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Sample records for antagonist drugs eptifibatide

  1. The GPIIb/IIIa antagonist eptifibatide markedly potentiates platelet-leukocyte interaction and tissue factor expression following platelet activation in whole blood in vitro.

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    Scholz, Thomas; Zhao, Lian; Temmler, Uta; Bath, Philip; Heptinstall, Stan; Lösche, Wolfgang

    2002-11-01

    Tissue factor (TF) is the most important initiator of intravascular coagulation. Activated platelets are able to adhere to leukocytes and this heterotypic cell-cell interaction results in a CD62P-dependent TF expression on monocytes. GPIIb/IIIa antagonists are inhibitors of the common pathway of platelet aggregation and they are widely used in patients with acute coronary syndromes undergoing coronary interventions. As GPIIb/IIIa antagonists do not prevent platelet activation we investigated the effect a GPIIb/IIIa antagonist, eptifibatide, on the formation of platelet-leukocyte conjugates and leukocyte TF expression. Flow cytometry was used to detect conjugates and TF. When platelets in citrated human blood were stimulated for 30 min with collagen there was a increase in the number of both neutrophils and monocytes with the platelet-specific antigen CD42a, indicating the formation of platelet-neutrophil (P/N) and platelet-monocyte (P/M) conjugates. P/M formation was associated with about a 2.5-fold increase in TF expression on monocytes, whereas P/N formation changed TF expression neutrophils only by about 10%. Eptifibatide enhanced dose-dependently (0.0625-1.5 microg/ml) both collagen-induced P/M formation and monocyte TF expression. Maximum enhancement by about 60 and 120%, respectively, was observed at 0.5 microg/ml eptifibatide. In contrast, eptifibatide had only a minor effect on P/N formation and no effect on neutrophil TF expression. The augmented P/M formation and monocyte TF expression in the presence of a GPIIb/IIIa antagonist may be relevant to the poor antithrombotic efficiency of oral GPIIb/IIIa antagonists as shown in recent large clinical trials.

  2. Investigation of interaction of human platelet membrane components with anticoagulant drugs Abciximab and Eptifibatide

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    Ewa Gorodkiewicz

    2010-04-01

    Full Text Available Abciximab (Abci and eptifibatide (Epti are antiaggregate drugs which may reduce thrombotic complications inacute coronary syndromes. The aim of this work was the investigation of the interaction between the phospholipid-GPIIb/IIIa glycoprotein complex and Abci or Epti, and the influence of these drugs on the phospholipid ratio in the plateletmembrane. The interaction between the phospholipid-GPIIb/IIIa glycoprotein complex and antiaggregate drugs were investigatedusing the Surface Plasmon Resonance Imaging technique (SPRI. Phospholipids phosphatidylinositol (PI, phosphatidylserine(PS, phosphatidylethanolamine (PE, phosphatidylcholine (PC and sphingomyelin (SM were first immobilizedonto the gold chip surface. The phospholipid ratio in the platelet membrane was determined by the HPLC. Only PI,PS, PE and PC were determined. Human platelets treated 'in vitro' with Abci or Epti exhibit changes in the phospholipidratio in the platelet membrane. The ratio of PS decreases and PC rises. The SPRI distinctly shows interactions between phospholipidsand glycoprotein GPIIb/IIIa, and between the phospholipid-glycoprotein GPIIb/IIIa complex and Abci or Epti.The interaction between phospholipids and glycoprotein GPIIb/IIIa is growing in the sequence: PI<

  3. Investigation of interaction of human platelet membrane components with anticoagulant drugs Abciximab and Eptifibatide.

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    Anna Sankiewicz

    2011-04-01

    Full Text Available Abciximab (Abci and eptifibatide (Epti are antiaggregate drugs which may reduce thrombotic complications in acute coronary syndromes. The aim of this work was the investigation of the interaction between the phospholipid-GPIIb/IIIa glycoprotein complex and Abci or Epti, and the influence of these drugs on the phospholipid ratio in the platelet membrane. The interaction between the phospholipid-GPIIb/IIIa glycoprotein complex and antiaggregate drugs were investigated using the Surface Plasmon Resonance Imaging technique (SPRI. Phospholipids phosphatidylinositol (PI, phosphatidylserine (PS, phosphatidylethanolamine (PE, phosphatidylcholine (PC and sphingomyelin (SM were first immobilized onto the gold chip surface. The phospholipid ratio in the platelet membrane was determined by the HPLC. Only PI, PS, PE and PC were determined. Human platelets treated 'in vitro' with Abci or Epti exhibit changes in the phospholipid ratio in the platelet membrane. The ratio of PS decreases and PC rises. The SPRI distinctly shows interactions between phospholipids and glycoprotein GPIIb/IIIa, and between the phospholipid-glycoprotein GPIIb/IIIa complex and Abci or Epti. The interaction between phospholipids and glycoprotein GPIIb/IIIa is growing in the sequence: PI

  4. Local Intracoronary Eptifibatide versus Mechanical Aspiration in Patients with Acute ST-Elevation Myocardial Infarction

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    Mohamed A. Hamza

    2014-01-01

    Full Text Available Objectives. We compared local delivery of intracoronary eptifibatide via perfusion catheter to thrombus aspiration in primary PCI. Background. Perfusion catheter increases local concentration of the drugs at the culprit site and prolongs their residency time. Methods. 75 patients with acute STEMI were randomized to three groups: 25 received local intracoronary eptifibatide and verapamil via perfusion catheter; 25 patients were managed by Diver CE thrombectomy device and 25 patients by primary PCI without thrombus aspiration. Primary end point was assessment of postprocedural TIMI flow, MPG, and corrected TIMI frame count (cTFC in the culprit vessel. Results. Perfusion catheter was superior to thrombus aspiration and conventional PCI as regards MBG (68% versus 36% in Diver CE and 20% in the control arm; P value = 0.002, with shorter cTFC rates than thrombectomy and control groups (20.76±4.44 versus 26.68±8.40 and 28.16±5.96, resp.; P=0.001. TIMI flow was not different between the 3 groups. Eptifibatide led to less time to peak CK (13.12 hours versus 16.5 and 19.5 hours, respectively, P value = 0.001. Conclusion. Local intracoronary eptifibatide by perfusion catheter reduces thrombus burden with better results in microvascular perfusion assessed by cTFC and MBG compared to aspiration device or conventional PCI.

  5. Early recovery of microvascular perfusion induced by t-PA in combination with abciximab or eptifibatide during postischemic reperfusion

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    Giusti Andrea

    2002-06-01

    Full Text Available Abstract Background GPIIb/IIIa inhibitors abciximab and eptifibatide have been shown to inhibit platelet aggregation in ischemic heart disease. Our aim was to test the efficacy of abiciximab (Reo Pro or eptifibatide (Integrilin alone or in combination with plasminogen activator (t-PA in an experimental model of ischemia reperfusion (I/R in hamster cheek pouch microcirculation visualized by fluorescence microscopy. Hamsters were treated with saline, or abiciximab or eptifibatide or these drugs combined with t-PA infused intravenously 10 minutes before ischemia and through reperfusion. We measured the microvessel diameter changes, the arteriolar red blood cell (RBC velocity, the increase in permeability, the perfused capillary length (PCL, and the platelet and leukocyte adhesion on microvessels. Results I/R elicited large increases in the platelet and leukocyte adhesion and a decrease in microvascular perfusion. These responses were significantly attenuated by abiciximab or eptifibatide (PCL:70 and 65% at 5–10 mins of reperfusion and 85 and 87% at 30 mins of reperfusion, respectively, p Conclusions Platelets are crucial in I/R injury, as shown by the treatment with abicixmab or eptifibatide, which decreased platelet aggregation in microvessels, and also decreased leukocyte adhesion in venules. Arterial vasoconstriction, decreased arterial RBC velocity and alterations in the endothelial barrier with increased permeability delayed the complete restoration of blood flow, while t-PA combined with inhibition of platelet aggregation speeded up the capillary perfusion after reperfusion.

  6. Pharmacoepidemiological assessment of drug interactions with vitamin K antagonists

    DEFF Research Database (Denmark)

    Pottegård, Anton; Christensen, Rene dePont; Wang, Shirley 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...

  7. Synergistic and antagonistic drug combinations depend on network topology.

    Science.gov (United States)

    Yin, Ning; Ma, Wenzhe; Pei, Jianfeng; Ouyang, Qi; Tang, Chao; Lai, Luhua

    2014-01-01

    Drug combinations may exhibit synergistic or antagonistic effects. Rational design of synergistic drug combinations remains a challenge despite active experimental and computational efforts. Because drugs manifest their action via their targets, the effects of drug combinations should depend on the interaction of their targets in a network manner. We therefore modeled the effects of drug combinations along with their targets interacting in a network, trying to elucidate the relationships between the network topology involving drug targets and drug combination effects. We used three-node enzymatic networks with various topologies and parameters to study two-drug combinations. These networks can be simplifications of more complex networks involving drug targets, or closely connected target networks themselves. We found that the effects of most of the combinations were not sensitive to parameter variation, indicating that drug combinational effects largely depend on network topology. We then identified and analyzed consistent synergistic or antagonistic drug combination motifs. Synergistic motifs encompass a diverse range of patterns, including both serial and parallel combinations, while antagonistic combinations are relatively less common and homogenous, mostly composed of a positive feedback loop and a downstream link. Overall our study indicated that designing novel synergistic drug combinations based on network topology could be promising, and the motifs we identified could be a useful catalog for rational drug combination design in enzymatic systems.

  8. Clinical and economic studies of eptifibatide in coronary stenting

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    Pasala T

    2014-08-01

    Full Text Available Tilak Pasala, Prasongchai Sattayaprasert, Pradeep K Bhat, Ganesh Athappan, Sanjay Gandhi The Heart and Vascular Center, Case Western Reserve University/MetroHealth, Cleveland, OH, USA Abstract: Platelet adhesion and aggregation at the site of coronary stenting can have catastrophic clinical and economic consequences. Therefore, effective platelet inhibition is vital during and after percutaneous coronary intervention. Eptifibatide is an intravenous antiplatelet agent that blocks the final common pathway of platelet aggregation and thrombus formation by binding to glycoprotein IIb/IIIa receptors on the surface of platelets. In clinical studies, eptifibatide was associated with a significant reduction of mortality, myocardial infarction, or target vessel revascularization in patients with acute coronary syndrome undergoing percutaneous coronary intervention. However, recent trials conducted in the era of dual antiplatelet therapy and newer anticoagulants failed to demonstrate similar results. The previously seen favorable benefit of eptifibatide was mainly offset by the increased risk of bleeding. Current American College of Cardiology/American Heart Association guidelines recommend its use as an adjunct in high-risk patients who are undergoing percutaneous coronary intervention with traditional anticoagulants (heparin or enoxaparin, who are not otherwise at high risk of bleeding. In patients receiving bivalirudin (a newer safer anticoagulant, routine use of eptifibatide is discouraged except in select situations (eg, angiographic complications. Although older pharmacoeconomic studies favor eptifibatide, in the current era of P2Y12 inhibitors and newer safer anticoagulants, the increased costs associated with bleeding make the routine use of eptifibatide an economically nonviable option. The cost-effectiveness of eptifibatide with the use of strategies that decrease the bleeding risk (eg, transradial access is unknown. This review provides an

  9. Structure-based drug design identifies novel LPA3 antagonists.

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    Fells, James I; Tsukahara, Ryoko; Liu, Jianxiong; Tigyi, Gabor; Parrill, Abby L

    2009-11-01

    Compound 5 ([5-(3-nitrophenoxy)-1,3-dioxo-1,3-dihydro-2-isoindol-2-yl]acetic acid) was identified as a weak selective LPA(3) antagonist (IC(50)=4504 nM) in a virtual screening effort to optimize a dual LPA(2 and 3) antagonist. Structure-based drug design techniques were used to prioritize similarity search matches of compound 5. This strategy rapidly identified 10 novel antagonists. The two most efficacious compounds identified inhibit activation of the LPA(3) receptor by 200 nM LPA with IC(50) values of 752 nM and 2992 nM. These compounds additionally define changes to our previously reported pharmacophore that will improve its ability to identify more potent and selective LPA(3) receptor antagonists. The results of the combined computational and experimental screening are reported.

  10. 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...... a self-controlled case series to estimate the incidence rate ratio (IRR) comparing the rate of INR measurements of 4.0 in concomitant tramadol and VKA-exposed periods to VKA-only-exposed periods. Secondary analyses considered specific subgroups, alternative exposure criteria, alternative outcome...... 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...

  11. Drug discovery and chemokine receptor antagonists: eppur si muove!

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    Terricabras, Emma; Benjamim, Claudia; Godessart, Nuria

    2004-11-01

    The blockade of leukocyte migration has been demonstrated to be a valid option for the treatment of several autoimmune diseases. Chemokines play an active role in regulating cell infiltration into inflammatory sites and disrupting chemokine-receptor interactions has emerged as an alternative therapeutic approach. Pharmaceutical companies have developed an intense activity in the drug discovery of chemokine receptor antagonists in the last 10 years. Potent and selective compounds have been obtained and some of them are currently being evaluated in the clinic. The success of these trials will demonstrate whether the blockade of a single receptor is of therapeutic benefit. Alternative approaches, such as pan-receptor antagonists or inhibitors of the signalling pathways evoked by chemokines, are also being explored. In the meantime, new relationships between chemokines and receptors will be revealed, increasing our knowledge of such a fascinating field.

  12. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview

    OpenAIRE

    Soltani, Hoda; Pardakhty, Abbas

    2016-01-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of “new drug delivery systems” is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  13. Marketed New Drug Delivery Systems for Opioid Agonists/Antagonists Administration: A Rapid Overview.

    Science.gov (United States)

    Soltani, Hoda; Pardakhty, Abbas

    2016-04-01

    Novel drug delivery systems for controlled-release of opioid agonists as a long time painkillers or opioid antagonists for opium, heroin, and alcohol addiction are under development or in clinical use today. In this article, the field of "new drug delivery systems" is momentarily reviewed from the viewpoint of the marketed opioid agonists/antagonists dosage forms today.

  14. Bleeding risk associated with eptifibatide (Integrilin) bridging in thoracic surgery patients.

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    Waldron, Nathan H; Dallas, Torijaun; Erhunmwunsee, Loretta; Wang, Tracy Y; Berry, Mark F; Welsby, Ian J

    2017-02-01

    Antiplatelet use for treatment of coronary artery disease (CAD) is common amongst thoracic surgery patients. Perioperative management of antiplatelet agents requires balancing the opposing risks of myocardial ischemia and excessive bleeding. Perioperative bridging with short-acting intravenous antiplatelet agents has shown promise in preventing myocardial ischemia, but may increase bleeding. We sought to determine whether perioperative bridging with eptifibatide increased bleeding associated with thoracic surgery. After Institutional Review Board approval, we identified thoracic surgery patients receiving eptifibatide at our institution (n = 30). These patients were matched 1:2 with control patients with CAD who did not receive eptifibatide from an institutional database of general thoracic surgery patients. The primary endpoint for our study was the number of units of blood transfused perioperatively. There were no differences in our primary endpoint, number of units of blood products transfused. There were also no differences noted between groups in intraoperative blood loss, chest tube duration, or postoperative length of stay (LOS). While there were no difference noted in overall complications, including our outcome of perioperative MI or death, composite cardiovascular events were more common in the eptifibatide group. In our retrospective exploratory analysis, eptifibatide bridging in patients with high-risk or recent PCI was not associated with an increased need for perioperative transfusion, bleeding, or increased LOS. In addition, we found a similar rate of perioperative mortality or myocardial infarction in both groups, though the ability of eptifibatide to protect against perioperative myocardial ischemia is unclear given different baseline CAD characteristics.

  15. Study of the n-methyl-d-aspartate antagonistic properties of anticholinergic drugs

    Energy Technology Data Exchange (ETDEWEB)

    McDonough, J.H.; Shih, T.M.

    1995-12-31

    A study of the N-methyl-D-aspartate antagonistic properties of anticholinergic drugs. PHARMACOL BIOCHEM BEHAV. 51(2/3) 249-253, 1995. Drugs that act at the N-methyl-D-aspartate (NMDA) receptor complex have the ability to terminate nerve agent-induced seizures and modulate the neuropathologic consequences of agent exposure. Drugs with mixed anticholinergic and anti-NMDA properties potentially provide an ideal class of compounds for development as anticonvulsant treatments for nerve agent casualties. The present experiment evaluated the potential NMDA antagonist activity of 11 anticholinergic drugs by determining whether pretreatment with the compound was capable of protecting mice from the lethal effects of NMDA. The following anticholinergic drugs antagonized NMDA lethality and are ranked according to their potency: mecamylamine > procyclidine = benactyzine > biperiden > tribexyphenidyl. The anticholinergics atropine, aprophen, azaprophen, benztropine, 3-quinudidinyl benzilate (QNB), and scopolamine failed to show NMDA antagonist properties. In addition, and unexpectedly, diazepam, ethanol, and pentobarbital were also shown to be capable of antagonizing NMDA lethality over a certain range of doses. The advantages and limitations of using antagonism of NMDA lethality in mice as a bioassay for determining the NMDA antagonist properties of drugs are also discussed.

  16. Eptifibatide-induced thrombocytopenia: with thrombosis and disseminated intravascular coagulation immediately after left main coronary artery percutaneous coronary angioplasty.

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    Tempelhof, Michael W; Benzuly, Keith H; Fintel, Dan; Krichavsky, Marc Z

    2012-01-01

    Early clinical trials of eptifibatide did not show a significant association between eptifibatide and the development of thrombocytopenia, thrombosis, or disseminated intravascular coagulation. However, more recent literature has suggested a significant association between eptifibatide and the development of thrombocytopenia and thrombosis. Although the true incidence and the pathophysiology of these associations are unknown, the development of these events can be life-threatening. Herein, we describe the case of a patient who experienced acute onset of profound thrombocytopenia, developing thrombosis, pulmonary emboli, and disseminated intravascular coagulation. This paper adds to the few previous reports of cases that suggested an association between thrombocytopenia, thrombosis, and the administration of eptifibatide. To the best of our knowledge, this is the first case report in the medical literature that associates the new onset of thrombocytopenia, thrombosis, and disseminated intravascular coagulation with the administration of eptifibatide. We also provide a subject review.

  17. Muscarinic receptor antagonists, from folklore to pharmacology; finding drugs that actually work in asthma and COPD.

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    Moulton, Bart C; Fryer, Allison D

    2011-05-01

    In the lungs, parasympathetic nerves provide the dominant control of airway smooth muscle with release of acetylcholine onto M3 muscarinic receptors. Treatment of airway disease with anticholinergic drugs that block muscarinic receptors began over 2000 years ago. Pharmacologic data all indicated that antimuscarinic drugs should be highly effective in asthma but clinical results were mixed. Thus, with the discovery of effective β-adrenergic receptor agonists the use of muscarinic antagonists declined. Lack of effectiveness of muscarinic antagonists is due to a variety of factors including unwanted side effects (ranging from dry mouth to coma) and the discovery of additional muscarinic receptor subtypes in the lungs with sometimes competing effects. Perhaps the most important problem is ineffective dosing due to poorly understood differences between routes of administration and no effective way of testing whether antagonists block receptors stimulated physiologically by acetylcholine. Newer muscarinic receptor antagonists are being developed that address the problems of side effects and receptor selectivity that appear to be quite promising in the treatment of asthma and chronic obstructive pulmonary disease.

  18. Drug therapy of apparent treatment-resistant hypertension: focus on mineralocorticoid receptor antagonists.

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    Glicklich, Daniel; Frishman, William H

    2015-04-01

    Apparent treatment-resistant hypertension (aTRH) is defined as blood pressure (BP) >140/90 mmHg despite three different antihypertensive drugs including a diuretic. aTRH is associated with an increased risk of cardiovascular events, including stroke, chronic renal failure, myocardial infarction, congestive heart failure, aortic aneurysm, atrial fibrillation, and sudden death. Preliminary studies of renal nerve ablation as a therapy to control aTRH were encouraging. However, these results were not confirmed by the Symplicity 3 trial. Therefore, attention has refocused on drug therapy. Secondary forms of hypertension and associated conditions such as obesity, sleep apnea, and primary aldosteronism are common in patients with aTRH. The pivotal role of aldosterone in the pathogenesis of aTRH in many cases is well recognized. For patients with aTRH, the Joint National Committee-8, the European Society of Hypertension, and a recent consensus conference recommend that a diuretic, ACE inhibitor, or angiotensin receptor blocker and calcium channel blocker combination be used to maximally tolerated doses before starting a 'fourth-line' drug such as a mineralocorticoid receptor (MR) antagonist. Although the best fourth-line drug for aTRH has not been extensively investigated, a number of studies summarized here show that an MR antagonist is effective in reducing BP when added to the standard multi-drug regimen.

  19. EO-199, a specific antagonist of antiarrhythmic drugs: Assessment by binding experiments and in vivo studies

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    Oppenheimer, E.; Harel, G.; Lipinsky, D.; Sarne, Y. (Tel-Aviv Univ. (Israel))

    1991-01-01

    EO-199, a demethylated analog of the novel class I antiarrhythmic drug EO-122 was found to antagonize the antiarrhythmic activity of EO-122 and that of procainamide (Class I{sub A}). EO-199 did not block significantly the activity of a class I{sub B} antiarrhythmic agent, lidocaine. EO-199 also displaced the specific binding of ({sup 3}H)EO-122 to rate heart membranes similarly to procainamide whereas lidocaine did not. The correlation between binding experiments and pharmacological effects points to a possible subclassification of these drugs; the two chemical analogs EO-199 and EO-122, as well as procainamide (I{sub A}) but not lidocaine (I{sub B}), compete at the same site or the same state of the sodium channel. The availability of a specific antagonist might be useful for studying the mechanism of action of antiarrhythmic drugs as well as an antidote in cases of antiarrhythmics overdose intoxication.

  20. Procognitive properties of drugs with single and multitargeting H3 receptor antagonist activities.

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    Nikolic, Katarina; Filipic, Slavica; Agbaba, Danica; Stark, Holger

    2014-07-01

    The histamine H3 receptor (H3 R) is an important modulator of numerous central control mechanisms. Novel lead optimizations for H3 R antagonists/inverse agonists involved studies of structure-activity relationships, cross-affinities, and pharmacokinetic properties of promising ligands. Blockade of inhibitory histamine H3 autoreceptors reinforces histaminergic transmission, while antagonism of H3 heteroreceptors accelerates the corticolimbic liberation of acetylcholine, norepinephrine, glutamate, dopamine, serotonin and gamma-aminobutyric acid (GABA). The H3 R positioned at numerous neurotransmission crossroads indicates therapeutic applications of small-molecule H3 R modulators in a number of psychiatric and neurodegenerative diseases with various clinical candidates available. Dual target drugs displaying H3 R antagonism/inverse agonism with inhibition of acetylcholine esterase (AChE), histamine N-methyltransferase (HMT), or serotonin transporter (SERT) are novel class of procognitive agents. Main chemical diversities, pharmacophores, and pharmacological profiles of procognitive agents acting as H3 R antagonists/inverse agonists and dual H3 R antagonists/inverse agonists with inhibiting activity on AChE, HMT, or SERT are highlighted here.

  1. MDM2 antagonist Nutlin-3a potentiates antitumour activity of cytotoxic drugs in sarcoma cell lines

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    Lothe Ragnhild A

    2011-05-01

    Full Text Available Abstract Background Frequent failure and severe side effects of current sarcoma therapy warrants new therapeutic approaches. The small-molecule MDM2 antagonist Nutlin-3a activates the p53 pathway and efficiently induces apoptosis in tumours with amplified MDM2 gene and overexpression of MDM2 protein. However, the majority of human sarcomas have normal level of MDM2 and the therapeutic potential of MDM2 antagonists in this group is still unclear. We have investigated if Nutlin-3a could be employed to augment the response to traditional therapy and/or reduce the genotoxic burden of chemotherapy. Methods A panel of sarcoma cell lines with different TP53 and MDM2 status were treated with Nutlin-3a combined with Doxorubicin, Methotrexate or Cisplatin, and their combination index determined. Results Clear synergism was observed when Doxorubicin and Nutlin-3a were combined in cell lines with wild-type TP53 and amplified MDM2, or with Methotrexate in both MDM2 normal and amplified sarcoma cell lines, allowing for up to tenfold reduction of cytotoxic drug dose. Interestingly, Nutlin-3a seemed to potentiate the effect of classical drugs as Doxorubicin and Cisplatin in cell lines with mutated TP53, but inhibited the effect of Methotrexate. Conclusion The use of Nutlin in combination with classical sarcoma chemotherapy shows promising preclinical potential, but since clear biomarkers are still lacking, clinical trials should be followed up with detailed tumour profiling.

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

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    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.

  3. Safety of eptifibatide when added to bivalirudin during ST-segment elevation myocardial infarction

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    Baker, Nevin C.; Escarcega, Ricardo O.; Magalhaes, Marco A.; Lipinski, Michael J.; Torguson, Rebecca; Waksman, Ron, E-mail: ron.waksman@medstar.net

    2014-07-15

    Background: Patients presenting with ST-segment elevation myocardial infarction (STEMI) represent a high-risk group for in-hospital adverse events and bleeding. The safety and outcomes of eptifibatide in addition to bivalirudin in this population have not been determined. Methods: Over an 11-year period, we identified 1849 STEMI patients undergoing primary percutaneous coronary intervention (PCI), of which 1639 received bivalirudin monotherapy compared with 210 patients who received both bivalirudin and provisional eptifibatide. Safety of combination therapy was assessed by the occurrence of thrombolysis in myocardial infarction (TIMI) major bleeding. In-hospital event rates of death, Q-wave myocardial infarction (MI), and acute stent thrombosis were evaluated for efficacy. Multivariate analysis was used to adjust for significant differences between groups. Results: Patients treated with bivalirudin plus eptifibatide, when compared with patients with bivalirudin monotherapy, had increased rates of cardiogenic shock (15.7% vs. 9.4%), aspiration thrombectomy (48.5% vs. 23.7%), pre-TIMI flow ≤ 1 (63.5% vs. 40%), and higher peak troponin I (93.65 ± 92.7 vs. 49.16 ± 81.59; all p < 0.01). These, however, were not associated with differences in the primary end point after adjusting for significant baseline and procedural characteristics (OR: 1.63; 95% CI, 0.90–2.96, p = 0.12). Importantly, TIMI major bleeding was not significantly different between groups (OR 1.78; 95% CI, 0.79–2.95, p = 0.20). Conclusion: The addition of eptifibatide to bivalirudin during primary PCI reflects a high-risk STEMI population. This therapy results in similar in-hospital outcomes without an increase in major bleeding. Therefore, when required, combination therapy may be considered in this population.

  4. Adverse drug events associated with vitamin K antagonists: factors of therapeutic imbalance

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    El-Helou N

    2013-03-01

    Full Text Available Nancy El-Helou, Amal Al-Hajje, Rola Ajrouche, Sanaa Awada, Samar Rachidi, Salam Zein, Pascale SalamehClinical and Epidemiological Research Laboratory, Faculty of Pharmacy, Lebanese University, Beirut, LebanonBackground: Adverse drug events (ADE occur frequently during treatment with vitamin K antagonists (AVK and contribute to increase hemorrhagic risks.Methods: A retrospective study was conducted over a period of 2 years. Patients treated with AVK and admitted to the emergency room of a tertiary care hospital in Beirut were included. The aim of the study was to identify ADE characterized by a high international normalized ratio (INR and to determine the predictive factors responsible for these events. Statistical analysis was performed with the SPSS statistical package.Results: We included 148 patients. Sixty-seven patients (47.3% with an INR above the therapeutic range were identified as cases. The control group consisted of 81 patients (54.7% with an INR within the therapeutic range. Hemorrhagic complications were observed in 53.7% of cases versus 6.2% of controls (P < 0.0001. No significant difference was noticed between cases and controls regarding the indication and the dose of AVK. Patients aged over 75 years were more likely to present an INR above the therapeutic range (58.2%, P = 0.049. Recent infection was present in 40.3% of cases versus 6.2% of controls (P < 0.0001 and hypoalbuminemia in 37.3% of cases versus 6.1% of controls (P < 0.0001. Treatment with antibiotics, amiodarone, and anti-inflammatory drugs were also factors of imbalance (P < 0.0001.Conclusion: Many factors may be associated with ADE related to AVK. Monitoring of INR and its stabilization in the therapeutic range are important for preventing these events.Keywords: adverse drug events, vitamin K antagonists, bleeding risks, therapeutic imbalance

  5. The substance P/NK-1 receptor system: NK-1 receptor antagonists as anti-cancer drugs

    Indian Academy of Sciences (India)

    Miguel Muñoz; Rafael Coveñas; Francisco Esteban; Maximino Redondo

    2015-06-01

    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, which are involved in their viability. This overexpression suggests the possibility of specific treatment against tumour cells using NK-1 receptor antagonists, thus promoting a considerable decrease in the side effects of the treatment. This strategy opens up new approaches for cancer treatment, since these antagonists, after binding to their molecular target, induce the death of tumour cells by apoptosis, exert an antiangiogenic action and inhibit the migration of tumour cells. The use of NK-1 receptor antagonists such as aprepitant (used in clinical practice) as antitumour agents could be a promising innovation. The value of aprepitant as an antitumour agent could be determined faster than for less well-known compounds because many studies addressing its safety and characterization have already been completed. The NK-1 receptor may be a promising target in the treatment of cancer; NK-1 receptor antagonists could act as specific drugs against tumour cells; and these antagonists could be new candidate anti-cancer drugs.

  6. Spectrophotometric determination of some histamine H1-antagonists drugs in their pharmaceutical preparations

    Science.gov (United States)

    Hassan, Wafaa S.; El-Henawee, Magda M.; Gouda, Ayman A.

    2008-01-01

    Two rapid, simple and sensitive extractive specrophotometric methods has been developed for the determination of three histamine H1-antagonists drugs, e.g., chlorphenoxamine hydrochloride (CPX), diphenhydramine hydrochloride (DPH) and clemastine (CMT) in bulk and in their pharmaceutical formulations. The first method depend upon the reaction of molybdenum(V) thiocyanate ions (Method A) with the cited drugs to form stable ion-pair complexes which extractable with methylene chloride, the orange red color complex was determined colorimetrically at λmax 470 nm. The second method is based on the formation of an ion-association complex with alizarin red S as chromogenic reagents in acidic medium (Method B), which is extracted into chloroform. The complexes have a maximum absorbance at 425 and 426 nm for (DPH or CMT) and CPX, respectively. Regression analysis of Beer-Lambert plots showed a good correlation in the concentration ranges of 5.0-40 and 5-70 μg mL -1 for molybdenum(V) thiocyanate (Method A) and alizarin red S (Method B), respectively. For more accurate analysis, Ringbom optimum concentration ranges were calculated. The molar absorptivity, Sandell sensitivity, detection and quantification limits were calculated. Applications of the procedure to the analysis of various pharmaceutical preparations gave reproducible and accurate results. Further, the validity of the procedure was confirmed by applying the standard addition technique and the results obtained in good agreement well with those obtained by the official method.

  7. Adjusting eptifibatide doses for renal impairment: a model of dosing agreement among various methods of estimating creatinine clearance.

    Science.gov (United States)

    Healy, Martha F; Speroni, Karen Gabel; Eugenio, Kenneth R; Murphy, Patricia M

    2012-04-01

    Because of the renal elimination and increased risk for bleeding events at supratherapeutic doses of eptifibatide, the manufacturer recommends dosing adjustment in patients with renal dysfunction. Methods commonly used to estimate renal dysfunction in hospital settings may be inconsistent with those studied and recommended by the manufacturer. To compare hypothetical renal dosing adjustments of eptifibatide using both the recommended method and several other commonly used formulas for estimating kidney function. Sex, age, weight, height, serum creatinine, and estimated glomerular filtration rate (eGFR) were obtained retrospectively from the records of patients who received eptifibatide during a 12-month period. Renal dosing decisions were determined for each patient based on creatinine clearance (CrCl) estimates via the Cockcroft-Gault formula (CG) with actual body weight (ABW), ideal body weight (IBW) or adjusted weight (ADJW), and eGFR from the Modification of Diet in Renal Disease formula. Percent agreement and Cohen κ were calculated comparing dosing decisions for each formula to the standard CG-ABW. In this analysis of 179 patients, percent agreement as compared to CG-ABW varied (CG-IBW: 90.50%, CG-ADJW: 95.53%, and eGFR: 93.30%). All κ coefficients were categorized as good. In the 20% of patients receiving an adjusted dose by any of the methods, 68.6% could have received a dose different from that determined using the CG-ABW formula. In the patients with renal impairment (CrCl <50 mL/min) in this study, two thirds would have received an unnecessary 50% dose adjustment discordant from the manufacturer's recommendation. Because failure to adjust eptifibatide doses in patients with renal impairment has led to increased bleeding events, practitioners may be inclined to err on the side of caution. However, studies have shown that suboptimal doses of eptifibatide lead to suboptimal outcomes. Therefore, correct dosing of eptifibatide is important to both patient

  8. Nitroester drug's effects and their antagonistic effects against morphine on human sphincter of Oddi motility

    Institute of Scientific and Technical Information of China (English)

    Shuo-Dong Wu; Zhen-Hai Zhang; Dong-Yan Li; Jun-Zhe Jin; Jing Kong; Zhong Tian; Wei Wang; Min-Fei Wang

    2005-01-01

    AIM: To evaluate the effects of nitroester drugs on human sphincter of Oddi (SO) motility and their antagonistic effects against morphine which shows excitatory effect on Oddi's sphincter motility.METHODS: The effects of these drugs on SO were evaluated by means of choledochofiberoscopy manometry.A total of 67 patients having T-tubes after cholecystectomy and choledochotomy were involved in the study, they were randomly divided into glyceryl trinitrate (GTN) group,isosorbide dinitrate (ISDN) group, pentaerythritol tetranitrate (PTN) group, morphine associated with GTN group, morphine associated with ISDN group and morphine associated with PTN group. Basal pressure of Oddi's sphincter (BPOS), amplitude of phasic contractions (SOCA), frequency of phasic contractions (SOF), duration of phasic contractions (SOD), duodenal pressure (DP) and common bile duct pressure (CBDP) were scored and analyzed. Morphine was given intramuscularly while nitroester drugs were applied sublingually.RESULTS: BPOS and SOCA decreased significantly after administration of ISDN and GTN, BPOS reduced from 10.95±7.49 mmHg to 5.92±4.04 mmHg (P<0.05) evidently after application of PTN. BPOS increased from 7.37±5.58mmHg to 16.60±13.87 mmHg, SOCA increased from 54.09±38.37 mmHg to 100.70±43.51 mmHg, SOF increased from 7.15±3.20 mmHg to 10.38±2.93 mmHg and CBDP increased 3.75±1.95 mmHg to 10.49±8.21 mmHg (P<0.01)evidently after injection of morphine. After associated application of ISDN and GTN, the four indications above decreased obviously. As for application associated with PTN,SOCA and SOF decreased separately from 100.64±44.99mmHg to 66.17±35.88 mmHg and from 10.70±2.76 mmHg to 9.04±1.71 mmHg (P<0.05) markedly.CONCLUSION: The regular dose of GTN, ISDN and PTN showed inhibitory effect on SO motility, morphine showed excitatory effect on SO while GTN, ISDN and PTN could antagonize the effect of morphine. Among the three nitroester drugs, the effect of ISDN on SO was most

  9. The role of exploratory drug metabolism and pharmacokinetics in new drug research: case study-selection of a thrombin receptor antagonist for development.

    Science.gov (United States)

    Hsieh, Yunsheng; Cheng, K-C; Wang, Yuguang; Chackalamannil, Samuel; Xia, Yan; Korfmacher, Walter A; White, Ronald E

    2009-01-01

    The rising costs and time associated with bringing new medicines to the market have created a need for a new paradigm for reducing the attrition rates of drug candidates in both preclinical and clinical development stages. Early appraisal of drug metabolism and pharmacokinetic (DMPK) parameters is now possible due to several higher throughput in vitro and in vivo screens. This knowledge of DMPK properties should not only shorten the timelines for the selection of drug candidates but also enhance the probability of their success for development. The role of DMPK researchers in the drug research paradigm should not be limited to screening a large array of compounds during the lead optimization process but should include a strive for an understanding of the absorption, distribution, metabolism, excretion, and potential drug-related toxicities of a chemical series. As an example, in this article we present a specific DMPK research screening paradigm and describe a case study using the Thrombin Receptor Antagonist program. This screening paradigm followed by the extensive lead optimization process culminated in the selection of SCH 530348, a potent, selective and orally active thrombin receptor antagonist for the treatment of thrombosis.

  10. Perspectives in Drug Development and Clinical Pharmacology: The Discovery of Histamine H1 and H2 Antagonists.

    Science.gov (United States)

    Jones, Alan Wayne

    2016-01-01

    Knowledge about the history and development of therapeutic agents holds a central position in the education and training of pharmacists and pharmacologists. Students enjoy learning about the discovery of drugs, including details about the pioneer workers involved (apothecaries, organic chemists, pharmacologists, and physiologists) and the role played by serendipity. The treatment of people suffering from allergies and the development of drugs that block the actions of histamine at H1 and H2 receptors are the subject of this review. Pharmaceutical products that block H1 receptors are widely used as prophylactic treatment for seasonal allergies that plague millions of people worldwide. The development of H2 receptor antagonists revolutionized treatment of gastric hyperacidity, the principal cause of peptic ulcers. Antihistamine research has changed focus toward the development of drugs that block the action of histamine at H3 and H4 receptors and the therapeutic potential is gradually being appreciated.

  11. Anesthetic effects of a three-drugs mixture--comparison of administrative routes and antagonistic effects of atipamezole in mice.

    Science.gov (United States)

    Kirihara, Yumiko; Takechi, Mayumi; Kurosaki, Kaoru; Kobayashi, Yuta; Saito, Yoji; Takeuchi, Takashi

    2015-01-01

    The anesthetic mixture of medetomidine (MED), midazolam (MID) and butorphanol (BUT) produced anesthetic duration of around 40 minutes (min) in ICR mice. We reported that this anesthetic mixture produced almost the same anesthetic effects in both male and female BALB/c and C57BL/6J strains. Intraperitoneal (IP) administration of drugs has been widely used in mice. However, various injectable routes of the anesthetic mixture may cause different anesthetic effects. First, we examined effects of the anesthetic mixture by subcutaneous (SC) and intravenous (IV) injection compared to IP injection. After injection of the anesthetic mixture, administration of atipamezole (ATI) induced mice recovery from anesthesia. Secondly, we examined how different dosage and optimum injection timing of ATI affected mice recovery from anesthesia. We used an anesthetic score to measure anesthetic duration and a pulse oximeter to monitor vital signs under anesthesia. Usually, drugs from SC injection work more weakly than IP or IV injection. However, we found no significant differences of anesthetic duration among the three different injection routes. Antagonistic effects of ATI (0.3 mg/kg and 1.5 mg/kg) worked equally when administered at 30 min after injection of the anesthetic mixture. Antagonistic effects of ATI (1.5 mg/kg) were stronger than ATI (0.3 mg/kg) at 10 min after injection of the anesthetic mixture. The anesthetic mixture is a useful drug to induce nearly the same anesthetic effects by different injection routes and has an antagonist of ATI which helps mice quickly recover from anesthesia. These results may contribute to the welfare of laboratory animals.

  12. Neurokinin-1 receptor antagonists as antitumor drugs in gastrointestinal cancer: A new approach

    Directory of Open Access Journals (Sweden)

    Miguel Muñoz

    2016-01-01

    Full Text Available Gastrointestinal (GI cancer is the term for a group of cancers affecting the digestive system. After binding to the neurokinin-1 (NK-1 receptor, the undecapeptide substance P (SP regulates GI cancer cell proliferation and migration for invasion and metastasis, and controls endothelial cell proliferation for angiogenesis. SP also exerts an antiapoptotic effect. Both SP and the NK-1 receptor are located in GI tumor cells, the NK-1 receptor being overexpressed. By contrast, after binding to the NK-1 receptor, NK-1 receptor antagonists elicit the inhibition (epidermal growth factor receptor inhibition of the proliferation of GI cancer cells in a concentration-dependent manner, induce the death of GI cancer cells by apoptosis, counteract the Warburg effect, inhibit cancer cell migration (counteracting invasion and metastasis, and inhibit angiogenesis (vascular endothelial growth factor inhibition. NK-1 receptor antagonists are safe and well tolerated. Thus, the NK-1 receptor could be considered as a new target in GI cancer and NK-1 receptor antagonists (eg, aprepitant could be a new promising approach for the treatment of GI cancer.

  13. Selective blockade of drug-induced place preference conditioning by ACPC, a functional NDMA-receptor antagonist.

    Science.gov (United States)

    Papp, Marius; Gruca, Piotr; Willner, Paul

    2002-11-01

    ACPC (1-aminocyclopropanecarboxylic acid) is a partial agonist at the strychnine-insensitive glycine receptor site on the NMDA receptor complex, and a functional NMDA antagonist. A series of experiments was conducted to assess the effects of ACPC in a biased place conditioning paradigm. As previously reported, ACPC itself did not support either appetitive or aversive place conditioning. However, co-administration of ACPC (200 mg/kg) blocked the acquisition of place preferences conditioned using a variety of psychoactive drugs (amphetamine, cocaine, nomifensine, diazepam, morphine, nicotine). No tolerance was seen to this effect following two weeks of chronic ACPC administration. Overall, ACPC did not affect the expression of place conditioning when administered immediately before the post-conditioning test. However, these effects appeared somewhat variable between drugs, and further analysis showed that ACPC did block the expression of preferences conditioned with some drugs (diazepam, morphine, nicotine), but not others (amphetamine, cocaine, nomifensine). The effects of ACPC could not be accounted for by state dependence, as ACPC blocked morphine and cocaine place preferences when administered during both the acquisition and the expression phase of conditioning. In contrast to the blockade by ACPC of drug-induced place preferences, ACPC had no effect on the acquisition of place preferences conditioned using a variety of natural non-drug reinforcers (food, sucrose, social interaction, novelty). ACPC also had no effect on the acquisition of drug-induced place aversions (naloxone, picrotoxin). Thus, ACPC selectively blocked appetitive conditioning by drug reinforcers, without affecting either appetitive conditioning by natural reinforcers or drug-induced aversions. As place preference conditioning has been demonstrated to have high predictive validity for detecting compounds with an abuse potential in humans, this selective action suggests that ACPC might have some

  14. Synthesis and evaluation of novel angiotensin II receptor 1 antagonists as anti-hypertension drugs.

    Science.gov (United States)

    Bao, Xiaolu; Zhu, Weibo; Zhang, Ruijing; Wen, Caihong; Wang, Li; Yan, Yijia; Tang, Hesheng; Chen, Zhilong

    2016-05-01

    Three new angiotensin II receptor 1 antagonists, 1, 2 and 3 were designed, synthesized and evaluated. The AT1 receptor-binding assays in vitro showed that all the synthesized compounds had nanomolar affinity for the AT1 receptor. From which compound 3 was found to be the most potent ligands with an IC50 value of 2.67±0.23 nM. Biological evaluation in vivo revealed that all the compounds could cause significant decrease on MBP in a dose dependent manner in spontaneously hypertensive rats, and compound 3 especially showed an efficient and long-lasting effect in reducing blood pressure, whose maximal response lowered 41 mmHg of MBP at 10mg/kg and 62 mmHg at 15 mg/kg after oral administration, the significant anti-hypertensive effect lasted beyond 12 h, which is better than the reference compound losartan. The pharmacokinetic experiments showed that compound 3 could be absorbed efficiently and metabolized smoothly both in blood and in tissues in Wistar rats. The acute toxicity assay suggested that it has low toxicity with the LD50 value of 2974.35 mg/kg. These results demonstrate that compound 3 is a potent angiotensin AT1 receptor antagonist which could be considered as a novel anti-hypertension candidate and deserved for further investigation.

  15. Validated spectroflurimetric determination of some H1 receptor antagonist drugs in pharmaceutical preparations through charge transfer complexation.

    Science.gov (United States)

    el-Din, Mohie K Sharaf; Ibrahim, Fawzia; Eid, Manal I; Wahba, Mary E K

    2012-01-01

    A validated simple, rapid, and selective spectrofluorimetric method was developed for the determination of some antihistaminic H(1) receptor antagonist drugs namely ebastine (EBS), cetirizine dihydrochloride (CTZ), and fexofenadine hydrochloride (FXD). The method is based on the reaction of the cited drugs with some Π acceptors namely p-chloranilic acid (CLA), tetracyanoethylene (TCNE), and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) to give highly fluorescent derivatives. The fluorescence intensity-concentration plots were rectilinear over the concentration ranges of 0.2-3.0, 0.2-2.5 and 0.15-2.0 μg/ml for EBS with CLA, DDQ, and TCNE respectively; 0.5-7.0, 0.5-6.0, and 0.2-4.0 μg/ml for CTZ with the previously mentioned reagents, and 0.2-3.5, 0.5-6.0, and 0.2-3.5 μg/ml for FXD. The factors affecting the formation of the reaction products were carefully studied and optimized. The method was applied for the determination of the studied drugs in their dosage forms. The results obtained were in good agreement with those obtained by the comparison methods. Reactions Stoichiometries of the complexes formed between the studied drugs and Π acceptors were defined by the Job's method of the continuous variation and found in 1:1 in all cases.

  16. Therapeutic effect of ifenprodil,a NMDA receptor antagonist,on drug dependence

    Institute of Scientific and Technical Information of China (English)

    SuzukT; NaritM

    2002-01-01

    Although drug dependence has been treated by the adonist-therapy,the specific drug therapy for drug dependence has not been established.Ifenprodil is consibdred to specifically block the NMDA receptor consisted of NR1/NR2B subunits without undesirable adverse reactions,such as psychotomimetic action and psychological dependence,while ketamine and MK-801 can block both NMDA receptors consisted of NR1/NR2A and NR1/NR2B subunits with the undesirable adverse reactions.In the present study,we designed to examine the effect of ifenprodil on drug dependence in rodents.Pretreatment with ifenprodil suppressed the expression of withdrawal signs in morphine-, diazepam-and alcohol-dependent rats and mics.Rewarding effects of morphine,methamphetamine and cocaine as well as physical dependence,were suppressed by pretreatment with ifenprodil in rats and mice.These results suggest that ifenprodil be useful in treating drug dependence.

  17. Rimonabant: an antagonist drug of the endocannabinoid system for the treatment of obesity.

    Science.gov (United States)

    Leite, Carlos E; Mocelin, Clei A; Petersen, Guilherme O; Leal, Mirna B; Thiesen, Flavia V

    2009-01-01

    Obesity, an ever-increasing problem in the industrialized world, has long been a target of research for a cure or, at least, control of its expansion. In the search for treatment, the recently discovered endocannabinoid system has emerged as a new target for controlling obesity and its associated conditions. The endocannabinoid system plays an important role in controlling weight and energy balance in humans. This system is activated to a greater extent in obese patients, and the specific blockage of its receptors is the aim of rimonabant, one of the most recent drugs created for the treatment of obesity. This drug acts as a blockade for endocannabinoid receptors found in the brain and peripheral organs that play an important role on carbohydrate and fat metabolism. Clinical studies have confirmed that, when used in combination with a low calorie diet, rimonabant promotes loss in body weight, loss in abdominal circumference, and improvements in dyslipidemia. Rimonabant is also being tested as a potential anti-smoking treatment since endocannabinoids are related to the pleasurable effect of nicotine. Thus, rimonabant constitutes a new therapeutic approach to obesity and cardiovascular risk factors. Studies show effectiveness in weight loss; however, side effects such as psychiatric alterations have been reported, including depression and anxiety. These side effects have led the FDA (Food and Drug Administration) to not approve this drug in the United States. For a more complete evaluation on the safety of this drug, additional studies are in progress.

  18. Preclinical toxicity and teratogenicity studies with the narcotic antagonist analgesic drug TR5379M.

    Science.gov (United States)

    Porter, M C; Hartnagel, R E; Clemens, G R; Kowalski, R L; Bare, J J; Halliwell, W E; Kitchen, D N

    1983-01-01

    The narcotic antagonist TR5379M had po LD50 values of 365 and 750 mg/kg and iv LD50 values of 35.0 and 22.3 mg/kg in the mouse and rat, respectively. Subchronic (one month) po administration to rats at 40, 120, or 400 mg/kg/day and to cynomolgus monkeys at 20, 45, or 100 mg/kg/day showed the compound to be well tolerated at doses of 40 and 45 mg/kg, respectively. Deaths during the subchronic studies included one monkey following a single dose of 100 mg/kg and six rats following repeated doses of 400 mg/kg. Signs of toxicosis in rats included clonic convulsions (high-dose animals only) and mild dose-related salivation and hyperactivity. Signs of toxicosis in monkeys were limited to sporadic emesis and transiently decreased food consumption at all three dose levels. Emesis was not observed at doses of 20 or 45 mg/kg after the first week. Slightly increased weights (not significant at 40 mg/kg) for thyroid and adrenal glands occurred in male rats. Gross, microscopic, and clinical pathologic examinations revealed no treatment-related adverse effects at any dose level for either species. Administration of TR5379M to pregnant rats (20, 70, or 250 mg/kg/day on Days 6-15 of gestation) caused no teratogenicity or embryotoxicity and did not adversely affect any of the reproductive parameters examined. Dams given TR5379M at doses of 70 and 250 mg/kg salivated and had reduced weight gain. It was concluded from these studies that TR5379M has an adequate margin of safety to begin clinical investigations.

  19. Comparison of drug survival rates for tumor necrosis factor antagonists in rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    Martínez-Santana V

    2013-07-01

    Full Text Available Virginia Martínez-Santana,1 E González-Sarmiento,2 MA Calleja-Hernández,3 T Sánchez-Sánchez1 1Pharmacy Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 2Internal Medicine Department, Hospital Clínico Universitario de Valladolid, Valladolid, Spain; 3Pharmacy Department, Hospital Universitario Virgen de las Nieves de Granada, Granada, Spain Background: Persistence of anti-tumor necrosis factor (TNF therapy in rheumatoid arthritis (RA is an overall marker of treatment success. Objective: To assess the survival of anti-TNF treatment and to define the potential predictors of drug discontinuation in RA, in order to verify the adequacy of current practices. Design: An observational, descriptive, longitudinal, retrospective study. Setting: The Hospital Clínico Universitario de Valladolid, Valladolid, Spain. Patients: RA patients treated with anti-TNF therapy between January 2011 and January 2012. Measurements: Demographic information and therapy assessments were gathered from medical and pharmaceutical records. Data is expressed as means (standard deviations for quantitative variables and frequency distribution for qualitative variables. Kaplan–Meier survival analysis was used to assess persistence, and Cox multivariate regression models were used to assess potential predictors of treatment discontinuation. Results: In total, 126 treatment series with infliximab (n = 53, etanercept (n = 51 or adalimumab (n = 22 were administered to 91 patients. Infliximab has mostly been used as a first-line treatment, but it was the drug with the shortest time until a change of treatment. Significant predictors of drug survival were: age; the anti-TNF agent; and the previous response to an anti-TNF drug. Limitation: The small sample size. Conclusion: The overall efficacy of anti-TNF drugs diminishes with time, with infliximab having the shortest time until a change of treatment. The management of biologic therapy in patients with

  20. The Antagonistic Action of Heat-Clearing and Detoxifying Chinese Drugs on Endotoxins

    Institute of Scientific and Technical Information of China (English)

    张霞; 崔乃杰; 王家泰

    2001-01-01

    @@In the recent decade, interest in treatment and prevention of many critical, severe and acute diseases caused by bacterial endotoxins has been aroused along with the advance of the knowledge on the nature of the endotoxin and the conditions involved. In abroad, attention has been mainly payed to raising antisera and monocolonal antibodies against the endotoxin and the induced mediators. However, the allergic reactions and the cost are still the problems. Till now, there is no drug that can antagonize endotoxin with high effectiveness and low toxicity. Clinical treatments are still confined in inhibiting or killing the pathogen, and correcting the internal environmental disturbance. Being less toxic and rich in resources with low cost and less side-effects, screening of effective Chinese drugs for antagonizing endotoxin is of important and practical significance. Endotoxin belongs to the category of toxic evils, or more precisely, the heat toxin in TCM. Therefore the application of heat-clearing and detoxifying Chinese drugs to antagonizing endotoxins is consistent with the theory of TCM. Some achievements in this field are reported as follows.

  1. A RETROSPECTIVE STUDY ON THE POTENTIAL DRUG INTERACTION BETWEEN ANGIOTENSIN CONVERTING ENZYME INHIBITOR OR ANGIOTENSIN RECEPTOR ANTAGONIST AND OTHER DRUGS IN END-STAGE CHRONIC RENAL FAILURE PATIENTS

    Directory of Open Access Journals (Sweden)

    Honey Iskandar

    2012-10-01

    Full Text Available Increasing number of chronic renal failure (CRF patients had reflected an increase in the number of patients with diabetes and hypertension. Therefore, health practitioners would be faced with management of complicated medical problems for the patients of chronic renal disease. In this way, various complications of chronic renal failure would lead to polypharmacy, where the patients receive three to five drugs in a dose. Development of polypharmacy had made the potential of drug interaction greater. The objective was to determine whether CRF patients admitted to hospital with specific adverse drug reactions were likely to have been prescribed with interacting drugs. Retrospective study was designed. The study was conducted at the General Practice Rooms Floor 1 – Floor VI of Central Army Hospital Gatot Soebroto Jakarta. The study was conducted from December 2011 – February 2012. The data were collected in a retrospective way for a year (January – December 2011. End-stage CRF patients who were having hemodialysis therapy and receiving ACE Inhibitor drugs or Angiotensin II Receptor Antagonist (AIIRA and receiving treatment at the General Practice Rooms at Central Army Hospital Gatot Soebroto Jakarta. During the period of January – December 2011, 84 patients were treated with end-stage CRF at the Central Army Hospital and having routine hemodialysis and 44 patients were receiving therapy with ACE Inhibitor and AIIRA. Other drugs simultaneously given with ACE Inhibitor and AIIRA were captopril-spironolactone, captopril-aspirin, captopril-allopurinol, captopril-KSR, captopril-furosemide, lisinopril-furosemide and valsartan-mefenemic acid. An increase in adverse effects of the drugs was found based on the clinical evaluation and laboratory examination. The adverse effects included hyperkalemia (9,09%, decrease in anti-hypertension effect (6,8%, acute hypotension (40%, and declining renal function (11,36%. The study identifies drug interaction

  2. Ensuring medication adherence with direct oral anticoagulant drugs: lessons from adherence with vitamin K antagonists (VKAs).

    Science.gov (United States)

    Di Minno, Alessandro; Spadarella, Gaia; Tufano, Antonella; Prisco, Domenico; Di Minno, Giovanni

    2014-05-01

    Medication adherence (taking drugs properly) is uncommon among patients on warfarin. Poor adherence to warfarin leads to an increase in adverse medical events, including stroke in atrial fibrillation (AF). Factors related to patients, physicians and the health system account for poor adherence. Direct oral anticoagulants (DOACs) are easier to use than warfarin, with fewer drug and food interactions and no need for routine blood monitoring. A proper use of DOACs may reduce the risk of stroke in AF. However, in clinical settings where no laboratory monitoring is needed, a poor medication adherence is common and may impact clinical outcomes. In the management of chronic disorders, careful knowledge of the individual patient's attitudes and behaviors is a pre-requisite for a successful doctor-patient communication. To increase patient's awareness of the risks and benefits of DOACs and, in turn, increase medication adherence, at each follow-up visit physicians should screen for priorities and motivational problems; check for the lack of understanding and/or knowledge; assess any health system or personal barriers to medication adherence; identify appropriate interventions and provide tailored support to patient needs. Dissemination of guidelines to the health care chain (prescribing physician, general practitioners, caregivers, nurses, pharmacists) further encourages medication adherence. However, the long-term effect of some of these strategies is unknown; one tool may not fit all patients, and the prescribing physician should consider individualization of these aids to ensure medication adherence and persistence (continuing to take drugs properly in long-term treatments) for DOACs in every day practice.

  3. An overview of economic evaluations for drugs used in rheumatoid arthritis : focus on tumour necrosis factor-alpha antagonists.

