage of individuals favors co-adapted offspring and parental behavior within a zone of equivalent outcomes. This antagonistic parent-offspring co-adaptation does not require solicitation to be costly, allows for rapid divergence and evolutionary novelty and potentially explains the origin and diversification of the observed provisioning forms in family life.

  6. Antagonist potential of Trichoderma indigenous isolates for ...

    African Journals Online (AJOL)

    STORAGESEVER

    2009-10-19

    Oct 19, 2009 ... Full Length Research Paper. Antagonist potential of Trichoderma indigenous isolates for biological control of Phytophthora palmivora the causative agent of black pod disease on cocoa (Theobroma cacao L.) in Côte d'Ivoire. J. Mpika1,4*, I. B. Kébé1, A. E. Issali2, F.K. N'Guessan1, S. Druzhinina3, ...

  7. Medicinal Chemistry of Competitive Kainate Receptor Antagonists

    Science.gov (United States)

    2010-01-01

    Kainic acid (KA) receptors belong to the group of ionotropic glutamate receptors and are expressed throughout in the central nervous system (CNS). The KA receptors have been shown to be involved in neurophysiological functions such as mossy fiber long-term potentiation (LTP) and synaptic plasticity and are thus potential therapeutic targets in CNS diseases such as schizophrenia, major depression, neuropathic pain and epilepsy. Extensive effort has been made to develop subtype-selective KA receptor antagonists in order to elucidate the physiological function of each of the five subunits known (GluK1−5). However, to date only selective antagonists for the GluK1 subunit have been discovered, which underlines the strong need for continued research in this area. The present review describes the structure−activity relationship and pharmacological profile for 10 chemically distinct classes of KA receptor antagonists comprising, in all, 45 compounds. To the medicinal chemist this information will serve as reference guidance as well as an inspiration for future effort in this field. PMID:22778857

  8. The sexually antagonistic genes of Drosophila melanogaster.

    Directory of Open Access Journals (Sweden)

    Paolo Innocenti

    2010-03-01

    Full Text Available When selective pressures differ between males and females, the genes experiencing these conflicting evolutionary forces are said to be sexually antagonistic. Although the phenotypic effect of these genes has been documented in both wild and laboratory populations, their identity, number, and location remains unknown. Here, by combining data on sex-specific fitness and genome-wide transcript abundance in a quantitative genetic framework, we identified a group of candidate genes experiencing sexually antagonistic selection in the adult, which correspond to 8% of Drosophila melanogaster genes. As predicted, the X chromosome is enriched for these genes, but surprisingly they represent only a small proportion of the total number of sex-biased transcripts, indicating that the latter is a poor predictor of sexual antagonism. Furthermore, the majority of genes whose expression profiles showed a significant relationship with either male or female adult fitness are also sexually antagonistic. These results provide a first insight into the genetic basis of intralocus sexual conflict and indicate that genetic variation for fitness is dominated and maintained by sexual antagonism, potentially neutralizing any indirect genetic benefits of sexual selection.

  9. Pharmacological analysis of calcium antagonist receptors

    International Nuclear Information System (INIS)

    Reynolds, I.J.

    1987-01-01

    This work focuses on two aspects of the action of calcium antagonist drugs, namely, the interaction of drugs with receptors for verapamil-like calcium antagonists, and the interactions of drugs with voltage-sensitive calcium fluxes in rat brain synaptosomes. From binding studies I have found that the ligand of choice for labeling the verapamil receptor is (-)[ 3 H]desmethoxy-verapamil. This drug labels potently, reversibly and stereoselectively two receptors in membranes prepared from rat brain and rabbit skeletal muscle tissues. In equilibrium studies dihydropyridine calcium antagonists interact in a non-competitive fashion, while many non-DHPs are apparently competitive. In-depth kinetic studies in skeletal muscle membranes indicate that the two receptors are linked in a negative heterotropic fashion, and that low-affinity binding of (-) [ 3 H]desmethoxy-verapamil may be to the diltiazem receptor. However, these studies were not able to distinguish between the hypothesis that diltiazem binds to spatially separate, allosterically coupled receptors, and the hypothesis that diltiazem binds to a subsite of the verapamil receptor

  10. NMDA Receptor Antagonists for Treatment of Depression

    Directory of Open Access Journals (Sweden)

    Zeynep Ates-Alagoz

    2013-04-01

    Full Text Available Depression is a psychiatric disorder that affects millions of people worldwide. Individuals battling this disorder commonly experience high rates of relapse, persistent residual symptoms, functional impairment, and diminished well-being. Medications have important utility in stabilizing moods and daily functions of many individuals. However, only one third of patients had considerable improvement with a standard antidepressant after 2 months and all patients had to deal with numerous side effects. The N-methyl-d-aspartate (NMDA receptor family has received special attention because of its critical role in psychiatric disorders. Direct targeting of the NMDA receptor could result in more rapid antidepressant effects. Antidepressant-like effects of NMDA receptor antagonists have been demonstrated in different animal models. MK-801 (a use-dependent channel blocker, and CGP 37849 (an NMDA receptor antagonist have shown antidepressant properties in preclinical studies, either alone or combined with traditional antidepressants. A recent development is use of ketamine clinically for refractory depression. The purpose of this review is to examine and analyze current literature on the role of NMDA receptor antagonists for treatment of depression and whether this is a feasible route in drug discovery.

  11. From the Cover: Glutamate antagonists limit tumor growth

    Science.gov (United States)

    Rzeski, Wojciech; Turski, Lechoslaw; Ikonomidou, Chrysanthy

    2001-05-01

    Neuronal progenitors and tumor cells possess propensity to proliferate and to migrate. Glutamate regulates proliferation and migration of neurons during development, but it is not known whether it influences proliferation and migration of tumor cells. We demonstrate that glutamate antagonists inhibit proliferation of human tumor cells. Colon adenocarcinoma, astrocytoma, and breast and lung carcinoma cells were most sensitive to the antiproliferative effect of the N-methyl-D-aspartate antagonist dizocilpine, whereas breast and lung carcinoma, colon adenocarcinoma, and neuroblastoma cells responded most favorably to the -amino-3-hydroxy-5-methyl-4-isoxazole-propionate antagonist GYKI52466. The antiproliferative effect of glutamate antagonists was Ca2+ dependent and resulted from decreased cell division and increased cell death. Morphological alterations induced by glutamate antagonists in tumor cells consisted of reduced membrane ruffling and pseudopodial protrusions. Furthermore, glutamate antagonists decreased motility and invasive growth of tumor cells. These findings suggest anticancer potential of glutamate antagonists.

  12. Investigations of stabilizing additives—III. Antagonistic effect of thioester on hindered amine antioxidants for radiation stability

    Science.gov (United States)

    Williams, J. L.; Williams, E. E.; Dunn, T. S.

    The use of hindered amines as primary antioxidants has been investigated both in a model antioxidant activity system and polypropylene. Also, the effectiveness of hindered amines in the presence of thioester has been evaluated. The antagonistic aspects of thioester on the ability of hindered amine to prevent polymer oxidation is discussed.

  13. Novel neurokinin-1 antagonists as antiemetics for the treatment of chemotherapy-induced emesis.

    Science.gov (United States)

    Reddy, G Kesava; Gralla, Richard J; Hesketh, Paul J

    2006-04-01

    Despite significant advances in supportive care in oncology, many patients with cancer still experience chemotherapy- induced nausea and vomiting (CINV). Historically, there were only 3 neurotransmitter receptors (dopamine D2, cannabinoid- 1, and 5-hydroxytryptamine-3) that were the known targets for antiemetic therapy. Major advances in the management of chemotherapy-induced emesis were seen with the introduction of 5-hydroxytryptamine-3 receptor antagonists, which include palonosetron, ondansetron, tropisetron, dolasetron, and granisetron. However, recently, selective inhibitors of substance P have shown promising activity in the management of CINV in patients with cancer. Substance P mediates a number of biologic effects by binding to a specific neuroreceptor, neurokinin-1 (NK-1). Among the NK-1 receptor antagonists, aprepitant has been approved for the treatment of CINV. Currently, several other NK-1 receptor antagonists, including casopitant, vestipitant, netupitant, and SCH619734, are undergoing clinical evaluation for the prevention of CINV in patients with a variety of malignancies. The clinical potential of these novel NK-1 receptor antagonists and their respective ongoing clinical trials for the management of chemotherapy-induced emesis are discussed briefly herein.

  14. A SOCS1/3 antagonist peptide protects mice against lethal infection with influenza A virus

    Directory of Open Access Journals (Sweden)

    Chulbul M. Ahmed

    2015-11-01

    Full Text Available We have developed an antagonist to suppressor of cytokine signaling 1 (SOCS1, pJAK2(1001-1013, that corresponds to the activation loop of the Janus kinase JAK2, which is the binding site for the kinase inhibitory region (KIR of SOCS1. Internalized pJAK2(1001-1013 inhibits SOCS1 and SOCS3. SOCS1 has been shown to be an influenza virus induced virulence factor that enhances infection of cells. The antagonist was protective in cell culture and in influenza virus PR8 lethally infected C57BL/6 mice. The SOCS antagonist also prevented adverse morbidity as assessed by parameters such as weight loss and drop in body temperature and showed potent induction of both the cellular and humoral immune responses to the influenza virus candidate universal antigen matrix protein 2 (M2e. The SOCS antagonist thus protected mice against lethal influenza virus infection and possessed potent adjuvancy against the M2e candidate influenza virus universal vaccine antigen.

  15. Bleeding and asymptomatic overdose in patients under Vitamin K antagonist therapy: Frequency and risk factors

    Directory of Open Access Journals (Sweden)

    F. Ben Mbarka

    2018-03-01

    Full Text Available Background: Vitamin K antagonists are widely used in the treatment and prevention of thromboembolic disease. However, these drugs can cause serious side effects, especially bleeding. This study aims to evaluate frequency and risk factors of both bleeding and asymptomatic overdose in North African patients undergoing Vitamin K antagonist therapy. Methods: We performed a cross-sectional study in patients undergoing Vitamin K antagonist therapy. A statistical analysis has been conducted to identify overdose and bleeding risk factors by using chi-square test (p < .05. Results: One hundred and eleven patients were included. We recorded 14 cases of bleeding and 26 cases of asymptomatic overdose. Advanced age, poor adherence, concomitant use of paracetamol and history of previous bleeding are significant risk factors of over-anticoagulation. An INR value over 6 at admission, a high therapeutic target range for INR, concomitant use of acetylsalicylic acid, lack of information on overdose signs and measures to be taken in case of bleeding were identified as risk factors for bleeding. Conclusion: Most of the risk factors identified in our study seem to be related to patients lack of information and education. These results highlight the importance of creating a therapeutic patient education program. Keywords: Vitamin K antagonist, Bleeding, Risk factor, Overdose

  16. Combination decongestion therapy in hospitalized heart failure: loop diuretics, mineralocorticoid receptor antagonists and vasopressin antagonists.

    Science.gov (United States)

    Vaduganathan, Muthiah; Mentz, Robert J; Greene, Stephen J; Senni, Michele; Sato, Naoki; Nodari, Savina; Butler, Javed; Gheorghiade, Mihai

    2015-01-01

    Congestion is the most common reason for admissions and readmissions for heart failure (HF). The vast majority of hospitalized HF patients appear to respond readily to loop diuretics, but available data suggest that a significant proportion are being discharged with persistent evidence of congestion. Although novel therapies targeting congestion should continue to be developed, currently available agents may be utilized more optimally to facilitate complete decongestion. The combination of loop diuretics, natriuretic doses of mineralocorticoid receptor antagonists and vasopressin antagonists represents a regimen of currently available therapies that affects early and persistent decongestion, while limiting the associated risks of electrolyte disturbances, hemodynamic fluctuations, renal dysfunction and mortality.

  17. Investigation of orexin-2 selective receptor antagonists: Structural modifications resulting in dual orexin receptor antagonists.

    Science.gov (United States)

    Skudlarek, Jason W; DiMarco, Christina N; Babaoglu, Kerim; Roecker, Anthony J; Bruno, Joseph G; Pausch, Mark A; O'Brien, Julie A; Cabalu, Tamara D; Stevens, Joanne; Brunner, Joseph; Tannenbaum, Pamela L; Wuelfing, W Peter; Garson, Susan L; Fox, Steven V; Savitz, Alan T; Harrell, Charles M; Gotter, Anthony L; Winrow, Christopher J; Renger, John J; Kuduk, Scott D; Coleman, Paul J

    2017-03-15

    In an ongoing effort to explore the use of orexin receptor antagonists for the treatment of insomnia, dual orexin receptor antagonists (DORAs) were structurally modified, resulting in compounds selective for the OX 2 R subtype and culminating in the discovery of 23, a highly potent, OX 2 R-selective molecule that exhibited a promising in vivo profile. Further structural modification led to an unexpected restoration of OX 1 R antagonism. Herein, these changes are discussed and a rationale for selectivity based on computational modeling is proposed. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. [Vascular calcifications, the hidden side effects of vitamin K antagonists].

    Science.gov (United States)

    Bennis, Youssef; Vengadessane, Subashini; Bodeau, Sandra; Gras, Valérie; Bricca, Giampiero; Kamel, Saïd; Liabeuf, Sophie

    2016-09-01

    Despite the availability of new oral anticoagulants, vitamin K antagonists (VKA, such as fluindione, acenocoumarol or warfarin) remain currently the goal standard medicines for oral prevention or treatment of thromboembolic disorders. They inhibit the cycle of the vitamin K and its participation in the enzymatic gamma-carboxylation of many proteins. The VKA prevent the activation of the vitamin K-dependent blood clotting factors limiting thus the initiation of the coagulation cascade. But other proteins are vitamin K-dependent and also remain inactive in the presence of VKA. This is the case of matrix Gla-protein (MGP), a protein that plays a major inhibitory role in the development of vascular calcifications. Several experimental and epidemiological results suggest that the use of the VKA could promote the development of vascular calcifications increasing thus the cardiovascular risk. This risk seems to be higher in patients with chronic kidney disease or mellitus diabetes who are more likely to develop vascular calcifications, and may be due to a decrease of the MGP activity. This review aims at summarizing the data currently available making vascular calcifications the probably underestimated side effects of VKA. Copyright © 2016 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.

  19. Reduction of periodontal pathogens adhesion by antagonistic strains.

    Science.gov (United States)

    Van Hoogmoed, C G; Geertsema-Doornbusch, G I; Teughels, W; Quirynen, M; Busscher, H J; Van der Mei, H C

    2008-02-01

    Periodontitis results from a shift in the subgingival microflora into a more pathogenic direction with Porphyromonas gingivalis, Prevotella intermedia, and Actinobacillus actinomycetemcomitans considered as periodontopathogens. In many cases, treatment procures only a temporary shift towards a less pathogenic microflora. An alternative treatment could be the deliberate colonization of pockets with antagonistic microorganisms to control the adhesion of periodontopathogens. The aim of this study was to identify bacterial strains that reduce adhesion of periodontopathogens to surfaces. Streptococcus sanguinis, Streptococcus crista, Streptococcus salivarius, Streptococcus mitis, Actinomyces naeslundii, and Haemophilus parainfluenzae were evaluated as potential antagonists against P. gingivalis ATCC 33277, P. intermedia ATCC 49046, and A. actinomycetemcomitans ATCC 43718 as periodontopathogens. Adhesion of periodontopathogens to the bottom plate of a parallel plate flow chamber was studied in the absence (control) and the presence of pre-adhering antagonistic strains up to a surface coverage of 5%. The largest reduction caused by antagonistic strains was observed for P. gingivalis. All antagonistic strains except S. crista ATCC 49999 inhibited the adhesion of P. gingivalis by at least 1.6 cells per adhering antagonist, with the largest significant reduction observed for A. naeslundii ATCC 51655 (3.8 cells per adhering antagonist). Adhering antagonists had a minimal effect on the adhesion of A. actinomycetemcomitans ATCC 43718. Intermediate but significant reductions were perceived for P. intermedia, most notably caused by S. mitis BMS. The adhesion of P. gingivalis was inhibited best by antagonistic strains, while S. mitis BMS appeared to be the most successful antagonist.

  20. Effect of Angiotensin-Converting Enzyme Inhibitor/Calcium Antagonist Combination Therapy on Renal Function in Hypertensive Patients With Chronic Kidney Disease: Chikushi Anti-Hypertension Trial - Benidipine and Perindopril.

    Science.gov (United States)

    Okuda, Tetsu; Okamura, Keisuke; Shirai, Kazuyuki; Urata, Hidenori

    2018-02-01

    Appropriate blood pressure control suppresses progression of chronic kidney disease (CKD). If an angiotensin-converting enzyme (ACE) inhibitor is ineffective, adding a calcium antagonist is recommended. We compared the long-term effect of two ACE inhibitor/calcium antagonist combinations on renal function in hypertensive patients with CKD. Patients who failed to achieve the target blood pressure (systolic/diastolic: calcium antagonist amlodipine (group A) or perindopril and the T/L type calcium antagonist benidipine (group B). The primary endpoint was the change of the estimated glomerular filtration rate (eGFR) after 2 years. Eligible patients had a systolic pressure ≥ 130 mm Hg and/or diastolic pressure ≥ 80 mm Hg and CKD (urine protein (+) or higher, eGFR calcium antagonist may prevent deterioration of renal function more effectively than an ACE inhibitor/L type calcium antagonist combination.

  1. Diphenyl Purine Derivatives as Peripherally Selective Cannabinoid Receptor 1 Antagonists

    Science.gov (United States)

    Fulp, Alan; Bortoff, Katherine; Zhang, Yanan; Seltzman, Herbert; Mathews, James; Snyder, Rodney; Fennell, Tim; Maitra, Rangan

    2015-01-01

    Cannabinoid receptor 1 (CB1) antagonists are potentially useful for the treatment of several diseases. However, clinical development of several CB1 antagonists was halted due to central nervous system (CNS)-related side effects including depression and suicidal ideation in some users. Recently, studies have indicated that selective regulation of CB1 receptors in the periphery is a viable strategy for treating several important disorders. Past efforts to develop peripherally selective antagonists of CB1 have largely targeted rimonabant, an inverse agonist of CB1. Reported here are our efforts toward developing a peripherally selective CB1 antagonist based on the otenabant scaffold. Even though otenabant penetrates the CNS, it is unique among CB1 antagonists that have been clinically tested because it has properties that are normally associated with peripherally selective compounds. Our efforts have resulted in an orally absorbed compound that is a potent and selective CB1 antagonist with limited penetration into the CNS. PMID:23098108

  2. Hypocretin antagonists in insomnia treatment and beyond.

    Science.gov (United States)

    Ruoff, Chad; Cao, Michelle; Guilleminault, Christian

    2011-01-01

    Hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep through stabilization of sleep promoting GABAergic and wake promoting cholinergic/monoaminergic neural pathways. Hypocretin also influences other physiologic processes such as metabolism, appetite, learning and memory, reward and addiction, and ventilatory drive. The discovery of hypocretin and its effect upon the sleep-wake cycle has led to the development of a new class of pharmacologic agents that antagonize the physiologic effects of hypocretin (i.e. hypocretin antagonists). Further investigation of these agents may lead to novel therapies for insomnia without the side-effect profile of currently available hypnotics (e.g. impaired cognition, confusional arousals, and motor balance difficulties). However, antagonizing a system that regulates the sleep-wake cycle while also influencing non-sleep physiologic processes may create an entirely different but equally concerning side-effect profile such as transient loss of muscle tone (i.e. cataplexy) and a dampened respiratory drive. In this review, we will discuss the discovery of hypocretin and its receptors, hypocretin and the sleep-wake cycle, hypocretin antagonists in the treatment of insomnia, and other implicated functions of the hypocretin system.

  3. Sexually antagonistic selection in human male homosexuality.

    Directory of Open Access Journals (Sweden)

    Andrea Camperio Ciani

    Full Text Available Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling 'Darwinian paradox'. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness, accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait.

  4. Sexually Antagonistic Selection in Human Male Homosexuality

    Science.gov (United States)

    Camperio Ciani, Andrea; Cermelli, Paolo; Zanzotto, Giovanni

    2008-01-01

    Several lines of evidence indicate the existence of genetic factors influencing male homosexuality and bisexuality. In spite of its relatively low frequency, the stable permanence in all human populations of this apparently detrimental trait constitutes a puzzling ‘Darwinian paradox’. Furthermore, several studies have pointed out relevant asymmetries in the distribution of both male homosexuality and of female fecundity in the parental lines of homosexual vs. heterosexual males. A number of hypotheses have attempted to give an evolutionary explanation for the long-standing persistence of this trait, and for its asymmetric distribution in family lines; however a satisfactory understanding of the population genetics of male homosexuality is lacking at present. We perform a systematic mathematical analysis of the propagation and equilibrium of the putative genetic factors for male homosexuality in the population, based on the selection equation for one or two diallelic loci and Bayesian statistics for pedigree investigation. We show that only the two-locus genetic model with at least one locus on the X chromosome, and in which gene expression is sexually antagonistic (increasing female fitness but decreasing male fitness), accounts for all known empirical data. Our results help clarify the basic evolutionary dynamics of male homosexuality, establishing this as a clearly ascertained sexually antagonistic human trait. PMID:18560521

  5. Calmodulin antagonists effect on Ca(2+ level in the mitochondria and cytoplasm of myometrium cells

    Directory of Open Access Journals (Sweden)

    S. G. Shlykov

    2015-10-01

    Full Text Available It is known that Са2+-dependent regulation of this cation exchange in mitochondria is carried out with participation of calmodulin. We had shown in a previous work using two experimental models: isolated mitochondria and intact myometrium cells, that calmodulin antagonists reduce the level of mitochondrial membrane polarization. The aim of this work was to investigate the influence of calmodulin antagonists on the level of ionized Са in mitochondria and cytoplasm of uterine smooth muscle cells using spectrofluorometry and confocal microscopy. It was shown that myometrium mitochondria, in the presence of АТР and MgCl2 in the incubation medium, accumulate Са ions in the matrix. Incubation of mitochondria in the presence of СССР inhibited cation accumulation, but did not cease it. Calmodulin antagonist such as trifluoperazine (100 µМ considerably increased the level of ionized Са in the mitochondrial matrix. Preliminary incubation of mitochondria with 100 µМ Са2+, before adding trifluoperazine to the incubation medium, partly prevented influence of the latter on the cation level in the matrix. Incubation of myometrium cells (primary culture with another calmodulin antagonist calmidazolium (10 µМ was accompanied by depolarization of mitochondrial membrane and an increase in the concentration of ionized Са in cytoplasm. Thus, using two models, namely, isolated mitochondria and intact myometrium cells, it has been shown that calmodulin antagonists cause depolarization of mitochondrial membranes and an increase of the ionized Са concentration in both the mitochondrial matrix and the cell cytoplasm.

  6. A Clinical Study on Administration of Opioid Antagonists in Terminal Cancer Patients: 7 Patients Receiving Opioid Antagonists Following Opioids among 2443 Terminal Cancer Patients Receiving Opioids.

    Science.gov (United States)

    Uekuzu, Yoshihiro; Higashiguchi, Takashi; Futamura, Akihiko; Ito, Akihiro; Mori, Naoharu; Murai, Miyo; Ohara, Hiroshi; Awa, Hiroko; Chihara, Takeshi

    2017-03-01

    There have been few detailed reports on respiratory depression due to overdoses of opioids in terminal cancer patients. We investigated the situation of treatment with opioid antagonists for respiratory depression that occurred after administration of opioid at optimal doses in terminal cancer patients, to clarify pathological changes as well as causative factors. In 2443 terminal cancer patients receiving opioids, 7 patients (0.3%) received opioid antagonists: 6, morphine (hydrochloride, 5; sulfate, 1); 1, oxycodone. The median dosage of opioids was 13.3 mg/d, as converted to morphine injection. Respiratory depression occurred on this daily dose in 4 patients and after changed dose and route in 3 patients. Opioids were given through the vein in 6 patients and by the enteral route in 1 patient. Concomitant drugs included nonsteroidal anti-inflammatory drugs in 3 patients and zoledronic acid in 2 patients. In morphine-receiving patients, renal functions were significantly worsened at the time of administration of an opioid antagonist than the day before the start of opioid administration. These findings indicate that the proper use of opioids was safe and acceptable in almost all terminal cancer patients. In rare cases, however, a risk toward respiratory depression onset is indicated because morphine and morphine-6-glucuronide become relatively excessive owing to systemic debility due to disease progression, especially respiratory and renal dysfunctions. At the onset of respiratory depression, appropriate administration of an opioid antagonist mitigated the symptoms. Thereafter, opioid switching or continuous administration at reduced dosages of the same opioids prevented the occurrence of serious adverse events.

  7. A Gly/Ala switch contributes to high affinity binding of benzoxazinone-based non-peptide oxytocin receptor antagonists.

    Science.gov (United States)

    Hawtin, Stuart R; Ha, Sookhee N; Pettibone, Douglas J; Wheatley, Mark

    2005-01-17

    Non-peptide antagonists of the oxytocin receptor (OTR) have been developed to prevent pre-term labour. The benzoxazinone-based antagonists L-371,257 and L-372,662 display pronounced species-dependent pharmacology with respect to selectivity for the OTR over the V(1a) vasopressin receptor. Examination of receptor sequences from different species identified Ala(318) in helix 7 of the human OTR as a candidate discriminator required for high affinity binding. The mutant receptor [A318G]OTR was engineered and characterised using ligands representing many different chemical classes. Of all the ligands investigated, only the benzoxazinone-based antagonists had decreased affinity for [A318G]OTR. Molecular modelling revealed that Ala(318) provides a direct hydrophobic contact with a methoxy group of L-371,257 and L-372,662.

  8. The Attractiveness of Opposites: Agonists and Antagonists.

    LENUS (Irish Health Repository)

    O'Brien, Tony

    2015-02-02

    ABSTRACT Opioid-induced bowel dysfunction, of which constipation is the most common aspect, is a major limiting factor in the use of opioids for pain management. The availability of an oral, long-acting formulation of oxycodone and naloxone represents a highly significant development in pain management. The combination of an opioid analgesic with an opioid antagonist offers reliable pain control with a significant reduction in the burden of opioid-induced constipation. This report is adapted from paineurope 2014; Issue 3, ©Haymarket Medical Publications Ltd, and is presented with permission. paineurope is provided as a service to pain management by Mundipharma International, LTD and is distributed free of charge to healthcare professionals in Europe. Archival issues can be accessed via the website: http:\\/\\/www.paineurope.com at which European health professionals can register online to receive copies of the quarterly publication.

  9. Antiallergic effects of H1-receptor antagonists.

    Science.gov (United States)

    Baroody, F M; Naclerio, R M

    2000-01-01

    The primary mechanism of antihistamine action in the treatment of allergic diseases is believed to be competitive antagonism of histamine binding to cellular receptors (specifically, the H1-receptors), which are present on nerve endings, smooth muscles, and glandular cells. This notion is supported by the fact that structurally unrelated drugs antagonize the H1-receptor and provide clinical benefit. However, H1-receptor antagonism may not be their sole mechanism of action in treating allergic rhinitis. On the basis of in vitro and animal experiments, drugs classified as H1-receptor antagonists have long been recognized to have additional pharmacological properties. Most first-generation H1-antihistamines have anticholinergic, sedative, local anaesthetic, and anti-5-HT effects, which might favourably affect the symptoms of the allergic response but also contribute to side-effects. These additional properties are not uniformly distributed among drugs classified as H1-receptor antagonists. Azatadine, for example, inhibits in vitro IgE-mediated histamine and leukotriene (LT) release from mast cells and basophils. In human challenge models, terfenadine, azatadine, and loratadine reduce IgE-mediated histamine release. Cetirizine reduces eosinophilic infiltration at the site of antigen challenge in the skin, but not the nose. In a nasal antigen challenge model, cetirizine pretreatment did not affect the levels of histamine and prostaglandin D2 recovered in postchallenge lavages, whereas the levels of albumin, N-tosyl-L-arginine methyl ester (TAME) esterase activity, and LTs were reduced. Terfenadine, cetirizine, and loratadine blocked allergen-induced hyperresponsiveness to methacholine. In view of the complexity of the pathophysiology of allergy, a number of H1 antagonists with additional properties are currently under development for allergic diseases. Mizolastine, a new H1-receptor antagonist, has been shown to have additional actions that should help reduce the

  10. Calcium antagonists and the diabetic hypertensive patient

    DEFF Research Database (Denmark)

    Parving, H H; Rossing, P

    1993-01-01

    reduces albuminuria, delays the progression of nephropathy, and postpones renal insufficiency in diabetic nephropathy. Calcium antagonists and angiotensin converting enzyme inhibitors induce an acute increase in the glomerular filtration rate, renal plasma flow, and renal sodium excretion......Roughly 40% of all diabetic patients, whether insulin dependent or not, develop persistent albuminuria (over 300 mg/24 hr), a decrease in the glomerular filtration rate, and elevated blood pressure, ie, diabetic nephropathy. Diabetic nephropathy is the single most important cause of end stage renal...... disease in the Western world, and accounts for over a quarter of all end stage renal disease. It also is a major cause of the increased morbidity and mortality seen in diabetic patients; for example, the cost of end stage renal care in the United States currently exceeds +1.8 billion per year for diabetic...

  11. Assay method for organic calcium antagonist drugs and a kit for such an assay

    International Nuclear Information System (INIS)

    Snyder, S. H.; Gould, R. J.

    1985-01-01

    A method for measuring the level of organic calcium antagonist drug in a body fluid comprises preparing a mixture of a radioactive calcium antagonist drug, a body fluid containing a calcium antagonist drug and a calcium antagonist receptor material, measuring the radioactivity of the radioactive calcium antagonist drug bound to said calcium antagonist receptor material and deriving the concentration of the calcium antagonist drug in the body fluid from a standard curve indicating the concentration of calcium antagonist drug versus inhibition of binding of said radioactive calcium antagonist drug to said receptor sites caused by the calcium antagonist drug in said body fluid. A kit for measuring the level of an organic calcium drug comprises a receptacle containing a radioactive calcium antagonist drug, a calcium antagonist receptor material and a standard amount of a nonradioactive calcium antagonist drug

  12. Antagonistic activity of marine sponges associated Actinobacteria

    Directory of Open Access Journals (Sweden)

    Selvakumar Dharmaraj

    2016-06-01

    Full Text Available Objective: To focus on the isolation and preliminary characterization of marine sponges associated Actinobacteria particularly Streptomyces species and also their antagonistic activities against bacterial and fungal pathogens. Methods: The sponges were collected from Kovalam and Vizhinjam port of south-west coast of Kerala, India. Isolation of strains was carried out from sponge extracts using international Streptomyces project media. For preliminary identification of the strains, morphological (mycelial colouration, soluble pigments, melanoid pigmentation, spore morphology, nutritional uptake (carbon utilisation, amonoacids influence, sodium chloride tolerance, physiological (pH, temperature and chemotaxonomical characterization were done. Antimicrobial studies were also carried out for the selected strains. Results: With the help of the spicule structures, the collected marine sponges were identified as Callyspongia diffusa, Mycale mytilorum, Tedania anhelans and Dysidea fragilis. Nearly 94 strains were primarily isolated from these sponges and further they were sub-cultured using international Streptomyces project media. The strains exhibited different mycelial colouration (aerial and substrate, soluble and melanoid pigmentations. The strains possessed three types of sporophore morphology namely rectus flexibilis, spiral and retinaculiaperti. Among the 94 isolates, seven exhibited antibacterial and antifungal activities with maximal zone of inhibition of 30 mm. The nutritional, physiological and chemotaxonomical characteristic study helped in the conventional identification of the seven strains and they all suggest that the strains to be grouped under the genus Streptomyces. Conclusions: The present study clearly helps in the preliminary identification of the isolates associated with marine sponges. Antagonistic activities prove the production of antimicrobial metabolites against the pathogens. Marine sponges associated Streptomyces are

  13. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

    Science.gov (United States)

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

    2016-04-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1-3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents.

  14. Receptor residence time trumps drug-likeness and oral bioavailability in determining efficacy of complement C5a antagonists

    Science.gov (United States)

    Seow, Vernon; Lim, Junxian; Cotterell, Adam J.; Yau, Mei-Kwan; Xu, Weijun; Lohman, Rink-Jan; Kok, W. Mei; Stoermer, Martin J.; Sweet, Matthew J.; Reid, Robert C.; Suen, Jacky Y.; Fairlie, David P.

    2016-01-01

    Drug discovery and translation are normally based on optimizing efficacy by increasing receptor affinity, functional potency, drug-likeness (rule-of-five compliance) and oral bioavailability. Here we demonstrate that residence time of a compound on its receptor has an overriding influence on efficacy, exemplified for antagonists of inflammatory protein complement C5a that activates immune cells and promotes disease. Three equipotent antagonists (3D53, W54011, JJ47) of inflammatory responses to C5a (3nM) were compared for drug-likeness, receptor affinity and antagonist potency in human macrophages, and anti-inflammatory efficacy in rats. Only the least drug-like antagonist (3D53) maintained potency in cells against higher C5a concentrations and had a much longer duration of action (t1/2 ~ 20 h) than W54011 or JJ47 (t1/2 ~ 1–3 h) in inhibiting macrophage responses. The unusually long residence time of 3D53 on its receptor was mechanistically probed by molecular dynamics simulations, which revealed long-lasting interactions that trap the antagonist within the receptor. Despite negligible oral bioavailability, 3D53 was much more orally efficacious than W54011 or JJ47 in preventing repeated agonist insults to induce rat paw oedema over 24 h. Thus, residence time on a receptor can trump drug-likeness in determining efficacy, even oral efficacy, of pharmacological agents. PMID:27094554

  15. Blood flow distribution with adrenergic and histaminergic antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-03-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects.

  16. Blood flow distribution with adrenergic and histaminergic antagonists

    International Nuclear Information System (INIS)

    Baker, C.H.; Davis, D.L.; Sutton, E.T.

    1989-01-01

    Superficial fibular nerve stimulation (SFNS) causes increased pre- and post-capillary resistances as well as increased capillary permeability in the dog hind paw. These responses indicate possible adrenergic and histaminergic interactions. The distribution of blood flow between capillaries and arteriovenous anastomoses (AVA) may depend on the relative effects of these neural inputs. Right hind paws of anesthetized heparinized dogs were vascularly and neurally isolated and perfused with controlled pressure. Blood flow distribution was calculated from the venous recovery of 85Sr-labeled microspheres (15 microns). The mean transit times of 131I-albumin and 85Sr-labeled microspheres were calculated. The effects of adrenergic and histaminergic antagonists with and without SFNS were determined. Phentolamine blocked the entire response to SFNS. Prazosin attenuated increases in total and AVA resistance. Yohimbine prevented increased total resistance, attenuated the AVA resistance increase, and revealed a decrease in capillary circuit resistance. Pyrilamine attenuated total resistance increase while SFNS increased capillary and AVA resistances. Metiamide had no effect on blood flow distribution with SFNS. The increase in AVA resistance with SFNS apparently resulted from a combination of alpha 1 and alpha 2 receptor stimulation but not histaminergic effects

  17. IL-1 Receptor Antagonist Inhibits Early Granulation Formation.

    Science.gov (United States)

    Nicolli, Elizabeth A; Ghosh, Ankona; Haft, Sunny; Frank, Renee; Saunders, Cecil James; Cohen, Noam; Mirza, Natasha

    2016-04-01

    Using a functional model of airway granulation tissue in laryngotracheal stenosis, we investigated changes in histopathology and inflammatory markers within granulation tissue in response to an interleukin-1 receptor antagonist (IL-1Ra). This study allows us to further delineate the immune response to wound healing and potentially identify treatment markers. Laryngotracheal complexes (LTCs) of donor mice underwent direct airway injury. The LTCs were transplanted into subcutaneous tissue of recipient mice in 2 groups: IL-1Ra treated and untreated. The IL-1Ra-treated arm received daily intraperitoneal injections of IL-1Ra for 3 weeks. The LTCs were then harvested. Granulation formation was measured. The mRNA expression of transforming growth factor (TGF) beta and IL-1 was quantified using real-time reverse transcript polymerase chain reaction. There were statistically significant differences in lamina propria thickness. There were no statistically significant changes in mRNA expression of TGF-β and IL-1β between the treated and untreated specimens. Using a previously described murine model, we delineate inflammatory markers that can be targeted for potential therapy. While the levels of inflammatory markers do not change significantly, the lamina propria thickness shows that the effects of IL-1 have been inhibited. The early use of the IL-1Ra will inhibit the efficacy of IL-1 in the inflammatory cascade and can prevent early granulation formation. © The Author(s) 2015.

  18. Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance

    Science.gov (United States)

    2013-12-18

    Effectiveness Directorate, Biosciences and Protection Division, Warfighter Fatigue Countermeasures Branch. 35. Golden, C.J. (1978). Stroop Color and Word Test: A...0080 TITLE: Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance PRINCIPAL INVESTIGATOR: Dr. Thomas Neylan...31August2013 4. TITLE AND SUBTITLE Effect of a Hypocretin/Orexin Antagonist on Neurocognitive Performance 5a. CONTRACT NUMBER W81XWH

  19. Using waste of Tofu production improved antagonistic activities of a ...

    African Journals Online (AJOL)

    Mrs. Hoa

    2012-10-04

    Oct 4, 2012 ... screened for their antagonistic activity against 10 races of Xoo causing rice bacterial blight disease. Three actinomycete strains ... antagonistic activity of VN10-A-44 against the Xoo pathogen and to make use of tofu waste for large- ..... vitamins and some essential amino acids which are very important for ...

  20. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

    DEFF Research Database (Denmark)

    Tricoci, Pierluigi; Huang, Zhen; Held, Claes

    2012-01-01

    Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation.......Vorapaxar is a new oral protease-activated-receptor 1 (PAR-1) antagonist that inhibits thrombin-induced platelet activation....

  1. Evaluation of antagonistic fungi against charcoal rot of sunflower ...

    African Journals Online (AJOL)

    In vitro, sensitivity of Macrophomina phaseolina (Tassi) Goid determined through inhibition zone technique to various antagonistic fungi viz., Aspergillus niger, Aspergillus flavus, Trichoderma viride, Trichoderma harzianum and Penicillium capsulatum amended into PDA medium. All the antagonists reduced the colony ...

  2. Calcium antagonists for ischemic stroke: a systematic review

    NARCIS (Netherlands)

    Horn, J.; Limburg, M.

    2001-01-01

    BACKGROUND AND PURPOSE: Stroke is a common disease, and many trials with calcium antagonists as possible neuroprotective agents have been conducted. The aim of this review is to determine whether calcium antagonists reduce the risk of death or dependency after acute ischemic stroke. METHODS: Acute

  3. Antagonistic and Bargaining Games in Optimal Marketing Decisions

    Science.gov (United States)

    Lipovetsky, S.

    2007-01-01

    Game theory approaches to find optimal marketing decisions are considered. Antagonistic games with and without complete information, and non-antagonistic games techniques are applied to paired comparison, ranking, or rating data for a firm and its competitors in the market. Mix strategy, equilibrium in bi-matrix games, bargaining models with…

  4. Interaction between Antagonist of Cannabinoid Receptor and Antagonist of Adrenergic Receptor on Anxiety in Male Rat

    Directory of Open Access Journals (Sweden)

    Alireza Komaki

    2014-07-01

    Full Text Available Introduction: Anxiety is among the most common and treatable mental disorders. Adrenergic and cannabinoid systems have an important role in the neurobiology of anxiety. The elevated plus-maze (EPM has broadly been used to investigate anxiolytic and anxiogenic compounds. The present study investigated the effects of intraperitoneal (IP injection of cannabinoid CB1 receptor antagonist (AM251 in the presence of alpha-1 adrenergic antagonist (Prazosin on rat behavior in the EPM. Methods: In this study, the data were obtained from male Wistar rat, which weighing 200- 250 g. Animal behavior in EPM were videotaped and saved in computer for 10 min after IP injection of saline, AM251 (0.3 mg/kg, Prazosin (0.3 mg/kg and AM251 + Prazosin, subsequently scored for conventional indices of anxiety. During the test period, the number of open and closed arms entries, the percentage of entries into the open arms of the EPM, and the spent time in open and closed arms were recorded. Diazepam was considered as a positive control drug with anxiolytic effect (0.3, 0.6, 1.2 mg/kg. Results: Diazepam increased the number of open arm entries and the percentage of spent time on the open arms. IP injection of AM251 before EPM trial decreased open arms exploration and open arm entry. Whereas, Prazosin increased open arms exploration and open arm entry. This study showed that both substances in simultaneous injection have conflicting effects on the responses of each of these two compounds in a single injection. Discussion: Injection of CB1 receptor antagonist may have an anxiogenic profile in rat, whereas adrenergic antagonist has an anxiolytic effect. Further investigations are essential for better understanding of anxiolytic and anxiogenic properties and neurobiological mechanisms of action and probable interactions of the two systems.

  5. The NK1 Receptor Antagonist L822429 Reduces Heroin Reinforcement

    Science.gov (United States)

    Barbier, Estelle; Vendruscolo, Leandro F; Schlosburg, Joel E; Edwards, Scott; Juergens, Nathan; Park, Paula E; Misra, Kaushik K; Cheng, Kejun; Rice, Kenner C; Schank, Jesse; Schulteis, Gery; Koob, George F; Heilig, Markus

    2013-01-01

    Genetic deletion of the neurokinin 1 receptor (NK1R) has been shown to decrease the reinforcing properties of opioids, but it is unknown whether pharmacological NK1R blockade has the same effect. Here, we examined the effect of L822429, a rat-specific NK1R antagonist, on the reinforcing properties of heroin in rats on short (1 h: ShA) or long (12 h: LgA) access to intravenous heroin self-administration. ShA produces heroin self-administration rates that are stable over time, whereas LgA leads to an escalation of heroin intake thought to model important dependence-related aspects of addiction. L822429 reduced heroin self-administration and the motivation to consume heroin, measured using a progressive-ratio schedule, in both ShA and LgA rats. L822429 also decreased anxiety-like behavior in both groups, measured on the elevated plus maze, but did not affect mechanical hypersensitivity observed in LgA rats. Expression of TacR1 (the gene encoding NK1R) was decreased in reward- and stress-related brain areas both in ShA and LgA rats compared with heroin-naïve rats, but did not differ between the two heroin-experienced groups. In contrast, passive exposure to heroin produced increases in TacR1 expression in the prefrontal cortex and nucleus accumbens. Taken together, these results show that pharmacological NK1R blockade attenuates heroin reinforcement. The observation that animals with ShA and LgA to heroin were similarly affected by L822429 indicates that the SP/NK1R system is not specifically involved in neuroadaptations that underlie escalation resulting from LgA self-administration. Instead, the NK1R antagonist appears to attenuate acute, positively reinforcing properties of heroin and may be useful as an adjunct to relapse prevention in detoxified opioid-dependent subjects. PMID:23303056

  6. Current position of 5HT3 antagonists and the additional value of NK1 antagonists; a new class of antiemetics

    NARCIS (Netherlands)

    R. de Wit (Ronald)

    2003-01-01

    textabstractThe advent of the 5HT3 receptor antagonists (5HT3 antagonists) in the 1990s and the combination with dexamethasone has resulted in acute emesis protection in 70% of patients receiving highly emetogenic chemotherapy. Despite complete protection in the acute phase, however, 40% of patients

  7. Identification of a New Morpholine Scaffold as a P2Y12 Receptor Antagonist

    Directory of Open Access Journals (Sweden)

    Young Ha Ahn

    2016-08-01

    Full Text Available The P2Y12 receptor is critical for platelet activation and is an attractive drug target for the prevention of atherothrombotic events. Despite the proven antithrombotic efficacy of P2Y12 inhibitors, these thienopyridine scaffolds are prodrugs that lack important features of the ideal antithrombotic agent. For this reason, ticagrelor—a new chemical class of P2Y12 receptor antagonist—was developed, but it can cause shortness of breath and various types of bleeding. Moreover, ticagrelor is a cytochrome P450 3A4 substrate/inhibitor and, therefore, caution should be exercised when it is used concomitantly with strong CYP3A4 inducers/inhibitors. There is a need for novel P2Y12 receptor antagonist scaffolds that are reversible and have high efficacy without associated side effects. Here, we describe a novel antagonist containing a morpholine moiety that was identified by screening libraries of commercially available compounds. The molecule, Compound E, acted on P2Y12, but not P2Y1 and P2Y13, and exhibited pharmacological characteristics that were distinct from those of ticagrelor, acting instead on P2Y12 via an allosteric mechanism. These results provide a basis for the development/optimization of a new class of P2Y12 antagonists.

  8. An α4β1 integrin antagonist decreases airway inflammation in ovalbumin-exposed mice

    Science.gov (United States)

    Kenyon, Nicholas J.; Liu, Ruiwu; O’Roark, Erin M.; Huang, Wenzhe; Peng, Li; Lam, Kit S.

    2008-01-01

    Inhibition of the α4 subunit of both the α4β1 and α4β7 integrins has shown promise in decreasing airway inflammation and airway hyperresponsiveness in various animal models. We hypothesized that a novel, high-affinity α4β1 antagonist (LLP2A) would decrease the migration of eosinophils to the lung and ameliorate the airway hyperresponsiveness in a mouse model of ovalbumin-induced airway inflammation. To test this hypothesis, we administered LLP2A, or scrambled LLP2A (a negative control), prior to exposure of sensitized BALB/c mice to ovalbumin aerosol. We can partially prevent, or reverse, the airway inflammatory response, but not airways hyperresponsiveness, by treatment of mice with LLP2A, a synthetic peptidomimetic α4β1 antagonist LLP2A. Specifically engineered, PEGylated (PEG) formulations of this antagonist further reduce the airway inflammatory response to ovalbumin lbumin, presumably by improving the circulating half-life of the drug. PMID:19103195

  9. Antagonistic neural networks underlying differentiated leadership roles

    Science.gov (United States)

    Boyatzis, Richard E.; Rochford, Kylie; Jack, Anthony I.

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks – the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success. PMID:24624074

  10. Antagonistic Neural Networks Underlying Differentiated Leadership Roles

    Directory of Open Access Journals (Sweden)

    Richard Eleftherios Boyatzis

    2014-03-01

    Full Text Available The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950’s. Recent research in neuroscience suggests that the division between task oriented and socio-emotional oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks -- the Task Positive Network (TPN and the Default Mode Network (DMN. Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  11. Antagonistic neural networks underlying differentiated leadership roles.

    Science.gov (United States)

    Boyatzis, Richard E; Rochford, Kylie; Jack, Anthony I

    2014-01-01

    The emergence of two distinct leadership roles, the task leader and the socio-emotional leader, has been documented in the leadership literature since the 1950s. Recent research in neuroscience suggests that the division between task-oriented and socio-emotional-oriented roles derives from a fundamental feature of our neurobiology: an antagonistic relationship between two large-scale cortical networks - the task-positive network (TPN) and the default mode network (DMN). Neural activity in TPN tends to inhibit activity in the DMN, and vice versa. The TPN is important for problem solving, focusing of attention, making decisions, and control of action. The DMN plays a central role in emotional self-awareness, social cognition, and ethical decision making. It is also strongly linked to creativity and openness to new ideas. Because activation of the TPN tends to suppress activity in the DMN, an over-emphasis on task-oriented leadership may prove deleterious to social and emotional aspects of leadership. Similarly, an overemphasis on the DMN would result in difficulty focusing attention, making decisions, and solving known problems. In this paper, we will review major streams of theory and research on leadership roles in the context of recent findings from neuroscience and psychology. We conclude by suggesting that emerging research challenges the assumption that role differentiation is both natural and necessary, in particular when openness to new ideas, people, emotions, and ethical concerns are important to success.

  12. Cannabinoid receptor antagonists: pharmacological opportunities, clinical experience, and translational prognosis.

    Science.gov (United States)

    Janero, David R; Makriyannis, Alexandros

    2009-03-01

    The endogenous cannabinoid (CB) (endocannabinoid) signaling system is involved in a variety of (patho)physiological processes, primarily by virtue of natural, arachidonic acid-derived lipids (endocannabinoids) that activate G protein-coupled CB1 and CB2 receptors. A hyperactive endocannabinoid system appears to contribute to the etiology of several disease states that constitute significant global threats to human health. Consequently, mounting interest surrounds the design and profiling of receptor-targeted CB antagonists as pharmacotherapeutics that attenuate endocannabinoid transmission for salutary gain. Experimental and clinical evidence supports the therapeutic potential of CB1 receptor antagonists to treat overweight/obesity, obesity-related cardiometabolic disorders, and substance abuse. Laboratory data suggest that CB2 receptor antagonists might be effective immunomodulatory and, perhaps, anti-inflammatory drugs. One CB1 receptor antagonist/inverse agonist, rimonabant, has emerged as the first-in-class drug approved outside the United States for weight control. Select follow-on agents (taranabant, otenabant, surinabant, rosonabant, SLV-319, AVE1625, V24343) have also been studied in the clinic. However, rimonabant's market withdrawal in the European Union and suspension of rimonabant's, taranabant's, and otenabant's ongoing development programs have highlighted some adverse clinical side effects (especially nausea and psychiatric disturbances) of CB1 receptor antagonists/inverse agonists. Novel CB1 receptor ligands that are peripherally directed and/or exhibit neutral antagonism (the latter not affecting constitutive CB1 receptor signaling) may optimize the benefits of CB1 receptor antagonists while minimizing any risk. Indeed, CB1 receptor-neutral antagonists appear from preclinical data to offer efficacy comparable to or better than that of prototype CB1 receptor antagonists/inverse agonists, with less propensity to induce nausea. Continued

  13. Effect of NMDA NR2B antagonist on neuropathic pain in two spinal cord injury models.

    Science.gov (United States)

    Kim, Youngkyung; Cho, Hwi-young; Ahn, Young Ju; Kim, Junesun; Yoon, Young Wook

    2012-05-01

    N-Methyl-d-aspartate (NMDA) receptors are thought to play an important role in the processes of central sensitization and pathogenesis of neuropathic pain, particularly after spinal cord injury (SCI). NMDA antagonists effectively reduce neuropathic pain, but serious side effects prevent their use as therapeutic drugs. NMDA NR2B antagonists have been reported to effectively reduce inflammatory and neuropathic pain. In this study, we investigated the effects of NR2B antagonists on neuropathic pain and the expression of NR2B in the spinal cord in 2 SCI models. SCI was induced at T12 by a New York University impactor (contusion) or by sectioning of the lateral half of the spinal cord (hemisection). Ifenprodil (100, 200, 500, 1000nmol) and Ro25-6981 (20, 50, 100, 200nmol) were intrathecally injected and behavioral tests were conducted. Ifenprodil increased the paw withdrawal threshold in both models but also produced mild motor depression at higher doses. Ro25-6981 increased the mechanical nociceptive threshold in a dose-dependent manner without motor depression. NR2B expression was significantly increased on both sides at the spinal segments of L1-2 and L4-5 in the hemisection model but did not change in the contusion model. Increased expression of NR2B in the hemisection model was reduced by intrathecal ifenprodil. These results suggest that intrathecal NMDA NR2B antagonist increased the mechanical nociceptive threshold after SCI without motor depression. A selective subtype of NMDA receptor, such as NR2B, may be a more selective target for pain control because NMDA receptors play a crucial role in the development and maintenance of chronic pain. Copyright © 2012 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.

  14. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Mohammad eKhanfar

    2016-05-01

    Full Text Available With the very recent market approval of pitolisant (Wakix®, the interest in clinical applications of novel multifunctional histamine H3 receptor antagonists has clearly increased. Since histamine H3 receptor antagonists in clinical development have been tested for a variety of different indications, the combination of pharmacological properties in one molecule for improved pharmacological effects and reduced unwanted side-effects is rationally based on the increasing knowledge on the complex neurotransmitter regulations. The polypharmacological approaches on histamine H3 receptor antagonists on different G-protein coupled receptors, transporters, enzymes as well as on NO-signaling mechanism are described, supported with some lead structures.

  15. Possible site of action of CGRP antagonists in migraine

    DEFF Research Database (Denmark)

    Tfelt-Hansen, Peer; Olesen, Jes

    2011-01-01

    The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP antagoni......The calcitonin gene-related peptide (CGRP) receptor antagonists olcegepant and telcagepant are very potent drugs. Both are effective in migraine but in doses much higher than would be predicted from receptor binding and other in vitro results. This could perhaps suggest an effect of CGRP...... antagonists behind the blood-brain barrier (BBB), i.e. in the central nervous system (CNS)....

  16. Choking Prevention

    Science.gov (United States)

    ... Healthy Living Healthy Living Healthy Living Nutrition Fitness Sports Oral Health Emotional Wellness Growing Healthy Sleep Safety & Prevention Safety & Prevention Safety and Prevention Immunizations At Home ...

  17. Inhibition by Isoptin (a calcium antagonist) of the mitogenic stimulation of lymphocytes prior to the S-phase

    International Nuclear Information System (INIS)

    Blitstein-Willinger, E.; Diamantstein, T.

