Novel agents for anti-platelet therapy

Directory of Open Access Journals (Sweden)

Ji Xuebin

2011-11-01

Full Text Available Abstract Anti-platelet therapy plays an important role in the treatment of patients with thrombotic diseases. The most commonly used anti-platelet drugs, namely, aspirin, ticlopidine, and clopidogrel, are effective in the prevention and treatment of cardio-cerebrovascular diseases. Glycoprotein IIb/IIIa antagonists (e.g., abciximab, eptifibatide and tirofiban have demonstrated good clinical benefits and safety profiles in decreasing ischemic events in acute coronary syndrome. However, adverse events related to thrombosis or bleeding have been reported in cases of therapy with glycoprotein IIb/IIIa antagonists. Cilostazol is an anti-platelet agent used in the treatment of patients with peripheral ischemia, such as intermittent claudication. Presently, platelet adenosine diphosphate P2Y(12 receptor antagonists (e.g., clopidogrel, prasugrel, cangrelor, and ticagrelor are being used in clinical settings for their pronounced protective effects. The new protease-activated receptor antagonists, vorapaxar and atopaxar, potentially decrease the risk of ischemic events without significantly increasing the rate of bleeding. Some other new anti-platelet drugs undergoing clinical trials have also been introduced. Indeed, the number of new anti-platelet drugs is increasing. Consequently, the efficacy of these anti-platelet agents in actual patients warrants scrutiny, especially in terms of the hemorrhagic risks. Hopefully, new selective platelet inhibitors with high anti-thrombotic efficiencies and low hemorrhagic side effects can be developed.

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

Directory of Open Access Journals (Sweden)

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

Adverse cutaneous reactions induced by TNF-alpha antagonist therapy.

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Borrás-Blasco, Joaquín; Navarro-Ruiz, Andrés; Borrás, Consuelo; Casterá, Elvira

2009-11-01

To review adverse cutaneous drug reactions induced by tumor necrosis factor alpha (TNF-alpha) antagonist therapy. A literature search was performed using PubMed (1996-March 2009), EMBASE, and selected MEDLINE Ovid bibliography searches. All language clinical trial data, case reports, letters, and review articles identified from the data sources were used. Since the introduction of TNF-alpha antagonist, the incidence of adverse cutaneous drug reactions has increased significantly. A wide range of different skin lesions might occur during TNF-alpha antagonist treatment. New onset or exacerbation of psoriasis has been reported in patients treated with TNF-alpha antagonists for a variety of rheumatologic conditions. TNF-alpha antagonist therapy has been associated with a lupus-like syndrome; most of these case reports occurred in patients receiving either etanercept or infliximab. Serious skin reactions such as erythema multiforme, Stevens-Johnson syndrome, and toxic epidermal necrolysis have been reported rarely with the use of TNF-alpha antagonists. As the use of TNF-alpha antagonists continues to increase, the diagnosis and management of cutaneous side effects will become an increasingly important challenge. In patients receiving TNF-alpha antagonist treatment, skin disease should be considered, and clinicians need to be aware of the adverse reactions of these drugs.

Naloxone : actions of an antagonist

NARCIS (Netherlands)

Dorp, Eveline Louise Arianna van

2009-01-01

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

Pharmacological analysis of calcium antagonist receptors

International Nuclear Information System (INIS)

Reynolds, I.J.

1987-01-01

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

Is glycoprotein IIb/IIIa antagonism as effective in women as in men following percutaneous coronary intervention?. Lessons from the ESPRIT study.

Science.gov (United States)

Fernandes, Laura S; Tcheng, James E; O'Shea, J Conor; Weiner, Bonnie; Lorenz, Todd J; Pacchiana, Cindy; Berdan, Lisa G; Maresh, Kelly J; Joseph, Diane; Madan, Mina; Mann, Tift; Kilaru, Rakhi; Hochman, Judith S; Kleiman, Neal S

2002-09-18

The study was done to determine whether eptifibatide, a platelet glycoprotein (GP) IIb/IIIa antagonist, prevents ischemic complications following percutaneous coronary interventions (PCIs) in women as well as in men. Eptifibatide reduces ischemic complications after nonurgent coronary stent interventions. We compared outcomes in women (n = 562) and men (n = 1,502) enrolled in the Enhanced Suppression of the Platelet GP IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of double-bolus eptifibatide during PCI. Women in the ESPRIT trial were older, and more frequently had hypertension, diabetes mellitus, or acute coronary syndromes, but were less likely to have prior PCI or coronary artery bypass graft surgery. The primary end point, a composite at 48 h of death, myocardial infarction (MI), urgent target vessel revascularization (TVR), and unplanned GP IIb/IIIa use, occurred in 10.5% of women and 7.9% of men (p = 0.082). The composite of death, MI, or TVR after one year occurred in 24.5% of women compared with 18% of men (p = 0.0008). At 48 h, eptifibatide reduced the composite of death, MI, and TVR from 14.5% to 6.0% in women versus 9.0% to 6.8% in men. At one year, these differences persisted: 28.9% versus 20.0% for women and 19.5% versus 16.6% for men. No statistical interaction existed between treatment and gender at either 48 h (p = 0.063) or one year (p = 0.2). Bleeding occurred more commonly in women (5.5% vs. 2.6%, p = 0.002), and was more common in eptifibatide-treated women. After adjustment for age, weight, and hypertension, no interaction between treatment and gender was present. Eptifibatide is effective to prevent ischemic complications of PCI in women and may eliminate gender-related differences in PCI outcomes.

Toxicological Differences Between NMDA Receptor Antagonists and Cholinesterase Inhibitors.

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Shi, Xiaodong; Lin, Xiaotian; Hu, Rui; Sun, Nan; Hao, Jingru; Gao, Can

2016-08-01

Cholinesterase inhibitors (ChEIs), represented by donepezil, rivastigmine, and galantamine, used to be the only approved class of drugs for the treatment of Alzheimer's disease. After the approval of memantine by the Food and Drug Administration (FDA), N-methyl-d-aspartic acid (NMDA) receptor antagonists have been recognized by authorities and broadly used in the treatment of Alzheimer's disease. Along with complementary mechanisms of action, NMDA antagonists and ChEIs differ not only in therapeutic effects but also in adverse reactions, which is an important consideration in clinical drug use. And the number of patients using NMDA antagonists and ChEIs concomitantly has increased, making the matter more complicated. Here we used the FDA Adverse Event Reporting System for statistical analysis , in order to compare the adverse events of memantine and ChEIs. In general, the clinical evidence confirmed the safety advantages of memantine over ChEIs, reiterating the precautions of clinical drug use and the future direction of antidementia drug development. © The Author(s) 2016.

Stimulant effects of adenosine antagonists on operant behavior: differential actions of selective A2A and A1 antagonists

Science.gov (United States)

Randall, Patrick A.; Nunes, Eric J.; Janniere, Simone L.; Stopper, Colin M.; Farrar, Andrew M.; Sager, Thomas N.; Baqi, Younis; Hockemeyer, Jörg; Müller, Christa E.

2012-01-01

Rationale Adenosine A2A antagonists can reverse many of the behavioral effects of dopamine antagonists, including actions on instrumental behavior. However, little is known about the effects of selective adenosine antagonists on operant behavior when these drugs are administered alone. Objective The present studies were undertaken to investigate the potential for rate-dependent stimulant effects of both selective and nonselective adenosine antagonists. Methods Six drugs were tested: two nonselective adenosine antagonists (caffeine and theophylline), two adenosine A1 antagonists (DPCPX and CPT), and two adenosine A2A antagonists (istradefylline (KW6002) and MSX-3). Two schedules of reinforcement were employed; a fixed interval 240-s (FI-240 sec) schedule was used to generate low baseline rates of responding and a fixed ratio 20 (FR20) schedule generated high rates. Results Caffeine and theophylline produced rate-dependent effects on lever pressing, increasing responding on the FI-240 sec schedule but decreasing responding on the FR20 schedule. The A2A antagonists MSX-3 and istradefylline increased FI-240 sec lever pressing but did not suppress FR20 lever pressing in the dose range tested. In fact, there was a tendency for istradefylline to increase FR20 responding at a moderate dose. A1 antagonists failed to increase lever pressing rate, but DPCPX decreased FR20 responding at higher doses. Conclusions These results suggest that adenosine A2A antagonists enhance operant response rates, but A1 antagonists do not. The involvement of adenosine A2A receptors in regulating aspects of instrumental response output and behavioral activation may have implications for the treatment of effort-related psychiatric dysfunctions, such as psychomotor slowing and anergia in depression. PMID:21347642

Cannabinoid-1 receptor (CB1R) blockers as medicines: beyond obesity and cardiometabolic disorders to substance abuse/drug addiction with CB1R neutral antagonists.

Science.gov (United States)

Janero, David R

2012-03-01

Addiction to chemical substances with abuse potential presents medical needs largely unsolved by extant therapeutic strategies. Signal transmission through the cannabinoid-1 receptor (CB1R) in the central nervous system (CNS) modulates neurotransmitters/neuronal pathways contributing to the rewarding properties and hedonic effects of certain nondrug stimuli (e.g., food) and many prototypical addictive drugs, promoting excessive intake and its pathological consequences. Typical CB1R antagonists/inverse agonists reduce the rewarding effects and normalize behavioral phenotypes associated with food and abused drugs, but carry an unacceptable adverse-event profile that may reflect, at least partly, their intrinsic ability to alter basal homeostatic CB1R signaling in the CNS and elicit a negative efficacy response. Alternatively, peripherally biased CB1R inverse agonists with limited CNS permeability and putative CB1R neutral antagonists expressing modest (if any) inverse-agonist efficacy are garnering attention for treating obesity and related cardiometabolic complications with a potentially enhanced benefit-to-risk profile. This mini-review calls attention to the proposition that CB1R neutral antagonists offer attractive opportunities for pharmacotherapeutic exploitation in the substance abuse/drug addiction space, whereas the restricted CNS accessibility of peripherally biased CB1R inverse agonists circumscribes their therapeutic utility for this indication. The unique preclinical pharmacology, efficacy profiles, and reduced adverse-event risk of CB1R neutral antagonists make them worthy of translational study for their potential therapeutic application beyond obesity/cardiometabolic disease to include substance-abuse/drug-addiction disorders.

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence

Science.gov (United States)

Murphy, Anna; Nestor, Liam J; McGonigle, John; Paterson, Louise; Boyapati, Venkataramana; Ersche, Karen D; Flechais, Remy; Kuchibatla, Shankar; Metastasio, Antonio; Orban, Csaba; Passetti, Filippo; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor; Robbins, Trevor W; Lingford-Hughes, Anne; Nutt, David J; Deakin, John FW; Elliott, Rebecca

2017-01-01

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction. PMID:28042871

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

Directory of Open Access Journals (Sweden)

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.

Chloroquine, quinine, procaine, quinidine, tricyclic antidepressants, and methylxanthines as prostaglandin agonists and antagonists.

Science.gov (United States)

Manku, M S; Horrobin, D F

1976-11-20

Chloroquine, quanine, procaine, quinidine, clomipramine, theophylline, and caffeine have been shown to be strong prostaglandin antagonists and weak agonists. The antagonist effect is clearly demonstrable at concentrations reached in human plasma when the drugs are used therapeutically. This suggests that prostaglandins are important in several situations in which their role has hitherto been unsuspected. New approaches to the development of prostaglandin antagonists and new uses for established drugs are indicated. In a preliminary study chloroquine has been successfully used to close patent ductus arteriosus in three infants.

Drug-Drug and Herb-Drug Interaction-A Comment | Esimone ...

African Journals Online (AJOL)

Clinically relevant drug-drug interactions may be pharmacodynamic or pharmacokinetic. And herbal medicinal products are becoming increasingly popular. Drug interactions can be in vivo or in vitro. Pharmacodynamic outcomes take such forms as Additive, Synergistic, Antagonistic or Indifferent. The paper reviews and ...

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.

Role for therapeutic drug monitoring during induction therapy with TNF antagonists in IBD: evolution in the definition and management of primary nonresponse.

Science.gov (United States)

Papamichael, Konstantinos; Gils, Ann; Rutgeerts, Paul; Levesque, Barrett G; Vermeire, Séverine; Sandborn, William J; Vande Casteele, Niels

2015-01-01

: Primary nonresponse and primary nonremission are important limitations of tumor necrosis factor (TNF) antagonists, occurring in 10% to 40% and 50% to 80% of patients with inflammatory bowel disease, respectively. The magnitude of primary nonresponse differs between phase III clinical trials and cohort studies, indicating differences, e.g., in definition, patient population or blinding. The causes of nonresponse can be attributed to the drug (pharmacokinetics, immunogenicity), the patient (genetics, disease activity), the disease (type, location, severity), and/or the treatment strategy (dosing regimen, combination therapy). Primary nonresponse has been attributed to "non-TNF-driven disease" which is an overly simplified and potentially misleading approach to the problem. Many patients with primary nonresponse could successfully be treated with dose optimization during the induction phase or switching to another TNF antagonist. Therefore, primary nonresponse is frequently not a non-TNF-driven disease. Recent studies from rheumatoid arthritis and preliminary data from inflammatory bowel disease evaluating therapeutic drug monitoring have suggested that early measurement of drug and anti-drug antibody concentrations could help to define primary nonresponse and rationalize patient management of this problem. Moreover, a modeling approach including pharmacological parameters and patient-related covariants could potentially be predictive for response to the treatment. We describe an overview of this evolution in thinking, underpinned by previous findings, and assess the potential role of early measurement of drug and antidrug antibody concentrations in the definition and management of primary nonresponse.

NK-1 receptor antagonists as anti-cancer drugs

Indian Academy of Sciences (India)

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

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

International Nuclear Information System (INIS)

Liu Baosheng; Zhao Fengli; Xue Chunli; Wang Jing; Lu Yunkai

2010-01-01

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.

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.

Small molecule antagonists of integrin receptors.

Science.gov (United States)

Perdih, A; Dolenc, M Sollner

2010-01-01

The complex and widespread family of integrin receptors is involved in numerous physiological processes, such as tissue remodeling, angiogenesis, development of the immune response and homeostasis. In addition, their key role has been elucidated in important pathological disorders such as cancer, cardiovascular diseases, osteoporosis, autoimmune and inflammatory diseases and in the pathogenesis of infectious diseases, making them highly important targets for modern drug design campaigns. In this review we seek to present a concise overview of the small molecule antagonists of this diverse and highly complex receptor family. Integrin antagonists are classified according to the targeted integrin receptor and are discussed in four sections. First we present the fibrinogen alpha(IIb)beta3 and the vitronectin alpha (V)beta(3) receptor antagonists. The remaining selective integrin antagonists are examined in the third section. The final section is dedicated to molecules with dual or multiple integrin activity. In addition, the use of antibodies and peptidomimetic approaches to modulate the integrin receptors are discussed, as well providing the reader with an overall appreciation of the field.

Temperature affects thrombolytic efficacy using rt-PA and eptifibatide, an in vitro study.

Science.gov (United States)

Meunier, Jason M; Chang, Wan-Tsu W; Bluett, Brent; Wenker, Evan; Lindsell, Christopher J; Shaw, George J

2012-09-01

The potential for hypothermia as a neuroprotectant during stroke has led to its increase in clinical use. At the same time, combination pharmaceutical therapies for ischemic stroke using recombinant tissue plasminogen activator (rt-PA), and GP IIb-IIIa inhibitors, such as Eptifibatide (Epf ), are under study. However, there is little data on how the reactions triggered by these agents are impacted by temperature. Here, clot lysis during exposure to the combination of rt-PA and Epf is measured in an in vitro human clot model at hypothermic temperatures. The hypothesis is that lytic efficacy of rt-PA and Epf decreases with decreasing temperature. Whole blood clots from 31 volunteers were exposed to rt-PA (0.5 μg/mL) and Epf (0.63 μg/mL) in human fresh-frozen plasma (rt-PA+Epf ), rt-PA alone in plasma (rt-PA Alone), or to plasma alone (Control), at temperatures from 30°C to 37°C, for 30 minutes. Clot lysis was measured using a microscopic imaging technique; the mean fractional clot loss (FCL) at 30 minutes was used to determine lytic efficacy. Temperature had a significant impact on FCL in clots exposed to rt-PA+Epf, with the FCL being lower at 30°C to 36°C than at 37°C. The FCL remained significantly higher for rt-PA+Epf–treated clots than Controls regardless of temperature, with the exception of measurements made at 30°C when no significant differences in the FCL were observed between groups. The use of hypothermia as a neuroprotectant may negatively impact the therapeutic benefit of thrombolytic agents.

Drug: D02104 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available gesic ... DG01586 ... Opioid receptor antagonist ... DG01587 ... Opioid receptor agonist/antagonist Other ... DG01718 ... Drugs... for addictive disorder ... DG01716 ... Drugs for alcohol dependence ATC code: N07BB05 Chemical group: DG00998 ...

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.

Drug: D05111 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available ... DG01586 ... Opioid receptor antagonist ... DG01587 ... Opioid receptor agonist/antagonist Other ... DG01718 ... Drugs for... addictive disorder ... DG01716 ... Drugs for alcohol dependence Same as: C08027 ATC code: N07BB05 Chemical group

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...

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

International Nuclear Information System (INIS)

Chen, Yi; Xie, Xiaoyan; Li, Xinyi; Wang, Peiqi; Jing, Qian; Yue, Jiaqi; Liu, Yang; Cheng, Zhong; Li, Jingyi; Song, Haixing; Li, Guoyu; Liu, Rui; Wang, Jinhui

2016-01-01

Breast cancer, representing approximately 30% of all gynecological cancer cases diagnosed yearly, is a leading cause of cancer-related mortality for women. Amplification of FGFR1 is frequently observed in breast cancers and is associated with poor prognosis. Though FGFRs have long been considered as anti-cancer drug targets, and a cluster of FGFR antagonists are currently under clinical trials, the precise cellular responses under the treatment of FGFR antagonists remains unclear. Here, we show that PD166866, an FGFR1-selective inhibitor, inhibits proliferation and triggers anoikis in FGFR1-amplified breast cancer cell lines. Notably, we demonstrate that PD166866 induces autophagy in FGFR1-amplified breast cancer cell lines, while blockage of autophagy by Atg5 knockdown further enhances the anti-proliferative activities of PD166866. Moreover, mechanistic study reveals that PD166866 induces autophagy through repressing Akt/mTOR signaling pathway. Together, the present study provides new insights into the molecular mechanisms underlying the anti-tumor activities of FGFR antagonists, and may further assist the FGFRs-based drug discovery. -- Highlights: •FGFR1 antagonist inhibits cell viability in FGFR1-amplified breast cancer cells. •FGFR1 antagonist induces autophagy in FGFR1-amplified breast cancer cells. •FGFR1 antagonist-induced autophagy is protective. •FGFR1 antagonist induces autophagy by inhibiting Akt/mTOR pathway.

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.

Dual antagonists of integrins.

Science.gov (United States)

Nadrah, K; Dolenc, M Sollner

2005-01-01

The roles of integrins in pathologies have been studied intensively and only partially explained. This has resulted in the development of several nanomolar antagonists to certain integrins. In most cases, the aim was to produce compounds which are highly selective towards specific integrins. This paradigm has recently shifted a little. Targeting two or more integrins with one compound has become a very attractive concept, especially since it has become clear that several severe disorders, such as pathological angiogenesis, cannot be treated just with highly specific integrin antagonists. This review is aimed to elucidate some aspects regarding the design of drugs with dual activity towards integrins. Integrin structure and tissue distribution will first be described, in order to provide the basis for their functions in various pathologies which will follow. Inhibitors of several pairs of integrins will be described.

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...

Kappa-Opioid Antagonists for Psychiatric Disorders: From Bench to Clinical Trials.

Science.gov (United States)

Carlezon, William A; Krystal, Andrew D

2016-10-01

Kappa-opioid receptor (KOR) antagonists are currently being considered for the treatment of a variety of neuropsychiatric conditions, including depressive, anxiety, and substance abuse disorders. A general ability to mitigate the effects of stress, which can trigger or exacerbate these conditions, may explain their putative efficacy across such a broad array of conditions. The discovery of their potentially therapeutic effects evolved from preclinical research designed to characterize the molecular mechanisms by which experience causes neuroadaptations in the nucleus accumbens (NAc), a key element of brain reward circuitry. This research established that exposure to drugs of abuse or stress increases the activity of the transcription factor CREB (cAMP response element binding protein) in the NAc, which leads to elevated expression of the opioid peptide dynorphin that in turn causes core signs of depressive- and anxiety-related disorders. Disruption of KORs-the endogenous receptors for dynorphin-produces antidepressant- and anxiolytic-like actions in screening procedures that identify standard drugs of these classes, and reduces stress effects in tests used to study addiction and stress-related disorders. Although interest in this target is high, prototypical KOR antagonists have extraordinarily persistent pharmacodynamic effects that complicate clinical trials. The development of shorter acting KOR antagonists together with more rapid designs for clinical trials may soon provide insight on whether these drugs are efficacious as would be predicted by preclinical work. If successful, KOR antagonists would represent a unique example in psychiatry where the therapeutic mechanism of a drug class is understood before it is shown to be efficacious in humans. © 2016 Wiley Periodicals, Inc.

Chloroquine, quinine, procaine, quinidine and clomipramine are prostaglandin agonists and antagonists.

Science.gov (United States)

Manku, M S; Horrobin, D F

1976-11-01

Chloroquine, quinine, procaine, quinidine and clomipramine behave as prostaglandin (PG) antagonists in a rat mesenteric vascular bed preparation. The ID50 concentrations were within the range of therapeutically effective human plasma levels in each case. Antagonism to PGE2 was studied in detail and seemed to be at least in part competitive. The drugs also antagonized the effects of PGs A1, A2, F2alpha and E1. Each drug also had weak prostaglandin agonist activity but only over a very narrow range of concentrations. It is possible that some of the clinical actions of these drugs may depend on blockade or imitation of natural PG effects. The findings suggest new approaches to the search for PG antagonists, a new screening technique for anti-inflammatory drugs and possible new uses for these established drugs. A preliminary study suggests that chloroquine may be successful in closing a patent ductus arteriosus in infants.

5-HT7 Receptor Antagonists with an Unprecedented Selectivity Profile.

Science.gov (United States)

Ates, Ali; Burssens, Pierre; Lorthioir, Olivier; Lo Brutto, Patrick; Dehon, Gwenael; Keyaerts, Jean; Coloretti, Francis; Lallemand, Bénédicte; Verbois, Valérie; Gillard, Michel; Vermeiren, Céline

2018-04-23

Selective leads: In this study, we generated a new series of serotonin 5-HT 7 receptor antagonists. Their synthesis, structure-activity relationships, and selectivity profiles are reported. This series includes 5-HT 7 antagonists with unprecedented high selectivity for the 5-HT 7 receptor, setting the stage for lead optimization of drugs acting on a range of neurological targets. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Serotonin antagonists fail to alter MDMA self-administration in rats.

Science.gov (United States)

Schenk, Susan; Foote, Jason; Aronsen, Dane; Bukholt, Natasha; Highgate, Quenten; Van de Wetering, Ross; Webster, Jeremy

2016-09-01

Acute exposure to ±3,4-methylenedioxymethamphetamine (MDMA) preferentially increases release of serotonin (5-HT), and a role of 5-HT in many of the behavioral effects of acute exposure to MDMA has been demonstrated. A role of 5-HT in MDMA self-administration in rats has not, however, been adequately determined. Therefore, the present study measured the effect of pharmacological manipulation of some 5-HT receptor subtypes on self-administration of MDMA. Rats received extensive experience with self-administered MDMA prior to tests with 5-HT ligands. Doses of the 5-HT1A antagonist, WAY 100635 (0.1-1.0mg/kg), 5-HT1B antagonist, GR 127935 (1.0-3.0mg/kg), and the 5-HT2A antagonist, ketanserin (1.0-3.0mg/kg) that have previously been shown to decrease self-administration of other psychostimulants and that decreased MDMA-produced hyperactivity in the present study did not alter MDMA self-administration. Experimenter-administered injections of MDMA (10.0mg/kg, ip) reinstated extinguished drug-taking behavior, but this also was not decreased by any of the antagonists. In contrast, both WAY 100635 and ketanserin, but not GR 127935, decreased cocaine-produced drug seeking in rats that had been trained to self-administered cocaine. The 5-HT1A agonist, 8-OH-DPAT (0.1-1.0mg/kg), but not the 5-HT1B/1A agonist, RU 24969 (0.3-3.0mg/kg), decreased drug-seeking produced by the reintroduction of a light stimulus that had been paired with self-administered MDMA infusions. These findings suggest a limited role of activation of 5-HT1A, 5-HT1B or 5-HT2 receptor mechanisms in MDMA self-administration or in MDMA-produced drug-seeking following extinction. The data suggest, however, that 5-HT1A agonists inhibit cue-induced drug-seeking following extinction of MDMA self-administration and might, therefore, be useful adjuncts to therapies to limit relapse to MDMA use. Copyright © 2016 Elsevier Inc. All rights reserved.

Thyroid Hormone Receptor Antagonists: From Environmental Pollution to Novel Small Molecules.

Science.gov (United States)

Mackenzie, Louise S

2018-01-01

Thyroid hormone receptors (TRs) are nuclear receptors which control transcription, and thereby have effects in all cells within the body. TRs are an important regulator in many basic physiological processes including development, growth, metabolism, and cardiac function. The hyperthyroid condition results from an over production of thyroid hormones resulting in a continual stimulation of thyroid receptors which is detrimental for the patient. Therapies for hyperthyroidism are available, but there is a need for new small molecules that act as TR antagonists to treat hyperthyroidism. Many compounds exhibit TR antagonism and are considered detrimental to health. Some drugs in the clinic (most importantly, amiodarone) and environmental pollution exhibit TR antagonist properties and thus have the potential to induce hypothyroidism in some people. This chapter provides an overview of novel small molecules that have been specifically designed or screened for their TR antagonist activity as novel treatments for hyperthyroidism. While novel compounds have been identified, to date none have been developed sufficiently to enter clinical trials. Furthermore, a discussion on other sources of TR antagonists is discussed in terms of side effects of current drugs in the clinic as well as environmental pollution. © 2018 Elsevier Inc. All rights reserved.

PARTIAL AGONISTS, FULL AGONISTS, ANTAGONISTS - DILEMMAS OF DEFINITION

NARCIS (Netherlands)

HOYER, D; BODDEKE, HWGM

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

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

Science.gov (United States)

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

2015-12-01

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

Suvorexant: The first orexin receptor antagonist to treat insomnia

OpenAIRE

Dubey, Ashok K.; Handu, Shailendra S.; Mediratta, Pramod K.

2015-01-01

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, hav...

Anti-HIV Effect of Liposomes Bearing CXCR4 Receptor Antagonist ...

African Journals Online (AJOL)

Keywords: Antagonist, CXCR4, Liposomes, Receptor, Inflammation, HIV. Tropical Journal of ... receptors and inhibits HIV-1 entry mediated through CCR3, CCR5, and ..... circulation, facilitating HIV-targeted drug delivery. By tissue distribution ...

Common influences of non-competitive NMDA receptor antagonists on the consolidation and reconsolidation of cocaine-cue memory.

Science.gov (United States)

Alaghband, Yasaman; Marshall, John F

2013-04-01

Environmental stimuli or contexts previously associated with rewarding drugs contribute importantly to relapse among addicts, and research has focused on neurobiological processes maintaining those memories. Much research shows contributions of cell surface receptors and intracellular signaling pathways in maintaining associations between rewarding drugs (e.g., cocaine) and concurrent cues/contexts; these memories can be degraded at the time of their retrieval through reconsolidation interference. Much less studied is the consolidation of drug-cue memories during their acquisition. The present experiments use the cocaine-conditioned place preference (CPP) paradigm in rats to directly compare, in a consistent setting, the effects of N-methyl-D-aspartate (NMDA) glutamate receptor antagonists MK-801 and memantine on the consolidation and reconsolidation of cocaine-cue memories. For the consolidation studies, animals were systemically administered MK-801 or memantine immediately following training sessions. To investigate the effects of these NMDA receptor antagonists on the retention of previously established cocaine-cue memories, animals were systemically administered MK-801 or memantine immediately after memory retrieval. Animals given either NMDA receptor antagonist immediately following training sessions did not establish a preference for the cocaine-paired compartment. Post-retrieval administration of either NMDA receptor antagonist attenuated the animals' preference for the cocaine-paired compartment. Furthermore, animals given NMDA receptor antagonists post-retrieval showed a blunted response to cocaine-primed reinstatement. Using two distinct NMDA receptor antagonists in a common setting, these findings demonstrate that NMDA receptor-dependent processes contribute both to the consolidation and reconsolidation of cocaine-cue memories, and they point to the potential utility of treatments that interfere with drug-cue memory reconsolidation.

Combination cancer chemotherapy with one compound: pluripotent bradykinin antagonists.

Science.gov (United States)

Stewart, John M; Gera, Lajos; Chan, Daniel C; York, Eunice J; Simkeviciene, Vitalija; Bunn, Paul A; Taraseviciene-Stewart, Laimute

2005-08-01

Lung and prostate cancers are major health problems worldwide. Treatments with standard chemotherapy agents are relatively ineffective. Combination chemotherapy gives better treatment than a single agent because the drugs can inhibit the cancer in different pathways, but new therapeutic agents are needed for the treatment of both tumor types. Bradykinin (BK) antagonists offer advantages of combination therapy in one compound. These promising multitargeted anti-cancer compounds selectively stimulate apoptosis in cancers and also inhibit both angiogenesis and matrix metalloprotease (MMP) action in treated lung and prostate tumors in nude mice. The highly potent, metabolism-resistant bradykinin antagonist peptide dimer, B-9870 [SUIM-(DArg-Arg-Pro-Hyp-Gly-Igl-Ser-DIgl-Oic-Arg)2] (SUIM=suberimidyl; Hyp=4-hydroxyproline; Igl=alpha-(2-indanyl)glycine; Oic=octahydroindole-2-carboxylic acid) and its non-peptide mimetic, BKM-570 [2,3,4,5,6-pentafluorocinnamoyl-(o-2,6-dichlorobenzyl)-L-tyrosine-N-(4-amino-2,2,6,6-tetramethylpiperidyl)amide] are superior to the widely used but toxic chemotherapeutic drugs cisplatin and taxotere. In certain combinations, they act synergistically with standard anti-cancer drugs. Due to its structure and biological activity, BKM-570 is an attractive lead compound for derivatization and evaluation for lung and prostate cancer drugs.

Oral tremor induced by the muscarinic agonist pilocarpine is suppressed by the adenosine A2A antagonists MSX-3 and SCH58261, but not the adenosine A1 antagonist DPCPX.

Science.gov (United States)

Collins, Lyndsey E; Galtieri, Daniel J; Brennum, Lise T; Sager, Thomas N; Hockemeyer, Jörg; Müller, Christa E; Hinman, James R; Chrobak, James J; Salamone, John D

2010-02-01

Tremulous jaw movements in rats, which can be induced by dopamine (DA) antagonists, DA depletion, and cholinomimetics, have served as a useful model for studies of tremor. Although adenosine A(2A) antagonists can reduce the tremulous jaw movements induced by DA antagonists and DA depletion, there are conflicting reports about the interaction between adenosine antagonists and cholinomimetic drugs. The present studies investigated the ability of adenosine antagonists to reverse the tremorogenic effect of the muscarinic agonist pilocarpine. While the adenosine A(2A) antagonist MSX-3 was incapable of reversing the tremulous jaw movements induced by the 4.0mg/kg dose of pilocarpine, both MSX-3 and the adenosine A(2A) antagonist SCH58261 reversed the tremulous jaw movements elicited by 0.5mg/kg pilocarpine. Systemic administration of the adenosine A(1) antagonist DPCPX failed to reverse the tremulous jaw movements induced by either an acute 0.5mg/kg dose of the cholinomimetic pilocarpine or the DA D2 antagonist pimozide, indicating that the tremorolytic effects of adenosine antagonists may be receptor subtype specific. Behaviorally active doses of MSX-3 and SCH 58261 showed substantial in vivo occupancy of A(2A) receptors, but DPCPX did not. The results of these studies support the use of adenosine A(2A) antagonists for the treatment of tremor. Copyright 2009 Elsevier Inc. All rights reserved.

Clinical relevance of cimetidine drug interactions.

Science.gov (United States)

Shinn, A F

1992-01-01

The excellent efficacy and tolerability profiles of H2-antagonists have established these agents as the leading class of antiulcer drugs. Attention has been focused on drug interactions with H2-antagonists as a means of product differentiation and because many patients are receiving multiple drug therapy. The main mechanism of most drug interactions involving cimetidine appears to be inhibition of the hepatic microsomal enzyme cytochrome P450, an effect which may be related to the different structures of H2-antagonists. Ranitidine appears to have less affinity than cimetidine for this system. There have been many published case reports and studies of drug interactions with cimetidine, but many of these have provided pharmacokinetic data only, with little information concerning the clinical significance of these findings. Nevertheless, the coadministration of cimetidine with drugs that have a narrow therapeutic margin (such as theophylline) may potentially result in clinically significant adverse effects. The monitoring of serum concentrations of drugs coadministered with cimetidine may reduce the risk of adverse events but does not abolish the problem. However, for most patients, concomitant administration of cimetidine with drugs possessing a wide therapeutic margin is unlikely to pose a significant problem.

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...

Intracoronary versus Intravenous eptifibatide during percutaneous coronary intervention for acute ST-segment elevation myocardial infarction; a randomized controlled trial.

Science.gov (United States)

Sanati, Hamid Reza; Zahedmehr, Ali; Firouzi, Ata; Farrashi, Melody; Amin, Kamyar; Peighambari, Mohammad Mehdi; Shakerian, Farshad; Kiani, Reza

2017-10-01

Although aspirin and clopidogrel seem to be quite enough during low risk percutaneous coronary intervention (PCI), the combination may need some reinforcement in complex situations such as primary PCI. By modifying the route and also the duration of administration, glycoprotein IIb/IIIa inhibitors might be a viable option. The aim of this study is to compare the benefits and disadvantages of three different methods of administration of eptifibatide in primary PCI population. Primary PCI candidates were randomized in three groups on which three different methods of administration of eptifibitide were tested: intravenous bolus injection followed by 12-h infusion (IV-IV), intracoronary bolus injection followed by intravenous infusion (IC-IV) and, only intracoronary bolus injection (IC). 99 patients were included in the present study. There was no significant difference among the three groups regarding all cause in hospital and one month mortality (p value = 0.99), re-myocardial infarction (p value = 0.89), post-PCI TIMI flow grade 3 (p value = 0.97), ST segment resolution (p value = 0.77) and peak troponin levels (p value = 0.82). The comparison of vascular access and major bleeding complications were not possible due to low events rate. By modifying the route of administration of eptifibitide, the clinical effect might be preserved without increasing the short-term mortality and procedural failure.

Drug: D02682 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available DG01941 ... Benzamide antipsychotic ... DG01478 ... Dopamine antagonist ... DG01474 ... Dopamine D2-receptor antagonist A... D02682 Drug Remoxipride (USAN) ... C16H23BrN2O3 D02682.gif ... Neuropsychiatric agent

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

African Journals Online (AJOL)

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

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...

Enhanced Chronic Pain Management Utilizing Chemokine Receptor Antagonists

Science.gov (United States)

2016-08-01

approximately halfway into the solution. All animals were tested at 60, 15 and 0 min before drug injection. For each animal , the first reading was discarded...approval (December 31, 2015), hiring new personnel, conducting baseline testing for procedures not involving animals , testing equipment, developing...treatment; Analgesia; Nociception; Antinociception; Inflammation; Chemokines; Chemokine receptor antagonists; Opioid analgesics; Animal models of pain

Study of antagonistic effects of Lactobacillus strains as probiotics on multi drug resistant (MDR) bacteria isolated from urinary tract infections (UTIs).

Science.gov (United States)

Naderi, Atiyeh; Kasra-Kermanshahi, Roha; Gharavi, Sara; Imani Fooladi, Abbas Ali; Abdollahpour Alitappeh, Meghdad; Saffarian, Parvaneh

2014-03-01

Urinary tract infection (UTI) caused by bacteria is one of the most frequent infections in human population. Inappropriate use of antibiotics, often leads to appearance of drug resistance in bacteria. However, use of probiotic bacteria has been suggested as a partial replacement. This study was aimed to assess the antagonistic effects of Lactobacillus standard strains against bacteria isolated from UTI infections. Among 600 samples; those with ≥10,000 cfu/ml were selected as UTI positive samples. Enterococcus sp., Klebsiella pneumoniae, Enterobacter sp., and Escherichia coli were found the most prevalent UTI causative agents. All isolates were screened for multi drug resistance and subjected to the antimicrobial effects of three Lactobacillus strains by using microplate technique and the MICs amounts were determined. In order to verify the origin of antibiotic resistance of isolates, plasmid curing using ethidium bromide and acridine orange was carried out. No antagonistic activity in Lactobacilli suspension was detected against test on Enterococcus and Enterobacter strains and K. pneumoniae, which were resistant to most antibiotics. However, an inhibitory effect was observed for E. coli which were resistant to 8-9 antibiotics. In addition, L. casei was determined to be the most effective probiotic. RESULTS from replica plating suggested one of the plasmids could be related to the gene responsible for ampicillin resistance. Treatment of E. coli with probiotic suspension was not effective on inhibition of the plasmid carrying hypothetical ampicillin resistant gene. Moreover, the plasmid profiles obtained from probiotic-treated isolates were identical to untreated isolates.

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...

Emerging growth factor receptor antagonists for the treatment of renal cell carcinoma.

Science.gov (United States)

Zahoor, Haris; Rini, Brian I

2016-12-01

The landscape of systemic treatment for metastatic renal cell carcinoma (RCC) has dramatically changed with the introduction of targeted agents including vascular endothelial growth factor (VEGF) inhibitors. Recently, multiple new agents including growth factor receptor antagonists and a checkpoint inhibitor were approved for the treatment of refractory metastatic RCC based on encouraging benefit shown in clinical trials. Areas covered: The background and biological rationale of existing treatment options including a brief discussion of clinical trials which led to their approval, is presented. This is followed by reviewing the limitations of these therapeutic options, medical need to develop new treatments and major goals of ongoing research. We then discuss two recently approved growth factor receptor antagonists i.e. cabozantinib and lenvatinib, and a recently approved checkpoint inhibitor, nivolumab, and issues pertaining to drug development, and future directions in treatment of metastatic RCC. Expert opinion: Recently approved growth factor receptor antagonists have shown encouraging survival benefit but associated drug toxicity is a major issue. Nivolumab, a programmed death 1 (PD-1) checkpoint inhibitor, has similarly shown survival benefit and is well tolerated. With multiple options now available in this patient population, the right sequence of these agents remains to be determined.

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.

Comparison of one-year outcomes following coronary artery stenting in diabetic versus nondiabetic patients (from the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy [ESPRIT] Trial).

Science.gov (United States)

Labinaz, Marino; Madan, Mina; O'Shea, J O'Conor; Kilaru, Rakhi; Chin, Wai; Pieper, Karen; McGuire, Darren K; Saucedo, Jorge F; Talley, J David; Lui, Henry; Kitt, Michael M; Califf, Robert M; Tcheng, James T

2002-09-15

For patients undergoing nonurgent coronary stent implantation, blockade of the glycoprotein IIb/IIIa receptor with eptifibatide reduces the incidence of ischemic complications. We evaluated the interaction of eptifibatide with diabetes in patients who underwent this procedure by analyzing the 1-year outcomes of those enrolled in the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial (466 diabetic and 1,595 nondiabetic patients). At 1 year, the composite end point of death, myocardial infarction (MI), or target vessel revascuarlization (TVR) was higher in diabetic patients (24.5% vs 18.4%; p = 0.008). At 1 year, eptifibatide had a similar effect on the composite end point of death, MI, or TVR in diabetic (hazards ratio [HR] 0.71, 95% confidence interval [CI] 0.49 to 1.04) and nondiabetic patients (HR 0.80, 95% CI 0.63 to 0.99). A similar treatment effect was also seen on death or MI in both groups. The 1-year mortality rate for diabetic patients assigned to placebo was 3.5% versus 1.3% for patients receiving eptifibatide (HR 0.37, 95% CI 0.10 to 1.41); the latter rate was similar to the mortality rate of 1.4% for nondiabetic patients in the eptifibatide group. However, eptifibatide did not have a significant effect on TVR in diabetic patients (HR 0.90, 95% CI 0.57 to 1.41). Our data suggest that treatment with eptifibatide is associated with a similar relative reduction in adverse ischemic complications in diabetic and nondiabetic patients undergoing coronary stent implantation. There is no evidence of a statistical interaction in the treatment effect of eptifibatide between patients with and without diabetes.

A prototypical Sigma-1 receptor antagonist protects against brain ischemia

OpenAIRE

Schetz, John A.; Perez, Evelyn; Liu, Ran; Chen, Shiuhwei; Lee, Ivan; Simpkins, James W.

2007-01-01

Previous studies indicate that the Sigma-1 ligand 4-phenyl-1-(4-phenylbutyl) piperidine (PPBP) protects the brain from ischemia. Less clear is whether protection is mediated by agonism or antagonism of the Sigma-1 receptor, and whether drugs already in use for other indications and that interact with the Sigma-1 receptor might also prevent oxidative damage due to conditions such as cerebral ischemic stroke. The antipsychotic drug haloperidol is an antagonist of Sigma-1 receptors and in this s...

Drug ratio-dependent antagonism: a new category of multidrug resistance and strategies for its circumvention.

Science.gov (United States)

Harasym, Troy O; Liboiron, Barry D; Mayer, Lawrence D

2010-01-01

A newly identified form of multidrug resistance (MDR) in tumor cells is presented, pertaining to the commonly encountered resistance of cancer cells to anticancer drug combinations at discrete drug:drug ratios. In vitro studies have revealed that whether anticancer drug combinations interact synergistically or antagonistically can depend on the ratio of the combined agents. Failure to control drug ratios in vivo due to uncoordinated pharmacokinetics could therefore lead to drug resistance if tumor cells are exposed to antagonistic drug ratios. Consequently, the most efficacious drug combination may not occur at the typically employed maximum tolerated doses of the combined drugs if this leads to antagonistic ratios in vivo after administration and resistance to therapeutic effects of the drug combination. Our approach to systematically screen a wide range of drug ratios and concentrations and encapsulate the drug combination in a liposomal delivery vehicle at identified synergistic ratios represents a means to mitigate this drug ratio-dependent MDR mechanism. The in vivo efficacy of the improved agents (CombiPlex formulations) is demonstrated and contrasted with the decreased efficacy when drug combinations are exposed to tumor cells in vivo at antagonistic ratios.

Antiallergic effects of H1-receptor antagonists.

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Baroody, F M; Naclerio, R M

2000-01-01

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

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

Directory of Open Access Journals (Sweden)

Alireza Komaki

2014-07-01

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

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

Science.gov (United States)

Komaki, Alireza; Abdollahzadeh, Fatemeh; Sarihi, Abdolrahman; Shahidi, Siamak; Salehi, Iraj

2014-01-01

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

Hazards and Benefits of Drug Interaction

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Labianca, Dominick A.

1978-01-01

Most cases of drug toxicity are direct consequences of drug misuse--either intentional or inadvertent. Discusses two types of drug interaction--synergistic and antagonistic. The former produces a combined effect greater than the sum of the effects of the individual drugs concerned; the latter is produced when the desired action of one drug is…

Drug: D00836 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D00836.gif ... Analgesic ... DG01984 ... Opioid analgesics ... DG01586 ... Opioid receptor antagonist Other ... DG01718 ... Drugs... for addictive disorder ... DG01717 ... Drugs for opioid dependence Therapeutic category: 1149 ATC code: N02AE0

Drug: D02780 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available )2. Ca D02780.gif ... Neuropsychiatric agent ... DG01498 ... NMDA receptor antagonist Other ... DG01718 ... Drugs for add...ictive disorder ... DG01716 ... Drugs for alcohol dependence Therapeutic category: 1190 ATC code: N07BB03 Chemica

A Time-course Study with the Androgen Receptor Antagonist Flutamide in Fish

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Flutamide, a drug registered to treat some types of prostate cancer in humans, has been used for many years as a model androgen receptor (AR) antagonist in studies aimed at characterizing disruption of the vertebrate hypothalamic-pituitary-gonadal (HPG) axis. Various studies hav...

Drug: D01340 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available gif ... Analgesic ... DG01586 ... Opioid receptor antagonist Other ... DG01718 ... Drugs for addictive disorder ... DG01717 ... Drugs for opioid depend...ence Therapeutic category: 2219 ATC code: A06AH04 V03AB15 Chemical group: DG01155 ...

The effects of N-methyl D-aspartate and B-adrenergic receptor antagonists on the reconsolidation of reward memory: a meta-analysis.

Science.gov (United States)

Das, Ravi K; Freeman, Tom P; Kamboj, Sunjeev K

2013-03-01

Pharmacological memory reconsolidation blockade provides a potential mechanism for ameliorating the maladaptive reward memories underlying relapse in addiction. Two of the most promising classes of drug that interfere with reconsolidation and have translational potential for human use are N-methyl-D-aspartate receptor (NMDAR) and B-Adrenergic receptor (B-AR) antagonists. We used meta-analysis and meta-regression to assess the effects of these drugs on the reconsolidation of reward memory in preclinical models of addiction. Pharmacokinetic, mnemonic and methodological factors were assessed for their moderating impact on effect sizes. An analysis of 52 independent effect sizes (NMDAR=30, B-AR=22) found robust effects of both classes of drug on memory reconsolidation, but a far greater overall effect of NMDAR antagonism than B-AR antagonism. Significant moderating effects of drug dose, relapse process and primary reinforcer were found. The findings suggest that reward memory reconsolidation can be robustly targeted by NMDAR antagonists and to a lesser extent, by B-AR antagonists. Implications for future clinical work are discussed. Copyright © 2012 Elsevier Ltd. All rights reserved.

Design and Synthesis of Benzimidazoles As Novel Corticotropin-Releasing Factor 1 Receptor Antagonists.

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Mochizuki, Michiyo; Kori, Masakuni; Kobayashi, Katsumi; Yano, Takahiko; Sako, Yuu; Tanaka, Maiko; Kanzaki, Naoyuki; Gyorkos, Albert C; Corrette, Christopher P; Cho, Suk Young; Pratt, Scott A; Aso, Kazuyoshi

2016-03-24

Benzazole derivatives with a flexible aryl group bonded through a one-atom linker as a new scaffold for a corticotropin-releasing factor 1 (CRF1) receptor antagonist were designed, synthesized, and evaluated. We expected that structural diversity could be expanded beyond that of reported CRF1 receptor antagonists. In a structure-activity relationship study, 4-chloro-N(2)-(4-chloro-2-methoxy-6-methylphenyl)-1-methyl-N(7),N(7)-dipropyl-1H-benzimidazole-2,7-diamine 29g had the most potent binding activity against a human CRF1 receptor and the antagonistic activity (IC50 = 9.5 and 88 nM, respectively) without concerns regarding cytotoxicity at 30 μM. Potent CRF1 receptor-binding activity in brain in an ex vivo test and suppression of stress-induced activation of the hypothalamus-pituitary-adrenocortical (HPA) axis were also observed at 138 μmol/kg of compound 29g after oral administration in mice. Thus, the newly designed benzimidazole 29g showed in vivo CRF1 receptor antagonistic activity and good brain penetration, indicating that it is a promising lead for CRF1 receptor antagonist drug discovery research.

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. Copyright © 2016 Elsevier Masson SAS. All rights reserved.

Drug: D08248 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available [veterinary] (TN) ... C19H21NO3. HCl D08248.gif ... Analgesic ... DG01586 ... Opioid receptor antagonist Other ... DG01718 ... Drugs... for addictive disorder ... DG01717 ... Drugs for opioid dependence ATC code: V03AB02 Chemical group: DG0

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.

Antagonist-agonist combinations as therapies for heroin addiction: back to the future?

Science.gov (United States)

Nutt, David J

2010-02-01

Psychopharmacology is a powerful approach to the treatment of many psychiatric disorders. In this article I discuss the conceptual and practical issues in relation to the use of mu opioid receptor agonist, antagonist and partial agonist drugs in the treatment of opioid addiction, as this is one therapeutic area where all three types of agents are currently available. The choice of pharmacological agent is largely determined by patient profile, existence of ongoing drug misuse, and the kinetics of the drugs available. These principles, however, can be applied to other disorders as and when other pharmacological approaches become refined in these areas.

AMD3465, a monomacrocyclic CXCR4 antagonist and potent HIV entry inhibitor

DEFF Research Database (Denmark)

Hatse, Sigrid; Princen, Katrien; De Clercq, Erik

2005-01-01

The chemokine receptors CCR5 and CXCR4 function as coreceptors for human immunodeficiency virus (HIV) and are attractive targets for the development of anti-HIV drugs. The most potent CXCR4 antagonists described until today are the bicyclams. The prototype compound, AMD3100, exhibits potent and s...

Effect of glycoprotein IIb/IIIa receptor inhibition on angiographic complications during percutaneous coronary intervention in the ESPRIT trial.

Science.gov (United States)

Blankenship, J C; Tasissa, G; O'Shea, J C; Iliadis, E A; Bachour, F A; Cohen, D J; Lui, H K; Mann, T; Cohen, E; Tcheng, J E

2001-09-01

We sought to determine whether eptifibatide decreases the incidence of in-laboratory angiographic complications and to determine the relationship of angiographically evident complications to elevations of creatine kinase-MB (CK-MB) enzyme levels during percutaneous coronary intervention. In the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial, eptifibatide during coronary intervention was associated with decreased ischemic complications at 48 h and 30 days. Patients (n = 2,064) were randomized to placebo versus eptifibatide (two 180 microg/kg boluses 10 min apart and as a continuous infusion of 2 microg/kg per min) during percutaneous coronary stenting. Angiographic complications including major dissection, distal embolization, residual thrombus, abrupt closure, residual stenosis >50% and side-branch occlusion were prospectively recorded by the operator. Creatine kinase-MB levels were measured after the procedure and every 6 h thereafter. The incidence of angiographic complications and CK-MB elevation was determined for eptifibatide versus placebo groups. Eptifibatide-treated patients demonstrated nonsignificant trends toward fewer angiographic complications (10 vs. 12% for placebo patients, p = 0.13) and, for patients with angiographic complications, fewer subsequent CK-MB elevations (43 vs. 50% for placebo patients, p = 0.31). In patients without any angiographic complications, the incidence of CK-MB elevation >3 times the normal was 7% with placebo and 4% with eptifibatide (p = 0.003). Eptifibatide during nonurgent coronary stent intervention only minimally (and insignificantly) reduces the incidence of angiographic complications and subsequent CK-MB elevations in patients developing an angiographic complication. The greater effect is to reduce myocardial infarction in patients undergoing otherwise uneventful coronary stent implantation as well as in the overall study population.

Secondary metabolites of Cynodon dactylon as an antagonist to angiotensin II type1 receptor: Novel in silico drug targeting approach for diabetic retinopathy

Science.gov (United States)

Jananie, R. K.; Priya, V.; Vijayalakshmi, K.

2012-01-01

Objectives: To study the ability of the secondary metabolites of Cynodon dactylon to serve as an antagonist to angiotensin II type 1 receptor (AT1); activation of this receptor plays a vital role in diabetic retinopathy (DR). Materials and Methods: In silico methods are mainly harnessed to reduce time, cost and risk associated with drug discovery. Twenty-four compounds were identified as the secondary metabolites of hydroalcoholic extract of C. dactylon using the GCMS technique. These were considered as the ligands or inhibitors that would serve as an antagonist to the AT1. The ACD/Chemsketch tool was used to generate 3D structures of the ligands. A molecular file format converter tool was used to convert the generated data to the PDB format (Protein Data Bank) and was used for docking studies. The AT1 structure was retrieved from the Swissprot data base and PDB and visualized using the Rasmol tool. Domain analysis was carried from the Pfam data base; following this, the active site of the target protein was identified using a Q-site finder tool. The ability of the ligands to bind with the active site of AT1 was studied using the Autodocking tool. The docking results were analyzed using the WebLab viewer tool. Results: Sixteen ligands showed effective binding with the target protein; diazoprogesteron, didodecyl phthalate, and 9,12-octadecadienoyl chloride (z,z) may be considered as compounds that could be used to bind with the active site sequence of AT1. Conclusions: The present study shows that the metabolites of C. dactylon could serve as a natural antagonist to AT1 that could be used to treat diabetic retinopathy. PMID:22368412

Opioid antagonists for pharmacological treatment of gambling disorder: Are they relevant?

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Victorri-Vigneau, Caroline; Spiers, Andrew; Caillet, Pascal; Bruneau, Mélanie; Challet-Bouju, Gaëlle; Grall-Bronnec, Marie

2017-07-18

Background: To date, no drugs have been approved for gambling disorder. Numerous publications have described the value of opioid antagonists. Indeed, the mesocorticolimbic dopaminergic pathway has been suggested as the underlying cause of reward-seeking behaviour, and it is modulated by the opioid system. Objective: This study aims to evaluate the relevance of opioid antagonists for treating GD. Method A systematic literature review was conducted. A search of the PubMed electronic database, PsycINFO and the Cochrane Systematic Review Database without any limits was performed. Results: There is little information concerning the effects of opioid antagonists on GD. The total search with "nalmefene and gambling" without any limits revealed only 11 articles. The search with "naltrexone and gambling" without any limits generated 47 articles. Nevertheless, the best available data support the use of opioid antagonists, particularly in individuals with a history of alcohol use disorder or strong gambling urges. Conclusion: Future trials are still needed. Indeed, opioid antagonists effectiveness has been investigated in only a limited number of patients, clinical trials do not reflect the heterogeneity of GD and there is little knowledge of the predictive factors of response to treatments. Moreover, differential affinity to nalmefene for kappa receptors may be associated with a particular effect in a yet to be defined addiction phenotype. Head to head comparisons between naltrexone and nalmefene would be helpful in combining with other medication or psychotherapy. The identification of subgroups of patients that are more likely to benefit from opioid antagonists should be a goal. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

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.

Virtual screening-driven repositioning of etoposide as CD44 antagonist in breast cancer cells

Science.gov (United States)

Aguirre-Alvarado, Charmina; Segura-Cabrera, Aldo; Velázquez-Quesada, Inés; Hernández-Esquivel, Miguel A.; García-Pérez, Carlos A.; Guerrero-Rodríguez, Sandra L.; Ruiz, Angel J.; Rodríguez-Moreno, Andrea; Pérez-Tapia, Sonia M.; Velasco-Velázquez, Marco A.

2016-01-01

CD44 is a receptor for hyaluronan (HA) that promotes epithelial-to-mesenchymal transition (EMT), induces cancer stem cell (CSC) expansion, and favors metastasis. Thus, CD44 is a target for the development of antineoplastic agents. In order to repurpose drugs as CD44 antagonists, we performed consensus-docking studies using the HA-binding domain of CD44 and 11,421 molecules. Drugs that performed best in docking were examined in molecular dynamics simulations, identifying etoposide as a potential CD44 antagonist. Ligand competition and cell adhesion assays in MDA-MB-231 cells demonstrated that etoposide decreased cell binding to HA as effectively as a blocking antibody. Etoposide-treated MDA-MB-231 cells developed an epithelial morphology; increased their expression of E-cadherin; and reduced their levels of EMT-associated genes and cell migration. By gene expression analysis, etoposide reverted an EMT signature similarly to CD44 knockdown, whereas other topoisomerase II (TOP2) inhibitors did not. Moreover, etoposide decreased the proportion of CD44+/CD24− cells, lowered chemoresistance, and blocked mammosphere formation. Our data indicate that etoposide blocks CD44 activation, impairing key cellular functions that drive malignancy, thus rendering it a candidate for further translational studies and a potential lead compound in the development of new CD44 antagonists. PMID:27009862

Antidepressant activity of nociceptin/orphanin FQ receptor antagonists in the mouse learned helplessness.

Science.gov (United States)

Holanda, Victor A D; Medeiros, Iris U; Asth, Laila; Guerrini, Remo; Calo', Girolamo; Gavioli, Elaine C

2016-07-01

Pharmacological and genetic evidence support antidepressant-like effects elicited by the blockade of the NOP receptor. The learned helplessness (LH) model employs uncontrollable and unpredictable electric footshocks as a stressor stimulus to induce a depressive-like phenotype that can be reversed by classical antidepressants. The present study aimed to evaluate the action of NOP receptor antagonists in helpless mice. Male Swiss mice were subjected to the three steps of the LH paradigm (i.e., (1) induction, (2) screening, and (3) test). Only helpless animals were subjected to the test session. During the test session, animals were placed in the electrified chamber and the latency to escape after the footshock and the frequency of escape failures were recorded. The effect of the following treatments administered before the test session were evaluated: nortriptyline (30 mg/kg, ip, 60 min), fluoxetine (30 mg/kg, ip, four consecutive days of treatment), and NOP antagonists SB-612111 (1-10 mg/kg, ip, 30 min) and UFP-101 (1-10 nmol, icv, 5 min). To rule out possible biases, the effects of treatments on controllable stressful and non stressful situations were assessed. In helpless mice, nortriptyline, fluoxetine, UFP-101 (3-10 nmol), and SB-612111 (3-10 mg/kg) significantly reduced escape latencies and escape failures. No effects of drug treatments were observed in mice subjected to the controllable electric footshocks and non stressful situations. Acute treatment with NOP antagonists reversed helplessness similarly to the classical antidepressants. These findings support the proposal that NOP receptor antagonists are worthy of development as innovative antidepressant drugs.

Opioid antagonists with minimal sedation for opioid withdrawal.

Science.gov (United States)

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

2017-05-29

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

NMDA receptor antagonists inhibit catalepsy induced by either dopamine D1 or D2 receptor antagonists.

Science.gov (United States)

Moore, N A; Blackman, A; Awere, S; Leander, J D

1993-06-11

In the present study, we investigated the ability of NMDA receptor antagonists to inhibit catalepsy induced by haloperidol, or SCH23390 and clebopride, selective dopamine D1 and D2 receptor antagonists respectively. Catalepsy was measured by recording the time the animal remained with its forepaws placed over a rod 6 cm above the bench. Pretreatment with either the non-competitive NMDA receptor antagonist, MK-801 (0.25-0.5 mg/kg i.p.) or the competitive antagonist, LY274614 (10-20 mg/kg i.p.) reduced the cataleptic response produced by haloperidol (10 mg/kg), SCH23390 (2.5-10 mg/kp i.p.) or clebopride (5-20 mg/kg i.p.). This demonstrates that NMDA receptor antagonists will reduce both dopamine D1 and D2 receptor antagonist-induced catalepsy. Muscle relaxant doses of chlordiazepoxide (10 mg/kg i.p.) failed to reduce the catalepsy induced by haloperidol, suggesting that the anticataleptic effect of the NMDA receptor antagonists was not due to a non-specific action. These results support the hypothesis that NMDA receptor antagonists may have beneficial effects in disorders involving reduced dopaminergic function, such as Parkinson's disease.

Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naïve atrial fibrillation patients

DEFF Research Database (Denmark)

Olesen, Jonas Bjerring; Sørensen, Rikke; Hansen, Morten Lock

2015-01-01

AIMS: Non-vitamin K antagonist oral anticoagulation (NOAC) agents have been approved for stroke prophylaxis in atrial fibrillation (AF). We investigated 'real-world' information on how these drugs are being adopted. METHODS AND RESULTS: Using Danish nationwide administrative registers, we identif...

High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations

Science.gov (United States)

Mott, Bryan T.; Eastman, Richard T.; Guha, Rajarshi; Sherlach, Katy S.; Siriwardana, Amila; Shinn, Paul; McKnight, Crystal; Michael, Sam; Lacerda-Queiroz, Norinne; Patel, Paresma R.; Khine, Pwint; Sun, Hongmao; Kasbekar, Monica; Aghdam, Nima; Fontaine, Shaun D.; Liu, Dongbo; Mierzwa, Tim; Mathews-Griner, Lesley A.; Ferrer, Marc; Renslo, Adam R.; Inglese, James; Yuan, Jing; Roepe, Paul D.; Su, Xin-zhuan; Thomas, Craig J.

2015-01-01

Drug resistance in Plasmodium parasites is a constant threat. Novel therapeutics, especially new drug combinations, must be identified at a faster rate. In response to the urgent need for new antimalarial drug combinations we screened a large collection of approved and investigational drugs, tested 13,910 drug pairs, and identified many promising antimalarial drug combinations. The activity of known antimalarial drug regimens was confirmed and a myriad of new classes of positively interacting drug pairings were discovered. Network and clustering analyses reinforced established mechanistic relationships for known drug combinations and identified several novel mechanistic hypotheses. From eleven screens comprising >4,600 combinations per parasite strain (including duplicates) we further investigated interactions between approved antimalarials, calcium homeostasis modulators, and inhibitors of phosphatidylinositide 3-kinases (PI3K) and the mammalian target of rapamycin (mTOR). These studies highlight important targets and pathways and provide promising leads for clinically actionable antimalarial therapy. PMID:26403635

X-ray analysis of the effect of the 5-HT3 receptor antagonist granisetron on gastrointestinal motility in rats repeatedly treated with the antitumoral drug cisplatin.

Science.gov (United States)

Vera, Gema; López-Pérez, Ana Esther; Martínez-Villaluenga, María; Cabezos, Pablo Antonio; Abalo, Raquel

2014-08-01

Cancer chemotherapy is associated with the development of numerous adverse effects, including nausea, emesis and other alterations in gastrointestinal (GI) motility. The administration of 5-HT3 receptor antagonists has provided a clinical advance in the treatment of chemotherapy-induced vomiting but these drugs lose efficacy throughout chronic treatment. The effects of these drugs in experimental animals under chronic administration are not well known. Our aim was to study, using radiographic methods, the effect of the 5-HT3 receptor antagonist granisetron on GI dysmotility induced in the rat by repeated cisplatin administration. First, invasive methods were used to select a dose of granisetron capable of reducing increased stomach weight due to acute cisplatin administration (6 mg/kg, ip). Second, rats received two intraperitoneal (ip) injections once a week for 4 weeks: granisetron (1 mg/kg, ip) or saline and, thirty min later, saline or cisplatin (2 mg/kg, ip). Body weight gain was measured throughout treatment. Radiological techniques were used to determine the acute (after first dose) and chronic (after last dose) effects of cisplatin and/or granisetron on GI motility. Repeated cisplatin-induced weight loss which granisetron did not prevent. Gastric emptying was delayed after the first cisplatin administration. Granisetron completely prevented this effect. After weekly administration, cisplatin-induced gastric dysmotility was enhanced and granisetron was not capable of completely preventing this effect. Granisetron prevents gastric emptying alterations, but its efficacy decreases throughout antineoplastic treatment. This might be due to the enhanced effect of cisplatin.

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

Science.gov (United States)

Nawata, Yoko; Kitaichi, Kiyoyuki; Yamamoto, Tsuneyuki

2016-03-01

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

Effects of chronic mild stress on the development of drug dependence in rats.

Science.gov (United States)

Papp, Mariusz; Gruca, Piotr; Lason-Tyburkiewicz, Magdalena; Litwa, Ewa; Willner, Paul

2014-09-01

There is high comorbidity between depression and addiction. Features of addiction relevant to depression have been studied extensively, but less is known about features of depression relevant to addiction. Here, we have studied the effects of chronic mild stress (CMS), a valid animal model of depression, on measures of physical and psychological dependence resulting from subchronic treatment of rats with three drugs of abuse that act through disparate neurobiological mechanisms: morphine, nicotine and diazepam. In animals not treated subchronically with drugs of abuse, CMS increased the withdrawal-like effects of the opiate antagonist naloxone, but not those of the nicotinic antagonist mecamylamine or the benzodiazepine antagonist flumazenil. In animals treated subchronically with drugs of abuse, CMS exacerbated, precipitated and conditioned withdrawal effects associated with all three antagonists. CMS also potentiated withdrawal-induced and cue-induced place aversions associated with all three antagonists. All of the effects of CMS were reversed by chronic treatment with the specific serotonin reuptake inhibitor citalopram. These results suggest that treatment of comorbid depression, although not a primary treatment for addiction, may facilitate other treatments for addiction, by decreasing the severity of withdrawal symptoms and the likelihood of relapse.

Novel quinolinone-phosphonic acid AMPA antagonists devoid of nephrotoxicity.

Science.gov (United States)

Cordi, Alex A; Desos, Patrice; Ruano, Elisabeth; Al-Badri, Hashim; Fugier, Claude; Chapman, Astrid G; Meldrum, Brian S; Thomas, Jean-Yves; Roger, Anita; Lestage, Pierre

2002-10-01

We reported previously the synthesis and structure-activity relationships (SAR) in a series of 2-(1H)-oxoquinolines bearing different acidic functions in the 3-position. Exploiting these SAR, we were able to identify 6,7-dichloro-2-(1H)-oxoquinoline-3-phosphonic acid compound 3 (S 17625) as a potent, in vivo active AMPA antagonist. Unfortunately, during the course of the development, nephrotoxicity was manifest at therapeutically effective doses. Considering that some similitude exists between S 17625 and probenecid, a compound known to protect against the nephrotoxicity and/or slow the clearance of different drugs, we decided to synthesise some new analogues of S 17625 incorporating some of the salient features of probenecid. Replacement of the chlorine in position 6 by a sulfonylamine led to very potent AMPA antagonists endowed with good in vivo activity and lacking nephrotoxicity potential. Amongst the compounds evaluated, derivatives 7a and 7s appear to be the most promising and are currently evaluated in therapeutically relevant stroke models.

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.

Evidence that diclofenac and celecoxib are thyroid hormone receptor beta antagonists.

Science.gov (United States)

Zloh, Mire; Perez-Diaz, Noelia; Tang, Leslie; Patel, Pryank; Mackenzie, Louise S

2016-02-01

Long term use of NSAIDs is linked to side effects such as gastric bleeding and myocardial infarction. Use of in silico methods and pharmacology to investigate the potential for NSAIDs diclofenac, celecoxib and naproxen to bind to nuclear receptors. In silico screening predicted that both diclofenac and celecoxib has the potential to bind to a number of different nuclear receptors; docking analysis confirmed a theoretical ability for diclofenac and celecoxib but not naproxen to bind to TRβ. Results from TRβ luciferase reporter assays confirmed that both diclofenac and celecoxib display TRβ antagonistic properties; celecoxib, IC50 3.6 × 10(-6)M, and diclofenac IC50 5.3 × 10(-6)M, comparable to the TRβ antagonist MLS (IC50 3.1 × 10(-6)M). In contrast naproxen, a cardio-sparing NSAID, lacked TRβ antagonist effects. In order to determine the effects of NSAIDs in whole organ in vitro, we used isometric wire myography to measure the changes to Triiodothyronine (T3) induced vasodilation of rat mesenteric arteries. Incubation of arteries in the presence of the TRβ antagonist MLS000389544 (10(-5)M), as well as diclofenac (10(-5)M) and celecoxib (10(-5)M) but not naproxen significantly inhibited T3 induced vasodilation compared to controls. These results highlight the benefits of computational chemistry methods used to retrospectively analyse well known drugs for side effects. Using in silico and in vitro methods we have shown that both celecoxib and diclofenac but not naproxen exhibit off-target TRβ antagonist behaviour, which may be linked to their detrimental side effects. Copyright © 2016 Elsevier Inc. All rights reserved.

Assessment of the abuse liability of a dual orexin receptor antagonist: a crossover study of almorexant and zolpidem in recreational drug users.

Science.gov (United States)

Cruz, Hans G; Hoever, Petra; Chakraborty, Bijan; Schoedel, Kerri; Sellers, Edward M; Dingemanse, Jasper

2014-04-01

Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000 mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40 mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24 h post-dose in 33 evaluable subjects. Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p<0.001). Almorexant 200 mg showed significantly less 'Drug Liking' than both zolpidem doses (p<0.01), and almorexant 400 mg had smaller effects than zolpidem 20 mg (p<0.05), while almorexant 1,000 mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.

Effects of matrix metalloproteinase inhibitor doxycycline and CD147 antagonist peptide-9 on gallbladder carcinoma cell lines.

Science.gov (United States)

Wang, Shihang; Liu, Chao; Liu, Xinjiang; He, Yanxin; Shen, Dongfang; Luo, Qiankun; Dong, Yuxi; Dong, Haifeng; Pang, Zhigang

2017-10-01

Gallbladder carcinoma is the most common and aggressive malignancy of the biliary tree and highly expresses CD147, which is closely related to disease prognosis in a variety of human cancers. Doxycycline exhibited anti-tumor properties in many cancer cells. CD147 antagonist peptide-9 is a polypeptide and can specifically bind to CD147. The effect of these two drugs on gallbladder cancer cells has not been studied. The aim of this study is to investigate the effect of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells and the possible mechanism of inhibition on cancer cell of doxycycline. To investigate the effects of doxycycline and antagonist peptide-9 on gallbladder carcinoma cells (GBC-SD and SGC-996), cell proliferation, CD147 expression, and early-stage apoptosis rate were measured after treated with doxycycline. Matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were measured after treated with different concentrations of doxycycline, antagonist peptide-9, and their combination. The results demonstrated that doxycycline inhibited cell proliferation, reduced CD147 expression level, and induced an early-stage apoptosis response in GBC-SD and SGC-996 cells. The matrix metalloproteinase-2 and matrix metalloproteinase-9 activities were inhibited by antagonist peptide-9 and doxycycline, and the inhibitory effects were enhanced by combined drugs in gallbladder carcinoma cell lines. Taken together, doxycycline showed inhibitory effects on gallbladder carcinoma cell lines and reduced the expression of CD147, and this may be the mechanism by which doxycycline inhibits cancer cells. This study provides new information and tries to implement the design of adjuvant therapy method for gallbladder carcinoma.

Subconjunctival Delivery of p75NTR Antagonists Reduces the Inflammatory, Vascular, and Neurodegenerative Pathologies of Diabetic Retinopathy.

Science.gov (United States)

Galan, Alba; Barcelona, Pablo F; Nedev, Hinyu; Sarunic, Marinko V; Jian, Yifan; Saragovi, H Uri

2017-06-01

The p75NTR is a novel therapeutic target validated in a streptozotocin mouse model of diabetic retinopathy. Intravitreal (IVT) injection of small molecule p75NTR antagonist THX-B was therapeutic and resolved the inflammatory, vascular, and neurodegenerative phases of the retinal pathology. To simplify clinical translation, we sought a superior drug delivery method that circumvents risks associated with IVT injections. We compared the pharmacokinetics of a single 40 μg subconjunctival (SCJ) depot to the reported effective 5 μg IVT injections of THX-B. We quantified therapeutic efficacy, with endpoints of inflammation, edema, and neuronal death. The subconjunctival depot affords retinal exposure equal to IVT injection, without resulting in detectable drug in circulation. At week 2 of diabetic retinopathy, the SCJ depot provided therapeutic efficacy similar to IVT injections, with reduced inflammation, reduced edema, reduced neuronal death, and a long-lasting protection of the retinal structure. Subconjunctival injections are a safe and effective route for retinal delivery of p75NTR antagonists. The subconjunctival route offers an advantageous, less-invasive, more compliant, and nonsystemic method to deliver p75NTR antagonists for the treatment of retinal diseases.

Drug: D08247 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D08247 Drug Nalorphine (INN); Nalorphine serb (TN) ... C19H21NO3 D08247.gif ... Analgesic ... DG01586 ... Opioid receptor antagonist Other ... DG01718 ... Drugs for addictive disorder ... DG01717 ... Drugs for opioid dependence Same as: C11787 ATC code: V03AB02 Chemical group: DG01151 ... CAS: 62-67-9 PubChem: 96024935 ChEBI: 7458 ChEMBL: CHEMBL415284 LigandBox: D08247 NIKKAJI: J4.825I ...

Re-prescribing of causative drugs in persons discharged after serious drug-induced upper gastrointestinal bleeding

DEFF Research Database (Denmark)

Dall, M; Christensen, René dePont; Schaffalitzky de Muckadell, O B

2012-01-01

Several drug classes are known to be associated with serious upper gastrointestinal bleeding (UGIB), among others NSAID, low-dose acetylsalicylic acid (ASA), vitamin K antagonists (VKA), clopidogrel and selective serotonin reuptake inhibitors (SSRIs). There are few data on how and to what extent...... these drugs are reintroduced in patients who have been discharged after a bleeding episode related to any of them....

Anticonvulsant and reproductive toxicological studies of the imidazole-based histamine H3R antagonist 2-18 in mice

Directory of Open Access Journals (Sweden)

Bastaki SM

2018-01-01

Full Text Available Salim M Bastaki,1 Yousef M Abdulrazzaq,2 Mohamed Shafiullah,1 Małgorzata Więcek,3 Katarzyna Kieć-Kononowicz,3 Bassem Sadek1 1Department of Pharmacology and Therapeutics, College of Medicine and Health Science, United Arab Emirates University, Al Ain, 2Department of Medical Education, Dubai Health Authority, Dubai, UAE; 3Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Medyczna, Kraków, Poland Abstract: The imidazole-based H3R antagonist 2-18 with high in vitro H3R antagonist affinity, excellent in vitro selectivity profile, and high in vivo H3R antagonist potency was tested for its anticonvulsant effect in maximal electroshock (MES-induced convulsions in mice having valproic acid (VPA as a reference antiepileptic drug (AED. Additionally, H3R antagonist 2-18 was evaluated for its reproductive toxicity in the same animal species. The results show that acute systemic administration (intraperitoneal; i.p. of H3R antagonist 2-18 (7.5, 15, 30, and 60 mg/kg, i.p. significantly and dose dependently protected male as well as female mice against MES-induced convulsion. The protective action observed for H3R antagonist 2-18 in both mice sexes was comparable to that of VPA and was reversed when mice were pretreated with the selective H3R agonist (R-alpha-methylhistamine (RAMH, 10 mg/kg, i.p.. Moreover, the results show that acute systemic administration of single (7.5, 15, 30, or 60 mg/kg, i.p. or multiple doses (15×3 mg/kg, i.p. of H3R antagonist 2-18 on gestation day (GD 8 or 13 did not affect the maternal body weight of mice when compared with the control group. Furthermore, no significant differences were observed in the average number of implantations and resorptions between the control and H3R antagonist 2-18-treated group at the early stages of gestation and the organogenesis period. However, oral treatment with H3R antagonist 2-18 (15 mg/kg on GD 8 induced a reduced number of

Serotonergic 5-HT6 Receptor Antagonists: Heterocyclic Chemistry and Potential Therapeutic Significance.

Science.gov (United States)

Bali, Alka; Singh, Shalu

2015-01-01

The serotonin 5-HT(6) receptor (5- HT(6)R) is amongst the recently discovered serotonergic receptors with almost exclusive localization in the brain. Hence, this receptor is fast emerging as a promising target for cognition enhancement in central nervous system (CNS) diseases such as Alzheimer's disease (cognitive function), obesity, schizophrenia and anxiety. The last decade has seen a surge of literature reports on the functional role of this receptor in learning and memory processes and investigations related to the chemistry and pharmacology of 5-HT(6) receptor ligands, especially 5- HT(6) receptor antagonists. Studies show the involvement of multiple neurotransmitter systems in cognitive enhancement by 5-HT(6)R antagonists including cholinergic, glutamatergic, and GABAergic systems. Several of the 5-HT(6)R ligands are indole based agents bearing structural similarity to the endogenous neurotransmitter serotonin. Based on the pharmacophoric models proposed for these agents, drug designing has been carried out incorporating various heterocyclic replacements for the indole nucleus. In this review, we have broadly summarized the medicinal chemistry and current status of this fairly recent class of drugs along with their potential therapeutic applications.

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.

THE USE OF GnRH ANTAGONISTS IN OVARIAN STIMULATION FOR INTRAUTERINE INSEMINATION

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Mete Işıkoğlu

2013-12-01

Full Text Available The first paper entitled intrauterine insemination (IUI was published in 1962. By time, several methods involving the technique and the ovulation induction schedules have evolved in order to improve the success rates. Although gonadotrophin releasing hormone antagonists (GnRHa is a crucial part of assisted reproductive treatments now, concerns also arouse regarding the need for the use of it in IUI cycles. These drugs may be considered in IUI programs basically in order to prevent premature LH surges and related cycle cancellations. Although administration of a GnRH antagonist almost completely abolishes premature luteinization, it does not substantially improve the pregnancy rate. The decision of using GnRH antagonists in IUI cycles should be based primarily on the local cost/benefit analysis of individual centers. It will be prudent to limit the involvement of the antagonists in ovulation induction protocols to: patients who frequently exhibit premature LH discharges and therefore either fail to complete treatment or result in unsuccessful outcome; initiated cycles intented for IUI but converted to ART; if it is not possible for logistic reasons (weekend to perform the insemination or for medical centers in which a gynecologist on call is not available and in order to decrease clinical task burden resulting from strict cycle monitoring such as serial transvaginal sonography and/or frequent urine tests.

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

Science.gov (United States)

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

2008-01-01

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

Synergism between dexketoprofen and meloxicam in an orofacial formalin test was not modified by opioid antagonists.

Science.gov (United States)

Gonzalez, Claudia; Zegpi, Carlos; Noriega, Viviana; Prieto, Juan C; Miranda, Hugo F

2011-01-01

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely used drugs for the management of acute and chronic pain. The role of the opioid system in the synergism between NSAIDs is not well characterized. Mice were injected with a 5% formalin solution (20 μl) into the upper right lip to perform an orofacial formalin test. The isobolographic method was used to determine the interaction between dexketoprofen, which is the (S)-(+) enantiomer of ketoprofen, and meloxicam co-administration. Additionally, the non-selective, opioid antagonist naltrexone, the selective δ opioid receptor (DOP) antagonist naltrindole and the selective κ opioid receptor (KOP) antagonist norbinaltorphimine were used to assess the opioid effects on this interaction. Intraperitoneal administration of dexketoprofen or meloxicam induced dose-dependent antinociception with different phase I and phase II potencies in the orofacial formalin test. Meloxicam displayed similar potencies (ED(50)) in phase I (7.20 mg/kg) and phase II (8.60 mg/kg). Dexketoprofen was more potent in phase I (19.96 mg/kg) than in phase II (50.90 mg/kg). The interactions between dexketoprofen and meloxicam were synergistic in both phases. This was determined based on the fixed ratios (1:1) of their ED(50) values, which were determined by isobolographic analysis. Furthermore, this antinociceptive activity does not seem to be modulated by opioid receptor blockers because they did not induce changes in the nature of this interaction. This finding may be relevant with regards to NSAID multi-modal analgesia where an opioid antagonist must be used.

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

Return of D4 Dopamine Receptor Antagonists in Drug Discovery.

Science.gov (United States)

Lindsley, Craig W; Hopkins, Corey R

2017-09-14

The dopamine D 4 receptor garnered a great deal of interest in the early 1990s when studies showed the atypical antipsychotic clozapine possessed higher affinity for D 4 , relative to other dopamine receptor subtypes, and that this activity might underlie the unique clinical efficacy of clozapine. Unfortunately, D 4 antagonists that were developed for schizophrenia failed in the clinic. Thus, D 4 fell out of favor as a therapeutic target, and work in this area was silent for decades. Recently, D 4 ligands with improved selectivity for D 4 against not only D 1-3,5 but also other biogenic amine targets have emerged, and D 4 is once again in the spotlight as a novel target for both addiction and Parkinson's disease (PD), as well as other emerging diseases. This report will review the historical data for D 4 , review the known D 4 ligands, and then highlight new data supporting a role for D 4 inhibition in addiction, PD, and cancer.

A Drug Discovery Partnership for Personalized Breast Cancer Therapy

Science.gov (United States)

2015-09-01

antagonists) and then virtually screen the USDA Phytochemical, Chinese Herbal Medicine , and the FDA Marketed Drug Databases for new estrogens. Task 1...and antagonists that are in the registered pharmaceuticals and herbal medicine databases. The 29 analogs obtained have been characterized for...Marleesa Bastian, Technician at Xavier University (Sridhar lab and is now pursuing graduation at Meharry Medical College school of Medicine , Tennessee

Effects of sigma(1) receptor ligand MS-377 on D(2) antagonists-induced behaviors.

Science.gov (United States)

Karasawa, Jun-ichi; Takahashi, Shinji; Takagi, Kaori; Horikomi, Kazutoshi

2002-10-01

(R)-(+)-1-(4-Chlorophenyl)-3-[4-(2-methoxyethyl)piperazin-1-yl]methyl-2-pyrrolidinone L-tartrate (MS-377) is a novel antipsychotic agent with selective and high affinity for sigma(1) receptor. The present study was carried out to clarify the interaction of MS-377 with dopamine D(2) receptor antagonists (D(2) antagonists) in concurrent administration, and then the involvement of sigma receptors in the interaction. The effects of MS-377 on haloperidol- or sultopride-induced inhibition of apomorphine-induced climbing behavior and catalepsy were investigated in mice and rats, respectively. In addition, the effects of (+)-SKF-10,047 and SA4503, both of which are sigma receptor agonists, and WAY-100,635, which is a 5-HT(1A) receptor antagonist, on the interaction due to the concurrent use were also investigated. MS-377 potentiated the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior in a dose-dependent manner. In contrast, MS-377 did not affect the catalepsy induction by these drugs. The potentiation of the inhibitory effects of haloperidol or sultopride on apomorphine-induced climbing behavior by MS-377 was not inhibited by WAY-100,635, but was inhibited by (+)-SKF-10,047 and SA4503. These findings showed that MS-377 potentiates the efficacy of D(2) antagonists, but it does not deteriorate the adverse effect. Moreover, sigma(1) receptors are involved in this potentiation of the efficacy of D(2) antagonists by MS-377.

Inhibition of Ebola and Marburg Virus Entry by G Protein-Coupled Receptor Antagonists.

Science.gov (United States)

Cheng, Han; Lear-Rooney, Calli M; Johansen, Lisa; Varhegyi, Elizabeth; Chen, Zheng W; Olinger, Gene G; Rong, Lijun

2015-10-01

Filoviruses, consisting of Ebola virus (EBOV) and Marburg virus (MARV), are among the most lethal infectious threats to mankind. Infections by these viruses can cause severe hemorrhagic fevers in humans and nonhuman primates with high mortality rates. Since there is currently no vaccine or antiviral therapy approved for humans, there is an urgent need to develop prophylactic and therapeutic options for use during filoviral outbreaks and bioterrorist attacks. One of the ideal targets against filoviral infection and diseases is at the entry step, which is mediated by the filoviral glycoprotein (GP). In this report, we screened a chemical library of small molecules and identified numerous inhibitors, which are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs, including histamine receptors, 5-HT (serotonin) receptors, muscarinic acetylcholine receptor, and adrenergic receptor. These inhibitors can effectively block replication of both infectious EBOV and MARV, indicating a broad antiviral activity of the GPCR antagonists. The time-of-addition experiment and microscopic studies suggest that GPCR antagonists block filoviral entry at a step following the initial attachment but prior to viral/cell membrane fusion. These results strongly suggest that GPCRs play a critical role in filoviral entry and GPCR antagonists can be developed as an effective anti-EBOV/MARV therapy. Infection of Ebola virus and Marburg virus can cause severe illness in humans with a high mortality rate, and currently there is no FDA-approved vaccine or therapeutic treatment available. The 2013-2015 epidemic in West Africa underscores a lack of our understanding in the infection and pathogenesis of these viruses and the urgency of drug discovery and development. In this study, we have identified numerous inhibitors that are known G protein-coupled receptor (GPCR) antagonists targeting different GPCRs. These inhibitors can effectively block replication of both infectious

75 FR 70933 - Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting

Science.gov (United States)

2010-11-19

...] Cardiovascular and Renal Drugs Advisory Committee; Notice of Meeting AGENCY: Food and Drug Administration, HHS... of Committee: Cardiovascular and Renal Drugs Advisory Committee. General Function of the Committees... appropriate clinical study design for thromboxane receptor antagonists for prevention of cardiovascular events...

Carbon adaptation influence the antagonistic ability of ...

African Journals Online (AJOL)

Jane

2011-10-24

Oct 24, 2011 ... INTRODUCTION. The use of antagonistic bacteria to control soil-borne ... plant was used to evaluate the antifungal activities of antagonistic bacteria. ..... antagonistic bacteria and cloning of its phenazine carboxylic acid genes.

Structural Biology of the TNFα Antagonists Used in the Treatment of Rheumatoid Arthritis

Directory of Open Access Journals (Sweden)

Heejin Lim

2018-03-01

Full Text Available The binding of the tumor necrosis factor α (TNFα to its cognate receptor initiates many immune and inflammatory processes. The drugs, etanercept (Enbrel®, infliximab (Remicade®, adalimumab (Humira®, certolizumab-pegol (Cimzia®, and golimumab (Simponi®, are anti-TNFα agents. These drugs block TNFα from interacting with its receptors and have enabled the development of breakthrough therapies for the treatment of several autoimmune inflammatory diseases, including rheumatoid arthritis, Crohn’s disease, and psoriatic arthritis. In this review, we describe the latest works on the structural characterization of TNFα–TNFα antagonist interactions related to their therapeutic efficacy at the atomic level. A comprehensive comparison of the interactions of the TNFα blockers would provide a better understanding of the molecular mechanisms by which they neutralize TNFα. In addition, an enhanced understanding of the higher order complex structures and quinary structures of the TNFα antagonists can support the development of better biologics with the improved pharmacokinetic properties. Accumulation of these structural studies can provide a basis for the improvement of therapeutic agents against TNFα for the treatment of rheumatoid arthritis and other autoimmune inflammatory diseases in which TNFα plays an important role in pathogenesis.

Structural refinement and prediction of potential CCR2 antagonists through validated multi-QSAR modeling studies.

Science.gov (United States)

Amin, Sk Abdul; Adhikari, Nilanjan; Baidya, Sandip Kumar; Gayen, Shovanlal; Jha, Tarun

2018-01-03

Chemokines trigger numerous inflammatory responses and modulate the immune system. The interaction between monocyte chemoattractant protein-1 and chemokine receptor 2 (CCR2) may be the cause of atherosclerosis, obesity, and insulin resistance. However, CCR2 is also implicated in other inflammatory diseases such as rheumatoid arthritis, multiple sclerosis, asthma, and neuropathic pain. Therefore, there is a paramount importance of designing potent and selective CCR2 antagonists despite a number of drug candidates failed in clinical trials. In this article, 83 CCR2 antagonists by Jhonson and Jhonson Pharmaceuticals have been considered for robust validated multi-QSAR modeling studies to get an idea about the structural and pharmacophoric requirements for designing more potent CCR2 antagonists. All these QSAR models were validated and statistically reliable. Observations resulted from different modeling studies correlated and validated results of other ones. Finally, depending on these QSAR observations, some new molecules were proposed that may exhibit higher activity against CCR2.

Effect of intrathecal non-NMDA EAA receptor antagonist LY293558 in rats: a new class of drugs for spinal anesthesia.

Science.gov (United States)

Von Bergen, Nicholas H; Subieta, Alberto; Brennan, Timothy J

2002-07-01

Excitatory amino acid receptors are important for both sensory and motor function in the spinal cord. We studied the effects of intrathecal LY293558, a competitive non-N-methyl-D-aspartate excitatory amino acid receptor antagonist, on motor and sensory function in rats to determine whether drugs blocking these receptors could potentially be used as alternative agents to local anesthetics for spinal anesthesia. Rats were tested before and 15-240 min after intrathecal injection of 5 nmol (in 10 microl) LY293558. Sensory function was tested at the hind paw using withdrawal response to pin prick and withdrawal to pinch with sharp forceps. Motor performance (ambulation, placing reflex, and Rotorod time), blood pressure, and heart rate were also evaluated. Some tests were repeated the next day. Responses after LY293558 were compared to injection of 40 microl bupivacaine, 0.75%. Pin-prick responses at the forepaw, chest, abdomen, hind leg, and hind paw were also examined after intrathecal LY293558. Intrathecal LY293558 blocked both sensory and motor responses through 180 min; complete recovery was present the following day. No change in blood pressure or heart rate occurred. The effects of LY293558 were more pronounced and sustained than those of bupivacaine. Segmental blockade of the response to pin prick was present after LY293558. Drugs like LY293558 that block alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)/kainate receptors may be an alternative to local anesthetics for spinal anesthesia in humans.

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.

5-HT6 receptor antagonist attenuates the memory deficits associated with neuropathic pain and improves the efficacy of gabapentinoids.

Science.gov (United States)

Jayarajan, Pradeep; Nirogi, Ramakrishna; Shinde, Anil; Goura, Venkatesh; Babu, Vuyyuru Arun; Yathavakilla, Sumanth; Bhyrapuneni, Gopinadh

2015-10-01

Memory deficit is a co-morbid disorder in patients suffering from neuropathic pain. Gabapentin and pregabalin (gabapentinoids) are among the widely prescribed medications for the treatment of neuropathic pain. Memory loss and sedation are the commonly reported side effects with gabapentinoids. Improving the cognitive functions and attenuating drug-induced side effects may play a crucial role in the management of pain. We evaluated the effects of 5-HT6 receptor antagonists on the memory deficits associated with neuropathy. We also studied the effects of 5-HT6 receptor antagonists on the side effects, and the analgesic effects of gabapentinoids. 5-HT6 receptor antagonists attenuated the cognitive deficits in neuropathic rats. Neuropathic rats co-treated with 5-HT6 receptor antagonist and gabapentinoids showed improvement in memory. 5-HT6 receptor antagonists enhanced the analgesic effects of gabapentinoids but had no effect on the motor side effects. The observed effects may not be due to pharmacokinetic interactions. 5-HT6 receptor antagonist attenuate the cognitive deficits associated with neuropathy, and this effect is also seen when co-treated with gabapentinoids. Since, 5-HT6 antagonists improved the effectiveness of gabapentinoids, reduction in the dosage and frequency of gabapentinoids treatment may reduce the side effects. Combining 5-HT6 receptor antagonist with gabapentinoids may offer a novel treatment strategy for neuropathic pain. Copyright © 2015 Institute of Pharmacology, Polish Academy of Sciences. Published by Elsevier Urban & Partner Sp. z o.o. All rights reserved.

Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data

DEFF Research Database (Denmark)

Sørensen, Rikke; Hansen, Morten L; Abildstrøm, Steen

2009-01-01

BACKGROUND: Combinations of aspirin, clopidogrel, and vitamin K antagonists are widely used in patients after myocardial infarction. However, data for the safety of combinations are sparse. We examined the risk of hospital admission for bleeding associated with different antithrombotic regimens...... according to the following groups: monotherapy with aspirin, clopidogrel, or vitamin K antagonist; dual therapy with aspirin plus clopidogrel, aspirin plus vitamin K antagonist, or clopidogrel plus vitamin K antagonist; or triple therapy including all three drugs. Risk of hospital admission for bleeding...... was 2.6% for the aspirin group, 4.6% for clopidogrel, 4.3% for vitamin K antagonist, 3.7% for aspirin plus clopidogrel, 5.1% for aspirin plus vitamin K antagonist, 12.3% for clopidogrel plus vitamin K antagonist, and 12.0% for triple therapy. With aspirin as reference, adjusted hazard ratios...

Inducible nitric oxide inhibitors block NMDA antagonist-stimulated motoric behaviors and medial prefrontal cortical glutamate efflux

Directory of Open Access Journals (Sweden)

Hadley C Bergstrom

2015-12-01

Full Text Available Nitric oxide (NO plays a critical role in the motoric and glutamate releasing action of N-methyl-D-aspartate (NMDA-antagonist stimulants. Earlier studies utilized neuronal nitric oxide synthase inhibitors (nNOS for studying the neurobehavioral effects of noncompetitive NMDA-antagonist stimulants such as dizocilpine (MK-801 and phencyclidine (PCP. This study explores the role of the inducible nitric oxide synthase inhibitors (iNOS aminoguanidine (AG and (--epigallocatechin-3-gallate (EGCG in NMDA-antagonist induced motoric behavior and prefrontal cortical glutamate efflux. Adult male rats were administered a dose range of AG, EGCG or vehicle prior to receiving NMDA antagonists MK-801, PCP or a conventional psychostimulant (cocaine and tested for motoric behavior in an open arena. Glutamate in the medial prefrontal cortex was measured using in vivo microdialysis after a combination of AG or EGCG prior to MK-801. Acute administration of AG or EGCG dose-dependently attenuated the locomotor and ataxic properties of MK-801 and PCP. Both AG and EGCG were unable to block the motoric effects of cocaine, indicating the acute pharmacologic action of AG and EGCG is specific to NMDA antagonism and not generalizable to all stimulant class drugs. AG and EGCG normalized MK-801-stimulated medial prefrontal cortical glutamate efflux. These data demonstrate that AG and EGCG attenuates NMDA antagonist-stimulated motoric behavior and cortical glutamate efflux. Our results suggest that EGCG-like polyphenol nutraceuticals (contained in green tea and chocolate may be clinically useful in protecting against the adverse behavioral dissociative and cortical glutamate stimulating effects of NMDA antagonists. Medications that interfere with NMDA antagonists such as MK-801 and PCP have been proposed as treatments for schizophrenia.

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...

Drug: D00966 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available if ... Antineoplastic ... DG01585 ... Estrogen receptor antagonist Other ... DG01619 ... Clomifene and tamoxifen derivative ... DG01620 ... Tam... D00966 Drug Tamoxifen citrate (JP17/USP); Nolvadex (TN) ... C26H29NO. C6H8O7 D00966.g

Emerging migraine treatments and drug targets

DEFF Research Database (Denmark)

Olesen, Jes; Ashina, Messoud

2011-01-01

Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5......-hydroxytrypamine (5-HT)(1F) receptor agonists, which are in late-stage development. Nitric oxide antagonists are also in development. New forms of administration of sumatriptan might improve efficacy and reduce side effects. Botulinum toxin A has recently been approved for the prophylaxis of chronic migraine....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development...

Calcium channel agonists and antagonists regulate protein phosphorylation in intact synaptosomes

International Nuclear Information System (INIS)

Robinson, P.J.; Lovenberg, Walter

1986-01-01

Protein phosphorylation in intact synaptosomes is highly sensitive to alterations in calcium fluxes and was used to probe the possible mechanism of action of the calcium channel agonist BAY K 8644 and antagonists verapamil and nifedipine. These agents (at 1μM) all increased the basal phosphorylation of a specific set of 4 synaptosomal phosphoproteins termed P139, P124, P96 and P60, but did not alter depolarization-dependent protein phosphorylation. The increases could not be explained by a direct stimulation of protein kinases and appears unrelated to the known effects of these + drugs on K + -stimulated neuro-transmitter release. This finding may reveal a possible new mechanism of action for drugs which interact with calcium channels. (Author)

Behavioral, biological, and chemical perspectives on targeting CRF1 receptor antagonists to treat alcoholism

Science.gov (United States)

Zorrilla, Eric P.; Heilig, Markus; de Wit, Harriet; Shaham, Yavin

2013-01-01

Background Alcohol use disorders are chronic disabling conditions for which existing pharmacotherapies have only modest efficacy. In the present review, derived from the 2012 Behavior, Biology and Chemistry “Translational Research in Addiction” symposium, we summarize the anti-relapse potential of corticotropin-releasing factor type 1 (CRF1) receptor antagonists to reduce negative emotional symptoms of acute and protracted alcohol withdrawal and stress-induced relapse to alcohol seeking. Methods We review the biology of CRF1 systems, the activity of CRF1 receptor antagonists in animal models of anxiolytic and antidepressant activity, and experimental findings in alcohol addiction models. We also update the clinical trial status of CRF1 receptor antagonists, including pexacerfont (BMS-562086), emicerfont (GW876008), verucerfont (GSK561679), CP316311, SSR125543A, R121919/NBI30775, R317573/19567470/CRA5626, and ONO-2333Ms. Finally, we discuss the potential heterogeneity and pharmacogenomics of CRF1 receptor pharmacotherapy for alcohol dependence. Results The evidence suggests that brain penetrant-CRF1 receptor antagonists have therapeutic potential for alcohol dependence. Lead compounds with clinically desirable pharmacokinetic properties now exist, and longer receptor residence rates (i.e., slow dissociation) may predict greater CRF1 receptor antagonist efficacy. Functional variants in genes that encode CRF system molecules, including polymorphisms in Crhr1 (rs110402, rs1876831, rs242938) and Crhbp genes (rs10055255, rs3811939) may promote alcohol seeking and consumption by altering basal or stress-induced CRF system activation. Conclusions Ongoing clinical trials with pexacerfont and verucerfont in moderately to highly severe dependent anxious alcoholics may yield insight as to the role of CRF1 receptor antagonists in a personalized medicine approach to treat drug or alcohol dependence. PMID:23294766

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

Directory of Open Access Journals (Sweden)

F. Ben Mbarka

2018-03-01

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

Role of imaging techniques in the evaluation of cardiovascular drugs

International Nuclear Information System (INIS)

Sugishita, Yasuro; Matsuda, Mitsuo; Ajisaka, Ryuichi

1985-01-01

In order to investigate the role of imaging in the evaluation of medical treatment in heart diseases, radionuclide angiocardiography, echocardiography and Doppler echocardiography were applied in the cases of various kinds of heart diseases. Acute and chronic effects of antianginal drugs (nitrates, calcium antagonists and beta-blockers) could be evaluated by exercise radionuclide angiocardiography or exercise echocardiography in the cases of effort angina. The effects of the drugs changing myocardial contractility, preload or afterload could be evaluated by echocardiography in various kinds of heart diseases, including valvular heart biseases. The effect of calcium antagonists in improving diastolic function in hypertrophic cardiomyopathy could be evaluated by echocardiography or Doppler echocardiography. In conclusion, imaging techniqus are valuable and useful methods to evaluate the effects of cardiovascular drugs, by offering various informations. (author)

Drugs for insomnia.

Science.gov (United States)

Zisapel, Nava

2012-09-01

Sleep is a vital neurochemical process involving sleep-promoting and arousal centers in the brain. Insomnia is a pervasive disorder characterized by difficulties in initiating or maintaining or non-refreshing (poor quality) sleep and clinically significant daytime distress. Insomnia is more prevalent in women and old age and puts sufferers at significant physical and mental health risks. This review summarizes published data on the current and emerging insomnia drug classes, rationale for development and associated risks/benefits. (Summary of Product Characteristics and Medline search on "hypnotic" or specific drug names and "Insomnia"). GABA(A) receptor modulators facilitate sleep onset and some improve maintenance but increase risk of dependence, memory, cognitive and psychomotor impairments, falls, accidents and mortality. Melatonin receptor agonists improve quality of sleep and/or sleep onset but response may develop over several days. They have more benign safety profiles and are indicated for milder insomnia, longer usage and (prolonged release melatonin) older patients. Histamine H-1 receptor antagonists improve sleep maintenance but their effects on cognition, memory and falls remain to be demonstrated. Late-stage pipeline orexin OX1/OX2 and serotonin 5HT2A receptor antagonists may hold the potential to address several unmet needs in insomnia pharmacotherapy but safety issues cast some doubts over their future. Current and new insomnia drugs in the pipeline target different sleep regulating mechanisms and symptoms and have different tolerability profiles. Drug selection would ideally be based on improvement in the quality of patients' sleep, overall quality of life and functional status weighed against risk to the individual and public health.

The Antidepressant 5-HT2A Receptor Antagonists Pizotifen and Cyproheptadine Inhibit Serotonin-Enhanced Platelet Function

Science.gov (United States)

Lin, Olivia A.; Karim, Zubair A.; Vemana, Hari Priya; Espinosa, Enma V. P.; Khasawneh, Fadi T.

2014-01-01

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 EMD 281014, their

GABAA receptor partial agonists and antagonists

DEFF Research Database (Denmark)

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

2015-01-01

to the local temporal pattern of GABA impact, enabling phasic or tonic inhibition. Specific GABAAR antagonists are essential tools for physiological and pharmacological elucidation of the different type of GABAAR inhibition. However, distinct selectivity among the receptor subtypes (populations) has been shown...... antagonists have been essential in defining the tonic current but both remaining issues concerning the GABAARs involved and the therapeutic possibilities of modulating tonic inhibition underline the need for GABAAR antagonists with improved selectivity....

Acute inhibition of selected membrane-proximal mouse T cell receptor signaling by mitochondrial antagonists.

Directory of Open Access Journals (Sweden)

Kwangmi Kim

2009-11-01

Full Text Available T cells absorb nanometric membrane vesicles, prepared from plasma membrane of antigen presenting cells, via dual receptor/ligand interactions of T cell receptor (TCR with cognate peptide/major histocompatibility complex (MHC plus lymphocyte function-associated antigen 1 (LFA-1 with intercellular adhesion molecule 1. TCR-mediated signaling for LFA-1 activation is also required for the vesicle absorption. Exploiting those findings, we had established a high throughput screening (HTS platform and screened a library for isolation of small molecules inhibiting the vesicle absorption. Follow-up studies confirmed that treatments (1 hour with various mitochondrial antagonists, including a class of anti-diabetic drugs (i.e., Metformin and Phenformin, resulted in ubiquitous inhibition of the vesicle absorption without compromising viability of T cells. Further studies revealed that the mitochondrial drug treatments caused impairment of specific membrane-proximal TCR signaling event(s. Thus, activation of Akt and PLC-gamma1 and entry of extracellular Ca(2+ following TCR stimulation were attenuated while polymerization of monomeric actins upon TCR triggering progressed normally after the treatments. Dynamic F-actin rearrangement concurring with the vesicle absorption was also found to be impaired by the drug treatments, implying that the inhibition by the drug treatments of downstream signaling events (and the vesicle absorption could result from lack of directional relocation of signaling and cell surface molecules. We also assessed the potential application of mitochondrial antagonists as immune modulators by probing effects of the long-term drug treatments (24 hours on viability of resting primary T cells and cell cycle progression of antigen-stimulated T cells. This study unveils a novel regulatory mechanism for T cell immunity in response to environmental factors having effects on mitochondrial function.

The effect of different classes of beta-antagonists on clinical and experimental hypertension.

Science.gov (United States)

Fitzgerald, J D

1982-01-01

The reference beta adrenoceptor antagonist propranolol reduces blood pressure in about 60% of patients with essential hypertension. Pressure is reduced in the supine, and erect positions without postural hypotension as well as during exercise. The average extent of pressure reduction is approximately 26/16 mm.Hg. Though all clinically available beta antagonists reduce blood pressure, the profile may be modified by both adrenotropic and non-adrenotropic ancillary properties. Of the adrenotropic properties, potency influences dose frequency and total body burden of drug. Selective beta 1 antagonism may enhance safety without reducing efficacy in patients with obstructive airways disease. Selective beta 2 blockade does not reduce blood pressure in experimental models or normal subjects, but the response in patients is unknown. Partial agonism may reduce efficacy if the degree of stimulant activity is too great. Of the non-adrenotropic properties, membrane stabilising properties are of relevance only in so far as such agents undergo extensive biotransformation resulting in either reduced efficacy when drugs are used at fixed doses or the formation of biologically active metabolites. The additional properties of either alpha adrenergic blockade or inhibition of vascular smooth muscle tone modify both the speed of onset and the haemodynamic profile. The interaction of these ancillary pharmacological properties is evaluated in this review.

Tachykinin NK₁ receptor antagonist co-administration attenuates opioid withdrawal-mediated spinal microglia and astrocyte activation.

Science.gov (United States)

Tumati, Suneeta; Largent-Milnes, Tally M; Keresztes, Attila I; Yamamoto, Takashi; Vanderah, Todd W; Roeske, William R; Hruby, Victor J; Varga, Eva V

2012-06-05

Prolonged morphine treatment increases pain sensitivity in many patients. Enhanced spinal Substance P release is one of the adaptive changes associated with sustained opioid exposure. In addition to pain transmitting second order neurons, spinal microglia and astrocytes also express functionally active Tachykinin NK₁ (Substance P) receptors. In the present work we investigated the role of glial Tachykinin NK₁ receptors in morphine withdrawal-mediated spinal microglia and astrocyte activation. Our data indicate that intrathecal co-administration (6 days, twice daily) of a selective Tachykinin NK₁ receptor antagonist (N-acetyl-L-tryptophan 3,5-bis(trifluoromethyl)benzylester (L-732,138; 20 μg/injection)) attenuates spinal microglia and astrocyte marker and pro-inflammatory mediator immunoreactivity as well as hyperalgesia in withdrawn rats. Furthermore, covalent linkage of the opioid agonist with a Tachykinin NK₁ antagonist pharmacophore yielded a bivalent compound that did not augment spinal microglia or astrocyte marker or pro-inflammatory mediator immunoreactivity and did not cause paradoxical pain sensitization upon drug withdrawal. Thus, bivalent opioid/Tachykinin NK₁ receptor antagonists may provide a novel paradigm for long-term pain management.

High-Throughput Screening of Small Molecules Identifies Hepcidin Antagonists

Science.gov (United States)

Fung, Eileen; Sugianto, Priscilla; Hsu, Jason; Damoiseaux, Robert; Ganz, Tomas

2013-01-01

Anemia of inflammation (AI) is common in patients with infection, autoimmune diseases, cancer, and chronic kidney disease. Unless the underlying condition can be reversed, treatment options are limited to erythropoiesis-stimulating agents with or without intravenous iron therapy, modalities that are not always effective and can cause serious adverse effects. Hepcidin, the iron regulatory hormone, has been identified as a pathogenic factor in the development of AI. To explore new therapeutic options for AI and other iron-related disorders caused by hepcidin excess, we developed a cell-based screen to identify hepcidin antagonists. Of the 70,000 small molecules in the library, we identified 14 compounds that antagonized the hepcidin effect on ferroportin. One of these was fursultiamine, a Food and Drug Administration (FDA)–approved thiamine derivative. Fursultiamine directly interfered with hepcidin binding to its receptor, ferroportin, by blocking ferroportin C326 thiol residue essential for hepcidin binding. Consequently, fursultiamine prevented hepcidin-induced ferroportin ubiquitination, endocytosis, and degradation in vitro and allowed continuous cellular iron export despite the presence of hepcidin, with IC50 in the submicromolar range. Thiamine, the fursultiamine metabolite, and benfotiamine, another thiamine derivative, did not interfere with the effect of hepcidin on ferroportin. Other FDA-approved thiol-reactive compounds were at least 1000-fold less potent than fursultiamine in antagonizing hepcidin. In vivo, fursultiamine did not reproducibly antagonize the effect of hepcidin on serum iron, likely because of its rapid conversion to inactive metabolites. Fursultiamine is a unique antagonist of hepcidin in vitro that could serve as a template for the development of drug candidates that inhibit the hepcidin-ferroportin interaction. PMID:23292796

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

Science.gov (United States)

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

2013-10-13

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

Similar efficacy from specific and non-specific mineralocorticoid receptor antagonist treatment of muscular dystrophy mice.

Science.gov (United States)

Lowe, Jeovanna; Floyd, Kyle T; Rastogi, Neha; Schultz, Eric J; Chadwick, Jessica A; Swager, Sarah A; Zins, Jonathan G; Kadakia, Feni K; Smart, Suzanne; Gomez-Sanchez, Elise P; Gomez-Sanchez, Celso E; Raman, Subha V; Janssen, Paul M L; Rafael-Fortney, Jill A

2016-01-01

Combined treatment with an angiotensin-converting enzyme inhibitor and a mineralocorticoid receptor (MR) antagonist improved cardiac and skeletal muscle function and pathology in a mouse model of Duchenne muscular dystrophy. MR is present in limb and respiratory skeletal muscles and functions as a steroid hormone receptor. The goals of the current study were to compare the efficacy of the specific MR antagonist eplerenone with the non-specific MR antagonist spironolactone, both in combination with the angiotensin-converting enzyme inhibitor lisinopril. Three groups of n=18 dystrophin-deficient, utrophin-haploinsufficient male mice were given chow containing: lisinopril plus spironolactone, lisinopril plus eplerenone, or no drug, from four to 20 weeks-of-age. Eighteen C57BL/10 male mice were used as wild-type controls. In vivo measurements included cardiac magnetic resonance imaging, conscious electrocardiography, and grip strength. From each mouse in the study, diaphragm, extensor digitorum longus , and cardiac papillary muscle force was measured ex vivo , followed by histological quantification of muscle damage in heart, diaphragm, quadriceps, and abdominal muscles. MR protein levels were also verified in treated muscles. Treatment with specific and non-specific MR antagonists did not result in any adverse effects to dystrophic skeletal muscles or heart. Both treatments resulted in similar functional and pathological improvements across a wide array of parameters. MR protein levels were not reduced by treatment. These data suggest that spironolactone and eplerenone show similar effects in dystrophic mice and support the clinical development of MR antagonists for treating skeletal muscles in Duchenne muscular dystrophy.

Decrement in operant performance produced by NMDA receptor antagonists in the rat: tolerance and cross-tolerance.

Science.gov (United States)

Dravolina, O A; Zvartau, E E; Bespalov, A Y

2000-04-01

Current perspectives on the clinical use of NMDA receptor antagonists infer repeated administration schedules for the management of different pathological states. The development of tolerance and cross-tolerance between different NMDA receptor antagonists may be an important factor contributing to the clinical efficacy of these drugs. The present study aimed to characterize the development of tolerance and cross-tolerance to the ability of various site-selective NMDA receptor antagonists to produce a decrement of operant responding (multiple extinction 9 s fixed-interval 1-s schedule of water reinforcement). Acute administration of D-CPPen (SDZ EAA 494; 1-5.6 mg/kg), dizocilpine (MK-801; 0.03-0.3 mg/kg), memantine (0.3-17 mg/kg), ACEA-1021 (10-56 mg/kg), and eliprodil (1-30 mg/kg) differentially affected operant responding. Both increases and decreases in response rates and accuracy of responding were observed. Repeated preexposure to D-CPPen (5.6 mg/kg, once a day for 7 days) attenuated a behavioral disruption produced by an acute challenge with D-CPPen or ACEA-1021, but potentiated the effects of dizocilpine, memantine, and eliprodil. Based on the present results, one can suggest that the repeated administration of a competitive NMDA receptor antagonist differentially affects the functional activity of various sites on NMDA receptor complex.

Adenosine A2A receptors in ventral striatum, hypothalamus and nociceptive circuitry. Implications for drug addiction, sleep and pain

Science.gov (United States)

Ferré, S.; Diamond, I.; Goldberg, S.R.; Yao, L.; Hourani, S.M.O.; Huang, Z.L.; Urade, Y.; Kitchen, I.

2007-01-01

Adenosine A2A receptors localized in the dorsal striatum are considered as a new target for the development of antiparkinsonian drugs. Co-administration of A2A receptor antagonists has shown a significant improvement of the effects of L-DOPA. The present review emphasizes the possible application of A2A receptor antagonists in pathological conditions other than parkinsonism, including drug addiction, sleep disorders and pain. In addition to the dorsal striatum, the ventral striatum (nucleus accumbens) contains a high density of A2A receptors, which presynaptically and postsynaptically regulate glutamatergic transmission in the cortical glutamatergic projections to the nucleus accumbens. It is currently believed that molecular adaptations of the cortico-accumbens glutamatergic synapses are involved in compulsive drug seeking and relapse. Here we review recent experimental evidence suggesting that A2A antagonists could become new therapeutic agents for drug addiction. Morphological and functional studies have identified lower levels of A2A receptors in brain areas other than the striatum, such as the ventrolateral preoptic area of the hypothalamus, where adenosine plays an important role in sleep regulation. Although initially believed to be mostly dependent on A1 receptors, here we review recent studies that demonstrate that the somnogenic effects of adenosine are largely mediated by hypothalamic A2A receptors. A2A receptor antagonists could therefore be considered as a possible treatment for narcolepsy and other sleep-related disorders. Finally, nociception is another adenosine-regulated neural function previously thought to mostly involve A1 receptors. Although there is some conflicting literature on the effects of agonists and antagonists, which may partly be due to the lack of selectivity of available drugs, the studies in A2A receptor knockout mice suggest that A2A receptor antagonists might have some therapeutic potential in pain states, in particular where

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 effects of brief periods of unrestricted vision differ for form-deprivation versus negative lens-wear, which may imply different growth

Influence of histamine and serotonin antagonists on the growth of xenografted human colorectal tumors.

Science.gov (United States)

Barkla, D H; Tutton, P J

1981-12-01

Four lines of human colorectal cancer were established and serially propagated as subcutaneous xenographs in immunosuppressed inbred CBA/Lac mice. Established xenografts were then used to investigate the influence of a serotonin antagonist (BW 501c) and a histamine H2 receptor antagonists (Cimetidine) on xenograft growth. The growth of each of the four tumor lines was significantly inhibited by BW 501c throughout the treatment, whereas the growth of only two tumor lines was significantly inhibited by Cimetidine treatment. The response of individual tumor lines was not predictable on the basis of either tumor histopathology or the natural growth rate of the untreated xenograft. A number of alternative, but not mutually exclusive, hypotheses are suggested to explain the results. One hypothesis proposes that colorectal tumors are composed of subpopulations of tumor cells that are variously dependent on or independent of amine hormones. Another hypothesis is that tumor cells exhibit temporal changes in hormone sensitivity to amine hormones during treatment. Finally, it is suggested that serotonin and/or histamine H2 antagonists may be useful in preventing the repopulation of colorectal carcinomas following antineoplastic therapy with the use of conventional drugs.

The role of nitrates, beta blockers, and calcium antagonists in stable angina pectoris.

Science.gov (United States)

Chan, P K; Heo, J Y; Garibian, G; Askenase, A; Segal, B L; Iskandrian, A S

1988-09-01

Numerous controlled studies have shown that nitrates, beta blockers, and calcium antagonists are effective in the treatment of stable angina pectoris. The pharmacokinetics, pharmacodynamics, and hemodynamic effects of these agents are different, and thus combination therapy offers additive improvement and also counterbalancing of the undesirable side effects of each drug. The choice of therapy depends on the severity of symptoms, associated diseases, compliance, side effects, and status of left ventricular function. The main mechanism of improvement is a decrease in myocardial oxygen consumption, though an increase in coronary blood flow is another potential reason for the use of calcium blockers. This review considers the properties of these drugs, their mechanism of action, and the results of randomized studies.

Multi-dose drug dispensing as a tool to improve medication adherence: A study in patients using vitamin K antagonists.

Science.gov (United States)

van Rein, Nienke; de Geus, Kristel S; Cannegieter, Suzanne C; Reitsma, Pieter H; van der Meer, Felix J M; Lijfering, Willem M

2018-01-01

Multi-dose drug dispensing (MDD) is a dosing aid that provides patients with disposable bags containing all drugs intended for 1 dosing moment. MDD is believed to increase medication adherence, but studies are based on self-reported data, and results may depend on socially desirable answers. Therefore, our purpose was to determine the effect of MDD on medication adherence in non-adherent patients taking vitamin K antagonists (VKAs), and to compare with instructing patients on medication use. We conducted a before-after study in non-adherent patients where MDD was the exposure and change in adherence after MDD initiation was the outcome (within patient comparison). Time in therapeutic range (TTR) was selected as a measure for adherence, as this reflects stability of VKA treatment. To analyze whether MDD improved adherence as compared with standard care (ie, letters or calls from nurses of the anticoagulation clinic), non-adherent patients without MDD were also followed to estimate their TTR change over time (between patient comparison). Eighty-three non-adherent VKA patients started using MDD. The median TTR was 63% before MDD and 73% 6 months after MDD. The within patient TTR increased on average by 13% (95%CI 6% to 21%) within 1 month after starting MDD and remained stable during the next 5 months. The TTR of MDD-patients increased 10% (95%CI 2% to 19%) higher as compared with non-MDD patients within 1 month but was similar after 4 months (TTR difference 3%, 95%CI -2% to 9%). Adherence improved after initiation of MDD. Compared with instructing patients, MDD was associated with better adherence within 1 month but was associated with similar improvement after 4 months. Copyright © 2017 John Wiley & Sons, Ltd.

Gemfibrozil, a lipid-lowering drug, upregulates interleukin-1 receptor antagonist in mouse cortical neurons: Implications for neuronal self-defense

Science.gov (United States)

Corbett, Grant T.; Roy, Avik; Pahan, Kalipada

2012-01-01

Chronic inflammation is becoming a hallmark of several neurodegenerative disorders and accordingly, interleukin-1 beta (IL-1β), a proinflammatory cytokine, is implicated in the pathogenesis of neurodegenerative diseases. While IL-1β binds to its high-affinity receptor, interleukin-1 receptor (IL-1R), and upregulates proinflammatory signaling pathways, interleukin-1 receptor antagonist (IL-1Ra) adheres to the same receptor and inhibits proinflammatory cell signaling. Therefore, upregulation of IL-1Ra is considered important in attenuating inflammation. The present study underlines a novel application of gemfibrozil, an FDA-approved lipid-lowering drug, in increasing the expression of IL-1Ra in primary mouse and human neurons. Gemfibrozil alone induced an early and pronounced increase in the expression of IL-1Ra in primary mouse cortical neurons. Activation of type IA p110α phosphatidylinositol 3-kinase (PI3-K) and Akt by gemfibrozil and abrogation of gemfibrozil-induced upregulation of IL-1Ra by inhibitors of PI3-K and Akt indicate a role of the PI3-K – Akt pathway in the upregulation of IL-1Ra. Gemfibrozil also induced the activation of cAMP response element-binding (CREB) via the PI3-K – Akt pathway and siRNA attenuation of CREB abolished the gemfibrozil-mediated increase in IL-1Ra. Furthermore, gemfibrozil was able to protect neurons from IL-1β insult. However, siRNA knockdown of neuronal IL-1Ra abrogated the protective effect of gemfibrozil against IL-1β suggesting that this drug increases the defense mechanism of cortical neurons via upregulation of IL-1Ra. Together, these results highlight the importance of the PI3-K – Akt – CREB pathway in mediating gemfibrozil-induced upregulation of IL-1Ra in neurons and suggest gemfibrozil as a possible therapeutic treatment for propagating neuronal self defense in neuroinflammatory and neurodegenerative disorders. PMID:22706077

Drug: D05801 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available D05801 Drug Saprisartan potassium (USAN) ... C25H21BrF3N4O4S. K D05801.gif ... Cardiov...01495 ... Angiotensin II receptor antagonist ... Treatment of hypertension and heart failure ... CAS: 146613-90-3 PubChem: 47207462 LigandBox: D05801 NIKKAJI: J776.888E ...