    Science.gov (United States)

    Bansback, Nick J; Regier, Dean A; Ara, Roberta; Brennan, Alan; Shojania, Kamran; Esdaile, John M; Anis, Aslam H; Marra, Carlo A

    2005-01-01

    Rheumatoid arthritis (RA) is a chronic, progressive, inflammatory disease that affects approximately 0.5-1% of the adult population. The introduction of new disease-modifying antirheumatic drugs (DMARDs) such as leflunomide, anakinra and the tumour necrosis factor (TNF)-alpha antagonists (infliximab, etanercept and adalimumab) have transformed the management of RA. In particular, the last class of agents has generated substantial controversy. Costing between 16,000 US dollars and 20,000 US dollars per patient-year (2001 values), the potential greater efficacy of treatment with TNFalpha antagonists comes at much higher drug costs, making these agents natural candidates for cost-effectiveness analyses (CEAs).A MEDLINE search (until 31 January 2004) identified six original CEAs evaluating TNFalpha antagonists in RA. The aim of a CEA is to facilitate the allocation of scarce health resources and to inform policy decisions. However, to enhance the reliability and relevance of these analyses to policy makers, there must be similarity between the methodologies used. Recently, the OMERACT (Outcome Measures in Rheumatoid Arthritis Clinical Trials) group produced a document to define such a reference case; the OMERACT document was used as a foundation to structure comparisons and highlight discrepancies. The methodologies employed in each analysis differed; in particular, disparate time horizons, comparators, quantities of drug and treatment sequences prohibit the comparison of cost effectiveness between studies. Outcomes also differed between the analyses. Most reported health-related quality of life (HR-QOL) in quality-adjusted life-years (QALYs). The QALYs metric was based on preference scores that were typically derived from linear regressions using the Health Assessment Questionnaire (HAQ). However, models also used American College of Rheumatology (ACR) criteria, as well as the disease activity score (DAS). Common to all studies was the lack of data from long

  4. The clinical pharmacology profile of the new antiepileptic drug perampanel: A novel noncompetitive AMPA receptor antagonist.

    Science.gov (United States)

    Patsalos, Philip N

    2015-01-01

    The clinical pharmacology profile of a drug critically determines its therapeutics, and this review summarizes the characteristics associated with the antiepileptic drug (AED) perampanel. A PubMed literature search was performed for perampanel. Congress abstract data are included where necessary and Eisai Ltd provided access to unpublished data on file. After oral ingestion, perampanel is rapidly absorbed and peak plasma concentrations occur 0.5-2.5 h later; its bioavailability is ~100%. Although the rate of perampanel absorption is slowed by food co-ingestion, the extent absorbed remains unchanged; therefore, perampanel can be administered without regard to meal times. The pharmacokinetics of perampanel are linear and predictable over the clinically relevant dose range (2-12 mg); perampanel is 95% protein-bound to albumin and α1-acid glycoprotein. Perampanel is extensively metabolized (>90%) in the liver, primarily by cytochrome P450 (CYP) 3A4, to various pharmacologically inactive metabolites. In healthy volunteers, the apparent terminal half-life is ~105 h, whereas the calculated effective half-life is 48 h. These half-life values allow for once-daily dosing, which will aid patient compliance and in the event of a missed dose, will have minimal impact on seizure control. In healthy volunteers prescribed carbamazepine, half-life decreases to 25 h. Clearance values are not significantly different in adolescents (~13.0 ml/min) and the elderly (~10.5 ml/min) compared with adults (10.9 ml/min). Perampanel has minimal propensity to cause pharmacokinetic interactions. However, it is the target of such interactions and CYP3A4-inducing AEDs enhance its clearance; this can be used to advantage because dose titration can be faster and thus optimum therapeutic outcome can be achieved sooner. Perampanel 12 mg, but not 4 or 8 mg, enhances the metabolism of the progesterone component of the oral contraceptive pill, necessitating the need for an additional reliable

  5. Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer.

    Science.gov (United States)

    Li, Jian; Yao, Qing-Yu; Xue, Jun-Sheng; Wang, Li-Jie; Yuan, Yin; Tian, Xiu-Yun; Su, Hong; Wang, Si-Yuan; Chen, Wen-Jun; Lu, Wei; Zhou, Tian-Yan

    2017-09-01

    Recent evidence shows that dopamine D2-like receptor (D2DR) antagonists, such as trifluoperazine and thioridazine, are effective for cancer therapy and inhibition of cancer stem-like cells (CSCs). In this study, we investigated the anti-cancer effects of combination therapy of dexamethasone (DEX) and sulpiride (SUL), an atypical antipsychotic, against drug-resistant and metastatic breast cancers and further explored the underlying mechanisms. Oral administration of SUL (25, 100 mg·kg(-1)·d(-1)) alone did not inhibit the tumor growth in human breast cancer MCF-7/Adr xenograft model, but dose-dependently decreased the proportion of CSCs in vitro and in vivo. In contrast, combination therapy of SUL (50 mg·kg(-1)·d(-1)) and DEX (8 mg·kg(-1)·d(-1)) markedly suppressed the tumor growth in MCF-7/Adr xenograft model with little systemic toxicity and lung metastasis in murine metastatic breast cancer 4T1 xenograft model. Among the metastasis-associated biomarkers analyzed, the combination therapy significantly decreased the levels of MMP-2, but increased E-cadherin levels in 4T1 xenograft tumors. Moreover, the combination therapy significantly inhibited the cell colony formation, migration and invasion of 4T1 and human breast cancer MDA-MB-231 cells in vitro. Addition of a specific D2DR agonist 7-OH-DPAT to the combination therapy reversed the enhanced anti-cancer effects in vivo and CSC population loss in tumor tissues. Our data demonstrate that SUL remarkably enhances the efficacy of DEX in the treatment of drug-resistant and metastatic breast cancer via the antagonism of D2DR, which might result from the eradication of CSCs.

  6. Dopamine D3/D2 Receptor Antagonist PF-4363467 Attenuates Opioid Drug-Seeking Behavior without Concomitant D2 Side Effects.

    Science.gov (United States)

    Wager, Travis T; Chappie, Thomas; Horton, David; Chandrasekaran, Ramalakshmi Y; Samas, Brian; Dunn-Sims, Elizabeth R; Hsu, Cathleen; Nawreen, Nawshaba; Vanase-Frawley, Michelle A; O'Connor, Rebecca E; Schmidt, Christopher J; Dlugolenski, Keith; Stratman, Nancy C; Majchrzak, Mark J; Kormos, Bethany L; Nguyen, David P; Sawant-Basak, Aarti; Mead, Andy N

    2017-01-18

    Dopamine receptor antagonism is a compelling molecular target for the treatment of a range of psychiatric disorders, including substance use disorders. From our corporate compound file, we identified a structurally unique D3 receptor (D3R) antagonist scaffold, 1. Through a hybrid approach, we merged key pharmacophore elements from 1 and D3 agonist 2 to yield the novel D3R/D2R antagonist PF-4363467 (3). Compound 3 was designed to possess CNS drug-like properties as defined by its CNS MPO desirability score (≥4/6). In addition to good physicochemical properties, 3 exhibited low nanomolar affinity for the D3R (D3 Ki = 3.1 nM), good subtype selectivity over D2R (D2 Ki = 692 nM), and high selectivity for D3R versus other biogenic amine receptors. In vivo, 3 dose-dependently attenuated opioid self-administration and opioid drug-seeking behavior in a rat operant reinstatement model using animals trained to self-administer fentanyl. Further, traditional extrapyramidal symptoms (EPS), adverse side effects arising from D2R antagonism, were not observed despite high D2 receptor occupancy (RO) in rodents, suggesting that compound 3 has a unique in vivo profile. Collectively, our data support further investigation of dual D3R and D2R antagonists for the treatment of drug addiction.

  7. Effect of food on pharmacokinetics of an inhaled drug: a case study with a VLA-4 antagonist, HMR1031.

    Science.gov (United States)

    Shah, Bharti; Jensen, Bradford K; Zhang, Jie; Hunt, Thomas; Rohatagi, Shashank

    2003-12-01

    HMR1031 is a potent and specific antagonist of the integrin VLA-4 (alpha4beta1) binding to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin. HMR1031 is an inhaled drug being developed for the treatment of asthma using an Ultrahaler dry-powder inhalation device. A pharmacoscintigraphic study of HMR1031 suggests a lung deposition of approximately 25% and gastrointestinal tract deposition of approximately 75%. Since oral absorption may be contributing to systemic plasma concentrations, the effect of food on HMR1031 was assessed. This was a single-dose (3 mg), open-label, randomized, two-way crossover (fasted vs. fed) study in 8 healthy male subjects. Blood samples were collected at predose and up to 24 hours postdose. Plasma concentrations were determined by the LC/MS/MS method. HMR1031 was rapidly absorbed, with median tmax values of 1.0 and 0.75 hours under fasted and fed conditions, respectively. Under fasted conditions, mean AUCinfinity and Cmax values were 16.4 ng x h/mL and 4.56 ng/mL, respectively. Under fed conditions, mean AUCinfinity and Cmax values decreased to 11.7 ng x h/mL and 2.81 ng/mL, respectively. The mean terminal elimination half-life (t1/2) for both treatment groups was similar (2.7 h). HMR1031 population estimates of the apparent clearance, apparent volume of distribution, and absorption rate were 225 L/h (4.1% coefficient of variation [CV]), 44.5 L (26% CV), and 0.340 h-1 (7.0% CV), respectively. Food is a significant covariate on clearance. These data suggest that food unexpectedly decreases the systemic exposure of inhaled HMR1031 by approximately 30%, probably due to increased liver blood flow and increased biliary excretion. This decrease in systemic exposure is unlikely to affect the topical effect of the drug but may result in increased variability in plasma pharmacokinetics. The disposition and food effect of HMR1031 can be described using mixed-effect modeling.

  8. The 5-HT3 receptor antagonists ICS 205-930 and GR38032F, putative anxiolytic drugs, differ from diazepam in their pharmacological profile.

    Science.gov (United States)

    Papp, M; Przegalinski, E

    1989-01-01

    The pharmacological profile of the two 5-HT(3) (5-hydroxytryptamine) receptor antagonists, the putative anxiolytics ICS 205-930 and GR38032F was compared with that of diazepam in four standard behavioural tests in rats. All the investigated drugs induced an anxiolytic effect in the passive avoidance test, having reduced the latency to re-enter the chamber previously associated with an inescapable footshock, and increased the time spent in that chamber. On the basis of the lowest effective dose, both ICS 205-930 and GR38032F were about 20 times more potent than diazepam, though the anxiolytic activity of either 5- HT(3) receptor antagonist was confined to a narrow dose range (ICS 205-930: 93.7-187.5 μg/ kg, GR38032F: 125-375 μg/kg), their higher doses having been ineffective. The anxiolytic effect of diazepam, but not of ICS 205-930, was abolished by flumazenil. In contrast to diazepam, neither ICS 205-930 nor GR38032F-both given in doses up to 20 mg/kg-showed any activity in the pentylenetetrazol-induced seizures, open field, and rota-rod tests. These results suggest that the 5-HT(3) receptor antagonists may represent a new class of anxiolytic drugs devoid of anticonvulsant, sedative or muscle-relaxant properties, and that their anxi olytic activity is not mediated by benzodiazepine receptors.

  9. Computational analysis of novel drugs designed for use as acetylcholinesterase inhibitors and histamine H3 receptor antagonists for Alzheimer's disease by docking, scoring and de novo evolution.

    Science.gov (United States)

    Chen, Po-Yuan; Tsai, Ching-Tsan; Ou, Che-Yen; Hsu, Wei-Tse; Jhuo, Mien-De; Wu, Chieh-Hsi; Shih, Tzu-Ching; Cheng, Tzu-Hurng; Chung, Jing-Gung

    2012-04-01

    Alzheimer's disease (AD) was first described by Alois Alzheimer in 1907. AD is the most prevalent dementia- related disease, affecting over 20 million individuals worldwide. Currently, however, only a handful of drugs are available and they are at best only able to offer some relief of symptoms. Acetylcholinesterase (AChE) inhibitors, antioxidants, metal chelators, monoamine oxidase inhibitors, anti-inflammatory drugs and NMDA inhibitors are usually used to attempt to cure this disease. AChE inhibitors are the most effective therapy for AD at present. Researchers have found that histamine H3 receptor antagonists decrease re-uptake of acetylcholine and the nervous transmitter substance acetylcholine increases. In this study, we designed compounds by using docking, de novo evolution and adsorption, distribution, metabolism, excretion and toxicity (ADMET) analysis to AChE inhibitors as well as histamine H3 receptor antagonists to forward drug research and investigate the potent compounds which can pass through the blood-brain barrier. The novel drugs may be useful for the treatment of AD, based on the results of this theoretical calculation study. We will subsequently examine them in future experiments.

  10. Histamine H3 receptor antagonists/inverse agonists on cognitive and motor processes: relevance to Alzheimer's disease, ADHD, schizophrenia, and drug abuse.

    Science.gov (United States)

    Vohora, Divya; Bhowmik, Malay

    2012-01-01

    Histamine H3 receptor (H3R) antagonists/inverse agonists possess potential to treat diverse disease states of the central nervous system (CNS). Cognitive dysfunction and motor impairments are the hallmark of multifarious neurodegenerative and/or psychiatric disorders. This review presents the various neurobiological/neurochemical evidences available so far following H3R antagonists in the pathophysiology of Alzheimer's disease (AD), attention-deficit hyperactivity disorder (ADHD), schizophrenia, and drug abuse each of which is accompanied by deficits of some aspects of cognitive and/or motor functions. Whether the H3R inverse agonism modulates the neurochemical basis underlying the disease condition or affects only the cognitive/motor component of the disease process is discussed with the aim to provide a rationale for their use in diverse disease states that are interlinked and are accompanied by some common motor, cognitive and attentional deficits.

  11. Dynamics of vitamin K antagonist and new oral anticoagulants use in atrial fibrillation: a Danish drug utilization study

    DEFF Research Database (Denmark)

    Pottegård, Anton; Poulsen, B. K.; Larsen, Michael Due;

    2014-01-01

    BackgroundDetailed data on real-life utilization of vitamin K antagonists (VKAs) and new oral anticoagulants (NOACs) in atrial fibrillation are sparse. ObjectivesTo describe the dynamics of VKA and NOAC use: that is, (i) how patients moved in and out of, as well as between, use of VKAs and NOACs...

  12. Serendipity in drug-discovery: a new series of 2-(benzyloxy)benzamides as TRPM8 antagonists.

    Science.gov (United States)

    Brown, Alan; Ellis, David; Favor, David A; Kirkup, Tony; Klute, Wolfgang; MacKenny, Malcolm; McMurray, Gordon; Stennett, Adam

    2013-11-15

    A new series of 2-(benzyloxy)benzamides are presented that are potent functional antagonists of TRPM8 and possess improved LipE and LE compared to the original lead. They were discovered through a series of compound libraries and we present a powerful visualization method for the chemical space explored with each library. Remarkably this new series originated from the highest risk design strategy where compounds were synthesised with the least degree of similarity to the lead structure.

  13. Floating drug delivery of a locally acting H2-antagonist: an approach using an in situ gelling liquid formulation.

    Science.gov (United States)

    Rohith, Ganapati; Sridhar, Bhimagoni Keshavamurthy; Srinatha, Anegundha

    2009-09-01

    In the present work, a gastroretentive in situ gelling liquid formulation for controlled delivery of ranitidine was formulated using sodium alginate (low, medium and high viscosity grades), calcium carbonate (source of cations) and ranitidine. Prepared formulations were evaluated for viscosity, buoyancy lag time and buoyancy duration, drug content and in vitro drug release. Formulation variables such as concentration of sodium alginate, calcium carbonate and drug significantly affected the formulation viscosity, floating behavior and in vitro drug release. Analysis of the release pattern showed that the drug release from in situ gel followed a diffusion mechanism.

  14. Dynamic Regulation of Quaternary Organization of the M1 Muscarinic Receptor by Subtype-selective Antagonist Drugs*

    Science.gov (United States)

    Pediani, John D.; Ward, Richard J.; Godin, Antoine G.; Marsango, Sara

    2016-01-01

    Although rhodopsin-like G protein-coupled receptors can exist as both monomers and non-covalently associated dimers/oligomers, the steady-state proportion of each form and whether this is regulated by receptor ligands are unknown. Herein we address these topics for the M1 muscarinic acetylcholine receptor, a key molecular target for novel cognition enhancers, by using spatial intensity distribution analysis. This method can measure fluorescent particle concentration and assess oligomerization states of proteins within defined regions of living cells. Imaging and analysis of the basolateral surface of cells expressing some 50 molecules·μm−2 human muscarinic M1 receptor identified a ∼75:25 mixture of receptor monomers and dimers/oligomers. Both sustained and shorter term treatment with the selective M1 antagonist pirenzepine resulted in a large shift in the distribution of receptor species to favor the dimeric/oligomeric state. Although sustained treatment with pirenzepine also resulted in marked up-regulation of the receptor, simple mass action effects were not the basis for ligand-induced stabilization of receptor dimers/oligomers. The related antagonist telenzepine also produced stabilization and enrichment of the M1 receptor dimer population, but the receptor subtype non-selective antagonists atropine and N-methylscopolamine did not. In contrast, neither pirenzepine nor telenzepine altered the quaternary organization of the related M3 muscarinic receptor. These data provide unique insights into the selective capacity of receptor ligands to promote and/or stabilize receptor dimers/oligomers and demonstrate that the dynamics of ligand regulation of the quaternary organization of G protein-coupled receptors is markedly more complex than previously appreciated. This may have major implications for receptor function and behavior. PMID:27080256

  15. Dynamic Regulation of Quaternary Organization of the M1 Muscarinic Receptor by Subtype-selective Antagonist Drugs.

    Science.gov (United States)

    Pediani, John D; Ward, Richard J; Godin, Antoine G; Marsango, Sara; Milligan, Graeme

    2016-06-17

    Although rhodopsin-like G protein-coupled receptors can exist as both monomers and non-covalently associated dimers/oligomers, the steady-state proportion of each form and whether this is regulated by receptor ligands are unknown. Herein we address these topics for the M1 muscarinic acetylcholine receptor, a key molecular target for novel cognition enhancers, by using spatial intensity distribution analysis. This method can measure fluorescent particle concentration and assess oligomerization states of proteins within defined regions of living cells. Imaging and analysis of the basolateral surface of cells expressing some 50 molecules·μm(-2) human muscarinic M1 receptor identified a ∼75:25 mixture of receptor monomers and dimers/oligomers. Both sustained and shorter term treatment with the selective M1 antagonist pirenzepine resulted in a large shift in the distribution of receptor species to favor the dimeric/oligomeric state. Although sustained treatment with pirenzepine also resulted in marked up-regulation of the receptor, simple mass action effects were not the basis for ligand-induced stabilization of receptor dimers/oligomers. The related antagonist telenzepine also produced stabilization and enrichment of the M1 receptor dimer population, but the receptor subtype non-selective antagonists atropine and N-methylscopolamine did not. In contrast, neither pirenzepine nor telenzepine altered the quaternary organization of the related M3 muscarinic receptor. These data provide unique insights into the selective capacity of receptor ligands to promote and/or stabilize receptor dimers/oligomers and demonstrate that the dynamics of ligand regulation of the quaternary organization of G protein-coupled receptors is markedly more complex than previously appreciated. This may have major implications for receptor function and behavior. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

  16. Orexin receptor antagonists differ from standard sleep drugs by promoting sleep at doses that do not disrupt cognition.

    Science.gov (United States)

    Uslaner, Jason M; Tye, Spencer J; Eddins, Donnie M; Wang, Xiaohai; Fox, Steven V; Savitz, Alan T; Binns, Jacquelyn; Cannon, Christopher E; Garson, Susan L; Yao, Lihang; Hodgson, Robert; Stevens, Joanne; Bowlby, Mark R; Tannenbaum, Pamela L; Brunner, Joseph; Mcdonald, Terrence P; Gotter, Anthony L; Kuduk, Scott D; Coleman, Paul J; Winrow, Christopher J; Renger, John J

    2013-04-03

    Current treatments for insomnia, such as zolpidem (Ambien) and eszopiclone (Lunesta), are γ-aminobutyric acid type A (GABAA)-positive allosteric modulators that carry a number of side effects including the potential to disrupt cognition. In an effort to develop better tolerated medicines, we have identified dual orexin 1 and 2 receptor antagonists (DORAs), which promote sleep in preclinical animal models and humans. We compare the effects of orally administered eszopiclone, zolpidem, and diazepam to the dual orexin receptor antagonist DORA-22 on sleep and the novel object recognition test in rat, and on sleep and two cognition tests (delayed match to sample and serial choice reaction time) in the rhesus monkey. Each compound's minimal dose that promoted sleep versus the minimal dose that exerted deficits in these cognitive tests was determined, and a therapeutic margin was established. We found that DORA-22 has a wider therapeutic margin for sleep versus cognitive impairment in rat and rhesus monkey compared to the other compounds tested. These data were further supported with the demonstration of a wider therapeutic margin for DORA-22 compared to the other compounds on sleep versus the expression of hippocampal activity-regulated cytoskeletal-associated protein (Arc), an immediate-early gene product involved in synaptic plasticity. These findings suggest that DORAs might provide an effective treatment for insomnia with a greater therapeutic margin for sleep versus cognitive disturbances compared to the GABAA-positive allosteric modulators currently in use.

  17. Influence of MPEP (a selective mGluR5 antagonist) on the anticonvulsant action of novel antiepileptic drugs against maximal electroshock-induced seizures in mice.

    Science.gov (United States)

    Zolkowska, Dorota; Kondrat-Wrobel, Maria W; Florek-Luszczki, Magdalena; Luszczki, Jarogniew J

    2016-02-04

    The aim of this study was to determine the effects of 2-methyl-6-(phenylethynyl)pyridine (MPEP - a selective antagonist for the glutamate metabotropic receptor subtype mGluR5) on the protective action of some novel antiepileptic drugs (lamotrigine, oxcarbazepine, pregabalin and topiramate) against maximal electroshock-induced seizures in mice. Brain concentrations of antiepileptic drugs were measured to determine whether MPEP altered pharmacokinetics of antiepileptic drugs. Intraperitoneal injection of 1.5 and 2mg/kg of MPEP significantly elevated the threshold for electroconvulsions in mice, whereas MPEP at a dose of 1mg/kg considerably enhanced the anticonvulsant activity of pregabalin and topiramate, but not that of lamotrigine or oxcarbazepine in the maximal electroshock-induced seizures in mice. Pharmacokinetic results revealed that MPEP (1mg/kg) did not alter total brain concentrations of pregabalin and topiramate, and the observed effect in the mouse maximal electroshock seizure model was pharmacodynamic in nature. Collectively, our preclinical data suggest that MPEP may be a safe and beneficial adjunct to the therapeutic effects of antiepileptic drugs in human patients. Copyright © 2015 Elsevier Inc. All rights reserved.

  18. Repositioning of Tyrosine Kinase Inhibitors as Antagonists of ATP-Binding Cassette Transporters in Anticancer Drug Resistance

    Directory of Open Access Journals (Sweden)

    Yi-Jun Wang

    2014-09-01

    Full Text Available The phenomenon of multidrug resistance (MDR has attenuated the efficacy of anticancer drugs and the possibility of successful cancer chemotherapy. ATP-binding cassette (ABC transporters play an essential role in mediating MDR in cancer cells by increasing efflux of drugs from cancer cells, hence reducing the intracellular accumulation of chemotherapeutic drugs. Interestingly, small-molecule tyrosine kinase inhibitors (TKIs, such as AST1306, lapatinib, linsitinib, masitinib, motesanib, nilotinib, telatinib and WHI-P154, have been found to have the capability to overcome anticancer drug resistance by inhibiting ABC transporters in recent years. This review will focus on some of the latest and clinical developments with ABC transporters, TKIs and anticancer drug resistance.

  19. Combined drug therapy in porcine endotoxemia. Hemodynamic and proteolytic effects of antagonists against histamine, serotonin and endorphin.

    Science.gov (United States)

    Naess, F; Roeise, O; Stadaas, J O; Aasen, A O

    1990-01-01

    In order to investigate the importance of potential mediators of pathophysiologic derangements in endotoxemia, we have examined the effects of the combined administration of antagonists against histamine, serotonin and endorphins in a porcine model of endotoxemia. The treatment regimen significantly reduced the increase in pulmonary artery pressure, pulmonary vascular resistance and systemic arterial pressure seen in the early stages of endotoxemia. Also, cardiac output was better maintained. However, the hemodynamic performance after an observation period of 5 h was not statistically different from untreated animals. The treatment regimen did not hinder the activation of the kallikreinkinin and fibrinolytic systems of plasma, which was evident in both treated and untreated animals, and could not counteract the increase in hematocrit or leukopenia seen in this model. This study shows that the combined blocking of histamine, serotonin and endorphines is not enough to abrogate the detrimental effects of endotoxin in a porcine model.

  20. The antagonistic effect of antipsychotic drugs on a HEK293 cell line stably expressing human alpha(1A1)-adrenoceptors

    DEFF Research Database (Denmark)

    Nourian, Zahra; Mulvany, Michael J; Nielsen, Karsten Bork

    2008-01-01

    challenged with phenylephrine (EC(50)=1.61x10(-8) M). From Schild analysis, prazosin, sertindole, risperidone, and haloperidol caused a concentration-dependent, rightward shift of the cumulative concentration-response curves for phenylephrine in cells expressing human recombinant alpha(1A1)-adrenoceptors...... human alpha(1A1)-adrenoceptors in competition binding studies confirmed much higher antagonist affinity of sertindole and risperidone than haloperidol for these receptors. In summary, it can be concluded that there is an approximately 10-fold higher adrenoceptor affinity of risperidone and sertindole...... for human alpha(1A1)-adrenoceptors compared to haloperidol. These findings are consistent with the observation that risperidone and sertindole have a higher incidence of orthostatic hypotension than haloperidol....

  1. Opposite effects of glutamate antagonists and antiparkinsonian drugs on the activities of DOPA decarboxylase and 5-HTP decarboxylase in the rat brain.

    Science.gov (United States)

    Fisher, A; Starr, M S

    2000-06-23

    This study measured the activities of L-DOPA and 5-HTP decarboxylase (DDC and 5-HTPDC) in the substantia nigra and corpus striatum of reserpine-treated rats. Acute injection of the NMDA receptor antagonists CGP 40116 (5 mg/kg) and HA 966 (5 mg/kg), and to a lesser extent eliprodil (10 mg/kg), greatly elevated DDC in both structures, whilst having no effect on (nigra) or inhibiting (striatum) 5-HTPDC. L-DOPA (25 mg/kg) on its own inhibited both enzymes in either brain region. The weak NMDA receptor-channel blockers (and antiparkinsonian drugs) budipine (10 mg/kg), memantine (40 mg/kg) and amantadine (40 mg/kg) strongly increased DDC, whilst not affecting or decreasing 5-HTPDC activity in nigra and striatum. The L-DOPA-induced suppression of DDC was mostly reversed by all three antiparkinsonian drugs, whilst L-DOPA-induced inhibition of 5-HTPDC was only reversed by CGP 40116 (striatum only). It is concluded that glutamate exerts a differential physiological influence on the biosynthesis of dopamine and 5-HT in the brain, by tonically suppressing DDC and tonically stimulating 5-HTPDC. The L-DOPA-induced reduction in DDC may help to explain the eventual loss of efficacy of L-DOPA therapy in parkinsonian patients. It is suggested, however, that it may be possible to extend the lifetime of L-DOPA therapy with drugs which potentiate the activity of DDC, such as budipine and the 1-aminoadamantanes.

  2. Antagonistic changes in sensitivity to antifungal drugs by mutations of an important ABC transporter gene in a fungal pathogen.

    Directory of Open Access Journals (Sweden)

    Wenjun Guan

    Full Text Available Fungal pathogens can be lethal, especially among immunocompromised populations, such as patients with AIDS and recipients of tissue transplantation or chemotherapy. Prolonged usage of antifungal reagents can lead to drug resistance and treatment failure. Understanding mechanisms that underlie drug resistance by pathogenic microorganisms is thus vital for dealing with this emerging issue. In this study, we show that dramatic sequence changes in PDR5, an ABC (ATP-binding cassette efflux transporter protein gene in an opportunistic fungal pathogen, caused the organism to become hypersensitive to azole, a widely used antifungal drug. Surprisingly, the same mutations conferred growth advantages to the organism on polyenes, which are also commonly used antimycotics. Our results indicate that Pdr5p might be important for ergosterol homeostasis. The observed remarkable sequence divergence in the PDR5 gene in yeast strain YJM789 may represent an interesting case of adaptive loss of gene function with significant clinical implications.

  3. Galanin receptor antagonists attenuate spinal antinociceptive effects of DAMGO, tramadol and non-opioid drugs in rats

    NARCIS (Netherlands)

    Selve, N; Englberger, W; Friderichs, E; Hennies, HH; Reimann, W; Wilffert, B

    1996-01-01

    The involvement of endogenous galanin to antinociception elicited by intrathecally (i.t.) or systemically administered drugs from different chemical and therapeutic classes was investigated using the rat Randall-Selitto or the rat tail-flick test, in the absence or presence of the i.t. administered

  4. Galanin receptor antagonists attenuate spinal antinociceptive effects of DAMGO, tramadol and non-opioid drugs in rats

    NARCIS (Netherlands)

    Selve, N; Englberger, W; Friderichs, E; Hennies, HH; Reimann, W; Wilffert, B

    1996-01-01

    The involvement of endogenous galanin to antinociception elicited by intrathecally (i.t.) or systemically administered drugs from different chemical and therapeutic classes was investigated using the rat Randall-Selitto or the rat tail-flick test, in the absence or presence of the i.t. administered

  5. GABAB antagonists

    DEFF Research Database (Denmark)

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

    1994-01-01

    Phaclofen, which is the phosphonic acid analogue of the GABAB agonist (RS)-3-(4-chlorophenyl)-4-aminobutyric acid (baclofen), is a GABAB antagonist. As part of our studies on the structural requirements for activation and blockade of GABAB receptors, we have resolved phaclofen using chiral chroma...

  6. Peripheral opioid antagonist enhances the effect of anti-tumor drug by blocking a cell growth-suppressive pathway in vivo.

    Directory of Open Access Journals (Sweden)

    Masami Suzuki

    Full Text Available The dormancy of tumor cells is a major problem in chemotherapy, since it limits the therapeutic efficacy of anti-tumor drugs that only target dividing cells. One potential way to overcome chemo-resistance is to "wake up" these dormant cells. Here we show that the opioid antagonist methylnaltrexone (MNTX enhances the effect of docetaxel (Doc by blocking a cell growth-suppressive pathway. We found that PENK, which encodes opioid growth factor (OGF and suppresses cell growth, is predominantly expressed in diffuse-type gastric cancers (GCs. The blockade of OGF signaling by MNTX releases cells from their arrest and boosts the effect of Doc. In comparison with the use of Doc alone, the combined use of Doc and MNTX significantly prolongs survival, alleviates abdominal pain, and diminishes Doc-resistant spheroids on the peritoneal membrane in model mice. These results suggest that blockade of the pathways that suppress cell growth may enhance the effects of anti-tumor drugs.

  7. A maraviroc-resistant HIV-1 with narrow cross-resistance to other CCR5 antagonists depends on both N-terminal and extracellular loop domains of drug-bound CCR5.

    Science.gov (United States)

    Tilton, John C; Wilen, Craig B; Didigu, Chukwuka A; Sinha, Rohini; Harrison, Jessamina E; Agrawal-Gamse, Caroline; Henning, Elizabeth A; Bushman, Frederick D; Martin, Jeffrey N; Deeks, Steven G; Doms, Robert W

    2010-10-01

    CCR5 antagonists inhibit HIV entry by binding to a coreceptor and inducing changes in the extracellular loops (ECLs) of CCR5. In this study, we analyzed viruses from 11 treatment-experienced patients who experienced virologic failure on treatment regimens containing the CCR5 antagonist maraviroc (MVC). Viruses from one patient developed high-level resistance to MVC during the course of treatment. Although resistance to one CCR5 antagonist is often associated with broad cross-resistance to other agents, these viruses remained sensitive to most other CCR5 antagonists, including vicriviroc and aplaviroc. MVC resistance was dependent upon mutations within the V3 loop of the viral envelope (Env) protein and was modulated by additional mutations in the V4 loop. Deep sequencing of pretreatment plasma viral RNA indicated that resistance appears to have occurred by evolution of drug-bound CCR5 use, despite the presence of viral sequences predictive of CXCR4 use. Envs obtained from this patient before and during MVC treatment were able to infect cells expressing very low CCR5 levels, indicating highly efficient use of a coreceptor. In contrast to previous reports in which CCR5 antagonist-resistant viruses interact predominantly with the N terminus of CCR5, these MVC-resistant Envs were also dependent upon the drug-modified ECLs of CCR5 for entry. Our results suggest a model of CCR5 cross-resistance whereby viruses that predominantly utilize the N terminus are broadly cross-resistant to multiple CCR5 antagonists, whereas viruses that require both the N terminus and antagonist-specific ECL changes demonstrate a narrow cross-resistance profile.

  8. Drug interactions between theophylline and H2-antagonists, roxatidine acetate hydrochloride and cimetidine: pharmacokinetic analysis in rats in vivo.

    Science.gov (United States)

    Nagai, N; Furuhata, M; Ogata, H

    1995-11-01

    The effects of roxatidine acetate hydrochloride (Rox) on the pharmacokinetics of theophylline were compared to those of cimetidine in rats in vivo, Cimetidine or Rox was maintained at a steady state level using continuous infusion, then theophylline was injected into the rats as a bolus (7.5 mg/kg). Cimetidine showed competitive inhibition of theophylline elimination in vivo, with an inhibition constant (Ki) of 28.5 microM. Cimetidine significantly decreased the total body clearance and extended the plasma half-life of theophylline, but did not change its volume of distribution. In contrast, Rox did not significantly influence the pharmacokinetics of theophylline in rats. The in vivo animal model used in the present study for investigating the mechanism of the drug interaction showed good agreement with the results obtained in clinical and in vitro studies.

  9. T-current related effects of antiepileptic drugs and a Ca2+ channel antagonist on thalamic relay and local circuit interneurons in a rat model of absence epilepsy.

    Science.gov (United States)

    Broicher, Tilman; Seidenbecher, Thomas; Meuth, Patrick; Munsch, Thomas; Meuth, Sven G; Kanyshkova, Tatyana; Pape, Hans-Christian; Budde, Thomas

    2007-09-01

    Channel blocking, anti-oscillatory, and anti-epileptic effects of clinically used anti-absence substances (ethosuximide, valproate) and the T-type Ca2+ current (IT) blocker mibefradil were tested by analyzing membrane currents in acutely isolated local circuit interneurons and thalamocortical relay (TC) neurons, slow intrathalamic oscillations in brain slices, and spike and wave discharges (SWDs) occurring in vivo in Wistar Albino Glaxo rats from Rijswijk (WAG/Rij). Substance effects in vitro were compared between WAG/Rij and a non-epileptic control strain, the ACI rats. Ethosuximide (ETX) and valproate were found to block IT in acutely isolated thalamic neurons. Block of IT by therapeutically relevant ETX concentrations (0.25-0.75 mM) was stronger in WAG/Rij, although the maximal effect at saturating concentrations (>or=10 mM) was stronger in ACI. Ethosuximide delayed the onset of the low threshold Ca2+ spike (LTS) of neurons recorded in slice preparations. Mibefradil (>or=2 microM) completely blocked IT and the LTS, dampened evoked thalamic oscillations, and attenuated SWDs in vivo. Computational modeling demonstrated that the complete effect of ETX can be replicated by a sole reduction of IT. However, the necessary degree of IT reduction was not induced by therapeutically relevant ETX concentrations. A combined reduction of IT, the persistent sodium current, and the Ca2+ activated K+ current resulted in an LTS alteration resembling the experimental observations. In summary, these results support the hypothesis of IT reduction as part of the mechanism of action of anti-absence drugs and demonstrate the ability of a specific IT antagonist to attenuate rhythmic burst firing and SWDs.

  10. A single center, open, randomized study investigating the clinical safety and the endothelial modulating effects of a prostacyclin analog in combination with eptifibatide in patients having undergone primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction

    DEFF Research Database (Denmark)

    Holmvang, Lene; Ostrowski, Sisse Rye; Dridi, Nadia Paarup

    2012-01-01

    Treatment with the endothelial modulator prostacyclin may be beneficial in patients with endothelial dysfunction. The primary aim of the present pilot study was to evaluate the safety and the potential endothelial modulating affect of the prostacyclin analog iloprost in patients with a recent ST...... segment elevation myocardial infarction (STEMI). Seventeen patients were randomized to either 24h of iloprost infusion in combination with low dose eptifibatide infusion or saline infusion+eptifibatide. The study was randomized and open labeled. None of the patients experienced any bleeding complications...... and vital signs were stable throughout the entire study period in both groups. None of the functional hemostatic whole blood assays applied in the present study differed between the active treatment and the placebo group. The endothelial marker, sE-selectin, displayed a decrease over time in the iloprost...

  11. ACTH antagonists

    Directory of Open Access Journals (Sweden)

    Adrian John Clark

    2016-08-01

    Full Text Available ACTH acts via a highly selective receptor that is a member of the melanocortin receptor subfamily of type 1 G protein-coupled receptors. The ACTH receptor, also known as the melanocortin 2 receptor (MC2R is unusual in that it is absolutely dependent on a small accessory protein, melanocortin receptor accessory protein (MRAP for cell surface expression and function. ACTH is the only known naturally occurring agonist for this receptor. This lack of redundancy and high degree of ligand specificity suggests that antagonism of this receptor could provide a useful therapeutic aid and a potential investigational tool. Clinical situations in which this could be useful include (1 Cushing’s disease and ectopic ACTH syndrome – especially whilst preparing for definitive treatment of a causative tumour, or in refractory cases, or (2 congenital adrenal hyperplasia – as an adjunct to glucocorticoid replacement. A case for antagonism in other clinical situations in which there is ACTH excess can also be made. In this article we will explore the scientific and clinical case for an ACTH antagonist, and will review the evidence for existing and recently described peptides and modified peptides in this role.

  12. Neuroprotection Against NMDA Induced Cell Death in Rat Nucleus Basalis by Ca2+ Antagonist Nimodipine, Influence of Aging and Developmental Drug Treatment

    NARCIS (Netherlands)

    Luiten, P.G.M.; Douma, B.R.K.; Zee, E.A. van der; Nyakas, C.

    1995-01-01

    In the current study the neuroprotective effect of the L-type calcium channel antagonist nimodipine in rat brain was investigated in N-methyl-D-aspartate-induced neuronal degeneration in vivo. In the present model NMDA was unilaterally injected in the magnocellular nucleus basalis and the neurotoxic

  13. Newer antithrombotic drugs

    Science.gov (United States)

    Sikka, Pranav; Bindra, V. K.

    2010-01-01

    Thromboembolic disorders are one of the disorders for which we are still on the look out for a safe and efficient drug. Despite the widespread use of antithrombotic drugs for the prevention and treatment of arterial and venous thrombosis, thromboembolic diseases continue to be a major cause of death and disability worldwide. This shows our inefficiency in searching efficacious and safe antithrombotic drugs. We have reached the basic mechanism of thrombus formation and by interrupting various steps of this mechanism, we can prevent as well as treat thromboembolic disorders. In continuation of Aspirin, now, we are using Clopidogrel, Ticlopidine and GpIIb/IIIa inhibitors (Abciximab, Tirofiban and Eptifibatide). Warfarin is an old antithrombotic drug which is still being used; but due to various side effects and drug interactions, we are bound to use newer drugs. Newer antiplatelet drugs include Prasugrel, Ticagrelor and Cangrelor, whereas newer thrombin inhibitors are Ximelgatran and Dabigatran. Apixaban is also a newer entry in this category as factor Xa inhibitor. Idrabiotaparinux is an indirect inhibitor of Xa as it accelerates the activity of antithrombin. Moreover, researches and trials for better and safe drugs are ongoing. PMID:21572750

  14. Chemical Feature-Based Molecular Modeling of Urotensin-II Receptor Antagonists: Generation of Predictive Pharmacophore Model for Early Drug Discovery

    Directory of Open Access Journals (Sweden)

    Anubhuti Pandey

    2014-01-01

    Full Text Available For a series of 35 piperazino-phthalimide and piperazino-isoindolinone based urotensin-II receptor (UT antagonists, a thoroughly validated 3D pharmacophore model has been developed, consisting of four chemical features: one hydrogen bond acceptor lipid (HBA_L, one hydrophobe (HY, and two ring aromatic (RA. Multiple validation techniques like CatScramble, test set prediction, and mapping analysis of advanced known antagonists have been employed to check the predictive power and robustness of the developed model. The results demonstrate that the best model, Hypo 1, shows a correlation (r of 0.902, a root mean square deviation (RMSD of 0.886, and the cost difference of 39.69 bits. The model obtained is highly predictive with good correlation values for both internal (r2=0.707 as well as external (r2=0.614 test set compounds. Moreover, the pharmacophore model has been used as a 3D query for virtual screening which served to detect prospective new lead compounds which can be further optimized as UT antagonists with potential for treatment of cardiovascular diseases.

  15. Simultaneous determination of moxifloxacin and H2 receptor antagonist in pharmaceutical dosage formulations by RP-HPLC: application to in vitro drug interactions

    Directory of Open Access Journals (Sweden)

    Najma Sultana

    2011-01-01

    Full Text Available Simultaneous determination of moxifloxacin (MOX and H2-antagonists was first time developed in bulk and formulations. Purospher STAR C18 (250 x 4.6 mm, 5 μm column was used. The mobile phase (methanol: water: ACN, 60:45:5 v/v/v, pH 2.7 was delivered at a flow rate of 1.0 mL min-1, eluent was monitored at 236, 270 and 310 nm for cimetidine, famotidine and ranitidine, respectively. The proposed method is specific, accurate (98-103%, precise (intra-day and inter-day variation 0.098-1.970% and linear (r>0.998. The LOD and LOQ were 0.006-0.018 and 0.019-0.005 μg mL-1, respectively. The statistical parameters were applied to verify the results. The method is applicable to routine analysis of formulations and interaction of MOX with H2-antagonist.

  16. The antidepressant drugs fluoxetine and duloxetine produce anxiolytic-like effects in a schedule-induced polydipsia paradigm in rats: enhancement of fluoxetine's effects by the α2 adrenoceptor antagonist yohimbine.

    Science.gov (United States)

    Prus, Adam J; Mooney-Leber, Sean M; Berquist, Michael D; Pehrson, Alan L; Porter, Nicholas P; Porter, Joseph H

    2015-08-01

    Similar to the time-course for treating depression, several weeks of administration are required for serotonin (5-HT) reuptake inhibitors to produce anxiolytic effects. Previous studies with the schedule-induced polydipsia paradigm (a putative preclinical anxiety model) have shown that repeated administration of antidepressant drugs is necessary to produce a suppression of polydipsia, which is interpreted as an anxiolytic-like effect. The present study sought to expand past findings by evaluating the selective 5-HT reuptake inhibitor (SSRI) fluoxetine and the 5-HT-norepinephrine reuptake inhibitor duloxetine in the schedule-induced polydipsia paradigm with rats. Dose combinations of the α2 adrenoceptor antagonist yohimbine with fluoxetine were also explored to determine whether α2 adrenoceptor antagonism could enhance the anxiolytic-like effects produced by an SSRI. Fluoxetine and duloxetine significantly reduced water intake over the course of daily administrations. Daily treatment with the combination of fluoxetine and yohimbine produced a significantly greater reduction in water intake than fluoxetine alone. The present results confirmed previous findings that inhibition of 5-HT reuptake reduces water consumption in this paradigm. The results for the α2 antagonist yohimbine (in combination with fluoxetine) also indicate that α2 adrenoceptor antagonism may significantly enhance anxiolytic-like effects of SSRIs.

  17. Emerging antithrombotic drugs: A review

    Directory of Open Access Journals (Sweden)

    P Sikka

    2011-01-01

    Full Text Available Thromboembolic disorders are one of the disorders for which the researchers are still in search for a safe and efficient drug. Despite the widespread use of antithrombotic drugs for the prevention and treatment of arterial and venous thrombosis, thromboembolic diseases continue to be a major cause of death and disability worldwide. This shows the researchers′ inefficiency in searching efficacious and safe antithrombotic drugs. The researchers have reached to the basic mechanism of thrombus formation and by interrupting various steps of this mechanism, they can prevent as well as treat thromboembolic disorders. In continuation of Aspirin, now, the researchers are using clopedogrel, Ticlopidine and GpIIb/IIIa inhibitors (Abciximab, Tirofiban and Eptifibatide. Warfarin is an old antithrombotic drug, which is still being used but due to various side effects and drug interactions, they are bound to use newer drugs. Newer antiplatelet drugs include prasugrel, ticagrelor, cangrelor and elinogrel whereas newer thrombin inhibitors are Ximelgatran and Dabigatran. Apixaban and edoxaban are also newer entry in this category as Factor Xa inhibitors. Idrabiotaparinux is an indirect inhibitor of Xa as it accelerates the activity of antithrombin. Moreover, researches and trials for better and safe drugs are going on.

  18. Characterization of preclinical in vitro and in vivo ADME properties and prediction of human PK using a physiologically based pharmacokinetic model for YQA-14, a new dopamine D3 receptor antagonist candidate for treatment of drug addiction.

    Science.gov (United States)

    Liu, Fei; Zhuang, Xiaomei; Yang, Cuiping; Li, Zheng; Xiong, Shan; Zhang, Zhiwei; Li, Jin; Lu, Chuang; Zhang, Zhenqing

    2014-07-01

    YQA-14 is a novel and selective dopamine D3 receptor antagonist, with potential for the treatment of drug addiction. However, earlier compounds in its structural class tend to have poor oral bioavailability. The objectives of this study were to characterize the preclinical absorption, distribution, metabolism and excretion (ADME) properties and pharmacokinetics (PK) of YQA-14, then to simulate the clinical PK of YQA-14 using a physiologically based pharmacokinetics (PBPK) model to assess the likelihood of developing YQA-14 as a clinical candidate. For human PK prediction, PBPK models were first built in preclinical species, rats and dogs, for validation purposes. The model was then modified by input of human in vitro ADME data obtained from in vitro studies. The study data showed that YQA-14 is a basic lipophilic compound, with rapid absorption (Tmax ~ 1 h) in both rats and dogs. Liver microsomal clearances and in vivo clearances were moderate in rats and dogs consistent with the moderate bioavailability observed in both species. The PBPK models built for rats and dogs simulated the observed PK data well in both species. The PBPK model refined with human data predicted that YQA-14 would have a clearance of 8.0 ml/min/kg, a volume distribution of 1.7 l/kg and a bioavailability of 16.9%. These acceptable PK properties make YQA-14 an improved candidate for further research and development as a potential dopamine D3R antagonism for the treatment of drug addiction in the clinic.

  19. The selective dopamine D₃ receptor antagonist SB-277011A attenuates drug- or food-deprivation reactivation of expression of conditioned place preference for cocaine in male Sprague-Dawley rats.

    Science.gov (United States)

    Ashby, Charles R; Rice, Onarae V; Heidbreder, Christian A; Gardner, Eliot L

    2015-06-01

    We determined the effect of the selective dopamine D3 receptor antagonist SB-277011A on reactivation of conditioned place preference (CPP) to cocaine elicited by priming injections of cocaine or exposure to food deprivation stress (21 h) in male Sprague-Dawley rats. Animals paired with the cocaine-associated chamber displayed a robust and consistent CPP response. This CPP was extinguished after repeated pairings of the conditioned stimuli (cocaine-paired chamber contextual cues) in the absence of the unconditioned stimulus (cocaine). Twenty-four hours later, the administration of 5 mg kg(-1) i.p. of cocaine (immediately before the test) or exposure to 21 h of food deprivation reactivated the expression of the cocaine-induced CPP. In contrast, administration of 1 ml kg(-1) i.p. of vehicle did not reactivate the CPP response. Administration of the selective dopamine D3 receptor antagonist SB-277011A (3-24 mg kg(-1) i.p.) 30 min before cocaine administration on the test day produced a significant attenuation of CPP reactivation. Reactivation of the CPP response produced by food deprivation was also significantly attenuated by SB-277011A (6 or 12 mg kg(-1) i.p.) given 30 min before the test session. SB-277011A (12 or 24 mg kg(-1) i.p.) did not itself produce reactivation of the CPP response. Overall, these results suggest that the reactivation of the incentive value of drug-associated cues by cocaine or food deprivation is attenuated by selective antagonism of D3 receptors. © 2015 Wiley Periodicals, Inc.

  20. PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

    NARCIS (Netherlands)

    HOYER, D; BODDEKE, HWGM

    1993-01-01

    The absence of selective antagonists makes receptor characterization difficult, and largely dependent on the use of agonists. However, there has been considerable debate as to whether certain drugs acting at G protein-coupled receptors are better described as agonists, partial agonists or antagonist

  1. Use of Spectroscopic, Zeta Potential and Molecular Dynamic Techniques to Study the Interaction between Human Holo-Transferrin and Two Antagonist Drugs: Comparison of Binary and Ternary Systems

    Directory of Open Access Journals (Sweden)

    Mohammad Reza Saberi

    2012-03-01

    Full Text Available For the first time, the binding of ropinirole hydrochloride (ROP and aspirin (ASA to human holo-transferrin (hTf has been investigated by spectroscopic approaches (fluorescence quenching, synchronous fluorescence, time-resolved fluorescence, three-dimensional fluorescence, UV-vis absorption, circular dichroism, resonance light scattering, as well as zeta potential and molecular modeling techniques, under simulated physiological conditions. Fluorescence analysis was used to estimate the effect of the ROP and ASA drugs on the fluorescence of hTf as well as to define the binding and quenching properties of binary and ternary complexes. The synchronized fluorescence and three-dimensional fluorescence spectra demonstrated some micro-environmental and conformational changes around the Trp and Tyr residues with a faint red shift. Thermodynamic analysis displayed the van der Waals forces and hydrogen bonds interactions are the major acting forces in stabilizing the complexes. Steady-state and time-resolved fluorescence data revealed that the fluorescence quenching of complexes are static mechanism. The effect of the drugs aggregating on the hTf resulted in an enhancement of the resonance light scattering (RLS intensity. The average binding distance between were computed according to the forster non-radiation energy transfer theory. The circular dichroism (CD spectral examinations indicated that the binding of the drugs induced a conformational change of hTf. Measurements of the zeta potential indicated that the combination of electrostatic and hydrophobic interactions between ROP, ASA and hTf formed micelle-like clusters. The molecular modeling confirmed the experimental results. This study is expected to provide important insight into the interaction of hTf with ROP and ASA to use in various toxicological and therapeutic processes.

  2. Influence of the Calmodulin Antagonist EBB on Cyclin B1 and Cdc2-p34 in Human Drug-resistant Breast Cancer MCF-7/ADR Cells

    Institute of Scientific and Technical Information of China (English)

    Xu Shi; Huifang Zhu; Yanhong Cheng; Linglin Zou; Dongsheng Xiong; Yuan Zhou; Ming Yang; Dongmei Fan; Xiaohua Dai; Chunzheng Yang

    2008-01-01

    OBJECTIVE To investigate the influence of O-(4-ethoxyl-butyl)-berbamine (EBB) on the expression of cyclin B1 and cdc2-p34 in the human drug-resistant breast cancer MCF-7/ADR cell line.METHODS The MTT assay was used to assess the cytotoxicity of EBB. Different levels of EBB were added to different cell lines at series of time points solely or combined with doxorubicin (DOX)to detect the effect on the expression of cyclinB1 and cdc2-p34 by Western blots, cdc2-p34 tyrosine phosphorylation was detected by immunoprecipitation. In addition, apoptosis and cytoplastic Ca2+concentrations were systematically examined by laser scanning confocal microscopy (LSCM).RESULTS EBB showed little inhibitory activity on human umbilical vein endothelial cells (ECV304), whereas EBB inhibited cell growth (IC50 range, 4.55~15.74 μmol/L) in a variety of sensitive and drug-resistance cell lines. EBB also down-regulated the expression of cyclin B1 and cdc2-p34 in a concentration and time dependent manner, which was an important reason for the G2/M phase arrest. EBB was shown to induce apoptosis of MCF-7/ADR cells while increasing the level of cytoplastic Ca2+.CONCLUSION The low cytotoxicity of EBB suggests it may be useful as a rational reversal agent. The effect of EBB on cell cycle arrest and related proteins, apoptosis, and cytoplastic Ca2+ concentration may be involved in reversing multidrug resistance.

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

    DEFF Research Database (Denmark)

    Nielsen, Hans Jørgen

    1996-01-01

    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....

  4. CCR2 antagonists.

    Science.gov (United States)

    Struthers, Mary; Pasternak, Alexander

    2010-01-01

    Inhibition of CCR2 has been considered as a target for multiple therapeutic diseases including autoimmune disease, atherosclerosis, pain, and metabolic disease, based in part on the critical role this receptor plays on monocyte migration. Numerous companies have reported programs to identify CCR2 antagonists. Common challenges to the development of CCR2 agents have included poor activity at the rodent receptor and selectivity for both other chemokine receptors and ion channels. This review summarizes the rationale for targeting CCR2 in disease, the recent progress in the identification of potent and select CCR2 antagonists, and the current status of clinical trials for CCR2 agents.

  5. Opioid Antagonist Impedes Exposure.

    Science.gov (United States)

    Merluzzi, Thomas V.; And Others

    1991-01-01

    Thirty spider-phobic adults underwent exposure to 17 phobic-related, graded performance tests. Fifteen subjects were assigned to naltrexone, an opioid antagonist, and 15 were assigned to placebo. Naltrexone had a significant effect on exposure, with naltrexone subjects taking significantly longer to complete first 10 steps of exposure and with…

  6. Traxoprodil, a selective antagonist of the NR2B subunit of the NMDA receptor, potentiates the antidepressant-like effects of certain antidepressant drugs in the forced swim test in mice.

    Science.gov (United States)

    Poleszak, Ewa; Stasiuk, Weronika; Szopa, Aleksandra; Wyska, Elżbieta; Serefko, Anna; Oniszczuk, Anna; Wośko, Sylwia; Świąder, Katarzyna; Wlaź, Piotr

    2016-08-01

    One of the newest substances, whose antidepressant activity was shown is traxoprodil, which is a selective antagonist of the NR2B subunit of the NMDA receptor. The main goal of the present study was to evaluate the effect of traxoprodil on animals' behavior using the forced swim test (FST), as well as the effect of traxoprodil (10 mg/kg) on the activity of antidepressants, such as imipramine (15 mg/kg), fluoxetine (5 mg/kg), escitalopram (2 mg/kg) and reboxetine (2.5 mg/kg). Serotonergic lesion and experiment using the selective agonists of serotonin receptors 5-HT1A and 5-HT2 was conducted to evaluate the role of the serotonergic system in the antidepressant action of traxoprodil. Brain concentrations of tested agents were determined using HPLC. The results showed that traxoprodil at a dose of 20 and 40 mg/kg exhibited antidepressant activity in the FST and it was not related to changes in animals' locomotor activity. Co-administration of traxoprodil with imipramine, fluoxetine or escitalopram, each in subtherapeutic doses, significantly affected the animals' behavior in the FST and, what is important, these changes were not due to the severity of locomotor activity. The observed effect of traxoprodil is only partially associated with serotonergic system and is independent of the effect on the 5-HT1A and 5-HT2 serotonin receptors. The results of an attempt to assess the nature of the interaction between traxoprodil and the tested drugs show that in the case of joint administration of traxoprodil and fluoxetine, imipramine or escitalopram, there were interactions in the pharmacokinetic phase.

  7. PXR antagonists and implication in drug metabolism

    OpenAIRE

    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 endob...

  8. Barnidipine, a long-acting slow onset calcium antagonist.

    Science.gov (United States)

    Korstanje, C

    2000-11-01

    Barnidipine is a stereochemically pure dihydropyridine calcium antagonist with a high potency. The drug showed a slow onset and long-lasting vasorelaxating effect in vitro, and strong antihypertensive activity in hypertension models. Barnidipine was shown to have a high vasoselectivity and offered protection in cardiac and renal ischaemia models. The in vitro drug:drug interaction profile suggests a low potential for clinically relevant interactions with concomitant medication. It can be anticipated that barnidipine is an attractive calcium antagonist, offering good blood pressure control without compensatory baroreflex activity.

  9. Calcium antagonists and vasospasm.

    Science.gov (United States)

    Meyer, F B

    1990-04-01

    A critical review of the clinical data supports the conclusion that nimodipine decreases the severity of neurologic deficits and improves outcome after subarachnoid hemorrhage. The mechanisms by which mortality and morbidity are reduced are still controversial. First, the frequency of vasospasm is not altered (Figs. 5 and 6). Second, the consistent reversal of vasospasm once present has not been demonstrated either angiographically or by noninvasive cerebral blood flow studies. These observations suggest that there is either modification of microcirculatory flow (i.e., dilation of pial conducting vessels or decreased platelet aggregation) or a direct neuronal protective effect. As suggested previously, support for either mechanism is not resolute, and further investigation is necessary. Currently, nimodipine has been the most thoroughly investigated calcium antagonist both from an experimental and clinical perspective. Oral administration has had few reported complications. Therefore, the benefit/risk ratio clearly supports the prophylactic use of this calcium antagonist in patients of all clinical grades after subarachnoid hemorrhage. Evidence also indicates that starting nimodipine after the onset of delayed ischemic deficits is of benefit. Finally, it can be predicted that in the future additional calcium antagonists with more selective vascular or neuronal effects will be developed for use in neurologic disorders.