    1978-01-01

    Isoptin (α-isopropyl-α-(N-methyl-N-homoveratryl) -γ-amino-propyl-3,4-dimethoxyphenylacetonitril-hydrochloride) - a calcium antagonist - inhibited mitogenic stimulation of lymphocytes. Isoptin acted prior to the S-phase of the cell cycle but did not prevent the early events involved in triggering of cell mitosis. The drug seems to be a good tool for studying the relevance of the 'early events' assumed to be involved in lymphocyte stimulation. (author)

  18. Practical recommendations for calcium channel antagonist poisoning.

    Science.gov (United States)

    Rietjens, S J; de Lange, D W; Donker, D W; Meulenbelt, J

    2016-02-01

    Calcium channel antagonists (CCAs) are widely used for different cardiovascular disorders. At therapeutic doses, CCAs have a favourable side effect profile. However, in overdose, CCAs can cause serious complications, such as severe hypotension and bradycardia. Patients in whom a moderate to severe intoxication is anticipated should be observed in a monitored setting for at least 12 hours if an immediate-release formulation is ingested, and at least 24 hours when a sustained-release formulation (or amlodipine) is involved, even if the patient is asymptomatic. Initial treatment is aimed at gastrointestinal decontamination and general supportive care, i.e., fluid resuscitation and correction of metabolic acidosis and electrolyte disturbances. In moderate to severe CCA poisoning, a combined medical strategy might be indispensable, such as administration of vasopressors, intravenous calcium and hyperinsulinaemia/euglycaemia therapy. Especially hyperinsulinaemia/euglycaemia therapy is an important first-line treatment in CCA-overdosed patients in whom a large ingestion is suspected. High-dose insulin, in combination with glucose, seems to be most effective when used early in the intoxication phase, even when the patient shows hardly any haemodynamic instability. Intravenous lipid emulsion therapy should only be considered in patients with life-threatening cardiovascular toxicity, such as refractory shock, which is unresponsive to conventional therapies. When supportive and specific pharmacological measures fail to adequately reverse refractory conditions in CCA overdose, the use of extracorporeal life support should be considered. The efficacy of these pharmacological and non-pharmacological interventions generally advocated in CCA poisoning needs further in-depth mechanistic foundation, in order to improve individualised treatment of CCA-overdosed patients.

  19. Characterization and design of antagonistic shape memory alloy actuators

    International Nuclear Information System (INIS)

    Georges, T; Brailovski, V; Terriault, P

    2012-01-01

    Antagonistic shape memory actuators use opposing shape memory alloy (SMA) elements to create devices capable of producing differential motion paths and two-way mechanical work in a very efficient manner. There is no requirement for additional bias elements to ‘re-arm’ the actuators and allow repetitive actuation. The work generation potential of antagonistic shape memory actuators is determined by specific SMA element characteristics and their assembly conditions. In this study, the selected SMA wires are assembled in antagonistic configuration and characterized using a dedicated test bench to evaluate their stress–strain characteristics as a function of the number of cycles. Using these functional characteristics, a so-called ‘working envelope’ is built to assist in the design of such an actuator. Finally, the test bench is used to simulate a real application of an antagonistic actuator (case study). (paper)

  20. A SELECTIVE ANTAGONIST OF MINERALOCORTICOID RECEPTOR EPLERENONE IN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-01-01

    Full Text Available The role of aldosterone in pathophysiological processes is considered. The effects of the selective antagonist of mineralocorticoid receptor eplerenone are analyzed. The advantages of eplerenone compared with spironolactone are discussed.

  1. Development of KGF Antagonist as a Breast Cancer Therapeutic

    National Research Council Canada - National Science Library

    Sugimoto, Yasuro

    2003-01-01

    .... We were able to show some potential intracellular KGFR target small molecules whereas extracellular target synthetic peptide antagonist was not able to do during this period We also added a new...

  2. Recent Development of Non-Peptide GnRH Antagonists

    Directory of Open Access Journals (Sweden)

    Feng-Ling Tukun

    2017-12-01

    Full Text Available The decapeptide gonadotropin-releasing hormone, also referred to as luteinizing hormone-releasing hormone with the sequence (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2 plays an important role in regulating the reproductive system. It stimulates differential release of the gonadotropins FSH and LH from pituitary tissue. To date, treatment of hormone-dependent diseases targeting the GnRH receptor, including peptide GnRH agonist and antagonists are now available on the market. The inherited issues associate with peptide agonists and antagonists have however, led to significant interest in developing orally active, small molecule, non-peptide antagonists. In this review, we will summarize all developed small molecule GnRH antagonists along with the most recent clinical data and therapeutic applications.

  3. Complications of TNF-α antagonists and iron homeostasis

    Science.gov (United States)

    TNF-α is a central regulator of inflammation and its blockade downregulates other proinflammatory cytokines, chemokines, and growth factors. Subsequently, TNF-α antagonists are currently used in treatment regimens directed toward several inflammatory diseases. Despite a beneficia...

  4. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    AWARD NUMBER: W81XWH-15 1-0252 TITLE: Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists PRINCIPAL INVESTIGATOR...14 Jul 2016 4. TITLE AND SUBTITLE Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists 5a. CONTRACT NUMBER 5b. GRANT...Center for Substance Abuse Research Lewis Katz School of Medicine at Temple University 3500 N, Broad Street Philadelphia, PA 19140 AND ADDRESS(ES) 8

  5. Interleukin-2 receptor antagonists as induction therapy after heart transplantation

    DEFF Research Database (Denmark)

    Møller, Christian H; Gustafsson, Finn; Gluud, Christian

    2008-01-01

    About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras.......About half of the transplantation centers use induction therapy after heart transplantation. Interleukin-2 receptor antagonists (IL-2Ras) are used increasingly for induction therapy. We conducted a systematic review of randomized trials assessing IL-2Ras....

  6. Platelet-activating factor (PAF)-antagonists of natural origin.

    Science.gov (United States)

    Singh, Preeti; Singh, Ishwari Narayan; Mondal, Sambhu Charan; Singh, Lubhan; Garg, Vipin Kumar

    2013-01-01

    Presently herbal medicines are being used by about 80% of the world population for primary health care as they stood the test of time for their safety, efficacy, cultural acceptability and lesser side effects. The discovery of platelet activating factor antagonists (PAF antagonists) during these decades are going on with different framework, but the researchers led their efficiency in studying in vitro test models. Since it is assumed that PAF play a central role in etiology of many diseases in humans such as asthma, neuronal damage, migraine, cardiac diseases, inflammatory, headache etc. Present days instinctively occurring PAF antagonist exists as a specific grade of therapeutic agents for the humans against these and different diseases either laid hold of immunological or non-immunological types. Ginkgolide, cedrol and many other natural PAF antagonists such as andrographolide, α-bulnesene, cinchonine, piperine, kadsurenone, different Piper species' natural products and marine origin plants extracts or even crude drugs having PAF antagonist properties are being used currently against different inflammatory pathologies. This review is an attempt to summarize the data on PAF and action of natural PAF antagonists on it, which were evaluated by in vivo and in vitro assays. Copyright © 2012 Elsevier B.V. All rights reserved.

  7. Effects of the calcium channel antagonist mibefradil on haemodynamic and morphological parameters in myocardial infarction-induced cardiac failure in rats

    NARCIS (Netherlands)

    Sandmann, S.; Spitznagel, H.; Chung, O.; Xia, Q. G.; Illner, S.; Jänichen, G.; Rossius, B.; Daemen, M. J.; Unger, T.

    1998-01-01

    Calcium channel antagonists (CCA) have been proposed for the prevention of cardiac events after myocardial infarction (MI). Mibefradil is a CCA featuring a selective blockade of T-type Ca2(+)-channels. The aim of the study was to characterize the effects of mibefradil on haemodynamic and

  8. The pharmacological effect of BGC20-1531, a novel prostanoid EP4 receptor antagonist, in the prostaglandin E2 human model of headache

    DEFF Research Database (Denmark)

    Antonova, Maria; Wienecke, Troels; Maubach, Karen

    2011-01-01

    Using a human Prostaglandin E(2) (PGE(2)) model of headache, we examined whether a novel potent and selective EP(4) receptor antagonist, BGC20-1531, may prevent headache and dilatation of the middle cerebral (MCA) and superficial temporal artery (STA). In a three-way cross-over trial, eight healt...

  9. alpha2-Adrenoceptor antagonists reverse the 5-HT2 receptor antagonist suppression of head-twitch behavior in mice.

    Science.gov (United States)

    Matsumoto, K; Mizowaki, M; Thongpraditchote, S; Murakami, Y; Watanabe, H

    1997-03-01

    The alpha2-adrenoceptor agonist clonidine, as well as 5-HT2 receptor antagonists, reportedly suppress 5-HT2 receptor-mediated head-twitch behavior. We investigated the effect of alpha2-adrenoceptor antagonists on the suppressive action of 5-HT2 receptor antagonists in mice pretreated with the noradrenaline toxin 6-hydroxydopamine (6-OHDA) or the 5-HT synthesis inhibitor p-chlorophenylalanine (p-CPA). In normal mice, idazoxan (0.08-0.2 mg/kg, IP) or yohimbine (0.2-2.0 mg/kg, IP), both alpha2-adrenoceptor antagonists, had no effect on the head-twitch response caused by 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT; 16 mg/kg, IP), but idazoxan significantly enhanced the response at 0.5 mg/kg. On the other hand, these alpha2-adrenoceptor antagonists, at doses that had no effect on the basal number of head-twitches (idazoxan 0.2 mg/kg and yohimbine 0.5 mg/kg), significantly attenuated not only the suppressive effect of clonidine (0.01 mg/kg, IP) on head-twitch response but also that of the 5-HT2 receptor antagonist ritanserin (0.03 mg/kg, IP). Moreover, idazoxan (0.2 mg/kg) also significantly reversed the inhibition by 0.01 mg/kg (IP) ketanserin, a selective 5-HT2 receptor antagonist. Pretreatment with 6-OHDA plus nomifensine but not with p-CPA significantly attenuated the effect of idazoxan (0.2-0.5 mg/kg) on the ritanserin inhibition of the head-twitch response. Prazosin, an alpha1-adrenoceptor antagonist, dose-dependently suppressed the response, and the effect of prazosin (1.25 mg/kg) was significantly attenuated by 0.5 mg/kg idazoxan. These results indicate that endogenous noradrenaline is involved in the apparent antagonistic interaction between selective alpha2-adrenoceptor antagonists and 5-HT2 receptor antagonists in the head-twitch response, and suggest that noradrenaline stimulation of alpha1-adrenoceptors may be involved in this apparent antagonism.

  10. Dual trigger of triptorelin and HCG optimizes clinical outcome for high ovarian responder in GnRH-antagonist protocols.

    Science.gov (United States)

    Li, Saijiao; Zhou, Danni; Yin, Tailang; Xu, Wangming; Xie, Qingzhen; Cheng, Dan; Yang, Jing

    2018-01-12

    In this paper, a retrospective cohort study was conducted to the high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. The purpose of the study is to investigate whether dual triggering of final oocyte maturation with a combination of gonadotropin-releasing hormone (GnRH) agonist and human chorionic gonadotropin (HCG) can improve the clinical outcome compared with traditional dose (10000IU) HCG trigger and low-dose (8000IU) HCG trigger for high ovarian responders in GnRH-antagonist in vitro fertilization/intracytoplasmic sperm injection (IVF-ICSI) cycles. Our study included 226 couples with high ovarian responders in GnRH-antagonist protocols of IVF/ICSI cycles. Standard dosage of HCG trigger (10000 IU of recombinant HCG) versus dual trigger (0.2 mg of triptorelin and 2000 IU of recombinant HCG) and low-dose HCG trigger (8000IU of recombinant HCG) were used for final oocyte maturation. Our main outcome measures were high quality embryo rate, the number of usable embryos, the risk of OHSS, duration of hospitalization and incidence rate of complications. Our evidence demonstrated that dual trigger is capable of preventing severe OHSS while still maintaining excellent high quality embryo rate in in high ovarian responders of GnRH-antagonist protocols.

  11. GnRH antagonist, cetrorelix, for pituitary suppression in modern, patient-friendly assisted reproductive technology.

    Science.gov (United States)

    Tur-Kaspa, Ilan; Ezcurra, Diego

    2009-10-01

    Gonadotropin-releasing hormone (GnRH) analogues are used routinely to prevent a premature luteinizing hormone (LH) surge in women undergoing assisted reproductive technology (ART) treatments. In contrast to GnRH agonists, antagonists produce rapid and reversible suppression of LH with no initial flare effect. To review the role of cetrorelix, the first GnRH antagonist approved for the prevention of premature LH surges during controlled ovarian stimulation in modern ART. A review of published literature on cetrorelix. Both multiple- and single-dose cetrorelix protocols were shown to be at least as effective as long GnRH agonist regimens for pituitary suppression in Phase II/III clinical trials. Furthermore, cetrorelix co-treatment resulted in similar live birth rates but a shorter duration of gonadotropin stimulation, a lower total gonadotropin dose requirement and lower incidence of ovarian hyperstimulation syndrome compared with long agonist regimens. A single-dose cetrorelix protocol further decreased the number of injections required. Preliminary studies have also produced promising data on the use of cetrorelix in modified ART protocols, such as frozen embryo transfer and donor oocyte recipient cycles. Cetrorelix offers a potential therapeutic alternative to GnRH agonists during controlled ovarian stimulation and has become an integral part of modern, patient-friendly reproductive medicine.

  12. Nonvitamin K antagonist oral anticoagulants (NOACs: the tide continues to come in

    Directory of Open Access Journals (Sweden)

    Blann A

    2015-08-01

    Full Text Available Andrew Blann University of Birmingham Centre for Cardiovascular Sciences, City Hospital, Birmingham, UKThrombosis is the major common endpoint in most human diseases. In the coronary circulation, occlusive thrombi and/or the rupture of atherosclerotic plaque causes myocardial infarction, and in the cerebral circulation thrombosis, causes ischemic stroke. In the venous circulation, venous thromboembolism (VTE, manifesting clinically as pulmonary embolus and deep vein thrombosis (DVT, is a frequent complication among inpatients, and contributes to longer hospital stays with increased morbidity and mortality. Until perhaps 5 years ago, heparinoids (unfractionated heparin, low molecular weight heparin [LMWH], and fondaparinux and vitamin K antagonists (VKAs: warfarin, acenocoumarol, phenocoumarol were the only options for the prevention of thrombotic stroke in atrial fibrillation, and of VTE in general. Although effective, these traditional drugs have several practical, management, and clinical disadvantages, a fact that our colleagues in industry have not been slow to recognize and address by developing improved drugs, now collectively known as nonvitamin K antagonist oral anti coagulants (NOACs. These agents are steadily replacing the heparinoids and VKAs in both inpatient and outpatient prevention and treatment of thrombosis.

  13. The Puller-Follower Control of Compliant and Noncompliant Antagonistic Tendon Drives in Robotic Systems

    Directory of Open Access Journals (Sweden)

    Veljko Potkonjak

    2011-11-01

    Full Text Available This paper proposes a new control strategy for noncompliant and compliant antagonistic tendon drives. It is applied to a succession of increasingly complex single‐joint systems, starting with a linear and noncompliant system and ending with a revolute, nonlinearly tendon coupled and compliant system. The last configuration mimics the typical human joint structure, used as a model for certain joints of the anthropomimetic robot ECCEROBOT. The control strategy is based on a biologically inspired puller‐ follower concept, which distinguishes the roles of the agonist and antagonist motors. One actuator, the puller, is considered as being primarily responsible for the motion, while the follower prevents its tendon from becoming slack by maintaining its tendon force at some non‐zero level. Certain movements require switching actuator roles; adaptive co‐contraction is used to prevent tendons slackening, while maintaining energetic efficiency. The single‐joint control strategy is then evaluated in a multi‐ joint system. Dealing with the gravitational and dynamic effects arising from the coupling in a multi‐joint system, a robust control design has to be applied with on‐line gravity compensation. Finally, an experiment corresponding to object grasping is presented to show the controller

  14. The Puller-Follower Control of Compliant and Noncompliant Antagonistic Tendon Drives in Robotic Systems

    Directory of Open Access Journals (Sweden)

    Veljko Potkonjak

    2011-11-01

    Full Text Available This paper proposes a new control strategy for noncompliant and compliant antagonistic tendon drives. It is applied to a succession of increasingly complex single-joint systems, starting with a linear and noncompliant system and ending with a revolute, nonlinearly tendon coupled and compliant system. The last configuration mimics the typical human joint structure, used as a model for certain joints of the anthropomimetic robot ECCEROBOT. The control strategy is based on a biologically inspired puller-follower concept, which distinguishes the roles of the agonist and antagonist motors. One actuator, the puller, is considered as being primarily responsible for the motion, while the follower prevents its tendon from becoming slack by maintaining its tendon force at some non-zero level. Certain movements require switching actuator roles; adaptive co-contraction is used to prevent tendons slackening, while maintaining energetic efficiency. The single-joint control strategy is then evaluated in a multi-joint system. Dealing with the gravitational and dynamic effects arising from the coupling in a multi-joint system, a robust control design has to be applied with on-line gravity compensation. Finally, an experiment corresponding to object grasping is presented to show the controller's robustness to external disturbances.

  15. Vitamin K antagonist use and mortality in dialysis patients.

    Science.gov (United States)

    Voskamp, Pauline W M; Rookmaaker, Maarten B; Verhaar, Marianne C; Dekker, Friedo W; Ocak, Gurbey

    2018-01-01

    The risk-benefit ratio of vitamin K antagonists for different CHA2DS2-VASc scores in patients with end-stage renal disease treated with dialysis is unknown. The aim of this study was to investigate the association between vitamin K antagonist use and mortality for different CHA2DS2-VASc scores in a cohort of end-stage renal disease patients receiving dialysis treatment. We prospectively followed 1718 incident dialysis patients. Hazard ratios were calculated for all-cause and cause-specific (stroke, bleeding, cardiovascular and other) mortality associated with vitamin K antagonist use. Vitamin K antagonist use as compared with no vitamin K antagonist use was associated with a 1.2-fold [95% confidence interval (95% CI) 1.0-1.5] increased all-cause mortality risk, a 1.5-fold (95% CI 0.6-4.0) increased stroke mortality risk, a 1.3-fold (95% CI 0.4-4.2) increased bleeding mortality risk, a 1.2-fold (95% CI 0.9-1.8) increased cardiovascular mortality risk and a 1.2-fold (95% CI 0.8-1.6) increased other mortality risk after adjustment. Within patients with a CHA2DS2-VASc score ≤1, vitamin K antagonist use was associated with a 2.8-fold (95% CI 1.0-7.8) increased all-cause mortality risk as compared with no vitamin K antagonist use, while vitamin K antagonist use within patients with a CHA2DS2-VASc score ≥2 was not associated with an increased mortality risk after adjustment. Vitamin K antagonist use was not associated with a protective effect on mortality in the different CHA2DS2-VASc scores in dialysis patients. The lack of knowledge on the indication for vitamin K antagonist use could lead to confounding by indication. © The Author 2017. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.

  16. Clinical study to evaluate the wear of natural enamel antagonist to zirconia and metal ceramic crowns.

    Science.gov (United States)

    Mundhe, Kailas; Jain, Veena; Pruthi, Gunjan; Shah, Naseem

    2015-09-01

    Tooth wear is a complex process, which, if not prevented, may adversely affect the integrity of the stomatognathic system. Different restorative dental materials may affect the amount of wear on natural enamel antagonists. The purpose of this in vivo study was to evaluate and compare the wear of enamel opposing natural enamel, zirconia, and metal ceramic crowns after 1 year. Ten participants between 18 and 35 years of age requiring 2 complete crowns, 1 on either side of maxillary or mandibular molar region, and having healthy natural teeth in the opposing arch were selected. For each participant, 1 monolithic polished zirconia crown and 1 glazed metal ceramic crown were fabricated and cemented. To evaluate the wear of the antagonistic natural enamel (premolar and molar), polyvinyl siloxane impressions were made immediately (baseline) and at 1 year after cementation. The wear of natural enamel against natural enamel was evaluated as the control. The resulting casts were scanned (using a 3D white light scanner), and 3D software was used to calculate the maximum amount of linear wear. One-way repeated measures ANOVA was conducted to analyze data. Mean ±SD occlusal wear of the antagonistic enamel 1 year after the cementation of metal ceramic crowns was 69.20 ±4.10 μm for premolar teeth and 179.70 ±8.09 μm for molar teeth, whereas for zirconia crowns, it was 42.10 ±4.30 μm for premolar teeth and 127.00 ±5.03 μm for molar teeth. Occlusal wear of natural enamel opposing natural enamel was 17.30 ±1.88 μm in the premolar region and 35.10 ±2.60 μm in the molar region. The Bonferroni post hoc test revealed that the occlusal wear of antagonistic enamel 1 year after the cementation of a metal ceramic crown was significantly higher (Pzirconia crown or natural enamel. Zirconia crowns led to less wear of antagonist enamel than metal ceramic crowns, but more than natural enamel. Copyright © 2015 Editorial Council for the Journal of Prosthetic Dentistry. Published by

  17. P2X1 Receptor Antagonists Inhibit HIV-1 Fusion by Blocking Virus-Coreceptor Interactions

    Science.gov (United States)

    Giroud, Charline; Marin, Mariana; Hammonds, Jason; Spearman, Paul

    2015-01-01

    ABSTRACT HIV-1 Env glycoprotein-mediated fusion is initiated upon sequential binding of Env to CD4 and the coreceptor CXCR4 or CCR5. Whereas these interactions are thought to be necessary and sufficient to promote HIV-1 fusion, other host factors can modulate this process. Previous studies reported potent inhibition of HIV-1 fusion by selective P2X1 receptor antagonists, including NF279, and suggested that these receptors play a role in HIV-1 entry. Here we investigated the mechanism of antiviral activity of NF279 and found that this compound does not inhibit HIV-1 fusion by preventing the activation of P2X1 channels but effectively blocks the binding of the virus to CXCR4 or CCR5. The notion of an off-target effect of NF279 on HIV-1 fusion is supported by the lack of detectable expression of P2X1 receptors in cells used in fusion experiments and by the fact that the addition of ATP or the enzymatic depletion of ATP in culture medium does not modulate viral fusion. Importantly, NF279 fails to inhibit HIV-1 fusion with cell lines and primary macrophages when added at an intermediate stage downstream of Env-CD4-coreceptor engagement. Conversely, in the presence of NF279, HIV-1 fusion is arrested downstream of CD4 binding but prior to coreceptor engagement. NF279 also antagonizes the signaling function of CCR5, CXCR4, and another chemokine receptor, as evidenced by the suppression of calcium responses elicited by specific ligands and by recombinant gp120. Collectively, our results demonstrate that NF279 is a dual HIV-1 coreceptor inhibitor that interferes with the functional engagement of CCR5 and CXCR4 by Env. IMPORTANCE Inhibition of P2X receptor activity suppresses HIV-1 fusion and replication, suggesting that P2X signaling is involved in HIV-1 entry. However, mechanistic experiments conducted in this study imply that P2X1 receptor is not expressed in target cells or involved in viral fusion. Instead, we found that inhibition of HIV-1 fusion by a specific P2X1

  18. Cannabinoid type 1 receptor antagonists for smoking cessation.

    Science.gov (United States)

    Cahill, Kate; Ussher, Michael H

    2011-03-16

    Selective type 1 cannabinoid (CB1) receptor antagonists may assist with smoking cessation by restoring the balance of the endocannabinoid system, which can be disrupted by prolonged use of nicotine. They also seeks to address many smokers' reluctance to persist with a quit attempt because of concerns about weight gain. To determine whether selective CB1 receptor antagonists (currently rimonabant and taranabant) increase the numbers of people stopping smoking To assess their effects on weight change in successful quitters and in those who try to quit but fail. We searched the Cochrane Tobacco Addiction Review Group specialized register for trials, using the terms ('rimonabant' or 'taranabant') and 'smoking' in the title or abstract, or as keywords. We also searched MEDLINE, EMBASE, CINAHL and PsycINFO, using major MESH terms. We acquired electronic or paper copies of posters of preliminary trial results presented at the American Thoracic Society Meeting in 2005, and at the Society for Research on Nicotine and Tobacco European Meeting 2006. We also attempted to contact the authors of ongoing studies of rimonabant, and Sanofi Aventis (manufacturers of rimonabant). The most recent search was in January 2011. Types of studies Randomized controlled trialsTypes of participants Adult smokersTypes of interventions Selective CB1 receptor antagonists, such as rimonabant and taranabant. Types of outcome measures The primary outcome is smoking status at a minimum of six months after the start of treatment. We preferred sustained cessation rates to point prevalence, and biochemically verified cessation to self-reported quitting. We regarded smokers who drop out or are lost to follow up as continuing smokers. We have noted any adverse effects of treatment.A secondary outcome is weight change associated with the cessation attempt. Two authors checked the abstracts for relevance, and attempted to acquire full trial reports. One author extracted the data, and a second author checked

  19. Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

    Directory of Open Access Journals (Sweden)

    Emmanuel Broussolle

    2015-09-01

    Full Text Available Background: Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste.Results: In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin.Discussion: Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia.

  20. Rape prevention

    Science.gov (United States)

    Date rape - prevention; Sexual assault - prevention ... Centers for Disease Control and Prevention website. Sexual assault and abuse and STDs. In: 2015 sexually transmitted diseases treatment guidelines 2015. www.cdc.gov/std/tg2015/sexual- ...

  1. Dengue Prevention

    Science.gov (United States)

    ... Address What's this? Submit What's this? Submit Button Prevention Recommend on Facebook Tweet Share Compartir This photograph ... medications to treat a dengue infection. This makes prevention the most important step, and prevention means avoiding ...

  2. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    of proliferation and angiogenesis. Specific histamine receptors have been identified on the surface of bone marrow cells, immune competent cells, endothelial cells, fibroblasts, and also on malignant cells. This has prompted research in regulation by specific histamine receptor agonists and antagonists. Results...... from such studies are currently accumulating and suggest that the histamine-2 receptor antagonists have potential beneficial effects in the treatment of certain malignant, autoimmune and skin diseases, either alone or in combination with other drugs. The beneficial effect of histamine-2 receptor...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  3. GnRH antagonist versus long agonist protocols in IVF

    DEFF Research Database (Denmark)

    Lambalk, C B; Banga, F R; Huirne, J A

    2017-01-01

    was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH......BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... METHODS: The Cochrane Menstrual Disorders and Subfertility Review Group specialized register of controlled trials and Pubmed and Embase databases were searched from inception until June 2016. Eligible trials were those that compared GnRH antagonist protocols and standard long GnRH agonist protocols...

  4. ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

    Directory of Open Access Journals (Sweden)

    ANTARJO DIKIN

    2006-01-01

    Full Text Available Schizophyllum commune Fr., is one of the important fungi, causes brown germ and seed rot of oil palm. Biodiversity of antagonistic bacteria from oil palm plantations in Peninsular Malaysia is expected to support in development of biopesticide. Isolation with liquid assay and screening antagonistic bacteria using dual culture assay were carried out in the bioexploration. A total of 265 bacterial isolates from plant parts of oil palm screened 52 antagonistic bacterial isolates against 5. commune. Bacterial isolates were identified by using Biolog* Identification System i.e. Bacillus macroccanus, B. thermoglucosidasius, Burkholderia cepacia, B. gladioli, B. multivorans, B pyrrocinia, B. spinosa, Corynebacterium agropyri, C. misitidis, Enterobacter aerogenes, Microbacterium testaceum, Pseudomonas aeruginosa, P. citronellolis, Rhodococcus rhodochrous, Serratia ficaria, Serratia sp., S. marcescens, Staphylococcus sciuri, Sternotrophomonas maltophilia.

  5. Histamine H4 receptor antagonists: the new antihistamines?

    Science.gov (United States)

    Fung-Leung, Wai-Ping; Thurmond, Robin L; Ling, Ping; Karlsson, Lars

    2004-11-01

    Antihistamines (histamine H1 receptor antagonists) are a mainstay treatment for atopic allergy, yet they are only partially effective in relieving the symptoms of the disease. They also have very limited value for the treatment of asthma, despite the well-characterized bronchoconstrictory effects of histamine. The recent discovery of a fourth histamine receptor (H4), and the realization that it is exclusively expressed on hematopoietic cell types that are most implicated in the development and symptomatology of allergy and asthma, suggests that pharmacological targeting of the H4 receptor, either alone or in combination with H1 receptor antagonists, may prove useful for treating both allergy and asthma. Here we review the known biology associated with the H4 receptor, as well the effects of a highly selective H1 receptor antagonist.

  6. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling.

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E; Zarnke, Allison L; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B; Nickisch, Klaus J; Long, Henry W; Becker, Lev; Brown, Myles; Greene, Geoffrey L

    2018-01-12

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  7. Progesterone receptor isoforms, agonists and antagonists differentially reprogram estrogen signaling

    Science.gov (United States)

    Singhal, Hari; Greene, Marianne E.; Zarnke, Allison L.; Laine, Muriel; Al Abosy, Rose; Chang, Ya-Fang; Dembo, Anna G.; Schoenfelt, Kelly; Vadhi, Raga; Qiu, Xintao; Rao, Prakash; Santhamma, Bindu; Nair, Hareesh B.; Nickisch, Klaus J.; Long, Henry W.; Becker, Lev; Brown, Myles; Greene, Geoffrey L.

    2018-01-01

    Major roadblocks to developing effective progesterone receptor (PR)-targeted therapies in breast cancer include the lack of highly-specific PR modulators, a poor understanding of the pro- or anti-tumorigenic networks for PR isoforms and ligands, and an incomplete understanding of the cross talk between PR and estrogen receptor (ER) signaling. Through genomic analyses of xenografts treated with various clinically-relevant ER and PR-targeting drugs, we describe how the activation or inhibition of PR differentially reprograms estrogen signaling, resulting in the segregation of transcriptomes into separate PR agonist and antagonist-mediated groups. These findings address an ongoing controversy regarding the clinical utility of PR agonists and antagonists, alone or in combination with tamoxifen, for breast cancer management. Additionally, the two PR isoforms PRA and PRB, bind distinct but overlapping genomic sites and interact with different sets of co-regulators to differentially modulate estrogen signaling to be either pro- or anti-tumorigenic. Of the two isoforms, PRA inhibited gene expression and ER chromatin binding significantly more than PRB. Differential gene expression was observed in PRA and PRB-rich patient tumors and PRA-rich gene signatures had poorer survival outcomes. In support of antiprogestin responsiveness of PRA-rich tumors, gene signatures associated with PR antagonists, but not PR agonists, predicted better survival outcomes. The better patient survival associated with PR antagonists versus PR agonists treatments was further reflected in the higher in vivo anti-tumor activity of therapies that combine tamoxifen with PR antagonists and modulators. This study suggests that distinguishing common effects observed due to concomitant interaction of another receptor with its ligand (agonist or antagonist), from unique isoform and ligand-specific effects will inform the development of biomarkers for patient selection and translation of PR

  8. Plague Prevention

    Science.gov (United States)

    ... Healthcare Professionals Clinicians Public Health Officials Veterinarians Prevention History of Plague Resources FAQ Prevention Recommend on Facebook Tweet Share Compartir Reduce rodent habitat around your ...

  9. Regulation of Carotenoid Biosynthesis by Shade Relies on Specific Subsets of Antagonistic Transcription Factors and Cofactors.

    Science.gov (United States)

    Bou-Torrent, Jordi; Toledo-Ortiz, Gabriela; Ortiz-Alcaide, Miriam; Cifuentes-Esquivel, Nicolas; Halliday, Karen J; Martinez-García, Jaime F; Rodriguez-Concepcion, Manuel

    2015-11-01

    Carotenoids are photosynthetic pigments essential for the protection against excess light. During deetiolation, their production is regulated by a dynamic repression-activation module formed by PHYTOCHROME-INTERACTING FACTOR1 (PIF1) and LONG HYPOCOTYL5 (HY5). These transcription factors directly and oppositely control the expression of the gene encoding PHYTOENE SYNTHASE (PSY), the first and main rate-determining enzyme of the carotenoid pathway. Antagonistic modules also regulate the responses of deetiolated plants to vegetation proximity and shade (i.e. to the perception of far-red light-enriched light filtered through or reflected from neighboring plants). These responses, aimed to adapt to eventual shading from plant competitors, include a reduced accumulation of carotenoids. Here, we show that PIF1 and related photolabile PIFs (but not photostable PIF7) promote the shade-triggered decrease in carotenoid accumulation. While HY5 does not appear to be required for this process, other known PIF antagonists were found to modulate the expression of the Arabidopsis (Arabidopsis thaliana) PSY gene and the biosynthesis of carotenoids early after exposure to shade. In particular, PHYTOCHROME-RAPIDLY REGULATED1, a transcriptional cofactor that prevents the binding of true transcription factors to their target promoters, was found to interact with PIF1 and hence directly induce PSY expression. By contrast, a change in the levels of the transcriptional cofactor LONG HYPOCOTYL IN FAR RED1, which also binds to PIF1 and other PIFs to regulate shade-related elongation responses, did not impact PSY expression or carotenoid accumulation. Our data suggest that the fine-regulation of carotenoid biosynthesis in response to shade relies on specific modules of antagonistic transcriptional factors and cofactors. © 2015 American Society of Plant Biologists. All Rights Reserved.

  10. NMDA antagonists exert distinct effects in experimental organophosphate or carbamate poisoning in mice

    International Nuclear Information System (INIS)

    Dekundy, Andrzej; Kaminski, Rafal M.; Zielinska, Elzbieta; Turski, Waldemar A.

    2007-01-01

    Organophosphate (OP) and carbamate acetylcholinesterase (AChE) inhibitors produce seizures and lethality in mammals. Anticonvulsant and neuroprotective properties of N-methyl-D-aspartate (NMDA) antagonists encourage the investigation of their effects in AChE inhibitor-induced poisonings. In the present study, the effects of dizocilpine (MK-801, 1 mg/kg) or 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP, 10 mg/kg), alone or combined with muscarinic antagonist atropine (1.8 mg/kg), on convulsant and lethal properties of an OP pesticide dichlorvos or a carbamate drug physostigmine, were studied in mice. Both dichlorvos and physostigmine induced dose-dependent seizure activity and lethality. Atropine did not prevent the occurrence of convulsions but decreased the lethal effects of both dichlorvos and physostigmine. MK-801 or CPP blocked or attenuated, respectively, dichlorvos-induced convulsions. Contrariwise, NMDA antagonists had no effect in physostigmine-induced seizures or lethality produced by dichlorvos or physostigmine. Concurrent pretreatment with atropine and either MK-801 or CPP blocked or alleviated seizures produced by dichlorvos, but not by physostigmine. Both MK-801 and CPP co-administered with atropine enhanced its antilethal effects in both dichlorvos and physostigmine poisoning. In both saline- and AChE inhibitor-treated mice, no interaction of the investigated antidotes with brain cholinesterase was found. The data indicate that both muscarinic ACh and NMDA receptor-mediated mechanisms contribute to the acute toxicity of AChE inhibitors, and NMDA receptors seem critical to OP-induced seizures

  11. Displacement of cortisol from human heart by acute administration of a mineralocorticoid receptor antagonist.

    Science.gov (United States)

    Iqbal, Javaid; Andrew, Ruth; Cruden, Nicholas L; Kenyon, Christopher J; Hughes, Katherine A; Newby, David E; Hadoke, Patrick W F; Walker, Brian R

    2014-03-01

    Mineralocorticoid receptor (MR) antagonists have beneficial effects in patients with heart failure and myocardial infarction, often attributed to blocking aldosterone action in the myocardium. However, binding of aldosterone to MR requires local activity of the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which inactivates cortisol to cortisone and thereby prevents receptor occupancy by cortisol. In vivo activity of 11β-HSD2 and potential occupancy of MR by cortisol in human heart have not been quantified. This study aimed to measure in vivo activity of 11β-HSD2 and to establish whether cortisol binds MR in human heart. Nine patients without heart failure undergoing diagnostic coronary angiography were infused to steady state with the stable isotope tracers 9,11,12,12-[(2)H]4-cortisol and 1,2-[(2)H]2-cortisone to quantify cortisol and cortisone production. Samples were obtained from the femoral artery and coronary sinus before and for 40 minutes after bolus iv administration of an MR antagonist, potassium canrenoate. Coronary sinus blood flow was measured by venography and Doppler flow wire. There was no detectable production of cortisol or cortisone across the myocardium. After potassium canrenoate administration, plasma aldosterone concentrations increased substantially but aldosterone was not detectably released from the myocardium. In contrast, plasma cortisol concentrations did not change in the systemic circulation but tissue-bound cortisol was released transiently from the myocardium after potassium canrenoate administration. Human cardiac 11β-HSD2 activity appears too low to inactivate cortisol to cortisone. Cortisol is displaced acutely from the myocardium by MR antagonists and may contribute to adverse MR activation in human heart.

  12. Antagonistic Donor Density Effect Conserved in Multiple Enterococcal Conjugative Plasmids

    Science.gov (United States)

    Bandyopadhyay, Arpan; O'Brien, Sofie; Frank, Kristi L.; Dunny, Gary M.

    2016-01-01

    ABSTRACT Enterococcus faecalis, a common causative agent of hospital-acquired infections, is resistant to many known antibiotics. Its ability to acquire and transfer resistance genes and virulence determinants through conjugative plasmids poses a serious concern for public health. In some cases, induction of transfer of E. faecalis plasmids results from peptide pheromones produced by plasmid-free recipient cells, which are sensed by the plasmid-bearing donor cells. These plasmids generally encode an inhibitory peptide that competes with the pheromone and suppresses self-induction of donors. We recently demonstrated that the inhibitor peptide encoded on plasmid pCF10 is part of a unique quorum-sensing system in which it functions as a “self-sensing signal,” reducing the response to the pheromone in a density-dependent fashion. Based on the similarities between regulatory features controlling conjugation in pAD1 and pAM373 and those controlling conjugation in pCF10, we hypothesized that these plasmids are likely to exhibit similar quorum-sensing behaviors. Experimental findings indicate that for both pAD1 and pAM373, high donor densities indeed resulted in decreased induction of the conjugation operon and reduced conjugation frequencies. This effect was restored by the addition of exogenous inhibitor, confirming that the inhibitor serves as an indicator for donor density. Donor density also affects cross-species conjugative plasmid transfer. Based on our experimental results, we propose models for induction and shutdown of the conjugation operon in pAD1 and pAM373. IMPORTANCE Enterococcus faecalis is a leading cause of hospital-acquired infections. Its ability to transfer antibiotic resistance and virulence determinants by sharing its genetic material with other bacteria through direct cell-cell contact via conjugation poses a serious threat. Two antagonistic signaling peptides control the transfer of plasmids pAD1 and pAM373: a peptide pheromone produced by

  13. Discovery of Tertiary Sulfonamides as Potent Liver X Receptor Antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Zuercher, William J.; Buckholz†, Richard G.; Campobasso, Nino; Collins, Jon L.; Galardi, Cristin M.; Gampe, Robert T.; Hyatt, Stephen M.; Merrihew, Susan L.; Moore, John T.; Oplinger, Jeffrey A.; Reid, Paul R.; Spearing, Paul K.; Stanley, Thomas B.; Stewart, Eugene L.; Willson, Timothy M. (GSKNC)

    2010-08-12

    Tertiary sulfonamides were identified in a HTS as dual liver X receptor (LXR, NR1H2, and NR1H3) ligands, and the binding affinity of the series was increased through iterative analogue synthesis. A ligand-bound cocrystal structure was determined which elucidated key interactions for high binding affinity. Further characterization of the tertiary sulfonamide series led to the identification of high affinity LXR antagonists. GSK2033 (17) is the first potent cell-active LXR antagonist described to date. 17 may be a useful chemical probe to explore the cell biology of this orphan nuclear receptor.

  14. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive...

  15. Effective management of venous thromboembolism in the community: non-vitamin K antagonist oral anticoagulants

    Directory of Open Access Journals (Sweden)

    Patel R

    2016-05-01

    Full Text Available Raj Patel Department of Haematological Medicine, King's Thrombosis Centre, King's College Hospital, London, UK Abstract: Anticoagulation therapy is essential for the effective treatment and secondary prevention of venous thromboembolism (VTE. For many years, anticoagulation for acute VTE was limited to the use of initial parenteral heparin, overlapping with and followed by a vitamin K antagonist. Although highly effective, this regimen has several limitations and is particularly challenging when given in an ambulatory setting. Current treatment pathways for most patients with deep-vein thrombosis typically involve initial hospital or community-based ambulatory care with subsequent follow-up in a secondary care setting. With the introduction of non-vitamin K antagonist oral anticoagulants (NOACs into routine clinical practice, it is now possible for the initial acute management of patients with deep-vein thrombosis to be undertaken by primary care. As hospital admissions associated with VTE become shorter, primary care will play an increasingly important role in the long-term management of these patients. Although the NOACs can potentially simplify patient management and improve clinical outcomes, primary care physicians may be less familiar with these new treatments compared with traditional therapy. To assist primary care physicians in further understanding the role of the NOACs, this article outlines the main differences between NOACs and traditional anticoagulation therapy and discusses the benefit–risk profile of the different NOACs in the treatment and secondary prevention of recurrent VTE. Key considerations for the use of NOACs in the primary care setting are highlighted, including dose transition, risk assessment and follow-up, duration of anticoagulant therapy, how to minimize bleeding risks, and the importance of patient education and counseling. Keywords: venous thromboembolism, oral anticoagulant, prevention, treatment, primary

  16. Changes in haematological indices following local application of interleukin-1 receptor antagonist protein after tenotomy in rabbits

    Directory of Open Access Journals (Sweden)

    Marko Pecin

    2017-01-01

    Full Text Available Interleukin-1 (IL-1 is the most important cytokine in the inflammation cascade activation in all tissues and is present in acute and chronic phases of inflammation. By blocking IL-1 binding to target cells, numerous inflammation processes are prevented. The use of autologous conditioned serum rich with IL-1 receptor antagonist protein (IL-1Ra is a novel treatment method of tendon inflammation in domestic animals and humans. Injections of autologous conditioned serum (ACS have demonstrated clinical efficacy and safety in animal models and humans in the treatment of osteoarthritis, disc prolapse and muscles and tendons injuries with low side effect. Neutropaenia, reduced white blood cell count, and infections or local irritations are described as side effects of IL-1 antagonist use in humans. Therefore, a study of blood changes in rabbits after local administration of IL-1Ra in the Achilles tendon tissue after iatrogenic inflammation was conducted. Interleukin-1 receptor antagonist protein was used to prevent and reduce tendon inflammation after longitudinal tenotomy. The study was done on 26 white Californian rabbits, divided into two equal groups consisting of 13 animals each; the experimental interleukin-1 receptor antagonist protein (irap group, and the control group. In the irap group, autologous serum rich with IL-1Ra was used (Orthokine®vet irap, Alfa-Arthro, Croatia. Differences between two groups were considered significant as changes in the blood for certain blood elements at P < 0.01. The P value was P = 0.0153 for the white blood cells, P = 0.00153 for neutrophils, P = 0.00017 and for platelets. In the control group, an increased platelet count was noticed in 70% of blood samples and a decreased neutrophil count was found in all of the irap group samples at the end of the study in comparison to the initial blood count prior to application.

  17. Preclinical anticonvulsant and neuroprotective profile of 8319, a non-competitive NMDA antagonist

    International Nuclear Information System (INIS)

    Fielding, S.; Wilker, J.C.; Chernack, J.; Ramirez, V.; Wilmot, C.A.; Martin, L.L.; Payack, J.F.; Cornfeldt, M.L.; Rudolphi, K.A.; Rush, D.K.

    1990-01-01

    8319, ((+-)-2-Amino-N-ethyl-alpha-(3-methyl-2-thienyl)benzeneethanamine 2HCl), is a novel compound with the profile of a non-competitive NMDA antagonist. The compound displaced [3H] TCP with high affinity (IC50 = 43 nM), but was inactive at the NMDA, benzodiazepine and GABA sites; in vivo, 8319 showed good efficacy as an anticonvulsant and potential neuroprotective agent. It blocked seizures induced by NMDLA, supramaximal electroshock, pentylenetetrazol (PTZ), picrotoxin, and thiosemicarbazide with ED50's of 1-20 mg/kg ip. As a neuroprotective agent, 8319 (30-100 mg/kg sc) prevented the death of dorsal hippocampal pyramidal cells induced by direct injection of 20 nmol NMDA. At 15 mg/kg ip, the compound was also effective against hippocampal neuronal necrosis induced via bilateral occlusion of the carotid arteries in gerbils. In summary, 8319 is a noncompetitive NMDA antagonist with good anticonvulsant activity and may possess neuroprotective properties useful in the treatment of brain ischemia

  18. G2 checkpoint abrogator abates the antagonistic interaction between antimicrotubule drugs and radiation therapy

    International Nuclear Information System (INIS)

    Sui Meihua; Zhang Hongfang; Di Xiaoyun; Chang Jinjia; Shen Youqing; Fan Weimin

    2012-01-01

    Background and purpose: We previously demonstrated that radiation may arrest tumor cells at G2 phase, which in turn prevents the cytotoxicity of antimicrotubule drugs and results in antagonistic interaction between these two modalities. Herein we tested whether G2 abrogators would attenuate the above antagonistic interaction and improve the therapeutic efficacy of combination therapy between radiation and antimicrotubule drugs. Materials and methods: Breast cancer BCap37 and epidermoid carcinoma KB cell lines were administered with radiation, UCN-01 (a model drug of G2 abrogator), paclitaxel or vincristine, alone or in combinations. The antitumor activities of single and combined treatments were analyzed by a series of cytotoxic, apoptotic, cell cycle, morphological and biochemical assays. Results: UCN-01 significantly enhanced the cytotoxicity of radiation, antimitotic drugs, and their combined treatments in vitro. Further investigations demonstrated that UCN-01 attenuated radiation-induced G2 arrest, and subsequently repressed the inhibitory effect of radiation on drug-induced mitotic arrest and apoptosis. Conclusions: This is the first report demonstrating that G2 checkpoint abrogation represses the inhibitory effect of radiation on antimicrotubule drugs, which may be implicated in cancer combination therapy. Considering that G2 abrogators are under extensive evaluation for cancer treatment, our findings provide valuable information for this class of promising compounds.

  19. Selective Glucocorticoid Receptor (GR-II Antagonist Reduces Body Weight Gain in Mice

    Directory of Open Access Journals (Sweden)

    Tomoko Asagami

    2011-01-01

    Full Text Available Previous research has shown that mifepristone can prevent and reverse weight gain in animals and human subjects taking antipsychotic medications. This proof-of-concept study tested whether a more potent and selective glucocorticoid receptor antagonist could block dietary-induced weight gain and increase insulin sensitivity in mice. Ten-week-old, male, C57BL/6J mice were fed a diet containing 60% fat calories and water supplemented with 11% sucrose for 4 weeks. Groups (=8 received one of the following: CORT 108297 (80 mg/kg QD, CORT 108297 (40 mg/kg BID, mifepristone (30 mg/kg BID, rosiglitazone (10 mg/kg QD, or vehicle. Compared to mice receiving a high-fat, high-sugar diet plus vehicle, mice receiving a high-fat, high-sugar diet plus either mifepristone or CORT 108297 gained significantly less weight. At the end of the four week treatment period, mice receiving CORT 108297 40 mg/kg BID or CORT 108297 80 mg/kg QD also had significantly lower steady plasma glucose than mice receiving vehicle. However, steady state plasma glucose after treatment was not highly correlated with reduced weight gain, suggesting that the effect of the glucocorticoid receptor antagonist on insulin sensitivity may be independent of its mitigating effect on weight gain.

  20. Genetically engineered bacteriophage delivers a tumor necrosis factor alpha antagonist coating on neural electrodes

    International Nuclear Information System (INIS)

    Kim, Young Jun; Nam, Chang-Hoon; Jin, Young-Hyun; Stieglitz, Thomas; Salieb-Beugelaar, Georgette B

    2014-01-01

    This paper reports a novel approach for the formation of anti-inflammatory surface coating on a neural electrode. The surface coating is realized using a recombinant f88 filamentous bacteriophage, which displays a short platinum binding motif and a tumor necrosis factor alpha antagonist (TNF-α antagonist) on p3 and p8 proteins, respectively. The recombinant bacteriophages are immobilized on the platinum surface by a simple dip coating process. The selective and stable immobilization of bacteriophages on a platinum electrode is confirmed by quartz crystal microbalance with dissipation monitoring, atomic force microscope and fluorescence microscope. From the in vitro cell viability test, the inflammatory cytokine (TNF-α) induced cell death was prevented by presenting recombinant bacteriophage coating, albeit with no significant cytotoxic effect. It is also observed that the bacteriophage coating does not have critical effects on the electrochemical properties such as impedance and charge storage capacities. Thus, this approach demonstrates a promising anti-apoptotic as well as anti-inflammatory surface coating for neural implant applications. (paper)

  1. Bronchoprotection with a leukotriene receptor antagonist in asthmatic preschool children

    DEFF Research Database (Denmark)

    Bisgaard, H; Nielsen, K G

    2000-01-01

    We hypothesized that a leukotriene receptor antagonist (LTRA) could provide bronchoprotection against the cold, dry air-induced response in asthmatic preschool children. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of the specific LTRA montelukast at 5...

  2. Manumycin from a new Streptomyces strain shows antagonistic ...

    African Journals Online (AJOL)

    Manumycin from a new Streptomyces strain shows antagonistic effect against methicillin-resistant Staphylococcus aureus (MRSA)/vancomycin-resistant enterococci (VRE) strains from Korean Hospitals. Yun Hee Choi, Seung Sik Cho, Jaya Ram Simkhada, Chi Nam Seong, Hyo Jeong Lee, Hong Seop Moon, Jin Cheol Yoo ...

  3. Diversity, distribution, and antagonistic activities of rhizobacteria of Panax notoginseng

    Directory of Open Access Journals (Sweden)

    Ze-Yan Fan

    2016-04-01

    Conclusion: The results suggest that diverse bacteria exist in the P. notoginseng rhizosphere soil, with differences in community in the same field, and antagonistic isolates may be good potential biological control agent for the notoginseng root-rot diseases caused by F. oxysporum, Fusarium solani, and Panax herbarum.

  4. Antagonistic effect of brevicin on Gram positive and Gram negative ...

    African Journals Online (AJOL)

    B. Senthil Kumar

    phylogenetic tree was constructed, based on evolutionary distances that were calculated by following the distance matrix method, using the Phylip package. Preparation and analysis of crude extract of protein (CEP) for their antagonistic activity against food borne pathogens. 24 h old MRS broth culture was prepared and ...

  5. Neuroprotection by NMDA receptor antagonists in a variety of neuropathologies.

    Science.gov (United States)

    Palmer, G C

    2001-09-01

    Because of adverse reactions, early efforts to introduce high affinity competitive or use-dependent NMDA receptor antagonists into patients suffering from stroke, head trauma or epilepsy met with failure. Later it was discovered that both low affinity use-dependent NMDA receptor antagonists and compounds with selective affinity for the NR2B receptor subunit met the criteria for safe administration into patients. Furthermore, these low affinity antagonists exhibit significant mechanistic differences from their higher affinity counterparts. Success of the latter is attested to the ability of the following low affinity compounds to be marketed: 1) Cough suppressant-dextromethorphan (available for decades); 2) Parkinson's disease--amantadine, memantine and budipine; 3) Dementia--memantine; and 4) Epilepsy--felbamate. Moreover, Phase III clinical trials are ongoing with remacemide for epilepsy and Huntington's disease and head trauma for HU-211. A host of compounds are or were under evaluation for the possible treatment of stroke, head trauma, hyperalgesia and various neurodegenerative disorders. Despite the fact that other drugs with associated NMDA receptor mechanisms have reached clinical status, this review focuses only on those competitive and use-dependent NMDA receptor antagonists that reached clinical trails. The ensuing discussions link the in vivo pharmacological investigations that led to the success/mistakes/ failures for eventual testing of promising compounds in the clinic.

  6. Epiminocyclohepta[b]indole analogs as 5-HT6 antagonists

    DEFF Research Database (Denmark)

    Henderson, Alan J; Guzzo, Peter R; Ghosh, Animesh

    2012-01-01

    A new series of epiminocyclohepta[b]indoles with potent 5-HT(6) antagonist activity were discovered and optimized using in vitro protocols. One compound from this series was progressed to advanced pharmacokinetic (PK) studies followed by 5-HT(6) receptor occupancy studies. The compound was found ...

  7. Sympatho-inhibitory properties of various AT1 receptor antagonists

    NARCIS (Netherlands)

    Balt, Jippe C.; Mathy, Marie-Jeanne; Pfaffendorf, Martin; van Zwieten, Peter A.

    2002-01-01

    It is well known that angiotensin II (Ang II) can facilitate the effects of sympathetic neurotransmission. In the present study, using various experimental models, we investigated the inhibitory effects of several Ang II subtype 1 receptor (AT1) antagonists on this Ang II-induced facilitation. We

  8. Management of hyperkalaemia consequent to mineralocorticoid-receptor antagonist therapy

    NARCIS (Netherlands)

    Roscioni, Sara S.; de Zeeuw, Dick; Bakker, Stephan J. L.; Lambers Heerspink, Hiddo J.

    2012-01-01

    Mineralocorticoid-receptor antagonists (MRAs) reduce blood pressure and albuminuria in patients treated with angiotensin-converting-enzyme inhibitors or angiotensin-II-receptor blockers. The use of MRAs, however, is limited by the occurrence of hyperkalaemia, which frequently occurs in patients

  9. Calcium antagonists: a ready prescription for treating infectious diseases?

    Science.gov (United States)

    Clark, Kevin B; Eisenstein, Edward M; Krahl, Scott E

    2013-01-01

    Emergence of new and medically resistant pathogenic microbes continues to escalate toward worldwide public health, wild habitat, and commercial crop and livestock catastrophes. Attempts at solving this problem with sophisticated modern biotechnologies, such as smart vaccines and microbicidal and microbistatic drugs that precisely target parasitic bacteria, fungi, and protozoa, remain promising without major clinical and industrial successes. However, discovery of a more immediate, broad spectrum prophylaxis beyond conventional epidemiological approaches might take no longer than the time required to fill a prescription at your neighborhood pharmacy. Findings from a growing body of research suggest calcium antagonists, long approved and marketed for various human cardiovascular and neurological indications, may produce safe, efficacious antimicrobial effects. As a general category of drugs, calcium antagonists include compounds that disrupt passage of Ca(2+) molecules across cell membranes and walls, sequestration and mobilization of free intracellular Ca(2+), and downstream binding proteins and sensors of Ca(2+)-dependent regulatory pathways important for proper cell function. Administration of calcium antagonists alone at current therapeutically relevant doses and schedules, or with synergistic compounds and additional antimicrobial medications, figures to enhance host immunoprotection by directly altering pathogen infection sequences, life cycles, homeostasis, antibiotic tolerances, and numerous other infective, survival, and reproductive processes. Short of being miracle drugs, calcium antagonists are welcome old drugs with new tricks capable of controlling some of the most virulent and pervasive global infectious diseases of plants, animals, and humans, including Chagas' disease, malaria, and tuberculosis.