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.

Return to fertility after extended chemical castration with a GnRH antagonist

International Nuclear Information System (INIS)

Kostanski, Janusz W; Jiang, Ge; Dani, Bhas A; Murty, Santos B; Qiu, Wei; Schrier, Bruce; Thanoo, B C; DeLuca, Patrick P

2001-01-01

Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days) or vehicle alone (control group). Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter) and control (10.6 offspring per litter) were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist

Return to fertility after extended chemical castration with a GnRH antagonist

Directory of Open Access Journals (Sweden)

Schrier Bruce

2001-10-01

Full Text Available Abstract Background Antagonistic analogues of GnRH for the treatment of prostate cancer may be used clinically in persons for whom return to fertility after such treatment is important or desirable. The purpose of this study was, therefore, to evaluate the effects of a long term treatment with orntide, a GnRH antagonist, on testosterone levels and fertility in male rats. Methods Two groups of male rats received either 120-day orntide microspheres (8.8 mg orntide/kg/120 days or vehicle alone (control group. Serum orntide and testosterone levels in both groups were monitored at certain intervals for 9 months from the initiation of treatment. After recovery of normal serum testosterone levels in the treated animals, each rat was housed with two proven breeder, but drug-naive, females. Results All mates of treated rats achieved pregnancy as rapidly as the mates of control rats although two of the control rats did not sire a litter with either female and one sired only one litter. The mean size of the litters of treated (12.3 offspring per litter and control (10.6 offspring per litter were similar. All offspring were grossly normal morphologically and behaviorally during the time to weaning. Conclusions These results suggest that lack of fertility due to testosterone suppression is reversible after cessation of treatment with this GnRH antagonist.

Behavioral consequences of NMDA antagonist-induced neuroapoptosis in the infant mouse brain.

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Carla M Yuede

2010-06-01

Full Text Available Exposure to NMDA glutamate antagonists during the brain growth spurt period causes widespread neuroapoptosis in the rodent brain. This period in rodents occurs during the first two weeks after birth, and corresponds to the third trimester of pregnancy and several years after birth in humans. The developing human brain may be exposed to NMDA antagonists through drug-abusing mothers or through anesthesia.We evaluated the long-term neurobehavioral effects of mice exposed to a single dose of the NMDA antagonist, phencyclidine (PCP, or saline, on postnatal day 2 (P2 or P7, or on both P2 and P7. PCP treatment on P2 + P7 caused more severe cognitive impairments than either single treatment. Histological examination of acute neuroapoptosis resulting from exposure to PCP indicated that the regional pattern of degeneration induced by PCP in P2 pups was different from that in P7 pups. The extent of damage when evaluated quantitatively on P7 was greater for pups previously treated on P2 compared to pups treated only on P7.These findings signify that PCP induces different patterns of neuroapoptosis depending on the developmental age at the time of exposure, and that exposure at two separate developmental ages causes more severe neuropathological and neurobehavioral consequences than a single treatment.

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

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Christina Ruhlmann

2009-05-01

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

Crystal structure of the[mu]-opioid receptor bound to a morphinan antagonist

Energy Technology Data Exchange (ETDEWEB)

Manglik, Aashish; Kruse, Andrew C.; Kobilka, Tong Sun; Thian, Foon Sun; Mathiesen, Jesper M.; Sunahara, Roger K.; Pardo, Leonardo; Weis, William I.; Kobilka, Brian K.; Granier, Sébastien (Michigan-Med); (Stanford-MED); (UAB, Spain)

2012-06-27

Opium is one of the world's oldest drugs, and its derivatives morphine and codeine are among the most used clinical drugs to relieve severe pain. These prototypical opioids produce analgesia as well as many undesirable side effects (sedation, apnoea and dependence) by binding to and activating the G-protein-coupled {mu}-opioid receptor ({mu}-OR) in the central nervous system. Here we describe the 2.8 {angstrom} crystal structure of the mouse {mu}-OR in complex with an irreversible morphinan antagonist. Compared to the buried binding pocket observed in most G-protein-coupled receptors published so far, the morphinan ligand binds deeply within a large solvent-exposed pocket. Of particular interest, the {mu}-OR crystallizes as a two-fold symmetrical dimer through a four-helix bundle motif formed by transmembrane segments 5 and 6. These high-resolution insights into opioid receptor structure will enable the application of structure-based approaches to develop better drugs for the management of pain and addiction.

Drug: D08559 [KEGG MEDICUS

Lifescience Database Archive (English)

Full Text Available Antineoplastic ... DG01585 ... Estrogen receptor antagonist Other ... DG01619 ... Clomifene and tamoxifen derivative ... DG01620 ... Tam... D08559 Drug Tamoxifen (INN); Tamoxifen (TN); Tamoplex (TN) ... C26H29NO D08559.gif ... ...en [CPD:C16547] Indication: Metastatic breast cancer Use Tamoxifen to Patients who have factor V leiden muta

Screening computer-assisted dosage programs for anticoagulation with warfarin and other vitamin K antagonists: minimum safety requirements for individual programs

DEFF Research Database (Denmark)

Poller, L; Roberts, C; Ibrahim, S

2009-01-01

Based on the results of the previous European Action on Anticoagulation (EAA) multicenter study, a simplified minimum procedure is described for screening the safety and effectiveness of marketed programs for dosage of oral anticoagulant drugs (vitamin K antagonists). The aim was to demonstrate non...

[New oral anticoagulant drugs].

Science.gov (United States)

Berkovits, Alejandro; Aizman, Andrés; Zúñiga, Pamela; Pereira, Jaime; Mezzano, Diego

2011-10-01

Thromboembolic disease (TED) is the leading cause of morbidity and mortality worldwide. The hallmark of oral long-term anticoagulant therapy has been the use of vitamin K antagonists, whose anticoagulant effect is exerted inhibiting vitamin K epoxide reductase. Warfarin and acenocoumarol are the most commonly used. In the last five years several new drugs for long term anticoagulation have been developed, which can inhibit single clotting factors with the purpose of improving drug therapeutic range and, ideally, minimizing bleeding risks. This review addresses the state of the art on the clinical use of inhibitors of activated factor X and thrombin.

[The trend of new drug development for the treatment of diabetes mellitus].

Science.gov (United States)

Kaku, Kohei

2015-12-01

The trend of new drug development in the field of diabetes mellitus is overviewed. The hypoglycemic drugs such as glucagon receptor antagonists, glucokinase activators, and GPR agonists and oral medication of GLP-1 receptor agonist are under phase 2 trial in Japan. As for therapeutic medicines for diabetic nephropathy, atrasentan as an endothelin A receptor antagonist is in phase 3 trial, and bardoxolone methyl as Nrf2 activator in phase 2 in Japan. Canagliflozin, a SGLT2 inhibitor, is in phase 3 study to obtain new indication of diabetic nephropathy. An environment surrounding development of therapeutic medicines for diabetes has been tough since FDA guidance in 2008.

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.

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.

Effects of TNF antagonists on immune and neuroendocrine system

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M. Cutolo

2011-09-01

Full Text Available In the article, the literature on the effects of TNFa-antagonists (etanercept, infliximab and adalimumab on the immune system is reviewed. These biologic agents are employed in chronic inflammatory diseases such as rheumatoid arthritis, seronegative spondyloarthritides, as well as psoriasis and Crohn’s disease. The differences of these drugs, testified by the different effects on the immune response, are discussed. These molecules exert their effect through cytokine inhibition, but they present striking differences since they can modulate macrophage activity, T cells apoptosis, leukocyte migration, and angiogenesis to a different degree. Some studies showed that these agents also affect the hypothalamo- pituitary-adrenal axis. The potential immunogenicity of these biologic agents is also discussed.

``In silico'' study of the binding of two novel antagonists to the nociceptin receptor

Science.gov (United States)

Della Longa, Stefano; Arcovito, Alessandro

2018-02-01

Antagonists of the nociceptin receptor (NOP) are raising interest for their possible clinical use as antidepressant drugs. Recently, the structure of NOP in complex with some piperidine-based antagonists has been revealed by X-ray crystallography. In this study, a multi-flexible docking (MF-docking) procedure, i.e. docking to multiple receptor conformations extracted by preliminary molecular dynamics trajectories, together with hybrid quantum mechanics/molecular mechanics (QM/MM) simulations have been carried out to provide the binding mode of two novel NOP antagonists, one of them selective (BTRX-246040, formerly named LY-2940094) and one non selective (AT-076), i.e. able to inactivate NOP as well as the classical µ- k- and δ-opioid receptors (MOP KOP and DOP). According to our results, the pivotal role of residue D1303,32 (upper indexes are Ballesteros-Weinstein notations) is analogous to that enlighten by the already known X-ray structures of opioid receptors: binding of the molecules are predicted to require a slight readjustment of the hydrophobic pocket (residues Y1313,33, M1343,36, I2195,43, Q2806,52 and V2836,55) in the orthosteric site of NOP, accommodating either the pyridine-pyrazole (BTRX-246040) or the isoquinoline (AT-076) moiety of the ligand, in turn allowing the protonated piperidine nitrogen to maximize interaction (salt-bridge) with residue D1303,32 of the NOP, and the aromatic head to be sandwiched in optimal π-stacking between Y1313,33 and M1343,36. The QM/MM optimization after the MF-docking procedure has provided the more likely conformations for the binding to the NOP receptor of BTRX-246040 and AT-076, based on different pharmacophores and exhibiting different selectivity profiles. While the high selectivity for NOP of BTRX-246040 can be explained by interactions with NOP specific residues, the lack of selectivity of AT-076 could be associated to its ability to penetrate into the deep hydrophobic pocket of NOP, while retaining a

Screening of chemokine receptor CCR4 antagonists by capillary zone electrophoresis

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Zhe Sun

2011-11-01

Full Text Available CC chemokine receptor 4 (CCR4 is a kind of G-protein-coupled receptor, which plays a pivotal role in allergic inflammation. The interaction between 2-(2-(4-chloro-phenyl-5-{[(naphthalen-1-ylmethyl-carbamoyl]-methyl}-4-oxo-thiazolidin-3-yl-N-(3-morpholin-4-yl-propyl-acetamide (S009 and the N-terminal extracellular tail (ML40 of CCR4 has been validated to be high affinity by capillary zone electrophoresis (CZE. The S009 is a known CCR4 antagonist. Now, a series of new thiourea derivatives have been synthesized. Compared with positive control S009, they were screened using ML40 as target by CZE to find some new drugs for allergic inflammation diseases. The synthesized compounds XJH-5, XJH-4, XJH-17 and XJH-1 displayed the interaction with ML40, but XJH-9, XJH-10, XJH-11, XJH-12, XJH-13, XJH-14, XJH-3, XJH-8, XJH-6, XJH-7, XJH-15, XJH-16 and XJH-2 did not bind to ML40. Both qualification and quantification characterizations of the binding were determined. The affinity of the four compounds was valued by the binding constant, which was similar with the results of chemotactic experiments. The established CEZ method is capable of sensitive and fast screening for a series of lactam analogs in the drug discovery for allergic inflammation diseases. Keywords: Capillary zone electrophoresis, CCR4 antagonist, 2-(2-(4-chloro-phenyl-5-{[(naphthalen-1-ylmethyl-carbamoyl]-methyl}-4-oxo-thiazolidin-3-yl-N-(3-morpholin-4-yl-propyl-acetamide, Interactions, Structural modification

Structure-based prediction of subtype selectivity of histamine H3 receptor selective antagonists in clinical trials.

Science.gov (United States)

Kim, Soo-Kyung; Fristrup, Peter; Abrol, Ravinder; Goddard, William A

2011-12-27

Histamine receptors (HRs) are excellent drug targets for the treatment of diseases, such as schizophrenia, psychosis, depression, migraine, allergies, asthma, ulcers, and hypertension. Among them, the human H(3) histamine receptor (hH(3)HR) antagonists have been proposed for specific therapeutic applications, including treatment of Alzheimer's disease, attention deficit hyperactivity disorder (ADHD), epilepsy, and obesity. 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 and activity for such treatments, it would be useful to have the three-dimensional structures for all four HRs. We report here the predicted structures of four HR subtypes (H(1), H(2), H(3), and H(4)) using the GEnSeMBLE (GPCR ensemble of structures in membrane bilayer environment) Monte Carlo protocol, sampling ∼35 million combinations of helix packings to predict the 10 most stable packings for each of the four subtypes. Then we used these 10 best protein structures with the DarwinDock Monte Carlo protocol to sample ∼50 000 × 10(20) poses to predict the optimum ligand-protein structures for various agonists and antagonists. We find that E206(5.46) contributes most in binding H(3) selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/S5.43 in both of hH(3)HR and hH(4)HR are involved in H(3)/ H(4) subtype selectivity. In addition, we find that M378(6.55) in hH(3)HR provides additional hydrophobic interactions different from hH(4)HR (the corresponding amino acid of T323(6.55) in hH(4)HR) to provide additional subtype bias. From these studies, we developed a pharmacophore model based on our predictions for known hH(3)HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2, PF-3654746 3, and BF2.649 (tiprolisant) 4] that suggests critical selectivity directing elements are: the basic proton

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

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

Cost-effectiveness of histamine receptor-2 antagonist versus proton pump inhibitor for stress ulcer prophylaxis in critically ill patients*.

Science.gov (United States)

MacLaren, Robert; Campbell, Jon

2014-04-01

To examine the cost-effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. Decision analysis model examining costs and effectiveness of using histamine receptor-2 antagonist or proton pump inhibitor for stress ulcer prophylaxis. Costs were expressed in 2012 U.S. dollars from the perspective of the institution and included drug regimens and the following outcomes: clinically significant stress-related mucosal bleed, ventilator-associated pneumonia, and Clostridium difficile infection. Effectiveness was the mortality risk associated with these outcomes and represented by survival. Costs, occurrence rates, and mortality probabilities were extracted from published data. A simulation model. A mixed adult ICU population. Histamine receptor-2 antagonist or proton pump inhibitor for 9 days of stress ulcer prophylaxis therapy. Output variables were expected costs, expected survival rates, incremental cost, and incremental survival rate. Univariate sensitivity analyses were conducted to determine the drivers of incremental cost and incremental survival. Probabilistic sensitivity analysis was conducted using second-order Monte Carlo simulation. For the base case analysis, the expected cost of providing stress ulcer prophylaxis was $6,707 with histamine receptor-2 antagonist and $7,802 with proton pump inhibitor, resulting in a cost saving of $1,095 with histamine receptor-2 antagonist. The associated mortality probabilities were 3.819% and 3.825%, respectively, resulting in an absolute survival benefit of 0.006% with histamine receptor-2 antagonist. The primary drivers of incremental cost and survival were the assumptions surrounding ventilator-associated pneumonia and bleed. The probabilities that histamine receptor-2 antagonist was less costly and provided favorable survival were 89.4% and 55.7%, respectively. A secondary analysis assuming equal rates of C. difficile infection showed a cost saving of $908 with histamine

Marijuana-based Drugs: Innovative Therapeutics or Designer Drugs of Abuse?

OpenAIRE

Seely, Kathryn A.; Prather, Paul L.; James, Laura P.; Moran, Jeffery H.

2011-01-01

Marijuana has been used recreationally and medicinally for centuries. The principle psychoactive component, Δ9-tetrahydrocannabinol (Δ9-THC), activates CB1 cannabinoid receptors (CB1Rs). CB1R agonists and antagonists could potentially treat a wide variety of diseases; unfortunately, therapeutic doses produce unacceptable psychiatric effects. “K2” or “Spice” (K2/Spice), an emerging drug of abuse, exhibits psychotropic actions via CB1R activation. Because of structural dissimilarity to Δ9-THC, ...

Contemporary Parenteral Antiplatelet Bridging Strategies: A Single-Center Real-World Experience at a Tertiary Care Center.

Science.gov (United States)

Stern, Gretchen; Rimsans, Jessica; Qamar, Arman; Vaduganathan, Muthiah; Bhatt, Deepak L

2018-03-13

Oral antiplatelet therapy may require interruption soon after percutaneous coronary intervention (PCI) or acute coronary syndrome. The optimal parenteral antiplatelet bridge strategy with glycoprotein IIb/IIIa inhibitors or cangrelor, a P2Y12 inhibitor, is unclear. We explore real-world use of cangrelor or eptifibatide for antiplatelet bridging at a large tertiary-care center. Thirty-one patients (9 eptifibatide, 20 cangrelor, and 2 both) received bridge therapy from October 2015 to June 2017. Primary bridge therapy indications included surgery (68%), limited enteral access/absorption (16%), and high-perceived bleed risk (16%). Median duration of bridge therapy was 61 (20-100) hours for cangrelor and 83 (19-98) hours for eptifibatide. Severe/life-threatening bleeding or stent thrombosis was not observed. GUSTO-defined bleeding occurred in 30% (cangrelor) and 27% (eptifibatide). Initial dosing errors occurred in 23% of patients. Death during hospitalization occurred in 16% of patients. Parenteral antiplatelet bridging was used for ~3 days in this single-center, tertiary care experience, commonly for unplanned surgery following PCI. Despite high-risk presentations with >15% in-hospital mortality, efficacy profiles were reassuring with no identified stent thrombosis, but bleeding and dosing errors were common. Antiplatelet bridging should only be used in well-selected patients at the appropriate dose for the minimal necessary duration.

Biotransformation of the mineralocorticoid receptor antagonists spironolactone and canrenone by human CYP11B1 and CYP11B2: Characterization of the products and their influence on mineralocorticoid receptor transactivation.

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Schiffer, Lina; Müller, Anne-Rose; Hobler, Anna; Brixius-Anderko, Simone; Zapp, Josef; Hannemann, Frank; Bernhardt, Rita

2016-10-01

Spironolactone and its major metabolite canrenone are potent mineralocorticoid receptor antagonists and are, therefore, applied as drugs for the treatment of primary aldosteronism and essential hypertension. We report that both compounds can be converted by the purified adrenocortical cytochromes P450 CYP11B1 and CYP11B2, while no conversion of the selective mineralocorticoid receptor antagonist eplerenone was observed. As their natural function, CYP11B1 and CYP11B2 carry out the final steps in the biosynthesis of gluco- and mineralocorticoids. Dissociation constants for the new exogenous substrates were determined by a spectroscopic binding assay and demonstrated to be comparable to those of the natural substrates, 11-deoxycortisol and 11-deoxycorticosterone. Metabolites were produced at preparative scale with a CYP11B2-dependent Escherichia coli whole-cell system and purified by HPLC. Using NMR spectroscopy, the metabolites of spironolactone were identified as 11β-OH-spironolactone, 18-OH-spironolactone and 19-OH-spironolactone. Canrenone was converted to 11β-OH-canrenone, 18-OH-canrenone as well as to the CYP11B2-specific product 11β,18-diOH-canrenone. Therefore, a contribution of CYP11B1 and CYP11B2 to the biotransformation of drugs should be taken into account and the metabolites should be tested for their potential toxic and pharmacological effects. A mineralocorticoid receptor transactivation assay in antagonist mode revealed 11β-OH-spironolactone as pharmaceutically active metabolite, whereas all other hydroxylation products negate the antagonist properties of spironolactone and canrenone. Thus, human CYP11B1 and CYP11B2 turned out to metabolize steroid-based drugs additionally to the liver-dependent biotransformation of drugs. Compared with the action of the parental drug, changed properties of the metabolites at the target site have been observed. Copyright © 2016 Elsevier Ltd. All rights reserved.

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

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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...

Gonadotrophin releasing hormone antagonist in IVF/ICSI

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M S Kamath

2008-01-01

Full Text Available Objective : To study the efficacy of gonadotrophin releasing hormone (GnRH antagonist in In-vitro-fertilization/Intracytoplasmic sperm injection (IVF/ICSI cycles. Type of Study : Observational study. Setting: Reproductive Medicine Unit, Christian Medical College Hospital, Vellore, Tamil Nadu. Materials and Methods: GnRH antagonists were introduced into our practice in November 2005. Fifty-two women undergoing the antagonist protocol were studied and information gathered regarding patient profile, treatment parameters (total gonadotrophin dosage, duration of treatment, and oocyte yield, and outcomes in terms of embryological parameters (cleavage rates, implantation rates and clinical pregnancy. These parameters were compared with 121 women undergoing the standard long protocol. The costs between the two groups were also compared. Main Outcome : Clinical pregnancy rate. Results : The clinical pregnancy rate per embryo transfer in the antagonist group was 31.7% which was comparable to the clinical pregnancy rate in women undergoing the standard long protocol (30.63%. The costs between the two groups were comparable. Conclusions : GnRH antagonist protocol was found to be effective and comparable to the standard long protocol regimen. In addition it was simple, convenient, and patient friendly.

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

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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.

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

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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.

History of the 'geste antagoniste' sign in cervical dystonia.

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Poisson, A; Krack, P; Thobois, S; Loiraud, C; Serra, G; Vial, C; Broussolle, E

2012-08-01

The geste antagoniste is a voluntary maneuver that temporarily reduces the severity of dystonic posture or movements. It is a classical feature of focal and particularly cervical dystonia. However, the precise historical aspects of geste antagoniste still remain obscure. The goals of this review were (1) to clarify the origin of the geste antagoniste sign; (2) to identify the factors that led to its diffusion in the international literature; (3) to follow the evolution of that term across the twentieth century. We used medical and neurological French, German and English literature of the late nineteenth and early twentieth centuries, and the PubMed database by entering the terms geste antagoniste, antagonistic gesture and sensory trick. The geste antagoniste sign is a legacy of the Paris Neurological School of the end of the nineteenth century. The term was introduced by Meige and Feindel in their 1902 book on tics, written in the vein of their master, Brissaud, who first described this sign in 1893. The almost immediate translations of this book by Giese into German and Kinnier Wilson into English contributed to the rapid spreading of the term geste antagoniste, which is still in use worldwide today. The term antagonistic gesture is the translation proposed by Kinnier Wilson, which also led to the use of the term geste antagonistique. The geste antagoniste sign has long been considered a solid argument for the psychogenic origins of dystonia until the 1980s when Marsden made strong arguments for its organic nature.

The Use of Physiology-Based Pharmacokinetic and Pharmacodynamic Modeling in the Discovery of the Dual Orexin Receptor Antagonist ACT-541468.

Science.gov (United States)

Treiber, Alexander; de Kanter, Ruben; Roch, Catherine; Gatfield, John; Boss, Christoph; von Raumer, Markus; Schindelholz, Benno; Muehlan, Clemens; van Gerven, Joop; Jenck, Francois

2017-09-01

The identification of new sleep drugs poses particular challenges in drug discovery owing to disease-specific requirements such as rapid onset of action, sleep maintenance throughout major parts of the night, and absence of residual next-day effects. Robust tools to estimate drug levels in human brain are therefore key for a successful discovery program. Animal models constitute an appropriate choice for drugs without species differences in receptor pharmacology or pharmacokinetics. Translation to man becomes more challenging when interspecies differences are prominent. This report describes the discovery of the dual orexin receptor 1 and 2 (OX 1 and OX 2 ) antagonist ACT-541468 out of a class of structurally related compounds, by use of physiology-based pharmacokinetic and pharmacodynamic (PBPK-PD) modeling applied early in drug discovery. Although all drug candidates exhibited similar target receptor potencies and efficacy in a rat sleep model, they exhibited large interspecies differences in key factors determining their pharmacokinetic profile. Human PK models were built on the basis of in vitro metabolism and physicochemical data and were then used to predict the time course of OX 2 receptor occupancy in brain. An active ACT-541468 dose of 25 mg was estimated on the basis of OX 2 receptor occupancy thresholds of about 65% derived from clinical data for two other orexin antagonists, almorexant and suvorexant. Modeling predictions for ACT-541468 in man were largely confirmed in a single-ascending dose trial in healthy subjects. PBPK-PD modeling applied early in drug discovery, therefore, has great potential to assist in the identification of drug molecules when specific pharmacokinetic and pharmacodynamic requirements need to be met. Copyright © 2017 by The American Society for Pharmacology and Experimental Therapeutics.

Formulation and optimisation of raft-forming chewable tablets containing H2 antagonist.

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Prajapati, Shailesh T; Mehta, Anant P; Modhia, Ishan P; Patel, Chhagan N

2012-10-01

The purpose of this research work was to formulate raft-forming chewable tablets of H2 antagonist (Famotidine) using a raft-forming agent along with an antacid- and gas-generating agent. Tablets were prepared by wet granulation and evaluated for raft strength, acid neutralisation capacity, weight variation, % drug content, thickness, hardness, friability and in vitro drug release. Various raft-forming agents were used in preliminary screening. A 2(3) full-factorial design was used in the present study for optimisation. The amount of sodium alginate, amount of calcium carbonate and amount sodium bicarbonate were selected as independent variables. Raft strength, acid neutralisation capacity and drug release at 30 min were selected as responses. Tablets containing sodium alginate were having maximum raft strength as compared with other raft-forming agents. Acid neutralisation capacity and in vitro drug release of all factorial batches were found to be satisfactory. The F5 batch was optimised based on maximum raft strength and good acid neutralisation capacity. Drug-excipient compatibility study showed no interaction between the drug and excipients. Stability study of the optimised formulation showed that the tablets were stable at accelerated environmental conditions. It was concluded that raft-forming chewable tablets prepared using an optimum amount of sodium alginate, calcium carbonate and sodium bicarbonate could be an efficient dosage form in the treatment of gastro oesophageal reflux disease.

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

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Abbas Aflatoonian

2017-08-01

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

Antinociceptive effect and interaction of uncompetitive and competitive NMDA receptor antagonists upon capsaicin and paw pressure testing in normal and monoarthritic rats.

Science.gov (United States)

Pelissier, Teresa; Infante, Claudio; Constandil, Luis; Espinosa, Jeannette; Lapeyra, Carolina De; Hernández, Alejandro

2008-01-01

We assessed whether intrathecal administration of the uncompetitive and competitive NMDA receptor antagonists ketamine and (+/-)CPP, respectively, could produce differential modulation on chemical and mechanical nociception in normal and monoarthritic rats. In addition, the antinociceptive interaction of ketamine and (+/-)CPP on monoarthritic pain was also studied using isobolographic analysis. Monoarthritis was produced by intra-articular injection of complete Freund's adjuvant into the tibio-tarsal joint. Four weeks later, the antinociceptive effect of intrathecal administration of the drugs alone or combined was evaluated by using the intraplantar capsaicin and the paw pressure tests. Ketamine (0.1, 1, 10, 30, 100, 300 and 1000 microg i.t.) and (+/-)CPP (0.125, 2.5, 7.5, 12.5, 25 and 50 microg i.t.) produced significantly greater dose-dependent antinociception in the capsaicin than in the paw pressure test. Irrespective of the nociceptive test employed, both antagonists showed greater antinociceptive activity in monoarthritic than in healthy rats. Combinations produced synergy of a supra-additive nature in the capsaicin test, but only additive antinociception in paw pressure testing. The efficacy of the drugs, alone or combined, is likely to depend on the differential sensitivity of tonic versus phasic pain and/or chemical versus mechanical pain to NMDA antagonists.

Dual- and triple-acting agents for treating core and co-morbid symptoms of major depression: novel concepts, new drugs.

Science.gov (United States)

Millan, Mark J

2009-01-01

The past decade of efforts to find improved treatment for major depression has been dominated by genome-driven programs of rational drug discovery directed toward highly selective ligands for nonmonoaminergic agents. Selective drugs may prove beneficial for specific symptoms, for certain patient subpopulations, or both. However, network analyses of the brain and its dysfunction suggest that agents with multiple and complementary modes of action are more likely to show broad-based efficacy against core and comorbid symptoms of depression. Strategies for improved multitarget exploitation of monoaminergic mechanisms include triple inhibitors of dopamine, serotonin (5-HT) and noradrenaline reuptake, and drugs interfering with feedback actions of monoamines at inhibitory 5-HT(1A), 5-HT(1B) and possibly 5-HT(5A) and 5-HT(7) receptors. Specific subsets of postsynaptic 5-HT receptors mediating antidepressant actions are under study (e.g., 5-HT(4) and 5-HT(6)). Association of a clinically characterized antidepressant mechanism with a nonmonoaminergic component of activity is an attractive strategy. For example, agomelatine (a melatonin agonist/5-HT(2C) antagonist) has clinically proven activity in major depression. Dual neurokinin(1) antagonists/5-HT reuptake inhibitors (SRIs) and melanocortin(4) antagonists/SRIs should display advantages over their selective counterparts, and histamine H(3) antagonists/SRIs, GABA(B) antagonists/SRIs, glutamatergic/SRIs, and cholinergic agents/SRIs may counter the compromised cognitive function of depression. Finally, drugs that suppress 5-HT reuptake and blunt hypothalamo-pituitary-adrenocorticotrophic axis overdrive, or that act at intracellular proteins such as GSK-3beta, may abrogate the negative effects of chronic stress on mood and neuronal integrity. This review discusses the discovery and development of dual- and triple-acting antidepressants, focusing on novel concepts and new drugs disclosed over the last 2 to 3 years.

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

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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.

[Control of generalized chronic periodontitis combined with calcium-antagonist-related gingival overgrowth by a complex periodontal-endodontic-prosthodontic treatment. Case report].

Science.gov (United States)

Szánto, Erika; Gera, István

2011-12-01

To day a relatively high percentage of elderly population of the industrialized world suffers with different cardiovascular diseases and are on permanent antihypertensive therapy. One of the most frequently used drugs is the calcium channel blockers prescribed against high blood pressure. The most common oral side effect of these drugs is the gingival enlargement that might develop even on otherwise healthy gingiva. The incidence of chronic periodontitis in this age group is also high and the Ca antagonist medication in those individuals might substantially modify the clinical course of periodontal inflammation leading to gingival enlargement and hypertrophic pocket wall. The case presented here is a 52 years old hypertonic woman with a long history of Ca-antagonist therapy and generalized chronic periodontitis combined with gingival hyperplasia. After the change of medication the 1,5 years comprehensive periodontal endodontic and prosthodontic therapy restored patient's periodontal health and provided complex dental rehabilitation. Nevertheless, only regular periodontal supportive therapy could ensure predictable outcome and guarantee long lasting periodontal health.

Developmental Potential for Endomorphin Opioidmimetic Drugs

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Yoshio Okada

2012-01-01

Full Text Available Morphine, which is agonist for μ-opioid receptors, has been used as an anti-pain drug for millennia. The opiate antagonists, naloxone and naltrexone, derived from morphine, were employed for drug addiction and alcohol abuse. However, these exogenous agonists and antagonists exhibit numerous and unacceptable side effects. Of the endogenous opioid peptides, endomorphin(EM-1 and endomorphin(EM-2 with their high μ-receptor affinity and exceptionally high selectivity relative to δ- and κ-receptors in vitro and in vivo provided a sufficiently sequence-flexible entity in order to prepare opioid-based drugs. We took advantage of this unique feature of the endomorphins by exchanging the N-terminal residue Tyr1 with 2′,6′-dimethyl-L-tyrosine (Dmt to increase their stability and the spectrum of bioactivity. We systematically altered specific residues of [Dmt1]EM-1 and [Dmt1]EM-2 to produce various analogues. Of these analogues, [N-allyl-Dmt1]EM-1 (47 and [N-allyl-Dmt1]EM-2 (48 exhibited potent and selective antagonism to μ-receptors: they completely inhibited naloxone- and naltrexone-induced withdrawal from following acute morphine dependency in mice and reversed the alcohol-induced changes observed in sIPSC in hippocampal slices. Overall, we developed novel and efficacious opioid drugs without deleterious side effects that were able to resist enzymatic degradation and were readily transported intact through epithelial membranes in the gastrointestinal tract and the blood-brain-barrier.

Small Molecule Antagonists of the Nuclear Androgen Receptor for the Treatment of Castration-Resistant Prostate Cancer.

Science.gov (United States)

Johnson, James K; Skoda, Erin M; Zhou, Jianhua; Parrinello, Erica; Wang, Dan; O'Malley, Katherine; Eyer, Benjamin R; Kazancioglu, Mustafa; Eisermann, Kurtis; Johnston, Paul A; Nelson, Joel B; Wang, Zhou; Wipf, Peter

2016-08-11

After a high-throughput screening campaign identified thioether 1 as an antagonist of the nuclear androgen receptor, a zone model was developed for structure-activity relationship (SAR) purposes and analogues were synthesized and evaluated in a cell-based luciferase assay. A novel thioether isostere, cyclopropane (1S,2R)-27, showed the desired increased potency and structural properties (stereospecific SAR response, absence of a readily oxidized sulfur atom, low molecular weight, reduced number of flexible bonds and polar surface area, and drug-likeness score) in the prostate-specific antigen luciferase assay in C4-2-PSA-rl cells to qualify as a new lead structure for prostate cancer drug development.

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...

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

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

2017-08-01

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

Antagonistic parent-offspring co-adaptation.

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Mathias Kölliker

2010-01-01

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

[Drug-induced oral ulcerations].

Science.gov (United States)

Madinier, I; Berry, N; Chichmanian, R M

2000-06-01

Different side effects of drugs have been described in the oral cavity, including oral ulcerations. Direct contact between drugs and oral mucosa may induce chemical burn or local hypersensitivity. Less frequently, these drug-induced oral ulcerations are part of a complex reaction with cutaneous or systemic manifestations. Sometimes, one or more oral ulcerations appear as the main side-effect of a drug, or exceptionally as solitary lesions. Solitary oral ulcerations usually appear after few weeks of treatment. In most of cases, these lesions resist to conventional treatments, with a rapid healing following the suppression of the responsible drug. This diagnosis is usually difficult, particularly with patients receiving multiple drug therapy. Besides, special attention must be paid to new drugs. Oral ulcerations following symptoms of burning mouth, metallic taste, dysgueusia or agueusia are strongly suggestive of a pharmacological origin. Most of the molecules able to induce solitary oral ulcerations are commonly prescribed in a) rheumatology: NSAI (diclofenac, flurbiprofen, indomethacin, naproxen), long-term rheumatoid arthritis therapy (azathioprine, methotrexate, penicillamine, gold compounds, tiopronin); b) cardiology: angiotensin-converting-enzyme inhibitors (captopril, enalapril), angiotensin 2-receptor antagonist (losartan), anti-angorous (nicorandil), c) psychiatry: antidepressants (fluoxetine, lithium), d) AIDS therapy (foscarnet, zalcitabine).

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....

Temporal and spatial transcriptional fingerprints by antipsychotic or propsychotic drugs in mouse brain.

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Kensuke Sakuma

Full Text Available Various types of antipsychotics have been developed for the treatment of schizophrenia since the accidental discovery of the antipsychotic activity of chlorpromazine. Although all clinically effective antipsychotic agents have common properties to interact with the dopamine D2 receptor (D2R activation, their precise mechanisms of action remain elusive. Antipsychotics are well known to induce transcriptional changes of immediate early genes (IEGs, raising the possibility that gene expressions play an essential role to improve psychiatric symptoms. Here, we report that while different classes of antipsychotics have complex pharmacological profiles against D2R, they share common transcriptome fingerprint (TFP profile of IEGs in the murine brain in vivo by quantitative real-time PCR (qPCR. Our data showed that various types of antipsychotics with a profound interaction of D2R including haloperidol (antagonist, olanzapine (antagonist, and aripiprazole (partial agonist all share common spatial TFPs closely homologous to those of D2R antagonist sulpiride, and elicited greater transcriptional responses in the striatum than in the nucleus accumbens. Meanwhile, D2R agonist quinpirole and propsychotic NMDA antagonists such as MK-801 and phencyclidine (PCP exhibited the contrasting TFP profiles. Clozapine and propsychotic drug methamphetamine (MAP displayed peculiar TFPs that reflect their unique pharmacological property. Our results suggest that transcriptional responses are conserved across various types of antipsychotics clinically effective in positive symptoms of schizophrenia and also show that temporal and spatial TFPs may reflect the pharmacological features of the drugs. Thus, we propose that a TFP approach is beneficial to evaluate novel drug candidates for antipsychotic development.

Emerging migraine treatments and drug targets

DEFF Research Database (Denmark)

Olesen, Jes; Ashina, Messoud

2011-01-01

Migraine has a 1-year prevalence of 10% and high socioeconomic costs. Despite recent drug developments, there is a huge unmet need for better pharmacotherapy. In this review we discuss promising anti-migraine strategies such as calcitonin gene-related peptide (CGRP) receptor antagonists and 5....... Tonabersat, a cortical spreading depression inhibitor, has shown efficacy in the prophylaxis of migraine with aura. Several new drug targets such as nitric oxide synthase, the 5-HT(1D) receptor, the prostanoid receptors EP(2) and EP(4), and the pituitary adenylate cyclase receptor PAC1 await development....... The greatest need is for new prophylactic drugs, and it seems likely that such compounds will be developed in the coming decade....

The influence of certain molecular descriptors of fecal elimination of angiotensin II receptor antagonists

Directory of Open Access Journals (Sweden)

Trbojević-Stanković Jasna B.

2015-01-01

Full Text Available Angiotensin II receptor antagonists (ARBs modulate the function of the renin-angiotensin-aldosterone system and are commonly prescribed antihypertensive drugs, especially in patients with renal failure. In this study, the relationship between several molecular properties of seven ARBs (candesartan, eprosartan, irbesartan, losartan, olmesartan, telmisartan, valsartan and their fecal elimination data obtained from the literature were investigated. The ARB molecular descriptors were calculated using three software packages. Simple linear regression analysis showed the best 2 correlation between fecal elimination data and lipophilicity descriptor, ClogP values (R2 = 0.725. Multiple linear regression was applied to examine the correlation of ARBs’ fecal elimination data with their lipophilicity and one additional, calculated descriptor. The best correlation (R2 = 0.909 with an acceptable probability value, P <0.05 was established between the ARB fecal elimination data and their lipophilicity and aqueous solubility data. Applying computed molecular descriptors for evaluating drug elimination is of great importance in drug research.

Pharmacological profiling an abundantly expressed schistosome serotonergic GPCR identifies nuciferine as a potent antagonist

Directory of Open Access Journals (Sweden)

John D. Chan

2016-12-01

Full Text Available 5-hydroxytryptamine (5-HT is a key regulator of muscle contraction in parasitic flatworms. In Schistosoma mansoni, the myoexcitatory action of 5-HT is effected through activation of a serotonergic GPCR (Sm.5HTRL, prioritizing pharmacological characterization of this target for anthelmintic drug discovery. Here, we have examined the effects of several aporphine alkaloids on the signaling activity of a heterologously expressed Sm.5HTRL construct using a cAMP biosensor assay. Four structurally related natural products – nuciferine, D-glaucine, boldine and bulbocapnine – were demonstrated to block Sm.5HTRL evoked cAMP generation with the potency of GPCR blockade correlating well with the ability of each drug to inhibit contractility of schistosomule larvae. Nuciferine was also effective at inhibiting both basal and 5-HT evoked motility of adult schistosomes. These data advance our understanding of structure-affinity relationships at Sm.5HTRL, and demonstrate the effectiveness of Sm.5HTRL antagonists as hypomotility-evoking drugs across different parasite life cycle stages.

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

International Nuclear Information System (INIS)

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

2007-01-01

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

Thrombin-receptor antagonist vorapaxar in acute coronary syndromes

DEFF Research Database (Denmark)

Tricoci, Pierluigi; Huang, Zhen; Held, Claes

2012-01-01

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

Development of novel drug delivery systems using phage display technology for clinical application of protein drugs.

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Nagano, Kazuya; Tsutsumi, Yasuo

2016-01-01

Attempts are being made to develop therapeutic proteins for cancer, hepatitis, and autoimmune conditions, but their clinical applications are limited, except in the cases of drugs based on erythropoietin, granulocyte colony-stimulating factor, interferon-alpha, and antibodies, owing to problems with fundamental technologies for protein drug discovery. It is difficult to identify proteins useful as therapeutic seeds or targets. Another problem in using bioactive proteins is pleiotropic actions through receptors, making it hard to elicit desired effects without side effects. Additionally, bioactive proteins have poor therapeutic effects owing to degradation by proteases and rapid excretion from the circulatory system. Therefore, it is essential to establish a series of novel drug delivery systems (DDS) to overcome these problems. Here, we review original technologies in DDS. First, we introduce antibody proteomics technology for effective selection of proteins useful as therapeutic seeds or targets and identification of various kinds of proteins, such as cancer-specific proteins, cancer metastasis-related proteins, and a cisplatin resistance-related protein. Especially Ephrin receptor A10 is expressed in breast tumor tissues but not in normal tissues and is a promising drug target potentially useful for breast cancer treatment. Moreover, we have developed a system for rapidly creating functional mutant proteins to optimize the seeds for therapeutic applications and used this system to generate various kinds of functional cytokine muteins. Among them, R1antTNF is a TNFR1-selective antagonistic mutant of TNF and is the first mutein converted from agonist to antagonist. We also review a novel polymer-conjugation system to improve the in vivo stability of bioactive proteins. Site-specific PEGylated R1antTNF is uniform at the molecular level, and its bioactivity is similar to that of unmodified R1antTNF. In the future, we hope that many innovative protein drugs will be

Selective and rapid monitoring of dual platelet inhibition by aspirin and P2Y12 antagonists by using multiple electrode aggregometry

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Lorenz Reinhard

2010-05-01

Full Text Available Abstract Background Poor platelet inhibition by aspirin or clopidogrel has been associated with adverse outcomes in patients with cardiovascular diseases. A reliable and facile assay to measure platelet inhibition after treatment with aspirin and a P2Y12 antagonist is lacking. Multiple electrode aggregometry (MEA, which is being increasingly used in clinical studies, is sensitive to platelet inhibition by aspirin and clopidogrel, but a critical evaluation of MEA monitoring of dual anti-platelet therapy with aspirin and P2Y12 antagonists is missing. Design and Methods By performing in vitro and ex vivo experiments, we evaluated in healthy subjects the feasibility of using MEA to monitor platelet inhibition of P2Y12 antagonists (clopidogrel in vivo, cangrelor in vitro and aspirin (100 mg per day in vivo, and 1 mM or 5.4 mM in vitro alone, and in combination. Statistical analyses were performed by the Mann-Whitney rank sum test, student' t-test, analysis of variance followed by the Holm-Sidak test, where appropriate. Results ADP-induced platelet aggregation in hirudin-anticoagulated blood was inhibited by 99.3 ± 1.4% by in vitro addition of cangrelor (100 nM; p 95% and 100 ± 3.2%, respectively (p in vitro or ex vivo. Oral intake of clopidogrel did not significantly reduce AA-induced aggregation, but P2Y12 blockade by cangrelor (100 nM in vitro diminished AA-stimulated aggregation by 53 ± 26% (p Conclusions Selective platelet inhibition by aspirin and P2Y12 antagonists alone and in combination can be rapidly measured by MEA. We suggest that dual anti-platelet therapy with these two types of anti-platelet drugs can be optimized individually by measuring platelet responsiveness to ADP and AA with MEA before and after drug intake.

Common drug-drug interactions in antifungal treatments for superficial fungal infections.

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Gupta, Aditya K; Versteeg, Sarah G; Shear, Neil H

2018-04-01

Antifungal agents can be co-administered alongside several other medications for a variety of reasons such as the presence of comorbidities. Pharmacodynamic interactions such as synergistic and antagonistic interactions could be the result of co-administered medications. Pharmacokinetic interactions could also transpire through the inhibition of metabolizing enzymes and drug transport systems, altering the absorption, metabolism and excretion of co-administered medications. Both pharmacodynamic and pharmacokinetic interactions can result in hospitalization due to serious adverse effects associated with antifungal agents, lower therapeutic doses required to achieve desired antifungal activity, and prevent antifungal resistance. Areas covered: The objective of this review is to summarize pharmacodynamic and pharmacokinetic interactions associated with common antifungal agents used to treat superficial fungal infections. Pharmacodynamic and pharmacokinetic interactions that impact the therapeutic effects of antifungal agents and drugs that are influenced by the presence of antifungal agents was the context to which these antifungal agents were addressed. Expert opinion: The potential for drug-drug interactions is minimal for topical antifungals as opposed to oral antifungals as they have minimal exposure to other co-administered medications. Developing non-lipophilic antifungals that have unique metabolizing pathways and are topical applied are suggested properties that could help limit drug-drug interactions associated with future treatments.

Structure of CC chemokine receptor 2 with orthosteric and allosteric antagonists

Energy Technology Data Exchange (ETDEWEB)

Zheng, Yi; Qin, Ling; Ortiz Zacarías, Natalia V.; de Vries, Henk; Han, Gye Won; Gustavsson, Martin; Dabros, Marta; Zhao, Chunxia; Cherney, Robert J.; Carter, Percy; Stamos, Dean; Abagyan, Ruben; Cherezov, Vadim; Stevens, Raymond C.; IJzerman, Adriaan P.; Heitman, Laura H.; Tebben, Andrew; Kufareva, Irina; Handel , Tracy M. (Vertex Pharm); (Leiden-MC); (USC); (BMS); (UCSD)

2016-12-07

CC chemokine receptor 2 (CCR2) is one of 19 members of the chemokine receptor subfamily of human class A G-protein-coupled receptors. CCR2 is expressed on monocytes, immature dendritic cells, and T-cell subpopulations, and mediates their migration towards endogenous CC chemokine ligands such as CCL2 (ref. 1). CCR2 and its ligands are implicated in numerous inflammatory and neurodegenerative diseases2 including atherosclerosis, multiple sclerosis, asthma, neuropathic pain, and diabetic nephropathy, as well as cancer3. These disease associations have motivated numerous preclinical studies and clinical trials4 (see http://www.clinicaltrials.gov) in search of therapies that target the CCR2–chemokine axis. To aid drug discovery efforts5, here we solve a structure of CCR2 in a ternary complex with an orthosteric (BMS-681 (ref. 6)) and allosteric (CCR2-RA-[R]7) antagonist. BMS-681 inhibits chemokine binding by occupying the orthosteric pocket of the receptor in a previously unseen binding mode. CCR2-RA-[R] binds in a novel, highly druggable pocket that is the most intracellular allosteric site observed in class A G-protein-coupled receptors so far; this site spatially overlaps the G-protein-binding site in homologous receptors. CCR2-RA-[R] inhibits CCR2 non-competitively by blocking activation-associated conformational changes and formation of the G-protein-binding interface. The conformational signature of the conserved microswitch residues observed in double-antagonist-bound CCR2 resembles the most inactive G-protein-coupled receptor structures solved so far. Like other protein–protein interactions, receptor–chemokine complexes are considered challenging therapeutic targets for small molecules, and the present structure suggests diverse pocket epitopes that can be exploited to overcome obstacles in drug design.

Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

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Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

2016-07-05

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.

Injectable In Situ Forming Microparticles: A Novel Drug Delivery ...

African Journals Online (AJOL)

HP

performance criteria for these systems. Ongoing studies have shown that this new multiparticulate drug delivery system is ... controlled, and this has also affect scale-up and cost [3]. In order to ... antagonists, growth factors, anti-inflammatory agents, antibiotic ..... confirm the pharmacokinetic profile of this innovative depot ...

The Combination of Marketed Antagonists of α1b-Adrenergic and 5-HT2A Receptors Inhibits Behavioral Sensitization and Preference to Alcohol in Mice: A Promising Approach for the Treatment of Alcohol Dependence.

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Fabrice Trovero

Full Text Available Alcohol-dependence is a chronic disease with a dramatic and expensive social impact. Previous studies have indicated that the blockade of two monoaminergic receptors, α1b-adrenergic and 5-HT2A, could inhibit the development of behavioral sensitization to drugs of abuse, a hallmark of drug-seeking and drug-taking behaviors in rodents. Here, in order to develop a potential therapeutic treatment of alcohol dependence in humans, we have blocked these two monoaminergic receptors by a combination of antagonists already approved by Health Agencies. We show that the association of ifenprodil (1 mg/kg and cyproheptadine (1 mg/kg (α1-adrenergic and 5-HT2 receptor antagonists marketed as Vadilex ® and Periactine ® in France, respectively blocks behavioral sensitization to amphetamine in C57Bl6 mice and to alcohol in DBA2 mice. Moreover, this combination of antagonists inhibits alcohol intake in mice habituated to alcohol (10% v/v and reverses their alcohol preference. Finally, in order to verify that the effect of ifenprodil was not due to its anti-NMDA receptors property, we have shown that a combination of prazosin (0.5 mg/kg, an α1b-adrenergic antagonist, Mini-Press ® in France and cyproheptadine (1 mg/kg could also reverse alcohol preference. Altogether these findings strongly suggest that combined prazosin and cyproheptadine could be efficient as a therapy to treat alcoholism in humans. Finally, because α1b-adrenergic and 5-HT2A receptors blockade also inhibits behavioral sensitization to psychostimulants, opioids and tobacco, it cannot be excluded that this combination will exhibit some efficacy in the treatment of addiction to other abused drugs.

Impact of the early use of immunomodulators or TNF antagonists on bowel damage and surgery in Crohn's disease.

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Safroneeva, E; Vavricka, S R; Fournier, N; Pittet, V; Peyrin-Biroulet, L; Straumann, A; Rogler, G; Schoepfer, A M

2015-10-01

The impact of early treatment with immunomodulators (IM) and/or TNF antagonists on bowel damage in Crohn's disease (CD) patients is unknown. To assess whether 'early treatment' with IM and/or TNF antagonists, defined as treatment within a 2-year period from the date of CD diagnosis, was associated with development of lesser number of disease complications when compared to 'late treatment', which was defined as treatment initiation after >2 years from the time of CD diagnosis. Data from the Swiss IBD Cohort Study were analysed. The following outcomes were assessed using Cox proportional hazard modelling: bowel strictures, perianal fistulas, internal fistulas, intestinal surgery, perianal surgery and any of the aforementioned complications. The 'early treatment' group of 292 CD patients was compared to the 'late treatment' group of 248 CD patients. We found that 'early treatment' with IM or TNF antagonists alone was associated with reduced risk of bowel strictures [hazard ratio (HR) 0.496, P = 0.004 for IM; HR 0.276, P = 0.018 for TNF antagonists]. Furthermore, 'early treatment' with IM was associated with reduced risk of undergoing intestinal surgery (HR 0.322, P = 0.005), and perianal surgery (HR 0.361, P = 0.042), as well as developing any complication (HR 0.567, P = 0.006). Treatment with immunomodulators or TNF antagonists within the first 2 years of CD diagnosis was associated with reduced risk of developing bowel strictures, when compared to initiating these drugs >2 years after diagnosis. Furthermore, early immunomodulators treatment was associated with reduced risk of intestinal surgery, perianal surgery and any complication. © 2015 John Wiley & Sons Ltd.

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

NARCIS (Netherlands)

R. de Wit (Ronald)

2003-01-01

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

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

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

2014-01-01

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

[Caffeine: a nutrient, a drug or a drug of abuse].

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Pardo Lozano, Ricardo; Alvarez García, Yolanda; Barral Tafalla, Diego; Farré Albaladejo, Magí

2007-01-01

Coffee, tea, chocolate and caffeinated drinks are the main sources of caffeine, which is consumed in almost all ages and socioeconomic levels. Caffeine acts as a non-selective adenosine receptor antagonist in the central nervous system. Its main effects are as psychostimulant, acting in addition on the respiratory, muscular and cardiovascular systems. Basically, caffeine is metabolized by the hepatic cytochrome P-450 1A2 enzymes (CYP1A2). Several drugs can interact with its metabolism. The observed interindividual differences of its effects can be explained by variations in its metabolism. The main therapeutic use of caffeine is bronchodilator in respiratory diseases. Other possible uses are under investigation. Acute or chronic consumption of caffeine can induce several adverse effects, including intoxication that can be lethal. Finally, caffeine can be considered a drug of abuse. It has positive reinforcing actions, produces tolerance, and a withdrawal syndrome after stopping its consumption. Caffeine can cause different mental disorders such as dependence, which is not included in the DSM-IV-R, withdrawal syndrome and intoxication. Depending on its use, caffeine can be considered a nutrient, a drug or a drug of abuse.

Characterization of the discriminative stimulus produced by the dopamine antagonist tiapride.

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Cohen, C; Sanger, D J; Perrault, G

1997-11-01

The ability of tiapride, a selective D2/D3 dopamine receptor antagonist, to exert discriminative stimulus control of responding was investigated by training rats to discriminate this drug (30 mg/kg) from saline in a two-lever, food-reinforcement procedure. Acquisition of tiapride discrimination required a relatively lengthy training period (mean of 76 sessions) but stable performance was maintained throughout the 18- month study. The dose of tiapride eliciting 50% tiapride-lever choice (ED50) was 2.2 mg/kg. After determination of the dose-effect curve with tiapride, substitution tests with several dopamine antagonists and other reference compounds were performed. All dopamine antagonists, including amisulpride (ED50 4 mg/kg), sulpiride (18 mg/kg), sultopride (1.5 mg/kg), clebopride (0.13 mg/kg), raclopride (0.16 mg/kg), metoclopramide (1.4 mg/kg), remoxipride (4.8 mg/kg), pimozide (2.7 mg/kg), thioridazine (3.4 mg/kg), olanzapine (0.97 mg/kg), chlorpromazine (1.9 mg/kg), risperidone (0.22 mg/kg) and haloperidol (0.14 mg/kg), except clozapine (>10 mg/kg), produced dose-dependent substitution for tiapride. Tiapride-like stimulus effects were observed at doses that decreased response rates. However, ED50 values for substitution by tiapride, amisulpride, sulpiride, sultopride, pimozide, clebopride and thioridazine were lower than ED50 values for decreasing responding. Additional studies were conducted to evaluate the ability of direct and indirect dopamine agonists to attenuate the tiapride discriminative stimulus. Pretreatment with d-amphetamine and nomifensine antagonized the discriminative stimulus effects of tiapride. Quinpirole, 7-OH-DPAT, bromocriptine and apomorphine partially blocked the stimulus effects of tiapride whereas SKF 38393 did not affect the discrimination. These results from substitution and antagonism tests indicated that the discriminative effects of tiapride are mediated by activity at D2/D3 dopamine receptors.

In Vitro Drug Metabolism by Human Carboxylesterase 1

DEFF Research Database (Denmark)

Thomsen, Ragnar; Rasmussen, Henrik B; Linnet, Kristian

2014-01-01

Carboxylesterase 1 (CES1) is the major hydrolase in human liver. The enzyme is involved in the metabolism of several important therapeutic agents, drugs of abuse, and endogenous compounds. However, no studies have described the role of human CES1 in the activation of two commonly prescribed...... a panel of therapeutic drugs and drugs of abuse to assess their inhibition of the hydrolysis of p-nitrophenyl acetate by recombinant CES1 and human liver microsomes. The screening assay confirmed several known inhibitors of CES1 and identified two previously unreported inhibitors: the dihydropyridine...... calcium antagonist, isradipine, and the immunosuppressive agent, tacrolimus. CES1 plays a role in the metabolism of several drugs used in the treatment of common conditions, including hypertension, congestive heart failure, and diabetes mellitus; thus, there is a potential for clinically relevant drug-drug...

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

Directory of Open Access Journals (Sweden)

Lixin Wang

2011-02-01

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

Exploring the binding energy profiles of full agonists, partial agonists, and antagonists of the α7 nicotinic acetylcholine receptor.

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Tabassum, Nargis; Ma, Qianyun; Wu, Guanzhao; Jiang, Tao; Yu, Rilei

2017-09-01

Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop receptor family and are important drug targets for the treatment of neurological diseases. However, the precise determinants of the binding efficacies of ligands for these receptors are unclear. Therefore, in this study, the binding energy profiles of various ligands (full agonists, partial agonists, and antagonists) were quantified by docking those ligands with structural ensembles of the α7 nAChR exhibiting different degrees of C-loop closure. This approximate treatment of interactions suggested that full agonists, partial agonists, and antagonists of the α7 nAChR possess distinctive binding energy profiles. Results from docking revealed that ligand binding efficacy may be related to the capacity of the ligand to stabilize conformational states with a closed C loop.

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

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

2015-01-01

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

Modulation of cytokine and cytokine receptor/antagonist by treatment with doxycycline and tetracycline in patients with dengue fever.

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Castro, J E Z; Vado-Solis, I; Perez-Osorio, C; Fredeking, T M

2011-01-01

Dengue virus infection can lead to dengue fever (DF) or dengue hemorrhagic fever (DHF). Disease severity has been linked to an increase in various cytokine levels. In this study, we evaluated the effectiveness of doxycycline and tetracycline to modulate serum levels of IL-6, IL-1B, and TNF and cytokine receptor/receptor antagonist TNF-R1 and IL-1RA in patients with DF or DHF. Hospitalized patients were randomized to receive standard supportive care or supportive care combined with doxycycline or tetracycline therapy. Serum cytokine and cytokine receptor/antagonist levels were determined at the onset of therapy and after 3 and 7 days. Cytokine and cytokine receptor/antagonist levels were substantially elevated at day 0. IL-6, IL-1β, and TNF remained at or above day 0 levels throughout the study period in untreated patients. Treatment with tetracycline or doxycycline resulted in a significant decline in cytokine levels. Similarly, IL-1RA and TNF-R1 serum concentrations were elevated at baseline and showed a moderate increase among untreated patients. Both drugs resulted in a significant rise in IL-1Ra levels by day 3 in patients. In contrast, treatment did not affect a similar result for TNF-R1. When compared to the control group, however, a significant rise post-treatment was seen upon intragroup analysis. Further analysis demonstrated that doxycycline was significantly more effective at modulating cytokine and cytokine receptor/antagonist levels than tetracycline.

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

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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.

Antagonistic studies and hyphal interactions of the new antagonist Aspergillus piperis against some phytopathogenic fungi in vitro in comparison with Trichoderma harzianum.

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El-Debaiky, Samah A

2017-12-01

The present study represents, for the first time, the detailed studies about the hyphal interactions of Aspergillus piperis, as a new antagonist, against some isolated plant pathogenic fungi (Alternaria alternata, Alternaria solani, Botrytis cinerea, Sclerotium cepivorum and Sclerotinia sclerotiorum) in vitro. The bio-controlling capability of A. piperis against the tested phytopathogens was tested using the dual culture method. This experiment revealed that A. piperis had antagonistic activity and reduced the growth of the tested phytopathogens and grew over their mycelia in the paired plates. Also, several antagonistic mechanisms were recorded, in this study, between A. piperis and the tested phytopathogens using the microscopic examination. The bio-controlling activity and the antagonistic mechanisms exhibited by the new antagonist, A. piperis were compared with those obtained by the common antagonist, Trichoderma harzianum against the same phytopathogens. The obtained results showed that, A. piperis was more effective than T. harzianum in inhibiting all the tested species in the dual culture plates. The best result was 81.85% inhibition percentage against S. sclerotiorum by A. piperis while, T. harzianum exhibits only 45.18%. Moreover, several antagonistic mechanisms and hyphal interactions were investigated among the hyphae of both A.piperis and T. harzianum and the hyphae of the tested phytopathogens. These mechanisms were summarized as; mycoparasitism (coiling and penetration of the hyphae) and antibiosis in the form of lysis of the hyphal cells and spores, denaturation and breaking of the hyphae. The indirect interaction (antibiosis) and the direct mycoparasitism were observed by A. piperis against all the tested phytopathogens, but it attacked the hyphae and conidiophores of A. alternata by only the antibiosis interaction. The microscopic examination revealed also that T. harzianum attacked the tested phytopathogens by both antibiosis and mycoparasitism

Quality of Vitamin K Antagonist Anticoagulation in Spain: Prevalence of Poor Control and Associated Factors.