  10. Identification of a novel conformationally constrained glucagon receptor antagonist.

    Science.gov (United States)

    Lee, Esther C Y; Tu, Meihua; Stevens, Benjamin D; Bian, Jianwei; Aspnes, Gary; Perreault, Christian; Sammons, Matthew F; Wright, Stephen W; Litchfield, John; Kalgutkar, Amit S; Sharma, Raman; Didiuk, Mary T; Ebner, David C; Filipski, Kevin J; Brown, Janice; Atkinson, Karen; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2014-02-01

    Identification of orally active, small molecule antagonists of the glucagon receptor represents a novel treatment paradigm for the management of type 2 diabetes mellitus. The present work discloses novel glucagon receptor antagonists, identified via conformational constraint of current existing literature antagonists. Optimization of lipophilic ligand efficiency (LLE or LipE) culminated in enantiomers (+)-trans-26 and (-)-trans-27 which exhibit good physicochemical and in vitro drug metabolism profiles. In vivo, significant pharmacokinetic differences were noted with the two enantiomers, which were primarily driven through differences in clearance rates. Enantioselective oxidation by cytochrome P450 was ruled out as a causative factor for pharmacokinetic differences.

  11. Tetrahydroindolizinone NK1 antagonists.

    Science.gov (United States)

    Bao, Jianming; Lu, Huagang; Morriello, Gregori J; Carlson, Emma J; Wheeldon, Alan; Chicchi, Gary G; Kurtz, Marc M; Tsao, Kwei-Lan C; Zheng, Song; Tong, Xinchun; Mills, Sander G; DeVita, Robert J

    2010-04-01

    A new class of potent NK(1) receptor antagonists with a tetrahydroindolizinone core has been identified. This series of compounds demonstrated improved functional activities as compared to previously identified 5,5-fused pyrrolidine lead structures. SAR at the 7-position of the tetrahydroindolizinone core is discussed in detail. A number of compounds displayed high NK(1) receptor occupancy at both 1 h and 24 h in a gerbil foot tapping model. Compound 40 has high NK(1) binding affinity, good selectivity for other NK receptors and promising in vivo properties. It also has clean P(450) inhibition and hPXR induction profiles.

  12. [Cutaneous adverse effects of TNFalpha antagonists].

    Science.gov (United States)

    Failla, V; Sabatiello, M; Lebas, E; de Schaetzen, V; Dezfoulian, B; Nikkels, A F

    2012-01-01

    The TNFalpha antagonists, including adalimumab, etanercept and infliximab, represent a class of anti-inflammatory and immunosuppressive drugs. Although cutaneous adverse effects are uncommon, they are varied. There is no particular risk profile to develop cutaneous adverse effects. The principal acute side effects are injection site reactions and pruritus. The major long term cutaneous side effects are infectious and inflammatory conditions. Neoplastic skin diseases are exceptional. The association with other immunosuppressive agents can increase the risk of developing cutaneous adverse effects. Some adverse effects, such as lupus erythematosus, require immediate withdrawal of the biological treatment, while in other cases temporary withdrawal is sufficient. The majority of the other cutaneous adverse effects can be dealt without interrupting biologic treatment. Preclinical and clinical investigations revealed that the new biologics, aiming IL12/23, IL23 and IL17, present a similar profile of cutaneous adverse effects, although inflammatory skin reactions may be less often encountered compared to TNFalpha antagonists.

  13. Drug: D08229 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available br08303] R RESPIRATORY SYSTEM R03 DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES R03D OTHE...R SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES R03DC Leukotriene receptor antagonists R03DC03 Montelukast

  14. Drug: D08408 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available :br08303] R RESPIRATORY SYSTEM R03 DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES R03D OTH...ER SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES R03DC Leukotriene receptor antagonists R03DC02 Pranlukast

  15. Drug: D00411 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Therapeutic Chemical (ATC) classification [BR:br08303] R RESPIRATORY SYSTEM R03 DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES... R03D OTHER SYSTEMIC DRUGS FOR OBSTRUCTIVE AIRWAY DISEASES R03DC Leukotriene receptor antagonists

  16. An Experiment Research on Drug-resistance Mechanism of Prolactinoma and the Effect of Estrogen Receptor Antagonist%泌乳素腺瘤耐药性机制及雌激素受体拮抗剂治疗有效性的实验研究

    Institute of Scientific and Technical Information of China (English)

    董家军; 彭逸龙; 钟明谷; 伍益

    2015-01-01

    Objective:To investigate the forming mechanism of the drug resistance of prolactinoma and the effect of estrogen receptor antagonist.Methods:Conduct a random in-vitro comparative experiment,inves-tigate the effect of estrogen receptor in different concentration on the proliferation of prolactinoma cells.Re-sults:Estrogen receptor antagonist in high concentration has an obvious inhibitory effect on the proliferation of prolactinoma cells.Conclusion:Estrogen receptor antagonist has somewhat inhibitory effect on the prolifer-ation of prolactinoma,clinically,it is suggested to conduct treatment with it complicated with dopamine re-ceptor agonist ,it is helpful to control the forming of drug resistance,thus it is of important significance to the clinical treatment for patients.%目的::探究泌乳素腺瘤耐药性的形成机制以及探究雌激素受体拮抗剂治疗的有效性。方法:通过设立体外随机对照试验,探究不同浓度下的雌激素受体拮抗剂对泌乳素腺瘤细胞生产增殖状况的影响。结果:高浓度的雌激素受体拮抗剂对于泌乳素腺瘤的生产增殖有明显抑制作用。结论:雌激素受体拮抗剂对泌乳素腺瘤有一定的抑制作用,临床上可联合多巴胺受体激动剂进行治疗,有利于减少药物耐受性的形成,对于患者的临床治疗有着重要意义。

  17. 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...

  18. 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.

  19. 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...

  20. Serotonin 2A receptor antagonists for treatment of schizophrenia

    DEFF Research Database (Denmark)

    Ebdrup, Bjørn Hylsebeck; Rasmussen, Hans; Arnt, Jørn

    2011-01-01

    Introduction: All approved antipsychotic drugs share an affinity for the dopamine 2 (D2) receptor; however, these drugs only partially ameliorate the symptoms of schizophrenia. It is, therefore, of paramount importance to identify new treatment strategies for schizophrenia. Areas covered......: Preclinical, clinical and post-mortem studies of the serotonin 5-HT2A system in schizophrenia are reviewed. The implications of a combined D2 and 5-HT2A receptor blockade, which is obtained by several current antipsychotic drugs, are discussed, and the rationale for the development of more selective 5-HT2A...... receptor antagonists is evaluated. Moreover, the investigational pipeline of major pharmaceutical companies is examined and an Internet search conducted to identify other pharmaceutical companies investigating 5-HT2A receptor antagonists for the treatment of schizophrenia. Expert opinion: 5-HT2A receptor...

  1. Drug: D07520 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07520 Drug Bepridil (INN); Bepadin (TN) C24H34N2O 366.2671 366.5396 D07520.gif Antiarrhythmic...; Calcium antagonist; Coronary vasodilator Same as: C06847 ATC code: C08EA02 Class IV antiarrhythmic...36 Calcium channel blocking drugs map07037 Antiarrhythmic drugs map07231 Sodium channel blocking drugs Anato

  2. [Comparative pharmacophore analysis of dual dopamine D2/5-HT(2A) receptor antagonists].

    Science.gov (United States)

    Guo, Yan-shen; Guo, Zong-ru

    2009-03-01

    Dual dopamine D2/5-HT2A receptor antagonists have potent activity and are referred to atypical antipsychotics due to their lower propensity to elicit EPS and their moderate efficacy toward negative symptoms. However, an on-going challenge in developing atypical antipsychotics drugs is to maintain the favorable profiles and avoid of cardiovascular risk. In this paper, comparative pharmacophore analysis of dual dopamine D2/5-HT2A receptor antagonists, hERG K+ channel blockers, and alA adrenoceptor antagonists is carried out, and the results could give some insight into multi-target drug design.

  3. ETA-receptor antagonists or allosteric modulators?

    DEFF Research Database (Denmark)

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

    2011-01-01

    The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects. In resista......The paracrine signaling peptide endothelin-1 (ET1) is involved in cardiovascular diseases, cancer and chronic pain. It acts on class A G-protein-coupled receptors (GPCRs) but displays atypical pharmacology. It binds tightly to ET receptor type A (ET(A)) and causes long-lasting effects....... 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...

  4. Zebrafish phenotypic screen identifies novel Notch antagonists.

    Science.gov (United States)

    Velaithan, Vithya; Okuda, Kazuhide Shaun; Ng, Mei Fong; Samat, Norazwana; Leong, Sze Wei; Faudzi, Siti Munirah Mohd; Abas, Faridah; Shaari, Khozirah; Cheong, Sok Ching; Tan, Pei Jean; Patel, Vyomesh

    2017-04-01

    Zebrafish represents a powerful in vivo model for phenotype-based drug discovery to identify clinically relevant small molecules. By utilizing this model, we evaluated natural product derived compounds that could potentially modulate Notch signaling that is important in both zebrafish embryogenesis and pathogenic in human cancers. A total of 234 compounds were screened using zebrafish embryos and 3 were identified to be conferring phenotypic alterations similar to embryos treated with known Notch inhibitors. Subsequent secondary screens using HEK293T cells overexpressing truncated Notch1 (HEK293TΔE) identified 2 compounds, EDD3 and 3H4MB, to be potential Notch antagonists. Both compounds reduced protein expression of NOTCH1, Notch intracellular domain (NICD) and hairy and enhancer of split-1 (HES1) in HEK293TΔE and downregulated Notch target genes. Importantly, EDD3 treatment of human oral cancer cell lines demonstrated reduction of Notch target proteins and genes. EDD3 also inhibited proliferation and induced G0/G1 cell cycle arrest of ORL-150 cells through inducing p27(KIP1). Our data demonstrates the utility of the zebrafish phenotypic screen and identifying EDD3 as a promising Notch antagonist for further development as a novel therapeutic agent.

  5. Drug: D03792 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available eceptors 3-Ketosteroid receptor mineralocorticoid receptor [HSA:4306] [KO:K08555] Dicirenone D03792 Dicireno...D03792 Drug Dicirenone (USAN) C26H36O5 428.2563 428.561 D03792.gif Hypotensive; Aldosterone antagonist miner...alocorticoid receptor antagonist [HSA:4306] [KO:K08555] hsa04960(4306) Aldosterone-

  6. Drug: D00951 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available agonists/antagonists Therapeutic category of drugs in Japan [BR:br08301] 2 Agents affecting individual organs 24 Hormones...lassification [BR:br08302] Hormonal Agents, Stimulant/Replacement/Modifying (Sex Hormones/Modifiers) Progest... acetate (JAN/USP) Antineoplastics [BR:br08308] Hormones and hormone antagonist P

  7. Drug: D02148 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ergic; Histamine, H1-receptor antagonist ATC code: R06AX04 H1-receptor antagonist [...D02148 Drug Phenindamine tartrate (USAN); Nolahist (TN) C19H19N. C4H6O6 411.1682 411.4477 D02148.gif Antiall

  8. Drug: D03210 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03210 Drug Ancriviroc (USAN/INN) C28H37BrN4O3 556.2049 557.5224 D03210.gif Antiviral; Treatment of autoimmu...ne conditions [CCR5 antagonist] chemokine receptor 5 (CCR5) antagonist [HSA:1234] [

  9. Synthesis of potential mescaline antagonists.

    Science.gov (United States)

    DeSantis, F; Nieforth, K A

    1976-10-01

    1-[2-(3,4,5-Trimethoxyphenyl)ethyl]-3-pyrroline, 2-(3,4,5-trimethoxybenzyl)-1,2,3,6-tetrahydropyridine, N-n-propylmescaline, N-cyclopropylmethylmescaline, and N-allylmescaline were synthesized as potential mescaline antagonists. The ability of these compounds to antagonize mescaline-induced disruption of swim behavior is also given.

  10. 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......)-phenylethylamine salt of N-BOC-(R)-ATAA. Like ATAA, neither (R)- nor (S)-ATAA significantly affected (IC50 > 100 microM) the receptor binding of tritiated AMPA, kainic acid, or (RS)-3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid, the latter being a competitive NMDA antagonist. Electrophysiological experiments......, using the rat cortical wedge preparation, showed the NMDA antagonist effect as well as the AMPA antagonist effect of ATAA to reside exclusively in the (R)-enantiomer (Ki = 75 +/- 5 microM and 57 +/- 1 microM, respectively). Neither (R)- nor (S)-ATAA significantly reduced kainic acid-induced excitation...

  11. DEVELOPMENT OF NEW LHRH ANTAGONISTS

    Institute of Scientific and Technical Information of China (English)

    PENGDun-Ren; XIAOShao-Bo

    1989-01-01

    An ideal antagonist of LHRH is one which can act on the pitutary to inhibit LHRH-stimulatod LH / FSH secretion by competitive occupying the LHRH receptor in the pitutary gland. Its action should be very specific, fast and highly effective, the durations

  12. Survey of H2-antagonist usage in acute upper gastrointestinal hemorrhage.

    Science.gov (United States)

    Bhatt, B D; Meriano, F V; Phipps, T L; Ho, H; Zuckerman, M J

    1990-02-01

    H2-antagonists are frequently used in the management of upper gastrointestinal (UGI) hemorrhage despite their lack of proven efficacy. In order to determine the pattern of H2-antagonist usage for this indication, we retrospectively reviewed the charts of 137 patients admitted with acute UGI bleeding over a 1-year period at two teaching hospitals in West Texas. An H2-antagonist was ordered in 89% of patients (77%) intravenous, 12% oral). It was administered within 2 h of admission in 25% of these patients, within 4 h in 54%, and within 8 h in 78%. An H2-antagonist was ordered among the initial six orders in 49% and among the initial 10 orders in 77% of patients. Considering orders for specific therapies, an H2-antagonist was in the initial three orders in 60% of patients and among the initial six orders in 97%. Of the patients who were prescribed an H2-antagonist and who also had upper endoscopy, the drug was ordered prior to endoscopy in 86%. This review of H2-antagonist usage in the management of acute UGI bleeding has identified a prescribing pattern of writing for these drugs early in the sequence of order writing, with the drugs being given early in the course of hospitalization.

  13. Potent and orally efficacious benzothiazole amides as TRPV1 antagonists.

    Science.gov (United States)

    Besidski, Yevgeni; Brown, William; Bylund, Johan; Dabrowski, Michael; Dautrey, Sophie; Harter, Magali; Horoszok, Lucy; Hu, Yin; Johnson, Dean; Johnstone, Shawn; Jones, Paul; Leclerc, Sandrine; Kolmodin, Karin; Kers, Inger; Labarre, Maryse; Labrecque, Denis; Laird, Jennifer; Lundström, Therese; Martino, John; Maudet, Mickaël; Munro, Alexander; Nylöf, Martin; Penwell, Andrea; Rotticci, Didier; Slaitas, Andis; Sundgren-Andersson, Anna; Svensson, Mats; Terp, Gitte; Villanueva, Huascar; Walpole, Christopher; Zemribo, Ronald; Griffin, Andrew M

    2012-10-01

    Benzothiazole amides were identified as TRPV1 antagonists from high throughput screening using recombinant human TRPV1 receptor and structure-activity relationships were explored to pinpoint key pharmacophore interactions. By increasing aqueous solubility, through the attachment of polar groups to the benzothiazole core, and enhancing metabolic stability, by blocking metabolic sites, the drug-like properties and pharmokinetic profiles of benzothiazole compounds were sufficiently optimized such that their therapeutic potential could be verified in rat pharmacological models of pain.

  14. Drug: D00456 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Antiemetics Emetogenic Therapy Adjuncts Ondansetron D00456 Ondansetron (JAN/USP/...(5HT3) antagonists A04AA01 Ondansetron D00456 Ondansetron (JAN/USP/INN) USP drug classification [BR:br08302

  15. Drug: D01782 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available antagonists Therapeutic category of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 44 Allergic agents 441 Antihista...mines 4412 Tripelennamines D01782 Triprolidine hydrochloride hydrate (JAN); Triprol

  16. Drug: D01172 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available r antagonists Therapeutic category of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 44 Allergic agents 441 Antihis...tamines 4415 Diphenylpyralines D01172 Diphenylpyraline hydrochloride (JAN) Anatomic

  17. Drug: D01115 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 5.gif Antihypertensive: Aldosterone antagonist Same as: C12512 Therapeutic category: 2149 ATC code: C03DA04 mineral...on of drugs [BR:br08310] Nuclear receptors Estrogen like receptors 3-Ketosteroid receptor mineralocorticoid

  18. Drug: D10284 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10284 Mixture, Drug Olmesartan medoxomil - hydrochlorothiazide mixt; Benicar hct (TN) Olmesa...Angiotensin II antagonists and diuretics C09DA08 Olmesartan medoxomil and diuretics D10284 Olmesartan medoxomil - hydrochlorothiazide mixt PubChem: 163312315 ...

  19. Drug: D01413 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available /antagonists Therapeutic category of drugs in Japan [BR:br08301] 2 Agents affecting individual organs 24 Hormones...cation [BR:br08302] Hormonal Agents, Stimulant/Replacement/Modifying (Sex Hormones

  20. Drug: D10283 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10283 Mixture, Drug Eprosartan mesylate - hydrochlorothiazide mixt; Teveten htc (TN) Eprosartan...giotensin II antagonists and diuretics C09DA02 Eprosartan and diuretics D10283 Eprosartan mesylate - hydrochlorothiazide mixt PubChem: 163312314 ...

  1. Drug: D00966 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available B HORMONE ANTAGONISTS AND RELATED AGENTS L02BA Anti-estrogens L02BA01 Tamoxifen D00966 Tamoxifen citrate (JP...16/USP) USP drug classification [BR:br08302] Antineoplastics Antiestrogens/Modifi

  2. Adding 5-hydroxytryptamine receptor type 3 antagonists may reduce drug-induced nausea in poor insight obsessive-compulsive patients taking off-label doses of selective serotonin reuptake inhibitors: a 52-week follow-up case report

    Directory of Open Access Journals (Sweden)

    Martino Matteo

    2010-12-01

    Full Text Available Abstract Poor-insight obsessive-compulsive disorder (PI-OCD is a severe form of OCD where the 'typically obsessive' features of intrusive, 'egodystonic' feelings and thoughts are absent. PI-OCD is difficult to treat, often requiring very high doses of serotonergic drugs as well as antipsychotic augmentation. When this occurs, unpleasant side effects as nausea are common, eventually further reducing compliance to medication and increasing the need for pharmacological alternatives. We present the case of a PI-OCD patient who developed severe nausea after response to off-label doses of the selective serotonin reuptake inhibitor (SSRI, fluoxetine. Drug choices are discussed, providing pharmacodynamic rationales and hypotheses along with reports of rating scale scores, administered within a follow-up period of 52 weeks. A slight reduction of fluoxetine dose, augmentation with mirtazapine and a switch from amisulpride to olanzapine led to resolution of nausea while preserving the anti-OCD therapeutic effect. Mirtazapine and olanzapine have already been suggested for OCD treatment, although a lack of evidence exists about their role in the course of PI-OCD. Both mirtazapine and olanzapine also act as 5-hydroxytryptamine receptor type 3 (5-HT3 blockers, making them preferred choices especially in cases of drug-induced nausea.

  3. Efficient Use of a Crude Drug/Herb Library Reveals Ephedra Herb As a Specific Antagonist for TH2-Specific Chemokine Receptors CCR3, CCR4, and CCR8.

    Science.gov (United States)

    Matsuo, Kazuhiko; Koizumi, Keiichi; Fujita, Mitsugu; Morikawa, Toshio; Jo, Michiko; Shibahara, Naotoshi; Saiki, Ikuo; Yoshie, Osamu; Nakayama, Takashi

    2016-01-01

    Chemokine receptors CCR3 and CCR4 are preferentially expressed by TH2 cells, mast cells, and/or eosinophils, all of which are involved in the pathogenesis of allergic diseases. Therefore, CCR3 and CCR4 have long been highlighted as potent therapeutic targets for allergic diseases. Japanese traditional herbal medicine Kampo consists of multiple crude drugs/herbs, which further consist of numerous chemical substances. Recent studies have demonstrated that such chemical substances appear to promising sources in the development of novel therapeutic agents. Based on these findings, we hypothesize that Kampo-related crude drugs/herbs would contain chemical substances that inhibit the cell migration mediated by CCR3 and/or CCR4. To test this hypothesis, we screened 80 crude drugs/herbs to identify candidate substances using chemotaxis assay. Among those tested, Ephedra Herb inhibited the chemotaxis mediated by both CCR3 and CCR4, Cornus Fruit inhibited that mediated by CCR3, and Rhubarb inhibited that mediated by CCR4. Furthermore, Ephedra Herb specifically inhibited the chemotaxis mediated by not only CCR3 and CCR4 but CCR8, all of which are selectively expressed by TH2 cells. This result led us to speculate that ephedrine, a major component of Ephedra Herb, would play a central role in the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8. However, ephedrine exhibited little effects on the chemotaxis. Therefore, we fractionated Ephedra Herb into four subfractions and examined the inhibitory effects of each subfraction. As the results, ethyl acetate-insoluble fraction exhibited the inhibitory effects on chemotaxis and calcium mobilization mediated by CCR3 and CCR4 most significantly. In contrast, chloroform-soluble fraction exhibited a weak inhibitory effect on the chemotaxis mediated by CCR8. Furthermore, maoto, one of the Kampo formulations containing Ephedra Herb, exhibited the inhibitory effects on the chemotaxis mediated by CCR3, CCR4, and CCR8

  4. Drug: D08233 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08233 Drug Morphine (BAN); Morfina Dosa (TN); Substitol (TN) C17H19NO3 285.1365 28...039 Opioid analgesics map07224 Opioid receptor agonists/antagonists map00982 Drug...] D08233 Morphine (BAN) CAS: 57-27-2 PubChem: 96024921 DrugBank: DB00295 PDB-CCD:

  5. Drug-induced immune thrombocytopenia: incidence, clinical features, laboratory testing, and pathogenic mechanisms.

    Science.gov (United States)

    Curtis, Brian R

    2014-01-01

    Drug-induced immune thrombocytopenia (DIIT) is a relatively uncommon adverse reaction caused by drug-dependent antibodies (DDAbs) that react with platelet membrane glycoproteins only when the implicated drug is present. Although more than 100 drugs have been associated with causing DIIT, recent reviews of available data show that carbamazepine, eptifibatide, ibuprofen, quinidine, quinine, oxaliplatin, rifampin, sulfamethoxazole, trimethoprim, and vancomycin are probably the most frequently implicated. Patients with DIIT typically present with petechiae, bruising, and epistaxis caused by an acute, severe drop in platelet count (often to transfusion refractoriness, and must be differentiated by temporal association of exposure to a candidate drug with an acute, severe drop in platelet count. Treatment consists of immediate withdrawal of the implicated drug. Criteria for strong evidence of DIIT include (1) exposure to candidate drug-preceded thrombocytopenia; (2) sustained normal platelet levels after discontinuing candidate drug; (3) candidate drug was only drug used before onset of thrombocytopenia or other drugs were continued or reintroduced after resolution of thrombocytopenia, and other causes for thrombocytopenia were excluded; and (4) reexposure to the candidate drug resulted in recurrent thrombocytopenia. Flow cytometry testing for DDAbs can be useful in confirmation of a clinical diagnosis, and monoclonal antibody enzyme-linked immunosorbent assay testing can be used to determine the platelet glycoprotein target(s), usually GPIIb/IIIa or GPIb/IX/V, but testing is not widely available. Several pathogenic mechanisms for DIIT have been proposed, including hapten, autoantibody, neoepitope, drug-specific, and quinine-type drug mechanisms. A recent proposal suggests weakly reactive platelet autoantibodies that develop greatly increased affinity for platelet glycoprotein epitopes through bridging interactions facilitated by the drug is a possible mechanism for the

  6. Glutamate antagonists limit tumor growth

    OpenAIRE

    2001-01-01

    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...

  7. Calcium Antagonists and Hypertension: Role of co-existent coronary disease, impaired renal function and diabetes

    NARCIS (Netherlands)

    G. Wagener (Gilbert)

    2007-01-01

    textabstractIt is generally accepted that blood pressure lowering drugs improve the prognosis of patients with elevated blood pressure. The dihydropyridine calcium antagonist nifedipine is a widely used blood pressure lowering drug. In the mid-1990ties questions were raised on the safety of the

  8. Drug: D08865 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08865 Drug Azilsartan kamedoxomil (USAN) C30H23N4O8. K 606.1153 606.6239 D08865.gi... ON THE RENIN-ANGIOTENSIN SYSTEM C09C ANGIOTENSIN II ANTAGONISTS, PLAIN C09CA Angiotensin II antagonists, plain C09CA09 Azilsartan... medoxomil D08865 Azilsartan kamedoxomil (USAN) USP drug cl...assification [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Azilsartan D08865 Azilsartan...ptor [HSA:185] [KO:K04166] Azilsartan medoxomil [ATC:C09CA09] D08865 Azilsartan kamedoxomil (USAN) CAS: 8630

  9. Drug: D02082 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02082 Drug Eprosartan mesylate (USAN); Teveten (TN) C23H24N2O4S. CH4SO3 520.1338 5...09C ANGIOTENSIN II ANTAGONISTS, PLAIN C09CA Angiotensin II antagonists, plain C09CA02 Eprosartan... D02082 Eprosartan mesylate (USAN) USP drug classification [BR:br08302] Cardiovascular Agents... Angiotensin II Receptor Antagonists Eprosartan D02082 Eprosartan mesylate (USAN) Target-based classificatio...angiotensin II stimulates angiotensin subtype 1 (AT1) receptor [HSA:185] [KO:K04166] Eprosartan [ATC:C09CA02] D02082 Eprosartan

  10. Drug: D04040 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D04040 Drug Eprosartan (USAN/INN) C23H24N2O4S 424.1457 424.5127 D04040.gif Antihype...NSIN II ANTAGONISTS, PLAIN C09CA Angiotensin II antagonists, plain C09CA02 Eprosartan D04040 Eprosartan...Receptor Antagonists Eprosartan D04040 Eprosartan (USAN/INN) Target-based classification of drugs [BR:br0831...ates angiotensin subtype 1 (AT1) receptor [HSA:185] [KO:K04166] Eprosartan [ATC:C09CA02] D04040 Eprosartan (

  11. 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.

  12. Structural insight into inactivation of plasminogen activator inhibitor-1 by a small-molecule antagonist

    DEFF Research Database (Denmark)

    Lin, Zhonghui; Jensen, Jan Kristian; Hong, Zebin

    2013-01-01

    and cancer. Several types of PAI-1 antagonist have been developed, but the structural basis for their action has remained largely unknown. Here we report X-ray crystal structure analysis of PAI-1 in complex with a small-molecule antagonist, embelin. We propose a mechanism for embelin-induced rapid conversion...... of PAI-1 into a substrate for its target proteases and the subsequent slow conversion of PAI-1 into an irreversibly inactivated form. Our work provides structural clues to an understanding of PAI-1 inactivation by small-molecule antagonists and an important step toward the design of drugs targeting PAI-1....

  13. Population pharmacokinetic modeling of a subcutaneous depot for GnRH antagonist degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone (GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  14. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg;

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  15. Population Pharmacokinetic Modeling of a Subcutaneous Depot for GnRH Antagonist Degarelix

    DEFF Research Database (Denmark)

    Tornøe, Christoffer Wenzel; Agersø, Henrik; Nielsen, Henrik Aalborg

    2004-01-01

    Purpose. The objective of this study is to develop a population pharmacokinetic (PK) model that describes the subcutaneous (SC) depot formation of gonadotropin-releasing hormone ( GnRH) antagonist degarelix, which is being developed for treatment of prostate cancer, exhibiting dose-volume and dose...... depot model describes the PK profile of GnRH antagonist degarelix. This modeling approach might also be applicable for other depot-formulated drugs exhibiting complex PK profiles....

  16. Inhibition of tryptase release from human colon mast cells by histamine receptor antagonists.

    Science.gov (United States)

    He, Shao-Heng; Xie, Hua; Fu, Yi-Ling

    2005-03-01

    The main objective of this study was to investigate the ability of histamine receptor antagonists to modulate tryptase release from human colon mast cells induced by histamine. Enzymatically dispersed cells from human colon were challenged with histamine in the absence or presence of the histamine receptor antagonists, and the tryptase release was determined. It was found that histamine induced tryptase release from colon mast cells was inhibited by up to approximately 61.5% and 24% by the H1 histamine receptor antagonist terfenadine and the H2 histamine receptor antagonist cimetidine, respectively, when histamine and its antagonists were added to cells at the same time. The H3 histamine receptor antagonist clobenpropit had no effect on histamine induced tryptase release from colon mast cells at all concentrations tested. Preincubation of terfenadine, cimetidine or clobenpropit with cells for 20 minutes before challenging with histamine did not enhance the ability of these antihistamines to inhibit histamine induced tryptase release. Apart from terfenadine at 100 microg/ml, the antagonists themselves did not stimulate tryptase release from colon mast cells following both 15 minutes and 35 minutes incubation periods. It was concluded that H1 and H2 histamine receptor antagonists were able to inhibit histamine induced tryptase release from colon mast cells. This not only added some new data to our hypothesis of self-amplification mechanisms of mast cell degranulation, but also suggested that combining these two types of antihistamine drugs could be useful for the treatment of inflammatory bowel disease (IBD).

  17. 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.

  18. Studies on the antagonistic action between chloramphenicol and quinolones with presence of bovine serum albumin by fluorescence spectroscopy

    Energy Technology Data Exchange (ETDEWEB)

    Liu Baosheng, E-mail: lbs@hbu.edu.c [Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education, Center of Physics and Chemistry, Hebei University, Baoding 071002 (China); Zhao Fengli; Xue Chunli; Wang Jing; Lu Yunkai [Key Laboratory of Medical Chemistry and Molecular Diagnosis, Ministry of Education, Center of Physics and Chemistry, Hebei University, Baoding 071002 (China)

    2010-05-15

    Chloramphenicol (CHL) and quinolone drugs like ofloxacin (OFLX), lomefloxacin (LMX) and ciprofloxacin (CPFX) can all quench the fluorescence of bovine serum albumin (BSA) in the aqueous solution of pH=7.40. This quenching effect becomes more significant when CHL and quinolone drugs coexist. Based on this, further studies on the interactions between CHL and quinolone drugs using fluorescence spectrum are established. The results showed that the interaction between the drugs would increase the binding constant and binding stability of the drug and protein, thus reducing the amount of drugs transported to their targets. Therefore, free drug concentration at targets would decrease, reducing the efficacy of the drugs. It indicated that there exists antagonistic action between drugs. The results also showed that the quenching mechanism of BSA by the drugs is a static procedure. The number of binding sites is 1 in various systems. Due to the existence of the antagonistic action between drugs, the binding distance r is reduced. Studies utilizing synchronous spectra showed that the antagonistic action between the drugs would affect the conformation of BSA, making protein molecules extend and hydrophobic decrease. The order of antagonistic action between CHL and quinolone drugs is: CPFX>OFLX>LMX with presence of BSA.

  19. Cell-Based Selection Expands the Utility of DNA-Encoded Small-Molecule Library Technology to Cell Surface Drug Targets: Identification of Novel Antagonists of the NK3 Tachykinin Receptor.

    Science.gov (United States)

    Wu, Zining; Graybill, Todd L; Zeng, Xin; Platchek, Michael; Zhang, Jean; Bodmer, Vera Q; Wisnoski, David D; Deng, Jianghe; Coppo, Frank T; Yao, Gang; Tamburino, Alex; Scavello, Genaro; Franklin, G Joseph; Mataruse, Sibongile; Bedard, Katie L; Ding, Yun; Chai, Jing; Summerfield, Jennifer; Centrella, Paolo A; Messer, Jeffrey A; Pope, Andrew J; Israel, David I

    2015-12-14

    DNA-encoded small-molecule library technology has recently emerged as a new paradigm for identifying ligands against drug targets. To date, this technology has been used with soluble protein targets that are produced and used in a purified state. Here, we describe a cell-based method for identifying small-molecule ligands from DNA-encoded libraries against integral membrane protein targets. We use this method to identify novel, potent, and specific inhibitors of NK3, a member of the tachykinin family of G-protein coupled receptors (GPCRs). The method is simple and broadly applicable to other GPCRs and integral membrane proteins. We have extended the application of DNA-encoded library technology to membrane-associated targets and demonstrate the feasibility of selecting DNA-tagged, small-molecule ligands from complex combinatorial libraries against targets in a heterogeneous milieu, such as the surface of a cell.

  20. Suvorexant: The first orexin receptor antagonist to treat insomnia

    Directory of Open Access Journals (Sweden)

    Ashok K Dubey

    2015-01-01

    Full Text Available Primary insomnia is mainly treated with drugs acting on benzodiazepine receptors and a few other classes of drugs used for different co-morbidities. A novel approach to treat insomnia has been introduced recently, with the approval of suvorexant, the first in a new class of orexin receptor antagonists. Orexin receptors in the brain have been found to play an important role in the regulation of various aspects of arousal and motivation. The drugs commonly used for insomnia therapy to date, have often been associated with adverse effects, such as, day-time somnolence, amnesia, confusion, and gait disturbance, apart from the risk of dependence on chronic use. Suvorexant has not shown these adverse effects because of its unique mechanism of action. It also appears to be suitable as a chronic therapy for insomnia, because of minimal physical dependence. The availability of this new drug as an effective and safe alternative is an important and welcome development in insomnia management.

  1. The pharmacological properties of lipophilic calcium antagonists.

    Science.gov (United States)

    van Zwieten, P A

    1998-01-01

    Several types of calcium antagonists (CA) (verapamil, diltiazem, nifedipine and related drugs) may be used as antihypertensives. In practice, the dihydropyridines (nifedipine and related drugs) are the CA used most frequently as antihypertensives. Apart from the lowering of blood pressure CA may lead to other, theoretically beneficial, effects: regression of left ventricular and vascular hypertrophy, renal protection, weak natriuretic, weak antiplatelet, anti-ischaemic and antiatherogenic activity. Several new dihydropyridine CA have been introduced in recent years. The advantages of the newer compounds, such as amlodipine, felodipine, isradipine, lacidipine and lercanidipine, may include: vasoselectivity, hence little or no cardiodepressant activity; an improved kinetic profile, resulting in a slow onset and long duration of action, fewer side-effects such as reflex tachycardia and headache, owing to the slow onset of the antihypertensive action. For a few newer CA a predominant effect on specialized circulatory beds (renal, coronary and cerebral) has been claimed. The new CA, which are clearly lipophilic, deserve special attention. Owing to the lipophilic character of such compounds considerable concentration occurs in lipid-containing membrane depots. The CA thus concentrated are slowly released from these depots and, subsequently, reach their targets, the L-type calcium channels. This phenomenon explains both the slow onset and the long duration of action of these CA. Owing to the slow onset of action reflex tachycardia is virtually absent. The long duration of action allows satisfactory control of blood pressure in hypertensives by means of a single daily dose. A few lipophilic dihydropyridine CA are vasoselective. This property implies that at therapeutic, vasodilatory dosages no cardiodepressant activity occurs. Lercanidipine is a recently introduced example of a lipophilic and vasoselective dihydropyridine CA. It is an effective vasodilator

  2. μ Opioid receptor: novel antagonists and structural modeling

    Science.gov (United States)

    Kaserer, Teresa; Lantero, Aquilino; Schmidhammer, Helmut; Spetea, Mariana; Schuster, Daniela

    2016-02-01

    The μ opioid receptor (MOR) is a prominent member of the G protein-coupled receptor family and the molecular target of morphine and other opioid drugs. Despite the long tradition of MOR-targeting drugs, still little is known about the ligand-receptor interactions and structure-function relationships underlying the distinct biological effects upon receptor activation or inhibition. With the resolved crystal structure of the β-funaltrexamine-MOR complex, we aimed at the discovery of novel agonists and antagonists using virtual screening tools, i.e. docking, pharmacophore- and shape-based modeling. We suggest important molecular interactions, which active molecules share and distinguish agonists and antagonists. These results allowed for the generation of theoretically validated in silico workflows that were employed for prospective virtual screening. Out of 18 virtual hits evaluated in in vitro pharmacological assays, three displayed antagonist activity and the most active compound significantly inhibited morphine-induced antinociception. The new identified chemotypes hold promise for further development into neurochemical tools for studying the MOR or as potential therapeutic lead candidates.

  3. IAP antagonists sensitize murine osteosarcoma cells to killing by TNFα

    Science.gov (United States)

    Shekhar, Tanmay M.; Miles, Mark A.; Gupte, Ankita; Taylor, Scott; Tascone, Brianna; Walkley, Carl R.; Hawkins, Christine J.

    2016-01-01

    Outcomes for patients diagnosed with the bone cancer osteosarcoma have not improved significantly in the last four decades. Only around 60% of patients and about a quarter of those with metastatic disease survive for more than five years. Although DNA-damaging chemotherapy drugs can be effective, they can provoke serious or fatal adverse effects including cardiotoxicity and therapy-related cancers. Better and safer treatments are therefore needed. We investigated the anti-osteosarcoma activity of IAP antagonists (also known as Smac mimetics) using cells from primary and metastatic osteosarcomas that arose spontaneously in mice engineered to lack p53 and Rb expression in osteoblast-derived cells. The IAP antagonists SM-164, GDC-0152 and LCL161, which efficiently target XIAP and cIAPs, sensitized cells from most osteosarcomas to killing by low levels of TNFα but not TRAIL. RIPK1 expression levels and activity correlated with sensitivity. RIPK3 levels varied considerably between tumors and RIPK3 was not required for IAP antagonism to sensitize osteosarcoma cells to TNFα. IAP antagonists, including SM-164, lacked mutagenic activity. These data suggest that drugs targeting XIAP and cIAP1/2 may be effective for osteosarcoma patients whose tumors express abundant RIPK1 and contain high levels of TNFα, and would be unlikely to provoke therapy-induced cancers in osteosarcoma survivors. PMID:27129149

  4. Muscarinic Receptor Agonists and Antagonists

    Directory of Open Access Journals (Sweden)

    David R. Kelly

    2001-02-01

    Full Text Available A comprehensive review of pharmacological and medical aspects of the muscarinic class of acetylcholine agonists and antagonists is presented. The therapeutic benefits of achieving receptor subtype selectivity are outlined and applications in the treatment of Alzheimer’s disease are discussed. A selection of chemical routes are described, which illustrate contemporary methodology for the synthesis of chiral medicinal compounds (asymmetric synthesis, chiral pool, enzymes. Routes to bicyclic intrannular amines and intramolecular Diels-Alder reactions are highlighted.

  5. Lead optimization studies of cinnamic amide EP2 antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Yang, Myung-Soon; Dingledine, Ray

    2014-05-22

    Prostanoid receptor EP2 can play a proinflammatory role, exacerbating disease pathology in a variety of central nervous system and peripheral diseases. A highly selective EP2 antagonist could be useful as a drug to mitigate the inflammatory consequences of EP2 activation. We recently identified a cinnamic amide class of EP2 antagonists. The lead compound in this class (5d) displays anti-inflammatory and neuroprotective actions. However, this compound exhibited moderate selectivity to EP2 over the DP1 prostanoid receptor (∼10-fold) and low aqueous solubility. We now report compounds that display up to 180-fold selectivity against DP1 and up to 9-fold higher aqueous solubility than our previous lead. The newly developed compounds also display higher selectivity against EP4 and IP receptors and a comparable plasma pharmacokinetics. Thus, these compounds are useful for proof of concept studies in a variety of models where EP2 activation is playing a deleterious role.

  6. Drug-drug interactions: antiretroviral drugs and recreational drugs.

    Science.gov (United States)

    Staltari, Orietta; Leporini, Christian; Caroleo, Benedetto; Russo, Emilio; Siniscalchi, Antonio; De Sarro, Giovambattista; Gallelli, Luca

    2014-01-01

    With the advances in antiretroviral (ARV) therapy, patients with Human Immunodeficiency Virus (HIV) infection are living longer, however, some patients encounter co- morbidities which sometimes require treatment. Therefore, during the treatment with ARV drugs these patients could take several recreational drugs (e.g. amphetamines, hallucinogenes, opiates, or alcohol) with a possible development of drug-drug interactions (DDIs). In particular, Nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs/NtRTIs) are mainly excreted through the kidney and are not substrates of the cytochrome P450 or P-glycoprotein, therefore the DDIs during this treatment are minimal. In contrast, the other ARV drugs (i.e. non-nucleoside reversetranscriptase inhibitors, Protease inhibitors, Integrase inhibitors, chemokine receptor 5 antagonists and HIV-fusion inhibitors) are an important class of antiretroviral medications that are frequent components of HAART regimens but show several DDIs related to interaction with the cytochrome P450 or P-glycoprotein. In this paper we will review data concerning the possibility of DDI in HIV patients treated with ARV and taking recreational drugs.

  7. Noradrenergic antagonists mitigate amphetamine-induced recovery.

    Science.gov (United States)

    Hylin, M J; Brenneman, M M; Corwin, J V

    2017-09-15

    Brain injury, including that due to stroke, leaves individuals with cognitive deficits that can disrupt daily aspect of living. As of now there are few treatments that shown limited amounts of success in improving functional outcome. The use of stimulants such as amphetamine have shown some success in improving outcome following brain injury. While the pharmacological mechanisms for amphetamine are known; the specific processes responsible for improving behavioral outcome following injury remain unknown. Understanding these mechanisms can help to refine the use of amphetamine as a potential treatment or lead to the use of other methods that share the same pharmacological properties. One proposed mechanism is amphetamine's impact upon noradrenaline (NA). In the current, study noradrenergic antagonists were administered prior to amphetamine to pharmacologically block α- and β-adrenergic receptors. The results demonstrated that the blockade of these receptors disrupted amphetamines ability to induce recovery from hemispatial neglect using an established aspiration lesion model. This suggests that amphetamine's ability to ameliorate neglect deficits may be due in part to noradrenaline. These results further support the role of noradrenaline in functional recovery. Finally, the development of polytherapies and combined therapeutics, while promising, may need to consider the possibility that drug interactions can negate the effectiveness of treatment. Copyright © 2017 Elsevier B.V. All rights reserved.

  8. Nalmefene: radioimmunoassay for a new opioid antagonist.

    Science.gov (United States)

    Dixon, R; Hsiao, J; Taaffe, W; Hahn, E; Tuttle, R

    1984-11-01

    A specific radioimmunoassay (RIA) has been developed for the quantitation of a new opioid antagonist, nalmefene, in human plasma. The method employs a rabbit antiserum to an albumin conjugate of naltrexone-6-(O-carboxymethyl)oxime and [3H]naltrexone as the radioligand. Assay specificity was achieved by extraction of nalmefene from plasma at pH 9 into ether prior to RIA. The procedure has a limit of sensitivity of 0.2 ng/mL of nalmefene using a 0.5-mL sample of plasma for analysis. The intra- and interassay coefficients of variation did not exceed 5.6 and 11%, respectively. The specificity of the RIA was established by demonstrating excellent agreement (r = 0.99) with a less sensitive and more time consuming HPLC procedure in the analysis of clinical plasma samples. The use of the RIA for the pharmacokinetic evaluation of nalmefene is illustrated with plasma concentration profiles of the drug in humans following intravenous and oral administration.

  9. 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.

  10. Screening for cardiovascular safety: a structure-activity approach for guiding lead selection of melanin concentrating hormone receptor 1 antagonists.

    Science.gov (United States)

    Kym, Philip R; Souers, Andrew J; Campbell, Thomas J; Lynch, John K; Judd, Andrew S; Iyengar, Rajesh; Vasudevan, Anil; Gao, Ju; Freeman, Jennifer C; Wodka, Dariusz; Mulhern, Mathew; Zhao, Gang; Wagaw, Seble H; Napier, James J; Brodjian, Sevan; Dayton, Brian D; Reilly, Regina M; Segreti, Jason A; Fryer, Ryan M; Preusser, Lee C; Reinhart, Glenn A; Hernandez, Lisa; Marsh, Kennan C; Sham, Hing L; Collins, Christine A; Polakowski, James S

    2006-04-06

    An inactin-anesthetized rat cardiovascular (CV) assay was employed in a screening mode to triage multiple classes of melanin-concentrating hormone receptor 1 (MCHr1) antagonists. Lead identification was based on a compound profile producing high drug concentration in both plasma (>40 microM) and brain (>20 microg/g) with optimization activities on multiple classes of MCHr1 antagonists were terminated. After providing evidence that the cardiovascular liabilities were not a function of MCHr1 antagonism, continued screening identified the chromone-substituted aminopiperidine amides as a class of MCHr1 antagonists that demonstrated a safe cardiovascular profile at high drug concentrations in both plasma and brain. The high incidence of adverse cardiovascular effects associated with an array of MCHr1 antagonists of significant chemical diversity, combined with the stringent safety requirements for antiobesity drugs, highlight the importance of incorporating cardiovascular safety assessment early in the lead selection process.

  11. Pharmacology of glutamate receptor antagonists in the kindling model of epilepsy.

    Science.gov (United States)

    Löscher, W

    1998-04-01

    It is widely accepted that excitatory amino acid transmitters such as glutamate are involved in the initiation of seizures and their propagation. Most attention has been directed to synapses using NMDA receptors, but more recent evidence indicates potential roles for ionotropic non-NMDA (AMPA/kainate) and metabotropic glutamate receptors as well. Based on the role of glutamate in the development and expression of seizures, antagonism of glutamate receptors has long been thought to provide a rational strategy in the search for new, effective anticonvulsant drugs. Furthermore, because glutamate receptor antagonists, particularly those acting on NMDA receptors, protect effectively in the induction of kindling, it was suggested that they may have utility in epilepsy prophylaxis, for example, after head trauma. However, first clinical trials with competitive and uncompetitive NMDA receptor antagonists in patients with partial (focal) seizures, showed that these drugs lack convincing anticonvulsant activity but induce severe neurotoxic adverse effects in doses which were well tolerated in healthy volunteers. Interestingly, the only animal model which predicted the unfavorable clinical activity of competitive NMDA antagonists in patients with chronic epilepsy was the kindling model of temporal lobe epilepsy, indicating that this model should be used in the search for more effective and less toxic glutamate receptor antagonists. In this review, results from a large series of experiments on different categories of glutamate receptor antagonists in fully kindled rats are summarized and discussed. NMDA antagonists, irrespective whether they are competitive, high- or low-affinity uncompetitive, glycine site or polyamine site antagonists, do not counteract focal seizure activity and only weakly, if at all, attenuate propagation to secondarily generalized seizures in this model, indicating that once kindling is established, NMDA receptors are not critical for the expression of

  12. Drug: D02372 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02372 Drug Perospirone hydrochloride hydrate (JAN); Lullan (TN) C23H30N4O2S. 2H2O....r agonists/antagonists map07213 Dopamine receptor agonists/antagonists Therapeutic category of drugs in Japa...ecting central nervous system 117 Psychotropics 1179 Others D02372 Perospirone hydrochloride hydrate (JAN) T...arget-based classification of drugs [BR:br08310] G Protein-coupled receptors Rhodopsin family Dopamine dopam...ine D2-receptor [HSA:1813] [KO:K04145] Perospirone D02372 Perospirone hydrochloride hydr

  13. Drug: D08146 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08146 Drug Losartan (INN); Losartic (TN) C22H23ClN6O 422.1622 422.9106 D08146.gif ...STS, PLAIN C09CA Angiotensin II antagonists, plain C09CA01 Losartan D08146 Losartan (INN) USP drug classific...ation [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Losartan D08146 Losartan...dopsin family Angiotensin angiotensin II stimulates angiotensin subtype 1 (AT1) receptor [HSA:185] [KO:K04166] Losartan... [ATC:C09CA01] D08146 Losartan (INN) CAS: 114798-26-4 PubChem: 96024836 DrugBank: DB00678 LigandB

  14. Drug: D00523 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00523 Drug Irbesartan (JAN/USAN/INN); Avapro (TN) C25H28N6O 428.2325 428.5294 D005...ensives 2149 Others D00523 Irbesartan (JAN/USAN/INN) Anatomical Therapeutic Chemical (ATC) classification [B...AGONISTS, PLAIN C09CA Angiotensin II antagonists, plain C09CA04 Irbesartan D00523 Irbesartan... (JAN/USAN/INN) USP drug classification [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Irbesartan... D00523 Irbesartan (JAN/USAN/INN) Target-based classification of drugs [BR:br08310

  15. 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.

  16. Drug: D09705 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ent of ocular itching, Antihistaminic second-generation antihistamine drug H1-receptor antagonist [HSA:3269]...D09705 Drug Bepotastine (USAN/INN) C21H25ClN2O3 388.1554 388.8878 D09705.gif Treatm

  17. Drug: D00066 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available eptor agonists/antagonists Therapeutic category of drugs in Japan [BR:br08301] 2 Agents affecting individual organs 24 Hormones...NN) USP drug classification [BR:br08302] Hormonal Agents, Stimulant/Replacement/Modifying (Sex Hormones/Modi

  18. Drug: D00843 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available drug classification [BR:br08302] Analgesics Opioid Analgesics, Short-acting Nalb...D00843 Drug Nalbuphine hydrochloride (USAN); Nubain (TN) C21H27NO4. HCl 393.1707 393.9043 D00843.gif Analges...ic; Antagonist [to narcotics] ATC code: N02AF02 kappa-opioid receptor agonist [HSA:

  19. Drug: D08123 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08123 Drug Levorphanol (INN) C17H23NO 257.178 257.3706 D08123.gif Opioid analgesic...r interaction map07039 Opioid analgesics map07224 Opioid receptor agonists/antagonists USP drug classificati

  20. Drug: D00225 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available /USP/INN) USP drug classification [BR:br08302] Anxiolytics Benzodiazepines Alprazolam D00225 Alprazolam (JP1...879) GABAergic synapse Enzyme: CYP3A4 [HSA:1576] CYP inhibition: CYP3A [HSA:1576 1577 1551] map07030 Anxio...lytics map07230 GABA-A receptor agonists/antagonists Therapeutic category of drugs

  1. The Effect of Sympathetic Antagonists on the Antidepressant Action of Alprazolam

    Directory of Open Access Journals (Sweden)

    Gorash ZM

    2008-01-01

    Full Text Available 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 antagonists with benzodiazepines, which may impact the clinical use of alprazolam, was also studied. Behavioral despair was examined in six groups of albino mice. Drugs were administered intraperitoneally. The control group received only a single dose of 1% Tween 80. The second group received a single dose of alprazolam, and the third group received an antagonist followed by alprazolam. The fourth group was treated with imipramine, and the fifth group received an antagonist followed by imipramine. The sixth group was treated with a single dose of an antagonist alone (atenolol, a β1-selective adrenoceptor antagonist; propranolol, a non selective β-adrenoceptor antagonist; and prazocin, an α1-adrenoceptor antagonist. Results confirmed the antidepressant action of alprazolam and imipramine. Prazocin treatment alone produced depression, but it significantly potentiated the antidepressant actions of imipramine and alprazolam. Atenolol alone produced an antidepressant effect and potentiated the antidepressant action of alprazolam. Propranolol treatment alone produced depression, and antagonized the effects of alprazolam and imipramine, even producing depression in combined treatments. In conclusion, our results reveal that alprazolam may produce antidepressant effects through the release of noradrenaline, which stimulates β2 receptors to produce an antidepressant action. Imipramine may act by activating β2 receptors by blocking or down-regulating β1 receptors.

  2. Development of a perfusion chamber assay to study in real time the kinetics of thrombosis and the antithrombotic characteristics of antiplatelet drugs

    Directory of Open Access Journals (Sweden)

    Stephens Gillian

    2012-08-01

    Full Text Available Abstract Background Arterial thrombosis triggered by vascular injury is a balance between thrombus growth and thrombus fragmentation (dethrombosis. Unbalance towards thrombus growth can lead to vascular occlusion, downstream ischemia and tissue damage. Here we describe the development of a simple methodology that allows for continuous real time monitoring and quantification of both processes during perfusion of human blood under arterial shear rate conditions. Using this methodology, we have studied the effects of antiplatelet agents targeting COX-1 (aspirin, P2Y12 (2-MeSAMP, clopidogrel, GP IIb-IIIa (eptifibatide and their combinations on the kinetics of thrombosis over time. Results Untreated samples of blood perfused over type III collagen at arterial rates of shear promoted the growth of stable thrombi. Modulation by eptifibatide affected thrombus growth, while that mediated by 2-MeSAMP and aspirin affected thrombus stability. Using this technique, we confirmed the primacy of continuous signaling by the ADP autocrine loop acting on P2Y12 in the maintenance of thrombus stability. Analysis of the kinetics of thrombosis revealed that continuous and prolonged analysis of thrombosis is required to capture the role of platelet signaling pathways in their entirety. Furthermore, studies evaluating the thrombotic profiles of 20 healthy volunteers treated with aspirin, clopidogrel or their combination indicated that while three individuals did not benefits from either aspirin or clopidogrel treatments, all individuals displayed marked destabilization profiles when treated with the combination regimen. Conclusions These results show the utility of a simple perfusion chamber technology to assess in real time the activity of antiplatelet drugs and their combinations. It offers the opportunity to perform pharmacodynamic monitoring of arterial thrombosis in clinical trials and to investigate novel strategies directed at inhibiting thrombus stability in the

  3. Angiotensin II AT1 receptor antagonists inhibit platelet adhesion and aggregation by nitric oxide release.

    Science.gov (United States)

    Kalinowski, Leszek; Matys, Tomasz; Chabielska, Ewa; Buczko, Włodzimierz; Malinski, Tadeusz

    2002-10-01

    This study investigated the process of nitric oxide (NO) release from platelets after stimulation with different angiotensin II type 1 (AT1)-receptor antagonists and its effect on platelet adhesion and aggregation. Angiotensin II AT1-receptor antagonist-stimulated NO release in platelets was compared with that in human umbilical vein endothelial cells by using a highly sensitive porphyrinic microsensor. In vitro and ex vivo effects of angiotensin II AT1-receptor antagonists on platelet adhesion to collagen and thromboxane A2 analog U46619-induced aggregation were evaluated. Losartan, EXP3174, and valsartan alone caused NO release from platelets and endothelial cells in a dose-dependent manner in the range of 0.01 to 100 micro mol/L, which was attenuated by NO synthase inhibitor N(G)-nitro-L-arginine methyl ester. The angiotensin II AT1-receptor antagonists had more than 70% greater potency in NO release in platelets than in endothelial cells. The degree of inhibition of platelet adhesion (collagen-stimulated) and aggregation (U46619-stimulated) elicited by losartan, EXP3174, and valsartan, either in vitro or ex vivo, closely correlated with the NO levels produced by each of these drugs alone. The inhibiting effects of angiotensin II AT1-receptor antagonists on collagen-stimulated adhesion and U46619-stimulated aggregation of platelets were significantly reduced by pretreatment with N(G)-nitro-L-arginine methyl ester. Neither the AT2 receptor antagonist PD123319, the cyclooxygenase synthase inhibitor indomethacin, nor the selective thromboxane A2/prostaglandin H2 receptor antagonist SQ29,548 had any effect on angiotensin II AT1-receptor antagonist-stimulated NO release in platelets and endothelial cells. The presented studies clearly indicate a crucial role of NO in the arterial antithrombotic effects of angiotensin II AT1-receptor antagonists.

  4. Receptor discrimination and control of agonist-antagonist binding.

    Science.gov (United States)

    Tallarida, R J

    1995-08-01

    The law of mass action is the common model for the interaction of agonist and antagonist compounds with cellular receptors. Parameters of the interaction, obtained from functional and radioligand-binding studies, allow discrimination and subtyping of receptors and aid in understanding specific mechanisms. This article reviews the theory and associated mathematical models and graphical transformations of data that underlie the determination of receptor parameters. The main theory assumes that agonist and antagonist compounds bind to cells that have a fixed number of receptors and provides the framework for obtaining drug-receptor parameters from data and their graphical transformations. Conditions that produce a change in receptor number, a newer concept in pharmacology, can have an important effect on the parameter values derived in the usual way. This review concludes with a discussion of the quantitative study of receptor-mediated feedback control of endogenous ligands, a very new topic with potentially important implications for understanding antagonist effectiveness, loss of control, and chaos in regulated mass action binding.