  10. Role of muscarinic receptor antagonists in urgency and nocturia

    NARCIS (Netherlands)

    Michel, Martin C.; de La Rosette, Jean J. M. C. H.

    2005-01-01

    The overactive bladder (OAB) syndrome is defined as urgency, with or without urgency incontinence, usually accompanied by frequency and nocturia. Muscarinic receptor antagonists are the most established form of treatment for OAB, but until recently their effectiveness was only confirmed for symptoms

  11. How Hybrid Organizations Turn Antagonistic Assets into Complementarities

    DEFF Research Database (Denmark)

    Hockerts, Kai

    2015-01-01

    This article focuses on people excluded from traditional markets as employees, producers, or consumers on the grounds that they lack the appropriate skills. It describes the processes through which these perceived liabilities can be overcome by so-called hybrid organizations. Hybrids pursue expli...... for complementarities, and by creating demands for antagonistic assets, or by using partnerships....

  12. Effects of calcium antagonists on hypertension and diastolic function ...

    African Journals Online (AJOL)

    Calcium antagonists are known to decrease blood pressure acutely and chronically in hypertensive patients with hypertensive heart disease, and also to improve their systolic function. However, disorders of diastolic function may occur early in hypertensive heart disease. The improvement of diastolic function by nifedipine ...

  13. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    International Nuclear Information System (INIS)

    Li, Qun-Yi; Zhang, Meng; Hallis, Tina M.; DeRosier, Therese A.; Yue, Jian-Min; Ye, Yang; Mais, Dale E.; Wang, Ming-Wei

    2010-01-01

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K i = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  14. Contrasting effects of intralocus sexual conflict on sexually antagonistic coevolution

    NARCIS (Netherlands)

    Pennell, Tanya M; de Haas, Freek J H; Morrow, Edward H; van Doorn, G Sander

    2016-01-01

    Evolutionary conflict between the sexes can induce arms races in which males evolve traits that are detrimental to the fitness of their female partners, and vice versa. This interlocus sexual conflict (IRSC) has been proposed as a cause of perpetual intersexual antagonistic coevolution with

  15. Effect of Three Calmodulin Antagonists on Subpopulations of CD44 ...

    African Journals Online (AJOL)

    Tropical Journal of Pharmaceutical Research is indexed by Science Citation Index (SciSearch), Scopus,. International Pharmaceutical ... cancer stem cells. It is not known, however, whether targeting CD44 can alter the fate of cancer stem cells themselves. In this study, the effect of the calmodulin antagonists (N-(10-.

  16. Effects of alpha(1)-adrenoceptor antagonists on male sexual function

    NARCIS (Netherlands)

    van Dijk, Marleen M.; de La Rosette, Jean J. M. C. H.; Michel, Martin C.

    2006-01-01

    alpha(1)-Adrenoceptor antagonists such as alfuzosin, doxazosin, tamsulosin and terazosin are first-line agents for the treatment of lower urinary tract symptoms suggestive of benign prostatic hyperplasia (BPH), but are only second-line agents (doxazosin and terazosin only) for the treatment of

  17. The Effect of Sympathetic Antagonists on the Antidepressant Action ...

    African Journals Online (AJOL)

    Alprazolam is an anti-anxiety drug shown to be effective in the treatment of depression. In this study, the effect of sympathetic receptor antagonists on alprazolam–induced antidepressant action was studied using a mouse model of forced swimming behavioral despair. The interaction of three sympathetic receptor ...

  18. Evaluation of antagonistic fungi against charcoal rot of sunflower ...

    African Journals Online (AJOL)

    user

    Results showed reduction in disease incidence of charcoal rot on sunflower cultivar G-66 with antagonist, A. flavus (100%) followed by A. niger (64.86%) P. capsulatum (63.79%) and T. viride (31.89%) over control. Decrease in disease incidence over control was 100% where seed was treated with combination of A. niger ...

  19. Non-NMDA receptor antagonist-induced drinking in rat

    Science.gov (United States)

    Xu, Z.; Johnson, A. K.

    1998-01-01

    Glutamate has been implicated in the central control of mechanisms that maintain body fluid homeostasis. The present studies demonstrate that intracerebroventricular (i.c.v.) injections of the non-N-methyl-d-aspartate (NMDA) receptor antagonists 6, 7-dinitroquinoxaline-2,3-dione (DNQX) and 6-cyano-7-nitroquinoxaline-2,3 dione (CNQX) induce drinking in rats. The dipsogenic effect of i.c.v. DNQX was antagonized by the non-NMDA receptor agonist alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA). The water intake induced by DNQX was also blocked by pretreatment with a NMDA receptor antagonist, MK-801, but not by angiotensin type 1 (AT1) or acetylcholine muscarinic receptor antagonists (losartan and atropine). The results indicate that non-NMDA receptors may exert a tonic inhibitory effect within brain circuits that control dipsogenic activity and that functional integrity of NMDA receptors may be required for the non-NMDA receptor antagonists to induce water intake. Copyright 1998 Published by Elsevier Science B.V.

  20. NK-1 receptor antagonists as anti-cancer drugs

    Indian Academy of Sciences (India)

    The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in cancer. SP promotes the proliferation of tumour cells, angiogenesis and the migration of tumour cells. We review the involvement of SP, the NK-1 receptor and NK-1 receptor antagonists in cancer. Tumour cells overexpress NK-1 receptors, ...

  1. About the use of antagonistic bacteria and fungi

    OpenAIRE

    Tilcher, R.; Schmidt, C.; Lorenz, D.; Wolf, G. A.

    2002-01-01

    Microorganisms isolated from the phylloplane of vine and cereal plants inhibiting different phytopathogenic fungi were tested as biological control agents against Plasmopara viticola (downy mildew of grapevine). Based on screening in vitro against Phytophthora infestans, P. parasitica, Pythium ultimum, Botrytis cinerea 62 bacterial isolates were selected for tests with Plasmopara viticola.. Antifungal bacterial strains were assayed for antagonistic activity towards the grapevine dieback fungu...

  2. Antagonistic bioactivity of endophytic strains isolated from Salvia ...

    African Journals Online (AJOL)

    The antibiotic-producing potential of endophytic populations from medical plant of Salvia miltiorrhiza was examined. A total of 63 isolates was screened against five fungal and three bacterial species for the production of antimicrobial compounds. It showed that more isolates was antagonistic to fungi than to bacteria.

  3. Voltage-Gated Calcium Channel Antagonists and Traumatic Brain Injury

    Directory of Open Access Journals (Sweden)

    Bruce Lyeth

    2013-06-01

    Full Text Available Traumatic brain injury (TBI is a leading cause of death and disability in the United States. Despite more than 30 years of research, no pharmacological agents have been identified that improve neurological function following TBI. However, several lines of research described in this review provide support for further development of voltage gated calcium channel (VGCC antagonists as potential therapeutic agents. Following TBI, neurons and astrocytes experience a rapid and sometimes enduring increase in intracellular calcium ([Ca2+]i. These fluxes in [Ca2+]i drive not only apoptotic and necrotic cell death, but also can lead to long-term cell dysfunction in surviving cells. In a limited number of in vitro experiments, both L-type and N-type VGCC antagonists successfully reduced calcium loads as well as neuronal and astrocytic cell death following mechanical injury. In rodent models of TBI, administration of VGCC antagonists reduced cell death and improved cognitive function. It is clear that there is a critical need to find effective therapeutics and rational drug delivery strategies for the management and treatment of TBI, and we believe that further investigation of VGCC antagonists should be pursued before ruling out the possibility of successful translation to the clinic.

  4. Antagonistic potential of fluorescent Pseudomonas and its impact on ...

    African Journals Online (AJOL)

    This study focused on the antagonistic potential of fluorescent Pseudomonas in vitro, and its inoculation effect on growth performance of Lycopersicon esculentum in Fusarium oxysporum and Rhizoctonia solani infested soil. Biochemical characteristics of fluorescent Pseudomonas showed that all ten isolates were positive ...

  5. Vasopressin receptor antagonists: pharmacological tools and potential therapeutic agents

    NARCIS (Netherlands)

    Streefkerk, J. O.; van Zwieten, P. A.

    2006-01-01

    The present survey deals with the development and applications of non-peptidergic vasopressin receptor antagonists. The existence of at least three vasopressin receptors (V(1), V(2) and V(3) respectively) is firmly established. V(1)-receptors play a relevant role in the regulation of vascular tone,

  6. Screening and Mechanism of Trapping Ligand Antagonist Peptide ...

    African Journals Online (AJOL)

    Purpose: The aim of the present study was to develop peptide H9 as an efficient antagonist of human cytomegalovirus (HCMV) chemokine receptor US28. Methods: US28 gene was amplified from HCMV, and a stable expression system was constructed using NIH/3T3 cells. Interaction between peptide H9 and receptor ...

  7. Characterization of a novel non-steroidal glucocorticoid receptor antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Li, Qun-Yi; Zhang, Meng [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Hallis, Tina M.; DeRosier, Therese A. [Cell Systems Division, Invitrogen, Madison, WI (United States); Yue, Jian-Min; Ye, Yang [State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China); Mais, Dale E. [The National Center for Drug Screening, Shanghai (China); MPI Research, Mattawan, MI (United States); Wang, Ming-Wei, E-mail: wangmw@mail.shcnc.ac.cn [The National Center for Drug Screening, Shanghai (China); State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai (China)

    2010-01-15

    Selective antagonists of the glucocorticoid receptor (GR) are desirable for the treatment of hypercortisolemia associated with Cushing's syndrome, psychic depression, obesity, diabetes, neurodegenerative diseases, and glaucoma. NC3327, a non-steroidal small molecule with potent binding affinity to GR (K{sub i} = 13.2 nM), was identified in a high-throughput screening effort. As a full GR antagonist, NC3327 greatly inhibits the dexamethasone (Dex) induction of marker genes involved in hepatic gluconeogenesis, but has a minimal effect on matrix metalloproteinase 9 (MMP-9), a GR responsive pro-inflammatory gene. Interestingly, the compound recruits neither coactivators nor corepressors to the GR complex but competes with glucocorticoids for the interaction between GR and a coactivator peptide. Moreover, NC3327 does not trigger GR nuclear translocation, but significantly blocks Dex-induced GR transportation to the nucleus, and thus appears to be a 'competitive' GR antagonist. Therefore, the non-steroidal compound, NC3327, may represent a new class of GR antagonists as potential therapeutics for a variety of cortisol-related endocrine disorders.

  8. Antagonistic activity of selected strains of Bacillus thuringiensis ...

    African Journals Online (AJOL)

    The aim of this work was to determine, in vitro, the antagonistic effectiveness of 60 strains of Bacillus thuringiensis against damping-off and root and stem rot caused by Rhizoctonia solani. The strains were obtained from the International Collection of Entomopathogenic Bacillus at the FCB-UANL. During the in vitro dual ...

  9. The Effect of Antagonist Muscle Sensory Input on Force Regulation.

    Directory of Open Access Journals (Sweden)

    Tanya Onushko

    Full Text Available The purpose of this study was to understand how stretch-related sensory feedback from an antagonist muscle affects agonist muscle output at different contraction levels in healthy adults. Ten young (25.3 ± 2.4 years, healthy subjects performed constant isometric knee flexion contractions (agonist at 6 torque levels: 5%, 10%, 15%, 20%, 30%, and 40% of their maximal voluntary contraction. For half of the trials, subjects received patellar tendon taps (antagonist sensory feedback during the contraction. We compared error in targeted knee flexion torque and hamstring muscle activity, with and without patellar tendon tapping, across the 6 torque levels. At lower torque levels (5%, 10%, and 15%, subjects produced greater knee torque error following tendon tapping compared with the same torque levels without tendon tapping. In contrast, we did not find any difference in torque output at higher target levels (20%, 30%, and 40% between trials with and without tendon tapping. We also observed a load-dependent increase in the magnitude of agonist muscle activity after tendon taps, with no associated load-dependent increase in agonist and antagonist co-activation, or reflex inhibition from the antagonist tapping. The findings suggest that at relatively low muscle activity there is a deficiency in the ability to correct motor output after sensory disturbances, and cortical centers (versus sub-cortical are likely involved.

  10. Isolation of Fusarium fujikuroi antagonistic bacteria and cloning of its ...

    African Journals Online (AJOL)

    PRECIOUS

    2009-12-01

    Dec 1, 2009 ... effects of volatile metabolites produced by antagonistic P. fluorescens found in the isolates inhibited growth of F. fujikuroi in vitro. ... secondary metabolites play critical roles in many aspects of bacterium-host interactions. ... Nocardia, Sorangium, Brevibacterium, and Burkholderia. (Mavrodi et al., 2006; ...

  11. THC Prevents MDMA Neurotoxicity in Mice.

    Directory of Open Access Journals (Sweden)

    Clara Touriño

    2010-02-01

    Full Text Available The majority of MDMA (ecstasy recreational users also consume cannabis. Despite the rewarding effects that both drugs have, they induce several opposite pharmacological responses. MDMA causes hyperthermia, oxidative stress and neuronal damage, especially at warm ambient temperature. However, THC, the main psychoactive compound of cannabis, produces hypothermic, anti-inflammatory and antioxidant effects. Therefore, THC may have a neuroprotective effect against MDMA-induced neurotoxicity. Mice receiving a neurotoxic regimen of MDMA (20 mg/kg x 4 were pretreated with THC (3 mg/kg x 4 at room (21 degrees C and at warm (26 degrees C temperature, and body temperature, striatal glial activation and DA terminal loss were assessed. To find out the mechanisms by which THC may prevent MDMA hyperthermia and neurotoxicity, the same procedure was carried out in animals pretreated with the CB(1 receptor antagonist AM251 and the CB(2 receptor antagonist AM630, as well as in CB(1, CB(2 and CB(1/CB(2 deficient mice. THC prevented MDMA-induced-hyperthermia and glial activation in animals housed at both room and warm temperature. Surprisingly, MDMA-induced DA terminal loss was only observed in animals housed at warm but not at room temperature, and this neurotoxic effect was reversed by THC administration. However, THC did not prevent MDMA-induced hyperthermia, glial activation, and DA terminal loss in animals treated with the CB(1 receptor antagonist AM251, neither in CB(1 and CB(1/CB(2 knockout mice. On the other hand, THC prevented MDMA-induced hyperthermia and DA terminal loss, but only partially suppressed glial activation in animals treated with the CB(2 cannabinoid antagonist and in CB(2 knockout animals. Our results indicate that THC protects against MDMA neurotoxicity, and suggest that these neuroprotective actions are primarily mediated by the reduction of hyperthermia through the activation of CB(1 receptor, although CB(2 receptors may also contribute to

  12. Metabotropic glutamate receptor antagonists but not NMDA antagonists affect conditioned taste aversion acquisition in the parabrachial nucleus of rats

    Czech Academy of Sciences Publication Activity Database

    Valeš, Karel; Zach, P.; Bielavská, Edita

    2006-01-01

    Roč. 169, č. 1 (2006), s. 50-57 ISSN 0014-4819 R&D Projects: GA MŠk(CZ) 1M0517 Institutional research plan: CEZ:AV0Z5011922 Keywords : learning * microdialysis * glutamate antagonists Subject RIV: FH - Neurology Impact factor: 1.959, year: 2006

  13. Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis

    Science.gov (United States)

    Arefiev, Kait; Fiorentino, David F.; Chung, Lorinda

    2011-01-01

    Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin, internal organs, and widespread vasculopathy. Raynaud's phenomenon and digital ulcers are vascular manifestations of this disease and cause significant morbidity. Current treatments are only moderately effective in reducing the severity of Raynaud's in a portion of patients and typically do not lead to substantial benefit in terms of the healing or prevention of digital ulcers. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 for the treatment of systemic sclerosis-associated vascular disease. The purpose of this paper is to summarize the published studies and case reports evaluating the efficacy of endothelin receptor antagonists in the treatment of Raynaud's phenomenon and digital ulcers associated with systemic sclerosis. PMID:22121371

  14. Endothelin Receptor Antagonists for the Treatment of Raynaud's Phenomenon and Digital Ulcers in Systemic Sclerosis

    Directory of Open Access Journals (Sweden)

    Kait Arefiev

    2011-01-01

    Full Text Available Systemic sclerosis is a connective tissue disease characterized by fibrosis of the skin, internal organs, and widespread vasculopathy. Raynaud's phenomenon and digital ulcers are vascular manifestations of this disease and cause significant morbidity. Current treatments are only moderately effective in reducing the severity of Raynaud's in a portion of patients and typically do not lead to substantial benefit in terms of the healing or prevention of digital ulcers. Several studies have evaluated the efficacy of targeting the vasoconstrictor endothelin-1 for the treatment of systemic sclerosis-associated vascular disease. The purpose of this paper is to summarize the published studies and case reports evaluating the efficacy of endothelin receptor antagonists in the treatment of Raynaud's phenomenon and digital ulcers associated with systemic sclerosis.

  15. Modification of Anxious Behavior after Psychogenic Trauma and Treatment with Galanin Receptor Antagonist.

    Science.gov (United States)

    Lyudyno, V I; Tsikunov, S G; Abdurasulova, I N; Kusov, A G; Klimenko, V M

    2015-07-01

    Effects of blockage of central galanin receptors on anxiety manifestations were studied in rats with psychogenic trauma. Psychogenic trauma was modeled by exposure of a group of rats to the situation when the partner was killed by a predator. Antagonist of galanin receptors was intranasally administered before stress exposure. Animal behavior was evaluated using the elevated-plus maze test, free exploratory paradigm, and open-field test. Psychogenic trauma was followed by an increase in anxiety level and appearance of agitated behavior. Blockage of galanin receptors aggravated behavioral impairment, which manifested in the pathological anxious reactions - manifestations of hypervigilance and hyperawareness. The results suggest that endogenous pool of galanin is involved into prevention of excessive CNS response to stressful stimuli typical of posttraumatic stress disorder.

  16. DIHYDROPYRIDINE CALCIUM ANTAGONISTS: DATA OF EVIDENCE BASED MEDICINE AND RECOM-MENDATIONS ON PRACTICAL USE

    Directory of Open Access Journals (Sweden)

    S. Y. Martsevich

    2007-01-01

    Full Text Available The classification of calcium antagonists is presented. There were considered the results of large randomized trials, which were devoted to study of influence of dihydropyridine calcium antagonists on the risk of cardiovascular complications. The place of dihydropyridine calcium antagonists in modern recommendations on treatment of arterial hypertension and ischemic heart disease is defined. The clinical importance of differences between various presentations of dihy-dropyridine calcium antagonists is stressed.

  17. DIHYDROPYRIDINE CALCIUM ANTAGONISTS: DATA OF EVIDENCE BASED MEDICINE AND RECOM-MENDATIONS ON PRACTICAL USE

    Directory of Open Access Journals (Sweden)

    S. Y. Martsevich

    2015-12-01

    Full Text Available The classification of calcium antagonists is presented. There were considered the results of large randomized trials, which were devoted to study of influence of dihydropyridine calcium antagonists on the risk of cardiovascular complications. The place of dihydropyridine calcium antagonists in modern recommendations on treatment of arterial hypertension and ischemic heart disease is defined. The clinical importance of differences between various presentations of dihy-dropyridine calcium antagonists is stressed.

  18. Serotonin 5-HT(2A) receptor antagonists in the treatment of insomnia: present status and future prospects.

    Science.gov (United States)

    Monti, J M

    2010-03-01

    Benzodiazepine (BZD) and non-BZD hypnotics improve sleep induction and sleep maintenance. BZD induces a further reduction of slow wave sleep (SWS) and rapid eye movement (REM) sleep, whereas SWS and REM values remain decreased during non-BZD administration. There is evidence indicating that the nonselective serotonin 5-HT(2A/2C) receptor antagonists, ritanserin, ketanserin, seganserin and ICI-169369, the selective 5-HT(2A) receptor antagonist eplivanserin and the 5-HT(2A) receptor inverse agonist pimavanserin, increase SWS in subjects with normal sleep. In addition, it has been shown that prior administration of ritanserin prevents the nitrazepam-induced suppression of SWS in normal subjects. Of note, ritanserin also induced an increase of SWS in poor sleepers, patients with chronic primary insomnia and psychiatric patients with a generalized anxiety disorder or a mood disorder. The 5-HT(2A) receptor inverse agonist APD-125 gave rise to a similar effect in patients with chronic primary insomnia. Thus, presently available evidence tends to indicate that the association of a 5-HT(2A) receptor antagonist or a 5-HT(2A) receptor inverse agonist with a BZD or a non-BZD hypnotic could be a valid alternative to normalize SWS in patients with primary or comorbid insomnia. Copyright 2010 Prous Science, S.A.U. or its licensors. All rights reserved.

  19. Preventing Addiction.

    Science.gov (United States)

    Moore, Susan Fordney

    The purpose of this paper is to provide the beginning counselor with an overview of prevention concepts. Prevention is a relatively new emphasis in community efforts to stem the rising costs of substance abuse and other high-risk behaviors. The paper discusses agent, host, and environmental prevention models and how they relate to causal theories…

  20. GnRH antagonist versus long agonist protocols in IVF: a systematic review and meta-analysis accounting for patient type.

    Science.gov (United States)

    Lambalk, C B; Banga, F R; Huirne, J A; Toftager, M; Pinborg, A; Homburg, R; van der Veen, F; van Wely, M

    2017-09-01

    pregnancy rate when the oral hormonal programming pill (OHP) pretreatment was combined with a flexible protocol (RR 0.74, 95% CI 0.59-0.91) while without OHP, the RR was 0.84, 95% CI 0.71-1.0. Subgroup analysis for the fixed antagonist schedule demonstrated no evidence of a significant difference with or without OHP (RR 0.94, 95% CI 0.79-1.12 and RR 0.94, 95% CI 0.83-1.05, respectively). Antagonists resulted in significantly lower OHSS rates both in the general IVF patients and in women with PCOS (RR 0.63, 95% CI 0.50-0.81 and RR 0.53, 95% CI 0.30-0.95, respectively). No data on OHSS was available from trials in poor responders. In a general IVF population, GnRH antagonists are associated with lower ongoing pregnancy rates when compared to long protocol agonists, but also with lower OHSS rates. Within this population, antagonist treatment prevents one case of OHSS in 40 patients but results in one less ongoing pregnancy out of every 28 women treated. Thus standard use of the long GnRH agonist treatment is perhaps still the approach of choice for prevention of premature luteinization. In couples with PCOS and poor responders, GnRH antagonists do not seem to compromise ongoing pregnancy rates and are associated with less OHSS and therefore could be considered as standard treatment. © The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please email: journals.permissions@oup.com

  1. Glutamate receptor antagonists and growth factors modulate dentate granule cell neurogenesis in organotypic, rat hippocampal slice cultures

    DEFF Research Database (Denmark)

    Poulsen, Frantz Rom; Blaabjerg, Morten; Montero, Maria

    2005-01-01

    Generation of dentate granule cells and its modulation by glutamate receptor antagonists, growth factors and pilocarpine-induced seizure-like activity was investigated in rat hippocampal slice cultures derived from 1-week-old rats and grown for 2 weeks. Focussing on the dentate granule cell layer...... the number of TUC-4-positive cells, just as combining pilocarpine with the neurogenesis-stimulating compounds, prevented or reduced the increase of TUC-4-positive cells. None of the treatments were found to induce dentate granule cell death within the observed period. Labeling of dividing cells by adding 5...

  2. Opioid antagonists with minimal sedation for opioid withdrawal.

    Science.gov (United States)

    Gowing, Linda; Ali, Robert; White, Jason M

    2017-05-29

    Managed withdrawal is a necessary step prior to drug-free treatment or as the endpoint of long-term substitution treatment. To assess the effects of opioid antagonists plus minimal sedation for opioid withdrawal. Comparators were placebo as well as more established approaches to detoxification, such as tapered doses of methadone, adrenergic agonists, buprenorphine and symptomatic medications. We updated our searches of the following databases to December 2016: CENTRAL, MEDLINE, Embase, PsycINFO and Web of Science. We also searched two trials registers and checked the reference lists of included studies for further references to relevant studies. We included randomised and quasi-randomised controlled clinical trials along with prospective controlled cohort studies comparing opioid antagonists plus minimal sedation versus other approaches or different opioid antagonist regimens for withdrawal in opioid-dependent participants. We used standard methodological procedures expected by Cochrane. Ten studies (6 randomised controlled trials and 4 prospective cohort studies, involving 955 participants) met the inclusion criteria for the review. We considered 7 of the 10 studies to be at high risk of bias in at least one of the domains we assessed.Nine studies compared an opioid antagonist-adrenergic agonist combination versus a treatment regimen based primarily on an alpha 2 -adrenergic agonist (clonidine or lofexidine). Other comparisons (placebo, tapered doses of methadone, buprenorphine) made by included studies were too diverse for any meaningful analysis. This review therefore focuses on the nine studies comparing an opioid antagonist (naltrexone or naloxone) plus clonidine or lofexidine versus treatment primarily based on clonidine or lofexidine.Five studies took place in an inpatient setting, two studies were in outpatients with day care, two used day care only for the first day of opioid antagonist administration, and one study described the setting as outpatient

  3. Crystal structure of the adenosine A2Areceptor bound to an antagonist reveals a potential allosteric pocket.

    Science.gov (United States)

    Sun, Bingfa; Bachhawat, Priti; Chu, Matthew Ling-Hon; Wood, Martyn; Ceska, Tom; Sands, Zara A; Mercier, Joel; Lebon, Florence; Kobilka, Tong Sun; Kobilka, Brian K

    2017-02-21

    The adenosine A 2A receptor (A 2A R) has long been implicated in cardiovascular disorders. As more selective A 2A R ligands are being identified, its roles in other disorders, such as Parkinson's disease, are starting to emerge, and A 2A R antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A 2A receptor bound to compound 1 (Cmpd-1), a novel A 2A R/ N -methyl d-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A 2A receptor with a cytochrome b562-RIL (BRIL) fusion (A 2A R-BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A 2A R-BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1-bound A 2A R-BRIL prevented formation of the lattice observed with the ZM241385-bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other A 2A R structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr9 1.35 and Tyr271 7.36 , which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A 2A R structures, highlighting flexibility in the binding pocket that may facilitate the development of A 2A R-selective compounds for the treatment of Parkinson's disease.

  4. Randomized controlled trial of the CGRP receptor antagonist telcagepant for migraine prevention

    DEFF Research Database (Denmark)

    Ho, Tony W; Connor, Kathryn M; Zhang, Ying

    2014-01-01

    elevations do not support the use of telcagepant for daily administration. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that in patients with migraine, telcagepant taken daily reduces headache days by 1.4 days per month compared to placebo and causes 2.5% of patients to have elevations......-14 migraine days during a 4-week baseline were randomized to telcagepant 140 mg, telcagepant 280 mg, or placebo twice daily for 12 weeks. Efficacy was assessed by mean monthly headache days and migraine/probable migraine days (headache plus ≥ 1 associated symptom). RESULTS: The trial was terminated following...... initiation and resolved after treatment discontinuation. The originally planned efficacy analysis over 12 weeks was not performed due to limited data at later time points, but there was evidence that telcagepant resulted in a larger reduction from baseline than placebo for mean monthly headache days (month 1...

  5. Prevention of Stimulant-Induced Euphoria with an Opioid Receptor Antagonist

    Science.gov (United States)

    2014-10-01

    unrelated to study medication. The third subject experienced a reoccurrence of her peptic stress ulcers , and was thus terminated from the study and...Events Log Subject ID Date of AE Description Severity Expected? Related? Changes/ Corrective Action Date Reported to IRB 1770701 7/16/13 Stomache ... Stomach Cramp/Upset stomache Mild Expected Possible None N/A 1772201 1/25/14 anxious/worried in AM Moderate Expected Probable None N/A 1772201 1/25

  6. Tactical Approaches to Interconverting GPCR Agonists and Antagonists.

    Science.gov (United States)

    Dosa, Peter I; Amin, Elizabeth Ambrose

    2016-02-11

    There are many reported examples of small structural modifications to GPCR-targeted ligands leading to major changes in their functional activity, converting agonists into antagonists or vice versa. These shifts in functional activity are often accompanied by negligible changes in binding affinity. The current perspective focuses on outlining and analyzing various approaches that have been used to interconvert GPCR agonists, partial agonists, and antagonists in order to achieve the intended functional activity at a GPCR of therapeutic interest. An improved understanding of specific structural modifications that are likely to alter the functional activity of a GPCR ligand may be of use to researchers designing GPCR-targeted drugs and/or probe compounds, specifically in cases where a particular ligand exhibits good potency but not the preferred functional activity at the GPCR of choice.

  7. Are peripheral opioid antagonists the solution to opioid side effects?

    LENUS (Irish Health Repository)

    Bates, John J

    2012-02-03

    Opioid medication is the mainstay of therapy for severe acute and chronic pain. Unfortunately, the side effects of these medications can affect patient comfort and safety, thus limiting their proven therapeutic potential. Whereas the main analgesic effects of opioids are centrally mediated, many of the common side effects are mediated via peripheral receptors. Novel peripheral opioid antagonists have been recently introduced that can block the peripheral actions of opioids without affecting centrally mediated analgesia. We review the clinical and experimental evidence of their efficacy in ameliorating opioid side effects and consider what further information might be useful in defining their role. IMPLICATIONS: The major analgesic effects of opioid medication are mediated within the brain and spinal cord. Many of the side effects of opioids are caused by activation of receptors outside these areas. Recently developed peripherally restricted opioid antagonists have the ability to block many opioid side effects without affecting analgesia.

  8. In-silico guided discovery of novel CCR9 antagonists

    Science.gov (United States)

    Zhang, Xin; Cross, Jason B.; Romero, Jan; Heifetz, Alexander; Humphries, Eric; Hall, Katie; Wu, Yuchuan; Stucka, Sabrina; Zhang, Jing; Chandonnet, Haoqun; Lippa, Blaise; Ryan, M. Dominic; Baber, J. Christian

    2018-03-01

    Antagonism of CCR9 is a promising mechanism for treatment of inflammatory bowel disease, including ulcerative colitis and Crohn's disease. There is limited experimental data on CCR9 and its ligands, complicating efforts to identify new small molecule antagonists. We present here results of a successful virtual screening and rational hit-to-lead campaign that led to the discovery and initial optimization of novel CCR9 antagonists. This work uses a novel data fusion strategy to integrate the output of multiple computational tools, such as 2D similarity search, shape similarity, pharmacophore searching, and molecular docking, as well as the identification and incorporation of privileged chemokine fragments. The application of various ranking strategies, which combined consensus and parallel selection methods to achieve a balance of enrichment and novelty, resulted in 198 virtual screening hits in total, with an overall hit rate of 18%. Several hits were developed into early leads through targeted synthesis and purchase of analogs.

  9. Interleukin-1-receptor antagonist in type 2 diabetes mellitus

    DEFF Research Database (Denmark)

    Larsen, Claus M; Faulenbach, Mirjam; Vaag, Allan

    2007-01-01

    BACKGROUND: The expression of interleukin-1-receptor antagonist is reduced in pancreatic islets of patients with type 2 diabetes mellitus, and high glucose concentrations induce the production of interleukin-1beta in human pancreatic beta cells, leading to impaired insulin secretion, decreased cell...... proliferation, and apoptosis. METHODS: In this double-blind, parallel-group trial involving 70 patients with type 2 diabetes, we randomly assigned 34 patients to receive 100 mg of anakinra (a recombinant human interleukin-1-receptor antagonist) subcutaneously once daily for 13 weeks and 36 patients to receive......, and the body-mass index were similar in the two study groups. Symptomatic hypoglycemia was not observed, and there were no apparent drug-related serious adverse events. CONCLUSIONS: The blockade of interleukin-1 with anakinra improved glycemia and beta-cell secretory function and reduced markers of systemic...

  10. Non-imidazole histamine NO-donor H3-antagonists.

    Science.gov (United States)

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Cena, Clara; Fruttero, Roberta; Gasco, Alberto

    2005-01-01

    Recently a series of H3-antagonists related to Imoproxifan was realised (I); in these products the oxime substructure of the lead was constrained in NO-donor furoxan systems and in the corresponding furazan derivatives. In this paper, a new series of compounds derived from I by substituting the imidazole ring with the ethoxycarbonylpiperazino moiety present in the non-imidazole H3-ligand A-923 is described. For all the products synthesis and preliminary pharmacological characterisation, as well as their hydrophilic-lipophilic balance, are reported. The imidazole ring replacement generally results in a decreased H3-antagonist activity with respect to the analogues of series I and, in some cases, induces relaxing effects on the electrically contracted guinea-pig ileum, probably due to increased affinity for other receptor systems.

  11. Potential Clinical Implications of the Urotensin II Receptor Antagonists

    Directory of Open Access Journals (Sweden)

    Emilie Kane

    2011-07-01

    Full Text Available Urotensin-II (UII, which binds to its receptor UT, plays an important role in the heart, kidneys, pancreas, adrenal gland and CNS. In the vasculature, it acts as a potent endothelium-independent vasoconstrictor and endothelium-dependent vasodilator. In disease states, this constriction-dilation equilibrium is disrupted. There is an upregulation of the UII system in heart disease, metabolic syndrome and kidney failure. The increase in UII release and UT expression suggest that UII system may be implicated in the pathology and pathogenesis of these diseases by causing an increase in ACAT-1 activity leading to SMC proliferation and foam cell infiltration, insulin resistance (DMII, as well as inflammation, high blood pressure and plaque formation. Recently, UT antagonists such as SB-611812, palosuran, and most recently a piperazino-isoindolinone based antagonist have been developed in the hope of better understanding the UII system and treating its associated diseases.

  12. Construction, purification, and characterization of a chimeric TH1 antagonist

    Directory of Open Access Journals (Sweden)

    Javier-González Luís

    2006-05-01

    Full Text Available Abstract Background TH1 immune response antagonism is a desirable approach to mitigate some autoimmune and inflammatory reactions during the course of several diseases where IL-2 and IFN-γ are two central players. Therefore, the neutralization of both cytokines could provide beneficial effects in patients suffering from autoimmune or inflammatory illnesses. Results A chimeric antagonist that can antagonize the action of TH1 immunity mediators, IFN-γ and IL-2, was designed, engineered, expressed in E. coli, purified and evaluated for its in vitro biological activities. The TH1 antagonist molecule consists of the extracellular region for the human IFNγ receptor chain 1 fused by a four-aminoacid linker peptide to human 60 N-terminal aminoacid residues of IL-2. The corresponding gene fragments were isolated by RT-PCR and cloned in the pTPV-1 vector. E. coli (W3110 strain was transformed with this vector. The chimeric protein was expressed at high level as inclusion bodies. The protein was partially purified by pelleting and washing. It was then solubilized with strong denaturant and finally refolded by gel filtration. In vitro biological activity of chimera was demonstrated by inhibition of IFN-γ-dependent HLA-DR expression in Colo 205 cells, inhibition of IFN-γ antiproliferative effect on HEp-2 cells, and by a bidirectional effect in assays for IL-2 T-cell dependent proliferation: agonism in the absence versus inhibition in the presence of IL-2. Conclusion TH1 antagonist is a chimeric protein that inhibits the in vitro biological activities of human IFN-γ, and is a partial agonist/antagonist of human IL-2. With these attributes, the chimera has the potential to offer a new opportunity for the treatment of autoimmune and inflammatory diseases.

  13. State Estimation For An Agonistic-Antagonistic Muscle System

    OpenAIRE

    Nguyen, Thang; Warner, Holly; La, Hung; Mohammadi, Hanieh; Simon, Dan; Richter, Hanz

    2017-01-01

    Research on assistive technology, rehabilitation, and prosthesis requires the understanding of human machine interaction, in which human muscular properties play a pivotal role. This paper studies a nonlinear agonistic-antagonistic muscle system based on the Hill muscle model. To investigate the characteristics of the muscle model, the problem of estimating the state variables and activation signals of the dual muscle system is considered. In this work, parameter uncertainty and unknown input...

  14. Histamine-2 receptor antagonists as immunomodulators: new therapeutic views?

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    Considerable evidence has emerged to suggest that histamine participates in the regulation of the inflammatory response, immune reaction, coagulation cascade, and cardiovascular function. Furthermore, histamine may play a major role in the growth of normal and malignant tissue as a regulator...... antagonists as adjuvant single drugs to reduce trauma-, blood transfusion- and sepsis-induced immunosuppression has led to research in combined treatment regimens in major surgery, particularly, of patients operated on for malignant diseases....

  15. Chitinolytic Enterobacter agglomerans Antagonistic to Fungal Plant Pathogens

    OpenAIRE

    Chernin, L.; Ismailov, Z.; Haran, S.; Chet, I.

    1995-01-01

    Three Enterobacter agglomerans strains which produce and excrete proteins with chitinolytic activity were found while screening soil-borne bacteria antagonistic to fungal plant pathogens. The chitinolytic activity was induced when the strains were grown in the presence of colloidal chitin as the sole carbon source. It was quantitated by using assays with chromogenic p-nitrophenyl analogs of disaccharide, trisaccharide, and tetrasaccharide derivatives of N-acetylglucosamine. A set of three flu...

  16. ANTIHYPERTENSIVE TREATMENT IN ELDERLY PATIENTS WITH DIHYDROPYRIDINE CALCIUM ANTAGONISTS

    OpenAIRE

    Y. A. Karpov; V. V. Buza

    2006-01-01

    The proofs of necessity of active arterial hypertension (AH) treatment in elderly patients are given. Peculiarities of pathogenesis of AH in elderly patients, connected predominantly with loss of big arteries elasticity and reasoning widely spread of isolated systolic AH in these patients, are discussed. Advantages of dihydropyridine calcium antagonists (DPCA) for AH treatment in elderly patients are proved, safety of treatment with DPCA is discussed. Data of clinical studies is analyzed. Ana...

  17. Renoprotective effects of calcium antagonists on kidney disease

    OpenAIRE

    Mochammad Sja'bani, Mochammad Sja'bani

    2015-01-01

    There has been a growing number of evidence that calcium antagonists provide a salutary effects in preserving kidneys against acute renal ischemia in patients at increasing risk. Their beneficial effects on cellular and mitochondrial calcium may explain the effects on renal hemodynamics and metabolics. It seems, that they do not directly vasodilate kidney vessels but alter the response towards vasoconstrictor agents. This effect may mediate diuretic and natriuretic effect of calcium antagonis...

  18. Prevention of atrial fibrillation in patients with aortic valve stenosis with candesartan treatment after aortic valve replacement

    DEFF Research Database (Denmark)

    Dahl, J. S.; Videbaek, L.; Poulsen, M. K.

    2013-01-01

    Background: Accumulating data has suggested that treatment with Angiotensin-II receptor antagonists can prevent the new onset of atrial fibrillation (AF). The aim of this study was to evaluate whether treatment with candesartan on top of conventional treatment could prevent new onset AF in patien...... with candesartan may prevent the new onset of atrial fibrillation. (C) 2011 Elsevier Ireland Ltd. All rights reserved....

  19. Deoxycholic acid conjugates are muscarinic cholinergic receptor antagonists.

    Science.gov (United States)

    Raufman, Jean-Pierre; Chen, Ying; Zimniak, Piotr; Cheng, Kunrong

    2002-08-01

    In the course of examining the actions of major human bile acids on cholinergic receptors, we discovered that conjugates of lithocholic acid are partial muscarinic agonists. In the present communication, we report that conjugates of deoxycholic acid (DC) act as cholinergic muscarinic receptor antagonists. Chinese hamster ovary (CHO) cells expressing rat M3-muscarinic receptors were used to test bile acids for inhibition of radioligand [N- (3)H-methylscopolamine ((3)H-NMS)] binding; alteration of inositol phosphate (IP) formation; mitogen-activated protein (MAP) kinase phosphorylation and cell toxicity. We observed approximately 18.8, 30.3 and 37.1% inhibition of (3)H-NMS binding with DC and its glycine (DCG) and taurine (DCT) conjugates, respectively (all 100 micromol/l, p exclusion or lactate dehydrogenase release from CHO-M3 cells. We observed the following rank order of potency (IC(50) micromol/l) for inhibition of (3)H-NMS by muscarinic antagonists and bile acids: NMS (0.0004) > 4-DAMP (0.009) > atropine (0.012) > DCT (170) > DCG (250). None of the bile acids tested were hydrolyzed by recombinant cholinesterase. At concentrations achieved in human bile, DC derivatives are natural muscarinic antagonists. Copyright 2002 S. Karger AG, Basel

  20. Glutamate receptor antagonists with the potential for migraine treatment.

    Science.gov (United States)

    Ferrari, Anna; Rustichelli, Cecilia; Baraldi, Carlo

    2017-12-01

    Preclinical, clinical, and other (e.g., genetic) evidence support the concept that migraine susceptibility may at least partially result from a glutamatergic system disorder. Therefore, the receptors of the glutamatergic system are considered relatively new targets for investigational drugs to treat migraine. Investigational and established glutamate receptor antagonists (GluRAs) have been shown to possess antinociceptive properties in preclinical models of trigeminovascular nociception and have been evaluated in clinical trials. This review focuses on preclinical and clinical studies of GluRAs for the treatment of migraine. Areas covered: A PubMed database search (from 1987 to December 2016) and a review of published studies on GluRAs in migraine were conducted. Expert opinion: All published clinical trials of investigational GluRAs have been unsuccessful in establishing benefit for acute migraine treatment. Clinical trial results contrast with the preclinical data, suggesting that glutamate (Glu) does not play a decisive role after the attack has already been triggered. These antagonists may instead be useful for migraine prophylaxis. Improving patient care requires further investigating and critically analyzing the role of Glu in migraine, designing experimental models to study more receptors and their corresponding antagonists, and identifying biomarkers to facilitate trials designed to target specific subgroups of migraine patients.

  1. Non-genetic inheritance and the patterns of antagonistic coevolution

    Directory of Open Access Journals (Sweden)

    Mostowy Rafal

    2012-06-01

    Full Text Available Abstract Background Antagonistic species interactions can lead to coevolutionary genotype or phenotype frequency oscillations, with important implications for ecological and evolutionary processes. However, direct empirical evidence of such oscillations is rare. The rarity of observations is generally attributed to inherent difficulties of ecological and evolutionary long-term studies, to weak or absent interaction between species, or to the absence of negative frequency-dependence. Results Here, we show that another factor – non-genetic inheritance, mediated for example by epigenetic mechanisms – can completely eliminate oscillations in the presence of such negative frequency dependence, even if only a small fraction of offspring are affected. We analytically derive the threshold value of this fraction at which the dynamics change from oscillatory to stable, and investigate how selection, mutation and generation times differences between the two species affect the threshold value. These results strongly suggest that the lack of phenotype frequency oscillations should not be attributed to the lack of strong interactions between antagonistic species. Conclusions Given increasing evidence of non-genetic effects on the outcomes of antagonistic species interactions, we suggest that these effects should be incorporated into ecological and evolutionary models of interacting species.

  2. Histamine H1 antagonists and clinical characteristics of febrile seizures

    Directory of Open Access Journals (Sweden)

    Zolaly MA

    2012-03-01

    Full Text Available Mohammed A ZolalyDepartment of Pediatrics, College of Medicine, Taibah University, Al-Madinah Al-Munawarah, Kingdom of Saudi ArabiaBackground: The purpose of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures.Methods: The current descriptive study was carried out from April 2009 to February 2011 in 250 infants and children who visited the Madinah Maternity and Children's Hospital as a result of febrile convulsions. They were divided into two groups according to administration of antihistamines at the onset of fever.Results: Detailed clinical manifestations were compared between patients with and without administration of antihistamines. The time from fever detection to seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than in the nonantihistamine group. No significant difference was found in time from fever detection to seizure onset or seizure duration between patients who received a first-generation antihistamine and those who received a second-generation antihistamine.Conclusion: Due to their central nervous system effects, H1 antagonists should not be administered to patients with febrile seizures and epilepsy. Caution should be exercised regarding the use of histamine H1 antagonists in young infants, because these drugs could potentially disturb the anticonvulsive central histaminergic system.Keywords: antihistamine, nonantihistamine, histamine H1 antagonist, febrile seizures

  3. Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

    Directory of Open Access Journals (Sweden)

    Sachiko Yamada

    Full Text Available Podocyte injury is the first step in the progression of glomerulosclerosis. Previous studies have demonstrated the beneficial effect of bone morphogenetic protein 7 (Bmp7 in podocyte injury and the existence of native Bmp signaling in podocytes. Local activity of Bmp7 is controlled by cell-type specific Bmp antagonists, which inhibit the binding of Bmp7 to its receptors. Here we show that the product of Twisted gastrulation (Twsg1, a Bmp antagonist, is the central negative regulator of Bmp function in podocytes and that Twsg1 null mice are resistant to podocyte injury. Twsg1 was the most abundant Bmp antagonist in murine cultured podocytes. The administration of Bmp induced podocyte differentiation through Smad signaling, whereas the simultaneous administration of Twsg1 antagonized the effect. The administration of Bmp also inhibited podocyte proliferation, whereas simultaneous administration of Twsg1 antagonized the effect. Twsg1 was expressed in the glomerular parietal cells (PECs and distal nephron of the healthy kidney, and additionally in damaged glomerular cells in a murine model of podocyte injury. Twsg1 null mice exhibited milder hypoalbuminemia and hyperlipidemia, and milder histological changes while maintaining the expression of podocyte markers during podocyte injury model. Taken together, our results show that Twsg1 plays a critical role in the modulation of protective action of Bmp7 on podocytes, and that inhibition of Twsg1 is a promising means of development of novel treatment for podocyte injury.

  4. Tachykinin NK2 receptor antagonists. A patent review (2006 - 2010).

    Science.gov (United States)

    Altamura, Maria

    2012-01-01

    Tachykinins are endogenous peptide neurotransmitters, acting through the NK1, NK2 and NK3 receptors, at central and peripheral level. At peripheral level, they are involved in contraction of smooth muscle, secretion of water and ion from epithelia, as well as modulation of visceral pain sensitivity. Tachykinin NK2 receptor antagonists have the potential to be useful in the treatment of various gastrointestinal, genitourinary and CNS diseases. In this review, an overview of the patenting activity in the last 5 years is provided. Patents from different companies and research groups are discussed for their novelty and evaluated in relation to proposed indications and clinical studies. Relevant biological data are also presented. Patents claiming new therapeutic indications are included in a dedicated section. Although there is still no tachykinin NK2 receptor antagonist approved for use in human therapy, research in the field is still proposing new compounds and possible uses. A number of candidates are being evaluated in Phase II clinical studies, in indications ranging from gastrointestinal disorders to inflammatory diseases. The results of these studies will indicate the role of tachykinin NK2 receptor antagonists in human therapy.

  5. [Necrotic leg ulcer revealing vasculitis induced by vitamin K antagonists].

    Science.gov (United States)

    Chabli, H; Hocar, O; Akhdari, N; Amal, S; Hakkou, M; Hamdaoui, A

    2015-12-01

    Vitamin K antagonists are widely used in thromboembolic diseases. Hemorrhagic complications related to drug overdose represent their main side effect. We report a rare side effect, a severe and unexpected type of skin vasculitis - necrotic leg ulcer - induced by vitamin K antagonist. A 63-year-old female with a history of diabetes developed hyperalgesic necrotic ulcerations on the lower limbs one month after starting an acenocoumarol-based treatment for ischemic heart disease. Histological examination revealed lymphocytic vasculitis with fibrinoid necrosis. Etiological explorations searching for vasculitis were negative. In the absence of a precise etiology, drug-induced ulcer was suspected. Low molecular weight heparin was prescribed to replace acenocoumarol. The lesions slowly resolved with topical treatment. The chronological criteria and the negativity of etiological explorations allowed the diagnosis of vitamin K antagonist-induced necrotic skin ulcer. Clinicians should be aware of this rare complication induced by oral anticoagulants because of its practical therapeutic implications. This is the first case of necrotic leg ulcer induced by acenocoumarol corresponding histologically to necrotising lymphocytic vasculitis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.

  6. Correlated EMG Oscillations between Antagonists during Cocontraction in Men.

    Science.gov (United States)

    Yoshitake, Yasuhide; Kanehisa, Hiroaki; Shinohara, Minoru

    2017-03-01

    The purpose of this study was to determine the modulation of common low-frequency oscillations in pools of motor units across antagonistic muscles because of the difference in the activation level of pools of spinal motor neurons and the presence of neuromuscular fatigue during intended cocontraction. Ten healthy young men (21.8 ± 1.5 yr) performed intended steady cocontractions of elbow flexors and extensors at maximal and a submaximal (10% of maximal EMG) effort. The submaximal cocontraction was repeated after sustained maximal contraction of elbow flexors. Surface EMG was recorded from the biceps brachii and triceps brachii muscles. Correlated EMG oscillations between the antagonistic muscles were quantified by the cross-correlation function (CCF) using rectified EMG for the EMG for the 3- to 15-Hz bands. The positive CCF peak in rectified EMG EMG, a negative CCF peak (i.e., out-of-phase oscillations) during submaximal cocontraction was smaller compared with maximal cocontraction but increased after the sustained contraction. Across subjects, the degree of reduction in maximal EMG amplitude after the sustained contraction was correlated with the amount of change in the CCF peak in EMG oscillations between antagonistic muscles occur during intended cocontraction, and 2) the magnitude of these correlated oscillations increases with the activation level of pools of spinal motor neurons and neuromuscular fatigue.

  7. Frequent epigenetic inactivation of Wnt antagonist genes in breast cancer

    Science.gov (United States)

    Suzuki, H; Toyota, M; Caraway, H; Gabrielson, E; Ohmura, T; Fujikane, T; Nishikawa, N; Sogabe, Y; Nojima, M; Sonoda, T; Mori, M; Hirata, K; Imai, K; Shinomura, Y; Baylin, S B; Tokino, T

    2008-01-01

    Although mutation of APC or CTNNB1 (β-catenin) is rare in breast cancer, activation of Wnt signalling is nonetheless thought to play an important role in breast tumorigenesis, and epigenetic silencing of Wnt antagonist genes, including the secreted frizzled-related protein (SFRP) and Dickkopf (DKK) families, has been observed in various tumours. In breast cancer, frequent methylation and silencing of SFRP1 was recently documented; however, altered expression of other Wnt antagonist genes is largely unknown. In the present study, we found frequent methylation of SFRP family genes in breast cancer cell lines (SFRP1, 7 out of 11, 64%; SFRP2, 11 out of 11, 100%; SFRP5, 10 out of 11, 91%) and primary breast tumours (SFRP1, 31 out of 78, 40%; SFRP2, 60 out of 78, 77%; SFRP5, 55 out of 78, 71%). We also observed methylation of DKK1, although less frequently, in cell lines (3 out of 11, 27%) and primary tumours (15 out of 78, 19%). Breast cancer cell lines express various Wnt ligands, and overexpression of SFRPs inhibited cancer cell growth. In addition, overexpression of a β-catenin mutant and depletion of SFRP1 using small interfering RNA synergistically upregulated transcriptional activity of T-cell factor/lymphocyte enhancer factor. Our results confirm the frequent methylation and silencing of Wnt antagonist genes in breast cancer, and suggest that their loss of function contributes to activation of Wnt signalling in breast carcinogenesis. PMID:18283316

  8. Abiotic conditions affect floral antagonists and mutualists of Impatiens capensis (Balsaminaceae).

    Science.gov (United States)

    Soper Gorden, Nicole L; Adler, Lynn S

    2013-04-01

    While the effect of abiotic factors on leaf herbivory is well known, the relative importance of abiotic conditions influencing both mutualists and antagonists is less well understood. Species interactions could enhance or reduce the direct effects of abiotic factors, depending on how mutualists and antagonists respond to abiotic conditions. We manipulated soil nutrients and shade in a factorial design and measured soil moisture in the annual Impatiens capensis. We then measured interactions with mutualists (two pollinating species) and antagonists (herbivores, florivores, nectar thieves, and flower bud gallers), as well as plant growth, floral rewards, and plant reproduction. Fertilizer increased plant growth, floral attractiveness, mutualist and antagonist interactions, and plant reproduction. Shade had no effects, and soil moisture was negatively associated with plant growth and reproduction. All effects were additive. Mutualist and antagonist floral interactions both increased on fertilized plants, but antagonists increased at a greater rate, leading to a larger ratio of antagonist to mutualist interactions on fertilized plants. Despite having more antagonists, fertilized plants still had significantly higher reproduction, suggesting higher tolerance to antagonists. Abiotic effects can have consistent effects on antagonists and mutualists, and on both floral and leaf antagonists. However, tolerance to antagonisms increased in favorable conditions. Thus, the direct positive effects of favorable abiotic conditions on plants outweighed negative indirect effects via increased antagonisms, which may lead to selection to grow in high-nutrient microsites in spite of increased herbivory.

