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Sample records for antidepressant drug design

  1. [Antidepressives and antidepressive interactions with other drugs].

    Science.gov (United States)

    Zavrsnik, Davorka; Spirtović, Selma; Becić, Fahir

    2006-01-01

    During the therapy with antidepressive agents, for the reason of its duration, numerous drug-drug interactions may occur. Antidepressive agents inhibit P450 enzyme activity and interfere with other drug metabolism. Many interactions are acceptable from the clinical point of view, and some are seriously dangerous indicating a need for their better knowledge. The aim of this work is to point out the possible interactions between antidepressive agents and other drugs. PMID:16425539

  2. Spadin, a Sortilin-derived peptide: a new concept in the antidepressant drug design

    Directory of Open Access Journals (Sweden)

    Heurteaux Catherine

    2011-07-01

    Full Text Available Depression is the most common of psychiatric illnesses. The design of effective treatments for this disorder is a challenging process. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. Deletion of TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate the fast antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the sortilin receptor and acting through TREK-1 inhibition.

  3. 21 CFR 862.3910 - Tricyclic antidepressant drugs test system.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 8 2010-04-01 2010-04-01 false Tricyclic antidepressant drugs test system. 862... Test Systems § 862.3910 Tricyclic antidepressant drugs test system. (a) Identification. A tricyclic antidepressant drugs test system is a device intended to measure any of the tricyclic antidepressant drugs...

  4. Antidepressant drugs: evaluation of price variation

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    Bhumika Jayantilal Patel

    2015-06-01

    Conclusion: Price variation was wide for antidepressant drugs. Generic drug prescribing can decrease the expenditure of patient on the drug. Prescribers should be provided updated knowledge of the cost of different drugs. Modifications in pharmaceutical policy are required, and prices of the drug should be controlled in effective way for all the drugs. [Int J Basic Clin Pharmacol 2015; 4(3.000: 432-437

  5. Antidepressant Drugs to Electroconvulsive Therapy: Kristina's Story.

    Science.gov (United States)

    Sammons, Kristina M; Abraham, Sam

    2016-08-01

    A mother of three children experienced depression after each delivery. The worst bout occurred after the birth of her third child. Antidepressant drugs helped initially, but a change in dosage caused severe decompensating symptoms that resulted in feelings and thoughts that life is not worth living. Health care providers would not facilitate entry into an inpatient program for help. She was told that unless actively suicidal or homicidal, she could not be admitted to an inpatient unit. None of the prescribed antidepressant medications seemed to work and the physicians said there was nothing else they could do. Family and friends searched for help and found a psychiatrist who recommended electroconvulsive therapy. Kristina tells her story of experiencing depression and recovery. [Journal of Psychosocial Nursing and Mental Health Nursing, 54(8), 43-47.].

  6. Association between antidepressant drug use during pregnancy and child healthcare utilisation

    NARCIS (Netherlands)

    Ververs, T. F.; van Wensen, K.; Freund, M. W.; van der Heide, M.; Visser, G. H. A.; Schobben, A. F. A. M.; de Jong-van den Berg, L. T. W.; Egberts, A. C. G.

    2009-01-01

    Objective To evaluate healthcare utilisation by children who were exposed to antidepressant drug use during pregnancy and those whose mothers stopped using antidepressants before pregnancy compared with a control group. Design Cohort study. Setting Health insurance records in the Netherlands. Popula

  7. Spadin, a sortilin-derived peptide, targeting rodent TREK-1 channels: a new concept in the antidepressant drug design.

    Directory of Open Access Journals (Sweden)

    Jean Mazella

    Full Text Available Current antidepressant treatments are inadequate for many individuals, and when they are effective, they require several weeks of administration before a therapeutic effect can be observed. Improving the treatment of depression is challenging. Recently, the two-pore domain potassium channel TREK-1 has been identified as a new target in depression, and its antagonists might become effective antidepressants. In mice, deletion of the TREK-1 gene results in a depression-resistant phenotype that mimics antidepressant treatments. Here, we validate in mice the antidepressant effects of spadin, a secreted peptide derived from the propeptide generated by the maturation of the neurotensin receptor 3 (NTSR3/Sortilin and acting through TREK-1 inhibition. NTSR3/Sortilin interacted with the TREK-1 channel, as shown by immunoprecipitation of TREK-1 and NTSR3/Sortilin from COS-7 cells and cortical neurons co-expressing both proteins. TREK-1 and NTSR3/Sortilin were colocalized in mouse cortical neurons. Spadin bound specifically to TREK-1 with an affinity of 10 nM. Electrophysiological studies showed that spadin efficiently blocked the TREK-1 activity in COS-7 cells, cultured hippocampal pyramidal neurons, and CA3 hippocampal neurons in brain slices. Spadin also induced in vivo an increase of the 5-HT neuron firing rate in the Dorsal Raphe Nucleus. In five behavioral tests predicting an antidepressant response, spadin-treated mice showed a resistance to depression as found in TREK-1 deficient mice. More importantly, an intravenous 4-d treatment with spadin not only induced a strong antidepressant effect but also enhanced hippocampal phosphorylation of CREB protein and neurogenesis, considered to be key markers of antidepressant action after chronic treatment with selective serotonin reuptake inhibitors. This work also shows the development of a reliable method for dosing the propeptide in serum of mice by using AlphaScreen technology. These findings point out

  8. [Driving fitness in therapy with antidepressive drugs].

    Science.gov (United States)

    Soyka, M; Dittert, S; Gartenmeier, A; Schäfer, M

    1998-04-01

    The driving ability of patients under therapy with antidepressives is seen less restrictive than some years ago. The inhibition of psychomotor performance is of special interest. Some empirical studies point at antidepressives increasing the risk for accidents at least in elderly patients. Different groups of antidepressants apparently show different effects. Tricyclic antidepressants were shown to worsen cognitive and psychomotor performance in some patients while serotonin reuptake inhibitors and some other new antidepressants may cause less behavioral toxicity. Methodological problems in assessing driving ability and some recent findings are discussed. PMID:9587241

  9. Degradation of antidepressant drug fluoxetine in aqueous media by ozone/H2O2 system: process optimization using central composite design.

    Science.gov (United States)

    Aghaeinejad-Meybodi, Abbas; Ebadi, Amanollah; Shafiei, Sirous; Khataee, Alireza; Rostampour, Mohammad

    2015-01-01

    The main objective of this work is the modelling and optimization of antidepressant drug fluoxetine degradation in aqueous solution by ozone/H2O2 process using central composite design. The operational parameters were ozone concentration, initial hydrogen peroxide concentration, reaction time and initial fluoxetine concentration. A good agreement between the predicted values of fluoxetine removal and experimental results were observed (R2=0.976 and Adj-R2=0.955). Pareto analysis indicated that all selected factors and some interactions were effective on the removal efficiency. It was found that the reaction time is the most effective parameter in the ozone/H2O2 process. The maximum removal efficiency (86.14%) was achieved at ozone concentration of 30 mg L(-1), initial H2O2 concentration of 0.02 mM, reaction time of 20 min and initial fluoxetine concentration of 50 mg L(-1) as the optimum conditions.

  10. Antidepressants and local anesthetics: drug interactions of interest to dentistry

    Directory of Open Access Journals (Sweden)

    Lea Rosa Chioca

    2010-10-01

    Full Text Available Introduction: Since there is a vast variety of pharmacological treatments for mental conditions, it has been increasingly more common that patients seeking dentistry treatment are continually using psychoactive drugs as antidepressants. The number of people taking antidepressants is increasing; consequently, dentists should update their knowledge on the interaction between this drug class and those used in dental daily practice, such as local anesthetics and vasoconstrictors. Objective: To conduct a literature review on this subject. Literature review and conclusion: Literature data suggest that sympathomimetic vasoconstrictors (epinephrine, norepinephrine, and phenylephrine associated with local anesthetics may potentiate the side effects of antidepressants, particularly tricyclics and MAO inhibitors, on the cardiovascular system. There are few clinical trials and preclinical studies on this subject, and most of them were carried out between the 60s and 80s. Current studies are needed, since many new antidepressant drugs with different mechanisms of action are currently marketed and being used.

  11. Reconsidering GHB: orphan drug or new model antidepressant?

    Science.gov (United States)

    Bosch, Oliver G; Quednow, Boris B; Seifritz, Erich; Wetter, Thomas C

    2012-05-01

    For six decades, the principal mode of action of antidepressant drugs is the inhibition of monoamine re-uptake from the synaptic cleft. Tricyclic antidepressants, selective serotonin re-uptake inhibitors (SSRIs) and the new generation of dual antidepressants all exert their antidepressant effects by this mechanism. In the early days of the monoaminergic era, other efforts have been made to ameliorate the symptoms of depression by pharmacological means. The gamma-aminobutyric acid (GABA) system was and possibly still is one of the main alternative drug targets. Gammahydroxybutyrate (GHB) was developed as an orally active GABA analogue. It was tested in animal models of depression and human studies. The effects on sleep, agitation, anhedonia and depression were promising. However, the rise of benzodiazepines and tricyclic antidepressants brought GHB out of the scope of possible treatment alternatives. GHB is a GABA(B) and GHB receptor agonist with a unique spectrum of behavioural, neuroendocrine and sleep effects, and improves daytime sleepiness in various disorders such as narcolepsy, Parkinson's disease and fibromyalgia. Although it was banned from the US market at the end of the 1990s because of its abuse and overdose potential, it later was approved for the treatment of narcolepsy. New research methods and an extended view on other neurotransmitter systems as possible treatment targets of antidepressant treatment brought GHB back to the scene. This article discusses the unique neurobiological effects of GHB, its misuse potential and possible role as a model substance for the development of novel pharmacological treatment strategies in depressive disorders.

  12. Antidepressants

    Science.gov (United States)

    Antidepressants are medicines that treat depression. Your doctor can prescribe them for you. They work to balance ... them to help. There are several types of antidepressants. You and your doctor may have to try ...

  13. Impact of Antidepressant Drugs on Sexual Function and Satisfaction.

    Science.gov (United States)

    Baldwin, David S; Manson, Chris; Nowak, Magda

    2015-11-01

    Pleasurable sexual activity is important in many human relationships and can provide a sense of physical, emotional and social well-being. Depressive symptoms and depressive illness are associated with impairments in sexual function and sexual dissatisfaction in untreated and treated patients. Most currently available antidepressant drugs are associated with development or worsening of sexual dysfunction in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts, but can persist over long periods, reducing self-esteem and affecting mood and relationships adversely. Sexual difficulties during antidepressant treatment typically have many possible causes but the incidence and nature of dysfunction varies between drugs. Many interventions can be considered when managing sexual dysfunction associated with antidepressants but no approach is 'ideal'. Because treatment-emergent sexual difficulties are less frequent with certain drugs, presumably related to differences in pharmacological properties, and since current interventions are suboptimal, a lower incidence of sexual dysfunction is a relevant tolerability target when developing novel antidepressants. PMID:26519341

  14. The failure of the antidepressant drug discovery process is systemic.

    Science.gov (United States)

    Hendrie, Colin; Pickles, Alasdair; Stanford, S Clare; Robinson, Emma

    2013-05-01

    Current antidepressants are crude compared with the ideal and patents on most have expired. There are therefore strong clinical and commercial pressures for new drugs to replace them. The prospects for this are, however, now markedly reduced as several major pharmaceutical companies have abandoned work in this area whilst many others have sharply decreased their research investment. These changes and the lack of progress over such a long period are indicative of a catastrophic systems failure which, it is argued, has been caused in large part by a logical flaw at the animal modelling stage. This tautology has served to lock the current antidepressant drug discovery process into an iterative loop capable only of producing further variations of that which has gone before. Drugs produced by this approach have proved to be only poorly effective in the context of the clinically depressed population as a whole. Hence, the inevitable failure of the current antidepressant drug discovery process has left little behind that can be salvaged. Therefore, it is suggested that this be urgently reformulated on more rational grounds using more appropriate species in new animal models based upon a thorough understanding of the behavioural expressions of depression in the clinic.

  15. Antidepressant Drugs for Chronic Urological Pelvic Pain: An Evidence-Based Review

    Directory of Open Access Journals (Sweden)

    Christos Papandreou

    2009-01-01

    Full Text Available The use of antidepressant drugs for the management of chronic pelvic pain has been supported in the past. This study aimed to evaluate the available evidence for the efficacy and acceptability of antidepressant drugs in the management of urological chronic pelvic pain. Studies were selected through a comprehensive literature search. We included all types of study designs due to the limited evidence. Studies were classified into levels of evidence according to their design. Ten studies were included with a total of 360 patients. Amitriptyline, sertraline, duloxetine, nortriptyline, and citalopram are the antidepressants that have been reported in the literature. Only four randomized controlled trials (RCTs were identified (two for amitriptyline and two for sertraline with mixed results. We conclude that the use of antidepressants for the management of chronic urological pelvic pain is not adequately supported by methodologically sound RCTs. From the existing studies amitriptyline may be effective in interstitial cystitis but publication bias should be considered as an alternative explanation. All drugs were generally well tolerated with no serious events reported.

  16. Prediction of drug-drug interactions between various antidepressants and ritonavir using a physiologically based pharmacokinetic model

    Directory of Open Access Journals (Sweden)

    M Siccardi

    2012-11-01

    not or weakly impacted by RTV. Although from a pharmacokinetic point of view, venlafaxine or citalopram represent better candidates for patients on RTV, there are many considerations in seeking to optimize antidepressant therapy. The next stage in this work is to simulate DDI between boosted protease inhibitors and antidepressants. IVIVE is a useful tool for both prediction of drug-drug interactions and design of prospective clinical trials, simulating optimal sample size, and selection of doses.

  17. Profitable failure: antidepressant drugs and the triumph of flawed experiments.

    Science.gov (United States)

    McGoey, Linsey

    2010-01-01

    Drawing on an analysis of Irving Kirsch and colleagues' controversial 2008 article in "PLoS [Public Library of Science] Magazine" on the efficacy of SSRI antidepressant drugs such as Prozac, I examine flaws within the methodologies of randomized controlled trials (RCTs) that have made it difficult for regulators, clinicians and patients to determine the therapeutic value of this class of drug. I then argue, drawing analogies to work by Pierre Bourdieu and Michael Power, that it is the very limitations of RCTs -- their inadequacies in producing reliable evidence of clinical effects -- that help to strengthen assumptions of their superiority as methodological tools. Finally, I suggest that the case of RCTs helps to explore the question of why failure is often useful in consolidating the authority of those who have presided over that failure, and why systems widely recognized to be ineffective tend to assume greater authority at the very moment when people speak of their malfunction.

  18. Provide optimized antidepressant monotherapy with multiple drugs before considering antidepressant polypharmacy

    OpenAIRE

    SAAH, Tammy; Garlow, Steven J.; Rapaport, Mark H.

    2014-01-01

    Summary Many patients with chronic or recurring major depressive disorder have suboptimal responses to the wide range of antidepressant medications available. When confronted with these patients, clinicians may augment the original antidepressant with other medications, including adjunctive treatment with a second or third antidepressant. Although it is a widely-used practice among psychiatrists and primary care physicians in high-income countries, evidence for the benefits of this type of an...

  19. Drug treatment episodes in pharmacoepidemiology - antidepressant use as a model

    NARCIS (Netherlands)

    Gardarsdottir, H.

    2009-01-01

    In the Netherlands, antidepressants are indicated for treating depression, generalized anxiety disorders, obsessive-compulsive disorders, social phobia, panic disorders, eating disorders, neuropathic pain and nocturnal enuresis. In addition, antidepressants are sometimes used for treating off-label

  20. Prescribing Pattern of Antidepressant Drugs among General Practitioners and Psychiatrists: a study from Iran

    OpenAIRE

    Hamid Reza Motevallyzadeh; Mohammad Reza Baneshi; Maryam Rameshk; Nouzar Nakhaee

    2013-01-01

    Aim – This study was aimed to investigate the pattern of antidepressant drugs prescription among general practitioners and psychiatrists of Kerman/Iran with the goal of preventing irrational drug use. Methods – A total of 279737 prescriptions by general practitioners and psychiatrists of Kerman in 2010-2011 were reviewed. The frequency of antidepressant drugs prescription based on patients’ sex and age group (10-year age groups), the prescribed drug group and the prescriber (general practitio...

  1. St. John's wort and antidepressant drug interactions in the elderly.

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    Lantz, M S; Buchalter, E; Giambanco, V

    1999-01-01

    There is increasing interest in and use of the herbal preparation St. John's wort. Hypericin, the major active ingredient, has many psychoactive properties. The agent is sold in the US as a nutritional supplement and is recommended for numerous conditions, including depression, anxiety, insomnia, and inflammation. We report a series of five cases of clinically diagnosed central serotonergic syndrome among elderly patients who combined prescription antidepressants with St. John's wort. Older adults are large consumers of both over-the-counter and prescription medications. They are particularly vulnerable to interactions between medications and products sold as nutritional or herbal supplements. St. John's wort requires further evaluation due to potential for drug interactions with central nervous system agents and for more definitive therapeutic indications.

  2. Drugs, genes and the blues: pharmacogenetics of the antidepressant response from mouse to man.

    Science.gov (United States)

    O'Leary, Olivia F; O'Brien, Fionn E; O'Connor, Richard M; Cryan, John F

    2014-08-01

    While antidepressant drugs are beneficial to many patients, current treatments for depression remain sub-optimal. Up to half of patients with a major depressive episode fail to achieve remission with a first line antidepressant treatment. Identification of the molecular mechanisms that dictate whether a patient will successfully respond to a particular antidepressant treatment while tolerating its side-effects is not only a major challenge in biological psychiatry research but is also one that shows great promise. This review summarises data from both clinical and preclinical studies that point to a role of specific genes in the response and resistance to antidepressant therapeutics. Moreover, we discuss how such findings have increased our understanding of the mechanism of action of antidepressant drugs. Finally, we comment on how this information may potentially influence the future development of personalised medicine approaches for the treatment of depression.

  3. ENZYMATIC RESOLUTION OF ANTIDEPRESSANT DRUG PRECURSORS IN AN UNDERGRADUATE LABORATORY

    Directory of Open Access Journals (Sweden)

    Luís M. R. Solano

    2015-02-01

    Full Text Available The use of biocatalysts in synthetic chemistry is a conventional methodology for preparing enantiomerically enriched compounds. Despite this fact, the number of experiments in chemical teaching laboratories that demonstrate the potential of enzymes in synthetic organic chemistry is limited. We describe a laboratory experiment in which students synthesized a chiral secondary alcohol that can be used in the preparation of antidepressant drugs. This experiment was conducted by individual students as part of a Drug Synthesis course held at the Pharmacy Faculty, Lisbon University. This laboratory experiment requires six laboratory periods, each lasting four hours. During the first four laboratory periods, students synthesized and characterized a racemic ester using nuclear magnetic resonance spectroscopy and gas chromatography. During the last two laboratory periods, they performed enzymatic hydrolysis resolution of the racemic ester using Candida antarctica lipase B to yield enantiomerically enriched secondary alcohol. Students successfully prepared the racemic ester with a 70%-81% overall yield in three steps. The enzymatic hydrolysis afforded (R- secondary alcohol with good enantioselectivity (90%-95% and reasonable yields (10%-19%. In these experiments, students were exposed to theoretical and practical concepts of aromatic acylation, ketone reduction, esterification, and enzymatic hydrolysis.

  4. Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice.

    Science.gov (United States)

    Szopa, Aleksandra; Poleszak, Ewa; Wyska, Elżbieta; Serefko, Anna; Wośko, Sylwia; Wlaź, Aleksandra; Pieróg, Mateusz; Wróbel, Andrzej; Wlaź, Piotr

    2016-02-01

    Caffeine is the most widely used behaviorally active drug in the world which exerts its activity on central nervous system through adenosine receptors. Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. The main goal of the present study was to evaluate the influence of caffeine on animals' behavior in forced swim test (FST) as well as the effect of caffeine (5 mg/kg) on the activity of six typical antidepressants, such as imipramine (15 mg/kg), desipramine (10 mg/kg), fluoxetine (5 mg/kg), paroxetine (0.5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). Locomotor activity was estimated to verify and exclude false-positive/negative results. In order to assess the influence of caffeine on the levels of antidepressant drugs studied, their concentrations were determined in murine serum and brains using high-performance liquid chromatography. The results showed that caffeine at a dose of 10, 20, and 50 mg/kg exhibited antidepressant activity in the FST, and it was not related to changes in locomotor activity in the animals. Caffeine at a dose of 5 mg/kg potentiated the activity of all antidepressants, and the observed effects were not due to the increase in locomotor activity in the animals. The interactions between caffeine and desipramine, fluoxetine, escitalopram, and reboxetine were exclusively of pharmacodynamic character, because caffeine did not cause any changes in the concentrations of these drugs neither in blood serum nor in brain tissue. As a result of joint administration of caffeine and paroxetine, an increase in the antidepressant drug concentrations in serum was observed. No such change was noticed in the brain tissue. A decrease in the antidepressant drug concentrations in brain was observed in the case of imipramine administered together with caffeine. Therefore, it can be assumed that the interactions caffeine-paroxetine and caffeine-imipramine occur at least in

  5. Caffeine enhances the antidepressant-like activity of common antidepressant drugs in the forced swim test in mice.

    Science.gov (United States)

    Szopa, Aleksandra; Poleszak, Ewa; Wyska, Elżbieta; Serefko, Anna; Wośko, Sylwia; Wlaź, Aleksandra; Pieróg, Mateusz; Wróbel, Andrzej; Wlaź, Piotr

    2016-02-01

    Caffeine is the most widely used behaviorally active drug in the world which exerts its activity on central nervous system through adenosine receptors. Worrying data indicate that excessive caffeine intake applies to patients suffering from mental disorders, including depression. The main goal of the present study was to evaluate the influence of caffeine on animals' behavior in forced swim test (FST) as well as the effect of caffeine (5 mg/kg) on the activity of six typical antidepressants, such as imipramine (15 mg/kg), desipramine (10 mg/kg), fluoxetine (5 mg/kg), paroxetine (0.5 mg/kg), escitalopram (2 mg/kg), and reboxetine (2.5 mg/kg). Locomotor activity was estimated to verify and exclude false-positive/negative results. In order to assess the influence of caffeine on the levels of antidepressant drugs studied, their concentrations were determined in murine serum and brains using high-performance liquid chromatography. The results showed that caffeine at a dose of 10, 20, and 50 mg/kg exhibited antidepressant activity in the FST, and it was not related to changes in locomotor activity in the animals. Caffeine at a dose of 5 mg/kg potentiated the activity of all antidepressants, and the observed effects were not due to the increase in locomotor activity in the animals. The interactions between caffeine and desipramine, fluoxetine, escitalopram, and reboxetine were exclusively of pharmacodynamic character, because caffeine did not cause any changes in the concentrations of these drugs neither in blood serum nor in brain tissue. As a result of joint administration of caffeine and paroxetine, an increase in the antidepressant drug concentrations in serum was observed. No such change was noticed in the brain tissue. A decrease in the antidepressant drug concentrations in brain was observed in the case of imipramine administered together with caffeine. Therefore, it can be assumed that the interactions caffeine-paroxetine and caffeine-imipramine occur at least in

  6. Testing the antidepressant properties of the peptide ARA290 in a human neuropsychological model of drug action

    DEFF Research Database (Denmark)

    Cerit, Hilâl; Veer, Ilya M; Dahan, Albert;

    2015-01-01

    such hematopoietic side-effects but may have neurotrophic and antidepressant effects. The aim of this study was to investigate the possible antidepressant effects of ARA290 in a neuropsychological model of drug action. Healthy participants (N=36) received ARA290 (2mg) or placebo in a double-blind, randomized......, parallel-group design. Neural and cognitive effects were assessed one week after administration. Primary outcome measures were the neural processing of fearful vs happy faces and the behavioral recognition of emotional facial expressions. ARA290-treated individuals displayed lower neural responses to happy...... positive emotional pictures. No effects were observed on mood and affective symptoms. ARA290 may modulate some aspects of emotional processing, however, the direction and the strength of its effects do not unequivocally support an antidepressant-like profile for ARA290. Future studies may investigate...

  7. Binding of the Multimodal Antidepressant Drug Vortioxetine to the Human Serotonin Transporter

    DEFF Research Database (Denmark)

    Andersen, Jacob; Ladefoged, Lucy Kate; Wang, Danyang;

    2015-01-01

    Selective inhibitors of the human serotonin transporter (hSERT) have been first-line treatment against depression for several decades. Recently, vortioxetine was approved as a new therapeutic option for the treatment of depression. Vortioxetine represents a new class of antidepressant drugs with ......-based drug discovery of novel multimodal drugs with fine-tuned selectivity across different transporter and receptor proteins in the human brain.......Selective inhibitors of the human serotonin transporter (hSERT) have been first-line treatment against depression for several decades. Recently, vortioxetine was approved as a new therapeutic option for the treatment of depression. Vortioxetine represents a new class of antidepressant drugs...

  8. A STUDY ON BIOPOLYMERIC NANOPARTICLES AS AN EFFECTIVE CARRIER FOR ANTIDEPRESSANT DRUG DELIVERY SYSTEM

    Directory of Open Access Journals (Sweden)

    A. Anita Margret* and S. Aishwarya

    2012-04-01

    Full Text Available Drug delivery is the most essential feature in drug administration facility and the design of Nanosystems makes the action more consistent an appropriate. Polymer nano particles bind efficiently to the drug and disperse the drug proficiently into the system. The efficacy of many drugs is often limited by their potential to reach the site of therapeutic action. In most cases (conventional dosage forms, only a small amount of administered dose reaches the target site, while the majority of the drug distributes throughout the rest of the body in accordance with its physicochemical and biochemical properties. Therefore, developing a drug delivery system that optimizes the pharmaceutical action of a drug while reducing its toxic side effects in vivo is a challenging task. This study focuses on the preparation and characterization of biopolymeric alginate and chitosan nanoparticles for encapsulating the antidepressant drug Venlafaxine XR and analyzing it as an effective drug carrier and delivery system. The study reports a method to predict the encapsulation efficiency of chitosan as an effective biopolymer. The profiles of FTIR’s spectra reveal the entrapment of chitosan, alginate and Venlafaxine XR. A comparative analysis was done by isolating chitosan from mushrooms and with that of commercially obtained chitosan. The distinct peak values enumerate the similarity in both the chitosans assayed. The binding affinity for the compounds chitosan and Alginate proves to be good and binding energy was found to be 0.21K Cal/mol. The Quantitative Structure Activity Relationship of the two compounds chitosan and alginate satisfied all the necessary parameters of LIPINSKI’S rule of five. It was observed that strong electrostatic interaction exists in the nanoparticles. Quantification of the drugs in a nano scale improves the dispersal and absorption rate of the drug. Entrapment of the drug venlafaxine XR is also significant because depression is nowadays

  9. Drug Design and Emotion

    Science.gov (United States)

    Folkers, Gerd; Wittwer, Amrei

    2007-11-01

    "Geteiltes Leid ist halbes Leid." The old German proverb reflects the fact that sharing a bad emotion or feeling with someone else may lower the psychological strain of the person experiencing sorrow, mourning or anger. On the other hand the person showing empathy will take literally a load from its counterpart, up to physiological reaction of the peripheral and central nervous pain system. Though subjective, mental and physical states can be shared. Visual perception of suffering may be important but also narrative description plays a role, all our senses are mixing in. It is hypothetized that literature, art and humanities allow this overlap. A change of mental states can lead to empirically observable effects as it is the case for the effect of role identity or placebo on pain perception. Antidepressants and other therapeutics are another choice to change the mental and bodily states. Their development follows today's notion of "rationality" in the design of therapeutics and is characterized solely by an atomic resolution approach to understand drug activity. Since emotional states and physiological states are entangled, given the difficulty of a physical description of emotion, the future rational drug design should encompass mental states as well.

  10. Acute antidepressant drug administration and autobiographical memory recall

    DEFF Research Database (Denmark)

    Papadatou-Pastou, Marietta; Miskowiak, Kamilla W; Williams, J Mark G;

    2012-01-01

    Antidepressants affect memory and neural responses to emotionally valenced stimuli in healthy volunteers. However, it is unclear whether this extends to autobiographical memory for personally experienced events. The current study investigated the effects of acute administration of the antidepress......Antidepressants affect memory and neural responses to emotionally valenced stimuli in healthy volunteers. However, it is unclear whether this extends to autobiographical memory for personally experienced events. The current study investigated the effects of acute administration...... in the processing of positive versus negative memories was reduced following reboxetine compared with placebo in the left frontal lobe (extending into the insula) and the right superior temporal gyrus. This was paired with increased memory speed in volunteers given reboxetine versus placebo. The effect...

  11. The discovery of antidepressant drugs by computer-analyzed human cerebral bio-electrical potentials (CEEG).

    Science.gov (United States)

    Itil, T M

    1983-01-01

    Antidepressant properties of six compounds were predicted based on their computer-analyzed human electroencephalographical (CEEG) profiles. The clinical investigations with mianserin (GB-94) confirmed the CEEG prediction. This compound has now been marketed as the first antidepressant of which the clinical effects were discovered solely by the quantitative pharmaco-EEG method. As predicted by the CEEG, clinical antidepressant properties of GC-46, mesterolone, and estradiol valerate were observed in preliminary investigations. No extensive studies with definite statistical results were yet carried out with these compounds. No systematic large studies could be conducted with cyclozocine and cyproterone acetate because of the intolerable side effects with these compounds. The optical isomers of mianserin, GF-59 and GF-60, both predicted as antidepressant by the computer EEG data base, have not yet been tested in depressive patients. None of these compounds possess the "typical" pharmacological and/or biochemical profiles of marketed antidepressants. Thus, the discovery of the established antidepressant properties of mianserin (GB-94) by computer analyzed EEG method challenges the well-known biochemical hypotheses of depression and the "classical" development of antidepressant drugs. PMID:6142498

  12. The discovery of antidepressant drugs by computer-analyzed human cerebral bio-electrical potentials (CEEG).

    Science.gov (United States)

    Itil, T M

    1983-01-01

    Antidepressant properties of six compounds were predicted based on their computer-analyzed human electroencephalographical (CEEG) profiles. The clinical investigations with mianserin (GB-94) confirmed the CEEG prediction. This compound has now been marketed as the first antidepressant of which the clinical effects were discovered solely by the quantitative pharmaco-EEG method. As predicted by the CEEG, clinical antidepressant properties of GC-46, mesterolone, and estradiol valerate were observed in preliminary investigations. No extensive studies with definite statistical results were yet carried out with these compounds. No systematic large studies could be conducted with cyclozocine and cyproterone acetate because of the intolerable side effects with these compounds. The optical isomers of mianserin, GF-59 and GF-60, both predicted as antidepressant by the computer EEG data base, have not yet been tested in depressive patients. None of these compounds possess the "typical" pharmacological and/or biochemical profiles of marketed antidepressants. Thus, the discovery of the established antidepressant properties of mianserin (GB-94) by computer analyzed EEG method challenges the well-known biochemical hypotheses of depression and the "classical" development of antidepressant drugs.

  13. Prevalence and patterns of antidepressant drug use during pregnancy

    NARCIS (Netherlands)

    Ververs, Tessa; Kaasenbrood, Hans; Visser, Gerard; Schobben, Fred; de Jong-van den Berg, Lolkje T. W.; Egberts, Toine

    2006-01-01

    Objective The aim of this study was to determine the extent and patterns of antidepressant use before, during and after pregnancy in a large population in The Netherlands. Methods Health care records and prescription data from one of the largest Dutch health insurance companies were analysed. The st

  14. Extrapyramidal symptoms and antidepressant drugs: neuropharmacological aspects of a frequent interaction in the elderly.

    Science.gov (United States)

    Govoni, S; Racchi, M; Masoero, E; Zamboni, M; Ferini-Strambi, L

    2001-03-01

    Depression is the most prevalent functional psychiatric disorder in late life. The problem of motor disorders associated with antidepressant use is relevant in the elderly. Elderly people are physically more frail and more likely to be suffering from physical illness, and any drug given may exacerbate pre-existing diseases, or interact with other drug treatments being administered for physical conditions. Antidepressants have been reported to induce extrapyramidal symptoms, including parkinsonism. These observations prompted us to review the neurobiological mechanism that may be involved in this complex interplay including neurotransmitters and neuronal circuits involved in movement and emotion control and their changes related to aging and disease. The study of the correlations between motor and mood disorders and their putative biochemical bases, as presented in this review, provide a rationale either to understand or to foresee motor side effects for psychotropic drugs, in particular antidepressants. PMID:11317214

  15. Antidepressant drugs specifically inhibiting noradrenaline reuptake enhance recognition memory in rats.

    Science.gov (United States)

    Feltmann, Kristin; Konradsson-Geuken, Åsa; De Bundel, Dimitri; Lindskog, Maria; Schilström, Björn

    2015-12-01

    Patients suffering from major depression often experience memory deficits even after the remission of mood symptoms, and many antidepressant drugs do not affect, or impair, memory in animals and humans. However, some antidepressant drugs, after a single dose, enhance cognition in humans (Harmer et al., 2009). To compare different classes of antidepressant drugs for their potential as memory enhancers, we used a version of the novel object recognition task in which rats spontaneously forget objects 24 hr after their presentation. Antidepressant drugs were injected systemically 30 min before or directly after the training phase (Session 1 [S1]). Post-S1 injections were used to test for specific memory-consolidation effects. The noradrenaline reuptake inhibitors reboxetine and atomoxetine, as well as the serotonin noradrenaline reuptake inhibitor duloxetine, injected prior to S1 significantly enhanced recognition memory. In contrast, the serotonin reuptake inhibitors citalopram and paroxetine and the cyclic antidepressant drugs desipramine and mianserin did not enhance recognition memory. Post-S1 injection of either reboxetine or citalopram significantly enhanced recognition memory, indicating an effect on memory consolidation. The fact that citalopram had an effect only when injected after S1 suggests that it may counteract its own consolidation-enhancing effect by interfering with memory acquisition. However, pretreatment with citalopram did not attenuate reboxetine's memory-enhancing effect. The D1/5-receptor antagonist SCH23390 blunted reboxetine's memory-enhancing effect, indicating a role of dopaminergic transmission in reboxetine-induced recognition memory enhancement. Our results suggest that antidepressant drugs specifically inhibiting noradrenaline reuptake enhance cognition and may be beneficial in the treatment of cognitive symptoms of depression. PMID:26501179

  16. Fear erasure in mice requires synergy between antidepressant drugs and extinction training.

    Science.gov (United States)

    Karpova, Nina N; Pickenhagen, Anouchka; Lindholm, Jesse; Tiraboschi, Ettore; Kulesskaya, Natalia; Agústsdóttir, Arna; Antila, Hanna; Popova, Dina; Akamine, Yumiko; Bahi, Amine; Sullivan, Regina; Hen, René; Drew, Liam J; Castrén, Eero

    2011-12-23

    Antidepressant drugs and psychotherapy combined are more effective in treating mood disorders than either treatment alone, but the neurobiological basis of this interaction is unknown. To investigate how antidepressants influence the response of mood-related systems to behavioral experience, we used a fear-conditioning and extinction paradigm in mice. Combining extinction training with chronic fluoxetine, but neither treatment alone, induced an enduring loss of conditioned fear memory in adult animals. Fluoxetine treatment increased synaptic plasticity, converted the fear memory circuitry to a more immature state, and acted through local brain-derived neurotrophic factor. Fluoxetine-induced plasticity may allow fear erasure by extinction-guided remodeling of the memory circuitry. Thus, the pharmacological effects of antidepressants need to be combined with psychological rehabilitation to reorganize networks rendered more plastic by the drug treatment.

  17. Drug use pattern of antidepressant agents in psychiatric patients – A prospective study

    Directory of Open Access Journals (Sweden)

    Aksha Memon

    2013-07-01

    Full Text Available Background: Depression is a major public health problem. It causes clinically significant distress, impairment of social, occupational or other important areas of function. Objective: To evaluate the prescribing pattern of antidepressant agents in patients attending psychiatry OPD at a tertiary care teaching hospital. Method: A prospective study was carried out at psychiatry outpatient department (OPD at VS General Hospital for 6 months. Patients who were prescribed any of the antidepressant medications irrespective of clinical indication either as monotherapy or in combination with other psychotherapeutic agents were included in the study. Result: Total 455 patients were enrolled for 6 months. Major Depressive Disorder (MDD was the most common diagnosis (85.93%. Tricyclic antidepressants (TCAs was the most commonly prescribed drug group (56.7% followed by selective serotonin reuptake inhibitors (SSRIs (46.8%. Amongst TCAs, imipramine was most frequently prescribed drug (65.89% followed by sertraline (56.8% among the SSRIs. Both the TCAs and newer antidepressants were prescribed with equal frequencies. Conclusion: Amongst antidepressants most frequently prescribed medication was imipramine followed by sertraline.

  18. Intra-lateral septal infusions of folic acid alone or combined with various antidepressant drugs produce antidepressant-like actions in male Wistar rats forced to swim.

    Science.gov (United States)

    Molina-Hernández, Miguel; Téllez-Alcántara, N Patricia; Olivera-López, Jorge I; Jaramillo, M Teresa

    2012-01-10

    Intra-cerebral administrations of folic acid produce antidepressant-like effects; either alone or combined with several antidepressant drugs. However, the specific limbic structures implied in the antidepressant-like actions of folic acid are un-known. Thus, intra-lateral septal infusions of folic acid (5.0 nmol, Pimmobility by increasing swimming behavior in the forced swimming test (FST) of male Wistar rats. Conversely, desipramine (10.0 mg/kg, Pimmobility by increasing climbing behavior. Subthreshold doses of folic acid (2.5 nmol/intra-LSN) combined with subthreshold doses of folic acid (25.0 mg/kg, p.o., Pimmobility in the FST. These antidepressant-like actions, probably, were due to modifications of the serotonergic system since swimming behavior was increased and these effects were canceled by ketanserin.

  19. The Utility of Impulsive Bias and Altered Decision Making as Predictors of Drug Efficacy and Target Selection: Rethinking Behavioral Screening for Antidepressant Drugs.

    Science.gov (United States)

    Marek, Gerard J; Day, Mark; Hudzik, Thomas J

    2016-03-01

    Cognitive dysfunction may be a core feature of major depressive disorder, including affective processing bias, abnormal response to negative feedback, changes in decision making, and increased impulsivity. Accordingly, a translational medicine paradigm predicts clinical action of novel antidepressants by examining drug-induced changes in affective processing bias. With some exceptions, these concepts have not been systematically applied to preclinical models to test new chemical entities. The purpose of this review is to examine whether an empirically derived behavioral screen for antidepressant drugs may screen for compounds, at least in part, by modulating an impulsive biasing of responding and altered decision making. The differential-reinforcement-of-low-rate (DRL) 72-second schedule is an operant schedule with a documented fidelity for discriminating antidepressant drugs from nonantidepressant drugs. However, a theoretical basis for this empirical relationship has been lacking. Therefore, this review will discuss whether response bias toward impulsive behavior may be a critical screening characteristic of DRL behavior requiring long inter-response times to obtain rewards. This review will compare and contrast DRL behavior with the five-choice serial reaction time task, a test specifically designed for assessing motoric impulsivity, with respect to psychopharmacological testing and the neural basis of distributed macrocircuits underlying these tasks. This comparison suggests that the existing empirical basis for the DRL 72-second schedule as a pharmacological screen for antidepressant drugs is complemented by a novel hypothesis that altering impulsive response bias for rodents trained on this operant schedule is a previously unrecognized theoretical cornerstone for this screening paradigm. PMID:26699144

  20. Genotoxicity induced by drug-drug interaction between the antidepressant sertraline and the antibiotic erythromycin in micebone marrow cells.

    Directory of Open Access Journals (Sweden)

    Amany A. Tohamy

    2006-03-01

    Full Text Available Drug-drug interaction represents a widely distributed health problem. The pharmacological action and side effects of two or more drugs can act additively or antagonistically. The present study was designed to evaluate the possible genotoxicity of concurrent treatment with the antidepressant sertraline, one of the serotonin reuptake inhibitors (SSRI and the broad spectrum macrolide antibiotic erythromycin. Sertraline and erythromycin are metabolized through CYP3A4 which is one of the cytochrome P-450 enzymes in liver and are responsible for the metabolism of large number of endogenous substrates and therapeutic agents. The frequency of micronucleated polychromatic erythrocytes (MNPCEs, micronucleated normochromatic erythrocytes (MNNCEs and the ratio PCE/NCE were evaluated to measure the genotoxicity of separate and combined treatment with the tested two drugs. Clinical doses of both sertraline (0.71 mg /kg b.w. and erythromcyin strearate (14.30 mg / kg b.w. were used. Groups of animals received single separate or combined doses of either sertraline and/or erythromycin, and sacrificed after 24 hours. Other groups of mice were treated in the same way but for five consecutive days and sacrificed 24 hours after the last injection. In all treated groups, the percentage of PCEs increased significantly when compared with that of the negative control group which may indicate a stimulation of proliferative activity to an early phase of cell depletion. The genotoxicity of multiple treatment for 5 consecutive days with sertraline alone or in combination with erythromcyin was expressed in increased number of MNPCEs. The observed increased genotoxicity after multiple combined treatment with sertraline and erythromycin may indicate increased risk of toxicity-based drug-drug interaction. This toxicity may be due to the ability of sertraline and erythromycin to inhibit the activity of CYP3A4 which lead to a prolonged storage period of drugs in the body and hence

  1. Brain ischemia changes the long term response to antidepressant drugs in mice.

    Science.gov (United States)

    Deplanque, Dominique; Venna, Venugopal Reddy; Bordet, Régis

    2011-06-01

    Depression is a frequent but often unrecognized and under treated complication of stroke that has scarcely been investigated in animal models particularly regarding treatment issues. Using the Forced Swim Test (FST) and testing spontaneous motor activity, we studied whether a transient focal cerebral ischemia modifies mice behaviours and antidepressant drug effects. We first evaluated whether FST realized 2 days or 1 week after brain reperfusion may be routinely used in male Swiss mice previously submitted to a 15, 30 or 60-min transient occlusion of the right middle cerebral artery. We then evaluated behavioural changes up to 5 weeks in mice previously submitted to a 15-min ischemia. Behaviours according to the administration of imipramine or fluvoxamine at 1 and 5 weeks after a 15-min ischemia were finally evaluated. Transient ischemia was associated with a decrease in immobility in the FST performed 2 days after reperfusion while no changes were observed in 1 and 5 weeks post-ischemia groups. Changes were related neither to brain ischemia duration nor to infarct volume. At both 1 and 5 weeks after brain ischemia, a dramatic decrease in the antidepressant response to imipramine related to a decrease in climbing behaviour was observed while the effects of fluvoxamine were improved through an increase in both climbing and swimming. Behaviours in the FST were unrelated to any spontaneous motor activity changes. Responses to anti-depressant drugs are strongly modified in mice previously submitted to brain ischemia. Present results underline that not all antidepressant drugs are appropriate after ischemic stroke.

  2. Identification of antidepressant drug leads through the evaluation of marine natural products with neuropsychiatric pharmacophores

    OpenAIRE

    Diers, Jeffrey A.; Ivey, Kelly D.; El-Alfy, Abir; Shaikh, Jamaluddin; Wang, Jiajia; Kochanowska, Anna J.; Stoker, John F.; Mark T. Hamann; Matsumoto, Rae R.

    2007-01-01

    The marine environment is a valuable resource for drug discovery due to its diversity of life and associated secondary metabolites. However, there is very little published data on the potential application of marine natural products to treat neuropsychiatric disorders. Many natural products derived from chemically defended organisms in the marine environment have pharmacophores related to serotonin or clinically utilized antidepressant drugs. Therefore, in the present study, compounds selecte...

  3. Repeatedly administered antidepressant drugs modulate humoral and cellular immune response in mice through action on macrophages.

    Science.gov (United States)

    Nazimek, Katarzyna; Kozlowski, Michael; Bryniarski, Pawel; Strobel, Spencer; Bryk, Agata; Myszka, Michal; Tyszka, Anna; Kuszmiersz, Piotr; Nowakowski, Jaroslaw; Filipczak-Bryniarska, Iwona

    2016-08-01

    Depression is associated with an altered immune response, which could be normalized by antidepressant drugs. However, little is known about the influence of antidepressants on the peripheral immune response and function of macrophages in individuals not suffering from depression. Our studies were aimed at determining the influence of antidepressant drugs on the humoral and cellular immune response in mice. Mice were treated intraperitoneally with imipramine, fluoxetine, venlafaxine, or moclobemide and contact immunized with trinitrophenyl hapten followed by elicitation and measurement of contact sensitivity by ear swelling response. Peritoneal macrophages from drug-treated mice were either pulsed with sheep erythrocytes or conjugated with trinitrophenyl and transferred into naive recipients to induce humoral or contact sensitivity response, respectively. Secretion of reactive oxygen intermediates, nitric oxide, and cytokines by macrophages from drug-treated mice was assessed, respectively, in chemiluminometry, Griess-based colorimetry and enzyme-linked immunosorbent assay, and the expression of macrophage surface markers was analyzed cytometrically. Treatment of mice with fluoxetine, venlafaxine, and moclobemide results in suppression of humoral and cell-mediated immunity with a reduction of the release of macrophage proinflammatory mediators and the expression of antigen-presentation markers. In contrast, treatment with imipramine enhanced the humoral immune response and macrophage secretory activity but slightly suppressed active contact sensitivity. Our studies demonstrated that systemically delivered antidepressant drugs modulate the peripheral humoral and cell-mediated immune responses, mostly through their action on macrophages. Imipramine was rather proinflammatory, whereas other tested drugs expressed immunosuppressive potential. Current observations may be applied to new therapeutic strategies dedicated to various disorders associated with excessive

  4. Recent advances in the understanding of the interaction of antidepressant drugs with serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Andersen, Jacob; Kristensen, Anders Skov; Bang-Andersen, Benny;

    2009-01-01

    The biogenic monoamine transporters are integral membrane proteins that perform active transport of extracellular dopamine, serotonin and norepinephrine into cells. These transporters are targets for therapeutic agents such as antidepressants, as well as addictive substances such as cocaine...... and amphetamine. Seminal advances in the understanding of the structure and function of this transporter family have recently been accomplished by structural studies of a bacterial transporter, as well as medicinal chemistry and pharmacological studies of mammalian transporters. This feature article focuses...... on antidepressant drugs that act on the serotonin and/or the norepinephrine transporters. Specifically, we focus on structure-activity relationships of these drugs with emphasis on relationships between their molecular properties and the current knowledge of transporter structure....

  5. The Comparison of Efficacy of Tricyclic Antidepressant with and without Non Steroidal Anti Inflammatory Drugs in Chronic Low Back Pain

    OpenAIRE

    A.R. Yavarikia

    2007-01-01

    Introduction & Objectives: Low back pain (LBP) is one of common medical problems with several accepted medical modalities such as drugs, physiotherapy, surgery, etc. We studied the efficacy of tricyclic antidepressant (TCA), and tricyclic antidepressant plus non steroidal anti inflammatory drugs (TCA + NSAID) in 200 patients with chronic LBP. Materials & Methods: In an experimental clinical trial study on patients with chronic low back pain without organic findings, patients were divided in t...

  6. Ten years after the FDA black box warning for antidepressant drugs: a critical narrative review

    Directory of Open Access Journals (Sweden)

    Juan Carlos Martínez-Aguayo

    2016-06-01

    Full Text Available ABSTRACT Background The United States Food and Drug Administration (FDA has warned about the increased suicidality risk associated with the use of selective serotonin reuptake inhibitors (SSRI and venlafaxine in children and adolescents. Objectives To critically appraise the available evidence supporting the FDA Black box warning concerning to the use of antidepressants in child and adolescents. Methods A critical review of articles in Medline/PubMed and SciELO databases regarding the FDA Black box warning for antidepressants, and the impact of FDA warnings on antidepressant prescriptions and suicide rates. Results The warning was based on surveys that did not report either cases of suicide nor a significant difference supporting an increased suicidality rate. The concept was defined in an ambiguous way and there is currently more available evidence to support such definition. The use of SSRI and venlafaxine has been associated to lower suicidality rates, but the prescription fall due to the warning increased suicide rates. Discussion Suicidality is an inherent feature of depressive disorders so it would be desirable to consider how much of the phenomenon may be attributed to antidepressants per se. It would be appropriate to consider that suicide rates might increase also as a consequence of the warning.

  7. Involvement of prolactin and somatostatin in depression and the mechanism of action of antidepressant drugs.

    Science.gov (United States)

    Faron-Górecka, Agata; Kuśmider, Maciej; Solich, Joanna; Kolasa, Magdalena; Szafran, Kinga; Zurawek, Dariusz; Pabian, Paulina; Dziedzicka-Wasylewska, Marta

    2013-01-01

    Neuropeptides have been implicated in the physiology and pathophysiology of stress responses and therefore may play an important role in the pathogenesis of affective disorders such as Major Depression Disorder (MDD). The data presented in this mini-review demonstrate the role of prolactin (PRL) and somatostatin (STT) in the pathology and pharmacotherapy of MDD, focusing particularly on the response to antidepressant treatment, and compare the available data with the results obtained in our laboratory using the well-validated chronic mild stress (CMS) animal model of MDD. Despite the availability of many pharmacological therapies for depression, ca. 35% patients remain treatment resistant. This clinical situation is also true for rats subjected to CMS; some animals do not respond to antidepressant therapy and are considered treatment resistant. The most interesting results presented in this mini-review concern the changes in PRL and SST receptors in the brains of rats subjected to the full CMS procedure and IMI treatment and demonstrate the role of these receptors in the mechanisms of antidepressant action. The possible interaction between SST and PRL, the involvement of the D2 dopamine receptor, and their direct protein-protein interactions are also discussed, with the conclusion that these two neurohormones play an important role in the mechanism of resilience after stress as well as in the mechanism of action of antidepressant drugs.