  5. 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

  6. Newer calcium channel antagonists and the treatment of hypertension.

    Science.gov (United States)

    Cummins, D F

    1999-07-01

    Calcium channel antagonists have become popular medications for the management of hypertension. These agents belong to the diphenylalkylamine, benzothiazepine, dihydropyridine, or tetralol chemical classes. Although the medications share a common pharmacological mechanism in reducing peripheral vascular resistance, clinical differences between the sub-classes can be linked to structural profiles. This heterogeneity is manifested by differences in vascular selectivity, effects on cardiac conduction and adverse events. The lack of differentiation between calcium channel antagonists in clinical trials has contributed to uncertainty associated with their impact on morbidity and mortality. Data from more recent studies in specific patient populations underscores the importance of investigating these antihypertensives as individual agents. A proposed therapeutic classification system suggests that newer agents should share the slow onset and long-acting antihypertensive effect of amlodipine. Additionally, a favourable trough-to-peak ratio has been recommended as an objective measurement of efficacy. The newer drugs, barnidipine and lacidipine, have a therapeutic profile similar to amlodipine, but trough-to-peak ratios are not substantially greater than the recommended minimum of 0.50. Aranidipine, cilnidipine and efonidipine have unique pharmacological properties that distinguish them from traditional dihydropyridines. Although clinical significance is unconfirmed, these newer options may be beneficial for patients with co-morbid conditions that preclude use of older antagonists.

  7. Approaches to the rational design of selective melanocortin receptor antagonists

    Science.gov (United States)

    Hruby, Victor J; Cai, Minying; Nyberg, Joel; Muthu, Dhanasekaran

    2015-01-01

    Introduction When establishing the physiological roles of specific receptors in normal and disease states, it is critical to have selective antagonist ligands for each receptor in a receptor system with several subtypes. The melanocortin receptors have five subtypes referred to as the melanocortin 1 receptor, melanocortin 2 receptor, melanocortin 3 receptor, melanocortin 4 receptor and melanocortin 5 receptor, and they are of critical importance for many aspects of human health and disease. Areas covered This article reviews the current efforts to design selective antagonistic ligands for the five human melanocortin receptors summarizing the currently published orthosteric and allosteric antagonists for each of these receptors. Expert opinion Though there has been progress, there are still few drugs available that address the many significant biological activities and diseases that are associated with these receptors, which is possibly due to the lack of receptor selectivity that these designed ligands are currently showing. The authors believe that further studies into the antagonists’ 3D conformational and topographical properties in addition to future mutagenesis studies will provide greater insight into these ligands which could play a role in the treatment of various diseases in the future. PMID:22646078

  8. Drug: D01830 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01830 Drug Arotinolol hydrochloride (JP16); Almarl (TN) C15H21N3O2S3. HCl 407.0563... 408.0021 D01830.gif Antihypertensive Therapeutic category: 2123 alpha1-adrenergic receptor antagonist [HSA:...146 147 148] [KO:K04137 K04136 K04135]; beta1-adrenergic receptor antagonist [HSA:153] [KO:K04141]; beta2-adr...energic receptor antagonist [HSA:154] [KO:K04142]; beta3-adrenergic receptor ant...48+153+154+155) Neuroactive ligand-receptor interaction hsa04261(146+147+148+153+154) Adrenergic signaling i

  9. Drug: D07465 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07465 Drug Arotinolol (INN) C15H21N3O2S3 371.0796 371.5411 D07465.gif Antiarrhythmic alpha1-adr...energic receptor antagonist [HSA:146 147 148] [KO:K04137 K04136 K04135]; beta1-adrenergic recep...tor antagonist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adre...61(146+147+148+153+154) Adrenergic signaling in cardiomyocytes hsa04270(146+147+148) Vascular smooth muscle ...contraction hsa04970(146+147+148+153+154+155) Salivary secretion map07214 beta-Adr

  10. Herbal drugs and drug interactions

    Directory of Open Access Journals (Sweden)

    Gül Dülger

    2012-01-01

    Full Text Available Herbal drugs are defined as any form of a plant or plant product that contains a single herb or combinations of herbs that are believed to have complementary effects. Although they are considered to be safe, because they are natural, they may have various adverse effects, and may interact with other herbal products or conventional drugs. These interactions are especially important for drugs with narrow therapeutic indices.In the present study, pharmacokinetic and pharmacodynamic interactions of some most commanly used herbals (St John's wort, ginkgo biloba, ginseng, ginger, garlic, echinacea, ephedra and valerian with the conventional drugs were reviewed. Pharmacokinetic interactions involve mainly induction or inhibition of the cytochrome P450 isozymes and p-glycoproteins by the herbal medicine, thus changing the absorption and/or elimination rate and consequently the efficacy of the concommitantly used drugs. St John's wort, a well known enzyme inducer, decreases the efficacy of most of the other drugs that are known to be the substrates of these enzymes.Pharmacodynamic interactions may be due to additive or synergistic effects which results in enhanced effect or toxicity, or herbal medicines with antagonistic properties reduce drug efficacy and result in therapeutic failure. For exampla, St John's wort may have synergistic effects with other antidepressant drugs used by the patient, resulting in increased CNS effects.Herbals like ginseng, ginkgo, garlic, ginger were reported to increase bleeding time, thus potentiating the effect of anticoagulant and antithrombotic agents. In conclusion, patients should be warned against the interaction between the herbal products and conventional medicines.

  11. GnRH antagonist in in vitro fertilization: where we are now.

    Science.gov (United States)

    Shapiro, D B; Mitchell-Leef, D

    2003-10-01

    This review focuses on the recent literature concerning the use of GnRH antagonists in ovulation induction for in vitro fertilization (IVF). The GnRH antagonists, ganirelix acetate (Orgalutran/Antagon) and cetrorelix (Cetrotide), have come into increasingly common use since their release in the last 3 years. This class of GnRH analogue has several potential advantages over GnRH agonists. Among these advantages are: 1) shorter duration of injectable drug treatment, 2) decreased gonadotropin requirement per cycle, 3) improved patient convenience and 4) lower overall treatment cost. As clinicians gain experience with these drugs, optimal treatment paradigms will likely emerge. This review will discuss current strategies and potential applications for the GnRH antagonists.

  12. [Effects of calcium antagonist drugs on glucide metabolism].

    Science.gov (United States)

    Gusmini, G; Lombardi, C; Rangoni, G; Spedini, C

    1988-10-01

    The extension of the clinical use of Calcium entry Blockers (CEBs) indicates the need for a careful evaluation of possible adverse effects. Recently, contrasting data have been reported in some studies on the effect of CEBs on oral and i.v. glucose tolerance tests. The aim of the present study was to evaluate the potential diabetogenic properties of CEBs in normal subjects and their activities in diabetic patients. The data present in literature and also personal observations outline the safety of CEBs. In fact, there is a low possibility to derange the balance between insulin and glucagon secretion after acute and chronic administration of CEBs at conventional dosages.

  13. Discovery of non-peptide small molecular CXCR4 antagonists as anti-HIV agents: Recent advances and future opportunities.

    Science.gov (United States)

    Zhang, Heng; Kang, Dongwei; Huang, Boshi; Liu, Na; Zhao, Fabao; Zhan, Peng; Liu, Xinyong

    2016-05-23

    CXCR4 plays vital roles in HIV-1 life cycle for it's essential in mediating the interaction of host and virus and completing the entry process in the lifecycle of HIV-1 infection. Compared with some traditional targets, CXCR4 provides a novel and less mutated drug target in the battle against AIDS. Its antagonists have no cross resistance with other antagonists. Great achievements have been made recent years and a number of small molecular CXCR4 antagonists with diversity scaffolds have been discovered. In this review, recent advances in the discovery of CXCR4 antagonists with special attentions on their evolution and structure-activity relationships of representative CXCR4 antagonists are described. Moreover, some classical medicinal chemistry strategies and novel methodologies are also introduced.

  14. Antagonistic formation motion of cooperative agents

    Institute of Scientific and Technical Information of China (English)

    卢婉婷; 代明香; 薛方正

    2015-01-01

    This paper investigates a new formation motion problem of a class of first-order multi-agent systems with antagonis-tic interactions. A distributed formation control algorithm is proposed for each agent to realize the antagonistic formation motion. A sufficient condition is derived to ensure that all agents make an antagonistic formation motion in a distributed manner. It is shown that all agents can be spontaneously divided into several groups, and agents in the same group collab-orate while agents in different groups compete. Finally, a numerical simulation is included to demonstrate our theoretical results.

  15. Antagonists of the kappa opioid receptor.

    Science.gov (United States)

    Urbano, Mariangela; Guerrero, Miguel; Rosen, Hugh; Roberts, Edward

    2014-05-01

    The research community has increasingly focused on the development of OPRK antagonists as pharmacotherapies for the treatment of depression, anxiety, addictive disorders and other psychiatric conditions produced or exacerbated by stress. Short-acting OPRK antagonists have been recently developed as a potential improvement over long-acting prototypic ligands including nor-BNI and JDTic. Remarkably the short-acting LY2456302 is undergoing phase II clinical trials for the augmentation of the antidepressant therapy in treatment-resistant depression. This Letter reviews relevant chemical and pharmacological advances in the identification and development of OPRK antagonists.

  16. Editing and Scaling of Instrument Packets for the Clinical Evaluation of Narcotic Antagonists. Final Report.

    Science.gov (United States)

    Boldt, Robert F.; Gitomer, Nancy L.

    Efforts of the National Academy of Sciences (NAS) as a contractor to the National Institute on Drug Abuse (NIDA) include: (1) assessment of the usefulness of naltrexone, a narcotic antagonist, in the rehabilitation of several types of opiate-dependent individuals; (2) assessment of any drawbacks to the use of naltrexone; and (3) appraisal of…

  17. Novel Small Molecule Antagonists of the Interaction of the Androgen Receptor and Transcriptional Co-regulators

    Science.gov (United States)

    2009-01-01

    Netherlands ) (see appendices). Small Molecule Inhibitors of the Androgen Receptor Transcriptional Activity for Prostate Cancer Drug Discovery...peritoneal injection, tail injection, oral gavage, retro-orbital blood sampling, isoflurane anesthesia, CO2 euthanasia , cardiac stick, organ harvesting...Discovery Poster Award, Androgens 2008 Meeting, Rotterdam (The Netherlands ), October 2008 Novel Small Molecules Antagonists of the Interaction of

  18. Intracerebroventricular administration of histamine H3 receptor antagonists decreases seizures in rat models of epilepsia.

    Science.gov (United States)

    Harada, C; Hirai, T; Fujii, Y; Harusawa, S; Kurihara, T; Kamei, C

    2004-05-01

    The effects of histamine H3 antagonists on amygdaloid kindled and maximal electroshock seizures in rats were studied to determine their potential as new antiepileptic drugs. Under pentobarbital anesthesia, rats were fixed to a stereotaxic apparatus and a stainless steel guide cannula for drug administration was implanted into the lateral ventricle. In amygdaloid kindled seizures, electrodes were implanted into the right amygdala and electroencephalogram was recorded bipolarly; stimulation was applied bipolarly every day by a constant current stimulator and continued until a generalized convulsion was obtained. In the maximal electroshock (MES) seizure test, electroconvulsion was induced by stimulating animals through ear-clip electrodes, and the durations of tonic and clonic seizures were measured. Thioperamide, clobenpropit, iodophenpropit, VUF5514, VUF5515 and VUF4929 caused a dose-dependent inhibition of both seizure stage and afterdischarge (AD) duration of amygdaloid kindled seizures. The duration of tonic seizure induced by MES was also inhibited by H3 antagonists, but the duration of clonic seizures were unchanged. Among the H3 antagonists tested, clobenpropit and iodophenpropit were somewhat more potent than the other drugs on amygdaloid kindled seizures and MES seizures, respectively. These results indicate that some H3 antagonists may be useful as antiepileptic drugs, especially for secondary generalized seizures and/or tonic-clonic seizures in humans.

  19. Cannabinoid receptor antagonists and the metabolic syndrome: Novel promising therapeutical approaches.

    Science.gov (United States)

    Cervino, C; Pasquali, R; Pagotto, U

    2007-01-01

    Recent findings in animals and in humans have shown that cannabinoid type 1 receptor antagonists are suitable to become the most promising validated class of drugs to tackle obesity and related disorders. This mini-review will provide a concise and updated revision of the state of art on this topic.

  20. Anti free radical action of calcium antagonists and H1 and H2 receptors antagonists in neoplastic disease.

    Science.gov (United States)

    della Rovere, F; Broccio, M; Granata, A; Zirilli, A; Brugnano, L; Artemisia, A; Broccio, G

    1996-01-01

    The blood of the subjects suffering from Neoplastic Disease (ND) shows phenomena of membrane peroxidation due to the presence of Free Radicals (FRs), in a quantity much greater than the one observed in the blood of healthy subjects. This can be detected either by calculating the time necessary for the formation of "Heinz bodies" (Hbs), (p < 0.00001) after oxidative stress of the blood in vitro with acetylphenylidrazine (APH), or by calculating the methemoglobin (metHb) quantity that forms after the same treatment (P < 0.00001). The statistical analyses we carried out showed that metHb formation was not affected by age, sex, smoking habits, red blood cell number, Hb, Ht or tumor staging. In this study, by using equal parameters of investigation, we noted that the blood of the subjects with ND who were previously treated with calcium-antagonists drugs and with antagonists of H1 and H2 receptors, gave results completely superimposable on the results obtained from healthy subjects, implying that the treatment had avoided the increase of FRs. Therefore we concluded that calcium-antagonists and the antagonists of the H1 and H2 receptors behave as antioxidant substances, having decreased the FRs damaging activity on the cellular membranes, thus controlling, although to a limited degree, the pejorative evolution of the disease. It is also important to remember that investigations into the ND, even possible screenings, must take into account the above said data, submitting the subjects under investigation to a pharmacological wash out, particularly with those substances which, are considered to be scavengers of FRs. Some of these substances are investigated in this work.

  1. Current perspectives on selective dopamine D(3) receptor antagonists as pharmacotherapeutics for addictions and related disorders.

    Science.gov (United States)

    Heidbreder, Christian A; Newman, Amy H

    2010-02-01

    Repeated exposure to drugs of abuse produces long-term molecular and neurochemical changes that may explain the core features of addiction, such as the compulsive seeking and taking of the drug, as well as the risk of relapse. A growing number of new molecular and cellular targets of addictive drugs have been identified, and rapid advances are being made in relating those targets to specific behavioral phenotypes in animal models of addiction. In this context, the pattern of expression of the dopamine (DA) D(3) receptor in the rodent and human brain and changes in this pattern in response to drugs of abuse have contributed primarily to direct research efforts toward the development of selective DA D(3) receptor antagonists. Growing preclinical evidence indicates that these compounds may actually regulate the motivation to self-administer drugs and disrupt drug-associated cue-induced craving. This report will be divided into three parts. First, preclinical evidence in support of the efficacy of selective DA D(3) receptor antagonists in animal models of drug addiction will be reviewed. The effects of mixed DA D(2)/D(3) receptor antagonists will not be discussed here because most of these compounds have low selectivity at the D(3) versus D(2) receptor, and their efficacy profile is related primarily to functional antagonism at D(2) receptors and possibly interactions with other neurotransmitter systems. Second, major advances in medicinal chemistry for the identification and optimization of selective DA D(3) receptor antagonists and partial agonists will be analyzed. Third, translational research from preclinical efficacy studies to so-called proof-of-concept studies for drug addiction indications will be discussed.

  2. Suppression of Aldosterone Synthesis and Secretion by Channel Antagonists

    Directory of Open Access Journals (Sweden)

    Keiichi Ikeda

    2012-01-01

    Full Text Available Aldosterone, a specific mineralocorticoid receptor (MR agonist and a key player in the development of hypertension, is synthesized as a final product of renin-angiotensin-aldosterone system. Hypertension can be generally treated by negating the effects of angiotensin II through the use of angiotensin-converting enzyme inhibitors (ACE-Is or angiotensin II type 1 receptor antagonists (ARBs. However, the efficacy of angiotensin II blockade by such drugs is sometimes diminished by the so-called “aldosterone breakthrough” effect, by which ACE-Is or ARBs (renin-angiotensin system (RAS inhibitors gradually lose their effectiveness against hypertension due to the overproduction of aldosterone, known as primary aldosteronism. Although MR antagonists are used to antagonize the effects of aldosterone, these drugs may, however, give rise to life-threatening adverse actions, such as hyperkalemia, particularly when used in conjunction with RAS inhibitors. Recently, several groups have reported that some dihydropyridine Ca2+ channel blockers (CCBs have inhibitory actions on aldosterone production in in vitro and in the clinical setting. Therefore, the use of such dihydropyridine CCBs to treat aldosterone-related hypertension may prove beneficial to circumvent such therapeutic problems. In this paper, we discuss the mechanism of action of CCBs on aldosterone production and clinical perspectives for CCB use to inhibit MR activity in hypertensive patients.

  3. Drug: D00678 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00678 Drug Ondansetron hydrochloride hydrate (JAN/USP); Ondansetron hydrochloride;...ts affecting individual organs 23 Digestive organ agents 239 Miscellaneous 2391 Antiemetics D00678 Ondansetr... ANTINAUSEANTS A04AA Serotonin (5HT3) antagonists A04AA01 Ondansetron D00678 Ondansetron hydrochloride hydra...te (JAN/USP) USP drug classification [BR:br08302] Antiemetics Emetogenic Therapy Adjuncts Ondanse...tron D00678 Ondansetron hydrochloride hydrate (JAN/USP) Target-based classification of drugs

  4. Studies on the Antihypertensive Mechanism of adrenergic Receptor Antagonist Propranolol : Special Reference to the Role of Vasodilatory Prostaglandins

    OpenAIRE

    西宮, 孝敏; Perry V., Halushka

    1988-01-01

    β-adrenergic receptor antagonists are widely used to treat the patients with hypertension. The mechanism of the antihypertensive effect of these drugs was thought to be associated with 1) negative cardiac inotropic and chronotropic action, 2) suppression of renin secretion, and 3) effects on the central nervous system. However, the precise mechanism is still unknown. Long term therapy with β-adrenergic receptor antagonists is also associated with a reduction in the peripheral vascular resista...

  5. A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined with Enzalutamide in Castrate Resistant Prostate Cancer

    Science.gov (United States)

    2015-12-01

    multifactorial, and likely due to disease, as well as the two study drugs enzalutamide and mifepristone . from There have been no dose limiting toxicities ...AWARD NUMBER: W81XWH-14-1-0021 TITLE: A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined...4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER A Pharmacokinetic/Pharmacodynamic Study of the Glucocorticoid Receptor Antagonist Mifepristone Combined

  6. Benzodiazepine receptor antagonists for hepatic encephalopathy

    DEFF Research Database (Denmark)

    Als-Nielsen, B; Gluud, L L; Gluud, C

    2004-01-01

    Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy.......Hepatic encephalopathy may be associated with accumulation of substances that bind to a receptor-complex in the brain resulting in neural inhibition. Benzodiazepine receptor antagonists may have a beneficial effect on patients with hepatic encephalopathy....

  7. Drug: D00586 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available eptor antagonist [HSA:367] [KO:K08557] hsa05200(367) Pathways in cancer hsa05215(367) Prostate cancer map07043 Antineoplastics...or agonists/antagonists Therapeutic category of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 42 Antineoplastics...BB01 Flutamide D00586 Flutamide (JP16/USP/INN) USP drug classification [BR:br08302] Antineoplastics Antiandr...] [KO:K08557] Flutamide [ATC:L02BB01] D00586 Flutamide (JP16/USP/INN) Antineoplastics [BR:br08308] Hormones

  8. Drug: D09400 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09400 Drug Degarelix acetate (JAN) C82H103ClN18O16. (C2H4O2)x D09400.gif Treatment...ellaneous 2499 Others D09400 Degarelix acetate (JAN) Anatomical Therapeutic Chemical (ATC) classification [B...B HORMONE ANTAGONISTS AND RELATED AGENTS L02BX Other hormone antagonists and related agents L02BX02 Degarelix D09400 Degareli...x acetate (JAN) USP drug classification [BR:br08302] Hormonal Agents, Suppressant (Pituitary) Degareli...ing hormone (GnRH) receptor [HSA:2798] [KO:K04280] Degarelix [ATC:L02BX02] D09400 Degarelix acetate (JAN) An

  9. Drug: D01204 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01204 Drug Olmesartan medoxomil (JAN/USAN); Benicar (TN); Olmetec (TN) C29H30N6O6 ...ategory: 2149 ATC code: C09CA08 prodrug, active substance: Olmesartan [DR:D05246] angiotensin II receptor ty...hypertensives 2149 Others D01204 Olmesartan medoxomil (JAN/USAN) Anatomical Therapeutic Chemical (ATC) class...IOTENSIN SYSTEM C09C ANGIOTENSIN II ANTAGONISTS, PLAIN C09CA Angiotensin II antagonists, plain C09CA08 Olmesa...rtan medoxomil D01204 Olmesartan medoxomil (JAN/USAN) USP drug classification [BR:br08302] Cardiovascular A

  10. Drug: D00357 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00357 Drug Losartan potassium (JP16/USAN); Cozaar (TN) C22H22ClN6O. K 460.1181 461...gans 21 Cardiovascular agents 214 Antihypertensives 2149 Others D00357 Losartan potassium (JP16/USAN) Anatom...n II antagonists, plain C09CA01 Losartan D00357 Losartan potassium (JP16/USAN) USP drug classification [BR:b...r08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Losartan D00357 Losartan potassium (JP16/U...sin angiotensin II stimulates angiotensin subtype 1 (AT1) receptor [HSA:185] [KO:K04166] Losartan

  11. Drug: D00522 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00522 Drug Candesartan (USAN/INN) C24H20N6O3 440.1597 440.454 D00522.gif Antagonis...S, PLAIN C09CA Angiotensin II antagonists, plain C09CA06 Candesartan D00522 Candesartan (USAN/INN) USP drug ...classification [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Candesartan D00522 Candesartan... [HSA:185] [KO:K04166] Candesartan [ATC:C09CA06] D00522 Candesartan (USAN/INN) CAS: 139481-59-7 PubChem: 784

  12. Drug: D01806 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01806 Drug Oxprenolol hydrochloride (JP16/USP); Okuspurecol (TN) C15H23NO3. HCl 30...1.1445 301.809 D01806.gif Vasodilator [coronary] Therapeutic category: 2123 ATC code: C07AA02 beta1-adrenerg...ic receptor antagonist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adr...lcium signaling pathway hsa04080(153+154+155) Neuroactive ligand-receptor interaction hsa04261(153+154) Adre...nergic signaling in cardiomyocytes hsa04970(153+154+155) Salivary secretion Therapeutic category of drugs in

  13. Drug: D02389 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02389 Drug Primidolol (USAN/INN) C17H23N3O4 333.1689 333.3822 D02389.gif Antihyper...tensive; Anti-anginal; Cardiac depressant [anti-arrhythmic] Same as: C11774 beta1-adrenergic receptor antago...nist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adrenergic rec...thway hsa04080(153+154+155) Neuroactive ligand-receptor interaction hsa04261(153+154) Adrenergic signaling i...n cardiomyocytes hsa04970(153+154+155) Salivary secretion Target-based classification of drugs [BR:br08310

  14. Drug: D01182 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01182 Drug Alprenolol hydrochloride (JP16/USAN); Regletin (TN) C15H23NO2. HCl 285....1496 285.8096 D01182.gif Anti-adrenergic [beta-receptor] Therapeutic category: 2123 ATC code: C07AA01 beta1-adr...energic receptor antagonist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adr...+155) Calcium signaling pathway hsa04080(153+154+155) Neuroactive ligand-receptor interaction hsa04261(153+154) Adr...] map07037 Antiarrhythmic drugs map07214 beta-Adrenergic receptor agonists/antago

  15. Perioperative management of a patient with recently placed drug-eluting stents requiring urgent spinal surgery.

    Science.gov (United States)

    Roth, Eira; Purnell, Chad; Shabalov, Olga; Moguillansky, Diego; Hernandez, Caridad A; Elnicki, Michael

    2012-08-01

    Patients receiving drug-eluting coronary stents (DES) require antiplatelet therapy for at least 12 months to prevent stent thrombosis (ST), a potentially calamitous event. Since interruption of antiplatelet therapy is the greatest risk factor for ST, it is imperative that the decision to discontinue these agents be based on an accurate assessment of the patient's risk for bleeding complications. Individuals who are regarded as being at a high risk are those undergoing intracranial, spinal or intraocular surgeries. These patients require alternative agents during the perioperative period to minimize both their risk of perioperative thrombosis and intraoperative hemorrhage. We report the case of a woman who required spinal surgery 3 months after she underwent placement of two drug-eluting stents. The patient's clopidogrel was stopped 5 days prior to surgery and an infusion of eptifibatide was used to "bridge" antiplatelet therapy during the perioperative period. Postoperatively, anticoagulation therapy was reinstituted using aspirin with clopidogrel. This case serves as a successful example of bridging therapy using a short acting and gycoprotein (GP) IIb/IIIa inhibitor as a means of maintaining antiplatelet therapy during the perioperative period to minimize the risk of stent thrombosis and the risk of intraoperative bleeding.

  16. 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...... for treatment of chronic migraine (attacks >15 days/month). Initial results from phase I and II clinical trials have revealed promising results with minimal side effects and significant relief from chronic migraine as compared with placebo. The effectiveness of these various molecules raises the question...... to understand the localization of CGRP and the CGRP receptor components in these possible sites of migraine-related regions and their relation to the BBB....

  17. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan;

    2011-01-01

    and pharmacological character: (1) chemogenomic lead identification through the first, to our knowledge, ligand inference between two different GPCR families, Families A and C; and (2) the discovery of the most selective GPRC6A allosteric antagonists discovered to date. The unprecedented inference of...... pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors...

  18. Discovery of 2-substituted benzoxazole carboxamides as 5-HT3 receptor antagonists.

    Science.gov (United States)

    Yang, Zhicai; Fairfax, David J; Maeng, Jun-Ho; Masih, Liaqat; Usyatinsky, Alexander; Hassler, Carla; Isaacson, Soshanna; Fitzpatrick, Kevin; DeOrazio, Russell J; Chen, Jianqing; Harding, James P; Isherwood, Matthew; Dobritsa, Svetlana; Christensen, Kevin L; Wierschke, Jonathan D; Bliss, Brian I; Peterson, Lisa H; Beer, Cathy M; Cioffi, Christopher; Lynch, Michael; Rennells, W Martin; Richards, Justin J; Rust, Timothy; Khmelnitsky, Yuri L; Cohen, Marlene L; Manning, David D

    2010-11-15

    A new class of 2-substituted benzoxazole carboxamides are presented as potent functional 5-HT(3) receptor antagonists. The chemical series possesses nanomolar in vitro activity against human 5-HT(3)A receptors. A chemistry optimization program was conducted and identified 2-aminobenzoxazoles as orally active 5-HT(3) receptor antagonists with good metabolic stability. These novel analogues possess drug-like characteristics and have potential utility for the treatment of diseases attributable to improper 5-HT(3) receptor function, especially diarrhea predominant irritable bowel syndrome (IBS-D).

  19. Chemogenomic discovery of allosteric antagonists at the GPRC6A receptor

    DEFF Research Database (Denmark)

    Gloriam, David E.; Wellendorph, Petrine; Johansen, Lars Dan

    2011-01-01

     pharmacological activity across GPCR families provides proof-of-concept for in silico approaches against Family C targets based on Family A templates, greatly expanding the prospects of successful drug design and discovery. The antagonists were tested against a panel of seven Family A and C G protein-coupled receptors......, calindol and NPS 2143, which both display ~30-fold selectivity for the calcium-sensing receptor compared to GPRC6A. The antagonists constitute novel research tools toward investigating the signaling mechanism of the GPRC6A receptor at the cellular level and serve as initial ligands for further optimization...

  20. Therapeutic approach in patients with concomitant disease/drug--drug interactions (roxatidine acetate).

    Science.gov (United States)

    Collins, J D

    1988-01-01

    Possible mechanisms of drug interactions with H2-antagonists are outlined. The mode of action of roxatidine acetate on hepatic microsomal enzymes is contrasted with those of cimetidine and ranitidine, and their differing structure-activity relationships are discussed. In the light of the mechanisms of drug interactions with H2-antagonists, clinical studies with roxatidine acetate are contrasted with published interaction data of cimetidine and ranitidine. The therapeutic consequences of these data are considered.

  1. Using a pharmacophore representation concept to elucidate molecular similarity of dopamine antagonists

    Science.gov (United States)

    Atlamazoglou, V.; Thireou, T.; Eliopoulos, E.

    2007-05-01

    The pharmacophoric concept plays an important role in ligand-based drug design methods to describe the similarity and diversity of molecules, and could also be exploited as a molecular representation scheme. A three-point pharmacophore method was used as a molecular representation perception. This procedure was implemented for dopamine antagonists of the D2 receptor subtype. The molecular structures of the antagonists included in this analysis were categorized into two structurally distinct classes. Using structural superposition with internal energy minimization, two pharmacophore models were deduced. Based on these two models other D2 antagonists that fulfil them were derived and studied. This procedure aided the identification of the common 3D patterns present in diverse molecules that act at the same biological target and the extraction of a common molecular framework for the two structural classes. The pharmacophoric information was found to be suitable for guiding superposition of structurally diverse molecules, using a more biologically meaningful selection of the targeting points.

  2. Auxin-Oxylipin Crosstalk: Relationship of Antagonists

    Institute of Scientific and Technical Information of China (English)

    Maik Hoffmann; Mathias Hentrich; Stephan Pollmann

    2011-01-01

    Phytohormones regulate a wide array of developmental processes throughout the life cycle of plants. Herein, the various plant hormones may interact additively, synergistically, or antagonistically. By their cooperation they create a delicate regulatory network whose net output largely depends on the action of specific phytohormone combinations rather than on the independent activities of separate hormones. While most classical studies of plant hormonal control have focused mainly on the action of single hormones or on the synergistic interaction of hormones in regulating various developmental processes, recent work is beginning to shed light on the crosstalk of nominally antagonistic plant hormones, such as gibberellins and auxins with oxylipins or abscisic acid. In this review, we summarize our current understanding of how two of the first sight antagonistic plant hormones, i.e. auxins and oxylipins,interact in controlling plant responses and development.

  3. New Antiplatelet Drugs

    Institute of Scientific and Technical Information of China (English)

    包承鑫

    2011-01-01

    @@ ADP- receptor antagonist Prasugrel is a thienopyridine of the third generation and needs conversion into an active drug metabolite (R138727).Preclinical and clinical studies showed a more rapid,potent and consistent inhibition of patelet function for prasugrel compared to clopidogrel.Prasugrel has been shown to be of particular benefit in patients with diabetes,especially those on insulin [30% relative risk reduction (RRR) in cardiovascular death, MI,or stroke (P <0.001 ) and 37% RRR,respectively] .

  4. Genetic determinants of response and adverse effects following vitamin K antagonist oral anticoagulants

    Directory of Open Access Journals (Sweden)

    Parameshwar S.

    2016-06-01

    Full Text Available Background: Vitamin K antagonist anticoagulants (warfarin/acenocoumarol are commonly used anticoagulants that require careful clinical management to balance the risks of over anticoagulation and bleeding with those of under anticoagulation and clotting. Genetic variants of the enzyme that metabolizes vitamin K antagonist anticoagulant, cytochrome P-450 2C9 (CYP2C9, and of a key pharmacologic target of vitamin K antagonists anticoagulant, vitamin K epoxide reductase (VKORC1, contribute to differences in patients responses to various anticoagulant doses. Methods: In thirty patients on oral vitamin K antagonist anticoagulant therapy, presented with either clotting manifestations (valve thrombosis, pulmonary embolism and DVT or prolonged INR/bleeding manifestations, we assessed CYP2C9 genotypes, VKORC1 haplotypes, clinical characteristics, response to therapy (as determined by the international normalized ratio [INR], and bleeding events. Results: Of the thirty patients, thirteen patients INR was high and four patients presented with major bleeding and four with minor bleeding manifestations. Out of thirteen patients with high INR, ten patients showed CYP2C9 polymorphism ( 1/ 3 and 2/ 3 of poor metabolizer genotype. Most of the high INR patients were recently started on oral vitamin K antagonist anticoagulant. Most patients presented with clotting manifestations with below therapeutic INR are noncompliant with anticoagulants. Conclusions: The results of this study suggest that the CYP2C9 polymorphisms are associated with an increased risk of over anticoagulation and of bleeding events among patients on vitamin K antagonists' anticoagulant setting. Screening for CYP2C9 variants may allow clinicians to develop dosing protocols and surveillance techniques to reduce the risk of adverse drug reactions in patients receiving vitamin K antagonist anticoagulants. However the cost-effectiveness of genotyping of patients must be considered. [Int J Res Med Sci

  5. Drug: D00627 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00627 Drug Telmisartan (JAN/USAN/INN); Micardis (TN) C33H30N4O2 514.2369 514.6169 ...BR:br08301] 2 Agents affecting individual organs 21 Cardiovascular agents 214 Antihypertensives 2149 Others D00627 Telmisartan...N II ANTAGONISTS, PLAIN C09CA Angiotensin II antagonists, plain C09CA07 Telmisartan D00627 Telmisartan (JAN/...USAN/INN) USP drug classification [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Telmisartan D00627 Telmisart...ubtype 1 (AT1) receptor [HSA:185] [KO:K04166] Telmisartan [ATC:C09CA07] D00627 Telmisartan (JAN/USAN/INN) CA

  6. Novel pyrazole derivatives as neutral CB₁ antagonists with significant activity towards food intake.

    Science.gov (United States)

    Manca, Ilaria; Mastinu, Andrea; Olimpieri, Francesca; Falzoi, Matteo; Sani, Monica; Ruiu, Stefania; Loriga, Giovanni; Volonterio, Alessandro; Tambaro, Simone; Bottazzi, Mirko Emilio Heiner; Zanda, Matteo; Pinna, Gérard Aimè; Lazzari, Paolo

    2013-04-01

    In spite of rimonabant's withdrawal from the European market due to its adverse effects, interest in the development of drugs based on CB1 antagonists is revamping on the basis of the peculiar properties of this class of compounds. In particular, new strategies have been proposed for the treatment of obesity and/or related risk factors through CB1 antagonists, i.e. by the development of selectively peripherally acting agents or by the identification of neutral CB1 antagonists. New compounds based on the lead CB1 antagonist/inverse agonist rimonabant have been synthesized with focus on obtaining neutral CB1 antagonists. Amongst the new derivatives described in this paper, the mixture of the two enantiomers (±)-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-(2-cyclohexyl-1-hydroxyethyl)-4-methyl-1H-pyrazole ((±)-5), and compound 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-[(Z)-2-cyclohexyl-1-fluorovinyl]-4-methyl-1H-pyrazole ((Z)-6), showed interesting pharmacological profiles. According to the preliminary pharmacological evaluation, these novel pyrazole derivatives showed in fact both neutral CB1 antagonism behaviour and significant in vivo activity towards food intake.

  7. Orexin 1 receptor antagonists in compulsive behaviour and anxiety: possible therapeutic use.

    Directory of Open Access Journals (Sweden)

    Emilio eMerlo-Pich

    2014-02-01

    Full Text Available 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 early on 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 behavioural 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.

  8. Personalized medicine: theranostics (therapeutics diagnostics) essential for rational use of tumor necrosis factor-alpha antagonists.

    Science.gov (United States)

    Bendtzen, Klaus

    2013-04-01

    With the discovery of the central pathogenic role of tumor necrosis factor (TNF)-alpha in many immunoinflammatory diseases, specific inhibition of this pleiotropic cytokine has revolutionized the treatment of patients with several non-infectious inflammatory disorders. As a result, genetically engineered anti-TNF-alpha antibody constructs now constitute one of the heaviest medicinal expenditures in many countries. All currently used TNF antagonists may dramatically lower disease activity and, in some patients, induce remission. Unfortunately, however, not all patients respond favorably, and safety can be severely impaired by immunogenicity, i.e., the ability of a drug to induce anti-drug antibodies (ADA). Assessment of ADA is therefore an important component of the evaluation of drug safety in both pre-clinical and clinical studies and in the process of developing less immunogenic and safer biopharmaceuticals. Therapeutics diagnostics, also called theranostics, i.e., monitoring functional drug levels and neutralizing ADA in the circulation, is central to more effective use of biopharmaceuticals. Hence, testing-based strategies rather than empirical dose-escalation may provide more cost-effective use of TNF antagonists as this allows therapies tailored according to individual requirements rather than the current universal approach to diagnosis. The objective of the present review is to discuss the reasons for recommending theranostics to implement an individualized use of TNF antagonists and to highlight some of the methodological obstacles that have obscured cost-effective ways of using these therapies.

  9. A cross-laboratory preclinical study on the effectiveness of interleukin-1 receptor antagonist in stroke.

    Science.gov (United States)

    Maysami, Samaneh; Wong, Raymond; Pradillo, Jesus M; Denes, Adam; Dhungana, Hiramani; Malm, Tarja; Koistinaho, Jari; Orset, Cyrille; Rahman, Mahbubur; Rubio, Marina; Schwaninger, Markus; Vivien, Denis; Bath, Philip M; Rothwell, Nancy J; Allan, Stuart M

    2016-03-01

    Stroke represents a global challenge and is a leading cause of permanent disability worldwide. Despite much effort, translation of research findings to clinical benefit has not yet been successful. Failure of neuroprotection trials is considered, in part, due to the low quality of preclinical studies, low level of reproducibility across different laboratories and that stroke co-morbidities have not been fully considered in experimental models. More rigorous testing of new drug candidates in different experimental models of stroke and initiation of preclinical cross-laboratory studies have been suggested as ways to improve translation. However, to our knowledge, no drugs currently in clinical stroke trials have been investigated in preclinical cross-laboratory studies. The cytokine interleukin 1 is a key mediator of neuronal injury, and the naturally occurring interleukin 1 receptor antagonist has been reported as beneficial in experimental studies of stroke. In the present paper, we report on a preclinical cross-laboratory stroke trial designed to investigate the efficacy of interleukin 1 receptor antagonist in different research laboratories across Europe. Our results strongly support the therapeutic potential of interleukin 1 receptor antagonist in experimental stroke and provide further evidence that interleukin 1 receptor antagonist should be evaluated in more extensive clinical stroke trials.

  10. Discovery and characterization of carbamothioylacrylamides as EP2 selective antagonists.

    Science.gov (United States)

    Ganesh, Thota; Jiang, Jianxiong; Shashidharamurthy, Rangaiah; Dingledine, Ray

    2013-07-11

    Prostanoid receptor EP2 is emerging as a novel target for development of anti-inflammatory drugs for the treatment of chronic neurodegenerative and peripheral diseases; however, the availability of EP2 antagonist probes for exploration of peripheral disease models is very limited. We now report identification and characterization of a novel chemical class of compounds that show nanomolar potency and competitive antagonism of the EP2 receptor. A compound in this class, TG6-129, showed prolonged plasma half-life and did not cross the blood brain barrier. This compound also suppressed the induction of inflammatory mRNA markers in a macrophage cell line upon activation of EP2. Thus, this compound could be useful as a probe for a variety of peripheral chronic inflammatory diseases such as rheumatoid arthritis and chronic obstructive pulmonary disease, in which EP2 appears to play a pathogenic role.

  11. Drug: D09953 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09953 Drug Pridopidine (USAN/INN) C15H23NO2S 281.145 281.4136 D09953.gif Treatment of schizophrenia, Parkin...son's disease and Huntington's disease dopamine D2 receptor agonist/antagonist [HSA

  12. Drug: D00965 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available (367) Prostate cancer Enzyme: CYP2C19 [HSA:1557] map07043 Antineoplastics - hormo...00965 Nilutamide (USAN/INN) USP drug classification [BR:br08302] Antineoplastics Antiandrogens Nilutamide D0...ide [ATC:L02BB02] D00965 Nilutamide (USAN/INN) Antineoplastics [BR:br08308] Hormones and hormone antagonist

  13. Drug: D10285 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10285 Mixture, Drug Amlodipine besylate - olmesartan medoxomil mixt; Azor (TN) Aml...nsin II antagonists and calcium channel blockers C09DB02 Olmesartan medoxomil and amlodipine D10285 Amlodipine besylate - olmesartan medoxomil mixt PubChem: 163312316 ...

  14. Drug: D03911 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D03911 Drug Droloxifene (USAN/INN) C26H29NO2 387.2198 387.514 D03911.gif Antineoplastic Same as: C14296 Sele...ctive estrogen receptor modifier (SERM) estrogen receptor 1 agonist/antagonist [HSA

  15. Drug: D08991 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available oporosis calcium sensing receptor antagonist [HSA:846] [KO:K04612] Target-based cla...D08991 Drug Ronacaleret hydrochloride (USAN) C25H31F2NO4. HCl 483.1988 483.9757 D08991.gif Treatment of oste

  16. Drug: D06622 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06622 Drug Nebivolol hydrochloride (USAN); Bystolic (TN) C22H25F2NO4. HCl 441.1518 441.8959 D06622.gif High...ly selective b1 antagonist with non-adrenergic vasodilating properties due to the r

  17. Drug: D05148 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available in-angiotensin system antagonist] ATC code: C01DX19 Recombinant of human B-type nat...D05148 Drug Nesiritide citrate (USAN) C143H244N50O42S4. (C6H8O7)x Treatment of congestive heart failure [ren

  18. Drug: D00234 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 0234.gif Anti-allergic; Antihistaminic Same as: C06832 ATC code: R06AX11 H1-receptor antagonist [HSA:3269] [...D00234 Drug Astemizole (JAN/USP/INN); Hismanal (TN) C28H31FN4O 458.2482 458.5703 D0

  19. Drug: D08768 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08768 Drug Promethazine hibenzate; Hiberna (TN) C17H20N2S. C14H10O4 526.1926 526.6459 D08768.gif Antihistam...inic Therapeutic category: 4413 ATC code: D04AA10 R06AD02 H1-receptor antagonist [H

  20. Drug: D00663 [KEGG MEDICUS

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    Full Text Available 41 435.3116 D00663.gif Antihistaminic ATC code: R06AB01 H1-receptor antagonist [HSA:3269] [KO:K04149] hsa040...D00663 Drug Brompheniramine maleate (USAN); Dimetane (TN) C16H19BrN2. C4H4O4 434.08

  1. Drug: D01143 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available histaminic ATC code: D04AA22 R06AD09 H1-receptor antagonist [HSA:3269] [KO:K04149] ...D01143 Drug Isothipendyl hydrochloride (JAN); Andantol (TN) C16H19N3S. HCl 321.1066 321.8681 D01143.gif Anti

  2. Drug: D00662 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00662 Drug Azatadine maleate (USP); Optimine (TN) C20H22N2. (C4H4O4)2 522.2002 522.5464 D00662.gif Antihist...aminic ATC code: R06AX09 H1-receptor antagonist [HSA:3269] [KO:K04149] hsa04020(326

  3. Drug: D02091 [KEGG MEDICUS

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    Full Text Available staminic ATC code: D04AA04 R06AC04 H1-receptor antagonist [HSA:3269] [KO:K04149] hs...D02091 Drug Tripelennamine hydrochloride (USP); PBZ-SR (TN) C16H21N3. HCl 291.1502 291.819 D02091.gif Antihi

  4. Drug: D07125 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available histaminic, H1-receptor antagonist, Neuroleptic Same as: C07172 ATC code: R06AD01 H...D07125 Drug Alimemazine (INN); Trimeprazine (BAN); Repeltin (TN) C18H22N2S 298.1504 298.4457 D07125.gif Anti

  5. Drug: D05246 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05246 Drug Olmesartan (USAN/INN) C24H26N6O3 446.2066 446.5016 D05246.gif Treatment...vascular Agents Angiotensin II Receptor Antagonists Olmesartan D05246 Olmesartan ...giotensin angiotensin II stimulates angiotensin subtype 1 (AT1) receptor [HSA:185] [KO:K04166] Olmesartan D05246 Olmesa

  6. Drug: D09610 [KEGG MEDICUS

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    Full Text Available ression, and IBS corticotropin releasing hormone receptor 1 (CRF1) antagonist [HSA:...D09610 Drug Emicerfont (USAN/INN) C22H24N6O2 404.1961 404.465 D09610.gif Treatment of anxiety disorders, dep

  7. Drug: D06633 [KEGG MEDICUS

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    Full Text Available 33.gif Insomnia, major depression, and schizophrenia 5-HT2A-receptor antagonist [HSA:3356] [KO:K04157] hsa04...D06633 Drug Pruvanserin hydrochloride (USAN) C22H21FN4O. HCl 412.1466 412.8877 D066

  8. Drug: D09651 [KEGG MEDICUS

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    Full Text Available D09651 Drug Orvepitant maleate (USAN) C31H35F7N4O2. C4H4O4 744.2758 744.6962 D09651.gif Treatment of depress...ion, anxiety and insomnia tachykinin receptor 1 / neurokinin-1 antagonist [HSA:6869

  9. Drug: D01159 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available tic category of drugs in Japan [BR:br08301] 2 Agents affecting individual organs 24 Hormones 247 Estrogen an...G03DA01] D01159 Gestonorone caproate (JAN/USAN) Antineoplastics [BR:br08308] Hormones and hormone antagonist

  10. Drug: D00408 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available or agonists/antagonists Therapeutic category of drugs in Japan [BR:br08301] 2 Agents affecting individual organs 24 Hormones...lassification [BR:br08302] Hormonal Agents, Stimulant/Replacement/Modifying (Sex Hormones/Modifiers) Androge

  11. Drug: D00554 [KEGG MEDICUS

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    Full Text Available an [BR:br08301] 2 Agents affecting individual organs 24 Hormones 247 Estrogen and progesterone preparations ...USP drug classification [BR:br08302] Hormonal Agents, Stimulant/Replacement/Modifying (Sex Hormones/Modifier...ntineoplastics [BR:br08308] Hormones and hormone antagonist Estrogen Ethinylestradiol [ATC:L02AA03] D00554 E

  12. Drug: D04752 [KEGG MEDICUS

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    Full Text Available onatremia [selective V2-receptor antagonist] arginine vasopressin receptor 2 (AVPR2...D04752 Drug Lixivaptan (USAN/INN) C27H21ClFN3O2 473.1306 473.9259 D04752.gif Treatment of nonhypovolemic hyp

  13. Drug: D06659 [KEGG MEDICUS

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    Full Text Available sthma and interstitial cystitis cysteinyl leukotriene receptor 1 (CYSLTR1) antagonist [HSA:10800] [KO:K04322...D06659 Drug Tipelukast (USAN) C29H38O7S 530.2338 530.6728 D06659.gif Treatment of a

  14. Drug: D00529 [KEGG MEDICUS

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    Full Text Available yme: CYP2C9 [HSA:1559], CYP3A4 [HSA:1576] CYP induction: CYP1A2 [HSA:1544] CYP inhibition: CYP2C8 [HSA:1558] map07034 Eicosanoid...s map07228 Eicosanoid receptor agonists/antagonists Therapeutic category of drugs in Jap

  15. Drug: D05732 [KEGG MEDICUS

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    Full Text Available or interaction map07228 Eicosanoid receptor agonists/antagonists Target-based classification of drugs [BR:br... [gastric] prostaglandin E2 receptor agonist [HSA:5732] [KO:K04259] hsa04080(5732) Neuroactive ligand-recept

  16. Drug: D07679 [KEGG MEDICUS

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    Full Text Available D07679 Drug Chloropyramine hydrochloride; Avapena (TN) C16H20ClN3. HCl 325.1113 326.264 D07679.gif Antialler...gic; Histamine, H1-receptor antagonist ATC code: D04AA09 R06AC03 H1-receptor antago

  17. Drug: D07684 [KEGG MEDICUS

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    Full Text Available 340.2873 D07684.gif Antiallergic; Histamine, H1-receptor antagonist ATC code: D04AA34 R06AA06 H1-receptor an...D07684 Drug Chlorphenoxamine hydrochloride; Allergex (TN) C18H22ClNO. HCl 339.1157

  18. Drug: D06060 [KEGG MEDICUS

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    Full Text Available D06060 Drug Teludipine hydrochloride (USAN) C28H38N2O6. HCl 534.2497 535.0721 D06060....gif Antagonist [calcium channel]; Antihypertensive CAS: 108700-03-4 PubChem: 47207718 LigandBox: D06060 AT

  19. Drug: D00844 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available HCl 337.1081 337.798 D00844.gif Analgesic [narcotic] mu-opioid receptor agonist [HSA:4988] [KO:K04215] hsa04...ts/antagonists USP drug classification [BR:br08302] Analgesics Opioid Analgesics,... Long-acting Oxymorphone D00844 Oxymorphone hydrochloride (USP) Opioid Analgesics, Short-acting Oxymorphone

  20. Drug: D08323 [KEGG MEDICUS

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    Full Text Available ics Opioid Analgesics, Long-acting Oxymorphone D08323 Ox...tor interaction map07039 Opioid analgesics map07224 Opioid receptor agonists/antagonists USP drug classification [BR:br08302] Analges...ymorphone (INN) Opioid Analgesics, Short-acting Oxymorphone D08323 Oxymorphone (INN) Target-based classifica

  1. Drug: D00841 [KEGG MEDICUS

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    Full Text Available an (TN) C17H23NO. C4H6O6. 2H2O 443.2155 443.488 D00841.gif Analgesic [narcotic] mu-opioid receptor agonist [...7224 Opioid receptor agonists/antagonists USP drug classification [BR:br08302] Analgesics Opioid Analgesic

  2. Drug: D01024 [KEGG MEDICUS

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    Full Text Available TC) classification [BR:br08303] G GENITO URINARY SYSTEM AND SEX HORMONES G04 UROLOGICALS G04C DRUGS USED IN BENIGN PROSTATIC HYPERTRO...PHY G04CA Alpha-adrenoreceptor antagonists G04CA02 Tamsu

  3. Drug: D06268 [KEGG MEDICUS

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    Full Text Available D06268 Drug Trimeperidine (INN) C17H25NO2 275.1885 275.3859 D06268.gif opioid analgesic... ligand-receptor interaction map07039 Opioid analgesics map07224 Opioid receptor agonists/antagonists Target

  4. Drug: D05473 [KEGG MEDICUS

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    Full Text Available D05473 Drug Picenadol hydrochloride (USAN) C16H25NO. HCl 283.1703 283.8367 D05473.g...if Analgesic an opioid agonist/antagonist CAS: 74685-16-8 PubChem: 47207142 LigandBox: D05473 ATOM 19 1 C8x

  5. Drug: D00815 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 06 316.8682 D00815.gif Antidepressant Same as: C07982 Therapeutic category: 1174 ATC code: N06AA02 Trycyclic antidepress...: CYP2D6 [HSA:1565] map07027 Antidepressants map07213 Dopamine receptor agonists/antagonists map07234 Neurot...(JP16/USP) USP drug classification [BR:br08302] Antidepressants Tricyclics Imipramine D00815 Imipramine hydr

  6. Drug: D01329 [KEGG MEDICUS

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    Full Text Available 329.gif Anti-androgen [benign prostatic hypertrophy] androgen receptor antagonist [HSA:367] [KO:K08557] map0...D01329 Drug Oxendolone (JAN/USAN/INN); Prostetin (TN) C20H30O2 302.2246 302.451 D01

  7. Drug: D10287 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10287 Mixture, Drug Aliskiren hemifumarate - valsartan mixt; Valturna (TN) Aliskir...en fumarate [DR:D06412], Valsartan [DR:D00400] Treatment of hypertension ATC code: C09DX02 Anatomical Therap... antagonists, other combinations C09DX02 Valsartan and aliskiren D10287 Aliskiren hemifumarate - valsartan mixt PubChem: 163312318 ...

  8. Drug: D10286 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10286 Mixture, Drug Amlodipine - valsartan -hydrochlorothiazide mixt; Exforge hct ...(TN) Amlodipine besilate [DR:D00615], Hydrochlorothiazide [DR:D00340], Valsartan [DR:D00400] Antihypertensiv...TS, COMBINATIONS C09DX Angiotensin II antagonists, other combinations C09DX01 Valsartan, amlodipine and hydr...ochlorothiazide D10286 Amlodipine - valsartan -hydrochlorothiazide mixt PubChem: 163312317 ...

  9. Drug: D09743 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09743 Mixture, Drug Telmisartan - amlodipine besilate mixt; Micamlo (TN) Telmisartan...l organs 21 Cardiovascular agents 214 Antihypertensives 2149 Others D09743 Telmisartan...NS C09DB Angiotensin II antagonists and calcium channel blockers C09DB04 Telmisartan... and amlodipine D09743 Telmisartan - amlodipine besilate mixt PubChem: 124490483 ...

  10. Drug: D07569 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07569 Mixture, Drug Candesartan cilexetil - amlodipine besilate mixt; Unisia (TN) Candesartan...ual organs 21 Cardiovascular agents 214 Antihypertensives 2149 Others D07569 Candesartan..., COMBINATIONS C09DB Angiotensin II antagonists and calcium channel blockers C09DB07 Candesartan... and amlodipine D07569 Candesartan cilexetil - amlodipine besilate mixt PubChem: 124490299 ...

  11. Drug: D09745 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09745 Mixture, Drug Valsartan - amlodipine besilate mixt; Exforge (TN) Valsartan [...cular agents 214 Antihypertensives 2149 Others D09745 Valsartan - amlodipine besi... antagonists and calcium channel blockers C09DB01 Valsartan and amlodipine D09745 Valsartan - amlodipine besilate mixt PubChem: 124490485 ...

  12. Drug: D10243 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10243 Mixture, Drug Irbesartan - amlodipine besilate mixt; Aimix (TN) Irbesartan [...gans 21 Cardiovascular agents 214 Antihypertensives 2149 Others D10243 Irbesartan...9DB Angiotensin II antagonists and calcium channel blockers C09DB05 irbesartan an...d amlodipine D10243 Irbesartan - amlodipine besilate mixt PubChem: 163312274 ...

  13. Drug: D09219 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09219 Mixture, Drug Telmisartan - hydrochlorothiazide mixt; Micombi (TN); Micardis hct (TN) Telmisartan...ar agents 214 Antihypertensives 2149 Others D09219 Telmisartan - hydrochlorothiaz...antagonists and diuretics C09DA07 Telmisartan and diuretics D09219 Telmisartan - hydrochlorothiazide mixt PubChem: 96025899 ...

  14. Drug: D10129 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10129 Drug Irdabisant hydrochloride (USAN) C18H23N3O2. HCl 349.1557 349.8551 D10129.gif Treatment of cognit...ive and sleep wake disorders H3-receptor antagonist/ inverse agonist [HSA:11255] [K

  15. Drug: D09878 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nt of HIV infection and arthritis chemokine receptor 5 (CCR5) antagonist [HSA:1234] [KO:K04180]; chemokine r...D09878 Drug Cenicriviroc (USAN/INN) C41H52N4O4S 696.3709 696.941 D09878.gif Treatme

  16. Drug: D09351 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available oimmune diseases zonulin antagonist CAS: 258818-34-7 PubChem: 96026031 LigandBox: D...D09351 Drug Larazotide (USAN/INN) C32H55N9O10 725.4072 725.8334 D09351.gif Treatment of inflammatory and aut

  17. Drug: D10100 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available heimer's disease 5-HT6-receptor antagonist [HSA:3362] [KO:K04162] hsa04020(3362) Ca...D10100 Drug Cerlapirdine hydrochloride (USAN) C22H23N3O3S. HCl 445.1227 445.9623 D10100.gif Treatment of Alz

  18. Drug: D06632 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available , major depression, and schizophrenia 5-HT2A-receptor antagonist [HSA:3356] [KO:K04157] hsa04020(3356) Calci...D06632 Drug Pruvanserin (USAN/INN) C22H21FN4O 376.1699 376.4267 D06632.gif Insomnia

  19. Drug: D06567 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available izophrenia [partial D2 antagonist/5HT1A agonist] 5-HT1A-receptor agonist [HSA:3350]...D06567 Drug Bifeprunox mesylate (USAN) C24H23N3O2. CH4SO3 481.1671 481.564 D06567.gif Treatment of acute sch

  20. Drug: D10418 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10418 Drug Delparantag pentahydrochloride (USAN) C56H79N13O12. 5HCl 1305.4805 1308.6111 D10418.gif Restorat...ion of normal coagulation (heparin antagonist) antithrombin III activator [HSA:462

  1. Drug: D03693 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available sonal allergic rhinitis [H1 receptor antagonist] ATC code: R06AX27 H1-receptor anta...D03693 Drug Desloratadine (USAN/INN); Clarinex (TN) C19H19ClN2 310.1237 310.8206 D03693.gif Treatment of sea

  2. Drug: D10479 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10479 Drug Naloxegol (USAN/INN) C34H53NO11 651.3619 651.7847 D10479.gif Treatment of opioid-induced constip...ation ATC code: A06AH03 mu-opioid receptor antagonist [HSA:4988] [KO:K04215] Anatom

  3. Drug: D09695 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09695 Drug Verucerfont (USAN/INN) C22H26N6O2 406.2117 406.4808 D09695.gif Treatment of depression and anxie...ty corticotropin releasing hormone receptor 1 antagonist [HSA:1394] [KO:K04578] hsa

  4. Drug-induced hyperkalemia.

    Science.gov (United States)

    Ben Salem, Chaker; Badreddine, Atef; Fathallah, Neila; Slim, Raoudha; Hmouda, Houssem

    2014-09-01

    Hyperkalemia is a common clinical condition that can be defined as a serum potassium concentration exceeding 5.0 mmol/L. Drug-induced hyperkalemia is the most important cause of increased potassium levels in everyday clinical practice. Drug-induced hyperkalemia may be asymptomatic. However, it may be dramatic and life threatening, posing diagnostic and management problems. A wide range of drugs can cause hyperkalemia by a variety of mechanisms. Drugs can interfere with potassium homoeostasis either by promoting transcellular potassium shift or by impairing renal potassium excretion. Drugs may also increase potassium supply. The reduction in renal potassium excretion due to inhibition of the renin-angiotensin-aldosterone system represents the most important mechanism by which drugs are known to cause hyperkalemia. Medications that alter transmembrane potassium movement include amino acids, beta-blockers, calcium channel blockers, suxamethonium, and mannitol. Drugs that impair renal potassium excretion are mainly represented by angiotensin-converting enzyme inhibitors, angiotensin-II receptor blockers, direct renin inhibitors, nonsteroidal anti-inflammatory drugs, calcineurin inhibitors, heparin and derivatives, aldosterone antagonists, potassium-sparing diuretics, trimethoprim, and pentamidine. Potassium-containing agents represent another group of medications causing hyperkalemia. Increased awareness of drugs that can induce hyperkalemia, and monitoring and prevention are key elements for reducing the number of hospital admissions, morbidity, and mortality related to drug-induced hyperkalemia.