  9. Fosaprepitant for the prevention of chemotherapy-induced nausea and vomiting

    DEFF Research Database (Denmark)

    Ruhlmann, Christina H. B.; Herrstedt, Jørn

    2012-01-01

    For patients receiving cancer chemotherapy, the ongoing development of antiemetic treatment is of significant importance. Patients consider nausea and vomiting among the most distressing symptoms of chemotherapy, and as new antiemetics have been very successful in prevention of vomiting, agents...... effective against nausea have become one of the major unmet needs. The neurokinin (NK)(1) receptor antagonist aprepitant potentiates the antiemetic efficacy of the combination of a serotonin receptor antagonist and a corticosteroid. Fosaprepitant (intravenous prodrug of aprepitant) given as a single...

  10. Prevention: Exercise

    Medline Plus

    Full Text Available ... Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen ...

  11. Prevention: Exercise

    Medline Plus

    Full Text Available ... Injections PREVENTION Lifestyle Choices 10 Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen Your Core! Stretching/Flexibility Aerobic Exercise ...

  12. Prevention: Exercise

    Medline Plus

    Full Text Available ... Watchful Waiting and Education Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 ...

  13. A selective and potent CXCR3 antagonist SCH 546738 attenuates the development of autoimmune diseases and delays graft rejection

    Directory of Open Access Journals (Sweden)

    Jenh Chung-Her

    2012-01-01

    Full Text Available Abstract Background The CXCR3 receptor and its three interferon-inducible ligands (CXCL9, CXCL10 and CXCL11 have been implicated as playing a central role in directing a Th1 inflammatory response. Recent studies strongly support that the CXCR3 receptor is a very attractive therapeutic target for treating autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis and psoriasis, and to prevent transplant rejection. We describe here the in vitro and in vivo pharmacological characterizations of a novel and potent small molecule CXCR3 antagonist, SCH 546738. Results In this study, we evaluated in vitro pharmacological properties of SCH 546738 by radioligand receptor binding and human activated T cell chemotaxis assays. In vivo efficacy of SCH 546738 was determined by mouse collagen-induced arthritis, rat and mouse experimental autoimmune encephalomyelitis, and rat cardiac transplantation models. We show that SCH 546738 binds to human CXCR3 with a high affinity of 0.4 nM. In addition, SCH 546738 displaces radiolabeled CXCL10 and CXCL11 from human CXCR3 with IC50 ranging from 0.8 to 2.2 nM in a non-competitive manner. SCH 546738 potently and specifically inhibits CXCR3-mediated chemotaxis in human activated T cells with IC90 about 10 nM. SCH 546738 attenuates the disease development in mouse collagen-induced arthritis model. SCH 546738 also significantly reduces disease severity in rat and mouse experimental autoimmune encephalomyelitis models. Furthermore, SCH 546738 alone achieves dose-dependent prolongation of rat cardiac allograft survival. Most significantly, SCH 546738 in combination with CsA supports permanent engraftment. Conclusions SCH 546738 is a novel, potent and non-competitive small molecule CXCR3 antagonist. It is efficacious in multiple preclinical disease models. These results demonstrate that therapy with CXCR3 antagonists may serve as a new strategy for treatment of autoimmune diseases, including rheumatoid arthritis and

  14. Protection from fatal viral encephalomyelitis: AMPA receptor antagonists have a direct effect on the inflammatory response to infection

    Science.gov (United States)

    Greene, Ivorlyne P.; Lee, Eun-Young; Prow, Natalie; Ngwang, Brownhilda; Griffin, Diane E.

    2008-01-01

    Neuronal cell death during fatal acute viral encephalomyelitis can result from damage caused by virus replication, glutamate excitotoxicity, and the immune response. A neurovirulent strain of the alphavirus Sindbis virus (NSV) causes fatal encephalomyelitis associated with motor neuron death in adult C57BL/6 mice that can be prevented by treatment with the prototypic noncompetitive α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) glutamate receptor antagonist GYKI 52466 [Nargi-Aizenman J, et al. (2004) Ann Neurol 55:541–549]. To determine the mechanism of protection, NSV-infected mice were treated with 7-acetyl-5-(4-aminophenyl)-8(R)-methyl-8,9-dihydro-7H-1,3-dioxolo-(4,5-h)-benzodiazepine (talampanel), a potent, orally available member of the 2,3 benzodiazepine class of noncompetitive AMPA glutamate receptor antagonists. Talampanel-treated mice were protected from NSV-induced paralysis and death. Examination of the brain during infection showed significantly less mononuclear cell infiltration and no increase in astrocyte expression of glial fibrillary acidic protein in treated mice compared with untreated mice. Lack of CNS inflammation was attributable to failure of treated mice to induce activation and proliferation of lymphocytes in secondary lymphoid tissue in response to infection. Antibody responses to NSV were also suppressed by talampanel treatment, and virus clearance was delayed. These studies reveal a previously unrecognized effect of AMPA receptor antagonists on the immune response and suggest that prevention of immune-mediated damage, in addition to inhibition of excitotoxicity, is a mechanism by which these drugs protect from death of motor neurons caused by viral infection. PMID:18296635

  15. Role of angiotensin II type 1 receptor antagonists in the treatment of hypertension in patients aged >or=65 years.

    Science.gov (United States)

    Gradman, Alan H

    2009-01-01

    Systolic blood pressure (SBP) increases with age, and hypertension affects approximately two-thirds of adults in the US aged >60 years. Blood pressure (BP) increases as a consequence of age-related structural changes in large arteries, which lead to loss of elasticity and reduced vascular compliance. Increased pulse wave velocity augments SBP, resulting in a high prevalence of isolated systolic hypertension. Because age itself elevates cardiovascular risk, effective treatment of hypertension in an older (aged >or=65 years) patient population prevents many more events per 1000 patients treated than treatment of younger hypertensive patients. Recommendations for treating hypertension are similar in older patients compared with the general population. The Seventh Report of the Joint National Committee on Detection, Prevention, Evaluation, and Treatment of High Blood Pressure recommends target BP goals of hypertension, and treatment goals to include patients with coronary artery disease, other types of vascular disease and heart failure. Randomized clinical trials have demonstrated the efficacy of calcium channel antagonists (calcium channel blockers [CCBs]), low-dose diuretics, ACE inhibitors and angiotensin II type 1 receptor antagonists (angiotensin receptor blockers [ARBs]) in reducing the risk of stroke and other adverse cardiovascular outcomes in older patients; beta-adrenoceptor antagonists are less effective in terms of endpoint reduction. The majority of older patients require two or more drugs to achieve BP goals. Despite active treatment, half of these patients do not achieve target BP, in part because of the reluctance of physicians to intensify treatment, a phenomenon referred to as 'clinical inertia'. ARBs are effective antihypertensive agents in older patients and have been shown to reduce cardiovascular endpoints in patients with hypertension, diabetic nephropathy, cerebrovascular disease and heart failure. ARBs produce additive BP reduction when

  16. Predictions of in vivo prolactin levels from in vitro k I values of d 2 receptor antagonists using an agonist-antagonist interaction model

    NARCIS (Netherlands)

    Petersson, K.J.; Vermeulen, A.M.J.; Friberg, L.E.

    2013-01-01

    Prolactin elevation is a side effect of all currently available D2 receptor antagonists used in the treatment of schizophrenia. Prolactin elevation is the result of a direct antagonistic D2 effect blocking the tonic inhibition of prolactin release by dopamine. The aims of this work were to assess

  17. Serotonin-1A receptor stimulation mediates effects of a metabotropic glutamate 2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and an N-methyl-D-aspartate receptor antagonist, ketamine, in the novelty-suppressed feeding test.

    Science.gov (United States)

    Fukumoto, Kenichi; Iijima, Michihiko; Chaki, Shigeyuki

    2014-06-01

    α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor stimulation has been proposed to be a common neural mechanism of metabotropic glutamate 2/3 (mGlu2/3) receptor antagonists and an N-methyl-D-aspartate receptor antagonist, ketamine, exerting antidepressant effects in animal models. AMPA receptor stimulation has also been shown to mediate an increase in the extracellular level of serotonin (5-HT) in the medial prefrontal cortex by an mGlu2/3 receptor antagonist in rats. However, involvement of the serotonergic system in the actions of mGlu2/3 receptor antagonists and ketamine is not well understood. We investigated involvement of the serotonergic system in the effects of an mGlu2/3 receptor antagonist, 2S-2-amino-2-(1S,2S-2-carboxycycloprop-1-yl)-3-(xanth-9-yl)propanoic acid (LY341495), and ketamine in a novelty-suppressed feeding (NSF) test in mice. The intraperitoneal administration of LY341495 or ketamine at 30 min prior to the test significantly shortened latency to feed, which was attenuated by an AMPA receptor antagonist, 2,3-dioxo-6-nitro-1,2,3,4-tetrahydr-obenzo[f]quinoxaline-7-sulfonamide (NBQX). The effects of LY341495 and ketamine were no longer observed in mice pretreated with a tryptophan hydroxylase inhibitor, para-chlorophenylalanine (PCPA). Moreover, the effects of LY341495 and ketamine were blocked by a 5-HT1A receptor antagonist, N-{2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl}-N-(2-pyridynyl) cyclohexane-carboxamide (WAY100635), but not by a 5-HT2A/2C receptor antagonist, ritanserin. Likewise, an AMPA receptor potentiator, 2,3-dihydro-1,4-benzodioxin-7-yl-(1-piperidyl)methanone (CX546), shortened latency to feed in the NSF test, which was prevented by depletion of 5-HT and blockade of 5-HT1A receptor. These results suggest that AMPA receptor-dependent 5-HT release and subsequent 5-HT1A receptor stimulation may be involved in the actions of an mGlu2/3 receptor antagonist and ketamine in the NSF test.

  18. Antagonistic activity of dairy lactobacilli against gram-foodborne pathogens - doi: 10.4025/actascitechnol.v36i1.18776

    Directory of Open Access Journals (Sweden)

    Marco Geria

    2014-01-01

    Full Text Available Thirty-five strains of lactic acid bacteria were isolated from artisanal raw milk cheese, presumptively identified and tested against one dairy Escherichia coli strain. Six lactobacilli, exhibiting antagonistic activity, were identified at the species level and their action was evaluated against four strains of Gram-foodborne pathogens (Escherichia coli O26, Escherichia coli O157:H7, Salmonella spp. 1023, and Salmonella Typhimurium and the control strain Escherichia coli ATCC 45922. The antagonistic activity was determined by spot method and the inhibition zones were measured by Autodesk AutoCAD 2007. Three strains, all Lactobacillus paracasei, were active against all the pathogens; the other strains, all Lactobacillus plantarum, showed antagonistic activity against some pathogens. This study highlights the intense and different antagonistic activity induced by lactobacilli against various foodborne pathogens thus demonstrating that using selected lactic acid bacteria strains as adjunct cultures could be an effective strategy to prevent the development of foodborne pathogens in artisanal raw milk cheeses, and thus improving their safety.

  19. The HIPOGAIA study: Monitoring of oral anticoagulation with vitamin K antagonists in the municipality of Gaia.

    Science.gov (United States)

    Guedes, Marta; Rego, Catarina

    2016-09-01

    Anticoagulant therapy is an effective measure in preventing thromboembolic adverse events. Of the diseases in which this treatment is indicated, atrial fibrillation (AF) has the highest incidence worldwide, with a prevalence of 1.5-2%. To assess the quality of monitoring of patients with non-valvular AF under oral anticoagulation with vitamin K antagonists in Vila Nova de Gaia healthcare units. This was a retrospective observational analytical study of the population registered at the 37 healthcare units of the Vila Nova de Gaia and Espinho health center area under oral anticoagulation with vitamin K antagonists during 2014. The data were collected using TAONet(®) software. The variables studied were health units, age, gender, INR value, time in therapeutic range (TTR) and medication. TTR was calculated for each patient using the Rosendaal linear interpolation method. It was stipulated that each patient should have undergone at least six INR measurements. Data were analyzed using Microsoft Excel(®) 2010 and SPSS(®) version 21, using descriptive and inferential statistical techniques. A total of 479 patients with non-valvular AF were studied, corresponding to 5883 INR tests. Mean TTR was 67.4±6.5%, and 35.3% of patients exhibited poor control (TTR <60%). Our study showed moderate control of coagulation parameters, but better than in many international clinical trials and in another Portuguese observational study. Nevertheless, there is still room for improvement in anticoagulation monitoring in primary health care. Copyright © 2016 Sociedade Portuguesa de Cardiologia. Publicado por Elsevier España, S.L.U. All rights reserved.

  20. Antagonistic activity of Bacillus probiotics against bacteria isolates of oral cavity of patients with periodontitis

    Directory of Open Access Journals (Sweden)

    O. Rivis

    2013-03-01

    Full Text Available It is admitted that the normal human microflora plays an important role in supporting homeostasis, forming immune mechanisms and metabolism. Nowadays, there is a constant growth of different diseases due to microbiological imbalance in a human organism. Preparations containing “good bacteria” have been used for therapeutic purposes since ancient times. The mechanism of probiotics influence comprises their ability to compete for adhesion sites with the pathogens, to exhibit antagonistic activity and stimulate the immune system of a host. Most of probiotics commonly used are the spores of Bacillus. Initially the main focus of their use was the prevention of gastrointestinal disorders. So, the use of probiotics in dental practice is a poorly studied area. In recent years, probiotics have been investigated to provide the oral health. Therefore the study of using probiotics for correction of the oral microflora in people with inflammatory diseases of the periodontal tissues is promising. Our previous studies have shown changes in microbial community of an oral cavity in patients with periodontitis. In particular, the reducing number of obligate microorganisms and increasing number of pathogens was demonstrated. The paper describes the current data on the potential benefits and basic properties of the Bacillus spore probiotics, which demonstrate the viability and relevance in dental practice. The study tested antagonistic activity of commercial Bacillus probiotics "Biosporin" ("Biopharma", Ukraine, "Subalinum" ("Biopharma", Ukraine, "Normaflore" ("Sanofi-Aventis Zrt.", Hungary and "Enterogermina" ("Sanofi-Synthelabo SpA", Italy against clinical strains of microorganisms isolated from the oral cavity of patients with periodontitis. Thus, further studies on the role of spore probiotics in correction of the oral cavity microflora as a part of complex treatment of periodontitis should be carried out.

  1. The effect of the leukotriene antagonist pranlukast on pediatric acute otitis media.

    Science.gov (United States)

    Nakamura, Yoshihisa; Hamajima, Yuki; Suzuki, Motohiko; Esaki, Shinichi; Yokota, Makoto; Oshika, Masanori; Takagi, Ippei; Yasui, Keiko; Miyamoto, Naoya; Sugiyama, Kazuko; Nakayama, Meiho; Murakami, Shingo

    2016-08-01

    Conventional treatment for acute otitis media mainly targets bacteria with antibiotics, neglecting to control for mediators of inflammation. Mediators of inflammation, such as leukotrienes, have been identified in patients with acute otitis media (AOM) or subsequent secretory otitis media (SOM). They can cause functional eustachian tube dysfunction or increase mucous in the middle ear, causing persistent SOM following AOM. The objective of the present study was to evaluate whether or not administration of pranlukast, a widely used leukotriene C4, D4, and E4 antagonist, together with antibiotics could inhibit the progression to SOM. Children with AOM, who were from two to 12 years old, were randomly divided into two groups as follows: a control group in which 50 patients received antibiotic-based conventional treatment according to guidelines for treating AOM proposed by the Japan Otological Society (version 2006); and a pranlukast group, in which 52 patients were administered pranlukast for up to 28 days as well as given conventional treatment. Cases were regarded as persistent SOM when a tympanogram was type B or C2 four weeks after treatment was initiated. Two patients in the pranlukast group and 3 patients in the control group were excluded because they relapsed AOM within 28 days after initial treatment. Therefore, the analysis included 50 and 47 subjects in the pranlukast and control groups, respectively. The percentage of patients diagnosed with persistent SOM (22.0%) was significantly smaller in the pranlukast group compared with the control group (44.7%) (p = 0.018, chi-squared test). The results indicate that combined treatment of AOM with antibiotics and a leukotriene antagonist to control inflammation is useful for preventing progression to persistent SOM. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Histamine-2 receptor antagonist famotidine modulates cardiac stem cell characteristics in hypertensive heart disease

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    Sherin Saheera

    2017-10-01

    Full Text Available Background Cardiac stem cells (CSCs play a vital role in cardiac homeostasis. A decrease in the efficiency of cardiac stem cells is speculated in various cardiac abnormalities. The maintenance of a healthy stem cell population is essential for the prevention of adverse cardiac remodeling leading to cardiac failure. Famotidine, a histamine-2 receptor antagonist, is currently used to treat ulcers of the stomach and intestines. In repurposing the use of the drug, reduction of cardiac hypertrophy and improvement in cardiac function of spontaneously hypertensive rats (SHR was reported by our group. Given that stem cells are affected in cardiac pathologies, the effect of histamine-2 receptor antagonism on CSC characteristics was investigated. Methods To examine whether famotidine has a positive effect on CSCs, spontaneously hypertensive rats (SHR treated with the drug were sacrificed; and CSCs isolated from atrial appendages was evaluated. Six-month-old male SHRs were treated with famotidine (30 mg/kg/day for two months. The effect of famotidine treatment on migration, proliferation and survival of CSCs was compared with untreated SHRs and normotensive Wistar rats. Results Functional efficiency of CSCs from SHR was compromised relative to that in Wistar rat. Famotidine increased the migration and proliferation potential, along with retention of stemness of CSCs in treated SHRs. Cellular senescence and oxidative stress were also reduced. The expression of H2R was unaffected by the treatment. Discussion As anticipated, CSCs from SHRs were functionally impaired. Stem cell attributes of famotidine-treated SHRs was comparable to that of Wistar rats. Therefore, in addition to being cardioprotective, the histamine 2 receptor antagonist modulated cardiac stem cells characteristics. Restoration of stem cell efficiency by famotidine is possibly mediated by reduction of oxidative stress as the expression of H2R was unaffected by the treatment. Maintenance of

  3. Administration of an oxytocin receptor antagonist attenuates sexual motivation in male rats.

    Science.gov (United States)

    Blitzer, D S; Wells, T E; Hawley, W R

    2017-08-01

    In male rats, oxytocin impacts both sexual arousal and certain types of consummatory sexual behaviors. However, the role of oxytocin in the motivational aspects of sexual behavior has received limited attention. Given the role that oxytocin signaling plays in consummatory sexual behaviors, it was hypothesized that pharmacological attenuation of oxytocin signaling would reduce sexual motivation in male rats. Sexually experienced Long-Evans male rats were administered either an oxytocin receptor antagonist (L368,899 hydrochloride; 1mg/kg) or vehicle control into the intraperitoneal cavity 40min prior to placement into the center chamber of a three-chambered arena designed to assess sexual motivation. During the 20-minute test, a sexually experienced stimulus male rat and a sexually receptive stimulus female rat were separately confined to smaller chambers that were attached to the larger end chambers of the arena. However, physical contact between test and stimulus rats was prevented by perforated dividers. Immediately following the sexual motivation test, test male rats were placed with a sexually receptive female to examine consummatory sexual behaviors. Although both drug and vehicle treated rats exhibited a preference for the female, treatment with an oxytocin receptor antagonist decreased the amount of time spent with the female. There were no differences between drug and vehicle treated rats in either general activity, exploratory behaviors, the amount of time spent near the stimulus male rat, or consummatory sexual behaviors. Extending previous findings, these results indicate that oxytocin receptors are involved in sexual motivation in male rats. Copyright © 2017 Elsevier Inc. All rights reserved.

  4. Formulation development for the orexin receptor antagonist almorexant: assessment in two clinical studies

    Directory of Open Access Journals (Sweden)

    Dingemanse J

    2014-04-01

    Full Text Available Jasper Dingemanse, Martine Gehin, Hans Gabriel Cruz, Petra HoeverDepartment of Clinical Pharmacology, Actelion Pharmaceuticals Ltd, Allschwil, SwitzerlandAbstract: Almorexant, a dual orexin receptor antagonist, was investigated for the treatment of insomnia. The following observations initiated further formulation development: the active pharmaceutical ingredient (API was sticking to the apparatus used during tablet compression; almorexant has an absolute bioavailability of 11.2%; and almorexant modestly decreased the latency to persistent sleep by 10.4 minutes in patients. Two randomized crossover studies were performed to investigate the pharmacokinetics of several new formulations in healthy subjects. In study I, the old “sticky” tablet was compared to two new formulations developed to prevent sticking: a qualitatively similar tablet but with a larger API crystal size and a tablet with 30% more excipients as well as a larger API crystal size. This latter formulation was available in two strengths. The geometric mean ratios and 90% confidence interval of the area under the curve (AUC were within the bioequivalence range of 0.80–1.25 for the different comparisons between formulations. In study II, 100 mg of the reference tablet was compared to 25 and 50 mg of a liquid-filled hard gelatin capsule developed to increase the bioavailability of almorexant. The geometric mean ratios of the maximum concentration and AUC comparing the new 25 and 50 mg capsule formulations to the reference tablet did not exceed 0.25 and 0.50, respectively, indicating that the new capsule formulation did not increase the maximum concentration of or the total exposure to almorexant. In conclusion, a new tablet was developed but formulation development aimed at increasing the bioavailability of almorexant failed.Keywords: almorexant, orexin receptor antagonist, pharmacokinetics, formulation development, healthy subjects

  5. Ectopic pregnancy risk factors for ART patients undergoing the GnRH antagonist protocol: a retrospective study.

    Science.gov (United States)

    Weiss, A; Beck-Fruchter, R; Golan, J; Lavee, M; Geslevich, Y; Shalev, E

    2016-03-23

    In-vitro fertilization is a known risk factor for ectopic pregnancies. We sought to establish the risk factors for ectopic pregnancy in GnRH antagonist cycles examining patient and stimulation parameters with an emphasis on ovulation trigger. We conducted a retrospective, cohort study of 343 patients undergoing 380 assisted reproductive technology (ART) cycles with the GnRH antagonist protocol and achieving a clinical pregnancy from November 2010 through December 2015. Significant risk factors for ectopic pregnancy in the univariate analysis included prior Cesarean section (CS), endometriosis, mechanical factor infertility, longer stimulation, elevated estradiol and progesterone levels, GnRH agonist trigger, higher number of oocytes aspirated, and insemination technique. Independent risk factors for ectopic pregnancy in the multivariate analysis included GnRH agonist trigger, higher number of oocytes aspirated, insemination technique, and prior Cesarean section. Excessive ovarian response, IVF (as opposed to ICSI), prior Cesarean section and GnRH agonist trigger were found to be independent risk factors for ectopic pregnancy. Caution should be exercised before incorporating the GnRH agonist trigger for indications other than preventing OHSS. When excessive ovarian response leads to utilization of GnRH agonist trigger, strategies for preventing ectopic pregnancy, such as a freeze all policy or blastocyst transfer, should be considered. Further studies should elucidate whether adjusting the luteal support can reduce the ectopic pregnancy risk.

  6. Isolation, identification and selection of antagonistic yeast against Alternaria alternata infection and tenuazonic acid production in wine grapes from Argentina.

    Science.gov (United States)

    Prendes, Luciana P; Merín, María G; Fontana, Ariel R; Bottini, Rubén A; Ramirez, María L; Morata de Ambrosini, Vilma I

    2018-02-02

    Epiphytic isolates with yeast characteristics from grapes of the Malbec cultivar were obtained in order to find antagonists against Alternaria alternata. From a total of 111 isolates, 82% corresponded to the yeast-like organism Aureobasidium pullulans and the rest to the non-Saccharomyces yeasts Hanseniaspora uvarum (6.3%), Metschnikowia pulcherrima or spp. (5.4%), Cryptoccocus laurentti II (2.7%), Starmerella bacilaris or Candida zemplinina (2.7%) and Rhodotorula spp. (0.9%). The 22.4% (15 out of 67) of epiphytic yeasts and yeast-like organisms evaluated were able to reduce A. alternata infection from 0.0 to 4.4% when applied 2h previous to pathogen inoculation on wounds of grape berries. From these selected strains, 14 out of 15 strains completely prevented A. alternata infection (0.0%), which implies potential for field application. All Metschnikowia (pulcherrima or spp.), S. bacillaris and almost all H. uvarum evaluated strains showed antagonist capability against A. alternata. Meanwhile, none of the lesser nutritional requirement strains belonging to A. pullulans, Cr. laurenti II and Rhodotorula spp. did. All the yeasts with capacity to prevent A. alternata infection also reduced tenuazonic acid (TA) production by 81.2 to 99.8%, finding TA levels similar to negative controls. Therefore, the epiphytic yeasts selected are promising as biological control agents against Alternaria infection and toxin production in grapes for winemaking. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma.

    Science.gov (United States)

    Yarova, Polina L; Stewart, Alecia L; Sathish, Venkatachalem; Britt, Rodney D; Thompson, Michael A; P Lowe, Alexander P; Freeman, Michelle; Aravamudan, Bharathi; Kita, Hirohito; Brennan, Sarah C; Schepelmann, Martin; Davies, Thomas; Yung, Sun; Cholisoh, Zakky; Kidd, Emma J; Ford, William R; Broadley, Kenneth J; Rietdorf, Katja; Chang, Wenhan; Bin Khayat, Mohd E; Ward, Donald T; Corrigan, Christopher J; T Ward, Jeremy P; Kemp, Paul J; Pabelick, Christina M; Prakash, Y S; Riccardi, Daniela

    2015-04-22

    Airway hyperresponsiveness and inflammation are fundamental hallmarks of allergic asthma that are accompanied by increases in certain polycations, such as eosinophil cationic protein. Levels of these cations in body fluids correlate with asthma severity. We show that polycations and elevated extracellular calcium activate the human recombinant and native calcium-sensing receptor (CaSR), leading to intracellular calcium mobilization, cyclic adenosine monophosphate breakdown, and p38 mitogen-activated protein kinase phosphorylation in airway smooth muscle (ASM) cells. These effects can be prevented by CaSR antagonists, termed calcilytics. Moreover, asthmatic patients and allergen-sensitized mice expressed more CaSR in ASMs than did their healthy counterparts. Indeed, polycations induced hyperreactivity in mouse bronchi, and this effect was prevented by calcilytics and absent in mice with CaSR ablation from ASM. Calcilytics also reduced airway hyperresponsiveness and inflammation in allergen-sensitized mice in vivo. These data show that a functional CaSR is up-regulated in asthmatic ASM and targeted by locally produced polycations to induce hyperresponsiveness and inflammation. Thus, calcilytics may represent effective asthma therapeutics. Copyright © 2015, American Association for the Advancement of Science.

  8. Poison Prevention

    Science.gov (United States)

    ... Prevention Listen Español Text Size Email Print Share Poison Prevention Page Content Article Body Post the Poison Help number 1-800-222-1222 on the ... or empty container of a toxic substance, call Poison Help immediately. More than a million American children ...

  9. Influence of specific and non-specific endothelin receptor antagonists on renal morphology in rats with surgical renal ablation.

    Science.gov (United States)

    Nabokov, A; Amann, K; Wagner, J; Gehlen, F; Münter, K; Ritz, E

    1996-03-01

    Studies in experimental models of chronic renal failure suggest an important role for the endothelin system in the development of renal scarring. Endothelin receptor (ETR) anatagonists interfere with progression, but it has not been resolved (i) whether this is true for all models of renal damage, (ii) to what extent the effect is modulated by systemic blood pressure and (iii) whether the effect is similar for ETAR and ETA/ETBR antagonists. 5/6 subtotal nephrectomy (SNX) by surgical ablation in male Sprague-Dawley rats. Comparison of ACE inhibitor Trandolapril (0.1 mg/kg/day), ETAR antagonist BMS 182874 (30 mg/kg/day) and ETAR/ETBR antagonist Ro 46-2005 (30 mg/kg/day) by gavage. Duration of the experiment eight weeks. Systolic blood pressure by tail plethysmography. Perfusion fixation of kidneys and morphometric analysis ET-1 and ETA/ETBR by quantitative PCR. SNX caused a significant (P < 0.01) increase of systolic blood pressure (170 +/- 8.6 mmHg) compared to sham operated controls (131 +/- 5.3 mmHg). Blood pressure was significantly (P < 0.001) lower with Trandolapril (128 +/- 5.3 mmHg), but not with BMS 182874 (153 +/- 5.9 mmHg) or Ro 46-2005 (167 +/- 7.6 mmHg). Compared to sham operated rats (0.03 +/- 0.01) glomerulosclerosis index (GSI) was significantly (P < 0.01) higher in the untreated SNX group (0.9 +/- 0.15). Significantly lower GSI was found in Trandolapril treated (0.29 +/- 0.04), BMS 182874 treated (0.36 +/- 0.05), and Ro 46-2005 treated animals (0.45 +/- 0.11). The effect of BMS 182874 was accompanied by lower tubulointerstitial damage index. Mean glomerular volume was dramatically increased (P < 0.001) in SNX rats as compared to sham operated animals. This glomerular enlargement was partially prevented by Trandolapril (P < 0.05), but not by either ETR antagonist. ET-1 mRNA tended to be higher in SNX irrespective of treatment, while ETAR and ETBR mRNA were significantly lower. Both specific (ETAR) and non-specific (ETA/ETBR) endothelin antagonists

  10. Does protein binding modulate the effect of angiotensin II receptor antagonists?

    Directory of Open Access Journals (Sweden)

    Marc P Maillard

    2001-03-01

    Full Text Available IntroductionAngiotensin II AT 1-receptor antagonists are highly bound to plasma proteins (≥ 99%. With some antagonists, such as DuP-532, the protein binding was such that no efficacy of the drug could be demonstrated clinically. Whether protein binding interferes with the efficacy of other antagonists is not known. We have therefore investigated in vitro how plasma proteins may affect the antagonistic effect of different AT1-receptor antagonists.MethodsA radio-receptor binding assay was used to analyse the interaction between proteins and the ability of various angiotensin II (Ang II antagonists to block AT1-receptors. In addition, the Biacore technology, a new technique which enables the real-time monitoring of binding events between two molecules, was used to evaluate the dissociation rate constants of five AT1-receptor antagonists from human serum albumin.ResultsThe in vitro AT 1-antagonistic effects of different Ang II receptor antagonists were differentially affected by the presence of human plasma, with rightward shifts of the IC50 ranging from one to several orders of magnitude. The importance of the shift correlates with the dissociation rate constants of these drugs from albumin. Our experiments also show that the way that AT1-receptor antagonists bind to proteins differs from one compound to another. These results suggest that the interaction with plasma proteins appears to modulate the efficacy of some Ang II antagonists.ConclusionAlthough the high binding level of Ang II receptor antagonist to plasma proteins appears to be a feature common to this class of compounds, the kinetics and characteristics of this binding is of great importance. With some antagonists, protein binding interferes markedly with their efficacy to block AT1-receptors.

  11. Sexually antagonistic "zygotic drive" of the sex chromosomes.

    Directory of Open Access Journals (Sweden)

    William R Rice

    2008-12-01

    Full Text Available Genomic conflict is perplexing because it causes the fitness of a species to decline rather than improve. Many diverse forms of genomic conflict have been identified, but this extant tally may be incomplete. Here, we show that the unusual characteristics of the sex chromosomes can, in principle, lead to a previously unappreciated form of sexual genomic conflict. The phenomenon occurs because there is selection in the heterogametic sex for sex-linked mutations that harm the sex of offspring that does not carry them, whenever there is competition among siblings. This harmful phenotype can be expressed as an antagonistic green-beard effect that is mediated by epigenetic parental effects, parental investment, and/or interactions among siblings. We call this form of genomic conflict sexually antagonistic "zygotic drive", because it is functionally equivalent to meiotic drive, except that it operates during the zygotic and postzygotic stages of the life cycle rather than the meiotic and gametic stages. A combination of mathematical modeling and a survey of empirical studies is used to show that sexually antagonistic zygotic drive is feasible, likely to be widespread in nature, and that it can promote a genetic "arms race" between the homo- and heteromorphic sex chromosomes. This new category of genomic conflict has the potential to strongly influence other fundamental evolutionary processes, such as speciation and the degeneration of the Y and W sex chromosomes. It also fosters a new genetic hypothesis for the evolution of enigmatic fitness-reducing traits like the high frequency of spontaneous abortion, sterility, and homosexuality observed in humans.

  12. Central actions of a novel and selective dopamine antagonist

    International Nuclear Information System (INIS)

    Schulz, D.W.

    1985-01-01

    Receptors for the neurotransmitter dopamine traditionally have been divided into two subgroups: the D 1 class, which is linked to the stimulation of adenylate cyclase-activity, and the D 2 class which is not. There is much evidence suggesting that it is the D 2 class which is not. There is much evidence suggesting that it is the D 2 dopamine receptor that mediates the physiological and behavioral actions of dopamine in the intact animal. However, the benzazepine SCH23390 is a dopamine antagonist which has potent behavioral actions while displaying apparent neurochemical selectivity for the D 1 class of dopamine receptors. The purpose of this dissertation was to (1) confirm and characterize this selectivity, and (2) test certain hypothesis related to possible modes of action of SCH233390. The inhibition of adenylate cyclase by SCH23390 occurred via an action at the dopamine receptor only. A radiolabeled analog of SCH23390 displayed the receptor binding properties of a specific high-affinity ligand, and regional receptor densities were highly correlated with dopamine levels. The subcellular distribution of [ 3 H]-SCH23390 binding did not correspond completely with that of dopamine-stimulated adenylate cyclase. The neurochemical potency of SCH23390 as a D 1 receptor antagonist was preserved following parental administration. A variety of dopamine agonists and antagonists displayed a high correlation between their abilities to compete for [ 3 H]-SCH23390 binding in vitro and to act at an adenylate cyclase-linked receptor. Finally, the relative affinities of dopamine and SCH23390 for both D 1 receptors and [ 3 H]-SCH23390 binding sites were comparable. It is concluded that the behavioral effects of SCH23390 are mediated by actions at D 1 dopamine receptors only, and that the physiological importance of this class of receptors should be reevaluated

  13. Classification and virtual screening of androgen receptor antagonists.

    Science.gov (United States)

    Li, Jiazhong; Gramatica, Paola

    2010-05-24

    Computational tools, such as quantitative structure-activity relationship (QSAR), are highly useful as screening support for prioritization of substances of very high concern (SVHC). From the practical point of view, QSAR models should be effective to pick out more active rather than inactive compounds, expressed as sensitivity in classification works. This research investigates the classification of a big data set of endocrine-disrupting chemicals (EDCs)-androgen receptor (AR) antagonists, mainly aiming to improve the external sensitivity and to screen for potential AR binders. The kNN, lazy IB1, and ADTree methods and the consensus approach were used to build different models, which improve the sensitivity on external chemicals from 57.1% (literature) to 76.4%. Additionally, the models' predictive abilities were further validated on a blind collected data set (sensitivity: 85.7%). Then the proposed classifiers were used: (i) to distinguish a set of AR binders into antagonists and agonists; (ii) to screen a combined estrogen receptor binder database to find out possible chemicals that can bind to both AR and ER; and (iii) to virtually screen our in-house environmental chemical database. The in silico screening results suggest: (i) that some compounds can affect the normal endocrine system through a complex mechanism binding both to ER and AR; (ii) new EDCs, which are nonER binders, but can in silico bind to AR, are recognized; and (iii) about 20% of compounds in a big data set of environmental chemicals are predicted as new AR antagonists. The priority should be given to them to experimentally test the binding activities with AR.

  14. Proton pump inhibitors versus histamine 2 receptor antagonists for stress ulcer prophylaxis in critically ill patients: a systematic review and meta-analysis.

    Science.gov (United States)

    Alhazzani, Waleed; Alenezi, Farhan; Jaeschke, Roman Z; Moayyedi, Paul; Cook, Deborah J

    2013-03-01

    Critically ill patients may develop bleeding caused by stress ulceration. Acid suppression is commonly prescribed for patients at risk of stress ulcer bleeding. Whether proton pump inhibitors are more effective than histamine 2 receptor antagonists is unclear. To determine the efficacy and safety of proton pump inhibitors vs. histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in the ICU. We searched Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, ACPJC, CINHAL, online trials registries (clinicaltrials.gov, ISRCTN Register, WHO ICTRP), conference proceedings databases, and reference lists of relevant articles. Randomized controlled parallel group trials comparing proton pump inhibitors to histamine 2 receptor antagonists for the prevention of upper gastrointestinal bleeding in critically ill patients, published before March 2012. Two reviewers independently applied eligibility criteria, assessed quality, and extracted data. The primary outcomes were clinically important upper gastrointestinal bleeding and overt upper gastrointestinal bleeding; secondary outcomes were nosocomial pneumonia, ICU mortality, ICU length of stay, and Clostridium difficile infection. Trial authors were contacted for additional or clarifying information. Fourteen trials enrolling a total of 1,720 patients were included. Proton pump inhibitors were more effective than histamine 2 receptor antagonists at reducing clinically important upper gastrointestinal bleeding (relative risk 0.36; 95% confidence interval 0.19-0.68; p = 0.002; I = 0%) and overt upper gastrointestinal bleeding (relative risk 0.35; 95% confidence interval 0.21-0.59; p inhibitors and histamine 2 receptor antagonists in the risk of nosocomial pneumonia (relative risk 1.06; 95% confidence interval 0.73-1.52; p = 0.76; I = 0%), ICU mortality (relative risk 1.01; 95% confidence interval 0.83-1.24; p = 0.91; I = 0%), or ICU length of stay (mean difference -0.54 days; 95

  15. Membrane Formation in Liquids by Adding an Antagonistic Salt

    Directory of Open Access Journals (Sweden)

    Koichiro Sadakane

    2018-03-01

    Full Text Available Antagonistic salts are composed of hydrophilic and hydrophobic ions. In a binary mixture, such as water and organic solvent, these ion pairs preferentially dissolve to those phases, respectively, and there is a coupling between the charge density and the composition. The heterogeneous distribution of ions forms a large electric double layer at the interface between these solvents. This reduces the interfacial tension between water and organic solvent, and stabilizes an ordered structure, such as a membrane. These phenomena have been extensively studied from both theoretical and experimental point of view. In addition, the numerical simulations can reproduce such ordered structures.

  16. Synthesis of carbon-11 labelled calcium channel antagonists

    Energy Technology Data Exchange (ETDEWEB)

    Holschbach, M.; Roden, W.; Hamkens, W. (Kernforschungsanlage Juelich GmbH (Germany). Inst. fuer Medizin)

    1991-04-01

    A useful synthetic approach to carbon-11 labelled 1,4-dihydropyridines is described. Carbon-11 labelled calcium channel antagonists {sup 11}C-Nifedipine, {sup 11}C-Nisoldipine, {sup 11}C-nitrendipine and {sup 11}C-CF{sub 3}-Nifedipine were synthesized by a modified Hantzsch method using protected carboxy functions. Deprotection of the carboxylic acids by alkaline hydrolysis followed by conversion into the corresponding potassium salts and subsequent methylation with {sup 11}CH{sub 3}I produced the labelled compounds in very good chemical and radiochemical yields (94%). (author).

  17. The opiate antagonist, naltrexone, in the treatment of trichotillomania

    DEFF Research Database (Denmark)

    Grant, Jon E; Odlaug, Brian Lawrence; Schreiber, Liana R N

    2014-01-01

    Trichotillomania (TTM) is characterized by repetitive hair pulling resulting in hair loss. Data on the pharmacological treatment of TTM are limited. This study examined the opioid antagonist, naltrexone, in adults with TTM who had urges to pull their hair. Fifty-one individuals with TTM were...... randomized to naltrexone or placebo in an 8-week, double-blind trial. Subjects were assessed with measures of TTM severity and selected cognitive tasks. Naltrexone failed to demonstrate significantly greater reductions in hair pulling compared to placebo. Cognitive flexibility, however, significantly...

  18. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, R. D.; Wang, S. V.

    2014-01-01

    PurposeWe present a database of prescription drugs and international normalized ratio (INR) data and the applied methodology for its use to assess drug-drug interactions with vitamin K antagonists (VKAs). We use the putative interaction between VKAs and tramadol as a case study. MethodsWe used...... definitions, and other drugs. ResultsWe identified 513 VKA users with at least 1 INR measurement 4.0 and concomitant tramadol and VKA exposure during the observation period. The overall IRR was 1.80 (95% confidence interval [CI], 1.53-2.10), with a stronger association among users of phenprocoumon compared...

  19. ANTIHYPERTENSIVE TREATMENT IN ELDERLY PATIENTS WITH DIHYDROPYRIDINE CALCIUM ANTAGONISTS

    Directory of Open Access Journals (Sweden)

    Y. A. Karpov

    2006-01-01

    Full Text Available The proofs of necessity of active arterial hypertension (AH treatment in elderly patients are given. Peculiarities of pathogenesis of AH in elderly patients, connected predominantly with loss of big arteries elasticity and reasoning widely spread of isolated systolic AH in these patients, are discussed. Advantages of dihydropyridine calcium antagonists (DPCA for AH treatment in elderly patients are proved, safety of treatment with DPCA is discussed. Data of clinical studies is analyzed. Analysis of target levels of blood pressure for antihypertensive treatment in elderly hypertensive patients is made. As a conclusion DPCA are the medicines of choice for AH treatment in elderly patients.

  20. Membrane formation in liquids by adding an antagonistic salt

    Science.gov (United States)

    Sadakane, Koichiro; Seto, Hideki

    2018-03-01

    Antagonistic salts are composed of hydrophilic and hydrophobic ions. In a binary mixture, such as water and organic solvent, these ion pairs preferentially dissolve to those phases, respectively, and there is a coupling between the charge density and the composition. The heterogeneous distribution of ions forms a large electric double layer at the interface between these solvents. This reduces the interfacial tension between water and organic solvent, and stabilizes an ordered structure, such as a membrane. These phenomena have been extensively studied from both theoretical and experimental point of view. In addition, the numerical simulations can reproduce such ordered structures.

  1. Preventive analgesia

    DEFF Research Database (Denmark)

    Dahl, Jørgen B; Kehlet, Henrik

    2011-01-01

    This paper will discuss the concepts of pre-emptive and preventive analgesia in acute and persistent postsurgical pain, based on the most recent experimental and clinical literature, with a special focus on injury-induced central sensitization and the development from acute to chronic pain. Recent...... of preventive analgesia for persistent postoperative pain are promising. However, clinicians must be aware of the demands for improved design of their clinical studies in order to get more conclusive answers regarding the different avenues for intervention. Summary: The concept of preventive analgesia is still...

  2. Alphavirus Encephalomyelitis: Mechanisms and Approaches to Prevention of Neuronal Damage.

    Science.gov (United States)

    Griffin, Diane E

    2016-07-01

    Mosquito-borne viruses are important causes of death and long-term neurologic disability due to encephalomyelitis. Studies of mice infected with the alphavirus Sindbis virus have shown that outcome is dependent on the age and genetic background of the mouse and virulence of the infecting virus. Age-dependent susceptibility reflects the acquisition by neurons of resistance to virus replication and virus-induced cell death with maturation. In mature mice, the populations of neurons most susceptible to infection are in the hippocampus and anterior horn of the spinal cord. Hippocampal infection leads to long-term memory deficits in mice that survive, while motor neuron infection can lead to paralysis and death. Neuronal death is immune-mediated, rather than a direct consequence of virus infection, and associated with entry and differentiation of pathogenic T helper 17 cells in the nervous system. To modulate glutamate excitotoxicity, mice were treated with an N-methyl-D-aspartate receptor antagonist, α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists or a glutamine antagonist. The N-methyl-D-aspartate receptor antagonist MK-801 protected hippocampal neurons but not motor neurons, and mice still became paralyzed and died. α-Amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor antagonists GYKI-52466 and talampanel protected both hippocampal and motor neurons and prevented paralysis and death. Glutamine antagonist 6-diazo-5-l-norleucine protected hippocampal neurons and improved memory generation in mice surviving infection with an avirulent virus. Surprisingly, in all cases protection was associated with inhibition of the antiviral immune response, reduced entry of inflammatory cells into the central nervous system, and delayed virus clearance, emphasizing the importance of treatment approaches that include prevention of immunopathologic damage.

  3. Evodiamine as a novel antagonist of aryl hydrocarbon receptor

    International Nuclear Information System (INIS)

    Yu, Hui; Tu, Yongjiu; Zhang, Chun; Fan, Xia; Wang, Xi; Wang, Zhanli; Liang, Huaping

    2010-01-01

    Research highlights: → Evodiamine interacted with the AhR. → Evodiamine inhibited the specific binding of [ 3 H]-TCDD to the AhR. → Evodiamine acts as an antagonist of the AhR. -- Abstract: Evodiamine, the major bioactive alkaloid isolated from Wu-Chu-Yu, has been shown to interact with a wide variety of proteins and modify their expression and activities. In this study, we investigated the interaction between evodiamine and the aryl hydrocarbon receptor (AhR). Molecular modeling results revealed that evodiamine directly interacted with the AhR. Cytosolic receptor binding assay also provided the evidence that evodiamine could interact with the AhR with the K i value of 28.4 ± 4.9 nM. In addition, we observed that evodiamine suppressed the 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced nuclear translocation of the AhR and the expression of CYP1A1 dose-dependently. These results suggested that evodiamine was able to bind to the AhR as ligand and exhibit antagonistic effects.

  4. Histamine H1 antagonists and clinical characteristics of febrile seizures.

    Science.gov (United States)

    Zolaly, Mohammed A

    2012-01-01

    The purpose of this study was to determine whether seizure susceptibility due to antihistamines is provoked in patients with febrile seizures. The current descriptive study was carried out from April 2009 to February 2011 in 250 infants and children who visited the Madinah Maternity and Children's Hospital as a result of febrile convulsions. They were divided into two groups according to administration of antihistamines at the onset of fever. Detailed clinical manifestations were compared between patients with and without administration of antihistamines. The time from fever detection to seizure onset was significantly shorter in the antihistamine group than that in the nonantihistamine group, and the duration of seizures was significantly longer in the antihistamine group than in the nonantihistamine group. No significant difference was found in time from fever detection to seizure onset or seizure duration between patients who received a first-generation antihistamine and those who received a second-generation antihistamine. Due to their central nervous system effects, H1 antagonists should not be administered to patients with febrile seizures and epilepsy. Caution should be exercised regarding the use of histamine H1 antagonists in young infants, because these drugs could potentially disturb the anticonvulsive central histaminergic system.

  5. Rogue sperm indicate sexually antagonistic coevolution in nematodes.

    Directory of Open Access Journals (Sweden)

    Ronald E Ellis

    2014-07-01

    Full Text Available Intense reproductive competition often continues long after animals finish mating. In many species, sperm from one male compete with those from others to find and fertilize oocytes. Since this competition occurs inside the female reproductive tract, she often influences the outcome through physical or chemical factors, leading to cryptic female choice. Finally, traits that help males compete with each other are sometimes harmful to females, and female countermeasures may thwart the interests of males, which can lead to an arms race between the sexes known as sexually antagonistic coevolution. New studies from Caenorhabditis nematodes suggest that males compete with each other by producing sperm that migrate aggressively and that these sperm may be more likely to win access to oocytes. However, one byproduct of this competition appears to be an increased probability that these sperm will go astray, invading the ovary, prematurely activating oocytes, and sometimes crossing basement membranes and leaving the gonad altogether. These harmful effects are sometimes observed in crosses between animals of the same species but are most easily detected in interspecies crosses, leading to dramatically lowered fitness, presumably because the competitiveness of the sperm and the associated female countermeasures are not precisely matched. This mismatch is most obvious in crosses involving individuals from androdioecious species (which have both hermaphrodites and males, as predicted by the lower levels of sperm competition these species experience. These results suggest a striking example of sexually antagonistic coevolution and dramatically expand the value of nematodes as a laboratory system for studying postcopulatory interactions.

  6. Human Homosexuality: A Paradigmatic Arena for Sexually Antagonistic Selection?

    Science.gov (United States)

    Ciani, Andrea Camperio; Battaglia, Umberto; Zanzotto, Giovanni

    2015-01-01

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. PMID:25635045

  7. Biological Control of Sclerotinia sclerotiorum in Lettuce Using Antagonistic Bacteria

    Directory of Open Access Journals (Sweden)

    Bong-Goan Chon

    2013-03-01

    Full Text Available To isolate antagonistic bacteria against sclerotinia rot of lettuce, caused by Sclerotinia sclerotiorum, soil samples were collected from the diseased greenhouse field in Namyangju city, Gyeong-gi province from 2007 to 2008. A total of 196 bacterial isolates were isolated using serial dilution method. In dual culture assay in vitro, 26 isolates showed more than 80% of inhibition rates of mycelial growth of S. sclerotiorum. Based on 16S rDNA sequence analysis, the 26 isolates were identified as Bacillus megaterium, B. cereus, B. subtilis, Arthrobacter nicotianae, A. ramosus, Pseudomonas filiscindens, Stenotrophomonas maltophilia, Brevibacterium frigoritolerans and Sphingobacterium faecium. The 26 isolates inhibited the mycelial growth of S. sclerotiorum up to 80% and the sclerotial germination 0−100%. In the greenhouse pot test of ten isolates conducted in summer, 2 isolates B. megaterium (DK6 and B. cereus (C210 showed control efficacy on sclerotia viability of S. sclerotiorum, 20% and 35%, respectively. In the greenhouse pot test in winter, the disease incidence of the control group was 80%, whereas those of 9 isolates among 26 were approximately 20%. From the result, the 9 isolates are expected as potentially antagonistic bacteria for biological control of sclerotinia rot of lettuce caused by S. sclerotiorum.

  8. Discovery of Novel Proline-Based Neuropeptide FF Receptor Antagonists.

    Science.gov (United States)

    Nguyen, Thuy; Decker, Ann M; Langston, Tiffany L; Mathews, Kelly M; Siemian, Justin N; Li, Jun-Xu; Harris, Danni L; Runyon, Scott P; Zhang, Yanan

    2017-10-18

    The neuropeptide FF (NPFF) system has been implicated in a number of physiological processes including modulating the pharmacological activity of opioid analgesics and several other classes of drugs of abuse. In this study, we report the discovery of a novel proline scaffold with antagonistic activity at the NPFF receptors through a high throughput screening campaign using a functional calcium mobilization assay. Focused structure-activity relationship studies on the initial hit 1 have resulted in several analogs with calcium mobilization potencies in the submicromolar range and modest selectivity for the NPFF1 receptor. Affinities and potencies of these compounds were confirmed in radioligand binding and functional cAMP assays. Two compounds, 16 and 33, had good solubility and blood-brain barrier permeability that fall within the range of CNS permeant candidates without the liability of being a P-glycoprotein substrate. Finally, both compounds reversed fentanyl-induced hyperalgesia in rats when administered intraperitoneally. Together, these results point to the potential of these proline analogs as promising NPFF receptor antagonists.

  9. Opioid antagonists in broadly defined behavioral addictions: a narrative review.

    Science.gov (United States)

    Piquet-Pessôa, Marcelo; Fontenelle, Leonardo F

    2016-01-01

    Naltrexone (NTX), a mu-opioid receptor antagonist, has been approved for the treatment of alcoholism and opioid dependence. More recently, however, NTX and a related drug, nalmefene (NMF), have also shown positive results for the treatment of gambling disorders. In this study, we reviewed the trials testing the effect of opioid antagonists (OA) in gambling disorders and in other broadly defined behavioral addictions, including selected DSM-5 disruptive, impulse-control, and conduct disorders, obsessive-compulsive and related disorders, eating disorders, and other conditions not currently recognized by official classification schemes. We found six randomized controlled trials (RCTs) of OA in gambling disorder, two RCTs of OA in trichotillomania (hair pulling disorder), two RCTs of OA in binge eating disorder, and one RCT of OA for kleptomania. We also reviewed case reports on hypersexual disorder, compulsive buying and skin picking disorders. The reviewed data supported the use of OA, namely NTX and NMF, in gambling disorder (both) and kleptomania (NTX). We did not find enough evidence to support the use of NTX or NMF in trichotillomania (hair pulling disorder), excoriation (skin-picking) disorder, compulsive buying disorder, hypersexual disorder, or binge eating disorder.

  10. Human homosexuality: a paradigmatic arena for sexually antagonistic selection?

    Science.gov (United States)

    Camperio Ciani, Andrea; Battaglia, Umberto; Zanzotto, Giovanni

    2015-01-29

    Sexual conflict likely plays a crucial role in the origin and maintenance of homosexuality in our species. Although environmental factors are known to affect human homosexual (HS) preference, sibling concordances and population patterns related to HS indicate that genetic components are also influencing this trait in humans. We argue that multilocus, partially X-linked genetic factors undergoing sexually antagonistic selection that promote maternal female fecundity at the cost of occasional male offspring homosexuality are the best candidates capable of explaining the frequency, familial clustering, and pedigree asymmetries observed in HS male proband families. This establishes male HS as a paradigmatic example of sexual conflict in human biology. HS in females, on the other hand, is currently a more elusive phenomenon from both the empirical and theoretical standpoints because of its fluidity and marked environmental influence. Genetic and epigenetic mechanisms, the latter involving sexually antagonistic components, have been hypothesized for the propagation and maintenance of female HS in the population. However, further data are needed to truly clarify the evolutionary dynamics of this trait. Copyright © 2015 Cold Spring Harbor Laboratory Press; all rights reserved.

  11. Prevention: Exercise

    Medline Plus

    Full Text Available ... Exercise Strength Training for the Elderly Other Back Pack Safety Pregnancy and Back Pain Preventing Osteoporosis Back ... in very slightly. Hold a ball directly in front of you. Keep your abdominal muscles tight and ...

  12. Prevention: Exercise

    Medline Plus

    Full Text Available ... Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen Your Core! Stretching/Flexibility Aerobic ... Strength Training for the Elderly Other Back Pack Safety Pregnancy and Back Pain Preventing Osteoporosis Back Pain ...

  13. Prevent Shingles

    Science.gov (United States)

    ... Submit What's this? Submit Button Past Emails Prevent Shingles Language: English (US) Español (Spanish) Recommend on Facebook ... that can result in vision loss. Older Adults & Shingles As you get older, you are more likely ...