  8. Pharmacoscintigraphic evaluation of potential of lipid nanocarriers for nose-to-brain delivery of antidepressant drug.

    Science.gov (United States)

    Alam, M Intakhab; Baboota, Sanjula; Ahuja, Alka; Ali, Mushir; Ali, Javed; Sahni, Jasjeet K; Bhatnagar, Aseem

    2014-08-15

    Efficacy of antidepressants relies upon their continued presence at the site of action (brain) over a prolonged period of time. The BBB restricts the access of antidepressants to the brain on oral as well as intravenous administration. Direct delivery (by-passing the BBB) of antidepressant drugs can increase the CSF concentration with concomitant reduction in dose and side effects. Intranasal administration of nanostructured lipid carriers (NLC) containing antidepressant drug circumvent the BBB and maintain the prolonged release at the site of action. The aim of the present study was to evaluate the enhancement in brain uptake of NLC containing duloxetine (DLX) after intranasal administration. Duloxetine loaded NLC (DLX-NLC) was evaluated pharmacoscintigraphically for drug targeting potential (DTP), drug targeting efficiency (DTE) and biodistribution studies in different organs including brain. The radiolabeling efficiency of DLX and DLX-NLC was found to be 98.41 ± 0.96 and 98.87 ± 0.82 after 30 min, respectively. The biodistribution studies exhibited higher percentage of radioactivity/g for DLX-NLC formulations in brain as compared with the DLX. The higher DTP (86.80%) and DTE (757.74%) suggested that DLX-NLC formulation has a better brain targeting efficiency than DLX solution (DTP=65.12%; DTE=287.34%) when administered intranasally. Moreover, the intranasal administration exhibited about 8-times higher concentration of DLX in brain when compared with the intravenous administration of DLX solution. The intranasal NLC containing DLX can be employed as an effective method for the treatment of depression.

  9. Treating Depression: Should You Consider an Antidepressant?

    Science.gov (United States)

    Treating Depression: Should You Consider An Antidepressant? What are antidepressants? Antidepressants are drugs used to treat the symptoms of depression. Do I need an antidepressant? You probably do not ...

  10. Antidepressant chronotherapeutics in a group of drug free outpatients.

    Science.gov (United States)

    Dallaspezia, Sara; van Jaarsveld, Astrid

    2016-07-30

    The combination of Total Sleep Deprivation (TSD) and Light Therapy (LT) has been shown to prevent the early relapses characterizing response to TSD. Despite their proved efficacy, TSD and LT are still far from being considered standard therapy in the inpatient units and no study has assessed their efficacy and feasibility in outpatient settings. We studied 27 drug-free out-patients affected by Major Depression, divided in 7 groups according to the date of the wake night. Patients were administered one night of TSD and received LT during consecutive mornings following a predictive algorithm based on Morningness-Eveningness Questionnaire scores. Severity of depression was rated on Back Depression Inventory Scale (BDI) at baseline, one week and three months after the end of treatment. BDI scores significantly decreased during treatment with no difference between the seven consecutively treated groups of patients. Significant differences in BDI scores were confirmed between the baseline and both one week and three months after the end of treatment. TSD and LT caused a significant amelioration of depressive symptoms in an outpatient setting. Similar effects were observed in seven independent groups, suggesting that there is repeatability in findings. Chronotherapeutics confirmed their efficacy in the treatment of depression. PMID:27173655

  11. Effect of molecular structure on the hydration of structurally related antidepressant drugs

    Science.gov (United States)

    Cheema, M. A.; Taboada, P.; Barbosa, S.; Siddiq, M.; Mosquera, V.

    Apparent molal volumes and adiabatic compressibilities of aqueous solutions of the amphiphilic cationic antidepressant drugs butriptyline and doxepin hydrochlorides have been determined from density and ultrasound velocity measurements in the temperature range 20-50°C. Critical concentrations for aggregation of these drugs were obtained from ultrasound velocity measurements. Negative deviations from the Debye-Hückel limiting law of the apparent molal volume were obtained from both drugs in all temperature ranges, except for doxepin at 50°C, which provides evidence of no pre-association at concentrations below the critical concentration. Apparent molal adiabatic compressibilities of the aggregates formed by these drugs were typical of those corresponding for an aggregate formed by a stacking process.

  12. Potential of Glutamate-Based Drug Discovery for Next Generation Antidepressants

    Directory of Open Access Journals (Sweden)

    Shigeyuki Chaki

    2015-09-01

    Full Text Available Recently, ketamine has been demonstrated to exert rapid-acting antidepressant effects in patients with depression, including those with treatment-resistant depression, and this discovery has been regarded as the most significant advance in drug development for the treatment of depression in over 50 years. To overcome unwanted side effects of ketamine, numerous approaches targeting glutamatergic systems have been vigorously investigated. For example, among agents targeting the NMDA receptor, the efficacies of selective GluN2B receptor antagonists and a low-trapping antagonist, as well as glycine site modulators such as GLYX-13 and sarcosine have been demonstrated clinically. Moreover, agents acting on metabotropic glutamate receptors, such as mGlu2/3 and mGlu5 receptors, have been proposed as useful approaches to mimicking the antidepressant effects of ketamine. Neural and synaptic mechanisms mediated through the antidepressant effects of ketamine have been being delineated, most of which indicate that ketamine improves abnormalities in synaptic transmission and connectivity observed in depressive states via the AMPA receptor and brain-derived neurotrophic factor-dependent mechanisms. Interestingly, some of the above agents may share some neural and synaptic mechanisms with ketamine. These studies should provide important insights for the development of superior pharmacotherapies for depression with more potent and faster onsets of actions.

  13. Initial severity and antidepressant benefits: a meta-analysis of data submitted to the Food and Drug Administration.

    Directory of Open Access Journals (Sweden)

    Irving Kirsch

    2008-02-01

    Full Text Available BACKGROUND: Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included, the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials. METHODS AND FINDINGS: We obtained data on all clinical trials submitted to the US Food and Drug Administration (FDA for the licensing of the four new-generation antidepressants for which full datasets were available. We then used meta-analytic techniques to assess linear and quadratic effects of initial severity on improvement scores for drug and placebo groups and on drug-placebo difference scores. Drug-placebo differences increased as a function of initial severity, rising from virtually no difference at moderate levels of initial depression to a relatively small difference for patients with very severe depression, reaching conventional criteria for clinical significance only for patients at the upper end of the very severely depressed category. Meta-regression analyses indicated that the relation of baseline severity and improvement was curvilinear in drug groups and showed a strong, negative linear component in placebo groups. CONCLUSIONS: Drug-placebo differences in antidepressant efficacy increase as a function of baseline severity, but are relatively small even for severely depressed patients. The relationship between initial severity and antidepressant efficacy is attributable to decreased responsiveness to placebo among very severely depressed patients, rather than to increased responsiveness to medication.

  14. Olfactory bulb ablation in the rat: behavioural changes and their reversal by antidepressant drugs.

    Science.gov (United States)

    van Riezen, H; Schnieden, H; Wren, A F

    1977-01-01

    1. The effects of bilateral olfactory bulbectomy, sham-operation and inducement of peripheral anosmia were studied on locomotor activity, passive avoidance acquisition and irritability. 2. Bulbectomized rats were hyperactive, deficient at learning a step-down passive avoidance response and hyperirritable. Peripheral anosmia, induced by intranasal infusion of ZnSO4 solution resulted in no behavioural changes. 3. Chronic pretreatment with amitriptyline (3 and 10 mg/kg) and a tetracyclic antidepressant mianserin (Org GB 94, 5 and 15 mg/kg) reversed the hyperactivity and reduced the learning deficit of bulbectomized rats. These drugs had no significant effects on sham-operated animals. 4. Neither amitriptyline nor mianserin reduced the exaggerated responses of bulbectomized rats to external stimuli. 5. (+)-Amphetamine (1 and 3 mg/kg) accelerated the acquisition of the passive avoidance response, greatly enhanced the locomotor activity and slightly increased the irritability score of both sham-operated and bulbectomized rats. 6. Chlorpromazine (1 and 3 mg/kg) and chlordiazepoxide (10 mg/kg) significantly reduced the acquisition, locomotor activity and irritability of experimental and control rats. 7. Lithium sulphate (1 and 3 mg/kg) had no effect on activity or irritability but produced a small impairment in acquistion of bulbectomized rats. 8. It is concluded that the reversal by antidepressant drugs of the behavioural syndrome seen after olfactory bulb ablation could constitute a new model for the detection of this group of centrally acting compounds. PMID:907867

  15. Drug interactions of new antidepressants%新型抗抑郁药物的药物相互作用

    Institute of Scientific and Technical Information of China (English)

    管晓波; 陆峥

    2012-01-01

    New types of antidepressants are widely used as therapeutic alliance and often in combination with other medications. It may modify the pharmacokinetics mediated by cytochrome P450. The investigation on drug interactions has important significance for rational use of medicine. This paper reviews the drug interactions of the new antidepressants to provide a guideline for combination therapy of antidepressants in clinic.%新型抗抑郁药物的联合治疗及其与其他药物的联合应用可引起经细胞色素P450酶介导的多种药物的药动学改变,药物相互作用研究对临床合理用药具有重要意义.本文综述新型抗抑郁药物的药物相互作用,以期为临床用药提供参考.

  16. Polymorphism in the metabolism of drugs, including antidepressant drugs: comments on phenotyping.

    OpenAIRE

    Coutts, R T

    1994-01-01

    In neurochemistry there are advantages in determining how patients are likely to react to psychoactive drugs prior to the commencement of drug therapy. Explanations of a patient's nonresponse, or unexpected adverse reactions to drugs are required. In many instances, a knowledge of the drug metabolism status of a patient can be helpful in the selection of a drug and its dosage regimen, and in the prediction of possible drug/drug interactions when two or more drugs have to be administered conco...

  17. Immunomodulatory effects of fluoxetine: A new potential pharmacological action for a classic antidepressant drug?

    Science.gov (United States)

    Di Rosso, María Emilia; Palumbo, María Laura; Genaro, Ana María

    2016-07-01

    Selective serotonin reuptake inhibitors are frequently used antidepressants. In particular, fluoxetine is usually chosen for the treatment of the symptoms of depression, obsessive-compulsive, panic attack and bulimia nervosa. Antidepressant therapy has been associated with immune dysfunction. However, there is contradictory evidence about the effect of fluoxetine on the immune system. Experimental findings indicate that lymphocytes express the serotonin transporter. Moreover it has been shown that fluoxetine is able to modulate the immune function through a serotonin-dependent pathway and through a novel independent mechanism. In addition, several studies have shown that fluoxetine can alter tumor cell viability. Thus, it was recently demonstrated in vivo that chronic fluoxetine treatment inhibits tumor growth by increasing antitumor T-cell activity. Here we briefly review some of the literature referring to how fluoxetine is able to modify, for better or worse, the functionality of the immune system. These results of our analysis point to the relevance of the novel pharmacological action of this drug as an immunomodulator helping to treat several pathologies in which immune deficiency and/or deregulation is present. PMID:26644208

  18. Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the activity of two atypical antidepressant drugs, mianserin and tianeptine, in the forced swim test in mice.

    Science.gov (United States)

    Socała, Katarzyna; Nieoczym, Dorota; Wyska, Elżbieta; Poleszak, Ewa; Wlaź, Piotr

    2012-08-01

    Sildenafil, a selective phosphodiesterase type 5 inhibitor, has recently been reported to abolish anti-immobility action of antidepressant drugs, i.e., bupropion, venlafaxine and S-citalopram, in the forced swim test in mice. The present study was designed to investigate the influence of sildenafil on the potential of two atypical antidepressants, namely mianserin and tianeptine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of the behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmocokinetic interaction, total brain concentrations of the studied antidepressants were determined by HPLC method. Sildenafil at a dose of 2.5 mg/kg did not affect the activity of mianserin (20 mg/kg) in the forced swim test. Interestingly, at higher doses (5 and 10 mg/kg), sildenafil significantly enhanced the anti-immobility action of mianserin. Likewise, sildenafil (5, 10 and 20 mg/kg) robustly augmented the antidepressant activity of tianeptine (30 mg/kg). Mianserin alone, as well as in a combination with sildenafil at the highest dose, caused a potent reduction in locomotor activity. However, the changes in motor activity did not interfere with the data obtained in the forced swim test. Sildenafil significantly increased the total brain tianeptine concentration. No alteration in mianserin level in the brain after sildenafil co-administration was observed. The present study suggests that sildenafil enhances the activity of mianserin and tianeptine in the forced swim test in mice. The changes in the antidepressant activity of mianserin evoked by sildenafil co-administration were related to pharmacodynamic interaction while the interaction between tianeptine and sildenafil was, at least in part, pharmacokinetic in nature.

  19. Tricyclic Antidepressants

    Science.gov (United States)

    Schmidt, Gary J.

    The use of tricyclic antidepressant drugs is becoming increasingly prevalent for the treatment of depressed patients. It has been suggested that, analogous to many other drug substances, the tricyclic drugs exhibit clinical effectiveness within a defined therapeutic concentration range (1-10). Very recently, both Dito (11) and Orsulak and Schildkraut (12) have summarized the usefulness of measuring serum concentrations of these drugs. These authors suggest that knowledge of the plasma concentrations of these drugs aid the physician in determining patient compliance and initiating the best possible drug treatment.

  20. Variability in the effect of antidepressants upon Wfs1-deficient mice is dependent on the drugs' mechanism of actions.

    Science.gov (United States)

    Reimets, Riin; Raud, Sirli; Loomets, Maarja; Visnapuu, Tanel; Volke, Vallo; Reimets, Ain; Plaas, Mario; Vasar, Eero

    2016-07-15

    There is significant comorbidity between mood disorders and diabetes. Wolfram syndrome-related to deficient WFS1 gene function-causes diabetes and mood disorders in humans. Mice lacking the Wfs1 gene display impaired emotional behaviour and glucose metabolism. Various antidepressant drugs are used for alleviating the symptoms of mood disorders. For this study the tail suspension test and locomotor activity test were used to compare the effects of different antidepressants upon homozygous Wfs1-deficient, heterozygous Wfs1-deficient and wild-type mice. Mouse glucose metabolism was concurrently studied using the glucose tolerance test. We showed that ketamine(10mg/kg),NMDA antagonist, escitalopram(2.5-10mg/kg), selective serotonin reuptake inhibitor(SSRI), and amitriptyline(10mg/kg), noradrenaline and serotonin reuptake inhibitor, elicited a stronger antidepressant-like effect in homozygous Wfs1-deficient mice compared to wild-type mice. The effect of noradrenaline and serotonin reuptake inhibitor desipramine(10 and 20mg/kg) did not differ between genotypes. The dopamine and noradrenaline reuptake inhibitor bupropion(5-20mg/kg) had no significant antidepressant-like effect upon any genotype. Amitriptyline and desipramine potentiated a glucose elevation, escitalopram and bupropion did not affect glucose concentrations, and ketamine improved impaired glucose metabolism in homozygous Wfs1-deficient mice. Therefore, the results of this study suggest that SSRIs are the drugs of choice for the treatment of depressive symptoms in diabetic patients. The efficacy of ketamine for these patients remains to be established. Nonetheless, employing the mechanism of action of ketamine that affected glucose metabolism positively, could be an approach for development of improved antidepressants. Wfs1-deficient mice are likely the good animal model to develop new antidepressants more suitable for depressed patients with diabetes. PMID:27080063

  1. Optical sensors for therapeutic drug monitoring of antidepressants for a better medication adjustment

    Science.gov (United States)

    Krieg, Anne K.; Hess, Stefan; Gauglitz, Günter

    2013-05-01

    Therapeutic drug monitoring provides the attending physicians with detailed information on a patient's individual serum level especially during long-term medication. Due to the fact that each patient tolerates drugs or their metabolites differently a medication adjustment can reduce the number and intensity of noticeable side-effects. In particular, psychotropic drugs can cause unpleasant side-effects that affect a patient's life almost as much as the mental disease itself. The tricyclic antidepressants amitriptyline is commonly used for treatment of depressions and was selected for the development of an immunoassay using the direct optical sensor technique Reflectometric Interference Spectroscopy (RIfS). RIfS is a simple, robust and label-free method for direct monitoring of binding events on glass surfaces. Binding to the surface causes a shift of the interference spectrum by a change of the refractive index or physical thickness. This technique can be used for time-resolved observation of association and dissociation of amitriptyline (antigen) and a specific antibody using the binding inhibition test format. An amitriptyline derivative is immobilized on the sensor surface and a specific amount of antibodies can bind to the surface unless the binding is inhibited by free amitriptyline in a sample. No fluorescent label is needed making the whole assay less expensive than label-based methods. With this recently developed immunoassay amitriptyline concentrations in buffer (PBS) can easily be detected down to 500 ng/L.

  2. Genetic dysfunction of serotonin 2A receptor hampers response to antidepressant drugs: A translational approach.

    Science.gov (United States)

    Qesseveur, Gaël; Petit, Anne Cécile; Nguyen, Hai Thanh; Dahan, Lionel; Colle, Romain; Rotenberg, Samuel; Seif, Isabelle; Robert, Pauline; David, Denis; Guilloux, Jean-Philippe; Gardier, Alain M; Verstuyft, Céline; Becquemont, Laurent; Corruble, Emmanuelle; Guiard, Bruno P

    2016-06-01

    Pharmacological studies have yielded valuable insights into the role of the serotonin 2A (5-HT2A) receptor in major depressive disorder (MDD) and antidepressant drugs (ADs) response. However, it is still unknown whether genetic variants in the HTR2A gene affect the therapeutic outcome of ADs and the mechanism underlying the regulation of such response remains poorly described. In this context, a translational human-mouse study offers a unique opportunity to address the possibility that variations in the HTR2A gene may represent a relevant marker to predict the efficacy of ADs. In a first part of this study, we investigated in depressed patients the effect of three HTR2A single nucleotide polymorphisms (SNPs), selected for their potential functional consequences on 5-HT2A receptor (rs6313, rs6314 and rs7333412), on response and remission rates after 3 months of antidepressant treatments. We also explored the consequences of the constitutive genetic inactivation of the 5-HT2A receptor (i.e. in 5-HT2A(-/-) mice) on the activity of acute and prolonged administration of SSRIs. Our clinical data indicate that GG patients for the rs7333412 SNP were less prone to respond to ADs than AA/AG patients. In the preclinical study, we demonstrated that the 5-HT2A receptor exerts an inhibitory influence on the neuronal activity of the serotonergic system after acute administration of SSRIs. However, while the chronic administration of the SSRIs escitalopram or fluoxetine elicited a progressive increased in the firing rate of 5-HT neurons in 5-HT2A(+/+) mice, it failed to do so in 5-HT2A(-/-) mutants. These electrophysiological impairments were associated with a decreased ability of the chronic administration of fluoxetine to stimulate hippocampal plasticity and to produce antidepressant-like activities. Genetic loss of the 5-HT2A receptor compromised the activity of chronic treatment with SSRIs, making this receptor a putative marker to predict ADs response. PMID:26764241

  3. Drug evaluation and the permissive principle: continuities and contradictions between standards and practices in antidepressant regulation.

    Science.gov (United States)

    Abraham, John; Davis, Courtney

    2009-08-01

    Pharmaceuticals are not permitted on to the market unless they are granted regulatory approval. The regulatory process is, therefore, crucial in whether or not a drug is widely prescribed. Regulatory agencies have developed standards of performance that pharmaceuticals are supposed to meet before entering the market. Regulation of technologies is often discussed by reference to the precautionary principle. In contrast, this paper develops the concept of the 'permissive principle' as a way of understanding the departure of regulators' practices from standards of drug efficacy to which regulatory agencies themselves subscribe. By taking a case study of antidepressant regulation in the UK and the USA, the mechanisms of permissive regulatory practices are examined. An STS methodology of both spatial (international) and temporal comparisons of regulatory practices with regulatory standards is employed to identify the nature and extent of the permissive regulation. It is found that the permissive principle was adopted by drug regulators in the UK and the USA, but more so by the former than the latter. Evidently, permissive regulation, which favours the commercial interests of the drug manufacturer, but is contrary to the interests of patients, may penetrate to the heart of regulatory science. On the other hand, permissive regulation of specific drugs should not be regarded as an inevitable result of marketing strategies and concomitant networks deployed by powerful pharmaceutical companies, because the extent of permissive regulation may vary according to the intra-institutional normative commitments of regulators to uphold their technical standards against the commercial interests of the manufacturer. Likely sociological factors that can account for such permissive regulatory practices are 'corporate bias', secrecy and excessive regulatory trust in the pharmaceutical industry in the UK, political expediency and ideological capture in the USA, combined in both countries

  4. Indications for antidepressant drug prescribing in general practice in the Netherlands.

    NARCIS (Netherlands)

    Gardarsdottir, H.; Heerdink, E.R.; Dijk, L. van; Egberts, A.C.G.

    2007-01-01

    BACKGROUND: The intensity of the use of antidepressants in large populations can nowadays relatively easily be estimated using databases encompassing prescription data. There are shortcomings when using prescription databases as they contain no clinical data on patient illness. Antidepressants are p

  5. 抗抑郁药在老年人群中的应用%Application of antidepressant drugs in the elderly

    Institute of Scientific and Technical Information of China (English)

    徐俊冕

    2013-01-01

    老年抑郁和焦虑障碍患者常和躯体疾病共病,主诉较多的是身体症状和睡眠障碍.老年患者对躯体疾病和药物不良反应比较敏感,临床抗抑郁药使用可能出现药物代谢和血药浓度改变,本文针对老年患者的特殊生理和心理变化,分析疗效和不良反应,综述抗抑郁药在老年人群中的使用原则、药物选用和注意事项等.%The elderly patients with depression or anxiety disorders usually have the complication of physical diseases, and they complain of more physical symptoms and sleep disorders. The elderly patients are more susceptible to physical diseases and adverse reactions. The use of antidepressant drugs may change the metabolism and plasma concentration of other medications. This review focuses on the antidepressant drugs usage to treat the elderly patients' symptoms and frequently to reassess the dosage of antidepressant drugs and their adverse reactions.

  6. The search for new off-label indications for antidepressant, antianxiety, antipsychotic and anticonvulsant drugs

    OpenAIRE

    Chouinard, Guy

    2006-01-01

    Most drugs are prescribed for several illnesses, but it took several years for psychotropic drugs to have multiple clinical indications. Our search for serotonergic drugs in affective illnesses and related disorders led to new off-label indications for fluoxetine, sertraline, tryptophan, clonazepam, alprazolam, tomoxetine, buproprion, duloxetine, risperidone and gabapentin. Various clinical trial designs were used for these proof-of-concept studies. Novel therapeutic uses of benzodiazepines, ...

  7. Highly Sensitive and Validated Spectrophotometric Technique for the Assay of Some Antidepressant Drugs

    Science.gov (United States)

    Deepakumari, H. N.; Prashanth, M. K.; Kumar, B. C. Vasantha; Revanasiddappa, H. D.

    2015-01-01

    The present paper describes a simple, rapid, reproducible, and highly sensitive spectrophotometric method for the determination of the tricyclic antidepressant drugs: amitriptyline hydrochloride (AMT), imipramine hydrochloride (IMH), clomipramine hydrochloride (CPH) and desipramine hydrochloride (DPH) in pure and in pharmaceutical preparations. The method is based on the bromination of the above drugs with known excess of bromine. The unreacted bromine is determined based on its ability to bleach the dye methyl red quantitatively at 520 nm. Regression analysis of Beer-Lambert plots showed a good correlation in the concentration range 0.0-2.5, 0-1.4, 0-1.4, and 0-1.0 μg/ml for AMT, IMH, CPH, and DPH, respectively. The molar absorptivity values were found to be 0.65 × 105, 1.41 × 105, 1.93 × 105, and 2.96 × 105l/mol/cm, with the corresponding Sandell's sensitivity values were 0.0048, 0.0022, 0.0018, and 0.0010 μg/cm2 for AMT, IMH, CPH, and DPH, respectively. The limits of detection (LOD) and quantification (LOQ) are also reported for the developed method. Intra- and inter-day accuracy and precision was established according to the current ICH guidelines. Application of the procedure to the analysis of various pharmaceutical preparations gave reproducible and accurate results. Further, the validity of the proposed method was confirmed by applying the standard addition technique, and the results obtained are in good agreement with those obtained by the official method.

  8. The antidepressant-like effects of glutamatergic drugs ketamine and AMPA receptor potentiator LY 451646 are preserved in bdnf⁺/⁻ heterozygous null mice.

    Science.gov (United States)

    Lindholm, Jesse S O; Autio, Henri; Vesa, Liisa; Antila, Hanna; Lindemann, Lothar; Hoener, Marius C; Skolnick, Phil; Rantamäki, Tomi; Castrén, Eero

    2012-01-01

    Accumulating evidence suggests that biogenic amine-based antidepressants act, at least in part, via regulation of brain-derived neurotrophic factor (BDNF) signaling. Biogenic amine-based antidepressants increase BDNF synthesis and activate its signaling pathway through TrkB receptors. Moreover, the antidepressant-like effects of these molecules are abolished in BDNF deficient mice. Glutamate-based drugs, including the NMDA antagonist ketamine, and the AMPA receptor potentiator LY 451646, mimic the effects of antidepressants in preclinical tests with high predictive validity. In humans, a single intravenous dose of ketamine produces an antidepressant effect that is rapid, robust and persistent. In this study, we examined the role of BDNF in expression of the antidepressant-like effects of ketamine and an AMPA receptor potentiator (LY 451646) in the forced swim test (FST). Ketamine and LY 451646 produced antidepressant-like effects in the FST in mice at 45 min after a single injection, but no effects were observed one week after a single ketamine injection. As previously reported, the effects of imipramine in the forced swim test were blunted in heterozygous BDNF knockout (bdnf(+/-)) mice. However ketamine and LY 451646 produced similar antidepressant-like responses in wildtype and bdnf(+/-) mice. Neither ketamine nor LY 451646 significantly influenced the levels BDNF or TrkB phosphorylation in the hippocampus when assessed at 45 min or 7 days after the drug administration. These data demonstrate that under the conditions tested, neither ketamine nor the AMPA-potentiator LY 451656 activate BDNF signaling, but produce a characteristic antidepressant-like response in heterozygous bdnf(+/-) mice. These data indicate that unlike biogenic amine-based agents, BDNF signaling does not play a pivotal role in the antidepressant effects of glutamate-based compounds. This article is part of a Special Issue entitled 'Anxiety and Depression'.

  9. Antidepressant-like drug effects in juvenile and adolescent mice in the tail suspension test: Relationship with hippocampal serotonin and norepinephrine transporter expression and function.

    Directory of Open Access Journals (Sweden)

    Nathan C Mitchell

    2013-10-01

    Full Text Available Depression is a major health problem for which most patients are not effectively treated. This problem is further compounded in children and adolescents where only two antidepressants [both selective serotonin reuptake inhibitors (SSRIs] are currently approved for clinical use. Mouse models provide tools to identify mechanisms that might account for poor treatment response to antidepressants. However, there are few studies in adolescent mice and none in juvenile mice. The tail suspension test (TST is commonly used to assay for antidepressant-like effects of drugs in adult mice. Here we show that the TST can also be used to assay antidepressant-like effects of drugs in C57Bl/6 mice aged 21 (juvenile and 28 (adolescent days post-partum (P. We found that the magnitude of antidepressant-like response to the SSRI escitalopram was less in P21 mice than in P28 or adult mice. The smaller antidepressant response of juveniles was not related to either maximal binding (Bmax or affinity (Kd for [3H]citalopram binding to the serotonin transporter (SERT in hippocampus, which did not vary significantly among ages. Magnitude of antidepressant-like response to the tricyclic desipramine was similar among ages, as were Bmax and Kd values for [3H]nisoxetine binding to the norepinephrine transporter (NET in hippocampus. Together, these findings suggest that juvenile mice are less responsive to the antidepressant-like effects of escitalopram than adults, but that this effect is not due to delayed maturation of SERT in hippocampus. Showing that the TST is a relevant behavioral assay of antidepressant-like activity in juvenile and adolescent mice sets the stage for future studies of the mechanisms underlying the antidepressant response in these young populations.

  10. Milnacipran: a unique antidepressant?

    Directory of Open Access Journals (Sweden)

    Siegfried Kasper

    2010-08-01

    Full Text Available Siegfried Kasper, Gerald PailDepartment of Psychiatry and Psychotherapy, Medical University of Vienna, AustriaAbstract: Tricyclic antidepressants (TCAs are among the most effective antidepressants available, although their poor tolerance at usual recommended doses and toxicity in ­overdose make them difficult to use. While selective serotonin reuptake inhibitors (SSRIs are ­better tolerated than TCAs, they have their own specific problems, such as the aggravation of sexual dysfunction, interaction with coadministered drugs, and for many, a discontinuation syndrome. In addition, some of them appear to be less effective than TCAs in more severely depressed patients. Increasing evidence of the importance of norepinephrine in the etiology of depression has led to the development of a new generation of antidepressants, the serotonin and ­norepinephrine reuptake inhibitors (SNRIs. Milnacipran, one of the pioneer SNRIs, was designed from theoretic considerations to be more effective than SSRIs and better tolerated than TCAs, and with a simple pharmacokinetic profile. Milnacipran has the most balanced potency ratio for reuptake inhibition of the two neurotransmitters compared with other SNRIs (1:1.6 for milnacipran, 1:10 for duloxetine, and 1:30 for venlafaxine, and in some studies milnacipran has been shown to inhibit norepinephrine uptake with greater potency than serotonin (2.2:1. Clinical studies have shown that milnacipran has efficacy comparable with the TCAs and is superior to SSRIs in severe depression. In addition, milnacipran is well tolerated, with a low potential for pharmacokinetic drug–drug interactions. Milnacipran is a first-line therapy suitable for most depressed patients. It is frequently successful when other treatments fail for reasons of efficacy or tolerability.Keywords: milnacipran, SNRI, antidepressant efficacy, tolerability

  11. 新型抗抑郁药物的研究进展%Advances in the development of new antidepressive drugs

    Institute of Scientific and Technical Information of China (English)

    孟秀君; 曲蕾; 马燕; 朱琳; 赵临襄

    2011-01-01

    With an increasing knowledge, neurotrophic hypothesis and cytokine hypothesis, neuroplastici-ty, hippocampus-neurogenesis, HPA axis and immune system are included in the pathogenesis of depression, which might be the antidepressant targets. Several potential therapeutic targets have been identified for the disease, such as glutamic acid receptors, neuropeptide receptors, glucocorticoid receptors, melatonin receptors and cytokine receptors. With the development of understanding the new drug targets of depression, the research on new depressive drugs becomes a new research hotspot. A lot of novel antidepressive compounds have been designed and synthesized ; more than ten of them are currently used in clinic or in advanced clinical trials. The mlatonin receptor agonist agomelatine and the corticotrophin releasing hormone receptor antagonist quetiapine have been approved as new antidepressive drugs. Mifepristone and saredutant, as a glucocorticoid receptor antagonist and a neurokinin 2 receptor antagonist, are in phase III clinical trials. Advances in the development of novel depressive targets and drugs in recent 5 years are discussed in the paper.%近年来对抑郁症发病机制和药物治疗靶标的研究取得了很大进展,围绕神经可塑性、神经发生、下丘脑-垂体-肾上腺( HPA)轴等后续神经系统适应性改变以及免疫系统变化,确定了谷氨酸受体、神经肽受体、糖皮质激素受体、褪黑激素受体和细胞因子受体等抗抑郁药物作用的新靶标.目前,已发现大量具有抗抑郁作用的新化合物,褪黑激素受体激动剂阿戈美拉丁、促肾上腺皮质激素释放激素受体拮抗剂喹硫平已经上市,神经激肽2受体拮抗剂沙瑞度坦、糖皮质激素受体拮抗剂米非司酮正在进行Ⅲ期临床研究,10余个药物进入临床研究阶段.本文对近5年新型抗抑郁药物的研究进展进行简要综述.

  12. Dispersion of hydrophobic magnetic nanoparticles using ultarsonic-assisted in combination with coacervative microextraction for the simultaneous preconcentration and determination of tricyclic antidepressant drugs in biological fluids.

    Science.gov (United States)

    Jannesar, Ramin; Zare, Fahimeh; Ghaedi, Mehrorang; Daneshfar, Ali

    2016-09-01

    A two-step sample preparation technique based on dispersive micro solid-phase extraction combined with coacervative microextraction is presented for preconcentration and determination of tricyclic antidepressant drugs in biological samples. An important feature of the method is the application of hydrophobic magnetic nanoparticles, which in combination with coacervative microextraction method enables development of rapid and efficient extraction procedure in order to achievement of a high extraction efficiency. Simultaneous optimization by experimental design lead to improvement of method with low cost which supply useful information about interaction among variables. Under the optimized conditions, a linear range of 5-1000ngmL(-1) with detection limits from 0.51 to 1.4ngmL(-1) were obtained for target analytes. The method was successfully used for the determination of analytes in biological fluids (plasma and urine) with relative recoveries in the range of 89-105% (RSDs<3.5%). PMID:27150784

  13. The Comparison of Efficacy of Tricyclic Antidepressant with and without Non Steroidal Anti Inflammatory Drugs in Chronic Low Back Pain

    Directory of Open Access Journals (Sweden)

    A.R. Yavarikia

    2007-07-01

    Full Text Available Introduction & Objectives: Low back pain (LBP is one of common medical problems with several accepted medical modalities such as drugs, physiotherapy, surgery, etc. We studied the efficacy of tricyclic antidepressant (TCA, and tricyclic antidepressant plus non steroidal anti inflammatory drugs (TCA + NSAID in 200 patients with chronic LBP. Materials & Methods: In an experimental clinical trial study on patients with chronic low back pain without organic findings, patients were divided in two groups of 100 cases. At certain times the response to treatment protocols were collected and compared using VAS system. Patient’s data including age, sex, smoking and response to treatment were recorded and analyzed using chi-square, t-tests, ANOVA and SPSS software. Results: 83 (41.5% of patients were males and 117 (58.5% were females. The age range was 21 to 75 (mean age 43.1 14.1y there was no meaning full statistical difference in demographic characteristics such as age, sex (respectively p=0.66, p=0.78 the ultimate pain was less (p0.05.Conclusion: TCA prescription is an efficient method of treatment of low back pain with or with out NSAIDS. But using NSAID+TCA will be almost more powerful and efficient method in the long term period.

  14. Study on Commonly Used Antidepressant Drugs and Reasonable Application%常用抗抑郁药物及合理应用的探讨

    Institute of Scientific and Technical Information of China (English)

    谢翠莹

    2016-01-01

    目的:了解常见抗抑郁药物的特点,作用原理和对患者的不良反应及注意事项。方法通过网上和资料室查阅相关文献,对抗抑郁药的临床应用进行分析归纳和总结。结果常用抗抑郁药可分为3类,三环类药物、选择性5-HT再摄取抑制药、非典型抗抑郁药。最后对药物的合理应用分为三个方面进行详述。结论应用抗抑郁药应重视常用抑郁药分类及药物的合理使用,根据临床效应选择抗抑郁药,避免药物相互作用与过度使用。%Objective To understand the characteristics of common antidepressants, action principle and the patient's adverse reactions and precautions.Methods The literature search online and by reference room, for the clinical application of antidepressants were analyzed and summarized. ResultsCommon antidepressants can be divided into three categories, tricyclics, selective 5-HT reuptake inhibitors, atypical antidepressants. Finally, the rational use of drugs in three aspects in detail. ConclusionThe application should pay attention to the rational use of antidepressants commonly used antidepressant drugs classification and choose based on clinical antidepressant effect, avoid drug interactions and overuse.

  15. 抗抑郁药物致性功能障碍的临床研究进展%Clinical Research Progress of Antidepressant Drugs Causing Sexual Dysfunction

    Institute of Scientific and Technical Information of China (English)

    林国华(综述); 江回春(审校)

    2016-01-01

    Antidepressants not only has the antidepressant and anxiolytic clinical effects , but also adverse reactions.General adverse antidepressant effects can be divided into central and peripheral side effects,where the influence of antidepressants on sexual function belongs to peripheral side effects .Antide-pressant drugs causing sexual dysfunction has become a consensus.Therefore,when selecting antidepressant, the adverse effect on sexual function should be taken into account,and the patient′s sexual function change after medication should be inquired ,so as to develop individualized treatment program ..%抗抑郁药除了具有抗抑郁及抗焦虑的临床治疗作用外,同样具有不良反应。抗抑郁药物的不良反应一般可分为中枢性不良反应和外周性不良反应。其中抗抑郁药物对患者性功能的影响属于外周性不良反应。抗抑郁药物会引起性功能障碍已成为共识。因此,在选择抗抑郁药物时应考虑到性功能方面的不良反应,了解患者服药后性功能的变化,以制订个性化的处理方案。

  16. Effects of self-aggregation on the hydration of an amphiphilic antidepressant drug in different aqueous media

    Energy Technology Data Exchange (ETDEWEB)

    Taboada, Pablo; Gutierrez-Pichel, Manuel; Mosquera, Victor

    2004-03-08

    Apparent molal volumes and adiabatic compressibilities of aqueous solutions of the amphiphilic antidepressant drug clomipramine hydrochloride have been determined from density and ultrasound velocity measurements in the temperature range 288.15-313.15 K in buffered aqueous solution of pH 3.0 and 5.5. Critical concentrations of aggregation of this drug were obtained from inflections on the plots of the sound velocity against drug concentration. Apparent molal adiabatic compressibilities of the aggregates formed by the drug, calculated by combining the ultrasound velocity and density data, were typical of those for a stacked aggregate. From the temperature dependence of the critical concentration and using the mass action model combined with the Phillips definition of the critical concentration the thermodynamic standard quantities: free Gibbs energy, enthalpy and entropy of aggregate formation were calculated. The critical concentration and energy involved in the aggregation process of this drug have been also evaluated experimentally using isothermal titration calorimetry at 298.15 K. The solvent-drug interactions have been discussed from compressibility and calorimetry data.

  17. The male heart and the female mind: a study in the gendering of antidepressants and cardiovascular drugs in advertisements in Irish medical publication.

    Science.gov (United States)

    Curry, Phillip; O'Brien, Marita

    2006-04-01

    Stereotypes which suggest that cardiovascular disease and depression are related to gender can have consequences for the mental and physical health outcomes of both men and women. This study examines how these stereotypes may be reinforced by medical publications advertising for cardiovascular and antidepressant medication. A random sample of 61 (with no repeats) advertisements which appeared in Irish medical publications between July 2001 and December 2002 were analysed using both content and semiotic analysis. Results indicate that the meanings created by advertisers for cardiovascular drugs and antidepressants did in fact gender these products. Women were depicted as the predominant users of antidepressants and men as the main users of cardiovascular drugs. The images used identified two stereotyped patients: the 'male' heart patient and the depressed 'female' patient. Furthermore, the imagery and language used to promote the two categories of medication tended to strengthen gendered associations. PMID:16214280

  18. Antidepressants versus placebo in major depression: an overview.

    Science.gov (United States)

    Khan, Arif; Brown, Walter A

    2015-10-01

    Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug-placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non-profit agencies. This narrowing of the drug-placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM-III and the broadening of the definition of major depression have led to the inclusion of mildly to moderately ill patients into antidepressant trials. These patients may experience a smaller magnitude of antidepressant-placebo differences. Second, drug development regulators, such as the U.S. Food and Drug Administration and the European Medicines Agency, have had a significant, albeit underappreciated, role in determining how modern antidepressant clinical trials are designed and conducted. Their concerns about possible false positive results have led to trial designs that are poor, difficult to conduct, and complicated to analyze. Attempts at better design and patient selection for antidepressant trials have not yielded the expected results. As of now, antidepressant clinical trials have an effect size of 0.30, which, although similar to the effects of treatments for many other chronic illnesses, such as hypertension, asthma and diabetes, is less than impressive. PMID:26407778

  19. Rational drug design paradigms: the odyssey for designing better drugs.

    Science.gov (United States)

    Kellici, Tahsin; Ntountaniotis, Dimitrios; Vrontaki, Eleni; Liapakis, George; Moutevelis-Minakakis, Panagiota; Kokotos, George; Hadjikakou, Sotiris; Tzakos, Andreas G; Afantitis, Antreas; Melagraki, Georgia; Bryant, Sharon; Langer, Thierry; Di Marzo, Vincenzo; Mavromoustakos, Thomas

    2015-01-01

    Due to the time and effort requirements for the development of a new drug, and the high attrition rates associated with this developmental process, there is an intense effort by academic and industrial researchers to find novel ways for more effective drug development schemes. The first step in the discovery process of a new drug is the identification of the lead compound. The modern research tendency is to avoid the synthesis of new molecules based on chemical intuition, which is time and cost consuming, and instead to apply in silico rational drug design. This approach reduces the consumables and human personnel involved in the initial steps of the drug design. In this review real examples from our research activity aiming to discover new leads will be given for various dire warnings diseases. There is no recipe to follow for discovering new leads. The strategy to be followed depends on the knowledge of the studied system and the experience of the researchers. The described examples constitute successful and unsuccessful efforts and reflect the reality which medicinal chemists have to face in drug design and development. The drug stability is also discussed in both organic molecules and metallotherapeutics. This is an important issue in drug discovery as drug metabolism in the body can lead to various toxic and undesired molecules.

  20. A Review for the Analysis of Antidepressant, Antiepileptic and Quinolone Type Drugs in Pharmaceuticals and Environmental Samples.

    Science.gov (United States)

    Rani, Susheela; Malik, Ashok Kumar; Kaur, Ramandeep; Kaur, Ripneel

    2016-09-01

    The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. After sampling of the biological fluid, the next step in the analytical process is sample preparation. Sample preparation is essential for isolation of desired components from complex biological matrices and greatly influences their reliable and accurate determination. The complexity of biological fluids adds to the challenge of direct determination of the drug by chromatographic analysis, therefore demanding a sample preparation step that is often time consuming, tedious and frequently overlooked. However, direct online injection methods offer the advantage of reducing sample preparation steps and enabling effective pre-concentration and clean-up of biological fluids. These procedures can be automated and therefore reduce the requirements for handling potentially infectious biomaterial, improve reproducibility, and minimize sample manipulations and potential contamination. This review is focused on the discovery and development of high-performance liquid chromatography (HPLC) and gas chromatography (GC) with different detectors. The drugs covered in this review are antiepileptics, antidepressant (AD), and quinolones. The application of these methods for determination of these drugs in biological, environmental and pharmaceutical samples has also been discussed.

  1. A Review for the Analysis of Antidepressant, Antiepileptic and Quinolone Type Drugs in Pharmaceuticals and Environmental Samples.

    Science.gov (United States)

    Rani, Susheela; Malik, Ashok Kumar; Kaur, Ramandeep; Kaur, Ripneel

    2016-09-01

    The analysis of drugs in various biological fluids is an important criterion for the determination of the physiological performance of a drug. After sampling of the biological fluid, the next step in the analytical process is sample preparation. Sample preparation is essential for isolation of desired components from complex biological matrices and greatly influences their reliable and accurate determination. The complexity of biological fluids adds to the challenge of direct determination of the drug by chromatographic analysis, therefore demanding a sample preparation step that is often time consuming, tedious and frequently overlooked. However, direct online injection methods offer the advantage of reducing sample preparation steps and enabling effective pre-concentration and clean-up of biological fluids. These procedures can be automated and therefore reduce the requirements for handling potentially infectious biomaterial, improve reproducibility, and minimize sample manipulations and potential contamination. This review is focused on the discovery and development of high-performance liquid chromatography (HPLC) and gas chromatography (GC) with different detectors. The drugs covered in this review are antiepileptics, antidepressant (AD), and quinolones. The application of these methods for determination of these drugs in biological, environmental and pharmaceutical samples has also been discussed. PMID:26939618

  2. Emergency Department Visits for Drug-Related Suicide Attempts Involving Antidepressants by Adolescents and Young Adults: 2004 to 2008. The DAWN Report

    Science.gov (United States)

    Substance Abuse and Mental Health Services Administration, 2011

    2011-01-01

    In 2008, adolescents made 23,124 visits to the emergency department (ED) for drug-related suicide attempts, and young adults made 38,036 such visits; of these visits, 23.0 percent (5,312 visits) among adolescents and 17.6 percent (6,700 visits) among young adults involved antidepressants. Among ED visits for suicide attempts involving…

  3. Combining antidepressants

    OpenAIRE

    Dunner, David L.

    2014-01-01

    Summary Treatment-resistant depression is a common problem encountered by psychiatrists. These patients are often difficult to treat effectively. Strategies for addressing patients with treatment-resistant depression include changing medications, adding another antidepressant (antidepressant polypharmacy), and augmenting treatment with a non-antidepressant.

  4. Chronic treatment with antidepressant drugs and the analgesia induced by 5-methoxy-N,N-dimethyltryptamine: attenuation by desipramine.

    Science.gov (United States)

    Danysz, W; Minor, B G; Post, C; Archer, T

    1986-08-01

    The effect of chronic and acute oral or intraperitoneal treatment with the antidepressant drugs, desipramine, amitriptyline, alaproclate and iprindole, upon pain thresholds in the tail flick, hot plate and shock titration tests of nociception in saline- and 5-MeODMT-treated rats was studied. Chronic desipramine treatment increased the pre-test tail flick latencies. In the saline-treated rats, chronic oral desipramine treatment increased tail flick latencies, whereas chronic oral amitriptyline treatment decreased tail flick latencies. In 5-MeODMT-treated rats, chronic oral desipramine treatment attenuated the effects of 5-MeODMT (1 mg/kg) in all three tests of nociception, whereas chronic amitriptyline caused a potentiation in the tail flick and hot plate tests. Chronic oral iprindole treatment attenuated 5-MeODMT-induced analgesia in the hot plate test. Chronic intraperitoneal desipramine treatment attenuated 5-MeODMT analgesia in the tail flick and shock titration tests. In a different chronic treatment experiment, oral desipramine treatment attenuated 5-MeODMT analgesia in the tail flick test and zimeldine did for both the tail flick and hot plate tests, whereas mianserin potentiated 5-MeODMT-induced analgesia in both the tail flick and hot plate tests. In the saline-treated rats, acute treatment with all four drugs, desipramine, amitriptyline, iprindole and alaproclate, elevated the shock thresholds, whereas in 5-MeODMT-treated rats, desipramine and amitriptyline elevated shock thresholds. Two main conclusions can be drawn: chronic desipramine caused a quite consistent attenuation of 5-MeODMT-induced analgesia and the effects of acute treatment differed strongly from that of the chronic treatment. The effects of chronic administration with these antidepressants were compared with other findings using different measures of behavioural and receptor function. PMID:3776549

  5. Ketamine Decreases Resting State Functional Network Connectivity in Healthy Subjects: Implications for Antidepressant Drug Action

    Science.gov (United States)

    Walter, Martin; Lehmann, Mick; Metzger, Coraline; Grimm, Simone; Boeker, Heinz; Boesiger, Peter; Henning, Anke; Seifritz, Erich

    2012-01-01

    Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI), the „dorsal nexus “(DN) was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN), the default mode network (DMN), and a rostral affective network (AN). Hence, Sheline and colleagues (2010) proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC) and medioprefrontal cortex (MPFC) via its representative hub, the posterior cingulate cortex (PCC). These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression. PMID:23049758

  6. Ketamine decreases resting state functional network connectivity in healthy subjects: implications for antidepressant drug action.

    Directory of Open Access Journals (Sweden)

    Milan Scheidegger

    Full Text Available Increasing preclinical and clinical evidence underscores the strong and rapid antidepressant properties of the glutamate-modulating NMDA receptor antagonist ketamine. Targeting the glutamatergic system might thus provide a novel molecular strategy for antidepressant treatment. Since glutamate is the most abundant and major excitatory neurotransmitter in the brain, pathophysiological changes in glutamatergic signaling are likely to affect neurobehavioral plasticity, information processing and large-scale changes in functional brain connectivity underlying certain symptoms of major depressive disorder. Using resting state functional magnetic resonance imaging (rsfMRI, the "dorsal nexus "(DN was recently identified as a bilateral dorsal medial prefrontal cortex region showing dramatically increased depression-associated functional connectivity with large portions of a cognitive control network (CCN, the default mode network (DMN, and a rostral affective network (AN. Hence, Sheline and colleagues (2010 proposed that reducing increased connectivity of the DN might play a critical role in reducing depression symptomatology and thus represent a potential therapy target for affective disorders. Here, using a randomized, placebo-controlled, double-blind, crossover rsfMRI challenge in healthy subjects we demonstrate that ketamine decreases functional connectivity of the DMN to the DN and to the pregenual anterior cingulate (PACC and medioprefrontal cortex (MPFC via its representative hub, the posterior cingulate cortex (PCC. These findings in healthy subjects may serve as a model to elucidate potential biomechanisms that are addressed by successful treatment of major depression. This notion is further supported by the temporal overlap of our observation of subacute functional network modulation after 24 hours with the peak of efficacy following an intravenous ketamine administration in treatment-resistant depression.

  7. Divergence and convergence of commercial and scientific priorities in drug development: The case of Zelmid, the first SSRI antidepressant.