  5. Genetic factors influencing pyrimidine-antagonist chemotherapy

    NARCIS (Netherlands)

    Maring, JG; Groen, HJM; Wachters, FM; Uges, DRA; de Vries, EGE

    2005-01-01

    Pyrimidine antagonists, for example, 5-fluorouracil (5-FU), cytarabine (ara-C) and gemcitabine (dFdC), are widely used in chemotherapy regimes for colorectal, breast, head and neck, non-small-cell lung cancer, pancreatic cancer and leukaemias. Extensive metabolism is a prerequisite for conversion of

  6. Practical recommendations for calcium channel antagonist poisoning

    NARCIS (Netherlands)

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

    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

  7. Why are mineralocorticoid receptor antagonists cardioprotective?

    NARCIS (Netherlands)

    W. Chai (Wenxia); A.H.J. Danser (Jan)

    2006-01-01

    textabstractTwo clinical trials, the Randomized ALdosterone Evaluation Study (RALES) and the EPlerenone HEart failure and SUrvival Study (EPHESUS), have recently shown that mineralocorticoid receptor (MR) antagonists reduce mortality in patients with heart failure on top of ACE inhibition. This effe

  8. Drug: D00967 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available HSA:1576] map07043 Antineoplastics - hormones map07226 Progesterone, androgen and estrogen receptor agonists.../antagonists Therapeutic category of drugs in Japan [BR:br08301] 4 Agents affecting cellular function 42 Antineoplastics...oremifene D00967 Toremifene citrate (JAN/USAN) USP drug classification [BR:br08302] Antineoplastics...2 [HSA:2100] [KO:K08551] Toremifene [ATC:L02BA02] D00967 Toremifene citrate (JAN/USAN) Antineoplastics

  9. Drug: D01231 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 31) Gastric acid secretion map07057 Antiparkinsonian agents Therapeutic category of drugs in Japan [BR:br083...ral nervous system 116 Antiparkinsonian agents 1169 Others D01231 Piroheptine hydrochloride (JAN) Target-bas...D01231 Drug Piroheptine hydrochloride (JAN); Trimol (TN) C22H25N. HCl 339.1754 339.9015 D01231.gif Antiparki...nsonian Therapeutic category: 1169 muscarinic cholinergic receptor antagonist [HSA:

  10. Drug: D00610 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00610 Drug Terazosin hydrochloride hydrate (JAN); Terazosin hydrochloride (USAN); ...ypertensives 2149 Others D00610 Terazosin hydrochloride hydrate (JAN); Terazosin hydrochloride (USAN) Anatom...or antagonists G04CA03 Terazosin D00610 Terazosin hydrochloride hydrate (JAN); Terazosin hydrochloride (USAN...) USP drug classification [BR:br08302] Cardiovascular Agents Alpha-adrenergic Blocking Agents Terazosin D00610 Terazosin... hydrochloride hydrate (JAN); Terazosin hydrochloride (USAN) Genitourinary Agents Benign Prostatic Hypertrophy Agents Ter

  11. Drug: D08067 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08067 Drug Azilsartan medoxomil (USAN); Edarbi (TN) C30H24N4O8 568.1594 568.5336 D...ists, plain C09CA09 Azilsartan medoxomil D08067 Azilsartan medoxomil (USAN) USP d...rug classification [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Azilsartan D08067 Azilsartan...receptor [HSA:185] [KO:K04166] Azilsartan medoxomil [ATC:C09CA09] D08067 Azilsartan medoxomil (USAN) CAS: 86

  12. Innovative drug development for infertility therapy

    NARCIS (Netherlands)

    Mannaerts, B.M.J.L.

    2013-01-01

    Innovative drug development is essential to improve therapy over time by offering better efficacy, safety and/or treatment convenience. This thesis summarizes the sequential clinical development of three innovative fertility drugs namely follitropin-b (recombinant FSH), ganirelix (GnRH antagonist)

  13. Combining Elements from Two Antagonists of Formyl Peptide Receptor 2 Generates More Potent Peptidomimetic Antagonists.

    Science.gov (United States)

    Skovbakke, Sarah Line; Holdfeldt, André; Nielsen, Christina; Hansen, Anna Mette; Perez-Gassol, Iris; Dahlgren, Claes; Forsman, Huamei; Franzyk, Henrik

    2017-08-24

    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, RhB-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.

  14. Immunoactive effects of cannabinoids: considerations for the therapeutic use of cannabinoid receptor agonists and antagonists.

    Science.gov (United States)

    Greineisen, William E; Turner, Helen

    2010-05-01

    The active constituents of Cannabis sativa have been used for centuries as recreational drugs and medicinal agents. Today, marijuana is the most prevalent drug of abuse in the United States and, conversely, therapeutic use of marijuana constituents are gaining mainstream clinical and political acceptance. Given the documented contributions of endocannabinoid signaling to a range of physiological systems, including cognitive function, and the control of eating behaviors, it is unsurprising that cannabinoid receptor agonists and antagonists are showing significant clinical potential. In addition to the neuroactive effects of cannabinoids, an emerging body of data suggests that both endogenous and exogenous cannabinoids are potently immunoactive. The central premise of this review article is that the immunological effects of cannabinoids should be considered in the context of each prescribing decision. We present evidence that the immunological effects of cannabinoid receptor agonists and antagonists are highly relevant to the spectrum of disorders for which cannabinoid therapeutics are currently offered.

  15. Postcountershock myocardial damage after pretreatment with adrenergic and calcium channel antagonists in halothane-anesthetized dogs

    Energy Technology Data Exchange (ETDEWEB)

    Gaba, D.M.; Metz, S.; Maze, M.

    1985-05-01

    Transthoracic electric countershock can cause necrotic myocardial lesions in humans as well as experimental animals. The authors investigated the effect on postcountershock myocardial damage of pretreatment with prazosin, an alpha-1 antagonist; L-metoprolol, a beta-1 antagonist, and verapamil, a calcium channel-blocking agent. Twenty dogs were anesthetized with halothane and given two transthoracic countershocks of 295 delivered joules each after drug or vehicle treatment. Myocardial injury was quantitated 24 h following countershock by measuring the uptake of technetium-99m pyrophosphate in the myocardium. Elevated technetium-99m pyrophosphate uptake occurred in visible lesions in most dogs regardless of drug treatment. For each of four parameters of myocardial damage there was no statistically significant difference between control animals and those treated with prazosin, metoprolol, or verapamil. These data suggest that adrenergic or calcium channel-mediated mechanisms are not involved in the pathogenesis of postcountershock myocardial damage.

  16. Investigation of the teratogenic potential of VLA-4 antagonist derivatives in rats.

    Science.gov (United States)

    Sakurai, Ken; Matsuoka, Toshiki; Suzuki, Chiharu; Kinoshita, Junzo; Takayama, Gensuke; Shimomura, Kazuhiro

    2014-11-01

    Very late antigen-4 (VLA-4), which is concerned with cell-cell adhesion, plays important roles in development of the heart, and some VLA-4 antagonists cause cardiac anomalies. In this study, we evaluated the teratogenic potential of VLA-4 antagonist derivatives as screening, and investigated the conditions that induce cardiac anomalies. Seventeen compounds were orally administered to pregnant rats throughout the organogenesis period, and fetal examinations were performed. In addition, drug concentrations in the embryos were assayed. As a result, the incidence of ventricular septal defect (VSD) ranged from 0 to 100% depending on the compound. Plasma drug concentrations in the dams were related to increased incidence of VSD; however, these incidences were not increased when the concentration of the compound in the embryos at 24h after dosing was low. It is considered that continuous pharmacological activity in the embryo for more than 24h might disrupt closure of the ventricular septum.

  17. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n=6,each): Control group, Nitroglycerin (Nit) group, Nit+ bosentan group and Nit+ losartan group. Nitroglycerin tolerance was induced by 2-day treatment of nitroglycerin patch (0.05 mg/h). AngiotensinⅡ receptor antagonist losartan ( 10 mg· kg- 1· d- 1 ) and endothelin receptor antagonist bosentan ( 100 mg· kg- 1· d- 1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group . The effective percentages of hypotensive response to SNP were increased in both Nit+ losartan group and Nit+ bosentan group compared with Nit group [(31.95± 4.45 ) % vs (21.00± 3.69 ) % , P Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance .

  18. A novel series of glucagon receptor antagonists with reduced molecular weight and lipophilicity.

    Science.gov (United States)

    Filipski, Kevin J; Bian, Jianwei; Ebner, David C; Lee, Esther C Y; Li, Jian-Cheng; Sammons, Matthew F; Wright, Stephen W; Stevens, Benjamin D; Didiuk, Mary T; Tu, Meihua; Perreault, Christian; Brown, Janice; Atkinson, Karen; Tan, Beijing; Salatto, Christopher T; Litchfield, John; Pfefferkorn, Jeffrey A; Guzman-Perez, Angel

    2012-01-01

    A novel series of glucagon receptor antagonists has been discovered. These pyrazole ethers and aminopyrazoles have lower molecular weight and increased polarity such that the molecules fall into better drug-like property space. This work has culminated in compounds 44 and 50 that were shown to have good pharmacokinetic attributes in dog, in contrast to rats, in which clearance was high; and compound 49, which demonstrated a dose-dependent reduction in glucose excursion in a rat glucagon challenge experiment.

  19. Development of potent antagonists for formyl peptide receptor 1 based on Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH.

    Science.gov (United States)

    Hayashi, Ryo; Kitajima, Toshiki; Mizuguchi, Hikaru; Fujimoto, Miki; Yamaguchi, Aya; Koga, Shuichiro; Koga, Yuya; Osada, Satoshi; Kodama, Hiroaki

    2014-08-01

    While stimulation of formyl peptide receptors (FPRs) on the surface of human neutrophils induces several immune responses, under conditions of continuous activation of the receptor by agonists such as formyl-Met-Leu-Phe-OH (fMLP), neutrophil-dependent tissue damage ensues. Thus, FPR antagonists could be anticipated as drugs for FPR-related disease. In this study, Boc-Phe-D-Leu-Phe-D-Leu-Phe-OH (Boc-FlFlF), one of several FPR subtype selective antagonists, was chosen and the positions at the Phe residues were optimized. We found that substitution with unnatural amino acids resulted in an improvement of two orders of magnitude. The most potent antagonist indicated FPR subtype selectivity at 1 μM. In addition to finding a potent antagonist, the structure-activity trends observed in this study should be valuable in designing a new type of FPR subtype selective antagonist. Copyright © 2014 Elsevier Ltd. All rights reserved.

  20. Inhibition of the development of morphine tolerance by a potent dual mu-delta-opioid antagonist, H-Dmt-Tic-Lys-NH-CH2-Ph.

    Science.gov (United States)

    Jinsmaa, Yunden; Marczak, Ewa D; Balboni, Gianfranco; Salvadori, Severo; Lazarus, Lawrence H

    2008-10-01

    Three analogues of the dual mu-/delta-antagonist, H-Dmt-Tic-R-NH-CH2-Ph (R = 1, Lys-Z; 2, Lys-Ac; 3, Lys) were examined in vivo: 1 and 2 exhibited weak bioactivity, while 3 injected intracerebroventricularly was a potent dual antagonist for morphine- and deltorphin C-induced antinociception comparable to naltrindole (delta-antagonist), but 93% as effective as naloxone (nonspecific opioid receptor antagonist) and 4% as active as CTOP, a mu antagonist. Subcutaneous or oral administration of 3 antagonized morphine-induced antinociception indicating passage across epithelial and blood-brain barriers. Mice pretreated with 3 before morphine did not develop morphine tolerance indicative of a potential clinical role to inhibit development of drug tolerance.

  1. Differential effects of ghrelin antagonists on alcohol drinking and reinforcement in mouse and rat models of alcohol dependence.

    Science.gov (United States)

    Gomez, Juan L; Cunningham, Christopher L; Finn, Deborah A; Young, Emily A; Helpenstell, Lily K; Schuette, Lindsey M; Fidler, Tara L; Kosten, Therese A; Ryabinin, Andrey E

    2015-10-01

    An effort has been mounted to understand the mechanisms of alcohol dependence in a way that may allow for greater efficacy in treatment. It has long been suggested that drugs of abuse seize fundamental reward pathways and disrupt homeostasis to produce compulsive drug seeking behaviors. Ghrelin, an endogenous hormone that affects hunger state and release of growth hormone, has been shown to increase alcohol intake following administration, while antagonists decrease intake. Using rodent models of dependence, the current study examined the effects of two ghrelin receptor antagonists, [DLys3]-GHRP-6 (DLys) and JMV2959, on dependence-induced alcohol self-administration. In two experiments adult male C57BL/6J mice and Wistar rats were made dependent via intermittent ethanol vapor exposure. In another experiment, adult male C57BL/6J mice were made dependent using the intragastric alcohol consumption (IGAC) procedure. Ghrelin receptor antagonists were given prior to voluntary ethanol drinking. Ghrelin antagonists reduced ethanol intake, preference, and operant self-administration of ethanol and sucrose across these models, but did not decrease food consumption in mice. In experiments 1 and 2, voluntary drinking was reduced by ghrelin receptor antagonists, however this reduction did not persist across days. Despite the transient effects of ghrelin antagonists, the drugs had renewed effectiveness following a break in administration as seen in experiment 1. The results show the ghrelin system as a potential target for studies of alcohol abuse. Further research is needed to determine the central mechanisms of these drugs and their influence on addiction in order to design effective pharmacotherapies.

  2. Novel benzimidazole-based MCH R1 antagonists.

    Science.gov (United States)

    Carpenter, Andrew J; Al-Barazanji, Kamal A; Barvian, Kevin K; Bishop, Michael J; Britt, Christy S; Cooper, Joel P; Goetz, Aaron S; Grizzle, Mary K; Hertzog, Donald L; Ignar, Diane M; Morgan, Ronda O; Peckham, Gregory E; Speake, Jason D; Swain, Will R

    2006-10-01

    The identification of an MCH R1 antagonist screening hit led to the optimization of a class of benzimidazole-based MCH R1 antagonists. Structure-activity relationships and efforts to optimize pharmacokinetic properties are detailed along with the demonstration of the effectiveness of an MCH R1 antagonist in an animal model of obesity.

  3. High affinity retinoic acid receptor antagonists: analogs of AGN 193109.

    Science.gov (United States)

    Johnson, A T; Wang, L; Gillett, S J; Chandraratna, R A

    1999-02-22

    A series of high affinity retinoic acid receptor (RAR) antagonists were prepared based upon the known antagonist AGN 193109 (2). Introduction of various phenyl groups revealed a preference for substitution at the para-position relative to the meta-site. Antagonists with the highest affinities for the RARs possessed hydrophobic groups, however, the presence of polar functionality was also well tolerated.

  4. Mineralocorticoid and glucocorticoid receptor antagonists in animal models of anxiety

    NARCIS (Netherlands)

    Korte, SM; KorteBouws, GAH; Koob, GF; DeKloet, ER; Bohus, B

    1996-01-01

    The behavioral effects of intracerebroventricular (ICV) administration of a specific mineralocorticoid receptor (MR) antagonist [RU28318 (10-50 ng/2 mu l)], a glucocorticoid receptor (GR) antagonist [RU38486 (1-50 ng/2 mu l)], or both antagonists (50 ng/2 mu l), were studied in two different animal

  5. Dopamine D3 receptor antagonists as potential therapeutics for the treatment of neurological diseases

    Directory of Open Access Journals (Sweden)

    Samuele Maramai

    2016-10-01

    Full Text Available D3 receptors represent a major focus of current drug design and development of therapeutics for dopamine-related pathological states. Their close homology with the D2 receptor subtype makes the development of D3 selective antagonists a challenging task. In this review, we explore the relevance and therapeutic utility of D3 antagonists or partial agonists endowed with multireceptor affinity profile in the field of central nervous system disorders such as schizophrenia and drug abuse. In fact, the peculiar distribution and low brain abundance of D3 receptors make them a valuable target for the development of drugs devoid of motor side effects classically elicited by D2 antagonists. Recent research efforts were devoted to the conception of chemical templates possibly endowed with a multi-target profile, especially with regards to other G-protein-coupled receptors (GPCRs.A comprehensive overview of the recent literature in the field is herein provided. In particular, the evolution of the chemical templates has been tracked, according to the growing advancements in both the structural information and the refinement of the key pharmacophoric elements.The receptor/multireceptor affinity and functional profiles for the examined compounds has been covered, together with their most significant pharmacological applications.

  6. Drug: D00507 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00507 Drug Phenoxybenzamine hydrochloride (USP); Dibenzyline (TN) C18H22ClNO. HCl ...C04AX02] D00507 Phenoxybenzamine hydrochloride (USP) CAS: 63-92-3 PubChem: 7847573 Dr...339.1157 340.2873 D00507.gif Antihypertensive Same as: C07436 ATC code: C04AX02 alpha1-adrenergic receptor a...ntagonist [HSA:146 147 148] [KO:K04137 K04136 K04135]; alpha2-adrenergic receptor antagonist [HSA:150 151 15...ERAL VASODILATORS C04AX Other peripheral vasodilators C04AX02 Phenoxybenzamine D00507 Phenoxybenzamine hydrochloride (USP) USP dr

  7. Antagonism of apomorphine-enhanced startle by alpha 1-adrenergic antagonists.

    Science.gov (United States)

    Davis, M; Kehne, J H; Commissaris, R L

    1985-02-05

    The present study investigated the possible involvement of central noradrenergic neurons in mediating the excitatory effect of the dopamine agonist apomorphine on the acoustic startle response in rats. Experiment 1 assessed the effects of intraperitoneal (i.p.) administration of adrenergic antagonists on apomorphine-enhanced startle. The excitation of startle produced by apomorphine (1.0-3.0 mg/kg i.p.) was blocked by the alpha 1-adrenergic antagonists prazosin (0.03-1.0 mg/kg) and WB-4101 (1.0 mg/kg). Prazosin was very potent in this regard, having an ED50 of 0.03 mg/kg. Blockade of beta-adrenergic receptors with propranolol (20 mg/kg) or blockade of peripheral alpha-adrenergic receptors with phentolamine (10 mg/kg) failed to alter the effect of apomorphine. Prazosin did not block the enhancement of startle produced by other drugs (5-methoxy-N,N-dimethyltryptamine, strychnine), nor did it alter the entry of apomorphine into the brain. The alpha 1-adrenergic antagonists piperoxane (0.03 mg/kg), yohimbine (0.03 mg/kg) or RX781094 (0.07 mg/kg) markedly potentiated apomorphine excitation. These data indicated that specific blockade of central alpha 1-adrenergic receptors prevents apomorphine-enhanced startle. In contrast to the effects of alpha 1-adrenergic antagonists, Experiment 2 found that other drugs that produce an acute (clonidine, 0.040 mg/kg) or chronic (intraventricular 6-hydroxydopamine, 2 X 200 micrograms; DSP4, 50 mg/kg i.p.) disruption of noradrenergic transmission failed to affect apomorphine excitation. Thus, the ability of alpha 1-adrenergic antagonists to block apomorphine's excitation of startle cannot be explained by a simple dopamine-norepinephrine interaction. Alternative hypothesis are discussed.

  8. Induction of enhanced postnatal expression of immunoreactive calbindin-D28k in rat forebrain by the calcium antagonist nimodipine

    NARCIS (Netherlands)

    Luiten, Paul G.M.; Buwalda, Bauke; Traber, Jörg; Nyakas, Csaba

    1994-01-01

    The early postnatal development of immunoreactive calbindin-D28k (CaB-ir) containing neuronal systems in hippocampus and parietal cortex was studied in offspring of Wistar rats chronically treated with either the Ca2+-channel antagonist nimodipine or placebo food. The drug was applied to the mother

  9. Evaluation of the abuse potential of AM281, a new synthetic cannabinoid CB1 receptor antagonist.

    Science.gov (United States)

    Botanas, Chrislean Jun; de la Peña, June Bryan; Dela Pena, Irene Joy; Tampus, Reinholdgher; Kim, Hee Jin; Yoon, Seong Shoon; Seo, Joung-Wook; Jeong, Eun Ju; Cheong, Jae Hoon

    2015-11-01

    AM281 (1-(2,4-dichlorophenyl)-5-(4-iodophenyl)-4-methyl-N-4-morpholinyl-1H-pyrazole-3-carboxamide) is a new synthetic cannabinoid CB1 receptor antagonist. Similar to other cannabinoid antagonists, AM281 has been suggested to have therapeutic indications. However, recent reports have suggested that cannabinoid CB1 receptor antagonists may share similar behavioral effects with other drugs of abuse such as cocaine and amphetamine. These reports cast doubts on the safety profile of AM281. Thus, in the present study we evaluated the abuse potential (rewarding and reinforcing effects) of AM281 through two of the most widely used animal models for assessing the abuse potential of drugs: the conditioned place preference (CPP) and self-administration (SA) tests. Experiments were performed in Sprague-Dawley rats in various dosages [CPP (0.1, 0.5 or 2.5mg/kg), SA (0.005, 0.025 or 0.1mg/kg/infusion)]. We also delved into the consequences of repeated drug exposure on the subsequent response to the drug. Thus, parallel experiments were carried out in rats pretreated with AM281 for 7 or 14 days. Our findings indicated that AM281, at any dose, did not induce CPP and SA in drug-naïve rats. Interestingly, significant CPP (0.5mg/kg of AM281), but not SA, was observed in 14 days pretreated rats. These observations suggest that AM281 per se has no or minimal rewarding and reinforcing properties, but alterations in neuronal functions and behavior due to repeated AM281 exposure may contribute in part to the abuse potential of this drug. In view of this finding, we advocate the careful use, monitoring, and dispensation of AM281.

  10. Challenges to antagonist blockade during sustained-release naltrexone treatment.

    Science.gov (United States)

    Kunøe, Nikolaj; Lobmaier, Philipp; Vederhus, John Kåre; Hjerkinn, Bjørg; Gossop, Michael; Hegstad, Solfrid; Kristensen, Øistein; Waal, Helge

    2010-09-01

    Naltrexone is a competitive opioid antagonist that effectively blocks the action of heroin and other opioid agonists. Sustained-release naltrexone formulations are now available that provide long-acting opioid blockade. This study investigates the use of heroin and other opioids among opioid-dependent patients receiving treatment with long-acting naltrexone implants, their subjective experience of drug 'high' after opioid use, and factors associated with opioid use. Participants (n = 60) were opioid-dependent patients receiving treatment with naltrexone implants. Outcome data on substance use, drug 'high', depression and criminal activity were collected over a 6-month period. Blood samples were taken to monitor naltrexone plasma levels, and hair samples to verify self-reported opioid use. More than half [n = 34 or 56%; 95% confidence interval (CI) 44-68%)] the patients challenged the blockade with illicit opioids during the 6-month treatment period; 44% (n = 26; 95% CI 32-56%) were abstinent from opioids. Mean opioid use was reduced from 18 [standard deviation (SD)13] days during the month preceding treatment to 6 days (SD 11) after 6 months. Of the respondents questioned on opioid 'high' (n = 31), nine patients (30%; 95% CI 16-47%) reported partial drug 'high' following illicit opioid use, and three (12%; 95% CI 3-26%) reported full 'high'. Opioid use was associated with use of non-opioid drugs and criminal behaviour. Challenging naltrexone blockade with heroin on at least one occasion is common among sustained-release naltrexone patients, but only a minority of patients use opioids regularly. Challenges represent a warning sign for poor outcomes and often occur in the context of polydrug use and social adjustment problems.

  11. Antagonistic parent-offspring co-adaptation.

    Directory of Open Access Journals (Sweden)

    Mathias Kölliker

    Full Text Available BACKGROUND: 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. METHODOLOGY/PRINCIPAL FINDINGS: 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. CONCLUSIONS/SIGNIFICANCE: 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.

  12. Aminopyrimidine derivatives as adenosine antagonists / Janke Kleynhans

    OpenAIRE

    Kleynhans, Janke

    2013-01-01

    Aims of this project - The aim of this study was to design and synthesise novel 2-aminopyrimidine derivatives as potential adenosine A1 and A2A receptor antagonists. Background and rationale - Parkinson’s disease is the second most common neurodegenerative disorder (after Alzheimer’s disease) and is characterised by the selective death of the dopaminergic neurons of the nigro-striatal pathway. Distinctive motor symptoms include bradykinesia, muscle rigidity and tremor, while non-m...

  13. The Justification of Antagonistic Response to Wrongdoing

    OpenAIRE

    Goldman, David Michael

    2012-01-01

    There is a strong Western tradition of opposing angry, hostile, or antagonistic reactions to wrongdoing. In the twentieth century, leaders like Mahatma Gandhi and Dr. Martin Luther King, Jr. counseled responding to wrongdoing with forgiveness and love rather than anger, hate, or vindictiveness.This ideal has taken on an exalted status in Western culture. Gandhi and King are widely regarded as moral saints. And yet sometimes antagonism seems deeply appropriate. Consider a very serious wrong: s...

  14. Nalmefene: intravenous safety and kinetics of a new opioid antagonist.

    Science.gov (United States)

    Dixon, R; Howes, J; Gentile, J; Hsu, H B; Hsiao, J; Garg, D; Weidler, D; Meyer, M; Tuttle, R

    1986-01-01

    In a placebo-controlled, double-blind study we evaluated the safety and kinetics of a new narcotic antagonist, nalmefene, after 2, 6, 12, and 24 mg intravenous doses to healthy men. At each dose level four subjects received active drug and two received placebo. The drug was well tolerated at all dose levels with only mild and transient side effects, the most common of which was lightheadedness. The plasma concentration-time data were best fit with a triexponential equation, and the terminal elimination phase had a harmonic mean t1/2 of 8 to 9 hours. Only about 5% of the dose was excreted in the urine as intact nalmefene, with up to 60% excreted as nalmefene glucuronide. Although intersubject differences were noted, mean or dose-normalized mean kinetic parameters such as clearance, steady-state volume of distribution, terminal t1/2, and AUC showed no consistent trends related to increasing doses, indicating that nalmefene has linear pharmacokinetics.

  15. 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

  16. 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.

  17. Anticonvulsive effect of nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Kuder, Kamil; Subramanian, Dhanasekaran; Shafiullah, Mohamed; Stark, Holger; Lażewska, Dorota; Adem, Abdu; Kieć-Kononowicz, Katarzyna

    2014-06-01

    To determine the potential of histamine H3 receptor (H3R) ligands as new antiepileptic drugs (AEDs), aromatic ether, and diether derivatives (1-12) belonging to the nonimidazole class of ligands, with high in-vitro binding affinity at human H3R, were tested for their in-vivo anticonvulsive activity in the maximal electroshock (MES)-induced and pentylenetetrazole (PTZ)-kindled seizure models in rats. The anticonvulsive effects of a systemic injection of 1-12 on MES-induced and PTZ-kindled seizures were evaluated against the reference AED phenytoin (PHT) and the structurally related H3R antagonist/inverse agonist pitolisant (PIT). Among the most promising ligands 2, 4, 5, and 11, there was a significant and dose-dependent reduction in the duration of tonic hind limb extension (THLE) in MES-induced seizure subsequent to administration of 4 and 5 [(5, 10, and 15 mg/kg, intraperitoneally (i.p.)]. The protective effects observed for the 1-(3-(3-(4-chlorophenyl)propoxy)propyl)-3-methylpiperidine derivative 11 at 10 mg/kg, i.p. were significantly greater than those of PIT, and were reversed by pretreatment with the central nervous system penetrant H1R antagonist pyrilamine (PYR) (10 mg/kg). Moreover, the protective action of the reference AED PHT, at a dose of 5 mg/kg (without considerable protection in the MES model), was significantly augmented when coadministered with derivative 11 (5 mg/kg, i.p.). Surprisingly, pretreatment with derivative 7 (10 mg/kg, i.p.), an ethylphenoxyhexyl-piperidine derivative without considerable protection in the MES model, potently altered PTZ-kindled seizure, significantly prolonged myoclonic latency time, and clearly shortened the total seizure time when compared with control, PHT, and PIT. These interesting results highlight the potential of H3R ligands as new AEDs or as adjuvants to available AED therapeutics.

  18. Effect of GnRH antagonist on follicular development and uterine biophysical profile in controlled ovarian stimulation

    Directory of Open Access Journals (Sweden)

    Bhawana Tiwary

    2015-02-01

    Full Text Available Background: Objective of current study was to assess the effect of GnRH antagonist on follicular development, premature luteinization, uterine biophysical profile and pregnancy rate in controlled ovarian stimulation with clomiphene and gonadotropins for intrauterine insemination in women with unexplained infertility. Methods: Randomised controlled trial. Minimal stimulation protocol with or without GnRH antagonist was compared. Setting: Infertility clinic, PGIMER, Chandigarh. Patients: Couples with unexplained infertility, age of female partner between 20-39 years. Intervention: GnRH antagonist 0.25 mg since follicle size 14 mm till hCG administration. Main outcome measures: Follicle characteristics, premature luteinisation, uterine biophysical profile and pregnancy rate. Results: The mean number of follicles recruited in group A was 2.32 +/- 1.01 while that in group B (receiving GnRH antagonist it was 4.10 +/- 1.69. Statistically significant increase in total biophysical profile score was observed in periovulatory phase in the antagonist group. 40% women in group A had premature luteinization whereas only 4% women in group B suffered from premature luteinization. 20% women who received GnRH antagonist conceived against only 6% in group A, this difference however was not statistically significant Conclusions: GnRH antagonist has a role in increasing the number of follicles recruited. Furthermore, GnRH antagonist can improve the total uterine biophysical profile score by improving the endometrial thickness, endometrial pattern, blood flow and decreasing the impedance to the blood flow in uterine artery. The drug can potentially help in improving pregnancy rates by decreasing the rate of premature luteinisation. [Int J Reprod Contracept Obstet Gynecol 2015; 4(1.000: 157-163

  19. Infusions of alpha-2 noradrenergic agonists and antagonists into the amygdala: effects on kindling.

    Science.gov (United States)

    Pelletier, M R; Corcoran, M E

    1993-12-31

    We reported previously that activation of alpha-2 adrenoceptors with infusions of clonidine into the amygdala/pyriform region is sufficient to retard kindling. To characterize further the involvement in kindling of alpha-2 receptors in the amygdala/pyriform, we exposed rats to unilateral intraamygdaloid infusions of a variety of noradrenergic drugs followed by either low-frequency stimulation of the amygdala, to induce rapid kindling, or conventional high-frequency stimulation. Infusions and electrical stimulation were administered once every 48 h. The prophylactic effects of clonidine were blocked by simultaneous infusion of idazoxan, an alpha-2 adrenergic antagonist, which suggests strongly that these effects were produced at an alpha-2 receptor. Intraamygdaloid infusions of xylazine, another alpha-2 agonist, also significantly retarded low-frequency kindling. Unexpectedly, intraamygdaloid infusions of the alpha-2 antagonists idazoxan, yohimbine, and SK&F 104856 failed to accelerate kindling. Infusion of the alpha-1 antagonist corynanthine also failed to affect kindling. We propose that the alpha-2 adrenoceptors in the amygdala/pyriform region contribute to the prophylactic effects of systemically administered clonidine and that the facilitation of kindling observed after systemic administration of alpha-2 antagonists may be due to blockade of alpha-2 adrenoceptors outside of the amygdala/pyriform region.

  20. [N-allyl-Dmt1]-endomorphins are micro-opioid receptor antagonists lacking inverse agonist properties.

    Science.gov (United States)

    Marczak, Ewa D; Jinsmaa, Yunden; Li, Tingyou; Bryant, Sharon D; Tsuda, Yuko; Okada, Yoshio; Lazarus, Lawrence H

    2007-10-01

    [N-allyl-Dmt1]-endomorphin-1 and -2 ([N-allyl-Dmt1]-EM-1 and -2) are new selective micro-opioid receptor antagonists obtained by N-alkylation with an allyl group on the amino terminus of 2',6'-dimethyl-L-tyrosine (Dmt) derivatives. To further characterize properties of these compounds, their intrinsic activities were assessed by functional guanosine 5'-O-(3-[35S]thiotriphosphate) binding assays and forskolin-stimulated cyclic AMP accumulation in cell membranes obtained from vehicle, morphine, and ethanol-treated SK-N-SH cells and brain membranes isolated from naive and morphine-dependent mice; their mode of action was compared with naloxone or naltrexone, which both are standard nonspecific opioid-receptor antagonists. [N-allyl-Dmt1]-EM-1 and -2 were neutral antagonists under all of the experimental conditions examined, in contrast to naloxone and naltrexone, which behave as neutral antagonists only in membranes from vehicle-treated cells and mice but act as inverse agonists in membranes from morphine- and ethanol-treated cells as well as morphine-treated mice. Both endomorphin analogs inhibited the naloxone- and naltrexone-elicited withdrawal syndromes from acute morphine dependence in mice. This suggests their potential therapeutic application in the treatment of drug addiction and alcohol abuse without the adverse effects observed with inverse agonist alkaloid-derived compounds that produce severe withdrawal symptoms.

  1. The necessity and effectiveness of mineralocorticoid receptor antagonist in the treatment of diabetic nephropathy.

    Science.gov (United States)

    Sato, Atsuhisa

    2015-06-01

    Diabetes mellitus is a major cause of chronic kidney disease (CKD), and diabetic nephropathy is the most common primary disease necessitating dialysis treatment in the world including Japan. Major guidelines for treatment of hypertension in Japan, the United States and Europe recommend the use of angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers, which suppress the renin-angiotensin system (RAS), as the antihypertensive drugs of first choice in patients with coexisting diabetes. However, even with the administration of RAS inhibitors, failure to achieve adequate anti-albuminuric, renoprotective effects and a reduction in cardiovascular events has also been reported. Inadequate blockade of aldosterone may be one of the reasons why long-term administration of RAS inhibitors may not be sufficiently effective in patients with diabetic nephropathy. This review focuses on treatment in diabetic nephropathy and discusses the significance of aldosterone blockade. In pre-nephropathy without overt nephropathy, a mineralocorticoid receptor antagonist can be used to enhance the blood pressure-lowering effects of RAS inhibitors, improve insulin resistance and prevent clinical progression of nephropathy. In CKD categories A2 and A3, the addition of a mineralocorticoid receptor antagonist to an RAS inhibitor can help to maintain 'long-term' antiproteinuric and anti-albuminuric effects. However, in category G3a and higher, sufficient attention must be paid to hyperkalemia. Mineralocorticoid receptor antagonists are not currently recommended as standard treatment in diabetic nephropathy. However, many studies have shown promise of better renoprotective effects if mineralocorticoid receptor antagonists are appropriately used.

  2. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use Hurts Kids Drug Use Hurts Unborn Children Drug Use Hurts Your Health Drug Use Hurts ... Find Treatment/Rehab Resources Prevent Drug Use Help Children and Teens Stay Drug-Free Talking to Kids ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... Get Addicted to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use and Other People Drug Use and Families Drug Use and Kids Drug Use and Unborn ...

  4. Xerostomia: prevalence and pharmacotherapy. With special reference to beta-adrenoceptor antagonists.

    Science.gov (United States)

    Nederfors, T

    1996-01-01

    The main objective of this thesis was to estimate the prevalence of subjectively perceived dry mouth, xerostomia, in a representative general adult population, and the possible co-morbidity between xerostomia and on-going pharmacotherapy. Further, to evaluate the effects of beta-adrenoceptor antagonists on saliva flow rate and composition. The prevalence of xerostomia was evaluated by means of a questionnaire mailed to a random sample of 4.200 adult subjects living in the southern part of the province of Halland, Sweden. Three hundred men and equally many women aged 20, 30, 40, 50, 60, 70 and 80 years were selected from the national census register. From 3311 (81%) evaluable questionnaires was concluded that, in the studied population, 21.3% of the men and 27.3% of the women reported xerostomia. The difference between the sexes was statistically significant, women reporting higher prevalence of dry mouth than men. It was also found that xerostomia was significantly age-related. Further, it was demonstrated that there was a strong co-morbidity between reported prevalence of dry mouth and on-going pharmacotherapy. Generally, no specific drug or drug-group proved to be especially xerogenic, rather, polypharmacy was strongly correlated to reported symptoms of dry mouth, and it was also a significant correlation between increasing xerostomia and the number of medications taken. The effects of beta-adrenoceptor antagonists on saliva flow rate and composition were evaluated both in healthy volunteers and in hypertensive patients. The effects of one week of treatment with the non-selective (propranolol) and the beta 1-selective (atenolol) adrenoceptor antagonists were compared with that of placebo in three different clinical trials, including 38, 11 and 19 healthy volunteers, respectively. Two of these studies were focused on the effects on whole saliva secretion rate and composition and the third study on the secretions from the parotid and the submandibular

  5. Drug: D02271 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02271 Drug Morphine hydrochloride hydrate (JP16); Morphine hydrochloride trihydrat...ceptor agonists/antagonists map05032 Morphine addiction Therapeutic category of drugs in Japan [BR:br08301] ...8 Narcotics 81 Alkaloidal narcotics 811 Opium alkaloids 8114 Morphines D02271 Morphine hydrochloride hydrate...US SYSTEM N02 ANALGESICS N02A OPIOIDS N02AA Natural opium alkaloids N02AA01 Morphine D02271 Morphine hydroch...loride hydrate (JP16) USP drug classification [BR:br08302] Analgesics Opioid Analgesics, Long-acting Morphine D02271 Morphine

  6. Comparative persistence of the TNF antagonists in rheumatoid arthritis--a population-based cohort study.

    Directory of Open Access Journals (Sweden)

    Anat Fisher

    Full Text Available To compare persistence with tumor necrosis factor alpha (TNF antagonists among rheumatoid arthritis patients in British Columbia. Treatment persistence has been suggested as a proxy for real-world therapeutic benefit and harm of treatments for chronic non-curable diseases, including rheumatoid arthritis. We hypothesized that the different pharmacological characteristics of infliximab, adalimumab and etanercept cause statistically and clinically significant differences in persistence.We conducted a population-based cohort study using administrative health data from the Canadian province of British Columbia. The study cohort included rheumatoid arthritis patients who initiated the first course of a TNF antagonist between 2001 and 2008. Persistence was measured as the time between first dispensing to discontinuation. Drug discontinuation was defined as a drug-free interval of 180 days or switching to another TNF antagonist, anakinra, rituximab or abatacept. Persistence was estimated and compared using survival analysis.The study cohort included 2,923 patients, 63% treated with etanercept. Median persistence in years (95% confidence interval with infliximab was 3.7 (2.9-4.9, with adalimumab 3.3 (2.6-4.1 and with etanercept 3.8 (3.3-4.3. Similar risk of discontinuation was observed for the three drugs: the hazard ratio (95% confidence interval was 0.98 (0.85-1.13 comparing infliximab with etanercept, 0.95 (0.78-1.15 comparing infliximab with adalimumab and 1.04 (0.88-1.22 comparing adalimumab with etanercept.Similar persistence was observed with infliximab, adalimumab and etanercept in rheumatoid arthritis patients during the first 9 years of use. If treatment persistence is a good proxy for the therapeutic benefit and harm of these drugs, then this finding suggests that the three drugs share an overall similar benefit-harm profile in rheumatoid arthritis patients.

  7. EFFECT OF ANGIOTENSIN II RECEPTOR ANTAGONIST AND ENDOTHELIN RECEPTOR ANTAGONIST ON NITROGLYCERIN TOLERANCE IN RATS

    Institute of Scientific and Technical Information of China (English)

    张建梅; 陈永红; 王晓红; 唐朝枢

    2001-01-01

    Objective. To investigate whether angiotensin II receptor antagonist and endothelin receptor antagonist can improve the nitroglycerin (Nit) tolerance in vivo. Methods. Twenty-four rats were divided into 4 groups (n =6, each): Control group, Nitroglycerin (Nit) group, Nit + bosentan group and Nit + losartan group. Nitroglycerin tolerance was induced by 2-day treatment ofnitroglycerin patch (0. 05mg/h). Angiotensin I1 receptor antagonist losartan (10mg ·kg-1·d-1) and endothe-lin receptor antagonist bosentan ( 100 mg·kg-1· d-1 ) were given by gavage for 2 days respectively. Results. The least hypotensive response to sodium nitroprusside (SNP) was observed in Nit group. The effec-tive percentages of hypotensive response to SNP were increased in both Nit + losartan group and Nit + bosentangroup compared with Nit group [(31.95±4.45) % vs (21.00±3.69) %, P <0.01and (33. 18±6. 16)% vs (21.00±3.69 ) %, P < 0. 01 , respectivelyl. The maximal vessel relaxation induced by SNP was thesame in 4 different groups but the highest EC50 (concentration which produces 50% of the maximal response toSNP) was found in tolerant group[ (34 ±10) nmol/L, P < 0. 01 ]. The ET-1 amounts in plasma and vasculartissue were markedly increased by 54% and 60% in Nit group compared with those in control group( P<0. 01). The ET-1 amounts in plasma and vascular tissue were decreased by 30% and 37% in Nit + losartangroup compared with those in Nit group ( P < 0.01 ). Conclusion. Endothelin receptor antagonist and angiotensin Ⅱ receptor antagonist could prevent against the Nit tolerance.

  8. Rationale in support of the use of selective dopamine D₃ receptor antagonists for the pharmacotherapeutic management of substance use disorders.

    Science.gov (United States)

    Heidbreder, Christian

    2013-02-01

    Growing evidence indicates that dopamine (DA) D(3) receptors are involved in the control of drug-seeking behavior and may play an important role in the pathophysiology of substance use disorders. First, DA D(3) receptors are distributed in strategic areas belonging to the mesolimbic DA system such as the ventral striatum, midbrain, and pallidum, which have been associated with behaviors controlled by the presentation of drug-associated cues. Second, repeated exposure to drugs of abuse has been shown to produce neuroadaptations in the DA D(3) system. Third, the synthesis and characterization of highly potent and selective DA D(3) receptor antagonists has permitted to further define the role of the DA D(3) receptor in drug addiction. Provided that the available preclinical and preliminary clinical evidence can be translated into clinical proof of concept in human, selective DA D(3) receptor antagonists show promise for the treatment of substance use disorders as reflected by their potential to (1) regulate the motivation to self-administered drugs under schedules of reinforcement that require an increase in work demand and (2) disrupt the responsiveness to drug-associated stimuli that play a key role in the reinstatement of drug-seeking behavior triggered by re-exposure to the drug itself, re-exposure to environmental cues that had been previously associated with drug-taking behavior, or stress.

  9. Casopitant: a novel NK(1)-receptor antagonist in the prevention of chemotherapy-induced nausea and vomiting

    DEFF Research Database (Denmark)

    Ruhlmann, Christina; Herrstedt, Jørn

    2009-01-01

    , whereas the effect on nausea seems to be limited. The first NK(1) 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......-hydroxytryptamine (5-HT)(3)- and neurokinin (NK)(1) 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...

  10. FGFR antagonist induces protective autophagy in FGFR1-amplified breast cancer cell.

    Science.gov (United States)

    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

    2016-05-20

    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.

  11. GABAA receptor partial agonists and antagonists

    DEFF Research Database (Denmark)

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

    2015-01-01

    A high degree of structural heterogeneity of the GABAA receptors (GABAARs) has been revealed and is reflected in multiple receptor subtypes. The subunit composition of GABAAR subtypes is believed to determine their localization relative to the synapses and adapt their functional properties...... 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...

  12. Internalization of the chemokine receptor CCR4 can be evoked by orthosteric and allosteric receptor antagonists.

    Science.gov (United States)

    Ajram, Laura; Begg, Malcolm; Slack, Robert; Cryan, Jenni; Hall, David; Hodgson, Simon; Ford, Alison; Barnes, Ashley; Swieboda, Dawid; Mousnier, Aurelie; Solari, Roberto

    2014-04-15

    The chemokine receptor CCR4 has at least two natural agonist ligands, MDC (CCL22) and TARC (CCL17) which bind to the same orthosteric site with a similar affinity. Both ligands are known to evoke chemotaxis of CCR4-bearing T cells and also elicit CCR4 receptor internalization. A series of small molecule allosteric antagonists have been described which displace the agonist ligand, and inhibit chemotaxis. The aim of this study was to determine which cellular coupling pathways are involved in internalization, and if antagonists binding to the CCR4 receptor could themselves evoke receptor internalization. CCL22 binding coupled CCR4 efficiently to β-arrestin and stimulated GTPγS binding however CCL17 did not couple to β-arrestin and only partially stimulated GTPγS binding. CCL22 potently induced internalization of almost all cell surface CCR4, while CCL17 showed only weak effects. We describe four small molecule antagonists that were demonstrated to bind to two distinct allosteric sites on the CCR4 receptor, and while both classes inhibited agonist ligand binding and chemotaxis, one of the allosteric sites also evoked receptor internalization. Furthermore, we also characterize an N-terminally truncated version of CCL22 which acts as a competitive antagonist at the orthosteric site, and surprisingly also evokes receptor internalization without demonstrating any agonist activity. Collectively this study demonstrates that orthosteric and allosteric antagonists of the CCR4 receptor are capable of evoking receptor internalization, providing a novel strategy for drug discovery against this class of target.

  13. CysLT(1)R antagonists inhibit tumor growth in a xenograft model of colon cancer.

    Science.gov (United States)

    Savari, Sayeh; Liu, Minghui; Zhang, Yuan; Sime, Wondossen; Sjölander, Anita

    2013-01-01

    The expression of the inflammatory G-protein coupled receptor CysLT1R has been shown to be upregulated in colon cancer patients and associated with poor prognosis. The present study investigated the correlation between CysLT1R and colon cancer development in vivo using CysLT1R antagonists (ZM198,615 or Montelukast) and the nude mouse xenograft model. Two drug administration regimens were established. The first regimen was established to investigate the importance of CysLT1R in tumor initiation. Nude mice were inoculated with 50 µM CysLT1R antagonist-pretreated HCT-116 colon cancer cells and received continued treatment (5 mg/kg/day, intraperitoneally). The second regimen aimed to address the role of CysLT1R in tumor progression. Nude mice were inoculated with non-pretreated HCT-116 cells and did not receive CysLT1R antagonist treatment until recordable tumor appearance. Both regimens resulted in significantly reduced tumor size, attributed to changes in proliferation and apoptosis as determined by reduced Ki-67 levels and increased levels of p21(WAF/Cip1) (Pcolon cancer cell line HCT-116 and CysLT1R antagonists. In addition to significant reductions in cell proliferation, adhesion and colony formation, we observed induction of cell cycle arrest and apoptosis in a dose-dependent manner. The ability of Montelukast to inhibit growth of human colon cancer xenograft was further validated by using two additional colon cancer cell lines, SW-480 and HT-29. Our results demonstrate that CysLT1R antagonists inhibit growth of colon cancer xenografts primarily by reducing proliferation and inducing apoptosis of the tumor cells.

  14. Predicting the relative binding affinity of mineralocorticoid receptor antagonists by density functional methods

    Science.gov (United States)

    Roos, Katarina; Hogner, Anders; Ogg, Derek; Packer, Martin J.; Hansson, Eva; Granberg, Kenneth L.; Evertsson, Emma; Nordqvist, Anneli

    2015-12-01

    In drug discovery, prediction of binding affinity ahead of synthesis to aid compound prioritization is still hampered by the low throughput of the more accurate methods and the lack of general pertinence of one method that fits all systems. Here we show the applicability of a method based on density functional theory using core fragments and a protein model with only the first shell residues surrounding the core, to predict relative binding affinity of a matched series of mineralocorticoid receptor (MR) antagonists. Antagonists of MR are used for treatment of chronic heart failure and hypertension. Marketed MR antagonists, spironolactone and eplerenone, are also believed to be highly efficacious in treatment of chronic kidney disease in diabetes patients, but is contra-indicated due to the increased risk for hyperkalemia. These findings and a significant unmet medical need among patients with chronic kidney disease continues to stimulate efforts in the discovery of new MR antagonist with maintained efficacy but low or no risk for hyperkalemia. Applied on a matched series of MR antagonists the quantum mechanical based method gave an R2 = 0.76 for the experimental lipophilic ligand efficiency versus relative predicted binding affinity calculated with the M06-2X functional in gas phase and an R2 = 0.64 for experimental binding affinity versus relative predicted binding affinity calculated with the M06-2X functional including an implicit solvation model. The quantum mechanical approach using core fragments was compared to free energy perturbation calculations using the full sized compound structures.

  15. Elucidating the `Jekyll and Hyde' Nature of PXR: The Case for Discovering Antagonists or Allosteric Antagonists

    Science.gov (United States)

    Biswas, Arunima; Mani, Sridhar; Redinbo, Matthew R.; Krasowski, Matthew D.; Li, Hao; Ekins, Sean

    2010-01-01

    The pregnane X receptor belongs to the nuclear hormone receptor superfamily and is involved in the transcriptional control of numerous genes. It was originally thought that it was a xenobiotic sensor controlling detoxification pathways. Recent studies have shown an increasingly important role in inflammation and cancer, supporting its function in abrogating tissue damage. PXR orthologs and PXR-like pathways have been identified in several non-mammalian species which corroborate a conserved role for PXR in cellular detoxification. In summary, PXR has a multiplicity of roles in vivo and is being revealed as behaving like a “Jekyll and Hyde” nuclear hormone receptor. The importance of this review is to elucidate the need for discovery of antagonists of PXR to further probe its biology and therapeutic applications. Although several PXR agonists are already reported, virtually nothing is known about PXR antagonists. Here, we propose the development of PXR antagonists through chemical, genetic and molecular modeling approaches. Based on this review it will be clear that antagonists of PXR and PXR-like pathways will have widespread utility in PXR biology and therapeutics. PMID:19415465

  16. Insights into cardio-oncology:Polypharmacology of quinazoline-based α1-adrenoceptor antagonists

    Institute of Scientific and Technical Information of China (English)

    Salvatore; Patanè

    2015-01-01

    New uses of cardiovascular drugs with proven experience are emerging,including for treating cancer.Quinazoline is a compound made up of two fused six member simple aromatic rings,benzene and pyrimidine rings,with several biological effects.Cardiologists first used quinazoline-based α1-adrenoceptor antagonists prazosin,doxazosin,and terazosin; currently available data support their use as safe,well tolerated,and effective add-on therapy in uncontrolled hypertension with additional favourable metabolic effects.Recent findings highlight the anticancer effects of quinazoline-based α1-adrenoceptor antagonists,indicating that they may have a significant role in uncontrolled hypertensive cancer patients without signs of ischemia.

  17. The safety of interleukin-1 receptor antagonist (anakinra in the treatment of rheumatoid arthritis

    Directory of Open Access Journals (Sweden)

    L. Riente

    2011-09-01

    Full Text Available The safety profile of interleukin-1 receptor antagonist (anakinra has been studied with randomised, placebo-controlled trials involving 2932 patients affected by rheumatoid arthritis. The most frequently reported adverse events were represented by injection site reactions (71% and headache (13.6%. No statistically significant difference in the incidence of infections was observed among the patients treated with the interleukin-1 receptor antagonist and the patients receiving placebo. In particular, the incidence of serious infections was 1,8% in rheumatoid arthritis patients on anakinra therapy and 0,7% in patients on placebo. The reported serious infections consisted of pneumonia, cellulitis, bone and joint infections, bursitis. No case of opportunistic infections or tubercolosis was observed. The results of clinical studies suggest that anakinra is a new well-tolerated drug for the treatment of patients affected by rheumatoid arthritis.

  18. 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.

  19. Activins and activin antagonists in hepatocellular carcinoma

    Institute of Scientific and Technical Information of China (English)

    Alev Deli; Emanuel Kreidl; Stefan Santifaller; Barbara Trotter; Katja Seir; Walter Berger; Rolf Schulte-Hermann; Chantal Rodgarkia-Dara; Michael Grusch

    2008-01-01

    In many parts of the world hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality but the underlying molecular pathology is still insufficiently understood. There is increasing evidence that activins, which are members of the transforming growth factor β (TGFβ) superfamily of growth and differentiation factors, could play important roles in liver carcinogenesis. Activins are disulphide-linked homo-or heterodimers formed from four different β subunits termed βA, βB, βC, and βE, respectively. Activin A, the dimer of two βA subunits, is critically involved in the regulation of cell growth, apoptosis, and tissue architecture in the liver, while the hepatic function of other activins is largely unexplored so far. Negative regulators of activin signals include antagonists in the extracellular space like the binding proteins follistatin and FLRG, and at the cell membrane antagonistic co-receptors like Cripto or BAMBI. Additionally, in the intracellular space inhibitory Smads can modulate and control activin activity. Accumulating data suggest that deregulation of activin signals contributes to pathologic conditions such as chronic inflammation, fibrosis and development of cancer. The current article reviews the alterations in components of the activin signaling pathway that have been observed in HCC and discusses their potential significance for liver tumorigenesis.

  20. Sexually antagonistic selection in human male homosexuality.

    Science.gov (United States)

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

    2008-06-18

    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.

  1. The antiatherogenic potential of calcium antagonists.

    Science.gov (United States)

    Weinstein, D B

    1988-01-01

    Atherosclerosis is an arterial disease characterized by focal accumulation of collagen, elastin, lipids, and calcium at sites associated with macrophage infiltration and altered smooth muscle metabolic function. Studies in several types of animal models, especially cholesterol-fed rabbits, have shown that calcium competitors, calcium chelators, anticalcifying agents, and calcium channel blockers can reduce the accumulation of atherogenic lesion components and thus apparently decrease the progression of lesions. Although there are some conflicting data in the animal model studies using calcium channel antagonists, as a result of differences in experimental designs, it is now apparent that several classes of calcium channel blockers inhibit the progression of early arterial lesions induced by cholesterol feeding. The dihydropyridine calcium channel blockers appear to be more potent antiatherosclerotic agents than other classes of calcium channel antagonists. Several mechanisms involving regulation of endothelial cell, smooth muscle cell, and macrophage metabolic functions may be responsible for the calcium channel blocker effects on early lesion progression. For example, recent studies in cell culture model systems suggest that calcium channel blockers may significantly alter activities that regulate lipoprotein-derived cholesterol accumulation by cells. Some of these activities are independent of calcium flux across voltage-operated calcium channels. Thus, calcium channel blockers may reduce the progression of atherogenic lesions by a combination of decreasing calcium accumulation within arterial wall cells and by altering calcium-independent metabolic activities.