Science.gov (United States)

Anguita Sánchez, Manuel; Bertomeu Martínez, Vicente; Cequier Fillat, Ángel

2015-09-01

To study the prevalence of poorly controlled vitamin K antagonist anticoagulation in Spain in patients with nonvalvular atrial fibrillation, and to identify associated factors. We studied 1056 consecutive patients seen at 120 cardiology clinics in Spain between November 2013 and March 2014. We analyzed the international normalized ratio from the 6 months prior to the patient's visit, calculating the prevalence of poorly controlled anticoagulation, defined as < 65% time in therapeutic range using the Rosendaal method. Mean age was 73.6 years (standard deviation, 9.8 years); women accounted for 42% of patients. The prevalence of poorly controlled anticoagulation was 47.3%. Mean time in therapeutic range was 63.8% (25.9%). The following factors were independently associated with poorly controlled anticoagulation: kidney disease (odds ratio = 1.53; 95% confidence interval, 1.08-2.18; P = .018), routine nonsteroidal anti-inflammatory drugs (odds ratio = 1.79; 95% confidence interval, 1.20-2.79; P = .004), antiplatelet therapy (odds ratio = 2.16; 95% confidence interval, 1.49-3.12; P < .0001) and absence of angiotensin receptor blockers (odds ratio = 1.39; 95% confidence interval, 1.08-1.79; P = .011). There is a high prevalence of poorly controlled vitamin K antagonist anticoagulation in Spain. Factors associated with poor control are kidney disease, routine nonsteroidal anti-inflammatory drugs, antiplatelet use, and absence of angiotensin receptor blockers. Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.

Efficacy of 5-HT3 receptor antagonists in radiotherapy-induced nausea and vomiting: A quantitative systematic review

International Nuclear Information System (INIS)

Tramer, M.R.; Reynolds, D.J.M.; Stoner, N.S.; Moore, R.A.; McQuay, H.J.

1998-01-01

5-HT 3 receptor antagonists are used to treat radiation-induced sickness. The purpose of this study was to define anti-emetic efficacy and potential for harm of these drugs in radiotherapy. A systematic search, critical appraisal and quantitative analysis of relevant data using the number-needed-to-treat or harm (NNT/H) were conducted. Acute (0 to 24 h) and delayed (beyond 24 h) anti-emetic efficacy were analysed separately. Data from 1,404 patients were found in 40 trials published in 36 reports. Data from 197 patients receiving ondansetron or granisetron in five randomised trials were regarded as valid according to preset criteria. One placebo-controlled trial had 10 patients per group and in this ondansetron was not significantly different from placebo. In a larger (n=105) placebo-controlled trial, ondansetron was significantly more efficacious than metoclopramide for complete control of acute vomiting (NNT 2.2, 95% confidence interval (CI) 1.7-3.3) and acute nausea (NNT 3.6, 95% CI 2.2-10.2). Three trials reported delayed outcomes with ondansetron or granisetron: there was no evidence of any difference compared with placebo or other anti-emetics. Two trials reported no acute or delayed but a 'worst day' outcome; in these ondansetron's antivomiting effect was significantly better than placebo (NNT 4.4, 95% CI 2.5-23) or prochlorperazine (NNT 3.8, 95% CI 2.4-10.3), but not its antinausea effect. Constipation and headache were associated significantly with 5-HT 3 receptor antagonists compared with other anti-emetics or placebo (NNH 6.4 and 17.1, respectively). Only 14% of published data enabled valid estimation of the anti-emetic efficacy of 5-HT 3 receptor antagonists in radiotherapy. There was some evidence that these drugs prevent acute vomiting: 40% of treated patients will benefit (NNT approximately 2.5). The evidence for nausea was less clear. There was no evidence that these drugs are of any benefit beyond 24 h. There was evidence that they produce specific

Dopamine antagonists for treatment resistance in autism spectrum disorders: review and focus on BDNF stimulators loxapine and amitriptyline.

Science.gov (United States)

Hellings, Jessica A; Arnold, L Eugene; Han, Joan C

2017-04-01

Drug development and repurposing are urgently needed for individuals with autism spectrum disorders (ASD) and psychiatric comorbidity, which often presents as aggression and self-injury. Areas covered: We review dopamine antagonists, including classical and atypical, as well as unconventional antipsychotics in ASD. The older antipsychotic loxapine is discussed in terms of preliminary albeit limited evidence in ASD. Emerging promise of amitriptyline in ASD is discussed, together with promising BDNF effects of loxapine and amitriptyline. Expert opinion: In ASD, pharmacotherapy and specifically dopamine antagonist drugs are often prescribed for challenging behaviors including aggression. The novel antipsychotics risperidone and aripiprazole have received most study in ASD and are FDA-approved for irritability in children with ASD over age 5 years; individuals with ASD are prone to weight gain, Type II diabetes and associated side effects. Low dose loxapine has properties of classical and novel antipsychotics but importantly appears more weight neutral, and with promising use in adolescents and adults with ASD. Amitriptyline appears effective in ASD for irritability, aggression, gastrointestinal problems, and insomnia, in children, adolescents and adults however our adult data on amitriptyline in ASD is still in preparation for publication. Both loxapine and amitriptyline may stimulate BDNF; further studies are warranted.

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…

Renal protection in diabetes--an emerging role for calcium antagonists

DEFF Research Database (Denmark)

Parving, H H; Tarnow, L; Rossing, P

1997-01-01

The combination of diabetes and hypertension increases the changes of progressive renal disorder and ultimately renal failure. Roughly 40% of all diabetics, whether insulin dependent or not, develop diabetic nephropathy. Diabetic nephropathy is the single most important cause of end-stage renal...... disease in the western world and accounts for more than a quarter of all end-stage renal diseases. It is also a major cause of increased morbidity and mortality in diabetic patients. Increased arterial blood pressure is an early and common phenomenon in incipient and overt diabetic nephropathy...... the ability to retard renal growth and possibly to attenuate mesangial entrapment of macromolecules and to attenuate the mitogenic effects of diverse growth factors. Calcium antagonists (except the old short-acting dihydropyridine drugs) reduce microalbuminuria and preserve kidney function in diabetic...

[The drug abuse patient as emergency].

Science.gov (United States)

Kessler, R; Ryser, D H

1991-01-15

Acute drug intoxication is a medical emergency considering its potential interference with vital functions. All 157 cases with drug overdose admitted to the emergency department of the "Inselspital" in Berne over 183 days between July 1989 and June 1990 were analyzed retrospectively. In the vast majority of cases heroin overdose was involved. In mixed poisonings with heroin mostly flunitrazepam and alcohol contributed to the clinical picture, less commonly cocaine. There were very few intoxications with cocaine alone. A practical approach to the management of patients with certain or suspected drug intoxication presenting with coma and depressed respiration is proposed. In the therapy of acute intoxications with opiates and benzodiazepines there are specific antagonists available. In contrast, therapy of cocaine overdose remains symptomatic. The medical complications of acute heroin and cocaine intoxications are discussed separately.

Interaction between anti-Alzheimer and antipsychotic drugs in modulating extrapyramidal motor disorders in mice

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Saki Shimizu

2015-04-01

Full Text Available Antipsychotics are often used in conjunction with anti-Alzheimer drugs to treat the behavioral and psychological symptoms of dementia (BPSD. Here, we examined the effects of cholinesterase inhibitors (ChEIs, donepezil and galantamine, on antipsychotic-induced extrapyramidal side effects (EPS in mice. The effects of serotonergic agents on the EPS drug interaction were also evaluated. Donepezil (0.3–3 mg/kg did not induce EPS signs by itself; however, it significantly potentiated bradykinesia induction with a low dose of haloperidol (0.5 mg/kg in dose-dependent and synergistic manners. Galantamine (0.3–3 mg/kg elicited mild bradykinesia at a high dose and dose-dependently augmented haloperidol-induced bradykinesia. The EPS potentiation by galantamine was blocked by trihexyphenidyl (a muscarinic antagonist, but not by mecamylamine (a nicotinic antagonist. In addition, the bradykinesia potentiation by galantamine was significantly reduced by (±-8-hydroxy-2-(di-n-propylamino-tetralin (a 5-HT1A agonist, ritanserin (a 5-HT2 antagonist, and SB-258585 (a 5-HT6 antagonist. The present results give us a caution for the antipsychotics and ChEIs interaction in inducing EPS in the treatment of BPSD. In addition, second generation antipsychotics, which can stimulate 5-HT1A receptors or antagonize 5-HT2 and 5-HT6 receptors, seem to be favorable as an adjunctive therapy for BPSD.

Characterization and design of antagonistic shape memory alloy actuators

International Nuclear Information System (INIS)

Georges, T; Brailovski, V; Terriault, P

2012-01-01

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

[Prevalence of Avoidable Potential Interactions Between Antidepressants and Other Drugs in Colombian Patients].

Science.gov (United States)

Machado-Alba, Jorge E; Morales-Plaza, Cristhian David

2013-06-01

To determine the possible drugs interactions with antidepressive agents in data bases of patients in the Health Insurance System of Colombia. From data bases of about 4 million users in Colombia, a systematic review of drugs dispensation statistics was made to identify drug interactions between antidepressive agents, cholinergic antagonists and tramadol in 2010. We identified 114,465 monthly users of antidepressive agents. Of these, 5776 (5.0%) received two, and 178 (0.2%) received three antidepressive agents simultaneously. The most frequent combination was fluoxetine+trazodone (n=3235; 56.9% of cases). About 1127 (1.0%) patients were prescribed a cholinergic antagonist simultaneously; 2523 (2.1%) users were dispensed tramadol at the same time, while raising the risk of serotonin syndrome. Drug interactions represent a potential risk that is often underestimated by physicians. Pharmacovigilance is a useful tool to optimize resources and prevent negative outcomes associated with medication. It is recommended that systematic search is made to enhance surveillance programs for the rational use of medicines in this country. Copyright © 2013 Asociación Colombiana de Psiquiatría. Publicado por Elsevier España. All rights reserved.

Comparison of the tumor inhibiting effects of three histamine H2-receptor antagonists.

Science.gov (United States)

Tutton, P J; Barkla, D H

1983-01-01

Three histamine H2-receptor antagonists, Cimetidine, Metiamide and Ranitidine, were tested for their inhibitory effect on two experimental bowel cancer models. In the first model mitotic rates were measured in dimethylhydrazine-induced tumors of rat colon and in the second model volumetric changes in human large bowel cancer xenografts were assessed. In tumors of rat colon all three drugs were able to suppress mitotic activity, but the effects of Metiamide and Ranitidine were more prolonged than that of Cimetidine in each of two lines of human bowel cancer that were used. Metiamide and Ranitidine were also more effective growth inhibitors than was Cimetidine.

Antagonist wear of monolithic zirconia crowns after 2 years.

Science.gov (United States)

Lohbauer, Ulrich; Reich, Sven

2017-05-01

The aim of this study was to evaluate the amount of wear on the antagonist occlusal surfaces of clinically placed monolithic zirconia premolar and molar crowns (LAVA Plus, 3M ESPE). Fourteen in situ monolithic zirconia crowns and their opposing antagonists (n = 26) are the subject of an ongoing clinical trial and have been clinically examined at baseline and after 24 months. Silicone impressions were taken and epoxy replicas produced for qualitative SEM analysis and quantitative analysis using optical profilometry. Based on the baseline replicas, the follow-up situation has been scanned and digitally matched with the initial topography in order to calculate the mean volume loss (in mm 3 ) as well as the mean maximum vertical loss (in mm) after 2 years in service. The mean volume loss for enamel antagonist contacts (n = 7) was measured to 0.361 mm 3 and the mean of the maximum vertical loss to 0.204 mm. The mean volume loss for pure ceramic contacts (n = 10) was measured to 0.333 mm 3 and the mean of the maximum vertical loss to 0.145 mm. The wear rates on enamel contacts were not significantly different from those measured on ceramic antagonists. Based on the limitations of this study, it can be concluded for the monolithic zirconia material LAVA Plus that the measured wear rates are in consensus with other in vivo studies on ceramic restorations. Further, that no significant difference was found between natural enamel antagonists and ceramic restorations as antagonists. The monolithic zirconia restorations do not seem to be affected by wear within the first 2 years. The monolithic zirconia crowns (LAVA Plus) show acceptable antagonist wear rates after 2 years in situ, regardless of natural enamel or ceramics as antagonist materials.

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. Copyright © 2016 Elsevier B.V. All rights reserved.

Role of endocannabinoids in regulating drug dependence

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Daniela Parolaro

2007-01-01

Full Text Available Daniela Parolaro, Daniela Vigano’, Natalia Realini, Tiziana RubinoNeuroscience Center, DBSF, University of Insubria, Busto Arsizio, ItalyAbstract: This review will discuss the latest knowledge of how the endocannabinoid system might be involved in treating addiction to the most common illicit drugs. Experimental models are providing increasing evidence for the pharmacological management of endocannabinoid signaling not only to block the direct reinforcing effects of cannabis, opioids, nicotine and ethanol, but also for preventing relapse to the various drugs of abuse, including opioids, cocaine, nicotine, alcohol and metamphetamine. Preclinical and clinical studies suggest that the endocannabinoid system can be manipulated by the CB1 receptor antagonist SR141716A, that might constitute a new generation of compounds for treating addiction across different classes of abused drugs.Keywords: Endocannabinoids, drug dependence, opioids, nicotine, alcohol, psychostimulants

Reinforcing and neurochemical effects of cannabinoid CB1 receptor agonists, but not cocaine, are altered by an adenosine A2A receptor antagonist.

Science.gov (United States)

Justinová, Zuzana; Ferré, Sergi; Redhi, Godfrey H; Mascia, Paola; Stroik, Jessica; Quarta, Davide; Yasar, Sevil; Müller, Christa E; Franco, Rafael; Goldberg, Steven R

2011-07-01

Several recent studies suggest functional and molecular interactions between striatal adenosine A(2A) and cannabinoid CB(1) receptors. Here, we demonstrate that A(2A) receptors selectively modulate reinforcing effects of cannabinoids. We studied effects of A(2A) receptor blockade on the reinforcing effects of delta-9-tetrahydrocannabinol (THC) and the endogenous CB(1) receptor ligand anandamide under a fixed-ratio schedule of intravenous drug injection in squirrel monkeys. A low dose of the selective adenosine A(2A) receptor antagonist MSX-3 (1 mg/kg) caused downward shifts of THC and anandamide dose-response curves. In contrast, a higher dose of MSX-3 (3 mg/kg) shifted THC and anandamide dose-response curves to the left. MSX-3 did not modify cocaine or food pellet self-administration. Also, MSX-3 neither promoted reinstatement of extinguished drug-seeking behavior nor altered reinstatement of drug-seeking behavior by non-contingent priming injections of THC. Finally, using in vivo microdialysis in freely-moving rats, a behaviorally active dose of MSX-3 significantly counteracted THC-induced, but not cocaine-induced, increases in extracellular dopamine levels in the nucleus accumbens shell. The significant and selective results obtained with the lower dose of MSX-3 suggest that adenosine A(2A) antagonists acting preferentially at presynaptic A(2A) receptors might selectively reduce reinforcing effects of cannabinoids that lead to their abuse. However, the appearance of potentiating rather than suppressing effects on cannabinoid reinforcement at the higher dose of MSX-3 would likely preclude the use of such a compound as a medication for cannabis abuse. Adenosine A(2A) antagonists with more selectivity for presynaptic versus postsynaptic receptors could be potential medications for treatment of cannabis abuse. Addiction Biology © 2010 Society for the Study of Addiction. No claim to original US government works.

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

African Journals Online (AJOL)

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

Development of description framework of pharmacodynamics ontology and its application to possible drug-drug interaction reasoning.

Science.gov (United States)

Imai, Takeshi; Hayakawa, Masayo; Ohe, Kazuhiko

2013-01-01

Prediction of synergistic or antagonistic effects of drug-drug interaction (DDI) in vivo has been of considerable interest over the years. Formal representation of pharmacological knowledge such as ontology is indispensable for machine reasoning of possible DDIs. However, current pharmacology knowledge bases are not sufficient to provide formal representation of DDI information. With this background, this paper presents: (1) a description framework of pharmacodynamics ontology; and (2) a methodology to utilize pharmacodynamics ontology to detect different types of possible DDI pairs with supporting information such as underlying pharmacodynamics mechanisms. We also evaluated our methodology in the field of drugs related to noradrenaline signal transduction process and 11 different types of possible DDI pairs were detected. The main features of our methodology are the explanation capability of the reason for possible DDIs and the distinguishability of different types of DDIs. These features will not only be useful for providing supporting information to prescribers, but also for large-scale monitoring of drug safety.

Optimal Anti-cancer Drug Profiles for Effective Penetration of the Anti-cancer Drug Market by Generic Drugs in Japan.

Science.gov (United States)

Shibata, Shoyo; Matsushita, Maiko; Saito, Yoshimasa; Suzuki, Takeshi

2017-01-01

The increased use of generic drugs is a good indicator of the need to reduce the increasing costs of prescription drugs. Since there are more expensive drugs compared with other therapeutic areas, "oncology" is an important one for generic drugs. The primary objective of this article was to quantify the extent to which generic drugs in Japan occupy each level of the Anatomical Therapeutic Chemical (ATC) classification system. The dataset used in this study was created from publicly available information obtained from the IMS Japan Pharmaceutical Market database. Data on the total amount of sales and number of prescriptions for anti-cancer drugs between 2010 and 2016 in Japan were selected. The data were categorized according to the third level of the ATC classification system. All categories of the ATC classification system had increased market shares in Japan between 2010 and 2016. The barriers to market entry were relatively low in L01F (platinum anti-neoplastics), L01C (plant-based neoplastics), L02B (cytostatic hormone antagonists), and L01D (anti-neoplastic antibiotics) but were high in L02A (cytostatic hormones), L01H (protein kinase inhibitors), and L01B (anti-metabolites). Generic cancer drugs could bring savings to Japanese health care systems. Therefore, their development should be directed toward niche markets, such as L02A, L01H, and L01B, and not competitive markets.

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.

Evidence that 5-hydroxytryptamine3 receptors mediate cytotoxic drug and radiation-evoked emesis

International Nuclear Information System (INIS)

Miner, W.D.; Sanger, G.J.; Turner, D.H.

1987-01-01

The involvement of 5-hydroxytryptamine (5-HT) 5-HT 3 receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT 3 receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT 3 receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT 3 receptors in the mechanisms mediating severely emetogenic cancer treatment therapies. (author)

Sulforaphane is not an effective antagonist of the human pregnane X-receptor in vivo

International Nuclear Information System (INIS)

Poulton, Emma Jane; Levy, Lisa; Lampe, Johanna W.; Shen, Danny D.; Tracy, Julia; Shuhart, Margaret C.; Thummel, Kenneth E.; Eaton, David L.

2013-01-01

Sulforaphane (SFN), is an effective in vitro antagonist of ligand activation of the human pregnane and xenobiotic receptor (PXR). PXR mediated CYP3A4 up-regulation is implicated in adverse drug-drug interactions making identification of small molecule antagonists a desirable therapeutic goal. SFN is not an antagonist to mouse or rat PXR in vitro; thus, normal rodent species are not suitable as in vivo models for human response. To evaluate whether SFN can effectively antagonize ligand activation of human PXR in vivo, a three-armed, randomized, crossover trial was conducted with 24 healthy adults. The potent PXR ligand — rifampicin (300 mg/d) was given alone for 7 days in arm 1, or in daily combination with 450 μmol SFN (Broccoli Sprout extract) in arm 2; SFN was given alone in arm 3. Midazolam as an in vivo phenotype marker of CYP3A was administered before and after each treatment arm. Rifampicin alone decreased midazolam AUC by 70%, indicative of the expected increase in CYP3A4 activity. Co-treatment with SFN did not reduce CYP3A4 induction. Treatment with SFN alone also did not affect CYP3A4 activity in the cohort as a whole, although in the subset with the highest basal CYP3A4 activity there was a statistically significant increase in midazolam AUC (i.e., decrease in CYP3A4 activity). A parallel study in humanized PXR mice yielded similar results. The parallel effects of SFN between humanized PXR mice and human subjects demonstrate the predictive value of humanized mouse models in situations where species differences in ligand-receptor interactions preclude the use of a native mouse model for studying human ligand-receptor pharmacology. -- Highlights: ► The effects of SFN on PXR mediated CYP3A4 induction in humanized PXR mice and humans were examined. ► SFN had no effect on rifampicin mediated CYP3A4 induction in humans or humanized mice. ► SFN had a modest effect on basal CYP3A4 activity among subjects with higher baseline activity. ► Humanized PXR

Discovery of Dual ETA/ETB Receptor Antagonists from Traditional Chinese Herbs through in Silico and in Vitro Screening

Directory of Open Access Journals (Sweden)

Xing Wang

2016-03-01

Full Text Available Endothelin-1 receptors (ETAR and ETBR act as a pivotal regulator in the biological effects of ET-1 and represent a potential drug target for the treatment of multiple cardiovascular diseases. The purpose of the study is to discover dual ETA/ETB receptor antagonists from traditional Chinese herbs. Ligand- and structure-based virtual screening was performed to screen an in-house database of traditional Chinese herbs, followed by a series of in vitro bioassay evaluation. Aristolochic acid A (AAA was first confirmed to be a dual ETA/ETB receptor antagonist based intracellular calcium influx assay and impedance-based assay. Dose-response curves showed that AAA can block both ETAR and ETBR with IC50 of 7.91 and 7.40 μM, respectively. Target specificity and cytotoxicity bioassay proved that AAA is a selective dual ETA/ETB receptor antagonist and has no significant cytotoxicity on HEK293/ETAR and HEK293/ETBR cells within 24 h. It is a feasible and effective approach to discover bioactive compounds from traditional Chinese herbs using in silico screening combined with in vitro bioassay evaluation. The structural characteristic of AAA for its activity was especially interpreted, which could provide valuable reference for the further structural modification of AAA.

Block of the delayed rectifier current (IK) by the 5-HT3 antagonists ondansetron and granisetron in feline ventricular myocytes.

Science.gov (United States)

de Lorenzi, F G; Bridal, T R; Spinelli, W

1994-01-01

1. We investigated the effects of two 5-HT3 antagonists, ondansetron and granisetron, on the action potential duration (APD) and the delayed rectifier current (IK) of feline isolated ventricular myocytes. Whole-cell current and action potential recordings were performed at 37 degrees C with the patch clamp technique. 2. Ondansetron and granisetron blocked IK with a KD of 1.7 +/- 1.0 and 4.3 +/- 1.7 microM, respectively. At a higher concentration (30 microM), both drugs blocked the inward rectifier (IKl). 3. The block of IK was dependent on channel activation. Both drugs slowed the decay of IK tail currents and produced a crossover with the pre-drug current trace. These results are consistent with block and unblock from the open state of the channel. 4. Granisetron showed an intrinsic voltage-dependence as the block increased with depolarization. The equivalent voltage-dependency of block (delta) was 0.10 +/- 0.04, suggesting that granisetron blocks from the intracellular side at a binding site located 10% across the transmembrane electrical field. 5. Ondansetron (1 microM) and granisetron (3 microM) prolonged APD by about 30% at 0.5 Hz. The prolongation of APD by ondansetron was abolished at faster frequencies (3 Hz) showing reverse rate dependence. 6. In conclusion, the 5-HT3 antagonists, ondansetron and granisetron, are open state blockers of the ventricular delayed rectifier and show a clear class III action. PMID:7834204

Efficacy of 5-HT{sub 3} receptor antagonists in radiotherapy-induced nausea and vomiting: A quantitative systematic review

Energy Technology Data Exchange (ETDEWEB)

Tramer, M.R. [Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford (United Kingdom); Reynolds, D.J.M. [Department of Clinical Pharmacology, Radcliffe Infirmary, Oxford, Radcliffe Hospital (United Kingdom); Stoner, N.S. [ICRF Department of Medical Oncology, Oxford Radcliffe Hospital (United Kingdom); Moore, R.A.; McQuay, H.J. [Pain Research and Nuffield Department of Anaesthetics, University of Oxford, Oxford Radcliffe Hospital, The Churchill, Headington, Oxford (United Kingdom)

1998-11-01

5-HT{sub 3} receptor antagonists are used to treat radiation-induced sickness. The purpose of this study was to define anti-emetic efficacy and potential for harm of these drugs in radiotherapy. A systematic search, critical appraisal and quantitative analysis of relevant data using the number-needed-to-treat or harm (NNT/H) were conducted. Acute (0 to 24 h) and delayed (beyond 24 h) anti-emetic efficacy were analysed separately. Data from 1,404 patients were found in 40 trials published in 36 reports. Data from 197 patients receiving ondansetron or granisetron in five randomised trials were regarded as valid according to preset criteria. One placebo-controlled trial had 10 patients per group and in this ondansetron was not significantly different from placebo. In a larger (n=105) placebo-controlled trial, ondansetron was significantly more efficacious than metoclopramide for complete control of acute vomiting (NNT 2.2, 95% confidence interval (CI) 1.7-3.3) and acute nausea (NNT 3.6, 95% CI 2.2-10.2). Three trials reported delayed outcomes with ondansetron or granisetron: there was no evidence of any difference compared with placebo or other anti-emetics. Two trials reported no acute or delayed but a 'worst day' outcome; in these ondansetron's antivomiting effect was significantly better than placebo (NNT 4.4, 95% CI 2.5-23) or prochlorperazine (NNT 3.8, 95% CI 2.4-10.3), but not its antinausea effect. Constipation and headache were associated significantly with 5-HT{sub 3} receptor antagonists compared with other anti-emetics or placebo (NNH 6.4 and 17.1, respectively). Only 14% of published data enabled valid estimation of the anti-emetic efficacy of 5-HT{sub 3} receptor antagonists in radiotherapy. There was some evidence that these drugs prevent acute vomiting: 40% of treated patients will benefit (NNT approximately 2.5). The evidence for nausea was less clear. There was no evidence that these drugs are of any benefit beyond 24 h. There was

Preclinical assessment of the abuse potential of the orexin receptor antagonist, suvorexant.

Science.gov (United States)

Born, Stephanie; Gauvin, David V; Mukherjee, Suman; Briscoe, Richard

2017-06-01

Suvorexant (Belsomra ® ) is a dual orexin receptor antagonist approved for the treatment of insomnia. Because of its pharmacology within the central nervous system, intended therapeutic indication, and first-in-class status, an assessment of suvorexant abuse liability potential was required prior to marketing approval. The nonclinical abuse liability potential studies for suvorexant included: 1) rat drug-dependence model to assess physical dependence following abrupt cessation; 2) rat drug-discrimination model to examine the potential similarity of the interoceptive or subjective effects of suvorexant to those elicited by zolpidem and morphine; 3) self-administration model to assess the relative reinforcing efficacy of suvorexant in rhesus monkeys conditioned to self-administer methohexital. No significant signs of spontaneous drug withdrawal or 'discontinuation syndrome' were observed in rats following abrupt discontinuation of suvorexant. Suvorexant did not elicit complete cross-generalization to either a zolpidem or morphine training/reference stimuli in rats, and suvorexant was devoid of behavioral evidence of positive reinforcing efficacy in monkeys. These nonclinical findings suggested that suvorexant will have low abuse potential in humans. In the final regulatory risk assessment, suvorexant was placed into Schedule IV, likely due to its first-in-class status, its sedative properties, and the outcome of the clinical abuse potential assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

[Effect of Chinese drugs for activating blood circulation and removing blood stasis on carotid atherosclerosis and ischemic cerebrovascular events].

Science.gov (United States)

Lu, Yan; Li, Tao

2014-03-01

To explore the effect of Chinese drugs for activating blood circulation and removing blood stasis (CDABCRBS) on carotid atherosclerotic plaque and long-term ischemic cerebrovascular events. By using open and control method, effect of 4 groups of platelet antagonists, platelet antagonists + CDABCRBS, platelet antagonists +atorvastatin, platelet antagonists +atorvastatin +CDABCRBS on carotid atherosclerotic plaque and long-term ischemic cerebrovascular events of 90 cerebral infarction patients were analyzed. Through survival analysis, there was no statistical difference in the effect of the 4 interventions on the variation of carotid stenosis rates or ischemic cerebrovascular events (P > 0.05). The occurrence of ischemic cerebrovascular events could be postponed by about 4 months in those treated with platelet antagonists + CDABCRBS and platelet antagonists + atorvastatin +CDABCRBS. By multivariate Logistic analysis, age, hypertension, and clopidogrel were associated with stenosis of extracranial carotid arteries (P cerebrovascular accidents (P cerebrovascular events. CDABCRBS could effectively prolong the occurrence time of ischemic cerebrovascular events.

Effects of the noncompetitive N-methyl-d-aspartate receptor antagonists ketamine and MK-801 on pain-stimulated and pain-depressed behaviour in rats.

Science.gov (United States)

Hillhouse, T M; Negus, S S

2016-09-01

Pain is a significant public health concern, and current pharmacological treatments have problematic side effects and limited effectiveness. N-methyl-d-aspartate (NMDA) glutamate receptor antagonists have emerged as one class of candidate treatments for pain because of the significant contribution of glutamate signalling in nociceptive processing. This study compared effects of the NMDA receptor antagonists ketamine and MK-801 in assays of pain-stimulated and pain-depressed behaviour in rats. The nonsteroidal anti-inflammatory drug ketoprofen was examined for comparison as a positive control. Intraperitoneal injection of dilute acid served as an acute visceral noxious stimulus to stimulate a stretching response or depress intracranial self-stimulation (ICSS) in male Sprague-Dawley rats. Ketamine (1.0-10.0 mg/kg) blocked acid-stimulated stretching but failed to block acid-induced depression of ICSS, whereas MK-801 (0.01-0.1 mg/kg) blocked both acid-stimulated stretching and acid-induced depression of ICSS. These doses of ketamine and MK-801 did not alter control ICSS in the absence of the noxious stimulus; however, higher doses of ketamine (10 mg/kg) and MK-801 (0.32 mg/kg) depressed all behaviour. Ketoprofen (1.0 mg/kg) blocked both acid-induced stimulation of stretching and depression of ICSS without altering control ICSS. These results support further consideration of NMDA receptor antagonists as analgesics; however, some NMDA receptor antagonists are more efficacious at attenuating pain-depressed behaviours. NMDA receptor antagonists produce dissociable effects on pain-depressed behaviour. Provides evidence that pain-depressed behaviours should be considered and evaluated when determining the antinociceptive effects of NMDA receptor antagonists. © 2016 European Pain Federation - EFIC®

ANTAGONISTIC POTENTIAL OF FLUORESCENT Pseudomonas ...

African Journals Online (AJOL)

Prof. Adipala Ekwamu

GROWTH OF TOMATO CHALLENGED WITH PHTOPATHOGENS ... This study focused on the antagonistic potential of fluorescent Pseudomonas in vitro, and its inoculation effect on growth .... the 5 days old culture in starch agar with Lugol's.

Targeting Hsp90 by 17-AAG in leukemia cells: mechanisms for synergistic and antagonistic drug combinations with arsenic trioxide and Ara-C.

Science.gov (United States)

Pelicano, H; Carew, J S; McQueen, T J; Andreeff, M; Plunkett, W; Keating, M J; Huang, P

2006-04-01

17-Allylamino-17-demethoxygeldanamycin (17-AAG) is a new anticancer agent currently in clinical trials. The ability of 17-AAG to abrogate the function of heat-shock protein Hsp90 and modulate cellular sensitivity to anticancer agents has prompted recent research to use this compound in drug combination therapy. Here we report that 17-AAG has striking opposite effects on the activity of arsenic trioxide (ATO) and ara-C. Combination of 17-AAG with ATO exhibited a synergistic effect in leukemia cells, whereas coincubation of 17-AAG and ara-C showed antagonistic activity. Mechanistic studies revealed that ATO exerted cytotoxic action by reactive oxygen species generation, and activated Akt survival pathway. 17-AAG abrogated Akt activation and enhanced the activity of ATO. In contrast, treatment of leukemia cells with 17-AAG caused a G1 arrest, a decrease in DNA synthesis and reduced ara-C incorporation into DNA, leading to antagonism. The ability of 17-AAG to enhance the antileukemia activity of ATO was further demonstrated in primary leukemia cells isolated from patients with acute myeloid leukemia and chronic lymphocytic leukemia, including cells from refractory patients. Our data suggest that combination of 17-AAG and ATO may be an effective therapeutic regimen. Caution should be exercised in using 17-AAG together with ara-C, as their combination effects are schedule dependent.

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

Chemotherapy-induced nausea and vomiting (CINV) are among the most feared and distressing symptoms experienced by patients with cancer. The knowledge of the pathogenesis and neuropharmacology of CINV has expanded enormously over the last decades, the most significant discoveries being the role of 5......-hydroxytryptamine (5-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...

Virus-encoded chemokine receptors--putative novel antiviral drug targets

DEFF Research Database (Denmark)

Rosenkilde, Mette M

2005-01-01

Large DNA viruses, in particular herpes- and poxviruses, have evolved proteins that serve as mimics or decoys for endogenous proteins in the host. The chemokines and their receptors serve key functions in both innate and adaptive immunity through control of leukocyte trafficking, and have...... receptors belong to the superfamily of G-protein coupled 7TM receptors that per se are excellent drug targets. At present, non-peptide antagonists have been developed against many chemokine receptors. The potentials of the virus-encoded chemokine receptors as drug targets--ie. as novel antiviral strategies...

Fasitibant chloride, a kinin B2 receptor antagonist, and dexamethasone interact to inhibit carrageenan-induced inflammatory arthritis in rats

Science.gov (United States)

Valenti, Claudio; Giuliani, Sandro; Cialdai, Cecilia; Tramontana, Manuela; Maggi, Carlo Alberto

2012-01-01

BACKGROUND AND PURPOSE Bradykinin, through the kinin B2 receptor, is involved in inflammatory processes related to arthropathies. B2 receptor antagonists inhibited carrageenan-induced arthritis in rats in synergy with anti-inflammatory steroids. The mechanism(s) underlying this drug interaction was investigated. EXPERIMENTAL APPROACH Drugs inhibiting inflammatory mediators released by carrageenan were injected, alone or in combination, into the knee joint of pentobarbital anaesthetized rats 30 min before intra-articular administration of carrageenan. Their effects on the carrageenan-induced inflammatory responses (joint pain, oedema and neutrophil recruitment) and release of inflammatory mediators (prostaglandins, IL-1β, IL-6 and the chemokine GRO/CINC-1), were assessed after 6 h. KEY RESULTS The combination of fasitibant chloride (MEN16132) and dexamethasone was more effective than each drug administered alone in inhibiting knee joint inflammation and release of inflammatory mediators. Fasitibant chloride, MK571, atenolol, des-Arg9-[Leu8]-bradykinin (B2 receptor, leukotriene, catecholamine and B1 receptor antagonists, respectively) and dexketoprofen (COX inhibitor), reduced joint pain and, except for the latter, also diminished joint oedema. A combination of drugs inhibiting joint pain (fasitibant chloride, des-Arg9-[Leu8]-bradykinin, dexketoprofen, MK571 and atenolol) and oedema (fasitibant chloride, des-Arg9-[Leu8]-bradykinin, MK571 and atenolol) abolished the respective inflammatory response, producing inhibition comparable with that achieved with the combination of fasitibant chloride and dexamethasone. MK571 alone was able to block neutrophil recruitment. CONCLUSIONS AND IMPLICATIONS Bradykinin-mediated inflammatory responses to intra-articular carrageenan were not controlled by steroids, which were not capable of preventing bradykinin effects either by direct activation of the B2 receptor, or through the indirect effects mediated by release of eicosanoids

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

Antagonistic interactions between plant competition and insect herbivory.

Science.gov (United States)

Schädler, Martin; Brandl, Roland; Haase, Josephine

2007-06-01

Interspecific competition between plants and herbivory by specialized insects can have synergistic effects on the growth and performance of the attacked host plant. We tested the hypothesis that competition between plants may also negatively affect the performance of herbivores as well as their top-down effect on the host plant. In such a case, the combined effects of competition and herbivory may be less than expected from a simple multiplicative response. In other words, competition and herbivory may interact antagonistically. In a greenhouse experiment, Poa annua was grown in the presence or absence of a competitor (either Plantago lanceolata or Trifolium repens), as well as with or without a Poa-specialist aphid herbivore. Both competition and herbivory negatively affected Poa growth. Competition also reduced aphid density on Poa. This effect could in part be explained by changes in the biomass and the nitrogen content of Poa shoots. In treatments with competitors, reduced aphid densities alleviated the negative effect of herbivory on above- and belowground Poa biomass. Hence, we were able to demonstrate an antagonistic interaction between plant-plant interspecific competition and herbivory. However, response indices suggested that antagonistic interactions between competition and herbivory were contingent on the identity of the competitor. We found the antagonistic effect only in treatments with T. repens as the competitor. We conclude that both competitor identity and the herbivore's ability to respond with changes in its density or activity to plant competition affect the magnitude and direction (synergistic vs. antagonistic) of the interaction between competition and herbivory on plant growth.

Early Illustrations of Geste Antagoniste in Cervical and Generalized Dystonia

Science.gov (United States)

Broussolle, Emmanuel; Laurencin, Chloé; Bernard, Emilien; Thobois, Stéphane; Danaila, Teodor; Krack, Paul

2015-01-01

Background Geste antagoniste, or sensory trick, is a voluntary maneuver that temporarily reduces the severity of dystonic postures or movements. We present a historical review of early reports and illustrations of geste antagoniste. Results In 1894, Brissaud described this phenomenon in Paris in patients with torticollis. He noted that a violent muscular contraction could be reversed by a minor voluntary action. He considered the improvement obtained by what he called “simple mannerisms, childish behaviour or fake pathological movements” was proof of the psychogenic origin of what he named mental torticollis. This concept was supported by photographical illustrations of the patients. The term geste antagoniste was used by Brissaud’s pupils, Meige and Feindel, in their 1902 monograph on movement disorders. Other reports and illustrations of this sign were published in Europe between 1894 and 1906. Although not mentioned explicitly, geste antagoniste was also illustrated in a case report of generalized dystonia in Oppenheim’s 1911 seminal description of dystonia musculorum deformans in Berlin. Discussion Brissaud-Meige’s misinterpretation of the geste antagoniste unfortunately anchored the psychogenic origin of dystonia for decades. In New York, Herz brought dystonia back into the realm of organic neurology in 1944. Thereafter, it was given prominence by other authors, notably Fahn and Marsden in the 1970–1980s. Nowadays, neurologists routinely investigate for geste antagoniste when a dystonic syndrome is suspected, because it provides a further argument in favor of dystonia. The term alleviating maneuver was proposed in 2014 to replace sensory trick or geste antagoniste. This major sign is now part of the motor phenomenology of the 2013 Movement Disorder Society’s classification of dystonia. PMID:26417535

Testosterone-induced benign prostatic hyperplasia rat and dog as facile models to assess drugs targeting lower urinary tract symptoms.

Directory of Open Access Journals (Sweden)

Jing Li

Full Text Available Benign prostatic hyperplasia (BPH is an age-related disease, affecting a majority of elderly men worldwide. Medical management of BPH is an alternative to surgical treatment of this disease. Currently, α1-adrenergic receptor (α1-AR antagonists are among the first line drugs to treat BPH by reducing the tension of urinary track and thus the obstructive symptoms in voiding. In drug development, old male dogs with spontaneous BPH are considered the golden standard of the animal models. However, old dogs (>6 years are expensive and not all old dogs develop BPH. So it is necessary to develop more accessible animal models for drug efficacy evaluation. Here we describe the development of testosterone-induced BPH models in both rats and young adult dogs and their applications in the in vivo evaluation of α1-AR antagonist. The BPH rats and dogs induced by chronic testosterone treatment have significantly increased micturition frequency and reduced mean voided volume, very similar to the clinical symptoms of BPH patients. Silodosin, an α1-AR antagonist, significantly reduces the urinary frequency and increases the voided volume in BPH model animals in a dose-dependent manner. The results demonstrate that testosterone-induced BPH rat and dog models might provide a more efficient way to evaluate micturition behavior in anti-BPH drug studies.

[Systematic review on the short-term efficacy and safety of nicorandil for stable angina pectoris in comparison with those of β-blockers, nitrates and calcium antagonists].

Science.gov (United States)

Hanai, Yuki; Mita, Mitsuo; Hishinuma, Shigeru; Shoji, Masaru

2010-11-01

Nicorandil significantly reducted the incidence of major coronary events in patients with stable angina in a long-term trial, although there are few reports on its short-term efficacy in the treatment and prevention of angina symptoms. We performed a meta-analysis of the short-term efficacy of nicorandil compared with antianginal drugs for stable angina. We selected 20 reports (vs. β-blockers, n=6; vs. nitrates, n=6; vs. calcium antagonists, n=8) of prospective controlled trials from MEDLINE, the Cochrane Library, and Japana Centra Revuo Medicina. The trials were short in duration (median 5 weeks). We combined the results using odds ratios (OR) for discrete data and weighted mean differences (WMD) for continuous data. Compared with antianginal drugs, nicorandil did not show significant reduction of angina episodes per week (vs. β-blockers, -1.50 [95% confidence interval (CI): -4.09, 1.09]; vs. nitrates, 0.22 [95% CI: -1.22, 1.65]; vs. calcium antagonists, -0.23 [95% CI: -1.37, 0.90]). Furthermore, there were no significant differences in time to ischemia (total exercise duration, time to 1-mm ST depression, time to onset of pain). Although the total numbers of adverse events with each antianginal drug were similar, heart rate and blood pressure were significantly decreased by calcium antagonists but not changed by nicorandil (8.09 [95% CI: 3.20, 12.98] and 8.64 [95% CI: 3.28, 13.99], respectively). Thus this study suggests that short-term therapy with nicorandil is as effective as standard therapy and that nicorandil can also be used as a first-line agent in patients with stable angina.

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.

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...... and antagonists. We find that E2065.46 contributes most in binding H3 selective agonists (5, 6, 7) in agreement with experimental mutation studies. We also find that conserved E5.46/S5.43 in both of hH3HR and hH4HR are involved in H3/ H4 subtype selectivity. In addition, we find that M3786.55 in hH3HR provides...... additional hydrophobic interactions different from hH4HR (the corresponding amino acid of T3236.55 in hH4HR) to provide additional subtype bias. From these studies, we developed a pharmacophore model based on our predictions for known hH3HR selective antagonists in clinical study [ABT-239 1, GSK-189,254 2...

Evidence that 5-hydroxytryptamine/sub 3/ receptors mediate cytotoxic drug and radiation-evoked emesis

Energy Technology Data Exchange (ETDEWEB)

Miner, W.D.; Sanger, G.J.; Turner, D.H.

1987-08-01

The involvement of 5-hydroxytryptamine (5-HT) 5-HT/sub 3/ receptors in the mechanisms of severe emesis evoked by cytotoxic drugs or by total body irradiation have been studied in ferrets. Anti-emetic compounds tested were domperidone (a dopamine antagonist), metoclopramide (a gastric motility stimulant and dopamine antagonist at conventional doses, a 5-HT/sub 3/ receptor antagonist at higher doses) and BRL 24924 (a potent gastric motility stimulant and a 5-HT/sub 3/ receptor antagonist). Domperidone or metoclopramide prevented apomorphine-evoked emesis, whereas BRL 24924 did not. Similar doses of domperidone did not prevent emesis evoked by cis-platin or by total body irradiation, whereas metoclopramide or BRL 24924 greatly reduced or prevented these types of emesis. Metoclopramide and BRL 24924 also prevented emesis evoked by a combination of doxorubicin and cyclophosphamide. These results are discussed in terms of a fundamental role for 5-HT/sub 3/ receptors in the mechanisms mediating severely emetogenic cancer treatment therapies.

antagonistic effect of native bacillus isolates against black root rot

African Journals Online (AJOL)

ACSS

A number of fungi and bacteria are known to be very effective .... Round. Convex. Smooth. Wrinkled. Slow. BS024. Irregular and spreading. Flat. Wavy .... Antibiotic effect of bacterial antagonist ..... antagonistic Bacillus and Trichoderma isolates ...

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.

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.

Rational use of calcium-channel antagonists in Raynaud's phenomenon.

Science.gov (United States)

Sturgill, M G; Seibold, J R

1998-11-01

Raynaud's phenomenon (RP) is a peripheral circulatory disorder characterized by sudden episodes of digital artery spasm, often precipitated by cold temperature or emotional stress. Although the cause of RP is not fully known, it appears to involve inappropriate adrenergic response to cold stimuli. Treatment of RP is conservative in most patients, but in patients with severe disease includes the use of agents that promote digital vasodilation. The calcium-channel antagonists, particularly the dihydropyridine derivative nifedipine, are the most thoroughly studied drug class for the treatment of RP. Approximately two thirds of patients respond favorably, with significant reductions in the frequency and severity of vasospastic attacks. Nifedipine use is often limited by the appearance of adverse vasodilatory effects such as headache or peripheral edema. The newer second-generation dihydropyridines such as amlodipine, isradipine, nicardipine, and felodipine also appear to be effective in patients with RP and may be associated with fewer adverse effects.

Vitamin K antagonist use and mortality in dialysis patients

NARCIS (Netherlands)

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

2018-01-01

Background. The risk-benefit ratio of vitamin K antagonists for different CHA2DS2-VASc scores in patients with end-stage renal disease treated with dialysis is unknown. The aim of this study was to investigate the association between vitamin K antagonist use and mortality for different CHA2DS2-VASc

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

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...... 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...

Position-aware deep multi-task learning for drug-drug interaction extraction.

Science.gov (United States)

Zhou, Deyu; Miao, Lei; He, Yulan

2018-05-01

A drug-drug interaction (DDI) is a situation in which a drug affects the activity of another drug synergistically or antagonistically when being administered together. The information of DDIs is crucial for healthcare professionals to prevent adverse drug events. Although some known DDIs can be found in purposely-built databases such as DrugBank, most information is still buried in scientific publications. Therefore, automatically extracting DDIs from biomedical texts is sorely needed. In this paper, we propose a novel position-aware deep multi-task learning approach for extracting DDIs from biomedical texts. In particular, sentences are represented as a sequence of word embeddings and position embeddings. An attention-based bidirectional long short-term memory (BiLSTM) network is used to encode each sentence. The relative position information of words with the target drugs in text is combined with the hidden states of BiLSTM to generate the position-aware attention weights. Moreover, the tasks of predicting whether or not two drugs interact with each other and further distinguishing the types of interactions are learned jointly in multi-task learning framework. The proposed approach has been evaluated on the DDIExtraction challenge 2013 corpus and the results show that with the position-aware attention only, our proposed approach outperforms the state-of-the-art method by 0.99% for binary DDI classification, and with both position-aware attention and multi-task learning, our approach achieves a micro F-score of 72.99% on interaction type identification, outperforming the state-of-the-art approach by 1.51%, which demonstrates the effectiveness of the proposed approach. Copyright © 2018 Elsevier B.V. All rights reserved.

Characterization of a novel non-steroidal glucocorticoid receptor antagonist

Energy Technology Data Exchange (ETDEWEB)

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

2010-01-15

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

Characterization of a novel non-steroidal glucocorticoid receptor antagonist

International Nuclear Information System (INIS)

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

2010-01-01

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

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

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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.

Role of dopamine D4 receptors in copulatory behavior: Studies with selective D4 agonists and antagonists in male rats.

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Sanna, Fabrizio; Contini, Andrea; Melis, Maria Rosaria; Argiolas, Antonio

2015-10-01

Dopamine influences the anticipatory and consummatory phases of sexual behavior, by acting on receptors of the D2 family (D2, D3 and D4) and in particular of the D2 subtype, although evidence for a role of D4 receptors in erectile function and copulatory behavior is also available. In order to clarify such a role of D4 receptors, the effect of selective D4 receptor agonists and antagonists on copulatory behavior of sexually potent male rats in classic copulation tests with a receptive female, was compared with that of apomorphine and haloperidol, a classic dopamine receptor agonist and antagonist, respectively. PD-168,077 (0.05-0.2mg/kg) and ABT-724 (0.01-0.04mg/kg), two selective D4 receptor agonists, given subcutaneously, improved dose-dependently copulatory behavior as shown by the decrease of mount frequency and post ejaculatory interval induced by PD-168,077, and of mount frequency, ejaculation latency, post ejaculatory and inter intromission intervals induced by ABT-724, and by the increase of ejaculation frequency and copulatory efficacy induced by both drugs. Conversely, L-745,870 (1-5mg/kg), a selective D4 receptor antagonist, given intraperitoneally, impaired dose-dependently copulatory behavior, as shown by the increase in intromission and ejaculation latencies, mount frequency, post ejaculatory interval and the decrease in ejaculation frequency and copulatory efficacy induced by this drug. L-745,870 (5mg/kg) administered before PD-168,077 (0.2mg/kg) or ABT-724 (0.04mg/kg), also abolished completely the facilitatory effects of both PD-168,077 and ABT-724 on sexual behavior. These results confirm the involvement of D4 receptors in specific aspects of male rat copulatory behavior that overlap only partially with those influenced by apomorphine and haloperidol. Copyright © 2015 Elsevier Inc. All rights reserved.

Medicinal Chemistry of Competitive Kainate Receptor Antagonists

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2010-01-01

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

Augmentation of Anticancer Drug Efficacy in Murine Hepatocellular Carcinoma Cells by a Peripherally Acting Competitive N-Methyl-d-aspartate (NMDA) Receptor Antagonist

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Gynther, Mikko; Proietti Silvestri, Ilaria; Hansen, Jacob C

2017-01-01

-acting ionotropic glutamate receptor antagonist 1a. Subsequently, we demonstrate that 1l augments the cytotoxic action of sorafenib in murine hepatocellular carcinoma cells. The underlying biological mechanism was shown to be interference with the lipid signaling pathway, leading to reduced expression of MDR...

Functional Characterization of 5-HT1B Receptor Drugs in Nonhuman Primates Using Simultaneous PET-MR.

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Hansen, Hanne D; Mandeville, Joseph B; Sander, Christin Y; Hooker, Jacob M; Catana, Ciprian; Rosen, Bruce R; Knudsen, Gitte M

2017-11-01

In the present study, we used a simultaneous PET-MR experimental design to investigate the effects of functionally different compounds (agonist, partial agonist, and antagonist) on 5-HT 1B receptor (5-HT 1B R) occupancy and the associated hemodynamic responses. In anesthetized male nonhuman primates ( n = 3), we used positron emission tomography (PET) imaging with the radioligand [ 11 C]AZ10419369 administered as a bolus followed by constant infusion to measure changes in 5-HT 1B R occupancy. Simultaneously, we measured changes in cerebral blood volume (CBV) as a proxy of drug effects on neuronal activity. The 5-HT 1B R partial agonist AZ10419369 elicited a dose-dependent biphasic hemodynamic response that was related to the 5-HT 1B R occupancy. The magnitude of the response was spatially overlapping with high cerebral 5-HT 1B R densities. High doses of AZ10419369 exerted an extracranial tissue vasoconstriction that was comparable to the less blood-brain barrier-permeable 5-HT 1B R agonist sumatriptan. By contrast, injection of the antagonist GR127935 did not elicit significant hemodynamic responses, even at a 5-HT 1B R cerebral occupancy similar to the one obtained with a high dose of AZ10419369. Given the knowledge we have of the 5-HT 1B R and its function and distribution in the brain, the hemodynamic response informs us about the functionality of the given drug: changes in CBV are only produced when the receptor is stimulated by the partial agonist AZ10419369 and not by the antagonist GR127935, consistent with low basal occupancy by endogenous serotonin. SIGNIFICANCE STATEMENT We here show that combined simultaneous positron emission tomography and magnetic resonance imaging uniquely enables the assessment of CNS active compounds. We conducted a series of pharmacological interventions to interrogate 5-HT 1B receptor binding and function and determined blood-brain barrier passage of drugs and demonstrate target involvement. Importantly, we show how the spatial

Antagonistic effect of alkaloids and saponins on bioactivity in the quinine tree (Rauvolfia caffra sond.): further evidence to support biotechnology in traditional medicinal plants.

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Milugo, Trizah K; Omosa, Leonida K; Ochanda, James O; Owuor, Bethwell O; Wamunyokoli, Fred A; Oyugi, Julius O; Ochieng, Joel W

2013-10-26

The Quinine tree (Rauvolfia caffra) is used as a medicinal plant among traditional communities in many countries to manage tumors and other diseases associated with oxidative stress. To validate indigenous knowledge and possibly position this herb for technology uptake and utilization, we established the level of antioxidant activity in R. caffra, and probed for the presence of associated phytochemicals. Antioxidant activity was determined on 1,1-diphenyl-2-picrylhydrazyl (DPPH) while major phytochemicals were identified by multiple tests on methanol fractions. R. caffra showed promise as a cure, with antioxidant activity comparable to the commercially used drug quercetin (R. caffra = 79.7% ±1.9; quercetin = 82.6% ± 2.0). However, we found two phytochemicals with possible antagonistic effect: co-occurrence of alkaloids and saponins significantly reduced antioxidant activity (alkaloids only = 63%; alkaloids plus saponins = 15%; steroids, terpenoids and cardiac glycosides = 82%), thus alkaloids and saponins should be exclusive to each other in drug formulations. Antagonistic relationship among phytochemicals would affect the efficacy of crude extracts as used in traditional medicine. Unlike in herbal medicine, use of modern biotechnology in extraction, purification and design of optimal combinations will ensure efficient drug formulations with optimum bioactivity and minimum toxicity. Metabolic pathway engineering under a controlled environment may optimize availability of desired compounds.

[Neonatal risks of drugs exposure at the end of pregnancy].

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Autret-Leca, Elisabeth; Cissoko, Hawaré; Jonville-Béra, Annie Pierre

2011-01-01

Foetal drugs exposure consequences depend according to the drug involved and to the length of the exposure which in the sum of length of treatment and of drug elimination (5 half life). Decisions are based upon risk evaluation and are a compromise between a risk banalisation and an excess of carefully. We described risks management for drugs used for a disease due to the pregnancy (glucocorticoïdes, antibiotics) then for drugs used for a chronic disease often preceding the pregnancy (non steroidal anti-inflammatory, serotonin recapture inhibitors, benzodiazepines, antiepileptics, conversion enzyme inhibitors/renine angiotensine antagonists, betabloquants). We also present the elements to take in account for the best drug choice at the end of pregnancy and/or for an adapted advice if the drug has been already taken: the drug itself (pharmacological effects, kinetics in neonate, toxicity marker, risk detection tool), drug amount possibly received by the neonate and literature data about neonatal manifestations due to the drug. © 2011 Société Française de Pharmacologie et de Thérapeutique.

Stent parameters predict major adverse clinical events and the response to platelet glycoprotein IIb/IIIa blockade: findings of the ESPRIT trial.

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Tcheng, James E; Lim, Ing Haan; Srinivasan, Shankar; Jozic, Joseph; Gibson, C Michael; O'Shea, J Conor; Puma, Joseph A; Simon, Daniel I

2009-02-01

Only limited data describe relationships between stent parameters (length and diameter), adverse events after percutaneous coronary intervention, and effects of platelet glycoprotein IIb/IIIa blockade by stent parameters. In this post hoc analysis of the 1983 patients receiving a stent in the Enhanced Suppression of the Platelet Glycoprotein IIb/IIIa Receptor with Integrilin Therapy randomized percutaneous coronary intervention trial of eptifibatide versus placebo, rates of the major adverse cardiac event (MACE) end point (death, myocardial infarction, urgent target-vessel revascularization, or thrombotic bailout) at 48 hours and 1 year were correlated with stent parameters and then analyzed by randomization to eptifibatide versus placebo. In the placebo group, MACE increased with number of stents implanted, total stent length (by quartiles of or=30 mm), and total stented vessel area (by quartiles of area or=292 mm(2)). By stent parameters, MACE at 48 hours was reduced in the eptifibatide group at stent lengths of 18 to or=30 mm (OR, 0.43; 95% CI, 0.25 to 0.75; P=0.003), stent diameters of >2.5 to <3.5 mm (OR, 0.56; 95% CI, 0.39 to 0.82; P=0.002), and with 2 stents implanted (OR, 0.39; 95% CI, 0.22 to 0.69; P=0.001). In the placebo group, near-linear relationships were observed between both increasing stent length and increasing stented vessel area and MACE at 48 hours and 1 year (all, P<0.001); these gradients were flattened in the eptifibatide group (P=0.005 for stent length). Stent parameters predict MACE after percutaneous coronary intervention. Glycoprotein IIb/IIIa blockade mitigates much of the hazard of increasing procedural complexity.

ANTAGONISTIC BACTERIA AGAINST SCHIZOPHYLLUM COMMUNE FR. IN PENINSULAR MALAYSIA

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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.

Oleoylethanolamide: A Novel Potential Pharmacological Alternative to Cannabinoid Antagonists for the Control of Appetite

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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.

Interleukin-1 antagonists in the treatment of autoinflammatory syndromes, including cryopyrin-associated periodic syndrome

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Pierre Quartier

2011-01-01

Full Text Available Pierre QuartierUnité d'Immunologie-Hématologie et Rhumatologie pédiatriques, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, FranceAbstract: Cryopyrin-associated periodic syndrome (CAPS include a group of rare autoinflammatory disorders, the spectrum of which ranges from the mildest form, ie, familial cold autoinflammatory syndrome to more severe phenotypes, ie, Muckle-Wells syndrome, and chronic infantile neurological cutaneous and articular syndrome, also known as neonatal-onset multisystem inflammatory disease. Three interleukin (IL-1 antagonists have been tested in adults and children with CAPS, ie, anakinra, a recombinant homolog of the human IL-1 receptor antagonist; rilonacept, a fusion protein comprising the extracellular domains of IL-1 receptor I and the IL-1 adaptor protein, IL-1RAcP, attached to a human immunoglobulin G molecule; and canakinumab, the anti-IL-1β monoclonal antibody. Following rapid clinical development, rilonacept and canakinumab were approved by both the US Food and Drug Administration and the European Medicines Agency for use in adults and children. This review describes how the study of CAPS has helped us to understand better the way the innate immune system works, the pathogenesis of autoinflammatory syndromes, and the key role of IL-1. It also reviews the effects of IL-1 blockade in CAPS and other disorders, in particular systemic juvenile idiopathic arthritis, adult-onset Still's disease, and gout. Finally, this review covers some issues addressed by very recent and ongoing work regarding treatment indications, from orphan diseases to common disorders, continuous versus intermittent treatment, the pharmacokinetics, pharmacodynamics, and optimal dosages of the different drugs, as well as the need for Phase IV trials, exhaustive registries, and long-term follow-up of several patient cohorts.Keywords: inflammation, interleukin-1, cytokines, treatment

Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings.