  14. Prevention: Exercise

    Medline Plus

    Full Text Available ... Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 Tips for a Healthy Back Smoking Weight Patient Safety Exercise Strengthening Strengthen Your Core! ...

  15. Prevention: Exercise

    Medline Plus

    Full Text Available ... and Education Injection Treatments for Spinal Pain Epidural Steroid Injections Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle ... Z Spine Specialists Videos 9 for Spine Epidural Steroid Injections Exercise: The Backbone of Spine Treatment Spondylolisthesis ...

  16. Prevention: Exercise

    Medline Plus

    Full Text Available ... A SPECIALIST Prevention Strengthening Exercise Committee Exercise Committee Core Strengthening Many popular forms of exercise focus on ... acute pain, you should stop doing it. Transverse Core Strengthening This strengthens the muscles that cross from ...

  17. Prevention: Exercise

    Medline Plus

    Full Text Available ... Lumbar Zygapophysical (Facet) Joint Injections PREVENTION Lifestyle Choices 10 Tips for a Healthy Back Smoking Weight Patient ... the floor; rotate from side to side. Repeat 10 times. Check with your physician; if you are ...

  18. Prevention: Exercise

    Medline Plus

    Full Text Available ... Pregnancy and Back Pain Preventing Osteoporosis Back Pain Basics Book RESOURCES Patient ... popular forms of exercise focus on core strengthening, or building the muscles that provide support for your body. Pilates, yoga and martial arts ...

  19. Pregnancy outcome of “delayed start” GnRH antagonist protocol versus GnRH antagonist protocol in poor responders: A clinical trial study

    Directory of Open Access Journals (Sweden)

    Abbas Aflatoonian

    2017-08-01

    Full Text Available Background: Management of poor-responding patients is still major challenge in assisted reproductive techniques (ART. Delayed-start GnRH antagonist protocol is recommended to these patients, but little is known in this regards. Objective: The goal of this study was assessment of delayed-start GnRH antagonist protocol in poor responders, and in vitro fertilization (IVF outcomes. Materials and Methods: This randomized clinical trial included sixty infertile women with Bologna criteria for ovarian poor responders who were candidate for IVF. In case group (n=30, delayed-start GnRH antagonist protocol administered estrogen priming followed by early follicular-phase GnRH antagonist treatment for 7 days before ovarian stimulation with gonadotropin. Control group (n=30 treated with estrogen priming antagonist protocol. Finally, endometrial thickness, the rates of oocytes maturation, , embryo formation, and pregnancy were compared between two groups. Results: Rates of implantation, chemical, clinical, and ongoing pregnancy in delayed-start cycles were higher although was not statistically significant. Endometrial thickness was significantly higher in case group. There were no statistically significant differences in the rates of oocyte maturation, embryo formation, and IVF outcomes between two groups. Conclusion: There is no significant difference between delayed-start GnRH antagonist protocol versus GnRH antagonist protocol.

  20. HIV Prevention

    Centers for Disease Control (CDC) Podcasts

    2012-02-01

    Dr. Kevin Fenton, Director of CDC’s National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, talks about steps people can take to protect their health from HIV.  Created: 2/1/2012 by National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention (NCHHSTP).   Date Released: 2/1/2012.

  1. CALCIUM ANTAGONISTS IN CLINICAL PRACTICE: FOCUS ON METABOLIC AND VASCULAR EFFECTS

    OpenAIRE

    D. V. Nebieridze

    2007-01-01

    The efficacy of calcium antagonists widely used in cardiological practice is proved both by placebo-controlled studies and in comparative trials with end-point control. Calcium antagonists are the most effective vasoprotective medicines. In our study we had shown antihypertensive efficacy and ability to improve endothelium function of non-dihydropyridine calcium antagonist, diltiazem (Altiazem RR). Altiazem RR can be drug of choice in wide profile of patients with arterial hypertension, espec...

  2. DIHYDROPYRIDINE CALCIUM ANTAGONISTS: DATA OF EVIDENCE BASED MEDICINE AND RECOM-MENDATIONS ON PRACTICAL USE

    OpenAIRE

    S. Y. Martsevich

    2015-01-01

    The classification of calcium antagonists is presented. There were considered the results of large randomized trials, which were devoted to study of influence of dihydropyridine calcium antagonists on the risk of cardiovascular complications. The place of dihydropyridine calcium antagonists in modern recommendations on treatment of arterial hypertension and ischemic heart disease is defined. The clinical importance of differences between various presentations of dihy-dropyridine calcium antag...

  3. DIHYDROPYRIDINE CALCIUM ANTAGONISTS: DATA OF EVIDENCE BASED MEDICINE AND RECOM-MENDATIONS ON PRACTICAL USE

    OpenAIRE

    S. Y. Martsevich

    2007-01-01

    The classification of calcium antagonists is presented. There were considered the results of large randomized trials, which were devoted to study of influence of dihydropyridine calcium antagonists on the risk of cardiovascular complications. The place of dihydropyridine calcium antagonists in modern recommendations on treatment of arterial hypertension and ischemic heart disease is defined. The clinical importance of differences between various presentations of dihy-dropyridine calcium antag...

  4. How European cardiologists perceive the role of calcium antagonists in follow-up after myocardial infarction

    OpenAIRE

    Opie, L. H.; Lüscher, T. F.; Ferrari, R.; Hansen, J. Fischer

    2017-01-01

    About one hundred European cardiologists discussed the role of calcium antagonists in the follow-up management of myocardial infarction, β-blockers are the treatment of choice. Where these are contra-indicated or otherwise unsuitable, many clinicians would use a non-dihydropyridine calcium antagonist alone or in combination with an ACE inhibitor. There is broad agreement that calcium antagonists should not be used in patients with concomitant left ventricular failure. Cholesterol estimation i...

  5. Characterization and bioactivity of novel calcium antagonists - N-methoxy-benzyl haloperidol quaternary ammonium salt

    OpenAIRE

    Chen, Yi-Cun; Zhu, Wei; Zhong, Shu-Ping; Zheng, Fu-Chun; Gao, Fen-Fei; Zhang, Yan-Mei; Xu, Han; Zheng, Yan-Shan; Shi, Gang-Gang

    2015-01-01

    BACKGROUND AND PURPOSE Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. ...

  6. CALCIUM ANTAGONISTS IN CLINICAL PRACTICE: FOCUS ON METABOLIC AND VASCULAR EFFECTS

    OpenAIRE

    D. V. Nebieridze

    2015-01-01

    The efficacy of calcium antagonists widely used in cardiological practice is proved both by placebo-controlled studies and in comparative trials with end-point control. Calcium antagonists are the most effective vasoprotective medicines. In our study we had shown antihypertensive efficacy and ability to improve endothelium function of non-dihydropyridine calcium antagonist, diltiazem (Altiazem RR). Altiazem RR can be drug of choice in wide profile of patients with arterial hypertension, espec...

  7. Oxytocin antagonist disrupts hypotension-evoked renin secretion and other responses in conscious rats

    DEFF Research Database (Denmark)

    Huang, W.; Sjöquist, M.; Skøtt, O.

    2001-01-01

    antagonist did not alter the hypotension induced by hydralazine or diazoxide, but it did markedly blunt the induced increase in PRA. The OT receptor antagonist also blunted the hypotension-evoked increase in heart rate and plasma vasopressin levels, suggesting that the antagonist may have generally disrupted...... afferent signaling of hypotension. Thus hypotension-evoked OT secretion may contribute to cardiovascular homeostasis by enhancing baroreceptor signals that stimulate increases in renin secretion, vasopressin secretion, and heart rate during arterial hypotension in rats....

  8. The effects of varenicline on sensory gating and exploratory behavior with pretreatment with nicotinic or 5-HT3A receptor antagonists.

    Science.gov (United States)

    Kucinski, Aaron; Wersinger, Scott; Stachowiak, Ewa K; Becker, Chani; Lippiello, Pat; Bencherif, Merouane; Stachowiak, Michal K

    2015-02-01

    Individuals with schizophrenia smoke at high frequency relative to the general population. Despite the harmful effects of cigarette smoking, smoking among schizophrenic patients improves cognitive impairments not addressed or worsened by common neuroleptics. Varenicline, a nonselective neuronal nicotinic receptor (NNR) agonist and full agonist of 5-HT3A receptors, helps reduce smoking among schizophrenic patients. To determine whether varenicline also improves a cognitive symptom of schizophrenia, namely, impaired sensory gating, a transgenic mouse with schizophrenia, th-fgfr1(tk-), was used. Varenicline dose-dependently increased prepulse inhibition (PPI) of the startle response, a measure of sensory gating, in th-fgfr1(tk-) mice and normalized PPI deficits relative to nontransgenic controls. With the highest dose (10 mg/kg), however, there was a robust elevation of PPI and startle response, as well as reduced exploratory behavior in the open field and elevated plus maze. Pretreatment with the nonspecific NNR antagonist mecamylamine attenuated the exaggerated PPI response and, similar to the 5-HT3A receptor antagonist ondansetron, it prevented the reduction in exploratory behavior. Collectively, these results indicate that varenicline at low-to-moderate doses may be beneficial against impaired sensory gating in schizophrenia; however, higher doses may induce anxiogenic effects, which can be prevented with antagonists of NNRs or 5-HT3A receptors.

  9. Dantrolene: A Selective Ryanodine Receptor Antagonist, Protects Against Pentylenetetrazole-Induced Seizure in Mice

    Directory of Open Access Journals (Sweden)

    Mojtaba Keshavarz

    2016-10-01

    Full Text Available Ryanodine receptor abnormalities has implicated in the generation and maintenance of seizure. Dantrolene, a selective ryanodine receptor antagonist, may be a potential drug for the prevention of seizure. Therefore, we aimed to clarify the protective effects of dantrolene against pentylenetetrazole seizure in mice. Male albino mice were received an intra-peritoneal injection of pentylenetetrazole (80 mg/kg in seven separate groups (n=8. We used dantrolene (10,20 and 40 mg/kg, caffeine (200 mg/kg, dantrolene (40 mg/kg + caffeine (200 mg/kg, diazepam (5 mg/kg as a positive control and vehicle 30 minutes before the injection of pentylenetetrazole. Then, we registered the latency time of the first seizure, the severity of seizures and the incidence of seizure and death. Kruskal-Wallis test followed by Mann-Whitney and Fisher’s exact test were used to analyze the data. Dantrolene (10,20 and 40 mg/kg significantly increased the latency time for the first seizure. Furthermore, dantrolene (20 and 40 mg/kg, but not 10 mg/kg attenuated the severity of seizures in comparison to the vehicle group. Moreover, dantrolene only at the dose of 40 mg/kg prevented from tonic-clonic seizure and death in comparison to the vehicle group. In contrast, the addition of caffeine abolished the protective effects of dantrolene on the tonic-clonic seizure/death and inhibited the beneficial effects of dantrolene on the severity of pentylenetetrazol seizures. The acute dantrolene administration produced an anticonvulsant effect in the pentylenetetrazole-induced seizure. Moreover, caffeine prevented from dantrolene anticonvulsant effects. These results may imply about ryanodine receptors and intracellular calcium roles in the generation and control of pentylenetetrazole seizure.

  10. VIP and endothelin receptor antagonist: An effective combination against experimental pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Szema Anthony M

    2011-10-01

    Full Text Available Abstract Background Pulmonary Arterial Hypertension (PAH remains a therapeutic challenge, and the search continues for more effective drugs and drug combinations. We recently reported that deletion of the vasoactive intestinal peptide (VIP gene caused the spontaneous expression of a PH phenotype that was fully corrected by VIP. The objectives of this investigation were to answer the questions: 1 Can VIP protect against PH in other experimental models? and 2 Does combining VIP with an endothelin (ET receptor antagonist bosentan enhance its efficacy? Methods Within 3 weeks of a single injection of monocrotaline (MCT, s.c. in Sprague Dawley rats, PAH developed, manifested by pulmonary vascular remodeling, lung inflammation, RV hypertrophy, and death within the next 2 weeks. MCT-injected animals were either untreated, treated with bosentan (p.o. alone, with VIP (i.p. alone, or with both together. We selected this particular combination upon finding that VIP down-regulates endothelin receptor expression which is further suppressed by bosentan. Therapeutic outcomes were compared as to hemodynamics, pulmonary vascular pathology, and survival. Results Treatment with VIP, every other day for 3 weeks, begun on the same day as MCT, almost totally prevented PAH pathology, and eliminated mortality for 45 days. Begun 3 weeks after MCT, however, VIP only partially reversed PAH pathology, though more effectively than bosentan. Combined therapy with both drugs fully reversed the pathology, while preventing mortality for at least 45 days. Conclusions 1 VIP completely prevented and significantly reversed MCT-induced PAH; 2 VIP was more effective than bosentan, probably because it targets a wider range of pro-remodeling pathways; and 3 combination therapy with VIP plus bosentan was more effective than either drug alone, probably because both drugs synergistically suppressed ET-ET receptor pathway.

  11. The ability of H1 or H2 receptor antagonists or their combination in counteracting the glucocorticoid-induced alveolar bone loss in rats.

    Science.gov (United States)

    Ezzat, Bassant A; Abbass, Marwa M S

    2014-02-01

    The aim of the present study was to compare between three possible osteoporotic treatments in prevention of glucocorticoid-induced alveolar bone loss. Fifty adult female Wistar rats with an average weight 150-200 g were randomized into five groups: group I (control) was intraperitoneally injected with saline. The other experimental groups (II & III, IV & V) were intraperitoneally injected with 200 µg/100 g body weight dexamethasone. The experimental groups III, IV and V received intraperitoneal injection of 10 mg/kg/day pheniramine maleate (H1 receptor antagonist), ranitidine hydrochloride (H2 receptor antagonist) and concomitant doses of both H1 & H2 receptor antagonists respectively. After 30 days, the rats have been sacrificed. The mandibles were examined histologically, histochemically and histomorphometrically. The bone mineral density was measured using dual-energy X-ray absorptiometry (DEXA). Histopathologically the glucocorticoid group showed wide medullary cavities with wide osteocytic lacunae. These marrow cavities were reduced in the prophylactic groups (III, IV) but increased in group V. Bone histomorphometric analysis revealed improvement in static bone parameters in groups III and IV and deterioration in group V in comparison to group II. The DEXA revealed significant reduction in the bone mineral density in all experimental groups compared to the control group. In a rat model, the administration of H1 or H2 receptor antagonists separately could minimize the alveolar bone loss caused by the administration of glucocorticoids while concomitant administration of both H1 and H2 receptor antagonists deteriorated the bone condition. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  12. The Cultivation of Antagonistic Bacteria in Irradiated Sludge for Biological Control of Soft Rot Erwinias : Screening of Antagonistic Bacteria for biological Control of Soft Rot Erwinias

    International Nuclear Information System (INIS)

    Sermkiattipong, Ng.; Sangsuk, L; Rattanapiriyakul, P; Dejsirilert, S.; Thaveechai, N.

    1998-01-01

    Pure cultures of 57 bacterial isolates for antagonistic activity screening were isolated from three areas of soft rot infested vegetable soil and 58 isolates were obtained from commercial seed compost and seed compost product of Division of Soil and Water Conservation, Department of Land Development. A total of 115 bacterial isolates were evaluated for antagonizing activity against Erwinia carotovora subsp. atroceptica in vitro. Out of them, 18 isolates were antagonists by showing zone of inhibition ranging from 1 to 17 mm by diameter. Most of antagonistic bacteria were identified as Bacillus spp. whereas only one isolate was Pseudomonas vesicularis

  13. Design of potent and specific integrin antagonists. Peptide antagonists with high specificity for glycoprotein IIb-IIIa.

    Science.gov (United States)

    Scarborough, R M; Naughton, M A; Teng, W; Rose, J W; Phillips, D R; Nannizzi, L; Arfsten, A; Campbell, A M; Charo, I F

    1993-01-15

    Members of the snake venon-derived, "disintegrin" peptide family containing the Arg-Gly-Asp (RGD) amino acid sequence are among the most potent inhibitors of the binding of adhesive proteins to platelet glycoprotein (GP) IIb-IIIa. However, GPIIb-IIIa antagonists containing the RGD sequence are not integrin specific and inhibit the adhesive functions of many other RGD-dependent integrins. The single disintegrin peptide, barbourin, containing a conservative amino acid substitution of Lys (K) for Arg (R) in the RGD sequence, is however, highly specific for GPIIb-IIIa. Using this information we have tested the hypothesis that both structural and conformational elements of barbourin are important for its high affinity and selectivity for platelet GPIIb-IIIa by synthesizing a series of conformationally constrained, disulfide-bridged peptides containing the KGD amino acid sequence. Incorporation of the KGD sequence into a cyclic peptide template, followed by systematic optimization of the cyclic ring size, optimization of secondary hydrophobic binding site interactions, and the derivatization of the lysyl side chain functionality of the KGD sequence has resulted in peptide analogs which display inhibitory potency and GPIIb-IIIa selectivity comparable to that of barbourin. This study demonstrates that the specificity and potency of the disintegrin family of antagonists, in particular barbourin, can be mimicked by small, conformationally restrained peptides.

  14. Stroke Prevention: Managing Modifiable Risk Factors

    Directory of Open Access Journals (Sweden)

    Silvia Di Legge

    2012-01-01

    Full Text Available Prevention plays a crucial role in counteracting morbidity and mortality related to ischemic stroke. It has been estimated that 50% of stroke are preventable through control of modifiable risk factors and lifestyle changes. Antihypertensive treatment is recommended for both prevention of recurrent stroke and other vascular events. The use of antiplatelets and statins has been shown to reduce the risk of recurrent stroke and other vascular events. Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin II receptor blockers (ARBs are indicated in stroke prevention because they also promote vascular health. Effective secondary-prevention strategies for selected patients include carotid revascularization for high-grade carotid stenosis and vitamin K antagonist treatment for atrial fibrillation. The results of recent clinical trials investigating new anticoagulants (factor Xa inhibitors and direct thrombin inhibitors clearly indicate alternative strategies in stroke prevention for patients with atrial fibrillation. This paper describes the current landscape and developments in stroke prevention with special reference to medical treatment in secondary prevention of ischemic stroke.

  15. βCCT, AN ANTAGONIST SELECTIVE FOR α1 GABAA RECEPTORS, REVERSES DIAZEPAM WITHDRAWAL-INDUCED ANXIETY IN RATS

    Science.gov (United States)

    Divljaković, Jovana; Milić, Marija; Namjoshi, Ojas A.; Tiruveedhula, Veera V.; Timić, Tamara; Cook, James M.; Savić, Miroslav M.

    2012-01-01

    The abrupt discontinuation of prolonged benzodiazepine treatment elicits a withdrawal syndrome with increased anxiety as a major symptom. The neural mechanisms underlying benzodiazepine physical dependence are still insufficiently understood. Flumazenil, the non-selective antagonist of the benzodiazepine binding site of GABAA receptors was capable of preventing and reversing the increased anxiety during benzodiazepine withdrawal in animals and humans in some, but not all studies. On the other hand, a number of data suggest that GABAA receptors containing α1 subunits are critically involved in processes developing during prolonged use of benzodiazepines, such are tolerance to sedative effects, liability to physical dependence and addiction. Hence, we investigated in the elevated plus maze the level of anxiety 24 h following 21 days of diazepam treatment and the influence of flumazenil or a preferential α1-subunit selective antagonist βCCt on diazepam withdrawal syndrome in rats. Abrupt cessation of protracted once-daily intraperitoneal administration of 2 mg/kg diazepam induced a withdrawal syndrome, measured by increased anxiety-like behavior in the elevated plus maze 24 h after treatment cessation. Acute challenge with either flumazenil (10 mg/kg) or βCCt (1.25, 5 and 20 mg/kg) alleviated the diazepam withdrawal-induced anxiety. Moreover, both antagonists induced an anxiolytic-like response close, though not identical, to that seen with acute administration of diazepam. These findings imply that the mechanism by which antagonism at GABAA receptors may reverse the withdrawal-induced anxiety involves the α1 subunit and prompt further studies aimed at linking the changes in behavior with possible adaptive changes in subunit expression and function of GABAA receptors. PMID:23149168

  16. Antagonistic Activity of Probiotic Bacteria Isolated from Traditional Dairy Products against E. coli O157:H7

    Directory of Open Access Journals (Sweden)

    Maryam Rahimpour Hesari

    2017-10-01

    Full Text Available Background:    Probiotics are living microorganisms that have useful effects on health of digestive system when acquired in a defined dosage. E. coli O157:H7 is known as one of the most important agents of diarrhea in developing countries. Therefore, attention to the treatment of such gastrointestinal disease is essential. The aim of this study was to determine antagonistic activity of food born lactobacilli against E. coli O157:H7.Methods:     Lactobacilli were isolated from traditional dairy products (yogurt and buttermilk samples. Then, they were characterized using biochemical and molecular tests. Bifidobacterium bifidum PTCC 1644 was obtained from the microbial collection of Iranian Research Organization for Science and Technology in Lyophilized form. Similarly, E. coli O157:H7 PTCC12900 was obtained from faculty of veterinary medicine university of Tehran. The antagonistic activity of probiotics supernatants against E. coli O157:H7 was investigated using the disk diffusion agar, well diffusion agar and pour plate methods.Results:   The isolates were characterized as Lactobacillus plantarum and Lactobacillus fermentum. All isolates showed antagonistic activities against E. coli O157:H7 in all of the three methods, where the activity of L. plantarum and B. bidifum PTCC 1644 was greater than that of L. fermentum. Conclusion:   Metabolites produced by the probiotic bacteria are able to inhibit the growth of E. coli O157:H7. This can be an important solution for the prevention and treatment of E. coli O157:H7 infection and ultimately improve human health.

  17. Functionalized Congeners of P2Y1 Receptor Antagonists:

    Energy Technology Data Exchange (ETDEWEB)

    de Castro, Sonia [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Maruoka, Hiroshi [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hong, Kunlun [ORNL; Kilbey, II, S Michael [ORNL; Costanzi, Stefano [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health; Hechler, Béatrice [University of Strasbourg; Gachet, Christian [EFS-Alsace, Strasbourg, France; Harden, T. Kendall [University of North Carolina School of Medicine; Jacobson, Kenneth A. [National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health

    2010-01-01

    The P2Y{sub 1} receptor is a prothrombotic G protein-coupled receptor (GPCR) activated by ADP. Preference for the North (N) ring conformation of the ribose moiety of adenine nucleotide 3',5'-bisphosphate antagonists of the P2Y{sub 1} receptor was established by using a ring-constrained methanocarba (a bicyclo[3.1.0]hexane) ring as a ribose substitute. A series of covalently linkable N{sup 6}-methyl-(N)-methanocarba-2'-deoxyadenosine-3',5'-bisphosphates containing extended 2-alkynyl chains was designed, and binding affinity at the human (h) P2Y{sub 1} receptor determined. The chain of these functionalized congeners contained hydrophilic moieties, a reactive substituent, or biotin, linked via an amide. Variation of the chain length and position of an intermediate amide group revealed high affinity of carboxylic congener 8 (K{sub i} 23 nM) and extended amine congener 15 (K{sub i} 132 nM), both having a 2-(1-pentynoyl) group. A biotin conjugate 18 containing an extended {epsilon}-aminocaproyl spacer chain exhibited higher affinity than a shorter biotinylated analogue. Alternatively, click coupling of terminal alkynes of homologous 2-dialkynyl nucleotide derivatives to alkyl azido groups produced triazole derivatives that bound to the P2Y{sub 1} receptor following deprotection of the bisphosphate groups. The preservation of receptor affinity of the functionalized congeners was consistent with new P2Y{sub 1} receptor modeling and ligand docking. Attempted P2Y{sub 1} antagonist conjugation to PAMAM dendrimer carriers by amide formation or palladium-catalyzed reaction between an alkyne on the dendrimer and a 2-iodopurine-derivatized nucleotide was unsuccessful. A dialkynyl intermediate containing the chain length favored in receptor binding was conjugated to an azide-derivatized dendrimer, and the conjugate inhibited ADP-promoted human platelet aggregation. This is the first example of attaching a strategically functionalized P2Y receptor

  18. Clinical experience in Europe with uroselective alpha1-antagonists.

    Science.gov (United States)

    Debruyne, F M; Van der Poel, H G

    1999-01-01

    alpha1-Adrenoreceptors are thought to be involved in prostate smooth muscle contractions and could hence play a role in the dynamic component of intravesical obstruction associated with symptomatic BPH. Consequently, since the mid-eighties alpha receptor blocking agents have been used for the treatment of BPH. Non-selective alpha blockers are usually associated with systemic side-effects which resulted in an exclusion or withdrawal of many patients from this form of treatment. With the availability of so-called uroselective alpha blockers the management picture has changed since it was anticipated that these compounds cause lesser side-effects with at least the same, or even better, efficacy. Comparative clinical studies are essential for determining the eventual advantages of the uroselective alpha1-antagonists and a large number of such studies have been performed worldwide studying the various available compounds. European studies with terazosin showed clear superiority of the drug over the placebo while causing only limited side-effects. Various other studies using alpha-blocking agents such as doxazosin, tamsulosin and alfuzosin yielded identical results. Especially with tamsulosin and alfuzosin, the side-effects were comparable with those encountered in the placebo group. About 7% of the patients using tamsulosin experienced retrograde ejaculation in one study which did not occur in the alfuzosin studies. Important studies in Europe have also investigated the value of a combination of an alpha blocker with a 5alpha-reductase inhibitor. Comparable studies in which both alfuzosin and doxazosin were combined with the 5alpha-reductase inhibitor Proscar have shown that a combination is not superior to a blocker monotherapy and especially in the ALFIN study the results show that alfuzosin monotherapy is superior to Proscar in the management of symptomatic BPH. European studies have evaluated Quality of Life, sexuality as well as socio-economical outcome of the

  19. Effects of H[sub 1]-receptor antagonists on [sup 14]C-aminopyrine accumulated in histamine-stimulated rabbit gastric glands

    Energy Technology Data Exchange (ETDEWEB)

    Nilsson, G.; Romell, B.; Girma, K.; Seensalu, R. (Swedish Univ. of Agricultural Science, Uppsala (Sweden))

    1993-01-01

    After stimulation of gastric acid production there is a considerable delay before the acid starts to appear in the gastric lumen. The present study was carried out on isolated gastric glands to test the hypothesis that there may be a mechanisms in the parietal cell that contributes to this delay by preventing emptying of the secretory canaliculi. Glands were incubated with [sup 14]C-aminopyrine and stimulated with histamine. After accumulation of [sup 14]C-aminopyrine, various concentration of H[sub 1]-receptor antagonists were added. Clemastine, promethazine, and hydroxyzine effectively and cetirizine and tripelennamine less effectively decreased the accumulated [sup 14]C-aminopyrine content in a dose-dependent manner without significantly reducing the oxygen consumption. The H[sub 1]-receptor antagonists influenced the [sup 14]C-aminopyrine content in another manner than H[sub 2]-receptor antagonists. No effects were obtained by atropine or lidocaine, indicating that the elimination of [sup 14]C-amionopyrine is not an inticholinergic effect or due to membrane effects as exerted by local anesthetics. Stimulation of glands by further addition of histamine did not significantly stimulate the uptake of [sup 14]C-aminopyrine in the glands, whereas stimulation with db-cAMP produced an increase that was most pronounced when low concentrations of hydroxyzine had been used. It is suggested that H[sub 1]-receptor antagonists do not inhibit stimulation of acid production in the secretory canaliculi. They may, however, interfere with a mechanism preventing acid from leaving the parietal cell. Such a mechanism may contribute to the delay in appearance of acid in the gastric lumen after stimulation of gastric acid production. 37 refs., 7 figs.

  20. 5-Hydroxytryptamine3 receptor antagonists and cardiac side effects

    DEFF Research Database (Denmark)

    Brygger, Louise; Herrstedt, Jørn

    2014-01-01

    INTRODUCTION: 5-Hydroxytryptamine3-receptor antagonists (5-HT3-RA) are the most widely used antiemetics in oncology, and although tolerability is high, QTC prolongation has been observed in some patients. AREAS COVERED: The purpose of this article is to outline the risk of cardiac adverse events...... in clinical trials. Furthermore, polypharmacy is frequent and drug-drug interactions between chemotherapy and other QTc-prolonging drugs may influence the pharmacokinetics and pharmacodynamics of the 5-HT3-RAs. During the next 10 - 15 years a huge increase in the number of cancer patients is expected......, primarily in the group of 65-plus-year old. Therefore it will be crucial to address the incidence of cardiac AEs in cancer patients with known heart disease receiving chemotherapy and a 5-HT3 RA for the prophylaxis of CINV....

  1. Mesenteric vascular reactivity to histamine receptor agonists and antagonists. [Dogs

    Energy Technology Data Exchange (ETDEWEB)

    Walus, K.M.; Fondacaro, J.D.; Jacobson, E.D.

    1981-05-01

    Response patterns of intestinal blood flow, oxygen extraction and consumption, blood flow distribution, and motility were assessed during intraarterial infusions of histamine, histamine after H1 or H2 blockade, dimaprit or dimaprit after H2 blockade. Histamine produced an initial peak response of blood flow with a slow decrease thereafter. Oxygen extraction was evenly depressed throughout the infusion, and oxygen consumption increased at the beginning. All initial responses were blocked by tripelennamine. Ranitidine, a new H2 antagonist, accelerated the decay of all responses. Dimaprit produced effects identical to those of histamine after tripelennamine. Distribution of blood flow was unchanged at the beginning of histamine infusion, but subsequently showed a shift to muscularis which was blocked by tripelennamine. Histamine usually stimulated intestinal contractions and this effect was abolished by tripelennamine. Thus, H1 stimulation, besides producing an initial vasodilation, increases oxygen uptake and redistributes flow to the muscularis.

  2. Identification of Bexarotene as a PPARγ Antagonist with HDX

    Directory of Open Access Journals (Sweden)

    David P. Marciano

    2015-01-01

    Full Text Available The retinoid x receptors (RXRs are the pharmacological target of Bexarotene, an antineoplastic agent indicated for the treatment of cutaneous T cell lymphoma (CTCL. The RXRs form heterodimers with several nuclear receptors (NRs, including peroxisome proliferator-activated receptor gamma (PPARγ, to regulate target gene expression through cooperative recruitment of transcriptional machinery. Here we have applied hydrogen/deuterium exchange (HDX mass spectrometry to characterize the effects of Bexarotene on the conformational plasticity of the intact RXRα:PPARγ heterodimer. Interestingly, addition of Bexarotene to PPARγ in the absence of RXRα induced protection from solvent exchange, suggesting direct receptor binding. This observation was confirmed using a competitive binding assay. Furthermore, Bexarotene functioned as a PPARγ antagonist able to alter rosiglitazone induced transactivation in a cell based promoter:reporter transactivation assay. Together these results highlight the complex polypharmacology of lipophilic NR targeted small molecules and the utility of HDX for identifying and characterizing these interactions.

  3. [Chitinolytic activity of Bacillus Cohn.--phytopathogenic fungus antagonist].

    Science.gov (United States)

    Aktuganov, G E; Melent'ev, A I; Kuz'mina, L Iu; Galimzianova, N F; Shirokov, A V

    2003-01-01

    Among the 70 tested Bacillus spp. strains antagonistic to phytopathogenic fungi, 19 were found to possess chitinolytic activity when grown on solid media with 0.5% colloidal chitin. The chitinolytic activity of almost all of these 19 strains grown in liquid cultures ranged from 0.1 to 0.3 U/ml. One of the 19 strains exhibited exochitinase activity. In addition to chitinase, two strains also produced chitosanase and one strain, beta-1,3-glucanase. No correlation was found between the antifungal activity of the bacillar strains studied and their ability to synthesize extracellular chitinase. Among the 19 chitinolytic strains, the correlation between these parameters was also low (r x,y = 0.45), although the enzymatic preparations of most of these strains inhibited the growth of the phytopathogenic fungus Helminthosporium sativum.

  4. Interaction intimacy organizes networks of antagonistic interactions in different ways.

    Science.gov (United States)

    Pires, Mathias M; Guimarães, Paulo R

    2013-01-06

    Interaction intimacy, the degree of biological integration between interacting individuals, shapes the ecology and evolution of species interactions. A major question in ecology is whether interaction intimacy also shapes the way interactions are organized within communities. We combined analyses of network structure and food web models to test the role of interaction intimacy in determining patterns of antagonistic interactions, such as host-parasite, predator-prey and plant-herbivore interactions. Networks describing interactions with low intimacy were more connected, more nested and less modular than high-intimacy networks. Moreover, the performance of the models differed across networks with different levels of intimacy. All models reproduced well low-intimacy networks, whereas the more elaborate models were also capable of reproducing networks depicting interactions with higher levels of intimacy. Our results indicate the key role of interaction intimacy in organizing antagonisms, suggesting that greater interaction intimacy might be associated with greater complexity in the assembly rules shaping ecological networks.

  5. Emerging therapies for atopic dermatitis: TRPV1 antagonists.

    Science.gov (United States)

    Bonchak, Jonathan G; Swerlick, Robert A

    2018-03-01

    Transient receptor potential (TRP) ion channels are important mediators of somatosensory signaling throughout the body. Our understanding of the contribution of TRPs to a multitude of cutaneous physiologic processes has grown substantially in the past decade. TRP cation channel subfamily V member 1 (TRPV1), one of the better-understood members of this large family of ion channels, affects multiple pathways involved in pruritus. Further, TRPV1 appears to play a role in maintaining skin barrier function. Together, these properties make TRPV1 a ripe target for new therapies in atopic dermatitis. Neurokinin antagonists may affect similar pathways and have been studied to this effect. Early trials data suggest that these therapies are safe, but assessment of their efficacy in atopic dermatitis is pending as we await publication of phase II and III clinical trials data. Copyright © 2017 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  6. Discovery of novel N-aryl piperazine CXCR4 antagonists.

    Science.gov (United States)

    Zhao, Huanyu; Prosser, Anthony R; Liotta, Dennis C; Wilson, Lawrence J

    2015-11-01

    A novel series of CXCR4 antagonists with substituted piperazines as benzimidazole replacements is described. These compounds showed micromolar to nanomolar potency in CXCR4-mediated functional and HIV assays, namely inhibition of X4 HIV-1(IIIB) virus in MAGI-CCR5/CXCR4 cells and inhibition of SDF-1 induced calcium release in Chem-1 cells. Preliminary SAR investigations led to the identification of a series of N-aryl piperazines as the most potent compounds. Results show SAR that indicates type and position of the aromatic ring, as well as type of linker and stereochemistry are significant for activity. Profiling of several lead compounds showed that one (49b) reduced susceptibility towards CYP450 and hERG, and the best overall profile when considering both SDF-1 and HIV potencies (6-20 nM). Copyright © 2015 Elsevier Ltd. All rights reserved.

  7. Alpha antagonists and intraoperative floppy iris syndrome: A spectrum

    Directory of Open Access Journals (Sweden)

    Sharif A Issa

    2008-07-01

    Full Text Available Sharif A Issa, Omar H Hadid, Oliver Baylis, Margaret DayanDepartment of Ophthalmology, Royal Victoria Infirmary, Newcastle upon Tyne, UKBackground: To determine occurrence of features of intraoperative floppy iris syndrome (IFIS during cataract surgery in patients taking systemic alpha-antagonists (AA.Methods: We prospectively studied patients on AA and who underwent phacoemulsification. The following were recorded: pupil diameter preoperatively, iris flaccidity, iris prolapse and peroperative miosis.Results: We studied 40 eyes of 31 subjects. Mean age was 78 years. Overall, 14 eyes (13 patients showed signs of IFIS: 9/13 (69% eyes of patients on tamsulosin, 1/18 (6% eyes in the doxazosin group, 2/2 prazosin patients, 1/4 eyes in the indoramin group, and 1/2 eyes in two patients on a combination of doxazosin and tamsulosin. Most cases (92% had only one or two signs of IFIS. Bilateral cataract surgery was undertaken in 9 patients but only one patient (on tamsulosin had features of IFIS in both eyes, while 4 patients (2 on tamsulosin and 2 on other AA showed signs of IFIS in one eye only, and 4 patients did not show IFIS in either eye.Conclusion: Most AA were associated with IFIS, but it tends to present as a spectrum of signs rather than full triad originally described. Tamsulosin was most likely to be associated with IFIS; however, its intake does not necessarily mean that IFIS will occur. For patients on AA, the behavior of the iris intraoperatively in one eye is a poor predictor of the other eye. Surgeons should anticipate the occurrence of IFIS in any patient on AA.Keywords: alpha blocker, alpha antagonist, cataract surgery, intraoperative floppy iris syndrome, tamsulosin.

  8. Adenosine receptor antagonist and augmented vasodilation during hypoxic exercise.

    Science.gov (United States)

    Casey, Darren P; Madery, Brandon D; Pike, Tasha L; Eisenach, John H; Dietz, Niki M; Joyner, Michael J; Wilkins, Brad W

    2009-10-01

    We tested the hypothesis that adenosine contributes to augmented skeletal muscle vasodilation during hypoxic exercise. In separate protocols, subjects performed incremental rhythmic forearm exercise (10% and 20% of maximum) during normoxia and normocapnic hypoxia (80% arterial O2 saturation). In protocol 1 (n = 8), subjects received an intra-arterial administration of saline (control) and aminophylline (adenosine receptor antagonist). In protocol 2 (n = 10), subjects received intra-arterial phentolamine (alpha-adrenoceptor antagonist) and combined phentolamine and aminophylline administration. Forearm vascular conductance (FVC; in ml x min(-1).100 mmHg(-1)) was calculated from forearm blood flow (in ml/min) and blood pressure (in mmHg). In protocol 1, the change in FVC (DeltaFVC; change from normoxic baseline) during hypoxic exercise with saline was 172 +/- 29 and 314 +/- 34 ml x min(-1) x 100 mmHg(-1) (10% and 20%, respectively). Aminophylline administration did not affect DeltaFVC during hypoxic exercise at 10% (190 +/- 29 ml x min(-1)x100 mmHg(-1), P = 0.4) or 20% (287 +/- 48 ml x min(-1) x 100 mmHg(-1), P = 0.3). In protocol 2, DeltaFVC due to hypoxic exercise with phentolamine infusion was 313 +/- 30 and 453 +/- 41 ml x min(-1) x 100 mmHg(-1) (10% and 20% respectively). DeltaFVC was similar at 10% (352 +/- 39 ml min(-1) x 100 mmHg(-1), P = 0.8) and 20% (528 +/- 45 ml x min(-1) x 100 mmHg(-1), P = 0.2) hypoxic exercise with combined phentolamine and aminophylline. In contrast, DeltaFVC to exogenous adenosine was reduced by aminophylline administration in both protocols (P < 0.05 for both). These observations suggest that adenosine receptor activation is not obligatory for the augmented hyperemia during hypoxic exercise in humans.

  9. Effects of oral cetirizine, a selective H1 antagonist, on allergen- and exercise-induced bronchoconstriction in subjects with asthma.

    LENUS (Irish Health Repository)

    Gong, H

    1990-03-01

    The protective efficacy of oral cetirizine, a selective and potent H1-receptor antagonist, against the immediate bronchoconstrictive response to allergen inhalation and exercise challenge was evaluated in 16 subjects with stable, predominantly mild asthma. The subjects underwent double-blind, crossover pretreatments in randomized order in two separate protocols with (1) three daily oral doses of 20 mg of cetirizine and placebo, followed by allergen inhalation, and (2) single oral doses of cetirizine (5, 10, and 20 mg), albuterol (4 mg), and placebo, followed by exercise with cold-air inhalation. Cetirizine failed to decrease bronchial sensitivity to inhaled allergen in eight of 10 subjects. Neither cetirizine nor albuterol uniformly inhibited exercise-induced bronchoconstriction. Serum concentrations of cetirizine were consistent with systemic H1-blocking activity. Modest bronchodilation occurred after administration of cetirizine and albuterol before exercise but not after the third dose of cetirizine in the allergen protocol. One subject developed moderate drowsiness during multiple dosing with cetirizine. Thus, cetirizine, in the doses studied, is not uniformly effective in preventing allergen- or exercise-induced bronchoconstriction. Histamine is one of many mediators participating in immediate asthmatic responses, and selective H1 antagonists do not completely block these airway events. However, cetirizine may still clinically benefit some patients with asthma, such as patients with allergic rhinitis or urticaria.

  10. The effect of systemic PTEN antagonist peptides on axon growth and functional recovery after spinal cord injury.

    Science.gov (United States)

    Ohtake, Yosuke; Park, Dongsun; Abdul-Muneer, P M; Li, Hui; Xu, Bin; Sharma, Kartavya; Smith, George M; Selzer, Michael E; Li, Shuxin

    2014-05-01

    Knockout studies suggest that PTEN limits the regenerative capacities of CNS axons as a dominant antagonist of PI3 kinase, but the transgenic approach is not feasible for treating patients. Although application of bisperoxovanadium may block PTEN function, it is a general inhibitor of phosphotyrosine phosphatases and may target enzymes other than PTEN, causing side effects and preventing firm conclusions about PTEN inhibition on regulating neuronal growth. A pharmacological method to selectively suppress PTEN post-injury could be a valuable strategy for promoting CNS axon regeneration. We identified PTEN antagonist peptides (PAPs) by targeting PTEN critical functional domains and evaluated their efficacy for promoting axon growth. Four PAPs (PAP 1-4) bound to PTEN protein expressed in COS7 cells and blocked PTEN signaling in vivo. Subcutaneous administration of PAPs initiated two days after dorsal over-hemisection injury significantly stimulated growth of descending serotonergic fibers in the caudal spinal cord of adult mice. Systemic PAPs induce significant sprouting of corticospinal fibers in the rostral spinal cord and limited growth of corticospinal axons in the caudal spinal cord. More importantly, PAP treatment enhanced recovery of locomotor function in adult rodents with spinal cord injury. This study may facilitate development of effective therapeutic agents for CNS injuries. Copyright © 2014 Elsevier Ltd. All rights reserved.

  11. Biocontrol of Fusarium graminearum Growth and Deoxynivalenol Production in Wheat Kernels with Bacterial Antagonists

    Directory of Open Access Journals (Sweden)

    Cuijuan Shi

    2014-01-01

    Full Text Available Fusarium graminearum is the main causal pathogen affecting small-grain cereals, and it produces deoxynivalenol, a kind of mycotoxin, which displays a wide range of toxic effects in human and animals. Bacterial strains isolated from peanut shells were investigated for their activities against F. graminearum by dual-culture plate and tip-culture assays. Among them, twenty strains exhibited potent inhibition to the growth of F. graminearum, and the inhibition rates ranged from 41.41% to 54.55% in dual-culture plate assay and 92.70% to 100% in tip-culture assay. Furthermore, eighteen strains reduced the production of deoxynivalenol by 16.69% to 90.30% in the wheat kernels assay. Finally, the strains with the strongest inhibitory activity were identified by morphological, physiological, biochemical methods and also 16S rDNA and gyrA gene analysis as Bacillus amyloliquefaciens. The current study highlights the potential application of antagonistic microorganisms and their metabolites in the prevention of fungal growth and mycotoxin production in wheat kernels. As a biological strategy, it might avoid safety problems and nutrition loss which always caused by physical and chemical strategies.

  12. Amniotic-fluid-derived mesenchymal stem cells overexpressing interleukin-1 receptor antagonist improve fulminant hepatic failure.

    Directory of Open Access Journals (Sweden)

    Yu-Bao Zheng

    Full Text Available Uncontrolled hepatic immunoactivation is regarded as the primary pathological mechanism of fulminant hepatic failure (FHF. The major acute-phase mediators associated with FHF, including IL-1β, IL-6, and TNF-α, impair the regeneration of liver cells and stem cell grafts. Amniotic-fluid-derived mesenchymal stem cells (AF-MSCs have the capacity, under specific conditions, to differentiate into hepatocytes. Interleukin-1-receptor antagonist (IL-1Ra plays an anti-inflammatory and anti-apoptotic role in acute and chronic inflammation, and has been used in many experimental and clinical applications. In the present study, we implanted IL-1Ra-expressing AF-MSCs into injured liver via the portal vein, using D-galactosamine-induced FHF in a rat model. IL-1Ra expression, hepatic injury, liver regeneration, cytokines (IL-1β, IL-6, and animal survival were assessed after cell transplantation. Our results showed that AF-MSCs over-expressing IL-1Ra prevented liver failure and reduced mortality in rats with FHF. These animals also exhibited improved liver function and increased survival rates after injection with these cells. Using green fluorescent protein as a marker, we demonstrated that the engrafted cells and their progeny were incorporated into injured livers and produced albumin. This study suggests that AF-MSCs genetically modified to over-express IL-1Ra can be implanted into the injured liver to provide a novel therapeutic approach to the treatment of FHF.

  13. Effect of Flos carthami Extract and α1-Adrenergic Antagonists on the Porcine Proximal Ureteral Peristalsis

    Directory of Open Access Journals (Sweden)

    San-Yuan Wu

    2014-01-01

    Full Text Available Traditional Chinese medicine (TCM has been proposed to prevent urolithiasis. In China, Flos carthami (FC, also known as Carthamus tinctorius (Safflower; Chinese name: Hong Hua/紅花 has been used to treat urological diseases for centuries. We previously performed a screening and confirmed the in vivo antilithic effect of FC extract. Here, ex vivo organ bath experiment was further performed to study the effect of FC extract on the inhibition of phenylepinephrine (PE (10−4 and 10−3 M ureteral peristalsis of porcine ureters with several α1-adrenergic antagonists (doxazosin, tamsulosin, and terazosin as experimental controls. The results showed that doxazosin, tamsulosin, and terazosin dose (approximately 4.5 × 10−6 − 4.5 × 10−1 μg/mL dependently inhibited both 10−4 and 10−3 M PE-induced ureteral peristalsis. FC extract achieved 6.2% ± 10.1%, 21.8% ± 6.8%, and 24.0% ± 5.6% inhibitions of 10−4 M PE-induced peristalsis at doses of 5 × 103, 1 × 104, and 2 × 104 μg/mL, respectively, since FC extract was unable to completely inhibit PE-induced ureteral peristalsis, suggesting the antilithic effect of FC extract is related to mechanisms other than modulation of ureteral peristalsis.

  14. Follistatin, an Activin Antagonist, Ameliorates Renal Interstitial Fibrosis in a Rat Model of Unilateral Ureteral Obstruction

    Directory of Open Access Journals (Sweden)

    Akito Maeshima

    2014-01-01

    Full Text Available Activin, a member of the TGF-β superfamily, regulates cell growth and differentiation in various cell types. Activin A acts as a negative regulator of renal development as well as tubular regeneration after renal injury. However, it remains unknown whether activin A is involved in renal fibrosis. To clarify this issue, we utilized a rat model of unilateral ureteral obstruction (UUO. The expression of activin A was significantly increased in the UUO kidneys compared to that in contralateral kidneys. Activin A was detected in glomerular mesangial cells and interstitial fibroblasts in normal kidneys. In UUO kidneys, activin A was abundantly expressed by interstitial α-SMA-positive myofibroblasts. Administration of recombinant follistatin, an activin antagonist, reduced the fibrotic area in the UUO kidneys. The number of proliferating cells in the interstitium, but not in the tubules, was significantly lower in the follistatin-treated kidneys. Expression of α-SMA, deposition of type I collagen and fibronectin, and CD68-positive macrophage infiltration were significantly suppressed in the follistatin-treated kidneys. These data suggest that activin A produced by interstitial fibroblasts acts as a potent profibrotic factor during renal fibrosis. Blockade of activin A action may be a novel approach for the prevention of renal fibrosis progression.

  15. P2X-Receptor Antagonists Inhibit the Interaction of S. aureus Hemolysin A with Membranes

    Directory of Open Access Journals (Sweden)

    Markus Schwiering

    2017-10-01

    Full Text Available The pore forming hemolysin A, Hla, is a major virulence factor of Staphylococcus aureus. Apparently, 1–2 pore(s per cell suffice(s to cause cell death. Accumulated experimental evidence points towards a major role of ATP-gated purinergic receptors (P2XR for hemolysis caused by Hla, complement and other pore forming proteins, presumably by increasing membrane permeability. Indeed, in experiments employing rabbit erythrocytes, inhibitory concentrations of frequently employed P2XR-antagonists were in a similar range as previously reported for erythrocytes of other species and other toxins. However, Hla-dependent hemolysis was not enhanced by extracellular ATP, and oxidized adenosinetriphosphate (oxATP had only a minor inhibitory effect. Unexpectedly, P2XR-inhibitors also prevented Hla-induced lysis of pure lipid membranes, demonstrating that the inhibition did not even depend on the presence of P2XR. Fluorescence microscopy and gel-electrophoresis clearly revealed that P2XR-inhibitors interfere with binding and subsequent oligomerisation of Hla with membranes. Similar results were obtained employing HaCaT-cells. Furthermore, calorimetric data and hemolysis experiments with Hla pre-treated with pyridoxal phosphate-6-azophenyl-2′,4′-disulfonic acid (PPADS showed that this compound directly binds to Hla. Our results call for a critical re-assessment of the appealing concept, which suggests that P2XR are general amplifiers of damage by pore-forming proteins.

  16. Sexually antagonistic coevolution for sexual harassment can act as a barrier to further invasions by parthenogenesis.

    Science.gov (United States)

    Kawatsu, Kazutaka

    2013-02-01

    The assumption of a twofold cost of sex not only complicates the maintenance of sex but also sets conditions for sexual conflict: in organisms with the twofold cost, males often sexually harass females. Sexual harassment is detrimental to female fitness and thus might help maintain sexual populations if male harassment inflicts a harsher cost on parthenogens than on sexual females (asymmetric harassment cost). However, the generality of this concept is now considered doubtful because selective harassment of parthenogens results in loss of mating opportunities for males. Using three mathematical models, I show here that sexual harassment still can impose the asymmetric cost on parthenogens. First, I apply the Lotka-Volterra model to show the degree of asymmetric harassment cost that permits sex to be maintained stably in the population. Second, using adaptive dynamics, I examine whether sexually antagonistic coevolution for sexual harassment, which occurs only in sexual populations, can promote the asymmetric harassment cost. Finally, an individual-based model, which assumes a spatial structure unlike that in the other two, demonstrates that the asymmetric evolution of harassment cost prevents further invasions of parthenogens from different patches into sexual lineages; these mechanisms may account for allopatric distributions of sexual and parthenogenetic lineages as well as the maintenance of sex.

  17. ANGIOTENSIN II RECEPTOR ANTAGONISTS AND ACE INHIBITORS: OPTIMIZATION OF CHOICE FOR TREATMENT OF CARDIOVASCULAR DISEASES

    Directory of Open Access Journals (Sweden)

    E. M. Khurs

    2010-01-01

    Full Text Available Aim. To evaluate the cardioprotective effects of ACE inhibitor, ramipril and angiotensin II receptor antagonist (ARA, valsartan at the cardiovascular continuum (CVC stages.Material and methods. 577 patients were examined. Patients with arterial hypertension (HT (n=283; group 1, with metabolic syndrome (n=137; group 2, with HT associated with ischemic heart disease (n=157; group 3 were randomized into treatment subgroups A (ramipril and B (valsartan. All patients had clinical examination, transthoracic echocardiography with remodeling indexes calculation, ambulatory blood pressure monitoring initially and after 6 months of therapy.Results. Valsartan had priority in prevention of early cardiac remodeling (reduction in left ventricular (LV hypertrophy and myocardial stress, improvement of functional heart parameters at early CVC stage (HT, metabolic syndrome. On the other hand ramipril had priority at advanced stage of CVC (reduction in systolic diameter-thickness ratio, LV hypertrophy, myocardial stress and myocardial stiffness. At the advance stage of CVC valsartan treatment also resulted in significant reduction in LV hypertrophy and myocardial stress, improvement in cardiac remodeling functional parameters but had no effect on LV diameter-thickness ratio.Conclusion. The ARA treatment is preferred at early CVC stage for better cardioprotection.

  18. Latent myofascial trigger points are associated with an increased antagonistic muscle activity during agonist muscle contraction.

    Science.gov (United States)

    Ibarra, José Miota; Ge, Hong-You; Wang, Chao; Martínez Vizcaíno, Vicente; Graven-Nielsen, Thomas; Arendt-Nielsen, Lars

    2011-12-01

    The aim of this study was to evaluate motor unit activity from a latent myofascial trigger point (MTP) in an antagonist muscle during isometric agonist muscle contraction. Intramuscular activity was recorded with an intramuscular electromyographic (EMG) needle inserted into a latent MTP or a non-MTP in the posterior deltoid muscle at rest and during isometric shoulder flexion performed at 25% of maximum voluntary contraction in 14 healthy subjects. Surface EMGs were recorded from the anterior and posterior deltoid muscles. Maximal pain intensity and referred pain induced by EMG needle insertion were recorded on a visual analogue scale. The results showed that higher local pain was observed following needle insertion into latent MTPs (4.64 ± .48 cm) than non-MTPs (2.35 ± .43 cm, P muscle was significantly higher at rest and during shoulder flexion at latent MTPs than non-MTPs (P muscle relaxation following exercise, disordered fine movement control, and unbalanced muscle activation. Elimination of latent MTPs and/or prevention of latent MTPs from becoming active may improve motor functions. Copyright © 2011 American Pain Society. Published by Elsevier Inc. All rights reserved.