  2. Antioxidant effects of calcium antagonists in rat brain homogenates.

    Science.gov (United States)

    Yao, K; Ina, Y; Nagashima, K; Ohmori, K; Ohno, T

    2000-06-01

    We studied the antioxidant activities of calcium antagonists against autoxidation in rat brain homogenates. The homogenates were incubated for 30 min at 37 degrees C with or without a calcium antagonist and subsequently assayed for lipid peroxide content. Percent inhibition of the lipid peroxidation was used as an index of the antioxidant effect. Dihydropyridine calcium antagonists exhibited concentration-dependent (3-300 micromol/l) inhibitory effects against lipid peroxidation. The relative order of antioxidant potency and associated IC50 values (micromol/l) of the calcium antagonists for inhibition of the lipid peroxidation were as follows: nifedipine (51.5)>barnidipine (58.6)>benidipine (71.2)>nicardipine (129.3)>amlodipine (135.5)>nilvadipine (167.3)>nitrendipine (252.1)> diltiazem (>300)=verapamil (>300). These results suggest that some dihydropyridine calcium antagonists show antioxidant properties. The antioxidant effects of the calcium antagonists may contribute to their pharmacological actions.

  3. Drug Facts

    Medline Plus

    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use Hurts Other People Drug Use Hurts Families Drug Use Hurts Kids Drug Use Hurts Unborn ...

  4. Drug Facts

    Medline Plus

    Full Text Available ... Use Hurts Unborn Children Drug Use Hurts Your Health Drug Use Hurts Bodies Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  5. Drug Allergy

    Science.gov (United States)

    ... Loss of consciousness Other conditions resulting from drug allergy Less common drug allergy reactions occur days or ... you take the drug. Drugs commonly linked to allergies Although any drug can cause an allergic reaction, ...

  6. Drug Facts

    Medline Plus

    Full Text Available ... Addiction? Addiction Risk Factors Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? ... Drug Use Hurts Other People Drug Use Hurts Families Drug Use Hurts Kids Drug Use Hurts Unborn ...

  7. Drug Facts

    Medline Plus

    Full Text Available ... The Link Between Drug Use and HIV/AIDS Recovery & Treatment Drug Treatment Facts Does Drug Treatment Work? ... and Family Can Help Find Treatment/Rehab Resources Prevent Drug Use Help Children and Teens Stay Drug- ...

  8. BIOLOGICAL CONTRAOL OF PHYTOPATHOGENS USING ANTAGONIST TRICHODERMA VIRIDE

    OpenAIRE

    D.S.R. RAJENDRA SINGH; SHAIK SAYEED; K. BRUNDA EVI; B. BHADRAIAH

    2006-01-01

    Antagonistic fungus i.e. Trichoderma viride was tested in vitro against seven phytopathogens viz., Aspergillus niger, A. fumigatus, Macrophimina phaseolina, Fusarium oxysporum, F. solani, Paecilomyces varoti and sclerotium rolfsii. Trichoderma viride exhibited the antagonistic effect against these phytopathogens. Under dual culture the hyphal growth of the phytopathogens was inhibited at the zone of contact with the hyphae of the antagonist. Microscopic examination revealed that hyphal tips o...

  9. Drug: D08901 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08901 Drug Degarelix (INN/USAN) C82H103ClN18O16 1630.7488 1632.2592 D08901.gif Tre...PY L02B HORMONE ANTAGONISTS AND RELATED AGENTS L02BX Other hormone antagonists and related agents L02BX02 Degarelix D08901 Degareli... Agents, Suppressant (Pituitary) Degarelix D08901 Degarelix (INN/USAN) Target-based classification of drugs ...ing hormone (GnRH) receptor [HSA:2798] [KO:K04280] Degarelix [ATC:L02BX02] D08901 Degareli... and related agents Degarelix [ATC:L02BX02] D08901 Degarelix (INN/USAN) CAS: 214766-78-6 PubChem: 96025584 L

  10. Drug: D07537 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07537 Drug Bopindolol (INN); Sandonorm (TN) C23H28N2O3 380.21 380.48 D07537.gif Antihypertensive; beta-Adr...energic blocking ATC code: C07AA17 Prodrug, active substance: Propranolol [DR:D08443] beta1-adr...energic receptor antagonist [HSA:153] [KO:K04141]; beta2-adrenergic receptor antagonist [HSA:154] [KO:K04142]; beta3-adr...(153+154+155) Calcium signaling pathway hsa04080(153+154+155) Neuroactive ligand-receptor interaction hsa04261(153+154) Adr...ive C07AA17 Bopindolol D07537 Bopindolol (INN) Target-based classification of drugs [BR:br08310] G Protein-c

  11. Low-dose calcium antagonists reduce energy demand and cellular damage of isolated hearts during both ischemia and reperfusion.

    Science.gov (United States)

    Becker, B F; Möbert, J

    1999-09-01

    Calcium antagonists may protect against postischemic reperfusion injury of the heart, but neither the time and mode of action leading to cardioprotection is resolved, nor is the generality of this effect proven. Accordingly, the functional and metabolic influence of four different Ca2+-antagonists (diltiazem, 3x10(-8) M; nifedipine, 3x10(-9) M; amlodipine, 3x 10(-9) M; barnidipine, 3x10(-11) M) was examined in preparations of guinea pig hearts (n=7/group) performing pressure-volume work after being subjected to low-flow ischemia (30 min) and reperfusion (35 min). The drugs were applied throughout the study at concentrations without negative inotropic or chronotropic effect, as would be mandatory for any therapeutic application, and without overt coronary dilatation. All calcium antagonists improved postischemic recovery of external heart work: from 42% in controls (post- vs. preischemic value) to 59% for diltiazem, 61% for nifedipine, 65% for amlodipine, and 73% for barnidipine (all Pbarnidipine (15% efficiency). Release of lactate dehydrogenase in the first 5 min of reperfusion, a sign of cell damage, increased from basal (65 mU/min) to 208 mU/min in controls. This increase was fully suppressed by all drugs tested. Myocardial release of lactate and of purine catabolites of adenine nucleotides (markers of anaerobic metabolism) was markedly reduced by Ca2+-antagonists. Interestingly, these metabolic effects were evident not only in the reperfusion phase, but already in the period of low-flow ischemia. Oxidative consumption of pyruvate was enhanced, whereas coronary flow and heart rate showed no postischemic effect of treatment. These findings on isolated guinea pig hearts suggest that Ca2+-antagonists generally improve postischemic pump function and aerobic metabolism without any requirements for negative inotropic action or coronary dilatation. The protective effects seemed to rely on an attenuation of both ischemic stress and reperfusion damage. This could

  12. BF-1--a novel selective 5-HT2B receptor antagonist blocking neurogenic dural plasma protein extravasation in guinea pigs.

    Science.gov (United States)

    Schmitz, Beate; Ullmer, Christoph; Segelcke, Daniel; Gwarek, Mirella; Zhu, Xin-Ran; Lübbert, Hermann

    2015-03-15

    Serotonin 5-HT2B receptor antagonists have been proposed as migraine prophylactic drugs, but previously available 5-HT2B receptor antagonists displayed multiple monoaminergic side effects and had to be withdrawn from the market. Here, we set out to identify a novel antagonist with high affinity and selectivity towards 5-HT2B receptors. To test the affinity of new compounds towards various receptors, we generated a broad series of cells functionally coupling human monoaminergic receptors to luciferase. Using the cell lines we revealed pimethixene (1-methyl-4-(9H-thioxanthen-9-ylidene)piperidine) as highly potent, albeit non-selective 5-HT2B receptor antagonist and optimized its chemical structure to create highly potent and selective 5-HT2B receptor antagonists. We selected the methoxythioxanthene BF-1 for further analysis. In comparison to pimethixene, it lacked high affinities to 5-HT1A, 5-HT2A, 5-HT2C, histamine H1, dopamine D1 and D2 as well as muscarinic M1 and M2 receptors. BF-1 was tested as potential migraine prophylactic drug by blocking meta-chlorophenylpiperazine, (mCPP) or BW723C86 (5-((thiophen-2-yl)methoxy)-α-methyltryptamine) induced neurogenic dural plasma protein extravasation in a guinea pig model that may resemble a migraine attack. BF-1 was significantly more potent in this assay compared to the well know non-selective 5-HT2B antagonists, methysergide ((6aR,9R)-N-[(2S)-1-Hydroxybutan-2-yl]-4,7-dimethyl-6,6a,8,9-tetrahydroindolo[4,3-fg]quinoline-9-carboxamide) or pizotifen (4-(1-methyl-4-piperidylidine)-9,10-dihydro-4H-benzo-[4,5]cyclohepta[1,2]-thiophene). Therefore, we propose BF-1 as a new compound that may be developed for prophylactic migraine treatment without the typical monoaminergic side effects.

  13. Performance of ultrasound to monitor Achilles enthesitis in patients with ankylosing spondylitis during TNF-a antagonist therapy.

    Science.gov (United States)

    Wang, Cong-hua; Feng, Yuan; Ren, Zhen; Yang, Xichao; Jia, Jun-feng; Rong, Meng-yao; Li, Xue-yi; Wu, Zhen-biao

    2015-06-01

    Enthesitis is considered as the primary anatomical lesion in ankylosing spondylitis (AS). We aimed to investigate the potential of ultrasound to detect early changes after TNF-a antagonist therapy of Achilles enthesitis of AS patients. One hundred AS patients with active disease, requiring TNF-a antagonist therapy, were included (etanercept n = 25, infliximab n = 25, adalimumab n = 25, non-biologic disease-modifying antirheumatic drugs (DMARDs) n = 25). Physical examination was performed to evaluate disease activity and detect Achilles enthesitis and/or retrocalcaneal bursitis. Ultrasound of the Achilles enthesitis was performed bilaterally. Follow-up examinations were performed 3 months after the initiation of therapy. Gray scale (GS) scores, Power Doppler (PD) scores, and total additive scores (TS) decreased significantly during TNF-a antagonist therapy but not in traditional non-biologic traditional DMARDs group. The bath ankylosing spondylitis disease activity index (BASDAI), bath ankylosing spondylitis metrology index (BASMI), bath ankylosing spondylitis functional index (BASFI), and Maastricht ankylosing spondylitis enthesitis score (MASES) all showed significant improvements. When three different TNF-a antagonists were analyzed separately, no significant difference was observed in GS, PD, and total scores. Subclinical Achilles enthesitis, detected only with GS ultrasound, is present in a subset of AS patients and a significant improvement can be demonstrated after 3 months of TNF-a antagonist therapy. Doppler ultrasound provides a reliable estimation to monitor the therapeutic response to TNF antagonists in AS patients with Achilles enthesitis. TNF-a antagonists have been shown to be effective in decreasing ultrasound signs of enthesitis after 3 months of therapy in AS patients.

  14. Cardiac β 2-adrenoceptor sensitization by chronic β1-selective antagonist treatment in patients with essential hypertension

    Institute of Scientific and Technical Information of China (English)

    Peng Yingxin; Qi Xiaoyong; Xue Hao; Zhang Jianqing; Ma Shuping

    2002-01-01

    Objective:It has been hypothesized that with drawal of treatment with β 1-selective antagonist leads to increased sensitivity of β - adrenoceptor stimulation with isoproterenol.Several studies in vitro have shown that cardiac β 2- adrenoceptor was sensitized by β 1-selective antagonist treatment in patients with coronary heart disease.Therefore,the object of the present study was to explore in vivo to demonstrate that the cardiac β 2- adrenoceptor is sensitized in patients with essential hypertension by the chronic β 1-selective antagonis. Methods: β - adrenoceptor in peripheral lymphocytes was assessed by 3H-dihydyoalprenolol(3H-DHA) radio ligand binding. β - adrenaleptor responsiveness was measured by sulbtamol( β 2-selective agonist) in male patients with essential hypertension after β 1-selective antagonist treatment for at least 4 months (twenty cases)and.with drugs other than β 1-antagonist for at least 4 months(twenty cases).Results:In patients with β 1-selective antagonist treatment and those with non- β -antagonist treatment the maximal number of binding sites( β max)in peripheral lymphocytes was not significantly different(528+104fmol/107cell v s.571±98fmol/107cell ,P>0.05) In β 1-selective antagonist treatment group the chronotropic dose of sulbtamol(in) required to increase heart rate by 30beats/min.(CD30) was significantly lower than that in non - β -antagonist treatment group(1.8±0.3 μ g/kg v s.2.7±0.2 μ g/kg,P<0.001).The maximal fall of diastolic pressure(0.96±0.50kPa v s.0.91±0.42kPa) were not significatn changed(P>0.05) after sulbtamol injection. Conclusion:The treatment with β 1-selective antagonist led to sensitization of β 2-adrenoceptor function,while no change in β 2- adrenoceptors density in peripheral lymphocytes in vivo in patients with essential hypertension,the dissociation between function and density of cardiac β 2- adrenoceptors may partially explain the mechanism of β -antagonist withdrawal syndrome.

  15. Spatial working memory in rats: effects of monoaminergic antagonists.

    Science.gov (United States)

    Beatty, W W; Rush, J R

    1983-01-01

    To assess the possible involvement of the monoaminergic neurotransmitters norepinephrine, dopamine and serotonin in the maintenance of spatial working memory rats were treated with antagonists 0 or 2 hr after completing the first 4 choices in an 8 arm maze. Haloperidol (0.25-1 mg/kg), when administered 2 hr after Choice 4, produced a small but consistent impairment in performance on retention tests given 5 hr after the first 4 choices. This deficit closely resembled natural forgetting in terms of the type of errors committed. By contrast, haloperidol in the same doses given 0 hr after Choice 4 or 3 hr before the first 4 choices did not affect retention. Likewise treatment with propranolol (10-20 mg/kg), phentolamine (5-20 mg/kg) or methysergide (5-15 mg/kg) did not impair spatial memory, regardless of when these drugs were injected within the session. Evidently dopaminergic neuronal systems are important in the maintenance of normal spatial working memory.

  16. 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.

  17. Mineralocorticoid Receptor Antagonists for Treatment of Hypertension and Heart Failure.

    Science.gov (United States)

    Sica, Domenic A

    2015-01-01

    Spironolactone and eplerenone are both mineralocorticoid-receptor antagonists. These compounds block both the epithelial and nonepithelial actions of aldosterone, with the latter assuming increasing clinical relevance. Spironolactone and eplerenone both affect reductions in blood pressure either as mono- or add-on therapy; moreover, they each afford survival benefits in diverse circumstances of heart failure and the probability of renal protection in proteinuric chronic kidney disease. However, as use of mineralocorticoid-blocking agents has expanded, the hazards inherent in taking such drugs have become more apparent. Whereas the endocrine side effects of spironolactone are in most cases little more than a cosmetic annoyance, the potassium-sparing effects of both spironolactone and eplerenone can prove disastrous, even fatal, if sufficient degrees of hyperkalemia emerge. For most patients, however, the risk of developing hyperkalemia in and of itself should not discourage the sensible clinician from bringing these compounds into play. Hyperkalemia should always be considered a possibility in patients receiving either of these medications; therefore, anticipatory steps should be taken to minimize the likelihood of its occurrence if long-term therapy of these agents is being considered.

  18. 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.

  19. Drug: D08635 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08635 Drug Degarelix acetate (USAN); Degarelix acetate hydrate; Firmagon (TN) C82H...s and related agents L02BX02 Degarelix D08635 Degarelix acetate (USAN) Target-bas...hormone gonadotropin-releasing hormone (GnRH) receptor [HSA:2798] [KO:K04280] Degarelix [ATC:L02BX02] D08635 Degareli...onist Other hormone antagonists and related agents Degarelix [ATC:L02BX02] D08635 Degarelix acetate (USAN) C

  20. Drug: D07538 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07538 Drug Bosentan (INN) C27H29N5O6S 551.1839 551.6141 D07538.gif Endothelin antagonist; Antihypertensive...[BR:br08303] C CARDIOVASCULAR SYSTEM C02 ANTIHYPERTENSIVES C02K OTHER ANTIHYPERTENSIVES C02KX Other antihypertensive...302] Respiratory Tract/Pulmonary Agents Pulmonary Antihypertensives Bosentan D07538 Bosentan (INN) Target-ba

  1. Drug: D10112 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10112 Drug Dexmecamylamine hydrochloride (USAN) C11H21N. HCl 203.1441 203.7521 D10112.gif Treatment of major depressive disorder nicotinic cholinergic receptor alpha4beta2 antagonist [HSA:11...04813] Dexmecamylamine D10112 Dexmecamylamine hydrochloride (USAN) CAS: 107596-30-5 PubChem: 135626830 LigandBox: D1011...s Cys-loop superfamily Acetylcholine (nicotinic) alpha4beta2 nicotinic receptor [HSA:1137 1141] [KO:K04806 K

  2. Drug: D08864 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08864 Drug Azilsartan (JAN/USAN/INN); Azilva (TN) C25H20N4O5 456.1434 456.4501 D08...assification [BR:br08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Azilsartan D08864 Azilsartan... [HSA:185] [KO:K04166] Azilsartan D08864 Azilsartan (JAN/USAN/INN) CAS: 147403-03-0 PubChem: 96025547 Ligand

  3. Drug: D09196 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09196 Mixture, Drug Candesartan cilexetil - hydrochlorothiadide mixt; Ecard HD (TN... individual organs 21 Cardiovascular agents 214 Antihypertensives 2149 Others D09196 Candesartan...AGONISTS, COMBINATIONS C09DA Angiotensin II antagonists and diuretics C09DA06 Candesartan... and diuretics D09196 Candesartan cilexetil - hydrochlorothiadide mixt PubChem: 96025876 ... ...); Ecard LD (TN) Candesartan cilexetil [DR:D00626], Hydrochlorothiazide [DR:D00340] Antihypertensive Therape

  4. Drug: D09197 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D09197 Mixture, Drug Valsartan - hydrochlorothiazide mixt; Co-dio (TN) Valsartan [D...R:D00400], Hydrochlorothiazide [DR:D00340] Therapeutic category: 2149 ATC code: C09DA03 The target of Valsartan...s 21 Cardiovascular agents 214 Antihypertensives 2149 Others D09197 Valsartan - h...Angiotensin II antagonists and diuretics C09DA03 Valsartan and diuretics D09197 Valsartan - hydrochlorothiazide mixt PubChem: 96025877 ...

  5. Drug: D07895 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07895 Mixture, Drug Hydrochlorothiazide - losartan potassium mixt; Hyzaar (TN) Hyd...rochlorothiazide [DR:D00340], Losartan potassium [DR:D00357] Antihypertensive Therapeutic category: 2149 ATC...D07895 Hydrochlorothiazide - losartan potassium mixt Anatomical Therapeutic Chemical (ATC) classification [B...AGONISTS, COMBINATIONS C09DA Angiotensin II antagonists and diuretics C09DA01 Losartan... and diuretics D07895 Hydrochlorothiazide - losartan potassium mixt PubChem: 96024591 ...

  6. Modelling of absorption, distribution and physicochemical properties of AT1 receptor antagonists / Modelovanie absorpcie, distribúcie a fyzikálnochemických vlastnosti antagonistov AT1 receptorov

    Directory of Open Access Journals (Sweden)

    Ježko Pavol

    2015-12-01

    Full Text Available The theoretical chemistry methods were used to elucidate absorption, distribution and physicochemical properties of AT1 receptor antagonists and dual angiotensin II and endothelin A receptor antagonist (PS-433540. Computed partition coefficients (ALOGPS method studied for drugs varied between 2.98 and 6.66. Neutral compounds are described as lipophilic drugs. Telmisartan is a drug with the highest lipophilicity. The neutral forms of the studied AT1 receptor antagonists are practically insoluble in water, and their computed solubilities is in interval between 2.04 and 22.65 mg/l (ALOGpS method. The calculated pKa values for tetrazolyle moiety are in the range 3.92-5.00 and for carboxylic moiety 3.12-5.50. Telmisartan (polar surface area = 72.95 A and irbesartan (polar surface area = 87.14 A belong to the AT1 receptor antagonists with increased absorption.

  7. Mutually-antagonistic interactions in baseball networks

    Science.gov (United States)

    Saavedra, Serguei; Powers, Scott; McCotter, Trent; Porter, Mason A.; Mucha, Peter J.

    2010-03-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit structural changes over time. We find interesting structure in the networks and examine their sensitivity to baseball’s rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to (1) compare the performance of players who competed under different conditions and (2) include information about which particular players a given player has faced. We find that a player’s position in the network does not correlate with his placement in the random walker ranking. However, network position does have a substantial effect on the robustness of ranking placement to changes in head-to-head matchups.

  8. Antagonists of IAP proteins as cancer therapeutics.

    Science.gov (United States)

    Dynek, Jasmin N; Vucic, Domagoj

    2013-05-28

    Inhibitor of apoptosis (IAP) proteins play pivotal roles in cellular survival by blocking apoptosis, modulating signal transduction, and affecting cellular proliferation. Through their interactions with inducers and effectors of apoptosis IAP proteins can effectively suppress apoptosis triggered by diverse stimuli including death receptor signaling, irradiation, chemotherapeutic agents, or growth factor withdrawal. Evasion of apoptosis, in part due to the action of IAP proteins, enhances resistance of cancer cells to treatment with chemotherapeutic agents and contributes to tumor progression. Additionally, IAP genes are known to be subject to amplification, mutation, and chromosomal translocation in human malignancies and autoimmune diseases. In this review we will discuss the role of IAP proteins in cancer and the development of antagonists targeting IAP proteins for cancer treatment.

  9. 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.

  10. Mutually-Antagonistic Interactions in Baseball Networks

    CERN Document Server

    Saavedra, Serguei; McCotter, Trent; Porter, Mason A; Mucha, Peter J

    2009-01-01

    We formulate the head-to-head matchups between Major League Baseball pitchers and batters from 1954 to 2008 as a bipartite network of mutually-antagonistic interactions. We consider both the full network and single-season networks, which exhibit interesting structural changes over time. We also find that these networks exhibit a significant network structure that is sensitive to baseball's rule changes. We then study a biased random walk on the matchup networks as a simple and transparent way to compare the performance of players who competed under different conditions. We find that a player's position in the network does not correlate with his success in the random walker ranking but instead has a substantial effect on its sensitivity to changes in his own aggregate performance.

  11. Antagonistic activity of marine sponges associated Actinobacteria

    Institute of Scientific and Technical Information of China (English)

    Selvakumar Dharmaraj; Dhevendaran Kandasamy

    2016-01-01

    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 universally well

  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. Identification of a novel series of orexin receptor antagonists with a distinct effect on sleep architecture for the treatment of insomnia.

    Science.gov (United States)

    Betschart, Claudia; Hintermann, Samuel; Behnke, Dirk; Cotesta, Simona; Fendt, Markus; Gee, Christine E; Jacobson, Laura H; Laue, Grit; Ofner, Silvio; Chaudhari, Vinod; Badiger, Sangamesh; Pandit, Chetan; Wagner, Juergen; Hoyer, Daniel

    2013-10-10

    Dual orexin receptor (OXR) antagonists (DORAs) such as almorexant, 1 (SB-649868), or suvorexant have shown promise for the treatment of insomnias and sleep disorders in several recent clinical trials in volunteers and primary insomnia patients. The relative contribution of antagonism of OX1R and OX2R for sleep induction is still a matter of debate. We therefore initiated a drug discovery project with the aim of creating both OX2R selective antagonists and DORAs. Here we report that the OX2R selective antagonist 26 induced sleep in mice primarily by increasing NREM sleep, whereas the DORA suvorexant induced sleep largely by increasing REM sleep. Thus, OX2R selective antagonists may also be beneficial for the treatment of insomnia.

  14. Survival of TNF antagonists in spondylarthritis is better than in rheumatoid arthritis. Data from the Spanish registry BIOBADASER.

    Science.gov (United States)

    Carmona, Loreto; Gómez-Reino, Juan J

    2006-01-01

    The aim of the present work is to compare drug survival and safety of infliximab, etanercept, and adalimumab (tumor necrosis factor [TNF] antagonists) in spondylarthritis (SpA) with those of rheumatoid arthritis (RA). To this purpose, we analysed the data in BIOBADASER (2000-2005), a drug registry launched in 2000 for long-term follow-up of the safety of these biologics in rheumatic diseases. The rates of drug discontinuation and adverse events (AEs) in SpA (n = 1,524) were estimated and compared with those of RA (n = 4,006). Cox regression analyses were used to adjust for independent factors. Total exposure to TNF antagonists for SpA was 2,430 patient-years and 7,865 for RA. Drug survival in SpA was significantly greater than in RA at 1, 2, and 3 years. The hazard ratio (HR) for discontinuation in SpA compared with RA was 0.66 (95% confidence interval [CI], 0.57-0.76) after adjustment for age, gender, and use of infliximab. The difference remained after controlling for the individual medication and its place in the sequence of treatment. There were fewer SpA patients with AEs (17%) than RA patients (26%; p < 0.001). The HR for AEs in SpA was 0.80 (95% CI, 0.70-0.91) compared with RA after adjustment for age, disease duration, and use of infliximab. In conclusion, due in part to a better safety profile, survival of TNF antagonists in SpA is better than in RA. TNF antagonists are at present a safe and effective therapeutic option for long-term treatment of patients with SpA failing to respond to traditional drugs. Because chronic therapy is necessary, continual review of this issue is necessary.

  15. A systematic review of calcium channel antagonists in bipolar disorder and some considerations for their future development

    Science.gov (United States)

    Cipriani, A; Saunders, K; Attenburrow, M-J; Stefaniak, J; Panchal, P; Stockton, S; Lane, T A; Tunbridge, E M; Geddes, J R; Harrison, P J

    2016-01-01

    l-type calcium channel (LTCC) antagonists have been used in bipolar disorder for over 30 years, without becoming an established therapeutic approach. Interest in this class of drugs has been rekindled by the discovery that LTCC genes are part of the genetic aetiology of bipolar disorder and related phenotypes. We have therefore conducted a systematic review of LTCC antagonists in the treatment and prophylaxis of bipolar disorder. We identified 23 eligible studies, with six randomised, double-blind, controlled clinical trials, all of which investigated verapamil in acute mania, and finding no evidence that it is effective. Data for other LTCC antagonists (diltiazem, nimodipine, nifedipine, methyoxyverapamil and isradipine) and for other phases of the illness are limited to observational studies, and therefore no robust conclusions can be drawn. Given the increasingly strong evidence for calcium signalling dysfunction in bipolar disorder, the therapeutic candidacy of this class of drugs has become stronger, and hence we also discuss issues relevant to their future development and evaluation. In particular, we consider how genetic, molecular and pharmacological data can be used to improve the selectivity, efficacy and tolerability of LTCC antagonists. We suggest that a renewed focus on LTCCs as targets, and the development of ‘brain-selective' LTCC ligands, could be one fruitful approach to innovative pharmacotherapy for bipolar disorder and related phenotypes. PMID:27240535

  16. The inability of CCK to block (or CCK antagonists to substitute for) the stimulus effects of chlordiazepoxide.

    Science.gov (United States)

    Fox, M A; Levine, E S; Riley, A L

    2001-01-01

    To further examine the relationship between cholecystokinin (CCK) and GABA, the present study assessed the ability of the CCK-A antagonist devazepide and the CCK-B antagonist L-365,260 to substitute for the stimulus effects of chlordiazepoxide (CDP), as well as the ability of CCK-8s to block these effects, in female Long-Evans rats within the conditioned taste aversion baseline of drug discrimination learning. Both devazepide and L-365,260 failed to substitute for the discriminative stimulus properties of CDP, and CCK-8s failed to block its stimulus effects. The benzodiazepine diazepam did substitute for, and the benzodiazepine antagonist flumazenil did block, the stimulus effects of CDP. This suggests that the lack of substitution for, or antagonism of, CDP by the CCK antagonists and CCK-8s, respectively, was not due to the inability of the present design to assess such effects. Possible bases for the current findings, e.g., necessity of an anxiogenic baseline, drug and receptor specificity, as well as the dose-response nature of the interaction, were discussed. Given that a relationship between CCK and GABA has been reported in other designs, the present results suggest that such a relationship may be preparation specific.

  17. Antischistosomal activity of a calcium channel antagonist on schistosomula and adult Schistosoma mansoni worms

    Directory of Open Access Journals (Sweden)

    Vanessa Silva-Moraes

    2013-08-01

    Full Text Available Current schistosomiasis control strategies are largely based on chemotherapeutic agents and a limited number of drugs are available today. Praziquantel (PZQ is the only drug currently used in schistosomiasis control programs. Unfortunately, this drug shows poor efficacy in patients during the earliest infection phases. The effects of PZQ appear to operate on the voltage-operated Ca2+channels, which are located on the external Schistosoma mansoni membrane. Because some Ca2+channels have dihydropyridine drug class (a class that includes nifedipine sensitivity, an in vitro analysis using a calcium channel antagonist (clinically used for cardiovascular hypertension was performed to determine the antischistosomal effects of nifedipine on schistosomula and adult worm cultures. Nifedipine demonstrated antischistosomal activity against schistosomula and significantly reduced viability at all of the concentrations used alone or in combination with PZQ. In contrast, PZQ did not show significant efficacy when used alone. Adult worms were also affected by nifedipine after a 24 h incubation and exhibited impaired motility, several lesions on the tegument and intense contractility. These data support the idea of Ca2+channels subunits as drug targets and favour alternative therapeutic schemes when drug resistance has been reported. In this paper, strong arguments encouraging drug research are presented, with a focus on exploring schistosomal Ca2+channels.

  18. Effect of the NMDA antagonist MK-801 on latent inhibition of fear conditioning.

    Science.gov (United States)

    Traverso, Luis M; Ruiz, Gabriel; De la Casa, Luis G

    2012-10-01

    N-methyl-D-aspartate (NMDA) receptors seem to play a central role in learning and memory processes involved in Latent Inhibition (LI). In fact, MK-801, a non-competitive NMDA receptor antagonist, has proved its effectiveness as a drug for attenuating LI when administered before or after stimulus preexposure and conditioning stages. This paper presents three experiments designed to analyze the effect of MK-801 on LI when the drug is administered before (Experiment 1A) or after (Experiment 1B) preexposure and conditioning stages with a conditioned emotional response procedure. Additionally, we analyze the effect of the drug when it was administered before preexposure, before conditioning or before both phases (Experiment 2). The results show that the effect of the drug varied as a function of the dose (with only the highest dose being effective), the moment of administration (with only the drug administered before the experimental treatments being effective), and the phase of procedure (reducing LI when the drug was administered only at preexposure, and disrupting fear conditioning when administered at conditioning). These differences may be due to several factors ranging from the role played by NMDA receptors in the processing of stimuli of different sensorial modalities to the molecular processes triggered by drug administration.

  19. Drugs and Drug Abuse.

    Science.gov (United States)

    Anastas, Robert, Comp.; And Others.

    GRADES OR AGES: Secondary grades. SUBJECT MATTER: Drugs and drug abuse. ORGANIZATION AND PHYSICAL APPEARANCE: The guide is divided into several sections, each of which is in outline or list form. It is xeroxed and spiral-bound with a paper cover. OBJECTIVES AND ACTIVITIES: No objectives are mentioned. The major portion of the guide contains a…

  20. Drug allergies

    Science.gov (United States)

    Allergic reaction - drug (medication); Drug hypersensitivity; Medication hypersensitivity ... A drug allergy involves an immune response in the body that produces an allergic reaction to a medicine. The ...

  1. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists.

    Science.gov (United States)

    Sadek, Bassem; Saad, Ali; Schwed, Johannes Stephan; Weizel, Lilia; Walter, Miriam; Stark, Holger

    2016-01-01

    Phenytoin (PHT), valproic acid, and modern antiepileptic drugs (AEDs), eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%-80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs) for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propanamide (1). In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R)-2-(4-(3-(piperidin-1-yl)propoxy)benzylamino)propaneamide (2) and analogs thereof, in maximum electroshock (MES)-, pentylenetetrazole (PTZ)-, and strychnine (STR)-induced convulsion models in rats having PHT and valproic acid (VPA) as reference AEDs. Unlike the S-enantiomer (1), the results show that animals pretreated intraperitoneally (ip) with the R-enantiomer 2 (10 mg/kg) were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R)-enantiomer (3), in which 3-piperidinopropan-1-ol in ligand 2 was replaced by (4-(3-(piperidin-1-yl)propoxy)phenyl)methanol, 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

  2. Optimisation of GnRH antagonist use in ART

    NARCIS (Netherlands)

    Hamdine, O.

    2014-01-01

    This thesis focuses on the optimisation of controlled ovarian stimulation for IVF using exogenous FSH and GnRH antagonist co-treatment, by studying the timing of the initiation of GnRH antagonist co-medication and the role of ovarian reserve markers in optimising ovarian response and reproductive ou

  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. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

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

    2016-01-01

    Background: 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 direct

  5. 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…

  6. Gonadotrophin-releasing hormone antagonists for assisted reproductive technology

    NARCIS (Netherlands)

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

    2016-01-01

    Background: 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

  7. Drugs to Treat Nausea and Vomiting

    Science.gov (United States)

    ... that are easy on your stomach, such as ginger ale, toast, and crackers; and eating small meals throughout the day. Evaluating the Oral 5-HT3 Antagonists: Drugs Used to ... provided by Wolters Kluwer Health, Pharmaceutical Audit Suite®. Wolters Kluwer Health is not ...

  8. Protective Role of GnRH Antagonist on Chemotherapy-induced Spermatogenesis Disorder: A Morphological Study

    Directory of Open Access Journals (Sweden)

    Daryosh Mohammadnejad

    2013-08-01

    Full Text Available Purpose: Anti cancer drugs is one of the most important chemotherapeutic factors which can influence spermatogenesis process and germinal epithelium. Since dividing cells are mainly affected by anticancer drugs, the aim of the present study is to investigate thepreventive effect of GnRH antagonist on spermatogenic defect produced by anticancer drugs. Methods: In the present study thirty adult male mice aging 6-8 weeks were divided into 3 groups as: Control, Experimental 1 and Experimental 2. Experimental 1 group received Cisplatin for 5 days as 2.5 mg/kg intraperitoneally and Experimental 2group received 0.25 mg/kg cetrorelix (GnRH antagonist one week before cisplatin treatment and continued for 3 weeks. The mice in all groups were sacrificed 35 days after the last injection and testis specimens were fixed in boueins, formaldehyde fixativeand 2.5% Glutaraldehide then prepared for light and electron microscopic examination. Results: Light microscopy (LM study showed that the number of spermatogonial cells, thickness of germinal epithelium, was decreased in Experimental 1group. Electronmicroscopy revealed that in this group several intercellular spaces appeared between spermatogenic cells and secretory granules in interstitial cells was increased. There were several vacuolated mitochondria and destroyed organelles in spermatogonial cells but inExperimental 2 group condition was similar to control group. Conclusion: These results indicate that the cetrorelix administration before cancer treatment may protect germinal epithelium against side effects of cisplatin.

  9. Early gonadotropin-releasing hormone antagonist start improves follicular synchronization and pregnancy outcome as compared to the conventional antagonist protocol.

    Science.gov (United States)

    Park, Chan Woo; Hwang, Yu Im; Koo, Hwa Seon; Kang, Inn Soo; Yang, Kwang Moon; Song, In Ok

    2014-12-01

    To assess whether an early GnRH antagonist start leads to better follicular synchronization and an improved clinical pregnancy rate (CPR). A retrospective cohort study. A total of 218 infertile women who underwent IVF between January 2011 and February 2013. The initial cohort (Cohort I) that underwent IVF between January 2011 and March 2012 included a total of 68 attempted IVF cycles. Thirty-four cycles were treated with the conventional GnRH antagonist protocol, and 34 cycles with an early GnRH antagonist start protocol. The second cohort (Cohort II) that underwent IVF between June 2012 and February 2013 included a total of 150 embryo-transfer (ET) cycles. Forty-three cycles were treated with the conventional GnRH antagonist protocol, 34 cycles with the modified early GnRH antagonist start protocol using highly purified human menopause gonadotropin and an addition of GnRH agonist to the luteal phase support, and 73 cycles with the GnRH agonist long protocol. The analysis of Cohort I showed that the number of mature oocytes retrieved was significantly higher in the early GnRH antagonist start cycles than in the conventional antagonist cycles (11.9 vs. 8.2, p=0.04). The analysis of Cohort II revealed higher but non-significant CPR/ET in the modified early GnRH antagonist start cycles (41.2%) than in the conventional antagonist cycles (30.2%), which was comparable to that of the GnRH agonist long protocol cycles (39.7%). The modified early antagonist start protocol may improve the mature oocyte yield, possibly via enhanced follicular synchronization, while resulting in superior CPR as compared to the conventional antagonist protocol, which needs to be studied further in prospective randomized controlled trials.

  10. Drug: D01965 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01965 Drug Silodosin (JAN/INN); KMD 3213; Rapaflo (TN); Urief (TN) C25H32F3N3O4 49...nal organ agents 259 Miscellaneous 2590 Miscellaneous D01965 Silodosin (JAN/INN) ...04 UROLOGICALS G04C DRUGS USED IN BENIGN PROSTATIC HYPERTROPHY G04CA Alpha-adrenoreceptor antagonists G04CA04 Silodosin D01965 Silodo...ourinary Agents Benign Prostatic Hypertrophy Agents Silodosin D01965 Silodosin (JAN/INN) Target-based classi...eptor [HSA:146 147 148] [KO:K04137 K04136 K04135] Silodosin [ATC:G04CA04] D01965 Silodosin (JAN/INN) CAS: 16

  11. Drug: D06618 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D06618 Drug Methylnaltrexone bromide (JAN/USAN); Relistor (TN) C21H26NO4. Br 435.10...FOR CONSTIPATION A06AH Peripheral opioid receptor antagonist A06AH01 Methylnaltrexone bromide... D06618 Methylnaltrexone bromide (USAN) USP drug classification [BR:br08302] Gastrointestinal Ag...ents Gastrointestinal Agents, Other Methylnaltrexone D06618 Methylnaltrexone bromide (USAN) Target-based cla...ioid mu-opioid receptor [HSA:4988] [KO:K04215] Methylnaltrexone bromide [ATC:A06AH01] D06618 Methylnaltrexone bromide

  12. Drug: D08569 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08569 Drug Terazosin (INN); Terazosabb (TN) C19H25N5O4 387.1907 387.4329 D08569.gi...or antagonists G04CA03 Terazosin D08569 Terazosin (INN) USP drug classification [BR:br08302] Cardiovascular ...Agents Alpha-adrenergic Blocking Agents Terazosin D08569 Terazosin (INN) Genitourinary Agents Benign Prostatic Hypertrophy Agents Ter...azosin D08569 Terazosin (INN) Target-based classificatio...HSA:146 147 148] [KO:K04137 K04136 K04135] Terazosin [ATC:G04CA03] D08569 Terazosin (INN) CAS: 63590-64-7 Pu

  13. Drug: D07729 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07729 Drug Clopidogrel (INN); Clopidogrel (TN); Plavix (TN) C16H16ClNO2S 321.059 3...status is associated with diminished response to Clopidogrel. P2Y12 receptor antagonist [HSA:64805] [KO:K042...rs excl. heparin B01AC04 Clopidogrel D07729 Clopidogrel (INN) USP drug classification [BR:br08302] Blood Pro...ducts/Modifiers/Volume Expanders Platelet Modifying Agents Clopidogrel D07729 Clopidogrel (INN) Target-based...y Purine / pyrimidine P2Y12 receptor [HSA:64805] [KO:K04298] Clopidogrel [ATC:B01AC04] D07729 Clopidogrel (I

  14. Drug: D00400 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00400 Drug Valsartan (JP16/USAN/INN); Diovan (TN) C24H29N5O3 435.227 435.5188 D004...ans 21 Cardiovascular agents 214 Antihypertensives 2149 Others D00400 Valsartan (JP16/USAN/INN) Anatomical T...ntagonists, plain C09CA03 Valsartan D00400 Valsartan (JAN/USAN/INN) USP drug classification [BR:br08302] Car...diovascular Agents Angiotensin II Receptor Antagonists Valsartan D00400 Valsartan (JAN/USAN/INN) Target-base...II stimulates angiotensin subtype 1 (AT1) receptor [HSA:185] [KO:K04166] Valsartan

  15. Drug: D00626 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00626 Drug Candesartan cilexetil (JP16/USAN); Atacand (TN) C33H34N6O6 610.254 610.... 2149 ATC code: C09CA06 Prodrug, active substance: Candesartan [DR:D00522] angiotensin II receptor type 1 (A...ardiovascular agents 214 Antihypertensives 2149 Others D00626 Candesartan cilexetil (JP16/USAN) Anatomical T...ntagonists, plain C09CA06 Candesartan D00626 Candesartan cilexetil (JP16/USAN) USP drug classification [BR:b...r08302] Cardiovascular Agents Angiotensin II Receptor Antagonists Candesartan D00626 Candesartan cilexetil (

  16. Churg-Strauss syndrome and leukotriene antagonist use: a respiratory perspective.

    LENUS (Irish Health Repository)

    Nathani, N

    2008-10-01

    Churg-Strauss syndrome (CSS) is a rare granulomatous small vessel vasculitis that occurs against a background of longstanding asthma. Leukotriene antagonists (LTAs) are used in the management of asthma and may facilitate a reduction in steroid dosage. Reports of the development of CSS in patients with asthma following the initiation of LTA therapy suggest either a causal association or an unmasking of latent CSS as steroid doses fall. We have undertaken a systematic review to establish whether evidence of a drug induced syndrome exists.

  17. Blonanserin, an antipsychotic and dopamine D₂/D₃receptor antagonist, and ameliorated alcohol dependence.

    Science.gov (United States)

    Takaki, Manabu; Ujike, Hiroshi

    2013-01-01

    Blonanserin (BNS) is used for treatment of both positive and negative symptoms of schizophrenia in Japan and Korea. Because BNS has weak α1 receptor blocking activities and is almost devoid of histamine H1 and muscarinic M1 antagonist activity, BNS is better tolerated than other atypical antipsychotics. A high degree of D₃ receptor blockage is reported to be predictive of drug abuse and alcoholism, and BNS has strong D₃ receptor antagonism. Thus, BNS may be useful in the treatment of alcoholism. We present a case in which BNS ameliorated alcohol dependence.

  18. Pharmacology of JB-9315, a new selective histamine H2-receptor antagonist.

    Science.gov (United States)

    Palacios, B; Montero, M J; Sevilla, M A; San Román, L

    1998-02-01

    1. The histamine H2-receptor antagonistic activity and antisecretory and antiulcer effects of JB-9315 were studied in comparison with the standard H2 blocker ranitidine. 2. In vitro, JB-9315 is a competitive antagonist of histamine H2 receptors in the isolated, spontaneously beating guinea-pig right atrium, with a pA2 value of 7.30 relative to a value of 7.36 for ranitidine. JB-9315 was specific for the histamine H2 receptor because, at high concentration, it did not affect histamine- or acetylcholine-induced contractions in guinea-pig isolated ileum or rat isolated duodenum, respectively. 3. JB-9315 dose dependently inhibited histamine-, pentagastrin- or carbachol-stimulated acid secretion and basal secretion in the perfused stomach preparation of the anesthetized rat. In the pylorus-ligated rat after intraperitoneal administration, total acid output over 4 h was inhibited by JB-9315 with an ID50 of 32.8 mg/kg, confirming its H2-receptor antagonist properties. 4. JB-9315 showed antiulcer activity against cold stress plus indomethacin-induced lesions with an ID50 of 6.8 mg/kg. 5. JB-9315, 50 and 100 mg/kg, inhibited macroscopic gastric hemorrhagic lesions induced by ethanol. In contrast, ranitidine (50 mg/kg) failed to reduce these lesions. 6. These results indicate that JB-9315 is a new antiulcer drug that exerts a cytoprotective effect in addition to its gastric antisecretory activity.

  19. A novel synthetic smoothened antagonist transiently inhibits pancreatic adenocarcinoma xenografts in a mouse model.

    Directory of Open Access Journals (Sweden)

    Martin F Strand

    Full Text Available BACKGROUND: Hedgehog (Hh signaling is over-activated in several solid tumors where it plays a central role in cell growth, stroma recruitment and tumor progression. In the Hh signaling pathway, the Smoothened (SMO receptor comprises a primary drug target with experimental small molecule SMO antagonists currently being evaluated in clinical trials. PRINCIPAL FINDINGS: Using Shh-Light II (Shh-L2 and alkaline phosphatase (AP based screening formats on a "focused diversity" library we identified a novel small molecule inhibitor of the Hh pathway, MS-0022 (2-bromo-N-(4-(8-methylimidazo[1,2-a]pyridin-2-ylphenylbenzamide. MS-0022 showed effective Hh signaling pathway inhibition at the level of SMO in the low nM range, and Hh pathway inhibition downstream of Suppressor of fused (SUFU in the low µM range. MS-0022 reduced growth in the tumor cell lines PANC-1, SUIT-2, PC-3 and FEMX in vitro. MS-0022 treatment led to a transient delay of tumor growth that correlated with a reduction of stromal Gli1 levels in SUIT-2 xenografts in vivo. SIGNIFICANCE: We document the in vitro and in vivo efficacy and bioavailability of a novel small molecule SMO antagonist, MS-0022. Although MS-0022 primarily interferes with Hh signaling at the level of SMO, it also has a downstream inhibitory effect and leads to a stronger reduction of growth in several tumor cell lines when compared to related SMO antagonists.

  20. Anticonvulsant effects of isomeric nonimidazole histamine H3 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Sadek B

    2016-11-01

    Full Text Available Bassem Sadek,1 Ali Saad,1 Johannes Stephan Schwed,2,3 Lilia Weizel,2 Miriam Walter,2 Holger Stark2,3 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Biocenter, Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt, Germany; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: Phenytoin (PHT, valproic acid, and modern antiepileptic drugs (AEDs, eg, remacemide, loreclezole, and safinamide, are only effective within a maximum of 70%–80% of epileptic patients, and in many cases the clinical use of AEDs is restricted by their side effects. Therefore, a continuous need remains to discover innovative chemical entities for the development of active and safer AEDs. Ligands targeting central histamine H3 receptors (H3Rs for epilepsy might be a promising therapeutic approach. To determine the potential of H3Rs ligands as new AEDs, we recently reported that no anticonvulsant effects were observed for the (S-2-(4-(3-(piperidin-1-ylpropoxybenzylaminopropanamide (1. In continuation of our research, we asked whether anticonvulsant differences in activities will be observed for its R-enantiomer, namely, (R-2-(4-(3-(piperidin-1-ylpropoxybenzylaminopropaneamide (2 and analogs thereof, in maximum electroshock (MES-, pentylenetetrazole (PTZ-, and strychnine (STR-induced convulsion models in rats having PHT and valproic acid (VPA as reference AEDs. Unlike the S-enantiomer (1, the results show that animals pretreated intraperitoneally (ip with the R-enantiomer 2 (10 mg/kg were moderately protected in MES and STR induced models, whereas proconvulsant effect was observed for the same ligand in PTZ-induced convulsion models. However, animals pretreated with intraperitoneal doses of 5, 10, or 15 mg/kg of structurally bulkier (R-enantiomer (3

  1. Drug Facts

    Medline Plus

    Full Text Available ... Use and Unborn Children Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug ...

  2. Club Drugs

    Science.gov (United States)

    ... uses. Other uses of these drugs are abuse. Club drugs are also sometimes used as "date rape" drugs, to make someone unable to say no to or fight back against sexual assault. Abusing these drugs can ...

  3. Drug Facts

    Medline Plus

    Full Text Available ... Nicotine Facts Other Drugs of Abuse What is Addiction? Do You or a Loved One Have a Drug Use Problem? Signs of Drug Use and Addiction How Does Drug Use Become Addiction? Addiction Risk ...

  4. Drug Facts

    Medline Plus

    Full Text Available ... Drug Use and Your Health Other Effects on the Body Drug Use Hurts Brains Drug Use and Mental Health Problems Often Happen Together The Link Between Drug Use and HIV/AIDS Treatment & ...

  5. [Metabotropic glutamate receptors as targets for new drug development].

    Science.gov (United States)

    Arkhipov, V I; Kapralova, M V

    2011-01-01

    The review is devoted to experimental investigations of metabotropic glutamate receptors and the properties of drugs (ligands) belonging to agonists, antagonists, and modulators of the activity of these receptors. Possibilities of the treatment of neurodegenerative disorders, cognitive disturbances in schizophrenia patients, and narcotic dependency by using drugs of this class are considered.

  6. Functional potencies of dopamine agonists and antagonists at human dopamine D₂ and D₃ receptors.

    Science.gov (United States)

    Tadori, Yoshihiro; Forbes, Robert A; McQuade, Robert D; Kikuchi, Tetsuro

    2011-09-01

    We measured the functional agonist potencies of dopamine agonists including antiparkinson drugs, and functional antagonist potencies of antipsychotics at human dopamine D(2) and D(3) receptors. In vitro pharmacological assessment included inhibition of forskolin-stimulated cAMP accumulation and the reversal of dopamine-induced inhibition in clonal Chinese hamster ovary cells expressing low and high densities of human dopamine D(2L) and D(2S) receptors (hD(2L)-Low, hD(2L)-High, hD(2S)-Low and hD(2S)-High, respectively) and human dopamine D(3) Ser-9 and D(3) Gly-9 receptors (hD(3)-Ser-9 and hD(3)-Gly-9, respectively). Cabergoline, bromocriptine, pergolide, (±)-7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT), talipexole, pramipexole, R-(+)-trans-3,4,4a,10b-tetrahydro-4-propyl-2H,5H-[1]benzopyrano[4,3-b]-1,4-oxazin-9-olhydrochloride (PD128907) and ropinirole behaved as dopamine D(2) and D(3) receptor full agonists and showed higher potencies in hD(2L)-High and hD(2S)-High compared to hD(2L)-Low and hD(2S)-Low. In hD(3)-Ser-9 and hD(3)-Gly-9 compared to hD(2L)-Low and hD(2S)-Low, dopamine, ropinirole, PD128907, and pramipexole potencies were clearly higher; talipexole and 7-OH-DPAT showed slightly higher potencies; pergolide showed slightly lower potency; and, cabergoline and bromocriptine potencies were lower. Aripiprazole acted as an antagonist in hD(2L)-Low; a low intrinsic activity partial agonist in hD(2S)-Low; a moderate partial agonist in hD(3)-Ser-9 and hD(3)-Gly-9; a robust partial agonist in hD(2L)-High; and a full agonist in hD(2S)-High. Amisulpride, sulpiride and perphenazine behaved as preferential antagonists; and chlorpromazine and asenapine behaved as modest preferential antagonists; whereas fluphenazine, haloperidol, and blonanserin behaved as non-preferential antagonists in hD(2S)-Low and hD(2S)-High compared to hD(3)-Ser-9 and hD(3)-Gly-9. These findings may help to elucidate the basis of therapeutic benefit observed with these drugs, with

  7. Dihydromorphine-peptide hybrids with delta receptor agonistic and mu receptor antagonistic actions

    Energy Technology Data Exchange (ETDEWEB)

    Smith, C.B.; Medzihradsky, F.; Woods, J.H.

    1986-03-05

    The actions of two morphine derivatives with short peptide side chains were evaluated upon the contraction of the isolated mouse vas deferens and upon displacement of /sup 3/H-etorphine from rat brain membranes. NIH-9833 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-phenylalanyl-L-leucine ethyl ester HCl) was a potent agonist upon the vas deferens. Its EC50 for inhibition of the twitch was 1.2 +/- 0.1 nM. Both naltrexone (10/sup -7/ M) a relatively nonselective opioid antagonist, and ICI-174864 (10/sup -/' M) a highly selective delta receptor antagonist, blocked the actions of NIH-9833 which indicates that this drug is a delta receptor agonist. In contrast, NIH-9835 (N-(6,14-endoetheno-7,8-dihydromorphine-7-alpha-carbonyl)-L-glycyl-L-phenylalanyl-L-leucine ethyl ester HCl), which differs from NIH-9835 by the presence of a single amino acid residue, was devoid of opioid agonistic activity but was a potent antagonist of the inhibitory actions on the vas deferens of morphine and sufentanil. NIH-9833 and NIH-9835 were potent displacers of /sup 3/H-etorphine from rat cerebral membranes with EC50's of 0.58 nM and 1.7 nM, respectively. The observation that addition of a single glycyl group changes a dihydromorphine-peptide analog from a potent delta receptor agonist to an equally potent mu receptor antagonist suggests that the two receptor sites might be structurally quite similar.

  8. Effects of GABAB receptor agonists and antagonists on glycemia regulation in mice.

    Science.gov (United States)

    Bonaventura, María M; Crivello, Martín; Ferreira, María Laura; Repetto, Martín; Cymeryng, Cora; Libertun, Carlos; Lux-Lantos, Victoria A

    2012-02-29

    γ-Aminobutyric acid (GABA) inhibits insulin secretion through GABA(B) receptors in pancreatic β-cells. We investigated whether GABA(B) receptors participated in the regulation of glucose homeostasis in vivo. BALB/c mice acutely pre-injected with the GABA(B) receptor agonist baclofen (7.5mg/kg, i.p.) presented glucose intolerance and diminished insulin secretion during a glucose tolerance test (GTT, 2g/kg body weight, i.p.). The GABA(B) receptor antagonist 2-hydroxysaclofen (15 mg/kg, i.p.) improved the GTT and reversed the baclofen effect. Also a slight increase in insulin secretion was observed with 2-hydroxysaclofen. In incubated islets 1.10(-5)M baclofen inhibited 20mM glucose-induced insulin secretion and this effect was reversed by coincubation with 1.10(-5)M 2-hydroxysaclofen. In chronically-treated animals (18 days) both the receptor agonist (5mg/kg/day i.p.) and the receptor antagonist (10mg/kg/day i.p.) induced impaired GTTs; the receptor antagonist, but not the agonist, also induced a decrease in insulin secretion. No alterations in insulin tolerance tests, body weight and food intake were observed with the treatments. In addition glucagon, insulin-like growth factor I, prolactin, corticosterone and growth hormone, other hormones involved in glucose metabolism regulation, were not affected by chronic baclofen or 2-hydroxysaclofen. In islets obtained from chronically injected animals with baclofen, 2-hydroxysaclofen or saline (as above), GABA(B2) mRNA expression was not altered. Results demonstrate that GABA(B) receptors are involved in the regulation of glucose homeostasis in vivo. Treatment with receptor agonists or antagonists, given acutely or chronically, altered glucose homeostasis and insulin secretion alerting to the need to evaluate glucose metabolism during the clinical use of these drugs. Copyright © 2011 Elsevier B.V. All rights reserved.

  9. New treatment options for HIV salvage patients: an overview of second generation PIs, NNRTIs, integrase inhibitors and CCR5 antagonists.

    Science.gov (United States)

    Hughes, Amelia; Barber, Tristan; Nelson, Mark

    2008-07-01

    Since 1996, the prognosis of those living with HIV and AIDS has improved significantly due to highly active antiretroviral therapy (HAART). Treatment failure can occur clinically, immunologically or virologically. Until recently, treatment options for those individuals harboring resistance to the three initial licensed classes of drug have been limited. These three classes are the nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs). New drugs are now available in these classes (second generation NNRTIs and novel PIs) as well as new classes of drugs, integrase inhibitors, CCR5 antagonists and fusion inhibitors. If these new drugs are used appropriately with other active antiretroviral agents, it is probable that antiretroviral therapy can achieve the optimum outcome of HIV therapy - durable suppression of HIV viraemia. This article is a review of currently available antiretroviral agents including the new classes and second generation drugs, resistance pathways and treatment options for salvage therapy.

  10. Identification and Drug Resistant Analysis of a Strain of Siderophores Producting Antagonist Bacteria From Rubber Tree%一株产铁载体橡胶树拮抗细菌的分离鉴定及耐药性分析

    Institute of Scientific and Technical Information of China (English)

    贺春萍; 赵璐璐; 孙亮; 李锐; 梁艳琼; 郑肖兰; 吴伟怀

    2012-01-01

    从橡胶树根部分离到一株拮抗细菌Czk1,该菌株在铬天青(CAS)检测平板上产生较大的桔黄色显色圈,具较强的铁载体产生能力.对其进行生理生化鉴定、16S rDNA序列分析,测定7种常见抗生素的抗性.结合该菌菌落、菌体特征,生理生化指标及16S rDNA序列分析,鉴定该内生菌为枯草芽孢杆菌(Bacillus subtilis),该菌对四环素、红霉素、氨苄青霉素、利福平、链霉素和卡那霉素高度敏感,对氯霉素表现抗性.%An antagonistic bacteria Czk1 from rubber tree root section was isolated against Ganoderma pseudoferreum, Phellinus noxius, Helicobasidium compaction, Rigidoporus lignosus, and Sphaerostilbe repens. A large orange color circle could be seen in the detection plate chromazurol (CAS), which meant Czk1, had a strong siderophore ability. The Czk1 was identified by using biochemical and physiological characteristics and 16S rDNA sequence analysis. Seven common antibiotics were detected its resistance by using antibiotic tablet and disk diffusion method. Combination of bacteria colonies, the cell characteristics, physiological and biochemical characteristics and 16S rDNA sequences analysis showed the Czk1 was Bacillus subtilis. Czk1 was highly sensitive to tetracycline, erythromycin, ampicillin, riafmpicin, streptomycin, kanamicin, and resistance to chloramphenicol.