    Science.gov (United States)

    Mulinari, Shai

    2015-08-01

    Based on a realist conceptualization of interests, this paper explores how commercial and scientific priorities appear to have converged and diverged during the development of the antidepressant Zelmid. The drug represents the first of the selective serotonin reuptake inhibitors (SSRIs) to reach the market. Zelmid was synthesized in 1971 and launched by the Swedish firm Astra in 1982, but subsequently withdrawn the next year because of adverse neurological effects. This paper draws on in-depth interviews with scientists representing both industry and academia who had high-level involvement in various phases of the project (experimental, pre-clinical and clinical), as well as on textual sources such as scientific articles and memoirs. Zelmid was a product of mechanism-based or "rational" drug discovery from the early 1960s and the associated intermingling of science and commerce. It is argued that both scientists and the pharmaceutical company shared an interest in embracing mechanism-based drug discovery because it simultaneously promised medico-scientific advances and profits. However, the intermingling of science and commerce also strained the relationship between scientific and commercial priorities further along the trajectory of the drug; for example, concerning issues such as dosage strategy and drug use in primary care, where corporate management allegedly took decisions contrary to the recommendations of both academic and company scientists. On such occasions the asymmetry in power became apparent in scientists' narratives: commercial considerations trumped those of science since, ultimately, decisions rest with management, not with scientists. In addition, temporality appears to be associated with the divergence of commercial and scientific priorities. While rare during experimental and pre-clinical phases, divergence was concentrated downstream to the clinical testing and post-marketing phases. It is hypothesized that a similar pattern of convergence and

  8. New Framework To Diagnose the Direct Disposal of Prescribed Drugs in Wastewater - A Case Study of the Antidepressant Fluoxetine.

    Science.gov (United States)

    Petrie, Bruce; Youdan, Jane; Barden, Ruth; Kasprzyk-Hordern, Barbara

    2016-04-01

    Intentional or accidental release (direct disposal) of high loads of unused pharmaceuticals into wastewater can go unnoticed. Here, direct disposal of a pharmaceutical drug via the sewer network was identified for the first time using wastewater analysis. An irregularly high load of the antidepressant fluoxetine in raw wastewater (10.5 ± 2.4 g d(-1)) was up to 11 times greater than any other day. National prescription data revealed a predicted daily fluoxetine load for the studied treatment works to be 0.4-1.6 g d(-1). Enantio-selective analysis showed the high load of fluoxetine was present as a racemic mixture, which is typical for fluoxetine in dispensed formulations. As fluoxetine undergoes stereoselective metabolism within the body, a racemic mixture in wastewater suggests a nonconsumed drug was the major contributor of the high load. This was confirmed by its major metabolite norfluoxetine whose load did not increase on this day. Considering the most commonly prescribed formulation of fluoxetine, this increased load accounts for the disposal of ∼915 capsules. Furthermore, as fluoxetine is prescribed as one capsule per day, disposal is unlikely to be at the patient level. It is postulated that direct disposal was from a facility which handles larger quantities of the drug (e.g., a pharmacy). PMID:26974167

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

    Science.gov (United States)

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

    2016-08-01

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

  10. The Safety, Tolerability and Risks Associated with the Use of Newer Generation Antidepressant Drugs: A Critical Review of the Literature.

    Science.gov (United States)

    Carvalho, André F; Sharma, Manu S; Brunoni, André R; Vieta, Eduard; Fava, Giovanni A

    2016-01-01

    Newer generation antidepressant drugs (ADs) are widely used as the first line of treatment for major depressive disorders and are considered to be safer than tricyclic agents. In this critical review, we evaluated the literature on adverse events, tolerability and safety of selective serotonin reuptake inhibitors, serotonin noradrenaline reuptake inhibitors, bupropion, mirtazapine, trazodone, agomelatine, vilazodone, levomilnacipran and vortioxetine. Several side effects are transient and may disappear after a few weeks following treatment initiation, but potentially serious adverse events may persist or ensue later. They encompass gastrointestinal symptoms (nausea, diarrhea, gastric bleeding, dyspepsia), hepatotoxicity, weight gain and metabolic abnormalities, cardiovascular disturbances (heart rate, QT interval prolongation, hypertension, orthostatic hypotension), genitourinary symptoms (urinary retention, incontinence), sexual dysfunction, hyponatremia, osteoporosis and risk of fractures, bleeding, central nervous system disturbances (lowering of seizure threshold, extrapyramidal side effects, cognitive disturbances), sweating, sleep disturbances, affective disturbances (apathy, switches, paradoxical effects), ophthalmic manifestations (glaucoma, cataract) and hyperprolactinemia. At times, such adverse events may persist after drug discontinuation, yielding iatrogenic comorbidity. Other areas of concern involve suicidality, safety in overdose, discontinuation syndromes, risks during pregnancy and breast feeding, as well as risk of malignancies. Thus, the rational selection of ADs should consider the potential benefits and risks, likelihood of responsiveness to the treatment option and vulnerability to adverse events. The findings of this review should alert the physician to carefully review the appropriateness of AD prescription on an individual basis and to consider alternative treatments if available. PMID:27508501

  11. Simultaneous Determination of 24 Antidepressant Drugs and Their Metabolites in Wastewater by Ultra-High Performance Liquid Chromatography–Tandem Mass Spectrometry

    Directory of Open Access Journals (Sweden)

    Ling-Hui Sheng

    2014-01-01

    Full Text Available Antidepressants are a new kind of pollutants being increasingly found in wastewater. In this study, a fast and sensitive ultra-high performance liquid chromatography-tandem mass spectrometry method was developed and validated for the analysis of 24 antidepressant drugs and six of their metabolites in wastewater. This is the first time that the antidepressant residues in wastewater of Beijing (China were systematically reported. A solid-phase extraction process was performed with 3 M cation disk, followed by ultra-high performance liquid chromatography–tandem mass spectrometry measurements. The chromatographic separation and mass parameters were optimized in order to achieve suitable retention time and good resolution for analytes. All compounds were satisfactorily determined in one single injection within 20 min. The limit of quantification (LOQ, linearity, and extraction recovery were validated. The LOQ for analytes were ranged from 0.02 to 0.51 ng/mL. The determination coefficients were more than 0.99 within the tested concentration range (0.1–25 ng/mL, and the recovery rate for each target compound was ranged from 81.2% to 118% at 1 ng/mL. This new developed method was successfully applied to analysis the samples collected from Beijing municipal wastewater treatment plants. At least ten target antidepressants were found in all samples and the highest mean concentration of desmethylvenlafaxin was up to 415.6 ng/L.

  12. [Switching and combining strategies of antidepressant medications].

    Science.gov (United States)

    Charpeaud, Thomas; Moliere, Fanny; Bubrovszky, Maxime; Haesebaert, Frédéric; Allaïli, Najib; Bation, Rémy; Nieto, Isabel; Richieri, Raphaëlle; Saba, Ghassen; Bellivier, Frank; Bennabi, Djamila; Holtzmann, Jérôme; Camus, Vincent; Courtet, Philippe; Courvoisier, Pierre; d'Amato, Thierry; Doumy, Olivier; Garnier, Marion; Bougerol, Thierry; Lançon, Christophe; Haffen, Emmanuel; Leboyer, Marion; Llorca, Pierre-Michel; Vaiva, Guillaume; El-Hage, Wissam; Aouizerate, Bruno

    2016-03-01

    Switching antidepressant medication may be helpful in depressed patients having no benefit from the initial antidepressant treatment. Before considering switching strategy, the initial antidepressant treatment should produce no therapeutic effect after at least 4 weeks of administration at adequate dosage. Choosing an antidepressant of pharmacologically distinct profile fails to consistently demonstrate a significant superiority in terms of effectiveness over the switching to another antidepressant within the same pharmacological class. Augmenting SSRI/SNRIs with mirtazapine/mianserin has become the most recommended strategy of antidepressant combinations. Augmenting SSRI with tricyclic drugs is now a less recommended strategy of antidepressant combinations given the increased risk for the occurrence of pharmacokinetic drug-drug interactions and adverse effects.

  13. Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms.

    Science.gov (United States)

    Gahr, Maximilian; Zeiss, René; Lang, Dirk; Connemann, Bernhard J; Hiemke, Christoph; Schönfeldt-Lecuona, Carlos

    2016-06-01

    Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance- and country-specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To allow for identification of agents that cause severe forms of hepatotoxic ADRs, we used 2 terms of the MedDRA ("drug-related hepatic disorders-comprehensive search" [DRHD-CS] and "… -severe events only" [DRHD-SEO]). Distribution of signals was heterogeneous throughout the different data sets, and consistent findings were present for only a few substances: agomelatine (AGM) and tianeptine as well as both positive control agents (amineptine, nefazodone) generated signals related to DRHD-CS and DRHD-SEO in all analyzed data sets. Tri- and tetracyclic antidepressants (here amitriptyline, clomipramine, mianserin, mirtazapine, trimipramine) were associated with hepatotoxicity in several data sets. Using 2 MedDRA terms did not allow for detection of agents that cause severe hepatotoxic ADR. Our results support the findings of previous, primarily literature-based, systematic analyses of hepatotoxicity related to antidepressive psychopharmacotherapy. No new safety information could be generated. Application of 2 MedDRA terms did not increase the substance-specific safety information.

  14. Drug-Induced Liver Injury Associated With Antidepressive Psychopharmacotherapy: An Explorative Assessment Based on Quantitative Signal Detection Using Different MedDRA Terms.

    Science.gov (United States)

    Gahr, Maximilian; Zeiss, René; Lang, Dirk; Connemann, Bernhard J; Hiemke, Christoph; Schönfeldt-Lecuona, Carlos

    2016-06-01

    Drug-induced liver injury is a major problem of pharmacotherapy and is also frequent with antidepressive psychopharmacotherapy. However, there are only few studies using a consistent methodologic approach to study hepatotoxicity of a larger group of antidepress ants. We performed a quantitative signal detection analysis using data from the Uppsala Monitoring Centre from the WHO that records adverse drug reaction (ADR) data from worldwide sources; we retrieved substance- and country-specific (Australia, France, Germany, Italy, Spain, the United Kingdom, and the United States) ADR data and calculated reporting odds ratios as measures for disproportionality within a case/noncase approach. To allow for identification of agents that cause severe forms of hepatotoxic ADRs, we used 2 terms of the MedDRA ("drug-related hepatic disorders-comprehensive search" [DRHD-CS] and "… -severe events only" [DRHD-SEO]). Distribution of signals was heterogeneous throughout the different data sets, and consistent findings were present for only a few substances: agomelatine (AGM) and tianeptine as well as both positive control agents (amineptine, nefazodone) generated signals related to DRHD-CS and DRHD-SEO in all analyzed data sets. Tri- and tetracyclic antidepressants (here amitriptyline, clomipramine, mianserin, mirtazapine, trimipramine) were associated with hepatotoxicity in several data sets. Using 2 MedDRA terms did not allow for detection of agents that cause severe hepatotoxic ADR. Our results support the findings of previous, primarily literature-based, systematic analyses of hepatotoxicity related to antidepressive psychopharmacotherapy. No new safety information could be generated. Application of 2 MedDRA terms did not increase the substance-specific safety information. PMID:26470856

  15. A Fluorescence Displacement Assay for Antidepressant Drug Discovery Based on Ligand-Conjugated Quantum Dots

    Energy Technology Data Exchange (ETDEWEB)

    Chang, Jerry [Vanderbilt University; Tomlinson, Ian [Oak Ridge National Laboratory (ORNL); Warnement, Michael [Vanderbilt University; Iwamoto, Hideki [Vanderbilt University

    2011-01-01

    The serotonin (5-hydroxytryptamine, 5-HT) transporter (SERT) protein plays a central role in terminating 5-HT neurotransmission and is the most important therapeutic target for the treatment of major depression and anxiety disorders. We report an innovative, versatile, and target-selective quantum dot (QD) labeling approach for SERT in single Xenopus oocytes that can be adopted as a drug-screening platform. Our labeling approach employs a custom-made, QD-tagged indoleamine derivative ligand, IDT318, that is structurally similar to 5-HT and accesses the primary binding site with enhanced human SERT selectivity. Incubating QD-labeled oocytes with paroxetine (Paxil), a high-affinity SERT-specific inhibitor, showed a concentration- and time-dependent decrease in QD fluorescence, demonstrating the utility of our approach for the identification of SERT modulators. Furthermore, with the development of ligands aimed at other pharmacologically relevant targets, our approach may potentially form the basis for a multitarget drug discovery platform.

  16. Bioanalysis of new designer drugs.

    Science.gov (United States)

    Wohlfarth, Ariane; Weinmann, Wolfgang

    2010-05-01

    Since the late 1990s the illicit drug market has undergone considerable change: along with the traditional drugs of abuse that still dominate, more than 100 psychotropic substances designed to bypass controlled substances legislation have appeared and led to intoxications and fatalities. Starting from the huge class of phenylalkylamines, containing many subgroups, the spectrum of structures has grown from tryptamines, piperazines, phenylcyclohexyl derivates and pyrrolidinophenones to synthetic cannabinoids and the first synthetic cocaine. Due to the small prevalence and high number of unknown substances, the detection of new designer drugs is a challenge for clinical and forensic toxicologists. Standard screening procedures might fail because a recently discovered or yet unknown substance has not been incorporated in the library used. Nevertheless, many metabolism studies, case reports, screening methods and substance-profiling papers concentrating on single compounds have been published. This review provides an overview of the developed bioanalytical and analytical methods, the matrices used, sample-preparation procedures, concentration of analytes in case of intoxication and also gives a résumé of immunoassay experiences. Additionally, six screening methods for biological matrices with a larger spectrum of analytes are described in more detail.

  17. Optimization of ultrasound assisted dispersive liquid-liquid microextraction of six antidepressants in human plasma using experimental design.

    Science.gov (United States)

    Fernández, P; Taboada, V; Regenjo, M; Morales, L; Alvarez, I; Carro, A M; Lorenzo, R A

    2016-05-30

    A simple Ultrasounds Assisted-Dispersive Liquid Liquid Microextraction (UA-DLLME) method is presented for the simultaneous determination of six second-generation antidepressants in plasma by Ultra Performance Liquid Chromatography with Photodiode Array Detector (UPLC-PDA). The main factors that potentially affect to DLLME were optimized by a screening design followed by a response surface design and desirability functions. The optimal conditions were 2.5mL of acetonitrile as dispersant solvent, 0.2mL of chloroform as extractant solvent, 3min of ultrasounds stirring and extraction pH 9.8.Under optimized conditions, the UPLC-PDA method showed good separation of antidepressants in 2.5min and good linearity in the range of 0.02-4μgmL(-1), with determination coefficients higher than 0.998. The limits of detection were in the range 4-5ngmL(-1). The method precision (n=5) was evaluated showing relative standard deviations (RSD) lower than 8.1% for all compounds. The average recoveries ranged from 92.5% for fluoxetine to 110% for mirtazapine. The applicability of DLLME/UPLC-PDA was successfully tested in twenty nine plasma samples from antidepressant consumers. Real samples were analyzed by the proposed method and the results were successfully submitted to comparison with those obtained by a Liquid Liquid Extraction-Gas Chromatography - Mass Spectrometry (LLE-GC-MS) method. The results confirmed the presence of venlafaxine in most cases (19 cases), followed by sertraline (3 cases) and fluoxetine (3 cases) at concentrations below toxic levels. PMID:26955756

  18. Liquid-phase microextraction for simultaneous chromatographic analysis of three antidepressant drugs in plasma

    Directory of Open Access Journals (Sweden)

    Carlos Eduardo Dobrovolskni Porto

    2012-01-01

    Full Text Available A method using Liquid Phase Microextraction for simultaneous detection of citalopram (CIT, paroxetine (PAR and fluoxetine (FLU, using venlafaxine as internal standard, in plasma by high performance liquid chromatography with fluorescence detection was developed. The linearity was evaluated between 5.0 and 500 ng mL-1 (r > 0.99 and the limit of quantification was 2.0, 3.0 and 5.0 ng mL-1 for CIT, PAR and FLU, respectively. Therefore, it can be applied to therapeutic drug monitoring, pharmacokinetics or bioavailability studies and its advantages are that it necessary relatively inexpensive equipment and sample preparation techniques.

  19. Clinical perspectives on the influence of drug formulation on patient tolerability and use of commonly prescribed antidepressants in major depressive disorder

    Directory of Open Access Journals (Sweden)

    Matthew A Fuller

    2013-01-01

    Full Text Available The purpose of this review is to summarize the formulation options for currently available antidepressants, and discuss examples of the influence that formulation may have on the pharmacologic and clinical profiles of the medications. A review of current literature suggests that differences in drug-delivery technologies can lead to variations in the pharmacokinetic and pharmacodynamic profiles of generic and branded drugs, despite generic drugs being required to meet bioequivalence standards compared with their branded counterparts. These differences may influence the effectiveness and tolerability of treatment. Recent reports have highlighted the need for individualized treatment regimens and careful assessment of tolerability and efficacy when switching patients from brand to generic formulations. There is a growing body of evidence indicating that differences in formulation can substantially impact drug pharmacokinetics and pharmacodynamics, which in turn, can affect drug effects. The clinical impact of these differences remains unclear. Further research is needed to clarify the influence of antidepressant formulations on treatment adherence, patient preference, and quality of life, and how this impacts clinical practice with regard to brand versus generic treatment selection.

  20. Trend analysis of antidepressant drug use in a three grade mental hospital%我院抗抑郁药使用趋势分析

    Institute of Scientific and Technical Information of China (English)

    李永红; 靳自斌; 朱静

    2015-01-01

    Objective Through the investigation, to understand our use of antidepressants, and trends.Methods A retrospective analysis of our hospital from January 2014 to January 2014 outpatient prescriptions and medicinal drugs in hospital prescription for depression during frequency statistics, sales amount, and so on and so forth.Results From January 2014 to January 2014 in the spirit of specialized pharmacy antidepressants for total sales of 5.3387 million yuan, the highest sales amount of paroxetine, followed by venlafaxine, again for sertraline. DDDs occupies the top three, respectively is paroxetine, followed by grammar Racine, sertraline for clinical commonly used antidepressant drugs. Paroxetine, venlafaxine, sertraline are new type of antidepressant drugs, the new depressive drugs sales amount is higher than traditional drugs (P < 0.05). Antidepressants and sedative hypnotic drugs most often used in combination, with mood stabilizers, antipsychotic medication use is also more frequent; Drugs are used for female patients, patients aged more than 40 or higher. Conclusion The spirit of our specialized pharmacy antidepressant use new drug use, this kind of adverse drug reaction, the effect is good, strong normative.%目的:通过用药调查,了解我院抗抑郁药使用情况及趋势.方法:回顾性分析我院2014年1月~2015年1月期间门诊处方与住院处方对抑郁药用药频度、销售金额等情况进行统计信息.结果:我院2014年1月~2015年1月年精神专科药房抗抑郁药物销售总量为533.87万元,销售金额最高的是帕罗西汀,其次为文拉法辛,再次为舍曲林.DDDs居于前三位的分别是帕罗西汀,其次为文法拉辛,舍曲林为临床较常用抗抑郁药.帕罗西汀、文拉法辛、舍曲林均为新型抗抑郁药,新型抗郁药物销售金额高于传统药物(P<0.05).抗抑郁药物最常与镇静催眠类药物联合使用,与心境稳定剂、抗精神病药物使用也较频繁;药物均多用于

  1. Carbonic anhydrase inhibitors drug design.

    Science.gov (United States)

    McKenna, Robert; Supuran, Claudiu T

    2014-01-01

    Inhibition of the metalloenzyme carbonic anhydrase (CA, EC 4.2.1.1) has pharmacologic applications in the field of antiglaucoma, anticonvulsant, antiobesity, and anticancer agents but is also emerging for designing anti-infectives (antifungal and antibacterial agents) with a novel mechanism of action. As a consequence, the drug design of CA inhibitors (CAIs) is a very dynamic field. Sulfonamides and their isosteres (sulfamates/sulfamides) constitute the main class of CAIs which bind to the metal ion in the enzyme active site. Recently the dithiocarbamates, possessing a similar mechanism of action, were reported as a new class of inhibitors. Other families of CAIs possess a distinct mechanism of action: phenols, polyamines, some carboxylates, and sulfocoumarins anchor to the zinc-coordinated water molecule. Coumarins and five/six-membered lactones are prodrug inhibitors, binding in hydrolyzed form at the entrance of the active site cavity. Novel drug design strategies have been reported principally based on the tail approach for obtaining all these types of CAIs, which exploit more external binding regions within the enzyme active site (in addition to coordination to the metal ion), leading thus to isoform-selective compounds. Sugar-based tails as well as click chemistry were the most fruitful developments of the tail approach. Promising compounds that inhibit CAs from bacterial and fungal pathogens, of the dithiocarbamate, phenol and carboxylate types have also been reported. PMID:24146385

  2. Antiepileptic, behavioral, and antidepressant effects of adjuvant lamotrigine therapy in drug-resistant epilepsy

    Directory of Open Access Journals (Sweden)

    Martinović Žarko J.

    2004-01-01

    Full Text Available Aim. To evaluate the behavioral effects of lamotrigine as add-on therapy in treatment-resistant epilepsy. Methods. An open, prospective, long-term study of lamotrigine as adjuvant therapy was performed in 56 patients with drug-resistant epilepsy (female/male ratio 35/21, age range 16-51 years. All the patients kept seizure diaries, and electroencephalograms were recorded at baseline and during 24 months of the treatment. Quality of life questionnaire, Hamilton depression scale (HMD, Beck depression scale (BDI, and Hamilton anxiety scale (HMA were used before and during lamotrigine therapy. Comparative assessments were made in an age- and sex-matched control group treated with other antiepileptic drugs. Results. Overall, seizure control was improved in 55.3% of the patients, remained unchanged in 39.3%, and deteriorated in 5.4%. Improvement in some quality of life measures occurred in 50% of the patients. The HMD subscales and BDI scale showed significant improvement in lamotrigine treated patients compared to the control group (ANOVA, p < 0.01. Negative behavioral effects occurred in 10.7% of the patients. Conclusion. Lamotrigine demonstrated significant antiepileptic long-term efficacy, and its positive effects on the mood and quality of life, which surpassed the negative behavioral effects, and contributed highly to the favorable treatment outcome.

  3. Designer drugs: the evolving science of drug discovery.

    Science.gov (United States)

    Wanke, L A; DuBose, R F

    1998-07-01

    Drug discovery and design are fundamental to drug development. Until recently, most drugs were discovered through random screening or developed through molecular modification. New technologies are revolutionizing this phase of drug development. Rational drug design, using powerful computers and computational chemistry and employing X-ray crystallography, nuclear magnetic resonance spectroscopy, and three-dimensional quantitative structure activity relationship analysis, is creating highly specific, biologically active molecules by virtual reality modeling. Sophisticated screening technologies are eliminating all but the most active lead compounds. These new technologies promise more efficacious, safe, and cost-effective medications, while minimizing drug development time and maximizing profits. PMID:10185235

  4. Cytogenetic and Developmental Effects of Antidepression Drug (Cipralex on Female Mice and Embryos

    Directory of Open Access Journals (Sweden)

    Hanaa M. Roshdy & Thanaa M.T Shoman

    2004-12-01

    Full Text Available Escitalopram (cipralex® a new highly selective serotonin reuptake inhibitor, it is effective in the treatment of patients with major depression. To evaluate the cytogenetics and developmental effects of cipralex throughout major organgenesis, mice were administrated orally with a doses of 0.06, 0.12 and 0.24 mg/kg/day cipralex on gestation days 1-18 and examined on the 19th day of gestation for evidence of maternal and fetal toxicity. Cipralex at different doses tested produce significant toxic effects in reproductive parameters. Significant embryo fetotoxic effects were observed at tested dose levels as evidenced by total number of implantations, post. Implantation loss and embryo malformations. There were increases in the frequencies of micronuclei and chromosomal aberrations in both maternal and embryonic cells treated with cipalex, these increases were dose dependent. These results indicate that cipralex is considered to be cytogenetic and embryo toxic drug when administered during pregnancy.

  5. Performance of Cpred/Cobs concentration ratios as a metric reflecting adherence to antidepressant drug therapy

    Directory of Open Access Journals (Sweden)

    Yan Feng

    2011-03-01

    Full Text Available Yan Feng1, Marc R Gastonguay2, Bruce G Pollock3,5, Ellen Frank3, Gail H Kepple4, Robert R Bies5,6,71Discovery Medicine and Clinical Pharmacology, Bristol-Myers Squibb, Lawrenceville, NJ, USA; 2Metrum Institute, Tariffville, CT, USA; 3Department of Psychiatry, School of Medicine, 4Department of Depression Prevention, University of Pittsburgh, PA, USA; 5Centre for Addiction and Mental Health, University of Toronto, Toronto, Canada; 6Division of Clinical Pharmacology, School of Medicine and Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA; 7Indiana Clinical Translational Research Institute, Indiana University School of Medicine, IN, USABackground: Nonadherence is very common among subjects undergoing pharmacotherapy for schizophrenia and depression. This study aimed to evaluate the performance of the ratio of the nonlinear mixed effects pharmacokinetic model predicted concentration to observed drug concentration (ratio of population predicted to observed concentration (Cpred/Cobs and ratio of individual predicted to observed concentration (Cipred/Cobs as a measure of erratic drug exposure, driven primarily by variable execution of the dosage regimen and unknown true dosage history.Methods: Modeling and simulation approaches in conjunction with dosage history information from the Medication Event Monitoring System (MEMS, provided by the “Depression: The search for treatment relevant phenotypes” study, was applied to evaluate the consistency of exposure via simulation studies with scenarios representing a long half-life drug (escitalopram. Adherence rates were calculated based on the percentage of the prescribed doses actually taken correctly during the treatment window of interest. The association between Cpred/Cobs, Cipred/Cobs ratio, and adherence rate was evaluated under various assumptions of known dosing history.Results: Simulations for those scenarios representing a known

  6. Antidepressive-drug-induced bodyweight gain is associated with polymorphisms in genes coding for COMT and TPH1

    DEFF Research Database (Denmark)

    Secher, Anna; Bukh, Jens; Bock, Camilla;

    2009-01-01

    of a single depressive episode and who were under antidepressive treatment. Weight gainers were identified based on rating with the Udvalg for Kliniske Undersøgelser Side Effect Rating Scale. Polymorphisms in catechol-O-methyltransferase, tryptophan hydroxylase (TPH1), serotonin receptor 2C (HTR2C......) and serotonin transporter (SLC6A4) genes were identified and associated with bodyweight gain during treatment. The AG genotype of catechol-O-methyltransferase rs4680 and the AA genotype of TPH1 rs18532 were significantly associated with bodyweight gain during antidepressive treatment, when adjusted for age...

  7. Antidepressants and testicular cancer: cause versus association.

    Science.gov (United States)

    Andrade, Chittaranjan

    2014-03-01

    A data mining study that examined associations between 105 drugs and 55 cancer sites found significant associations between 2 selective serotonin reuptake inhibitors (fluoxetine and paroxetine) and testicular cancer. The study suggested several reasons why these associations merited further investigation. A later study tested specific relationships between 12 antidepressant drugs and testicular cancer and subtypes thereof; whereas significant relationships were again found, these disappeared after adjusting for confounding variables. These 2 studies are educative because they illustrate how false-positive results can easily arise in exploratory research and how confounding may be responsible for statistically significant relationships in study designs that are not randomized controlled trials. PMID:24717391

  8. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr;

    2010-01-01

    Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The current...... study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients....

  9. Erythropoietin modulates neural and cognitive processing of emotional information in biomarker models of antidepressant drug action in depressed patients

    DEFF Research Database (Denmark)

    Miskowiak, Kamilla W; Favaron, Elisa; Hafizi, Sepehr;

    2010-01-01

    Erythropoietin (Epo) has neuroprotective and neurotrophic effects, and may be a novel therapeutic agent in the treatment of psychiatric disorders. We have demonstrated antidepressant-like effects of Epo on the neural and cognitive processing of facial expressions in healthy volunteers. The curren...... study investigates the effects of Epo on the neural and cognitive response to emotional facial expressions in depressed patients....

  10. The responsiveness of TrkB to BDNF and antidepressant drugs is differentially regulated during mouse development.

    Directory of Open Access Journals (Sweden)

    Antonio Di Lieto

    Full Text Available BACKGROUND: Previous studies suggest that the responsiveness of TrkB receptor to BDNF is developmentally regulated in rats. Antidepressant drugs (AD have been shown to increase TrkB signalling in the adult rodent brain, and recent findings implicate a BDNF-independent mechanism behind this phenomenon. When administered during early postnatal life, ADs produce long-lasting biochemical and behavioural alterations that are observed in adult animals. METHODOLOGY: We have here examined the responsiveness of brain TrkB receptors to BDNF and ADs during early postnatal life of mouse, measured as autophosphorylation of TrkB (pTrkB. PRINCIPAL FINDINGS: We found that ADs fail to induce TrkB signalling before postnatal day 12 (P12 after which an adult response of TrkB to ADs was observed. Interestingly, there was a temporally inverse correlation between the appearance of the responsiveness of TrkB to systemic ADs and the marked developmental reduction of BDNF-induced TrkB in brain microslices ex vivo. Basal p-TrkB status in the brain of BDNF deficient mice was significantly reduced only during early postnatal period. Enhancing cAMP (cyclic adenosine monophosphate signalling failed to facilitate TrkB responsiveness to BDNF. Reduced responsiveness of TrkB to BDNF was not produced by the developmental increase in the expression of dominant-negative truncated TrkB.T1 because this reduction was similarly observed in the brain microslices of trkB.T1(-/- mice. Moreover, postnatal AD administration produced long-lasting behavioural alterations observable in adult mice, but the responses were different when mice were treated during the time when ADs did not (P4-9 or did (P16-21 activate TrkB. CONCLUSIONS: We have found that ADs induce the activation of TrkB only in mice older than 2 weeks and that responsiveness of brain microslices to BDNF is reduced during the same time period. Exposure to ADs before and after the age when ADs activate TrkB produces differential

  11. Antidepressant drugs transactivate TrkB neurotrophin receptors in the adult rodent brain independently of BDNF and monoamine transporter blockade.

    Directory of Open Access Journals (Sweden)

    Tomi Rantamäki

    Full Text Available BACKGROUND: Antidepressant drugs (ADs have been shown to activate BDNF (brain-derived neurotrophic factor receptor TrkB in the rodent brain but the mechanism underlying this phenomenon remains unclear. ADs act as monoamine reuptake inhibitors and after prolonged treatments regulate brain bdnf mRNA levels indicating that monoamine-BDNF signaling regulate AD-induced TrkB activation in vivo. However, recent findings demonstrate that Trk receptors can be transactivated independently of their neurotrophin ligands. METHODOLOGY: In this study we examined the role of BDNF, TrkB kinase activity and monoamine reuptake in the AD-induced TrkB activation in vivo and in vitro by employing several transgenic mouse models, cultured neurons and TrkB-expressing cell lines. PRINCIPAL FINDINGS: Using a chemical-genetic TrkB(F616A mutant and TrkB overexpressing mice, we demonstrate that ADs specifically activate both the maturely and immaturely glycosylated forms of TrkB receptors in the brain in a TrkB kinase dependent manner. However, the tricyclic AD imipramine readily induced the phosphorylation of TrkB receptors in conditional bdnf⁻/⁻ knock-out mice (132.4±8.5% of control; P = 0.01, indicating that BDNF is not required for the TrkB activation. Moreover, using serotonin transporter (SERT deficient mice and chemical lesions of monoaminergic neurons we show that neither a functional SERT nor monoamines are required for the TrkB phosphorylation response induced by the serotonin selective reuptake inhibitors fluoxetine or citalopram, or norepinephrine selective reuptake inhibitor reboxetine. However, neither ADs nor monoamine transmitters activated TrkB in cultured neurons or cell lines expressing TrkB receptors, arguing that ADs do not directly bind to TrkB. CONCLUSIONS: The present findings suggest that ADs transactivate brain TrkB receptors independently of BDNF and monoamine reuptake blockade and emphasize the need of an intact tissue context for the

  12. Adherence to antidepressants

    Directory of Open Access Journals (Sweden)

    Abimbola Farinde

    2013-01-01

    Full Text Available While major depression is considered a frequent mental illness there are ongoing reports of high non-adherence to antidepressant medications which places suffers at high risk for relapse, recurrence, or greater impairment,. The World Health Organization (WHO defines adherence as the extent to which a person′s behavior (e.g. taking medications can align with the agreed recommendations of a health care provider. Unfortunately while patient may recognize the importance of adherence to antidepressant medications the majority of patients do not adhere to their prescribed antidepressants. Some of the factors that may contribute to or lead to non-adherence include knowingly or unknowingly missing doses, taking extra doses, delaying administration times, or taking drug holidays. Pharmacists have the unique ability to deter non-adherence through the performance of continuous assessment and monitoring of adherence in this population given these accessibility. Additionally, pharmacists are able to develop therapeutic alliances with patients that can help to increase the likelihood of achieving positive patient outcomes. Antidepressant non-adherence can be viewed as a significant public health concern so it is important for patients to be educated about the importance of adherence, and health care professionals should be aware of factors or patient characteristics that can serve as barriers to non-adherence.

  13. Neurogenesis and The Effect of Antidepressants

    Directory of Open Access Journals (Sweden)

    Philippe Taupin

    2006-01-01

    Full Text Available The recent evidence that neurogenesis occurs throughout adulthood and neural stem cells (NSCs reside in the adult central nervous system (CNS suggests that the CNS has the potential for self-repair. Beside this potential, the function of newly generated neuronal cells in the adult brain remains the focus of intense research. The hippocampus of patients with depression show signs of atrophy and neuronal loss. This suggests that adult neurogenesis may contribute to the biology of depression. The observations that antidepressants, like fluoxetine, increase neurogenesis in the dentate gyrus (DG and neurogenesis is required for the behavioral effect of antidepressants, lead to a new theory for depression and the design of new strategies and drugs for the treatment of depression. However, the role of adult neurogenesis in the etiology of depression remains the source of controversies and debates.

  14. VGF, a New Player in Antidepressant Action?

    OpenAIRE

    Malberg, Jessica E.; Monteggia, Lisa M.

    2008-01-01

    Recent studies have identified adaptations of intracellular signaling pathways and target genes that could contribute or modulate the action of antidepressant drugs, as well as exercise-mediated antidepressant responses. Understanding these adaptations, particularly those changes that are common to diverse antidepressant treatments, is important for the development of more potent and specific treatments of depression. There is growing evidence that growth factors may be important mediators of...

  15. Analysis on the Use of Antidepressant Drugs in 285 Patients With Psychological Hospital in Changchun City%长春市心理医院285例住院患者使用抗抑郁药用药分析

    Institute of Scientific and Technical Information of China (English)

    丁秀君

    2015-01-01

    Objective To understand the application of antidepressant drugs in open ward in our hospital, and provide reference for clinical rational drug use. Source: Changchun city hospital open area, from January 1st, 2014 to December 31st, hospitalized patients. Methods Self designed survey form was recorded in the patient's gender, age, diagnosis, the name of the antidepressant drugs, and the combination of drug use, and the contents of the general demographic data, medical records and drug use. Results One kind of antidepressant, which was mainly new type of antidepressants, was used in 206 cases (72.3%), combined application of two kinds of antidepressants was used in 79 cases, while mirtazapine combined with venlafaxine was most common used 38 cases. Conclusion References for clinical rational drug use. Most patients use only one kind of antidepressant, and the ratio of new type of antidepressants was higher than traditional antidepressants. Mirtazapine combined with venlafaxine works faster and better in the cases which combination of two kinds of antidepressants was used.%目的:了解我院开放病区住院患者抗抑郁药的应用情况,为临床合理用药提供参考。资料来源:长春市心理医院开放病区,2014年1月1日~12月31日住院患者。方法自行设计调查表格,记录患者性别、年龄、诊断、服用抗抑郁药名称及合并用药情况,内容涉及一般人口学资料,病案资料和用药情况。结果单一使用1种抗抑郁药治疗者206例(72.3%);目前应用以新型抗抑郁药为主;联合2种抗抑郁药物治疗者79例,以米氮平+文拉法辛最为多见38例。结论为临床合理用药提供参考;患者单一使用1种抗抑郁药治疗者较多;新型抗抑郁药物应用比例高于传统抗抑郁药;联合2种抗抑郁药物治疗的,米氮平+文拉法辛抗抑郁速度和疗效俱佳。

  16. Solid phase extraction of antidepressant drugs amitriptyline and nortriptyline from plasma samples using core-shell nanoparticles of the type Fe3O4-ZrO2-N- cetylpyridinium, and their subsequent determination by HPLC with UV detection

    International Nuclear Information System (INIS)

    The solid phase extraction (SPE) is described for preconcentration of the antidepressant drugs amitriptyline and nortriptyline prior to their determination by HPLC with UV detection. It is based on the use of water-dispersible core-shell nanoparticles (NPs) of the Fe3O4-ZrO2-N-cetylpyridinium type. The positively charged surfactant N-cetylpyridinium forms mixed aggregates with the drugs on the surface of the core-shell and thereby improves the adsorption of amitriptyline and nortriptyline through hydrophobic and/or ionic interactions. Their extraction depends on the type and amount of surfactant, sample pH, extraction time, desorption conditions, sample volume and amount of NPs that were optimized by application of experimental design. The enrichment factors are 220 and 250, respectively, for amitriptyline and nortriptyline, and the detection limits are 0.04 and 0.08 ng·mL-1. This protocol enables accurate and precise quantification of the two drugs in complex and low content samples. It was applied to the determination of the two drugs in plasma samples with relative recoveries in the range from 89 to 105 % and RSDs less than 4 %. (author)

  17. 21 CFR 316.24 - Granting orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Granting orphan-drug designation. 316.24 Section...) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.24 Granting orphan-drug designation. (a) FDA will grant the request for orphan-drug designation if none of the reasons described in §...

  18. 我院门诊抗抑郁药处方分析%Analysis of Outpatient Prescriptions of Antidepressant Drugs

    Institute of Scientific and Technical Information of China (English)

    李燕平; 胡新伟

    2014-01-01

    目的:研究我院抗抑郁药的应用情况。方法:选取我院门诊2012年7-9月1080张诊断为抑郁症的处方进行分析。结果:1080例患者中,男425例(39.35%),女655例(60.65%),女性多于男性。各类抗抑郁药中,以选择性5-羟色胺再摄取抑制剂(SSRI)使用频率最高。各种抗抑郁药的平均使用剂量均在安全范围之内。697例(64.54%)患者联用苯二氮类药物治疗,476例(44.07%)患者联用抗精神病药,233例(21.57%)患者联用心境稳定剂。结论:以SSRI为主的新型抗抑郁药已经成为我院临床抗抑郁治疗的主流药物,抗抑郁药的使用以单一用药为主。%Objective:To evaluate the utilization of antidepressants in our hospital. Methods:The prescription analy-sis was conducted of 1 080 depression outpatients during Jul.-Sep. of 2012. Results:Of the selected patients female and male patients were 655(60.65%) and 425(39.35%) respectively. Among the antidepressants used,selective serotonin re-uptake inhibitors (SSRIs) were the most frequently used.The average dose of various antidepressants was all within the range of safety. The frequency of combined use of benzodiazepines,antipsychotics and mood stabilizers used was 64.54%, 44.07%and 21.57%respectively. Conclusion:New types of antidepressants based on SSRIs have become the mainstream treatment of depression in our hospital and antidepressants were mainly used as the single agent.

  19. Mechanisms of antidepressant resistance

    Directory of Open Access Journals (Sweden)

    Wissam eEl Hage

    2013-11-01

    Full Text Available Depression is one of the most frequent and severe mental disorder. Since the discovery of antidepressant properties of the imipramine and then after of other tricyclic compounds, several classes of psychotropic drugs have shown be effective in treating major depressive disorder. However, there is a wide range of variability in response to antidepressants that might lead to non response or partial response or in increased rate of relapse or recurrence. The mechanisms of response to antidepressant therapy are poorly understood, and few biomarkers are available than can predict response to pharmacotherapy. Here, we will first review markers that can be used to predict response to pharmacotherapy, such as markers of drug metabolism or blood-brain barrier function, the activity of specific brain areas or neurotransmitter systems, hormonal dysregulations or plasticity, and related molecular targets. We will describe both clinical and preclinical studies and describe factors that might affect the expression of these markers, including environmental or genetic factors and comorbidities. This information will permit us to suggest practical recommendations and innovative treatment strategies to improve therapeutic outcomes.

  20. 21 CFR 316.23 - Timing of requests for orphan-drug designation; designation of already approved drugs.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Timing of requests for orphan-drug designation..., DEPARTMENT OF HEALTH AND HUMAN SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.23 Timing of requests for orphan-drug designation; designation of already approved drugs....

  1. Ultra-high-pressure liquid chromatography tandem mass spectrometry determination of antidepressant and anxiolytic drugs in neonatal meconium and maternal hair.

    Science.gov (United States)

    Pichini, Simona; Cortes, Laura; Marchei, Emilia; Solimini, Renata; Pacifici, Roberta; Gomez-Roig, Maria Dolores; García-Algar, Oscar

    2016-01-25

    A procedure based on ultra-high-pressure liquid chromatography tandem mass spectrometry has been developed for the determination of 22 antidepressant and anxiolytic drugs ad metabolites in the three consecutive maternal hair segments representing the pregnancy trimesters and paired neonatal meconium samples. After hair washing with methyl alcohol and diethyl ether and subsequent addition of internal standards, hair samples were treated with 500 μl VMA-T M3 reagent for 1h at 100 °C. After cooling, 100 μl M3 extract were diluted with 400 μl water and a volume of 10 μl was injected into chromatographic system. Meconium samples were firstly treated with 1 ml methyl alcohol and the organic layer back-extracted twice with 1.5 ml of a mixture of ethylacetate:hexane (80:20, v/v). Chromatographic separation was achieved at ambient temperature using a reverse-phase column and a linear gradient elution with two solvents: 0.3% formic acid in acetonitrile and 5mM ammonium formate pH 3. The mass spectrometer was operated in positive ion mode, using multiple reaction monitoring via positive electrospray ionization. The method was linear from the limit of quantification (0.05-1 ng/mg hair and 5-25 ng/g meconium depending on analyte under investigation;) to 10 ng/mg hair and 1000 ng/g meconium, with an intra- and inter-assay imprecision and inaccuracy always less than 20% and an analytical recovery between 66.6% and 95.3%, depending on the considered analyte and biological matrix. Using the validated method, 7 mothers were found positive to one or more hair segments and 5 meconium samples were found positive to one or more antidepressant and anxiolytic drugs, assessing prenatal exposure to these drugs following maternal consumption in one or more pregnancy trimesters.

  2. Thermodynamic Studies for Drug Design and Screening

    Science.gov (United States)

    Garbett, Nichola C.; Chaires, Jonathan B.

    2012-01-01

    Introduction A key part of drug design and development is the optimization of molecular interactions between an engineered drug candidate and its binding target. Thermodynamic characterization provides information about the balance of energetic forces driving binding interactions and is essential for understanding and optimizing molecular interactions. Areas covered This review discusses the information that can be obtained from thermodynamic measurements and how this can be applied to the drug development process. Current approaches for the measurement and optimization of thermodynamic parameters are presented, specifically higher throughput and calorimetric methods. Relevant literature for this review was identified in part by bibliographic searches for the period 2004 – 2011 using the Science Citation Index and PUBMED and the keywords listed below. Expert opinion The most effective drug design and development platform comes from an integrated process utilizing all available information from structural, thermodynamic and biological studies. Continuing evolution in our understanding of the energetic basis of molecular interactions and advances in thermodynamic methods for widespread application are essential to realize the goal of thermodynamically-driven drug design. Comprehensive thermodynamic evaluation is vital early in the drug development process to speed drug development towards an optimal energetic interaction profile while retaining good pharmacological properties. Practical thermodynamic approaches, such as enthalpic optimization, thermodynamic optimization plots and the enthalpic efficiency index, have now matured to provide proven utility in design process. Improved throughput in calorimetric methods remains essential for even greater integration of thermodynamics into drug design. PMID:22458502

  3. Clinical application of antidepressants in the treatment of insomnia symptoms

    Directory of Open Access Journals (Sweden)

    WONG Iok-man

    2013-11-01

    Full Text Available Insomnia is one of the common complaints among all clinical departments. In recent years, some studies have demonstrated that insomnia symptoms can be improved or treated by some antidepressants. Based on literature search both at home and abroad, this paper summarized the effect of various antidepressants with different pharmacological properties on sleep, and the progress of clinical application of antidepressants in treating insomnia according to the classification of antidepressant drugs.

  4. Designer Drug Confusion: A Focus on MDMA.

    Science.gov (United States)

    Beck, Jerome; Morgan, Patricia A.

    1986-01-01

    Discusses the competing definitions and issues surrounding various designer drugs, primarily 3, 4-methylenedioxy-methamphetamine (MDMA). Offers a rationale for why interest in MDMA, which possesses both stimulant and psychedelic properties, will continue to grow despite the drug's recent illegality and increasing evidence of neurotoxicity.…

  5. Smarter Drugs: How Protein Crystallography Revolutionizes Drug Design

    International Nuclear Information System (INIS)

    According to Smith, protein crystallography allows scientists to design drugs in a much more efficient way than the standard methods traditionally used by large drug companies, which can cost close to a billion dollars and take 10 to 15 years. 'A lot of the work can be compressed down,' Smith said. Protein crystallography enables researchers to learn the structure of molecules involved in disease and health. Seeing the loops, folds and placement of atoms in anything from a virus to a healthy cell membrane gives important information about how these things work - and how to encourage, sidestep or stop their functions. Drug design can be much faster when the relationship between structure and function tells you what area of a molecule to target. Smith will use a timeline to illustrate the traditional methods of drug development and the new ways it can be done now. 'It is very exciting work. There have been some failures, but many successes too.' A new drug to combat the flu was developed in a year or so. Smith will tell us how. He will also highlight drugs developed to combat HIV, Tuberculosis, hypertension and Anthrax.

  6. Antidepressant-like activity of flunarizine in modified tail suspension test in rats

    Directory of Open Access Journals (Sweden)

    Vinod Shinde

    2015-01-01

    Full Text Available Background: Flunarizine, a Ca 2+ channel blocker, crosses blood brain barrier (BBB, antagonizes calcium influx and interferes with neurotransmitter system. Flunarizine 20 mg/kg exhibited significant antidepressant activity in our previous study using forced swim test (FST in mice, which was contradictory to the findings of other authors. Hence, the present study was designed to strengthen the results of our previous study, using the modified tail suspension test (TST in rats. Aim: Aim of this study was to evaluate the antidepressant activity of flunarizine versus standard antidepressant drug fluoxetine in modified TST in rats. Materials and Methods: The study approved by Institutional Animal Ethics Committee was conducted using 24 adult albino rats (n = 6 in each group. Antidepressant effect of normal saline (0.1 ml/100 g, fluoxetine (10 mg/kg, intraperitoneally (ip, and flunarizine (2 and 10 mg/kg, ip was evaluated by using modified TST in rats. Thirty minutes after administration of all test drugs the duration of immobility was recorded for a period of 5 min in all rats by using modified TST. The data was analyzed by Student′s t-test and one-way analysis of variance (ANOVA and P 0.05. Also, currently used human dose of flunarizine when extrapolated to rats (i. e., 2 mg/kg, ip failed to show significant antidepressant effect in modified TST in rats. Conclusion: The results of the present study indicate antidepressant-like activity of flunarizine.

  7. Designer Drugs: A Synthetic Catastrophe

    Directory of Open Access Journals (Sweden)

    James Fratantonio

    2015-08-01

    Full Text Available Synthetic stimulants can cause hallucinations, aggressive behaviors, death and are sometimes legal. These substances are sold as plant food and bath salts that are "Not for Human Consumption", therefore skirting the 1986 Federal Analogue Act and giving a false pretense of safety. Studies have proved that these substances are toxic, have a high abuse potential, and are becoming extremely prevalent in the United States. This creates a dilemma for law enforcement agents, hospitals, and substance use disorder treatment centers. Urine Drug Testing is utilized as a clinical diagnostic tool in substance use disorder treatment centers, and the furious pace at which new synthetic stimulants are introduced to the black market are making the detection via urine increasingly difficult. This article will discuss the prevalence, pharmacology and difficulty developing laboratory assays to detect synthetic stimulants.

  8. Evolution and intelligent design in drug development

    Directory of Open Access Journals (Sweden)

    Dorothee eKern

    2015-05-01

    Full Text Available Sophisticated protein kinase networks, empowering complexity in higher organisms, are also drivers of devastating diseases such as cancer. Accordingly, these enzymes have become major drug targets of the 21st century. However, the holy grail of designing specific kinase inhibitors aimed at specific cancers has not been found. Can new approaches in cancer drug design help win the battle with this multi-faced and quickly evolving enemy? In this perspective we discuss new strategies and ideas that were born out of a recent breakthrough in understanding the molecular basis underlying the clinical success of the cancer drug Gleevec. An old method, stopped-flow kinetics, combined with old enzymes, the ancestors dating back up to about billion years, provides an unexpected outlook for future intelligent design of drugs.

  9. Targeted proteins for diabetes drug design

    Science.gov (United States)

    Doan Trang Nguyen, Ngoc; Thi Le, Ly

    2012-03-01

    Type 2 diabetes mellitus is a common metabolism disorder characterized by high glucose in the bloodstream, especially in the case of insulin resistance and relative insulin deficiency. Nowadays, it is very common in middle-aged people and involves such dangerous symptoms as increasing risk of stroke, obesity and heart failure. In Vietnam, besides the common treatment of insulin injection, some herbal medication is used but no unified optimum remedy for the disease yet exists and there is no production of antidiabetic drugs in the domestic market yet. In the development of nanomedicine at the present time, drug design is considered as an innovative tool for researchers to study the mechanisms of diseases at the molecular level. The aim of this article is to review some common protein targets involved in type 2 diabetes, offering a new idea for designing new drug candidates to produce antidiabetic drugs against type 2 diabetes for Vietnamese people.