  19. Dual orexin receptor antagonists - promising agents in the treatment of sleep disorders.

    Science.gov (United States)

    Pałasz, Artur; Lapray, Damien; Peyron, Christelle; Rojczyk-Gołębiewska, Ewa; Skowronek, Rafał; Markowski, Grzegorz; Czajkowska, Beata; Krzystanek, Marek; Wiaderkiewicz, Ryszard

    2014-01-01

    Insomnia is a serious medical and social problem, its prevalence in the general population ranges from 9 to 35% depending on the country and assessment method. Often, patients are subject to inappropriate and therefore dangerous pharmacotherapies that include prolonged administration of hypnotic drugs, benzodiazepines and other GABAA receptor modulators. This usually does not lead to a satisfactory improvement in patients' clinical states and may cause lifelong drug dependence. Brain state transitions require the coordinated activity of numerous neuronal pathways and brain structures. It is thought that orexin-expressing neurons play a crucial role in this process. Due to their interaction with the sleep-wake-regulating neuronal population, they can activate vigilance-promoting regions and prevent unwanted sleep intrusions. Understanding the multiple orexin modulatory effects is crucial in the context of pathogenesis of insomnia and should lead to the development of novel treatments. An important step in this process was the synthesis of dual antagonists of orexin receptors. Crucially, these drugs, as opposed to benzodiazepines, do not change the sleep architecture and have limited side-effects. This new pharmacological approach might be the most appropriate to treat insomnia.

  20. Travel habits and complications in patients treated with vitamin K antagonists: a cross sectional analysis.

    Science.gov (United States)

    Ringwald, Juergen; Lehmann, Marina; Niemeyer, Nicole; Seifert, Isabell; Daubmann, Anne; Wegscheider, Karl; Salzwedel, Annett; Luxembourg, Beate; Eckstein, Reinhold; Voeller, Heinz

    2014-01-01

    Travel-related conditions have impact on the quality of oral anticoagulation therapy (OAT) with vitamin K-antagonists. No predictors for travel activity and for travel-associated haemorrhage or thromboembolic complications of patients on OAT are known. A standardised questionnaire was sent to 2500 patients on long-term OAT in Austria, Switzerland and Germany. 997 questionnaires were received (responder rate 39.9%). Ordinal or logistic regression models with travel activity before and after onset of OAT or travel-associated haemorrhages and thromboembolic complications as outcome measures were applied. 43.4% changed travel habits since onset of OAT with 24.9% and 18.5% reporting decreased or increased travel activity, respectively. Long-distance worldwide before OAT or having suffered from thromboembolic complications was associated with reduced travel activity. Increased travel activity was associated with more intensive travel experience, increased duration of OAT, higher education, or performing patient self-management (PSM). Travel-associated haemorrhages or thromboembolic complications were reported by 6.5% and 0.9% of the patients, respectively. Former thromboembolic complications, former bleedings and PSM were significant predictors of travel-associated complications. OAT also increases travel intensity. Specific medical advice prior travelling to prevent complications should be given especially to patients with former bleedings or thromboembolic complications and to those performing PSM. Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. Bullying Prevention

    Science.gov (United States)

    Kemp, Patrice

    2016-01-01

    The focus of the milestone project is to focus on bridging the gap of bullying and classroom instruction methods. There has to be a defined expectations and level of accountability that has to be defined when supporting and implementing a plan linked to bullying prevention. All individuals involved in the student's learning have to be aware of…

  2. Prevention: Exercise

    Medline Plus

    Full Text Available ... Strengthen Your Core! Stretching/Flexibility Aerobic Exercise Cervical Exercise Strength Training for the Elderly Other Back Pack Safety Pregnancy and Back Pain Preventing Osteoporosis Back Pain Basics Book RESOURCES ... The Backbone of Spine Treatment Spondylolisthesis BLOG FIND ...

  3. Prevent Pneumonia

    Centers for Disease Control (CDC) Podcasts

    2015-08-06

    CDC’s Matthew Westercamp explains what pneumonia is, its symptoms, and how to prevent it.  Created: 8/6/2015 by National Center for Immunization and Respiratory Diseases (NCIRD), Division of Bacterial Diseases (DBD), Respiratory Diseases Branch (RDB).   Date Released: 8/6/2015.

  4. HIV Prevention

    Science.gov (United States)

    ... Abroad Treatment Basic Statistics Get Tested Find an HIV testing site near you. Enter ZIP code or city Follow HIV/AIDS CDC HIV CDC HIV/AIDS See RSS | ... Collapse All Is abstinence the only 100% effective HIV prevention option? Yes. Abstinence means not having oral, ...

  5. Prevention: Exercise

    Medline Plus

    Full Text Available ... Information Feature Articles Patient Q&A Success Stories Definitions Anatomy of the Spine Definitions A-Z Spine Specialists Videos 9 for Spine Epidural Steroid Injections Exercise: The Backbone of Spine Treatment Spondylolisthesis BLOG FIND A SPECIALIST Prevention ...

  6. Economic evaluation of apixaban for the prevention of stroke in non-valvular atrial fibrillation in the Netherlands

    NARCIS (Netherlands)

    Stevanovic, Jelena; Pompen, Marjolein; Le, Hoa H.; Rozenbaum, Mark H.; Tieleman, Robert G.; Postma, Maarten J.

    2014-01-01

    BACKGROUND: Stroke prevention is the main goal of treating patients with atrial fibrillation (AF). Vitamin-K antagonists (VKAs) present an effective treatment in stroke prevention, however, the risk of bleeding and the requirement for regular coagulation monitoring are limiting their use. Apixaban

  7. Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist

    DEFF Research Database (Denmark)

    Klementiev, Boris; Li, Shizhong; Korshunova, Irina

    2014-01-01

    Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide.......Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide....

  8. Translational modelling of prolactin response following administration of D2 antagonists in rats

    NARCIS (Netherlands)

    Taneja, Amit; Vermeulen, An; Huntjens, D.; Danhof, Meindert; de Lange, ECM; Proost, Johannes

    2015-01-01

    Objectives: Treatment with D2 antagonists results in prolactin release, and thus prolactin is a biomarker of dopamine antagonism. We compare the model performance of two semi-mechanistic PKPD models, the pool model and the agonist-antagonist interaction model, to describe prolactin release following

  9. CGRP receptor antagonists and antibodies against CGRP and its receptor in migraine treatment

    DEFF Research Database (Denmark)

    Edvinsson, Lars

    2015-01-01

    Recently developed calcitonin gene-related peptide (CGRP) receptor antagonistic molecules have shown promising results in clinical trials for acute treatment of migraine attacks. Drugs from the gepant class of CGRP receptor antagonists are effective and do not cause vasoconstriction, one...

  10. Effects of ionotropic glutamate receptor antagonists on rat dural artery diameter in an intravital microscopy model

    DEFF Research Database (Denmark)

    Chan, K Y; Gupta, S; de Vries, R

    2010-01-01

    studies have shown that glutamate receptor antagonists affect the pathophysiology of migraine. This study investigated whether antagonists of NMDA (ketamine and MK801), AMPA (GYKI52466) and kainate (LY466195) glutamate receptors affected dural vasodilatation induced by alpha-CGRP, capsaicin...

  11. Does treatment with beta-adrenoceptor antagonists in vivo alter human adenylate cyclase responsiveness in vitro?

    NARCIS (Netherlands)

    Michel, M. C.; Klüppel, M.; Philipp, T.; Brodde, O. E.

    1991-01-01

    1. Treatment with beta-adrenoceptor antagonists in vivo can alter adenylate cyclase responsiveness in the human heart. We have determined the effects of treatment with four different beta-adrenoceptor antagonists in vivo on the responsiveness of lymphocyte and platelet adenylate cyclase in vitro in

  12. Folic acid sensitive birth defects in association with intrauterine exposure to folic acid antagonists

    NARCIS (Netherlands)

    Meijer, W.M.; Walle, H.E.K.de; Kerstjens-Frederikse, W.S; de Jong-van den Berg, Lolkje Theodora Wilhelmina

    2005-01-01

    Since the protective effect of folic acid (FA) on birth defects is well known, it is reasonable to assume intrauterine exposure to FA antagonists increases the risk on these defects. We have therefore performed case-control analyses to investigate the risk of intrauterine exposure to FA antagonists,

  13. Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

    NARCIS (Netherlands)

    Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart

    2016-01-01

    Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

  14. Antagonistic activity of autosimbionts А. viridans, B. subtilis and their probiotic association to conditionally microflora

    Directory of Open Access Journals (Sweden)

    Stepansky D.A.

    2015-03-01

    Full Text Available In this research the data on examination of antagonist qualities of bioassotiantes A. viridans and strain B. subtilis 3 towards pathogenic and opportunistic pathogenic microflora isolated from oropharynx and nasopharynx of children who were in contact with patients with pulmonary tuberculosis (MBT + are submitted. The expressed antagonist activity of autosimbionts A. viridans towards pathogenic and opportunistic pathogenic microflora was shown. Common antagonist activity of A. viridans (k N 1 and B. subtilis 3 towards diverse strains of test-cultures is 1,5-2 times higher, than separate antagonist activity of A. viridans (k №1 and B. subtilis 3. Received research data showed the possibility of continuing work on development of probiotic associations, that contain representatives of normal microflora - bioassociants A. viridans and probiotic strains B. subtilis 3 with broadspectrum of antagonistic activity in relation to the various groups of bacterium.

  15. The opioid receptor antagonist, naloxone, protects spinal motor neurons in a murine model of alphavirus encephalomyelitis

    Science.gov (United States)

    Prow, Natalie A.; Irani, David N.

    2007-01-01

    Spread of neuroadapted Sindbis virus (NSV) to motor neurons (MN) of the spinal cord (SC) causes severe hind limb weakness in C57BL/6 mice and models the paralysis that can accompany alphavirus and flavivirus encephalomyelitis in humans. The fate of spinal MN dictates the severity of NSV-induced paralysis, and recent data suggest that MN damage can occur indirectly via the actions of activated microglial cells. Because the opioid receptor antagonist, naloxone (NAL), blocks microglial-mediated neurodegeneration in other models, we examined its effects during NSV infection. Drug treatment prevented paralysis and enhanced the survival of MN without altering NSV tropism, replication, or clearance from SC tissue. Further studies showed that NAL most effectively inhibited paralysis in a 72-hour window after NSV challenge, suggesting that the drug inhibits an early event in SC pathogenesis. Histochemical studies demonstrated that NAL blocked early microglial activation in SC tissue sections, and protein assays showed that the early induction of pathogenic IL-1β was blunted in SC homogenates. Finally, loss of glutamate transporter-1 (GLT-1) expression in SC, an astrocyte glutamate reuptake protein responsible for lowering toxic extracellular levels of glutamate and preventing MN damage, was reversed by NAL treatment. This GLT-1 loss proved to be highly IL-1β-dependent. Taken together, these data suggest that NAL is neuroprotective in the SC by inhibiting microglial activation that, in turn, maintains normal astrocyte glutamate homeostasis. We propose that drugs targeting such microglial responses may have therapeutic benefit in humans with related viral infections. PMID:17459376

  16. New oral anticoagulants in the prevention of stroke

    Directory of Open Access Journals (Sweden)

    Konrad Jarząbek

    2013-10-01

    Full Text Available Atrial fibrillation is associated with a few folds higher risk of stroke. Traditional vitamin K antagonists used in the prevention of stroke in patients with non-valvular atrial fibrillation are often not efficient enough due to their interactions with a broad range of substances including medicines or food ingridients and problems with monitoring the treatment. New oral anticoagulants pose an alternative for the vitamin K antagonists. They are equally efficient in the prevention of stroke, but are safer and have no requirement for routine coagulation monitoring. We present a case of a patient with atrial fibrillation, high risk of tromboembolism and recurring episodes of hemorrhages. Considering the possible complications, rivaroxaban was administered.

  17. Exercise-induced bronchoconstriction: The effects of montelukast, a leukotriene receptor antagonist

    Directory of Open Access Journals (Sweden)

    James P Kemp

    2009-11-01

    Full Text Available James P KempClinical Professor of Pediatrics, Division of Immunology and Allergy, University of California School of Medicine, San Diego, CA, USAAbstract: Exercise-induced bronchoconstriction (EIB is very common in both patients with asthma and those who are otherwise thought to be normal. The intensity of exercise as well as the type of exercise is important in producing symptoms. This may make some types of exercise such as swimming more suitable and extended running more difficult for patients with this condition. A better understanding of EIB will allow the physician to direct the patient towards a type of exercise and medications that can result in a more active lifestyle without the same concern for resulting symptoms. This is especially important for schoolchildren who are usually enrolled in physical education classes and elite athletes who may desire to participate in competitive sports. Fortunately several medications (short- and long-acting β2-agonists, cromolyn, nedocromil, inhaled corticosteroids, and more recently leukotriene modifiers have been shown to be effective in preventing or attenuating the effects of exercise in many patients. In addition, inhaled β2-agonists have been shown to quickly reverse the airway obstruction that develops in patients and continue to be the reliever medications of choice. Inhaled corticosteroids are increasingly being recommended as regular therapy now that the role of inflammation and airway injury has been identified in EIB. With the discovery that there is a release of mediators such as histamine and leukotrienes from cells in the airway following exercise with resulting airway obstruction in susceptible individuals, interest has turned to attenuating their effects with mediator antagonists especially those that block the effects of leukotrienes. Studies with an oral leukotriene antagonist, montelukast, have shown beneficial effects in adults and children aged as young as 6 years with EIB

  18. Paradoxical effects of the opioid antagonist naltrexone on morphine analgesia, tolerance, and reward in rats.

    Science.gov (United States)

    Powell, Kelly J; Abul-Husn, Noura S; Jhamandas, Asha; Olmstead, Mary C; Beninger, Richard J; Jhamandas, Khem

    2002-02-01

    Opioid agonists such as morphine have been found to exert excitatory and inhibitory receptor-mediated effects at low and high doses, respectively. Ultra-low doses of opioid antagonists (naloxone and naltrexone), which selectively inhibit the excitatory effects, have been reported to augment systemic morphine analgesia and inhibit the development of tolerance/physical dependence. This study investigated the site of action of the paradoxical effects of naltrexone and the generality of this effect. The potential of ultra-low doses of naltrexone to influence morphine-induced analgesia was investigated in tests of nociception. Administration of intrathecal (0.05 and 0.1 ng) or systemic (10 ng/kg i.p.) naltrexone augmented the antinociception produced by an acute submaximal dose of intrathecal (5 microg) or systemic (7.5 mg/kg i.p.) morphine in the tail-flick test. Chronic intrathecal (0.005 and 0.05 ng) or systemic (10 ng/kg) naltrexone combined with morphine (15 microg i.t.; 15 mg/kg i.p.) over a 7-day period inhibited the decline in morphine antinociception and prevented the loss of morphine potency. In animals rendered tolerant to intrathecal (15 microg) or systemic (15 mg/kg) morphine, administration of naltrexone (0.05 ng i.t.; 10 and 50 ng/kg i.p.) significantly restored the antinociceptive effect and potency of morphine. Thus, in ultra-low doses, naltrexone paradoxically enhances morphine analgesia and inhibits or reverses tolerance through a spinal action. The potential of naltrexone to influence morphine-induced reward was also investigated using a place preference paradigm. Systemic administration of ultra-low doses of naltrexone (16.7, 20.0, and 25.0 ng/kg) with morphine (1.0 mg/kg) extended the duration of the morphine-induced conditioned place preference. These effects of naltrexone on morphine-induced reward may have implications for chronic treatment with agonist-antagonist combinations.

  19. Fitting the right non-vitamin K antagonist oral anticoagulant to the right patient with non-valvular atrial fibrillation

    DEFF Research Database (Denmark)

    Li, Yanguang; Pastori, Daniele; Lip, Gregory YH

    2018-01-01

    Atrial fibrillation (AF) is the most prevalent arrhythmia and is associated with an increased risk of ischemic stroke (IS) and systemic embolism (SE). Stroke prevention is a key element for the overall management of AF patients. The non-vitamin K antagonist oral anticoagulants (NOACs......), such as dabigatran, rivaroxaban, apixaban and edoxaban, are at least as effective as warfarin in reducing IS/SE with a lower rate of major bleeding. Various analyses from the large Phase III randomised trials demonstrated different efficacy and safety of NOACs in specific subgroups of patients. The randomised trials...... are supplemented by effectiveness and safety data from real world observational cohorts following the availability of these drugs for use in everyday clinical practice. Given the clinical heterogeneity of AF patients, the available data from trials and real-world studies allow us to fit the right NOAC...

  20. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    , in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-ylpropoxyphenylmethanol, and its (S-enantiomer (4 significantly and in a dose-dependent manner reduced convulsions or exhibited full protection in MES and PTZ convulsions model, respectively. Interestingly, the protective effects observed for the (R-enantiomer (3 in MES model were significantly greater than those of the standard H3R inverse agonist/antagonist pitolisant, comparable with those observed for PHT, and reversed when rats were pretreated with the selective H3R agonist R-(α-methyl-histamine. Comparisons of the observed antagonistic in vitro affinities among the ligands 1–6 revealed profound stereoselectivity at human H3Rs with varying preferences for this receptor subtype. Moreover, the in vivo anticonvulsant effects observed in this study for ligands 1–6 showed stereoselectivity in different convulsion models in male adult rats. Keywords: histamine, H3 receptor, isomeric antagonists, anticonvulsant activity, stereo­selectivity

  1. Real-World Use of Apixaban for Stroke Prevention in Atrial Fibrillation

    DEFF Research Database (Denmark)

    Proietti, Marco; Romanazzi, Imma; Romiti, Giulio Francesco

    2018-01-01

    BACKGROUND AND PURPOSE: The use of oral anticoagulant therapy for stroke prevention in atrial fibrillation has been transformed by the availability of the nonvitamin K antagonist oral anticoagulants. Real-world studies on the use of nonvitamin K antagonist oral anticoagulants would help elucidate...... their effectiveness and safety in daily clinical practice. Apixaban was the third nonvitamin K antagonist oral anticoagulants introduced to clinical practice, and increasing real-world studies have been published. Our aim was to summarize current evidence about real-world studies on apixaban for stroke prevention...... in atrial fibrillation. METHODS: We performed a systematic review and meta-analysis of all observational real-world studies comparing apixaban with other available oral anticoagulant drugs. RESULTS: From the original 9680 results retrieved, 16 studies have been included in the final meta-analysis. Compared...

  2. Quinidine, but not eicosanoid antagonists or dexamethasone, protect the gut from platelet activating factor-induced vasoconstriction, edema and paralysis.

    Science.gov (United States)

    Lautenschläger, Ingmar; Frerichs, Inéz; Dombrowsky, Heike; Sarau, Jürgen; Goldmann, Torsten; Zitta, Karina; Albrecht, Martin; Weiler, Norbert; Uhlig, Stefan

    2015-01-01

    Intestinal circulatory disturbances, atony, edema and swelling are of great clinical relevance, but the related mechanisms and possible therapeutic options are poorly characterized, in part because of the difficulties to comprehensively analyze these conditions. To overcome these limitations we have developed a model of the isolated perfused rat small intestine where all of these symptoms can be studied simultaneously. Here we used this model to study the role of eicosanoids, steroids and quinidine in platelet-activating factor (PAF)-induced intestinal disorders. A vascular bolus of PAF (0.5 nmol) triggered release of thromboxane and peptidoleukotrienes into the vascular bed (peak concentration 35 nM and 0.8 nM) and reproduced all symptoms of intestinal failure: mesenteric vasoconstriction, translocation of fluid and macromolecules from the vasculature to the lumen and lymphatics, intestinal edema formation, loss of intestinal peristalsis and decreased galactose uptake. All effects of PAF were abolished by the PAF-receptor antagonist ABT491 (2.5 μM). The COX and LOX inhibitors ASA and AA861 (500 μM, 10 μM) did not exhibit barrier-protective effects and the eicosanoid antagonists SQ29548 and MK571 (10 μM, each) only moderately attenuated the loss of vascular fluid, the redistribution to the lumen and the transfer of FITC dextran to the lumen. The steroid dexamethasone (10 μM) showed no barrier-protective properties and failed to prevent edema formation. Quinidine (100 μM) inhibited the increase in arterial pressure, stabilized all the intestinal barriers, and reduced lymph production and the transfer of FITC dextran to the lymph. While quinidine by itself reduced peristalsis, it also obviated paralysis, preserved intestinal functions and prevented edema formation. We conclude that quinidine exerts multiple protective effects against vasoconstriction, edema formation and paralysis in the intestine. The therapeutic use of quinidine for intestinal ailments

  3. Neuroprotection, excitotoxicicity and nmda antagonists Neuroproteção, excitotoxicidade e antagonistas do NMDA

    Directory of Open Access Journals (Sweden)

    RUBENS JOSÉ GAGLIARDI

    2000-06-01

    Full Text Available PURPOSE: To analyze the main aspects of neuroprotection and excitotoxicity. DISCUSSION: This is a significant theory on the pathophysiology of cerebral ischemia; it is based on the release of excitatory aminoacid (EAA, mainly glutamate. The sequence starts with a decrease of the blood flow and ends in neuronal death. The main stages of this reaction are herein presented and discussed. An in depth study of the effects of the excessive intracellular calcium is undertaken. Neuroprotectors (NP are a group of drugs that reduce the excitotoxicity, opposing the excessive release of EAA and its intracellular effects. Neuroprotectors represent a rational approach to stroke treatment and offer a number of potential advantages. They prevent or limit ischemia-induced damage. CONCLUSION: There are many experimental and clinical NP trials. A minimum of 800 trials are currently under study worldwide. The most important NP subgroups are: N-methyl D-aspartate (NMDA antagonists, gamma-amino butyric acid (GABA agonists, amino-hydroxy-methyl-isoxalone propionic acid (AMPA antagonists, reducers of intracellular Ca++ inhibitors of nitric oxide modulation pathway free radicals scavengers, sodium channel antagonists, glutamate release inhibitor, growth factors, hypothermia and potassium channel activators.PROPÓSITO: Analisar importantes aspectos da neuroproteção e da excitotoxicidade. DISCUSSÃO: Excitotoxicidade é teoria que explica os mecanismos básicos da fisiopatologia da isquemia cerebral; é baseada na liberação excessiva de amino-ácidos excitatórios (AAE, principalmente o glutamato. A sequência se inicia com o decréscimo do fluxo sanguíneo cerebral e termina com a morte neuronal. Os principais aspectos desta cadeia de reações são apresentados e discutidos. Os efeitos do excesso de cálcio intracelular são analisados. Neuroprotetores (NP são um grupo de drogas que reduzem a excitotoxicidade combatendo a excessiva liberação de AAE e os seus

  4. Effect of an oral contraceptive pill on follicular development in IVF/ICSI patients receiving a GnRH antagonist: a randomized study.

    Science.gov (United States)

    Huirne, Judith A F; van Loenen, Andre C D; Donnez, Jacques; Pirard, Céline; Homburg, Roy; Schats, Roel; McDonnell, Joseph; Lambalk, Cornelis B

    2006-08-01

    This randomized controlled study compared the effectiveness of a gonadotrophin releasing hormone (GnRH) antagonist protocol with or without oral contraceptive (OC) pretreatment on the number of oocytes retrieved in IVF or intracytoplasmic sperm injection (ICSI) patients. Sixty-four patients were randomized to start recombinant human FSH (r-hFSH) on day 2 or 3 after OC withdrawal (OC group) or on day 2 of a natural cycle (control group). From stimulation day 6 onwards, all patients were treated with daily (0.5 mg/ml) GnRH antagonist (Antide). OC pretreatment resulted in significantly lower starting concentrations of FSH, LH and oestradiol (P after OC pretreatment, leading to a significantly extended stimulation period (11.6 versus 8.7 days, P day of recombinant human chorionic gonadotrophin administration (15.4 versus 12.5, P = 0.02) and more oocytes retrieved (13.5 versus 10.2, P < 0.001) as compared with the control group. GnRH antagonist regimen, pretreated with OC, prevented the early endogenous FSH rise and improved follicular homogeneity, resulting in more oocytes. As a consequence of the extended treatment period, more rhFSH was required.

  5. The IL-6 receptor super-antagonist Sant7 enhances antiproliferative and apoptotic effects induced by dexamethasone and zoledronic acid on multiple myeloma cells.

    Science.gov (United States)

    Tassone, Pierfrancesco; Galea, Eulalia; Forciniti, Samantha; Tagliaferri, Pierosandro; Venuta, Salvatore

    2002-10-01

    Interleukin-6 (IL-6) is the major growth and survival factor for multiple myeloma (MM), and has been shown to protect MM cells from apoptosis induced by a variety of agents. IL-6 receptor antagonists, which prevent the assembly of functional IL-6 receptor complexes, inhibit cell proliferation and induce apoptosis in MM cells. We have investigated whether the IL-6 receptor super-antagonist Sant7 might enhance the antiproliferative and apoptotic effects induced by the combination of dexamethasone (Dex) and zoledronic acid (Zln) on human MM cell lines and primary cells from MM patients. Here we show that each of these compounds individually induced detectable antiproliferative effects on MM cells. Sant7 significantly enhanced growth inhibition and apoptosis induced by Dex and Zln on both MM cell lines and primary MM cells. These results indicate that overcoming IL-6 mediated cell resistance by Sant7 potentiates the effect of glucocorticoides and bisphosphonates on MM cell growth and survival, providing a rationale for therapies including IL-6 antagonists in MM.

  6. In vitro and in vivo effects of kisspeptin antagonists p234, p271, p354, and p356 on GPR54 activation.

    Directory of Open Access Journals (Sweden)

    C H J Albers-Wolthers

    Full Text Available Kisspeptins (KPs and their receptor (GPR54 or KiSS1R play a key-role in regulation of the hypothalamic-pituitary-gonadal axis and are therefore interesting targets for therapeutic interventions in the field of reproductive endocrinology. As dogs show a rapid and robust LH response after the administration of KP10, they can serve as a good animal model for research concerning KP signaling. The aims of the present study were to test the antagonistic properties of KP analogs p234, p271, p354, and p356 in vitro, by determining the intracellular Ca2+ response of CHEM1 cells that stably express human GPR54, and to study the in vivo effects of these peptides on basal plasma LH concentration and the KP10-induced LH response in female dogs. Exposure of the CHEM1 cells to KP-10 resulted in a clear Ca2+ response. P234, p271, p354, and p356 did not prevent or lower the KP10-induced Ca2+ response. Moreover, the in vivo studies in the dogs showed that none of these supposed antagonists lowered the basal plasma LH concentration and none of the peptides lowered the KP10-induced LH response. In conclusion, p234, p271, p354, and p356 had no antagonistic effects in vitro nor any effect on basal and kisspeptin-stimulated plasma LH concentration in female dogs.

  7. Protective Effects of Glutamine Antagonist 6-Diazo-5-Oxo-l-Norleucine in Mice with Alphavirus Encephalomyelitis

    Science.gov (United States)

    Manivannan, Sivabalan; Baxter, Victoria K.; Schultz, Kimberly L. W.; Slusher, Barbara S.

    2016-01-01

    ABSTRACT Inflammation is a necessary part of the response to infection but can also cause neuronal injury in both infectious and autoimmune diseases of the central nervous system (CNS). A neurovirulent strain of Sindbis virus (NSV) causes fatal paralysis in adult C57BL/6 mice during clearance of infectious virus from the CNS, and the virus-specific immune response is implicated as a mediator of neuronal damage. Previous studies have shown that survival is improved in T-cell-deficient mice and in mice with pharmacological inhibition of the inflammatory response and glutamate excitotoxicity. Because glutamine metabolism is important in the CNS for the generation of glutamate and in the immune system for lymphocyte proliferation, we tested the effect of the glutamine antagonist DON (6-diazo-5-oxo-l-norleucine) on the outcome of NSV infection in mice. DON treatment for 7 days from the time of infection delayed the onset of paralysis and death. Protection was associated with reduced lymphocyte proliferation in the draining cervical lymph nodes, decreased leukocyte infiltration into the CNS, lower levels of inflammatory cytokines, and delayed viral clearance. In vitro studies showed that DON inhibited stimulus-induced proliferation of lymphocytes. When in vivo treatment with DON was stopped, paralytic disease developed along with the inflammatory response and viral clearance. These studies show that fatal NSV-induced encephalomyelitis is immune mediated and that antagonists of glutamine metabolism can modulate the immune response and protect against virus-induced neuroinflammatory disease. IMPORTANCE Encephalomyelitis due to infection with mosquito-borne alphaviruses is an important cause of death and of long-term neurological disability in those who survive infection. This study demonstrates the role of the virus-induced immune response in the generation of neurological disease. DON, a glutamine antagonist, inhibited the proliferation of lymphocytes in response to

  8. Protective Effects of Glutamine Antagonist 6-Diazo-5-Oxo-l-Norleucine in Mice with Alphavirus Encephalomyelitis.

    Science.gov (United States)

    Manivannan, Sivabalan; Baxter, Victoria K; Schultz, Kimberly L W; Slusher, Barbara S; Griffin, Diane E

    2016-10-15

    Inflammation is a necessary part of the response to infection but can also cause neuronal injury in both infectious and autoimmune diseases of the central nervous system (CNS). A neurovirulent strain of Sindbis virus (NSV) causes fatal paralysis in adult C57BL/6 mice during clearance of infectious virus from the CNS, and the virus-specific immune response is implicated as a mediator of neuronal damage. Previous studies have shown that survival is improved in T-cell-deficient mice and in mice with pharmacological inhibition of the inflammatory response and glutamate excitotoxicity. Because glutamine metabolism is important in the CNS for the generation of glutamate and in the immune system for lymphocyte proliferation, we tested the effect of the glutamine antagonist DON (6-diazo-5-oxo-l-norleucine) on the outcome of NSV infection in mice. DON treatment for 7 days from the time of infection delayed the onset of paralysis and death. Protection was associated with reduced lymphocyte proliferation in the draining cervical lymph nodes, decreased leukocyte infiltration into the CNS, lower levels of inflammatory cytokines, and delayed viral clearance. In vitro studies showed that DON inhibited stimulus-induced proliferation of lymphocytes. When in vivo treatment with DON was stopped, paralytic disease developed along with the inflammatory response and viral clearance. These studies show that fatal NSV-induced encephalomyelitis is immune mediated and that antagonists of glutamine metabolism can modulate the immune response and protect against virus-induced neuroinflammatory disease. Encephalomyelitis due to infection with mosquito-borne alphaviruses is an important cause of death and of long-term neurological disability in those who survive infection. This study demonstrates the role of the virus-induced immune response in the generation of neurological disease. DON, a glutamine antagonist, inhibited the proliferation of lymphocytes in response to infection, prevented the

  9. Recent Advances in Preventing Chemotherapy-Induced Nausea and Vomiting.

    Science.gov (United States)

    Nasir, Syed Sameer; Schwartzberg, Lee S

    2016-08-01

    Chemotherapy-induced nausea and vomiting (CINV) remains an important adverse effect of cancer therapy. The goal of CINV prophylaxis is to reduce the morbidity associated with nausea and vomiting, as well as to preserve quality of life, while maintaining the desired chemotherapy regimen. The US Food and Drug Administration has recently approved new therapies for prevention of CINV, including the neurokinin-1 (NK1) receptor antagonist rolapitant and the fixed-dose combination of the second-generation 5-hydroxytryptamine type 3 receptor antagonist palonosetron with the novel NK1 receptor antagonist netupitant. Alternative agents, like the atypical antipsychotic olanzapine, have also expanded the options available for preventing delayed and refractory CINV. Consensus guidelines for prevention of CINV from several organizations are generally consistent with one another and are updated based on expert review of available clinical trial data. This article will address changes in CINV guidelines over the past 5 years and provide updates on recently approved agents and agents that are expected to be approved, based on published phase III trials. It will also explore other factors affecting optimal CINV control, including the role of patient-related risk factors and the role of physician adherence to antiemetic guidelines in reducing the residual risk of CINV.

  10. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    Energy Technology Data Exchange (ETDEWEB)

    Chen, Yi [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Jing, Qian; Yue, Jiaqi; Liu, Yang [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Cheng, Zhong [Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu (China); Li, Jingyi, E-mail: li--jingyi@hotmail.com [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Song, Haixing [The School of Biomedical Sciences, Chengdu Medical College, Chengdu 610083 (China); Li, Guoyu, E-mail: liguoyulisa@163.com [School of Pharmacy, Shihezi University, Shihezi 832003 (China); Liu, Rui, E-mail: liurui_scu@hotmail.com [State Key Laboratory of Oral Diseases, West China College of Stomatology, Sichuan University (China); Wang, Jinhui [School of Pharmacy, Shihezi University, Shihezi 832003 (China)

    2016-05-20

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  11. Association of calcium antagonist use with lower hemoglobin levels in hemodialysis patients.

    Science.gov (United States)

    Cikrikcioglu, M A; Ozdemir, A A; Sekin, Y; Yalcin, B; Altay, M; Gundogdu, A; Erkal, S N; Kazancioglu, R; Erkoc, R

    2015-09-01

    Objective of the present study was to investigate whether calcium antagonist use is associated with lower hemoglobin levels and/or higher erythropoiesis stimulating agent (ESA) requirement in hemodialysis patients. A total of 130 adult hemodialysis patients were classified into two groups based on calcium antagonist usage for a period of at least 3 months as calcium antagonist users and calcium antagonist non-users. The two groups were compared cross-sectionally in a retrospective manner in terms of demographics, chronic kidney disease aetiologies, Charlson's Comorbidty Index, blood pressure, type of dialysis access, interdialytic body weight gain, cardiothoracic index, complete blood count, biochemistry, regular medication use and consumption of ESA. All independent variables that were different between the groups were subjected to logistic regression analysis. Linear regression analysis with dependent variable of hemoglobin value was also performed ESA consumption and blood pressure were higher, diabetic nephropathy, doxazosin and ACE inhibitor use were more frequent, and hemoglobin was lower in the calcium antagonist users. After logistic regression analysis, diabetic nephropathy, doxazosin use, ACE inhibitor use and lower hemoglobin were associated with calcium antagonist use. After lineer regression analysis, Age, BMI, gender, predialysis creatinine value, dialysis duration, systolic and diastolic blood pressure, doxazosin use, diabetes mellitus and diabetic nephropathy were not related with hemoglobin value. But, higher amount of ESA consumption, ACE inhibitor use and calcium antagonist use were significantly associated with lower hemoglobin value. CA use was associated with lower hemoglobin levels in our hemodialysis patient population.

  12. Exploitation of microbial antagonists for the control of postharvest diseases of fruits: a review.

    Science.gov (United States)

    Dukare, Ajinath Shridhar; Paul, Sangeeta; Nambi, V Eyarkai; Gupta, Ram Kishore; Singh, Rajbir; Sharma, Kalyani; Vishwakarma, Rajesh Kumar

    2018-01-16

    Fungal diseases result in significant losses of fruits and vegetables during handling, transportation and storage. At present, post-production fungal spoilage is predominantly controlled by using synthetic fungicides. Under the global climate change scenario and with the need for sustainable agriculture, biological control methods of fungal diseases, using antagonistic microorganisms, are emerging as ecofriendly alternatives to the use of fungicides. The potential of microbial antagonists, isolated from a diversity of natural habitats, for postharvest disease suppression has been investigated. Postharvest biocontrol systems involve tripartite interaction between microbial antagonists, the pathogen and the host, affected by environmental conditions. Several modes for fungistatic activities of microbial antagonists have been suggested, including competition for nutrients and space, mycoparasitism, secretion of antifungal antibiotics and volatile metabolites and induction of host resistance. Postharvest application of microbial antagonists is more successful for efficient disease control in comparison to pre-harvest application. Attempts have also been made to improve the overall efficacy of antagonists by combining them with different physical and chemical substances and methods. Globally, many microbe-based biocontrol products have been developed and registered for commercial use. The present review provides a brief overview on the use of microbial antagonists as postharvest biocontrol agents and summarises information on their isolation, mechanisms of action, application methods, efficacy enhancement, product formulation and commercialisation.

  13. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell

    International Nuclear Information System (INIS)

    Chen, Yi; Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi; Jing, Qian; Yue, Jiaqi; Liu, Yang; Cheng, Zhong; Li, Jingyi; Song, Haixing; Li, Guoyu; Liu, Rui; Wang, Jinhui

    2016-01-01

    Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

  14. Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus.

    Science.gov (United States)

    Dunford, Paul J; Williams, Kacy N; Desai, Pragnya J; Karlsson, Lars; McQueen, Daniel; Thurmond, Robin L

    2007-01-01

    Histamine is a potent mediator of itch in humans, yet histamine H(1) receptor antagonists have been shown to be of limited use in the treatment of certain chronic pruritic diseases. The histamine H(4) receptor is a recently described histamine receptor, expressed on hematopoietic cells, linked to the pathology of allergy and asthma. The contribution of the novel histamine H(4) receptor to histaminergic and allergic pruritus was investigated. Histamine and a selective histamine H(4) receptor agonist caused scratching responses in mice, which were almost completely attenuated in histamine H(4) receptor knockout mice or by pretreatment with the selective histamine H(4) receptor antagonist, JNJ 7777120. Pruritus induced by allergic mechanisms was also potently inhibited with histamine H(4) receptor antagonist treatment or in histamine H(4) receptor knockout mice. In all cases, the inhibitory effect of histamine H(4) receptor antagonist was greater than those observed with histamine H(1) receptor antagonists. The histamine H(4) receptor-mediated pruritus was shown to be independent of mast cells or other hematopoietic cells and may result from actions on peripheral neurons. These results demonstrate that the histamine H(4) receptor is involved in pruritic responses in mice to a greater extent than the histamine H(1) receptor. Histamine H(4) receptor antagonists may have therapeutic utility for treating chronic pruritic diseases in humans where histamine H(1) receptor antagonists are not effective.

  15. Allergy prevention.

    Science.gov (United States)

    Muche-Borowski, Cathleen; Kopp, Matthias; Reese, Imke; Sitter, Helmut; Werfel, Thomas; Schäfer, Torsten

    2010-09-01

    The further increase of allergies in industrialized countries demands evidence-based measures of primary prevention. The recommendations as published in the guideline of 2004 were updated and consented on the basis of a systematic literature search. Evidence from the period February 2003-May 2008 was searched in the electronic databases Cochrane and MEDLINE as well as in reference lists of recent reviews and by contacting experts. The retrieved citations were screened for relevance first by title and abstract and in a second step as full paper. Levels of evidence were assigned to each included study and the methodological quality of the studies was assessed as high or low. Finally the revised recommendations were formally consented (nominal group process) by representatives of relevant societies and organizations including a self-help group. Of originally 4556 hits, 217 studies (4 Cochrane Reviews, 14 meta-analyses, 19 randomized controlled trials, 135 cohort and 45 case-control studies) were included and critically appraised. Grossly unchanged remained the recommendations on avoiding environmental tobacco smoke, breast-feeding over 4 months (alternatively hypoallergenic formulas for children at risk), avoiding a mold-promoting indoor climate, vaccination according to current recommendations, and avoidance of furry pets (especially cats) in children at risk. The recommendation on reducing the house dust mite allergen exposure as a measure of primary prevention was omitted and the impact of a delayed introduction of supplementary food was reduced. New recommendations were adopted concerning fish consumption (during pregnancy / breast-feeding and as supplementary food in the first year), avoidance of overweight, and reducing the exposure to indoor and outdoor air pollutants. The revision of this guideline on a profound evidence basis led to (1) a confirmation of existing recommendations, (2) substantial revisions, and (3) new recommendations. Thereby it is possible

  16. How I treat poisoning with vitamin K antagonists.

    Science.gov (United States)

    Schulman, Sol; Furie, Bruce

    2015-01-15

    Severe deficiency of vitamin K-dependent proteins in patients not maintained on vitamin K antagonists is most commonly associated with poisoning by or surreptitious ingestion of warfarin, warfarin-like anticoagulants, or potent rodenticides ("superwarfarins"), such as brodifacoum. Serious bleeding manifestations are common. Superwarfarins are 2 orders of magnitude more potent than warfarin and have a half-life measured in weeks. These rodenticides are readily available household environmental hazards and are sometimes consumed accidentally or as manifestations of psychiatric disease. Immediate diagnosis and proper therapy is critically important to minimize morbidity and mortality because this condition, affecting thousands of patients annually, is reversible. Treatment with large doses of oral vitamin K1, often over months to years, to maintain a near-normal prothrombin time can reverse the coagulopathy associated with superwarfarins. Although these patients initially present to various medical specialties, the hematologist is often consulted to offer the definitive diagnosis and proper therapy. © 2015 by The American Society of Hematology.

  17. Anaphylactic shock: catecholamine actions in the responses to opioid antagonists.

    Science.gov (United States)

    Amir, S

    1988-01-01

    The pathophysiological consequences of endorphin release in anaphylactic shock were investigated through pharmacological studies using opiate antagonists (naloxone, naltrexone, natrexone methyl bromide) as well as agonists (morphine, beta-endorphin). These studies suggest that induction of anaphylaxis provokes the release of endogenous opioids, possibly from the hypothalamus, which contribute to the shock process by stimulating opiate receptors in the CNS. The mechanism of pathophysiologic action of endorphin in anaphylaxis involves, at least in part, inhibition of the central component of the sympatho-adrenalmedullary system. This results in reduced effectiveness of the sympathetic system to physiologically reverse the circulatory effects of the toxic mediators of anaphylaxis. Naloxone, by blocking endorphin action at CNS opiate receptors located at autonomic regulatory centers (e.g. hypothalamus), reverses the sympatho-inhibitory effect of the endorphin peptides. This results in increased central sympathetic outflow to peripheral sympathetic neuroeffector mechanisms; it affords improved sympathetic compensatory responses and increases survival. TRH and DT gamma E physiologically oppose the action of endorphins upon the autonomic system. They stimulate central sympathetic mechanisms through their own receptor systems and increase outflow to peripheral sympathetic effectors. This also results in improved circulatory function and survival.

  18. Effect of platelet activating factor antagonist treatment on gentamicin nephrotoxicity

    Directory of Open Access Journals (Sweden)

    A. Rodriguez-Barbero

    1992-01-01

    Full Text Available To assess whether PAF could be involved in the gentamicin-induced nephrotoxicity, we have studied the effect of PAF antagonist BN-52021 on renal function in rats after gentamicin (GENTA treatment. Experiments were completed in 21 Wistar rats divided into three groups: group GENTA was injected with gentamicin 100 mg kg−1 body wt/day s.c. for 6 days. Group GENTA + BN received gentamicin and BN-52021 i.p. 5 mg kg−1 body wt/day. A third group served as control. Rats were placed in meta-bolic cages and plasma creatinine and creatinine clearance were measured daily. GENTA group showed a progressive increase in plasma creatinine, a drop in creatinine clearance and an increase in urinary excretion of N-acetyl-β-D-glucosaminidase and alkaline phosphatase. GENTA + BN group showed a lesser change in plasma creatinine and a creatinine clearance, but no difference with GENTA group in urinary excretion of NAG and AP were observed. Histological examination revealed a massive cortical tubular necrosis in rats treated with gentamicin, whereas in BN-52021 injected animals tubular damage was markedly attenuated. The present results suggest a role for PAF in the gentamicininduced nephro-toxicity.

  19. Discovery and Characterization of an Endogenous CXCR4 Antagonist

    Directory of Open Access Journals (Sweden)

    Onofrio Zirafi

    2015-05-01

    Full Text Available CXCL12-CXCR4 signaling controls multiple physiological processes and its dysregulation is associated with cancers and inflammatory diseases. To discover as-yet-unknown endogenous ligands of CXCR4, we screened a blood-derived peptide library for inhibitors of CXCR4-tropic HIV-1 strains. This approach identified a 16 amino acid fragment of serum albumin as an effective and highly specific CXCR4 antagonist. The endogenous peptide, termed EPI-X4, is evolutionarily conserved and generated from the highly abundant albumin precursor by pH-regulated proteases. EPI-X4 forms an unusual lasso-like structure and antagonizes CXCL12-induced tumor cell migration, mobilizes stem cells, and suppresses inflammatory responses in mice. Furthermore, the peptide is abundant in the urine of patients with inflammatory kidney diseases and may serve as a biomarker. Our results identify EPI-X4 as a key regulator of CXCR4 signaling and introduce proteolysis of an abundant precursor protein as an alternative concept for chemokine receptor regulation.

  20. Chitinolytic Enterobacter agglomerans Antagonistic to Fungal Plant Pathogens.

    Science.gov (United States)

    Chernin, L; Ismailov, Z; Haran, S; Chet, I

    1995-05-01

    Three Enterobacter agglomerans strains which produce and excrete proteins with chitinolytic activity were found while screening soil-borne bacteria antagonistic to fungal plant pathogens. The chitinolytic activity was induced when the strains were grown in the presence of colloidal chitin as the sole carbon source. It was quantitated by using assays with chromogenic p-nitrophenyl analogs of disaccharide, trisaccharide, and tetrasaccharide derivatives of N-acetylglucosamine. A set of three fluorescent substrates with a 4-methylumbelliferyl group linked by (beta)-1,4 linkage to N-acetylglucosamine mono- or oligosaccharides were used to identify the chitinolytic activities of proteins which had been renatured following their separation by electrophoresis. This study provides the most complete evidence for the presence of a complex of chitinolytic enzymes in Enterobacter strains. Four enzymes were detected: two N-acetyl-(beta)-d-glucosaminidases of 89 and 67 kDa, an endochitinase with an apparent molecular mass of 59 kDa, and a chitobiosidase of 50 kDa. The biocontrol ability of the chitinolytic strains was demonstrated under greenhouse conditions. The bacteria decreased the incidence of disease caused by Rhizoctonia solani in cotton by 64 to 86%. Two Tn5 mutants of one of the isolates, which were deficient in chitinolytic activity, were unable to protect plants against the disease.

  1. Antagonist effects of calcium on borosilicate glass alteration

    Energy Technology Data Exchange (ETDEWEB)

    Mercado-Depierre, S. [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France); Angeli, F., E-mail: frederic.angeli@cea.fr [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France); Frizon, F. [CEA Marcoule, DTCD SECM LP2C, 30207 Bagnols sur Cèze (France); Gin, S. [CEA Marcoule, DTCD SPDE LCLT, 30207 Bagnols sur Cèze (France)

    2013-10-15

    Graphical abstract: Display Omitted -- Highlights: •Kinetic study of glass alteration is investigated in calcium-enriched solutions. •New insights into silicon–calcium interactions in glass/cement systems are proposed. •Glass alteration is controlled by pH, Ca concentration and reaction progress. •Evidence of antagonist effects according to the importance of these parameters. -- Abstract: Numerous studies have been conducted on glass and cement durability in contact with water, but very little work to date has focused directly on interactions between the two materials. These interactions are mostly controlled by silicon–calcium reactivity. However, the physical and chemical processes involved remain insufficiently understood to predict the evolution of coupled glass–cement systems used in several industrial applications. Results are reported from borosilicate glass alteration in calcium-rich solutions. Our data show that four distinct behaviors can be expected according to the relative importance of three key parameters: the pH, the reaction progress (short- or long-term alteration) and the calcium concentration. Glass alteration is thus controlled by specific mechanisms depending on the solution chemistry: calcium complexation at the glass surface, precipitation of calcium silicate hydrates (C–S–H) or calcium incorporation in the altered layer. These findings highlight the impact of silicon–calcium interactions on glass durability and open the way for a better understanding of glass–cement mixing in civil engineering applications as well as in nuclear waste storage.

  2. Development of specific dopamine D-1 agonists and antagonists

    International Nuclear Information System (INIS)

    Sakolchai, S.

    1987-01-01

    To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

  3. Streptomycetes and micromycetes as perspective antagonists of fungal phytopathogens.

    Science.gov (United States)

    Postolaky, O; Syrbu, T; Poiras, N; Baltsat, K; Maslobrod, S; Boortseva, S

    2012-01-01

    Among natural factors that permanently influence on the plants, the soil microorganisms play a special role for the growing of plants as habitants of their rhizosphere. Mainly they are the representatives of actinomycetes genus Streptomyces and fungal genus Penicillium and their metabolic products stimulate plant growth and inhibit the growth of pathogenic fungi and bacteria. The aim of our study was to determine the antagonism of actinomycetes and micromycetes isolated from soils of R. Moldova against the fungal pathogens of agricultural plants. The strains were isolated from 5 types of chernozem (black soil) from central zone of R. Moldova, with different concentration of humus. Most of micromycetes and streptomycetes were isolated from soil sample 1 (monoculture of maize) and soil sample 2 (Poltava road border) with similar humus content (2.4-2.6%). The antifungal activity of micromycetes strains was occurring mostly against Fusarium solani and Thelaviopsis basicola, at streptomycetes against Alternaria alternata and Botrytis cinerea. It was revealed the strains completely inhibit the growth of Alt. alternata (streptomycetes strains 23, 33, 37), B. cinerea (Streptomyces sp. 17), and F. solani (Penicillium sp. 104). Our results allow to consider the actinomycetes Streptomyces sp.9, Streptomyces sp. 12, Streptomyces sp. 17, Streptomyces sp. 37 Streptomyces sp. 66 and micromycetes Penicillium sp. 5, Penicillium sp. 65, Penicillium sp. 104 isolated from soils of R. Moldova, as prospective strains-antagonists against the phytopathogenic fungus, the causative agents of agricultural plants deseasis.

  4. Locomotor adaptation to a soleus EMG-controlled antagonistic exoskeleton

    Science.gov (United States)

    Kinnaird, Catherine R.; Ferris, Daniel P.

    2013-01-01

    Locomotor adaptation in humans is not well understood. To provide insight into the neural reorganization that occurs following a significant disruption to one's learned neuromuscular map relating a given motor command to its resulting muscular action, we tied the mechanical action of a robotic exoskeleton to the electromyography (EMG) profile of the soleus muscle during walking. The powered exoskeleton produced an ankle dorsiflexion torque proportional to soleus muscle recruitment thus limiting the soleus' plantar flexion torque capability. We hypothesized that neurologically intact subjects would alter muscle activation patterns in response to the antagonistic exoskeleton by decreasing soleus recruitment. Subjects practiced walking with the exoskeleton for two 30-min sessions. The initial response to the perturbation was to “fight” the resistive exoskeleton by increasing soleus activation. By the end of training, subjects had significantly reduced soleus recruitment resulting in a gait pattern with almost no ankle push-off. In addition, there was a trend for subjects to reduce gastrocnemius recruitment in proportion to the soleus even though only the soleus EMG was used to control the exoskeleton. The results from this study demonstrate the ability of the nervous system to recalibrate locomotor output in response to substantial changes in the mechanical output of the soleus muscle and associated sensory feedback. This study provides further evidence that the human locomotor system of intact individuals is highly flexible and able to adapt to achieve effective locomotion in response to a broad range of neuromuscular perturbations. PMID:23307949

  5. Orexin receptor antagonists as therapeutic agents for insomnia

    Directory of Open Access Journals (Sweden)

    Ana Clementina Equihua

    2013-12-01

    Full Text Available Insomnia is a common clinical condition characterized by difficulty initiating or maintaining sleep, or non-restorative sleep with impairment of daytime functioning.Currently, treatment for insomnia involves a combination of cognitive behavioral therapy and pharmacological therapy. Among pharmacological interventions, the most evidence exists for benzodiazepine receptor agonist drugs (GABAA receptor, although concerns persist regarding their safety and their limited efficacy. The use of these hypnotic medications must be carefully monitored for adverse effects.Orexin (hypocretin neuropeptides have been shown to regulate transitions between wakefulness and sleep by promoting cholinergic/monoaminergic neural pathways. This has led to the development of a new class of pharmacological agents that antagonize the physiological effects of orexin. The development of these agents may lead to novel therapies for insomnia without the side effect profile of hypnotics (e.g. impaired cognition, disturbed arousal, and motor balance difficulties. However, antagonizing a system that regulates the sleep-wake cycle may create an entirely different side effect profile. In this review, we discuss the role of orexin and its receptors on the sleep-wake cycle and that of orexin antagonists in the treatment of insomnia.

  6. CALCIUM ANTAGONISTS IN THE TREATMENT OF ARTERIAL HYPERTENSION DURING PREGNANCY

    Directory of Open Access Journals (Sweden)

    R. I. Striuk

    2006-01-01

    Full Text Available According to WHO data, arterial hypertension (HT is revealed in 15-20% of pregnant women. In different regions of Russia the incidence of pregnancy HT varies from 7 to 29%. In women with HT started before pregnancy , perinatal losses are observed in 3, 8%, premature births – in 15, 3% and intrauterine growth retardation - in 16, 6%. Physiological gestational changes of hemodynamics are described. Hypertensive pregnant patients of high and low risk are defined. Non-pharmacological treatment of pregnant women with HT is presented in details. Antihypertensive therapy may not be used in hypertensive patients of low risk with blood pressure (BP of 140-160\\90-110 mm Hg. If BP is higher antihypertensive therapy should be used immediately. Dihydropyridine calcium antagonists (CA is drugs of choice for HT treatment during pregnancy , especially “advanced” CA of the third generation. They have predictable efficacy. It is possible to use short-acting nifedipine for treatment of acute HT in pregnant patients.

  7. Antagonistic Activity of Lactobacillus Isolates against Salmonella typhi In Vitro

    Science.gov (United States)

    Abdel-Daim, Amira; Hassouna, Nadia; Hafez, Mohamed; Ashor, Mohamed Seif Aldeen; Aboulwafa, Mohammad M.