  11. In Vitro Characterization of Six Month Dosage Forms for a GnRH Antagonist

    Directory of Open Access Journals (Sweden)

    Susan D’Souza

    2014-01-01

    Full Text Available The objective of this study was to develop long-acting injectable dosage forms of Orntide, a peptide GnRH antagonist, to provide tailored release for 6-month duration. Using a polylactide homopolymer and the solvent extraction/evaporation method, three microsphere formulations (Formulations A, B, and C were prepared at various drug loadings (11.85–15.79%. The microspheres were characterized for particle size by laser diffractometry, surface morphology by scanning electron microscopy (SEM, and bulk density by tapping, as well as long-term in vitro drug release, mass loss and hydration at 37°C, and short-term in vitro drug release at elevated temperatures (51–59°C. Experiments at 37°C revealed that drug release was triphasic and occurred due to slow degradation of the polylactide polymer. Short-term in vitro release results indicated that drug release was diffusional. Application of the Higuchi equation to short-term release confirmed the temperature dependency of the diffusional rate constant. Using the rate constant and the Arrhenius equation, an Ea value of 45 kcal/mol (Formulation A and approximately 25 kcal/mol (Formulations B and C was obtained for diffusional release. Study results suggest that by selection of an appropriate biodegradable polymer, injectable dosing forms that release drug for 6 months or longer can be developed.

  12. A Drug Discovery Partnership for Personalized Breast Cancer Therapy

    Science.gov (United States)

    2014-09-01

    agonists or antagonists) and then virtually screen the USDA Phytochemical, Chinese Herbal Medicine, and the FDA Marketed Drug Databases for new estrogens...the basis for potent ER agonists and antagonists that are in the registered pharmaceuticals and herbal medicine databases. The 29 analogs obtained...Kundu, Biology Department, “Formulation of a targeted nanoparticle system for the treatment of breast cancer” 7- Monday November 25, 2013, Dr. Partha

  13. HIGH AFFINITY ACYLATING ANTAGONISTS FOR MUSCARINIC RECEPTORS

    Science.gov (United States)

    Baumgold, Jesse; Karton, Yishai; Malka, Naftali; Jacobson, Kenneth A.

    2012-01-01

    Summary The muscarinic antagonists pirenzepine and telenzepine were derivitized as alkylamino derivatives at a site on the molecules corresponding to a region of bulk tolerance in receptor binding. The distal primary amino groups were coupled to the cross-linking reagent meta-phenylene diisothiocyanate, resulting in two isothiocyanate derivatives that were found to inhibit muscarinic receptors irreversibly and in a dose-dependent fashion. Preincubation of rat forebrain membranes with an isothiocyanate derivative followed by radioligand binding using [3H]N-methylscopolamine diminished the Bmax value, but did not affect the Kd value. The receptor binding site was not restored upon repeated washing, indicating that irreversible inhibition had occurred. IC50 values for the irreversible inhibition at rat forebrain muscarinic receptors were 0.15 nM and 0.19 nM, for derivatives of pirenzepine and telenzepine, respectively. The isothiocyanate derivative of pirenzepine was non-selective as an irreversible muscarinic inhibitor, and the corresponding derivative prepared from telenzepine was 5-fold selective for forebrain (mainly m1) vs. heart (m2) muscarinic receptors. PMID:1625525

  14. 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.

  15. Fine Tuning of a Type 1 Interferon Antagonist.

    Directory of Open Access Journals (Sweden)

    Victoria Urin

    Full Text Available Type I interferons are multi-potent cytokines that serve as first line of defense against viruses and other pathogens, posses immunomudolatory functions and elicit a growth inhibitory response. In recent years it has been shown that interferons are also detrimental, for example in lupus, AIDS, tuberculosis and cognitive decline, highlighted the need to develop interferon antagonists. We have previously developed the antagonist IFN-1ant, with much reduced binding to the IFNAR1 receptor and enhanced binding to IFNAR2. Here, we further tune the IFN-1ant by producing three additional antagonists based on IFN-1ant but with altered activity profiles. We show that in all three cases the antiproliferative activity of interferons is blocked and the induction of gene transcription of immunomudolatory and antiproliferative associated genes are substantially decreased. Conversely, each of the new antagonists elicits a different degree of antiviral response, STAT phosphorylation and related gene induction. Two of the new antagonists promote decreased activity in relation to the original IFN-1ant, while one of them promotes increased activity. As we do not know the exact causes of the detrimental effects of IFNs, the four antagonists that were produced and analyzed provide the opportunity to investigate the extent of antagonistic and agonistic activity optimal for a given condition.

  16. Zatosetron, a potent, selective, and long-acting 5HT3 receptor antagonist: synthesis and structure-activity relationships.

    Science.gov (United States)

    Robertson, D W; Lacefield, W B; Bloomquist, W; Pfeifer, W; Simon, R L; Cohen, M L

    1992-01-24

    Antagonists of 5HT3 receptors are clinically effective in treating nausea and emesis associated with certain oncolytic drugs, including cisplatin. Moreover, these agents may be useful in pharmacological management of several central nervous system disorders, including anxiety, schizophrenia, dementia, and substance abuse. Our studies on aroyltropanamides led to the discovery that dihydrobenzofuranyl esters and amides are potent 5HT3 receptor antagonists. Simple benzoyl derivatives of tropine and 3 alpha-aminotropane possessed weak 5HT3 receptor antagonist activity, as judged by blockade of bradycardia produced by iv injection of serotonin (5HT) to anesthetized rats. Within this series, use of benzofuran-7-carboxamide as the aroyl moiety led to a substantial increase of 5HT3 receptor affinity. The optimal 5HT3 receptor antagonist identified via extensive SAR studies was endo-5-chloro-2,3-dihydro-2,2-dimethyl-N-(8-methyl-8-azabicyclo[3.2.1]oc t- 3-yl)-7-benzofurancarboxamide (Z)-2-butenedioate (zatosetron maleate). The 7-carbamyl regiochemistry, dimethyl substitution, chloro substituent, and endo stereochemistry were all crucial elements of the SAR. Zatosetron maleate was a potent antagonist of 5HT-induced bradycardia in rats (ED50 = 0.86 micrograms/kg i.v.). Low oral doses of zatosetron (30 micrograms/kg) produced long-lasting antagonism of 5HT3 receptors, as evidenced by blockade of 5HT-induced bradycardia for longer than 6 h in rats. Moreover, this compound did not produce hemodynamic effects after i.v. administration to rats, nor did it block carbamylcholine-induced bradycardia in doses that markedly blocked 5HT3 receptors. Thus, zatosetron is a potent, selective, orally effective 5HT3 receptor antagonist with a long duration of action in rats.

  17. Kinetic properties of 'dual' orexin receptor antagonists at OX1R and OX2R orexin receptors.

    Directory of Open Access Journals (Sweden)

    Gabrielle Elizabeth Callander

    2013-12-01

    Full Text Available Orexin receptor antagonists represent attractive targets for the development of drugs for the treatment of insomnia. Both efficacy and safety are crucial in clinical settings and thorough investigations of pharmacokinetics and pharmacodynamics can predict contributing factors such as duration of action and undesirable effects. To this end, we studied the interactions between various ‘dual’ orexin receptor antagonists and the orexin receptors, OX1R and OX2R, over time using saturation and competition radioligand binding with [3H]-BBAC ((S-N-([1,1'-biphenyl]-2-yl-1-(2-((1-methyl-1H-benzo[d]imidazol-2-ylthioacetylpyrrolidine-2-carboxamide. In addition, the kinetics of these compounds were investigated in cells expressing human, mouse and rat OX1R and OX2R using FLIPR® assays for calcium accumulation. We demonstrate that almorexant reaches equilibrium very slowly at OX2R, whereas SB-649868, suvorexant and filorexant may take hours to reach steady state at both orexin receptors. By contrast, compounds such as BBAC or the selective OX2R antagonist IPSU ((2-((1H-Indol-3-ylmethyl-9-(4-methoxypyrimidin-2-yl-2,9-diazaspiro[5.5]undecan-1-one bind rapidly and reach equilibrium very quickly in both binding and / or functional assays. Overall, the dual antagonists tested here tend to be rather unselective under non-equilibrium conditions and reach equilibrium very slowly. Once equilibrium is reached, each ligand demonstrates a selectivity profile that is however, distinct from the non-equilibrium condition. The slow kinetics of the dual antagonists tested suggest that in vitro receptor occupancy may be longer lasting than would be predicted. This raises questions as to whether pharmacokinetic studies measuring plasma or brain levels of these antagonists are accurate reflections of receptor occupancy in vivo.

  18. Antiarthritic activity of an orally active C5a receptor antagonist against antigen-induced monarticular arthritis in the rat.

    Science.gov (United States)

    Woodruff, Trent M; Strachan, Anna J; Dryburgh, Nathan; Shiels, Ian A; Reid, Robert C; Fairlie, David P; Taylor, Stephen M

    2002-09-01

    To determine if the new, orally active C5a receptor antagonist, the cyclic peptide AcF-[OPdChaWR], reduces the severity of pathology in a rat model of immune-mediated monarticular arthritis. Arthritis was induced in the right knee of previously sensitized rats by the intraarticular injection of methylated bovine serum albumin. Rats were examined for either 14 days or 28 days, or for 49 days following a second antigen challenge at 28 days. The C5a antagonist (1 or 3 mg/kg/day) and/or ibuprofen (30 mg/kg/day) were administered orally on a daily basis either before or after arthritis induction. Rats receiving AcF-[OPdChaWR] had significant reductions in right knee swelling, gait disturbance, lavaged joint cell numbers, and right knee histopathology, as well as in serum levels of tumor necrosis factor alpha (TNFalpha) and intraarticular levels of interleukin-6 and TNFalpha on day 14. In the 14- and 28-day studies, ibuprofen resulted in a similar reduction in gait abnormalities and intraarticular inflammatory cells compared with the C5a antagonist, but was less effective in reducing knee swelling over the course of the study and had no effect on knee histopathology. Combination therapy with AcF-[OPdChaWR] and ibuprofen resulted in no greater efficacy than with the C5a antagonist alone. Rats injected twice with the antigen in the 49-day study displayed the most severe histopathology and this, as well as knee swelling and gait abnormalities, was significantly reduced by repeated treatment with the C5a antagonist. An agent that inhibits the action of C5a in this model significantly reduced joint pathology, while ibuprofen was not effective. C5a antagonists could therefore have broader therapeutic benefits than nonsteroidal antiinflammatory drugs as antiarthritic agents for rheumatoid arthritis.

  19. 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.

  20. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists.

    Science.gov (United States)

    Khanfar, Mohammad A; Affini, Anna; Lutsenko, Kiril; Nikolic, Katarina; Butini, Stefania; Stark, Holger

    2016-01-01

    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.

  1. Intractable pneumococcal meningoencephalitis associated with a TNF-α antagonist.

    Science.gov (United States)

    Kang, Seok-Jae; Kim, Hyun Young; Kim, Young Seo; Lee, Ha Neul; Kim, Hee Tae; Kim, Seung H

    2014-09-15

    A 34-year-old man was treated with a TNF-α antagonist for ankylosing spondylitis, and this subsequently developed a CNS infection. Magnetic resonance imaging showed diffuse subcortical white matter lesions. Streptococcus pneumoniae was cultured from the cerebrospinal fluid and blood. The patient died of multifocal widespread brain damage and subarachnoid hemorrhage, despite intensive antibacterial medication. Pneumococcal meningoencephalitis can occur in association with TNF-α antagonists. Clinicians should be aware of both the risk of fatal bacterial meningoencephalitis associated with TNF-α antagonists and the possibility of an unusual presentation of bacterial meningitis. Copyright © 2014. Published by Elsevier B.V.

  2. New potential uroselective NO-donor alpha1-antagonists.

    Science.gov (United States)

    Boschi, Donatella; Tron, Gian Cesare; Di Stilo, Antonella; Fruttero, Roberta; Gasco, Alberto; Poggesi, Elena; Motta, Gianni; Leonardi, Amedeo

    2003-08-14

    A recent uroselective alpha(1)-adrenoceptor antagonist, REC15/2739, has been joined with nitrooxy and furoxan NO-donor moieties to give new NO-donor alpha(1)-antagonists. All the compounds studied proved to be potent and selective ligands of human cloned alpha(1a)-receptor subtype. Derivatives 6 and 7 were able to relax the prostatic portion of rat vas deferens contracted by (-)-noradrenaline because of both their alpha(1A)-antagonist and their NO-donor properties.

  3. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    2016-01-01

    Aim: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of differe

  4. Pharmacokinetic/pharmaco-dynamic modelling and simulation of the effects of different cannabinoid receptor type 1 antagonists on (9)-tetrahydrocannabinol challenge tests

    NARCIS (Netherlands)

    Guan, Zheng; Klumpers, Linda E.; Oyetayo, Olubukayo-Opeyemi; Heuberger, Jules; van Gerven, Joop M. A.; Stevens, Jasper

    2016-01-01

    AimThe severe psychiatric side effects of cannabinoid receptor type 1 (CB1) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different

  5. Expression of complement C5a receptor and the viability of 4T1 tumor cells following agonist–antagonist treatment

    Directory of Open Access Journals (Sweden)

    Nurneqman Nashreq Kosni

    2016-01-01

    Conclusion: This experiment shows the presence of C5a receptor on 4T1 cell line. We believe that the antagonist peptide is eligible to be used widely in cancer immunotherapy field; but in vivo studies need to be carried out first in the future, as it will determine how these drugs affect the tumor cell growth.

  6. Cost-Effectiveness of Dabigatran Compared to Vitamin-K Antagonists for the Treatment of Deep Venous Thrombosis in the Netherlands Using Real-World Data

    NARCIS (Netherlands)

    van Leent, Merlijn W. J.; Stevanovic, Jelena; Jansman, Frank G.; Beinema, Maarten J.; Brouwers, Jacobus R. B. J.; Postma, Maarten J.

    2015-01-01

    Background Vitamin-K antagonists (VKAs) present an effective anticoagulant treatment in deep venous thrombosis (DVT). However, the use of VKAs is limited because of the risk of bleeding and the necessity of frequent and long-term laboratory monitoring. Therefore, new oral anticoagulant drugs (NOACs)

  7. Involvement of ET-1 in diabetic cardiomyopathy, vascular abnormality and nepropathy which are regressed by a novel endothelin receptor antagonist Dajisentan.

    Institute of Scientific and Technical Information of China (English)

    De-zaiDAI; MinJI

    2004-01-01

    AIM: An impaired endothelium contributes to diabetic cardiomyopathy (CMP), vascular pathy (VSP) and nephropathy (NPP) in diabetes. It is hypothesized that these disorders which are the consequence to damaged endothelium could be recovered by Dajisentan, a novel dual endothelin receptor antagonist, developed by us as an investigated new drug. METHODS: Rat diabetes model was developed by ip streptozotocin and the

  8. The AMPA antagonist, NBQX, protects against ischemia-induced loss of cerebellar Purkinje cells

    DEFF Research Database (Denmark)

    Balchen, T.; Diemer, Nils Henrik

    1992-01-01

    Neuropathology, NBQX, AMPA antagonist, cerebellar cells, ischemia, rats, Purkinje, neuronal death......Neuropathology, NBQX, AMPA antagonist, cerebellar cells, ischemia, rats, Purkinje, neuronal death...

  9. Update on leukotriene receptor antagonists in preschool children wheezing disorders

    Directory of Open Access Journals (Sweden)

    Montella Silvia

    2012-06-01

    Full Text Available Abstract Asthma is the most common chronic disease in young children. About 40% of all preschool children regularly wheeze during common cold infections. The heterogeneity of wheezing phenotypes early in life and various anatomical and emotional factors unique to young children present significant challenges in the clinical management of this problem. Anti-inflammatory therapy, mainly consisting of inhaled corticosteroids (ICS, is the cornerstone of asthma management. Since Leukotrienes (LTs are chemical mediators of airway inflammation in asthma, the leukotriene receptor antagonists (LTRAs are traditionally used as potent anti-inflammatory drugs in the long-term treatment of asthma in adults, adolescents, and school-age children. In particular, montelukast decreases airway inflammation, and has also a bronchoprotective effect. The main guidelines on asthma management have confirmed the clinical utility of LTRAs in children older than five years. In the present review we describe the most recent advances on the use of LTRAs in the treatment of preschool wheezing disorders. LTRAs are effective in young children with virus-induced wheeze and with multiple-trigger disease. Conflicting data do not allow to reach definitive conclusions on LTRAs efficacy in bronchiolitis or post-bronchiolitis wheeze, and in acute asthma. The excellent safety profile of montelukast and the possibility of oral administration, that entails better compliance from young children, represent the main strengths of its use in preschool children. Montelukast is a valid alternative to ICS especially in poorly compliant preschool children, or in subjects who show adverse effects related to long-term steroid therapy.

  10. Effects of NMDA receptor antagonists on probability discounting depend on the order of probability presentation.

    Science.gov (United States)

    Yates, Justin R; Breitenstein, Kerry A; Gunkel, Benjamin T; Hughes, Mallory N; Johnson, Anthony B; Rogers, Katherine K; Shape, Sara M

    Risky decision making can be measured using a probability-discounting procedure, in which animals choose between a small, certain reinforcer and a large, uncertain reinforcer. Recent evidence has identified glutamate as a mediator of risky decision making, as blocking the N-methyl-d-aspartate (NMDA) receptor with MK-801 increases preference for a large, uncertain reinforcer. Because the order in which probabilities associated with the large reinforcer can modulate the effects of drugs on choice, the current study determined if NMDA receptor ligands alter probability discounting using ascending and descending schedules. Sixteen rats were trained in a probability-discounting procedure in which the odds against obtaining the large reinforcer increased (n=8) or decreased (n=8) across blocks of trials. Following behavioral training, rats received treatments of the NMDA receptor ligands MK-801 (uncompetitive antagonist; 0, 0.003, 0.01, or 0.03mg/kg), ketamine (uncompetitive antagonist; 0, 1.0, 5.0, or 10.0mg/kg), and ifenprodil (NR2B-selective non-competitive antagonist; 0, 1.0, 3.0, or 10.0mg/kg). Results showed discounting was steeper (indicating increased risk aversion) for rats on an ascending schedule relative to rats on the descending schedule. Furthermore, the effects of MK-801, ketamine, and ifenprodil on discounting were dependent on the schedule used. Specifically, the highest dose of each drug decreased risk taking in rats in the descending schedule, but only MK-801 (0.03mg/kg) increased risk taking in rats on an ascending schedule. These results show that probability presentation order modulates the effects of NMDA receptor ligands on risky decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

  11. Dopamine agonist and antagonist responders as related to types of nicotine craving and facets of extraversion.

    Science.gov (United States)

    Reuter, Martin; Netter, Petra; Toll, Claudia; Hennig, Juergen

    2002-06-01

    The role of dopamine (DA) in drug seeking behavior has been a matter of debate in the literature: One theory claims that DA triggers incentive motivational behavior, the other one favors the idea that DA itself is the rewarding property induced by the positive stimuli. The present experiment tries to contribute to a solution of the controversy by the approach of relating DA-associated motivational behavior to constellations of hormone response to a DA agonistic and DA antagonistic challenge performed in the same subjects and by relating their responses to different aspects of personality and smoking motivation. DA agonist (lisuride = LIS), DA antagonist (fluphenazine = FLU), and placebo (P) were applied to 36 male smokers who were deprived from smoking for 3.5 h in a balanced crossover design. Cigarette craving and prolactin (PRL) responses to the drugs were compared under the three pharmacological conditions and related to personality and smoking motivation. Results showed that PRL responder types to LIS and FLU, defined as differences from respective placebo values, emerged as pure agonist or antagonist responders in two-thirds of the cases and as mixed types in one-third. PRL-LIS responders developed more craving in the LIS condition and PRL-FLU responders when exposed to FLU. Furthermore, the first group scored high on the sensation seeking scale (SSS), which related to the concept of incentive motivation and the FLU responders high on extraversion and smoking motivation for stimulating purposes suggesting the endeavor to replace DA. Thus, evidence for the validity of both theories is proven.

  12. Comparison of relaxation responses of cavernous and trigonal smooth muscles from rabbits by alpha1-adrenoceptor antagonists; prazosin, terazosin, doxazosin, and tamsulosin.

    Science.gov (United States)

    Seo, K. K.; Lee, M. Y.; Lim, S. W.; Kim, S. C.

    1999-01-01

    Alpha1a-adrenergic receptor (AR) primarily mediates the contraction of the prostatic and cavernous smooth muscles. Among clinically available alpha1-AR antagonists for the medical management of benign prostatic hyperplasia (BPH), tamsulosin has a modest selectivity for alpha1A- and alpha1D- over alpha1B-ARs. To compare the effects of various alpha1-AR antagonists on relaxation responses of cavernous and trigonal smooth muscles, isometric tension studies with relatively selective (tamsulosin) and non-selective (prazosin, doxazosin, and terazosin) alpha1A-AR antagonists, were conducted in the cavernous and trigonal muscle strips of rabbits (n=10 each). Tamsulosin had the strongest inhibitory effect on contraction of trigonal smooth muscle among the various alpha1-AR antagonists, and the inhibitory activities of prazosin, doxazosin, and terazosin were not statistically different. All alpha1-AR antagonists caused concentration-dependent relaxation of the cavernous muscle strips. Tamsulosin was shown to have greater potency than prazosin (more than 100-fold), doxazosin (more than 1000-fold), and terazosin (more than 1000-fold), in relaxation of cavernous smooth muscle. In conclusion, tamsulosin might be the most effective drug among the four commonly used alpha1-AR antagonists for the medical management of BPH. Tamsulosin might be a potential substitute for phentolamine in combination with vasoactive agents as an intracavernous injection therapy for patients with erectile dysfunction. PMID:10102527

  13. Structure-Based Prediction of Subtype Selectivity of Histamine H3 Receptor Selective Antagonists in Clinical Trials

    DEFF Research Database (Denmark)

    Kim, Soo-Kyung; Fristrup, Peter; Abrol, Ravinder

    2011-01-01

    applications, including treatment of Alzheimer’s disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity.(1) However, many of these drug candidates cause undesired side effects through the cross-reactivity with other histamine receptor subtypes. In order to develop improved selectivity......–5–6 and the aliphatic ring located in TMs 2–3–7. These 3D structures for all four HRs should help guide the rational design of novel drugs for the subtype selective antagonists and agonists with reduced side effects....

  14. Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFα antagonists

    DEFF Research Database (Denmark)

    Lallemand, Christophe; Kavrochorianou, Nadia; Steenholdt, Casper;

    2011-01-01

    relative to Renilla luciferase expression. Thus, results are independent of cell number or differences in cell viability, resulting in intra and inter assay coefficients of variation of 10% or less. Normalization of results relative to the expression of an internal standard also provides a means......A cell-based assay has been developed for the quantification of the activity of TNFa antagonists based on human erythroleukemic K562 cells transfected with a NF¿B regulated firefly luciferase reporter-gene construct. Both drug activity and anti-drug neutralizing antibodies can be quantified...... with a high degree of precision within 2h, and without interference from cytokines and other factors known to activate NF¿B. The assay cells also contain the Renilla luciferase reporter gene under the control of a constitutive promoter that allows TNFa-induced firefly luciferase activity to be normalized...

  15. Reporter gene assay for the quantification of the activity and neutralizing antibody response to TNFα antagonists

    DEFF Research Database (Denmark)

    Lallemand, Christophe; Kavrochorianou, Nadia; Steenholdt, Casper;

    2011-01-01

    relative to Renilla luciferase expression. Thus, results are independent of cell number or differences in cell viability, resulting in intra and inter assay coefficients of variation of 10% or less. Normalization of results relative to the expression of an internal standard also provides a means......A cell-based assay has been developed for the quantification of the activity of TNFα antagonists based on human erythroleukemic K562 cells transfected with a NFκB regulated firefly luciferase reporter-gene construct. Both drug activity and anti-drug neutralizing antibodies can be quantified...... with a high degree of precision within 2h, and without interference from cytokines and other factors known to activate NFκB. The assay cells also contain the Renilla luciferase reporter gene under the control of a constitutive promoter that allows TNFα-induced firefly luciferase activity to be normalized...

  16. Alpha adrenoceptor antagonists in the year 2000: is there anything new?

    Science.gov (United States)

    Chapple, C R

    2001-01-01

    Selective alpha1-adrenergic blockade is now a well accepted and widely used therapeutic treatment for patients presenting with symptomatic bladder outlet obstruction thought to be associated with benign prostatic hyperplasia. This review summarizes the recent developments in this field relating to the subject of receptor subtype selectivity and the potential relevance of this to clinical usefulness of existing drug therapy. Whilst a number of unanswered questions remain as to the exact mechanisms of both drug action and side-effect profile, nevertheless it is clear that existing clinically available alpha1-antagonists provide a safe, effective and generally well tolerated therapy for patients with lower urinary tract symptoms thought to be associated with benign prostatic obstruction. The implications of the ALLHAT study are discussed.

  17. Evaluation of growth hormone (GH) action in mice: discovery of GH receptor antagonists and clinical indications.

    Science.gov (United States)

    Kopchick, John J; List, Edward O; Kelder, Bruce; Gosney, Elahu S; Berryman, Darlene E

    2014-04-05

    The discovery of a growth hormone receptor antagonist (GHA) was initially established via expression of mutated GH genes in transgenic mice. Following this discovery, development of the compound resulted in a drug termed pegvisomant, which has been approved for use in patients with acromegaly. Pegvisomant treatment in a dose dependent manner results in normalization of IGF-1 levels in most patients. Thus, it is a very efficacious and safe drug. Since the GH/IGF-1 axis has been implicated in the progression of several types of cancers, many have suggested the use of pegvisomant as an anti-cancer therapeutic. In this manuscript, we will review the use of mouse strains that possess elevated or depressed levels of GH action for unraveling many of GH actions. Additionally, we will describe experiments in which the GHA was discovered, review results of pegvisomant's preclinical and clinical trials, and provide data suggesting pegvisomant's therapeutic value in selected types of cancer.

  18. Learned Avoidance in the Male Syrian Hamster: Investigating the Outcome of a Glucocorticoid Antagonist on Reconsolidation

    Directory of Open Access Journals (Sweden)

    Erik Haugsnes

    2015-02-01

    Full Text Available In this experiment, we used our Conflict Alleyway Apparatus and a glucocorticoid antagonist, mifepristone, to investigate the role of glucocorticoids in the reconsolidation of learned avoidance in defeated male Syrian hamsters. Subjects were tested for memory deficits 48 hours and 96 hours after the drug/vehicle was administered. It were hypothesized that mifepristone administration would produce memory deficits when the defeat memory had been reactivated, and that this deficit would be present 48 hours and 96 hours after the administration. Prolonged deficits that are dependent upon memory reactivation would suggest that glucocorticoids play a role in reconsolidation of learned avoidance. Our results indicated a strong evidence for learned avoidance after defeat; however, we did not find any significant drug effect.

  19. The α1 Antagonist Doxazosin Alters the Behavioral Effects of Cocaine in Rats

    Directory of Open Access Journals (Sweden)

    Colin N. Haile

    2012-11-01

    Full Text Available Medications that target norepinephrine (NE neurotransmission alter the behavioral effects of cocaine and may be beneficial for stimulant-use disorders. We showed previously that the short-acting, α1-adrenergic antagonist, prazosin, blocked drug-induced reinstatement of cocaine-seeking in rats and doxazosin (DOX, a longer-acting α1 antagonist blocked cocaine’s subjective effects in cocaine-dependent volunteers. To further characterize DOX as a possible pharmacotherapy for cocaine dependence, we assessed its impact on the development and expression of cocaine-induced locomotor sensitization in rats. Rats (n = 6–8 were administered saline, cocaine (COC, 10 mg/kg or DOX (0.3 or 1.0 mg/kg alone or in combination for 5 consecutive days (development. Following 10-days of drug withdrawal, all rats were administered COC and locomotor activity was again assessed (expression. COC increased locomotor activity across days indicative of sensitization. The high dose (1.0 mg/kg, but not the low dose (0.3 mg/kg of DOX significantly decreased the development and expression of COC sensitization. DOX alone did not differ from saline. These results are consistent with studies showing that α1 receptors are essential for the development and expression of cocaine’s behavioral effects. Results also suggest that blockade of both the development and expression of locomotor sensitization may be important characteristics of possible pharmacotherapies for cocaine dependence in humans.

  20. Transport of beta-blockers and calcium antagonists by diffusion in cat myocardium

    DEFF Research Database (Denmark)

    Haunsø, Stig; Sejrsen, Per; Svendsen, Jesper Hastrup

    1991-01-01

    Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion. In anesthet......Beta-blockers and calcium antagonists have been claimed to possess cardioprotective properties. This study addresses the question of whether a significant amount of these drugs will reach the cardiac myocytes during no-flow ischemia, where solute transport depends solely on diffusion....... In anesthetized cats the hearts were excised. Apparent diffusion coefficients in cat myocardium at 37 degrees C (D'37) for 14C-verapamil (protein bound), 3H-metoprolol (lipophilic), 3H-atenolol (hydrophilic), and 3H-propranolol (lipophilic and protein bound) were determined by means of a "true transient diffusion......" method and compared with the free diffusion coefficients in water (D37). D'37 of 14C-verapamil, 3H-metoprolol, 3H-atenolol, and 3H-propranolol (in cm2 s-1 10(5)) were (mean +/- SEM) 0.025 +/- 0.002, 0.055 +/- 0.003, 0.041 +/- 0.007, and 0.025 +/- 0.002, respectively. The mean diffusive progression...

  1. 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.

  2. Synthesis and evaluation of orally active small molecule HIV-1 Nef antagonists.

    Science.gov (United States)

    Emert-Sedlak, Lori A; Loughran, H Marie; Shi, Haibin; Kulp, John L; Shu, Sherry T; Zhao, Jielu; Day, Billy W; Wrobel, Jay E; Reitz, Allen B; Smithgall, Thomas E

    2016-03-01

    The HIV-1 Nef accessory factor enhances viral replication and promotes immune system evasion of HIV-infected cells, making it an attractive target for drug discovery. Recently we described a novel class of diphenylpyrazolodiazene compounds that bind directly to Nef in vitro and inhibit Nef-dependent HIV-1 infectivity and replication in cell culture. However, these first-generation Nef antagonists have several structural liabilities, including an azo linkage that led to poor oral bioavailability. The azo group was therefore replaced with either a one- or two-carbon linker. The resulting set of non-azo analogs retained nanomolar binding affinity for Nef by surface plasmon resonance, while inhibiting HIV-1 replication with micromolar potency in cell-based assays without cytotoxicity. Computational docking studies show that these non-azo analogs occupy the same predicted binding site within the HIV-1 Nef dimer interface as the original azo compound. Computational methods also identified a hot spot for inhibitor binding within this site that is defined by conserved HIV-1 Nef residues Asp108, Leu112, and Pro122. Pharmacokinetic evaluation of the non-azo B9 analogs in mice showed that replacement of the azo linkage dramatically enhanced oral bioavailability without substantially affecting plasma half-life or clearance. The improved oral bioavailability of non-azo diphenylpyrazolo Nef antagonists provides a starting point for further drug lead optimization in support of future efficacy testing in animal models of HIV/AIDS.

  3. Drug: D02738 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D02738 Drug Abarelix (USAN/INN); Plenaxis (TN) C72H95ClN14O14 1414.6841 1416.0631 D...L02 ENDOCRINE THERAPY L02B HORMONE ANTAGONISTS AND RELATED AGENTS L02BX Other hormone antagonists and related agents L02BX01 Abareli...x D02738 Abarelix (USAN/INN) Target-based classification ...in-releasing hormone (GnRH) receptor [HSA:2798] [KO:K04280] Abarelix [ATC:L02BX01] D02738 Abarelix (USAN/INN...gonists and related agents Abarelix [ATC:L02BX01] D02738 Abarelix (USAN/INN) CAS: 183552-38-7 PubChem: 17396

  4. Secondary prevention with calcium antagonists after acute myocardial infarction

    DEFF Research Database (Denmark)

    Hansen, J F

    1992-01-01

    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...

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

    Directory of Open Access Journals (Sweden)

    B. B. Gegenava

    2015-09-01

    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.

  6. Perampanel: A Selective AMPA Antagonist for Treating Seizures

    OpenAIRE

    Krauss, Gregory L.

    2013-01-01

    Perampanel is a selective, noncompetitive AMPA receptor antagonist that has recently been approved for treating localization-related epilepsy. This article reviews the pharmacology, clinical development, efficacy, and safety/tolerability of perampanel.

  7. 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...

  8. A network inference method for large-scale unsupervised identification of novel drug-drug interactions.

    Directory of Open Access Journals (Sweden)

    Roger Guimerà

    Full Text Available Characterizing interactions between drugs is important to avoid potentially harmful combinations, to reduce off-target effects of treatments and to fight antibiotic resistant pathogens, among others. Here we present a network inference algorithm to predict uncharacterized drug-drug interactions. Our algorithm takes, as its only input, sets of previously reported interactions, and does not require any pharmacological or biochemical information about the drugs, their targets or their mechanisms of action. Because the models we use are abstract, our approach can deal with adverse interactions, synergistic/antagonistic/suppressing interactions, or any other type of drug interaction. We show that our method is able to accurately predict interactions, both in exhaustive pairwise interaction data between small sets of drugs, and in large-scale databases. We also demonstrate that our algorithm can be used efficiently to discover interactions of new drugs as part of the drug discovery process.

  9. Characterization of a novel small molecule subtype specific estrogen-related receptor alpha antagonist in MCF-7 breast cancer cells.

    Directory of Open Access Journals (Sweden)

    Michael J Chisamore

    Full Text Available BACKGROUND: The orphan nuclear receptor estrogen-related receptor alpha (ERRalpha is a member of the nuclear receptor superfamily. It was identified through a search for genes encoding proteins related to estrogen receptor alpha (ERalpha. An endogenous ligand has not been found. Novel ERRalpha antagonists that are highly specific for binding to the ligand binding domain (LBD of ERRalpha have been recently reported. Research suggests that ERRalpha may be a novel drug target to treat breast cancer and/or metabolic disorders and this has led to an effort to characterize the mechanisms of action of N-[(2Z-3-(4,5-dihydro-1,3-thiazol-2-yl-1,3-thiazolidin-2-yl idene]-5H dibenzo[a,d][7]annulen-5-amine, a novel ERRalpha specific antagonist. METHODOLOGY/PRINCIPAL FINDINGS: We demonstrate this ERRalpha ligand inhibits ERRalpha transcriptional activity in MCF-7 cells by luciferase assay but does not affect mRNA levels measured by real-time RT-PCR. Also, ERalpha (ESR1 mRNA levels were not affected upon treatment with the ERRalpha antagonist, but other ERRalpha (ESRRA target genes such as pS2 (TFF1, osteopontin (SPP1, and aromatase (CYP19A1 mRNA levels decreased. In vitro, the ERRalpha antagonist prevents the constitutive interaction between ERRalpha and nuclear receptor coactivators. Furthermore, we use Western blots to demonstrate ERRalpha protein degradation via the ubiquitin proteasome pathway is increased by the ERRalpha-subtype specific antagonist. We demonstrate by chromatin immunoprecipitation (ChIP that the interaction between ACADM, ESRRA, and TFF1 endogenous gene promoters and ERRalpha protein is decreased when cells are treated with the ligand. Knocking-down ERRalpha (shRNA led to similar genomic effects seen when MCF-7 cells were treated with our ERRalpha antagonist. CONCLUSIONS/SIGNIFICANCE: We report the mechanism of action of a novel ERRalpha specific antagonist that inhibits transcriptional activity of ERRalpha, disrupts the constitutive

  10. Attenuation of pain behaviour by local administration of alpha-2 adrenoceptor antagonists to dorsal root ganglia in a rat radiculopathy model.

    Science.gov (United States)

    Ogon, I; Takebayashi, T; Miyakawa, T; Iwase, T; Tanimoto, K; Terashima, Y; Jimbo, S; Kobayashi, T; Tohse, N; Yamashita, T

    2016-05-01

    There were several reports suggesting α-adrenoceptor antagonists are effective to treat neuropathic pain. The aims of this study were as follows: (1) to introduce drug delivery system for dorsal root ganglion (DRG) neurons; (2) to elucidate the effects of α-adrenoceptor antagonists in acute, subacute or chronic phase and (3) to determine which subtype of adrenoceptor was mainly involved. We used 130 male Sprague-Dawley rats. After root constriction, rats received three local injections of α-adrenoceptor antagonists around DRG. We administered the non-selective α-adrenoceptor antagonist phentolamine for 3 consecutive days from day 0, 4 or 11 after the surgery, and the α1-adrenoceptor antagonist prazosin, the α1-adrenoceptor antagonist silodosin, the more preferred α1-adrenoceptor than prazosin and the α2-adrenoceptor antagonist yohimbine for 3 consecutive days from day 0 after the surgery. Phentolamine and yohimbine continually attenuated pain behaviour. Prazosin at high dose attenuated pain behaviour, however, prazosin at low dose did not attenuate pain behaviour every experimental day. Silodosin had no analgesic effect. Phentolamine injections from day 4 after surgery attenuated pain behaviour that had been established on the 3rd experimental day until the 28th post-operative day, although effect of phentolamine wore off. Phentolamine injections from day 11 after surgery temporarily attenuated pain behaviour that had been established on the 3rd, 7th and 10th experimental days. This study showed α-adrenoceptor antagonists could suppress pain behaviour via α2-adrenoceptor in acute phase and temporary attenuate pain behaviour in chronic phase. These findings presented potentials sympathetic nerve blockade contributed to treat neuropathic pain. © 2015 European Pain Federation - EFIC®

  11. Multiple Targeting Approaches on Histamine H3 Receptor Antagonists

    OpenAIRE

    Mohammad eKhanfar; Anna eAffini; Kiril eLutsenko; Katarina eNikolic; Stefania eButini; Holger eStark

    2016-01-01

    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...

  12. Deficiency of interleukin-1 receptor antagonist responsive to anakinra.

    Science.gov (United States)

    Schnellbacher, Charlotte; Ciocca, Giovanna; Menendez, Roxanna; Aksentijevich, Ivona; Goldbach-Mansky, Raphaela; Duarte, Ana M; Rivas-Chacon, Rafael

    2013-01-01

    We describe a 3-month-old infant who presented to our institution with interleukin (IL)-1 receptor antagonist deficiency (DIRA), which consists of neutrophilic pustular dermatosis, periostitis, aseptic multifocal osteomyelitis, and persistently high acute-phase reactants. Skin findings promptly improved upon initiation of treatment with anakinra (recombinant human IL-1 receptor antagonist), and the bony lesions and systemic inflammation resolved with continued therapy.

  13. Structure-activity relationships of benzothiazole GPR35 antagonists.

    Science.gov (United States)

    Abdalhameed, Manahil M; Zhao, Pingwei; Hurst, Dow P; Reggio, Patricia H; Abood, Mary E; Croatt, Mitchell P

    2017-02-01

    The first structure-activity relationships for a benzothiazole scaffold acting as an antagonist at GPR35 is presented. Analogues were designed based on a lead compound that was previously determined to have selective activity as a GPR35 antagonist. The synthetic route was modular in nature to independently explore the role of the middle and both ends of the scaffold. The activities of the analogues illustrate the importance of all three segments of the compound.

  14. 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....

  15. Effects of 2,3-benzodiazepine AMPA receptor antagonists on dopamine turnover in the striatum of rats with experimental parkinsonism.

    Science.gov (United States)

    Megyeri, Katalin; Marko, Bernadett; Sziray, Nora; Gacsalyi, Istvan; Juranyi, Zsolt; Levay, Gyorgy; Harsing, Laszlo G

    2007-03-15

    Although levodopa is the current "gold standard" for treatment of Parkinson's disease, there has been disputation on whether AMPA receptor antagonists can be used as adjuvant therapy to improve the effects of levodopa. Systemic administration of levodopa, the precursor of dopamine, increases brain dopamine turnover rate and this elevated turnover is believed to be essential for successful treatment of Parkinson's disease. However, long-term treatment of patients with levodopa often leads to development of dyskinesia. Therefore, drugs that feature potentiation of dopamine turnover rate and are able to reduce daily levodopa dosages might be used as adjuvant in the treatment of patients suffering from Parkinson's disease. To investigate such combined treatment, we have examined the effects of two non-competitive AMPA receptor antagonists, GYKI-52466 and GYKI-53405, alone or in combination with levodopa on dopamine turnover rate in 6-hydroxydopamine-lesioned striatum of the rat. We found here that repeated administration of levodopa, added with the peripheral DOPA decarboxylase inhibitor carbidopa, increased dopamine turnover rate after lesioning the striatum with 6-hydroxydopamine. Moreover, combination of levodopa with GYKI-52466 or GYKI-53405 further increased dopamine turnover enhanced by levodopa administration while the AMPA receptor antagonists by themselves failed to influence striatal dopamine turnover. We concluded from the present data that potentiation observed between levodopa and AMPA receptor antagonists may reflect levodopa-sparing effects in clinical treatment indicating the therapeutic potential of such combination in the management of Parkinson's disease.

  16. Effects of dopamine D1-like and D2-like antagonists on cocaine discrimination in muscarinic receptor knockout mice.

    Science.gov (United States)

    Thomsen, Morgane; Caine, Simon Barak

    2016-04-05

    Muscarinic and dopamine brain systems interact intimately, and muscarinic receptor ligands, like dopamine ligands, can modulate the reinforcing and discriminative stimulus (S(D)) effects of cocaine. To enlighten the dopamine/muscarinic interactions as they pertain to the S(D) effects of cocaine, we evaluated whether muscarinic M1, M2 or M4 receptors are necessary for dopamine D1 and/or D2 antagonist mediated modulation of the S(D) effects of cocaine. Knockout mice lacking M1, M2, or M4 receptors, as well as control wild-type mice and outbred Swiss-Webster mice, were trained to discriminate 10mg/kg cocaine from saline in a food-reinforced drug discrimination procedure. Effects of pretreatments with the dopamine D1 antagonist SCH 23390 and the dopamine D2 antagonist eticlopride were evaluated. In intact mice, both SCH 23390 and eticlopride attenuated the cocaine discriminative stimulus effect, as expected. SCH 23390 similarly attenuated the cocaine discriminative stimulus effect in M1 knockout mice, but not in mice lacking M2 or M4 receptors. The effects of eticlopride were comparable in each knockout strain. These findings demonstrate differences in the way that D1 and D2 antagonists modulate the S(D) effects of cocaine, D1 modulation being at least partially dependent upon activity at the inhibitory M2/M4 muscarinic subtypes, while D2 modulation appeared independent of these systems.

  17. Antiatherogenic properties of calcium antagonists. State of the art.

    Science.gov (United States)

    Weinstein, D B; Heider, J G

    1989-04-17

    Atherosclerosis is an arterial disease characterized by localized accumulation of collagen, elastin, lipids, and calcium at sites associated with macrophage infiltration and altered smooth muscle metabolism. Studies in several types of animal models, especially cholesterol-fed rabbits, have shown that calcium competitors, calcium chelators, anticalcifying agents, and calcium antagonists can reduce the accumulation of atherogenic lesion components and decrease the progression of lesions. Although there are some conflicting data in the animal model studies, it is now apparent that several classes of calcium antagonists inhibit the progression of early arterial lesions induced by cholesterol-feeding in animals. The dihydropyridine class of calcium antagonists may be more potent as anti-atherosclerotic agents than the other classes. Mechanisms involving regulation of endothelial cell, smooth muscle cell, and macrophage metabolism may be responsible for the effects of calcium antagonists on early lesion progression. Recent studies in cell culture-model systems suggest that calcium antagonists may significantly alter activities that regulate lipoprotein-derived cholesterol accumulation by arterial wall cells. Some of these activities are independent of calcium flux across voltage-operated calcium channels. Thus, calcium antagonists may reduce the progression of atherogenic lesions by a combination of decreasing calcium accumulation within arterial wall cells and by altering calcium channel-independent metabolic activities, which affect lesion development.

  18. Drug Facts

    Medline Plus

    Full Text Available ... and Nicotine Facts Other Drugs of Abuse What is Addiction? What are some signs and symptoms of ... to Drugs? Does Addiction Run in Families? Why Is It So Hard to Quit Drugs? Effects of ...

  19. Drug Reactions

    Science.gov (United States)

    ... problem is interactions, which may occur between Two drugs, such as aspirin and blood thinners Drugs and food, such as statins and grapefruit Drugs and supplements, such as ginkgo and blood thinners ...

  20. Drug Resistance

    Science.gov (United States)

    HIV Treatment Drug Resistance (Last updated 3/2/2017; last reviewed 3/2/2017) Key Points As HIV multiplies in the ... the risk of drug resistance. What is HIV drug resistance? Once a person becomes infected with HIV, ...

  1. Reduced expression of haloperidol conditioned catalepsy in rats by the dopamine D3 receptor antagonists nafadotride and NGB 2904.

    Science.gov (United States)

    Banasikowski, Tomek J; Beninger, Richard J

    2012-10-01

    Haloperidol, a dopamine (DA) D2 receptor-preferring antagonist, produces catalepsy whereby animals maintain awkward posture for a period of time. Sub-threshold doses of haloperidol fail to produce catalepsy initially, however, when the drug is given repeatedly in the same test environment, gradual day-to-day increases in catalepsy are observed. More importantly, if sensitized rats are injected with saline instead of haloperidol they continue to be cataleptic in the test environment suggesting that environment-drug associations may play a role. DA D3 receptors have been implicated in a number of conditioned behaviors. We were interested if DA D3 receptors contribute to catalepsy sensitization and conditioning in rats. We tested this hypothesis using the DA D3 receptor-selective antagonist NGB 2904 (0.5, 1.8 mg/kg) and the DA D3 receptor-preferring antagonist nafadotride (0.1, 0.5 mg/kg). For 10 consecutive conditioning days rats were treated with one of the D3 receptor antagonists alone or in combination with haloperidol (0.25 mg/kg) and tested for catalepsy, quantified by the time a rat remained with its forepaws on a horizontal bar. On test day (day 11), rats were injected with saline or the D3 receptor antagonist and tested for conditioned catalepsy in the previously drug-paired environment. Rats treated with NGB 2904 or nafadotride alone did not develop catalepsy. Rats treated with haloperidol or haloperidol plus NGB 2904 or nafadotride developed catalepsy sensitization with repeated conditioning. When injected with saline they continued to exhibit catalepsy in the test environment--now conditioned. On the other hand, NGB 2904 (1.8 mg/kg) or nafadotride (0.5 mg/kg) given on the test day (after sensitization to haloperidol) significantly attenuated the expression of conditioned catalepsy. Our data suggest that the D3 receptor antagonist NGB 2904 (1.8 mg/kg) and nafadotride (0.5 mg/kg) significantly attenuate conditioned catalepsy in rats when given in test but

  2. Pharmacological characterization of a dopamine transporter ligand that functions as a cocaine antagonist.

    Science.gov (United States)

    Desai, Rajeev I; Grandy, David K; Lupica, Carl R; Katz, Jonathan L

    2014-01-01

    that are deviate from its DAT occupancy and that some other mechanism, possibly σ-receptor antagonist activity, may contribute to the cocaine-antagonist effect of JHW007 and like drugs.

  3. Comparison of the effects of the M1-receptor antagonist telenzepine and the CCK-receptor antagonist loxiglumide on the pancreatic secretory response to intraduodenal tryptophan in dogs.

    Science.gov (United States)

    Teyssen, S; Niebergall-Roth, E; Rausch, A; Beglinger, C; Riepl, R L; Chari, S; Singer, M V

    1996-11-01

    In six conscious dogs with chronic gastric and pancreatic fistulas we compared the action of different doses (20.25 to 81.0 nmol/kg/h) of the muscarinic M1-receptor antagonist telenzepine, the cholecystokinin (CCK) antagonist loxiglumide (2.5 to 10.0 mg/kg/h) and several combinations of both drugs on the pancreatic secretory response to intraduodenal perfusion of graded loads of tryptophan (0.37-10.0 mmol/h) given against a background of secretin (20.5 pmol/kg/h i.v.). Except for 20.25 nmol/kg/h telenzepine, all tested doses of telenzepine and/or loxiglumide decreased the 180-min integrated bicarbonate response to tryptophan by 55 to 119%. Except of 20.25 nmol/kg/h telenzepine and/or 2.5 mg/kg/h loxiglumide, all tested doses of telezepine and/or loxiglumide inhibited the tryptophan stimulated integrated pancreatic protein responses by 54 to 88%. While telenzepine mainly inhibited the bicarbonate and protein response to the lower loads of tryptophan (0.37-1.1 mmol/h), loxiglumide decreased the response to all loads of tryptophan. The inhibition evoked by the combinations of telenzepine and loxiglumide was not significantly greater than that by single infusion of either drug. The CCK plasma levels basally and in response to tryptophan were not significantly altered by telenzepine and/or loxiglumide. These findings indicate that (1) both enteropancreatic cholinergic reflexes and the hormone CCK are mediators of the protein response to intraduodenal trytophan (2) enteropancreatic cholinergic reflexes are probably the dominant mediators of the response to low amounts of tryptophan, whereas CCK is the major mediator of the response to high loads of tryptophan, (3) the two mediators seem to act independently of each other, and (4) the release of CCK by intestinal trytophan is not influenced by telenzepine or loxiglumide.

  4. Selective Allosteric Antagonists for the G Protein-Coupled Receptor GPRC6A Based on the 2-Phenylindole Privileged Structure Scaffold

    DEFF Research Database (Denmark)

    Johansson, Henrik; Boesgaard, Michael Worch; Nørskov-Lauritsen, Lenea

    2015-01-01

    G protein-coupled receptors (GPCRs) represent a biological target class of fundamental importance in drug therapy. The GPRC6A receptor is a newly deorphanized class C GPCR that we recently reported for the first allosteric antagonists based on the 2-arylindole privileged structure scaffold (e.g., 1......-3). Herein, we present the first structure-activity relationship study for the 2-arylindole antagonist 3, comprising the design, synthesis, and pharmacological evaluation of a focused library of 3-substituted 2-arylindoles. In a FRET-based inositol monophosphate (IP1) assay we identified compounds 7, 13e...

  5. Dopamine antagonists and brief vision distinguish lens-induced- and form-deprivation-induced myopia.

    Science.gov (United States)

    Nickla, Debora L; Totonelly, Kristen

    2011-11-01

    In eyes wearing negative lenses, the D2 dopamine antagonist spiperone was only partly effective in preventing the ameliorative effects of brief periods of vision (Nickla et al., 2010), in contrast to reports from studies using form-deprivation. The present study was done to directly compare the effects of spiperone, and the D1 antagonist SCH-23390, on the two different myopiagenic paradigms. 12-day old chickens wore monocular diffusers (form-deprivation) or -10 D lenses attached to the feathers with matching rings of Velcro. Each day for 4 days, 10 μl intravitreal injections of the dopamine D2/D4 antagonist spiperone (5 nmoles) or the D1 antagonist SCH-23390, were given under isoflurane anesthesia, and the diffusers (n = 16; n = 5, respectively) or lenses (n = 20; n = 6) were removed for 2 h immediately after. Saline injections prior to vision were done as controls (form-deprivation: n = 11; lenses: n = 10). Two other saline-injected groups wore the lenses (n = 12) or diffusers (n = 4) continuously. Axial dimensions were measured by high frequency A-scan ultrasonography at the start, and on the last day immediately prior to, and 3 h after the injection. Refractive errors were measured at the end of the experiment using a Hartinger's refractometer. In form-deprived eyes, spiperone, but not SCH-23390, prevented the ocular growth inhibition normally effected by the brief periods of vision (change in vitreous chamber depth, spiperone vs saline: 322 vs 211 μm; p = 0.01). By contrast, neither had any effect on negative lens-wearing eyes given similar unrestricted vision (210 and 234 μm respectively, vs 264 μm). The increased elongation in the spiperone-injected form-deprived eyes did not, however, result in a myopic shift, probably due to the inhibitory effect of the drug on anterior chamber growth (drug vs saline: 96 vs 160 μm; p < 0.01). Finally, spiperone inhibited the vision-induced transient choroidal thickening in form-deprived eyes, while SCH-23390 did not

  6. Successful virtual screening for a submicromolar antagonist of the neurokinin-1 receptor based on a ligand-supported homology model.

    Science.gov (United States)

    Evers, Andreas; Klebe, Gerhard

    2004-10-21

    The neurokinin-1 (NK1) receptor belongs to the family of G-protein-coupled receptors (GPCRs), which represents one of the most relevant target families in small-molecule drug design. In this paper, we describe a homology modeling of the NK1 receptor based on the high-resolution X-ray structure of rhodopsin and the successful virtual screening based on this protein model. The NK1 receptor model has been generated using our new MOBILE (modeling binding sites including ligand information explicitly) approach. Starting with preliminary homology models, it generates improved models of the protein binding pocket together with bound ligands. Ligand information is used as an integral part in the homology modeling process. For the construction of the NK1 receptor, antagonist CP-96345 was used to restrain the modeling. The quality of the obtained model was validated by probing its ability to accommodate additional known NK1 antagonists from structurally diverse classes. On the basis of the generated model and on the analysis of known NK1 antagonists, a pharmacophore model was deduced, which subsequently guided the 2D and 3D database search with UNITY. As a following step, the remaining hits were docked into the modeled binding pocket of the NK1 receptor. Finally, seven compounds were selected for biochemical testing, from which one showed affinity in the submicromolar range. Our results suggest that ligand-supported homology models of GPCRs may be used as effective platforms for structure-based drug design.

  7. Effects of 7-day repeated treatment with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in male rhesus monkeys.

    Science.gov (United States)

    Banks, Matthew L

    2016-08-01

    Preclinical drug vs. food choice is an emerging group of drug self-administration procedures that have shown predictive validity to clinical drug addiction. Emerging data suggest that serotonin (5-HT)2A receptors modulate mesolimbic dopamine function, such that 5-HT2A antagonists blunt the abuse-related neurochemical effects of monoamine transporter substrates, such as amphetamine or methamphetamine. Whether subchronic 5-HT2A antagonist treatment attenuates methamphetamine reinforcement in any preclinical drug self-administration procedure is unknown. The study aim was therefore to determine 7-day treatment effects with the 5-HT2A inverse agonist/antagonist pimavanserin on methamphetamine vs. food choice in monkeys. Behavior was maintained under a concurrent schedule of food delivery (1g pellets, fixed-ratio 100 schedule) and intravenous methamphetamine injections (0-0.32 mg/kg/injection, fixed-ratio 10 schedule) in male rhesus monkeys (n=3). Methamphetamine choice dose-effect functions were determined daily before and during 7-day repeated pimavanserin (1.0-10mg/kg/day, intramuscular) treatment periods. Under control conditions, increasing methamphetamine doses resulted in a corresponding increase in methamphetamine vs. food choice. Repeated pimavanserin administration failed to attenuate methamphetamine choice and produce a reciprocal increase in food choice in any monkey up to doses (3.2-10mg/kg) that suppressed rates of operant responding primarily during components where behavior was maintained by food pellets. Repeated 5-HT2A receptor inverse agonist/antagonist treatment did not attenuate methamphetamine reinforcement under a concurrent schedule of intravenous methamphetamine and food presentation in nonhuman primates. Overall, these results do not support the therapeutic potential of 5-HT2A inverse agonists/antagonists as candidate medications for methamphetamine addiction. Copyright © 2016 The Author(s). Published by Elsevier Ireland Ltd.. All rights

  8. Ratiometric dosing of anticancer drug combinations: controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice.

    Science.gov (United States)

    Mayer, Lawrence D; Harasym, Troy O; Tardi, Paul G; Harasym, Natashia L; Shew, Clifford R; Johnstone, Sharon A; Ramsay, Euan C; Bally, Marcel B; Janoff, Andrew S

    2006-07-01

    Anticancer drug combinations can act synergistically or antagonistically against tumor cells in vitro depending on the ratios of the individual agents comprising the combination. The importance of drug ratios in vivo, however, has heretofore not been investigated, and combination chemotherapy treatment regimens continue to be developed based on the maximum tolerated dose of the individual agents. We systematically examined three different drug combinations representing a range of anticancer drug classes with distinct molecular mechanisms (irinotecan/floxuridine, cytarabine/daunorubicin, and cisplatin/daunorubicin) for drug ratio-dependent synergy. In each case, synergistic interactions were observed in vitro at certain drug/drug molar ratio ranges (1:1, 5:1, and 10:1, respectively), whereas other ratios were additive or antagonistic. We were able to maintain fixed drug ratios in plasma of mice for 24 hours after i.v. injection for all three combinations by controlling and overcoming the inherent dissimilar pharmacokinetics of individual drugs through encapsulation in liposomal carrier systems. The liposomes not only maintained drug ratios in the plasma after injection, but also delivered the formulated drug ratio directly to tumor tissue. In vivo maintenance of drug ratios shown to be synergistic in vitro provided increased efficacy in preclinical tumor models, whereas attenuated antitumor activity was observed when antagonistic drug ratios were maintained. Fixing synergistic drug ratios in pharmaceutical carriers provides an avenue by which anticancer drug combinations can be optimized prospectively for maximum therapeutic activity during preclinical development and differs from current practice in which dosing regimens are developed empirically in late-stage clinical trials based on tolerability.