  10. Drug: D08257 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available apeutic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepress...ants N06AX06 Nefazodone D08257 Nefazodone (INN) USP drug

  11. Synergistic interaction between ketoconazole and several antidepressant drugs with allopregnanolone treatments in ovariectomized Wistar rats forced to swim.

    Science.gov (United States)

    Molina-Hernández, Miguel; Tellez-Alcántara, Norma Patricia; García, Julían Pérez; Lopez, Jorge Ivan Olivera; Jaramillo, M Teresa

    2004-12-01

    This article was aimed to investigate the interest of the combination allopregnanolone plus ketoconazole in depression with the time-sampling method in the forced swimming task. Dose-response curves for fluoxetine (0.5, 1.0 or 2.0 mg/kg, twice day, during 2 weeks; i.p.), desipramine (0.5, 1.0 or 2.14 mg/kg, twice a day, during 2 weeks; i.p.), ketoconazole (6.25, 12.5, 25.0 and 37.5 mg/kg, once a day, during 2 weeks; i.p.) and allopregnanolone (0.5, 1.5, 2.0 mg/kg; once a day, during 2 weeks; s.c.) were established. Fluoxetine (1.0 mg/kg, p swimming, highlighting a serotonergic mechanism while desipramine (1.0 mg/kg, p climbing behavior highlighting noradrenergic or dopaminergic effects. Subthreshold doses of fluoxetine (p immobility by increasing climbing. In conclusion, fluoxetine, desipramine, ketoconazole and allopregnanolone produced differential antidepressant-like actions in ovariectomized rats forced to swim. Ketoconazole, fluoxetine or desipramine synergized with allopregnanolone.

  12. The theoretical investigation of solvent effects on the relative stability and 15N NMR shielding of antidepressant heterocyclic drug

    Science.gov (United States)

    Tahan, Arezoo; Khojandi, Mahya; Salari, Ali Akbar

    2016-01-01

    The density functional theory (DFT) and Tomasi's polarized continuum model (PCM) were used for the investigation of solvent polarity and its dielectric constant effects on the relative stability and NMR shielding tensors of antidepressant mirtazapine (MIR). The obtained results indicated that the relative stability in the polar solvents is higher than that in non-polar solvents and the most stable structure was observed in the water at the B3LYP/6-311++G ( d, p) level of theory. Also, natural bond orbital (NBO) interpretation demonstrated that by increase of solvent dielectric constant, negative charge on nitrogen atoms of heterocycles and resonance energy for LP(N10) → σ* and π* delocalization of the structure's azepine ring increase and the highest values of them were observed in water. On the other hand, NMR calculations showed that with an increase in negative charge of nitrogen atoms, isotropic chemical shielding (σiso) around them increase and nitrogen of piperazine ring (N19) has the highest values of negative charge and σiso among nitrogen atoms. NMR calculations also represented that direct solvent effect on nitrogen of pyridine ring (N15) is more than other nitrogens, while its effect on N19 is less than other ones. Based on NMR data and NBO interpretation, it can be deduced that with a decrease in the negative charge on nitrogen atoms, the intramolecular effects on them decrease, while direct solvent effect increases.

  13. Defining Patient Centric Pharmaceutical Drug Product Design.

    Science.gov (United States)

    Stegemann, Sven; Ternik, Robert L; Onder, Graziano; Khan, Mansoor A; van Riet-Nales, Diana A

    2016-09-01

    The term "patient centered," "patient centric," or "patient centricity" is increasingly used in the scientific literature in a wide variety of contexts. Generally, patient centric medicines are recognized as an essential contributor to healthy aging and the overall patient's quality of life and life expectancy. Besides the selection of the appropriate type of drug substance and strength for a particular indication in a particular patient, due attention must be paid that the pharmaceutical drug product design is also adequately addressing the particular patient's needs, i.e., assuring adequate patient adherence and the anticipate drug safety and effectiveness. Relevant pharmaceutical design aspects may e.g., involve the selection of the route of administration, the tablet size and shape, the ease of opening the package, the ability to read the user instruction, or the ability to follow the recommended (in-use) storage conditions. Currently, a harmonized definition on patient centric drug development/design has not yet been established. To stimulate scientific research and discussions and the consistent interpretation of test results, it is essential that such a definition is established. We have developed a first draft definition through various rounds of discussions within an interdisciplinary AAPS focus group of experts. This publication summarizes the outcomes and is intended to stimulate further discussions with all stakeholders towards a common definition of patient centric pharmaceutical drug product design that is useable across all disciplines involved. PMID:27317470

  14. Designer drugs 2015: assessment and management.

    Science.gov (United States)

    Weaver, Michael F; Hopper, John A; Gunderson, Erik W

    2015-01-01

    Recent designer drugs, also known as "legal highs," include substituted cathinones (e.g., mephedrone, methylone, and methylenedioxypyrovalerone, often referred to as "bath salts"); synthetic cannabinoids (SCs; e.g., Spice); and synthetic hallucinogens (25I-NBOMe, or N-bomb). Compound availability has evolved rapidly to evade legal regulation and detection by routine drug testing. Young adults are the primary users, but trends are changing rapidly; use has become popular among members of the military. Acute toxicity is common and often manifests with a constellation of psychiatric and medical effects, which may be severe (e.g., anxiety, agitation, psychosis, and tachycardia), and multiple deaths have been reported with each of these types of designer drugs. Clinicians should keep designer drugs in mind when evaluating substance use in young adults or in anyone presenting with acute neuropsychiatric complaints. Treatment of acute intoxication involves supportive care targeting manifesting signs and symptoms. Long-term treatment of designer drug use disorder can be challenging and is complicated by a lack of evidence to guide treatment.

  15. Defining Patient Centric Pharmaceutical Drug Product Design.

    Science.gov (United States)

    Stegemann, Sven; Ternik, Robert L; Onder, Graziano; Khan, Mansoor A; van Riet-Nales, Diana A

    2016-09-01

    The term "patient centered," "patient centric," or "patient centricity" is increasingly used in the scientific literature in a wide variety of contexts. Generally, patient centric medicines are recognized as an essential contributor to healthy aging and the overall patient's quality of life and life expectancy. Besides the selection of the appropriate type of drug substance and strength for a particular indication in a particular patient, due attention must be paid that the pharmaceutical drug product design is also adequately addressing the particular patient's needs, i.e., assuring adequate patient adherence and the anticipate drug safety and effectiveness. Relevant pharmaceutical design aspects may e.g., involve the selection of the route of administration, the tablet size and shape, the ease of opening the package, the ability to read the user instruction, or the ability to follow the recommended (in-use) storage conditions. Currently, a harmonized definition on patient centric drug development/design has not yet been established. To stimulate scientific research and discussions and the consistent interpretation of test results, it is essential that such a definition is established. We have developed a first draft definition through various rounds of discussions within an interdisciplinary AAPS focus group of experts. This publication summarizes the outcomes and is intended to stimulate further discussions with all stakeholders towards a common definition of patient centric pharmaceutical drug product design that is useable across all disciplines involved.

  16. Application of antidepressant drugs in the treatment of pregnancy and breastfeeding women%抗抑郁药在妊娠期及哺乳期妇女中的应用

    Institute of Scientific and Technical Information of China (English)

    施慎逊

    2013-01-01

    尽管抗抑郁药已广泛应用于抑郁发作的治疗,但抗抑郁药在妊娠期或哺乳期妇女中的应用,如针对该人群使用抗抑郁药应注意些什么和哪些药物使用相对安全等问题一直是临床关注的焦点.本文综合文献及笔者的临床经验综述上述相关问题.%Antidepressant drugs have been widely used in the treatment of depressive disorders. However, the application of antidepressant drugs used in the pregnancy and breastfeeding women has been a clinical concern. Based on literature and author's clinical experience, this review describes what attention should be paid when antidepressant drugs are used in the pregnancy and breastfeeding women and which drugs are relatively safer.

  17. Design, Characterization, and Optimization of Controlled Drug Delivery System Containing Antibiotic Drug/s.

    Science.gov (United States)

    Patel, Apurv; Dodiya, Hitesh; Shelate, Pragna; Shastri, Divyesh; Dave, Divyang

    2016-01-01

    The objective of this work was design, characterization, and optimization of controlled drug delivery system containing antibiotic drug/s. Osmotic drug delivery system was chosen as controlled drug delivery system. The porous osmotic pump tablets were designed using Plackett-Burman and Box-Behnken factorial design to find out the best formulation. For screening of three categories of polymers, six independent variables were chosen for Plackett-Burman design. Osmotic agent sodium chloride and microcrystalline cellulose, pore forming agent sodium lauryl sulphate and sucrose, and coating agent ethyl cellulose and cellulose acetate were chosen as independent variables. Optimization of osmotic tablets was done by Box-Behnken design by selecting three independent variables. Osmotic agent sodium chloride, pore forming agent sodium lauryl sulphate, and coating agent cellulose acetate were chosen as independent variables. The result of Plackett-Burman and Box-Behnken design and ANOVA studies revealed that osmotic agent and pore former had significant effect on the drug release up to 12 hr. The observed independent variables were found to be very close to predicted values of most satisfactory formulation which demonstrates the feasibility of the optimization procedure in successful development of porous osmotic pump tablets containing antibiotic drug/s by using sodium chloride, sodium lauryl sulphate, and cellulose acetate as key excipients. PMID:27610247

  18. Evaluation of Antidepressant activity of Simvastatin, Lovastatin and Atorvastatin in Male Swiss Mice - An Experimental Study

    Directory of Open Access Journals (Sweden)

    Gudadappanavar Anupama M

    2013-06-01

    Full Text Available Context: Depression is the commonest mood disorder, could also be secondary to a number of physical disorders. Pharmacological treatment of such co-morbidities is difficult. If statins show antidepressant activity that could appear to be better lipid-lowering agents as they provide additional benefits in cardiovascular disorders with co-morbidity like depression. Aims: To investigate the effect of simvastatin, lovastatin and atorvastatin for their antidepressant activity using forced swim test and tail suspension test on behavioral models of depression in male swiss mice. Design: Experimental Study Methods and Material: The in vivo antidepressant activity of simvastatin and lovastatin was studied using forced swim test and tail suspension test. The mice received the drug as per their weight and subjected for experimentation. Group mean immobility time was calculated in treated and control groups for comparison. Statistical analysis used: One-way analysis of variance (ANOVA followed by Bonferroni’s multiple comparison test. (P / 0.05 Results: Simvastatin and Lovastatin used in the present study showed significant antidepressant activity in both behavioral models of depression (p<0.05 while atorvastatin failed to show significant antidepressant action. Conclusion: The study suggests that the antidepressant activity of simvastatin and lovastatin, if could be extrapolated to clinical situations, appear to be better lipid-lowering agents as they provide additional benefits in cardiovascular disorders with co-morbidity like depression.

  19. Disrupting the rhythm of depression: design and protocol of a randomized controlled trial on preventing relapse using brief cognitive therapy with or without antidepressants

    Directory of Open Access Journals (Sweden)

    Huibers Marcus JH

    2011-01-01

    Full Text Available Abstract Background Maintenance treatment with antidepressants is the leading strategy to prevent relapse and recurrence in patients with recurrent major depressive disorder (MDD who have responded to acute treatment with antidepressants (AD. However, in clinical practice most patients (up to 70-80% are not willing to take this medication after remission or take too low dosages. Moreover, as patients need to take medication for several years, it may not be the most cost-effective strategy. The best established effective and available alternative is brief cognitive therapy (CT. However, it is unclear whether brief CT while tapering antidepressants (AD is an effective alternative for long term use of AD in recurrent depression. In addition, it is unclear whether the combination of AD to brief CT is beneficial. Methods/design Therefore, we will compare the effectiveness and cost-effectiveness of brief CT while tapering AD to maintenance AD and the combination of CT with maintenance AD. In addition, we examine whether the prophylactic effect of CT was due to CT tackling illness related risk factors for recurrence such as residual symptoms or to its efficacy to modify presumed vulnerability factors of recurrence (e.g. rigid explicit and/or implicit dysfunctional attitudes. This is a multicenter RCT comparing the above treatment scenarios. Remitted patients on AD with at least two previous depressive episodes in the past five years (n = 276 will be recruited. The primary outcome is time related proportion of depression relapse/recurrence during minimal 15 months using DSM-IV-R criteria as assessed by the Structural Clinical Interview for Depression. Secondary outcome: economic evaluation (using a societal perspective and number, duration and severity of relapses/recurrences. Discussion This will be the first trial to investigate whether CT is effective in preventing relapse to depression in recurrent depression while tapering antidepressant treatment

  20. IC Treatment: Antidepressants

    Science.gov (United States)

    ... in Combined Federal Campaign ICA Resources for Donors Social Media ... you first hear the name antidepressant you may think of a medicine used to treat depression. Did you know that antidepressants are also effective ...

  1. Antidepressive interventions : On state and vulnerability of the brain

    NARCIS (Netherlands)

    Korf, J

    1996-01-01

    An attempt is made to relate drug and non-drug antidepressive interventions to brain processes. In the present context two concepts are proposed: vulnerability towards depressogenic factors and depression as a state of the brain. Accordingly, it is assumed that the current antidepressants make the b

  2. The effects of antidepressants on gastric ulcer

    Directory of Open Access Journals (Sweden)

    Mehmet Latif Güneş

    2013-12-01

    Full Text Available In their daily practice, psychiatrists often experience gastriccomplaints in patients beside psychiatric disorders.Peptic ulcer is one of the diseases, which accompanyto psychiatric disorders including mainly depression. Itis shown that antidepressants can inflame the bleedingsincluding gastrointestinal (GI bleedings, while they havepositive effect on ulcer healing. In this review, studies,which conducted about the positive or negative effects ofantidepressant drugs on ulcer treatment were examined.Accordingly; it was found that opipramol, amitriptyline,imipramine that of tricyclic antidepressants was found tobe helpful in healing of the ulcer. It was stated that SelectiveSerotonin Reuptake Inhibitors generally inflamedulcers, exceptionally fluvoxamine and fluoxetine reducedulcer; moclobemide that of monoamine-oxidase inhibitorand tianeptine and mirtazapine that of atypical antidepressantshad positive effect in ulcer healing. To be carefulin choosing the appropriate antidepressant in psychiatricpatients with gastric ulcer is important in the prognosisof both ulcer and depression.Key words: peptic ulcer; depression; antidepressant drugs

  3. Antidepressants modulate glycine action in rat hippocampus

    OpenAIRE

    Chang, Hyun-Kyung; Kim, Khae Hawn; Kang, Ki-Woon; Kang, Yoo-Jin; Kim, Tae-Wook; Park, Hun-Kyung; Kim, Sung-Eun; Kim, Chang-Ju

    2015-01-01

    Antidepressants are drugs that relieve symptoms of depressive disorders. Fluoxetine, tianeptine, and milnacipran are different types of antidepressants, and they have widely been used for relieving of depression symptoms. In the present study, the effects of fluoxetine, tianeptine, and milnacipran on the glycine-induced ion current by nystatin-perforated patch clamp and on the amplitude of field potential in the hippocampal CA1 region by multichannel extracellular recording, MED64, system, we...

  4. An algorithm to identify antidepressant users with a diagnosis of depression from prescription data.

    NARCIS (Netherlands)

    Gardarsdottir, H.; Egberts, T.C.G.; Dijk, L. van; Sturkenboom, M.; Heerdink, E.R.

    2008-01-01

    Background: Investigating depression treatment outcomes in prescription databases is problematic when information on indication for antidepressant prescriptions is unavailable. Objectives: To develop and validate an algorithm using prescription data to identify antidepressant drug users who suffer f

  5. Influence of antidepressants on hemostasis.

    Science.gov (United States)

    Halperin, Demian; Reber, Guido

    2007-01-01

    Antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs), are widely used for the treatment of depression and anxious disorders. The observation that depression is an independent risk factor for cardiovascular mortality and morbidity in patients with ischemic heart disease, the assessment of the central role of serotonin in pathophysiological mechanisms of depression, and reports of cases of abnormal bleeding associated with antidepressant therapy have led to investigations of the influence of antidepressants on hemostasis markers. In this review, we summarize data regarding modifications of these markers, drawn from clinical studies and case reports. We observed an association between the type of antidepressant drug and the number of abnormal bleeding case reports, with or without modifications of hemostasis markers. Drugs with the highest degree of serotonin reuptake inhibition--fluoxetine, paroxetine, and sertraline--are more frequently associated with abnormal bleeding and modifications of hemostasis markers. The most frequent hemostatic abnormalities are decreased platelet aggregability and activity, and prolongation of bleeding time. Patients with a history of coagulation disorders, especially suspected or documented thrombocytopenia or platelet disorder, should be monitored in case of prescription of any serotonin reuptake inhibitor (SRI). Platelet dysfunction, coagulation disorder, and von Willebrand disease should be sought in any case of abnormal bleeding occurring during treatment with an SRI. Also, a non-SSRI antidepressant should be favored over an SSRI or an SRI in such a context. Considering the difficulty in performing platelet aggregation tests, which are the most sensitive in SRI-associated bleeding, and the low sensitivity of hemostasis tests when performed in case of uncomplicated bleeding in the general population, establishing guidelines for the assessment of SRI-associated bleeding complications remains a challenge. PMID

  6. Counting on natural products for drug design

    Science.gov (United States)

    Rodrigues, Tiago; Reker, Daniel; Schneider, Petra; Schneider, Gisbert

    2016-06-01

    Natural products and their molecular frameworks have a long tradition as valuable starting points for medicinal chemistry and drug discovery. Recently, there has been a revitalization of interest in the inclusion of these chemotypes in compound collections for screening and achieving selective target modulation. Here we discuss natural-product-inspired drug discovery with a focus on recent advances in the design of synthetically tractable small molecules that mimic nature's chemistry. We highlight the potential of innovative computational tools in processing structurally complex natural products to predict their macromolecular targets and attempt to forecast the role that natural-product-derived fragments and fragment-like natural products will play in next-generation drug discovery.

  7. Application analysis on antidepressant drugs of 22 hospitals in Beijing from 2010 to 2014%2010-2014年北京地区22家医院抗抑郁药物应用研究

    Institute of Scientific and Technical Information of China (English)

    陈瑞玲; 赵志刚; 王雅杰

    2016-01-01

    Objective:To investigate the status and the development tendency of clinical application of antidepressants in Beijing area, and provide evidence for rational usage of antidepressants. Methods: Using the analytical method of the deifned daily dose (DDD) recommended by WHO, consumption sum, DDDs and deifned daily cost (DDC) of antidepressants in 22 hospitals in Beijing area from 2010 to 2014 were analyzed retrospectively.Results:Within 5 years, 19 kinds of antidepressants were used. DDDs and consumption sum of antidepressants showed increased trend year by year in 22 hospital of Beijing. Average annual growth rates of consumption sum and DDDs were 14.79%and 16.47%respectively. DDC remained unchanged. Selective serotonin reuptake inhibitors (SSRIs), selective serotonin and norepinephrine reuptake inhibitors (sSNRIs) used predominantly. The consumption sum of SSRIs and sSNRIs accounted for over 60%–70%and 20%among the total consumption sum of antidepressant drugs respectively. The top 3 drugs in DDDs were paroxetine, lfupentixol and melitracen compound tablets, citalopram or escitalopram. Conclusion:Antidepressant drugs played an increasingly important role in clinical treatment. New types of antidepressants, such as SSRIs and sSNRIs, have already become the ifrst-line antidepressants in clinic practice.%目的:了解北京地区抗抑郁药物使用情况,为临床合理用药提供参考。方法:采用回顾性分析方法,以WHO推荐的限定日剂量(DDD)作为药物利用研究评价单位,对2010–2014年北京地区22家医院抗抑郁药物的销售金额、DDDs以及DDC进行统计分析。结果:2010–2014年,北京地区22家医院共使用了19种抗抑郁药物;抗抑郁药物的用药金额和DDDs均呈增长趋势;用药金额和DDDs年均增幅分别为14.79%和16.47%;各品种各年度的DDC保持不变。SSRIs和sSNRIs分别占用药金额的60%~70%和20%。DDDs排序前3位是帕罗西汀、氟哌噻吨/美利曲辛复

  8. Comparison of the antidepressant effects of venlafaxine and dosulepin in a naturalistic setting

    DEFF Research Database (Denmark)

    Bukh, Jens Drachmann; Jørgensen, Martin Balslev; Dam, Henrik;

    2009-01-01

    The relative efficacy of the various classes of antidepressants has not been established. Observational studies in naturalistic settings are important in evaluating treatment outcomes with antidepressants, since controlled clinical trials include only a minority of patients present in clinical...... practice. This study sought to evaluate in a naturalistic setting the treatment outcomes of dosulepin and venlafaxine for patients with depressive episodes. At the university hospital in Copenhagen, Denmark, between 1998 and early 2001, the first-line treatment for psychiatric inpatients with depression...... because of an underpowered design) after replacing dosulepin with venlafaxine as first-line drug for depression in a naturalistic inpatient setting....

  9. Accessible haptic technology for drug design applications.

    Science.gov (United States)

    Zonta, Nicola; Grimstead, Ian J; Avis, Nick J; Brancale, Andrea

    2009-02-01

    Structure-based drug design is a creative process that displays several features that make it closer to human reasoning than to machine automation. However, very often the user intervention is limited to the preparation of the input and analysis of the output of a computer simulation. In some cases, allowing human intervention directly in the process could improve the quality of the results by applying the researcher intuition directly into the simulation. Haptic technology has been previously explored as a useful method to interact with a chemical system. However, the need of expensive hardware and the lack of accessible software have limited the use of this technology to date. Here we are reporting the implementation of a haptic-based molecular mechanics environment aimed for interactive drug design and ligand optimization, using an easily accessible software/hardware combination. PMID:19048316

  10. Antidepressants and dementia

    DEFF Research Database (Denmark)

    Kessing, Lars Vedel; Søndergård, Lars; Forman, Julie Lyng;

    2009-01-01

    BACKGROUND: It has been suggested that antidepressants may have neuroprotective abilities but it has newer been investigated lately whether treatment with antidepressants reduces the risk of dementia. METHOD: Linkage of registers of all prescribed antidepressants and diagnoses of dementia...... in Denmark during a period from 1995 to 2005. RESULTS: Persons who purchased antidepressants once (N=687,552) had an increased rate of dementia compared to persons unexposed to antidepressants (N=779,831). Nevertheless, the rate of dementia changed over time; thus during the initial prescription periods...... the rate increased with the number of prescriptions but continued long-term antidepressants treatment was associated with a reduction in the rate of dementia, however, not to the same level as the rate for the general population. This pattern was found for all classes of antidepressants (SSRIs, newer non...

  11. Antidepressants and dementia

    DEFF Research Database (Denmark)

    2009-01-01

    BACKGROUND: It has been suggested that antidepressants may have neuroprotective abilities but it has newer been investigated lately whether treatment with antidepressants reduces the risk of dementia. METHOD: Linkage of registers of all prescribed antidepressants and diagnoses of dementia in...... Denmark during a period from 1995 to 2005. RESULTS: Persons who purchased antidepressants once (N=687,552) had an increased rate of dementia compared to persons unexposed to antidepressants (N=779,831). Nevertheless, the rate of dementia changed over time; thus during the initial prescription periods the...... rate increased with the number of prescriptions but continued long-term antidepressants treatment was associated with a reduction in the rate of dementia, however, not to the same level as the rate for the general population. This pattern was found for all classes of antidepressants (SSRIs, newer non...

  12. EVALUATION OF ANTIDEPRESSANT ACTIVITY OF ALOCASIA MACRORRHIZOS ON MICE

    Directory of Open Access Journals (Sweden)

    Kateel Ramya

    2013-06-01

    Full Text Available The increased prevalence of depression at 12.3% rate and side effect profile of the existing antidepressants led to the present study which was designed to establish the role of natural herbal medicine Alocasia macrorrhizos as an antidepressant and to extend these results before the safe application in humans. 48 Albino male mice were divided into 2 sets each consisting of 4 groups with 6 animals in each group. Group1and 2 served as control and standard where as group3 and 4 were treated with hydroalcoholic extract of Alocasia macrorrhizos at the dose of 250mg/kg and 500mg/kg respectively. Drugs were suspended in 1% gumacasia and administered to mice orally one hour before test procedure. Forced swim test and tail suspension tests were standard animal models used for assessing antidepressant activity by recording the immobility time. Results from the study showed that hydroalcoholic extract of Alocasia macrorrhizos had significantly reduced immobility duration at the dose of 250mg/kg and 500mg/kg where it has shown better result than control group when subjected to the test procedures. Significant difference in immobility duration were noticed when these groups were compared to standard imipramine and there was a definite antidepressant effect observed with AM 500mg/kg whereas AM 250mg/kg values were comparable to imipramine. Hence we have concluded from the results of the study that hydroalcoholic extract of leaves of Alocasia macrorrhizos has the definite antidepressant effect which is comparable to Imipramine at 250mg/kg dose.

  13. Antidepressants are selective serotonin neuronal reuptake inhibitors: 40-year history

    Directory of Open Access Journals (Sweden)

    D. S. Danilov

    2015-01-01

    Full Text Available The paper presents historical prerequisites for designing antidepressants from a group of selective serotonin neuronal reuptake inhibitors (SSRIs: to determine a lower serotonin concentration in the different tissues of depressed patients; to establish a higher serotonin concentration in the treatment of depressed patients with tricyclic antidepressants, and to formulate the serotonergic theory of depression. It also provides a consecutive account of the history of clinical introduction of individual SSRI representatives, such as fluoxetine, zimelidine, fluvoxamine, indalpine, citalopram, sertraline, paroxetine, and escitalopram. There are data from the history of studying the mechanism of SSRI action: from the theory of the importance of an increase in the concentration of serotonin in the synaptic cleft to the current understanding of complex successive intracellular rearrangements at the level of the postsynaptic neuron. The history of studying the efficacy of SSRIs in treating depression is considered in detail. Emphasis is laid on the reasons for a paradoxical difference in the evaluations of the efficiency of therapy with SSRIs versus other groups of antidepressants at different developmental stages of psychopharmacology. The role of marketing technologies in disseminating the data on the efficacy of this or that group of antidepressants is described. The practical significance of differences in individual SSRI representatives (the potency of serotonin uptake inhibition; the degree of selectivity and activity against the serotonergic system; the likelihood of an unfavorable pharmacokinetic interaction with other drugs; the half-life of elimination; the quickness of achieving a therapeutic dose is analyzed. Whether it is possible and reasonable to differentially choose different SSRI representatives in the treatment of depressions at the present stage is discussed. The authors state their belief that researches should be continued to

  14. Antidepressant mechanism of ketamine: perspective from preclinical studies

    OpenAIRE

    Scheuing, Lisa; Chiu, Chi-Tso; Liao, Hsiao-Mei; Chuang, De-Maw

    2015-01-01

    A debilitating mental disorder, major depressive disorder is a leading cause of global disease burden. Existing antidepressant drugs are not adequate for the majority of depressed patients, and large clinical studies have demonstrated their limited efficacy and slow response onset. Growing evidence of low-dose ketamine's rapid and potent antidepressant effects offers strong potential for future antidepressant agents. However, ketamine has considerable drawbacks such as its abuse potential, ps...

  15. Brain 5-HT deficiency increases stress vulnerability and impairs antidepressant responses following psychosocial stress.

    Science.gov (United States)

    Sachs, Benjamin D; Ni, Jason R; Caron, Marc G

    2015-02-24

    Brain serotonin (5-HT) deficiency and exposure to psychosocial stress have both been implicated in the etiology of depression and anxiety disorders, but whether 5-HT deficiency influences susceptibility to depression- and anxiety-like phenotypes induced by psychosocial stress has not been formally established. Most clinically effective antidepressants increase the extracellular levels of 5-HT, and thus it has been hypothesized that antidepressant responses result from the reversal of endogenous 5-HT deficiency, but this hypothesis remains highly controversial. Here we evaluated the impact of brain 5-HT deficiency on stress susceptibility and antidepressant-like responses using tryptophan hydroxylase 2 knockin (Tph2KI) mice, which display 60-80% reductions in brain 5-HT. Our results demonstrate that 5-HT deficiency leads to increased susceptibility to social defeat stress (SDS), a model of psychosocial stress, and prevents the fluoxetine (FLX)-induced reversal of SDS-induced social avoidance, suggesting that 5-HT deficiency may impair antidepressant responses. In light of recent clinical and preclinical studies highlighting the potential of inhibiting the lateral habenula (LHb) to achieve antidepressant and antidepressant-like responses, we also examined whether LHb inhibition could achieve antidepressant-like responses in FLX-insensitive Tph2KI mice subjected to SDS. Our data reveal that using designer receptors exclusively activated by designer drugs (DREADDs) to inhibit LHb activity leads to reduced SDS-induced social avoidance behavior in both WT and Tph2KI mice. This observation provides additional preclinical evidence that inhibiting the LHb might represent a promising alternative therapeutic approach under conditions in which selective 5-HT reuptake inhibitors are ineffective.

  16. New generation of antidepressants in pregnant women

    Directory of Open Access Journals (Sweden)

    Ladan Kashani

    2007-03-01

    Full Text Available Although pregnancy was once thought to protect against psychiatric disorders, gravid and non gravid women have similar risks for major depression, at 10% to 15%. Both depression and antidepressant treatment during pregnancy have been associated with risks. Few medications have been proved unequivocally safe during pregnancy. Although certain antidepressants have not been linked with an increased risk of birth defects or impaired development including bupropion, citalopram, escitalopram and venlafaxine, the latest studies aren't necessarily reassuring. As researchers continue to learn more about antidepressants, the risks and benefits of taking the drugs during pregnancy must be weighed carefully on a case-by-case basis. This review discusses about the use of new generation of antidepressants in pregnancy

  17. The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

    Directory of Open Access Journals (Sweden)

    Patrick A Randall

    Full Text Available Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2 inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA. Rats were assessed using a concurrent progressive ratio (PROG/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1 and eticlopride (D2, but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a

  18. The VMAT-2 inhibitor tetrabenazine affects effort-related decision making in a progressive ratio/chow feeding choice task: reversal with antidepressant drugs.

    Science.gov (United States)

    Randall, Patrick A; Lee, Christie A; Nunes, Eric J; Yohn, Samantha E; Nowak, Victoria; Khan, Bilal; Shah, Priya; Pandit, Saagar; Vemuri, V Kiran; Makriyannis, Alex; Baqi, Younis; Müller, Christa E; Correa, Merce; Salamone, John D

    2014-01-01

    Behavioral activation is a fundamental feature of motivation, and organisms frequently make effort-related decisions based upon evaluations of reinforcement value and response costs. Furthermore, people with major depression and other disorders often show anergia, psychomotor retardation, fatigue, and alterations in effort-related decision making. Tasks measuring effort-based decision making can be used as animal models of the motivational symptoms of depression, and the present studies characterized the effort-related effects of the vesicular monoamine transport (VMAT-2) inhibitor tetrabenazine. Tetrabenazine induces depressive symptoms in humans, and also preferentially depletes dopamine (DA). Rats were assessed using a concurrent progressive ratio (PROG)/chow feeding task, in which they can either lever press on a PROG schedule for preferred high-carbohydrate food, or approach and consume a less-preferred lab chow that is freely available in the chamber. Previous work has shown that the DA antagonist haloperidol reduced PROG work output on this task, but did not reduce chow intake, effects that differed substantially from those of reinforcer devaluation or appetite suppressant drugs. The present work demonstrated that tetrabenazine produced an effort-related shift in responding on the PROG/chow procedure, reducing lever presses, highest ratio achieved and time spent responding, but not reducing chow intake. Similar effects were produced by administration of the subtype selective DA antagonists ecopipam (D1) and eticlopride (D2), but not by the cannabinoid CB1 receptor neutral antagonist and putative appetite suppressant AM 4413, which suppressed both lever pressing and chow intake. The adenosine A2A antagonist MSX-3, the antidepressant and catecholamine uptake inhibitor bupropion, and the MAO-B inhibitor deprenyl, all reversed the impairments induced by tetrabenazine. This work demonstrates the potential utility of the PROG/chow procedure as a rodent model of

  19. Evaluation of the binding of the radiolabeled antidepressant drug, {sup 18}F-fluoxetine in the rodent brain: an in vitro and in vivo study

    Energy Technology Data Exchange (ETDEWEB)

    Mukherjee, Jogeshwar E-mail: jogeshwar_mukherjee@ketthealth.com; Das, Malay K.; Yang Zhiying; Lew, Robert

    1998-10-01

    We have developed {sup 18}F-fluoxetine as a radiotracer analog of the antidepressant drug fluoxetine (Prozac). In vitro saturation experiments of {sup 18}F-fluoxetine were carried out on rat midbrain tissue and citalopram was used for measuring nonspecific binding. A saturation curve for the binding of {sup 18}F-fluoxetine was not obtained. Even when fluoxetine (10 {mu}M) was used for measurements of nonspecific binding, a saturation curve was difficult to obtain. Other compounds, such as deprenyl, clorgyline, amphetamine, and reserpine were also not able to reduce the binding of {sup 18}F-fluoxetine. Ex vivo autoradiographic experiments with {sup 18}F-fluoxetine did not reveal any specific uptake in various brain regions. In vivo administration of {sup 18}F-fluoxetine in rats showed similar uptake in all the brain regions with little regional selectivity. A subcellular analysis of rat brain tissue after intravenous (IV) administration of {sup 18}F-fluoxetine indicated significant amounts of binding in mitochondria and synaptosomes. In summary, in vitro experiments with {sup 18}F-fluoxetine indicate little specific binding. Binding to the serotonin transporter was not identifiable. High nonspecific binding of the tracer resulting from its subcellular nature in the brain masks the ability to detect binding to the serotonin uptake sites in vivo. These findings indicate that a large portion of the binding of {sup 18}F-fluoxetine in rat brains is subcellular and clears slowly out of the cells. Other sites, such as monoamine oxidase, may also play a significant role in the action of fluoxetine.

  20. Activation of a ventral hippocampus-medial prefrontal cortex pathway is both necessary and sufficient for an antidepressant response to ketamine.

    Science.gov (United States)

    Carreno, F R; Donegan, J J; Boley, A M; Shah, A; DeGuzman, M; Frazer, A; Lodge, D J

    2016-09-01

    A single sub-anesthetic dose of ketamine exerts rapid and sustained antidepressant effects. Here, we examined the role of the ventral hippocampus (vHipp)-medial prefrontal cortex (mPFC) pathway in ketamine's antidepressant response. Inactivation of the vHipp with lidocaine prevented the sustained, but not acute, antidepressant-like effect of ketamine as measured by the forced swim test (FST). Moreover, optogenetic as well as pharmacogenetic specific activation of the vHipp-mPFC pathway using DREADDs (designer receptors exclusively activated by designer drugs) mimicked the antidepressant-like response to ketamine; importantly, this was pathway specific, in that activation of a vHipp to nucleus accumbens circuit did not do this. Furthermore, optogenetic inactivation of the vHipp/mPFC pathway at the time of FST completely reversed ketamine's antidepressant response. In addition, we found that a transient increase in TrkB receptor phosphorylation in the vHipp contributes to ketamine's sustained antidepressant response. These data demonstrate that activity in the vHipp-mPFC pathway is both necessary and sufficient for the antidepressant-like effect of ketamine. PMID:26619811

  1. 我院2007-2011年抗抑郁药物应用情况分析%Analysis of the utilization of antidepressant drug in our hospital during 2007-2011

    Institute of Scientific and Technical Information of China (English)

    肖林; 成孝林

    2012-01-01

      目的:通过分析我院抗抑郁药使用特点,了解我院抗抑郁药物的应用现状,分析用药特点,预测用药趋势,为促进临床合理用药提供参考.方法:采用回顾性分析方法,对我院2007-2011年抗抑郁药物的销售金额、用药频度(defined daily dose, DDDs)和日均费用(defined daily cost, DDC)等进行统计、分析.结果:新型药物的使用量逐年上升,5年销售金额增长2.2倍,DDDs增长1.89倍;三环类抗抑郁药(TCAs)类药物使用量则逐年下降,5年销售金额下降近40%,DDDs下降近30%.抗抑郁药物的DDC稳中有降,新型药物的DDC是TCAs类药物的10倍.结论:我院抗精神病药物应用基本合理.选择性5-羟色胺再摄取抑制剂(SSRIs)类药物使用的品种最多,使用份额最大;SNRIs类药物呈现快速增长;更多使用国产药物能有效降低抗抑郁药物的DDC.%  Objective:To understand the application status of the antidepressants in our hospital, analysis of drug characteristics, forecast of medication trends so as to provide a reference for the promotion of rational clinical use of drugs. Methods:The sales of antidepressant,defined daily dose(DDDs)and defined daily cost(DDC)in our hospital during 2007-2011 were statistically analyzed by retrospective analysis. Results:The use of new classes of drugs increased year by year and the sales increased by 2.2 times in five years, and DDDs increased by 1.89 times. Tricyclic antidepressants(TCAs)drugs has been declining and five-year sales of TCAs and DDDs have dropped by nearly 40%and 30%, respectively. DDC of antidepressant drugs is flat to down while DDC of the new drug increases 10 times than that of the TCAs drugs. Conclusion:The application of antipsychotics in our hospital is reasonable. Selective 5-serotonin reuptake inhibitors(SSRIs)class of drugs were used in the most varieties and largest share and the SNRIs drugs showed a rapid growth. A great use of domestic drug can effectively

  2. Outcome measures of antidepressive therapy.

    Science.gov (United States)

    Rosenberg, R

    2000-01-01

    A variety of outcome measures assessing antidepressive therapy are available. However, in randomized clinical trials, the Hamilton Rating Scale for Depression (HAM-D) is often the primary outcome measure. Results from factor analysis and Rasch item analysis indicate that the HAM-D is heterogeneous and that the sum of items scores may not be an adequate measure of the severity of depression. A Melancholia Scale of 11 items has been suggested as a more valid measure of the core symptoms of affective syndrome. Other global outcome measures, focusing on health-related quality of life issues and on social functioning as well as macro-economic analyses are also used in depression. Applying stringent and well-documented outcome measures in randomized clinical trials of antidepressants may give the clinician a better indication of the most appropriate drug for treatment of the individual patient.

  3. Antidepressant effects of ketamine: mechanisms underlying fast-acting novel antidepressants

    Directory of Open Access Journals (Sweden)

    Caroline Ann Browne

    2013-12-01

    Full Text Available Newer antidepressants are needed for the many individuals with major depressive disorder that do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent evidence from clinical trials shows that the NMDA antagonist ketamine is a revolutionary novel antidepressant because it acts rapidly and is effective for treatment-resistant patients. A single infusion of ketamine alleviates depressive symptoms in treatment-resistant depressed patients within hours and these effects may be sustained for up to 2 weeks. Although the discovery of ketamine’s effects has reshaped drug discovery for antidepressants, the psychotomimetic properties of this compound limit the use of this therapy to the most severely ill patients. In order to develop additional antidepressants like ketamine, adequate preclinical behavioral screening paradigms for fast-acting antidepressants need to be established and used to identify the underlying neural mechanisms. This review examines the preclinical literature attempting to model the antidepressant-like effects of ketamine. Acute administration of ketamine has produced effects in behavioral screens for antidepressants like the forced swim test, novelty suppression of feeding and in rodent models for depression. Protracted behavioral effects of ketamine have been reported to appear after a single treatment that last for days. This temporal pattern is similar to its clinical effects and may serve as a new animal paradigm for rapid antidepressant effects in humans. In addition, protracted changes in molecules mediating synaptic plasticity have been implicated in mediating the antidepressant-like behavioral effects of ketamine. Current preclinical studies are examining compounds with more specific pharmacological effects at glutamate receptors and synapses in order to develop additional rapidly acting antidepressants without the hallucinogenic side effects or abuse

  4. The depressogenic-like effect of acute and chronic treatment with dexamethasone and its influence on the activity of antidepressant drugs in the forced swim test in adult mice.

    Science.gov (United States)

    Wróbel, Andrzej; Serefko, Anna; Wlaź, Piotr; Poleszak, Ewa

    2014-10-01

    There is a close relationship between chronic stress, glucocorticoids and depression. Psychiatric and cognitive symptoms resembling major depression have been observed in patients experiencing elevated glucocorticoid levels, and a high percentage of people suffering from depression have undergone a stressful event/events prior to the onset of this mental disorder. In our study, we investigated whether acute and chronic treatment of dexamethasone induces depression-like behavior in mice and if dexamethasone therapy influences the activity of antidepressant drugs with diverse modes of action. The antidepressant-like effect was assessed by the forced swim test in adult mice. The depressogenic-like activity of dexamethasone turned out to be dose-dependent: only the highest tested dose of the glucocorticoid (i.e., 64μg/kg) given as a single injection increased immobility time, whereas 16μg/kg/day of dexamethasone (but not 4μg/kg/day) administered repeatedly induced a significant alteration in animal behavior. These depressogenic doses of dexamethasone (i.e., 64μg/kg and 16μg/kg/day for an acute and repeated administration, respectively) diminished the antidepressant potential of the therapeutic doses of imipramine (10mg/kg), amitriptyline (10mg/kg), tianeptine (25mg/kg), mianserin (10mg/kg), citalopram (15mg/kg) and moclobemide (25mg/kg). Two main findings of our study should be particularly underlined: (1) both single and repeated administration of dexamethasone evoked a depression-like behavior of mice, (2) both single and repeated administration of dexamethasone were able to modify the activity of the antidepressant agents from various pharmacological groups, which may lead to a considerable reduction in the efficacy of pharmacotherapy prescribed for patients with mood disorders.

  5. Phytosterols and anabolic agents versus designer drugs

    International Nuclear Information System (INIS)

    Cholesterol is a well-known component in fats of animal origin and it also is the precursor of natural hormones. Phytosterols appear in plants and only differ slightly in structure from cholesterol. An important difference however is the low absorption in the gut of phytosterols and their saturated derivatives, the phytostanols. As a result, there is time for all kind of reactions in faecal material inside and outside of the gut. Determination of the abuse of natural hormones may be based on gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Abuse of natural hormones changes the 13C/12C ratio of some metabolites during a relatively long time. The formation of (natural) hormones in the gut may interfere with this method. Designer drugs are mainly known from sports doping. In animal fattening, designer drugs may be used as well. Small changes in the structure of (natural) hormones may lead to a new group of substances asking for new strategies for their detection and the constatation of their abuse

  6. Phytosterols and anabolic agents versus designer drugs

    Energy Technology Data Exchange (ETDEWEB)

    Brabander, H.F. de [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium)]. E-mail: Hubert.DeBrabander@UGent.be; Verheyden, K. [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium); Mortier, V. [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium); Le Bizec, B. [LABERCA, Ecole Nationale Veterinaire de Nantes, BP 50707, F-44087 Nantes Cedex 03 (France); Verbeke, W. [Ghent University, Department of Agricultural Economics, Coupure links 653, B-9000 Ghent (Belgium); Courtheyn, D. [Federal Feed and Food Laboratory, Braemkasteelstraat 59, B-9050 Ghentbruges (Belgium); Noppe, H. [Ghent University, Faculty of Veterinary Medicine, Research group of Veterinary Public Health and Zoonoses, Laboratory of Chemical Analysis, Salisburylaan 133, B-9820 Merelbeke (Belgium)

    2007-03-14

    Cholesterol is a well-known component in fats of animal origin and it also is the precursor of natural hormones. Phytosterols appear in plants and only differ slightly in structure from cholesterol. An important difference however is the low absorption in the gut of phytosterols and their saturated derivatives, the phytostanols. As a result, there is time for all kind of reactions in faecal material inside and outside of the gut. Determination of the abuse of natural hormones may be based on gas chromatography-combustion-isotope ratio mass spectrometry (GC-C-IRMS). Abuse of natural hormones changes the {sup 13}C/{sup 12}C ratio of some metabolites during a relatively long time. The formation of (natural) hormones in the gut may interfere with this method. Designer drugs are mainly known from sports doping. In animal fattening, designer drugs may be used as well. Small changes in the structure of (natural) hormones may lead to a new group of substances asking for new strategies for their detection and the constatation of their abuse.

  7. Detecção de risco de interações entre fármacos antidepressivos e associados prescritos a pacientes adultos Interaction risk detection between antidepressant and associated drugs prescribed for adult patients

    Directory of Open Access Journals (Sweden)

    Kassia Fernanda Campigotto

    2008-01-01

    Full Text Available CONTEXTO: O uso de fármacos combinados para o tratamento de patologias diversas em psiquiatria tem aumentado progressivamente. Os antidepressivos estão envolvidos em diversas interações farmacológicas clinicamente importantes. OBJETIVO: Detectar risco de interações entre fármacos antidepressivos e associados prescritos a pacientes adultos. MÉTODOS: Pesquisa retrospectiva e descritiva foi desenvolvida em uma farmácia magistral da cidade de Cascavel, Paraná. Os dados foram coletados de 151 receituários médicos de pacientes adultos (19 anos ou mais, envolvendo fármacos antidepressivos e associados entre outubro e novembro de 2005. O estudo limitou-se às variáveis registradas no receituário médico (sexo, idade, fármaco antidepressivo e associado prescrito. RESULTADOS: A categoria de 31 a 40 anos de idade foi a mais freqüente (32,46% e o sexo foi o feminino (64,90%. Os fármacos antidepressivos tricíclicos (ADT e associados apresentaram um total de oito episódios de interações relativos ao grau de severidade, sendo quatro de grau moderado e quatro menor. Em relação aos fármacos antidepressivos inibidores seletivos da recaptura de serotonina (ISRS e associados, o risco de ocorrência foi de 16 casos; quatro de severidade menor, dez moderada e dois maior. CONCLUSÃO: Os dados mostram que os pacientes com prescrição de fármacos ISRS e associados possuíam mais risco de interações de maior severidade, totalizando o dobro de interações em relação aos ADTs.BACKGROUND: The combination of drugs for the treatment of psychiatric disorders has become a relatively frequent practice. The antidepressants are involved in several clinically important pharmacological interactions. OBJECTIVES: To detect the risk of interactions between antidepressants and associated drugs prescribed for adults patients. METHODS: Data on 151 medical prescriptions of antidepressants and other psychiatric drugs were retrospectively assessed at a

  8. Experimental study of searching for new antidepressant drugs by applying high throughput screening method%应用高通量筛选体系寻找抗抑郁新药的实验研究

    Institute of Scientific and Technical Information of China (English)

    张莉; 尚念勇; 杜冠华

    2004-01-01

    increasing. It is of great significance to use new technologies and new methods to develop antidepressant drugs with high efficacy and low toxicity.OBJECTIVE: To establish research system for finding new antidepressant leading compounds by the combination of high throughput screening method and in vivo experiment.DESIGN: A randomized and controlled experiment.SETTING, MATERIALS and INTERVENTIONS: The experiment was carried out in the Drug Institute of Chinese Academy of Medical Science. Seventy Kunming male mice weighing(20 ±2) g, and 10 male Wistar rats weighing(200 ± 20) g were used. Wister rats were killed with decollation, and the 5-Hydroxythryptamine (5-HT) reuptake in rat brain synaptosomes was measured. The mice were randomly divided into control group, fluoxetine group(2.6 mg/kg), J01113 group(30 mg/kg), J01114 group(30 mg/kg)and J10745 group(30 mg/Kg). Continuous gastric lavage and administration lasted for 5 days, once per day, and mice hanging experiment was performed every other day since the second day. The mice were administrated and compared separately in 6 minutes after self-hanging in the administration and control group. Forced swimming test was made every other day and compared in 4 minutes of rats in the administration and control group.MAIN OUTCOME MEASURE: The 5-HT reuptake inhibition in synaptosomes and the immobility time in depression models.RESULTS: The effects of more than 5 000 compounds on 5-HT reuptake were tested with high throughput screening(HTS) in vitro. Three active compounds, J01113, J01114 and J10745 were selected to test their antidepressant effects in the forced swimming test and the tail suspension test in mice. J01113, J01114 and J10745 strongly inhibited 5-HT reuptake. The IC50 of J01113, J01114 and J10745 was 1. 304 × 10-10, 9. 036 × 10-10, and 1. 447 × 10-7 mol/L respectively. After the J01113 was administrated for 3 and 5 days, the immobility time of the hanging mice[(67.2 ±47.33),(95.2 ± 47.5 ) s] was significantly less

  9. Antidepressants modulate glycine action in rat hippocampus.

    Science.gov (United States)

    Chang, Hyun-Kyung; Kim, Khae Hawn; Kang, Ki-Woon; Kang, Yoo-Jin; Kim, Tae-Wook; Park, Hun-Kyung; Kim, Sung-Eun; Kim, Chang-Ju

    2015-12-01

    Antidepressants are drugs that relieve symptoms of depressive disorders. Fluoxetine, tianeptine, and milnacipran are different types of antidepressants, and they have widely been used for relieving of depression symptoms. In the present study, the effects of fluoxetine, tianeptine, and milnacipran on the glycine-induced ion current by nystatin-perforated patch clamp and on the amplitude of field potential in the hippocampal CA1 region by multichannel extracellular recording, MED64, system, were studied. In the present results, fluoxetine, tianeptine, and milnacipran reduced glycine-induced ion current in the hippocampal CA1 neurons in nystatin-perforated patch clamp method. These drugs enhanced the amplitude of the field potential in the hippocampal CA1 region in MED64 system. These results suggest that antidepressants may increase neuronal activity by enhancing field potential through inhibition on glycine-induced ion current. PMID:26730381

  10. The role of sodium channels in the mechanism of action of antidepressants and mood stabilizers.

    Science.gov (United States)

    Bourin, Michel; Chenu, Franck; Hascoët, Martine

    2009-11-01

    Antidepressant drugs modify in different ways the activity of neurons, by increasing monoamines levels and by modulating ion channels. Sodium channels are molecular targets for antiepileptic drugs, which can also be mood stabilizers (i.e. lamotrigine, topiramate, phenytoin, carbamazepine, valproic acid). After a short overview on the sodium channels and the interaction with antidepressants and mood stabilizers, a comparison of the activity of both antidepressants and mood stabilizers with the addition of veratrine (sodium channel opener) on the forced swimming test (FST) in mice was presented. By comparing the antidepressant-like effect of the antidepressants (paroxetine, imipramine and desipramine) with the one of anticonvulsants (lamotrigine, phenytoin and topiramate) on the FST, it seems that the mechanism of action of anticonvulsants and antidepressants are different, because veratrine limits the activity of anticonvulsants but not of antidepressants. The anticonvulsants topiramate and phenytoin reduce the immobility time in the FST in a range of time similar to those induced by antidepressants, suggesting that the FST could be sensitive to both drugs. The magnitude of antidepressant-like effect of the lamotrigine (acting through an increase in monoaminergic neurotransmission and a blockade of sodium channels) in the FST is greater than what is obtained after administration of the other drugs, suggesting that this dual activity could be used as an augmentation strategy. Authors conclude that the development of new drugs acting on sodium channels could potentially be of interest as antidepressants, but also as augmentation strategies for classical antidepressants.