    2013-01-01

    Background. Enteric fever is a global health problem, and rapidly developing resistance to various drugs makes the situation more alarming. The potential use of Lactobacillus to control typhoid fever represents a promising approach, as it may exert protective actions through various mechanisms. Methods. In this study, the probiotic potential and antagonistic activities of 32 Lactobacillus isolates against Salmonella typhi were evaluated. The antimicrobial activity of cell free supernatants of Lactobacillus isolates, interference of Lactobacillus isolates with the Salmonella adherence and invasion, cytoprotective effect of Lactobacillus isolates, and possibility of concurrent use of tested Lactobacillus isolates and antibiotics were evaluated by testing their susceptibilities to antimicrobial agents, and their oxygen tolerance was also examined. Results. The results revealed that twelve Lactobacillus isolates could protect against Salmonella typhi infection through interference with both its growth and its virulence properties, such as adherence, invasion, and cytotoxicity. These Lactobacillus isolates exhibited MIC values for ciprofloxacin higher than those of Salmonella typhi and oxygen tolerance and were identified as Lactobacillus plantarum. Conclusion. The tested Lactobacillus plantarum isolates can be introduced as potential novel candidates that have to be subjected for in vivo and application studies for treatment and control of typhoid fever. PMID:24191248

  8. Iontophoresis of endothelin receptor antagonists in rats and men.

    Directory of Open Access Journals (Sweden)

    Matthieu Roustit

    Full Text Available The treatment of scleroderma-related digital ulcers is challenging. The oral endothelin receptor antagonist (ERA bosentan has been approved but it may induce liver toxicity. The objective of this study was to test whether ERAs bosentan and sitaxentan could be locally delivered using iontophoresis.Cathodal and anodal iontophoresis of bosentan and sitaxentan were performed on anaesthetized rat hindquarters without and during endothelin-1 infusion. Skin blood flow was quantified using laser-Doppler imaging and cutaneous tolerability was assessed. Iontophoresis of sitaxentan (20 min, 20 or 100 µA was subsequently performed on the forearm skin of healthy men (n = 5.In rats neither bosentan nor sitaxentan increased skin blood flux compared to NaCl. When simultaneously infusing endothelin-1, cathodal iontophoresis of sitaxentan increased skin blood flux compared to NaCl (AUC(0-20 were 44032.2 ± 12277 and 14957.5 ± 23818.8 %BL.s, respectively; P = 0.01. In humans, sitaxentan did not significantly increase skin blood flux as compared to NaCl. Iontophoresis of ERAs was well tolerated both in animals and humans.This study shows that cathodal iontophoresis of sitaxentan but not bosentan partially reverses endothelin-induced skin vasoconstriction in rats, suggesting that sitaxentan diffuses into the dermis. However, sitaxentan does not influence basal skin microvascular tone in rats or in humans.

  9. A new class of NO-donor H3-antagonists.

    Science.gov (United States)

    Tosco, Paolo; Bertinaria, Massimo; Di Stilo, Antonella; Marini, Elisabetta; Rolando, Barbara; Sorba, Giovanni; Fruttero, Roberta; Gasco, Alberto

    2004-05-01

    Synthesis and pharmacological characterisation of a series of compounds obtained by joining, through appropriate spacers, NO-donor furoxan and nitrooxy moieties to the imidazole ring, as well as their structurally related analogues devoid of NO-donating properties are described. All the products were studied for their capacity to interact with H3-receptors present on the guinea-pig ileum and with H2-receptors present on guinea-pig right atrium. The whole series of products displayed reversible H3-antagonistic activity. No activity on H2-receptors was observed when the products were tested at 10 microM concentration. Many of the products were also able to induce partial relaxation when added to the bath after electrical contraction of the guinea-pig ileum during the study of their H3-antagonism. This phenomenon seems to be dependent on various factors; for some compounds it proved to be dependent on NO-mediated sGC activation, for other products it could be due to their weak M3-antagonism. The investigation of the lipophilic-hydrophilic balance of all the products indicates, for many of them, an ideal value to cross the blood-brain barrier. Copyright 2004 Elsevier SAS

  10. Torque values of antagonistic muscles of the hipjoint. Pilot study.

    Science.gov (United States)

    Derewiecki, Tomasz; Duda, Marta; Majcher, Piotr; Mroczek, Krzysztof

    2012-01-01

    The hip joint is a multiaxial articulation and the most mobile joint of the lower extremity. It can be subject to overloading by the repetition of a motor pattern produced by imbalanced muscle groups. To determine mean torque values of the external forces acting on the hip joint in various age groups; to compare the relations between the torque values of antagonistic hip muscles; to correlate changes in mean torque values of the hip muscles with age. The study involved a group of 120 women aged 19-85 years divided into 6 age groups of 20 subjects each. The presence of knee or hip pathology was an exclusion criterion. The tests were carried out in the Zamość Rehabilitation Department of CMPA in an SPB2-FM unit. The highest mean torque values for all muscle groups were seen in women aged 19-25 years. The values gradually decreased with age. 1. The SPB2-FM unit is an objective tool for evaluating torques of the hip muscles and makes it possible to monitor changes occurring in the process of rehabilitation, as well as to diagnose risks resulting from a decrease in hip muscle strength. 2. The present study of healthy subjects provides baseline data for further comparisons with patients suffering from hip pathology and preliminary input for determining reference values of pelvic girdle muscle strength.

  11. Crystal structure of the adenosine A 2A receptor bound to an antagonist reveals a potential allosteric pocket

    Energy Technology Data Exchange (ETDEWEB)

    Sun, Bingfa; Bachhawat, Priti; Chu, Matthew Ling-Hon; Wood, Martyn; Ceska, Tom; Sands, Zara A.; Mercier, Joel; Lebon, Florence; Kobilka, Tong Sun; Kobilka, Brian K. (Stanford-MED); (ConfometRx); (UCB Pharma)

    2017-02-06

    The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson’s disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl D-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A2A receptor with a cytochrome b562-RIL (BRIL) fusion (A2AR–BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A2AR–BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1–bound A2AR–BRIL prevented formation of the lattice observed with the ZM241385–bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other A2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr91.35 and Tyr2717.36, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A2AR-selective compounds for the treatment of Parkinson’s disease.

  12. ASSESSMENT OF EFFICACY OF LEUKOTRIENE RECEPTOR ANTAGONISTS IN THERAPY OF BRONCHIAL ASTHMA IN CHILDREN

    Directory of Open Access Journals (Sweden)

    Yu.G. Levina

    2009-01-01

    Full Text Available The article provides data regarding the clinical efficacy and safety of leukotriene receptor antagonists in treatment of bronchial asthma in children. The only representative of this group that is allowed in Russia for treatment of children over 6 years of age is Montelukast. Approval of new 4 mg dosage of Montelukast for children from 2 years of age is expected in Russia in July 2009. Leukotriene receptor antagonists have a high safety profile and can be used as an alternative first-line therapy for persistent asthma.Key words: leukotriene receptor antagonists, montelukast, bronchial asthma, children.

  13. Antagonist muscle moment is increased in ACL deficient subjects during maximal dynamic knee extension

    DEFF Research Database (Denmark)

    Alkjær, Tine; Simonsen, Erik B; Magnusson, S Peter

    2012-01-01

    -10°, angular speed: 30°/s). Hamstring antagonist EMG recorded during concentric quadriceps contraction was converted into antagonist moment based on the EMG-moment relationship observed during eccentric agonist contractions. RESULTS: The magnitude of antagonist hamstring EMG was 65.5% higher in ACL deficient...... in subjects with anterior cruciate ligament (ACL) deficiency compared to age-matched healthy controls. METHODS: Electromyography (EMG) and net knee joint moments were recorded during maximal concentric quadriceps and eccentric hamstring contractions, performed in an isokinetic dynamometer (ROM: 90...

  14. CALCIUM ANTAGONISTS IN CLINICAL PRACTICE: FOCUS ON METABOLIC AND VASCULAR EFFECTS

    Directory of Open Access Journals (Sweden)

    D. V. Nebieridze

    2007-01-01

    Full Text Available The efficacy of calcium antagonists widely used in cardiological practice is proved both by placebo-controlled studies and in comparative trials with end-point control. Calcium antagonists are the most effective vasoprotective medicines. In our study we had shown antihypertensive efficacy and ability to improve endothelium function of non-dihydropyridine calcium antagonist, diltiazem (Altiazem RR. Altiazem RR can be drug of choice in wide profile of patients with arterial hypertension, especially in those with concomitant metabolic abnormalities, diabetes mellitus and ischemic heart disease.

  15. CALCIUM ANTAGONISTS IN CLINICAL PRACTICE: FOCUS ON METABOLIC AND VASCULAR EFFECTS

    Directory of Open Access Journals (Sweden)

    D. V. Nebieridze

    2015-12-01

    Full Text Available The efficacy of calcium antagonists widely used in cardiological practice is proved both by placebo-controlled studies and in comparative trials with end-point control. Calcium antagonists are the most effective vasoprotective medicines. In our study we had shown antihypertensive efficacy and ability to improve endothelium function of non-dihydropyridine calcium antagonist, diltiazem (Altiazem RR. Altiazem RR can be drug of choice in wide profile of patients with arterial hypertension, especially in those with concomitant metabolic abnormalities, diabetes mellitus and ischemic heart disease.

  16. West syndrome associated with administration of a histamine H1 antagonist, oxatomide.

    Science.gov (United States)

    Yamashita, Yushiro; Isagai, Takeo; Seki, Yoshitaka; Ohya, Takashi; Nagamitsu, Shinichiro; Matsuishi, Toyojiro

    2004-01-01

    We report a 4-month-old female infant who developed West syndrome eleven days after administration of a histamine H1 antagonist, oxatomide, for atopic dermatitis. It has been reported that some histamine H1 antagonists induce seizures in epileptic patients. The age, the interval between oxatomide administration, and the onset of West syndrome and its clinical course were similar to two previously reported 3-month-old infants with West syndrome associated with ketotifen administration. We should be cautious in using the histamine H1 antagonists, oxatomide and ketotifen, in young infants because such agents could potentially disturb the anticonvulsive central histaminergic system.

  17. EARLY CHILDHOOD CARIES: CAN YOU PREVENT IT?

    Directory of Open Access Journals (Sweden)

    K. B. Miloserdova

    2014-01-01

    Full Text Available The probability of the caries development largely depends on the oral microflora imbalance. This imbalance can be corrected with probiotics. The article analyzes the results of studies on the use of adapted milk formulas with probiotics to prevent caries in early childhood. It shows that the use of adapted formulas with probiotics is accompanied by a decrease in the frequency of releasing cariogenic streptococci and actinomycetes with a simultaneous increase in the frequency of detecting bacterial antagonists of the cariogenic flora, normalization of sIgA concentration in saliva, and decrease in the severity of the caries process. The survey results will contribute to the development of effective approaches to prevention of dental caries in children.

  18. Prevention of calcium-induced membrane structural alterations in erythrocyte membranes by flunarizine

    NARCIS (Netherlands)

    Thomas, Peter G.; Zimmermann, A.G.; Verkleij, A.J.

    1988-01-01

    The calcium antagonist flunarizine is shown to be able to prevent particle aggregation, membrane aggregation and blebbing resulting from elevated calcium concentrations. The anti-ischemic effects of flunarizine may therefore result in part from its ability to directly interfere with calcium-membrane

  19. Economic evaluation of apixaban for the prevention of stroke in atrial fibrillation in the Netherlands

    NARCIS (Netherlands)

    Stevanovic, J.; Pompen, M.; Le, H.H.; Rozenbaum, M.H.; Postma, M.J.

    2013-01-01

    Objectives: Stroke prevention is the main goal in treating patients with atrial fibrillation (AF). Treatment with anticoagulants, such as vitamin-K antagonists (VKAs; e.g. warfarin and cumarines), was demonstrated to be an effective strategy. However, even though VKAs are the current standard

  20. Rotating preventers

    International Nuclear Information System (INIS)

    Tangedahl, M.J.; Stone, C.R.

    1992-01-01

    This paper reports that recent changes in the oil and gas industry and ongoing developments in horizontal and underbalanced drilling necessitated development of a better rotating head. A new device called the rotating blowout preventer (RBOP) was developed by Seal-Tech. It is designed to replace the conventional rotating control head on top of BOP stacks and allows drilling operations to continue even on live (underbalanced) wells. Its low wear characteristics and high working pressure (1,500 psi) allow drilling rig crews to drill safely in slightly underbalanced conditions or handle severe well control problems during the time required to actuate other BOPs in the stack. Drilling with a RBOP allows wellbores to be completely closed in tat the drill floor rather than open as with conventional BOPs

  1. Adenosine versus intravenous calcium channel antagonists for supraventricular tachycardia.

    Science.gov (United States)

    Alabed, Samer; Sabouni, Ammar; Providencia, Rui; Atallah, Edmond; Qintar, Mohammed; Chico, Timothy Ja

    2017-10-12

    People with supraventricular tachycardia (SVT) frequently are symptomatic and present to the emergency department for treatment. Although vagal manoeuvres may terminate SVT, they often fail, and subsequently adenosine or calcium channel antagonists (CCAs) are administered. Both are known to be effective, but both have a significant side effect profile. This is an update of a Cochrane review previously published in 2006. To review all randomised controlled trials (RCTs) that compare effects of adenosine versus CCAs in terminating SVT. We identified studies by searching CENTRAL, MEDLINE, Embase, and two trial registers in July 2017. We checked bibliographies of identified studies and applied no language restrictions. We planned to include all RCTs that compare adenosine versus a CCA for patients of any age presenting with SVT. We used standard methodological procedures as expected by Cochrane. Two review authors independently checked results of searches to identify relevant studies and resolved differences by discussion with a third review author. At least two review authors independently assessed each included study and extracted study data. We entered extracted data into Review Manager 5. Primary outcomes were rate of reversion to sinus rhythm and major adverse effects of adenosine and CCAs. Secondary outcomes were rate of recurrence, time to reversion, and minor adverse outcomes. We measured outcomes by calculating odds ratios (ORs) and assessed the quality of primary outcomes using the GRADE approach through the GRADEproGDT website. We identified two new studies for inclusion in the review update; the review now includes seven trials with 622 participants who presented to an emergency department with SVT. All included studies were RCTs, but only three described the randomisation process, and none had blinded participants, personnel, or outcome assessors to the intervention given. Moderate-quality evidence shows no differences in the number of people reverting to

  2. CXCR4-antagonist Peptide R-liposomes for combined therapy against lung metastasis

    Science.gov (United States)

    Ieranò, Caterina; Portella, Luigi; Lusa, Sara; Salzano, Giuseppina; D'Alterio, Crescenzo; Napolitano, Maria; Buoncervello, Maria; Macchia, Daniele; Spada, Massimo; Barbieri, Antonio; Luciano, Antonio; Barone, Maria Vittoria; Gabriele, Lucia; Caraglia, Michele; Arra, Claudio; De Rosa, Giuseppe; Scala, Stefania

    2016-03-01

    The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide R were developed (PL-Peptide R). In vitro PL-Peptide R efficiently inhibited CXCR4-dependent migration and in vivo it significantly reduced lung metastases and increased overall survival in B16-CXCR4 injected C57BL/6 mice. To evaluate if PL-Peptide R could also be a drug delivery system for CXCR4 expressing tumors, the PL-Peptide R was loaded with doxorubicin (DOX) (PL-Peptide R-DOX). PL-Peptide R-DOX efficiently delivered DOX to CXCR4 expressing cell lines with a consequent decrease in the DOX IC50 efficient dose. In vivo, B16-CXCR4 injected C57BL/6 mice treated with PL-Peptide R-DOX developed fewer lung metastases compared to PL-DOX treated mice. This work provides the proof-of-concept to prevent metastasis by using combined nanomedicine.The chemokine CXCL12 activates CXCR4, initiating multiple pathways that control immune cell trafficking, angiogenesis and embryogenesis; CXCR4 is also overexpressed in multiple tumors affecting metastatic dissemination. While there has been great enthusiasm for exploiting the CXCR4-CXCL12 axis as a target in cancer therapy, to date the promise has yet to be fulfilled. A new class of CXCR4-antagonist cyclic peptides was recently developed and the compound named Peptide R was identified as the most active. With the intent to improve the efficacy and biodistribution of Peptide R, stealth liposomes decorated with Peptide

  3. Hepcidin antagonists for potential treatments of disorders with hepcidin excess

    Directory of Open Access Journals (Sweden)

    Poli eMaura

    2014-04-01

    Full Text Available The discovery of hepcidin clarified the basic mechanism of the control of systemic iron homeostasis. Hepcidin is mainly produced by the liver as a propeptide and processed by furin into the mature active peptide. Hepcidin binds ferroportin, the only cellular iron exporter, causing the internalization and degradation of both. Thus hepcidin blocks iron export from the key cells for dietary iron absorption (enterocytes, recycling of haemoglobin iron (the macrophages and the release of storage iron from hepatocytes, resulting in the reduction of systemic iron availability. The BMP/HJV/SMAD pathway is the major regulator of hepcidin expression that responds to iron status. Also inflammation stimulates hepcidin via the IL6/STAT3 pathway with a support of an active BMP/HJV/SMAD pathway. In some pathological conditions hepcidin level is inadequately elevated and reduces iron availability in the body, resulting in anemia. These conditions occur in the genetic Iron Refractory Iron Deficiency Anemia (IRIDA and the common Anemia of Chronic Disease (ACD or Anemia of Inflammation. Currently, there is no definite treatment for ACD. Erythropoiesis stimulating agents and intravenous iron have been proposed in some cases but they are scarcely effective and may have adverse effects. Alternative approaches aimed to a pharmacological control of hepcidin expression have been attempted, targeting different regulatory steps. They include hepcidin sequestering agents (antibodies, anticalins and aptamers, inhibitors of BMP/SMAD or of IL6/STAT3 pathway or of hepcidin transduction (siRNA/shRNA or ferroportin stabilizers. In this review we summarized the biochemical interactions of the proteins involved in the BMP/HJV/SMAD pathway and its natural inhibitors, the murine and rat models with high hepcidin levels currently available and finally the progresses in the development of hepcidin antagonists, with particular attention to the role of heparins and heparin sulphate

  4. Micro1-opioid antagonist naloxonazine alters ethanol discrimination and consumption.

    Science.gov (United States)

    Mhatre, Molina; Holloway, Frank

    2003-02-01

    The endogenous opioid system is implicated in excessive ethanol-drinking behavior. However, the role of individual opioid receptor subtypes in the mechanism underlying excessive ethanol-drinking behavior is not yet well understood. Therefore, we investigated the ability of a selective micro1-opioid antagonist, naloxonazine, to modulate ethanol-drinking behavior and ethanol discrimination in a rat model with the use of ethanol self-administration and drug discrimination paradigms. The effects of naloxonazine (0.001-10 mg/kg) on ethanol intake were examined in Sprague-Dawley rats under conditions of limited access to 10% (wt./vol.) ethanol and ad libitum access to food and water. Pretreatment with high doses of naloxonazine (1-10 mg/kg) significantly reduced ethanol consumption. When the effects of naloxonazine on food intake in free-feeding male rats were examined, naloxonazine (1.8-10 mg/kg) significantly suppressed 24-h food intake. Another group of rats was trained to discriminate ethanol (1.25 g/kg, i.p.) from saline on a fixed-ratio schedule (FR 10), and ethanol dose-response tests were conducted once rats had acquired ethanol-saline discrimination. Injections were given 15 min before ethanol dose-response tests were conducted, and after characterization of the ethanol dose-response curve, the effects of naloxonazine on ethanol discrimination were assessed by administering naloxonazine (0.001-10 mg/kg, i.p.) 15 min before ethanol administration. Treatment with naloxonazine (0.001-1.8 mg/kg, i.p.) before the ED(100) dose of ethanol partially antagonized the discriminative stimulus of ethanol without having any effect on the response rate. The results support the suggestion of involvement of micro1-opioid receptors in the discriminative effects of ethanol and ethanol-drinking behavior.

  5. 8-Azaxanthine derivatives as antagonists of adenosine receptors.

    Science.gov (United States)

    Franchetti, P; Messini, L; Cappellacci, L; Grifantini, M; Lucacchini, A; Martini, C; Senatore, G

    1994-09-02

    A series of 1,3-dimethyl- and 1,3-dipropyl-8-azaxanthines, substituted at the N8 or N7 position with substituents which usually increase the affinity of the xanthines for the adenosine receptors, was synthesized and studied in radioligand binding experiments. The substitution of CH with N at the 8-position of both theophylline and caffeine dramatically reduced the affinity, as demonstrated by the fact that 8-azatheophylline and 8-azacaffeine were inert. The introduction of a methyl group at 8-position of 8-azatheophylline restored the antagonistic activity at A2 receptors, while a 8-cycloalkyl substituent increased the affinity for both receptor subtypes. A more favorable effect on affinity was produced by the substitution of the 7-methyl group in 8-azacaffeine with cycloalkyl groups. 7-Cyclopentyl-1,3-dimethyl-8-azaxanthine was 3 times more potent than caffeine at A1 receptors and 6 times less active at A2 receptors. On the contrary, the 7-cyclohexyl-1,3-dimethyl-8-azaxanthine was more potent than caffeine at A2 receptors. The substitution of 1- and 3-methyl groups with propyl in both 7- and 8-substituted 8-azatheophylline increased remarkably the affinity for A1 receptors. The 7-cyclopentyl-1,3-dipropyl-8-azaxanthine appears to be one of the most potent and selective among 7-alkyl-substituted xanthines at A1 receptors so far known. Because the 8-aza analogues of 8-substituted 1,3-dialkylxanthine were in any case less active than the corresponding xanthine derivatives, it was confirmed that the hydrogen atom at the 7-position of xanthines plays an important role in the binding to adenosine receptors.

  6. Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.

    Science.gov (United States)

    Cappato, Riccardo; Ezekowitz, Michael D; Klein, Allan L; Camm, A John; Ma, Chang-Sheng; Le Heuzey, Jean-Yves; Talajic, Mario; Scanavacca, Maurício; Vardas, Panos E; Kirchhof, Paulus; Hemmrich, Melanie; Lanius, Vivian; Meng, Isabelle Ling; Wildgoose, Peter; van Eickels, Martin; Hohnloser, Stefan H

    2014-12-14

    X-VeRT is the first prospective randomized trial of a novel oral anticoagulant in patients with atrial fibrillation undergoing elective cardioversion. We assigned 1504 patients to rivaroxaban (20 mg once daily, 15 mg if creatinine clearance was between 30 and 49 mL/min) or dose-adjusted vitamin K antagonists (VKAs) in a 2:1 ratio. Investigators selected either an early (target period of 1-5 days after randomization) or delayed (3-8 weeks) cardioversion strategy. The primary efficacy outcome was the composite of stroke, transient ischaemic attack, peripheral embolism, myocardial infarction, and cardiovascular death. The primary safety outcome was major bleeding. The primary efficacy outcome occurred in 5 (two strokes) of 978 patients (0.51%) in the rivaroxaban group and in 5 (two strokes) of 492 patients (1.02%) in the VKA group [risk ratio 0.50; 95% confidence interval (CI) 0.15-1.73]. In the rivaroxaban group, four patients experienced primary efficacy events following early cardioversion (0.71%) and one following delayed cardioversion (0.24%). In the VKA group, three patients had primary efficacy events following early cardioversion (1.08%) and two following delayed cardioversion (0.93%). Rivaroxaban was associated with a significantly shorter time to cardioversion compared with VKAs (P four patients (0.8%) in the VKA group (risk ratio 0.76; 95% CI 0.21-2.67). Oral rivaroxaban appears to be an effective and safe alternative to VKAs and may allow prompt cardioversion. Clinicaltrials.gov; NCT01674647. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2014. For permissions please email: journals.permissions@oup.com.

  7. Icatibant, a new bradykinin-receptor antagonist, in hereditary angioedema.

    Science.gov (United States)

    Cicardi, Marco; Banerji, Aleena; Bracho, Francisco; Malbrán, Alejandro; Rosenkranz, Bernd; Riedl, Marc; Bork, Konrad; Lumry, William; Aberer, Werner; Bier, Henning; Bas, Murat; Greve, Jens; Hoffmann, Thomas K; Farkas, Henriette; Reshef, Avner; Ritchie, Bruce; Yang, William; Grabbe, Jürgen; Kivity, Shmuel; Kreuz, Wolfhart; Levy, Robyn J; Luger, Thomas; Obtulowicz, Krystyna; Schmid-Grendelmeier, Peter; Bull, Christian; Sitkauskiene, Brigita; Smith, William B; Toubi, Elias; Werner, Sonja; Anné, Suresh; Björkander, Janne; Bouillet, Laurence; Cillari, Enrico; Hurewitz, David; Jacobson, Kraig W; Katelaris, Constance H; Maurer, Marcus; Merk, Hans; Bernstein, Jonathan A; Feighery, Conleth; Floccard, Bernard; Gleich, Gerald; Hébert, Jacques; Kaatz, Martin; Keith, Paul; Kirkpatrick, Charles H; Langton, David; Martin, Ludovic; Pichler, Christiane; Resnick, David; Wombolt, Duane; Fernández Romero, Diego S; Zanichelli, Andrea; Arcoleo, Francesco; Knolle, Jochen; Kravec, Irina; Dong, Liying; Zimmermann, Jens; Rosen, Kimberly; Fan, Wing-Tze

    2010-08-05

    Hereditary angioedema is characterized by recurrent attacks of angioedema of the skin, larynx, and gastrointestinal tract. Bradykinin is the key mediator of symptoms. Icatibant is a selective bradykinin B2 receptor antagonist. In two double-blind, randomized, multicenter trials, we evaluated the effect of icatibant in patients with hereditary angioedema presenting with cutaneous or abdominal attacks. In the For Angioedema Subcutaneous Treatment (FAST) 1 trial, patients received either icatibant or placebo; in FAST-2, patients received either icatibant or oral tranexamic acid, at a dose of 3 g daily for 2 days. Icatibant was given once, subcutaneously, at a dose of 30 mg. The primary end point was the median time to clinically significant relief of symptoms. A total of 56 and 74 patients underwent randomization in the FAST-1 and FAST-2 trials, respectively. The primary end point was reached in 2.5 hours with icatibant versus 4.6 hours with placebo in the FAST-1 trial (P=0.14) and in 2.0 hours with icatibant versus 12.0 hours with tranexamic acid in the FAST-2 trial (P<0.001). In the FAST-1 study, 3 recipients of icatibant and 13 recipients of placebo needed treatment with rescue medication. The median time to first improvement of symptoms, as assessed by patients and by investigators, was significantly shorter with icatibant in both trials. No icatibant-related serious adverse events were reported. In patients with hereditary angioedema having acute attacks, we found a significant benefit of icatibant as compared with tranexamic acid in one trial and a nonsignificant benefit of icatibant as compared with placebo in the other trial with regard to the primary end point. The early use of rescue medication may have obscured the benefit of icatibant in the placebo trial. (Funded by Jerini; ClinicalTrials.gov numbers, NCT00097695 and NCT00500656.)

  8. Endothelin receptor antagonist and airway dysfunction in pulmonary arterial hypertension

    Directory of Open Access Journals (Sweden)

    Borst Mathias M

    2009-12-01

    Full Text Available Abstract Background In idiopathic pulmonary arterial hypertension (IPAH, peripheral airway obstruction is frequent. This is partially attributed to the mediator dysbalance, particularly an excess of endothelin-1 (ET-1, to increased pulmonary vascular and airway tonus and to local inflammation. Bosentan (ET-1 receptor antagonist improves pulmonary hemodynamics, exercise limitation, and disease severity in IPAH. We hypothesized that bosentan might affect airway obstruction. Methods In 32 IPAH-patients (19 female, WHO functional class II (n = 10, III (n = 22; (data presented as mean ± standard deviation pulmonary vascular resistance (11 ± 5 Wood units, lung function, 6 minute walk test (6-MWT; 364 ± 363.7 (range 179.0-627.0 m, systolic pulmonary artery pressure, sPAP, 79 ± 19 mmHg, and NT-proBNP serum levels (1427 ± 2162.7 (range 59.3-10342.0 ng/L were measured at baseline, after 3 and 12 months of oral bosentan (125 mg twice per day. Results and Discussion At baseline, maximal expiratory flow at 50 and 25% vital capacity were reduced to 65 ± 25 and 45 ± 24% predicted. Total lung capacity was 95.6 ± 12.5% predicted and residual volume was 109 ± 21.4% predicted. During 3 and 12 months of treatment, 6-MWT increased by 32 ± 19 and 53 ± 69 m, respectively; p Conclusion This study gives first evidence in IPAH, that during long-term bosentan, improvement of hemodynamics, functional parameters or serum biomarker occur independently from persisting peripheral airway obstruction.

  9. Statin use decreases coagulation in users of vitamin K antagonists.

    Science.gov (United States)

    van Rein, Nienke; Biedermann, J S; Bonafacio, S M; Kruip, M J H A; van der Meer, F J M; Lijfering, W M

    2016-12-01

    The purpose of the study is to determine the immediate and long-term effect of statins on coagulation in patients treated with vitamin K antagonists (VKAs). We selected patients on VKAs of two Dutch anticoagulation clinics who initiated treatment with a statin between 2009 and 2013. Patients who initiated or stopped concomitant drugs that interact with VKAs or were hospitalised during follow-up were excluded. The VKA dosage (mg/day) after statin initiation was compared with the last VKA dosage before the statin was started. Immediate and long-term differences in VKA dosage (at 6 and 12 weeks) were calculated with a paired student t test. Four hundred thirty-five phenprocoumon users (mean age 70 years, 60 % men) and 303 acenocoumarol users (mean age 69 years, 58 % men) were included. After start of statin use, the immediate phenprocoumon dosage was 0.02 mg/day (95 % CI, 0.00 to 0.03) lower. At 6 and 12 weeks, these phenprocoumon dosages were 0.03 (95 % CI, 0.01 to 0.05) and 0.07 mg/day (95 % CI, 0.04 to 0.09) lower as compared with the dosage before first statin use. In acenocoumarol users, VKA dosage was 0.04 mg/day (95%CI, 0.01 to 0.07) (immediate effect), 0.10 (95 % CI, 0.03 to 0.16) (at 6 weeks), and 0.11 mg/day (95 % CI, 0.04 to 0.18) (after 12 weeks) lower. Initiation of statin treatment was associated with an immediate and long-term minor although statistically significant decrease in VKA dosage in both phenprocoumon and acenocoumarol users, which suggests that statins may have anticoagulant properties.

  10. Oxycodone combined with opioid receptor antagonists: efficacy and safety.

    Science.gov (United States)

    Davis, Mellar; Goforth, Harold W; Gamier, Pam

    2013-05-01

    A mu receptor antagonist combined with oxycodone (OXY) may improve pain control, reduce physical tolerance and withdrawal, minimizing opioid-related bowel dysfunction and act as an abuse deterrent. The authors cover the use of OXY plus ultra-low-dose naltrexone for analgesia and the use of sustained-release OXY plus sustained-release naloxone to reduce the opioid bowel syndrome. The authors briefly describe the use of sustained-release OXY and naltrexone pellets as a drug abuse deterrent formulation. Combinations of ultra-low-dose naltrexone plus OXY have been in separate trials involved in patients with chronic pain from osteoarthritis and idiopathic low back pain. High attrition and marginal differences between ultra-low-dose naltrexone plus OXY and OXY led to discontinuation of development. Prolonged-release (PR) naloxone combined with PR OXY demonstrates a consistent reduction in opioid-related bowel dysfunction in multiple randomized controlled trials. However, gastrointestinal side effects, including diarrhea, were increased in several trials with the combination compared with PR OXY alone. Analgesia appeared to be maintained although non-inferiority to PR OXY is not formally established. There were flaws to trial design and safety monitoring. Naltrexone has been combined with OXY in individual pellets encased in a capsule. This combination has been reported in a Phase II trial and is presently undergoing Phase III studies. Due to the lack of efficacy the combination of altered low-dose naltrexone with oxycodone should cease in development. The combination of sustained release oxycodone plus naloxone reduces constipation with a consistent benefit. Safety has been suboptimally evaluated which is a concern. Although the drug is commercially available in several countries, ongoing safety monitoring particularly high doses would be important.

  11. Treatment of the overactive bladder syndrome with muscarinic receptor antagonists: a matter of metabolites?

    NARCIS (Netherlands)

    Michel, Martin C.; Hegde, Sharath S.

    2006-01-01

    Antagonists of muscarinic acetylcholine receptors, such as darifenacin, oxybutynin, propiverine, solifenacin, tolterodine, and trospium, are the mainstay of the treatment of the overactive bladder syndrome. Fesoterodine is a newer drug awaiting regulatory approval. We briefly review the

  12. Comparison of Agonist vs. Antagonist Stimulation on Triceps Surae Spasticity in Spinal Cord

    Directory of Open Access Journals (Sweden)

    Sneha Khanna

    2017-06-01

    Discussion: This study provides evidence that both agonist electrical stimulation and antagonist electrical stimulations are equally effective in reducing spasticity in triceps surae muscle in patients with spinal cord injury.

  13. Sympatholytic properties of several AT(1)-receptor antagonists in the isolated rabbit thoracic aorta

    NARCIS (Netherlands)

    Nap, Alexander; Balt, Jippe C.; Pfaffendorf, Martin; van Zwieten, Pieter A.

    2002-01-01

    Objective To evaluate the facilitating effect of angiotensin II on sympathetic neurotransmission to quantitatively compare the sympatho-inhibitory potencies of the selective AT(1)-receptor antagonists losartan, irbesartan and telmisartan in the isolated rabbit thoracic aorta. Design To investigate

  14. Cyclic benzamidines as orally efficacious NR2B-selective NMDA receptor antagonists.

    Science.gov (United States)

    Nguyen, Kevin T; Claiborne, Christopher F; McCauley, John A; Libby, Brian E; Claremon, David A; Bednar, Rodney A; Mosser, Scott D; Gaul, Stanley L; Connolly, Thomas M; Condra, Cindra L; Bednar, Bohumil; Stump, Gary L; Lynch, Joseph J; Koblan, Kenneth S; Liverton, Nigel J

    2007-07-15

    A novel series of cyclic benzamidines was synthesized and shown to exhibit NR2B-subtype selective NMDA antagonist activity. Compound 29 is orally active in a carrageenan-induced rat hyperalgesia model of pain.

  15. Discovery and mapping of an intracellular antagonist binding site at the chemokine receptor CCR2

    DEFF Research Database (Denmark)

    Zweemer, Annelien J M; Bunnik, Julia; Veenhuizen, Margo

    2014-01-01

    The chemokine receptor CCR2 is a G protein-coupled receptor that is involved in many diseases characterized by chronic inflammation, and therefore a large variety of CCR2 small molecule antagonists has been developed. On the basis of their chemical structures these antagonists can roughly...... be divided into two groups with most likely two topographically distinct binding sites. The aim of the current study was to identify the binding site of one such group of ligands, exemplified by three allosteric antagonists, CCR2-RA-[R], JNJ-27141491, and SD-24. We first used a chimeric CCR2/CCR5 receptor...... approach to obtain insight into the binding site of the allosteric antagonists and additionally introduced eight single point mutations in CCR2 to further characterize the putative binding pocket. All constructs were studied in radioligand binding and/or functional IP turnover assays, providing evidence...

  16. Effect of beta-adrenergic receptor antagonists on nicotine-induced tail-tremor in rats.

    Science.gov (United States)

    Suemaru, K; Gomita, Y; Furuno, K; Araki, Y

    1993-09-01

    The effects of various beta-adrenergic receptor antagonists on nicotine-induced tail-tremor were investigated in rats. Atenolol (5 and 10 mg/kg, IP), arotinolol (5 and 10 mg/kg, IP), and carteolol (5 and 10 mg/kg, IP), hydrophilic beta-adrenergic receptor antagonists, did not affect the tail-tremor induced by nicotine given at a dose of 0.5 mg/kg SC. However, propranolol (5-20 mg/kg, IP) and pindolol (5-20 mg/kg, IP), nonselective and lipophilic beta-adrenergic receptor antagonists, did suppress the tail-tremor dose dependently. In contrast, metoprolol (5-20 mg/kg, IP), lipophilic and beta 1-selective adrenergic receptor antagonists, did not show such an effect. These results suggest that nicotine-induced tail-tremors may be mediated through central beta 2-adrenergic receptors as an appearance and developmental mechanism.

  17. Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

    DEFF Research Database (Denmark)

    Goto, K.; Doessing, S.; Nielsen, R.H.

    2009-01-01

    between the groups in terms of changes in serum free fatty acids, glycerol, (V) over dotO(2), or relative fat oxidation. Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise. (J Clin Endocrinol......Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...... period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed...

  18. The endothelin antagonist atrasentan lowers residual albuminuria in patients with type 2 diabetic nephropathy

    DEFF Research Database (Denmark)

    de Zeeuw, Dick; Coll, Blai; Andress, Dennis

    2014-01-01

    Despite optimal treatment, including renin-angiotensin system (RAS) inhibitors, patients with type 2 diabetic nephropathy have high cardiorenal morbidity and mortality related to residual albuminuria. We evaluated whether or not atrasentan, a selective endothelin A receptor antagonist, further re...

  19. A novel antagonistic role of natural compound icariin on neurotoxicity of amyloid β peptide

    Directory of Open Access Journals (Sweden)

    Jianhui Liu

    2015-01-01

    Interpretation & conclusions: The results indicated a novel antagonistic role of icariin in the neurotoxicity of Aβ1-42 via inhibiting its aggregation, suggesting that icariin might have potential therapeutic benefits to delay or modify the progression of AD.

  20. Oxytocin antagonist disrupts hypotension-evoked renin secretion and other responses in conscious rats

    DEFF Research Database (Denmark)

    Huang, W.; Sjöquist, M.; Skøtt, O.

    2001-01-01

    Previous experiments have indicated that arterial hypotension increases plasma oxytocin (OT) levels in rats and that OT infused intravenously causes an increase in plasma renin activity (PRA). The goal of the present study was to determine whether systemic administration of an OT receptor...... antagonist would attenuate the increase in PRA that is normally evoked by arterial hypotension in rats. In conscious male rats, intravenous injection of hydralazine or diazoxide produced sustained hypotension and evoked a significant increase in PRA, as expected. Intravenous infusion of an OT receptor...... antagonist did not alter the hypotension induced by hydralazine or diazoxide, but it did markedly blunt the induced increase in PRA. The OT receptor antagonist also blunted the hypotension-evoked increase in heart rate and plasma vasopressin levels, suggesting that the antagonist may have generally disrupted...

  1. Antiviral activity of formyl peptide receptor 2 antagonists against influenza viruses.

    Science.gov (United States)

    Courtin, Noémie; Fotso, Aurélien Fotso; Fautrad, Pierre; Mas, Floriane; Alessi, Marie-Christine; Riteau, Béatrice

    2017-07-01

    Influenza viruses are one of the most important respiratory pathogens worldwide, causing both epidemic and pandemic infections. The aim of the study was to evaluate the effect of FPR2 antagonists PBP10 and BOC2 on influenza virus replication. We determined that these molecules exhibit antiviral effects against influenza A (H1N1, H3N2, H6N2) and B viruses. FPR2 antagonists used in combination with oseltamivir showed additive antiviral effects. Mechanistically, the antiviral effect of PBP10 and BOC2 is mediated through early inhibition of virus-induced ERK activation. Finally, our preclinical studies showed that FPR2 antagonists protected mice from lethal infections induced by influenza, both in a prophylactic and therapeutic manner. Thus, FPR2 antagonists might be explored for novel treatments against influenza. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment : a randomized controlled trial

    NARCIS (Netherlands)

    De Jong, Cor A J; Laheij, Robert J F; Krabbe, Paul F M

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  3. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomized controlled trial.

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    AIM: Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  4. General anaesthesia does not improve outcome in opioid antagonist detoxification treatment: a randomised controlled trial

    NARCIS (Netherlands)

    Jong, C.A.J. de; Laheij, R.J.F.; Krabbe, P.F.M.

    2005-01-01

    Aim  Opioid detoxification by administering opioid-antagonists under general anaesthesia has caused considerable controversy. This study is conducted to determine whether rapid detoxification under general anaesthesia results in higher levels of opioid abstinence than rapid detoxification without

  5. Successful treatment of hereditary angioedema with bradykinin B2-receptor antagonist icatibant.

    Science.gov (United States)

    Krause, Karoline; Metz, Martin; Zuberbier, Torsten; Maurer, Marcus; Magerl, Markus

    2010-04-01

    The bradykinin B2 receptor antagonist icatibant has recently become available for treating hereditary angioedema. Our observations demonstrate icatibant to be effective and safe for the treatment of both, abdominal and cutaneous attacks in a practice setting beyond clinical studies.

  6. Antagonistic Functions of USAG-1 and RUNX2 during Tooth Development.

    Directory of Open Access Journals (Sweden)

    Yumiko Togo

    Full Text Available Supernumerary teeth and tooth agenesis are common morphological anomalies in humans. We previously obtained evidence that supernumerary maxillary incisors form as a result of the successive development of the rudimentary maxillary incisor tooth germ in Usag-1 null mice. The development of tooth germs is arrested in Runx2 null mice, and such mice also exhibit lingual epithelial buds associated with the upper molars and incisors. The aim of this study is to investigate the potential crosstalk between Usag-1 and Runx2 during tooth development. In the present study, three interesting phenomena were observed in double null Usag-1-/-/Runx2-/- mice: the prevalence of supernumerary teeth was lower than in Usag-1 null mice; tooth development progressed further compared than in Runx2 null mice; and the frequency of molar lingual buds was lower than in Runx2 null mice. Therefore, we suggest that RUNX2 and USAG-1 act in an antagonistic manner. The lingual bud was completely filled with odontogenic epithelial Sox2-positive cells in the Usag-1+/+/Runx2-/- mice, whereas almost no odontogenic epithelial Sox2-positive cells contributed to supernumerary tooth formation in the rudimentary maxillary incisors of the Usag-1-/-/Runx2+/+ mice. Our findings suggest that RUNX2 directly or indirectly prevents the differentiation and/or proliferation of odontogenic epithelial Sox2-positive cells. We hypothesize that RUNX2 inhibits the bone morphogenetic protein (BMP and/or Wnt signaling pathways regulated by USAG-1, whereas RUNX2 expression is induced by BMP signaling independently of USAG-1.

  7. Interleukin-1 receptor antagonist protects against lipopolysaccharide induced diaphragm weakness in preterm lambs.

    Directory of Open Access Journals (Sweden)

    Kanakeswary Karisnan

    Full Text Available Chorioamnionitis (inflammation of the fetal membranes is strongly associated with preterm birth and in utero exposure to inflammation significantly impairs contractile function in the preterm lamb diaphragm. The fetal inflammatory response to intra-amniotic (IA lipopolysaccharide (LPS is orchestrated via interleukin 1 (IL-1. We aimed to determine if LPS induced contractile dysfunction in the preterm diaphragm is mediated via the IL-1 pathway. Pregnant ewes received IA injections of recombinant human IL-1 receptor antagonist (rhIL-1ra (Anakinra; 100 mg or saline (Sal 3 h prior to second IA injections of LPS (4 mg or Sal at 119d gestational age (GA. Preterm lambs were killed after delivery at 121d GA (term = 150 d. Muscle fibres dissected from the right hemi-diaphragm were mounted in an in vitro muscle test system for assessment of contractile function. The left hemi-diaphragm was snap frozen for molecular and biochemical analyses. Maximum specific force in lambs exposed to IA LPS (Sal/LPS group was 25% lower than in control lambs (Sal/Sal group; p=0.025. LPS-induced diaphragm weakness was associated with higher plasma IL-6 protein, diaphragm IL-1β mRNA and oxidised glutathione levels. Pre-treatment with rhIL-1ra (rhIL-1ra/LPS ameliorated the LPS-induced diaphragm weakness and blocked systemic and local inflammatory responses, but did not prevent the rise in oxidised glutathione. These findings indicate that LPS induced diaphragm dysfunction is mediated via IL-1 and occurs independently of oxidative stress. Therefore, the IL-1 pathway represents a potential therapeutic target in the management of impaired diaphragm function in preterm infants.

  8. Inhibitory Effect of Serotonin Antagonist on Leukocyte-Endothelial Interactions In Vivo and In Vitro.

    Directory of Open Access Journals (Sweden)

    Hiroshi Kataoka

    Full Text Available Although 5-HT2A serotonergic antagonists have been used to treat vascular disease in patients with diabetes mellitus or obesity, their effects on leukocyte-endothelial interactions have not been fully investigated. In this study, we assessed the effects of sarpogrelate hydrochloride (SRPO, a 5-HT2A receptor inverse agonist, on leukocyte-endothelial cell interactions in obesity both in vivo and in vitro.In the in vivo experiment, C57BL/6 mice were fed a high-fat high-fructose diet (HFFD, comprising 20% fat and 30% fructose, with or without intraperitoneal injection of 5 mg/kg/day SRPO for 4 weeks. The body weight, visceral fat weight, and serum monocyte chemoattractant protein-1 levels in the mice increased significantly with the HFFD, but these effects were prevented by chronic injections of SRPO. Intravital microscopy of the femoral artery detected significant leukocyte-endothelial interactions after treatment with HFFD, but these leukocyte-endothelial interactions were reduced in the mice injected with SRPO. In the in vitro experiment, pre-incubation of activated human umbilical vein endothelial cells (HUVECs with platelet-rich plasma (PRP induced THP-1 cell adhesion under physiological flow conditions, but the adhesion was reduced by pretreatment of PRP with SRPO. A fluorescent immunobinding assay showed that PRP induced significant upregulation of E-selectin in HUVECs, but this upregulation was reduced by pretreatment of PRP with SRPO. In other in vitro conditions, pre-incubation of THP-1 cells with phorbol 12-myristate 13-acetate increased the adhesion of THP-1 cells to activated HUVECs under rotational conditions, but this adhesion was reduced by pretreatment with SRPO. Western blotting analysis showed that protein kinase C α activation in THP-1 cells was inhibited by SRPO.Our findings indicated that SRPO inhibits vascular inflammation in obesity via inactivation of platelets and leukocytes, and improvement of obese.

  9. Characteristics of Symptomatic Intracranial Hemorrhage in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulant Therapy.

    Directory of Open Access Journals (Sweden)

    Hisanao Akiyama

    Full Text Available The first non-vitamin K antagonist oral anticoagulant (NOAC introduced to the market in Japan was dabigatran in March 2011, and three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Randomized controlled trials of NOACs have revealed that intracranial hemorrhage (ICH occurs less frequently with NOACs compared with warfarin. However, the absolute incidence of ICH associated with NOACs has increased with greater use of these anticoagulants, and we wanted to explore the incidence, clinical characteristics, and treatment course of patients with NOACs-associated ICH.We retrospectively analyzed the characteristics of symptomatic ICH patients receiving NOACs between March 2011 and September 2014.ICH occurred in 6 patients (5 men, 1 woman; mean ± SD age, 72.8 ± 3.2 years. Mean time to onset was 146.2 ± 111.5 days after starting NOACs. Five patients received rivaroxaban and 1 patient received apixaban. None received dabigatran or edoxaban. Notably, no hematoma expansion was observed within 24 h of onset in the absence of infusion of fresh frozen plasma, activated prothrombin complex concentrate, recombinant activated factor VIIa or hemodialysis. When NOAC therapy was initiated, mean HAS-BLED and PANWARDS scores were 1.5 ± 0.5 and 39.5 ± 7.7, respectively. Mean systolic blood pressure was 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset.Six symptomatic ICHs occurred early in NOAC therapy but hematoma volume was small and did not expand in the absence of infusion of reversal agents or hemodialysis. The occurrence of ICH during NOAC therapy is possible even when there is acceptable mean systolic blood pressure control (137.8 ± 15.9 mmHg and HAS-BLED score ≤ 2. Even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy.

  10. The potential for substance P antagonists as anti-cancer agents in brain tumours.

    Science.gov (United States)

    Harford-Wright, Elizabeth; Lewis, Kate M; Vink, Robert

    2013-04-01

    Despite recent advances in cancer treatment and diagnosis, the prognosis for patients with CNS tumours remains extremely poor. This is, in part, due to the difficulty in completely removing tumours surgically, and also because of the presence of the blood brain barrier, which can prevent the entry of chemotherapeutic agents typically used in cancer treatment. Despite the presence of the blood brain barrier, tumour cells are capable of entering and colonising the brain to form secondary brain tumours. Additionally, tumour related disruption of the blood brain barrier is associated with the clinical presentation of many patients, with accompanying increases in intracranial pressure due, in part, to the development of vasogenic oedema. Vasogenic oedema results because the newly formed angiogenic vessels within brain tumours do not retain the highly selective properties of the blood brain barrier, and thus allow for the extravasation of plasma proteins and water into the brain parenchyma. Tachykinins, and in particular substance P, have been implicated in blood brain barrier disruption and the genesis of cerebral oedema in other CNS insults via a process known as neurogenic inflammation. Recent evidence suggests that substance P may play a similar role in CNS tumours. It has been well established that an upregulation of substance P and its receptors occurs in a number of different cancer types, including CNS neoplasms. In addition to disrupting blood brain barrier permeability, substance P and the NK1 receptors facilitate promotion of tumour growth and the development of cerebral oedema. Accordingly, recent patents describe the potential of NK1 receptor antagonists as anti-cancer agents suggesting that substance P may provide a novel cancer treatment target. This review will examine the role of substance P in the development of CNS tumours.

  11. Anticoagulation Quality and Complications of using Vitamin K Antagonists in the Cardiac Surgery Outpatient Clinic

    Directory of Open Access Journals (Sweden)

    Mário Augusto Cray da Costa

    Full Text Available ABSTRACT Introduction: In patients with mechanical prosthetic heart valves or atrial fibrillation requiring anticoagulation to prevent thromboembolic events, several factors influence adherence and anticoagulation complications. Objective: To evaluate the factors that interfere with the quality and complications of anticoagulation with vitamin K antagonists. Methods: A retrospective cohort study of 100 patients, in the period from 2011 to 2014, was performed. Anticoagulation conditions in the last year, regarding the presence of complications (embolisms/bleeding and inadequate treatment were assessed: achievement of less than 8 annual prothrombin times and International Normalized Ratio outside therapeutic target in more than 40% of prothrombin times. Results: There were 31 complications (22 minor bleeding without hospitalization and 9 major complications: 7 bleeding with hospitalization and two emboli; 70 were with International Normalized Ratio outside the target in more than 40% of the tests and 36 with insufficient number of prothrombin times. Socioeconomic factors, anticoagulant type and anticoagulation reason had no relationship with complications or with inadequate treatment. There were more complications in patients with longer duration of anticoagulation (P=0.001. Women had more International Normalized Ratio outside the target range (OR 2.61, CI:1.0-6.5; P=0.04. Patients with lower number of annual prothrombin times had longer times of anticoagulation (P=0.03, less annual consultations (P=0.02 and less dose adjustments (P=0.003. Patients with longer duration of anticoagulation have more complications (P=0.001. Conclusion: There was a high rate of major complications and International Normalized Ratio was outside the goal. Less annual prothrombin times was related to longer duration of anticoagulation, less annual consultations and less dose adjustments. More major complications occurred in patients with longer duration of

  12. Cannabinoid antagonist in nanostructured lipid carriers (NLCs): design, characterization and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Esposito, Elisabetta; Ravani, Laura [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy); Drechsler, Markus [BIMF/Soft Matter Electron Microscopy, University of Bayreuth (Germany); Mariani, Paolo [Department of Life and Environmental Sciences and CNISM, Università Politecnica delle Marche, I-60100 Ancona (Italy); Contado, Catia [Department of Chemical and Pharmaceutical Sciences, University of Ferrara, I-44121 Ferrara (Italy); Ruokolainen, Janne [Department of Applied Physics, Aalto University, 00076 Aalto (Finland); Ratano, Patrizia; Campolongo, Patrizia [Department of Physiology and Pharmacology, Sapienza University of Rome, 00185 Roma (Italy); Trezza, Viviana [Department of Science, Roma Tre University, 00146 Roma (Italy); Nastruzzi, Claudio, E-mail: nas@unife.it [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy); Cortesi, Rita [Department of Life Sciences and Biotechnology, University of Ferrara, I-44121 Ferrara (Italy)

    2015-03-01

    This study describes the preparation, characterization, and in vivo evaluation in rats of nanostructured lipid carriers (NLCs) encapsulating rimonabant (RMN) as prototypical cannabinoid antagonist. A study was conducted in order to optimize NLC production by melt and ultrasonication method. NLCs were prepared by alternatively adding the lipid phase into the aqueous one (direct protocol) or the aqueous phase into the lipid one (reverse protocol). RMN-NLCs have been characterized by cryogenic transmission electron microscopy (cryo-TEM), X-ray, photon correlation spectroscopy (PCS) and sedimentation field flow fractionation (SdFFF). Reverse NLCs were treated with polysorbate 80. RMN release kinetics have been determined in vitro by dialysis method. In vivo RMN biodistribution in rats was evaluated after intranasal (i.n.) administration of reverse RMN-NLC. The reverse protocol enabled to prevent the lost of lipid phase and to achieve higher RMN encapsulation efficacy (EE) with respect to the direct protocol (98% w/w versus 67% w/w). The use of different protocols did not affect NLC morphology and dimensional distribution. An in vitro dissolutive release rate of RMN was calculated. The in vivo data indicate that i.n. administration of RMN by reverse NLC treated with polysorbate 80 increased RMN concentration in the brain with respect to the drug in solution. The nanoencapsulation protocol presented here appears as an optimal strategy to improve the low solubility of cannabinoid compounds in an aqueous system suitable for in vivo administration. - Highlights: • Rimonabant (RMN) can be encapsulated in nanostructured lipid carriers (NLCs). • Nanoencapsulation improves RMN solubility in a stable physiologic aqueous formulation. • RMN is released in vitro from NLC by a controlled dissolutive release modality. • I.n. administration leads to higher RMN concentration in the brain with respect to plasma. • NLC increases RMN concentration in the brain with respect to

  13. Nationwide cohort study of the leukotriene receptor antagonist montelukast and incident or recurrent cardiovascular disease.