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Le Foll, Bernard; Collo, Ginetta; Rabiner, Eugenii A; Boileau, Isabelle; Merlo Pich, Emilio; Sokoloff, Pierre

2014-01-01

The dopamine D3 receptor is located in the limbic area and apparently mediates selective effects on motivation to take drugs and drug-seeking behaviors, so that there has been considerable interest on the possible use of D3 receptor ligands to treat drug addiction. However, only recently selective tools allowing studying this receptor have been developed. This chapter presents an overview of findings that were presented at a symposium on the conference Dopamine 2013 in Sardinia in May 2013. Novel neurobiological findings indicate that drugs of abuse can lead to significant structural plasticity in rodent brain and that this is dependent on the availability of functional dopamine D3 autoreceptor, whose activation increased phosphorylation in the ERK pathway and in the Akt/mTORC1 pathway indicating the parallel engagement of a series of intracellular signaling pathways all involved in cell growth and survival. Preclinical findings using animal models of drug-seeking behaviors confirm that D3 antagonists have a promising profile to treat drug addiction across drugs of abuse type. Imaging the D3 is now feasible in human subjects. Notably, the development of (+)-4-propyl-9-hydroxynaphthoxazine ligand used in positron emission tomography (PET) studies in humans allows to measure D3 and D2 receptors based on the area of the brain under study. This PET ligand has been used to confirm up-regulation of D3 sites in psychostimulant users and to reveal that tobacco smoking produces elevation of dopamine at the level of D3 sites. There are now novel antagonists being developed, but also old drugs such as buspirone, that are available to test the D3 hypothesis in humans. The first results of clinical investigations are now being provided. Overall, those recent findings support further exploration of D3 ligands to treat drug addiction. © 2014 Elsevier B.V. All rights reserved.

A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer

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Wenbo Yao

2017-08-01

Full Text Available Hepatocellular carcinoma (HCC is a common malignant tumor in the digestive tract with limited therapeutic choices. Although sorafenib, an orally administered multikinase inhibitor, has produced survival benefits for patients with advanced HCC, favorable clinical outcomes are limited due to individual differences and resistance. The application of immunotherapy, a promising approach for HCC is urgently needed. Macrophage infiltration, mediated by the CCL2/CCR2 axis, is a potential immunotherapeutic target. Here, we report that a natural product from Abies georgei, named 747 and related in structure to kaempferol, exhibits sensitivity and selectivity as a CCR2 antagonist. The specificity of 747 on CCR2 was demonstrated via calcium flux, the binding domain of CCR2 was identified in an extracellular loop by chimera binding assay, and in vivo antagonistic activity of 747 was confirmed through a thioglycollate-induced peritonitis model. In animals, 747 elevated the number of CD8+ T cells in tumors via blocking tumor-infiltrating macrophage-mediated immunosuppression and inhibited orthotopic and subcutaneous tumor growth in a CD8+ T cell-dependent manner. Further, 747 enhanced the therapeutic efficacy of low-dose sorafenib without obvious toxicity, through elevating the numbers of intra-tumoral CD8+ T cells and increasing death of tumor cells. Thus, we have discovered a natural CCR2 antagonist and have provided a new perspective on development of this antagonist for treatment of HCC. In mouse models of HCC, 747 enhanced the tumor immunosuppressive microenvironment and potentiated the therapeutic effect of sorafenib, indicating that the combination of an immunomodulator with a chemotherapeutic drug could be a new approach for treating HCC.

Skin-targeted inhibition of PPAR β/δ by selective antagonists to treat PPAR β/δ-mediated psoriasis-like skin disease in vivo.

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Katrin Hack

Full Text Available We have previously shown that peroxisome proliferator activating receptor ß/δ (PPAR β/δ is overexpressed in psoriasis. PPAR β/δ is not present in adult epidermis of mice. Targeted expression of PPAR β/δ and activation by a selective synthetic agonist is sufficient to induce an inflammatory skin disease resembling psoriasis. Several signalling pathways dysregulated in psoriasis are replicated in this model, suggesting that PPAR β/δ activation contributes to psoriasis pathogenesis. Thus, inhibition of PPAR β/δ might harbour therapeutical potential. Since PPAR β/δ has pleiotropic functions in metabolism, skin-targeted inhibition offer the potential of reducing systemic adverse effects. Here, we report that three selective PPAR β/δ antagonists, GSK0660, compound 3 h, and GSK3787 can be formulated for topical application to the skin and that their skin concentration can be accurately quantified using ultra-high performance liquid chromatography (UPLC/mass spectrometry. These antagonists show efficacy in our transgenic mouse model in reducing psoriasis-like changes triggered by activation of PPAR β/δ. PPAR β/δ antagonists GSK0660 and compound 3 do not exhibit systemic drug accumulation after prolonged application to the skin, nor do they induce inflammatory or irritant changes. Significantly, the irreversible PPAR β/δ antagonist (GSK3787 retains efficacy when applied topically only three times per week which could be of practical clinical usefulness. Our data suggest that topical inhibition of PPAR β/δ to treat psoriasis may warrant further exploration.

Essential oils of culinary herbs and spices display agonist and antagonist activities at human aryl hydrocarbon receptor AhR.

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Bartoňková, Iveta; Dvořák, Zdeněk

2018-01-01

Essential oils (EOs) of culinary herbs and spices are used to flavor, color and preserve foods and drinks. Dietary intake of EOs is significant, deserving an attention of toxicologists. We examined the effects of 31 EOs of culinary herbs and spices on the transcriptional activity of human aryl hydrocarbon receptor (AhR), which is a pivotal xenobiotic sensor, having also multiple roles in human physiology. Tested EOs were sorted out into AhR-inactive ones (14 EOs) and AhR-active ones, including full agonists (cumin, jasmine, vanilla, bay leaf), partial agonists (cloves, dill, thyme, nutmeg, oregano) and antagonists (tarragon, caraway, turmeric, lovage, fennel, spearmint, star anise, anise). Major constituents (>10%) of AhR-active EOs were studied in more detail. We identified AhR partial agonists (carvacrol, ligustilide, eugenol, eugenyl acetate, thymol, ar-turmerone) and antagonists (trans-anethole, butylidine phtalide, R/S-carvones, p-cymene), which account for AhR-mediated activities of EOs of fennel, anise, star anise, caraway, spearmint, tarragon, cloves, dill, turmeric, lovage, thyme and oregano. We also show that AhR-mediated effects of some individual constituents of EOs differ from those manifested in mixtures. In conclusion, EOs of culinary herbs and spices are agonists and antagonists of human AhR, implying a potential for food-drug interactions and interference with endocrine pathways. Copyright © 2017 Elsevier Ltd. All rights reserved.

Antihypertensive drug use in resistant and nonresistant hypertension and in controlled and uncontrolled resistant hypertension.

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de la Sierra, Alejandro; Armario, Pedro; Oliveras, Anna; Banegas, José R; Gorostidi, Manuel; Vinyoles, Ernest; de la Cruz, Juan J; Segura, Julián; Ruilope, Luis M

2018-07-01

Treatment-resistant hypertension (TRH) is associated with particular clinical features, nonadherence, and suboptimal treatment. We assessed possible associations of antihypertensive drug classes, specific agents inside each class, and types of combinations, with the presence of non-TRH vs. TRH, and with controlled vs. uncontrolled TRH. Comparisons were done in 14 264 patients treated with three drugs (non-TRH: 2988; TRH: 11 276) and in 6974 treated with at least four drugs (controlled TRH: 1383; uncontrolled TRH: 5591). Associations were adjusted for age, sex, and previous cardiovascular event. In both groups of patients treated with three or with at least four drugs, aldosterone antagonists among drug classes [adjusted odds ratio (OR): 1.82 and 1.41, respectively], and ramipril (OR: 1.28 and 1.30), olmesartan (OR: 1.31 and 1.37), and amlodipine (OR: 1.11 and 1.41) inside each class were significantly associated with blood pressure control (non-TRH or controlled TRH). In patients treated with three drugs, non-TRH was also associated with the use of chlorthalidone (OR: 1.50) and bisoprolol (OR: 1.19), whereas in patients treated with at least four drugs, controlled TRH was significantly associated with the triple combination of a renin-angiotensin system blocker, a calcium channel blocker, and a diuretic (OR: 1.17). The use of aldosterone antagonists is associated with blood pressure control in patients treated with three or more drugs. Similar results are observed with specific agents inside each class, being ramipril, olmesartan, chlorthalidone, amlodipine, and bisoprolol those exhibiting significant results. An increased use of these drugs might probably reduce the burden of TRH.

Primary care physicians' adoption of new drugs is not associated with their clinical interests: A pharmacoepidemiologic study

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Dybdahl, Torben; Søndergaard, Jens; Kragstrup, Jakob

2011-01-01

Abstract Objectives. Increasing drug expenditures call for better understanding of the reasons behind individual general practitioners' (GPs') prescribing decisions. The aim was to analyse associations between GPs' clinical interests and their preference for new drugs. Design. Historical cohort...... association between GPs' self-rated clinical interest and their prescribing of new drugs was found.......-II antagonists) were analysed. The preference was defined as the percentage of patients receiving a new drug among first-time users of either the new drug or an older alternative. The GPs' preference proportion was modelled using linear regression analysis. Data from a questionnaire on GPs' interest...

Evaluation of the protagonist-antagonist dichotomy in Spanish television content targeting children

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José A. García-Castillo, Ph.D.

2010-01-01

Full Text Available The goal of this study is to analyse the profile of the protagonist-antagonist dichotomy in all children’s television content, of all genres, offered by Spanish television channels. The analysis of protagonist and antagonist characters focuses on variables such as: type and number, age, gender, nationality, skills, relationship between the characters, characterisation, means used to achieve goals, consequences of the action of the antagonist over the antagonist and vice versa. The sample consists of 168 series that were analysed using descriptive content analysis and multivariate analysis. The results showed that over 50% of the series do not have an antagonist and that when there is one the most common type is a single human, which appears in more than 15% of the analysed series, followed by the fantastic creature type, which is present in just 10%. In 80% of the series the skills of the protagonists are social and human, and in 45.24% the exhibited skill is intelligence.

Calcium-antagonists and islet function. V. Effect of R33711

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Malaisse, W J; Sener, A; Devis, G; Somers, G [Brussels Univ. (Belgium). Lab. of Experimental Medicine

1976-11-01

R33711, a new drug with presumed potent calcium-antagonistic property, was found to suppress the insulinotropic action of glucose und gliclazide but not that of theophylline. A 0.2 ..mu..M concentration of R33711 was sufficient to abolish glucose-induced insulin release. At this concentration, R33711 inhibited the net uptake of /sup 45/Ca/sup 2 +/ by isolated islets, whether in the absence or presence of either glucose or sulfonylurea. In the isolated islets, R33711 failed to affect the glucose-stimulated production of lactate, the rate of /sup 45/Ca/sup 2 +/ efflux, the inhibitory action of glucose upon such an efflux and its increase in response to theophylline. These data are compatible with the view that R33711 inhibits entry of Ca/sup 2 +/ into the B-cell and that integrity of such an inward cationic movement usually plays a permissive role in the maintenance of the Ca/sup 2 +/-dependent insulin secretory process.

Pharmacological modulation of the short-lasting effects of antagonistic direct current-stimulation over the human motor cortex

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Leila eChaieb

2012-07-01

Full Text Available Combined administration of transcranial direct current stimulation (tDCS with either pergolide (PGL or D-cycloserine (D-CYC can prolong the excitability-diminishing effects of cathodal, or the excitability enhancing effect of anodal stimulation for up to 24hrs poststimulation. However, it remains unclear whether the potentiation of the observed aftereffects is dominated by the polarity and duration of the stimulation, or the dual application of combined stimulation and drug administration. The present study looks at whether the aftereffects of oral administration of PGL (a D1/D2 agonist or D-CYC (a partial NMDA receptor agonist, in conjunction with the short duration antagonistic application of tDCS (either 5 min cathodal followed immediately by 5 min anodal or vice versa, that alone only induces short lasting aftereffects, can modulate cortical excitability in healthy human subjects, as revealed by a single-pulse MEP (motor-evoked-potential paradigm. Results indicate that the antagonistic application of DC currents induces short-term neuroplastic aftereffects that are dependent upon the polarity of the second application of short-duration tDCS. The application of D-cycloserine resulted in a reversal of this trend and so consequently a marked inhibition of cortical excitability with the cathodal-anodal stimulation order was observed. The administration of pergolide showed no significant aftereffects in either case. These results emphasise that the aftereffects of tDCS are dependent upon the stimulation orientation, and mirror the findings of other studies reporting the neuroplasticity inducing aftereffects of tDCS, and their prolongation when combined with the administration of CNS active drugs.

Growth Hormone Receptor Antagonist Treatment Reduces Exercise Performance in Young Males

DEFF Research Database (Denmark)

Goto, K.; Doessing, S.; Nielsen, R.H.

2009-01-01

between the groups in terms of changes in serum free fatty acids, glycerol, (V) over dotO(2), or relative fat oxidation. Conclusion: GH might be an important determinant of exercise capacity during prolonged exercise, but GHR antagonist did not alter fat metabolism during exercise. (J Clin Endocrinol......Context: The effects of GH on exercise performance remain unclear. Objective: The aim of the study was to examine the effects of GH receptor (GHR) antagonist treatment on exercise performance. Design: Subjects were treated with the GHR antagonist pegvisomant or placebo for 16 d. After the treatment...... period, they exercised to determine exercise performance and hormonal and metabolic responses. Participants: Twenty healthy males participated in the study. Intervention: Subjects were treated with the GHR antagonist (n = 10; 10 mg/d) or placebo (n = 10). After the treatment period, they performed...

The effects of dopamine receptor 1 and 2 agonists and antagonists on sexual and aggressive behaviors in male green anoles.

Science.gov (United States)

Smith, Alexandra N; Kabelik, David

2017-01-01

The propensity to exhibit social behaviors during interactions with same-sex and opposite-sex conspecifics is modulated by various neurotransmitters, including dopamine. Dopamine is a conserved neurotransmitter among vertebrates and dopaminergic receptors are also highly conserved among taxa. Activation of D1 and D2 dopamine receptor subtypes has been shown to modulate social behaviors, especially in mammalian and avian studies. However, the specific behavioral functions of these receptors vary across taxa. In reptiles there have been few studies examining the relationship between dopaminergic receptors and social behaviors. We therefore examined the effects of D1 and D2 agonists and antagonists on sexual and aggressive behaviors in the male green anole lizard (Anolis carolinensis). Treatment with high doses of both D1 and D2 agonists was found to impair both sexual and aggressive behaviors. However, the D1 agonist treatment was also found to impair motor function, suggesting that those effects were likely nonspecific. Lower doses of both agonists and antagonists failed to affect social behaviors. These findings provide some evidence for D2 receptor regulation of social behaviors, but in contrast with previous research, these effects are all inhibitory and no effects were found for manipulations of D1 receptors. A potential reason for the lack of more widespread effects on social behaviors using moderate or low drug doses is that systemic injection of drugs resulted in effects throughout the whole brain, thus affecting counteracting circuits which negated one another, making measurable changes in behavioral output difficult to detect. Future studies should administer drugs directly into brain regions known to regulate sexual and aggressive behaviors.

The effects of dopamine receptor 1 and 2 agonists and antagonists on sexual and aggressive behaviors in male green anoles.

Directory of Open Access Journals (Sweden)

Alexandra N Smith

Full Text Available The propensity to exhibit social behaviors during interactions with same-sex and opposite-sex conspecifics is modulated by various neurotransmitters, including dopamine. Dopamine is a conserved neurotransmitter among vertebrates and dopaminergic receptors are also highly conserved among taxa. Activation of D1 and D2 dopamine receptor subtypes has been shown to modulate social behaviors, especially in mammalian and avian studies. However, the specific behavioral functions of these receptors vary across taxa. In reptiles there have been few studies examining the relationship between dopaminergic receptors and social behaviors. We therefore examined the effects of D1 and D2 agonists and antagonists on sexual and aggressive behaviors in the male green anole lizard (Anolis carolinensis. Treatment with high doses of both D1 and D2 agonists was found to impair both sexual and aggressive behaviors. However, the D1 agonist treatment was also found to impair motor function, suggesting that those effects were likely nonspecific. Lower doses of both agonists and antagonists failed to affect social behaviors. These findings provide some evidence for D2 receptor regulation of social behaviors, but in contrast with previous research, these effects are all inhibitory and no effects were found for manipulations of D1 receptors. A potential reason for the lack of more widespread effects on social behaviors using moderate or low drug doses is that systemic injection of drugs resulted in effects throughout the whole brain, thus affecting counteracting circuits which negated one another, making measurable changes in behavioral output difficult to detect. Future studies should administer drugs directly into brain regions known to regulate sexual and aggressive behaviors.

Agonist and antagonist actions of antipsychotic agents at 5-HT1A receptors: a [35S]GTPgammaS binding study.

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Newman-Tancredi, A; Gavaudan, S; Conte, C; Chaput, C; Touzard, M; Verrièle, L; Audinot, V; Millan, M J

1998-08-21

Recombinant human (h) 5-HT1A receptor-mediated G-protein activation was characterised in membranes of transfected Chinese hamster ovary (CHO) cells by use of guanosine-5'-O-(3-[35S]thio)-triphosphate ([35S]GTPgammaS binding). The potency and efficacy of 21 5-HT receptor agonists and antagonists was determined. The agonists, 5-CT (carboxamidotryptamine) and flesinoxan displayed high affinity (subnanomolar Ki values) and high efficacy (Emax > 90%, relative to 5-HT = 100%). In contrast, ipsapirone, zalospirone and buspirone displayed partial agonist activity. EC50s for agonist stimulation of [35S]GTPgammaS binding correlated well with Ki values from competition binding (r = +0.99). Among the compounds tested for antagonist activity, methiothepin and (+)butaclamol exhibited 'inverse agonist' behaviour, inhibiting basal [35S]GTPgammaS binding. The actions of 17 antipsychotic agents were investigated. Clozapine and several putatively 'atypical' antipsychotic agents, including ziprasidone, quetiapine and tiospirone, exhibited partial agonist activity and marked affinity at h5-HT1A receptors, similar to their affinity at hD2 dopamine receptors. In contrast, risperidone and sertindole displayed low affinity at h5-HT1A receptors and behaved as 'neutral' antagonists, inhibiting 5-HT-stimulated [35S]GTPgammaS binding. Likewise the 'typical' neuroleptics, haloperidol, pimozide, raclopride and chlorpromazine exhibited relatively low affinity and 'neutral' antagonist activity at h5-HT1A receptors with Ki values which correlated with their respective Kb values. The present data show that (i) [35S]GTPgammaS binding is an effective method to evaluate the efficacy and potency of agonists and antagonists at recombinant human 5-HT1A receptors. (ii) Like clozapine, several putatively 'atypical' antipsychotic drugs display balanced serotonin h5-HT1A/dopamine hD2 receptor affinity and partial agonist activity at h5-HT1A receptors. (iii) Several 'typical' and some putatively 'atypical

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

International Nuclear Information System (INIS)

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

1998-01-01

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

Drug-induced psoriasis: clinical perspectives

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Balak DMW

2017-12-01

Full Text Available Deepak MW Balak, Enes Hajdarbegovic Department of Dermatology, Erasmus University Medical Center, Rotterdam, the Netherlands Abstract: Exposure to certain drugs can elicit an induction or exacerbation of psoriasis. Although well-conducted systematic studies on drug-related psoriasis are mostly lacking, traditionally strong associations have been documented for beta-blockers, lithium, antimalarial drugs such as (hydroxychloroquine, interferons, imiquimod, and terbinafine. More recently, new associations have been reported for monoclonal antibody- and small-molecule-based targeted therapies used for oncological and immunological indications, such as tumor necrosis factor-alpha antagonists and anti-programmed cell death protein 1 immune checkpoint inhibitors. Recognizing potential drug-related psoriasis is of clinical relevance to allow an optimal management of psoriasis. However, in clinical practice, identifying medication-related exacerbations and induction of psoriasis can be challenging. The clinical and histopathological features of drug-provoked psoriasis may differ little from that of “classical” nondrug-related forms of psoriasis. In addition, the latency period between start of the medication and onset of psoriasis can be significantly long for some drugs. Assessment of the Naranjo adverse drug reaction probability scale could be used as a practical tool to better differentiate drug-related psoriasis. The first step in the management of drug-related psoriasis is cessation and replacement of the offending drug when deemed clinically possible. However, the induced psoriasis skin lesions may persist after treatment withdrawal. Additional skin-directed treatment options for drug-related psoriasis follows the conventional psoriasis treatment guidelines and includes topical steroids and vitamin D analogs, ultraviolet phototherapy, systemic treatments, such as acitretin, methotrexate, and fumaric acid esters, and biological treatments

Can human allergy drug fexofenadine, an antagonist of histamine (H1) receptor, be used to treat dog and cat? Homology modeling, docking and molecular dynamic Simulation of three H1 receptors in complex with fexofenadine.

Science.gov (United States)

Sader, Safaa; Cai, Jun; Muller, Anna C G; Wu, Chun

2017-08-01

Fexofenadine, a potent antagonist to human histamine 1 (H 1 ) receptor, is a non-sedative third generation antihistamine that is widely used to treat various human allergic conditions such as allergic rhinitis, conjunctivitis and atopic dermatitis. Encouragingly, it's been successfully used to treat canine atopic dermatitis, this supports the notion that it might have a great potential for treating other canine allergic conditions and other mammal pets such as dog. Regrettably, while there is a myriad of studies conducted on the interactions of antihistamines with human H 1 receptor, the similar studies on non-human pet H 1 are considerably scarce. The published studies using the first and second generation antihistamines drugs have shown that the antihistamine response is varied and unpredictable. Thus, to probe its efficacy on pet, the homology models of dog and cat H 1 receptors were built based on the crystal structure of human H 1 receptor bound to antagonist doxepin (PDB 3RZE) and fexofenadine was subsequently docked to human, dog and cat H 1 receptors. The docked complexes are then subjected to 1000ns molecular dynamics (MD) simulations with explicit membrane. Our calculated MM/GBSA binding energies indicated that fexofenadine binds comparably to the three receptors; and our MD data also showed the binding poses, structural and dynamic features among three receptors are very similar. Therefore, our data supported the application of fexofenadine to the H 1 related allergic conditions of dog and cat. Nonetheless, subtle systemic differences among human, dog and cat H 1 receptors were also identified. Clearly, there is still a space to develop a more selective, potent and safe antihistamine alternatives such as Fexofenadine for dog or cat based on these differences. Our computation approach might provide a fast and economic way to predict if human antihistamine drugs can also be safely and efficaciously administered to animals. Copyright © 2017 Elsevier Inc

POST-NOAC: Portuguese observational study of intracranial hemorrhage on non-vitamin K antagonist oral anticoagulants.

Science.gov (United States)

Marques-Matos, Cláudia; Alves, José Nuno; Marto, João Pedro; Ribeiro, Joana Afonso; Monteiro, Ana; Araújo, José; Silva, Fernando; Grenho, Fátima; Viana-Baptista, Miguel; Sargento-Freitas, João; Pinho, João; Azevedo, Elsa

2017-08-01

Background There is a lower reported incidence of intracranial hemorrhage with non-vitamin K antagonist oral anticoagulants compared with vitamin K antagonist. However, the functional outcome and mortality of intracranial hemorrhage patients were not assessed. Aims To compare the outcome of vitamin K antagonists- and non-vitamin K antagonist oral anticoagulants-related intracranial hemorrhage. Methods We included consecutive patients with acute non-traumatic intracranial hemorrhage on oral anticoagulation therapy admitted between January 2013 and June 2015 at four university hospitals. Clinical and demographic data were obtained from individual medical records. Intracranial hemorrhage was classified as intracerebral, extra-axial, or multifocal using brain computed tomography. Three-month functional outcome was assessed using the modified Rankin Scale. Results Among 246 patients included, 24 (9.8%) were anticoagulated with a non-vitamin K antagonist oral anticoagulants and 222 (90.2%) with a vitamin K antagonists. Non-vitamin K antagonist oral anticoagulants patients were older (81.5 vs. 76 years, p = 0.048) and had intracerebral hemorrhage more often (83.3% vs. 63.1%, p = 0.048). We detected a non-significant trend for larger intracerebral hemorrhage volumes in vitamin K antagonists patients ( p = 0.368). Survival analysis adjusted for age, CHA 2 DS 2 VASc, HAS-BLED, and anticoagulation reversal revealed that non-vitamin K antagonist oral anticoagulants did not influence three-month mortality (hazard ratio (HR) = 0.83, 95% confidence interval (CI) = 0.39-1.80, p = 0.638). Multivariable ordinal regression for three-month functional outcome did not show a significant shift of modified Rankin Scale scores in non-vitamin K antagonist oral anticoagulants patients (odds ratio (OR) 1.26, 95%CI 0.55-2.87, p = 0.585). Conclusions We detected no significant differences in the three-month outcome between non-vitamin K antagonist oral anticoagulants

[Benefits of spironolactone as the optimal treatment for drug resistant hypertension. Pathway-2 trial review].

Science.gov (United States)

Prado, J C; Ruilope, L M; Segura, J

Pathway-2 is the first randomised, double-blind and crossover trial that compares spironolactone as a fourth drug with alfa-blocker, beta-blocker and placebo. This study shows that spironolactone is the drug with more possibilities of success for the management of patients with difficult-to-treat hypertension in patients with a combination of three drugs and poor control. The results validate the widespread treatment with mineralocorticoid receptor antagonists in resistant hypertension. Copyright © 2016 SEH-LELHA. Publicado por Elsevier España, S.L.U. All rights reserved.

Cost of vitamin K antagonist anticoagulant treatment in patients with metallic prosthetic valve in mitral position.

Science.gov (United States)

Ene, Gabriela; Garcia Raso, Aránzazu; Gonzalez-Dominguez Weber, Almudena; Hidalgo-Vega, Álvaro; Llamas, Pilar

2016-01-01

The initiation of oral anticoagulation therapy after valve replacement surgery requires strict monitoring because these patients are at high risk for the development of thrombotic complications and present an increased risk of bleeding. The aim of this study was to examine the total healthcare costs of oral anticoagulant treatment with vitamin K antagonists in patients with metallic prosthetic valves in the mitral position. Data from clinical records were used in the study including international normalized ratio results, number of medical visits, type of anticoagulant, use of rescue medication and hospital admissions from related complications. The drug cost was calculated based on the official Spanish Ministry of Health price list. Monitoring expenses were included in the cost of the medical supplies used in the procedures. Hospitalization costs were calculated using the diagnosis-related group price for each case. We collected data from 151 patients receiving oral anticoagulation therapy with vitamin K antagonist who were diagnosed with mitral prosthesis (n = 90), mitro-aortic prosthesis (n = 57), and mitral and tricuspid prosthesis (n = 4). The total direct healthcare cost was €15302.59, with a mean total cost per patient per year of €1558.15 (±2774.58) consisting of 44.38 (±42.30) for drug cost, €71.41 (±21.43) for international normalized ratio monitoring, €429.52 (±126.87) for medical visits, €26.31 (±28.38) for rescue medication and €986.53 (±2735.68) for related complications. Most direct healthcare costs associated with the sampled patients arose from the specialist-care monitoring required for treatment. Good monitoring is inversely related to direct healthcare costs.

New oral anticoagulants: their advantages and disadvantages compared with vitamin K antagonists in the prevention and treatment of patients with thromboembolic events.

Science.gov (United States)

Mekaj, Ymer H; Mekaj, Agon Y; Duci, Shkelzen B; Miftari, Ermira I

2015-01-01

Despite the discovery and application of many parenteral (unfractionated and low-molecular-weight heparins) and oral anticoagulant vitamin K antagonist (VKA) drugs, the prevention and treatment of venous and arterial thrombotic phenomena remain major medical challenges. Furthermore, VKAs are the only oral anticoagulants used during the past 60 years. The main objective of this study is to present recent data on non-vitamin K antagonist oral anticoagulants (NOACs) and to analyze their advantages and disadvantages compared with those of VKAs based on a large number of recent studies. NOACs are novel direct-acting medications that are selective for one specific coagulation factor, either thrombin (IIa) or activated factor X (Xa). Several NOACs, such as dabigatran (a direct inhibitor of FIIa) and rivaroxaban, apixaban and edoxaban (direct inhibitors of factor Xa), have been used for at least 5 years but possibly 10 years. Unlike traditional VKAs, which prevent the coagulation process by suppressing the synthesis of vitamin K-dependent factors, NOACs directly inhibit key proteases (factors IIa and Xa). The important indications of these drugs are the prevention and treatment of deep vein thrombosis and pulmonary embolisms, and the prevention of atherothrombotic events in the heart and brain of patients with acute coronary syndrome and atrial fibrillation. They are not fixed, and dose-various strengths are available. Most studies have reported that more advantages than disadvantages for NOACs when compared with VKAs, with the most important advantages of NOACs including safety issues (ie, a lower incidence of major bleeding), convenience of use, minor drug and food interactions, a wide therapeutic window, and no need for laboratory monitoring. Nonetheless, there are some conditions for which VKAs remain the drug of choice. Based on the available data, we can conclude that NOACs have greater advantages and fewer disadvantages compared with VKAs. New studies are required

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

Science.gov (United States)

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

2007-06-15

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

Psychotropic drugs and bruxism.

Science.gov (United States)

Falisi, Giovanni; Rastelli, Claudio; Panti, Fabrizio; Maglione, Horacio; Quezada Arcega, Raul

2014-10-01

Sleep and awake bruxism is defined as 'a parafunctional activity including clenching, bracing, gnashing, and grinding of the teeth'. Some evidence suggests that bruxism may be caused by, or associated with, alterations in the CNS neurotransmission. Several classes of psychotropic drugs interfering with CNS activity may potentially contribute to bruxism. Thus, the purpose of this study was to examine relevant peer-reviewed papers to identify and describe the various classes of psychotropic substances that may cause, exacerbate or reduce bruxism as the result of their pharmacological action in CNS neurons. A literature search from 1980 to the present was performed using PubMed database. The term 'bruxism' was used in association with 'psychotropic', 'dopamine (DA)', 'serotonin', 'histamine', 'antipsychotics', 'antidepressants', 'antihistaminergics' and 'stimulants'. Studies on the effects of DA agonists (Levo-DOPA, psychostimulants) and antagonists (antipsychotics) identified a central role of DA in the pathogenesis of pharmacologically induced bruxism. Important information from studies on drugs acting on serotonin neurotransmission (antidepressants) was recognized. Other mechanisms involving different neurotransmitters are emerging. This is the case of antihistaminergic drugs which may induce bruxism as a consequence of their disinhibitory effect on the serotonergic system.

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.

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. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.

Alpha-Adrenoceptor Antagonists Improve Memory by Activating -methyl-D-Aspartate-Induced Ion Currents in the Rat Hippocampus

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Chang Hee Kim

2015-12-01

Full Text Available Purpose: Alpha1 (α1-adrenoceptor antagonists are widely used to treat lower urinary tract symptoms. These drugs not only act on peripheral tissues, but also cross the blood-brain barrier and affect the central nervous system. Therefore, α1-adrenoceptor antagonists may enhance brain functions. In the present study, we investigated the effects of tamsulosin, an α1-adrenoceptor antagonist, on short-term memory, as well as spatial learning and memory, in rats. Methods: The step-down avoidance test was used to evaluate short-term memory, and an eight-arm radial maze test was used to evaluate spatial learning and memory. TUNEL (terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling staining was performed in order to evaluate the effect of tamsulosin on apoptosis in the hippocampal dentate gyrus. Patch clamp recordings were used to evaluate the effect of tamsulosin on ionotropic glutamate receptors, such as N-methyl-D-aspartate (NMDA, amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA, and kainate receptors, in hippocampal CA1 neurons. Results: Tamsulosin treatment improved short-term memory, as well as spatial learning and memory, without altering apoptosis. The amplitudes of NMDA-induced ion currents were dose-dependently increased by tamsulosin. However, the amplitudes of AMPA- and kainate-induced ion currents were not affected by tamsulosin. Conclusions: Tamsulosin enhanced memory function by activating NMDA receptor-mediated ion currents in the hippocampus without initiating apoptosis. The present study suggests the possibility of using tamsulosin to enhance memory under normal conditions, in addition to its use in treating overactive bladder.

Modulation of haloperidol-induced patterns of the transcription factor Nur77 and Nor-1 expression by serotonergic and adrenergic drugs in the mouse brain

Science.gov (United States)

Maheux, Jérôme; Vuillier, Laura; Mahfouz, Mylène; Rouillard, Claude; Lévesque, Daniel

2015-01-01

Different patterns of expression of the transcription factors of Nur77 and Nor-1 are induced following acute administration of typical and atypical antipsychotic drugs. The pharmacological profile of atypical antipsychotics suggests that serotonergic and/or adrenergic receptors might contribute to these reported differences. In order to test this possibility, we examined the abilities of serotonin 5-HT1A and 5-HT2A/2C, and α1- and α2-adrenergic receptor drugs to modify the pattern of Nur77 (NR4A1) and Nor-1 (NR4A3) mRNA expression induced by haloperidol. Various groups of mice were treated with either saline, DOI, a 5-HT2A/2C agonist, MDL11939, a 5-HT2A antagonist, 8-OH-DPAT, a 5-HT1A agonist, prazosin, an α1-adrenergic antagonist and idazoxan, an α2-adrenergic antagonist, alone or in combination with haloperidol. The 5-HT2A/2C agonist DOI alone significantly increased Nur77 expression in the medial striatum and nucleus accumbens. DOI reduced Nor-1 expression, while MDL11939 increased the expression of this transcript in the cortex. Prazosin reduced Nur77 expression in the dorsal striatum and nucleus accumbens. Interestingly, 8-OH-DPAT and MDL11939 partially prevented haloperidol-induced Nur77 up-regulation, while MDL11939 completely abolished Nor-1 expression in the striatum. In addition, MDL11939 decreased haloperidol-induced Nur77 and Nor-1 mRNA levels in the ventral tegmental area. On the contrary, idazoxan (α2 antagonist) consistently potentiated haloperidol-induced Nur77, but not Nor-1 mRNA levels in the striatum, whereas prazosin (α1 antagonist) remained without effect. Taken together, these results show the ability of a 5-HT1A agonist or a 5-HT2A antagonist to reduce haloperidol-induced Nur77 and Nor-1 striatal expression, suggesting that these serotonin receptor subtypes participate in the differential pattern of gene expression induced by typical and atypical antipsychotic drugs. PMID:21524335

Drug safety in pregnancy: utopia or achievable prospect? Risk information, risk research and advocacy in Teratology Information Services.

Science.gov (United States)

Schaefer, Christof

2011-03-01

Even though from preclinical testing to drug risk labeling, the situation with drugs in pregnancy has improved substantially since the thalidomide scandal, there is still an increasing need to provide healthcare professionals and patients with updated individualized risk information for clinical decision making. For the majority of drugs, clinical experience is still insufficient with respect to their safety in pregnancy. There is often uncertainty in how to interpret the available scientific data. Based on 20 years of experience with Teratology Information Services (TIS) cooperating in the European Network of Teratology Information Services (ENTIS) methods of risk interpretation, follow-up of exposed pregnancies through the consultation process and their evaluation is discussed. Vitamin K antagonists, isotretinoin and angiotensin (AT) II-receptor-antagonists are presented as examples of misinterpretation of drug risks and subjects of research based on observational clinical data recorded in TIS. As many TIS are poorly funded, advocacy is necessary by establishing contacts with decision makers in health politics and administration, informing them of the high return in terms of health outcomes and cost savings provided by TIS as reference institutions in clinical teratology. © 2011 The Author. Congenital Anomalies © 2011 Japanese Teratology Society.

Typical and Atypical Antipsychotic Drugs Increase Extracellular Histamine Levels in the Rat Medial Prefrontal Cortex: Contribution of Histamine H1 Receptor Blockade

Directory of Open Access Journals (Sweden)

Kjell A Svensson

2012-05-01

Full Text Available Atypical antipsychotics such as clozapine and olanzapine have been shown to enhance histamine turnover and this effect has been hypothesized to contribute to their improved therapeutic profile compared to typical antipsychotics. In the present study, we examined the effects of antipsychotic drugs on histamine (HA efflux in the mPFC of the rat by means of in vivo microdialysis and sought to differentiate the receptor mechanisms which underlie such effects. Olanzapine and clozapine increased mPFC HA efflux in a dose related manner. Increased HA efflux was also observed after quetiapine, chlorpromazine and perphenazine treatment. We found no effect of the selective 5-HT2A antagonist MDL100907, 5-HT2c antagonist SB242084 or the 5-HT6 antagonist Ro 04-6790 on mPFC HA efflux. HA efflux was increased following treatment with selective H1 receptor antagonists pyrilamine, diphenhydramine and triprolidine, the H3 receptor antagonist ciproxifan and the mixed 5HT2A/H1 receptor antagonist ketanserin. The potential novel antipsychotic drug FMPD, which has a lower affinity at H1 receptors than olanzapine, did not affect HA efflux. Similarly, other antipsychotics with lower H1 receptor affinity (risperidone, aripiprazole and haloperidol were also without effect on HA efflux. Perfusion of clozapine and pyrilamine into the TMN, but not the mPFC, increased local HA efflux. Finally, HA efflux after antipsychotic treatment was significantly correlated with affinity at H1 receptors whereas 9 other receptors, including 5-HT2A, were not. These results demonstrate that both typical and atypical antipsychotics increase mPFC histamine efflux and this effect may be mediated via antagonism of histamine H1 receptors.

Calcium antagonists for aneurysmal subarachnoid haemorrhage

NARCIS (Netherlands)

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

2007-01-01

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

Peri- and Postoperative Treatment with the Interleukin-1 Receptor Antagonist Anakinra Is Safe in Patients Undergoing Renal Transplantation: Case Series and Review of the Literature

Directory of Open Access Journals (Sweden)

Catharina M. Mulders-Manders

2017-05-01

Full Text Available In patients undergoing solid organ transplantation, the presence of an interleukin-1 (IL-1 driven disease may require the addition of IL-1 inhibiting drugs to the standard immunosuppressive regimen to protect against inflammation and negative graft outcome. Three patients undergoing renal transplantation were treated perioperatively with the interleukin-1 receptor antagonist anakinra. Kidney function increased rapidly in all three and the only complications seen were minor infections. In vitro studies report associations between serum and urinary levels of IL-1β and IL-1 receptor antagonist and negative graft outcome, and studies in animals and two small human trials illustrate a possible protective effect of anti-IL-1 therapy after solid organ transplantation. Peri- and postoperative use of anakinra is safe and effective in patients undergoing renal transplantation.

Inhibition of common cold-induced aggravation of childhood asthma by leukotriene receptor antagonists.

Science.gov (United States)

Yoshihara, Shigemi; Fukuda, Hironobu; Abe, Toshio; Nishida, Mitsuhiro; Yamada, Yumi; Kanno, Noriko; Arisaka, Osamu

2012-09-01

Virus infection is an important risk factor for aggravation of childhood asthma. The objective of this study was to examine the effect of drugs on aggravation of asthma induced by a common cold. Asthma control was examined in a survey of 1,014 Japanese pediatric patients with bronchial asthma. The occurrence of common cold, asthma control, and drugs used for asthma control were investigated using a modified Childhood Asthma Control Test (C-ACT) for patients aged cold and aggravation of asthma were significantly higher in patients aged cold-induced aggravation was significantly less effective in patients aged cold, asthma control was significantly more effective for those treated with leukotriene receptor antagonists (LTRAs) compared to treatment without LTRAs. Asthma control did not differ between patients who did or did not take inhaled corticosteroids or long-acting β2 stimulants. These findings showed a high prevalence of common cold in younger patients with childhood asthma and indicated that common cold can induce aggravation of asthma. LTRAs are useful for long-term asthma control in very young patients who develop an asthma attack due to a common cold.

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.

Aldosterone and aldosterone receptor antagonists in patients with chronic heart failure

Directory of Open Access Journals (Sweden)

Nappi J

2011-06-01

Full Text Available Jean M Nappi, Adam SiegClinical Pharmacy and Outcome Sciences, South Carolina College of Pharmacy, Medical University of South Carolina Campus, Charleston, SC, USAAbstract: Aldosterone is a mineralocorticoid hormone synthesized by the adrenal glands that has several regulatory functions to help the body maintain normal volume status and electrolyte balance. Studies have shown significantly higher levels of aldosterone secretion in patients with congestive heart failure compared with normal patients. Elevated levels of aldosterone have been shown to elevate blood pressure, cause left ventricular hypertrophy, and promote cardiac fibrosis. An appreciation of the true role of aldosterone in patients with chronic heart failure did not become apparent until the publication of the Randomized Aldactone Evaluation Study. Until recently, the use of aldosterone receptor antagonists has been limited to patients with severe heart failure and patients with heart failure following myocardial infarction. The Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF study added additional evidence to support the expanded use of aldosterone receptor antagonists in heart failure patients. The results of the EMPHASIS-HF trial showed that patients with mild-to-moderate (New York Heart Association Class II heart failure had reductions in mortality and hospitalizations from the addition of eplerenone to optimal medical therapy. Evidence remains elusive about the exact mechanism by which aldosterone receptor antagonists improve heart failure morbidity and mortality. The benefits of aldosterone receptor antagonist use in heart failure must be weighed against the potential risk of complications, ie, hyperkalemia and, in the case of spironolactone, possible endocrine abnormalities, in particular gynecomastia. With appropriate monitoring, these risks can be minimized. We now have evidence that patients with mild-to-severe symptoms

A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

Energy Technology Data Exchange (ETDEWEB)

Li, Xiaoguang [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Department of Medical Microbiology, Harbin Medical University, Harbin 150086 (China); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Qian, Hua [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Kumamoto 860-0811 (Japan); Miyamoto, Fusako [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Naito, Takeshi [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Kawaji, Kumi [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Kajiwara, Kazumi [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); JST Innovation Plaza Kyoto, Japan Science and Technology Agency, Nishigyo-ku, Kyoto 615-8245 (Japan); Hattori, Toshio [Tohoku University Graduate School of Medicine, Department of Internal Medicine/Division of Emerging Infectious Diseases, Sendai 980-8575 (Japan); Matsuoka, Masao [Laboratory of Virus Control, Institute for Virus Research, Kyoto University, 53 Kawaramachi, Shogoin, Sakyo-ku, Kyoto 606-8507 (Japan); Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka [Graduate School of Pharmaceutical Sciences, Kyoto University, Sakyo-ku, Kyoto 606-8501 (Japan); and others

2012-07-27

Highlights: Black-Right-Pointing-Pointer We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. Black-Right-Pointing-Pointer The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. Black-Right-Pointing-Pointer In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1{sub IIIB} and HIV-1{sub BaL} as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1{sub IIIB} activity, whereas fusion inhibitors showed both anti-HIV-1{sub IIIB} and anti-HIV-1{sub BaL} activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, 'phenotypic drug evaluation', may be applicable for the evaluation of various antiviral drugs in vivo.

A simple, rapid, and sensitive system for the evaluation of anti-viral drugs in rats

International Nuclear Information System (INIS)

Li, Xiaoguang; Qian, Hua; Miyamoto, Fusako; Naito, Takeshi; Kawaji, Kumi; Kajiwara, Kazumi; Hattori, Toshio; Matsuoka, Masao; Watanabe, Kentaro; Oishi, Shinya; Fujii, Nobutaka

2012-01-01

Highlights: ► We established a novel, simple and rapid in vivo system for evaluation of anti-HIV-1 drugs with rats. ► The system may be applicable for other antiviral drugs, and/or useful for initial screening in vivo. ► In this system, TRI-1144 displayed the most potent anti-HIV-1 activity in vivo. -- Abstract: The lack of small animal models for the evaluation of anti-human immunodeficiency virus type 1 (HIV-1) agents hampers drug development. Here, we describe the establishment of a simple and rapid evaluation system in a rat model without animal infection facilities. After intraperitoneal administration of test drugs to rats, antiviral activity in the sera was examined by the MAGI assay. Recently developed inhibitors for HIV-1 entry, two CXCR4 antagonists, TF14016 and FC131, and four fusion inhibitors, T-20, T-20EK, SC29EK, and TRI-1144, were evaluated using HIV-1 IIIB and HIV-1 BaL as representative CXCR4- and CCR5-tropic HIV-1 strains, respectively. CXCR4 antagonists were shown to only possess anti-HIV-1 IIIB activity, whereas fusion inhibitors showed both anti-HIV-1 IIIB and anti-HIV-1 BaL activities in rat sera. These results indicate that test drugs were successfully processed into the rat sera and could be detected by the MAGI assay. In this system, TRI-1144 showed the most potent and sustained antiviral activity. Sera from animals not administered drugs showed substantial anti-HIV-1 activity, indicating that relatively high dose or activity of the test drugs might be needed. In conclusion, the novel rat system established here, “phenotypic drug evaluation”, may be applicable for the evaluation of various antiviral drugs in vivo.

WAY 267,464, a non-peptide oxytocin receptor agonist, impairs social recognition memory in rats through a vasopressin 1A receptor antagonist action.

Science.gov (United States)

Hicks, Callum; Ramos, Linnet; Reekie, Tristan A; Narlawar, Rajeshwar; Kassiou, Michael; McGregor, Iain S

2015-08-01

Recent in vitro studies suggest that the oxytocin receptor (OTR) agonist WAY 267,464 has vasopressin 1A receptor (V1AR) antagonist effects. This might limit its therapeutic potential due to the positive involvement of the V1AR in social behavior. The objective of this study was to assess functional V1AR antagonist-like effects of WAY 267,464 in vivo using a test of social recognition memory. Adult experimental rats were tested for their recognition of a juvenile conspecific rat that they had briefly met 30 or 120 min previously. The modulatory effects of vasopressin (AVP), the selective V1AR antagonist SR49059, and WAY 267,464 were examined together with those of the selective OTR antagonist Compound 25 (C25). Drugs were administered immediately after the first meeting. Control rats showed recognition of juveniles at a 30 min, but not a 120 min retention interval. AVP (0.005, but not 0.001 mg/kg intraperitoneal (i.p.)) improved memory such that recognition was evident after 120 min. This was prevented by pretreatment with SR49059 (1 mg/kg) and WAY 267,464 (10, 30, and 100 mg/kg). Given alone, SR49059 (1 mg/kg) and WAY 267,464 (30 and 100 mg/kg) impaired memory at a 30 min retention interval. The impairment with WAY 267,464 was not prevented by C25 (5 mg/kg), suggesting V1AR rather than OTR mediation of the effect. Given alone, C25 also impaired memory. These results highlight a tonic role for endogenous AVP (and oxytocin) in social recognition memory and indicate that WAY 267,464 functions in vivo as a V1AR antagonist to prevent the memory-enhancing effects of AVP.

Purification and reconstitution of the calcium antagonist receptor of the voltage-sensitive calcium channel

International Nuclear Information System (INIS)

Curtis, B.M.

1986-01-01

Treatment with digitonin solubilized the calcium antagonist receptor as a stable complex with [ 3 H]nitrendipine from rat brain membranes. The solubilized complex retains allosteric coupling to binding sites for diltiazem, verapamil, and inorganic calcium antagonist sites. The calcium antagonist receptor from cardiac sarcolemma and the transverse-tubule membrane of skeletal muscle is also efficiently solubilized with digitonin and the receptor in all three tissues is a large glycoprotein with a sedimentation coefficient of 20 S. The T-tubule calcium antagonist receptor complex was extensively purified by a combination of chromatography on WGA-Sepharose, ion exchange chromatography, and sedimentation on sucrose gradients to yield preparations estimated to be 41% homogeneous by specific activity and 63% homogeneous by SDS gel electrophoresis. Analysis of SDS gels detect three polypeptides termed α(Mr 135,000), β(Mr 50,000), and γ(Mr 32,000) as noncovalently associated subunits of the calcium antagonist receptor. The α and γ subunits are glycosylated polypeptides, and the molecular weight of the core polypeptides are 108,000 and 24,000 respectively. The calcium antagonist receptor was reconstituted into a phospholipid bilayer by adding CHAPS and exogeneous lipid to the purified receptor followed by rapid detergent removal. This procedure resulted in the incorporation of 45% of the calcium antagonist receptor into closed phospholipid vesicles. Data suggests that the α, β, and γ subunits of the T-tubule calcium antagonist receptor are sufficient to form a functional calcium channel

Nonthionamide Drugs for the Treatment of Hyperthyroidism: From Present to Future

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Nattakarn Suwansaksri

2018-01-01

Full Text Available Hyperthyroidism is a common endocrine disease. Although thionamide antithyroid drugs are the cornerstone of hyperthyroidism treatment, some patients cannot tolerate this drug class because of its serious side effects including agranulocytosis, hepatotoxicity, and vasculitis. Therefore, nonthionamide antithyroid drugs (NTADs still have an important role in controlling hyperthyroidism in clinical practice. Furthermore, some situations such as thyroid storm or preoperative preparation require a rapid decrease in thyroid hormone by combination treatment with multiple classes of antithyroid drugs. NTADs include iodine-containing compounds, lithium carbonate, perchlorate, glucocorticoid, and cholestyramine. In this narrative review, we summarize the mechanisms of action, indications, dosages, and side effects of currently used NTADs for the treatment of hyperthyroidism. In addition, we also describe the state-of-the-art in future drugs under development including rituximab, small-molecule ligands (SMLs, and monoclonal antibodies with a thyroid-stimulating hormone receptor (TSHR antagonist effect.

Perspectives of CB1 Antagonist in Treatment of Obesity: Experience of RIO-Asia

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Changyu Pan

2011-01-01

Full Text Available Rimonabant, a selective cannabinoid-1 (CB1 receptor antagonist, has been shown to reduce weight and enhance improvements in cardiometabolic risk parameters in Western populations. This study assessed these effects of rimonabant in Asian population. A total of 643 patients (BMI 25 kg/m2 or greater without diabetes from China, Republic of Korea, and Taiwan were prescribed a hypocaloric diet (600 kcal/day deficit and randomized to rimonabant 20 mg (n=318 or placebo (n=325 for 9months. The primary efficacy variable was weight change from baseline after 9 months of treatment. Results showed that rimonabant group lost more weight than placebo, (LSM ± SEM of −4.7 ± 0.3 kg vs. −1.7 ± 0.3 kg, P<.0001. The 5% and 10% responders were 2 or 3 folds more in the rimonabant group (53.0% vs. 20.0% and 21.5% vs. 5.7%, resp. (P<.0001. Rimonabant also significantly increased HDL-cholesterol, decreased triglycerides and waist circumference,by 7.1%, 10.6%, and 2.8 cm, respectively (P<.0001. This study confirmed the comparable efficacy and safety profile of rimonabant in Asian population to Caucasians. Owing to the recent suspension of all the CB1 antagonists off the pharmaceutical market for weight reduction in Europe and USA, a perspective in drug discovery for intervening peripheral CB1 receptor in the management of obesity is discussed.

New Insights into the Pros and Cons of the Clinical Use of Vitamin K Antagonists (VKAs Versus Direct Oral Anticoagulants (DOACs

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Rick H. van Gorp

2015-11-01

Full Text Available Vitamin K-antagonists (VKA are the most widely used anticoagulant drugs to treat patients at risk of arterial and venous thrombosis for the past 50 years. Due to unfavorable pharmacokinetics VKA have a small therapeutic window, require frequent monitoring, and are susceptible to drug and nutritional interactions. Additionally, the effect of VKA is not limited to coagulation, but affects all vitamin K-dependent proteins. As a consequence, VKA have detrimental side effects by enhancing medial and intimal calcification. These limitations stimulated the development of alternative anticoagulant drugs, resulting in direct oral anticoagulant (DOAC drugs, which specifically target coagulation factor Xa and thrombin. DOACs also display non-hemostatic vascular effects via protease-activated receptors (PARs. As atherosclerosis is characterized by a hypercoagulable state indicating the involvement of activated coagulation factors in the genesis of atherosclerosis, anticoagulation could have beneficial effects on atherosclerosis. Additionally, accumulating evidence demonstrates vascular benefit from high vitamin K intake. This review gives an update on oral anticoagulant treatment on the vasculature with a special focus on calcification and vitamin K interaction.

Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation

DEFF Research Database (Denmark)

Fosbøl, Emil L; Vinding, Naja Emborg; Lamberts, Morten

2017-01-01

Aims: After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran...

Palliation of bone cancer pain by antagonists of platelet-activating factor receptors.

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Katsuya Morita

Full Text Available Bone cancer pain is the most severe among cancer pain and is often resistant to current analgesics. Thus, the development of novel analgesics effective at treating bone cancer pain are desired. Platelet-activating factor (PAF receptor antagonists were recently demonstrated to have effective pain relieving effects on neuropathic pain in several animal models. The present study examined the pain relieving effect of PAF receptor antagonists on bone cancer pain using the femur bone cancer (FBC model in mice. Animals were injected with osteolytic NCTC2472 cells into the tibia, and subsequently the effects of PAF receptor antagonists on pain behaviors were evaluated. Chemical structurally different type of antagonists, TCV-309, BN 50739 and WEB 2086 ameliorated the allodynia and improved pain behaviors such as guarding behavior and limb-use abnormalities in FBC model mice. The pain relieving effects of these antagonists were achieved with low doses and were long lasting. Blockade of spinal PAF receptors by intrathecal injection of TCV-309 and WEB 2086 or knockdown of the expression of spinal PAF receptor protein by intrathecal transfer of PAF receptor siRNA also produced a pain relieving effect. The amount of an inducible PAF synthesis enzyme, lysophosphatidylcholine acyltransferase 2 (LPCAT2 protein significantly increased in the spinal cord after transplantation of NCTC 2472 tumor cells into mouse tibia. The combination of morphine with PAF receptor antagonists develops marked enhancement of the analgesic effect against bone cancer pain without affecting morphine-induced constipation. Repeated administration of TCV-309 suppressed the appearance of pain behaviors and prolonged survival of FBC mice. The present results suggest that PAF receptor antagonists in combination with, or without, opioids may represent a new strategy for the treatment of persistent bone cancer pain and improve the quality of life of patients.

Agar composition affects in vitro screening of biocontrol activity of antagonistic microorganisms

NARCIS (Netherlands)

Bosmans, Lien; De Bruijn, I.; de Mot, Rene; Readers, Hans; Lievens, Bart

2016-01-01

Agar-based screening assays are the method of choice when evaluating antagonistic potential of bacterial biocontrol-candidates against pathogens.Weshowed thatwhen using the samemedium, but different agar compositions, the activity of a bacterial antagonist against Agrobacteriumwas strongly affected.

Novel CRTH2 antagonists: a review of patents from 2006 to 2009.

Science.gov (United States)

Ulven, Trond; Kostenis, Evi

2010-11-01

The receptor CRTH2 (also known as DP₂) is an important mediator of the inflammatory effects of prostaglandin D₂ and has attracted much attention as a therapeutic target for the treatment of conditions such as asthma, COPD, allergic rhinitis and atopic dermatitis. The validation of CRTH2 as a therapeutic target and the early antagonists are summarized, CRTH2 antagonists published in the patent literature from 2006 to 2009 are comprehensively covered and a general update on the recent progress in the development of CRTH2 antagonists for the treatment of inflammatory diseases is provided. Insight into the validation of CRTH2 as a therapeutic target, a comprehensive overview of the development of new CRTH2 ligands between 2006 and 2009, and a general overview of the state of the art. Many diverse potent CRTH2 antagonists are now available, and several are in or on the way into the clinic. It is still early to draw final conclusions, but preliminary results give reason for optimism, and the prospect that we will see new CRTH2 antagonists reaching the market for the treatment of asthma, rhinitis, atopic dermatitis and/or COPD seems good.

BCL2-BH4 antagonist BDA-366 suppresses human myeloma growth.

Science.gov (United States)

Deng, Jiusheng; Park, Dongkyoo; Wang, Mengchang; Nooka, Ajay; Deng, Qiaoya; Matulis, Shannon; Kaufman, Jonathan; Lonial, Sagar; Boise, Lawrence H; Galipeau, Jacques; Deng, Xingming

2016-05-10

Multiple myeloma (MM) is a heterogeneous plasma cell malignancy and remains incurable. B-cell lymphoma-2 (BCL2) protein correlates with the survival and the drug resistance of myeloma cells. BH3 mimetics have been developed to disrupt the binding between BCL2 and its pro-apoptotic BCL2 family partners for the treatment of MM, but with limited therapeutic efficacy. We recently identified a small molecule BDA-366 as a BCL2 BH4 domain antagonist, converting it from an anti-apoptotic into a pro-apoptotic molecule. In this study, we demonstrated that BDA-366 induces robust apoptosis in MM cell lines and primary MM cells by inducing BCL2 conformational change. Delivery of BDA-366 substantially suppressed the growth of human MM xenografts in NOD-scid/IL2Rγnull mice, without significant cytotoxic effects on normal hematopoietic cells or body weight. Thus, BDA-366 functions as a novel BH4-based BCL2 inhibitor and offers an entirely new tool for MM therapy.

Optimization of vitamin K antagonist drug dose finding by replacement of the international normalized ratio by a bidirectional factor : validation of a new algorithm

NARCIS (Netherlands)

Beinema, M J; van der Meer, F J M; Brouwers, J R B J; Rosendaal, F R

2016-01-01

UNLABELLED: Essentials We developed a new algorithm to optimize vitamin K antagonist dose finding. Validation was by comparing actual dosing to algorithm predictions. Predicted and actual dosing of well performing centers were highly associated. The method is promising and should be tested in a

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

Science.gov (United States)

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

2015-01-01

BACKGROUND AND PURPOSE Calcium antagonists play an important role in clinical practice. However, most of them have serious side effects. We have synthesized a series of novel calcium antagonists, quaternary ammonium salt derivatives of haloperidol with N-p-methoxybenzyl (X1), N-m-methoxybenzyl (X2) and N-o-methoxybenzyl (X3) groups. The objective of this study was to investigate the bioactivity of these novel calcium antagonists, especially the vasodilation activity and cardiac side-effects. The possible working mechanisms of these haloperidol derivatives were also explored. EXPERIMENTAL APPROACH Novel calcium antagonists were synthesized by amination. Compounds were screened for their activity of vasodilation on isolated thoracic aortic ring of rats. Their cardiac side effects were explored. The patch-clamp, confocal laser microscopy and the computer-fitting molecular docking experiments were employed to investigate the possible working mechanisms of these calcium antagonists. RESULTS The novel calcium antagonists, X1, X2 and X3 showed stronger vasodilation effect and less cardiac side effect than that of classical calcium antagonists. They blocked L-type calcium channels with an potent effect order of X1 > X2 > X3. Consistently, X1, X2 and X3 interacted with different regions of Ca2+-CaM-CaV1.2 with an affinity order of X1 > X2 > X3. CONCLUSIONS The new halopedidol derivatives X1, X2 and X3 are novel calcium antagonists with stronger vasodilation effect and less cardiac side effect. They could have wide clinical application. PMID:26544729

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.