  11. 我院2014年抗抑郁药应用分析%Analysis of Antidepressant Drugs Application in Our Hospital During 2014

    Institute of Scientific and Technical Information of China (English)

    周晓明

    2015-01-01

    目的:分析我院抗抑郁药的用药情况,促进临床合理应用。方法对我院2014年抗抑郁药的销售金额、用药频度( DDDs)、日均费用(DDC)等进行统计分析。结果我院抗抑郁药销售金额排序列前3的是氟哌噻吨美利曲辛片、米氮平(派迪生)、氟西汀;DDDs排序列前3位的是氟哌噻吨美利曲辛片、米氮平(派迪生)、帕罗西汀。结论说明我院抗抑郁药使用合理,新型的抗抑郁药物在临床上得到了广泛应用,符合抗抑郁药的应用趋势。%ABSTRACT:OBJECTIVE To analyze the application of antidepressant durgs in our hospital and provide refer -ence for clinical rational administration.METHODS Antidepressant durgs used in our hospital during in 2014 were performed the statistical analysis in respect of consumption sum ,DDDs,DDC etc.RESULTS The top 3 consump-tion sum of antidepressant durgs included flupentixol melitmcen , mirtazapin fluoxetine;the top 3 DDDs included flu-pentixol melitmcen ,mirtazapin ,paroxetine.CONCLUSION\\ The application of antidepressant durgs in our hospital is rational .New-type antidepressant durgs were widely used in the clinic and consistent with the trend of their ap -plication.

  12. Antidepressant prescribing in five European countries

    DEFF Research Database (Denmark)

    Abbing-Karahagopian, V; Huerta, C; Souverein, P C;

    2014-01-01

    PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalen...

  13. Antidepressants in the treatment of neuropathic pain

    DEFF Research Database (Denmark)

    Sindrup, Søren H.; Otto, Marit; Finnerup, Nanna Brix;

    2005-01-01

    options such as tramadol and oxycodone, whereas the serotonin noradrenaline reuptake inhibitor venlafaxine appears to be equally effective with these drugs and selective serotonin reuptake inhibitors apparently have lower efficacy. Head-to-head comparisons between antidepressants and the other analgesics...

  14. Synthesis of the Commercial Antidepressant Moclobemide

    Science.gov (United States)

    More, Jesse D.

    2008-01-01

    An experiment for the undergraduate organic chemistry laboratory is described in which students synthesize the commercial antidepressant drug moclobemide, marketed under the trade name Manerix. This one-step synthesis starts from commercially available material and produces moclobemide in high yield. The product is initially isolated as its…

  15. Molecular Rift: Virtual Reality for Drug Designers.

    Science.gov (United States)

    Norrby, Magnus; Grebner, Christoph; Eriksson, Joakim; Boström, Jonas

    2015-11-23

    Recent advances in interaction design have created new ways to use computers. One example is the ability to create enhanced 3D environments that simulate physical presence in the real world--a virtual reality. This is relevant to drug discovery since molecular models are frequently used to obtain deeper understandings of, say, ligand-protein complexes. We have developed a tool (Molecular Rift), which creates a virtual reality environment steered with hand movements. Oculus Rift, a head-mounted display, is used to create the virtual settings. The program is controlled by gesture-recognition, using the gaming sensor MS Kinect v2, eliminating the need for standard input devices. The Open Babel toolkit was integrated to provide access to powerful cheminformatics functions. Molecular Rift was developed with a focus on usability, including iterative test-group evaluations. We conclude with reflections on virtual reality's future capabilities in chemistry and education. Molecular Rift is open source and can be downloaded from GitHub. PMID:26558887

  16. Molecular Rift: Virtual Reality for Drug Designers.

    Science.gov (United States)

    Norrby, Magnus; Grebner, Christoph; Eriksson, Joakim; Boström, Jonas

    2015-11-23

    Recent advances in interaction design have created new ways to use computers. One example is the ability to create enhanced 3D environments that simulate physical presence in the real world--a virtual reality. This is relevant to drug discovery since molecular models are frequently used to obtain deeper understandings of, say, ligand-protein complexes. We have developed a tool (Molecular Rift), which creates a virtual reality environment steered with hand movements. Oculus Rift, a head-mounted display, is used to create the virtual settings. The program is controlled by gesture-recognition, using the gaming sensor MS Kinect v2, eliminating the need for standard input devices. The Open Babel toolkit was integrated to provide access to powerful cheminformatics functions. Molecular Rift was developed with a focus on usability, including iterative test-group evaluations. We conclude with reflections on virtual reality's future capabilities in chemistry and education. Molecular Rift is open source and can be downloaded from GitHub.

  17. Bioinformatics in cancer therapy and drug design

    International Nuclear Information System (INIS)

    One of the mechanisms of external signal transduction (ionizing radiation, toxicants, stress) to the target cell is the existence of membrane and intracellular proteins with intrinsic tyrosine kinase activity. No wonder that etiology of malignant growth links to abnormalities in signal transduction through tyrosine kinases. The epidermal growth factor receptor (EGFR) tyrosine kinases play fundamental roles in development, proliferation and differentiation of tissues of epithelial, mesenchymal and neuronal origin. There are four types of EGFR: EGF receptor (ErbB1/HER1), ErbB2/Neu/HER2, ErbB3/HER3 and ErbB4/HER4. Abnormal expression of EGFR, appearance of receptor mutants with changed ability to protein-protein interactions or increased tyrosine kinase activity have been implicated in the malignancy of different types of human tumors. Bioinformatics is currently using in investigation on design and selection of drugs that can make alterations in structure or competitively bind with receptors and so display antagonistic characteristics. (authors)

  18. STABLE DRUG DESIGNING BY MINIMIZING DRUG PROTEIN INTERACTION ENERGY USING PSO

    Directory of Open Access Journals (Sweden)

    Anupam Ghosh

    2015-07-01

    Full Text Available Each and every biological function in living organism happens as a result of protein-protein interactions. The diseases are no exception to this. Identifying one or more proteins for a particular disease and then designing a suitable chemical compound (known as drug to destroy these proteins has been an interesting topic of research in bio-informatics. In previous methods, drugs were designed using only seven chemical components and were represented as a fixedlength tree. But in reality, a drug contains many chemical groups collectively known as pharmacophore. Moreover, the chemical length of the drug cannot be determined before designing the drug.

  19. Nanogel Carrier Design for Targeted Drug Delivery

    OpenAIRE

    Eckmann, D.M.; Composto, R. J.; Tsourkas, A; Muzykantov, V. R.

    2014-01-01

    Polymer-based nanogel formulations offer features attractive for drug delivery, including ease of synthesis, controllable swelling and viscoelasticity as well as drug loading and release characteristics, passive and active targeting, and the ability to formulate nanogel carriers that can respond to biological stimuli. These unique features and low toxicity make the nanogels a favorable option for vascular drug targeting. In this review, we address key chemical and biological aspects of nanoge...

  20. Hippocampal Neurogenesis, Depressive Disorders, and Antidepressant Therapy

    Directory of Open Access Journals (Sweden)

    Eleni Paizanis

    2007-01-01

    Full Text Available There is a growing body of evidence that neural stem cells reside in the adult central nervous system where neurogenesis occurs throughout lifespan. Neurogenesis concerns mainly two areas in the brain: the subgranular zone of the dentate gyrus in the hippocampus and the subventricular zone, where it is controlled by several trophic factors and neuroactive molecules. Neurogenesis is involved in processes such as learning and memory and accumulating evidence implicates hippocampal neurogenesis in the physiopathology of depression. We herein review experimental and clinical data demonstrating that stress and antidepressant treatments affect neurogenesis in opposite direction in rodents. In particular, the stimulation of hippocampal neurogenesis by all types of antidepressant drugs supports the view that neuroplastic phenomena are involved in the physiopathology of depression and underlie—at least partly—antidepressant therapy.

  1. Evaluation of antidepressant activity of tramadol in mice

    Directory of Open Access Journals (Sweden)

    Tayal Vandana

    2008-01-01

    Full Text Available Objective: To evaluate antidepressant like effect of tramadol in mice. Materials and Methods: Tramadol was administered at three different doses (10,20 and 40 mg/kg,i.p once daily for 7 days to Swiss albino mice of either sex. The immobility period of control and drug treated mice were recorded in tail suspension test (TST.The antidepressant effect of tramadol was compared to that of fluoxetine (20 mg/kg, i.p, administered for seven days. Results: Tramadol produced significant antidepressant effect at all the doses, as indicated by reduction in immobility times as compared to control. The efficacy of tramadol at doses of 20 and 40 mg/kg was comparable with that of fluoxetine. Tramadol at 10 mg/kg dose showed significantly less antidepressant activity compared to fluoxetine. Conclusion: The results of the present study indicate antidepressant like activity of tramadol.

  2. 21 CFR 316.28 - Publication of orphan-drug designations.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Publication of orphan-drug designations. 316.28... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.28 Publication of orphan-drug designations. Each month FDA will update a publically available list of drugs designated as...

  3. 21 CFR 316.26 - Amendment to orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Amendment to orphan-drug designation. 316.26... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.26 Amendment to orphan-drug designation. (a) At any time prior to approval of a marketing application for a designated orphan drug,...

  4. 21 CFR 316.25 - Refusal to grant orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Refusal to grant orphan-drug designation. 316.25... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.25 Refusal to grant orphan-drug designation. (a) FDA will refuse to grant a request for orphan-drug designation if any of...

  5. Organic carbamates in drug design and medicinal chemistry.

    Science.gov (United States)

    Ghosh, Arun K; Brindisi, Margherita

    2015-04-01

    The carbamate group is a key structural motif in many approved drugs and prodrugs. There is an increasing use of carbamates in medicinal chemistry and many derivatives are specifically designed to make drug-target interactions through their carbamate moiety. In this Perspective, we present properties and stabilities of carbamates, reagents and chemical methodologies for the synthesis of carbamates, and recent applications of carbamates in drug design and medicinal chemistry.

  6. Design of Nanoparticle-Based Carriers for Targeted Drug Delivery

    OpenAIRE

    Xiaojiao Yu; Ian Trase; Muqing Ren; Kayla Duval; Xing Guo; Zi Chen

    2016-01-01

    Nanoparticles have shown promise as both drug delivery vehicles and direct antitumor systems, but they must be properly designed in order to maximize efficacy. Computational modeling is often used both to design new nanoparticles and to better understand existing ones. Modeled processes include the release of drugs at the tumor site and the physical interaction between the nanoparticle and cancer cells. In this paper, we provide an overview of three different targeted drug delivery methods (p...

  7. Role of computer-aided drug design in modern drug discovery.

    Science.gov (United States)

    Macalino, Stephani Joy Y; Gosu, Vijayakumar; Hong, Sunhye; Choi, Sun

    2015-09-01

    Drug discovery utilizes chemical biology and computational drug design approaches for the efficient identification and optimization of lead compounds. Chemical biology is mostly involved in the elucidation of the biological function of a target and the mechanism of action of a chemical modulator. On the other hand, computer-aided drug design makes use of the structural knowledge of either the target (structure-based) or known ligands with bioactivity (ligand-based) to facilitate the determination of promising candidate drugs. Various virtual screening techniques are now being used by both pharmaceutical companies and academic research groups to reduce the cost and time required for the discovery of a potent drug. Despite the rapid advances in these methods, continuous improvements are critical for future drug discovery tools. Advantages presented by structure-based and ligand-based drug design suggest that their complementary use, as well as their integration with experimental routines, has a powerful impact on rational drug design. In this article, we give an overview of the current computational drug design and their application in integrated rational drug development to aid in the progress of drug discovery research.

  8. Antidepressant Use and Risk of Out-of-Hospital Cardiac Arrest

    DEFF Research Database (Denmark)

    Weeke, P; Jensen, Aksel Karl Georg; Folke, F;

    2012-01-01

    Treatment with some types of antidepressants has been associated with sudden cardiac death. It is unknown whether the increased risk is due to a class effect or related to specific antidepressants within drug classes. All patients in Denmark with an out-of-hospital cardiac arrest (OHCA) were.......17-12.2). An association between cardiac arrest and antidepressant use could be documented in both the SSRI and TCA classes of drugs....

  9. Effects of calcium channel blocker, nifedipine, on antidepressant activity of fluvoxamine, venlafaxine and tianeptine in mice

    OpenAIRE

    SHARMA, Ashok K.; Anjan Khadka; Navdeep Dahiya

    2015-01-01

    Background: Cardiovascular diseases are commonly associated with depression. Calcium channel blockers (CCBs) form commonly used group of drugs for the treatment of a number of cardiovascular diseases. Nifedipine, a CCB, has been shown to possess antidepressant activity and potentiate antidepressant activity of imipramine and sertraline, however, literature on its interaction with newer antidepressant drugs such as fluvoxamine, venlafaxine and tianeptine is limited. Hence, the present study wa...

  10. "Not for human consumption": a review of emerging designer drugs.

    Science.gov (United States)

    Musselman, Megan E; Hampton, Jeremy P

    2014-07-01

    Synthetic, or "designer" drugs, are created by manipulating the chemical structures of other psychoactive drugs so that the resulting product is structurally similar but not identical to illegal psychoactive drugs. Originally developed in the 1960s as a way to evade existing drug laws, the use of designer drugs has increased dramatically over the past few years. These drugs are deceptively packaged as "research chemicals," "incense," "bath salts," or "plant food," among other names, with labels that may contain warnings such as "not for human consumption" or "not for sale to minors." The clinical effects of most new designer drugs can be described as either hallucinogenic, stimulant, or opioid-like. They may also have a combination of these effects due to designer side-chain substitutions. The easy accessibility and rapid emergence of new designer drugs have created challenges for health care providers when treating patients presenting with acute toxicity from these substances, many of which can produce significant and/or life-threatening adverse effects. Moreover, the health care provider has no way to verify the contents and/or potency of the agent ingested because it can vary between packages and distributors. Therefore, a thorough knowledge of the available designer drugs, common signs and symptoms of toxicity associated with these agents, and potential effective treatment modalities are essential to appropriately manage these patients.

  11. Evaluation of the antidepressant-like effects of acute and sub-acute administration of crocin and crocetin in mice

    Directory of Open Access Journals (Sweden)

    Bahareh Amin

    2015-08-01

    Full Text Available Objective: The present study was designed to investigate the putative antidepressant effects of crocin and crocetin, two major active ingredients of Crocus sativus L. (saffron using mice in two different regimens of acute and sub-acute administration. Material and Methods: In acute treatment, antidepressant-like activities of crocin and crocetin (10, 20 and 40 mg/kg, i.p. were evaluated using forced swim test (FST. In sub-acute study (21 times with 24-h intervals, antidepressant-like effects of oral administration of drugs were examined using FST and tail suspension test (TST. Locomotor activity and motor coordination were studied using open field and rotarod tests, respectively. Results: Acute treatment with crocin (40 mg/kg and crocetin (20 and 40 mg/kg produced antidepressant-like effect in FST without affecting the baseline locomotion in mice. Sub-acute oral administration of crocin significantly decreased immobility time only at the highest dose (100 mg/kg. Crocetin (12.5, 25 and 50 mg/kg was able to decrease immobility time in FST and TST. Locomotor activity and coordination of mice were not affected by crocin or crocetin. Conclusion: Since higher doses of crocin was required to show antidepressant effects, more efficacy of crocetin may be concluded. This observation provides further support for metabolism of crocin to crocetin following oral administration.

  12. Antidepressant-like effects of curcumin in WKY rat model of depression is associated with an increase in hippocampal BDNF

    Science.gov (United States)

    Hurley, Laura L.; Akinfiresoye, Luli; Nwulia, Evaristus; Kamiya, Atsushi; Kulkarni, Amol; Tizabi, Yousef

    2012-01-01

    Curcumin is the principal active ingredient found in turmeric (Curcuma longa), a plant used in traditional Asian diets and herbal medicines. It is known to have a wide range of biological actions including antidepressant-like effects which have been observed in stress-induced depression models. This study was designed to investigate the antidepressant potential of curcumin in a non-induced model of depression. Moreover, since brain derived neurotrophic factor (BDNF) has been implicated in antidepressant effects of many drugs, we also evaluated the effects of curcumin on BDNF in the hippocampus. Adult male Wistar Kyoto (WKY) rats, a putative model of depression, were injected acutely or chronically (10 d) with 50, 100, and 200mg/kg curcumin. Open field locomotor activity (OFLA) and forced swim test (FST), a measure of helplessness, were measured 1 hour after acute and 18–20 hours after last chronic injection. Results showed a dose-dependent reduction of immobility in the FST by curcumin in both acute and chronic studies, without any significant effect on OFLA. The effect of higher chronic curcumin dose in FST was still evident a week later. Chronic curcumin also resulted in a dose-dependent increase in hippocampal BDNF. This data provides evidence for an antidepressant-like effect of curcumin, possibly through increased neurotrophic activity, in the WKY model of depression, and support the notion that curcumin may prove an effective and lasting natural antidepressant. PMID:23142609

  13. Multiscale Modeling in the Clinic: Drug Design and Development.

    Science.gov (United States)

    Clancy, Colleen E; An, Gary; Cannon, William R; Liu, Yaling; May, Elebeoba E; Ortoleva, Peter; Popel, Aleksander S; Sluka, James P; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M

    2016-09-01

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multiscale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical and computational techniques employed for multiscale modeling approaches used in pharmacometric and systems pharmacology models in drug development and present several examples illustrating the current state-of-the-art models for (1) excitable systems and applications in cardiac disease; (2) stem cell driven complex biosystems; (3) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (4) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (5) computer-aided design of nanomedical systems. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multiscale models. PMID:26885640

  14. Multiscale Modeling in the Clinic: Drug Design and Development.

    Science.gov (United States)

    Clancy, Colleen E; An, Gary; Cannon, William R; Liu, Yaling; May, Elebeoba E; Ortoleva, Peter; Popel, Aleksander S; Sluka, James P; Su, Jing; Vicini, Paolo; Zhou, Xiaobo; Eckmann, David M

    2016-09-01

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multiscale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multiscale approaches present in silico opportunities to advance laboratory research to bedside clinical applications in pharmaceuticals research. This is achievable through the capability of modeling to reveal phenomena occurring across multiple spatial and temporal scales, which are not otherwise readily accessible to experimentation. The resultant models, when validated, are capable of making testable predictions to guide drug design and delivery. In this review we describe the goals, methods, and opportunities of multiscale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical and computational techniques employed for multiscale modeling approaches used in pharmacometric and systems pharmacology models in drug development and present several examples illustrating the current state-of-the-art models for (1) excitable systems and applications in cardiac disease; (2) stem cell driven complex biosystems; (3) nanoparticle delivery, with applications to angiogenesis and cancer therapy; (4) host-pathogen interactions and their use in metabolic disorders, inflammation and sepsis; and (5) computer-aided design of nanomedical systems. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multiscale models.

  15. Serotonergic antidepressants decrease hedonic signals but leave learning signals in the nucleus accumbens unaffected.

    Science.gov (United States)

    Graf, Heiko; Metzger, Coraline D; Walter, Martin; Abler, Birgit

    2016-01-01

    Investigating the effects of serotonergic antidepressants on neural correlates of visual erotic stimulation revealed decreased reactivity within the dopaminergic reward network along with decreased subjective sexual functioning compared with placebo. However, a global dampening of the reward system under serotonergic drugs is not intuitive considering clinical observations of their beneficial effects in the treatment of depression. Particularly, learning signals as coded in prediction error processing within the dopaminergic reward system can be assumed to be rather enhanced as antidepressant drugs have been demonstrated to facilitate the efficacy of psychotherapeutic interventions relying on learning processes. Within the same study sample, we now explored the effects of serotonergic and dopaminergic/noradrenergic antidepressants on prediction error signals compared with placebo by functional MRI. A total of 17 healthy male participants (mean age: 25.4 years) were investigated under the administration of paroxetine, bupropion and placebo for 7 days each within a randomized, double-blind, within-subject cross-over design. During functional MRI, we used an established monetary incentive task to explore neural prediction error signals within the bilateral nucleus accumbens as region of interest within the dopaminergic reward system. In contrast to diminished neural activations and subjective sexual functioning under the serotonergic agent paroxetine under visual erotic stimulation, we revealed unaffected or even enhanced neural prediction error processing within the nucleus accumbens under this antidepressant along with unaffected behavioural processing. Our study provides evidence that serotonergic antidepressants facilitate prediction error signalling and may support suggestions of beneficial effects of these agents on reinforced learning as an essential element in behavioural psychotherapy. PMID:26555033

  16. Anti-malarial Drug Design by Targeting Apicoplasts: New Perspectives

    Directory of Open Access Journals (Sweden)

    Avinaba Mukherjee

    2016-03-01

    Full Text Available Objectives: Malaria has been a major global health problem in recent times with increasing mortality. Current treatment methods include parasiticidal drugs and vaccinations. However, resistance among malarial parasites to the existing drugs has emerged as a significant area of concern in anti-malarial drug design. Researchers are now desperately looking for new targets to develop anti-malarials drug which is more target specific. Malarial parasites harbor a plastid-like organelle known as the ‘apicoplast’, which is thought to provide an exciting new outlook for the development of drugs to be used against the parasite. This review elaborates on the current state of development of novel compounds targeted againstemerging malaria parasites. Methods: The apicoplast, originates by an endosymbiotic process, contains a range of metabolic pathways and housekeeping processes that differ from the host body and thereby presents ideal strategies for anti-malarial drug therapy. Drugs are designed by targeting the unique mechanism of the apicoplasts genetic machinery. Several anabolic and catabolic processes, like fatty acid, isopenetyl diphosphate and heme synthess in this organelle, have also been targeted by drugs. Results: Apicoplasts offer exciting opportunities for the development of malarial treatment specific drugs have been found to act by disrupting this organelle’s function, which wouldimpede the survival of the parasite. Conclusion: Recent advanced drugs, their modes of action, and their advantages in the treatment of malaria by using apicoplasts as a target are discussed in this review which thought to be very useful in desigining anti-malarial drugs. Targetting the genetic machinery of apicoplast shows a great advantange regarding anti-malarial drug design. Critical knowledge of these new drugs would give a healthier understanding for deciphering the mechanism of action of anti-malarial drugs when targeting apicoplasts to overcome drug

  17. Antipsychotics as antidepressants.

    Science.gov (United States)

    Roberts, Rona Jeannie; Lohano, Kavita K; El-Mallakh, Rif S

    2016-09-01

    Three second-generation antipsychotic (SGA) agents have received FDA approval for adjunctive treatment, to antidepressant, of major depressive disorder: quetiapine, aripiprazole, and olanzapine. Additionally, quetiapine and lurasidone have been approved for the treatment of bipolar depression. There are data suggesting that quetiapine is effective for major depressive disorder as monotherapy. These agents are effective for depression only at subantipsychotic doses. Receptor profiles predict that all SGA will have anxiolytic effects as subantipsychotic doses but that all will be dysphorogenic at full antipsychotic doses (i.e., produce a depression-like clinical picture). The antidepressant effect appears to be unique to some agents, with direct evidence of insignificant antidepressant action for ziprasidone. Three general principles can guide the use of antipsychotics as antidepressants: (i) All SGAs may have anxiolytic effects; (ii) full antipsychotic doses are dysphorogenic, and therefore, subantipsychotic doses are to be used; and (iii) SGAs do not have a general antidepressant effect, rather, this appears to be unique to quetiapine and aripiprazole, and possibly lurasidone. PMID:25963405

  18. Prognosis in heart failure and the value of {beta}-blockers are altered by the use of antidepressants and depend on the type of antidepressants used

    DEFF Research Database (Denmark)

    Fosbøl, Emil Loldrup; Gislason, Gunnar H; Poulsen, Henrik Enghusen;

    2009-01-01

    BACKGROUND: Depression worsens the prognosis in patients with cardiac disease, and treatment with antidepressants may improve survival. Guidelines recommend use of selective serotonin reuptake inhibitors (SSRIs), but knowledge of the prognostic effect of different classes of antidepressants...... death associated with antidepressants, HF medication, and coadministration of these 2 drug classes was estimated by Cox proportional hazard analyses. Propensity adjusted models were performed as sensitivity analysis. During the study period, there were 53 988 deaths, of which 83.0% were due...

  19. Cardiovascular Effects of Antidepressants and Mood Stabilizers

    Directory of Open Access Journals (Sweden)

    Shahin Akhondzadeh

    2007-08-01

    Full Text Available Depression is a serious disorder in today’s society, with the estimates of lifetime prevalence being as high as 21% of the general population in some developed countries. As defined by the American Psychiatric Association, depression is a heterogeneous disorder often manifested with symptoms at the psychological, behavioral, and physiological levels. Such patients are often reluctant to take synthetic antidepressants in their appropriate doses due to their anticipated side effects including inability to drive a car, dry mouth, constipation, and sexual dysfunction. As a therapeutic alternative, effective herbal drugs may offer advantages in terms of safety and tolerability, possibly also improving patient compliance. The advent of the first antidepressants, Monoamine Oxidase Inhibitors (MAOIs and Tricyclic Antidepressants (TCAs, in the 1950s and 1960s represented a dramatic leap forward in the clinical management of depression. The subsequent development of the Selective Serotonin Reuptake Inhibitors (SSRIs and the Serotonin Norepinephrine Reuptake Inhibitor (SNRI venlafaxine in the past decade and a half has greatly enhanced the treatment of depression by offering patients medications that are as effective as the older agents but are generally more tolerable and safer in an overdose. The introduction of atypical antidepressants, such as bupropion, nefazadone, and mirtazapine, has added substantially to the available pharmacopoeia for depression. Nonetheless, rates of remission tend to be low and the risk of relapse and recurrence remains high. One of the concerns regarding the safety of antidepressant is its potential risk of cardiotoxicity and cardiovascular side effects. In this review, we will focus on the cardiovascular side effects of different types of antidepressants.

  20. Ketamine: A New Antidepressant?

    Directory of Open Access Journals (Sweden)

    Feride Karacaer

    2015-03-01

    Full Text Available Standart antidepressants are needed for the many individuals with major depressive disorder. However they do not respond adequately to treatment and because of a delay of weeks before the emergence of therapeutic effects. Recent studies show that subanesthetic dose of ketamine is efficacy and safety for the treatment of depression. Antidepressant effects of ketamine have been found to be short-lived and its psychotomimetic properties may limit the use of ketamine to depressive patients. Future research studies should focus on identifying predictors of response (pharmalogical and clinical , investigating application of different doses and routes of administration and maintaining antidepressant effect. [Psikiyatride Guncel Yaklasimlar - Current Approaches in Psychiatry 2015; 7(1: 30-40

  1. Factors influencing the choice of antidepressants: A study of antidepressant prescribing practice at University psychiatric clinic in Belgrade

    Directory of Open Access Journals (Sweden)

    Marić Nađa P.

    2012-01-01

    Full Text Available Background/Aim. Antidepressants are a widely used class of drugs. The aim of this study was to investigate different aspects of antidepressant prescribing practice at University Psychiatric Clinic in Belgrade. Methods. This cross-sectional study was carried out by retrospective analysis of the patient's medical charts. The study included all patients with antidepressant prescribed at discharge during 2009 (n = 296. The evaluation was focused on patient- related factors (socio-demographic and illness related, psychiatrist-related factors (sex and duration of working experience and drug related factors (type of antidepressant, dose, polypharmacy and reimbursement by national health insurance. Results. Antidepressants were prescribed for unipolar depression (F32-34, ICD X either without comorbidity (46.2% or with comorbidity (24.7%, mostly as a monotherapy (91% had one antidepressant, to the patients who were 65% female, aged 50.1 ± 8.9, most of them with 12 years of education (52.6%, married (69.3% and employed (55.9%. The majority of patients had a history of two hospitalizations (Med 2; 25th-75th perc. 1-4 during nine years (Med 9; 25th-75th perc. 2-15 after the first episode of depression. Among them, 19% were found to be suicidal in a lifetime. The single most prescribed antidepressant was sertraline (20.4%, followed by fluoxetine (13.3% and maprotiline (11.7%. Utilization of antidepressants was positively correlated with the rate of reimbursement (p < 0.01. The most prescribed antidepressant group was selective serotonin reuptake inhibitors (SSRI (47.8%, followed by tricyclic antidepresants (TCA (25.3% and new antidepressants - venlafaxine, tianeptine, mirtazapine, bupropion, trazodone (15.1%. Most of the drugs were prescribed in doses which are at the lower end of the recommended dose-range. Regarding severity of the actual depressive episode, TCA were prescribed for severe depression with psychotic features, while SSRI were choice for

  2. DESIGN OF GASTRO RETENTIVE DRUG DELIVERY SYSTEM OF DILTIAZEM HYDROCHLORIDE

    OpenAIRE

    L. K. Omray

    2014-01-01

    Gastro retentive drug delivery system of diltiazem hydrochloride was designed and evaluated for its effectiveness for the management of mild to moderate hypertension. Gastro retentive drug delivery system were prepared using polyvinyl alcohol and sodium carboxy methyl cellulose as the polymers and sodium bicarbonate as a gas generating agent for the reduction of floating lag time. Gastro retentive drug delivery system tablets were prepared by wet granulation method by compression in tablet co...

  3. Increased use of antidepressants and decreasing suicide rates

    DEFF Research Database (Denmark)

    Erlangsen, Annette; Canudas-Romo, V; Conwell, Y

    2008-01-01

    OBJECTIVE: The objective of the present study was to examine if the change in the suicide rate is associated with individuals' use of antidepressants as has been suggested by ecological studies. DESIGN: Decomposition of suicide rates by antidepressant treatment group. SETTING: Population......-based record linkage. PARTICIPANTS: All individuals aged 50 years and older living in Denmark between 1 January 1996 and 31 December 2000 (N = 2,100,808). MAIN OUTCOME MEASURES: Suicide rates are calculated according to current antidepressant treatment status (no treatment, tricyclic antidepressants (TCA......), selective serotonin reuptake inhibitors (SSRI), other antidepressants). The change in the suicide rate during 1996-2000 was decomposed by treatment group. RESULTS: Only one in five older adults dying by suicide was in treatment at the time of death. Whereas the male suicide rate declined by 9.7 suicides per...

  4. Ab initio and density functional computations of the vibrational spectrum, molecular geometry and some molecular properties of the antidepressant drug sertraline (Zoloft) hydrochloride

    Science.gov (United States)

    Sagdinc, Seda; Kandemirli, Fatma; Bayari, Sevgi Haman

    2007-02-01

    Sertraline hydrochloride is a highly potent and selective inhibitor of serotonin (5HT). It is a basic compound of pharmaceutical application for antidepressant treatment (brand name: Zoloft). Ab initio and density functional computations of the vibrational (IR) spectrum, the molecular geometry, the atomic charges and polarizabilities were carried out. The infrared spectrum of sertraline is recorded in the solid state. The observed IR wave numbers were analysed in light of the computed vibrational spectrum. On the basis of the comparison between calculated and experimental results and the comparison with related molecules, assignments of fundamental vibrational modes are examined. The X-ray geometry and experimental frequencies are compared with the results of our theoretical calculations.

  5. Virtual screening and its integration with modern drug design technologies.

    Science.gov (United States)

    Guido, Rafael V C; Oliva, Glaucius; Andricopulo, Adriano D

    2008-01-01

    Drug discovery is a highly complex and costly process, which demands integrated efforts in several relevant aspects involving innovation, knowledge, information, technologies, expertise, R&D investments and management skills. The shift from traditional to genomics- and proteomics-based drug research has fundamentally transformed key R&D strategies in the pharmaceutical industry addressed to the design of new chemical entities as drug candidates against a variety of biological targets. Therefore, drug discovery has moved toward more rational strategies based on our increasing understanding of the fundamental principles of protein-ligand interactions. The combination of available knowledge of several 3D protein structures with hundreds of thousands of small-molecules have attracted the attention of scientists from all over the world for the application of structure- and ligand-based drug design approaches. In this context, virtual screening technologies have largely enhanced the impact of computational methods applied to chemistry and biology and the goal of applying such methods is to reduce large compound databases and to select a limited number of promising candidates for drug design. This review provides a perspective of the utility of virtual screening in drug design and its integration with other important drug discovery technologies such as high-throughput screening (HTS) and QSAR, highlighting the present challenges, limitations, and future perspectives in medicinal chemistry.

  6. Meta-analysis of the antidepressant response to sleep deprivation and its correlates: towards a better antidepressant therapy

    OpenAIRE

    Pollock, Michael

    2010-01-01

    Unlike antidepressant drugs, which typically require several weeks to produce an antidepressant response, sleep deprivation produces a response literally overnight. Quantification (meta-analysis) of 166 articles, including data from a total of 3951 depressed patients, reveals that consistently half of all depressed patients are responders to a night of sleep deprivation, with the degree of response shown by these responders being on average a 55% decrease in depression levels. While the level...

  7. Design and Optimization of Floating Drug Delivery System of Acyclovir

    OpenAIRE

    Kharia A; Hiremath S; Singhai A; Omray L; Jain S

    2010-01-01

    The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 32 full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50...

  8. Emergency Physicians' Knowledge of Cannabinoid Designer Drugs

    Directory of Open Access Journals (Sweden)

    Patrick M Lank

    2013-09-01

    Full Text Available Introduction: The use of synthetic drugs of abuse in the United States has grown in the last few years, with little information available on how much physicians know about these drugs and how they are treating patients using them. The objective of this study was to assess emergency physician (EP knowledge of synthetic cannabinoids (SC.Methods: A self-administered internet-based survey of resident and attending EPs at a large urban emergency department (ED was administered to assess familiarity with the terms Spice or K2 and basic knowledge of SC, and to describe some practice patterns when managing SC intoxication in the ED.Results: Of the 83 physicians invited to participate, 73 (88% completed surveys. The terms “Spice” and “K2” for SC were known to 25/73 (34% and 36/73 (49% of respondents. Knowledge of SC came most commonly (72% from non-medical sources, with lay publications and the internet providing most respondents with information. Among those with previous knowledge of synthetic cannabinoids, 25% were not aware that SC are synthetic drugs, and 17% did not know they are chemically most similar to marijuana. Among all participants, 80% felt unprepared caring for a patient in the ED who had used synthetic cannabinoids.Conclusion: Clinically active EPs are unfamiliar with synthetic cannabinoids. Even those who stated they had heard of synthetic cannabinoids answered poorly on basic knowledge questions. More education is needed among EPs of all ages and levels of training on synthetic cannabinoids. [West J Emerg Med. 2013;14(5:467–470.

  9. Design and Synthesis of Epigenetic Drugs

    DEFF Research Database (Denmark)

    Leurs, Ulrike

    2014-01-01

    of histone- and DNA-modifying enzymes can lead to the development of diseases such as cancer. The histone demethylases of the KDM4 family have been implicated in a wide range of diseases, and are hence important drug targets. KDM4s belong to the bigger family of 2-OG oxygenases, an enzyme class sharing high......Epigenetics have within the last decade evolved into an exciting new strategy to target diseases linked to changes in the transcriptome of a cell. Both DNA methylation and posttranslational modifications of histone proteins are important regulators of gene expression, and aberrant regulation...

  10. Potential antidepressant constituents of Nigella sativa seeds

    Directory of Open Access Journals (Sweden)

    Ehab S Elkhayat

    2016-01-01

    Full Text Available Background: Nigella sativa Linn. is well known seed in the Middle East, Asia, and the Far East as a natural remedy for many ailments and as a flavoring agent proclaimed medicinal usage dating back to the ancient Egyptians, Greeks, and Romans. An authentic saying of the Prophet Muhammad (Peace Be Upon Him about black seed is also quoted in Al-Bukhari. Objective: This study was carried out to evaluate the antidepressant effect and isolate the potential antidepressant constituents of the polar extract of N. sativa seeds. Materials and Methods: The antidepressant effect was evaluated through the immobility duration in tail suspension and forced swim tests (FSTs. Albino mice were orally treated with N. sativa polar extract and its RP-18 column chromatography fractions (50 and 100 mg/kg,. Results: The polar extract and two of its sub-fractions were significantly able to decrease the immobility time of mice when subjected to both tail suspension and FSTs, the effects are comparable to standard drug (Sertraline, 5 mg/kg. However, these treatments did not affect the number of crossings and rearing in the open field test. Phytochemical investigation of the two active fractions led to the isolation of quercetin-3-O-α-L-rhamnopyranoside 1, quercetin-7-O-β-D-gluco- pyranoside 2, tauroside E 3, and sapindoside B as the potential antidepressant constituents.

  11. Antidepressant medications and osteoporosis

    DEFF Research Database (Denmark)

    Rizzoli, R; Cooper, C; Reginster, J-Y;

    2012-01-01

    Use of antidepressant medications that act on the serotonin system has been linked to detrimental impacts on bone mineral density (BMD), and to osteoporosis. This article reviews current evidence for such effects, and identifies themes for future research. Serotonin receptors are found in all major...

  12. Antidepressant activity of fingolimod in mice

    OpenAIRE

    di Nuzzo, Luigi; Orlando, Rosamaria; Tognoli, Cristina; Di Pietro, Paola; Bertini, Giuseppe; Miele, Jessica; Bucci, Domenico; Motolese, Marta; Scaccianoce, Sergio; Caruso, Alessandra; Mauro, Gianluca; De Lucia, Carmine; Battaglia, Giuseppe; Bruno, Valeria; Fabene, Paolo Francesco

    2015-01-01

    Recent findings indicate that fingolimod, the first oral drug approved for the treatment of multiple sclerosis (MS), acts as a direct inhibitor of histone deacetylases (HDACs) and enhances the production of brain-derived neurotrophic factor (BDNF) in the CNS. Both mechanisms are relevant to the pathophysiology and treatment of major depression. We examined the antidepressant activity of fingolimod in mice subjected to chronic unpredictable stress (CUS), a model of reactive depression endowed ...

  13. Sub-threshold depression and antidepressants use in a community sample: searching anxiety and finding bipolar disorder

    OpenAIRE

    Hardoy Maria; Faravelli Carlo; Di Sciascio Guido; Dell'Osso Liliana; Caraci Filippo; Balestrieri Matteo; Tondo Leonardo; Carta Mauro G; Lecca Maria E; Moro Maria; Bhat Krishna M; Casacchia Massimo; Drago Filippo

    2011-01-01

    Abstract Background To determine the use of antidepressants (ADs) in people with sub-threshold depression (SD); the lifetime prevalence of mania and hypomania in SD and the link between ADs use, bipolarity and anxiety disorders in SD. Methods Study design: community survey. Study population: samples randomly drawn, after stratification from the adult population of municipal records. Sample size: 4999 people from seven areas within six Italian regions. Tools: Questionnaire on psychotropic drug...

  14. CNS drug design: balancing physicochemical properties for optimal brain exposure.

    Science.gov (United States)

    Rankovic, Zoran

    2015-03-26

    The human brain is a uniquely complex organ, which has evolved a sophisticated protection system to prevent injury from external insults and toxins. Designing molecules that can overcome this protection system and achieve optimal concentration at the desired therapeutic target in the brain is a specific and major challenge for medicinal chemists working in CNS drug discovery. Analogous to the now widely accepted rule of 5 in the design of oral drugs, the physicochemical properties required for optimal brain exposure have been extensively studied in an attempt to similarly define the attributes of successful CNS drugs and drug candidates. This body of work is systematically reviewed here, with a particular emphasis on the interplay between the most critical physicochemical and pharmacokinetic parameters of CNS drugs as well as their impact on medicinal chemistry strategies toward molecules with optimal brain exposure. A summary of modern CNS pharmacokinetic concepts and methods is also provided.

  15. 21 CFR 316.30 - Annual reports of holder of orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Annual reports of holder of orphan-drug... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.30 Annual reports of holder of orphan-drug designation. Within 14 months after the date on which a drug was...

  16. Design and optimization of floating drug delivery system of acyclovir

    Directory of Open Access Journals (Sweden)

    Kharia A

    2010-01-01

    Full Text Available The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 32 full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1 and hydroxypropylmethylcellulose K4M (X2 were selected as independent variables. The times required for 50% (t 50% and 70% (t 70% drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2. The closeness of predicted and observed values for t 50% and t 70% indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi′s kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix.

  17. Design and optimization of floating drug delivery system of acyclovir.

    Science.gov (United States)

    Kharia, A A; Hiremath, S N; Singhai, A K; Omray, L K; Jain, S K

    2010-09-01

    The purpose of the present work was to design and optimize floating drug delivery systems of acyclovir using psyllium husk and hydroxypropylmethylcellulose K4M as the polymers and sodium bicarbonate as a gas generating agent. The tablets were prepared by wet granulation method. A 3(2) full factorial design was used for optimization of drug release profile. The amount of psyllium husk (X1) and hydroxypropylmethylcellulose K4M (X2) were selected as independent variables. The times required for 50% (t(50%)) and 70% (t(70%)) drug dissolution were selected as dependent variables. All the designed nine batches of formulations were evaluated for hardness, friability, weight variation, drug content uniformity, swelling index, in vitro buoyancy, and in vitro drug release profile. All formulations had floating lag time below 3 min and constantly floated on dissolution medium for more than 24 h. Validity of the developed polynomial equation was verified by designing two check point formulations (C1 and C2). The closeness of predicted and observed values for t(50%) and t(70%) indicates validity of derived equations for the dependent variables. These studies indicated that the proper balance between psyllium husk and hydroxypropylmethylcellulose K4M can produce a drug dissolution profile similar to the predicted dissolution profile. The optimized formulations followed Higuchi's kinetics while the drug release mechanism was found to be anomalous type, controlled by diffusion through the swollen matrix. PMID:21694992

  18. 21 CFR 316.27 - Change in ownership of orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Change in ownership of orphan-drug designation... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.27 Change in ownership of orphan-drug designation. (a) A sponsor may transfer ownership of or any beneficial interest...

  19. Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination : trial design and protocol of the MOMENT study

    NARCIS (Netherlands)

    Huijbers, M.J.; Spijker, J.; Donders, A.R.T.; van Schaik, D.J.F.; van Oppen, P.; Ruhe, H.G.; Blom, M.B.J.; Nolen, W.A.; Ormel, J.; van der Wilt, G.J.; Kuyken, W.; Spinhoven, P.; Speckens, A.E.M.

    2012-01-01

    Background: Depression is a common psychiatric disorder characterized by a high rate of relapse and recurrence. The most commonly used strategy to prevent relapse/recurrence is maintenance treatment with antidepressant medication (mADM). Recently, it has been shown that Mindfulness-Based Cognitive T

  20. Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination: Trial design and protocol of the MOMENT study

    NARCIS (Netherlands)

    Huijbers, M.J.; Spijker, J.; Donders, A.R.T.; Schaik, D.J.F. van; Oppen, P. van; Ruhe, H.G.; Blom, M.B.J.; Nolen, W.A.; Ormel, J.; Wilt, G.J. van der; Kuyken, W.; Spinhoven, P.; Speckens, A.E.M.

    2012-01-01

    Background: Depression is a common psychiatric disorder characterized by a high rate of relapse and recurrence. The most commonly used strategy to prevent relapse/recurrence is maintenance treatment with antidepressant medication (mADM). Recently, it has been shown that Mindfulness-Based Cognitive T

  1. Experience With and Attitudes Toward Psychotherapy and Antidepressants Among Patients With Inflammatory Bowel Disease and Functional Gastrointestinal Disorders: An Online Patient Survey to Inform System Design.

    Science.gov (United States)

    Mikocka-Walus, Antonina; Andrews, Jane M

    2016-01-01

    This study aimed to explore and compare experiences with and attitudes toward psychotherapy and antidepressants of patients with inflammatory bowel disease (IBD) and functional gastrointestinal disorders (FGiDs). Patients from gastroenterology clinic databases were invited to an online survey. Student's t test, Mann-Whitney U test, chi-square test, and Fisher's test were used to compare patients with IBD and FGiD on demographics and variables of interest. Of 86 participants, 56 (65%) had IBD and 30 (35%) had FGiDs. Mean levels of anxiety, depressive, and stress symptoms were within the moderate to severe range. Psychological care and antidepressants were offered to significantly more FGiD than to IBD respondents (37% vs. 9%; p = .009). Although the symptoms were generally reduced after the prescription of antidepressants, only 30% of IBD respondents and 21% of FGiD respondents using antidepressants would recommend them to others. In contrast, 53% of IBD respondents and 69% of FGiD respondents who used psychotherapy would recommend it to others. Both these therapies were valued by recipients; however, neither was reported to improve gastrointestinal (GI) symptoms. Given the high desire for and positive experiences of psychological care for these 2 common GI conditions, access to formal psychological support services within GI clinics would appear to be the most efficient model. PMID:27148830

  2. Antidepressant-like activity of gallic acid in mice subjected to unpredictable chronic mild stress.

    Science.gov (United States)

    Chhillar, Ritu; Dhingra, Dinesh

    2013-08-01

    This study was designed to evaluate antidepressant-like activity of gallic acid in Swiss young male albino mice subjected to unpredictable chronic mild stress and to explore the possible underlying mechanisms for this activity. Gallic acid (5, 10, 20 mg/kg, i.p.) and fluoxetine (10 mg/kg, i.p.) per se were administered daily to unstressed mice and other groups of mice subjected to unpredictable mild stress, 30 min after the injection for 21 successive days. The antidepressant-like activity was evaluated using forced swim test (FST) and sucrose preference test. Stress significantly increased immobility period of mice in FST. Gallic acid (10 and 20 mg/kg, i.p.) and fluoxetine significantly decreased immobility period of unstressed and stressed mice in FST and prevented the stress-induced decrease in sucrose preference, indicating significant antidepressant-like activity. There was no significant effect on locomotor activity of the mice by the drugs. Gallic acid (10 and 20 mg/kg, i.p.) significantly decreased Monoamine oxidase-A (MAO-A) activity, malondialdehyde levels, and catalase activity in unstressed mice; and significantly prevented the stress-induced decrease in reduced glutathione and catalase activity; and also significantly prevented stress-induced increase in MAO-A activity, malondialdehyde levels, plasma nitrite, and corticosterone levels. Thus, gallic acid showed antidepressant-like activity in unstressed and stressed mice probably due to its antioxidant activity and through inhibition of MAO-A activity and decrease in plasma nitrite levels. In addition, gallic acid also showed antidepressant-like activity in stressed mice probably through decrease in plasma corticosterone levels.

  3. Acute effect of different antidepressants on glycemia in diabetic and non-diabetic rats

    OpenAIRE

    Gomez, R.; Huber, J.; G. Tombini; H.M.T. Barros

    2001-01-01

    Diabetic patients have a 20% higher risk of depression than the general population. Treatment with antidepressant drugs can directly interfere with blood glucose levels or may interact with hypoglycemic agents. The treatment of depression in diabetic patients must take into account variations of glycemic levels at different times and a comparison of the available antidepressant agents is important. In the present study we evaluated the interference of antidepressants with blood glucose levels...

  4. Antidepressant Induced Mania : Is it a risk factor for Antidepressant Abuse?

    OpenAIRE

    Ramesh, S; Khandelwal, Sudhir K

    2003-01-01

    Induction of mania is a common occurrence with antidepressant use. A case of antidepressant induced hypomania leading to antidepressant abuse is presented. The clinical implications of antidepressant abuse in bipolar disorder are discussed.

  5. Effectiveness of antidepressants: an evidence myth constructed from a thousand randomized trials?

    Directory of Open Access Journals (Sweden)

    Ioannidis John PA

    2008-05-01

    Full Text Available Abstract Antidepressants, in particular newer agents, are among the most widely prescribed medications worldwide with annual sales of billions of dollars. The introduction of these agents in the market has passed through seemingly strict regulatory control. Over a thousand randomized trials have been conducted with antidepressants. Statistically significant benefits have been repeatedly demonstrated and the medical literature is flooded with several hundreds of "positive" trials (both pre-approval and post-approval. However, two recent meta-analyses question this picture. The first meta-analysis used data that were submitted to FDA for the approval of 12 antidepressant drugs. While only half of these trials had formally significant effectiveness, published reports almost ubiquitously claimed significant results. "Negative" trials were either left unpublished or were distorted to present "positive" results. The average benefit of these drugs based on the FDA data was of small magnitude, while the published literature suggested larger benefits. A second meta-analysis using also FDA-submitted data examined the relationship between treatment effect and baseline severity of depression. Drug-placebo differences increased with increasing baseline severity and the difference became large enough to be clinically important only in the very small minority of patient populations with severe major depression. In severe major depression, antidepressants did not become more effective, simply placebo lost effectiveness. These data suggest that antidepressants may be less effective than their wide marketing suggests. Short-term benefits are small and long-term balance of benefits and harms is understudied. I discuss how the use of many small randomized trials with clinically non-relevant outcomes, improper interpretation of statistical significance, manipulated study design, biased selection of study populations, short follow-up, and selective and distorted

  6. Interaction of antidepressants with the serotonin and norepinephrine transporters

    DEFF Research Database (Denmark)

    Sørensen, Lena; Andersen, Jacob; Thomsen, Mette;

    2012-01-01

    as treatment of depression and anxiety disorders or as psychostimulant drugs of abuse. Despite their clinical importance, the molecular mechanisms by which various types of antidepressant drugs bind and inhibit SERT and NET are still elusive for the majority of the inhibitors, including the molecular basis...