    Science.gov (United States)

    Ingelsson, Erik; Yin, Li; Bäck, Magnus

    2012-03-01

    The leukotriene pathway has been associated with an increased cardiovascular risk. However, the effects of the antileukotriene treatment used in asthmatic patients on cardiovascular outcomes have remained largely unexplored. We sought to examine a potential protective role of the leukotriene receptor antagonist montelukast on future risk of incident and recurrent myocardial infarction and ischemic stroke. A nationwide population-based cohort of approximately 7 million persons integrating data from the Prescribed Drug, Patient, Cause of Death, Income, Educational, and Emigration Registers was followed from July 1, 2005, to December 31, 2008. Analyses were performed in the whole population after exclusion of subjects with a prior cardiovascular diagnosis (incident events; sample size, n = 6,910,923 for myocardial infarction and n = 6,932,578 for stroke) and in subjects with a prior diagnosis (recurrent events; n = 153,937 and n = 132,291 for stroke and myocardial infarction, respectively). Cox proportional hazard ratios (HRs) did not reveal an association of montelukast use with incident events. In contrast to these findings, montelukast use was associated with a lower risk for recurrent stroke (HR, 0.62; 95% CI, 0.38-0.99) accounting for age, sex, education level, and yearly income. Adjusting the latter finding also for respiratory and cardiovascular medications and diagnoses revealed similar point estimates (HR, 0.62; 95% CI, 0.39-1.0). Post hoc analyses revealed a significant association of montelukast use with a lower risk for recurrent myocardial infarction in male subjects (HR, 0.65; 95% CI, 0.43-0.99). These data provide a first indication for a potential role of the antiasthma drug montelukast for secondary prevention of cardiovascular disease. Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.

  14. Characteristics of Symptomatic Intracranial Hemorrhage in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulant Therapy

    Science.gov (United States)

    2015-01-01

    Objectives The first non-vitamin K antagonist oral anticoagulant (NOAC) introduced to the market in Japan was dabigatran in March 2011, and three more NOACs, rivaroxaban, apixaban, and edoxaban, have since become available. Randomized controlled trials of NOACs have revealed that intracranial hemorrhage (ICH) occurs less frequently with NOACs compared with warfarin. However, the absolute incidence of ICH associated with NOACs has increased with greater use of these anticoagulants, and we wanted to explore the incidence, clinical characteristics, and treatment course of patients with NOACs-associated ICH. Methods We retrospectively analyzed the characteristics of symptomatic ICH patients receiving NOACs between March 2011 and September 2014. Results ICH occurred in 6 patients (5 men, 1 woman; mean ± SD age, 72.8 ± 3.2 years). Mean time to onset was 146.2 ± 111.5 days after starting NOACs. Five patients received rivaroxaban and 1 patient received apixaban. None received dabigatran or edoxaban. Notably, no hematoma expansion was observed within 24 h of onset in the absence of infusion of fresh frozen plasma, activated prothrombin complex concentrate, recombinant activated factor VIIa or hemodialysis. When NOAC therapy was initiated, mean HAS-BLED and PANWARDS scores were 1.5 ± 0.5 and 39.5 ± 7.7, respectively. Mean systolic blood pressure was 137.8 ± 15.9 mmHg within 1 month before spontaneous ICH onset. Conclusion Six symptomatic ICHs occurred early in NOAC therapy but hematoma volume was small and did not expand in the absence of infusion of reversal agents or hemodialysis. The occurrence of ICH during NOAC therapy is possible even when there is acceptable mean systolic blood pressure control (137.8 ± 15.9 mmHg) and HAS-BLED score ≤ 2. Even stricter blood pressure lowering and control within the acceptable range may be advisable to prevent ICH during NOAC therapy. PMID:26171862

  15. Evaluation of antagonistic activities of Bacillus spp. against certain bacteria of medical importance

    OpenAIRE

    Gupta, K.K. and Rana, D.

    2017-01-01

    In this work we focused on the antagonistic potential of Bacillus spp. isolates from cow dung. Out of fourteen bacterial strains, isolate KD104 and KD117 were probably identified as Bacillus spp. These two isolates were screened for their antagonistic activity against 14 test organisms viz., Vibrio Cholera (MTCC 3904), Salmonella typhi (MTCC 3216), Escherichia coli (SGPGI), Staphylococcus aureus (MTCC 7443), Bacillus subtilis (MTCC 441), Bacillus cereus (MTCC 6728), Proteus vulgaris (MTCC 426...

  16. Antagonist wear of monolithic zirconia crowns after 2 years.

    Science.gov (United States)

    Lohbauer, Ulrich; Reich, Sven

    2017-05-01

    The aim of this study was to evaluate the amount of wear on the antagonist occlusal surfaces of clinically placed monolithic zirconia premolar and molar crowns (LAVA Plus, 3M ESPE). Fourteen in situ monolithic zirconia crowns and their opposing antagonists (n = 26) are the subject of an ongoing clinical trial and have been clinically examined at baseline and after 24 months. Silicone impressions were taken and epoxy replicas produced for qualitative SEM analysis and quantitative analysis using optical profilometry. Based on the baseline replicas, the follow-up situation has been scanned and digitally matched with the initial topography in order to calculate the mean volume loss (in mm 3 ) as well as the mean maximum vertical loss (in mm) after 2 years in service. The mean volume loss for enamel antagonist contacts (n = 7) was measured to 0.361 mm 3 and the mean of the maximum vertical loss to 0.204 mm. The mean volume loss for pure ceramic contacts (n = 10) was measured to 0.333 mm 3 and the mean of the maximum vertical loss to 0.145 mm. The wear rates on enamel contacts were not significantly different from those measured on ceramic antagonists. Based on the limitations of this study, it can be concluded for the monolithic zirconia material LAVA Plus that the measured wear rates are in consensus with other in vivo studies on ceramic restorations. Further, that no significant difference was found between natural enamel antagonists and ceramic restorations as antagonists. The monolithic zirconia restorations do not seem to be affected by wear within the first 2 years. The monolithic zirconia crowns (LAVA Plus) show acceptable antagonist wear rates after 2 years in situ, regardless of natural enamel or ceramics as antagonist materials.

  17. Wear Behavior of Ceramic CAD/CAM Crowns and Natural Antagonists

    OpenAIRE

    Naumova, Ella A.; Schneider, Stephan; Arnold, Wolfgang H.; Piwowarczyk, Andree

    2017-01-01

    Objective: Evaluation of wear behavior of computer-aided design/computer-aided manufacturing (CAD/CAM) crowns from various restorative materials and natural antagonists. Method: Full CAD/CAM crowns fabricated with nanoceramic resin (Lava Ultimate (LU)), a glass ceramic in a resin interpenetrating matrix (Vita Enamic (VE)) and a lithium silicate reinforced ceramic enriched with zirconia (Vita Suprinity (VS)) were cemented on human molars. The crown and antagonists were subjected to simulated c...

  18. Antimüllerian hormone in gonadotropin releasing-hormone antagonist cycles

    DEFF Research Database (Denmark)

    Arce, Joan-Carles; La Marca, Antonio; Mirner Klein, Bjarke

    2013-01-01

    To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol.......To assess the relationships between serum antimüllerian hormone (AMH) and ovarian response and treatment outcomes in good-prognosis patients undergoing controlled ovarian stimulation using a gonadotropin-releasing hormone (GnRH) antagonist protocol....

  19. CCR5 receptor antagonists: discovery and SAR study of guanylhydrazone derivatives.

    Science.gov (United States)

    Wei, Robert G; Arnaiz, Damian O; Chou, Yuo-Ling; Davey, Dave; Dunning, Laura; Lee, Wheeseong; Lu, Shou-Fu; Onuffer, James; Ye, Bin; Phillips, Gary

    2007-01-01

    High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.

  20. Histamine and histamine type-2 receptor antagonists in psoriasis. Mechanisms and speculations

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1991-01-01

    antagonists, previously reported to have a clinical effect on psoriasis. But randomised short-term studies have disclosed that these drugs have no beneficial or even an aggravating effect on the disease. This article reports on recent findings of improvement in psoriasis using high doses of the histamine-2...... receptor antagonist ranitidine in long-term studies. Also presented are a hypothetical action of histamine in development of psoriasis and a rationale for ranitidine as a potential agent in the therapy of psoriasis....

  1. Growth of cultured human glioma tumour cells can be regulated with histamine and histamine antagonists.

    OpenAIRE

    Van der Ven, L. T.; Prinsen, I. M.; Jansen, G. H.; Roholl, P. J.; Defferrari, R.; Slater, R.; Den Otter, W.

    1993-01-01

    The 50% survival time for low grade astrocytomas is 50 months and for high grade astrocytomas it is 13 months, underlining the need for new therapies. Several reports show that in vivo histamine antagonists cause retardation of tumour growth in some animal models and prolonged survival in cancer patients. Therefore we have tested the growth modulating effects of histamine and histamine antagonists on human glioma cultures. Twelve freshly excised human gliomas were cultured and tested for thei...

  2. High-throughput screening of antagonists for the orphan G-protein coupled receptor GPR139.

    Science.gov (United States)

    Wang, Jia; Zhu, Lin-yun; Liu, Qing; Hentzer, Morten; Smith, Garrick Paul; Wang, Ming-wei

    2015-07-01

    To discover antagonists of the orphan G-protein coupled receptor GPR139 through high-throughput screening of a collection of diverse small molecules. Calcium mobilization assays were used to identify initial hits and for subsequent confirmation studies. Five small molecule antagonists, representing 4 different scaffolds, were identified following high-throughput screening of 16 000 synthetic compounds. The findings provide important tools for further study of this orphan G-protein coupled receptor.

  3. Serotonin 2C receptor antagonists induce fast-onset antidepressant effects.

    Science.gov (United States)

    Opal, M D; Klenotich, S C; Morais, M; Bessa, J; Winkle, J; Doukas, D; Kay, L J; Sousa, N; Dulawa, S M

    2014-10-01

    Current antidepressants must be administered for several weeks to produce therapeutic effects. We show that selective serotonin 2C (5-HT2C) antagonists exert antidepressant actions with a faster-onset (5 days) than that of current antidepressants (14 days) in mice. Subchronic (5 days) treatment with 5-HT2C antagonists induced antidepressant behavioral effects in the chronic forced swim test (cFST), chronic mild stress (CMS) paradigm and olfactory bulbectomy paradigm. This treatment regimen also induced classical markers of antidepressant action: activation of cAMP response element-binding protein (CREB) and induction of brain-derived neurotrophic factor (BDNF) in the medial prefrontal cortex (mPFC). None of these effects were induced by subchronic treatment with citalopram, a prototypical selective serotonin reuptake inhibitor (SSRI). Local infusion of 5-HT2C antagonists into the ventral tegmental area was sufficient to induce BDNF in the mPFC, and dopamine D1 receptor antagonist treatment blocked the antidepressant behavioral effects of 5-HT2C antagonists. 5-HT2C antagonists also activated mammalian target of rapamycin (mTOR) and eukaryotic elongation factor 2 (eEF2) in the mPFC, effects recently linked to rapid antidepressant action. Furthermore, 5-HT2C antagonists reversed CMS-induced atrophy of mPFC pyramidal neurons. Subchronic SSRI treatment, which does not induce antidepressant behavioral effects, also activated mTOR and eEF2 and reversed CMS-induced neuronal atrophy, indicating that these effects are not sufficient for antidepressant onset. Our findings reveal that 5-HT2C antagonists are putative fast-onset antidepressants, which act through enhancement of mesocortical dopaminergic signaling.

  4. Treating and Preventing Burns

    Science.gov (United States)

    ... Healthy Living Healthy Living Healthy Living Nutrition Fitness Sports Oral Health Emotional Wellness Growing Healthy Sleep Safety & Prevention Safety & Prevention Safety and Prevention Immunizations At Home ...

  5. DIHYDROPYRIDINE CALCIUM ANTAGONISTS. POSITION OF NIFEDIPINE IN MODERN CARDIOLOGY PRACTICE

    OpenAIRE

    A. A. Garganeeva

    2011-01-01

    Position of nifedipine in modern cardiology practice is highlighted. Nifedipine usage for arterial hypertension therapy , including combined one, stroke prevention, treatment of hypertensive crisis and ischemic heart disease is considered. Advantages of nifedipine innovative formulations are presented. Possible usage of nifedipine in pulmonary hypertension as well as pregnancy is discussed specially.

  6. DIHYDROPYRIDINE CALCIUM ANTAGONISTS. POSITION OF NIFEDIPINE IN MODERN CARDIOLOGY PRACTICE

    Directory of Open Access Journals (Sweden)

    A. A. Garganeeva

    2011-01-01

    Full Text Available Position of nifedipine in modern cardiology practice is highlighted. Nifedipine usage for arterial hypertension therapy , including combined one, stroke prevention, treatment of hypertensive crisis and ischemic heart disease is considered. Advantages of nifedipine innovative formulations are presented. Possible usage of nifedipine in pulmonary hypertension as well as pregnancy is discussed specially.

  7. Prevention of thromboembolism during radiosynoviorthesis?

    International Nuclear Information System (INIS)

    Fischer, M.; Ritter, B.

    2006-01-01

    The question of pharmacological prevention of thromboembolic disease during radiosynoviorthesis with concomitant immobilization of the treated joint is discussed by means of a recent case report. The possible advantages must be balanced against the potential risks of hemorrhage and heparine-induced thrombocytopenia in every patient. The intraarticular radionuclide therapy might be ranked as ''low risk'', comparable to small or medium interventions with minor trauma according to surgical and perioperative classifications, provided that there are no individual risk factors. With respect to the possible side effects, a general thromboembolic prophylaxis is not recommended in these patients. After radiosynoviorthesis of the knee and an additional joint of the same limb which requires an immobilization spanning both joints, a ''medium risk'' of thromboembolic disease must be assumed. In these cases, as well as with two or more predisposing risk factors, a pharmacological prevention of thromboembolism is mandatory. Ready-to-use syringes containing low-molecular-weight heparine are available for this purpose. Although serious side effects from LMW heparine are rare, monitoring of the thrombocyte counts prior to and 1-2 times during heparine application are advisable. Pharmacological prophylaxis of thromboembolic disease is strictly contraindicated in patients with acute bleeding, cerebral aneurysms and known aortic dissections. In case of concomitant treatment with NSAIDs, antagonists of platelet aggregation or valproic acid, the indication for heparine treatment should be discussed very seriously. Both the verbal and written information of each patient must be complete and precise with respect to possible advantages and potential risks of pharmacological prevention of thromboembolic disease. (orig.)

  8. Crystal Structures of Human Orexin 2 Receptor Bound to the Subtype-Selective Antagonist EMPA.

    Science.gov (United States)

    Suno, Ryoji; Kimura, Kanako Terakado; Nakane, Takanori; Yamashita, Keitaro; Wang, Junmei; Fujiwara, Takaaki; Yamanaka, Yasuaki; Im, Dohyun; Horita, Shoichiro; Tsujimoto, Hirokazu; Tawaramoto, Maki S; Hirokawa, Takatsugu; Nango, Eriko; Tono, Kensuke; Kameshima, Takashi; Hatsui, Takaki; Joti, Yasumasa; Yabashi, Makina; Shimamoto, Keiko; Yamamoto, Masaki; Rosenbaum, Daniel M; Iwata, So; Shimamura, Tatsuro; Kobayashi, Takuya

    2018-01-02

    Orexin peptides in the brain regulate physiological functions such as the sleep-wake cycle, and are thus drug targets for the treatment of insomnia. Using serial femtosecond crystallography and multi-crystal data collection with a synchrotron light source, we determined structures of human orexin 2 receptor in complex with the subtype-selective antagonist EMPA (N-ethyl-2-[(6-methoxy-pyridin-3-yl)-(toluene-2-sulfonyl)-amino]-N-pyridin-3-ylmethyl-acetamide) at 2.30-Å and 1.96-Å resolution. In comparison with the non-subtype-selective antagonist suvorexant, EMPA contacted fewer residues through hydrogen bonds at the orthosteric site, explaining the faster dissociation rate. Comparisons among these OX 2 R structures in complex with selective antagonists and previously determined OX 1 R/OX 2 R structures bound to non-selective antagonists revealed that the residue at positions 2.61 and 3.33 were critical for the antagonist selectivity in OX 2 R. The importance of these residues for binding selectivity to OX 2 R was also revealed by molecular dynamics simulation. These results should facilitate the development of antagonists for orexin receptors. Copyright © 2017 Elsevier Ltd. All rights reserved.

  9. Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower

    Directory of Open Access Journals (Sweden)

    Veronika Zengerer

    2018-02-01

    Full Text Available In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora, the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0.

  10. The effect of H 1 and H 2 receptor antagonists on melanogenesis

    Directory of Open Access Journals (Sweden)

    Tag S Anbar

    2012-01-01

    Full Text Available Background: Histamine was found to stimulate melanogenesis in cultured human melanocytes specifically mediated by histamine H 2 receptors via protein kinase A activation. Based on this finding, the effect of topically applied H 2 antagonist on UVB-irradiated Guinea pigs′ skin was examined and found to be suppressive on the post-irradiation melanogenesis. Aims: In this study, we tried to explore the role of topically applied H 1 and H 2 receptor antagonists, in inhibition of UVB-induced melanization. Methods: The effect of topically applied H 1 and H 2 receptor antagonists in inhibition of melanization was done clinically and histochemically using Fontana Masson and DOPA reactions compared with placebo. Results: The post-irradiation pigmentation was found to be brownish/black instead of the original light brown color. This color change occurred below the shaved orange-red fur suggesting a switch of melanogenesis from pheomelanin to eumelanin. The induced pigmentation was suppressed by topically applied H 2 antagonist while both H 1 antagonist and vehicle had no effect. The microscopic examination showed that the keratinocytes in the H 2 antagonist-treated areas contained few melanosomes while the nearby dendrites are full of them. Conclusion: H 2 antagonists′ inhibition of UVB-induced pigmentation is not only due to suppression of melanization but also due to a specific action on melanosomes′ transfer.

  11. Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower.

    Science.gov (United States)

    Zengerer, Veronika; Schmid, Michael; Bieri, Marco; Müller, Denise C; Remus-Emsermann, Mitja N P; Ahrens, Christian H; Pelludat, Cosima

    2018-01-01

    In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora , the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430 Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0.

  12. Molecular Gymnastics: Mechanisms of HIV-1 Resistance to CCR5 Antagonists and Impact on Virus Phenotypes.

    Science.gov (United States)

    Roche, Michael; Borm, Katharina; Flynn, Jacqueline K; Lewin, Sharon R; Churchill, Melissa J; Gorry, Paul R

    2016-01-01

    Human immunodeficiency virus type 1 (HIV-1) enters host cells through the binding of its envelope glycoproteins (Env) to the host cell receptor CD4 and then subsequent binding to a chemokine coreceptor, either CCR5 or CXCR4. CCR5 antagonists are a relatively recent class addition to the armamentarium of anti-HIV-1 drugs. These compounds act by binding to a hydrophobic pocket formed by the transmembrane helices of CCR5 and altering the conformation of the extracellular domains, such that they are no longer recognized by Env. Maraviroc is the first drug within this class to be licenced for use in HIV-1 therapy regimens. HIV resistance to CCR5 antagonists occurs either through outgrowth of pre-existing CXCR4-using viruses, or through acquisition of the ability of CCR5-using HIV-1 to use the antagonist bound form of CCR5. In the latter scenario, the mechanism underlying resistance is through complex alterations in the way that resistant Envs engage CCR5. These significant changes are unlikely to occur without consequence to the viral entry phenotype and may also open up new avenues to target CCR5 antagonist resistant viruses. This review discusses the mechanism of action of CCR5 antagonists, how HIV resistance to CCR5 antagonists occurs, and the subsequent effects on Env function.

  13. Relapse prevention.

    Science.gov (United States)

    Hall, S M; Wasserman, D A; Havassy, B E

    1991-01-01

    Although knowledge about relapse prevention is still at an early stage, the extant data highlight the importance of several constructs. 1. Motivation for abstinence remains central. The construct itself is often clouded because of its association with mystical notions such as willpower and self-control. We know that manipulation of environmental events can increase motivation. These interventions are effective, however, only as long as the contingencies are in effect. We need to develop and evaluate strategies for transferring contingency management to the natural environment, that is, to institutions and groups that can perpetuate them for the long term. Also, clarification of the kinds of abstinence goals needed to prevent relapse is important. 2. Coping skills have been studied by several investigators, but research on these, except for job-finding skills, is not encouraging. The skills usually taught may be too basic. Skills training oriented to complex targets, such as building nondrug-using networks, may be useful and should be further explored. 3. Social support is clearly important, yet we do not know how best to use it to promote abstinence. The little research available suggests that both familial and nonfamilial systems should be mobilized. We need to define abstinence-promoting supportive behaviors, identify and engage important support systems in treatment, and help patients expand their nondrug-using contacts. 4. Negative affect may be causally related to relapse. We need to continue efforts to identify dysphoric patients and develop interventions to ameliorate dysphoria concurrent with drug abuse treatment (cf. Zweben and Smith 1989). 5. Drug cue reactivity and extinction to drug cues have been demonstrated in the laboratory. What is needed in this promising line of research are (1) investigation of cues and cue-reactivity phenomena in the natural environment or in conditions closely mimicking that environment and (2) extinction methods that transfer

  14. RF313, an orally bioavailable neuropeptide FF receptor antagonist, opposes effects of RF-amide-related peptide-3 and opioid-induced hyperalgesia in rodents.

    Science.gov (United States)

    Elhabazi, Khadija; Humbert, Jean-Paul; Bertin, Isabelle; Quillet, Raphaelle; Utard, Valérie; Schneider, Séverine; Schmitt, Martine; Bourguignon, Jean-Jacques; Laboureyras, Emilie; Ben Boujema, Meric; Simonnet, Guy; Ancel, Caroline; Simonneaux, Valérie; Beltramo, Massimiliano; Bucher, Bernard; Sorg, Tania; Meziane, Hamid; Schneider, Elodie; Petit-Demoulière, Benoit; Ilien, Brigitte; Bihel, Frédéric; Simonin, Frédéric

    2017-05-15

    Although opiates represent the most effective analgesics, their use in chronic treatments is associated with numerous side effects including the development of pain hypersensitivity and analgesic tolerance. We recently identified a novel orally active neuropeptide FF (NPFF) receptor antagonist, RF313, which efficiently prevents the development of fentanyl-induced hyperalgesia in rats. In this study, we investigated the properties of this compound into more details. We show that RF313 exhibited a pronounced selectivity for NPFF receptors, antagonist activity at NPFF1 receptor (NPFF1R) subtype both in vitro and in vivo and no major side effects when administered in mice up to 30 mg/kg. When co-administered with opiates in rats and mice, it improved their analgesic efficacy and prevented the development of long lasting opioid-induced hyperalgesia. Moreover, and in marked contrast with the dipeptidic NPFF receptor antagonist RF9, RF313 displayed negligible affinity and no agonist activity (up to 100 μM) toward the kisspeptin receptor. Finally, in male hamster, RF313 had no effect when administered alone but fully blocked the increase in LH induced by RFRP-3, while RF9 per se induced a significant increase in LH levels which is consistent with its ability to activate kisspeptin receptors. Altogether, our data indicate that RF313 represents an interesting compound for the development of therapeutic tools aiming at improving analgesic action of opiates and reducing adverse side effects associated with their chronic administration. Moreover, its lack of agonist activity at the kisspeptin receptor indicates that RF313 might be considered a better pharmacological tool, when compared to RF9, to examine the regulatory roles of RF-amide-related peptides and NPFF1R in reproduction. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. CCR5 Antagonist TD-0680 Uses a Novel Mechanism for Enhanced Potency against HIV-1 Entry, Cell-mediated Infection, and a Resistant Variant*

    Science.gov (United States)

    Kang, Yuanxi; Wu, Zhiwei; Lau, Terrence C. K.; Lu, Xiaofan; Liu, Li; Cheung, Allen K. L.; Tan, Zhiwu; Ng, Jenny; Liang, Jianguo; Wang, Haibo; Li, Saikam; Zheng, Bojian; Li, Ben; Chen, Li; Chen, Zhiwei

    2012-01-01

    Regardless of the route of transmission, R5-tropic HIV-1 predominates early in infection, rendering C-C chemokine receptor type 5 (CCR5) antagonists as attractive agents not only for antiretroviral therapy but also for prevention. Here, we report the specificity, potency, and underlying mechanism of action of a novel small molecule CCR5 antagonist, TD-0680. TD-0680 displayed the greatest potency against a diverse group of R5-tropic HIV-1 and SIV strains when compared with its prodrug, TD-0232, the Food and Drug Administration-approved CCR5 antagonist Maraviroc, and TAK-779, with EC50 values in the subnanomolar range (0.09–2.29 nm). Importantly, TD-0680 was equally potent at blocking envelope-mediated cell-cell fusion and cell-mediated viral transmission as well as the replication of a TAK-779/Maraviroc-resistant HIV-1 variant. Interestingly, TD-0232 and TD-0680 functioned differently despite binding to a similar transmembrane pocket of CCR5. Site-directed mutagenesis, drug combination, and antibody blocking assays identified a novel mechanism of action of TD-0680. In addition to binding to the transmembrane pocket, the unique exo configuration of this molecule protrudes and sterically blocks access to the extracellular loop 2 (ECL2) region of CCR5, thereby interrupting the interaction between virus and its co-receptor more effectively. This mechanism of action was supported by the observations of similar TD-0680 potency against CD4-dependent and -independent SIV strains and by molecular docking analysis using a CCR5 model. TD-0680, therefore, merits development as an anti-HIV-1 agent for therapeutic purposes and/or as a topical microbicide for the prevention of sexual transmission of R5-tropic HIV-1. PMID:22447925

  16. Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation.

    Science.gov (United States)

    Fosbøl, Emil L; Vinding, Naja Emborg; Lamberts, Morten; Staerk, Laila; Gundlund, Anna; Gadsbøll, Kasper; Køber, Lars; Gislason, Gunnar H; Olesen, Jonas Bjerring

    2017-06-28

    After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations. Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%). In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

  17. Nonsupplemented luteal phase characteristics after the administration of recombinant human chorionic gonadotropin, recombinant luteinizing hormone, or gonadotropin-releasing hormone (GnRH) agonist to induce final oocyte maturation in in vitro fertilization patients after ovarian stimulation with recombinant follicle-stimulating hormone and GnRH antagonist cotreatment

    NARCIS (Netherlands)

    N.S. Macklon (Nick); M.J.C. Eijkemans (René); M. Ludwig (Michael); R.E. Felberbaum; K. Diedrich; S. Bustion; E. Loumaye; B.C.J.M. Fauser (Bart); N.G.M. Beckers (Nicole)

    2003-01-01

    textabstractReplacing GnRH agonist cotreatment for the prevention of a premature rise in LH during ovarian stimulation for in vitro fertilization (IVF) by the late follicular phase administration of GnRH antagonist may render supplementation of the luteal phase redundant, because

  18. MODIFIED USE OF A DYNAMIC BITE OPENER - TREATMENT AND PREVENTION OF TRISMUS IN A CHILD WITH HEAD AND NECK-CANCER - A CASE-REPORT

    NARCIS (Netherlands)

    DIJKSTRA, PU; KROPMANS, TJB; TAMMINGA, RYJ

    1992-01-01

    Trismus may be a complication arising during or after treatment of patients with head and neck cancer. Treatment of trismus is difficult, making prevention very important. To prevent and treat trismus in a patient with a nasopharyngeal tumor, the Contract-Relax-Antagonist-Contract (CRAC) technique

  19. Partial to complete antagonism by putative antagonists at the wild-type α2C-adrenoceptor based on kinetic analyses of agonist : antagonist interactions

    Science.gov (United States)

    Pauwels, Petrus J; Colpaert, Francis C

    2000-01-01

    Activation of the recombinant human α2C-adrenoceptor (α2C AR) by (−)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric Gαq/i1 protein induced a rapid, transient Ca2+ response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). Activation of the α2C AR by various α2 AR agonists revealed the following rank order of high-magnitude Ca2+ response [Emax (%) versus 10 μM (−)-adrenaline]: UK 14304 (102±4)=talipexole (101±3)=(−)-adrenaline (100)=d-medetomidine (98±1)>oxymetazoline (81±4)⋍clonidine (75±5). The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca2+ response. However, though acting as full antagonists of the high-magnitude response, the further putative α2 AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. In conclusion, kinetic analyses of agonist : antagonist interactions at the α2C AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca2+ response for structurally related α2 AR ligands. PMID:11090111

  20. Fasitibant chloride, a kinin B2 receptor antagonist, and dexamethasone interact to inhibit carrageenan-induced inflammatory arthritis in rats

    Science.gov (United States)

    Valenti, Claudio; Giuliani, Sandro; Cialdai, Cecilia; Tramontana, Manuela; Maggi, Carlo Alberto

    2012-01-01

    BACKGROUND AND PURPOSE Bradykinin, through the kinin B2 receptor, is involved in inflammatory processes related to arthropathies. B2 receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated. EXPERIMENTAL APPROACH Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1β, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h. KEY RESULTS The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg9-[Leu8]-bradykinin (B2 receptor, leukotriene, catecholamine and B1 receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg9-[Leu8]-bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg9-[Leu8]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment. CONCLUSIONS AND IMPLICATIONS Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B2 receptor, or through the indirect effects mediated by release of eicosanoids

  1. DNA polymorphisms and biocontrol of Bacillus antagonistic to citrus bacterial canker with indication of the interference of phyllosphere biofilms.

    Directory of Open Access Journals (Sweden)

    Tzu-Pi Huang

    Full Text Available Citrus bacterial canker caused by Xanthomonas axonopodis pv. citri is a devastating disease resulting in significant crop losses in various citrus cultivars worldwide. A biocontrol agent has not been recommended for this disease. To explore the potential of bacilli native to Taiwan to control this disease, Bacillus species with a broad spectrum of antagonistic activity against various phytopathogens were isolated from plant potting mixes, organic compost and the rhizosphere soil. Seven strains TKS1-1, OF3-16, SP4-17, HSP1, WG6-14, TLB7-7, and WP8-12 showing superior antagonistic activity were chosen for biopesticide development. The genetic identity based on 16S rDNA sequences indicated that all seven native strains were close relatives of the B. subtilis group and appeared to be discrete from the B. cereus group. DNA polymorphisms in strains WG6-14, SP4-17, TKS1-1, and WP8-12, as revealed by repetitive sequence-based PCR with the BOXA1R primers were similar to each other, but different from those of the respective Bacillus type strains. However, molecular typing of the strains using either tDNA-intergenic spacer regions or 16S-23S intergenic transcribed spacer regions was unable to differentiate the strains at the species level. Strains TKS1-1 and WG6-14 attenuated symptom development of citrus bacterial canker, which was found to be correlated with a reduction in colonization and biofilm formation by X. axonopodis pv. citri on leaf surfaces. The application of a Bacillus strain TKS1-1 endospore formulation to the leaf surfaces of citrus reduced the incidence of citrus bacterial canker and could prevent development of the disease.

  2. Advantages of Papio anubis for preclinical testing of immunotoxicity of candidate therapeutic antagonist antibodies targeting CD28

    Science.gov (United States)

    Poirier, Nicolas; Mary, Caroline; Le Bas-Bernardet, Stephanie; Daguin, Veronique; Belarif, Lyssia; Chevalier, Melanie; Hervouet, Jeremy; Minault, David; Ville, Simon; Charpy, Vianney; Blancho, Gilles; Vanhove, Bernard

    2014-01-01

    Antagonist anti-CD28 antibodies prevent T-cell costimulation and are functionally different from CTLA4Ig since they cannot block CTLA-4 and PDL-1 co-inhibitory signals. They demonstrated preclinical efficacy in suppressing effector T cells while enhancing immunoregulatory mechanisms. Because a severe cytokine release syndrome was observed during the Phase 1 study with the superagonist anti-CD28 TGN1412, development of other anti-CD28 antibodies requires careful preclinical evaluation to exclude any potential immunotoxicity side-effects. The failure to identify immunological toxicity of TGN1412 using macaques led us to investigate more relevant preclinical models. We report here that contrary to macaques, and like in man, all baboon CD4-positive T lymphocytes express CD28 in their effector memory cells compartment, a lymphocyte subtype that is the most prone to releasing cytokines after reactivation. Baboon lymphocytes are able to release pro-inflammatory cytokines in vitro in response to agonist or superagonist anti-CD28 antibodies. Furthermore, we compared the reactivity of human and baboon lymphocytes after transfer into non obese diabetic/severe combined immunodeficiency (NOD/SCID) interleukin-2rγ knockout mice and confirmed that both cell types could release inflammatory cytokines in situ after injection of agonistic anti-CD28 antibodies. In contrast, FR104, a monovalent antagonistic anti-CD28 antibody, did not elicit T cell activation in these assays, even in the presence of anti-drug antibodies. Infusion to baboons also resulted in an absence of cytokine release. In conclusion, the baboon represents a suitable species for preclinical immunotoxicity evaluation of anti-CD28 antibodies because their effector memory T cells do express CD28 and because cytokine release can be assessed in vitro and trans vivo. PMID:24598534

  3. The effect of ondansetron, a 5-HT3 receptor antagonist, in chronic fatigue syndrome: a randomized controlled trial.

    Science.gov (United States)

    The, Gerard K H; Bleijenberg, Gijs; Buitelaar, Jan K; van der Meer, Jos W M

    2010-05-01

    Accumulating data support the involvement of the serotonin (5-hydroxytryptamine [5-HT]) system in the pathophysiology of chronic fatigue syndrome. Neuropharmacologic studies point to a hyperactive 5-HT system, and open-label treatment studies with 5-HT(3) receptor antagonists have shown promising results. In this randomized controlled clinical trial, the effect of ondansetron, a 5-HT(3) receptor antagonist, was assessed on fatigue severity and functional impairment in adult patients with chronic fatigue syndrome. A randomized, placebo-controlled, double-blind clinical trial was conducted at Radboud University Nijmegen Medical Centre, The Netherlands. Sixty-seven adult patients who fulfilled the US Centers for Disease Control and Prevention (CDC) criteria for chronic fatigue syndrome and who were free from current psychiatric comorbidity participated in the clinical trial. Participants received either ondansetron 16 mg per day or placebo for 10 weeks. The primary outcome variables were fatigue severity (Checklist Individual Strength fatigue severity subscale [CIS-fatigue]) and functional impairment (Sickness Impact Profile-8 [SIP-8]). The effect of ondansetron was assessed by analysis of covariance. Data were analyzed on an intention-to-treat basis. All patients were recruited between June 2003 and March 2006. Thirty-three patients were allocated to the ondansetron condition, 34 to the placebo condition. The 2 groups were well matched in terms of age, sex, fatigue severity, functional impairment, and CDC symptoms. Analysis of covariance showed no significant differences between the ondansetron- and placebo-treated groups during the 10-week treatment period in fatigue severity and functional impairment. This clinical trial demonstrates no benefit of ondansetron compared to placebo in the treatment of chronic fatigue syndrome. www.trialregister.nl: ISRCTN02536681. ©Copyright 2010 Physicians Postgraduate Press, Inc.

  4. Polio and Prevention

    Science.gov (United States)

    ... Photo Collections Videos Polio Today → Polio + Prevention Polio + Prevention Polio and prevention Polio is a crippling and ... a child for life. Learn more about polio + prevention The Virus The Vaccines The Communities Related resources ...

  5. Diabetes Prevention Program (DPP)

    Science.gov (United States)

    ... Recruiting Patients & Families Consortia, Networks & Centers Reports & Planning Diabetes Prevention Program (DPP) The NIDDK-sponsored Diabetes Prevention ... Diabetes Prevention Program for those who are eligible. Diabetes Prevention Program (DPP) DPP Goal The DPP looked ...

  6. Pre-treatment with Toll-like receptor 4 antagonist inhibits lipopolysaccharide-induced preterm uterine contractility, cytokines, and prostaglandins in rhesus monkeys

    Science.gov (United States)

    Adams Waldorf, Kristina M.; Persing, David; Novy, Miles J.; Sadowsky, Drew W.; Gravett, Michael G.

    2009-01-01

    Intra-uterine infection, which occurs in the majority of early preterm births, triggers an immune response culminating in preterm labor. We hypothesized that blockade of lipopolysaccharide (LPS)-induced immune responses by a Toll-like receptor 4 antagonist (TLR4A) would prevent elevations in amniotic fluid (AF) cytokines, prostaglandins, and uterine contractility. Chronically catheterized rhesus monkeys at 128-147 days gestation received intra-amniotic infusions of either: 1) saline (n=6), 2) LPS (0.15-10μg; n=4), or 3) TLR4A pre-treatment with LPS (10 μg) one hour later (n=4). AF cytokines, prostaglandins, and uterine contractility were compared using oneway ANOVA with Bonferroni-adjusted pairwise comparisons. Compared to saline controls, LPS induced significant elevations in AF IL-8, TNF-α, PGE2, PGF2α, and uterine contractility (p<0.05). In contrast, TLR4A pre-treatment inhibited LPS-induced uterine activity and was associated with significantly lower AF IL-8, TNF-α, PGE2, and PGF2α versus LPS alone (p<0.05). Toll-like receptor antagonists, together with antibiotics, may delay or prevent infection-associated preterm birth. PMID:18187405

  7. Penicillium expansum versus antagonist yeasts and patulin degradation in vitro

    Directory of Open Access Journals (Sweden)

    Alexandre Rodrigo Coelho

    2007-07-01

    Full Text Available Taking into account the preliminary antagonistic/biodegradation property showed by Pichia membranifaciens and Sporobolomyces roseus, which decreased the initial patulin concentration of 588.4 to 290.0 µg/mL, ability of P. ohmeri 158 in biocontrol against Penicillium expansum and patulin decrease in vitro was performed. The culture supernatant of P. ohmeri 158 was effective against 66.17% micelial growth, indicating antibiosis related with the killer phenomenon. The initial patulin concentration of 223 µg in the presence of P. ohmeri 158 cells was decreased over 83% of the original concentration, when incubated at 25ºC/2 days and > 99% after 5 days incubation time, with undetectable patulin level after 15 days. The initial pH 4.0 decreased to pH 3.3 along 15 days experiment, suggesting that patulin decrease was an active process and a consequence of yeast metabolism. The results suggested that P. ohmeri 158 could be a promising alternative for the inhibition of P. expansum growth and patulin degradation.Considerando o antagonismo e degradação de patulina detectados em Pichia membranifaciens e Sporobolomyces roseus no estudo preliminar, este trabalho avaliou o efeito antagônico de Pichia ohmeri 158 no desenvolvimento de Penicillium expansum e a degradação de patulina "in vitro". O sobrenadante do cultivo de P. ohmeri 158 inibiu 66,17% do desenvolvimento micelial, indicando antibiose relacionada ao fator killer. A concentração inicial de patulina (223 µg na presença de células íntegras de P. ohmeri foi reduzida em mais de 83% após dois dias de incubação a 25ºC e superior a 99% após 5 dias, com níveis indetectáveis no 15º dia. O decréscimo do pH 4,0 inicial para pH 3,3 sugeriu que a eliminação de patulina é um processo ativo e uma conseqüência do metabolismo da levedura. Os resultados obtidos concluem que P. ohmeri 158 é uma alternativa promissora na inibição do desenvolvimento de P. expansum e na degradação de

  8. RU28318, an Aldosterone Antagonist, in Combination with an ACE Inhibitor and Angiotensin Receptor Blocker Attenuates Cardiac Dysfunction in Diabetes

    Directory of Open Access Journals (Sweden)

    Ibrahim F. Benter

    2013-01-01

    Full Text Available Aims. We evaluated the effects of RU28318 (RU, a selective mineralocorticoid receptor (MR antagonist, Captopril (Capt, an angiotensin converting enzyme inhibitor, and Losartan (Los, an angiotensin receptor blocker, alone or in combination with ischemia/reperfusion- (I/R- induced cardiac dysfunction in hearts obtained from normal and diabetic rats. Methods. Isolated hearts were perfused for 30 min and then subjected to 30 min of global ischemia (I followed by a period of 30 min of reperfusion (R. Drugs were administered for 30 min either before or after ischemia. Drug regimens tested were RU, Capt, Los, RU + Capt, RU + Los, Capt + Los, and RU + Capt + Los (Triple. Recovery of cardiac hemodynamics was evaluated. Results. Recovery of cardiac function was up to 5-fold worse in hearts obtained from diabetic animals compared to controls. Treatment with RU was generally better in preventing or reversing ischemia-induced cardiac dysfunction in normal hearts compared to treatment with Capt or Los alone. In diabetic hearts, RU was generally similarly effective as Capt or Los treatment. Conclusions. RU treatment locally might be considered as an effective therapy or preventative measure in cardiac I/R injury. Importantly, RU was the most effective at improving -dP/dt (a measure of diastolic function when administered to diabetic hearts after ischemia.

  9. Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.

    Directory of Open Access Journals (Sweden)

    Katsuya Morita

    Full Text Available Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2 protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

  10. Serum progranulin levels in Hispanic rheumatoid arthritis patients treated with TNF antagonists: a prospective, observational study.

    Science.gov (United States)

    Johnson, Jennifer; Yeter, Karen; Rajbhandary, Rosy; Neal, Rebekah; Tian, Qingyun; Jian, Jinlong; Fadle, Natalie; Thurner, Lorenz; Liu, Chuanju; Stohl, William

    2017-03-01

    Since progranulin (PGRN) is a natural ligand of TNF receptors, we assessed whether serum PGRN levels predict and/or reflect responsiveness of RA patients to TNF-antagonist therapy. TNF-antagonist-naïve RA patients (N = 35) were started on TNF-antagonist therapy. At baseline and at follow-up visits, DAS28-ESR, DAS28-CRP, and CDAI were calculated, and venous blood was collected for serum PGRN determination. Disease activity and clinical response were based on EULAR criteria. Baseline serum PGRN levels varied considerably and correlated with ESR and CRP. DAS28-ESR, DAS28-CRP, and CDAI were greater in "PGRN-high" than in "PGRN-low". Baseline serum PGRN levels did not predict clinical responsiveness to TNF-antagonist therapy. Nevertheless, changes in serum PGRN levels at 274+ days following initiation of TNF-antagonist therapy correlated with changes in ESR, CRP, DAS28-ESR, DAS28-CRP, and CDAI. At this time, DAS28-ESR, DAS28-CRP, and CDAI in PGRN-high and PGRN-low equalized, but serum PGRN levels remained greater in PGRN-high than in PGRN-low. To our knowledge, the present report is the first prospective study to longitudinally assess changes in serum PGRN levels following initiation of TNF-antagonist therapy. Although pre-treatment serum PGRN levels may not predict clinical responsiveness to TNF-antagonist therapy, changes in serum PGRN levels correlate with changes in disease metrics over time. By inference, administration of PGRN may represent an effective therapeutic option for development in RA patients.

  11. Enhanced adenylate cyclase activity of turkey erythrocytes following treatment with beta-adrenergic receptor antagonists.

    Science.gov (United States)

    Peters, J R; Nambi, P; Sibley, D R; Lefkowitz, R J

    1984-12-15

    The turkey erythrocyte contains a beta 1-adrenergic receptor-linked adenylate cyclase system. We have examined the effects of pretreatment with receptor antagonists on adenylate cyclase activity and the individual components in the pathway of enzyme activation in this system. Isoproterenol-stimulated adenylate cyclase activity is increased by 30% (P less than 0.01) over control in membranes derived from cells preincubated with the antagonist propranolol. The effect is stereospecific and dose-related with a EC50 of 100 nM for the (-) isomer. The time course of effect is rapid being complete by 90 min. Non-receptor mediated stimulation of adenylate cyclase activity by manganese ion, forskolin and NaF is similarly enhanced following propranolol pretreatment. Sensitization of adenylate cyclase activity also occurs following pretreatment with a number of antagonists but is not seen after preincubation with pindolol or practolol. Quantitation of beta-adrenergic receptor (R) density using [125I]cyanopindolol indicates no difference between membranes derived from control and antagonist pretreated cells. Coupling of R with the guanine nucleotide regulatory protein (N) as assessed by high affinity agonist binding is unchanged following pretreatment. The efficacy of 5'-guanylylimidodiphosphate Gpp(NH)p in producing a shift of agonist binding curves associated with destabilization of high affinity H-R-N complexes, is also the same (EC50 = 0.2 microM) in membranes from control and antagonist treated cells. The isoproterenol stimulated rate of release of [3H]GDP from membranes preloaded with [3H]GTP as an index of formation of an active form of the N protein is similarly unaffected by antagonist preincubation. We conclude that the mechanism of the observed sensitization of turkey erythrocyte adenylate cyclase by beta-adrenergic antagonists is receptor mediated and likely involves facilitation of N interaction with the catalytic subunit of the enzyme.

  12. Is it time to repair a Fairly Fast SAAB Convertible? Testing an evidence-based mnemonic for the secondary prevention of cardiovascular disease.

    Science.gov (United States)

    Chin, Jialiang; Fulcher, Jordan; Jenkins, Alicia; Keech, Anthony

    2015-05-01

    Optimising secondary prevention of cardiovascular disease has the greatest potential to reduce recurrent events, yet despite major guidelines there are ongoing treatment gaps. FFSAABC (Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers and Clopidogrel) is one mnemonic previously adopted to assist clinicians in remembering medications for use in secondary prevention. The aim of this narrative review is to examine the current evidence base for medications recommended for patients with established cardiovascular disease and the current applicability of this, or a revised mnemonic for their use. Randomised controlled trials and systematic reviews were sought examining Fish oils, Fibrates, Statins, Aspirin, Angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, Beta blockers or Clopidogrel vs placebo in secondary prevention. The emerging evidence base for other contemporary therapies including the P2Y12 inhibitors (ticagrelor and prasugrel) and aldosterone antagonists was also reviewed. Definitive evidence supports the use of statins, aspirin, angiotensin converting enzyme inhibitors or angiotensin 2 receptor antagonists, and P2Y12 antagonists (clopidogrel, ticagrelor or prasugrel) for the secondary prevention of cardiovascular disease. Aldosterone antagonists have strong evidence in the presence of systolic heart failure. There is a weaker evidence base for the routine use of omega-3 fatty acid supplementation although this therapy carries minimal harms. Fenofibrate reduces cardiovascular events in dyslipidaemic patients, with additional benefits in patients with diabetes. Mnemonic upgrading from a Fairly Fast SAAB Convertible to a Fairly Fast SA(2)A(2)B (Fish oils, Fibrate, Statin, Antiplatelets (Aspirin+Other), ACE/ARB, Aldosterone Antagonist, Beta-blocker) may help to ensure patients receive best practice evidence-based pharmacotherapies for the secondary

  13. Prevention of postoperative ileus

    DEFF Research Database (Denmark)

    Holte, Kathrine; Kehlet, H

    2002-01-01

    generally been disappointing with the exception of cisapride and the introduction of the new selective peripherally acting m-opioid antagonists. Presently, introduction of a multi-modal rehabilitation programme (including continuous epidural analgesia with local anesthetics, early oral feeding and enforced...

  14. The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

    OpenAIRE

    Sirohi, Sunil; Dighe, Shveta V.; Madia, Priyanka A.; Yoburn, Byron C.

    2009-01-01

    Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was exa...

  15. CXCR4 Antagonists: A Screening Strategy for Identification of Functionally Selective Ligands.

    Science.gov (United States)

    Castaldo, C; Benicchi, T; Otrocka, M; Mori, E; Pilli, E; Ferruzzi, P; Valensin, S; Diamanti, D; Fecke, W; Varrone, M; Porcari, V

    2014-07-01

    The CXC chemokine receptor 4 (CXCR4) is a widely expressed G protein-coupled receptor implicated in several diseases. In cancer, an increased number of surface CXCR4 receptors, in parallel with aberrant signaling, have been reported to influence several aspects of malignancy progression. CXCR4 activation by the specific ligand C-X-C motif chemokine 12 (CXCL12) induces several intracellular signaling pathways that have been selectively related to malignancy depending on the tissue or cell type. We developed a panel of CXCR4 screening assays investigating Gα(i)-mediated cyclic adenosine monophosphate modulation, β-arrestin recruitment, and receptor internalization. All of the assays were set up in recombinant cells and were used to test four reported CXCR4 antagonists. Consequently, a set of hit compounds, deriving from a screening campaign of a 30,000-small-molecule internal library, was profiled with the different assays. We identified several compounds showing a pathway-selective activity: antagonists on a Gα(i)-dependent pathway; antagonists on both the β-arrestin and Gα(i)-dependent pathways, some of which induce receptor internalization; and compounds with an antagonist behavior in all of the readouts. The identified biased antagonists induce different functional states on CXCR4 and preferentially affect specific downstream responses from the activated receptor, thus providing an improved therapeutic profile for correction of CXCR4 abnormal signaling. © 2014 Society for Laboratory Automation and Screening.

  16. Wear Behavior of Ceramic CAD/CAM Crowns and Natural Antagonists

    Directory of Open Access Journals (Sweden)

    Ella A. Naumova

    2017-02-01

    Full Text Available Objective: Evaluation of wear behavior of computer-aided design/computer-aided manufacturing (CAD/CAM crowns from various restorative materials and natural antagonists. Method: Full CAD/CAM crowns fabricated with nanoceramic resin (Lava Ultimate (LU, a glass ceramic in a resin interpenetrating matrix (Vita Enamic (VE and a lithium silicate reinforced ceramic enriched with zirconia (Vita Suprinity (VS were cemented on human molars. The crown and antagonists were subjected to simulated chewing. 3D data sets, before and after the chewing simulation, were generated and matched. Occlusal surface roughness, vertical and volume loss of the crowns and antagonists were analyzed. Results: Crown roughness was significantly different between the LU and VE groups after chewing simulation. Crown vertical loss differed in all groups. The highest crown volume loss was found in the LU group, and the lowest in the VE group. Comparisons between the LU and VE groups and the LU and VS groups were significantly different. The highest antagonist volume loss was reached in the VE group, the lowest was in the LU group. Conclusion: Roughness increased after chewing simulation. LU crowns are the most natural antagonist-friendly; these were the most susceptible to vertical and volume loss. Of the tested materials, the VE crowns are the most stable regarding occlusion.

  17. Evaluation of the protagonist-antagonist dichotomy in Spanish television content targeting children

    Directory of Open Access Journals (Sweden)

    José A. García-Castillo, Ph.D.

    2010-01-01

    Full Text Available The goal of this study is to analyse the profile of the protagonist-antagonist dichotomy in all children’s television content, of all genres, offered by Spanish television channels. The analysis of protagonist and antagonist characters focuses on variables such as: type and number, age, gender, nationality, skills, relationship between the characters, characterisation, means used to achieve goals, consequences of the action of the antagonist over the antagonist and vice versa. The sample consists of 168 series that were analysed using descriptive content analysis and multivariate analysis. The results showed that over 50% of the series do not have an antagonist and that when there is one the most common type is a single human, which appears in more than 15% of the analysed series, followed by the fantastic creature type, which is present in just 10%. In 80% of the series the skills of the protagonists are social and human, and in 45.24% the exhibited skill is intelligence.

  18. Orexin 1 receptor antagonists in compulsive behavior and anxiety: possible therapeutic use.

    Science.gov (United States)

    Merlo Pich, Emilio; Melotto, Sergio

    2014-01-01

    Fifteen years after the discovery of hypocretin/orexin a large body of evidence has been collected supporting its critical role in the modulation of several regulatory physiological functions. While reduced levels of hypocretin/orexin were initially associated with narcolepsy, increased levels have been linked in recent years to pathological states of hypervigilance and, in particular, to insomnia. The filing to FDA of the dual-activity orexin receptor antagonist (DORA) suvorexant for the indication of insomnia further corroborates the robustness of such evidences. However, as excessive vigilance is also typical of anxiety and panic episodes, as well as of abstinence and craving in substance misuse disorders. In this review we briefly discuss the evidence supporting the development of hypocretin/orexin receptor 1 (OX1) antagonists for these indications. Experiments using the OX1 antagonist SB-334867 and mutant mice have involved the OX1 receptor in mediating the compulsive reinstatement of drug seeking for ethanol, nicotine, cocaine, cannabinoids and morphine. More recently, data have been generated with the novel selective OX1 antagonists GSK1059865 and ACT-335827 on behavioral and cardiovascular response to stressors and panic-inducing agents in animals. Concluding, while waiting for pharmacologic data to become available in humans, risks and benefits for the development of an OX1 receptor antagonist for Binge Eating and Anxiety Disorders are discussed.

  19. Human muscle spindle sensitivity reflects the balance of activity between antagonistic muscles.

    Science.gov (United States)

    Dimitriou, Michael

    2014-10-08

    Muscle spindles are commonly considered as stretch receptors encoding movement, but the functional consequence of their efferent control has remained unclear. The "α-γ coactivation" hypothesis states that activity in a muscle is positively related to the output of its spindle afferents. However, in addition to the above, possible reciprocal inhibition of spindle controllers entails a negative relationship between contractile activity in one muscle and spindle afferent output from its antagonist. By recording spindle afferent responses from alert humans using microneurography, I show that spindle output does reflect antagonistic muscle balance. Specifically, regardless of identical kinematic profiles across active finger movements, stretch of the loaded antagonist muscle (i.e., extensor) was accompanied by increased afferent firing rates from this muscle compared with the baseline case of no constant external load. In contrast, spindle firing rates from the stretching antagonist were lowest when the agonist muscle powering movement (i.e., flexor) acted against an additional resistive load. Stepwise regressions confirmed that instantaneous velocity, extensor, and flexor muscle activity had a significant effect on spindle afferent responses, with flexor activity having a negative effect. Therefore, the results indicate that, as consequence of their efferent control, spindle sensitivity (gain) to muscle stretch reflects the balance of activity between antagonistic muscles rather than only the activity of the spindle-bearing muscle. Copyright © 2014 the authors 0270-6474/14/3413644-12$15.00/0.

  20. Effects of sigma(1) receptor ligand MS-377 on D(2) antagonists-induced behaviors.

    Science.gov (United States)

    Karasawa, Jun-ichi; Takahashi, Shinji; Takagi, Kaori; Horikomi, Kazutoshi

    2002-10-01

    (R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.