Crystal structure of the adenosine A _2A receptor bound to an antagonist reveals a potential allosteric pocket

Energy Technology Data Exchange (ETDEWEB)

Sun, Bingfa; Bachhawat, Priti; Chu, Matthew Ling-Hon; Wood, Martyn; Ceska, Tom; Sands, Zara A.; Mercier, Joel; Lebon, Florence; Kobilka, Tong Sun; Kobilka, Brian K. (Stanford-MED); (ConfometRx); (UCB Pharma)

2017-02-06

The adenosine A2A receptor (A2AR) has long been implicated in cardiovascular disorders. As more selective A2AR ligands are being identified, its roles in other disorders, such as Parkinson’s disease, are starting to emerge, and A2AR antagonists are important drug candidates for nondopaminergic anti-Parkinson treatment. Here we report the crystal structure of A2A receptor bound to compound 1 (Cmpd-1), a novel A2AR/N-methyl D-aspartate receptor subtype 2B (NR2B) dual antagonist and potential anti-Parkinson candidate compound, at 3.5 Å resolution. The A2A receptor with a cytochrome b562-RIL (BRIL) fusion (A2AR–BRIL) in the intracellular loop 3 (ICL3) was crystallized in detergent micelles using vapor-phase diffusion. Whereas A2AR–BRIL bound to the antagonist ZM241385 has previously been crystallized in lipidic cubic phase (LCP), structural differences in the Cmpd-1–bound A2AR–BRIL prevented formation of the lattice observed with the ZM241385–bound receptor. The crystals grew with a type II crystal lattice in contrast to the typical type I packing seen from membrane protein structures crystallized in LCP. Cmpd-1 binds in a position that overlaps with the native ligand adenosine, but its methoxyphenyl group extends to an exosite not previously observed in other A2AR structures. Structural analysis revealed that Cmpd-1 binding results in the unique conformations of two tyrosine residues, Tyr91.35 and Tyr2717.36, which are critical for the formation of the exosite. The structure reveals insights into antagonist binding that are not observed in other A2AR structures, highlighting flexibility in the binding pocket that may facilitate the development of A2AR-selective compounds for the treatment of Parkinson’s disease.

Cost of vitamin K antagonist anticoagulant treatment in patients with metallic prosthetic valve in mitral position

Directory of Open Access Journals (Sweden)

Gabriela Ene

2016-08-01

Full Text Available Background: The initiation of oral anticoagulation therapy after valve replacement surgery requires strict monitoring because these patients are at high risk for the development of thrombotic complications and present an increased risk of bleeding. Objectives: The aim of this study was to examine the total healthcare costs of oral anticoagulant treatment with vitamin K antagonists in patients with metallic prosthetic valves in the mitral position. Methods: Data from clinical records were used in the study including international normalized ratio results, number of medical visits, type of anticoagulant, use of rescue medication and hospital admissions from related complications. The drug cost was calculated based on the official Spanish Ministry of Health price list. Monitoring expenses were included in the cost of the medical supplies used in the procedures. Hospitalization costs were calculated using the diagnosis-related group price for each case. Results: We collected data from 151 patients receiving oral anticoagulation therapy with vitamin K antagonist who were diagnosed with mitral prosthesis (n = 90, mitro-aortic prosthesis (n = 57, and mitral and tricuspid prosthesis (n = 4. The total direct healthcare cost was €15302.59, with a mean total cost per patient per year of €1558.15 (±2774.58 consisting of 44.38 (±42.30 for drug cost, €71.41 (±21.43 for international normalized ratio monitoring, €429.52 (±126.87 for medical visits, €26.31 (±28.38 for rescue medication and €986.53 (±2735.68 for related complications. Conclusion: Most direct healthcare costs associated with the sampled patients arose from the specialist-care monitoring required for treatment. Good monitoring is inversely related to direct healthcare costs.

A general population genetic framework for antagonistic selection that accounts for demography and recurrent mutation.

Science.gov (United States)

Connallon, Tim; Clark, Andrew G

2012-04-01

Antagonistic selection--where alleles at a locus have opposing effects on male and female fitness ("sexual antagonism") or between components of fitness ("antagonistic pleiotropy")--might play an important role in maintaining population genetic variation and in driving phylogenetic and genomic patterns of sexual dimorphism and life-history evolution. While prior theory has thoroughly characterized the conditions necessary for antagonistic balancing selection to operate, we currently know little about the evolutionary interactions between antagonistic selection, recurrent mutation, and genetic drift, which should collectively shape empirical patterns of genetic variation. To fill this void, we developed and analyzed a series of population genetic models that simultaneously incorporate these processes. Our models identify two general properties of antagonistically selected loci. First, antagonistic selection inflates heterozygosity and fitness variance across a broad parameter range--a result that applies to alleles maintained by balancing selection and by recurrent mutation. Second, effective population size and genetic drift profoundly affect the statistical frequency distributions of antagonistically selected alleles. The "efficacy" of antagonistic selection (i.e., its tendency to dominate over genetic drift) is extremely weak relative to classical models, such as directional selection and overdominance. Alleles meeting traditional criteria for strong selection (N(e)s > 1, where N(e) is the effective population size, and s is a selection coefficient for a given sex or fitness component) may nevertheless evolve as if neutral. The effects of mutation and demography may generate population differences in overall levels of antagonistic fitness variation, as well as molecular population genetic signatures of balancing selection.

Interactions of DB75, a Novel Antimalarial Agent, with Other Antimalarial Drugs In Vitro▿

OpenAIRE

Purfield, Anne E.; Tidwell, Richard R.; Meshnick, Steven R.

2008-01-01

Pafuramidine is a novel orally active antimalarial. To identify a combination partner, we measured the in vitro antimalarial activities of the active metabolite, DB75, with amodiaquine, artemisinin, atovaquone, azithromycin, chloroquine, clindamycin, mefloquine, piperaquine, pyronaridine, tafenoquine, and tetracycline. None of the drugs tested demonstrated antagonistic or synergistic activity in combination with pafuramidine.

HIV-1 entry inhibition by small-molecule CCR5 antagonists: A combined molecular modeling and mutant study using a high-throughput assay

International Nuclear Information System (INIS)

Labrecque, Jean; Metz, Markus; Lau, Gloria; Darkes, Marilyn C.; Wong, Rebecca S.Y.; Bogucki, David; Carpenter, Bryon; Chen Gang; Li Tongshuang; Nan, Susan; Schols, Dominique; Bridger, Gary J.; Fricker, Simon P.; Skerlj, Renato T.

2011-01-01

Based on the attrition rate of CCR5 small molecule antagonists in the clinic the discovery and development of next generation antagonists with an improved pharmacology and safety profile is necessary. Herein, we describe a combined molecular modeling, CCR5-mediated cell fusion, and receptor site-directed mutagenesis approach to study the molecular interactions of six structurally diverse compounds (aplaviroc, maraviroc, vicriviroc, TAK-779, SCH-C and a benzyloxycarbonyl-aminopiperidin-1-yl-butane derivative) with CCR5, a coreceptor for CCR5-tropic HIV-1 strains. This is the first study using an antifusogenic assay, a model of the interaction of the gp120 envelope protein with CCR5. This assay avoids the use of radioactivity and HIV infection assays, and can be used in a high throughput mode. The assay was validated by comparison with other established CCR5 assays. Given the hydrophobic nature of the binding pocket several binding models are suggested which could prove useful in the rational drug design of new lead compounds.

Striatal pre- and postsynaptic profile of adenosine A(2A receptor antagonists.

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Marco Orru

2011-01-01

Full Text Available Striatal adenosine A(2A receptors (A(2ARs are highly expressed in medium spiny neurons (MSNs of the indirect efferent pathway, where they heteromerize with dopamine D(2 receptors (D(2Rs. A(2ARs are also localized presynaptically in cortico-striatal glutamatergic terminals contacting MSNs of the direct efferent pathway, where they heteromerize with adenosine A(1 receptors (A(1Rs. It has been hypothesized that postsynaptic A(2AR antagonists should be useful in Parkinson's disease, while presynaptic A(2AR antagonists could be beneficial in dyskinetic disorders, such as Huntington's disease, obsessive-compulsive disorders and drug addiction. The aim or this work was to determine whether selective A(2AR antagonists may be subdivided according to a preferential pre- versus postsynaptic mechanism of action. The potency at blocking the motor output and striatal glutamate release induced by cortical electrical stimulation and the potency at inducing locomotor activation were used as in vivo measures of pre- and postsynaptic activities, respectively. SCH-442416 and KW-6002 showed a significant preferential pre- and postsynaptic profile, respectively, while the other tested compounds (MSX-2, SCH-420814, ZM-241385 and SCH-58261 showed no clear preference. Radioligand-binding experiments were performed in cells expressing A(2AR-D(2R and A(1R-A(2AR heteromers to determine possible differences in the affinity of these compounds for different A(2AR heteromers. Heteromerization played a key role in the presynaptic profile of SCH-442416, since it bound with much less affinity to A(2AR when co-expressed with D(2R than with A(1R. KW-6002 showed the best relative affinity for A(2AR co-expressed with D(2R than co-expressed with A(1R, which can at least partially explain the postsynaptic profile of this compound. Also, the in vitro pharmacological profile of MSX-2, SCH-420814, ZM-241385 and SCH-58261 was is in accordance with their mixed pre- and postsynaptic profile

Exploitation of microbial antagonists for the control of postharvest diseases of fruits: a review.

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Dukare, Ajinath Shridhar; Paul, Sangeeta; Nambi, V Eyarkai; Gupta, Ram Kishore; Singh, Rajbir; Sharma, Kalyani; Vishwakarma, Rajesh Kumar

2018-01-16

Fungal diseases result in significant losses of fruits and vegetables during handling, transportation and storage. At present, post-production fungal spoilage is predominantly controlled by using synthetic fungicides. Under the global climate change scenario and with the need for sustainable agriculture, biological control methods of fungal diseases, using antagonistic microorganisms, are emerging as ecofriendly alternatives to the use of fungicides. The potential of microbial antagonists, isolated from a diversity of natural habitats, for postharvest disease suppression has been investigated. Postharvest biocontrol systems involve tripartite interaction between microbial antagonists, the pathogen and the host, affected by environmental conditions. Several modes for fungistatic activities of microbial antagonists have been suggested, including competition for nutrients and space, mycoparasitism, secretion of antifungal antibiotics and volatile metabolites and induction of host resistance. Postharvest application of microbial antagonists is more successful for efficient disease control in comparison to pre-harvest application. Attempts have also been made to improve the overall efficacy of antagonists by combining them with different physical and chemical substances and methods. Globally, many microbe-based biocontrol products have been developed and registered for commercial use. The present review provides a brief overview on the use of microbial antagonists as postharvest biocontrol agents and summarises information on their isolation, mechanisms of action, application methods, efficacy enhancement, product formulation and commercialisation.

Recent progress in the development of small-molecule glucagon receptor antagonists.

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Sammons, Matthew F; Lee, Esther C Y

2015-10-01

The endocrine hormone glucagon stimulates hepatic glucose output via its action at the glucagon receptor (GCGr) in the liver. In the diabetic state, dysregulation of glucagon secretion contributes to abnormally elevated hepatic glucose output. The inhibition of glucagon-induced hepatic glucose output via antagonism of the GCGr using small-molecule ligands is a promising mechanism for improving glycemic control in the diabetic state. Clinical data evaluating the therapeutic potential of small-molecule GCGr antagonists is currently emerging. Recently disclosed clinical data demonstrates the potential efficacy and possible therapeutic limitations of small-molecule GCGr antagonists. Recent pre-clinical work on the development of GCGr antagonists is also summarized. Copyright © 2015 Elsevier Ltd. All rights reserved.

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

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Sherin Saheera

2017-10-01

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

The role of ecology, neutral processes and antagonistic coevolution in an apparent sexual arms race.

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Perry, Jennifer C; Garroway, Colin J; Rowe, Locke

2017-09-01

Some of the strongest examples of a sexual 'arms race' come from observations of correlated evolution in sexually antagonistic traits among populations. However, it remains unclear whether these cases truly represent sexually antagonistic coevolution; alternatively, ecological or neutral processes might also drive correlated evolution. To investigate these alternatives, we evaluated the contributions of intersex genetic correlations, ecological context, neutral genetic divergence and sexual coevolution in the correlated evolution of antagonistic traits among populations of Gerris incognitus water striders. We could not detect intersex genetic correlations for these sexually antagonistic traits. Ecological variation was related to population variation in the key female antagonistic trait (spine length, a defence against males), as well as body size. Nevertheless, population covariation between sexually antagonistic traits remained substantial and significant even after accounting for all of these processes. Our results therefore provide strong evidence for a contemporary sexual arms race. © 2017 John Wiley & Sons Ltd/CNRS.

Stability of tramadol with three 5-HT3 receptor antagonists in polyolefin bags for patient-controlled delivery systems

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Chen FC

2016-06-01

Full Text Available Fu-chao Chen,1 Jun Zhu,1 Bin Li,1 Fang-jun Yuan,1 Lin-hai Wang2 1Department of Pharmacy, Dongfeng Hospital, 2Department of Pharmacy, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei, People’s Republic of China Background: Mixing 5-hydroxytryptamine-3 (5-HT3 receptor antagonists with patient-controlled analgesia (PCA solutions of tramadol has been shown to decrease the incidence of nausea and vomiting associated with the use of tramadol PCA for postoperative pain. However, such mixtures are not commercially available, and the stability of the drug combinations has not been duly studied. The study aimed to evaluate the stability of tramadol with three 5-HT3 receptor antagonists in 0.9% sodium chloride injection for PCA administration.Materials and methods: Test samples were prepared by adding 1,000 mg tramadol hydrochloride, 8 mg ondansetron hydrochloride, and 6 mg granisetron hydrochloride or 5 mg tropisetron hydrochloride to 100 mL of 0.9% sodium chloride injection in polyolefin bags. The samples were prepared in triplicates, stored at either 25°C or 4°C for 14 days, and assessed using the following compatibility parameters: precipitation, cloudiness, discoloration, and pH. Chemical stability was also determined using a validated high-pressure liquid chromatography method.Results: All of the mixtures were clear and colorless throughout the initial observation period. No change in the concentration of tramadol hydrochloride occurred with any of the 5-HT3 receptor antagonists during the 14 days. Similarly, little or no loss of the 5-HT3 receptor antagonists occurred over the 14-day period.Conclusion: Our results suggest that mixtures of tramadol hydrochloride, ondansetron hydrochloride, granisetron hydrochloride, or tropisetron hydrochloride in 0.9% sodium chloride injection were physically and chemically stable for 14 days when stored in polyolefin bags at both 4°C and 25°C. Keywords: tramadol, ondansetron, granisetron

Novel delivery systems with nonsteroidal anti-inflammatory drugs

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Cvijić Sandra

2016-01-01

Full Text Available Chronic use of oral nonsteroidal anti-inflammatory drugs (NSAIDs is associated with increased risk of serious gastrointestinal side effects. Therefore, recent trends in the development of NSAIDs aim to reduce the incidence of side effects, and improve patient compliance. One of the strategies to improve efficacy and safety of oral NSAIDs is the development of combination products that contain gastroprotective agents. Several products containing NSAID in combination with proton pump inhibitors (ketoprofen/omeprazole, naproxen/esomeprazole, H2-receptor antagonists (ibuprofen/famotidine, and prostaglandin analogues (diclofenac/misoprostol are currently available on the market. Another approach refer to the special formulation design to allow dose reduction while preserving drug therapeutic efficacy. An example is SoluMatrix® technology, a manufacturing process that produce submicron-sized drug particles with enhanced dissolution and absorption properties. Patented SoluMatrix® technology has been successfully employed to develop low-dose diclofenac, meloxicam, indomethacin and naproxen products. Topical NSAID formulations enable drug delivery to target tissues, while reducing systemic exposure and concomitant side effects associated with oral NSAIDs. Dermal/transdermal NSAID delivery systems are subject of intensive investigation. So far, several 'advanced' drug delivery systems with diclofenac, ibuprofen and ketoprofen have been designed.

West syndrome associated with administration of a histamine H1 antagonist, oxatomide.

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Yamashita, Yushiro; Isagai, Takeo; Seki, Yoshitaka; Ohya, Takashi; Nagamitsu, Shinichiro; Matsuishi, Toyojiro

2004-01-01

We report a 4-month-old female infant who developed West syndrome eleven days after administration of a histamine H1 antagonist, oxatomide, for atopic dermatitis. It has been reported that some histamine H1 antagonists induce seizures in epileptic patients. The age, the interval between oxatomide administration, and the onset of West syndrome and its clinical course were similar to two previously reported 3-month-old infants with West syndrome associated with ketotifen administration. We should be cautious in using the histamine H1 antagonists, oxatomide and ketotifen, in young infants because such agents could potentially disturb the anticonvulsive central histaminergic system.

Reprogramming antitumor immunity against chemoresistant ovarian cancer by a CXCR4 antagonist-armed viral oncotherapy

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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.

Synthesis and Evaluation of Orexin-1 Receptor Antagonists with Improved Solubility and CNS Permeability.

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Perrey, David A; Decker, Ann M; Zhang, Yanan

2018-03-21

Orexins are hypothalamic neuropeptides playing important roles in many functions including the motivation of addictive behaviors. Blockade of the orexin-1 receptor has been suggested as a potential strategy for the treatment of drug addiction. We have previously reported OX 1 receptor antagonists based on the tetrahydroisoquinoline scaffold with excellent OX 1 potency and selectivity; however, these compounds had high lipophilicity (clogP > 5) and low to moderate solubility. In an effort to improve their properties, we have designed and synthesized a series of analogues where the 7-position substituents known to favor OX 1 potency and selectivity were retained, and groups of different nature were introduced at the 1-position where substitution was generally tolerated as demonstrated in previous studies. Compound 44 with lower lipophilicity (clogP = 3.07) displayed excellent OX 1 potency ( K e = 5.7 nM) and selectivity (>1,760-fold over OX 2 ) in calcium mobilization assays. In preliminary ADME studies, 44 showed excellent kinetic solubility (>200 μM), good CNS permeability ( P app = 14.7 × 10 -6 cm/sec in MDCK assay), and low drug efflux (efflux ratio = 3.3).

The comparision of effect of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients.

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Ozcan Cenksoy, Pinar; Ficicioglu, Cem; Kizilkale, Ozge; Suhha Bostanci, Mehmet; Bakacak, Murat; Yesiladali, Mert; Kaspar, Cigdem

2014-07-01

To compare the effects of microdose GnRH-a flare-up, GnRH antagonist/aromatase inhibitor letrozole and GnRH antagonist/clomiphene citrate protocols on IVF outcomes in poor responder patients. Of 225 patients, 83 patients were in microdose flare-up group (Group 1), 70 patients were in GnRH antagonist/letrozole group (Group 2) and 72 patients were in GnRH antagonist/clomiphene citrate group (Group 3). Demographic and endocrine characteristics, the total number of oocytes retrieved, cancellation rate and clinical pregnancy rate were collected Results: Total dosage of gonadotropins (p=0.002) and serum E2 levels on the day of hCG administration (p=0.010) were significantly higher and duration of stimulations (p=0.03) was significantly longer in group 1. The number of oocytes retrieved was significantly greater in group 1 and 2 when compare to those of group 3 (p=0,000). There was a trend towards increasing cycle cancellation rates with GnRH antagonist/clomiphene citrate and GnRH antagonist/letrozole. Our finding suggest that the results of microdose flare-up protocol are better than other two used treatment protocols, in terms of maximum estradiol levels, number of mature oocytes retrieved, and cancellation rate and it still seems to be superior the ovarian stimulation regime for the poor responder patients.

Pharmacogenetic Aspects of the Interaction of AT1 Receptor Antagonists With ATP-Binding Cassette Transporter ABCG2

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Anne Ripperger

2018-05-01

Full Text Available The ATP-binding cassette transporter ABCG2 (BCRP and MXR is involved in the absorption, distribution, and elimination of numerous drugs. Thus, drugs that are able to reduce the activity of ABCG2, e.g., antihypertensive AT1 receptor antagonists (ARBs, may cause drug-drug interactions and compromise drug safety and efficacy. In addition, genetic variability within the ABCG2 gene may influence the ability of the transporter to interact with ARBs. Thus, the aim of this study was to characterize the ARB-ABCG2 interaction in the light of naturally occurring variations (F489L, R482G or amino acid substitutions with in silico-predicted relevance for the ARB-ABCG2 interaction (Y469A; M483F; Y570A. For this purpose, ABCG2 variants were expressed in HEK293 cells and the impact of ARBs on ABCG2 activity was studied in vitro using the pheophorbide A (PhA efflux assay. First, we demonstrated that both the F489L and the Y469A substitution, respectively, reduced ABCG2 protein levels in these cells. Moreover, both substitutions enhanced the inhibitory effect of candesartan cilexetil, irbesartan, losartan, and telmisartan on ABCG2-mediated PhA efflux, whereas the R482G substitution blunted the inhibitory effect of candesartan cilexetil and telmisartan in this regard. In contrast, the ARB-ABCG2 interaction was not altered in cells expressing either the M483F or the Y570A variant, respectively. In conclusion, our data indicate that the third transmembrane helix and adjacent regions of ABCG2 may be of major importance for the interaction of ARBs with the ABC transporter. Moreover, we conclude from our data that individuals carrying the F489L polymorphism may be at increased risk of developing ABCG2-related drug-drug interactions in multi-drug regimens involving ARBs.

Non-imidazole-based histamine H3 receptor antagonists with anticonvulsant activity in different seizure models in male adult rats

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Sadek B

2016-11-01

Full Text Available Bassem Sadek,1 Ali Saad,1 Gniewomir Latacz,2 Kamil Kuder,2 Agnieszka Olejarz,2 Tadeusz Karcz,2 Holger Stark,3 Katarzyna Kieć-Kononowicz2 1Department of Pharmacology and Therapeutics, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, United Arab Emirates; 2Department of Technology and Biotechnology of Drugs, Faculty of Pharmacy, Jagiellonian University Medical College, Kraków, Poland; 3Department of Pharmaceutical and Medicinal Chemistry, Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University, Düsseldorf, Germany Abstract: A series of twelve novel non-imidazole-based ligands (3–14 was developed and evaluated for its in vitro binding properties at the human histamine H3 receptor (hH3R. The novel ligands were investigated for their in vivo protective effects in different seizure models in male adult rats. Among the H3R ligands (3–14 tested, ligand 14 showed significant and dose-dependent reduction in the duration of tonic hind limb extension in maximal electroshock (MES-induced seizure model subsequent to acute systemic administration (5, 10, and 20 mg/kg, intraperitoneally, whereas ligands 4, 6, and 7 without appreciable protection in MES model were most promising in pentylenetetrazole (PTZ model. Moreover, the protective effect observed for ligand 14 in MES model was lower than that observed for the reference drug phenytoin and was entirely abrogated when rats were co-administered with the brain-penetrant H1R antagonist pyrilamine (PYR but not the brain-penetrant H2R antagonist zolantidine (ZOL, demonstrating that histaminergic neurotransmission by activation of postsynaptically located H1Rs seems to be involved in the protective action. On the contrary, PYR and ZOL failed to abrogate the full protection provided by 4 in PTZ model and the moderate protective effect by 14 in strychnine (STR model. Moreover, the experimental and in silico estimation of properties such as metabolism was

The successes and failures of HIV drug discovery.

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Hashimoto, Chie; Tanaka, Tomohiro; Narumi, Tetsuo; Nomura, Wataru; Tamamura, Hirokazu

2011-10-01

To date, several anti-human immunodeficiency virus (HIV) drugs, including reverse transcriptase inhibitors and protease inhibitors, have been developed and used clinically for the treatment of patients infected with HIV. Recently, novel drugs have been discovered which have different mechanisms of action from those of the above inhibitors, including entry inhibitors and integrase (IN) inhibitors; the clinical use of three of these inhibitors has been approved. Other inhibitors are still in development. This review article summarizes the history of the development of anti-HIV drugs and also focuses on successes in the development of these entry and IN inhibitors, along with looking at exploratory approaches for the development of other inhibitors. Currently used highly active antiretroviral therapy can be subject to a loss of efficacy, due to the emergence of multi-drug resistant (MDR) strains; a change of regimens of the drug combination is required to combat this, along with careful monitoring of the virus and CD4 in the blood, by methods such as cellular tropism testing. In such a situation, entry inhibitors such as CCR5/CXCR4 antagonists, CD4 mimics, fusion inhibitors and IN inhibitors might be optional agents for an expansion of the drug repertoire available to patients at all stages of HIV infection.

Novel approach for a PTX/VEGF dual drug delivery system in cardiovascular applications-an innovative bulk and surface drug immobilization.

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Wulf, Katharina; Teske, Michael; Matschegewski, Claudia; Arbeiter, Daniela; Bajer, Dalibor; Eickner, Thomas; Schmitz, Klaus-Peter; Grabow, Niels

2018-06-01

The successive incorporation of several drugs into the polymeric bulk of implants mostly results in loss of considerable quantity of one drug, and/or the loss in quality of the coating and also in changes of drug release time points. A dual drug delivery system (DDDS) based on poly-L-lactide (PLLA) copolymers combining the effective inhibition of smooth muscle cell proliferation while simultaneously promoting re-endothelialization was successfully developed. To overcome possible antagonistic drug interactions and the limitation of the polymeric bulk material as release system for dual drugs, a novel concept which combines the bulk and surface drug immobilization for a DDDS was investigated. The advantage of this DDDS is that the bulk incorporation of fluorescein diacetate (FDAc) (model drug for paclitaxel (PTX)) via spray coating enhanced the subsequent cleavable surface coupling of vascular endothelial growth factor (VEGF) via the crosslinker bissulfosuccinimidyl suberate (BS 3 ). In the presence of the embedded FDAc, the VEGF loading and release are about twice times higher than in absence. Furthermore, the DDDS combines the diffusion drug delivery (FDAc or PTX) and the chemical controlled drug release, VEGF via hydrolysable ester bonds, without loss in quantity and quality of the drug release curves. Additionally, the performed in vitro biocompatibility study showed the bimodal influences of PTX and VEGF on human endothelial EA.hy926 cells. In conclusion, it was possible to show the feasibility to develop a novel DDDS which has a high potential for the medical application due to the possible easy and short modification of a polymer-based PTX delivery system.

The Two Faces of Social Interaction Reward in Animal Models of Drug Dependence.

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El Rawas, Rana; Saria, Alois

2016-03-01

Drug dependence is a serious health and social problem. Social factors can modify vulnerability to developing drug dependence, acting as risk factors or protective factors. Whereas stress and peer environment that encourage substance use may increase drug taking, strong attachments between family members and peer environment that do not experience drug use may protect against drug taking and, ultimately, drug dependence. The rewarding effects of drug abuse and social interaction can be evaluated using animal models. In this review we focus on evaluating social interaction reward in the conditioned place preference paradigm. We give an overview of how social interaction, if made available within the drug context, may facilitate, promote and interact with the drug's effects. However, social interaction, if offered alternatively outside the drug context, may have pronounced protective effects against drug abuse and relapse. We also address the importance of the weight difference parameter between the social partners in determining the positive or "agonistic" versus the hostile or "antagonistic" social interaction. We conclude that understanding social interaction reward and its subsequent effects on drug reward is sorely needed for therapeutic interventions against drug dependence.

Randomized, controlled trial of TNF-α antagonist in CTL-mediated severe cutaneous adverse reactions.

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Wang, Chuang-Wei; Yang, Lan-Yan; Chen, Chun-Bing; Ho, Hsin-Chun; Hung, Shuen-Iu; Yang, Chih-Hsun; Chang, Chee-Jen; Su, Shih-Chi; Hui, Rosaline Chung-Yee; Chin, See-Wen; Huang, Li-Fang; Lin, Yang Yu-Wei; Chang, Wei-Yang; Fan, Wen-Lang; Yang, Chin-Yi; Ho, Ji-Chen; Chang, Ya-Ching; Lu, Chun-Wei; Chung, Wen-Hung

2018-03-01

Cytotoxic T lymphocyte-mediated (CTL-mediated) severe cutaneous adverse reactions (SCARs), including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), are rare but life-threatening adverse reactions commonly induced by drugs. Although high levels of CTL-associated cytokines, chemokines, or cytotoxic proteins, including TNF-α and granulysin, were observed in SJS-TEN patients in recent studies, the optimal treatment for these diseases remains controversial. We aimed to evaluate the efficacy, safety, and therapeutic mechanism of a TNF-α antagonist in CTL-mediated SCARs. We enrolled 96 patients with SJS-TEN in a randomized trial to compare the effects of the TNF-α antagonist etanercept versus traditional corticosteroids. Etanercept improved clinical outcomes in patients with SJS-TEN. Etanercept decreased the SCORTEN-based predicted mortality rate (predicted and observed rates, 17.7% and 8.3%, respectively). Compared with corticosteroids, etanercept further reduced the skin-healing time in moderate-to-severe SJS-TEN patients (median time for skin healing was 14 and 19 days for etanercept and corticosteroids, respectively; P = 0.010), with a lower incidence of gastrointestinal hemorrhage in all SJS-TEN patients (2.6% for etanercept and 18.2% for corticosteroids; P = 0.03). In the therapeutic mechanism study, etanercept decreased the TNF-α and granulysin secretions in blister fluids and plasma (45.7%-62.5% decrease after treatment; all P etanercept serves as an effective alternative for the treatment of CTL-mediated SCARs. ClinicalTrials.gov NCT01276314. Ministry of Science and Technology of Taiwan.

Interaction of celecoxib with different anti-cancer drugs is antagonistic in breast but not in other cancer cells

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El-Awady, Raafat A.; Saleh, Ekram M.; Ezz, Marwa; Elsayed, Abeer M.

2011-01-01

Celecoxib, an inhibitor of cyclooxygenase-2, is being investigated for enhancement of chemotherapy efficacy in cancer clinical trials. This study investigates the ability of cyclooxygenase-2 inhibitors to sensitize cells from different origins to several chemotherapeutic agents. The effect of the drug's mechanism of action and sequence of administration are also investigated. The sensitivity, cell cycle, apoptosis and DNA damage of five different cancer cell lines (HeLa, HCT116, HepG2, MCF7 and U251) to 5-FU, cisplatin, doxorubicin and etoposide ± celecoxib following different incubation schedules were analyzed. We found antagonism between celecoxib and the four drugs in the breast cancer cells MCF7 following all incubation schedules and between celecoxib and doxorubicin in all cell lines except for two combinations in HCT116 cells. Celecoxib with the other three drugs in the remaining four cell lines resulted in variable interactions. Mechanistic investigations revealed that celecoxib exerts different molecular effects in different cells. In some lines, it abrogates the drug-induced G2/M arrest enhancing pre-mature entry into mitosis with damaged DNA thus increasing apoptosis and resulting in synergism. In other cells, it enhances drug-induced G2/M arrest allowing time to repair drug-induced DNA damage before entry into mitosis and decreasing cell death resulting in antagonism. In some synergistic combinations, celecoxib-induced abrogation of G2/M arrest was not associated with apoptosis but permanent arrest in G1 phase. These results, if confirmed in-vivo, indicate that celecoxib is not a suitable chemosensitizer for breast cancer or with doxorubicin for other cancers. Moreover, combination of celecoxib with other drugs should be tailored to the tumor type, drug and administration schedule. - Graphical abstract: Display Omitted Highlights: → Celecoxib may enhance effects of anticancer drugs. → Its combination with four drugs was tested in five cancer cell

[Development of anti-Alzheimer's disease drug based on beta-amyloid hypothesis].

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Sugimoto, Hachiro

2010-04-01

Currently, there are five anti-Alzheimer's disease drugs approved. These are tacrine, donepezil, rivastigmine, galantamine, and memantine. The mechanism of the first four drugs is acetylcholinesterase inhibition, while memantine is an NMDA-receptor antagonist. However, these drugs do not cure Alzheimer's, but are only symptomatic treatments. Therefore, a cure for Alzheimer's disease is truly needed. Alzheimer's disease is a progressive neurodegenerative disease characterized by cognitive deficits. The cause of the disease is not well understood, but research indicates that the aggregation of beta-amyloid is the fundamental cause. This theory suggests that beta-amyloid aggregation causes neurotoxicity. Therefore, development of the next anti-Alzheimer's disease drug is based on the beta-amyloid theory. We are now studying natural products, such as mulberry leaf extracts and curcumin derivatives, as potential cure for Alzheimer's disease. In this report, we describe some data about these natural products and derivatives.

Prototypical antipsychotic drugs protect hippocampal neuronal cultures against cell death induced by growth medium deprivation

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Williams Sylvain

2006-03-01

Full Text Available Abstract Background Several clinical studies suggested that antipsychotic-based medications could ameliorate cognitive functions impaired in certain schizophrenic patients. Accordingly, we investigated the effects of various dopaminergic receptor antagonists – including atypical antipsychotics that are prescribed for the treatment of schizophrenia – in a model of toxicity using cultured hippocampal neurons, the hippocampus being a region of particular relevance to cognition. Results Hippocampal cell death induced by deprivation of growth medium constituents was strongly blocked by drugs including antipsychotics (10-10-10-6 M that display nM affinities for D2 and/or D4 receptors (clozapine, haloperidol, (±-sulpiride, domperidone, clozapine, risperidone, chlorpromazine, (+-butaclamol and L-741,742. These effects were shared by some caspases inhibitors and were not accompanied by inhibition of reactive oxygen species. In contrast, (--raclopride and remoxipride, two drugs that preferentially bind D2 over D4 receptors were ineffective, as well as the selective D3 receptor antagonist U 99194. Interestingly, (--raclopride (10-6 M was able to block the neuroprotective effect of the atypical antipsychotic clozapine (10-6 M. Conclusion Taken together, these data suggest that D2-like receptors, particularly the D4 subtype, mediate the neuroprotective effects of antipsychotic drugs possibly through a ROS-independent, caspase-dependent mechanism.

Overcoming hERG affinity in the discovery of maraviroc; a CCR5 antagonist for the treatment of HIV.

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Price, David A; Armour, Duncan; de Groot, Marcel; Leishman, Derek; Napier, Carolyn; Perros, Manos; Stammen, Blanda L; Wood, Anthony

2008-01-01

Avoiding cardiac liability associated with blockade of hERG (human ether a go-go) is key for successful drug discovery and development. This paper describes the work undertaken in the discovery of a potent CCR5 antagonist, maraviroc 34, for the treatment of HIV. In particular the use of a pharmacophore model of the hERG channel and a high throughput binding assay for the hERG channel are described that were critical to elucidate SAR to overcome hERG liabilities. The key SAR involves the introduction of polar substituents into regions of the molecule where it is postulated to undergo hydrophobic interactions with the ion channel. Within the CCR5 project there appeared to be no strong correlation between hERG affinity and physiochemical parameters such as pKa or lipophilicity. It is believed that chemists could apply these same strategies early in drug discovery to remove hERG interactions associated with lead compounds while retaining potency at the primary target.

Computerized clinical decision support systems for therapeutic drug monitoring and dosing: A decision-maker-researcher partnership systematic review

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Weise-Kelly Lorraine

2011-08-01

Full Text Available Abstract Background Some drugs have a narrow therapeutic range and require monitoring and dose adjustments to optimize their efficacy and safety. Computerized clinical decision support systems (CCDSSs may improve the net benefit of these drugs. The objective of this review was to determine if CCDSSs improve processes of care or patient outcomes for therapeutic drug monitoring and dosing. Methods We conducted a decision-maker-researcher partnership systematic review. Studies from our previous review were included, and new studies were sought until January 2010 in MEDLINE, EMBASE, Evidence-Based Medicine Reviews, and Inspec databases. Randomized controlled trials assessing the effect of a CCDSS on process of care or patient outcomes were selected by pairs of independent reviewers. A study was considered to have a positive effect (i.e., CCDSS showed improvement if at least 50% of the relevant study outcomes were statistically significantly positive. Results Thirty-three randomized controlled trials were identified, assessing the effect of a CCDSS on management of vitamin K antagonists (14, insulin (6, theophylline/aminophylline (4, aminoglycosides (3, digoxin (2, lidocaine (1, or as part of a multifaceted approach (3. Cluster randomization was rarely used (18% and CCDSSs were usually stand-alone systems (76% primarily used by physicians (85%. Overall, 18 of 30 studies (60% showed an improvement in the process of care and 4 of 19 (21% an improvement in patient outcomes. All evaluable studies assessing insulin dosing for glycaemic control showed an improvement. In meta-analysis, CCDSSs for vitamin K antagonist dosing significantly improved time in therapeutic range. Conclusions CCDSSs have potential for improving process of care for therapeutic drug monitoring and dosing, specifically insulin and vitamin K antagonist dosing. However, studies were small and generally of modest quality, and effects on patient outcomes were uncertain, with no convincing

The Effect of Antagonist Muscle Sensory Input on Force Regulation.

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Tanya Onushko

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

Radioprotective effects of histamine H2 receptor antagonists famotidine and ranitidine on gamma ray induced chromosome damage

International Nuclear Information System (INIS)

Sharma, N.K.

2013-01-01

Histamine H2 receptor antagonist such as Cimetidine, Famotidine and Ranitidine are used in the clinical treatment of peptic ulcer. In vitro metaphase analysis and micronucleus assay were used to test the effects of famotidine and ranitidine on Cobalt 60 γ-ray induced clastogenic effects. Heparinised whole blood was obtained from healthy non-smoker volunteers. Blood samples were irradiated at a dose of 3Gy and incubated at 37 deg C for 1h. Lymphocyte cultures were initiated for metaphase chromosomes and cytochalasin B blocked micronucleus analysis. Aqueous solution of Famotidine (150 g/ml) and Ranitidine (500 g/ml) was added to the whole blood cultures at 0h and 24h. Cultures were harvested and processed at 48h and 72h for chromosome aberrations and micronucleus analysis respectively. Cultures treated with Famotidine at 0h and 24h after 3Gy γ-ray irradiation induce 60.90% and 56.52% inhibition in dicentrics, 48.70% and 43.61% inhibition in total aberrations. Ranitidine at 0h and 24h after 3Gy γ-ray irradiation induce 52.17% and 43.47% inhibition in dicentrics, 33.60% and 46.15% inhibition in total aberrations, when compared with 3Gy γ-ray irradiation alone. 43-54% inhibition in Binucleated cells with micronuclei and 47.72% inhibition in micronuclei at 0h treatment respectively. In conclusion radioprotective effects of Histamine H2 receptor antagonists famotidine and ranitidine on γ-ray induced chromosome damage is observed and the drugs effectively reduced the frequency of radiation induced chromosome aberrations and micronucleus. Famotidine was found to be more effective. The mechanism in which these drugs reduce clastogenic effect of γ-radiation is not fully understood. It might be due to their antioxidant and free radical-scavenging properties. (author)

Meiotic drive influences the outcome of sexually antagonistic selection at a linked locus.

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Patten, M M

2014-11-01

Most meiotic drivers, such as the t-haplotype in Mus and the segregation distorter (SD) in Drosophila, act in a sex-specific manner, gaining a transmission advantage through one sex although suffering only the fitness costs associated with the driver in the other. Their inheritance is thus more likely through one of the two sexes, a property they share with sexually antagonistic alleles. Previous theory has shown that pairs of linked loci segregating for sexually antagonistic alleles are more likely to remain polymorphic and that linkage disequilibrium accrues between them. I probe this similarity between drive and sexual antagonism and examine the evolution of chromosomes experiencing these selection pressures simultaneously. Reminiscent of previous theory, I find that: the opportunity for polymorphism increases for a sexually antagonistic locus that is physically linked to a driving locus; the opportunity for polymorphism at a driving locus also increases when linked to a sexually antagonistic locus; and stable linkage disequilibrium accompanies any polymorphic equilibrium. Additionally, I find that drive at a linked locus favours the fixation of sexually antagonistic alleles that benefit the sex in which drive occurs. Further, I show that under certain conditions reduced recombination between these two loci is selectively favoured. These theoretical results provide clear, testable predictions about the nature of sexually antagonistic variation on driving chromosomes and have implications for the evolution of genomic architecture. © 2014 European Society For Evolutionary Biology. Journal of Evolutionary Biology © 2014 European Society For Evolutionary Biology.

L-type Ca²⁺ channel blockade with antihypertensive medication disrupts VTA synaptic plasticity and drug-associated contextual memory.

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Degoulet, M; Stelly, C E; Ahn, K-C; Morikawa, H

2016-03-01

Drug addiction is driven, in part, by powerful and enduring memories of sensory cues associated with drug intake. As such, relapse to drug use during abstinence is frequently triggered by an encounter with drug-associated cues, including the drug itself. L-type Ca(2+) channels (LTCCs) are known to regulate different forms of synaptic plasticity, the major neural substrate for learning and memory, in various brain areas. Long-term potentiation (LTP) of NMDA receptor (NMDAR)-mediated glutamatergic transmission in the ventral tegmental area (VTA) may contribute to the increased motivational valence of drug-associated cues triggering relapse. In this study, using rat brain slices, we found that isradipine, a general LTCC antagonist used as antihypertensive medication, not only blocks the induction of NMDAR LTP but also promotes the reversal of previously induced LTP in the VTA. In behaving rats, isradipine injected into the VTA suppressed the acquisition of cocaine-paired contextual cue memory assessed using a conditioned place preference (CPP) paradigm. Furthermore, administration of isradipine or a CaV1.3 subtype-selective LTCC antagonist (systemic or intra-VTA) before a single extinction or reinstatement session, while having no immediate effect at the time of administration, abolished previously acquired cocaine and alcohol (ethanol) CPP on subsequent days. Notably, CPP thus extinguished cannot be reinstated by drug re-exposure, even after 2 weeks of withdrawal. These results suggest that LTCC blockade during exposure to drug-associated cues may cause unlearning of the increased valence of those cues, presumably via reversal of glutamatergic synaptic plasticity in the VTA.

Human fetal malformations associated with the use of an angiotensin II receptor antagonist: Case Report

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Henri Augusto Korkes

2014-09-01

Full Text Available Introduction: The potential risks related to drug exposure during pregnancy represent a vast chapter in modern obstetrics and data regarding the safety of antihypertensive drugs during pregnancy are relatively scarce. Case report: A 37-year-old patient discovered her fifth pregnancy at our hospital after 26 weeks and 4 days of gestation. She reported a history of hypertension and was currently being treated with Losartan. Hospitalization was recommended for the patient and further evaluation of fetal vitality was performed. On the fourth day an ultrasound was performed, resulting in a severe oligohydramnios, fetal centralization and abnormal ductus venosus. After 36 hours, the newborn died. Pathologic evaluation: At autopsy, the skullcap had large fontanels and deficient ossification. The kidneys were slightly enlarged. A microscopic examination detected underdevelopment of the tubules and the presence of some dilated lumens. Immunohistochemical detection of epithelial membrane antigen was positive. Immunoreactivity of CD 15 was also assayed to characterize the proximal tubules, and lumen collapse was observed in some regions. Discussion: Angiotensin-converting enzyme inhibitors (ACEIs and angiotensin receptor antagonists (ARAs are among the most widely prescribed drugs for hypertension. They are often used by hypertensive women who are considering become pregnant. While their fetal toxicity in the second or third trimesters has been documented, their teratogenic effect during the first trimester has only recently been demonstrated. Conclusion: Constant awareness by physicians and patients should be encouraged, particularly in regard to the prescription of antihypertensive drugs in women of childbearing age who are or intend to become pregnant.

Secreted Wnt antagonists in leukemia: A road yet to be paved.

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Pehlivan, Melek; Çalışkan, Ceyda; Yüce, Zeynep; Sercan, Hakki Ogun

2018-03-28

Wnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies. Copyright © 2018 Elsevier Ltd. All rights reserved.

Anti-chemokine small molecule drugs: a promising future?

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Proudfoot, Amanda E I; Power, Christine A; Schwarz, Matthias K

2010-03-01

Chemokines have principally been associated with inflammation due to their role in the control of leukocyte migration, but just over a decade ago chemokine receptors were also identified as playing a pivotal role in the entry of the HIV virus into cells. Chemokines activate seven transmembrane G protein-coupled receptors, making them extremely attractive therapeutic targets for the pharmaceutical industry. Although there are now a large number of molecules targeting chemokines and chemokine receptors including neutralizing antibodies in clinical trials for inflammatory diseases, the results to date have not always been positive, which has been disappointing for the field. These failures have often been attributed to redundancy in the chemokine system. However, other difficulties have been encountered in drug discovery processes targeting the chemokine system, and these will be addressed in this review. In this review, the reader will get an insight into the hurdles that have to be overcome, learn about some of the pitfalls that may explain the lack of success, and get a glimpse of the outlook for the future. In 2007, the FDA approved maraviroc, an inhibitor of CCR5 for the prevention of HIV infection, the first triumph for a small-molecule drug acting on the chemokine system. The time to market, 11 years from discovery of CCR5, was fast by industry standards. A second small-molecule drug, a CXCR4 antagonist for hematopoietic stem cell mobilization, was approved by the FDA at the end of 2008. The results of a Phase III trial with a CCR9 inhibitor for Crohn's disease are also promising. This could herald the first success for a chemokine receptor antagonist as an anti-inflammatory therapeutic and confirms the importance of chemokine receptors as a target class for anti-inflammatory and autoimmune diseases.

Reinforcing the membrane-mediated mechanism of action of the anti-tuberculosis candidate drug thioridazine with molecular simulations

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Kopec, Wojciech; Khandelia, Himanshu

2014-01-01

Thioridazine is a well-known dopamine-antagonist drug with a wide range of pharmacological properties ranging from neuroleptic to antimicrobial and even anticancer activity. Thioridazine is a critical component of a promising multi-drug therapy against M. tuberculosis. Amongst the various propose......-membrane interactions, and reinforce the wider, emerging view of action of many small, bioactive compounds....... mechanisms of action, the cell membrane-mediated one is peculiarly tempting due to the distinctive feature of phenothiazine drug family to accumulate in selected body tissues. In this study, we employ long-scale molecular dynamics simulations to investigate the interactions of three different concentrations...

"Hyperglutamatergic cortico-striato-thalamo-cortical circuit" breaker drugs alleviate tics in a transgenic circuit model of Tourette׳s syndrome.

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Nordstrom, Eric J; Bittner, Katie C; McGrath, Michael J; Parks, Clinton R; Burton, Frank H

2015-12-10

The brain circuits underlying tics in Tourette׳s syndrome (TS) are unknown but thought to involve cortico/amygdalo-striato-thalamo-cortical (CSTC) loop hyperactivity. We previously engineered a transgenic mouse "circuit model" of TS by expressing an artificial neuropotentiating transgene (encoding the cAMP-elevating, intracellular A1 subunit of cholera toxin) within a small population of dopamine D1 receptor-expressing somatosensory cortical and limbic neurons that hyperactivate cortico/amygdalostriatal glutamatergic output circuits thought to be hyperactive in TS and comorbid obsessive-compulsive (OC) disorders. As in TS, these D1CT-7 ("Ticcy") transgenic mice׳s tics were alleviated by the TS drugs clonidine and dopamine D2 receptor antagonists; and their chronic glutamate-excited striatal motor output was unbalanced toward hyperactivity of the motoric direct pathway and inactivity of the cataleptic indirect pathway. Here we have examined whether these mice׳s tics are countered by drugs that "break" sequential elements of their hyperactive cortical/amygdalar glutamatergic and efferent striatal circuit: anti-serotonoceptive and anti-noradrenoceptive corticostriatal glutamate output blockers (the serotonin 5-HT2a,c receptor antagonist ritanserin and the NE alpha-1 receptor antagonist prazosin); agmatinergic striatothalamic GABA output blockers (the presynaptic agmatine/imidazoline I1 receptor agonist moxonidine); and nigrostriatal dopamine output blockers (the presynaptic D2 receptor agonist bromocriptine). Each drug class alleviates tics in the Ticcy mice, suggesting a hyperglutamatergic CSTC "tic circuit" could exist in TS wherein cortical/amygdalar pyramidal projection neurons׳ glutamatergic overexcitation of both striatal output neurons and nigrostriatal dopaminergic modulatory neurons unbalances their circuit integration to excite striatothalamic output and create tics, and illuminating new TS drug strategies. Copyright © 2015 The Authors. Published by

Sepsis Strengthens Antagonistic Actions of Neostigmine on Rocuronium in a Rat Model of Cecal Ligation and Puncture

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Wu, Jin; Jin, Tian; Wang, Hong; Li, Shi-Tong

2016-01-01

Background: The antagonistic actions of anticholinesterase drugs on non-depolarizing muscle relaxants are theoretically related to the activity of acetylcholinesterase (AChE) in the neuromuscular junction (NMJ). However, till date the changes of AChE activity in the NMJ during sepsis have not been directly investigated. We aimed to investigate the effects of sepsis on the antagonistic actions of neostigmine on rocuronium (Roc) and the underlying changes of AChE activity in the NMJ in a rat model of cecal ligation and puncture (CLP). Methods: A total of 28 male adult Sprague-Dawley rats were randomized to undergo a sham surgery (the sham group, n = 12) or CLP (the septic group, n = 16). After 24 h, the time-response curves of the antagonistic actions of 0.1 or 0.5 μmol/L of neostigmine on Roc (10 μmol/L)-depressed diaphragm twitch tension were measured. Meanwhile, the activity of AChE in the NMJ was detected using a modified Karnovsky and Roots method. The mRNA levels of the primary transcript and the type T transcript of AChE (AChET) in the diaphragm were determined by real-time reverse transcription-polymerase chain reaction. Results: Four of 16 rats in the septic group died within 24 h. The time-response curves of both two concentrations of neostigmine in the septic group showed significant upward shifts from those in the sham group (P < 0.001 for 0.1 μmol/L; P = 0.009 for 0.5 μmol/L). Meanwhile, the average optical density of AChE in the NMJ in the septic group was significantly lower than that in the sham group (0.517 ± 0.045 vs. 1.047 ± 0.087, P < 0.001). The AChE and AChET mRNA expression levels in the septic group were significantly lower than those in the sham group (P = 0.002 for AChE; P = 0.001 for AChET). Conclusions: Sepsis strengthened the antagonistic actions of neostigmine on Roc-depressed twitch tension of the diaphragm by inhibiting the activity of AChE in the NMJ. The reduced content of AChE might be one of the possible causes of the

Phosphatase Inhibitors Function as Novel, Broad Spectrum Botulinum Neurotoxin Antagonists in Mouse and Human Embryonic Stem Cell-Derived Motor Neuron-Based Assays.

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Erkan Kiris

Full Text Available There is an urgent need to develop novel treatments to counter Botulinum neurotoxin (BoNT poisoning. Currently, the majority of BoNT drug development efforts focus on directly inhibiting the proteolytic components of BoNT, i.e. light chains (LC. Although this is a rational approach, previous research has shown that LCs are extremely difficult drug targets and that inhibiting multi-serotype BoNTs with a single LC inhibitor may not be feasible. An alternative approach would target neuronal pathways involved in intoxication/recovery, rather than the LC itself. Phosphorylation-related mechanisms have been implicated in the intoxication pathway(s of BoNTs. However, the effects of phosphatase inhibitors upon BoNT activity in the physiological target of BoNTs, i.e. motor neurons, have not been investigated. In this study, a small library of phosphatase inhibitors was screened for BoNT antagonism in the context of mouse embryonic stem cell-derived motor neurons (ES-MNs. Four inhibitors were found to function as BoNT/A antagonists. Subsequently, we confirmed that these inhibitors protect against BoNT/A in a dose-dependent manner in human ES-MNs. Additionally, these compounds provide protection when administered in post-intoxication scenario. Importantly, the inhibitors were also effective against BoNT serotypes B and E. To the best of our knowledge, this is the first study showing phosphatase inhibitors as broad-spectrum BoNT antagonists.

Effects of some dopamine antagonists on spatial memory performance in rats--experimental research.

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Rusu, Gabriela; Popa, Gratiela; Ochiuz, Lacramioara; Nechifor, M; Tartau, Liliana

2014-01-01

Dopamine is a neurotransmitter with an important role in forming long-lasting memories for some time, especially in episodic memory. Literature data show that dopamine receptor stimulation may be detrimental to spatial working memory functions in lab animals. (R)-(+)-7-Chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride derivative--SCH-23390 is a synthetic compound that acts as a selective, high-affinity antagonist of D1 receptors. Experimental studies suggest that SCH 23390 may prevent the spatial working memory disturbances induced by the active substances of marijuana. Melperone is an atypic antipsychotic drug presenting also dopaminergic D2 and 5-HT2A receptor antagonistic activity. This neuroleptic agent is used in the treatment of some types of schizophrenia. Experimental research on the effects of two dopamine receptor antagonists on spatial memory performance in rats. The experiment was carried out in white Wistar rats (200-250g), divided into 3 groups of 7 animals each, treated intraperitoneally with the same volume of solution for 14 days, as follows: Group I (Control): saline solution 0.1 ml/10g kbw; Group II (coded SCH): SCH-23390 0.3 mg/kbw; Group III (coded MLP): melperone 2 mg/kbw. The dopaminergic agent spatial memory performance was assessed by recording spontaneous alternation behavior in a single session in Y-maze. Each animal was placed at the end of one arm and allowed to move freely through the maze during an 8 min session. Alternation was defined as a consecutive entry in three different arms. The alternation percentage was computed with the following formula: number of alternations divided by total number of arm visits minus 2. Data were presented as +/- standard deviation and significance was tested by SPSS Statistics for Windows version 13.0 and ANOVA method. P-values less than 0.05 were considered statistically significant compared to those in the control group. Experimental researches were carried out in

Cyclic degradation of antagonistic shape memory actuated structures

International Nuclear Information System (INIS)

Sofla, A Y N; Elzey, D M; Wadley, H N G

2008-01-01

Antagonistic shape memory actuated structures exploit opposing pairs of one-way shape memory alloy (SMA) linear actuators to create devices capable of a fully reversible response. Unlike many conventional reversible SMA devices they do not require bias force components (springs) to return them to their pre-actuated configuration. However, the repeated use of SMA antagonistic devices results in the accumulation of plastic strain in the actuators which can diminish their actuation stroke. We have investigated this phenomenon and the effect of shape memory alloy pre-strain upon it for near equi-atomic NiTi actuators. We find that the degradation eventually stabilizes during cycling. A thermomechanical treatment has been found to significantly reduce degradation in cyclic response of the actuators

Differential effects of antipsychotic and propsychotic drugs on prepulse inhibition and locomotor activity in Roman high- (RHA) and low-avoidance (RLA) rats

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Oliveras, Ignasi; Sánchez-González, Ana; Sampedro-Viana, Daniel

2017-01-01

acutely administered propsychotic (DOI, MK-801) and antipsychotic drugs (haloperidol, clozapine), as well as apomorphine, on prepulse inhibition (PPI) of startle and locomotor activity (activity cages). RESULTS: RHA-I rats display a consistent deficit of PPI compared with RLA-I rats. The typical...... antipsychotic haloperidol (dopamine D2 receptor antagonist) reversed the PPI deficit characteristic of RHA-I rats (in particular at 65 and 70 dB prepulse intensities) and reduced locomotion in both strains. The atypical antipsychotic clozapine (serotonin/dopamine receptor antagonist) did not affect PPI...

TRPV1: A Target for Rational Drug Design

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Vincenzo Carnevale

2016-08-01

Full Text Available Transient Receptor Potential Vanilloid 1 (TRPV1 is a non-selective, Ca2+ permeable cation channel activated by noxious heat, and chemical ligands, such as capsaicin and resiniferatoxin (RTX. Many compounds have been developed that either activate or inhibit TRPV1, but none of them are in routine clinical practice. This review will discuss the rationale for antagonists and agonists of TRPV1 for pain relief and other conditions, and strategies to develop new, better drugs to target this ion channel, using the newly available high-resolution structures.

Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

Energy Technology Data Exchange (ETDEWEB)

Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsuneyama, Koichi [Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Sugitani, Toyama 930‐0194 (Japan); Endo, Shinya [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Tsukui, Tohru [Research Center for Genomic Medicine, Saitama Medical University, Yamane, Hidaka 350‐1241 (Japan); Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan); Yokoi, Tsuyoshi, E-mail: tyokoi@p.kanazawa-u.ac.jp [Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920‐1192 (Japan)

2012-10-01

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

Mechanisms of the hepatoprotective effects of tamoxifen against drug-induced and chemical-induced acute liver injuries

International Nuclear Information System (INIS)

Yoshikawa, Yukitaka; Miyashita, Taishi; Higuchi, Satonori; Tsuneyama, Koichi; Endo, Shinya; Tsukui, Tohru; Toyoda, Yasuyuki; Fukami, Tatsuki; Nakajima, Miki; Yokoi, Tsuyoshi

2012-01-01

Although estrogen receptor (ER)α agonists, such as estradiol and ethinylestradiol (EE2), cause cholestasis in mice, they also reduce the degree of liver injury caused by hepatotoxicants as well as ischemia–reperfusion. The functional mechanisms of ERα have yet to be elucidated in drug-induced or chemical-induced liver injury. The present study investigated the effects of an ERα agonist, selective ER modulators (SERMs) and an ER antagonist on drug-induced and chemical-induced liver injuries caused by acetaminophen, bromobenzene, diclofenac, and thioacetamide (TA). We observed hepatoprotective effects of EE2, tamoxifen (TAM) and raloxifene pretreatment in female mice that were exposed to a variety of hepatotoxic compounds. In contrast, the ER antagonist did not show any hepatoprotective effects. DNA microarray analyses suggested that monocyte to macrophage differentiation-associated 2 (Mmd2) protein, which has an unknown function, is commonly increased by TAM and RAL pretreatment, but not by pretreatment with the ER antagonist. In ERα-knockout mice, the hepatoprotective effects of TAM and the increased expression of Mmd2 mRNA were not observed in TA-induced liver injury. To investigate the function of Mmd2, the expression level of Mmd2 mRNA was significantly knocked down to approximately 30% in mice by injection of siRNA for Mmd2 (siMmd2). Mmd2 knockdown resulted in a reduction of the protective effects of TAM on TA-induced liver injury in mice. This is the first report of the involvement of ERα in drug-induced or chemical-induced liver injury. Upregulation of Mmd2 protein in the liver was suggested as the mechanism of the hepatoprotective effects of EE2 and SERMs. -- Highlights: ► Liver injury induced by drugs or chemicals was investigated in mice. ► Liver injury was suppressed by pretreatment with tamoxifen in female mice. ► Mmd2, whose function was unknown, could be a candidate gene for liver protection. ► Tamoxifen up-regulated Mmd2 mRNA expression

Isolation, identification, and biocontrol of antagonistic bacterium against Botrytis cinerea after tomato harvest

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Jun-Feng Shi

Full Text Available ABSTRACT Tomato is one of the most important vegetables in the world. Decay after harvest is a major issue in the development of tomato industry. Currently, the most effective method for controlling decay after harvest is storage of tomato at low temperature combined with usage of chemical bactericide; however, long-term usage of chemical bactericide not only causes pathogen resistance but also is harmful for human health and environment. Biocontrol method for the management of disease after tomato harvest has great practical significance. In this study, antagonistic bacterium B-6-1 strain was isolated from the surface of tomato and identified as Enterobacter cowanii based on morphological characteristics and physiological and biochemical features combined with sequence analysis of 16SrDNA and ropB gene and construction of dendrogram. Effects of different concentrations of antagonistic bacterium E. cowanii suspension on antifungal activity after tomato harvest were analyzed by mycelium growth rate method. Results revealed that antifungal activity was also enhanced with increasing concentrations of antagonistic bacterium; inhibitory rates of 1 × 105 colony-forming units (cfu/mL antagonistic bacterial solution on Fusarium verticillioides, Alternaria tenuissima, and Botrytis cinerea were 46.31%, 67.48%, and 75.67%, respectively. By using in vivo inoculation method, it was further confirmed that antagonistic bacterium could effectively inhibit the occurrence of B. cinerae after tomato harvest, biocontrol effect of 1 × 109 cfu/mL zymotic fluid reached up to 95.24%, and antagonistic bacterium E. cowanii has biocontrol potential against B. cinerea after harvest of fruits and vegetables.

Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

International Nuclear Information System (INIS)

Waser, Beatrice; Reubi, Jean Claude

2014-01-01

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the 125 iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer 125 I-GLP-1(7-36)amide. Receptor autoradiography studies with 125 I-GLP-1(7-36)amide agonist or 125 I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist 125 I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer 125 I-GLP-1(7-36)amide. For comparison, 125 I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with 125 I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

Pellitorine, an extract of Tetradium daniellii, is an antagonist of the ion channel TRPV1.

Science.gov (United States)

Oláh, Zoltán; Rédei, Dóra; Pecze, László; Vizler, Csaba; Jósvay, Katalin; Forgó, Péter; Winter, Zoltán; Dombi, György; Szakonyi, Gerda; Hohmann, Judit

2017-10-15

Transient Receptor Potential Vanilloid 1 (TRPV1) confers noxious heat and inflammatory pain signals in the peripheral nervous system. Clinical trial of resiniferatoxin from Euphorbia species is successfully aimed at TRPV1 in cancer pain management and heading toward new selective painkiller status that further validates this target for drug discovery efforts. Evodia species, used in traditional medicine for hundreds of years, are a recognised source of different TRPV1 agonists, but no antagonist has yet been reported. In a search for painkiller leads, we noted for the first time a TRPV1 antagonist activity in the fresh fruits of Tetradium daniellii (Benn.) T.G. Hartley (syn. Evodia hupehensis Dode). Through a combination of extraction and purification methods with functional TRPV1-specific Ca 2+ uptake assays (bioactivity-guided fractionation/isolation/purification); we isolated a new painkiller candidate that is a distant structural homologue of capsiate exovanilloids and endovanilloids such as anandamide, but a putative competitive inhibitor of the TRPV1. Four additional inactive compounds (N-isobutyl-4,5-epoxy-2E-decadienamide, geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol) were also co-purified with pellitorine. Their structures were established by extensive 1D- and 2D-NMR spectroscopic analysis. 1 H- and 13 C NMR determination of the chemical structure revealed it to be pellitorine, (2E,4E)-N-(2-methylpropyl)deca-2,4-dienamide, which can compete structurally with algesics released in inflammation. In contrast to previous isolates from Evodia species, pellitorine blocked capsaicin-evoked Ca 2+ uptake with an IC 50 of 154 µg/ml (0.69 mM/l). N-Isobutyl-4,5-epoxy-2E-decadienamide and geranylpsoralen, 8-(7',8'-epoxygeranyloxy)psoralen, and xanthotoxol did not affect the TRPV1. This is the first evidence that pellitorine, an aliphatic alkylamide analogue of capsaicin, can serve as an antagonist of the TRPV1 and may inhibit exovanilloid

Survivin mRNA antagonists using locked nucleic acid, potential for molecular cancer therapy

DEFF Research Database (Denmark)

Fisker, Niels; Westergaard, Majken; Hansen, Henrik Frydenlund

2007-01-01

We have investigated the effects of different locked nucleic acid modified antisense mRNA antagonists against Survivin in a prostate cancer model. These mRNA antagonists were found to be potent inhibitors of Survivin expression at low nanomolar concentrations. Additionally there was a pronounced ...

From Chemotherapy-Induced Emesis to Neuroprotection: Therapeutic Opportunities for 5-HT3 Receptor Antagonists.

Science.gov (United States)

Fakhfouri, Gohar; Mousavizadeh, Kazem; Mehr, Sharam Ejtemaei; Dehpour, Ahmad Reza; Zirak, Mohammad Reza; Ghia, Jean-Eric; Rahimian, Reza

2015-12-01

5-HT3 receptor antagonists are extensively used as efficacious agents in counteracting chemotherapy-induced emesis. Recent investigations have shed light on other potential effects (analgesic, anxiolytic, and anti-psychotic). Some studies have reported neuroprotective properties for the 5-HT3 receptor antagonists in vitro and in vivo. When administered to Aβ-challenged rat cortical neurons, 5-HT3 receptor antagonists substantially abated apoptosis, elevation of cytosolic Ca(2), glutamate release, reactive oxygen species (ROS) generation, and caspase-3 activity. In addition, in vivo studies show that 5-HT3 receptor antagonists possess, alongside their anti-emetic effects, notable immunomodulatory properties in CNS. We found that pretreatment with tropisetron significantly improved neurological deficits and diminished leukocyte transmigration into the brain, TNF-α level, and brain infarction in a murine model of embolic stroke. Our recent investigation revealed that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and -independent pathways. Tropisetron, in vitro, was found to be an efficacious inhibitor of the signaling pathway leading to the activation of pro-inflammatory NF-κB, a transcription factor pivotal to the upregulation of several neuroinflammatory mediators in brain. This mini review summarizes novel evidence concerning effects of 5-HT3 antagonists and their possible mechanisms of action in ameliorating neurodegenerative diseases including Alzheimer, multiple sclerosis, and stroke. Further, we discuss some newly synthesized 5-HT3 receptor antagonists with dual properties of 5-HT3 receptor blockade/alpha-7 nicotinic receptor activator and their potential in management of memory impairment. Since 5-HT3 receptor antagonists possess a large therapeutic window, they can constitute a scaffold for design and synthesis of new neuroprotective medications.

Selective adenosine A2A receptor agonists and antagonists protect against spinal cord injury through peripheral and central effects

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Esposito Emanuela

2011-04-01

Full Text Available Abstract Background Permanent functional deficits following spinal cord injury (SCI arise both from mechanical injury and from secondary tissue reactions involving inflammation. Enhanced release of adenosine and glutamate soon after SCI represents a component in the sequelae that may be responsible for resulting functional deficits. The role of adenosine A2A receptor in central ischemia/trauma is still to be elucidated. In our previous studies we have demonstrated that the adenosine A2A receptor-selective agonist CGS21680, systemically administered after SCI, protects from tissue damage, locomotor dysfunction and different inflammatory readouts. In this work we studied the effect of the adenosine A2A receptor antagonist SCH58261, systemically administered after SCI, on the same parameters. We investigated the hypothesis that the main action mechanism of agonists and antagonists is at peripheral or central sites. Methods Spinal trauma was induced by extradural compression of SC exposed via a four-level T5-T8 laminectomy in mouse. Three drug-dosing protocols were utilized: a short-term systemic administration by intraperitoneal injection, a chronic administration via osmotic minipump, and direct injection into the spinal cord. Results SCH58261, systemically administered (0.01 mg/kg intraperitoneal. 1, 6 and 10 hours after SCI, reduced demyelination and levels of TNF-α, Fas-L, PAR, Bax expression and activation of JNK mitogen-activated protein kinase (MAPK 24 hours after SCI. Chronic SCH58261 administration, by mini-osmotic pump delivery for 10 days, improved the neurological deficit up to 10 days after SCI. Adenosine A2A receptors are physiologically expressed in the spinal cord by astrocytes, microglia and oligodendrocytes. Soon after SCI (24 hours, these receptors showed enhanced expression in neurons. Both the A2A agonist and antagonist, administered intraperitoneally, reduced expression of the A2A receptor, ruling out the possibility that the

CCR5 receptor antagonists: discovery and SAR study of guanylhydrazone derivatives.

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Wei, Robert G; Arnaiz, Damian O; Chou, Yuo-Ling; Davey, Dave; Dunning, Laura; Lee, Wheeseong; Lu, Shou-Fu; Onuffer, James; Ye, Bin; Phillips, Gary

2007-01-01

High throughput screening (HTS) led to the identification of the guanylhydrazone of 2-(4-chlorobenzyloxy)-5-bromobenzaldehyde as a CCR5 receptor antagonist. Initial modifications of the guanylhydrazone series indicated that substitution of the benzyl group at the para-position was well tolerated. Substitution at the 5-position of the central phenyl ring was critical for potency. Replacement of the guanylhydrazone group led to the discovery of a novel series of CCR5 antagonists.

Opioid analgesics as noncompetitive N-methyl-D-aspartate (NMDA) antagonists

DEFF Research Database (Denmark)

Ebert, B; Thorkildsen, C; Andersen, S

1998-01-01

Much evidence points to the involvement of N-methyl-D-aspartate (NMDA) receptors in the development and maintainance of neuropathic pain. In neuropathic pain, there is generally involved a presumed opioid-insensitive component, which apparently can be blocked by NMDA receptor antagonists. However...... for the NMDA receptor antagonism of these compounds and its relevance for clinical pain treatment; an overview of structure-activity relationships for the relevant opioids as noncompetitive NMDA receptor antagonists also is given. It is concluded that although the finding that some opioids are weak...

Drug therapy in patients with Parkinson’s disease

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Müller Thomas

2012-05-01

Full Text Available Abstract Parkinson`s disease (PD is a progressive, disabling neurodegenerative disorder with onset of motor and non-motor features. Both reduce quality of life of PD patients and cause caregiver burden. This review aims to provide a survey of possible therapeutic options for treatment of motor and non motor symptoms of PD and to discuss their relation to each other. MAO-B-Inhibitors, NMDA antagonists, dopamine agonists and levodopa with its various application modes mainly improve the dopamine associated motor symptoms in PD. This armentarium of PD drugs only partially influences the onset and occurrence of non motor symptoms. These PD features predominantly result from non dopaminergic neurodegeneration. Autonomic features, such as seborrhea, hyperhidrosis, orthostatic syndrome, salivation, bladder dysfunction, gastrointestinal disturbances, and neuropsychiatric symptoms, such as depression, sleep disorders, psychosis, cognitive dysfunction with impaired execution and impulse control may appear. Drug therapy of these non motor symptoms complicates long-term PD drug therapy due to possible occurrence of drug interactions, - side effects, and altered pharmacokinetic behaviour of applied compounds. Dopamine substituting compounds themselves may contribute to onset of these non motor symptoms. This complicates the differentiation from the disease process itself and influences therapeutic options, which are often limited because of additional morbidity with necessary concomitant drug therapy.

Antagonistic properties of microogranisms associated with cassava ...

African Journals Online (AJOL)

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

Acute Liver Failure from Tumor Necrosis Factor-α Antagonists: Report of Four Cases and Literature Review.

Science.gov (United States)

Kok, Beverley; Lester, Erica L W; Lee, William M; Hanje, A James; Stravitz, R Todd; Girgis, Safwat; Patel, Vaishali; Peck, Joshua R; Esber, Christopher; Karvellas, Constantine J

2018-03-21

Tumor necrosis factor-α antagonists (anti-TNF-α) have been associated with drug-induced liver injury. However, cases of anti-TNF-α-associated acute liver failure have only been rarely reported. To identify cases of anti-TNF-α-associated acute liver failure and evaluate patterns of liver injury and common characteristics to the cases. The United States Acute Liver Failure Study Group database was searched from 1998 to 2014. Four subjects were identified. A PubMed search for articles that reported anti-TNF-α-associated acute liver failure identified five additional cases. The majority of individuals affected were female (eight of nine cases). Age of individual ranged from 20 to 53 years. The most common anti-TNF-α agent associated with acute liver failure was infliximab (n = 8). The latency between initial drug exposure and acute liver failure ranged from 3 days to over a year. Of the nine cases, six required emergency LT. Liver biopsy was obtained in seven cases with a preponderance toward cholestatic-hepatitic features; none showed clear autoimmune features. Anti-TNF-α-associated acute liver failure displays somewhat different characteristics compared with anti-TNF-α-induced drug-induced liver injury. Infliximab was implicated in the majority of cases. Cholestatic-hepatitic features were frequently found on pre-transplant and explant histology.

The pre-ischaemic neuroprotective effect of a novel polyamine antagonist, N1-dansyl-spermine in a permanent focal cerebral ischaemia model in mice.

Science.gov (United States)

Li, Jun; Henman, Martin C; Doyle, Karen M; Strbian, Daniel; Kirby, Brian P; Tatlisumak, Turgut; Shaw, Graham G

2004-12-10

The polyamine sites on the NMDA receptor complex offer a therapeutic target for focal ischaemia, potentially devoid of most side effects associated with NMDA antagonists. In this study, we investigated the effect of a novel polyamine antagonist, N(1)-dansyl-spermine (0.5-10 mg kg(-1)) in a permanent focal cerebral ischaemia model in mice, and compared its effect to that of MK-801 (0.3-3 mg kg(-1)) following administration 30 min prior to ischaemia. A battery of histological and behavioural tests was employed following permanent middle cerebral artery occlusion to assess any neuroprotective effect. Following middle cerebral artery occlusion, N(1)-dansyl-spermine (1-5 mg kg(-1)) and MK-801 (1 or 3 mg kg(-1)) caused a comparable and significant reduction in the percentage hemisphere lesion volume. Similarly, both drugs significantly reduced oedema and neurological deficit score to a similar extent. Locomotor activity in MCAO mice was not significantly improved by MK-801 or N(1)-dansyl-spermine, although N(1)-dansyl-spermine induced a trend towards significant improvement. Significant improvement in rotarod performance was observed at neuroprotective doses with both drugs. Upon comparison of the profile of effects, N(1)-dansyl-spermine at least matched the effectiveness of MK-801 as a neuroprotective agent in this model. In addition, in sham-operated control mice, N(1)-dansyl-spermine was well tolerated, in contrast to the pronounced adverse effects of MK-801 on locomotor activity and rotarod performance. In conclusion, this study has shown that N(1)-dansyl-spermine is as effective a neuroprotective drug as MK-801 in this model. Moreover, in contrast to MK-801, N(1)-dansyl-spermine could be a promising therapeutic candidate for stroke as it is well tolerated at neuroprotective doses in sham-operated animals.

Activity of oxantel pamoate monotherapy and combination chemotherapy against Trichuris muris and hookworms: revival of an old drug.

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Jennifer Keiser

Full Text Available BACKGROUND: It is widely recognized that only a handful of drugs are available against soil-transmitted helminthiasis, all of which are characterized by a low efficacy against Trichuris trichiura, when administered as single doses. The re-evaluation of old, forgotten drugs is a promising strategy to identify alternative anthelminthic drug candidates or drug combinations. METHODOLOGY: We studied the activity of the veterinary drug oxantel pamoate against Trichuris muris, Ancylostoma ceylanicum and Necator americanus in vitro and in vivo. In addition, the dose-effect of oxantel pamoate combined with albendazole, mebendazole, levamisole, pyrantel pamoate and ivermectin was studied against T. muris in vitro and additive or synergistic combinations were followed up in vivo. PRINCIPAL FINDINGS: We calculated an ED50 of 4.7 mg/kg for oxantel pamoate against T. muris in mice. Combinations of oxantel pamoate with pyrantel pamoate behaved antagonistically in vitro (combination index (CI = 2.53. Oxantel pamoate combined with levamisole, albendazole or ivermectin using ratios based on their ED50s revealed antagonistic effects in vivo (CI = 1.27, 1.90 and 1.27, respectively. A highly synergistic effect (CI = 0.15 was observed when oxantel pamoate-mebendazole was administered to T. muris-infected mice. Oxantel pamoate (10 mg/kg lacked activity against Ancylostoma ceylanicum and Necator americanus in vivo. CONCLUSION/SIGNIFICANCE: Our study confirms the excellent trichuricidal properties of oxantel pamoate. Since the drug lacks activity against hookworms it is necessary to combine oxantel pamoate with a partner drug with anti-hookworm properties. Synergistic effects were observed for oxantel pamoate-mebendazole, hence this combination should be studied in more detail. Since, of the standard drugs, albendazole has the highest efficacy against hookworms, additional investigations on the combination effect of oxantel pamoate-albendazole should be

[Assessment of anti-tremorogenic drugs--nicotine-induced tail-tremor model].

Science.gov (United States)

Suemaru, K; Kawasaki, H; Gomita, Y

1997-06-01

The repeated administration of nicotine at small doses, which do not produce whole body tremor or convulsion, causes tremor only in the tail (tail-tremor) of rats. The tremor is accompanied by locomotor hyperactivity without rigidity and immobility of the whole body, suggesting that the nicotine-induced tail-tremor model is useful for studying the mechanism underlying tremor associated with movement. The tail-tremor induced by nicotine was suppressed by mecamylamine, a nicotinic antagonist, but not by atropine or scopolamine, muscalinic antagonists. Moreover, the tail-tremor was suppressed by the beta-blockers propranolol and pindolol, as well as the benzodiazepines diazepam and clonazepam. Tremor at rest is observed only in Parkinson's disease, which is improved with anti-muscalinic drugs. Essential tremor is one of the typical tremors connected with movement (postural and kinetic tremor) and is improved with beta-blocker. These findings and results suggest that nicotine-induced tail-tremor is useful for the study of essential tremor in animal models.

Radiolabelled GLP-1 receptor antagonist binds to GLP-1 receptor-expressing human tissues

Energy Technology Data Exchange (ETDEWEB)

Waser, Beatrice; Reubi, Jean Claude [University of Berne, Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, PO Box 62, Berne (Switzerland)

2014-06-15

Radiolabelled glucagon-like peptide 1 (GLP-1) receptor agonists have recently been shown to successfully image benign insulinomas in patients. For the somatostatin receptor targeting of tumours, however, it was recently reported that antagonist tracers were superior to agonist tracers. The present study therefore evaluated various forms of the {sup 125}iodinated-Bolton-Hunter (BH)-exendin(9-39) antagonist tracer for the in vitro visualization of GLP-1 receptor-expressing tissues in rats and humans and compared it with the agonist tracer {sup 125}I-GLP-1(7-36)amide. Receptor autoradiography studies with {sup 125}I-GLP-1(7-36)amide agonist or {sup 125}I-BH-exendin(9-39) antagonist radioligands were performed in human and rat tissues. The antagonist {sup 125}I-BH-exendin(9-39) labelled at lysine 19 identifies all human and rat GLP-1 target tissues and GLP-1 receptor-expressing tumours. Binding is of high affinity and is comparable in all tested tissues in its binding properties with the agonist tracer {sup 125}I-GLP-1(7-36)amide. For comparison, {sup 125}I-BH-exendin(9-39) with the BH labelled at lysine 4 did identify the GLP-1 receptor in rat tissues but not in human tissues. The GLP-1 receptor antagonist exendin(9-39) labelled with {sup 125}I-BH at lysine 19 is an excellent GLP-1 radioligand that identifies human and rat GLP-1 receptors in normal and tumoural tissues. It may therefore be the molecular basis to develop suitable GLP-1 receptor antagonist radioligands for in vivo imaging of GLP-1 receptor-expressing tissues in patients. (orig.)

Anti-idiotypic antibody: A new strategy for the development of a growth hormone receptor antagonist.

Science.gov (United States)

Lan, Hainan; Zheng, Xin; Khan, Muhammad Akram; Li, Steven

2015-11-01

In general, traditional growth hormone receptor antagonist can be divided into two major classes: growth hormone (GH) analogues and anti-growth hormone receptor (GHR) antibodies. Herein, we tried to explore a new class of growth hormone receptor (GHR) antagonist that may have potential advantages over the traditional antagonists. For this, we developed a monoclonal anti-idiotypic antibody growth hormone, termed CG-86. A series of experiments were conducted to characterize and evaluate this antibody, and the results from a competitive receptor-binding assay, Enzyme Linked Immunosorbent Assays (ELISA) and epitope mapping demonstrate that CG-86 behaved as a typical Ab2β. Next, we examined its antagonistic activity using in vitro cell models, and the results showed that CG-86 could effectively inhibit growth hormone receptor-mediated signalling and effectively inhibit growth hormone-induced Ba/F3-GHR638 proliferation. In summary, these studies show that an anti-idiotypic antibody (CG-86) has promise as a novel growth hormone receptor antagonist. Furthermore, the current findings also suggest that anti-idiotypic antibody may represent a novel strategy to produce a new class of growth hormone receptor antagonist, and this strategy may be applied with other cytokines or growth factors. Copyright © 2015 Elsevier Ltd. All rights reserved.

Clinically important drug interactions with zopiclone, zolpidem and zaleplon.

Science.gov (United States)

Hesse, Leah M; von Moltke, Lisa L; Greenblatt, David J

2003-01-01

Insomnia, an inability to initiate or maintain sleep, affects approximately one-third of the American population. Conventional benzodiazepines, such as triazolam and midazolam, were the treatment of choice for short-term insomnia for many years but are associated with adverse effects such as rebound insomnia, withdrawal and dependency. The newer hypnosedatives include zolpidem, zaleplon and zopiclone. These agents may be preferred over conventional benzodiazepines to treat short-term insomnia because they may be less likely to cause significant rebound insomnia or tolerance and are as efficacious as the conventional benzodiazepines. This review aims to summarise the published clinical drug interaction studies involving zolpidem, zaleplon and zopiclone. The pharmacokinetic and pharmacodynamic interactions that may be clinically important are highlighted. Clinical trials have studied potential interactions of zaleplon, zolpidem and zopiclone with the following types of drugs: cytochrome P450 (CYP) inducers (rifampicin), CYP inhibitors (azoles, ritonavir and erythromycin), histamine H(2) receptor antagonists (cimetidine and ranitidine), antidepressants, antipsychotics, antagonists of benzodiazepines and drugs causing sedation. Rifampicin significantly induced the metabolism of the newer hypnosedatives and decreased their sedative effects, indicating that a dose increase of these agents may be necessary when they are administered with rifampicin. Ketoconazole, erythromycin and cimetidine inhibited the metabolism of the newer hypnosedatives and enhanced their sedative effects, suggesting that a dose reduction may be required. Addition of ethanol to treatment with the newer hypnosedatives resulted in additive sedative effects without altering the pharmacokinetic parameters of the drugs. Compared with some of the conventional benzodiazepines, fewer clinically important interactions appear to have been reported in the literature with zaleplon, zolpidem and zopiclone. The

Komplikationer til langtidsbehandling med vitamin K-antagonister

DEFF Research Database (Denmark)

May, O; Garne, E; Mickley, H

1990-01-01

Long-term treatment with vitamin K antagonists (vKA) frequently involves complications. The commonest complication is haemorrhage and cases of serious haemorrhage are stated in the literature to occur with a frequency per 1,000 treatment years of 12-108, of which 2-17 are fatal. The majority...

Antagonist Anti-CD28 Therapeutics for the Treatment of Autoimmune Disorders

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Bernard Vanhove

2017-11-01

Full Text Available The effector functions of T lymphocytes are responsible for most autoimmune disorders and act by directly damaging tissues or by indirectly promoting inflammation and antibody responses. Co-stimulatory and co-inhibitory T cell receptor molecules are the primary pharmacological targets that enable interference with immune-mediated diseases. Among these, selective CD28 antagonists have drawn special interest, since they tip the co-stimulation/co-inhibition balance towards efficiently inhibiting effector T cells while promoting suppression by pre-existing regulatory T-cells. After having demonstrated outstanding therapeutic efficacy in multiple models of autoimmunity, inflammation and transplantation, and safety in phase-I studies in humans, selective CD28 antagonists are currently in early clinical development for the treatment of systemic lupus erythematous and rheumatoid arthritis. Here, we review the available proof of concept studies for CD28 antagonists in autoimmunity, with a special focus on the mechanisms of action.

Drug treatment of lower urinary tract symptoms in males. Role uroselectivity in the choice of drug

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Yu. G. Alyaev

2014-12-01

Full Text Available Most patients lower urinary tract symptoms (LUTS caused both mechanical and functional factors. Timely identification of the nature of urodynamics, primarily of bladder outlet obstruction and detrusor overactivity, in patients with benign prostatic hyperplasia is of practical importance, since without this factor significantly worse functional outcome of surgical treatment. α1-adrenoblockers are the first line therapy for men with bothersome LUTS. They should be offered to patients with moderate to severe LUTS. Choosing α1-adrenoblocker should lean toward more selective class representatives. Selectivity α1-adrenoblocker provides high efficiency along with a low percentage of adverse effects, especially for cardiovascular system.As well as α-adrenoblockers, M-cholinobloсkers varying degrees of selectivity of the impact is on the bladder. Solifenacin is more selective for the bladder than tolterodine and oxybutynin. The selectivity of the drug with respect to the bladder is reflected in the relatively low frequency of adverse effects, especially occurrence of dry mouth in its application, as well as the possibility of long term therapy. Combined treatment with α1-adrenoreceptor antagonist with M-cholinergic antagonists may be considered in patients with moderate to severe LUTS with a predominance of filling symptoms, especially if monotherapy led to relief of symptoms.

Human trabecular meshwork cells express BMP antagonist mRNAs and proteins.

Science.gov (United States)

Tovar-Vidales, Tara; Fitzgerald, Ashley M; Clark, Abbot F

2016-06-01

Glaucoma patients have elevated aqueous humor and trabecular meshwork (TM) levels of transforming growth factor-beta2 (TGF-β2). TGF-β2 has been associated with increased extracellular matrix (ECM) deposition (i.e. fibronectin), which is attributed to the increased resistance of aqueous humor outflow through the TM. We have previously demonstrated that bone morphogenetic protein (BMP) 4 selectively counteracts the profibrotic effect of TGF-β2 with respect to ECM synthesis in the TM, and this action is reversed by the BMP antagonist gremlin. Thus, the BMP and TGF-β signaling pathways antagonize each other's antifibrotic and profibrotic roles. The purpose of this study was to determine whether cultured human TM cells: (a) express other BMP antagonists including noggin, chordin, BMPER, BAMBI, Smurf1 and 2, and (b) whether expression of these proteins is regulated by exogenous TGF-β2 treatment. Primary human trabecular meshwork (TM) cells were grown to confluency and treated with TGF-β2 (5 ng/ml) for 24 or 48 h in serum-free medium. Untreated cell served as controls. qPCR and Western immunoblots (WB) determined that human TM cells expressed mRNAs and proteins for the BMP antagonist proteins: noggin, chordin, BMPER, BAMBI, and Smurf1/2. Exogenous TGF-β2 decreased chordin, BMPER, BAMBI, and Smurf1 mRNA and protein expression. In contrast, TGF-β2 increased secreted noggin and Smurf2 mRNA and protein levels. BMP antagonist members are expressed in the human TM. These molecules may be involved in the normal function of the TM as well as TM pathogenesis. Altered expression of BMP antagonist members may lead to functional changes in the human TM. Copyright © 2016 Elsevier Ltd. All rights reserved.

Structure-based drug design for G protein-coupled receptors.

Science.gov (United States)

Congreve, Miles; Dias, João M; Marshall, Fiona H

2014-01-01

Our understanding of the structural biology of G protein-coupled receptors has undergone a transformation over the past 5 years. New protein-ligand complexes are described almost monthly in high profile journals. Appreciation of how small molecules and natural ligands bind to their receptors has the potential to impact enormously how medicinal chemists approach this major class of receptor targets. An outline of the key topics in this field and some recent examples of structure- and fragment-based drug design are described. A table is presented with example views of each G protein-coupled receptor for which there is a published X-ray structure, including interactions with small molecule antagonists, partial and full agonists. The possible implications of these new data for drug design are discussed. © 2014 Elsevier B.V. All rights reserved.

Antagonism of presynaptic dopamine receptors by phenothiazine drug metabolites

International Nuclear Information System (INIS)

Nowak, J.Z.; Arbilla, S.; Langer, S.Z.; Dahl, S.G.

1990-01-01

Electrically evoked release of dopamine from the caudate nucleus is reduced by the dopamine receptor agonists, apomorphine and bromocriptine, and facilitated by neuroleptic drugs, which act as dopamine autoreceptor antagonists. The potencies of chlorpromazine, fluphenazine, levomepromazine and their hydroxy-metabolites in modulating electrically evoked release of dopamine were examined by superfusion of rabbit caudate nucleus slices pre-incubated with 3 H-dopamine. O-Desmethyl levomepromazine, 3-hydroxy- and 7-hydroxy metabolites of chlorpromazine and levomepromazine facilitated electrically evoked release of 3 H-dopamine, having potencies similar to that of the parent compounds. 7-Hydroxy fluphenazine was less active than fluphenazine in this system. These results indicate that phenolic metabolites of chlorpromazine and levomepromazine, but not of fluphenazine, may contribute to effects of the drugs mediated by presynaptic dopamine receptors

Development of specific dopamine D-1 agonists and antagonists

International Nuclear Information System (INIS)

Sakolchai, S.

1987-01-01

To develop potentially selective dopamine D-1 agonists and to investigate on the structural requirement for D-1 activity, the derivatives of dibenzocycloheptadiene are synthesized and pharmacologically evaluated. The target compounds are 5-aminomethyl-10,11-dihydro-1,2-dihydroxy-5H-dibenzo[a,d]cycloheptene hydrobromide 10 and 9,10-dihydroxy-1,2,3,7,8,12b-hexahydrobenzo[1,2]cyclohepta[3,4,5d,e]isoquinoline hydrobromide 11. In a dopamine-sensitive rat retinal adenylate cyclase assay, a model for D-1 activity, compound 10 is essentially inert for both agonist and antagonist activity. In contrast, compound 11 is approximately equipotent to dopamine in activation of the D-1 receptor. Based on radioligand and binding data, IC 50 of compound 11 for displacement of 3 H-SCH 23390, a D-1 ligand, is about 7 fold less than that for displacement of 3 H-spiperone, a D-2 ligand. These data indicate that compound 11 is a potent selective dopamine D-1 agonist. This study provides a new structural class of dopamine D-1 acting agent: dihydroxy-benzocycloheptadiene analog which can serve as a lead compound for further drug development and as a probe for investigation on the nature of dopamine D-1 receptor

Selective delivery of interleukine-1 receptor antagonist to inflamed joint by albumin fusion

Directory of Open Access Journals (Sweden)

Liu Mengyuan

2012-09-01

Full Text Available Abstract Background Interleukin-1 receptor antagonist, a cytokine that is highly therapeutic to rheumatoid arthritis and several other inflammatory diseases, exhibits rapid blood clearance and poor retention time on the target in clinical application due to its small size and lack of specificity to target tissue. Albumin has been widely employed as macromolecular carrier for drug delivery purpose to extend the plasma half-life of therapeutic molecules and has been shown to selectively accumulate and to be metabolized in the inflamed joints of patients with rheumatoid arthritis. This suggests that genetic fusion of IL-1ra to albumin can probably overcome the drawbacks of in vivo application of IL-1ra. Result A recombinant protein, engineered by fusing human serum albumin (HSA to the carboxyl terminal of IL-1ra, was produced in Pichia pastoris and purified to homogeneity. The fusion protein retained the antagonist activity of IL-1ra and had a plasma half-life of approximately 30-fold more than that of IL-1ra in healthy mice. In vivo bio-distribution studies demonstrated that the fusion protein selectively accumulated in arthritic paws for a long period of time in mice with collagen-induced arthritis, showing low uptake rates in normal organs such as liver, kidney, spleen and lung in contrast to IL-1ra alone. Moreover, this fusion protein was able to significantly improve the therapeutic efficacy of IL-1ra in collagen-induced arthritis mouse model. Conclusions The fusion protein described here, able to selectively deliver IL-1ra to inflamed tissue, could yield important contributions for the therapy of rheumatoid arthritis and other inflammatory diseases.

Drug development for neurodevelopmental disorders

DEFF Research Database (Denmark)

Berry-Kravis, Elizabeth M; Lindemann, Lothar; Jønch, Aia E

2018-01-01

Neurodevelopmental disorders such as fragile X syndrome (FXS) result in lifelong cognitive and behavioural deficits and represent a major public health burden. FXS is the most frequent monogenic form of intellectual disability and autism, and the underlying pathophysiology linked to its causal ge......, FMR1, has been the focus of intense research. Key alterations in synaptic function thought to underlie this neurodevelopmental disorder have been characterized and rescued in animal models of FXS using genetic and pharmacological approaches. These robust preclinical findings have led...... to the implementation of the most comprehensive drug development programme undertaken thus far for a genetically defined neurodevelopmental disorder, including phase IIb trials of metabotropic glutamate receptor 5 (mGluR5) antagonists and a phase III trial of a GABAB receptor agonist. However, none of the trials has...... been able to unambiguously demonstrate efficacy, and they have also highlighted the extent of the knowledge gaps in drug development for FXS and other neurodevelopmental disorders. In this Review, we examine potential issues in the previous studies and future directions for preclinical and clinical...

Monepantel is a non-competitive antagonist of nicotinic acetylcholine receptors from Ascaris suum and Oesophagostomum dentatum

Directory of Open Access Journals (Sweden)

Melanie Abongwa

2018-04-01

Full Text Available Zolvix® is a recently introduced anthelmintic drench containing monepantel as the active ingredient. Monepantel is a positive allosteric modulator of DEG-3/DES-2 type nicotinic acetylcholine receptors (nAChRs in several nematode species. The drug has been reported to produce hypercontraction of Caenorhabditis elegans and Haemonchus contortus somatic muscle. We investigated the effects of monepantel on nAChRs from Ascaris suum and Oesophagostomum dentatum heterologously expressed in Xenopus laevis oocytes. Using two-electrode voltage-clamp electrophysiology, we studied the effects of monepantel on a nicotine preferring homomeric nAChR subtype from A. suum comprising of ACR-16; a pyrantel/tribendimidine preferring heteromeric subtype from O. dentatum comprising UNC-29, UNC-38 and UNC-63 subunits; and a levamisole preferring subtype (O. dentatum comprising UNC-29, UNC-38, UNC-63 and ACR-8 subunits. For each subtype tested, monepantel applied in isolation produced no measurable currents thereby ruling out an agonist action. When monepantel was continuously applied, it reduced the amplitude of acetylcholine induced currents in a concentration-dependent manner. In all three subtypes, monepantel acted as a non-competitive antagonist on the expressed receptors. ACR-16 from A. suum was particularly sensitive to monepantel inhibition (IC50 values: 1.6 ± 3.1 nM and 0.2 ± 2.3 μM. We also investigated the effects of monepantel on muscle flaps isolated from adult A. suum. The drug did not significantly increase baseline tension when applied on its own. As with acetylcholine induced currents in the heterologously expressed receptors, contractions induced by acetylcholine were antagonized by monepantel. Further investigation revealed that the inhibition was a mixture of competitive and non-competitive antagonism. Our findings suggest that monepantel is active on multiple nAChR subtypes. Keywords: Monepantel, Zolvix®, Nicotinic acetylcholine

DESIGN AND DEVELOPMENT OF MUCOADHESIVE DRUG DELIVERY SYSTEM OF MONTELUKAST SODIUM

OpenAIRE

N. G. Raghavendra Rao; V. B. Suryakar

2011-01-01

The Montelukast sodium is a leukotrine receptor antagonist used for the maintenance treatment of asthma, chronic asthma attacks and to relieve symptoms of seasonal allergies. The biological half life of montelukast sodium is 2.5 to 5.5 hrs and poor bioavailability upto 64%. Because of poor bioavailability of montelukast sodium by oral route, there is a need to increase its bioavailability by formulating it into buccal dosage forms. Hence, montelukast sodium is a suitable drug for buccal dosa...

[Leukotriene antagonists: a new approach in the treatment of asthma].

Science.gov (United States)

Devillier, P; Bessard, G; Advenier, C

1997-06-01

Inflammation plays an essential role in the genesis of airflow obstruction and bronchial hyper-reactivity in the early stages of clinical asthma. The treatment of bronchial inflammation has become an essential element in the therapeutic strategy and principally rests on inhaled glucocorticoids. Amongst a number of inflammatory mediators leukotrienes occupy a privileged place by the power of their inflammatory and constrictor effects on bronchial smooth muscles. These properties have justified the clinical development of inhibitors of their synthesis and of specific antagonists to their receptors. Leukotriene antagonists are specific for a sub type of leukotriene receptors C4, D4 and E4 which is implicated in the majority of the bronchial constrictor and inflammatory effects of leukotrienes. The antagonists of Cys-LT1 receptor but also the inhibitors of the leukotriene synthesis exert an additive bronchodilator effect to those of B2 stimulants confirming an efficacious protection vis a vis bronchial provocation tests and above all they improve the clinical scores, lung function and also enable a decrease in the consumption of beta 2 agonists. The marketing of these products represents a major event because it corresponds to the advent of a new therapeutic class. The ease of administration by the oral route, their demonstrated efficacy and their good tolerance profile (in particular for ICI 204.219, and antagonists to Cys-LT1 receptors) are elements which foresee a success for this new asthmatic treatment. However numerous studies, notably comparative studies vis a vis reference treatments will be necessary to define their place in the strategic approach to the treatment of asthma.

Disease-modifying drugs in Alzheimer's disease

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Ghezzi L

2013-12-01

Full Text Available Laura Ghezzi, Elio Scarpini, Daniela Galimberti Neurology Unit, Department of Pathophysiology and Transplantation, University of Milan, Fondazione Cà Granda, IRCCS Ospedale Maggiore Policlinico, Milan, Italy Abstract: Alzheimer's disease (AD is an age-dependent neurodegenerative disorder and the most common cause of dementia. The early stages of AD are characterized by short-term memory loss. Once the disease progresses, patients experience difficulties in sense of direction, oral communication, calculation, ability to learn, and cognitive thinking. The median duration of the disease is 10 years. The pathology is characterized by deposition of amyloid beta peptide (so-called senile plaques and tau protein in the form of neurofibrillary tangles. Currently, two classes of drugs are licensed by the European Medicines Agency for the treatment of AD, ie, acetylcholinesterase inhibitors for mild to moderate AD, and memantine, an N-methyl-D-aspartate receptor antagonist, for moderate and severe AD. Treatment with acetylcholinesterase inhibitors or memantine aims at slowing progression and controlling symptoms, whereas drugs under development are intended to modify the pathologic steps leading to AD. Herein, we review the clinical features, pharmacologic properties, and cost-effectiveness of the available acetylcholinesterase inhibitors and memantine, and focus on disease-modifying drugs aiming to interfere with the amyloid beta peptide, including vaccination, passive immunization, and tau deposition. Keywords: Alzheimer's disease, acetylcholinesterase inhibitors, memantine, disease-modifying drugs, diagnosis, treatment

Long-lasting effect of NMDA receptor antagonist memantine on ethanol-cue association and relapse.

Science.gov (United States)

Vengeliene, Valentina; Olevska, Anastasia; Spanagel, Rainer

2015-12-01

It is well known that the glutamatergic system plays a crucial role in alcohol addiction and especially in relapse-like behaviour. However, results of clinical studies on compounds that influence the activity of the glutamatergic system have been disappointing so far. The aim of our study was to establish treatment conditions under which the N-methyl-d-aspartate receptor (NMDAR) antagonist memantine may produce more reliable treatment effect with respect to alcohol relapse-like behaviour. For this purpose, male Wistar rats were trained to associate several discrete stimuli with ethanol delivery. Thereafter, half of the animals received a brief memory reactivation session followed by two administrations of 20 mg/kg of memantine, while the other half received the same treatment without memory reactivation. Afterwards, a cue-induced ethanol-seeking behaviour test was performed followed by repeated extinction sessions and a reacquisition test. Our data show that administration of memantine reduced responding on the ethanol-associated lever in a cue-induced ethanol-seeking test. This reduction did not depend on whether or not a memory reactivation session was introduced prior to memantine administration. Following extinction, however, reacquisition of ethanol self-administration was only impaired in the group where memantine was given after a short memory reactivation session, showing that this schedule of drug administration produced a long-lasting disruption of the association between the conditioned stimuli and the delivery of ethanol. In conclusion, we show that memantine disrupted the drug-cue association, which consequently interfered with relapse-like behaviour supporting the possibility that memantine is a treatment option for alcoholism. Our data supports the possibility that memantine is a treatment option for alcoholism. However, the effectiveness of this drug seems to lie in its ability to disrupt conditioned behaviours and should be given in conjunction

Lifitegrast: First LFA-1/ICAM-1 antagonist for treatment of dry eye disease.

Science.gov (United States)

Paton, D M

2016-09-01

Dry eye disease is an extremely common condition affecting millions worldwide. The underlying pathophysiological mechanism is thought to be localized inflammation of the ocular surface resulting in the localization of T cells at this surface followed by their activation and subsequent liberation of cytokines. This effect on T cells results from the binding of lymphocyte function-associated antigen-1 (LFA-1) located on T cells to intercellular adhesion molecule 1 (ICAM-1) expressed on inflamed epithelium and endothelium, and on T cells. Lifitegrast is a T-cell integrin antagonist designed to mimic ICAM-1, thus blocking the interaction of LFA-1 and ICAM-1. Lifitegrast enters the systemic circulation to a limited extent thus reducing the likelihood of unwanted systemic reactions. Clinical trials in over 2,500 subjects with dry eye disease have shown that 5.0% lifitegrast given by ocular instillation causes a significant reduction in objective and subjective signs and symptoms of the disease. These beneficial effects are associated with a relatively low incidence of unwanted effects, almost all local in nature. In light of these findings, lifitegrast was approved by the Food and Drug Administration (FDA) in 2016 for the treatment of dry eye disease, the first drug with this mechanism of action to be so approved. Copyright 2016 Prous Science, S.A.U. or its licensors. All rights reserved.

Carbon adaptation influence the antagonistic ability of ...

African Journals Online (AJOL)

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

Twisted gastrulation, a BMP antagonist, exacerbates podocyte injury.

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Sachiko Yamada

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

Apoptosis and the FLIP and NF-kappa B proteins as pharmacodynamic criteria for biosimilar TNF-alpha antagonists

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Urbano PCM

2014-07-01

Full Text Available Paulo César Martins Urbano,1 Vanete Thomaz Soccol,1 Valderilio Feijó Azevedo2 1Biotechnology and Bioprocess Engineering Program, Federal University of Parana, Curitiba, Parana, Brazil; 2Hospital de Clínicas, Federal University of Parana, Curitiba, Parana, Brazil Abstract: Various criteria are necessary to assess the efficacy and safety of biological medications in order to grant companies the right to register these medications with the appropriate bodies that regulate their sale. The imminent expiration of the patents on reference biological products which block the cytokine TNF-α (tumor necrosis factor-α raises the possibility of bringing so-called biosimilars to the market (similar to the biologicals of reference products. This occurrence is inevitable, but criteria to adequately evaluate these medications are now needed. Even among controversy, there is a demand from publications correlating the pro-apoptotic mechanism of the original TNF-α antagonists (etanercept, infliximab, adalimumab, golimumab, and certolizumab pegol in the treatment of rheumatoid arthritis and other diseases. In this article, the authors discuss the possibility of utilizing the pro-apoptotic effect correlated with the regulation of the anti-apoptotic proteins FLIP and NF-κB as new criteria for analyzing the pharmacodynamics of possible biosimilar TNF-α antagonists which should be submitted to regulatory agencies for evaluation. Keywords: anti-TNF drugs, rheumatoid arthritis, apoptosis, NF-κB, FLIP

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

DEFF Research Database (Denmark)

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

2010-01-01

risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-gamma release assays or, as an alternative in individuals without...... a history of bacille Calmette-Guerin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...... and an interferon-gamma release assay, as there are insufficient data in children to recommend one test over the other. Consequently, targeted preventive chemotherapy is highly recommended for all individuals with persistent M. tuberculosis-specific immune responses undergoing TNF antagonist therapy...

SSTR-Mediated Imaging in Breast Cancer: Is There a Role for Radiolabeled Somatostatin Receptor Antagonists?

Science.gov (United States)

Dalm, Simone U; Haeck, Joost; Doeswijk, Gabriela N; de Blois, Erik; de Jong, Marion; van Deurzen, Carolien H M

2017-10-01

Recent studies have shown enhanced tumor targeting by novel somatostatin receptor (SSTR) antagonists compared with clinically widely used agonists. However, these results have been obtained mostly in neuroendocrine tumors, and only limited data are available for cancer types with lower SSTR expression, including breast cancer (BC). To date, two studies have reported higher binding of the antagonist than the agonist in BC, but in both studies only a limited number of cases were evaluated. In this preclinical study, we further investigated whether the application of an SSTR antagonist can improve SSTR-mediated BC imaging in a large panel of BC specimens. We also generated an in vivo BC mouse model and performed SPECT/MRI and biodistribution studies. Methods: Binding of 111 In-DOTA-Tyr 3 -octreotate (SSTR agonist) and 111 In-DOTA-JR11 (SSTR antagonist) to 40 human BC specimens was compared using in vitro autoradiography. SSTR2 immunostaining was performed to confirm SSTR2 expression of the tumor cells. Furthermore, binding of the radiolabeled SSTR agonist and antagonist was analyzed in tissue material from 6 patient-derived xenografts. One patient-derived xenograft, the estrogen receptor-positive model T126, was chosen to generate in vivo mouse models containing orthotopic breast tumors for in vivo SPECT/MRI and biodistribution studies after injection with 177 Lu-DOTA-Tyr 3 -octreotate or 177 Lu-DOTA-JR11. Results: 111 In-DOTA-JR11 binding to human BC tissue was significantly higher than 111 In-DOTA-Tyr 3 -octreotate binding ( P < 0.001). The median ratio of antagonist binding versus agonist binding was 3.39 (interquartile range, 2-5). SSTR2 immunostaining confirmed SSTR2 expression on the tumor cells. SPECT/MRI of the mouse model found better tumor visualization with the antagonist. This result was in line with the significantly higher tumor uptake of the radiolabeled antagonist than of the agonist as measured in biodistribution studies 285 min after radiotracer

In silico machine learning methods in drug development.

Science.gov (United States)

Dobchev, Dimitar A; Pillai, Girinath G; Karelson, Mati

2014-01-01

Machine learning (ML) computational methods for predicting compounds with pharmacological activity, specific pharmacodynamic and ADMET (absorption, distribution, metabolism, excretion and toxicity) properties are being increasingly applied in drug discovery and evaluation. Recently, machine learning techniques such as artificial neural networks, support vector machines and genetic programming have been explored for predicting inhibitors, antagonists, blockers, agonists, activators and substrates of proteins related to specific therapeutic targets. These methods are particularly useful for screening compound libraries of diverse chemical structures, "noisy" and high-dimensional data to complement QSAR methods, and in cases of unavailable receptor 3D structure to complement structure-based methods. A variety of studies have demonstrated the potential of machine-learning methods for predicting compounds as potential drug candidates. The present review is intended to give an overview of the strategies and current progress in using machine learning methods for drug design and the potential of the respective model development tools. We also regard a number of applications of the machine learning algorithms based on common classes of diseases.

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.

Discovery of tertiary sulfonamides as potent liver X receptor antagonists.

Science.gov (United States)

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

2010-04-22

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

Opioid antagonist naltrexone for the treatment of pathological gambling in Parkinson disease.

Science.gov (United States)

Bosco, Domenico; Plastino, Massimiliano; Colica, Carmela; Bosco, Francesca; Arianna, Spanò; Vecchio, Antonino; Galati, Francesco; Cristiano, Dario; Consoli, Arturo; Consoli, Domenico

2012-01-01

Pathological gambling (PG) is a potential complication related to the treatment of Parkinson disease (PD) with dopamine agonists (DA). The cause of this disorder is unknown, but altered dopamine neurotransmission may be involved. We evaluated the efficacy and tolerability of the opioid antagonist naltrexone in the treatment of PG in PD. Our cases included 3 patients with PD who developed PG after DA treatment. Pathological gambling did not improve after reduction or discontinuation of DA. These patients responded poorly to serotonin reuptake inhibitors, whereas treatment with opioid antagonist naltrexone resulted in the remission of PG. Naltrexone treatment was well tolerated. In one patient, higher dose of naltrexone resulted in hepatic abnormalities, which resolved after dosage reduction. The opioid antagonist naltrexone could be an effective option for the treatment of PG in PD.

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

Drugs in development for Parkinson's disease: an update.

Science.gov (United States)

Johnston, Tom H; Brotchie, Jonathan M

2006-01-01

The current development of emerging pharmacological treatments for Parkinson's disease (PD), front preclinical to launch, is summarized. Advances over the past year are highlighted, including the significant progress of several drugs through various stages of development. Several agents have been discontinued from development, either because of adverse effects or lack of clinical efficacy. The methyl-esterified form of L-DOPA (melevodopa) and the monoamine oxidase type B inhibitor rasagiline have both been launched. With regard to the monoamine re-uptake inhibitors, many changes have been witnessed, with new agents reaching preclinical development and pre-existing ones being discontinued or having no development reported. Of the dopamine agonists, many continue to progress successfully through clinical trials. Others have struggled to demonstrate a significant advantage over currently available treatments and have been discontinued. The field of non-dopaminergic treatments remains dynamic. The alpha2 adrenergic receptor antagonists and the adenosine A2A receptor antagonists remain in clinical trials. Trials of the neuronal' synchronization modulator levetiracetam are at an advanced stage, and there has also been a new addition to the class (ie, seletracetam). There has been a change in the landscape of neuroprotective agents that modulate disease progression. Candidates from the classes of growth factors and glyceraldehyde-3-phosphate dehydrogenase inhibitors have been discontinued, or no development has been reported, and the mixed lineage kinase inhibitor CEP-1347 has been discontinued for PD treatment. Other drugs in this field, such as neuroimmunophilins, estrogens and alpha-synuclein oligomerization inhibitors, remain in development.

Multistable wireless micro-actuator based on antagonistic pre-shaped double beams

International Nuclear Information System (INIS)

Liu, X; Lamarque, F; Doré, E; Pouille, P

2015-01-01

This paper presents a monolithic multistable micro-actuator based on antagonistic pre-shaped double beams. The designed micro-actuator is formed by two rows of bistable micro-actuators providing four stable positions. The bistable mechanism for each row is a pair of antagonistic pre-shaped beams. This bistable mechanism has an easier pre-load operation compared to the pre-compressed bistable beams method. Furthermore, it solves the asymmetrical force output problem of parallel pre-shaped bistable double beams. At the same time, the geometrical limit is lower than parallel pre-shaped bistable double beams, which ensures a smaller stroke of the micro-actuator with the same dimensions. The designed micro-actuator is fabricated using laser cutting machine on medium density fiberboard (MDF). The bistability and merits of antagonistic pre-shaped double beams are experimentally validated. Finally, a contactless actuation test is performed using 660 nm wavelength laser heating shape memory alloy (SMA) active elements. (paper)

Multistable wireless micro-actuator based on antagonistic pre-shaped double beams

Science.gov (United States)

Liu, X.; Lamarque, F.; Doré, E.; Pouille, P.

2015-07-01

This paper presents a monolithic multistable micro-actuator based on antagonistic pre-shaped double beams. The designed micro-actuator is formed by two rows of bistable micro-actuators providing four stable positions. The bistable mechanism for each row is a pair of antagonistic pre-shaped beams. This bistable mechanism has an easier pre-load operation compared to the pre-compressed bistable beams method. Furthermore, it solves the asymmetrical force output problem of parallel pre-shaped bistable double beams. At the same time, the geometrical limit is lower than parallel pre-shaped bistable double beams, which ensures a smaller stroke of the micro-actuator with the same dimensions. The designed micro-actuator is fabricated using laser cutting machine on medium density fiberboard (MDF). The bistability and merits of antagonistic pre-shaped double beams are experimentally validated. Finally, a contactless actuation test is performed using 660 nm wavelength laser heating shape memory alloy (SMA) active elements.

Synthesis and evaluation of calcium channel antagonist activity of new 1, 4-dihydropyridines containing phenylamineimidazolyl substitute in guinea-pig ileal smooth muscle

Directory of Open Access Journals (Sweden)

A Fassihi

2004-02-01

Full Text Available Background: 1,4-dihydropyridines are a class of drugs which are used in the treatment of some cardiovascular disorders. The prototype, Nifedipine, does not have optimal pharmacokinetic and pharmacodynamic properties. Several new derivatives of 1, 4-dihydropyridine have been produced and pharmacologically evaluated in order to find drugs with better pharmacological properties. Among them, those with a substituted heteroaromatic ring in the C4 position of the 1, 4-dihydropyridine ring, instead of the phenyl ring in Nifedipine, are most considered. In this study, eight novel derivatives of this class with “2-methylthio-1-(phenylaminoimidazole-5-yl” in the C4, C3 and C5 positions were prepared and evaluated as calcium channel antagonist agents. Methods: To prepare these compounds, Hantzsch method for the synthesis of 1, 4-dihydropyridine derivatives was deployed. An aldehyde was reacted with appropriate acetoacetate ester and ammonium acetate. This aldehyde was prepared in three steps. Cumulative doses were applied to determine the relaxing effect of the compounds on the longitudinal smooth muscle of male albino guinea pigs. Results: Chemical structures of the compounds were characterized by 1H nuclear magnetic resonance, infrared and mass spectroscopy. The IC50 of each compound was graphically determined from the concentration-response curves. Conclusions: Two compounds were more active than Nifedipine. Both had lipophilic ester groups with low steric hindrance that met the merits of a better receptor binding of 1, 4-dihydropyridines. These derivatives have high potential for further study. Keywords: 1, 4-dihydropyridine, Calcium channel antagonist, Phenylamineimidazolyl, Cardiovascular disorder

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....

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.

Discovery of (1R,2S)-2-{[(2,4-Dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006): A Potent and Efficacious Oral Orexin Receptor Antagonist.

Science.gov (United States)

Yoshida, Yu; Naoe, Yoshimitsu; Terauchi, Taro; Ozaki, Fumihiro; Doko, Takashi; Takemura, Ayumi; Tanaka, Toshiaki; Sorimachi, Keiichi; Beuckmann, Carsten T; Suzuki, Michiyuki; Ueno, Takashi; Ozaki, Shunsuke; Yonaga, Masahiro

2015-06-11

The orexin/hypocretin receptors are a family of G protein-coupled receptors and consist of orexin-1 (OX1) and orexin-2 (OX2) receptor subtypes. Orexin receptors are expressed throughout the central nervous system and are involved in the regulation of the sleep/wake cycle. Because modulation of these receptors constitutes a promising target for novel treatments of disorders associated with the control of sleep and wakefulness, such as insomnia, the development of orexin receptor antagonists has emerged as an important focus in drug discovery research. Here, we report the design, synthesis, characterization, and structure-activity relationships (SARs) of novel orexin receptor antagonists. Various modifications made to the core structure of a previously developed compound (-)-5, the lead molecule, resulted in compounds with improved chemical and pharmacological profiles. The investigation afforded a potential therapeutic agent, (1R,2S)-2-{[(2,4-dimethylpyrimidin-5-yl)oxy]methyl}-2-(3-fluorophenyl)-N-(5-fluoropyridin-2-yl)cyclopropanecarboxamide (E2006), an orally active, potent orexin antagonist. The efficacy was demonstrated in mice in an in vivo study by using sleep parameter measurements.

Glutamic acid and its derivatives: candidates for rational design of anticancer drugs.

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Ali, Imran; Wani, Waseem A; Haque, Ashanul; Saleem, Kishwar

2013-05-01

Throughout the history of human civilizations, cancer has been a major health problem. Its treatment has been interesting but challenging to scientists. Glutamic acid and its derivative glutamine are known to play interesting roles in cancer genesis, hence, it was realized that structurally variant glutamic acid derivatives may be designed and developed and, might be having antagonistic effects on cancer. The present article describes the state-of-art of glutamic acid and its derivatives as anticancer agents. Attempts have been made to explore the effectivity of drug-delivery systems based on glutamic acid for the delivery of anticancer drugs. Moreover, efforts have also been made to discuss the mechanism of action of glutamic acid derivatives as anticancer agents, clinical applications of glutamic acid derivatives, as well as recent developments and future perspectives of glutamic acid drug development have also been discussed.

Use of hydroxypropyl-beta-cyclodextrin ad polymer matrix for formation of inclusion complex with drug nifedipine

International Nuclear Information System (INIS)

Carneiro, Elisa F.; Araujo, Marcia V.G. de; Barbosa, Ronilson V.; Silva, Caroline W.P. da; Barisson, Andersson; Zawadzki, Sonia F.; Andrade, George Ricardo S.; Costa Junior, Nivan B. da

2009-01-01

In this work it was prepared and characterized an inclusion complex between the polymeric matrix hydroxypropyl-beta cyclodextrin and nifedipine, a hydrophobic drug calcium antagonistic, used for the cardiovascular diseases treatment. The study of the phase- solubility diagram showed an increase of the aqueous solubility of the drug after inclusion, was observed and The differential scanning calorimetry analysis did not show the melting point temperature of the drug in the formed complex. This fact is considered as an evidence of the encapsulation process. 1 H NMR studies suggested that the non-aromatic ring of the nifedipine would be inserted in the cavity of the hydroxypropyl-beta-cyclodextrin.This orientation was also proposed by the used molecular modelling methods. (author)

Drug discrimination: A versatile tool for characterization of CNS safety pharmacology and potential for drug abuse.