  7. Increased risk of antidepressant use in childhood cancer survivors

    DEFF Research Database (Denmark)

    Lund, Lasse Wegener; Winther, J.F.; Cederkvist, L;

    2015-01-01

    AIM: Childhood cancer survivors are at risk of both somatic and mental late effects, but large population-based studies of depression are lacking. METHODS: Risk of antidepressant use was evaluated in a population-based cohort of 5452 Danish children treated for cancer in 1975-2009 by linkage to the...... National Prescription Drug Database, which worldwide is the oldest nationwide registry of prescription medication. Hazard ratios (HRs) for antidepressant use were estimated in a Cox proportional hazards model stratified on sex, with population comparisons as referents. RESULTS: Overall, childhood cancer...... survivors were at increased risk of having antidepressants prescribed (HR, 1.4; 95% confidence interval (CI), 1.3-1.5). The excess absolute risk of antidepressant use was 2.5 per 1000 person-years (95% CI, 1.7-3.3), equivalent to an excess of 2.5 survivors for every 100 survivors followed for 10years...

  8. [Critical evaluation of the use of antidepressives in childhood].

    Science.gov (United States)

    Conde López, V J; Ballesteros Alcalde, M C; Franco Martín, M A; Geijo Uribe, M S

    1997-01-01

    In the introduction the authors study some technical, methodological, ethical, administrative and marketing problems about the evaluation and investigation in child and adolescence psychopharmacology. They make a revision and critical evaluation about. As a whole the clinic use of antidepressive drugs in childhood psychiatry. Then, some open and controlled trial about tricyclic antidepressives are evaluated. After this, the authors present the most important advances about the open and controlled clinic trials with several antidepressives: tricyclic, tetracyclic, ISSR and MAO-Inhibitors and other drugs (placebo response, psychotherapy, imipramine, nortryptiline, amitriptyline, fluoxetine, MAO-Inhibitors, lithium, mianserin, maprotyline, etc.). Beside, placebo effect, response prediction factors, biologic markers, diagnostic criteria, evaluation methods and technics, drugs associations, clinic types of child depression, etc, are studied. In the last, the authors present some clinical conclusions about this subject. PMID:9245188

  9. Rational design of purely peptidic amphiphiles for drug delivery applications

    OpenAIRE

    Bruyn Ouboter, Dirk de

    2011-01-01

    A broad range of new properties is emerging from supramolecular aggregates. Self-assembled structures of purely peptidic amphiphiles exploit these properties to produce biocompatible, biodegradable, smart materials for drug administration. This thesis explores the design, synthesis, purification, characterization of purely peptidic amphiphiles, and evaluates potential applications. The first chapter provides a general introduction to the field of self-assembly, and of drug delivery as com...

  10. Breastfeeding and Antidepressants

    OpenAIRE

    Field, Tiffany

    2008-01-01

    Although a large literature supports the benefits of breastfeeding, this review suggests that breastfeeding is less common among postpartum depressed women, even though their infants benefit from the breastfeeding. Depressed mothers, in part, do not breastfeed because of their concern about potentially negative effects of antidepressants on their infants. Although sertraline (Zoloft) and paroxetine (Paxol) concentrations are not detectable in infants’ sera, fluoxetine (Prozac) and citalopram ...

  11. Preventing relapse in recurrent depression using mindfulness-based cognitive therapy, antidepressant medication or the combination: trial design and protocol of the MOMENT study

    Directory of Open Access Journals (Sweden)

    Huijbers Marloes J

    2012-08-01

    Full Text Available Abstract Background Depression is a common psychiatric disorder characterized by a high rate of relapse and recurrence. The most commonly used strategy to prevent relapse/recurrence is maintenance treatment with antidepressant medication (mADM. Recently, it has been shown that Mindfulness-Based Cognitive Therapy (MBCT is at least as effective as mADM in reducing the relapse/recurrence risk. However, it is not yet known whether combination treatment of MBCT and mADM is more effective than either of these treatments alone. Given the fact that most patients have a preference for either mADM or for MBCT, the aim of the present study is to answer the following questions. First, what is the effectiveness of MBCT in addition to mADM? Second, how large is the risk of relapse/recurrence in patients withdrawing from mADM after participating in MBCT, compared to those who continue to use mADM after MBCT? Methods/design Two parallel-group, multi-center randomized controlled trials are conducted. Adult patients with a history of depression (3 or more episodes, currently either in full or partial remission and currently treated with mADM (6 months or longer are recruited. In the first trial, we compare mADM on its own with mADM plus MBCT. In the second trial, we compare MBCT on its own, including tapering of mADM, with mADM plus MBCT. Follow-up assessments are administered at 3-month intervals for 15 months. Primary outcome is relapse/recurrence. Secondary outcomes are time to, duration and severity of relapse/recurrence, quality of life, personality, several process variables, and incremental cost-effectiveness ratio. Discussion Taking into account patient preferences, this study will provide information about a the clinical and cost-effectiveness of mADM only compared with mADM plus MBCT, in patients with a preference for mADM, and b the clinical and cost-effectiveness of withdrawing from mADM after MBCT, compared with mADM plus MBCT, in patients with a

  12. 21 CFR 316.20 - Content and format of a request for orphan-drug designation.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Content and format of a request for orphan-drug... SERVICES (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Designation of an Orphan Drug § 316.20 Content and format of a request for orphan-drug designation. (a) A sponsor that submits a request for...

  13. Antidepressant-Induced Female Sexual Dysfunction.

    Science.gov (United States)

    Lorenz, Tierney; Rullo, Jordan; Faubion, Stephanie

    2016-09-01

    Because 1 in 6 women in the United States takes antidepressants and a substantial proportion of patients report some disturbance of sexual function while taking these medications, it is a near certainty that the practicing clinician will need to know how to assess and manage antidepressant-related female sexual dysfunction. Adverse sexual effects can be complex because there are several potentially overlapping etiologies, including sexual dysfunction associated with the underlying mood disorder. As such, careful assessment of sexual function at the premedication visit followed by monitoring at subsequent visits is critical. Treatment of adverse sexual effects can be pharmacological (dose reduction, drug discontinuation or switching, augmentation, or using medications with lower adverse effect profiles), behavioral (exercising before sexual activity, scheduling sexual activity, vibratory stimulation, psychotherapy), complementary and integrative (acupuncture, nutraceuticals), or some combination of these modalities. PMID:27594188

  14. Drug: D00823 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 7 345.7871 D00823.gif Antidepressant ATC code: N06AB03 Selective serotonin reuptake inhibitor (SSRI) seroton...sification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective... USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/S

  15. Drug: D07705 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 29 D07705.gif Antidepressant ATC code: N06AB04 Selective serotonin reuptake inhibitor (SSRI) serotonin trans...SYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective serotonin reuptake inhibitor...s N06AB04 Citalopram D07705 Citalopram hydrochloride USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective

  16. 21 CFR 316.40 - Treatment use of a designated orphan drug.

    Science.gov (United States)

    2010-04-01

    ... 21 Food and Drugs 5 2010-04-01 2010-04-01 false Treatment use of a designated orphan drug. 316.40... (CONTINUED) DRUGS FOR HUMAN USE ORPHAN DRUGS Open Protocols for Investigations § 316.40 Treatment use of a designated orphan drug. Prospective investigators seeking to obtain treatment use of designated orphan...

  17. [Design of the novel dipeptide neuropsychotropic drug preparations].

    Science.gov (United States)

    Gudasheva, T A; Skoldinov, A P

    2003-01-01

    The paper considers a new strategy in the field of neuropsychotropic dipeptide drug design, the main points being as follows: (i) determination of the structural elements of dipeptides, such as fragments of amino acid side radicals and peptide bonds, in nonpeptide drugs; (ii) design of peptide analogs topologically close to the drug; (iii) synthesis and activity testing of these analogs; (iv) determination of the corresponding endogenous neuropeptide among the known neuropeptides or identification of the new neuropeptides in the brain of experimental animals. Using this approach, new pyroglutamyl- and prolyl-containing dipeptides were obtained based on the structure of the well-known classical nootropic drug piracetam. The new drugs exhibit nootropic activity in doses 100-10,000 times lower than those of piracetam. The structure of most active pyroglutamyl dipeptide pGlu-Asn-NH2 coincides with that of the N-end fragment of the endogenous memory peptide AVP(4-9). Noopept (N-phenylacetylprolylglycine ethyl ester), patented in Russia and USA as a new nootropic drug, is currently under stage 2 of successful clinical trials. The main metabolite of noopept, cyclo-Pro-Gly, is identical to the endogenous dipeptide designed in this work and is most close analog of piracetam with respect to pharmacological activity. The universal character of the proposed strategy is demonstrated by the design of active dipeptide analogs of an atypical neuroleptic drug sulpiride. As a result, a potential dipeptide neuroleptic dilept was obtained, which has been patented in Russia and now passes broad preclinical trials. PMID:12962042

  18. Design Features of Drug-Drug Interaction Trials Between Antivirals and Oral Contraceptives.

    Science.gov (United States)

    Ayala, Ruben C; Arya, Vikram; Younis, Islam R

    2016-05-01

    The aim of this work was to explore the major design features of drug-drug interaction trials between antiviral medications (AVs) and oral contraceptives (OCs). Information on these trials (n = 27) was collected from approved drug labels and clinical pharmacology reviews conducted by the U.S. Food and Drug Administration. The primary objective of all trials was to evaluate changes in OC exposure following the coadministration of AVs. In addition, an evaluation of potential pharmacodynamic interaction was performed in 10 of these trials. Twenty-two trials were open label with a fixed-sequence design, and 5 trials used a double-blind crossover design. The trials were conducted using one, two, or three 28-day ovulatory cycles in 10, 8, and 9 trials, respectively. Only 1 trial enrolled HIV-infected women. The median number of women in a trial was 20 (range, 12 to 52). Norethindrone/ethinyl estradiol (EE) combination was the most commonly used OC (n = 16, 59%) followed by norgestimate/EE (n = 9, 33%). Labeling recommendations were based on exposure changes in 25 cases and on safety observations in the trial in 2 cases. In conclusion, a wide variety of trial designs was used, and there is no preferred design. The answer to the exposure question can be achieved using multiple designs.

  19. An introduction to quantum chemical methods applied to drug design.

    Science.gov (United States)

    Stenta, Marco; Dal Peraro, Matteo

    2011-06-01

    The advent of molecular medicine allowed identifying the malfunctioning of subcellular processes as the source of many diseases. Since then, drugs are not only discovered, but actually designed to fulfill a precise task. Modern computational techniques, based on molecular modeling, play a relevant role both in target identification and drug lead development. By flanking and integrating standard experimental techniques, modeling has proven itself as a powerful tool across the drug design process. The success of computational methods depends on a balance between cost (computation time) and accuracy. Thus, the integration of innovative theories and more powerful hardware architectures allows molecular modeling to be used as a reliable tool for rationalizing the results of experiments and accelerating the development of new drug design strategies. We present an overview of the most common quantum chemistry computational approaches, providing for each one a general theoretical introduction to highlight limitations and strong points. We then discuss recent developments in software and hardware resources, which have allowed state-of-the-art of computational quantum chemistry to be applied to drug development.

  20. Sexual dysfunction with the use of antidepressants in a tertiary care mental health setting - a retrospective case series

    Directory of Open Access Journals (Sweden)

    Kingshuk Lahon

    2011-01-01

    Full Text Available Sexual dysfunction affects patients′ quality of life. It can occur secondary to physical or mental disorders, substance abuse and treatment with prescription drugs like antidepressants. We wanted to study the prevalence of sexual dysfunction associated with antidepressant use in the psychiatric unit of a tertiary care hospital and assess for causality, severity and preventability. We did a retrospective data collection from case records of patients on antidepressants from the Psychiatry outpatient clinic of a tertiary care teaching hospital during the period 1 st January 2006 to 31 st December 2006, excluding those with complaints of sexual dysfunction prior to treatment. Data are presented as a case series. Documented adverse events were subjected to analysis for causality, severity and preventability using Naranjo′s, modified Hartwig and Siegel and modified Schumock and Thornton′s Preventability scales respectively. Out of 169 patients, four patients developed sexual dysfunction (2.36% associated with duloxetine, mirtazapine, trazodone and sertraline. We observed a possible causal relationship of mild to moderately severe ADR (sexual dysfunction which was not preventable. Prevalence of antidepressant associated sexual dysfunction was lower than quoted in Western literature probably due to the retrospective nature of our study design. Active monitoring and intervention can greatly improve the quality of life and compliance to treatment.

  1. Drug design and discovery: translational biomedical science varies among countries.

    Science.gov (United States)

    Weaver, Ian N; Weaver, Donald F

    2013-10-01

    Drug design and discovery is an innovation process that translates the outcomes of fundamental biomedical research into therapeutics that are ultimately made available to people with medical disorders in many countries throughout the world. To identify which nations succeed, exceed, or fail at the drug design/discovery endeavor--more specifically, which countries, within the context of their national size and wealth, are "pulling their weight" when it comes to developing medications targeting the myriad of diseases that afflict humankind--we compiled and analyzed a comprehensive survey of all new drugs (small molecular entities and biologics) approved annually throughout the world over the 20-year period from 1991 to 2010. Based upon this analysis, we have devised prediction algorithms to ascertain which countries are successful (or not) in contributing to the worldwide need for effective new therapeutics.

  2. Drug Design, Development, and Delivery: An Interdisciplinary Course on Pharmaceuticals

    Science.gov (United States)

    Prausnitz, Mark R.; Bommarius, Andreas S.

    2011-01-01

    We developed a new interdisciplinary course on pharmaceuticals to address needs of undergraduate and graduate students in chemical engineering and other departments. This course introduces drug design, development, and delivery in an integrated fashion that provides scientific depth in context with broader impacts in business, policy, and ethics.…

  3. Antidepressant-Resistant Depression and Antidepressant-Associated Suicidal Behaviour: The Role of Underlying Bipolarity

    OpenAIRE

    Zoltan Rihmer; Xenia Gonda

    2011-01-01

    The complex relationship between the use of antidepressants and suicidal behaviour is one of the hottest topics of our contemporary psychiatry. Based on the literature, this paper summarizes the author's view on antidepressant-resistant depression and antidepressant-associated suicidal behaviour. Antidepressant-resistance, antidepressant-induced worsening of depression, antidepressant-associated (hypo)manic switches, mixed depressive episode, and antidepressant-associated suicidality among d...

  4. Psychosocial work environment and antidepressant medication: a prospective cohort study

    DEFF Research Database (Denmark)

    Bonde, Jens Peter; Munch-Hansen, T.; Wieclaw, J.;

    2009-01-01

    alone. None of the measured psychosocial work environment factors were consistently related to prescription of antidepressant drugs during the follow-up period. CONCLUSION: The study does not indicate that a poor psychosocial work environment among public service employees is related to prescription......BACKGROUND: Adverse psychosocial work environments may lead to impaired mental health, but it is still a matter of conjecture if demonstrated associations are causal or biased. We aimed at verifying whether poor psychosocial working climate is related to increase of redeemed subscription...... of antidepressant medication. METHODS: Information on all antidepressant drugs (AD) purchased at pharmacies from 1995 through 2006 was obtained for a cohort of 21,129 Danish public service workers that participated in work climate surveys carried out during the period 2002-2005. Individual self...

  5. Trimipramine: a challenge to current concepts on antidepressives.

    Science.gov (United States)

    Berger, M; Gastpar, M

    1996-01-01

    Although it is chemically a classical tricyclic antidepressant agent, trimipramine shows atypical pharmacological properties. Its well-documented antidepressant action cannot be explained by noradrenaline or serotonin reuptake inhibition or by a down-regulation of beta-adrenoceptors. Furthermore, its receptor affinity profile resembles more that of clozapine, a neuroleptic drug, than that of tricyclic antidepressants. Trimipramine does not reduce, but rather increases, rapid eye movement sleep. It stimulates nocturnal prolactin secretion and inhibits nocturnal cortisol secretion and may act at the level of the hypothalamus on corticotropin-releasing hormone secretion. Trimipramine is of particular value in depressed patients with insomnia, and it has been shown to be effective in the therapy of primary insomnia. As the pharmacological profile indicates, and an open clinical study has shown, trimipramine might also be active as an antipsychotic. The drug is both a tool for increasing our understanding of depression and a potential therapy for several psychiatric disorders. PMID:8863001

  6. Drug treatments for schizophrenia: pragmatism in trial design shows lack of progress in drug design.

    Science.gov (United States)

    Cheng, F; Jones, P B

    2013-09-01

    Aims. The introduction of second generation antipsychotic (SGA) medication over a decade ago led to changes in prescribing practices; these drugs have eclipsed their predecessors as treatments for schizophrenia. However, the metabolic side effects of these newer antipsychotics have been marked and there are increasing concerns as to whether these novel drugs really are superior to their predecessors in terms of the balance between risks and benefits. In this article, we review the literature regarding comparisons between first generation antipsychotic (FGA) and SGA in terms of clinical effectiveness. Methods. Large (n > 150) randomized-controlled trials (RCTs) comparing the effectiveness (efficacy and side effects) of FGA and SGA medications other than clozapine were reviewed, as were meta-analyses that included smaller studies. Results. The superiority in efficacy and reduced extrapyramidal side effects (EPSE) of SGAs is modest, especially when compared with low-dose FGAs. However, the high risk of weight gain and other metabolic disturbances associated with certain SGAs such as olanzapine is markedly higher than the risk with FGAs at the doses used in the trials. Conclusions. The efficacy profiles of various FGAs and SGAs are relatively similar, but their side effects vary between and within classes. Overall, large pragmatic trials of clinical effectiveness indicate that the care used in prescribing and managing drug treatments to ensure tolerability may be more important than the class of drug used. PMID:23388168

  7. Antidepressants and Advertising: Psychopharmaceuticals in Crisis

    Science.gov (United States)

    Greenslit, Nathan P.; Kaptchuk, Ted J.

    2012-01-01

    As the efficacy and science of psychopharmaceuticals has become increasingly uncertain, marketing of these drugs to both physicians and consumers continues to a central part of a multi-billion dollar per year industry in the United States. We explore how such drug marketing portrays idealized scientific relationships between psychopharmaceuticals and depression; how multiple stakeholders, including scientists, regulatory agencies, and patient advocacy groups, negotiate neurobiological explanations of mental illness; and how the placebo effect has become a critical issue in these debates, including the possible role of drug advertising to influence the placebo effect directly. We argue that if and how antidepressants “work” is not a straightforward objective question, but rather a larger social contest involving scientific debate, the political history of the pharmaceutical industry, cultural discourses surrounding the role of drugs in society, and the interpretive flexibility of personal experience. PMID:22461754

  8. Antidepressants and advertising: psychopharmaceuticals in crisis.

    Science.gov (United States)

    Greenslit, Nathan P; Kaptchuk, Ted J

    2012-03-01

    As the efficacy and science of psychopharmaceuticals has become increasingly uncertain, marketing of these drugs to both physicians and consumers continues to a central part of a multi-billion dollar per year industry in the United States. We explore how such drug marketing portrays idealized scientific relationships between psychopharmaceuticals and depression; how multiple stakeholders, including scientists, regulatory agencies, and patient advocacy groups, negotiate neurobiological explanations of mental illness; and how the placebo effect has become a critical issue in these debates, including the possible role of drug advertising to influence the placebo effect directly. We argue that if and how antidepressants "work" is not a straightforward objective question, but rather a larger social contest involving scientific debate, the political history of the pharmaceutical industry, cultural discourses surrounding the role of drugs in society, and the interpretive flexibility of personal experience. PMID:22461754

  9. DESIGN OF GASTRO RETENTIVE DRUG DELIVERY SYSTEM OF DILTIAZEM HYDROCHLORIDE

    Directory of Open Access Journals (Sweden)

    L. K. Omray

    2014-02-01

    Full Text Available Gastro retentive drug delivery system of diltiazem hydrochloride was designed and evaluated for its effectiveness for the management of mild to moderate hypertension. Gastro retentive drug delivery system were prepared using polyvinyl alcohol and sodium carboxy methyl cellulose as the polymers and sodium bicarbonate as a gas generating agent for the reduction of floating lag time. Gastro retentive drug delivery system tablets were prepared by wet granulation method by compression in tablet compression machine. Formulations DL1, DL2, DL3, DL4 and DL5 were developed which differed in the ratio of polyvinyl alcohol and sodium carboxy methyl cellulose polymers. All the formulations were evaluated for hardness, weight variation, friability, drug content, swelling index, buoyancy studies and in vitro drug release study. In vitro drug release study was performed using United State Pharmacopoeia 23 type 2 dissolution test apparatus employing paddle stirrer at 50 r/pm. Dissolution medium was 900 ml of 0.1N hydrochloric acid at 37ºC ± 3ºC. Formulations DL3 was found to be better as compared to other formulation.

  10. Drugs, structures, fragments : substructure-based approaches to GPCR drug discovery and design

    NARCIS (Netherlands)

    Horst, Eelke van der

    2012-01-01

    This thesis is all about cheminformatics, and its impact on drug discovery. A number of strategies are discussed that apply computational methods for the analysis and design of G protein-coupled receptor (GPCR) ligands. Frequent substructure mining is applied to find the common structural motifs tha

  11. Antidepressant-like actions of pregnancy, and progesterone in Wistar rats forced to swim.

    Science.gov (United States)

    Molina-Hernández, M; Téllez-Alcántara, N P

    2001-07-01

    In rats, some behavioral changes occurring during pregnancy related to the presence of progesterone may be analyzed in the forced swimming task (FST), which is designed to test the antidepressant profile of drugs. The present study was aimed to analyze in pregnant rats, in rats after delivery, or in rats after receiving progesterone those behavioral changes displayed in the FST. We hypothesize that pregnancy and progesterone will produce antidepressant-like effects in rats forced to swim. Therefore, pregnant rats (14th, 17th, and 20th days), or rats after delivery (3rd, and 7th days) were tested in the FST. Ovariectomized rats receiving saline (0.9%; i.p.), clomipramine (1.25 mg/kg; i.p.), or desipramine (2.14 mg/kg; i.p.) for 28 days were also tested in the FST. In a second series of experiments, ovariectomized rats receiving vehicle or progesterone (0.5 mg/kg; or 2.0 mg/kg; sc.) were tested in the FST. Locomotion was evaluated in the open field test. Results showed that in the FST: 1) pregnancy (P immobility by increasing climbing; 2) clomipramine (P immobility by increasing swimming; 3) rats tested after delivery displayed similar behavior than control rats. A lower locomotion was observed only at the end of pregnancy. In conclusion, results suggest that during pregnancy, a reproductive process characterized by its high levels of progesterone, antidepressant-like effects can be found.

  12. Radioactive cDNA microarrys for gene expression profiles in antidepressant therapy

    Energy Technology Data Exchange (ETDEWEB)

    Lee, M. S.; Han, B. J.; Cha, J. H.; Ryu, Y. M.; Shin, E. K.; Park, J. H.; Park, Y. H.; Kim, M. K. [Korea University Medical College, Seoul (Korea, Republic of)

    2002-07-01

    Using radioactive cDNA microarray, we investigated a pattern of gene regulation under treatment of antidepressant on patients of depressive disoder. Basic microarray technology was performed as previously described in our research. The bioinformatic selection of human cDNAs, which is specifically designed for psychiatry, neurology, and signal transduction, were arrayed on nylon membranes. Using with 33P-labeled probes, this method provided highly sensitive gene expression profiles of our interest including brain receptors, drug metabolism, and cellular signalings. Gene expression profiles were also classified into several categories in accordance with the gene-regulation of antidepressant. The gene profiles of our interest were significantly up- (16 genes, >2.0 of Z-ratio) or down- (24 genes, <-2.0 of Z ratio) regulated when compared the good responsed group with the bad-responsed one. Consequently, we demonstrated that radioactive human cDNA microarray is highly likely to be an efficient technology for evaluating the gene regulation of antidepressants, such as selective serotonin-reuptake inhibitors (SSRIs), by using high-throughput biotechnology.

  13. Rational design of anticoagulant drugs using oligosaccharide chemistry.

    Science.gov (United States)

    El Hadri, Ahmed; Petitou, Maurice

    2011-01-01

    For a long time, heparin and low molecular weight heparins have been the drugs of choice for the management of thrombosis. Discovery of the antithrombin binding domain in heparin, a critical element in the anticoagulant activity of this polysaccharide, allowed a rational approach based on medicinal carbohydrate chemistry in the design of new anticoagulants. The fully synthetic pentasaccharide fondaparinux that selectively targets blood coagulation factor Xa was first to be developed as a drug. Fondaparinux was followed by various heparin mimicking oligosaccharides prepared with a view to replace polydisperse heparin and low molecular weight heparins by structurally-defined anticoagulants with no unwanted side-effects. PMID:21469438

  14. ANTI-DEPRESSANT POTENTIAL OF GHIYA

    Directory of Open Access Journals (Sweden)

    Kaur Satbir

    2012-04-01

    Full Text Available Lagenaria siceraria (Cucurbitaceae, popularly known as bottle gourd, lauki or ghiya, is a climbing plant, which bears hard-shelled and bottle-shaped gourds as fruits. Ghiya forms an excellent diet for people having digestive problems being rich in vitamins, iron and minerals. Since, it contains low calories, bottle gourd is an awesome foodstuff for shedding extra calories. The fruit possesses diuretic, emetic, and refrigerant properties. The ghiya (lauki juice is helpful in constipation, premature graying hair, urinary disorders and insomnia. However, there are no reports in literature pertaining to CNS actions of Lagenaria siceraria fruit. In the light of above, the present study was undertaken to test the anti-depressant potential of Lagenaria siceraria juice (LSJ. Lagenaria siceraria juice was administered at various concentrations ranging from 4%-16% v/v orally to Swiss mice (30g, once daily for 15 successive days. The anti-depressant activity was measured using Forced Swim Test (FST and Tail Suspension Test (TST. The efficacy of Lagenaria siceraria was compared to standard anti-depressant drugs viz: fluoxetine (20mg/kg, p.o, imipramine (15mg/kg, p.o and phenelzine (20 mg/kg, p.o. Lagenaria siceraria significantly reduced the immobility time of mice in both FST and TST. Prazosin, Baclofen, Sulpiride and p-CPA significantly antagonized this reduction in immobility duration. Furthermore, Lagenaria siceraria juice inhibited the monoamine oxidase (MAO enzyme and reduced significantly malondialdehyde (MDA levels. These findings reveal the anti-depressant potential of ghiya.

  15. Virtual Screening and Structure Generation Applied to Drug Design

    Institute of Scientific and Technical Information of China (English)

    FAN B.T.; CHEN H. F.; XIE L.; YUAN S. G.; A. PANAYE; J-P. DOUCET

    2004-01-01

    The methods of computer-aided drug design can be divided into two categories according to whether or not the structures of receptors are known1, corresponding to two principal strategies:(1) searching the bio-active ligands against virtual combinatorial libraries and calculating the affinity energy between ligand and receptor by docking ; (2) QSAR and 3D-structure data-mining.3D-QSAR method is now applied widely to drug discovery, but this method is generally limited to refine the structures of known bio-active compounds. During the process of drug design, we have usually the prejudice that certain groups or structural fragments will play or not important roles on the activity. This will sometimes be misleading, and prevent us from obtaining expected results.The method of generating firstly diverse structures, then screening out the promising structures by means of a computational method or QSAR model, is an efficient way for drug discovery. We developed an efficient virtual and rational drag design method. It combines virtual bioactive compound generation using genetic algorithms with 3D-QSAR model and docking. Using this method can generate a lot of highly diverse molecules and find virtual active lead compounds. The method was validated by the study on a set of anti-tumor drugs, colchicine analogs2. With the constraints of pharmacophore obtained determined by DISCO, 97 virtual bioactive compounds were generated,and their anti-tumor activities were predicted by CoMFA. 8 structures with high activity were selected and screened by 3D-QSAR model. The most active generated structure was further investigated by modifying its structure in order to increase the activity (see fig.1). This drug design method could also avoid the conflict between the insufficiency of active structures and the great quantity of compounds needed for high-throughput screening. This method has been also applied to anti-HIV drug design.We have developed equally another approach of virtual

  16. The mechanism and research progress of antidepressant drugs%抗抑郁药物的作用机理与研究进展

    Institute of Scientific and Technical Information of China (English)

    潘晶

    2016-01-01

    随着生活节奏的加快,在现在的生活状态下,抑郁症患者的数量呈明显的上升趋势。面对抑郁症病情,在我国还是以药物为主。经过查阅国内外相关资料,整合其中关于抑郁症药物作用机理的相关内容,在此就抑郁症药物的作用机理与研究进展做简要说明。%Along with the accelerating rhythm of life, the number of patients with depression is obviously rising trend. In the face of depression, in our country is mostly about drugs. This article through access to domestic and foreign relevant data, including the relevant contents about depression drug action mechanism, mechanism and research progress of depression drugs were reviewed.

  17. Molecular docking and structure-based drug design strategies.

    Science.gov (United States)

    Ferreira, Leonardo G; Dos Santos, Ricardo N; Oliva, Glaucius; Andricopulo, Adriano D

    2015-07-22

    Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods.

  18. Antidepressant Treatment for Acute Bipolar Depression: An Update

    Directory of Open Access Journals (Sweden)

    Ben H. Amit

    2012-01-01

    Full Text Available While studies in the past have focused more on treatment of the manic phase of bipolar disorder (BD, recent findings demonstrate the depressive phase to be at least as debilitating. However, in contrast to unipolar depression, depression in bipolar patients exhibits a varying response to antidepressants, raising questions regarding their efficacy and tolerability. Methods. We conducted a MEDLINE and Cochrane Collaboration Library search for papers published between 2005 and 2011 on the subject of antidepressant treatment of bipolar depression. Sixty-eight articles were included in the present review. Results. While a few studies did advocate the use of antidepressants, most well-controlled studies failed to show a robust effect of antidepressants in bipolar depression, regardless of antidepressant class or bipolar subtype. There was no significant increase in the rate of manic/hypomanic switch, especially with concurrent use of mood stabilizers. Prescribing guidelines published in recent years rely more on atypical antipsychotics, especially quetiapine, as a first-line therapy. Conclusions. Antidepressants probably have no substantial role in acute bipolar depression. However, in light of conflicting results between studies, more well-designed trials are warranted.

  19. Antidepressants and inflammatory bowel disease: a systematic review

    Directory of Open Access Journals (Sweden)

    Andrews Jane M

    2006-09-01

    Full Text Available Abstract Background A number of studies have suggested a link between the patient's psyche and the course of inflammatory bowel disease (IBD. Although pharmacotherapy with antidepressants has not been widely explored, some investigators have proposed that treating psychological co-morbidities with antidepressants may help to control disease activity. To date a systematic analysis of the available studies assessing the efficacy of antidepressants for the control of somatic symptoms in IBD patients has not been performed. Methods We searched electronic databases, without any language restriction. All relevant papers issued after 1990 were examined. Results 12 relevant publications were identified. All of them referred to non-randomised studies. Antidepressants reported in these publications included paroxetine, bupropion, amitriptyline, phenelzine, and mirtazapine. In 10 articles, paroxetine, bupropion, and phenelzine were suggested to be effective for treating both psychological and somatic symptoms in patients suffering from IBD. Amitriptyline was found ineffective for treating somatic symptoms of IBD. Mirtazapine was not recommended for IBD patients. Conclusion Although most of reviewed papers suggest a beneficial effect of treatment with antidepressants in patients with IBD, due to the lack of reliable data, it is impossible to judge the efficacy of antidepressants in IBD. Properly designed trials are justified and needed based upon the available uncontrolled data.

  20. Evaluation on efficacy of long period antidepressant drug therapy in COPD-associated depression%帕罗西汀对COPD合并焦虑抑郁患者的长程治疗

    Institute of Scientific and Technical Information of China (English)

    文红; 徐立; 欧雪珍; 张平; 邓念强

    2012-01-01

    [Objective]To evaluate the efficacy of antidepressant drug therapy in COPD-associated depression.[Methods]Outpatients were evaluated with moderate to severe,stable COPD completed Hospital Anxiety and Depression (HAD).Those with psychiatrist interviewed with high score s [HADS scale(anxiety or depression score) > 10]were brought into study.Depressed or anxious COPD patients took a selective serotonin reuptake inhibitor,paroxetine 20 mg daily.All patients took paroxetine for 16 weeks.After 2,8,12 and 16 weeks,the HADS was repeated.[Results]Among the 41outpatients who entered the study,29 patients completed the study.Anxiety (only HADS anxiety score of > 10) was indicated in 9 patienta and depression (only HADS depression score of > 10) in 5,anxiety and depression (HADS anxiety+depression score all > 10) in 15.12 weeks' treatment produced significant improvement in either anxiety or depression(P< 0.05).However,there were no significant differences in HADS scales at 12 weeks and 16 weeks(P> 0.05).[Conclusion]We conclude that at least 12 weeks of antidepressant drug therapy can produce significant improvement in either anxiety or depression in patients with COPD-associated depression.Longer period treatment could not acquire better curative effect.%[目的]探索长程抗焦虑抑郁药物治疗对稳定期慢性阻塞性肺疾病合并焦虑抑郁患者的治疗效果.[方法]采用医院焦虑和抑郁量表(Hospital Anxiety and Depression Scale,HADS)对门]诊COPD患者进行 焦虑抑郁评分,分值大干10分并经过心理专科医生明确诊断者纳入研究,口服帕罗西汀Paroxetine(赛乐特),每天20 mg,于治疗后2周、8周、12周、16周进行HADS评分,比较治疗前后各项评分变化.[结果]29例合并焦虑抑郁的稳定期COPD患者完成实验,其中单独存在焦虑者9例,单独存在抑郁者5例,焦虑抑郁并存者15例.12周后患者的焦虑抑郁评分显著改善(P<0.05),16周与12周评分差异无显著性(P>0

  1. Prescribing patterns of medicine classified as 'antidepressants' in South African children and adolescents

    Directory of Open Access Journals (Sweden)

    Jan H. P. Serfontein

    2009-04-01

    Full Text Available

    The main objective of this study was to characterise prescribing patterns of medicine classified as 'antidepressants' (hereafter simply referred to as antidepressants in children and adolescents in the private health care sector of South Africa. A retrospective drug utilisation design was used to identify patients aged 19 years and younger from a South African pharmaceutical benefit management company’s database, whom were issued at least one antidepressant between 1 January 2006 and 31 December 2006. Prescribed daily dosages (PDDs were calculated using the Statistical Analysis System® program. A total of 1 013 patients received a mean number of 2.88 (SD 3.04 prescriptions per patient. Females received more prescriptions than their male counterparts, with the highest prevalence in the 15 ≤ 19 years age group. The pharmacological groups most prescribed were the selective serotonin reuptake inhibitors (43.0% and the tricyclics (42.7%, with imipramine (22.04% and amitriptyline (19% as the most commonly prescribed drugs. Approximately 30% (n = 2 300 of all antidepressants in the study population were prescribed off-label. Amitriptyline and clomipramine were prescribed at daily dosages higher than recommended in children and adolescents aged 9 ≤ 15 years. Lithium, trimipramine, trazodone and sulpiride were prescribed at sub-therapeutic dosages in adolescents. This study provided insight in the prescribing patterns of medicine classified as antidepressants in South African children and adolescents. These drugs, however, have many indications. Further research is needed to determine reasons why specific drugs are prescribed in this population.

    Opsomming

    Die algemene doelstelling van hierdie studie was om die voorskrifpatrone van middels wat as 'antidepressante' geklassifiseer word (hierna verwys na as slegs antidepressante wat vir kinders en adolessente in die Suid-Afrikaanse private gesondheidsorgsektor

  2. Drugs, structures, fragments: substructure-based approaches to GPCR drug discovery and design

    OpenAIRE

    Horst, Eelke van der

    2012-01-01

    This thesis is all about cheminformatics, and its impact on drug discovery. A number of strategies are discussed that apply computational methods for the analysis and design of G protein-coupled receptor (GPCR) ligands. Frequent substructure mining is applied to find the common structural motifs that are discriminative for predefined classes of GPCR ligands. In addtion, this approach is extended to cluster GPCRs to suggest a new classification for this receptor superfamily. Furthermore, subst...

  3. iDrug: a web-accessible and interactive drug discovery and design platform

    OpenAIRE

    Wang, Xia; Chen, Haipeng (Allan); Yang, Feng; Gong, Jiayu; Li, Shiliang; Pei, Jianfeng; Liu, Xiaofeng; Jiang, Hualiang; Lai, Luhua; Li, Honglin

    2014-01-01

    Background The progress in computer-aided drug design (CADD) approaches over the past decades accelerated the early-stage pharmaceutical research. Many powerful standalone tools for CADD have been developed in academia. As programs are developed by various research groups, a consistent user-friendly online graphical working environment, combining computational techniques such as pharmacophore mapping, similarity calculation, scoring, and target identification is needed. Results We presented a...

  4. Neuroimmune endocrine effects of antidepressants

    OpenAIRE

    Antonioli M; Rybka J; Carvalho LA

    2012-01-01

    Marco Antonioli, Joanna Rybka, LA CarvalhoPsychoimmunology Translational Laboratory, Health Science Research Centre, Roehampton University, London, UKAbstract: Antidepressant pharmacotherapy is to date the most often used treatment for depression, but the exact mechanism of action underlying its therapeutic effect is still unclear. Many theories have been put forward to account for depression, as well as antidepressant activity, but none of them is exhaustive. Neuroimmune endocrine impairment...

  5. Nanotechnology-based intelligent drug design for cancer metastasis treatment.

    Science.gov (United States)

    Gao, Yu; Xie, Jingjing; Chen, Haijun; Gu, Songen; Zhao, Rongli; Shao, Jingwei; Jia, Lee

    2014-01-01

    Traditional chemotherapy used today at clinics is mainly inherited from the thinking and designs made four decades ago when the Cancer War was declared. The potency of those chemotherapy drugs on in-vitro cancer cells is clearly demonstrated at even nanomolar levels. However, due to their non-specific effects in the body on normal tissues, these drugs cause toxicity, deteriorate patient's life quality, weaken the host immunosurveillance system, and result in an irreversible damage to human's own recovery power. Owing to their unique physical and biological properties, nanotechnology-based chemotherapies seem to have an ability to specifically and safely reach tumor foci with enhanced efficacy and low toxicity. Herein, we comprehensively examine the current nanotechnology-based pharmaceutical platforms and strategies for intelligent design of new nanomedicines based on targeted drug delivery system (TDDS) for cancer metastasis treatment, analyze the pros and cons of nanomedicines versus traditional chemotherapy, and evaluate the importance that nanomaterials can bring in to significantly improve cancer metastasis treatment.

  6. Tricyclic antidepressant overdose: an unusual method of administration

    OpenAIRE

    Barton, Marc; Harris, Dan

    2010-01-01

    Drug poisoning as a result of tricyclic antidepressant overdose is frequently encountered in emergency departments and is a significant cause of mortality and morbidity. The usual route of administration is oral. Here we report the case of a 42-year-old man with a history of depression who had taken a large overdose of amitriptyline by the rectal route. This case highlights the management difficulties that arose as a result of rectal administration of the drug and possible ways in which treat...

  7. Antidepressants versus placebo in major depression: an overview

    OpenAIRE

    KHAN, Arif; Walter A Brown

    2015-01-01

    Although the early antidepressant trials which included severely ill and hospitalized patients showed substantial drug-placebo differences, these robust differences have not held up in the trials of the past couple of decades, whether sponsored by pharmaceutical companies or non-profit agencies. This narrowing of the drug-placebo difference has been attributed to a number of changes in the conduct of clinical trials. First, the advent of DSM-III and the broadening of the definition of major d...

  8. 75 FR 21368 - Designation of Five Counties as High Intensity Drug Trafficking Areas

    Science.gov (United States)

    2010-04-23

    ... PRESIDENT Office of National Drug Control Policy Designation of Five Counties as High Intensity Drug Trafficking Areas ACTION: Notice. SUMMARY: The Director of the Office of National Drug Control Policy designated five additional counties as High Drug Trafficking Areas pursuant to 21 U.S.C. 1706. The...

  9. Antidepressants self-poisoning and ICU admissions in a University Hospital in the Netherlands

    NARCIS (Netherlands)

    Bosch, Tessa M.; van der Werf, Tjip S.; Uges, Donald R.A.; Ligtenberg, Jack .M.J; Fijen, Jan-Willem; Tulleken, Jaap E.; Zijlstra, Jan G.

    2000-01-01

    Objectives: Many overdosed patients are admitted to an ICU. Antidepressants are frequently used. We examined clinical end-points of toxicity recorded during admission to our ICU of all antidepressants used in overdose. Design: Single centre; retrospective analysis, 5 consecutive years (1994 - 1998).

  10. The quetiapine active metabolite N-desalkylquetiapine and the neurotensin NTS₁ receptor agonist PD149163 exhibit antidepressant-like effects on operant responding in male rats.

    Science.gov (United States)

    Hillhouse, Todd M; Shankland, Zachary; Matazel, Katelin S; Keiser, Ashley A; Prus, Adam J

    2014-12-01

    Major depressive disorder is the most common mood disorder in the United States and European Union; however, the limitations of clinically available antidepressant drugs have led researchers to pursue novel pharmacological treatments. Clinical studies have reported that monotherapy with the atypical antipsychotic drug quetiapine produces a rapid reduction in depressive symptoms that is apparent after 1 week of treatment, and it is possible that the active metabolite N-desalkylquetiapine, which structurally resembles an antidepressant drug, produces antidepressant effects. Neuropharmacological evaluations of the neurotensin NTS1 receptor agonist PD149163 suggest antidepressant efficacy, but the effects of a NTS₁ receptor agonist in an antidepressant animal model have yet to be reported. The present study examined the antidepressant-like effects of N-desalkylquetiapine, PD14916, quetiapine, the tricyclic antidepressant drug imipramine, the atypical antipsychotic drug risperidone, and the typical antipsychotic drug raclopride on responding in male Sprague-Dawley rats trained on a differential-reinforcement-of-low-rate 72-s operant schedule, a procedure used for screening antidepressant drugs. Quetiapine, PD149163, risperidone, and imipramine exhibited antidepressant-like effects by increasing the number of reinforcers earned, decreasing the number of responses emitted, and shifting the interresponse time (IRT) distributions to the right. N-Desalkylquetiapine produced a partial antidepressant-like effect by decreasing the number of responses emitted and producing a rightward shift in the IRT distributions, but it did not significantly alter the number of reinforcers earned. Raclopride decreased reinforcers and responses. These data suggest that N-desalkylquetiapine likely contributes to quetiapine's antidepressant efficacy and identify NTS₁ receptor activation as a potential novel pharmacologic strategy for antidepressant drugs.

  11. Evaluations of antidepressant activity of Anacyclus pyrethrum root extract

    Directory of Open Access Journals (Sweden)

    Badhe S

    2010-01-01

    Full Text Available The present study was designed to screen antidepressant activity of Anacyclus pyrethrum (AP root extract. An experiment was designed by different method such as Locomotor activity, Haloperidol-induced catalepsy, Forced swim test (FST, Tail suspension test (TST, Clonidine-induced hypothermia and Reserpine-induced hypothermia on Swiss male albino mice. Standard root extract of Anacyclus pyrethrum (AP root extract showed an increase in ambulatory behaviour indicating a stimulant effect of the photoactometer. AP root extract produces a significant antidepressant effect in both FST and TST as they reduced the immobility. AP root extract was found to be effective in reversing hypothermia produced by clonidine and reserpine. In our study, we found that AP root extract inhibited haloperidol-induced catalepsy. These study suggest that AP root extract might produce antidepressant effect by interaction with adrenergic and dopamine receptor thereby increasing the level of noradrenaline and dopamine in brains of mice.

  12. The antidepressant tianeptine persistently modulates glutamate receptor currents of the hippocampal CA3 commissural associational synapse in chronically stressed rats

    NARCIS (Netherlands)

    Kole, MHP; Swan, L; Fuchs, E

    2002-01-01

    Recent hypotheses on the action of antidepressants imply a modulation of excitatory amino acid transmission. Here, the effects of long-term antidepressant application in rats with the drug tianeptine were examined at hippocampal CA3 commissural associational (c/a) glutamate receptor ion channels, em

  13. Pharmacogenetics of antidepressants

    Directory of Open Access Journals (Sweden)

    Concetta eCrisafulli

    2011-02-01

    Full Text Available Up to 60% of depressed patients do not respond completely to antidepressants (AD and up to 30% do not respond at all. Genetic factors contribute for about 50% of the AD response. During the recent years the possible influence of a set of candidate genes as genetic predictors of AD response efficacy was investigated by us and others. They include the cytochrome P450 (CYP superfamily, the P-glycoprotein (ABCB1, the tryptophan hydroxylase (TPH, the catechol-O-methyltransferase (COMT, the monoamine oxidase A (MAOA, the serotonin transporter (5-HTTLPR, the norepinephrine transporter (NET, the dopamine transporter (DAT, variants in the 5HT1A, 2A , 3A, 3B and 6 receptors, adrenoreceptor beta-1 (ADRB1 and alpha-2 (ADRA2A, the dopamine receptors (D2, the G-protein beta3-subunit (GNB3, the corticotropin releasing hormone (CRH receptors (CRHR1 and CRHR2, the glucocorticoid receptors (GR, the c-AMP response-element binding (CREB and the brain-derived neurotrophic factor (BDNF. Marginal associations were reported for angiotensin I converting enzyme (ACE, circadian locomoter output cycles kaput protein (CLOCK, glutamatergic system, nitric oxide synthase (NOS and interleukin 1-beta (IL-1beta gene. In conclusion, gene variants seem to influence human behavior, liability to disorders and treatment response. Nonetheless, gene x enviroment interactions have been hypothesized to modulate several of these effects.

  14. Design attributes of long-circulating polymeric drug delivery vehicles.

    Science.gov (United States)

    Beck-Broichsitter, Moritz; Nicolas, Julien; Couvreur, Patrick

    2015-11-01

    Following systemic administration polymeric drug delivery vehicles allow for a controlled and targeted release of the encapsulated medication at the desired site of action. For an elevated and organ specific accumulation of their cargo, nanocarriers need to avoid opsonization, activation of the complement system and uptake by macrophages of the mononuclear phagocyte system. In this respect, camouflaged vehicles revealed a delayed elimination from systemic circulation and an improved target organ deposition. For instance, a steric shielding of the carrier surface by poly(ethylene glycol) substantially decreased interactions with the biological environment. However, recent studies disclosed possible deficits of this approach, where most notably, poly(ethylene glycol)-modified drug delivery vehicles caused significant immune responses. At present, identification of novel potential carrier coating strategies facilitating negligible immune reactions is an emerging field of interest in drug delivery research. Moreover, physical carrier properties including geometry and elasticity seem to be very promising design attributes to surpass numerous biological barriers, in order to improve the efficacy of the delivered medication.

  15. Molecular Docking and Structure-Based Drug Design Strategies

    Directory of Open Access Journals (Sweden)

    Leonardo G. Ferreira

    2015-07-01

    Full Text Available Pharmaceutical research has successfully incorporated a wealth of molecular modeling methods, within a variety of drug discovery programs, to study complex biological and chemical systems. The integration of computational and experimental strategies has been of great value in the identification and development of novel promising compounds. Broadly used in modern drug design, molecular docking methods explore the ligand conformations adopted within the binding sites of macromolecular targets. This approach also estimates the ligand-receptor binding free energy by evaluating critical phenomena involved in the intermolecular recognition process. Today, as a variety of docking algorithms are available, an understanding of the advantages and limitations of each method is of fundamental importance in the development of effective strategies and the generation of relevant results. The purpose of this review is to examine current molecular docking strategies used in drug discovery and medicinal chemistry, exploring the advances in the field and the role played by the integration of structure- and ligand-based methods.

  16. Multistep Reaction Based De Novo Drug Design: Generating Synthetically Feasible Design Ideas.

    Science.gov (United States)

    Masek, Brian B; Baker, David S; Dorfman, Roman J; DuBrucq, Karen; Francis, Victoria C; Nagy, Stephan; Richey, Bree L; Soltanshahi, Farhad

    2016-04-25

    We describe a "multistep reaction driven" evolutionary algorithm approach to de novo molecular design. Structures generated by the approach include a proposed synthesis path intended to aid the chemist in assessing the synthetic feasibility of the ideas that are generated. The methodology is independent of how the design ideas are scored, allowing multicriteria drug design to address multiple issues including activity at one or more pharmacological targets, selectivity, physical and ADME properties, and off target liabilities; the methods are compatible with common computer-aided drug discovery "scoring" methodologies such as 2D- and 3D-ligand similarity, docking, desirability functions based on physiochemical properties, and/or predictions from 2D/3D QSAR or machine learning models and combinations thereof to be used to guide design. We have performed experiments to assess the extent to which known drug space can be covered by our approach. Using a library of 88 generic reactions and a database of ∼20 000 reactants, we find that our methods can identify "close" analogs for ∼50% of the known small molecule drugs with molecular weight less than 300. To assess the quality of the in silico generated synthetic pathways, synthesis chemists were asked to rate the viability of synthesis pathways: both "real" and in silico generated. In silico reaction schemes generated by our methods were rated as very plausible with scores similar to known literature synthesis schemes. PMID:27031173

  17. Efficacy and safety of antidepressant's use in the treatment of depressive episodes in bipolar disorder - review of research.