  9. The incentive amplifying effects of nicotine are reduced by selective and non-selective dopamine antagonists in rats.

    Science.gov (United States)

    Palmatier, Matthew I; Kellicut, Marissa R; Brianna Sheppard, A; Brown, Russell W; Robinson, Donita L

    2014-11-01

    Nicotine is a psychomotor stimulant with 'reinforcement enhancing' effects--the actions of nicotine in the brain increase responding for non-nicotine rewards. We hypothesized that this latter effect of nicotine depends on increased incentive properties of anticipatory cues; consistent with this hypothesis, multiple laboratories have reported that nicotine increases sign tracking, i.e. approach to a conditioned stimulus (CS), in Pavlovian conditioned-approach tasks. Incentive motivation and sign tracking are mediated by mesolimbic dopamine (DA) transmission and nicotine facilitates mesolimbic DA release. Therefore, we hypothesized that the incentive-promoting effects of nicotine would be impaired by DA antagonists. To test this hypothesis, separate groups of rats were injected with nicotine (0.4mg/kg base) or saline prior to Pavlovian conditioning sessions in which a CS (30s illumination of a light or presentation of a lever) was immediately followed by a sweet reward delivered in an adjacent location. Both saline and nicotine pretreated rats exhibited similar levels of conditioned approach to the reward location (goal tracking), but nicotine pretreatment significantly increased approach to the CS (sign tracking), regardless of type (lever or light). The DAD1 antagonist SCH-23390 and the DAD2/3 antagonist eticlopride reduced conditioned approach in all rats, but specifically reduced goal tracking in the saline pretreated rats and sign tracking in the nicotine pretreated rats. The non-selective DA antagonist flupenthixol reduced sign-tracking in nicotine rats at all doses tested; however, only the highest dose of flupenthixol reduced goal tracking in both nicotine and saline groups. The reductions in conditioned approach behavior, especially those by SCH-23390, were dissociated from simple motor suppressant effects of the antagonists. These experiments are the first to investigate the effects of dopaminergic drugs on the facilitation of sign-tracking engendered by

  10. Idalopirdine - a small molecule antagonist of 5-HT6 with therapeutic potential against obesity.

    Science.gov (United States)

    Dudek, Magdalena; Marcinkowska, Monika; Bucki, Adam; Olczyk, Adrian; Kołaczkowski, Marcin

    2015-12-01

    5HT6 receptor antagonists offer the potential for safe and effective drugs against obesity, because they can reduce weight without causing serious side effects in the cardiovascular system. Also, their anorexic effect is associated with reduced food intake via an enhancement of satiety. In the present study we investigated the anorexic effect of idalopirdine (LuAE58054) in a model of obesity induced by high-fat diet. To induce obesity in rats, the animals were treated with feed with a fat content of 40 %. Body weight was controlled and the amount of food and water consumed was determined. The influence of the test compound on the lipid profile and glucose level was measured, as well as locomotor activity in home cages on the 20th day of the treatment. LuAE58054, at 5 mg kg(-1)/day i.p., was significantly anorectic in this model of obesity. Animals treated with LuAE58054 weighed 8 and 9.2 % less than the control obese animals on the 12th and 21st days, respectively. It significantly reduced food intake and the amount of peritoneal fat in animals, and reduced the level of triglycerides in plasma. LuAE58054 did not have a statistically significant effect on the spontaneous activity of diet-induced obese rats. The present study clearly demonstrates the effectiveness of LuAE58054 in reducing body weight. This compound is in phase III of clinical trials for the treatment of cognitive deficits associated with Alzheimer's disease and schizophrenia. It is a 5HT6 receptor antagonist and is, therefore, free of those unacceptable side effects that preclude chronic use of anti-obesity drugs with other mechanisms of action. The search for an effective and safe anti-obesity drug is essential for an increasingly obese population; therefore, the anorectic action of LuAE58054 is important and there is a need for more research in this direction.

  11. The alpha1-adrenergic antagonist prazosin improves sleep and nightmares in civilian trauma posttraumatic stress disorder.

    Science.gov (United States)

    Taylor, Fletcher; Raskind, Murray A

    2002-02-01

    Heightened noradrenergic reactivity may be a contributing factor in the pathophysiology of posttraumatic stress disorder (PTSD). Prazosin is an alpha1-adrenoceptor antagonist commonly used as an antihypertensive agent. Because alpha1-adrenergic activity has been associated with fear and startle responses, a drug that blocks central alpha1-adrenergic activity may be useful in the treatment of PTSD symptoms. An outpatient who had been exposed to civilian trauma and had subsequent chronic refractory PTSD was thus prescribed prazosin. The marked reduction in PTSD symptoms, particularly sleep and nightmares, prompted the following open-label feasibility trial. Five outpatients with non-combat-related PTSD were consecutively identified and received prazosin in a 6-week open-label trial. In each case, the prazosin doses were slowly increased until optimal benefit was achieved. Change was assessed with the Clinician-Administered PTSD Scale for DSM-IV, One Week Symptom Version (CAPS-SX), the Clinical Global Impression of Change Scale (CGIC), and the Clinical Impression of Change-Nightmares (CIC-Nightmares) score. All five patients experienced moderate to marked improvement on the CGIC. The CAPS-SX PTSD nightmare and sleep PTSD categories showed at least a four-point reduction of those symptoms. All patients reported at least moderate improvement on the CIC-Nightmare score. Optimal doses of prazosin ranged from 1 to 4 mg/day. The drug was reasonably tolerated, and there were no drug discontinuations. These preliminary findings provide a rationale for blind placebo-controlled efficacy trials of the alpha 1 antagonist prazosin for PTSD.

  12. Spectrophotometric determination of H 2-receptor antagonists via their oxidation with cerium(IV)

    Science.gov (United States)

    Darwish, Ibrahim A.; Hussein, Samiha A.; Mahmoud, Ashraf M.; Hassan, Ahmed I.

    2008-01-01

    A simple, accurate and sensitive spectrophotometric method has been developed and validated for determination of H 2-receptor antagonists: cimetidine, famotidine, nizatidine and ranitidine hydrochloride. The method was based on the oxidation of these drugs with cerium(IV) in presence of perchloric acid and subsequent measurement of the excess Ce(IV) by its reaction with p-dimethylaminobenzaldehyde to give a red colored product ( λmax at 464 nm). The decrease in the absorption intensity of the colored product (Δ A), due to the presence of the drug was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9990-0.9994) were found between Δ A values and the concentrations of the drugs in a concentration range of 1-20 μg ml -1. The assay limits of detection and quantitation were 0.18-0.60 and 0.54-1.53 μg ml -1, respectively. The method was validated, in terms of accuracy, precision, ruggedness and robustness; the results were satisfactory. The proposed method was successfully applied to the determination of the investigated drugs in pure and pharmaceutical dosage forms (recovery was 98.3-102.6 ± 0.57-1.90%) without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods.

  13. Spectrophotometric determination of H(2)-receptor antagonists via their oxidation with cerium(IV).

    Science.gov (United States)

    Darwish, Ibrahim A; Hussein, Samiha A; Mahmoud, Ashraf M; Hassan, Ahmed I

    2008-01-01

    A simple, accurate and sensitive spectrophotometric method has been developed and validated for determination of H(2)-receptor antagonists: cimetidine, famotidine, nizatidine and ranitidine hydrochloride. The method was based on the oxidation of these drugs with cerium(IV) in presence of perchloric acid and subsequent measurement of the excess Ce(IV) by its reaction with p-dimethylaminobenzaldehyde to give a red colored product (lambda(max) at 464nm). The decrease in the absorption intensity of the colored product (DeltaA), due to the presence of the drug was correlated with its concentration in the sample solution. Different variables affecting the reaction were carefully studied and optimized. Under the optimum conditions, linear relationships with good correlation coefficients (0.9990-0.9994) were found between DeltaA values and the concentrations of the drugs in a concentration range of 1-20microgml(-1). The assay limits of detection and quantitation were 0.18-0.60 and 0.54-1.53microgml(-1), respectively. The method was validated, in terms of accuracy, precision, ruggedness and robustness; the results were satisfactory. The proposed method was successfully applied to the determination of the investigated drugs in pure and pharmaceutical dosage forms (recovery was 98.3-102.6+/-0.57-1.90%) without interference from the common excipients. The results obtained by the proposed method were comparable with those obtained by the official methods.

  14. The cardiovascular effects of PFRFamide and PFR(Tic)amide, a possible agonist and antagonist of neuropeptide FF (NPFF).

    Science.gov (United States)

    Huang, E Y; Li, J Y; Tan, P P; Wong, C H; Chen, J C

    2000-02-01

    Neuropeptide FF (NPFF), an endogenous opioid-related neuromodulater, has been reported to show significant effects on the cardiovascular system, namely elevation of arterial blood pressure (BP) and heart rate (HR) in rats. In the present study, we synthesized two novel NPFF analogs, PFRFamide (putative NPFF agonist) and PFR(Tic)amide (putative NPFF antagonist), and examined their cardiovascular effect on BP and HR in anesthetized rats. The arterial mean BP and HR were measured by way of direct femoral artery catheterization. The data showed that PFRFamide increased BP in a dose-dependent manner, while PFR(Tic)amide decreased BP dose-dependently. These results revealed the possibility of PFRFamide and PFR(Tic)amide to be NPFF agonist and antagonist (or inverse agonist), respectively. These two NPFF analogs may possess potential in new drug design, and the NPFF system could be very important in mammalian cardiovascular function.

  15. The role of angiotensin converting enzyme inhibitors and angiotensin II receptor antagonists in the management of diabetic complications.

    Science.gov (United States)

    Podar, Toomas; Tuomilehto, Jaakko

    2002-01-01

    Evidence suggests that ACE inhibitors can be advantageous for prevention and halting progression of both micro- and macrovascular complications in patients with diabetes mellitus. ACE inhibitors are useful antihypertensive agents in both type 1 and type 2 diabetes; however, ACE inhibitor therapy often needs to be supplemented with calcium channel antagonists, beta-blockers or diuretics to achieve good blood pressure control. ACE inhibitors are also indicated in non-hypertensive patients with type 1 and type 2 diabetes who have micro- or macroalbuminuria. The effect of ACE inhibitors in halting the development and progression of retinopathy and, potentially, neuropathy needs further proof in large-scale studies. More recently, angiotensin II receptor antagonists are emerging as drugs with the potential to be successfully included in the management of diabetic complications, especially when ACE inhibitors are not suitable because of adverse effects.

  16. Structure of the Human Dopamine D3 Receptor in Complex with a D2/D3 Selective Antagonist

    Energy Technology Data Exchange (ETDEWEB)

    Chien, Ellen Y.T.; Liu, Wei; Zhao, Qiang; Katritch, Vsevolod; Han, Gye Won; Hanson, Michael A.; Shi, Lei; Newman, Amy Hauck; Javitch, Jonathan A.; Cherezov, Vadim; Stevens, Raymond C. (Cornell); (Scripps); (NIDA); (Columbia); (UCSD); (Receptos)

    2010-11-30

    Dopamine modulates movement, cognition, and emotion through activation of dopamine G protein-coupled receptors in the brain. The crystal structure of the human dopamine D3 receptor (D3R) in complex with the small molecule D2R/D3R-specific antagonist eticlopride reveals important features of the ligand binding pocket and extracellular loops. On the intracellular side of the receptor, a locked conformation of the ionic lock and two distinctly different conformations of intracellular loop 2 are observed. Docking of R-22, a D3R-selective antagonist, reveals an extracellular extension of the eticlopride binding site that comprises a second binding pocket for the aryl amide of R-22, which differs between the highly homologous D2R and D3R. This difference provides direction to the design of D3R-selective agents for treating drug abuse and other neuropsychiatric indications.

  17. Blocking of the PD-1/PD-L1 Interaction by a D-Peptide Antagonist for Cancer Immunotherapy.

    Science.gov (United States)

    Chang, Hao-Nan; Liu, Bei-Yuan; Qi, Yun-Kun; Zhou, Yang; Chen, Yan-Ping; Pan, Kai-Mai; Li, Wen-Wen; Zhou, Xiu-Man; Ma, Wei-Wei; Fu, Cai-Yun; Qi, Yuan-Ming; Liu, Lei; Gao, Yan-Feng

    2015-09-28

    Blockade of the protein-protein interaction between the transmembrane protein programmed cell death protein 1 (PD-1) and its ligand PD-L1 has emerged as a promising immunotherapy for treating cancers. Using the technology of mirror-image phage display, we developed the first hydrolysis-resistant D-peptide antagonists to target the PD-1/PD-L1 pathway. The optimized compound (D) PPA-1 could bind PD-L1 at an affinity of 0.51 μM in vitro. A blockade assay at the cellular level and tumor-bearing mice experiments indicated that (D) PPA-1 could also effectively disrupt the PD-1/PD-L1 interaction in vivo. Thus D-peptide antagonists may provide novel low-molecular-weight drug candidates for cancer immunotherapy.

  18. A pharmacophore model for dopamine D4 receptor antagonists

    Science.gov (United States)

    Boström, Jonas; Gundertofte, Klaus; Liljefors, Tommy

    2000-11-01

    A pharmacophore model for dopamine D4 antagonists has been developed on the basis of a previously reported dopamine D2 model. By using exhaustive conformational analyses (MM3* force field and the GB/SA hydration model) and least-squares molecular superimposition studies, a set of eighteen structurally diverse high affinity D4 antagonists have successfully been accommodated in the D4 pharmacophore model. Enantioselectivities may be rationalized by conformational energies required for the enantiomers to adopt their proposed bioactive conformations. The pharmacophore models for antagonists at the D4 and D2 receptor subtypes have been compared in order to get insight into molecular properties of importance for D2/D4 receptor selectivity. It is concluded that the bioactive conformations of antagonists at the two receptor subtypes are essentially identical. Receptor essential volumes previously identified for the D2 receptor are shown to be present also in the D4 receptor. In addition, a novel receptor essential volume in the D4 receptor, not present in the D2 receptor, has been identified. This feature may be exploited for the design of D4 selective antagonists. However, it is concluded that the major determinant for D2/D4 selectivity is the nature of the interactions between the receptor and aromatic ring systems. The effects of the electronic properties of these ring systems on the affinities for the two receptor subtypes differ substantially.

  19. Design and synthesis of novel 3-substituted-indole derivatives as selective H3 receptor antagonists and potent free radical scavengers.

    Science.gov (United States)

    Tang, Li; Zhao, Liying; Hong, Lingjuan; Yang, Fenyan; Sheng, Rong; Chen, Jianzhong; Shi, Ying; Zhou, Naimin; Hu, Yongzhou

    2013-10-01

    A series of novel 3-substituted-indole derivatives with a benzyl tertiary amino moiety were designed, synthesized and evaluated as H3 receptor antagonists and free radical scavengers for Alzheimer's disease therapy. Most of these synthesized compounds exhibited moderate to potent antagonistic activities in CREs driven luciferase assay. In particular, compound 2d demonstrated the most favorable H3 receptor antagonistic activity with the IC50 value of 0.049μM. Besides, it also displayed high binding affinity to H3 receptor (Ki=4.26±2.55nM) and high selectivity over other three histamine receptors. Moreover, 2d and other two 3-substituted indole derivatives 1d and 3d exerted potent ABTS radical cation scavenging capacities similar to melatonin. Above results illustrate that 2d is an interesting lead for extensive optimization to explore new drug candidate for AD therapy.

  20. HPLC method development, validation and its application to investigate in vitro effect of pioglitazone on the availability of H1 receptor antagonists

    Directory of Open Access Journals (Sweden)

    Agha Zeeshan Mirza

    2017-02-01

    Full Text Available The method has been developed and validated for the simultaneous determination of pioglitazone and H1-receptor antagonists (fexofenadine, cetirizine and levocetirizine in formulations and human serum. Utilizing HPLC techniques, an assay was designed to determine the in vitro effects of pioglitazone on H1-receptor antagonists. Obtained results were verified using the UV spectrophotometric technique. First-derivative values versus concentrations were used to plot calibration curves of these drugs and were found to similar with the HPLC data. The availability of pioglitazone remained unchanged in absence or presence of fexofenadine, cetirizine and levocetirizine. This in vitro analysis confirms the harmless co-administration of pioglitazone and H1-receptor antagonists, and can serve as the foundation for designing further in vivo studies.

  1. Drug: D02347 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available odine and IP3 receptors Ryanodine receptor (RYR) ryanodine receptor (RYR1) [HSA:6261] [KO:K...skeletal muscle] Same as: C06939 ATC code: M03CA01 ryanodine receptor antagonist [HSA:6261 6262 6263] [KO:K0...e D02347 Dantrolene (USAN/INN) Target-based classification of drugs [BR:br08310] Ion channels Ryan...04961] Dantrolene [ATC:M03CA01] D02347 Dantrolene (USAN/INN) ryanodine receptor (RYR2) [HSA:6262] [KO:K04962...] Dantrolene [ATC:M03CA01] D02347 Dantrolene (USAN/INN) ryanodine receptor (RYR3)

  2. Drug: D05004 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05004 Drug Metiamide (USAN/INN) C9H16N4S2 244.0816 244.3801 D05004.gif Antagonist ...] [KO:K04150] Metiamide D05004 Metiamide (USAN/INN) CAS: 34839-70-8 PubChem: 17398245 LigandBox: D05004 NIKK...AJI: J19.552I ATOM 15 1 C8y C 28.3107 -17.0626 2 C8y C 26.9898 -17.5319 3 N5x N 28.2672 -15.6500

  3. Drug: D10119 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D10119 Drug Erismodegib (USAN); Sonidegib (INN) C26H26F3N3O3 485.1926 485.4982 D10119.gif Oncology smoothened (SMO) antagonist [HSA:6608] [KO:K06226] hsa04340(6608) Hedgehog signaling pathway...eptors Others Wnt signaling SMO [HSA:6608] [KO:K06226] Erismodegib D10119 Erismod...egib (USAN) CAS: 956697-53-3 PubChem: 135626837 LigandBox: D10119 ATOM 35 1 O2x O 14.2100 -20.3000 2 C1y C 1

  4. Drug: D08216 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08216 Drug Mianserin (INN); Tolvon (TN) C18H20N2 264.1626 264.3648 D08216.gif Antidepress...ant, tetracyclic ATC code: N06AX03 tetracyclic antidepressants 5-HT1-receptor antagonist [HSA:3350 33...2 [HSA:1544], CYP2C19 [HSA:1557], CYP2D6 [HSA:1565] map07027 Antidepressants Anatomical Therapeutic Chemical...IDEPRESSANTS N06AX Other antidepressants N06AX03 Mianserin D08216 Mianserin (INN) Target-based classificatio

  5. Drug: D00644 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00644 Drug Esmolol hydrochloride (JAN/USAN); Brevibloc (TN) C16H25NO4. HCl 331.155... 331.8349 D00644.gif Anti-adrenergic [beta-receptor] Therapeutic category: 2123 ATC code: C07AB09 beta1-adre...active ligand-receptor interaction hsa04261(153) Adrenergic signaling in cardiomy...ocytes hsa04970(153) Salivary secretion map07214 beta-Adrenergic receptor agonists/antagonists Therapeutic category of dr...iarrhythmic agents 2123 Beta blockers D00644 Esmolol hydrochloride (JAN/USAN) Ana

  6. Enhanced in vivo absorption of CB-1 antagonist in rats via solid solutions prepared by hot-melt extrusion.

    Science.gov (United States)

    Ranzani, L S; Font, J; Galimany, F; Santanach, A; Gomez-Gomar, A M; Casadevall, G; Gryczke, A

    2011-06-01

    The aim of the present work was to investigate in vitro dissolution properties of three binary solid solutions prepared by a hot-melt extrusion (HME) process with vinyl pirrolidone--vinyl acetate copolymer (Kollidon VA 64), ethyl acrylate, methyl methacrylate polymer (Eudragit E) polyetilenglicol 8000 (PEG 8000) with a cannabinoid type 1 (CB-1) antagonist. Hansen solubility parameters were calculated from the chemical structures of the drug and the individual polymers in order to predict miscibility. Solid state characterizations of drug substance, physical blends and HME formulations were performed with differential scanning calorimetry. The dissolution testing conducted under sink conditions revealed that the dissolution rate of HME formulations improved around 1.8-fold vs drug substance. Supersaturation dissolution study demonstrated that HME formulations composed by Eudragit E and Kollidon VA64 increased drug solubility between 30- and 35-fold, respectively comparing to the drug substance. Physical and chemical stability of formulations were studied at 40°C/75%HR with open dish during 15 days. The formulation composed by the drug and Eudragit E at 10:90 was evaluated for in vivo drug absorption in male Wistar-Hannover rats and it was found to increase CB-1 absorption threefold greater than pure drug oral suspension.

  7. The neurokinin 1 receptor antagonist, ezlopitant, reduces appetitive responding for sucrose and ethanol.

    Directory of Open Access Journals (Sweden)

    Pia Steensland

    Full Text Available BACKGROUND: The current obesity epidemic is thought to be partly driven by over-consumption of sugar-sweetened diets and soft drinks. Loss-of-control over eating and addiction to drugs of abuse share overlapping brain mechanisms including changes in motivational drive, such that stimuli that are often no longer 'liked' are still intensely 'wanted' [7], . The neurokinin 1 (NK1 receptor system has been implicated in both learned appetitive behaviors and addiction to alcohol and opioids; however, its role in natural reward seeking remains unknown. METHODOLOGY/PRINCIPAL FINDINGS: We sought to determine whether the NK1-receptor system plays a role in the reinforcing properties of sucrose using a novel selective and clinically safe NK1-receptor antagonist, ezlopitant (CJ-11,974, in three animal models of sucrose consumption and seeking. Furthermore, we compared the effect of ezlopitant on ethanol consumption and seeking in rodents. The NK1-receptor antagonist, ezlopitant decreased appetitive responding for sucrose more potently than for ethanol using an operant self-administration protocol without affecting general locomotor activity. To further evaluate the selectivity of the NK1-receptor antagonist in decreasing consumption of sweetened solutions, we compared the effects of ezlopitant on water, saccharin-, and sodium chloride (NaCl solution consumption. Ezlopitant decreased intake of saccharin but had no effect on water or salty solution consumption. CONCLUSIONS/SIGNIFICANCE: The present study indicates that the NK1-receptor may be a part of a common pathway regulating the self-administration, motivational and reinforcing aspects of sweetened solutions, regardless of caloric value, and those of substances of abuse. Additionally, these results indicate that the NK1-receptor system may serve as a therapeutic target for obesity induced by over-consumption of natural reinforcers.

  8. Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure.

    Science.gov (United States)

    Moore, Tera D; Nawarskas, James J; Anderson, Joe R

    2003-01-01

    Aldosterone has been implicated for many years as an important substance in the pathogenesis of heart disease. Elevated aldosterone concentrations have been documented in patients with hypertension and heart failure, leading to the use of aldosterone antagonists for the treatment of these conditions. Spironolactone has been used for nearly 2 decades for the treatment of hypertension, and more recently, has become a standard agent for the treatment of systolic heart failure. Spironolactone, however, is a nonselective antagonist of the aldosterone receptor, binding also to other steroid receptors and causing a significant percentage of patients to have sex hormone-related adverse effects such as gynecomastia. Eplerenone is the first of a new class of drugs known as selective aldosterone receptor antagonists, which selectively block the aldosterone receptor with minimal effect at other steroid receptors, thereby minimizing many of the hormonal side effects seen with spironolactone. Eplerenone has been shown to be beneficial both as monotherapy and combination therapy for lowering elevated blood pressure in patients with hypertension. The antihypertensive efficacy of eplerenone is roughly similar to that of other antihypertensive agents, although in 1 study black patients responded better with eplerenone than losartan. In addition, eplerenone has demonstrated some renoprotective effects in diabetic patients with hypertension. Recently, eplerenone was shown to significantly reduce mortality and cardiovascular morbidity in post-myocardial infarction patients with systolic heart failure currently taking standard heart failure medications. Eplerenone is generally well tolerated, although hyperkalemia with this agent is of some concern. Eplerenone is metabolized by CYP3A4 and administration with potent inhibitors of this enzyme is contraindicated because of the risk of hyperkalemia. In summary, eplerenone has proven to be beneficial in treating hypertension and post

  9. Effects of dopamine D1 and D2 receptor antagonists on laryngeal neurophysiology in the rat.

    Science.gov (United States)

    Feng, Xin; Henriquez, Victor M; Walters, Judith R; Ludlow, Christy L

    2009-08-01

    Hypophonia is an early symptom in Parkinson's disease (PD) that involves an increase in laryngeal muscle activity, interfering with voice production. Our aim was to use an animal model to better understand the role of different dopamine receptor subtypes in the control of laryngeal neurophysiology. First, we evaluated the combined effects of SCH23390-a D(1) receptor antagonist with a D(2) receptor antagonist (eticlopride) on laryngeal neurophysiology, and then tested the separate effects of selective receptor antagonists. Thyroarytenoid (TA) and gastrocnemius (GN) muscle activity was measured at rest and while stimulating the internal branch of superior laryngeal nerve to elicit the laryngeal adductor response (LAR) in alpha-chloralose-anesthetized rats. Paired stimuli at different interstimulus intervals between 250 and 5,000 ms measured central conditioning of the LAR. Changes in resting muscle activity, response latency, amplitude, and LAR conditioning after each drug were compared with the saline control. SCH23390 alone increased the resting TA muscle activity (P < 0.05). With the combined SCH23390 + eticlopride or SCH23390 alone, response latency decreased (P < 0.01), amplitude increased (P < 0.01), and the test LAR was reduced at 2,000-ms ISI (P < 0.01). No LAR changes occurred when eticlopride was administered alone at a low dose and only a tendency to suppress responses was found at a high dose. No changes in GN muscle activity occurred in any of the groups. The results suggest that a loss of stimulation of D(1) receptors plays a significant role in laryngeal pathophysiology in PD.

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

    Directory of Open Access Journals (Sweden)

    Lixin Wang

    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.

  11. Novel class of medications, orexin receptor antagonists, in the treatment of insomnia - critical appraisal of suvorexant.

    Science.gov (United States)

    Norman, Jessica L; Anderson, Sarah L

    2016-01-01

    Insomnia, a highly prevalent disorder, can be detrimental to patients' overall health and worsen existing comorbidities. Patients may have acute episodes of insomnia related to a traumatic event, but more commonly insomnia occurs chronically. While proper sleep hygiene and behavioral therapy play important roles in the nonpharmacologic management of short-term and chronic insomnia, medications may also be required. Historically, insomnia has been treated with agents such as benzodiazepines, nonbenzodiazepine receptor agonists, and melatonin agonists. Dual orexin receptor antagonists represent a new class of medications for the treatment of insomnia, which block the binding of wakefulness-promoting neuropeptides orexin A and orexin B to their respective receptor sites. Suvorexant (Belsomra) is the first dual orexin receptor antagonist to be approved in the US and Japan and has demonstrated efficacy in decreasing time to sleep onset and increasing total sleep time. Its unique mechanism of action, data to support efficacy and safety over 12 months of use, and relative lack of withdrawal effects when discontinued may represent an alternative for patients with chronic insomnia who cannot tolerate or do not receive benefit from more traditional sleep agents. Suvorexant is effective and well tolerated, but precautions exist for certain patient populations, including females, obese patients, and those with respiratory disease. Suvorexant has only been studied vs placebo, and hence it is unknown how it directly compares with other medications approved by the US Food and Drug Administration for insomnia. Suvorexant is not likely to replace benzodiazepines or nonbenzodiazepine receptor antagonists as a first-line sleep agent but does represent a novel option for the treatment of patients with chronic insomnia.

  12. Effect of dopamine and serotonin receptor antagonists on fencamfamine-induced abolition of latent inhibition.

    Science.gov (United States)

    de Aguiar, Cilene Rejane Ramos Alves; de Aguiar, Marlison José Lima; DeLucia, Roberto; Silva, Maria Teresa Araujo

    2013-01-05

    The purpose of this investigation was to verify the role of dopamine and serotonin receptors in the effect of fencamfamine (FCF) on latent inhibition. FCF is a psychomotor stimulant with an indirect dopaminergic action. Latent inhibition is a model of attention. Latent inhibition is blocked by dopaminergic agents and facilitated by dopamine receptor agonists. FCF has been shown to abolish latent inhibition. The serotonergic system may also participate in the neurochemical mediation of latent inhibition. The selective dopamine D(1) receptor antagonist SCH 23390 (7-chloro-3-methyl-1-phenyl-1,2,4,5-tetrahydro-3-benzazepin-8-ol), D(2) receptor antagonists pimozide (PIM) and methoclopramide (METH), and serotonin 5-HT(2A/C) receptor antagonist ritanserin (RIT) were used in the present study. Latent inhibition was evaluated using a conditioned emotional response procedure. Male Wistar rats that were water-restricted were subjected to a three-phase procedure: preexposure to a tone, tone-shock conditioning, and a test of the effect of the tone on licking frequency. All of the drugs were administered before the preexposure and conditioning phases. The results showed that FCF abolished latent inhibition, and this effect was clearly antagonized by PIM and METH and moderately attenuated by SCH 23390. At the doses used in the present study, RIT pretreatment did not affect latent inhibition and did not eliminate the effect of FCF, suggesting that the FCF-induced abolition of latent inhibition is not mediated by serotonin 5-HT(2A/C) receptors. These results suggest that the effect of FCF on latent inhibition is predominantly related to dopamine D(2) receptors and that dopamine D(2) receptors participate in attention processes.

  13. The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function.

    Directory of Open Access Journals (Sweden)

    Olivia A Lin

    Full Text Available There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin-enhanced ADP-induced phosphatidylserine (PS exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and

  14. Neuroprotective Effects of Glutamate Antagonists and Extracellular Acidity

    Science.gov (United States)

    Kaku, David A.; Giffard, Rona G.; Choi, Dennis W.

    1993-06-01

    Glutamate antagonists protect neurons from hypoxic injury both in vivo and in vitro, but in vitro studies have not been done under the acidic conditions typical of hypoxia-ischemia in vivo. Consistent with glutamate receptor antagonism, extracellular acidity reduced neuronal death in murine cortical cultures that were deprived of oxygen and glucose. Under these acid conditions, N-methyl-D-aspartate and α-amino-3-hydroxy-5-methyl-4-isox-azolepropionate-kainate antagonists further reduced neuronal death, such that some neurons tolerated prolonged oxygen and glucose deprivation almost as well as did astrocytes. Neuroprotection induced by this combination exceeded that induced by glutamate antagonists alone, suggesting that extracellular acidity has beneficial effects beyond the attenuation of ionotropic glutamate receptor activation.

  15. Discovery of the improved antagonistic prolactin variants by library screening.

    Science.gov (United States)

    Liu, Yun; Gong, Wei; Breinholt, Jens; Nørskov-Lauritsen, Leif; Zhang, Jinchao; Ma, Qinhong; Chen, Jianhe; Panina, Svetlana; Guo, Wei; Li, Tengkun; Zhang, Jingyuan; Kong, Meng; Liu, Zibing; Mao, Jingjing; Christensen, Leif; Hu, Sean; Wang, Lingyun

    2011-11-01

    Prolactin (PRL), a potent growth stimulator of the mammary epithelium, has been suggested to be a factor contributing to the development and progression of breast and prostate cancer. Several PRL receptor (PRLR) antagonists have been identified in the past decades, but their in vivo growth inhibitory potency was restricted by low receptor affinity, rendering them pharmacologically unattractive for clinical treatment. Thus, higher receptor affinity is essential for the development of improved PRLR antagonistic variants with improved in vivo potency. In this study, we generated Site 1 focused protein libraries of human G129R-PRL mutants and screened for those with increased affinity to the human PRLR. By combining the mutations with enhanced affinities for PRLR, we identified a novel G129R-PRL variant with mutations at Site 1 that render nearly 50-fold increase in the antagonistic potency in vitro.

  16. 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.

  17. 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.

  18. The Apolipoprotein E Antagonistic Pleiotropy Hypothesis: Review and Recommendations

    Directory of Open Access Journals (Sweden)

    Elizabeth R. Tuminello

    2011-01-01

    Full Text Available Research on apolipoprotein E (APOE has consistently revealed a relationship between the gene's ε4 allele and risk for development of Alzheimer's disease (AD. However, research with younger populations of ε4 carriers has suggested that the APOE ε4 allele may in fact be beneficial in earlier ages and may only confer risk of cognitive decline later in life. Accordingly, we and others have proposed that APOE may represent an example of antagonistic pleiotropy. Antagonistic pleiotropy is an evolutionary biology concept that proposes certain genes or alleles that may differentially impact fitness during different life stages. We critically review this hypothesis in light of new research of the impact of APOE on cognition and neural integrity across the lifespan. We provide recommendations for the revision of the antagonistic pleiotropy hypothesis of APOE and suggest important avenues for future research in this area.

  19. 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.

  20. Development and characterization of high affinity leptins and leptin antagonists.

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-02-11

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin.

  1. Development and Characterization of High Affinity Leptins and Leptin Antagonists*

    Science.gov (United States)

    Shpilman, Michal; Niv-Spector, Leonora; Katz, Meirav; Varol, Chen; Solomon, Gili; Ayalon-Soffer, Michal; Boder, Eric; Halpern, Zamir; Elinav, Eran; Gertler, Arieh

    2011-01-01

    Leptin is a pleiotropic hormone acting both centrally and peripherally. It participates in a variety of biological processes, including energy metabolism, reproduction, and modulation of the immune response. So far, structural elements affecting leptin binding to its receptor remain unknown. We employed random mutagenesis of leptin, followed by selection of high affinity mutants by yeast surface display and discovered that replacing residue Asp-23 with a non-negatively charged amino acid leads to dramatically enhanced affinity of leptin for its soluble receptor. Rational mutagenesis of Asp-23 revealed the D23L substitution to be most effective. Coupling the Asp-23 mutation with alanine mutagenesis of three amino acids (L39A/D40A/F41A) previously reported to convert leptin into antagonist resulted in potent antagonistic activity. These novel superactive mouse and human leptin antagonists (D23L/L39A/D40A/F41A), termed SMLA and SHLA, respectively, exhibited over 60-fold increased binding to leptin receptor and 14-fold higher antagonistic activity in vitro relative to the L39A/D40A/F41A mutants. To prolong and enhance in vivo activity, SMLA and SHLA were monopegylated mainly at the N terminus. Administration of the pegylated SMLA to mice resulted in a remarkably rapid, significant, and reversible 27-fold more potent increase in body weight (as compared with pegylated mouse leptin antagonist), because of increased food consumption. Thus, recognition and mutagenesis of Asp-23 enabled construction of novel compounds that induce potent and reversible central and peripheral leptin deficiency. In addition to enhancing our understanding of leptin interactions with its receptor, these antagonists enable in vivo study of the role of leptin in metabolic and immune processes and hold potential for future therapeutic use in disease pathologies involving leptin. PMID:21119198

  2. [Discovering L-type calcium channels inhibitors of antihypertensive drugs based on drug repositioning].

    Science.gov (United States)

    Liang, Ying-xi; He, Yu-su; Jiang, Lu-di; Yue, Qiao-xin; Cui, Shuai; Bin, Li; Ye, Xiao-tong; Zhang, Xiao-hua; Zhang, Yang-ling

    2015-09-01

    This study was amid to construct the pharmacophore model of L-type calcium channel antagonist in the application of screening Drugbank and TCMD. This paper repositions the approved drugs resulting from virtual screening and discusses the relocation-based drug discovery methods, screening antihypertensive drugs with L-type calcium channel function from TCMD. Qualitative hypotheses wre generated by HipHop separately on the basis of 12 compounds with antagonistic action on L-type calcium channel expressed in rabbit cardiac muscle. Datebase searching method was used to evaluate the generated hypotheses. The optimum hypothesis was used to search Drugbank and TCMD. This paper repositions the approved drugs and evaluates the antihypertensive effect of the chemical constituent of traditional Chinese medicine resulting from virtual screening by the matching score and literature. The results showed that optimum qualitative hypothesis is with six features, which were two hydrogen-bond acceptors, four hydrophobic groups, and the CAI value of 2.78. Screening Drugbank achieves 93 approved drugs. Screening TCMD achieves 285 chemical constituents of traditional Chinese medicine. It was concluded that the hypothesis is reliable and can be used to screen datebase. The approved drugs resulting from virtual screening, such as pravastatin, are potentially L-type calcium channels inhibitors. The chemical constituents of traditional Chinese medicine, such as Arctigenin III and Arctigenin are potentially antihypertensive drugs. It indicates that Drug Repositioning based on hypothesis is possible.

  3. Antagonistic Effects of Sodium Butyrate and N-(4-Hydroxyphenyl-retinamide on Prostate Cancer

    Directory of Open Access Journals (Sweden)

    Rainer Kuefer

    2007-03-01

    Full Text Available Butyrates and retinoids are promising antineoplastic agents. Here we analyzed effects of sodium butyrate and N-(4-hydroxyphenyl-retinamide (4-HPR on prostate cancer cells as monotherapy or in combination in vitro and in vivo. Sodium butyrate and 4-HPR induced concentration-dependent growth inhibition in prostate cancer cells in vitro. The isobologram analysis revealed that sodium butyrate and 4-HPR administered together antagonize effects of each other. For the in vivo studies, a water-soluble complex (4-HPR with a cyclodextrin was created. A single dose of sodium butyrate and 4-HPR showed a peak level in chicken plasma within 30 minutes. Both compounds induced inhibition of proliferation and apoptosis in xenografts of the chicken chorioallantoic membrane. Analysis of the cytotoxic effects of the drugs used in combination demonstrated an antagonistic effect on inhibition of proliferation and on induction of apoptosis. Prolonged jun N-terminal kinase phosphorylation induced by sodium butyrate and 4-HPR was strongly attenuated when both compounds were used in combination. Both compounds induced inhibition of NF-κ,B. This effect was strongly antagonized in LNCaP cells when the compounds were used in combination. These results indicate that combinational therapies have to be carefully investigated due to potential antagonistic effects in the clinical setting despite promising results of a monotherapy.

  4. Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy

    Directory of Open Access Journals (Sweden)

    Marcin P Komorowski

    2016-01-01

    Full Text Available Ovarian cancer remains the most lethal gynecologic malignancy owing to late detection, intrinsic and acquired chemoresistance, and remarkable heterogeneity. Here, we explored approaches to inhibit metastatic growth of murine and human ovarian tumor variants resistant to paclitaxel and carboplatin by oncolytic vaccinia virus expressing a CXCR4 antagonist to target the CXCL12 chemokine/CXCR4 receptor signaling axis alone or in combination with doxorubicin. The resistant variants exhibited augmented expression of the hyaluronan receptor CD44 and CXCR4 along with elevated Akt and ERK1/2 activation and displayed an increased susceptibility to viral infection compared with the parental counterparts. The infected cultures were more sensitive to doxorubicin-mediated killing both in vitro and in tumor-challenged mice. Mechanistically, the combination treatment increased apoptosis and phagocytosis of tumor material by dendritic cells associated with induction of antitumor immunity. Targeting syngeneic tumors with this regimen increased intratumoral infiltration of antitumor CD8+ T cells. This was further enhanced by reducing the immunosuppressive network by the virally-delivered CXCR4 antagonist, which augmented antitumor immune responses and led to tumor-free survival. Our results define novel strategies for treatment of drug-resistant ovarian cancer that increase immunogenic cell death and reverse the immunosuppressive tumor microenvironment, culminating in antitumor immune responses that control metastatic tumor growth.

  5. Anti-epileptic effects of focal micro-injection of excitatory amino acid antagonists.

    Science.gov (United States)

    Meldrum, B; Millan, M; Patel, S; de Sarro, G

    1988-01-01

    The role of excitatory synaptic activity at various brain regions in the development and spread of seizure activity has been investigated by the focal microinjection of 2-amino-7-phosphono-heptanoate (2-APH), a selective antagonist at the N-methyl-D-aspartate preferring receptor, or gamma-D-glutamyl-aminomethyl sulphonate (GAMS), a partially selective antagonist at the kainate receptor. In genetically epilepsy prone rats the seizure response to a loud sound in most effectively suppressed by focal injections of 2-APH, 0.1-1.0 nmol, in the inferior colliculus. Protection is also seen after injections of 2-APH, 25 nmoles, in the substantia nigra (pars reticulata) or the midbrain reticular formation. Motor limbic seizures induced by pilocarpine, 380 mg/kg intraperitoneally, are prevented by prior injection into the substantia nigra, pars reticulata, or the entopeduncular nucleus, of 2-APH, 10 nmol or 10 pmol, respectively. Similar protection follows the injection of 2-APH, 1-5 pmol in the piriform cortex. The convulsant effects of pilocarpine are also blocked by the focal injection of GAMS, 10 nmol in the entopeduncular nucleus. This experimental approach can indicate critical sites at which seizure activity is initiated in particular models (e.g., inferior colliculus in sound-induced seizures, and piriform cortex in limbic seizures) and the pathways controlling seizure expression, such as the basal ganglia outputs. It also identifies specific receptors at which anticonvulsant drugs may operate.

  6. Retro-inverso Urokinase Receptor Antagonists for the Treatment of Metastatic Sarcomas.

    Science.gov (United States)

    Carriero, Maria Vincenza; Bifulco, Katia; Ingangi, Vincenzo; Costantini, Susan; Botti, Giovanni; Ragone, Concetta; Minopoli, Michele; Motti, Maria Letizia; Rea, Domenica; Scognamiglio, Giosuè; Botti, Gerardo; Arra, Claudio; Ciliberto, Gennaro; Pessi, Antonello

    2017-05-02

    The development of metastases is a multistep process that requires the activation of physiological and biochemical processes that govern migration, invasion and entry of metastatic cells into blood vessels. The urokinase receptor (uPAR) promotes cell migration by interacting with the Formyl Peptide Receptors (FPRs). Since both uPAR and FPR1 are involved in tumor progression, the uPAR-FPR1 interaction is an attractive therapeutic target. We previously described peptide antagonists of the uPAR-FPR1 interaction that inhibited cell migration and angiogenesis. To develop enzyme-resistant analogues, we applied here the Retro-Inverso (RI) approach, whereby the topology of the side chains is maintained by inverting the sequence of the peptide and the chirality of all residues. Molecular dynamics suggests that peptide RI-3 adopts the turn structure typical of uPAR-FPR1 antagonists. Accordingly, RI-3 is a nanomolar competitor of N-formyl-Met-Leu-Phe for binding to FPR1 and inhibits migration, invasion, trans-endothelial migration of sarcoma cells and VEGF-triggered endothelial tube formation. When sarcoma cells were subcutaneously injected in nude mice, tumor size, intra-tumoral microvessel density, circulating tumor cells and pulmonary metastases were significantly reduced in animals treated daily with 6 mg/Kg RI-3 as compared to animals treated with vehicle only. Thus, RI-3 represents a promising lead for anti-metastatic drugs.

  7. Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

    Directory of Open Access Journals (Sweden)

    Adrian E. Roitberg

    2008-06-01

    Full Text Available Estrogen receptors (ER are known as nuclear receptors. They exist in the cytoplasm of human cells and serves as a DNA binding transcription factor that regulates gene expression. However the estrogen receptor also has additional functions independent of DNA binding. The human estrogen receptor comes in two forms, alpha and beta. This work focuses on the alpha form of the estrogen receptor. The ERα is found in breast cancer cells, ovarian stroma cells, endometrium, and the hypothalamus. It has been suggested that exposure to DDE, a metabolite of DDT, and other pesticides causes conformational changes in the estrogen receptor. Before examining these factors, this work examines the protein unfolding from the antagonist form found in the 3ERT PDB crystal structure. The 3ERT PDB crystal structure has the estrogen receptor bound to the cancer drug 4-hydroxytamoxifen. The 4-hydroxytamoxifen ligand was extracted before the simulation, resulting in new conformational freedom due to absence of van der Waals contacts between the ligand and the receptor. The conformational changes that result expose the binding clef of the co peptide beside Helix 12 of the receptor forming an apo conformation. Two key conformations in the loops at either end of the H12 are produced resulting in the antagonist to apo conformation transformation. The results were produced over a 42ns Molecular Dynamics simulation using the AMBER FF99SB force field.

  8. Structural and energetic effects of A2A adenosine receptor mutations on agonist and antagonist binding.

    Directory of Open Access Journals (Sweden)

    Henrik Keränen

    Full Text Available To predict structural and energetic effects of point mutations on ligand binding is of considerable interest in biochemistry and pharmacology. This is not only useful in connection with site-directed mutagenesis experiments, but could also allow interpretation and prediction of individual responses to drug treatment. For G-protein coupled receptors systematic mutagenesis has provided the major part of functional data as structural information until recently has been very limited. For the pharmacologically important A(2A adenosine receptor, extensive site-directed mutagenesis data on agonist and antagonist binding is available and crystal structures of both types of complexes have been determined. Here, we employ a computational strategy, based on molecular dynamics free energy simulations, to rationalize and interpret available alanine-scanning experiments for both agonist and antagonist binding to this receptor. These computer simulations show excellent agreement with the experimental data and, most importantly, reveal the molecular details behind the observed effects which are often not immediately evident from the crystal structures. The work further provides a distinct validation of the computational strategy used to assess effects of point-mutations on ligand binding. It also highlights the importance of considering not only protein-ligand interactions but also those mediated by solvent water molecules, in ligand design projects.

  9. Pegvisomant: a growth hormone receptor antagonist used in the treatment of acromegaly.

    Science.gov (United States)

    Tritos, Nicholas A; Biller, Beverly M K

    2017-02-01

    To review published data on pegvisomant and its therapeutic role in acromegaly. Electronic searches of the published literature were conducted using the keywords: acromegaly, growth hormone (GH) receptor (antagonist), pegvisomant, therapy. Relevant articles (n = 141) were retrieved and considered for inclusion in this manuscript. Pegvisomant is a genetically engineered, recombinant growth hormone receptor antagonist, which is effective in normalizing serum insulin-like growth factor 1 (IGF-1) levels in the majority of patients with acromegaly and ameliorating symptoms and signs associated with GH excess. Pegvisomant does not have direct antiproliferative effects on the underlying somatotroph pituitary adenoma, which is the etiology of GH excess in the vast majority of patients with acromegaly. Therefore, patients receiving pegvisomant monotherapy require regular pituitary imaging in order to monitor for possible increase in tumor size. Adverse events in patients on pegvisomant therapy include skin rashes, lipohypertrophy at injection sites, and idiosyncratic liver toxicity (generally asymptomatic transaminitis that is reversible upon drug discontinuation), thus necessitating regular patient monitoring. Pegvisomant is an effective therapeutic agent in patients with acromegaly who are not in remission after undergoing pituitary surgery. It mitigates excess GH action, as demonstrated by IGF-1 normalization, but has no direct effects on pituitary tumors causing acromegaly. Regular surveillance for possible tumor growth and adverse effects (hepatotoxicity, skin manifestations) is warranted.

  10. Suppressant effects of selective 5-HT2 antagonists on rapid eye movement sleep in rats.

    Science.gov (United States)

    Tortella, F C; Echevarria, E; Pastel, R H; Cox, B; Blackburn, T P

    1989-04-24

    The effects of the novel, highly selective serotonin-2 (5-HT2) antagonists, ICI 169,369 and ICI 170,809, on 24 h EEG sleep-wake activity were studied in the rat. Both compounds caused a dose-related increase in the latency to rapid eye movement sleep (REMS) and significantly suppressed cumulative REMS time up to 12 h postinjection. In contrast, neither drug disrupted slow-wave sleep continuity in as much as the latency to non-REMS (NREMS) and cumulative NREMS time were unchanged. However, at the highest dose tested (20 mg/kg) ICI 170,809 did produce a significant increase in total NREMS time during the second half of the sleep-awake cycle. These results demonstrate effects of selective 5-HT2 antagonists on sleep in rats which appear to be specific for REMS behavior, suggesting that the priming influence of serotonin on REMS may involve 5-HT2 receptor subtypes. The relationship between the REMS suppressant actions of these compounds and their consideration as therapeutic agents in depression is discussed.

  11. A Combined Quantitative Structure-Activity Relationship Research of Quinolinone Derivatives as Androgen Receptor Antagonists.

    Science.gov (United States)

    Wang, Yuwei; Bai, Fang; Cao, Hong; Li, Jiazhong; Liu, Huanxiang; Gramatica, Paola

    2015-01-01

    Antiandrogens bicalutamide, flutamide and enzalutamide etc. have been used in clinical trials to treat prostate cancer by binding to and antagonizing androgen receptor (AR). Although initially effective, the drug resistance problem will emerge eventually, which results in a high medical need for novel AR antagonist exploitation. Here in this work, to facilitate the rational design of novel AR antagonists, we studied the structure-activity relationships of a series of 2-quinolinone derivatives and investigated the structural requirements for their antiandrogenic activities. Different modeling methods, including 2D MLR, 3D CoMFA and CoMSIA, were implemented to evolve QSAR models. All these models, thoroughly validated, demonstrated satisfactory results especially for the good predictive abilities. The contour maps from 3D CoMFA and CoMSIA models provide visualized explanation of key structural characteristics relevant to the antiandrogenic activities, which is summarized to a position-specific conclusion at the end. The obtained results from this research are practically useful for rational design and screening of promising chemicals with high antiandrogenic activities.

  12. Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

    Directory of Open Access Journals (Sweden)

    Adele Romano

    2014-01-01

    Full Text Available The initial pharmaceutical interest for the endocannabinoid system as a target for antiobesity therapies has been restricted by the severe adverse effects of the CB1 antagonist rimonabant. This study points at oleoylethanolamide (OEA, a monounsaturated analogue, and functional antagonist of anandamide, as a potential and safer antiobesity alternative to CB1 antagonism. Mice treated with equal doses (5 or 10 mg/kg, i.p. of OEA or rimonabant were analyzed for the progressive expression of spontaneous behaviors (eating, grooming, rearing, locomotion, and resting occurring during the development of satiety, according to the paradigm called behavioral satiety sequence (BSS. Both drugs reduced food (wet mash intake to a similar extent. OEA treatment decreased eating activity within the first 30 min and caused a temporary increase of resting time that was not accompanied by any decline of horizontal, vertical and total motor activity. Besides decreasing eating activity, rimonabant caused a marked increase of the time spent grooming and decreased horizontal motor activity, alterations that might be indicative of aversive nonmotivational effects on feeding. These results support the idea that OEA suppresses appetite by stimulating satiety and that its profile of action might be predictive of safer effects in humans as a novel antiobesity treatment.

  13. Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

    Science.gov (United States)

    2016-08-01

    swelling and pain determined, along with initial experiments on the chemokine receptor antagonist (CRA) AMD3100. Methods were established for measuring a...Presentations………………………….22 7. Inventions , Patents and Licenses……………………..………….22 8. Reportable Outcomes……………………………………………….22 9. Other Achievements...Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain; Chemokine and cytokine measurements 3. OVERALL PROJECT

  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. Hyperglycemia of Diabetic Rats Decreased by a Glucagon Receptor Antagonist

    Science.gov (United States)

    Johnson, David G.; Ulichny Goebel, Camy; Hruby, Victor J.; Bregman, Marvin D.; Trivedi, Dev

    1982-02-01

    The glucagon analog [l-Nα-trinitrophenylhistidine, 12-homoarginine]-glucagon (THG) was examined for its ability to lower blood glucose concentrations in rats made diabetic with streptozotocin. In vitro, THG is a potent antagonist of glucagon activation of the hepatic adenylate cyclase assay system. Intravenous bolus injections of THG caused rapid decreases (20 to 35 percent) of short duration in blood glucose. Continuous infusion of low concentrations of the inhibitor led to larger sustained decreases in blood glucose (30 to 65 percent). These studies demonstrate that a glucagon receptor antagonist can substantially reduce blood glucose levels in diabetic animals without addition of exogenous insulin.

  16. Synthesis, crystal structure, biological evaluation, and molecular docking studies of quinoline-arylpiperazine derivative as potent α1A-adrenoceptor antagonist

    Science.gov (United States)

    Xu, Wei; Jiang, Renwang; Yuan, Mu

    2017-02-01

    Arylpiperazine derivatives received special attention owing to their antagonist potency on α1-adrenoceptors (α1-ARs). In this work, quinoline-arylpiperazine derivative (1) was synthesized and its structural properties were investigated using single crystal X-ray diffraction analysis and theoretical calculations. Biological evaluation in vitro revealed that compound 1 exhibited a 3-fold higher selectivity for α1A-AR over than α1B subtype when compared to non-selective antagonist prazosin. Molecular docking studies shed light on the antagonistic activity of both 1 and prazosin on α1A and α1B-AR. The docking results suggested that residues Gln177, Phe86, Phe288, Phe308, Phe312 and Tyr316 were identified as the major sites for the two agents binding to the α1A receptor. As depicted by pharmacophoric model, 1 was deemed to be the α1A-selective antagonist on the basis of pharmacophoric features. Our present work may provide valuable information for better drug design of subtype-selective α1-AR antagonists.

  17. Detailed analysis of food-reinforced operant lever pressing distinguishes effects of a cannabinoid CB1 inverse agonist and dopamine D1 and D2 antagonists.

    Science.gov (United States)

    McLaughlin, P J; Winston, K M; Swezey, L A; Vemuri, V K; Makriyannis, A; Salamone, J D

    2010-07-01

    Overt similarities exist between the effects of systemic cannabinoid CB1 inverse agonists and dopamine (DA) antagonists on appetitive behavior. The present set of studies was undertaken to apply a fine-grained analysis of food-reinforced operant lever pressing in rats in order to compare the pattern of effects produced by administration of the CB1 inverse agonist AM 251 and those induced by the DA D1 antagonist SKF 83566, and the D2 antagonist raclopride. Three groups of rats were trained on a fixed-ratio 5 (FR5) schedule and administered these compounds over a range of doses expected to suppress responding. All three drugs produced a dose-related suppression of total lever pressing. In addition to main effects of dose, regression analyses were performed to determine which of several response timing- and rate-related variables correlated most strongly with overall responding in each group. It was found that total session time spent pausing from responding was significantly better at predicting responding in the AM 251 group, while both DA antagonists produced significantly stronger regression coefficients (versus AM 251) from fast responding measures. These results suggest that, while several similarities exist, CB1, D1, and D2 antagonists are not identical in their pattern of suppression of food-maintained lever pressing.

  18. Unraveling structural mechanisms of allosteric drug action.

    Science.gov (United States)

    Nussinov, Ruth; Tsai, Chung-Jung

    2014-05-01

    Orthosteric drugs block the active site to obstruct function; allosteric drugs modify the population of the active state, to modulate function. Available data lead us to propose that allosteric drugs can constitute anchors and drivers. The anchor docks into an allosteric pocket. The conformation with which it interacts is unchanged during the transition between the inactive and active states. The anchor provides the foundation that allows the driver to exert a 'pull' and/or 'push' action that shifts the receptor population from the inactive to the active state. The presence or absence of driver atom in an allosteric drug can exert opposite agonism. We map a strategy for driver identification and expect the allosteric trigger concept to transform agonist/antagonist drug discovery.

  19. Domino Reactions in Drug Design and Discovery.

    Science.gov (United States)

    Bhar, Shanta; Ramana, Mucheli M V

    2016-01-01

    With reference to challenges in developing varied and exceedingly complex scaffolds expeditiously through atom economy, domino reactions have assumed a significant role in several transformative endeavors towards established pharmaceuticals and new chemical entities across diverse therapeutic classes such as HIV integrase inhibitors, DPP4 [dipeptidyl peptidase IV] inhibitors, GSK- 3 (Glycogen Synthase Kinase 3) inhibitors, neoplastic drugs and microtubule antagonists. The very large chemical space of Domino Reactions can be leveraged for the design strategy of drugs and drug- like candidates with leading examples like Indinavir (Crixivan), Trandolapril (Mavik), Biyouyanagin A, endo pyrrolizidinone diastereomer [GSK] and several others. Domino reactions therefore constitute an integral part of both creative and functional aspects of drug design and discovery, contributing both enhanced efficiency as well as synthetic versatility to pharmaceutical drug design.

  20. Drug Facts

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