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Swedberg, Michael D B

2016-01-01

Drug discrimination studies for assessment of psychoactive properties of drugs in safety pharmacology and drug abuse and drug dependence potential evaluation have traditionally been focused on testing novel compounds against standard drugs for which drug abuse has been documented, e.g. opioids, CNS stimulants, cannabinoids etc. (e.g. Swedberg & Giarola, 2015), and results are interpreted such that the extent to which the test drug causes discriminative effects similar to those of the standard training drug, the test drug would be further characterized as a potential drug of abuse. Regulatory guidance for preclinical assessment of abuse liability by the European Medicines Agency (EMA, 2006), the U.S. Food and Drug Administration (FDA, 2010), the International Conference of Harmonization (ICH, 2009), and the Japanese Ministry of Health Education and Welfare (MHLW, 1994) detail that compounds with central nervous system (CNS) activity, whether by design or not, need abuse and dependence liability assessment. Therefore, drugs with peripheral targets and a potential to enter the CNS, as parent or metabolite, are also within scope (see Swedberg, 2013, for a recent review and strategy). Compounds with novel mechanisms of action present a special challenge due to unknown abuse potential, and should be carefully assessed against defined risk criteria. Apart from compounds sharing mechanisms of action with known drugs of abuse, compounds intended for indications currently treated with drugs with potential for abuse and or dependence are also within scope, regardless of mechanism of action. Examples of such compounds are analgesics, anxiolytics, cognition enhancers, appetite control drugs, sleep control drugs and drugs for psychiatric indications. Recent results (Swedberg et al., 2014; Swedberg & Raboisson, 2014; Swedberg, 2015) on the metabotropic glutamate receptor type 5 (mGluR5) antagonists demonstrate that compounds causing hallucinatory effects in humans did not exhibit

Opioid Antagonists and the A118G Polymorphism in the μ-Opioid Receptor Gene: Effects of GSK1521498 and Naltrexone in Healthy Drinkers Stratified by OPRM1 Genotype

Science.gov (United States)

Ziauddeen, Hisham; Nestor, Liam J; Subramaniam, Naresh; Dodds, Chris; Nathan, Pradeep J; Miller, Sam R; Sarai, Bhopinder K; Maltby, Kay; Fernando, Disala; Warren, Liling; Hosking, Louise K; Waterworth, Dawn; Korzeniowska, Anna; Win, Beta; Richards, Duncan B; Vasist Johnson, Lakshmi; Fletcher, Paul C; Bullmore, Edward T

2016-01-01

The A118G single-nucleotide polymorphism (SNP rs1799971) in the μ-opioid receptor gene, OPRM1, has been much studied in relation to alcohol use disorders. The reported effects of allelic variation at this SNP on alcohol-related behaviors, and on opioid receptor antagonist treatments, have been inconsistent. We investigated the pharmacogenetic interaction between A118G variation and the effects of two μ-opioid receptor antagonists in a clinical lab setting. Fifty-six overweight and moderate–heavy drinkers were prospectively stratified by genotype (29 AA homozygotes, 27 carriers of at least 1 G allele) in a double-blind placebo-controlled, three-period crossover design with naltrexone (NTX; 25 mg OD for 2 days, then 50 mg OD for 3 days) and GSK1521498 (10 mg OD for 5 days). The primary end point was regional brain activation by the contrast between alcohol and neutral tastes measured using functional magnetic resonance imaging (fMRI). Secondary end points included other fMRI contrasts, subjective responses to intravenous alcohol challenge, and food intake. GSK1521498 (but not NTX) significantly attenuated fMRI activation by appetitive tastes in the midbrain and amygdala. GSK1521498 (and NTX to a lesser extent) significantly affected self-reported responses to alcohol infusion. Both drugs reduced food intake. Across all end points, there was less robust evidence for significant effects of OPRM1 allelic variation, or for pharmacogenetic interactions between genotype and drug treatment. These results do not support strong modulatory effects of OPRM1 genetic variation on opioid receptor antagonist attenuation of alcohol- and food-related behaviors. However, they do support further investigation of GSK1521498 as a potential therapeutic for alcohol use and eating disorders. PMID:27109624

Contributions of different modes of TRPV1 activation to TRPV1 antagonist-induced hyperthermia.

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Garami, Andras; Shimansky, Yury P; Pakai, Eszter; Oliveira, Daniela L; Gavva, Narender R; Romanovsky, Andrej A

2010-01-27

Transient receptor potential vanilloid-1 (TRPV1) antagonists are widely viewed as next-generation pain therapeutics. However, these compounds cause hyperthermia, a serious side effect. TRPV1 antagonists differentially block three modes of TRPV1 activation: by heat, protons, and chemical ligands (e.g., capsaicin). We asked what combination of potencies in these three modes of TRPV1 activation corresponds to the lowest potency of a TRPV1 antagonist to cause hyperthermia. We studied hyperthermic responses of rats, mice, and guinea pigs to eight TRPV1 antagonists with different pharmacological profiles and used mathematical modeling to find a relative contribution of the blockade of each activation mode to the development of hyperthermia. We found that the hyperthermic effect has the highest sensitivity to the extent of TRPV1 blockade in the proton mode (0.43 to 0.65) with no to moderate sensitivity in the capsaicin mode (-0.01 to 0.34) and no sensitivity in the heat mode (0.00 to 0.01). We conclude that hyperthermia-free TRPV1 antagonists do not block TRPV1 activation by protons, even if they are potent blockers of the heat mode, and that decreasing the potency to block the capsaicin mode may further decrease the potency to cause hyperthermia.

Preliminary Molecular Dynamic Simulations of the Estrogen Receptor Alpha Ligand Binding Domain from Antagonist to Apo

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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.

5-HT2A receptor antagonists improve motor impairments in the MPTP mouse model of Parkinson's disease.

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Ferguson, Marcus C; Nayyar, Tultul; Deutch, Ariel Y; Ansah, Twum A

2010-01-01

Clinical observations have suggested that ritanserin, a 5-HT(2A/C) receptor antagonist may reduce motor deficits in persons with Parkinson's Disease (PD). To better understand the potential antiparkinsonian actions of ritanserin, we compared the effects of ritanserin with the selective 5-HT(2A) receptor antagonist M100907 and the selective 5-HT(2C) receptor antagonist SB 206553 on motor impairments in mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). MPTP-treated mice exhibited decreased performance on the beam-walking apparatus. These motor deficits were reversed by acute treatment with L-3,4-dihydroxyphenylalanine (levodopa). Both the mixed 5-HT(2A/C) antagonist ritanserin and the selective 5-HT(2A) antagonist M100907 improved motor performance on the beam-walking apparatus. In contrast, SB 206553 was ineffective in improving the motor deficits in MPTP-treated mice. These data suggest that 5-HT(2A) receptor antagonists may represent a novel approach to ameliorate motor symptoms of Parkinson's disease. Published by Elsevier Ltd.

Regarding the unitary theory of agonist and antagonist action at presynaptic adrenoceptors.

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Kalsner, S; Abdali, S A

2001-06-01

1. The linkage between potentiation of field stimulation-induced noradrenaline release and blockade of the presynaptic inhibitory effect of exogenous noradrenaline by a presynaptic antagonist was examined in superfused rabbit aorta preparations. 2. Rauwolscine clearly potentiated the release of noradrenaline in response to 100 pulses at 2 Hz but reduced the capacity of noradrenaline to inhibit transmitter release to a questionable extent, and then only when comparisons were made with untreated, rather then to rauwolscine-treated, controls. 3. Aortic preparations exposed for 60 min to rauwolscine followed by superfusion with antagonist-free Krebs for 60 min retained the potentiation of stimulation-induced transmitter release but no antagonism of the noradrenaline-induced inhibition could be detected at either of two noradrenaline concentrations when comparisons were made with rauwolscine treated controls. 4. Comparisons of the inhibitory effect of exogenous noradrenaline (1.8 x 10-6 M) on transmitter efflux in the presence and absence of rauwolscine pretreatment revealed that the antagonist enhanced rather than antagonized the presynaptic inhibition by noradrenaline. 5 It is concluded that the unitary hypothesis that asserts that antagonist enhancement of transmitter release and its blockade of noradrenaline induced inhibition are manifestations of a unitary event are not supportable.

Blinded prospective evaluation of computer-based mechanistic schizophrenia disease model for predicting drug response.

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Hugo Geerts

Full Text Available The tremendous advances in understanding the neurobiological circuits involved in schizophrenia have not translated into more effective treatments. An alternative strategy is to use a recently published 'Quantitative Systems Pharmacology' computer-based mechanistic disease model of cortical/subcortical and striatal circuits based upon preclinical physiology, human pathology and pharmacology. The physiology of 27 relevant dopamine, serotonin, acetylcholine, norepinephrine, gamma-aminobutyric acid (GABA and glutamate-mediated targets is calibrated using retrospective clinical data on 24 different antipsychotics. The model was challenged to predict quantitatively the clinical outcome in a blinded fashion of two experimental antipsychotic drugs; JNJ37822681, a highly selective low-affinity dopamine D(2 antagonist and ocaperidone, a very high affinity dopamine D(2 antagonist, using only pharmacology and human positron emission tomography (PET imaging data. The model correctly predicted the lower performance of JNJ37822681 on the positive and negative syndrome scale (PANSS total score and the higher extra-pyramidal symptom (EPS liability compared to olanzapine and the relative performance of ocaperidone against olanzapine, but did not predict the absolute PANSS total score outcome and EPS liability for ocaperidone, possibly due to placebo responses and EPS assessment methods. Because of its virtual nature, this modeling approach can support central nervous system research and development by accounting for unique human drug properties, such as human metabolites, exposure, genotypes and off-target effects and can be a helpful tool for drug discovery and development.

Microbial herd protection mediated by antagonistic interaction in polymicrobial communities.

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Wong, Megan; Liang, Xiaoye; Smart, Matt; Tang, Le; Moore, Richard; Ingalls, Brian; Dong, Tao G

2016-09-16

In the host and natural environments, microbes often exist in complex multispecies communities. The molecular mechanisms through which such communities develop and persist - despite significant antagonistic interactions between species - are not well understood. The type VI secretion system (T6SS) is a lethal weapon commonly employed by Gram-negative bacteria to inhibit neighboring species through delivery of toxic effectors. It is well established that intra-species protection is conferred by immunity proteins that neutralize effector toxicities. By contrast, the mechanisms for interspecies protection are not clear. Here we use two T6SS active antagonistic bacteria, Aeromonas hydrophila (AH) and Vibrio cholerae (VC), to demonstrate that interspecies protection is dependent on effectors. AH and VC do not share conserved immunity genes but could equally co-exist in a mixture. However, mutants lacking the T6SS or effectors were effectively eliminated by the other competing wild type. Time-lapse microscopy analyses show that mutually lethal interactions drive the segregation of mixed species into distinct single-species clusters by eliminating interspersed single cells. Cluster formation provides herd protection by abolishing lethal interaction inside each cluster and restricting it to the boundary. Using an agent-based modeling approach, we simulated the antagonistic interactions of two hypothetical species. The resulting simulations recapitulate our experimental observation. These results provide mechanistic insights for the general role of microbial weapons in determining the structures of complex multispecies communities. Investigating the warfare of microbes allows us to better understand the ecological relationships in complex microbial communities such as the human microbiota. Here we use the T6SS, a deadly bacterial weapon, as a model to demonstrate the importance of lethal interactions in determining community structures and exchange of genetic materials

Microbial Herd Protection Mediated by Antagonistic Interaction in Polymicrobial Communities

Science.gov (United States)

Wong, Megan J. Q.; Liang, Xiaoye; Smart, Matt; Tang, Le; Moore, Richard; Ingalls, Brian

2016-01-01

ABSTRACT In host and natural environments, microbes often exist in complex multispecies communities. The molecular mechanisms through which such communities develop and persist, despite significant antagonistic interactions between species, are not well understood. The type VI secretion system (T6SS) is a lethal weapon commonly employed by Gram-negative bacteria to inhibit neighboring species through the delivery of toxic effectors. It is well established that intraspecies protection is conferred by immunity proteins that neutralize effector toxicities. In contrast, the mechanisms for interspecies protection are not clear. Here we use two T6SS-active antagonistic bacterial species, Aeromonas hydrophila and Vibrio cholerae, to demonstrate that interspecies protection is dependent on effectors. A. hydrophila and V. cholerae do not share conserved immunity genes but could coexist equally in a mixture. However, mutants lacking the T6SS or effectors were effectively eliminated by the competing wild-type strain. Time-lapse microscopic analyses showed that mutually lethal interactions drive the segregation of mixed species into distinct single-species clusters by eliminating interspersed single cells. Cluster formation provides herd protection by abolishing lethal interactions inside each cluster and restricting the interactions to the boundary. Using an agent-based modeling approach, we simulated the antagonistic interactions of two hypothetical species. The resulting simulations recapitulated our experimental observations. These results provide mechanistic insights regarding the general role of microbial weapons in determining the structures of complex multispecies communities. IMPORTANCE Investigating the warfare of microbes allows us to better understand the ecological relationships in complex microbial communities such as the human microbiota. Here we use the T6SS, a deadly bacterial weapon, as a model to demonstrate the importance of lethal interactions in

Preparation and Characterization of an Antibody Antagonist That Targets the Porcine Growth Hormone Receptor

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Huanzhong Cui

2016-10-01

Full Text Available A series of antagonists specifically targeting growth hormone receptors (GHR in different species, such as humans, rats, bovines, and mice, have been designed; however, there are currently no antagonists that target the porcine growth hormone (GH. Therefore, in this study, we developed and characterized a porcine GHR (pGHR antibody antagonist (denoted by AN98 via the hybridoma technique. The results from enzyme-linked immunosorbent assay, fluorescence activated cell sorter, indirect immunoinfluscent assay, and competitive receptor binding analysis showed that AN98 could specifically recognize pGHR, and further experiments indicated that AN98 could effectively inhibit pGH-induced signalling in CHO-pGHR cells and porcine hepatocytes. In addition, AN98 also inhibited GH-induced insulin-like growth factor-1 (IGF-1 secretion in porcine hepatocytes. In summary, these findings indicated that AN98, as a pGHR-specific antagonist, has potential applications in pGH-pGHR-related research on domestic pigs.

Drugs of abuse specifically sensitize noradrenergic and serotonergic neurons via a non-dopaminergic mechanism.

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Lanteri, Christophe; Salomon, Lucas; Torrens, Yvette; Glowinski, Jacques; Tassin, Jean-Pol

2008-06-01

A challenge in drug dependence is to delineate long-term neurochemical modifications induced by drugs of abuse. Repeated d-amphetamine was recently shown to disrupt a mutual regulatory link between noradrenergic and serotonergic neurons, thus inducing long-term increased responses to d-amphetamine and para-chloroamphetamine, respectively. We show here that such a sensitization of noradrenergic and serotonergic neurons also occurs following repeated treatment with cocaine, morphine, or alcohol, three compounds belonging to main groups of addictive substances. In all cases, this sensitization is prevented by alpha 1b-adrenergic and 5-HT2A receptors blockade, indicating the critical role of these receptors on long-term effects of drugs of abuse. However, repeated treatments with two non-addictive antidepressants, venlafaxine, and clorimipramine, which nevertheless inhibit noradrenergic and serotonergic reuptake, do not induce noradrenergic and serotonergic neurons sensitization. Similarly, this sensitization does not occur following repeated treatments with a specific inhibitor of dopamine (DA) reuptake, GBR12783. Moreover, we show that the effects of SCH23390, a D1 receptor antagonist known to inhibit development of d-amphetamine behavioral sensitization, are due to its 5-HT2C receptor agonist property. SCH23390 blocks amphetamine-induced release of norepinephrine and RS102221, a 5-HT2C antagonist, can reverse this inhibition as well as inhibition of noradrenergic sensitization and development of behavioral sensitization induced by repeated d-amphetamine. We propose that noradrenergic/serotonergic uncoupling is a common neurochemical consequence of repeated consumption of drugs of abuse, unrelated with DA release. Our data also suggest that compounds able to restore the link between noradrenergic and serotonergic modulatory systems could represent important therapeutic targets for investigation.

Peptide drugs to target G protein-coupled receptors.

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Bellmann-Sickert, Kathrin; Beck-Sickinger, Annette G

2010-09-01

Major indications for use of peptide-based therapeutics include endocrine functions (especially diabetes mellitus and obesity), infectious diseases, and cancer. Whereas some peptide pharmaceuticals are drugs, acting as agonists or antagonists to directly treat cancer, others (including peptide diagnostics and tumour-targeting pharmaceuticals) use peptides to 'shuttle' a chemotherapeutic agent or a tracer to the tumour and allow sensitive imaging or targeted therapy. Significant progress has been made in the last few years to overcome disadvantages in peptide design such as short half-life, fast proteolytic cleavage, and low oral bioavailability. These advances include peptide PEGylation, lipidisation or multimerisation; the introduction of peptidomimetic elements into the sequences; and innovative uptake strategies such as liposomal, capsule or subcutaneous formulations. This review focuses on peptides targeting G protein-coupled receptors that are promising drug candidates or that have recently entered the pharmaceutical market. Copyright 2010 Elsevier Ltd. All rights reserved.

The Relative Potency of Inverse Opioid Agonists and a Neutral Opioid Antagonist in Precipitated Withdrawal and Antagonism of Analgesia and Toxicity

OpenAIRE

Sirohi, Sunil; Dighe, Shveta V.; Madia, Priyanka A.; Yoburn, Byron C.

2009-01-01

Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was exa...

Sexually antagonistic "zygotic drive" of the sex chromosomes.

Directory of Open Access Journals (Sweden)

William R Rice

2008-12-01

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

Interactions of CB1 and mGlu5 receptor antagonists in food intake, anxiety and memory models in rats.

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Varga, Balázs; Kassai, Ferenc; Gyertyán, István

2012-12-01

CB(1) receptor antagonists proved to be effective anti-obesity drugs, however, their depressive and anxiogenic effects became also evident. Finding solution to overcome these psychiatric side effects is still in focus of research. Based on the available clinical and preclinical results we hypothesized that the combination of CB(1) and mGlu(5) receptor antagonisms may result in a pharmacological intervention, where the anxiolytic mGlu(5) receptor inhibition may counteract the anxiogenic psychiatric side effects of CB(1) antagonism, while CB(1) antagonism may ameliorate the memory impairing effect of mGlu(5) receptor antagonism. Further, the two components will synergistically interact in blocking food-intake and reducing obesity. For testing the interaction of mGlu(5) and CB(1) receptor antagonism MTEP [3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pridine; SIB-1757, 6-methyl-2-(phenylazo)-3-pyridinol)] (mGlu(5) antagonist) and rimonabant [(5-(4-Chlorophenyl)-1-(2,4-dichloro-phenyl)-4-methyl-N-(piperidin-1-yl)-1H-pyrazole-3-carboxamide)hydrochloride] (CB(1) antagonist) were used. All experiments were carried out in rats. Effects of the compounds on anxiety were tested in two foot shock induced ultrasonic vocalization paradigms, appetite suppression was assessed in the food intake test, while memory effects were tested in a context conditioned ultrasonic vocalization setup. MTEP abolished the anxiogenic effect of rimonabant, while there was an additive cooperation in suppressing appetite. However, rimonabant did not ameliorate the memory impairing effect of MTEP. By combination of CB(1) and mGluR5 antagonism, anxiety related side effects might be attenuated, appetite suppression maintained, nevertheless, the possible emergence of unwanted memory impairments can overshadow its therapeutic success. Copyright © 2012 Elsevier Inc. All rights reserved.

Viability of D283 medulloblastoma cells treated with a histone deacetylase inhibitor combined with bombesin receptor antagonists.

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Jaeger, Mariane; Ghisleni, Eduarda C; Fratini, Lívia; Brunetto, Algemir L; Gregianin, Lauro José; Brunetto, André T; Schwartsmann, Gilberto; de Farias, Caroline B; Roesler, Rafael

2016-01-01

Medulloblastoma (MB) comprises four distinct molecular subgroups, and survival remains particularly poor in patients with Group 3 tumors. Mutations and copy number variations result in altered epigenetic regulation of gene expression in Group 3 MB. Histone deacetylase inhibitors (HDACi) reduce proliferation, promote cell death and neuronal differentiation, and increase sensitivity to radiation and chemotherapy in experimental MB. Bombesin receptor antagonists potentiate the antiproliferative effects of HDACi in lung cancer cells and show promise as experimental therapies for several human cancers. Here, we examined the viability of D283 cells, which belong to Group 3 MB, treated with an HDACi alone or combined with bombesin receptor antagonists. D283 MB cells were treated with different doses of the HDACi sodium butyrate (NaB), the neuromedin B receptor (NMBR) antagonist BIM-23127, the gastrin releasing peptide receptor (GRPR) antagonist RC-3095, or combinations of NaB with each receptor antagonist. Cell viability was examined by cell counting. NaB alone or combined with receptor antagonists reduced cell viability at all doses tested. BIM-23127 alone did not affect cell viability, whereas RC-3095 at an intermediate dose significantly increased cell number. Although HDACi are promising agents to inhibit MB growth, the present results provide preliminary evidence that combining HDACi with bombesin receptor antagonists is not an effective strategy to improve the effects of HDACi against MB cells.

Design and synthesis of novel sulfonamide-containing bradykinin hB2 receptor antagonists. 2. Synthesis and structure-activity relationships of alpha,alpha-cycloalkylglycine sulfonamides.

Science.gov (United States)

Fattori, Daniela; Rossi, Cristina; Fincham, Christopher I; Caciagli, Valerio; Catrambone, Fernando; D'Andrea, Piero; Felicetti, Patrizia; Gensini, Martina; Marastoni, Elena; Nannicini, Rossano; Paris, Marielle; Terracciano, Rosa; Bressan, Alessandro; Giuliani, Sandro; Maggi, Carlo A; Meini, Stefania; Valenti, Claudio; Quartara, Laura

2007-02-08

Recently we reported on the design and synthesis of a novel class of selective nonpeptide bradykinin (BK) B2 receptor antagonists (J. Med. Chem. 2006, 3602-3613). This work led to the discovery of MEN 15442, an antagonist with subnanomolar affinity for the human B2 receptor (hB2R), which also displayed significant and prolonged activity in vivo (for up to 210 min) against BK-induced bronchoconstriction in the guinea-pig at a dose of 300 nmol/kg (it), while demonstrating only a slight effect on BK-induced hypotension. Here we describe the further optimization of this series of compounds aimed at maximizing the effect on bronchoconstriction and minimizing the effect on hypotension, with a view to developing topically delivered drugs for airway diseases. The work led to the discovery of MEN 16132, a compound which, after intratracheal or aerosol administration, inhibited, in a dose-dependent manner, BK-induced bronchoconstricton in the airways, while showing minimal systemic activity. This compound was selected as a preclinical candidate for the topical treatment of airway diseases involving kinin B2 receptor stimulation.

Manumycin from a new Streptomyces strain shows antagonistic ...

African Journals Online (AJOL)

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

Effects of mineralocorticoid receptor antagonists in patients with hypertension and diabetes mellitus: a systematic review and meta-analysis.

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Takahashi, S; Katada, J; Daida, H; Kitamura, F; Yokoyama, K

2016-09-01

Blood pressure (BP) control is important to ameliorate cardiovascular events in patients with diabetes mellitus (DM). However, achieving the target BP with a single drug is often difficult. The objective of this study was to evaluate the antihypertensive effects of mineralocorticoid receptor antagonists (MRAs) as add-on therapy to renin-angiotensin system (RAS) inhibitor(s) in patients with hypertension and DM. Studies were searched through October 2014 in MEDLINE, Embase and the Cochrane Central Register of Controlled Trials. Randomized, controlled trials or prospective, observational studies regarding concomitant administration of MRA and RAS inhibitor(s) in patients with DM were included. Articles were excluded if the mean systolic BP (SBP) was hypertension and DM already taking RAS inhibitors. Serum potassium levels should be monitored to prevent hyperkalemia.

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

DEFF Research Database (Denmark)

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

2010-01-01

risk of reactivating latent infections, especially tuberculosis (TB). Following TNF antagonist therapy, the relative risk for TB is increased up to 25 times, depending on the clinical setting and the TNF antagonist used. Interferon-¿ release assays or, as an alternative in individuals without a history...... of bacille Calmette-Guérin vaccination, tuberculin skin testing is recommended to screen all adult candidates for TNF antagonist treatment for the presence of latent infection with Mycobacterium tuberculosis. Moreover, paediatric practice suggests concomitant use of both the tuberculin skin test...

Effects of cannabinoid CB1 receptor antagonist rimonabant in consolidation and reconsolidation of methamphetamine reward memory in mice.

Science.gov (United States)

Yu, Lu-lu; Wang, Xue-yi; Zhao, Mei; Liu, Yu; Li, Yan-qin; Li, Fang-qiong; Wang, Xiaoyi; Xue, Yan-xue; Lu, Lin

2009-06-01

Previous studies have shown that cannabinoid CB1 receptors play an important role in specific aspects of learning and memory, yet there has been no systematic study focusing on the involvement of cannabinoid CB1 receptors in methamphetamine-related reward memory. The purpose of this study was to examine whether rimonabant, a cannabinoid CB1 receptor antagonist, would disrupt the consolidation and reconsolidation of methamphetamine-related reward memory, using conditioned place preference paradigm (CPP). Separate groups of male Kunming mice were trained to acquire methamphetamine CPP. Vehicle or rimonabant (1 mg/kg or 3 mg/kg, i.p.) was given at different time points: immediately after each CPP training session (consolidation), 30 min before the reactivation of CPP (retrieval), or immediately after the reactivation of CPP (reconsolidation). Methamphetamine CPP was retested 24 h and 1 and 2 weeks after rimonabant administration. Rimonabant at doses of 1 and 3 mg/kg significantly inhibited the consolidation of methamphetamine CPP. Only high-dose rimonabant (3 mg/kg) disrupted the retrieval and reconsolidation of methamphetamine CPP. Rimonabant had no effect on methamphetamine CPP in the absence of methamphetamine CPP reactivation. Our findings suggest that cannabinoid CB1 receptors play a major role in methamphetamine reward memory, and cannabinoid CB1 receptor antagonists may be a potential pharmacotherapy to manage relapse associated with drug-reward-related memory.

Effects of a 5-HT3 agonist and antagonist on inter-male aggression in Mus musculus

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Michael Kerchner

2006-01-01

Full Text Available Research has revealed an inverse relationship between serotonin (5-HT levels in the brain and aggressive behavior. However, effects on aggression at the level of the receptor have yet to be elucidated for many 5-HT receptor subtypes. This study examined the effects of the 5-HT3 receptor agonist m-chlorophenylbiguanide (mCPBG and antagonist ondansetron on inter-male aggression in mice. Using a resident-intruder paradigm designed to assess both offensive and defensive aggression, male C57BL/6J mice received 1 mg/kg i.p. injections of either mCPBG, ondansetron, or an inactive vehicle and were subsequently exposed to male AKR/J mice for a period of 10 minutes. Attack latency and the proportion of time engaged in a range of defensive behaviors were recorded. Subject C57BL/6J mice were then immediately run in an open field test for an additional 10 minutes to examine any anxiolytic or sedative effects of the drugs. Results show no significant differences between drug groups in either offensive or defensive behavior. No significant differences were observed between drug groups and open field activity; however, significant differences were seen between the offensive and defensive condition in the open field. In conclusion, this study fails to reveal any significant effects of the 5-HT3 agents on inter-male aggression, which may reflect a functional difference between the 5-HT3 receptor and the remaining G-protein coupled 5-HT receptor. However, this conclusion is limited by the large variance in behavior combined with small sample sizes, or the possibility of a drug dose insufficient for behavioral effects.

Medicinal importance of grapefruit juice and its interaction with various drugs

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Imam Sardar Z

2007-10-01

Full Text Available Abstract Grapefruit juice is consumed widely in today's health conscious world as a protector against cardiovascular diseases and cancers. It has however, been found to be an inhibitor of the intestinal cytochrome P – 450 3A4 system, which is responsible for the first pass metabolism of many drugs. The P – glycoprotein pump, found in the brush border of the intestinal wall which transports many of these cytochrome P – 450 3A4 substrates, has also been implicated to be inhibited by grapefruit juice. By inhibiting these enzyme systems, grapefruit juice alters the pharmacokinetics of a variety of medications, leading to elevation of their serum concentrations. Most notable are its effects on the calcium channel antagonist and the statin group of drugs. In the case of many drugs, the increased serum concentration has been found to be associated with increased frequency of dose dependent adverse effects. In this review, we have discussed the phytochemistry of grapefruit juice, the various drugs involved in the drug – grapefruit juice eraction with their mechanisms of action and have presented the clinical implications of these interactions.

The relative potency of inverse opioid agonists and a neutral opioid antagonist in precipitated withdrawal and antagonism of analgesia and toxicity.

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Sirohi, Sunil; Dighe, Shveta V; Madia, Priyanka A; Yoburn, Byron C

2009-08-01

Opioid antagonists can be classified as inverse agonists and neutral antagonists. In the opioid-dependent state, neutral antagonists are significantly less potent in precipitating withdrawal than inverse agonists. Consequently, neutral opioid antagonists may offer advantages over inverse agonists in the management of opioid overdose. In this study, the relative potency of three opioid antagonists to block opioid analgesia and toxicity and precipitate withdrawal was examined. First, the potency of two opioid inverse agonists (naltrexone and naloxone) and a neutral antagonist (6beta-naltrexol) to antagonize fentanyl-induced analgesia and lethality was determined. The order of potency to block analgesia was naltrexone > naloxone > 6beta-naltrexol (17, 4, 1), which was similar to that to block lethality (13, 2, 1). Next, the antagonists were compared using withdrawal jumping in fentanyl-dependent mice. The order of potency to precipitate withdrawal jumping was naltrexone > naloxone 6beta-naltrexol (1107, 415, 1). The relative potencies to precipitate withdrawal for the inverse agonists compared with the neutral antagonist were dramatically different from that for antagonism of analgesia and lethality. Finally, the effect of 6beta-naltrexol pretreatment on naloxone-precipitated jumping was determined in morphine and fentanyl-dependent mice. 6beta-Naltrexol pretreatment decreased naloxone precipitated withdrawal, indicating that 6beta-naltrexol is a neutral antagonist. These data demonstrate that inverse agonists and neutral antagonists have generally comparable potencies to block opioid analgesia and lethality, whereas the neutral opioid antagonist is substantially less potent in precipitating opioid withdrawal. These results support suggestions that neutral antagonists may have advantages over inverse agonists in the management of opioid overdose.

Efficacité de l'agent antagoniste Trichoderma harzianum sur ...

African Journals Online (AJOL)

Efficacité de l'agent antagoniste Trichoderma harzianum sur Fusarium oxysporum f. sp. lycopersiciagent pathogène de la tomate. LS Gnancadja, DHE Tonon, EMO Faton, KO Douro Kpindou, E Dannon, A Akoegninou ...

Medicinal Chemistry, Pharmacology, and Clinical Implications of TRPV1 Receptor Antagonists.

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Aghazadeh Tabrizi, Mojgan; Baraldi, Pier Giovanni; Baraldi, Stefania; Gessi, Stefania; Merighi, Stefania; Borea, Pier Andrea

2017-07-01

Transient receptor potential vanilloid 1 (TRPV1) is an ion channel expressed on sensory neurons triggering an influx of cations. TRPV1 receptors function as homotetramers responsive to heat, proinflammatory substances, lipoxygenase products, resiniferatoxin, endocannabinoids, protons, and peptide toxins. Its phosphorylation increases sensitivity to both chemical and thermal stimuli, while desensitization involves a calcium-dependent mechanism resulting in receptor dephosphorylation. TRPV1 functions as a sensor of noxious stimuli and may represent a target to avoid pain and injury. TRPV1 activation has been associated to chronic inflammatory pain and peripheral neuropathy. Its expression is also detected in nonneuronal areas such as bladder, lungs, and cochlea where TRPV1 activation is responsible for pathology development of cystitis, asthma, and hearing loss. This review offers a comprehensive overview about TRPV1 receptor in the pathophysiology of chronic pain, epilepsy, cough, bladder disorders, diabetes, obesity, and hearing loss, highlighting how drug development targeting this channel could have a clinical therapeutic potential. Furthermore, it summarizes the advances of medicinal chemistry research leading to the identification of highly selective TRPV1 antagonists and their analysis of structure-activity relationships (SARs) focusing on new strategies to target this channel. © 2016 Wiley Periodicals, Inc.

Comparison of long GnRH agonist versus GnRH antagonist protocol in poor responders

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Sadık Şahin

2014-12-01

Full Text Available Objective: To compare long GnRH agonist with GnRH antagonist protocol in poor responders. Materials and Methods: Medical charts of 531 poor responder women undergoing in-vitro fertilization (IVF cycle at Zeynep Kamil Maternity and Children’s Hospital, IVF Center were retrospectively analysed. Those who received at least 300 IU/daily gonadotropin and had ≤3 oocytes retrieved were enrolled in the study. Poor responders were categorized into two groups as those who received long GnRH agonist or GnRH antagonist regimen. Results: Treatment duration and total gonadotropin dosage were significantly higher in women undergoing the long GnRH agonist regimen compared with the GnRH antagonist regimen (p<0.001 for both. Although the number of total and mature oocytes retrieved was similar between the groups, good quality embryos were found to be higher in the GnRH antagonist regimen. The day of embryo transfer and number of transferred embryos were similar in the groups. No statistically significant differences were detected in pregnancy (10.5% vs 14.1%, clinical pregnancy (7.7% vs 10.6% and early pregnancy loss rates (27.2% vs 35% between the groups. Conclusion: GnRH antagonist regimen may be preferable to long GnRH regimen as it could decrease the cost and treatment duration in poor responders.

GnRH antagonist versus long agonist protocols in IVF

DEFF Research Database (Denmark)

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

2017-01-01

BACKGROUND: Most reviews of IVF ovarian stimulation protocols have insufficiently accounted for various patient populations, such as ovulatory women, women with polycystic ovary syndrome (PCOS) or women with poor ovarian response, and have included studies in which the agonist or antagonist...... was not the only variable between the compared study arms. OBJECTIVE AND RATIONALE: The aim of the current study was to compare GnRH antagonist protocols versus standard long agonist protocols in couples undergoing IVF or ICSI, while accounting for various patient populations and treatment schedules. SEARCH...... in couples undergoing IVF or ICSI. The primary outcome was ongoing pregnancy rate. Secondary outcomes were: live birth rate, clinical pregnancy rate, number of oocytes retrieved and safety with regard to ovarian hyperstimulation syndrome (OHSS). Separate comparisons were performed for the general IVF...

Mutational analysis of the antagonist-binding site of the histamine H(1) receptor.

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Wieland, K; Laak, A M; Smit, M J; Kühne, R; Timmerman, H; Leurs, R

1999-10-15

We combined in a previously derived three-dimensional model of the histamine H(1) receptor (Ter Laak, A. M., Timmerman, H., Leurs, H., Nederkoorn, P. H. J., Smit, M. J., and Donne-Op den Kelder, G. M. (1995) J. Comp. Aid. Mol. Design. 9, 319-330) a pharmacophore for the H(1) antagonist binding site (Ter Laak, A. M., Venhorst, J., Timmerman, H., and Donné-Op de Kelder, G. M. (1994) J. Med. Chem. 38, 3351-3360) with the known interacting amino acid residue Asp(116) (in transmembrane domain III) of the H(1) receptor and verified the predicted receptor-ligand interactions by site-directed mutagenesis. This resulted in the identification of the aromatic amino acids Trp(167), Phe(433), and Phe(436) in transmembrane domains IV and VI of the H(1) receptor as probable interaction points for the trans-aromatic ring of the H(1) antagonists. Subsequently, a specific interaction of carboxylate moieties of two therapeutically important, zwitterionic H(1) antagonists with Lys(200) in transmembrane domain V was predicted. A Lys(200) --> Ala mutation results in a 50- (acrivastine) to 8-fold (d-cetirizine) loss of affinity of these zwitterionic antagonists. In contrast, the affinities of structural analogs of acrivastine and cetirizine lacking the carboxylate group, triprolidine and meclozine, respectively, are unaffected by the Lys(200) --> Ala mutation. These data strongly suggest that Lys(200), unique for the H(1) receptor, acts as a specific anchor point for these "second generation" H(1) antagonists.

Antagonistic bioactivity of endophytic strains isolated from Salvia ...

African Journals Online (AJOL)

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

Efficacy and safety of histamine-2 receptor antagonists

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van der Pol, Rachel; Langendam, Miranda; Benninga, Marc; van Wijk, Michiel; Tabbers, Merit

2014-01-01

Histamine-2 receptor antagonists (H2RAs) are frequently used in the treatment of gastroesophageal reflux disease (GERD) in children; however, their efficacy and safety is questionable. To systematically review the literature to assess the efficacy and safety of H2RAs in pediatric GERD. PubMed,

Rational design, synthesis, biologic evaluation, and structure-activity relationship studies of novel 1-indanone alpha(1)-adrenoceptor antagonists.

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Li, Minyong; Xia, Lin

2007-11-01

In the present report, a novel series of 1-indanone alpha(1)-adrenoceptor antagonists were designed and synthesized based on 3D-pharmacophore model. Their in vitro alpha(1)-adrenoceptor antagonistic assay showed that three compounds (2a, 2m, and 2o) had similar or improved alpha(1)-adrenoceptor antagonistic activities relative to the positive control prazosin. Based on these results, a three-dimensional quantitative structure-activity relationship study was performed using a Self-Organizing Molecular Field Analysis method to provide insight for the future development of alpha(1)-adrenoceptor antagonists.

Effects of Combination Therapy With Immunomodulators on Trough Levels and Antibodies Against Tumor Necrosis Factor Antagonists in Patients With Inflammatory Bowel Disease: A Meta-analysis.

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Qiu, Yun; Mao, Ren; Chen, Bai-Li; Zhang, Sheng-Hong; Guo, Jing; He, Yao; Zeng, Zhi-Rong; Ben-Horin, Shomron; Chen, Min-Hu

2017-09-01

It is not clear whether combination therapy with immunomodulators affects the immunogenicity of tumor necrosis factor (TNF) antagonists in patients with inflammatory bowel disease. We performed a meta-analysis to quantify the effects of combined immunomodulator therapy on the presence of antibodies against TNF antagonists (antidrug antibodies [ADAs]) and trough levels of anti-TNF agents. We systematically searched publication databases for studies that reported prevalence of ADAs in patients who received anti-TNF agents. Raw data from studies that met the inclusion criteria were pooled to determine effect estimates. We performed subgroup and metaregression analyses to determine the level of heterogeneity among study outcomes. We analyzed findings from 35 studies that met inclusion criteria (results reported from 6790 patients with inflammatory bowel disease). The pooled risk ratio for formation of ADAs in patients receiving combined therapy with immunomodulators, versus that of patients receiving anti-TNF monotherapy, was 0.49 (95% confidence interval, 0.41-0.59; P immunomodulators (standardized mean difference, 0.11; 95% confidence interval, 0.19-0.41; P = .47). Subgroup analyses of patients treated with different TNF antagonists revealed no difference in the formation of ADAs (P = .50 for interaction); the protective effect of immunomodulators did not differ with type of drug patients were given (methotrexate vs thiopurines), or assay for ADA. We observed heterogeneity only among studies of patients with ulcerative colitis (I 2  = 76%). Funnel plot and Egger test analyses indicated publication bias in the studies (P = .001). In a meta-analysis of published studies, we associated combined treatment with immunomodulators with reduced risk of formation of antibodies against TNF antagonists in patients with inflammatory bowel disease. Copyright © 2017 AGA Institute. Published by Elsevier Inc. All rights reserved.

Construction, purification, and characterization of a chimeric TH1 antagonist

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Javier-González Luís

2006-05-01

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

Novel investigational drugs for constipation-predominant irritable bowel syndrome: a review.

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Mosińska, Paula; Salaga, Maciej; Fichna, Jakub

2016-01-01

Constipation-predominant irritable bowel syndrome (IBS-C) is a functional gastrointestinal (GI) disorder with an unknown etiology. A number of the drugs tested for IBS-C have also been applied to chronic constipation and chronic idiopathic constipation. Unfortunately, due to severe adverse effects, many drugs envisioned for IBS-C had been withdrawn from the market. Nevertheless, a number of potential new agents for this indication are now under development. The following review describes the most recently developed agents in preclinical as well as Phase 1 and Phase 2 clinical studies. Information was obtained from published literature, abstracts and the latest results found in Clinicaltrial.gov database. The authors put a special interest on glucagon-like peptide 1 analogue, bile acid modulators, serotonergic agents, guanylate cyclase C and cannabinoid antagonists. To enter the market, a newly-developed drug has to meet several criteria, such as good bioavailability or the absence of drug-related adverse events. Taking into account constipation and abdominal pain as the main symptoms in IBS-C, a novel successful drug is usually able to improve both at the same time. Four out of fifteen investigational drugs described in this paper belong to the serotonergic family and have a good prognosis to reach the market; still, more long-term clinical studies are warranted.

Isolation and characterization of a novel analyte from Bacillus subtilis SC-8 antagonistic to Bacillus cereus.

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Lee, Nam Keun; Yeo, In-Cheol; Park, Joung Whan; Kang, Byung-Sun; Hahm, Young Tae

2010-09-01

In this study, an effective substance was isolated from Bacillus subtilis SC-8, which was obtained from traditionally fermented soybean paste, cheonggukjang. The substance was purified by HPLC, and its properties were analyzed. It had an adequate antagonistic effect on Bacilluscereus, and its spectrum of activity was narrow. When tested on several gram-negative and gram-positive foodborne pathogenic bacteria such as Salmonella enterica, Salmonella enteritidis, Staphylococcus aureus, and Listeria monocytogenes, no antagonistic effect was observed. Applying the derivative from B. subtilis SC-8 within the same genus did not inhibit the growth of major soybean-fermenting bacteria such as Bacillus subtilis, Bacillus licheniformis, and Bacillus amyloquefaciens. The range of pH stability of the purified antagonistic substance was wide (from 4.0 to >10.0), and the substance was thermally stable up to 60 degrees C. In the various enzyme treatments, the antagonistic activity of the purified substance was reduced with proteinase K, protease, and lipase; its activity was partially destroyed with esterase. Spores of B. cereus did not grow at all in the presence of 5mug/mL of the purified antagonistic substance. The isolated antagonistic substance was thought to be an antibiotic-like lipopeptidal compound and was tentatively named BSAP-254 because it absorbed to UV radiation at 254nm. Copyright 2010 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower

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Veronika Zengerer

2018-02-01

Full Text Available In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora, the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0.

Pseudomonas orientalis F9: A Potent Antagonist against Phytopathogens with Phytotoxic Effect in the Apple Flower.

Science.gov (United States)

Zengerer, Veronika; Schmid, Michael; Bieri, Marco; Müller, Denise C; Remus-Emsermann, Mitja N P; Ahrens, Christian H; Pelludat, Cosima

2018-01-01

In light of public concerns over the use of pesticides and antibiotics in plant protection and the subsequent selection for spread of resistant bacteria in the environment, it is inevitable to broaden our knowledge about viable alternatives, such as natural antagonists and their mode of action. The genus Pseudomonas is known for its metabolic versatility and genetic plasticity, encompassing pathogens as well as antagonists. We characterized strain Pseudomonas orientalis F9, an isolate from apple flowers in a Swiss orchard, and determined its antagonistic activity against several phytopathogenic bacteria, in particular Erwinia amylovora , the causal agent of fire blight. P. orientalis F9 displayed antagonistic activity against a broad suite of phytopathogenic bacteria in the in vitro tests. The promising results from this analysis led to an ex vivo assay with E. amylovora CFBP1430 Rif and P. orientalis F9 infected detached apple flowers. F9 diminished the fire blight pathogen in the flowers but also revealed phytotoxic traits. The experimental results were discussed in light of the complete genome sequence of F9, which revealed the strain to carry phenazine genes. Phenazines are known to contribute to antagonistic activity of bacterial strains against soil pathogens. When tested in the cress assay with Pythium ultimum as pathogen, F9 showed results comparable to the known antagonist P. protegens CHA0.

Tools and drugs for uracil nucleotide-activated P2Y receptors.

Science.gov (United States)

Rafehi, Muhammad; Müller, Christa E

2018-04-13

P2Y receptors (P2YRs) are a family of G protein-coupled receptors activated by extracellular nucleotides. Physiological P2YR agonists include purine and pyrimidine nucleoside di- and triphosphates, such as ATP, ADP, UTP, UDP, nucleotide sugars, and dinucleotides. Eight subtypes exist, P2Y 1 , P2Y 2 , P2Y 4 , P2Y 6 , P2Y 11 , P2Y 12 , P2Y 13 , and P2Y 14 , which represent current or potential future drug targets. Here we provide a comprehensive overview of ligands for the subgroup of the P2YR family that is activated by uracil nucleotides: P2Y 2 (UTP, also ATP and dinucleotides), P2Y 4 (UTP), P2Y 6 (UDP), and P2Y 14 (UDP, UDP-glucose, UDP-galactose). The physiological agonists are metabolically unstable due to their fast hydrolysis by ectonucleotidases. A number of agonists with increased potency, subtype-selectivity and/or enzymatic stability have been developed in recent years. Useful P2Y 2 R agonists include MRS2698 (6-01, highly selective) and PSB-1114 (6-05, increased metabolic stability). A potent and selective P2Y 2 R antagonist is AR-C118925 (10-01). For studies of the P2Y 4 R, MRS4062 (3-15) may be used as a selective agonist, while PSB-16133 (10-06) represents a selective antagonist. Several potent P2Y 6 R agonists have been developed including 5-methoxyuridine 5'-O-((R p )α-boranodiphosphate) (6-12), PSB-0474 (3-11), and MRS2693 (3-26). The isocyanate MRS2578 (10-08) is used as a selective P2Y 6 R antagonist, although its reactivity and low water-solubility are limiting. With MRS2905 (6-08), a potent and metabolically stable P2Y 14 R agonist is available, while PPTN (10-14) represents a potent and selective P2Y 14 R antagonist. The radioligand [ 3 H]UDP can be used to label P2Y 14 Rs. In addition, several fluorescent probes have been developed. Uracil nucleotide-activated P2YRs show great potential as drug targets, especially in inflammation, cancer, cardiovascular and neurodegenerative diseases. Copyright © 2018. Published by Elsevier Inc.

Generation of cell lines for drug discovery through random activation of gene expression: application to the human histamine H3 receptor.

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Song, J; Doucette, C; Hanniford, D; Hunady, K; Wang, N; Sherf, B; Harrington, J J; Brunden, K R; Stricker-Krongrad, A

2005-06-01

Target-based high-throughput screening (HTS) plays an integral role in drug discovery. The implementation of HTS assays generally requires high expression levels of the target protein, and this is typically accomplished using recombinant cDNA methodologies. However, the isolated gene sequences to many drug targets have intellectual property claims that restrict the ability to implement drug discovery programs. The present study describes the pharmacological characterization of the human histamine H3 receptor that was expressed using random activation of gene expression (RAGE), a technology that over-expresses proteins by up-regulating endogenous genes rather than introducing cDNA expression vectors into the cell. Saturation binding analysis using [125I]iodoproxyfan and RAGE-H3 membranes revealed a single class of binding sites with a K(D) value of 0.77 nM and a B(max) equal to 756 fmol/mg of protein. Competition binding studies showed that the rank order of potency for H3 agonists was N(alpha)-methylhistamine approximately (R)-alpha- methylhistamine > histamine and that the rank order of potency for H3 antagonists was clobenpropit > iodophenpropit > thioperamide. The same rank order of potency for H3 agonists and antagonists was observed in the functional assays as in the binding assays. The Fluorometic Imaging Plate Reader assays in RAGE-H3 cells gave high Z' values for agonist and antagonist screening, respectively. These results reveal that the human H3 receptor expressed with the RAGE technology is pharmacologically comparable to that expressed through recombinant methods. Moreover, the level of expression of the H3 receptor in the RAGE-H3 cells is suitable for HTS and secondary assays.

Evolution of systemic treatment for hormone-sensitive breast cancer: from sequential use of single agents to the upfront administration of drug combinations

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E. N. Imyanitov

2016-01-01

Full Text Available Current standards of treatment of endocrine-dependent cancers (breast cancer (BC, prostate cancer imply sequential use of endocrine therapy and cytotoxic agents: it is believed, that steroid hormone antagonists cease the division of transformed cells and therefore make them resistant to other therapeutic modalities. It is important to recognize that conceptual investigations in this field were carried out dozens of years ago, and often involved relatively non-efficient drugs, imperfect laboratory tests, etc. There are several recent examples of combined use of endocrine therapy and other compounds. The addition of docetaxel (6 cycles to androgen deprivation resulted in significant improvement of overall survival in men with metastatic prostate cancer. Clinical trial involving the combined use of exemestane and everolimus demonstrated promising results. There are ongoing studies on inhibitors of cycline-dependent kinases. Use of these drugs in the beginning of endocrine therapy may significantly delay resistance to the antagonists of estrogen signaling.

New antagonists of LHRH. II. Inhibition and potentiation of LHRH by closely related analogues.

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Bajusz, S; Csernus, V J; Janaky, T; Bokser, L; Fekete, M; Schally, A V

1988-12-01

Modifications of the previously described LHRH antagonists, [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Trp3, D-Cit6, D-Ala10]LHRH and the corresponding D-Hci6 analogue, have been made to alter the hydrophobicity of the N-terminal acetyl-tripeptide portion. Substitution of D-Trp3 with the less hydrophobic D-Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of the D-Cit/D-Hci6 analogues, but it appeared to further improve the toxicity lowering effect of D-Cit/D-Hci6 substitution. Antagonists containing D-Pal(3)3 and D-Cit/D-Hci6 residues, i.e. [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]LHRH (SB-75) and [Ac-D-Nal(2)1, D-Phe(4Cl)2, D-Pal(3)3, D-Hci6, D-Ala10]LHRH (SB-88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with the D-Trp3, D-Arg6 antagonist and related antagonists. Replacement of the N-acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularly in vitro. Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t-butoxycarbonyl (Boc) led to analogues that showed LHRH-potentiating effect. The increase in potency induced by these analogues, e.g. [Moc-D-Nal(2)1, D-Phe(4Cl)2, D-Trp3, D-Cit6, D-Ala10]LHRH and [Boc-D-Phe1, D-Phe(4Cl)2, D-Pal(3)3, D-Cit6, D-Ala10]LHRH, was 170-260% and persisted for more than 2 h when studied in a superfused rat pituitary system.

Sedation and memory: studies with a histamine H-1 receptor antagonist.

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Turner, Claire; Handford, Alison D F; Nicholson, Anthony N

2006-07-01

The influence of sedation on the effect of an H-1 receptor antagonist on various cognitive functions, including memory, were evaluated. Diphenhydramine (50, 75 and 100 mg) and lorazepam (0.5 and 1.5 mg) were given on single occasions to 12 healthy volunteers (six males, six females) aged 20-33 (mean 23.4) years. Subjective assessments of sedation, sleep latencies, digit symbol substitution, choice reaction time, sustained attention and memory recall were studied 1.0 h before and 0.5, 2.0 and 3.5 h after drug ingestion. The study was double blind, placebo controlled and with a crossover design. With all doses of diphenhydramine there was subjective sedation, reduced sleep latencies and impairments in performance on the digit symbol substitution, choice reaction time and sustained attention tasks. No effects were observed with 0.5 mg lorazepam. With 1.5 mg lorazepam there was subjective sedation, fewer digit symbol substitutions, slowed choice reaction time, impaired attention and memory, but no effect on sleep latencies. Contrast analysis of data measured at all time points showed that although there was no difference in the effect of diphenhydramine (100 mg) and lorazepam (1.5 mg) on those tasks without a memory component, response times were slower with lorazepam on those tasks with a memory component. However, both 100 mg diphenhydramine and 1.5 mg lorazepam impaired prompted recall measured at 2 h post-ingestion only. It is considered that impaired memory is not necessarily associated with sedation, and that impairment of memory with drugs that lead to sedation may be effected through neuronal systems independent of those that affect arousal.

Behavioural profiles in the mouse defence test battery suggest anxiolytic potential of 5-HT(1A) receptor antagonists.

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Griebel, G; Rodgers, R J; Perrault, G; Sanger, D J

1999-05-01

Compounds varying in selectivity as 5-HT1A receptor antagonists have recently been reported to produce anxiolytic-like effects comparable to those of benzodiazepines in the mouse elevated plus-maze procedure. In view of the potential clinical significance of these findings, the present experiments compared the behavioural effects of diazepam (0.5-3.0 mg/kg) with those of several non-selective 5-HT1A receptor antagonists [NAN-190, 0.1-3.0 mg/kg, MM-77, 0.03-1.0 mg/kg, (S)-UH-301, 0.3-3.0 mg/kg and pindobind-5-HT1A, 0.03-1.0 mg/kg], and three selective 5-HT1A receptor antagonists (WAY100635, 0.01-3.0 mg/kg, p-MPPI, 0.1-3.0 mg/kg and SL88.0338, 0.3-3.0 mg/kg) in the mouse defence test battery (MDTB). In this well-validated anxiolytic screening test, Swiss mice are directly confronted with a natural threat (a rat) as well as situations associated with this threat. Primary measures taken during and after rat confrontation were flight, risk assessment (RA), defensive threat/attack and escape attempts. Diazepam significantly decreased flight reactions after the rat was introduced into the runway, reduced RA activities of mice chased by the rat, increased RA responses displayed when subjects were constrained in a straight alley and reduced defensive upright postures and biting upon forced contact. All the selective 5-HT1A receptor antagonists and NAN-190 also reduced flight, RA in the chase test, and defensive threat and attack behaviours. (S)-UH-301 and pindobind-5-HT1A reduced RA in the chase test, but only partially modified defensive threat and attack. Unlike the other drugs tested, MM-77 produced significant effects only at doses which also markedly reduced spontaneous locomotor activity, suggesting a behaviourally non-specific action. In contrast to diazepam, the 5-HT1A receptor ligands failed to affect RA in the straight alley test. Following removal of the rat from the test area, only diazepam and (S)-UH-301 reduced escape behaviour (contextual defence) at doses

AM-37 and ST-36 Are Small Molecule Bombesin Receptor Antagonists

OpenAIRE

Terry W. Moody; Nicole Tashakkori; Samuel A. Mantey; Paola Moreno; Irene Ramos-Alvarez; Marcello Leopoldo; Robert T. Jensen

2017-01-01

While peptide antagonists for the gastrin-releasing peptide receptor (BB2R), neuromedin B receptor (BB1R), and bombesin (BB) receptor subtype-3 (BRS-3) exist, there is a need to develop non-peptide small molecule inhibitors for all three BBR. The BB agonist (BA)1 binds with high affinity to the BB1R, BB2R, and BRS-3. In this communication, small molecule BBR antagonists were evaluated using human lung cancer cells. AM-37 and ST-36 inhibited binding to human BB1R, BB2R, and BRS-3 with similar ...

Dopamine antagonists during parturition disrupt maternal care and the retention of maternal behavior in rats.

Science.gov (United States)

Byrnes, Elizabeth M; Rigero, Beth A; Bridges, Robert S

2002-11-01

Brief contact with pups at parturition enables the female rat to establish and retain the full repertoire of maternal behaviors, allowing her to respond rapidly to pups in the future. To determine whether the dopamine system is involved in the retention of maternal behavior, females were continuously infused with dopamine antagonists during the periparturitional period and then allowed either a brief interaction period with pups (3 h) or no interaction with pups (pups removed as they were born). Females were exposed to either the D1-like antagonist SCH 23390 (0.1 or 1.0 mg/kg/day) or the D2-like antagonist clebopride (0.5 or 1.0 mg/kg/day). The high dose of either DA antagonist resulted in significant attenuation of maternal care immediately postpartum. When tested for the retention of maternal behavior 7 days later, however, only the females exposed to the D2 antagonist displayed a delayed response to shown full maternal behavior (FMB) towards donor pups. Thus, while both dopamine receptor subtypes appear necessary for the full and rapid expression of maternal behavior during the early postpartum period, only the D2 receptor subtype appears to be involved in the retention of this behavior.

Shifting to a non-vitamin K antagonist oral anticoagulation agent from vitamin K antagonist in atrial fibrillation.

Science.gov (United States)

Fosbøl, Emil L; Vinding, Naja Emborg; Lamberts, Morten; Staerk, Laila; Gundlund, Anna; Gadsbøll, Kasper; Køber, Lars; Gislason, Gunnar H; Olesen, Jonas Bjerring

2017-06-28

After non-vitamin K antagonist (VKA) oral anticoagulation agents (NOAC) have been approved for thrombo-embolic prophylaxis in non-valvular atrial fibrillation (NVAF), utilization of oral anticoagulants (OAC) in NVAF has changed. Contemporary shifting from a VKA to a NOAC (dabigatran, rivaroxaban, or apixaban) has not been quantified, and could help assess whether these drugs are used according to recommendations. Using Danish nationwide registries, we identified all VKA-experienced NVAF patients initiating a NOAC from 22 August 2011 to 31 December 2015 (shifters) and all VKA-experienced NVAF patients who were not switched to NOACs (non-shifters). Baseline characteristics and temporal utilization trends were examined. We included 62 065 patients with NVAF; of these, 19 386 (29.6%) shifted from a VKA to a NOAC (9973 (54.2%) shifted to dabigatran, 4775 (26.0%) to rivaroxaban, and 3638 (19.8%) to apixaban). Shifting was associated with lower age [odds ratio (OR) 0.95, 95% confidence interval (95% CI) 0.94-0.96 per 5 year increments], female gender (OR 1.33, 95% CI 1.28-1.38), and certain co-morbidities: more often stroke, bleeding, heart failure, and alcohol abuse, and less often hypertension, ischaemic heart disease, and diabetes. Shifting was common and initially dominated by shifting from VKA to dabigatran, but at the end of 2015, most shifters were shifted to rivaroxaban (45%) or apixaban (45%) whereas shifting to dabigatran decreased (to 10%). In a contemporary setting among VKA-experienced NVAF patients; VKA is still prevalent although about 30% by December 2015 had shifted to a NOAC. Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2017. For permissions, please email: journals.permissions@oup.com.

Hypocretin antagonists in insomnia treatment and beyond.

Science.gov (United States)

Ruoff, Chad; Cao, Michelle; Guilleminault, Christian

2011-01-01

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

Effects of combined administration of 5-HT1A and/or 5-HT1B receptor antagonists and paroxetine or fluoxetine in the forced swimming test in rats.

Science.gov (United States)

Tatarczyńska, Ewa; Kłodzińska, Aleksandra; Chojnacka-Wójcik, Ewa

2002-01-01

Clinical data suggest that coadministration of pindolol, a 5-HT1A/5-HT1B/beta-adrenoceptor antagonist, and selective serotonin reuptake inhibitors (SSRIs) may shorten the time of onset of a clinical action and may increase beneficial effects of the therapy of drug-resistant depression. Effects of combined administration of SSRIs and 5-HT receptor ligands are currently evaluated in animal models for the detection of an antidepressant-like activity; however, the obtained results turned out to be inconsistent. The aim of the present study was to investigate effects of a 5-HT1A antagonist (WAY 100635), 5-HT1B antagonists (SB 216641 and GR 127935) or pindolol, given in combination with paroxetine or fluoxetine (SSRIs), in the forced swimming test in rats (Porsolt test). When given alone, paroxetine (10 and 20 mg/kg), fluoxetine (10 and 20 mg/kg), WAY 100635 (0.1 and 1 mg/kg), SB 216641 (2 mg/kg), GR 127935 (10 and 20 mg/kg) and pindolol (4 and 8 mg/kg) did not shorten the immobility time of rats in that test. Interestingly, SB 216641 administered alone at a dose of 4 mg/kg produced a significant reduction of the immobility time in that test. A combination of paroxetine (20 mg/kg) and WAY 100635 or pindolol failed to reveal a significant interaction; on the other hand, when paroxetine was given jointly with SB 216641 (2 mg/kg) or GR 127935 (10 and 20 mg/kg), that combination showed a significant antiimmobility action in the forced swimming test in rats. The active behaviors in that test did not reflect increased general activity because combined administration of both the 5-HT1B antagonists and paroxetine failed to alter the locomotor activity of rats, measured in the open field test. Coadministration of fluoxetine and all the antagonists used did not affect the behavior of rats in the forced swimming test. The obtained results seem to indicate that blockade of 5-HT1B receptors, but not 5-HT1A ones, can facilitate the antidepressant-like effect of paroxetine in the

Interleukin-1-receptor antagonist in type 2 diabetes mellitus

DEFF Research Database (Denmark)