    Science.gov (United States)

    Antosik-Wójcińska, Anna Zofia; Stefanowski, Bogdan; Święcicki, Łukasz

    2015-01-01

    The use of antidepressants in treatment of depression in course of bipolar disorders (BD) is controversial. In case of no improvement during monotherapy with mood stabilizer, the use of antidepressants is often necessary. The safety of this group (in context of phase change, mixed states and rapid cycling) is essential and is the subject of many research. In the paper, the authors review the literature concerning efficacy and safety of use of antidepressants in the treatment of affective disorders and long-term impact on the course of the disease. Selection of articles have been made by searching the Medline and Pubmed databases using keywords: antidepressant drugs, bipolar depression, bipolar disorder, efficacy, safety, mania, hypomania. The risk of mania is greater in bipolar disorder type I, than in type II or during treatment with Tricyclic antidepressants (TCAs) and treatment with venlafaxine. The use of SSRIs and bupropion is associated with a relatively small increase of phase change risk. There are different opinions concerning recommended duration of antidepressant treatment. Generally antidepressant use should end after 2-3 months of remission, the risk of recurrence of depression after discontinuation of antidepressants is, however, higher than in case of continuation. In BD type II or BD spectrum, antidepressant monotherapy is allowed in severe depression. In bipolar disorder type I and in case of phase change after antidepressants use in the past, use of antidepressants should be very cautious. Antidepressants are contraindicated in rapid cycling and in mixed episodes. Further work is needed to evaluate the efficacy and safety of antidepressants use. PMID:26909398

  18. Neuroimmune endocrine effects of antidepressants

    Directory of Open Access Journals (Sweden)

    Antonioli M

    2012-02-01

    Full Text Available Marco Antonioli, Joanna Rybka, LA CarvalhoPsychoimmunology Translational Laboratory, Health Science Research Centre, Roehampton University, London, UKAbstract: Antidepressant pharmacotherapy is to date the most often used treatment for depression, but the exact mechanism of action underlying its therapeutic effect is still unclear. Many theories have been put forward to account for depression, as well as antidepressant activity, but none of them is exhaustive. Neuroimmune endocrine impairment is found in depressed patients; high levels of circulating corticosteroids along with hyperactivation of the immune system, high levels of proinflammatory cytokines, low levels of melatonin in plasma and urine, and disentrainment of circadian rhythms have been demonstrated. Moreover, antidepressant treatment seems to correct or at least to interfere with these alterations. In this review, we summarize the complex neuroimmune endocrine and chronobiological alterations found in patients with depression and how these systems interact with each other. We also explain how antidepressant therapy can modify these systems, along with some possible mechanisms of action shown in animal and human models.Keywords: antidepressant agents, biological markers, human, cytokines, neuroinflammation, psychoneuroimmunology, endophenotype

  19. Olanzapine and fluoxetine combination therapy for treatment-resistant depression: review of efficacy, safety, and study design issues

    Directory of Open Access Journals (Sweden)

    William V Bobo

    2009-07-01

    Full Text Available William V Bobo, Richard C SheltonDepartment of Psychiatry, Vanderbilt University School of Medicine, Nashville, TN, USAAbstract: Treatment-resistant depression (TRD is a common occurrence in clinical practice. Up to 30% of patients with major depression do not respond to conventional antidepressant treatment, while a significantly greater number of patients experience only partial symptom reduction. Numerous strategies may be applied by the practicing clinician to overcome limitations in the effectiveness of antidepressant monotherapy, including combining drug treatment with evidence-supported psychotherapies, combining antidepressants (combination pharmacotherapy, and combining antidepressants with other non-antidepressant psychotropic medications (augmentation treatment. One such augmentation strategy, the combination of the selective serotonin reuptake inhibitor, fluoxetine (FLX, with the atypical antipsychotic drug, olanzapine (OLZ, is supported by the results of four randomized, double-blind, acute phase studies of patients who had responded inadequately to antidepressant monotherapy. In each study, the FLX/OLZ combination caused rapid reduction in Montgomery-Asberg Depression Rating scale scores, with two of the four studies showing significantly greater improvement than antidepressant monotherapy at study endpoint. Effects of the FLX/OLZ combination were strongest in cases where failure to respond to two antidepressants prior to randomization was established during the current depressive episode. The FLX/OLZ combination was well-tolerated; however, body weight gain and increases in prolactin were greater than that of the antidepressant monotherapy groups, and were comparable to that of OLZ monotherapy. While effective during acute-phase treatment, questions remain regarding the long-term efficacy and safety of FLX/OLZ relative to antidepressant monotherapy and other combination strategies. Efforts aimed at determining the placement of

  20. Biomembrane models and drug-biomembrane interaction studies: Involvement in drug design and development

    Directory of Open Access Journals (Sweden)

    R Pignatello

    2011-01-01

    Full Text Available Contact with many different biological membranes goes along the destiny of a drug after its systemic administration. From the circulating macrophage cells to the vessel endothelium, to more complex absorption barriers, the interaction of a biomolecule with these membranes largely affects its rate and time of biodistribution in the body and at the target sites. Therefore, investigating the phenomena occurring on the cell membranes, as well as their different interaction with drugs in the physiological or pathological conditions, is important to exploit the molecular basis of many diseases and to identify new potential therapeutic strategies. Of course, the complexity of the structure and functions of biological and cell membranes, has pushed researchers toward the proposition and validation of simpler two- and three-dimensional membrane models, whose utility and drawbacks will be discussed. This review also describes the analytical methods used to look at the interactions among bioactive compounds with biological membrane models, with a particular accent on the calorimetric techniques. These studies can be considered as a powerful tool for medicinal chemistry and pharmaceutical technology, in the steps of designing new drugs and optimizing the activity and safety profile of compounds already used in the therapy.

  1. Application of Absorption Modeling in Rational Design of Drug Product Under Quality-by-Design Paradigm.

    Science.gov (United States)

    Kesisoglou, Filippos; Mitra, Amitava

    2015-09-01

    Physiologically based absorption models can be an important tool in understanding product performance and hence implementation of Quality by Design (QbD) in drug product development. In this report, we show several case studies to demonstrate the potential application of absorption modeling in rational design of drug product under the QbD paradigm. The examples include application of absorption modeling—(1) prior to first-in-human studies to guide development of a formulation with minimal sensitivity to higher gastric pH and hence reduced interaction when co-administered with PPIs and/or H2RAs, (2) design of a controlled release formulation with optimal release rate to meet trough plasma concentrations and enable QD dosing, (3) understanding the impact of API particle size distribution on tablet bioavailability and guide formulation design in late-stage development, (4) assess impact of API phase change on product performance to guide specification setting, and (5) investigate the effect of dissolution rate changes on formulation bioperformance and enable appropriate specification setting. These case studies are meant to highlight the utility of physiologically based absorption modeling in gaining a thorough understanding of the product performance and the critical factors impacting performance to drive design of a robust drug product that would deliver the optimal benefit to the patients.

  2. Signaling pathways regulating Homer1a expression: implications for antidepressant therapy.

    Science.gov (United States)

    Serchov, Tsvetan; Heumann, Rolf; van Calker, Dietrich; Biber, Knut

    2016-03-01

    Homer1a is upregulated by several different antidepressant measures, including non-pharmacological treatments, like sleep deprivation (SD) and electroconvulsive therapy (ECT) and antidepressant drugs, such as imipramine, fluoxetine and ketamine. Homer1a induction might thus be a crucial joint mechanism for antidepressant therapy in general. However, the upstream signaling pathways that regulate or induce Homer1a expression are still not well understood. The main focus of the present review is to offer an overview of the current knowledge about the potential role of Homer1a in depression and the signaling pathways responsible for Homer1a regulation. It is suggested here that a detailed characterization of the signaling mechanisms leading to Homer1a expression might provide novel therapeutic targets for antidepressant drug development. PMID:26641965

  3. Antidepressant-Resistant Depression and Antidepressant-Associated Suicidal Behaviour: The Role of Underlying Bipolarity

    Directory of Open Access Journals (Sweden)

    Zoltan Rihmer

    2011-01-01

    Full Text Available The complex relationship between the use of antidepressants and suicidal behaviour is one of the hottest topics of our contemporary psychiatry. Based on the literature, this paper summarizes the author's view on antidepressant-resistant depression and antidepressant-associated suicidal behaviour. Antidepressant-resistance, antidepressant-induced worsening of depression, antidepressant-associated (hypomanic switches, mixed depressive episode, and antidepressant-associated suicidality among depressed patients are relatively most frequent in bipolar/bipolar spectrum depression and in children and adolescents. As early age at onset of major depressive episode and mixed depression are powerful clinical markers of bipolarity and the manic component of bipolar disorder (and possible its biological background shows a declining tendency with age antidepressant-resistance/worsening, antidepressant-induced (hypomanic switches and “suicide-inducing” potential of antidepressants seem to be related to the underlying bipolarity.

  4. RAS GTPase AS THE DRUG TARGET FOR ANTI-CANCER DESIGNING OF DRUG FROM TEMPLATE

    Directory of Open Access Journals (Sweden)

    A.S. Krishnapriya and P.K. Krishnan Namboori*

    2013-11-01

    Full Text Available Ras proteins in association with GTP and GDP act as a bio-molecular switch for signaling cell growth, cell survival and signal transduction. The presence of mutated Ras proteins is found to vary in different cancer types and the highest occurrence of about 90% is observed in pancreatic cancer. The Ras GTPase binding site is mainly involved in signal cell proliferation. Hence, this binding site has been considered as a major target. At the same time, targeting a specific protein and designing the drug molecule with respect to that is practically of no use as the target proteins are fast mutating. In this scenario, designing the template from the hot spot of proteins and fitting the template for all the target protein molecules seem to be a promising technique. The templates are initially screened on the basis of pharmacokinetic and pharmacodynamic requirements. Six templates are found to be satisfying conditions like IC50, lipophilic efficiency, ligand efficiency etc. and their efficiencies are compared with standard reference molecules. The computed enrichment factors support these templates to be leads for effective anti-cancer drugs subject to further in vitro and in vivo evaluation.

  5. Antidepressant therapy with milnacipran and venlafaxine

    Directory of Open Access Journals (Sweden)

    Lucilla Mansuy

    2010-08-01

    Full Text Available Lucilla MansuyPierre Fabre Médicament, Toulouse, FranceAbstract: Specific serotonin norepinephrine reuptake inhibitors (SNRIs have been described as “better tolerated tricyclic antidepressants” or as “boosted” selective serotonin reuptake inhibitors (SSRIs. Venlafaxine has become a therapeutic reference treatment for major depression. Although less widely studied, indirect comparisons with another SNRI, milnacipran, suggest an equivalent efficacy. This paper discusses these indirect comparisons and the recently published first double-blind, head-to-head comparison. Venlafaxine has potency at serotonin transporters which is about 30-fold greater than that at norepinephrine transporters while milnacipran has a similar potency at each transporter. Thus, at low doses, venlafaxine acts essentially as a SSRI, with significant noradrenergic activity only occurring at higher doses. To overcome the problem of the differing profile of venlafaxine at increasing doses, the first head-to-head study compared the therapeutic effects and tolerability of the two antidepressants when flexibly titrated to the high dose of 200 mg/day. The study showed that the two SNRIs have similar efficacy and safety profiles. Both drugs produced about 42% remissions at the end of the 20-week study. The most frequent adverse events in both groups were nausea, dizziness, headache, and sweating. Certain specific differences in tolerability are discussed.Keywords: milnacipran, venlafaxine, antidepressant efficacy, tolerability, dose-titration

  6. [Prospective evaluation of antidepressant discontinuation].

    Science.gov (United States)

    Mourad, I; Lejoyeux, M; Adès, J

    1998-01-01

    The authors prospectively assessed symptoms induced by the interruption of antidepressants in 16 patients (11 women and 5 men), aged from 33 to 85 years (mean = 52.4 +/- 16.4), treated with antidepressants since at least two weeks. All patients were free of alcohol abuse or dependence disorder and of other dependence to psychoactive substances. None of them presented medical illness. Diagnosis were made by separate evaluations by two authors and confirmed with a semistructered assessment instrument: the Schedule for Affective Disorders and Schizophrenia (Lifetime Version). All patients were submitted to a brutal discontinuation of their antidepressant agent. Patients were assessed twice, before the interruption of the antidepressant, and 72 hours later. Effects of antidepressant interruption were assessed by several means. Modification of anxiety and depression were evaluated using the Montgomery Asberg Depression Rating Scale (MADRS) and the Hamilton Anxiety Scale. Symptoms of withdrawal were assessed with Cassano and al.'s scale SESSH including an evaluation of anxiety, agitation, irritability, anergy, difficulty on concentrating, depersonalization, sleep and appetite disorders, muscle pains, nausea, tremor, sweating, altered taste, hyperosmia, paresthesias, photophobia, motor incoordination, dizziness, hyperacousia pain, delirium. Fourteen of the 16 patients (87.5%) presented modifications of their somatic or psychic state 3 days after the interruption of the antidepressant treatment. Most frequent symptoms were: increase in anxiety (31%), increase in irritability (25%), sleep disorders (19%), decrease of anergia and fatigue (19%). Mean scores of anxiety and depression were not significantly modified by the withdrawal. Following TCAs interruption (7 patients) most frequent symptoms were sleep disorders; increase in anxiety, nausea. Among patients withdrawn from SSRIs (6 patients), most frequent symptoms were increase in anxiety, increase in irritability

  7. 77 FR 74195 - Draft Guidance for Industry and Food and Drug Administration Staff; Design Considerations for...

    Science.gov (United States)

    2012-12-13

    ... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry and Food and Drug Administration Staff; Design Considerations for Devices Intended for Home Use; Availability AGENCY: Food and Drug Administration, HHS. ACTION: Notice. SUMMARY: The Food and Drug Administration (FDA) is announcing...

  8. Antidepressant therapy in epilepsy: can treating the comorbidities affect the underlying disorder?

    OpenAIRE

    Cardamone, L.; Salzberg, MR; O'Brien, TJ; Jones, NC

    2013-01-01

    There is a high incidence of psychiatric comorbidity in people with epilepsy (PWE), particularly depression. The manifold adverse consequences of comorbid depression have been more clearly mapped in recent years. Accordingly, considerable efforts have been made to improve detection and diagnosis, with the result that many PWE are treated with antidepressant drugs, medications with the potential to influence both epilepsy and depression. Exposure to older generations of antidepressants (notabl...

  9. Sensitivity during the forced swim test is a key factor in evaluating the antidepressant effects of abscisic acid in mice.

    Science.gov (United States)

    Qi, Cong-Cong; Shu, Yu-Mian; Chen, Fang-Han; Ding, Yu-Qiang; Zhou, Jiang-Ning

    2016-03-01

    Abscisic acid (ABA), a crucial phytohormone, is distributed in the brains of mammals and has been shown to have antidepressant effects in the chronic unpredictable mild stress test. The forced swim test (FST) is another animal model that can be used to assess antidepressant-like behavior in rodents. Here, we report that the antidepressant effects of ABA are associated with sensitivities to the FST in mice. Based on mean immobility in the 5-min forced swim pre-test, ICR mice were divided into short immobility mice (SIM) and long immobility mice (LIM) substrains. FST was carried out 8 days after drug administration. Learned helplessness, as shown by increased immobility, was only observed in SIM substrain and could be prevented by an 8-day ABA treatment. Our results show that ABA has antidepressant effects in SIM substrain and suggest that mice with learned helplessness might be more suitable for screening potential antidepressant drugs.

  10. DDGrid: a grid computing system for drug discovery and design

    Institute of Scientific and Technical Information of China (English)

    Chen Shudong; Zhang Liang; Ma Fanyuan; Shen Jianhua

    2005-01-01

    This paper presents DDGrid, a novel Grid computing system for drug discovery and design. By utilizing the idle resources donated by the clusters that scatter over the Internet, DDGrid can implement efficient data-intensive biologic applications. The high-level resource management framework with a Grid-P2P hybrid architecture is described. With P2P technologies, some problems which are inevitable in the master-slave model can be avoided, such as single point of failure or performance bottleneck. Then an agent-based resource scheduling algorithm is presented. With this scheduling algorithm, the idle computational resources are dynamically scheduled according to the real-time working load on each execution node. Thus DDGrid can hold an excellent load balance state. Furthermore, the framework is introduced into the practical protein molecules docking applications. Solid experimental results show the load balance and robustness of the proposed system, which can greatly speed up the process of protein molecules docking.

  11. Computational design of nanoparticle drug delivery systems for selective targeting.

    Science.gov (United States)

    Duncan, Gregg A; Bevan, Michael A

    2015-10-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.

  12. Integrated Teaching of Structure-Based Drug Design and Biopharmaceutics: A Computer-Based Approach

    Science.gov (United States)

    Sutch, Brian T.; Romero, Rebecca M.; Neamati, Nouri; Haworth, Ian S.

    2012-01-01

    Rational drug design requires expertise in structural biology, medicinal chemistry, physiology, and related fields. In teaching structure-based drug design, it is important to develop an understanding of the need for early recognition of molecules with "drug-like" properties as a key component. That is, it is not merely sufficient to teach…

  13. Phase advance is an actimetric correlate of antidepressant response to sleep deprivation and light therapy in bipolar depression.

    Science.gov (United States)

    Benedetti, Francesco; Dallaspezia, Sara; Fulgosi, Mara Cigala; Barbini, Barbara; Colombo, Cristina; Smeraldi, Enrico

    2007-01-01

    The combination of total sleep deprivation (TSD) and light therapy (LT) in bipolar depression causes rapid antidepressant effects, and its mechanism of action has been hypothesized to involve the enhancement of all of the monoaminergic systems targeted by antidepressant drugs (serotonin, dopamine, norepinephrine). It is still unknown if the clinical effects are paralleled by changes in biological rhythms. In a before/after design of a study of biological correlates of response, 39 inpatients affected by Type I Bipolar Disorder whose current depressive episode was without psychotic features were treated for one week with repeated TSD combined with morning LT. Wrist actigraphy was recorded throughout the study. Two-thirds of the patients responded to treatment (50% reduction in Hamilton Depression score). Responders showed an increase in daytime activity, phase-advance of the activity-rest rhythm of 57 min compared to the pre-treatment baseline, and reduced nighttime sleep. Non-responders did not show significant changes in the parameters of their activity-rest rhythm. Phase advance of the activity-rest rhythm is an actimetric correlate of the antidepressant response to TSD and LT in bipolar depression. Results are consistent with the known effects of sleep-wake manipulations and neurotransmitter function on the suprachiasmatic nucleus.

  14. [Unpredictable chronic mild stress effects on antidepressants activities in forced swim test].

    Science.gov (United States)

    Kudryashov, N V; Kalinina, T S; Voronina, T A

    2015-02-01

    The experiments has been designed to study unpredictable chronic mild stress effect on anti-depressive activities of amitriptyline (10 mg/kg) and fluoxetine (20 mg/kg) in forced swim test in male outbred mice. It is shown that acute treatment with fluoxetine does not produce any antidepressant effects in mice following stress of 14 days while the sub-chronic injections of fluoxetine result in more deep depressive-like behavior. In 28 daily stressed mice, antidepressant effect of fluoxetine is observed independently of the injection rates. Amitriptyline demonstrates the antidepressant activity regardless of the duration of stress or administration scheduling, but at the same time the severity of anti-immobilization effect of amitriptyline in stressed mice is weaker in compare to non-stressed trails. Thus, the injection rates and duration of unpredictable mild chronic stress are the parameters that determine the efficiency of antidepressants in the mouse forced swimming test.

  15. Liver Function Test Abnormalities in Depressed Patients Treated with Antidepressants: A Real-World Systematic Observational Study in Psychiatric Settings

    Science.gov (United States)

    Verstuyft, Céline; Corruble, Emmanuelle; Perlemuter, Gabriel; Colle, Romain

    2016-01-01

    Background Concerning the risk of antidepressant induced liver injury, it is not clear whether psychiatrists perform a liver function test (LFT) and whether an increase in aminotransferase levels should contraindicate antidepressant treatment. Aim To evaluate LFT availability, the prevalence of LFT abnormalities and the probable cause of an altered LFT in patients with a major depressive episode (MDE) requiring an antidepressant drug. Methods We studied LFT evaluation in a real world psychiatric setting, in a sample of 321 consecutive patients with a current major depressive episode (MDE) requiring an antidepressant drug treatment, but without current alcohol or drug dependence or unstable medical disease. Results An LFT is performed in 36.1% (116/321) of depressed patients. One fifth of antidepressant-treated patients who had an LFT evaluation had abnormal results. The most frequent causes of LFT abnormalities were: NAFLD (nonalcoholic fatty liver disease) (7/321; 2.1%), acute alcohol consumption (4/321; 1.2%), antidepressant-induced liver injury (3/321; 0.9%), hepatitis C virus infection (2/321; 0.6%) and heart failure (1/321; 0.3%). The cause of LFT abnormalities was unknown in 32% of patients (8/25) due to the absence of etiological investigations. Conclusion These results demonstrate that an LFT is infrequently performed by psychiatrists in depressed patients requiring an antidepressant drug. Baseline LFT assessment and observations during the first six months of antidepressant treatment may be useful for detection of patients with pre-existing liver disease such as NAFLD, and early identification of cases of antidepressant-induced liver injury. An increase in aminotransferase levels may be related to an underlying liver disease, but does not contraindicate antidepressant treatment. PMID:27171561

  16. [What is next in the development of antidepressives?].

    Science.gov (United States)

    Valchár, M

    1991-04-01

    After some findings concerning the mode of action of antidepressants, it was possible to hypothesize the molecular basis of depressive disorders (monoamine hypothesis, receptor hypothesis). These informations made the preparation of drugs acting by a completely new mechanism. Possible an antidepressant effect was observed after the administration of GABA-ergic agonists, or agents influencing dopaminergic transmission, S-adenosylmethionine, and drugs influencing second messenger systems. As a consequence of these findings, the GABA-ergic hypothesis, hypothesis of endogenous ligand (barinine hypothesis is discussed in more detail), and second messenger hypothesis of affective disorders were formulated. Agents influencing second messenger systems and S-adenosylmethionine seem to be a promising field of future investigation. PMID:1913947

  17. Alzheimer's disease drug development based on Computer-Aided Drug Design.

    Science.gov (United States)

    Zeng, Huahui; Wu, Xiangxiang

    2016-10-01

    Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by the excessive deposition of amyloids in the brain. The pathological features mainly include the extracellular amyloid plaques and intracellular neurofibrillary tangles, which are the production of amyloid precursor protein (APP) processed by the α-, β- and γ-secretases. Based on the amyloid cascade hypotheses of AD, a large number of amyloid-β agents and secretase inhibitors against AD have been recently developed by using computational methods. This review article describes pathophysiology of AD and the structure of the Aβ plaques, β- and γ-secretases, and discusses the recent advances in the development of the amyloid agents for AD therapy and diagnosis by using Computer-Aided Drug Design approach. PMID:26415837

  18. 均匀设计法优选酸枣仁抗抑郁有效组分配伍研究%Compatibility of Effective Antidepressant Components of semen Ziziphi spinosae Based on Uniform Design Method

    Institute of Scientific and Technical Information of China (English)

    赵启铎; 舒乐新; 高岚

    2014-01-01

    Objective To optimize the best compatibility of effective antidepressant components (total fat oil, total flavonoids, total saponins) of Semen Ziziphi Spinosae. Methods 90 mice were randomly divided into 9 groups, the control group and administration A -H groups by the uniform design method. The mice forced swimming and the tail suspension test in each group were observed. With the immobility time at latter 4 min within 6 min as the evaluating index, the best compatibility of effective antidepressant components was screened. The pharmaceutical effects of obtained optimal compatibility of the effective components were to be proved by the comparison and verification experiment. Results The immobility time of mice during the forced swimming test in the administration A, B, C, F, H groups were significantly less than those in the control group( P < 0. 05); the immobility time of mice during the tail suspension test in the administration A, B, D, E, F, H groups were significantly less than those in the control group( P < 0. 05, P < 0. 01). After the multivariate statistical analysis, the optimal compatibility of effective antidepressant components of Semen Ziziphi Spinosae was total fat oil 10 mg / kg, to-tal flavonoids 100 mg / kg and total saponins 10 mg / kg. Conclusion The compatibility of effective components determined by the combina-tion of the uniform design, mathematical statistics and pharmacodynamics is feasible, the pharmaceutical effect of optimized active component compatibility reaches or surpasses that of the original medicinal materials.%目的:优选酸枣仁抗抑郁有效组分(总脂肪油、总黄酮、总皂苷)的最佳配伍。方法采用均匀设计法将90只小鼠随机分为9组,分别为对照组及给药 A ~ H 组,观察各组小鼠强迫游泳和悬尾试验情况,以小鼠在6 min 中后4 min 内不动时间为评价指标,筛选酸枣仁抗抑郁有效组分的最佳配伍,对所得有效组分最佳配伍的药效进

  19. Vortioxetine (Brintellix®) and levomilnacipran (Fetzima®): the two newest additions to the antidepressant formulary.

    Science.gov (United States)

    Roman, Marian W; Wilkinson, Shannon M

    2014-12-01

    In the final months of 2013, the US Food and Drug Administration approved two new antidepressant formulations. This column presents a review of the pertinent literature on both: vortioxetine (Brintellix(®)) and levomilnacipran (Fetzima(®)). PMID:25426751

  20. Design and development of gastro retentive drug delivery System of tramadol hydrochloride

    OpenAIRE

    Rathore, Devashish; Dahima, Rashmi

    2011-01-01

    The present investigation concerns the development of floating tablets of tramadol hydrochloride, which after oral administration are designed to prolong the gastric residence time; improves the drug bioavailability, reduces drug waste and diminish the side effects of drug. The D-optimal experimental design was employed to evaluate contribution of hydroxypropyl methyl cellulose (HPMC) K4M concentration, lactose concentration and kollidone SR concentration on drug release from floating tablets...

  1. [Antidepressant active constituents in the roots of Morinda officinalis How].

    Science.gov (United States)

    Cui, C; Yang, M; Yao, Z; Cao, B; Luo, Z; Xu, Y; Chen, Y

    1995-01-01

    Five compounds having antidepressant activities have been isolated from the roots of Morinda officinalis, a Chinese traditional Yang-tonic drug. These compounds were identified as succinic acid (1), nystose (2), 1F-fructofuranosylnystose (3), inulin-type hexasaccharide (4) and heptasaccharide (5) by chemical and spectroscopic methods. All of the compounds are isolated from the species of genus Morinda for the first time. PMID:7626209

  2. Drug: D05374 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available .8263 D05374.gif Antidepressant ATC code: N06AB05 Selective serotonin reuptake inhibitor (SSRI) serotonin tr...eutic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective...e hydrochloride (USP) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin ...ride (USP) Anxiolytics SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/Serot

  3. Drug: D07913 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available f Antidepressant ATC code: N06AB10 Selective serotonin reuptake inhibitor (SSRI) serotonin transporter inhib...cal (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective... USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/S...erotonin and Norepinephrine Reuptake Inhibitors) Escitalopram D07913 Escitalopram (INN) Anxiolytics SSRIs/SNRIs (Selective

  4. Drug: D00825 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 05 342.6905 D00825.gif Antidepressant Therapeutic category: 1179 ATC code: N06AB06 Selective serotonin reupt...l Therapeutic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective...ertraline hydrochloride (JAN/USAN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective...ine hydrochloride (JAN/USAN) Anxiolytics SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/Serotonin and

  5. Assessing substrates underlying the behavioral effects of antidepressants using the modified rat forced swimming test.

    Science.gov (United States)

    Cryan, John F; Valentino, Rita J; Lucki, Irwin

    2005-01-01

    Selective serotonin reuptake inhibitors (SSRIs) are the most widely prescribed antidepressant class today and exert their antidepressant-like effects by increasing synaptic concentrations of serotonin (5-HT). The rat forced swim test (FST) is the most widely used animal test predictive of antidepressant action. Procedural modifications recently introduced by our laboratory have enabled SSRI-induced behavioral responses to be measured in the modified FST. The use of this model to understand the pharmacological and physiological mechanisms underlying the role of 5-HT in the behavioral effects of antidepressant drugs is reviewed. Although all antidepressants reduced behavioral immobility, those antidepressants that increase serotonergic neurotransmission predominantly increase swimming behavior whereas those that increase catacholaminergic neurotransmission increase climbing behavior. The 5-HT(1A), 5-HT(1B/1D) and 5-HT(2C) receptors are the 5-HT receptors most important to the therapeutic effects of SSRIs, based on extensive evaluation of agonists and antagonists of individual 5-HT receptor subtypes. Studies involving chronic administration have shown that the effects of antidepressants are augmented following chronic treatment. Other studies have demonstrated strain differences in the response to serotonergic compounds. Finally, a physiological model of performance in the rat FST has been proposed involving the regulation of 5-HT transmission by corticotropin releasing factor (CRF).

  6. Advanced drug delivery systems: Nanotechnology of health design A review

    Directory of Open Access Journals (Sweden)

    Javad Safari

    2014-04-01

    Full Text Available Nanotechnology has finally and firmly entered the realm of drug delivery. Performances of intelligent drug delivery systems are continuously improved with the purpose to maximize therapeutic activity and to minimize undesirable side-effects. This review describes the advanced drug delivery systems based on micelles, polymeric nanoparticles, and dendrimers. Polymeric carbon nanotubes and many others demonstrate a broad variety of useful properties. This review emphasizes the main requirements for developing new nanotech-nology-based drug delivery systems.

  7. Anxiolytic, antidepressant, and antistress activities of the aqueous extract of Cinnamomum tamala Nees and Eberm in rats

    Science.gov (United States)

    Upadhyay, Gayaprasad; Khoshla, Sarvesh; Kosuru, Ramoji; Singh, Sanjay

    2016-01-01

    Objective: The current study was designed to explore anxiolytic, antidepressant, and antistress actions of Cinnamomum tamala (CT) leaves (aqueous extract) in rats. Materials and Methods: Behavioral procedures of anxiety, depression, and stress were assessed in rats. CT (100, 200, and 400 mg/kg) was given once a daily for 7 days via oral route and the efficacy was matched by those elicited by lorazepam (1 mg/kg, p.o.), imipramine (10 mg/kg, p.o.), and Withania somnifera (100 mg/kg, p.o.) for anxiolytic, antidepressant, and antistress studies, respectively. Standard drugs were given 1 time, 30 min preceding the behavioral trials. Results: One-way analysis of variance followed by Newman–Keuls multiple comparison test was employed to analyze the results. P < 0.05 was considered statistically significant as compared to control. CT at 400 mg/kg produced an antianxiety effect equivalent to lorazepam, in the elevated plus maze, open field, and social interaction tests among selected doses of the CT. CT at 400 mg/kg also induced an antidepressant activity similar to imipramine, in the behavioral despair, learned helplessness test, and tail suspension among selected doses of the CT. Moreover, CT at 400 mg/kg produced a significant antistress effect comparable to W. somnifera in water immersion-restraint stress by decreasing ulcer index, adrenal gland weight, and by normalizing the plasma levels of corticosterone, glucose, cholesterol, and triglyceride levels when related to stress control. Conclusion: The study shows that among the different CT doses, CT at 400 mg/kg possesses significant anxiolytic, antidepressant, and anti-stress effects and has therapeutic beneficial for the management of psychological ailments.

  8. Augmentation of antidepressants with unsaturated fatty acids omega-3 in drug-resistant depression [Potencjalizacja leków przeciwdepresyjnych kwasami tłuszczowymi omega-3 w depresji lekoopornej

    Directory of Open Access Journals (Sweden)

    Krawczyk, Kamila

    2012-08-01

    Full Text Available Aim. The aim of this paper was to evaluate the impact of augmenting administered antidepressant treatment of patients suffering from a severe episode of treatment-resistant recurrent depression or bipolar affective disorder with omega-3 fatty acids and comparing the obtained results with those achieved in the groups of patients potentiated with lithium or lamotrigine. Methods. The research subjects were 21 patients diagnosed with a severe episode of treatment-resistant recurring depression in the course of recurrent depression disorders – or bipolar affective disorders. Patient eligibility included failure to respond to at least two 4-week antidepressant treatments (venlafaxine at a dose of up to 300 mg/day or paroxetine at up to 60 mg/day. The regular antidepressant treatment regimen was augmented by the “eye-q” preparation with a course of 24 capsules per day (2.2 g of EPA, 700 mg of DHA, 240 mg of GLA, 40 mg of vitamin E, primrose oil. The patients received the preparation for at least 4 weeks. The comparison groups consisted of the patients suffering from the current episode of severe treatment-resistant depression, treated by potentiating antidepressant treatment with lithium and lamotrigine. Results. The initial intensity of depression symptoms on the HDRS scale was 30±6, following a 4-week potentiation HDRS score was 11±10. Taking into account a significantly higher initial intensity of depression, clinical improvement upon administering fatty acids was proportional to the one achieved by potentiating therapeutic effects with lithium and lamotrigine. Effectiveness resulting from the use of omega-3 fatty acids in a positive correlated with baseline severity of depression and in a manner adverse to the duration of the current episode. The use of high doses of omega-3 significantly decreased the levels of triglycerides, increased the HDL and LDL, did not result in adverse changes in liver enzyme values. Conclusions. Augmenting a

  9. The centrally acting non-narcotic antitussive tipepidine produces antidepressant-like effect in the forced swimming test in rats.

    Science.gov (United States)

    Kawaura, Kazuaki; Ogata, Yukino; Inoue, Masako; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

    2009-12-14

    The antidepressant-like effect of tipepidine was studied in rats. Tipepidine at 20 and 40 mg/kg i.p. reduced immobility in the forced swimming test and tipepidine at 40 mg/kg, i.p. increased climbing in the test. The drug at 40 mg/kg, i.p. had no effect on the locomotor activity and motor coordination. These results suggest that tipepidine may be a novel drug with antidepressant-like activity.

  10. Interactions between antidepressants and antihypertensive and glucose lowering drugs among patients in the HIPERDIA Program, Coronel Fabriciano, Minas Gerais State, Brazil Interações entre antidepressivos e medicamentos e anti-hipertensivos e hipo-glicemiantes em pacientes do Programa HIPERDIA em Coronel Fabriciano, Minas Gerais, Brasil

    Directory of Open Access Journals (Sweden)

    Paula Vieira Coelho

    2009-10-01

    Full Text Available The aims of this study were to investigate the prevalence and to describe the most frequent potential interactions between antidepressants and antihypertensive and glucose lowering drugs in the HIPERDIA Program at two primary care units in Coronel Fabriciano, Minas Gerais State, Brazil. Data were collected through the patient registry in the HIPERDIA Program and the local psychoactive drug dispensing system. Interactions were classified as due to pharmacokinetic and/or pharmacodynamic mechanisms. Prevalence of antidepressant use in the HIPERDIA Program was 4.37% (29 of patient 663 records. Of the HIPERDIA patients in treatment with antidepressants, 19 were exposed to 47 interactions, 23.4% of which involving pharmacokinetic, 61.7% pharmacodynamic synergy, and 15.9% simultaneous pharmacokinetic and pharmacodynamic mechanisms. Complications can arise from drug-drug interactions, a situation that can escape the attention of prescribing health professionals.O objetivo do estudo foi investigar a prevalência e descrever as possíveis interações de medicamentos mais freqüentes entre antidepressivos e anti-hipertensivos/hipoglicemiantes do programa HIPERDIA de duas unidades básicas de saúde do Município de Coronel Fabriciano, Minas Gerais, Brasil. A coleta de dados foi realizada mediante consulta ao caderno de cadastro dos pacientes usuários do programa de HIPERDIA e pela consulta ao sistema de dispensação de psicotrópicos do município. As interações foram classificadas segundo o mecanismo farmacocinético e farmacodinâmico. A prevalência do uso de antidepressivos em pacientes do HIPERDIA foi de 4,37% (29 de 663 cadastros analisados. Dos pacientes do HIPERDIA em tratamento com antidepressivos, 19 estão expostos a 47 interações, 23,4% delas ocorrem por mecanismos farmacocinéticos, 61,7% por mecanismos farmacodinâmicos de sinergismo e 15,9% interagem das duas formas simultaneamente. Complicações podem ser provocadas por intera

  11. Precursors to suicidality and violence on antidepressants: systematic review of trials in adult healthy volunteers

    Science.gov (United States)

    Bielefeldt, Andreas Ø; Danborg, Pia B

    2016-01-01

    Objective To quantify the risk of suicidality and violence when selective serotonin and serotonin-norepinephrine reuptake inhibitors are given to adult healthy volunteers with no signs of a mental disorder. Design Systematic review and meta-analysis. Main outcome measure Harms related to suicidality, hostility, activation events, psychotic events and mood disturbances. Setting Published trials identified by searching PubMed and Embase and clinical study reports obtained from the European and UK drug regulators. Participants Double-blind, placebo-controlled trials in adult healthy volunteers that reported on suicidality or violence or precursor events to suicidality or violence. Results A total of 5787 publications were screened and 130 trials fulfilled our inclusion criteria. The trials were generally uninformative; 97 trials did not report the randomisation method, 75 trials did not report any discontinuations and 63 trials did not report any adverse events or lack thereof. Eleven of the 130 published trials and two of 29 clinical study reports we received from the regulatory agencies presented data for our meta-analysis. Treatment of adult healthy volunteers with antidepressants doubled their risk of harms related to suicidality and violence, odds ratio 1.85 (95% confidence interval 1.11 to 3.08, p = 0.02, I2 = 18%). The number needed to treat to harm one healthy person was 16 (95% confidence interval 8 to 100; Mantel-Haenszel risk difference 0.06). There can be little doubt that we underestimated the harms of antidepressants, as we only had access to the published articles for 11 of our 13 trials. Conclusions Antidepressants double the occurrence of events in adult healthy volunteers that can lead to suicide and violence. PMID:27729596

  12. Computational design of nanoparticle drug delivery systems for selective targeting

    Science.gov (United States)

    Duncan, Gregg A.; Bevan, Michael A.

    2015-09-01

    Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting diseased cells and tissues.Ligand-functionalized nanoparticles capable of selectively binding to diseased versus healthy cell populations are attractive for improved efficacy of nanoparticle-based drug and gene therapies. However, nanoparticles functionalized with high affinity targeting ligands may lead to undesired off-target binding to healthy cells. In this work, Monte Carlo simulations were used to quantitatively determine net surface interactions, binding valency, and selectivity between targeted nanoparticles and cell surfaces. Dissociation constant, KD, and target membrane protein density, ρR, are explored over a range representative of healthy and cancerous cell surfaces. Our findings show highly selective binding to diseased cell surfaces can be achieved with multiple, weaker affinity targeting ligands that can be further optimized by varying the targeting ligand density, ρL. Using the approach developed in this work, nanomedicines can be optimally designed for exclusively targeting

  13. Antidepressant- like effects of BCEF0083 in the chronic unpredictable stress models

    Institute of Scientific and Technical Information of China (English)

    LanlanZhou; LiangMING; ChuangengMa; YanCheng; QinJiang

    2004-01-01

    AIM: Depression is a complicated disease, There are no satisfactory drugs to therapy depression so far. BCEF is a new type of bioactive compounds from entomogenous fungi. Depression animal models are effective to evaluate the antidepressant property of drugs. Several animal models of depression have been inn'oduced, however, only a few have been

  14. Reduced Treatment-Emergent Sexual Dysfunction as a Potential Target in the Development of New Antidepressants

    Directory of Open Access Journals (Sweden)

    David S. Baldwin

    2013-01-01

    Full Text Available Pleasurable sexual activity is an essential component of many human relationships, providing a sense of physical, psychological, and social well-being. Epidemiological and clinical studies show that depressive symptoms and depressive illness are associated with impairments in sexual function and satisfaction, both in untreated and treated patients. The findings of randomized placebo-controlled trials demonstrate that most of the currently available antidepressant drugs are associated with the development or worsening of sexual dysfunction, in a substantial proportion of patients. Sexual difficulties during antidepressant treatment often resolve as depression lifts but can endure over long periods and may reduce self-esteem and affect mood and relationships adversely. Sexual dysfunction during antidepressant treatment is typically associated with many possible causes, but the risk and type of dysfunction vary with differing compounds and should be considered when making decisions about the relative merits and drawbacks of differing antidepressants. A range of interventions can be considered when managing patients with sexual dysfunction associated with antidepressants, including the prescription of phosphodiesterase-5 inhibitors, but none of these approaches can be considered “ideal.” As treatment-emergent sexual dysfunction is less frequent with certain drugs, presumably related to differences in their pharmacological properties, and because current management approaches are less than ideal, a reduced burden of treatment-emergent sexual dysfunction represents a tolerability target in the development of novel antidepressants.

  15. Antidepressants for older people: what can we learn from the current evidence base?

    Science.gov (United States)

    Katona, Cornelius; Bindman, Dorothea C; Katona, Cara P

    2014-10-01

    This paper updates our previous review of the evidence base for managing depression in old age while focusing more specifically on the use of antidepressants. Overall, recent systematic reviews and meta-analyses indicate that antidepressants are effective in the acute treatment of depression in old age but that the superiority of active drug over placebo is quite modest. The depression of Alzheimer's disease is probably not treated effectively with antidepressants. The most consistent evidence is for the effectiveness of continued antidepressant treatment in those depressed patients who respond well to acute treatment. There remains a clear need for more research to identify effective treatments for resistant depression though therapeutic nihilism should be avoided if first-line treatment fails. PMID:24975955

  16. Studies on antidepressant action of a new oxazolidinone derivative AS-8.

    Science.gov (United States)

    Kostowski, W; Płaźnik, A; Bidziński, A; Rosnowska, E; Jessa, M; Nazar, M

    1994-01-01

    On the basis of previous laboratory studies AS-8 was suggested to possess antidepressant-like activity. Forced swim test, learned helplessness and conflict Vogel's test were performed after three prior administrations of AS-8 (24, 5 and 1 h before the test). The data have shown that AS-8 produces moderate antidepressant effect but did not induce anxiolytic-like action. Biochemical data revealed increased brain 5-HT and 5-HIAA levels following AS-8 administration. The combined treatment of rats with AS-8 (100 mg/kg) and amitriptyline (5 mg/kg) or desipramine (1.25 mg/kg) significantly stimulated active behavior in the forced swim test above the level obtained with each of the drug given separately. The present data suggest the potential antidepressant efficacy of AS-8 in conjunction with small doses of tricyclic antidepressants.

  17. "Herbal incense": designer drug blends as cannabimimetics and their assessment by drug discrimination and other in vivo bioassays.

    Science.gov (United States)

    Järbe, Torbjörn U C; Gifford, Roger S

    2014-02-27

    Recently, synthetic cannabinoids originally designed for testing in the laboratory only have found use recreationally in designer herbal blends, originally called "Spice". The myriad of compounds found are for the most part potent full agonists of the cannabinoid receptor 1, producing effects similar to tetrahydrocannabinol (THC) and marijuana. Drug discrimination of these compounds offers a specific behavioral test that can help determine whether these new synthetic compounds share a similar "subjective high" with the effects of marijuana/THC. By utilization of drug discrimination and other behavioral techniques, a better understanding of these new "designer" cannabinoids may be reached to assist in treating both the acute and chronic effects of these drugs. The paper provides a brief exposé of modern cannabinoid research as a backdrop to the recreational use of designer herbal blend cannabimimetics.

  18. The mesolimbic dopamine system as a target for rapid antidepressant action.

    Science.gov (United States)

    Willner, P

    1997-07-01

    Chronic treatment with antidepressant drugs produces a variety of changes in dopaminergic neurotransmission, most notably a sensitization of behavioural responses to agonists acting at dopamine D2/D3 receptors within the nucleus accumbens. Evidence from animal models of depression (the forced swim test and the chronic mild stress procedure) indicates that these effects are crucial for the therapeutic effect of antidepressants in these models. Antidepressant-like effects in animal models are also seen with drugs that act directly on the dopaminergic system. Because of its prolonged time-course, the chronic mild stress procedure can be used to examine onset latencies. Some dopamine-active drugs (e.g. the catechol-O-methyltransferase inhibitor tolcapone; D2/D3 agonists administered intermittently) are active in this procedure but have a time-course comparable to that of conventional antidepressants. Other dopamine-active drugs may have a more rapid onset; the evidence to date suggests this possibility for the D2/D3 agonist pramipexole and the preferential presynaptic antagonist amisulpride. In clinical studies, rapid-onset latencies have been claimed for the D2/D3 agonist roxindole, the preferential presynaptic antagonist sulpiride and the relatively selective dopamine-uptake inhibitor amineptine. The mechanisms that might give rise to a rapid onset of dopamine-mediated antidepressant effects are discussed. PMID:9347387

  19. Pharmacogenomics of the human ABC transporter ABCG2: from functional evaluation to drug molecular design

    Science.gov (United States)

    Ishikawa, Toshihisa; Tamura, Ai; Saito, Hikaru; Wakabayashi, Kanako; Nakagawa, Hiroshi

    2005-10-01

    In the post-genome-sequencing era, emerging genomic technologies are shifting the paradigm for drug discovery and development. Nevertheless, drug discovery and development still remain high-risk and high-stakes ventures with long and costly timelines. Indeed, the attrition of drug candidates in preclinical and development stages is a major problem in drug design. For at least 30% of the candidates, this attrition is due to poor pharmacokinetics and toxicity. Thus, pharmaceutical companies have begun to seriously re-evaluate their current strategies of drug discovery and development. In that light, we propose that a transport mechanism-based design might help to create new, pharmacokinetically advantageous drugs, and as such should be considered an important component of drug design strategy. Performing enzyme- and/or cell-based drug transporter, interaction tests may greatly facilitate drug development and allow the prediction of drug-drug interactions. We recently developed methods for high-speed functional screening and quantitative structure-activity relationship analysis to study the substrate specificity of ABC transporters and to evaluate the effect of genetic polymorphisms on their function. These methods would provide a practical tool to screen synthetic and natural compounds, and these data can be applied to the molecular design of new drugs. In this review article, we present an overview on the genetic polymorphisms of human ABC transporter ABCG2 and new camptothecin analogues that can circumvent AGCG2-associated multidrug resistance of cancer.

  20. Using Free Computational Resources to Illustrate the Drug Design Process in an Undergraduate Medicinal Chemistry Course

    Science.gov (United States)

    Rodrigues, Ricardo P.; Andrade, Saulo F.; Mantoani, Susimaire P.; Eifler-Lima, Vera L.; Silva, Vinicius B.; Kawano, Daniel F.

    2015-01-01

    Advances in, and dissemination of, computer technologies in the field of drug research now enable the use of molecular modeling tools to teach important concepts of drug design to chemistry and pharmacy students. A series of computer laboratories is described to introduce undergraduate students to commonly adopted "in silico" drug design…

  1. Antiepileptic and Antidepressive Polypharmacy in Patients with Multiple Sclerosis

    Directory of Open Access Journals (Sweden)

    Georg Anton Giæver Beiske

    2015-01-01

    Full Text Available Objective. Patients with multiple sclerosis (MS are often suffering from neuropathic pain. Antiepileptic drugs (AEDs and tricyclic antidepressants (TCAs are commonly used and are susceptible to be involved in drug interactions. The aim of this retrospective study was to investigate the prevalence of use of antiepileptic and antidepressive drugs in MS patients and to discuss the theoretical potential for interactions. Methods. Review of the medical records from all patients treated at a dedicated MS rehabilitation centre in Norway between 2009 and 2012. Results. In total 1090 patients attended a rehabilitation stay during the study period. Of these, 342 (31%; 249 females with mean age of 53 (±10 years and EDSS 4.8 (±1.7 used at least one AED (gabapentin 12.7%, pregabalin 7.7%, clonazepam 7.8%, and carbamazepine 2.6% or amitriptyline (9.7%. Polypharmacy was widespread (mean 5.4 drugs with 60% using additional CNS-active drugs with a propensity to be involved in interactions. Age, gender, and EDSS scores did not differ significantly between those using and not using AED/amitriptyline. Conclusion. One-third of MS patients attending a rehabilitation stay receive AED/amitriptyline treatment. The high prevalence of polypharmacy and use of CNS-active drugs calls for awareness of especially pharmacodynamic interactions and possible excessive adverse effects.

  2. Protein crystallization for drug design in the last 50 years

    Directory of Open Access Journals (Sweden)

    Stura, Enrico A.

    2015-04-01

    Full Text Available We live in an era where we expect to be able to visit our doctor and obtain a pill to cure any ailment from which we suffer. Yet, this is still not the case. Many of the current cures are still derived from natural sources although new drugs are increasingly the result of intelligent design. In this process, X-ray protein crystallography now plays a major and effective role in the discovery of new treatments. The developments that have made this possible have evolved during the past fifty years. The methods for crystallizing macromolecules and determining their structures by X-ray crystallography have been automated and the speed for X-ray data acquisition is several orders of magnitude faster. Fifty years ago it took several years to solve a single structure. Now, several protein–ligand complexes can be determined in single day. High-throughput crystallography is considered to be a great asset to the drug discovery process, providing a fast way to tailor drug candidates to their targets by analysing their binding mode in detail. Crystallization remains the main challenge.Vivimos en una época en la que esperamos ir al médico y obtener una pastilla para curar cualquier dolencia que padezcamos; por desgracia, esta expectativa no es real. Aunque muchos de los remedios en uso provienen de fuentes naturales, la mayoría de los nuevos medicamentos son el resultado de la investigación científica. En el proceso de diseño y descubrimiento de fármacos, la cristalografía de proteínas juega un papel central. Los conocimientos que han hecho esto posible han venido evolucionando desde hace cincuenta años aproximadamente. Los métodos de cristalización de macromoléculas y la determinación de sus estructuras a través de la cristalografía de rayos X han sido automatizados y miniaturizados y la velocidad de la adquisición de datos de difracción ha aumentado en varios órdenes de magnitud. Si hace cincuenta años la resolución de una sola

  3. Antidepressant chronotherapeutics for bipolar depression

    OpenAIRE

    Benedetti, Francesco

    2012-01-01

    Chronotherapeutics refers to treatments based on the principles of circadian rhythm organization and sleep physiology, which control the exposure to environmental stimuli that act on biological rhythms, in order to achieve therapeutic effects in the treatment of psychiatric conditions. It includes manipulations of the sleep-wake cycle such as sleep deprivation and sleep phase advance, and controlled exposure to light and dark. The antidepressant effects of chronotherapeutics are evident in di...

  4. Mixed-effects Poisson regression analysis of adverse event reports: the relationship between antidepressants and suicide.

    Science.gov (United States)

    Gibbons, Robert D; Segawa, Eisuke; Karabatsos, George; Amatya, Anup K; Bhaumik, Dulal K; Brown, C Hendricks; Kapur, Kush; Marcus, Sue M; Hur, Kwan; Mann, J John

    2008-05-20

    A new statistical methodology is developed for the analysis of spontaneous adverse event (AE) reports from post-marketing drug surveillance data. The method involves both empirical Bayes (EB) and fully Bayes estimation of rate multipliers for each drug within a class of drugs, for a particular AE, based on a mixed-effects Poisson regression model. Both parametric and semiparametric models for the random-effect distribution are examined. The method is applied to data from Food and Drug Administration (FDA)'s Adverse Event Reporting System (AERS) on the relationship between antidepressants and suicide. We obtain point estimates and 95 per cent confidence (posterior) intervals for the rate multiplier for each drug (e.g. antidepressants), which can be used to determine whether a particular drug has an increased risk of association with a particular AE (e.g. suicide). Confidence (posterior) intervals that do not include 1.0 provide evidence for either significant protective or harmful associations of the drug and the adverse effect. We also examine EB, parametric Bayes, and semiparametric Bayes estimators of the rate multipliers and associated confidence (posterior) intervals. Results of our analysis of the FDA AERS data revealed that newer antidepressants are associated with lower rates of suicide adverse event reports compared with older antidepressants. We recommend improvements to the existing AERS system, which are likely to improve its public health value as an early warning system. PMID:18404622

  5. Drug: D07984 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ant Same as: C07571 ATC code: N06AB08 Selective serotonin reuptake inhibitor (SSRI) serotonin transporter in...3] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective serotonin reuptake inhibitors ...N06AB08 Fluvoxamine D07984 Fluvoxamine (INN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective

  6. Drug: D00824 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 65 434.4068 D00824.gif Antiobsessional agent Therapeutic category: 1179 ATC code: N06AB08 Selective serotoni...HOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective serotonin reuptake inhibitors N06AB08 Fluvoxamine D00824 F...luvoxamine maleate (JP16/USAN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective S

  7. Drug: D07340 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07340 Drug Oxaflozane (INN) C14H18F3NO 273.134 273.294 D07340.gif ATC code: N06AX1...6A ANTIDEPRESSANTS N06AX Other antidepressants N06AX10 Oxaflozane D07340 Oxaflozane (INN) CAS: 26629-87-8 Pu

  8. Antidepressants Accumulate in Lipid Rafts Independent of Monoamine Transporters to Modulate Redistribution of the G Protein, Gαs.

    Science.gov (United States)

    Erb, Samuel J; Schappi, Jeffrey M; Rasenick, Mark M

    2016-09-16

    Depression is a significant public health problem for which currently available medications, if effective, require weeks to months of treatment before patients respond. Previous studies have shown that the G protein responsible for increasing cAMP (Gαs) is increasingly localized to lipid rafts in depressed subjects and that chronic antidepressant treatment translocates Gαs from lipid rafts. Translocation of Gαs, which shows delayed onset after chronic antidepressant treatment of rats or of C6 glioma cells, tracks with the delayed onset of therapeutic action of antidepressants. Because antidepressants appear to specifically modify Gαs localized to lipid rafts, we sought to determine whether structurally diverse antidepressants accumulate in lipid rafts. Sustained treatment of C6 glioma cells, which lack 5-hydroxytryptamine transporters, showed marked concentration of several antidepressants in raft fractions, as revealed by increased absorbance and by mass fingerprint. Closely related molecules without antidepressant activity did not concentrate in raft fractions. Thus, at least two classes of antidepressants accumulate in lipid rafts and effect translocation of Gαs to the non-raft membrane fraction, where it activates the cAMP-signaling cascade. Analysis of the structural determinants of raft localization may both help to explain the hysteresis of antidepressant action and lead to design and development of novel substrates for depression therapeutics.

  9. 76 FR 53912 - FDA's Public Database of Products With Orphan-Drug Designation: Replacing Non-Informative Code...

    Science.gov (United States)

    2011-08-30

    ...The Food and Drug Administration (FDA), Office of Orphan Products Development, is announcing that it has replaced non- informative code names with descriptive identifiers on its public database of products that have received orphan-drug designation. The Orphan Drug Act mandates that FDA provide notice to the public respecting the designation of a drug as an orphan-drug. FDA typically provides......

  10. Concurrent use of amphetamine stimulants and antidepressants by undergraduate students

    Directory of Open Access Journals (Sweden)

    Vo K

    2015-01-01

    Full Text Available Kim Vo,1 Patricia J Neafsey,2 Carolyn A Lin3 1University of Connecticut Health Center, Farmington, 2School of Nursing and Center for Health Information and Prevention, University of Connecticut, Storrs, 3Department of Communication Sciences and Center for Health Information and Prevention, University of Connecticut, Storrs, CT, USA Abstract: Undergraduate students were recruited to participate in an online survey to report their use of amphetamine stimulants and other drugs. Significant differences were found between students reporting (n=79; 4.0% and not reporting (n=1,897; 96% amphetamine-stimulant use in the past month – in terms of race/ethnicity, class standing, residence, health symptoms, self-health report – in addition to alcohol, tobacco, pain-reliever, and antidepressant use. Health symptoms reported more often by stimulant users included depression, diarrhea, difficulty sleeping, fatigue, dizziness, difficulty concentrating, and nicotine craving. Health care providers of college students should query these patients about symptoms that could be related to depression and amphetamine use. In particular, they should provide education at the point of care around the risks of amphetamine use in general and the specific risks in those students who have symptoms of depression and/or are taking antidepressant medication. Prevention programs should also target the risks of concurrent use of amphetamines, antidepressants, and other drugs among college students. Keywords: stimulant use, depression, college students, self-medication

  11. Evaluation of antidepressant activity of vanillin in mice

    OpenAIRE

    Ahsan Shoeb; Mukta Chowta; Gokul Pallempati; Amritha Rai; Ashish Singh

    2013-01-01

    Objective: The main objective of this study was to evaluate antidepressant activity of vanillin in mice models of depression. Materials and Methods: Animals were divided into five groups, consisting six mice in each group. Out of these, three groups served as control (distilled water, imipramine,and fluoxetine) and the remaining two groups received test drug in two different doses (10mg/kg and 100mg/kg). All the drugs were administered orally one hour before the test procedure for acute s...

  12. The study of antidepressive drugs Fluoxetine combined with language training in improvement of neurological function and depression in patients with stroke aphasia%抗抑郁药氟西汀配合语言训练改善脑卒中失语患者语言神经功能及抑郁的研究

    Institute of Scientific and Technical Information of China (English)

    刘靖

    2012-01-01

    目的 探讨氟西汀联合语言训练改善脑卒中失语患者神经功能及抑郁状态的效果.方法 选择本院收治的脑卒中伴失语患者96例,随机分为抗抑郁药组与药物加训练组.抗抑郁药组患者给予常规的脑卒中治疗及抗抑郁药氟西汀20 mg/d,共3个月;药物加训练组患者在抗抑郁药组基础上配合Schuell刺激法语言训练,30 min/次,每周2次,共2个月.采用爱丁堡-斯堪的那维亚量表(MESSS)评价患者神经功能缺损改善情况,采用日常生活能力量表(ADL)评价日常生活能力改善情况,采用HAMD抑郁量表和SDS抑郁自评量表评价患者抑郁改善情况.结果 两组治疗前MESSS、ADL、HAMD、SDS评分差异无统计学意义(P>0.05);治疗2周后两组HAMD 、SDS评分均较治疗前降低,药物加训练组明显低于抗抑郁药组,差异有统计学意义(P<0.05);治疗4周后两组MESSS、ADL较治疗前改善,但药物加训练组MESSS评分低于抗抑郁药组,ADL评分高于抗抑郁药组,组间差异有统计学意义(P<0.05).结论 抗抑郁药配合语言康复训练可改善脑卒中失语患者抑郁状态,减轻神经功能缺损,在脑卒中抑郁患者尤其是失语患者中有较好的应用意义.%Objective To investigate the effects of Fluoxetine combined with language training in improvement of neurological function and depression in patients with stroke aphasia. Methods 96 cases of stroke patients combined with aphasia were randomly divided into the antidepressant group and drugs combined with training group. Patients in the antidepressant group were given conventional treatment of stroke combined with Fluoxetine 20 mg/d, for 3 months; patients in the drugs combined with training group combined with Schuell stimulation language training treatment, 30 min/times, 2 times a week, a total of 2 months, on the basis of the antidepressant group. The improvement of neurological deficits was evaluated with Edinburgh Scandinavia scale

  13. Parasomnias and Antidepressant Therapy: A Review of the Literature

    Directory of Open Access Journals (Sweden)

    Lara eKierlin

    2011-12-01

    Full Text Available There exists a varying level of evidence linking the use of antidepressant medication to the parasomnias, ranging from larger, more comprehensive studies in the area of RBD to primarily case reports in the NREM parasomnias. As such, practice guidelines are lacking regarding specific direction to the clinician who may be faced with a patient who has developed a parasomnia that appears to be temporally related to use of an antidepressant. In general, knowledge of the mechanisms of action of the medications, particularly with regard to the impact on sleep architecture, can provide some guidance. There is a potential for SSRIs, TCAs, and SNRIs to suppress REM, as well as the anticholinergic properties of the individual drugs to further disturb normal sleep architecture.

  14. The Antidepressant WebMarketing depression and making medicines work.

    Science.gov (United States)

    Medawar, C

    1997-01-01

    This paper was conceived as chapters two and three of the still unwritten book, and as a basis for discussion on an Internet website and elsewhere. These chapters examine hard evidence relating to a wholly rhetorical and hypothetical question, "Do antidepressants work?" The question provides the broadest possible framework for looking at the meaning and values of medicine. Implicitly, the question also asks: what is better than nothing, and how much better are antidepressant drugs than the placebos they are compared with in clinical trials? Between the lines of the paper lie basic questions about the ethics, activities, performance and impact of the three main centres of power in medicine - government, professionals and the pharmaceutical industry. The underlying issue is whether people who are miserably unfulfilled, sad, anguished or depressed are in hands as safe as they might imagine or need. PMID:23511318

  15. Cre-dependent DREADD (Designer Receptors Exclusively Activated by Designer Drugs) mice.

    Science.gov (United States)

    Zhu, Hu; Aryal, Dipendra K; Olsen, Reid H J; Urban, Daniel J; Swearingen, Amanda; Forbes, Stacy; Roth, Bryan L; Hochgeschwender, Ute

    2016-08-01

    DREADDs, designer receptors exclusively activated by designer drugs, are engineered G protein-coupled receptors (GPCR) which can precisely control GPCR signaling pathways (for example, Gq, Gs, and Gi). This chemogenetic technology for control of GPCR signaling has been successfully applied in a variety of in vivo studies, including in mice, to remotely control GPCR signaling, for example, in neurons, glia cells, pancreatic β-cells, or cancer cells. In order to fully explore the in vivo applications of the DREADD technology, we generated hM3Dq and hM4Di strains of mice which allow for Cre recombinase-mediated restricted expression of these pathway-selective DREADDs. With the many Cre driver lines now available, these DREADD lines will be applicable to studying a wide array of research and preclinical questions. genesis 54:439-446, 2016. © 2016 Wiley Periodicals, Inc. PMID:27194399

  16. Resolving Behavioral Output via Chemogenetic Designer Receptors Exclusively Activated by Designer Drugs.

    Science.gov (United States)

    Burnett, C Joseph; Krashes, Michael J

    2016-09-01

    Designer receptors exclusively activated by designer drugs (DREADDs) have proven to be highly effective neuromodulatory tools for the investigation of neural circuits underlying behavioral outputs. They exhibit a number of advantages: they rely on cell-specific manipulations through canonical intracellular signaling pathways, they are easy and cost-effective to implement in a laboratory setting, and they are easily scalable for single-region or full-brain manipulations. On the other hand, DREADDs rely on ligand-G-protein-coupled receptor interactions, leading to coarse temporal dynamics. In this review we will provide a brief overview of DREADDs, their implementation, and the advantages and disadvantages of their use in animal systems. We also will provide numerous examples of their use across a broad variety of biomedical research fields. PMID:27605603

  17. Drug: D08222 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08222 Drug Milnacipran (INN) C15H22N2O 246.1732 246.348 D08222.gif Antidepressant ...S N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX17 Milnacipran D08222 Milnacipran (INN) USP drug cla...ssification [BR:br08302] Central Nervous System Agents Fibromyalgia Agents Milnacipran D08222 Mil...nacipran (INN) Target-based classification of drugs [BR:br08310] Transporters Solute carrier famil...y SLC6 SLC6A2 (noradrenalin transporter) [HSA:6530] [KO:K05035] Milnacipran [ATC:N06AX17] D08222 Milna

  18. Drug: D07938 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07938 Drug Bupropion hydrobromide (USAN) C13H18ClNO. HBr 319.0339 320.6531 D07938....SSANTS N06AX Other antidepressants N06AX12 Bupropion D07938 Bupropion hydrobromide (USAN) USP drug classific...ation [BR:br08302] Anti-Addiction/Substance Abuse Treatment Agents Smoking Cessation Agents Bupropion D07938 Bupropion hydrobromide... (USAN) Antidepressants Antidepressants, Other Bupropion D07938 Bupropion hydrobrom...ide (USAN) CAS: 905818-69-1 PubChem: 96024633 DrugBank: DB01156 LigandBox: D07938 A

  19. Psychosocial work environment and antidepressant medication: a prospective cohort study

    Directory of Open Access Journals (Sweden)

    Westergaard-Nielsen Niels

    2009-07-01

    Full Text Available Abstract Background Adverse psychosocial work environments may lead to impaired mental health, but it is still a matter of conjecture if demonstrated associations are causal or biased. We aimed at verifying whether poor psychosocial working climate is related to increase of redeemed subscription of antidepressant medication. Methods Information on all antidepressant drugs (AD purchased at pharmacies from 1995 through 2006 was obtained for a cohort of 21,129 Danish public service workers that participated in work climate surveys carried out during the period 2002–2005. Individual self-reports of psychosocial factors at work including satisfaction with the work climate and dimensions of the job strain model were obtained by self-administered questionnaires (response rate 77,2%. Each employee was assigned the average score value for all employees at his/her managerial work unit [1094 units with an average of 18 employees (range 3–120]. The risk of first-time AD prescription during follow-up was examined according to level of satisfaction and psychosocial strain by Cox regression with adjustment for gender, age, marital status, occupational status and calendar year of the survey. Results The proportion of employees that received at least one prescription of ADs from 1995 through 2006 was 11.9% and prescriptions rose steadily from 1.50% in 1996 to the highest level 6.47% in 2006. ADs were prescribed more frequent among women, middle aged, employees with low occupational status and those living alone. None of the measured psychosocial work environment factors were consistently related to prescription of antidepressant drugs during the follow-up period. Conclusion The study does not indicate that a poor psychosocial work environment among public service employees is related to prescription of antidepressant pharmaceuticals. These findings need cautious interpretation because of lacking individual exposure assessments.

  20. Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate

    Directory of Open Access Journals (Sweden)

    João P. Costa-Nunes

    2015-01-01

    Full Text Available Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day and dicholine succinate (50 mg/kg/day, against standard antidepressants, imipramine (7 mg/kg/day and citalopram (15 mg/kg/day, utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies.

  1. Animal Models of Depression and Drug Delivery with Food as an Effective Dosing Method: Evidences from Studies with Celecoxib and Dicholine Succinate.

    Science.gov (United States)

    Costa-Nunes, João P; Cline, Brandon H; Araújo-Correia, Margarida; Valença, Andreia; Markova, Natalyia; Dolgov, Oleg; Kubatiev, Aslan; Yeritsyan, Naira; Steinbusch, Harry W M; Strekalova, Tatyana

    2015-01-01

    Multiple models of human neuropsychiatric pathologies have been generated during the last decades which frequently use chronic dosing. Unfortunately, some drug administration methods may result in undesirable effects creating analysis confounds hampering model validity and preclinical assay outcomes. Here, automated analysis of floating behaviour, a sign of a depressive-like state, revealed that mice, subjected to a three-week intraperitoneal injection regimen, had increased floating. In order to probe an alternative dosing design that would preclude this effect, we studied the efficacy of a low dose of the antidepressant imipramine (7 mg/kg/day) delivered via food pellets. Antidepressant action for this treatment was found while no other behavioural effects were observed. We further investigated the potential efficacy of chronic dosing via food pellets by testing the antidepressant activity of new drug candidates, celecoxib (30 mg/kg/day) and dicholine succinate (50 mg/kg/day), against standard antidepressants, imipramine (7 mg/kg/day) and citalopram (15 mg/kg/day), utilizing the forced swim and tail suspension tests. Antidepressant effects of these compounds were found in both assays. Thus, chronic dosing via food pellets is efficacious in small rodents, even with a low drug dose design, and can prevail against potential confounds in translational research within depression models applicable to adverse chronic invasive pharmacotherapies. PMID:26064929

  2. 3D Printing of Medicines: Engineering Novel Oral Devices with Unique Design and Drug Release Characteristics.

    Science.gov (United States)

    Goyanes, Alvaro; Wang, Jie; Buanz, Asma; Martínez-Pacheco, Ramón; Telford, Richard; Gaisford, Simon; Basit, Abdul W

    2015-11-01

    Three dimensional printing (3D printing) was used to fabricate novel oral drug delivery devices with specialized design configurations. Each device was loaded with multiple actives, with the intent of applying this process to the production of personalized medicines tailored at the point of dispensing or use. A filament extruder was used to obtain drug-loaded--paracetamol (acetaminophen) or caffeine--filaments of poly(vinyl alcohol) with characteristics suitable for use in fused-deposition modeling 3D printing. A multinozzle 3D printer enabled fabrication of capsule-shaped solid devices containing the drug with different internal structures. The design configurations included a multilayer device, with each layer containing drug, whose identity was different to the drug in the adjacent layers, and a two-compartment device comprising a caplet embedded within a larger caplet (DuoCaplet), with each compartment containing a different drug. Raman spectroscopy was used to collect 2-dimensional hyper spectral arrays across the entire surface of the devices. Processing of the arrays using direct classical least-squares component matching to produce false color representations of distribution of the drugs was used. This clearly showed a definitive separation between the drug layers of paracetamol and caffeine. Drug release tests in biorelevant bicarbonate media showed unique drug release profiles dependent on the macrostructure of the devices. In the case of the multilayer devices, release of both paracetamol and caffeine was simultaneous and independent of drug solubility. With the DuoCaplet design, it was possible to engineer either rapid drug release or delayed release by selecting the site of incorporation of the drug in the device; the lag-time for release from the internal compartment was dependent on the characteristics of the external layer. The study confirms the potential of 3D printing to fabricate multiple-drug containing devices with specialized design

  3. Cyclotides : Tuning Parameters Toward Their Use in Drug Design

    OpenAIRE

    Yeshak, Mariamawit Yonathan

    2012-01-01

    Cyclotides are plant proteins with a unique topology, defined as the cyclic cystine knot motif. The motif endows cyclotides with exceptional chemical and biological stability. They also exhibit a wide range of biological activities including insecticidal, cytotoxic, anti-HIV and antimicrobial effects. Hence, cyclotides have become potential candidates in the development of peptide-based drugs; either as scaffolds to stabilize susceptible peptide sequences or as drugs by their own right. In th...

  4. Key Considerations in Designing Oral Drug Delivery Systems for Dogs.

    Science.gov (United States)

    Song, Yunmei; Peressin, Karl; Wong, Pooi Yin; Page, Stephen W; Garg, Sanjay

    2016-05-01

    The present review discusses the pharmaceutical impact of the anatomy and physiology of the canine gastrointestinal tract to provide a comprehensive guide to the theories and challenges associated with the development of oral drug delivery systems for dogs. Novel pharmaceutical technologies applied to veterinary drugs are discussed indicating the advantages and benefits for animals. There are currently immense research and development efforts being funneled into novel canine health products. Such products are being used to overcome limitations of drugs that display site-dependent absorption or possess poor biopharmaceutical properties. Techniques that are employed to increase bioavailability of the Biopharmaceutics Classification System class II drugs are discussed in this article. Furthermore, an overview of palatable oral formulations for dog care is provided as an approach to easy administration. In vitro and in vivo evaluation and correlation of oral drug formulations in dogs are also addressed. This article assesses the outlook of canine oral drug development recognizing substantial growth forecasts of the dog care market. PMID:27056627

  5. Membrane Transporters: Structure, Function and Targets for Drug Design

    Science.gov (United States)

    Ravna, Aina W.; Sager, Georg; Dahl, Svein G.; Sylte, Ingebrigt

    Current therapeutic drugs act on four main types of molecular targets: enzymes, receptors, ion channels and transporters, among which a major part (60-70%) are membrane proteins. This review discusses the molecular structures and potential impact of membrane transporter proteins on new drug discovery. The three-dimensional (3D) molecular structure of a protein contains information about the active site and possible ligand binding, and about evolutionary relationships within the protein family. Transporters have a recognition site for a particular substrate, which may be used as a target for drugs inhibiting the transporter or acting as a false substrate. Three groups of transporters have particular interest as drug targets: the major facilitator superfamily, which includes almost 4000 different proteins transporting sugars, polyols, drugs, neurotransmitters, metabolites, amino acids, peptides, organic and inorganic anions and many other substrates; the ATP-binding cassette superfamily, which plays an important role in multidrug resistance in cancer chemotherapy; and the neurotransmitter:sodium symporter family, which includes the molecular targets for some of the most widely used psychotropic drugs. Recent technical advances have increased the number of known 3D structures of membrane transporters, and demonstrated that they form a divergent group of proteins with large conformational flexibility which facilitates transport of the substrate.

  6. Assessing the neuronal serotonergic target-based antidepressant stratagem: impact of in vivo interaction studies and knockout models.

    Science.gov (United States)

    Rajkumar, R; Mahesh, R

    2008-09-01

    Depression remains a challenge in the field of affective neuroscience, despite a steady research progress. Six out of nine basic antidepressant mechanisms rely on serotonin neurotransmitter system. Preclinical studies have demonstrated the significance of serotonin receptors (5-HT(1-3,6,7)), its signal transduction pathways and classical down stream targets (including neurotrophins, neurokinins, other peptides and their receptors) in antidepressant drug action. Serotonergic control of depression embraces the recent molecular requirements such as influence on proliferation, neurogenesis, plasticity, synaptic (re)modeling and transmission in the central nervous system. The present progress report analyses the credibility of each protein as therapeutically relevant target of depression. In vivo interaction studies and knockout models which identified these targets are foreseen to unearth new ligands and help them transform to drug candidates. The importance of the antidepressant assay selection at the preclinical level using salient animal models/assay systems is discussed. Such test batteries would definitely provide antidepressants with faster onset, efficacy in resistant (and co-morbid) types and with least adverse effects. Apart from the selective ligands, only those molecules which bring an overall harmony, by virtue of their affinities to various receptor subtypes, could qualify as effective antidepressants. Synchronised modulation of various serotonergic sub-pathways is the basis for a unique and balanced antidepressant profile, as that of fluoxetine (most exploited antidepressant) and such a profile may be considered as a template for the upcoming antidepressants. In conclusion, 5-HT based multi-targeted antidepressant drug discovery supported by in vivo interaction studies and knockout models is advocated as a strategy to provide classic molecules for clinical trials. PMID:19506722

  7. In-Silico Drug Design: A revolutionary approach to change the concept of current Drug Discovery Process

    Directory of Open Access Journals (Sweden)

    Lakhyajit Boruah, Aparoop Das, Lalit Mohan Nainwal, Neha Agarwal*, Brajesh Shankar

    2013-06-01

    Full Text Available Computational methods play a central role in modern drug discovery process. It includes the design andmanagement of small molecule libraries, initial hit identification through virtual screening, optimization ofthe affinity as well as selectivity of hits and improving the physicochemical properties of the leadcompounds. In this review article, computational drug designing approaches have been elucidated anddiscussed. The key considerations and guidelines for virtual chemical library design and whole drugdiscovery process. Traditional approach for discovery of a new drug is a costly and time consuming affairbesides not being so productive. A number of potential reasons witness choosing the In-silico method ofdrug design to be a more wise and productive approach. There is a general perception that applied sciencehas not kept pace with the advances of basic science. Therefore, there is a need for the use of alternativetools to get answers on efficacy and safety faster, with more certainty and at lower cost. In-silico drugdesign can play a significant role in all stages of drug development from the initial lead designing to finalstage clinical development.

  8. Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors.

    Science.gov (United States)

    Santos, Lucianna Helene; Ferreira, Rafaela Salgado; Caffarena, Ernesto Raúl

    2015-11-01

    Reverse transcriptase (RT) is a multifunctional enzyme in the human immunodeficiency virus (HIV)-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs) and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted. PMID:26560977

  9. Computational drug design strategies applied to the modelling of human immunodeficiency virus-1 reverse transcriptase inhibitors

    Directory of Open Access Journals (Sweden)

    Lucianna Helene Santos

    2015-11-01

    Full Text Available Reverse transcriptase (RT is a multifunctional enzyme in the human immunodeficiency virus (HIV-1 life cycle and represents a primary target for drug discovery efforts against HIV-1 infection. Two classes of RT inhibitors, the nucleoside RT inhibitors (NRTIs and the nonnucleoside transcriptase inhibitors are prominently used in the highly active antiretroviral therapy in combination with other anti-HIV drugs. However, the rapid emergence of drug-resistant viral strains has limited the successful rate of the anti-HIV agents. Computational methods are a significant part of the drug design process and indispensable to study drug resistance. In this review, recent advances in computer-aided drug design for the rational design of new compounds against HIV-1 RT using methods such as molecular docking, molecular dynamics, free energy calculations, quantitative structure-activity relationships, pharmacophore modelling and absorption, distribution, metabolism, excretion and toxicity prediction are discussed. Successful applications of these methodologies are also highlighted.

  10. Antidepressant-like effects of Acorus calamus in forced swimming and tail suspension test in mice

    Institute of Scientific and Technical Information of China (English)

    Pawar Vinod S; Anup Akhade; Shrikrishna Baokar; Shivakumar H

    2011-01-01

    Objective: To evaluate the antidepressant activity of methanolic extract of rhizomes of Acoruscalamus (A. calamus). Methods: Tail suspension test (TST) and forced swimming test (FST) in mice were used to evaluate the antidepressant activity of methanolic extract of rhizomes of A. calamus. Methanolic extracts (50 and 100 mg/kg i.p.) were administered daily for 7 days. Imipramine 5 mg/kg was used as standard antidepressant agent throughout the study. Results: Test extracts of A. calamus decreased immobility periods significantly in a dose dependent manner in both TST and FST. The observed results were also comparable with known standard drug i.e. imipramine. The flavonoid apigenin, which selectively binds with high affinity to the central benzodiazepines receptor, possesses important anxiolytic and antidepressant activities. The review of literature reveals that the A. calamus contains saponin, glycosides, tannin and flavonoid. Conclusions:Methanolic extract of A. calamus rhizomes shows antidepressant activity probably through interaction with adrenergic, dopaminergic serotonergic and γ-aminobutyric acid (GABA) nergic system. Both the models have been proved to be equally valuable for demonstration of substances with a potential antidepressant activity.

  11. Prevalence and factors associated with off-label antidepressant prescriptions for insomnia

    Directory of Open Access Journals (Sweden)

    Lai L

    2011-07-01

    Full Text Available L Leanne Lai¹, Mooi Heong Tan¹, Yen Chi Lai²¹Department of Sociobehavioral and Administrative Pharmacy, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA; ²Department of Internal Medicine, Golen Hospital, Pintong City, TaiwanBackground: The primary objective of our study was to investigate the prevalence of off-label antidepressant drug use in insomnia. The secondary objective was to compare prescribing patterns between off-label antidepressants vs hypnotics approved by the US Food and Drug Administration for insomnia, with particular emphasis on socioeconomic characteristics of patients and physicians.Methods: We undertook a secondary data analysis using the national longitudinal database from the 2006 National Ambulatory Medical Care Survey. Subjects were identified from outpatient visits in which at least one insomnia drug was prescribed. A series of weighted Chi-squared statistics was used to compare drug use for insomnia across various patient and physician characteristics. Multivariate logistic regression was conducted to identify factors associated with off-label antidepressant drug use.Results: Among 901.95 million outpatient visits that took place in the US in 2006, an estimated 30.43 million visits included at least one drug prescription for insomnia. Off-label antidepressants were prescribed significantly more frequently (45.1% than nonbenzodiazepine z-hypnotics (43.2% and benzodiazepines (11.7%. Insomnia prescribing patterns were significantly influenced by physician specialty and physician office settings. Pediatricians (odds ratio [OR]: 65.892; 95% confidence interval [CI]: 5.536–810.564 and neurologists (OR: 4.784; 95% CI: 2.044–11.201 were more likely to prescribe off-label antidepressants than psychiatrists. Self-paying patients were more likely to receive off-label antidepressants as treatment for insomnia than patients with private insurance (OR 2.594; 95% CI: 1.128–5.967.Conclusion: Our

  12. Persistence and compliance to antidepressant treatment in patients with depression: A chart review

    Directory of Open Access Journals (Sweden)

    Sawada Norifusa

    2009-06-01

    Full Text Available Abstract Background Adherence has recently been suggested to be divided into these two components: persistence (i.e., whether patients continue treatment or not and compliance (i.e., whether patients take doses as instructed. However, no study has yet assessed these two clinically relevant components at the same time in adherence to antidepressant treatment in the clinical outpatient setting. Methods In this retrospective chart-review, 6-month adherence to antidepressants was examined in 367 outpatients with a major depressive disorder (ICD-10 (170 males; mean ± SD age 37.6 ± 13.9 years, who started antidepressant treatment from April 2006 through March 2007. Additionally, we evaluated Medication Possession Rate (MPR, defined as the total days a medication was dispensed to patients divided by the treatment period. Results Only 161 patients (44.3% continued antidepressant treatment for 6 months. Among 252 patients who discontinued their initial antidepressant, 63.1% of these patients did so without consulting their physicians. Sertraline use was associated with a higher persistence rate at month 6 (odds ratio 2.59 in comparison with sulpiride, and the use of anxiolytic benzodiazepines had a positive effect on persistence to antidepressant treatment only at month 1 (odds ratio 2.14. An overall MPR was 0.77; 55.6% of patients were considered compliant (i.e., a MPR of ≥ 0.8. Conclusion Given a high rate of antidepressant discontinuation without consulting their physicians, closer communication between patients and their physicians should be encouraged. Although the use of anxiolytic benzodiazepines was associated with a higher persistence to antidepressant treatment at month 1, the use of these drugs should be avoided as a rule, given their well-known serious adverse effects.

  13. A fatal intoxication related to MDPV and pentedrone combined with antipsychotic and antidepressant substances in Cyprus.

    Science.gov (United States)

    Liveri, Katerina; Constantinou, Maria A; Afxentiou, Maria; Kanari, Popi

    2016-08-01

    This is a case report of a fatal intoxication in Cyprus related to 3,4-methylenedioxypyrovalerone (MDPV) and 2-(methylamino)-1-phenylpentan-1-one (pentedrone) intake combined with antipsychotic and antidepressant substances. A 42- year old man with a history of serious psychiatric illness was found unresponsive in his bed. Seized materials were also found close to his body. The forensic autopsy reported myocardial infarction due to multidrug intoxication. Toxicology screening in blood and urine was applied. Biological specimens were analysed by enzyme immunoassay procedure and GC/MS. MDPV, pentedrone and etizolam detected and quantitated in blood and urine. Other drugs quantitated in blood were also olanzapine, mirtazapine, and ephedrine. This was the first fatal case reported in Cyprus associated with new psychoactive substances. Additionally, this was the first case reported to Early Warning System of the European Monitoring Center of Drugs and Drug Abuse (EMCDDA), related to multidrug intoxication, attributed to the consumption of cathinones, designer benzodiazepines, and other drugs. PMID:26930452

  14. Antidepressant-like effect of centrally acting non-narcotic antitussive caramiphen in a forced swimming test.

    Science.gov (United States)

    Kawaura, Kazuaki; Miki, Risa; Shima, Eriko; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

    2010-09-13

    Recently, we reported that a centrally acting non-narcotic antitussive (cough suppressant drug), tipepidine produces an antidepressant-like effect in the forced swimming test in rats. Because pharmacological properties of tipepidine apparently differ from those of typical antidepressants developed to date, we speculated that caramiphen, another centrally acting antitussive, has an antidepressant-like effect. That effect of caramiphen was studied in rats using the forced swimming test. Caramiphen at 20 and 40mg/kg i.p. significantly reduced immobility. At 40mg/kg i.p., it increased climbing behavior. Even at 40mg/kg, this drug had no effect on locomotor activity. Results suggest that a centrally acting antitussive possessing inhibition of GIRK channels has an antidepressant-like effect. PMID:20621160

  15. Antidepressant-like effect of centrally acting non-narcotic antitussive caramiphen in a forced swimming test.

    Science.gov (United States)

    Kawaura, Kazuaki; Miki, Risa; Shima, Eriko; Honda, Sokichi; Soeda, Fumio; Shirasaki, Tetsuya; Takahama, Kazuo

    2010-09-13

    Recently, we reported that a centrally acting non-narcotic antitussive (cough suppressant drug), tipepidine produces an antidepressant-like effect in the forced swimming test in rats. Because pharmacological properties of tipepidine apparently differ from those of typical antidepressants developed to date, we speculated that caramiphen, another centrally acting antitussive, has an antidepressant-like effect. That effect of caramiphen was studied in rats using the forced swimming test. Caramiphen at 20 and 40mg/kg i.p. significantly reduced immobility. At 40mg/kg i.p., it increased climbing behavior. Even at 40mg/kg, this drug had no effect on locomotor activity. Results suggest that a centrally acting antitussive possessing inhibition of GIRK channels has an antidepressant-like effect.

  16. Antidepressant activity of standardized extract of Bacopa monniera in experimental models of depression in rats.

    Science.gov (United States)

    Sairam, K; Dorababu, M; Goel, R K; Bhattacharya, S K

    2002-04-01

    Bacopa monniera Wettst. (syn. Herpestis monniera L.; Scrophulariaceae) is a commonly used Ayurvedic drug for mental disorders. The standardized extract was reported earlier to have significant anti-oxidant effect, anxiolytic activity and improve memory retention in Alzheimer's disease. Presently, the standardized methanolic extract of Bacopa monniera (bacoside A - 38.0+/-0.9) was investigated for potential antidepressant activity in rodent models of depression. The effect was compared with the standard antidepressant drug imipramine (15 mg/kg, ip). The extract when given in the dose of 20 and 40 mg/kg, orally once daily for 5 days was found to have significant antidepressant activity in forced swim and learned helplessness models of depression and was comparable to that of imipramine.

  17. Placebo and antidepressant treatment for major depression

    DEFF Research Database (Denmark)

    Hougaard, Esben

    2010-01-01

    Antidepressant medication is generally considered the primary treatment for major depressive disorders (MDD), but antidepressant treatment has recently approached a crisis with shrinking specific effects and growing placebo responses in current trials. The aim of the paper is to review the placebo...

  18. Sleep deprivation and antidepressant treatment

    OpenAIRE

    Voderholzer, Ulrich

    2003-01-01

    The mood-improving effect of sleep deprivation (SD) in depression is even today still not fully understood. Despite the fact that mood and cognitive functions are lowered by prolonged sleep loss and despite convincing data that insomnia is a strong risk factor for subsequent depression, 1 acute SD for one night or even partial SD in the second half of the night improves mood in about 60% of depressed patients the day after. 2,3 In this respect, among alt types of antidepressant treatments, SD...

  19. Antidepressant-like action of the hydromethanolic flower extract of Tagetes erecta L. in mice and its possible mechanism of action

    Directory of Open Access Journals (Sweden)

    Aarti Khulbe

    2013-01-01

    Full Text Available Objective: Tagetes erecta, the marigold, has commercial and ethnomedicinal use; however, reports concerning its efficacy for the treatment of depression are lacking. This study was carried out to elucidate the antidepressant effect of hydromethanolic flower extract of T. erecta. Materials and Methods: Hydromethanolic extract of flowers of Tagetes erecta was subjected to preliminary phytochemical screening. The extract (12.5, 25, and 50 mg/kg, i.p. was evaluated for antidepressant effect using forced swim test in mice. The mechanism of antidepressant action was further examined using different drugs and imipramine was used as standard drug. Results: T. erecta significantly inhibited the immobility period in forced swim test in mice P<0.05. T. erecta (25 mg/kg, i.p. enhanced the anti-immobility effect of antidepressant drugs like imipramine, fluoxetine, and p-chlorophenylalanine, an inhibitor of serotonin synthesis significantly attenuated its antidepressant effect. The antidepressant effect of T. erecta in the forced swim test was prevented by pretreatment with L-arginine and sildenafil, whereas pretreatment of mice with nitric oxide synthase inhibitors potentiated the action. Pentazocine, a high-affinity sigma receptor agonist, produced synergism with effective dose of T. erecta while progesterone, a sigma receptor antagonist, reversed the antidepressant effect of T. erecta. However, the locomotor activity was not affected at tested doses. Conclusions: Serotonergic, nitrergic pathway, and sigma receptors are possibly involved in mediating antidepressant action of T. erecta in mouse forced swim test.

  20. IN SILICO MODELLING AND DRUG DESIGN – A REVIEW

    Directory of Open Access Journals (Sweden)

    Gupta Praveen kumar

    2011-09-01

    Full Text Available Bioinformatics and Computational biology is an interdisciplinary field that applies the techniques of computer science, applied mathematics and statistics to address biological problems. Research in computational biology often overlaps with systems biology. Major research efforts in the field include sequence alignment, gene finding, genome assembly, protein structure alignment, protein structure prediction, prediction of gene expression and protein-protein interactions, and the in silico drug modelling. Drug discovery is an intense, lengthy and interdisciplinary endeavour. It is mostly portrayed as a linear, consecutive process that starts with target and lead discovery, followed by lead optimization and pre-clinical in vivo and in vitro studies to determine if such compounds satisfy a numbers of pre-set criteria for initiating clinical developments. In silico methods help in identifying drug targets via bioinformatics tools. They can be used to analyze the target structures for possible binding sites, generate candidate molecules, check for their drug likeness, dock these molecules with the target, rank them according to their binding affinities and further optimize the molecules to improve binding characteristics.

  1. Effects of antidepressants on P2X7 receptors.

    Science.gov (United States)

    Wang, Wei; Xiang, Zheng-Hua; Jiang, Chun-Lei; Liu, Wei-Zhi; Shang, Zhi-Lei

    2016-08-30

    Antidepressants including paroxetine, fluoxetine and desipramine are commonly used for treating depression. P2×7 receptors are member of the P2X family. Recent studies indicate that these receptors may constitute a novel potential target for the treatment of depression. In the present study, we examined the action of these antidepressants on cloned rat P2×7 receptors that were stably expressed in human embryonic kidney (HEK) 293 cells by using the whole-cell patch-clamp technique, and found that paroxetine at a dose of 10µM could significantly reduce the inward currents evoked by the P2×7 receptors agonist BzATP by pre-incubation for 6-12 but not by acute application (10µM) or pre-incubation for 2-6h at a dose of 1µM, 3µM or 10µM paroxetine. Neither fluoxetine nor desipramine had significant effects on currents evoked by BzATP either applied acutely or by pre-incubation at various concentrations. These results suggest that the sensitivity of rat P2×7 receptors to antidepressants is different, which may represent an unknown mechanism by which these drugs exert their therapeutic effects and side effects. PMID:27318632

  2. 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.

  3. Beyond THC: the new generation of cannabinoid designer drugs

    Directory of Open Access Journals (Sweden)

    Liana eFattore

    2011-09-01

    Full Text Available Synthetic cannabinoids are functionally similar to delta9-tetrahydrocannabinol (THC, the psychoactive principle of cannabis, and bind to the same cannabinoid receptors in the brain and peripheral organs. From 2008, synthetic cannabinoids were detected in herbal smoking mixtures sold on websites and in head shops under the brand name of Spice Gold, Yucatan Fire, Aroma, and others. Although these products (also known as Spice drugs or legal highs do not contain tobacco or cannabis, when smoked they produce effects similar to THC. Intoxication, withdrawal, psychosis and death have been recently reported after consumption, posing difficult social, political and health challenges. More than 140 different Spice products have been identified to date. The ability to induce strong cannabis-like psychoactive effects, along with the fact that they are readily available on the Internet, still legal in many countries, marketed as natural safe substances, and undetectable by conventional drug screening tests, has rendered these drugs very popular and particularly appealing to young and drug-naïve individuals seeking new experiences. An escalating number of compounds with cannabinoid receptor activity are currently being found as ingredients of Spice, of which almost nothing is known in terms of pharmacology, toxicology and safety. Since legislation started to control the synthetic cannabinoids identified in these herbal mixtures, many new analogs have appeared on the market. New cannabimimetic compounds are likely to be synthesized in the near future to replace banned synthetic cannabinoids, leading to a dog chasing its tail situation. Spice smokers are exposed to drugs that are extremely variable in composition and potency, and are at risk of serious, if not lethal, outcomes. Social and health professionals should maintain a high degree of alertness for Spice use and its possible psychiatric effects in vulnerable people.

  4. Evaluation of anti-depressant and anxiolytic activity of Rasayana Ghana Tablet (A compound Ayurvedic formulation) in albino mice

    OpenAIRE

    Deole, Yogesh S.; Chavan, Sulakshan S.; Ashok, B. K.; Ravishankar, B.; Thakar, A.B.; Chandola, H. M.

    2011-01-01

    In recent years, many Ayurvedic formulations are being researched to provide an effective antidepressant and anxiolytic drug in the field of psycho-pharmacology. The present study was planned to evaluate the anti-depressant and anxiolytic activity of Rasayana Ghana Tablet comprising three herbs Guduchi (Tinospora cordifolia Miers), Aamalaki (Emblica officinalis Garten) (RGT) and Gokshura (Tribulus terrestris Linn). Swiss albino mice were divided into four groups of six animals each, comprisin...

  5. Hippocampal-Dependent Antidepressant Action of the H3 Receptor Antagonist Clobenpropit in a Rat Model of Depression

    OpenAIRE

    Femenía, Teresa; Magara, Salvatore; DuPont, Caitlin M.; Lindskog, Maria

    2015-01-01

    Background: Histamine is a modulatory neurotransmitter regulating neuronal activity. Antidepressant drugs target modulatory neurotransmitters, thus ultimately regulating glutamatergic transmission and plasticity. Histamine H3 receptor (H3R) antagonists have both pro-cognitive and antidepressant effects; however, the mechanism by which they modulate glutamate transmission is not clear. We measured the effects of the H3R antagonist clobenpropit in the Flinders Sensitive Line (FSL), a rat model ...

  6. Design, development and optimization of selfmicroemulsifying drug delivery system of an anti-obesity drug

    Directory of Open Access Journals (Sweden)

    Jagruti Desai

    2012-01-01

    Full Text Available The aim of the present work was to formulate a self-microemulsifying drug delivery system (SMEDDS containing orlistat. The oil, surfactant and co-surfactant were decided based on the solubility studies. Pseudoternary phase diagrams were plotted, microemulsification area was determined and different formulations were prepared. Particle size, zeta potential, dispersibility test and thermodynamic stability studies were measured. In-vitro dissolution test of thermodynamically stable formulations OS-B and OS-C were carried and results were compared with those of plain drug and suspension formulation. Stability studies performed indicated that formulation OS-C remained stable over 12 months period. Thus this investigation concluded that hydrophobic drugs like orlistat can be delivered effectively through the formulation of SMEDDS.

  7. Drug: D08670 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available nlafaxine D08670 Venlafaxine (INN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective...axine (INN) Anxiolytics SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/Sero

  8. Drug: D08469 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 4728(4129) Dopaminergic synapse map07027 Antidepressants map07057 Antiparkinsonia...hibitors N04BD02 Rasagiline D08469 Rasagiline (USAN/INN) USP drug classification [BR:br08302] Antiparkins

  9. Miniaturization In Rational drug design of Pharmaceuticals – A Review

    OpenAIRE

    Ghazala Yasmeen; Mohd. Ibrahim; V. Murli Balram; S. Imam Pasha; Sadaf Rahman; Mohsina Abid

    2016-01-01

    Miniaturization in High Throughput Screening (HTS) is perceived as essential by pharmaceutical screening laboratories to accommodate the enormous increase in compounds and targets over the past few years. The two primary goals are to increase throughput while decreasing costs. The ability to perform primary screening assays in high-density micro-well plates at volumes of 1–2µl will accelerate the early stages of drug discovery. Ultra-HTS (uHTS) assays require an accurate and reliable means of...

  10. Drug: D01546 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01546 Drug Dosulepin hydrochloride (JAN); Dothiepin hydrochloride (USAN); Dosulepi...6 Tricyclic antidepressants serotonin transporter inhibitor [HSA:6532] [KO:K05037]; noradrenalin transporter...nts map07234 Neurotransmitter transporter inhibitors Therapeutic category of drugs in Japan [BR:br08301] 1 A...cs 1179 Others D01546 Dosulepin hydrochloride (JAN); Dothiepin hydrochloride (USA...06A ANTIDEPRESSANTS N06AA Non-selective monoamine reuptake inhibitors N06AA16 Dosulepin D01546 Dosulepin hydr

  11. Declining efficacy in controlled trials of antidepressants: effects of placebo dropout

    NARCIS (Netherlands)

    Schalkwijk, S.J.; Undurraga, J.; Tondo, L.; Baldessarini, R.J.

    2014-01-01

    Drug-placebo differences (effect-sizes) in controlled trials of antidepressants for major depressive episodes have declined for several decades, in association with selectively increasing clinical improvement associated with placebo-treatment. As these trends require adequate explanation, we tested

  12. Ketamine enantiomers in the rapid and sustained antidepressant effects.

    Science.gov (United States)

    Muller, John; Pentyala, Sahana; Dilger, James; Pentyala, Srinivas

    2016-06-01

    Recent evidence has suggested that the N-methyl-D-aspartate receptor antagonist ketamine shows significant therapeutic effects in major depression and bipolar disorder. This effect is especially important in treatment-resistant depression and depression with suicidal ideation. In this review we explain the mechanism of action, drug efficacy, and the side effects of ketamine; the antidepressive effects of ketamine; the individual effects of ketamine isomers, R(-) ketamine and S(+) ketamine; the effects of the combination of ketamine with electroconvulsive therapy; and the possible use of ketamine in treating depression. PMID:27354907

  13. Application of Design of Experiment for Floating Drug Delivery of Tapentadol Hydrochloride

    OpenAIRE

    Jagdale, Swati C.; Somnath Patil; KUCHEKAR, BHANUDAS S.

    2013-01-01

    The aim of the present study was to apply design of experiment (DOE) to optimize floating drug delivery of tapentadol hydrochloride. Tapentadol hydrochloride is a synthetic opioid used as a centrally acting analgesic and effective in both experimental and clinical pain. The half-life of the drug is about 4 hours and oral dose is 50 to 250 mg twice a day. For optimization 32 full factorial design was employed for formulation of tapentadol hydrochloride tablets. Sodium bicarbonate was incorpora...

  14. Scientists meet in Lugano, share Computational Methods in Drug Design research

    OpenAIRE

    Micale, Barbara L.

    2005-01-01

    More than 20 stellar scientists from the United States and Europe convened for a three-day symposium recently at Casa Maderni, Virginia Tech's Center for European Studies and Architecture at Riva San Vitale, Switzerland, to discuss the scientific challenges associated with new opportunities to exploit computational approaches to drug design. The group shared research studies and findings during the symposium, Looking to the Future: Computational Methods in Drug Design, sponsored by Virginia T...

  15. Improving Protocol Design Feasibility to Drive Drug Development Economics and Performance

    OpenAIRE

    Kenneth Getz

    2014-01-01

    Protocol design complexity has increased substantially during the past decade and this in turn has adversely impacted drug development economics and performance. This article reviews the results of two major Tufts Center for the Study of Drug Development studies quantifying the direct cost of conducting less essential and unnecessary protocol procedures and of implementing amendments to protocol designs. Indirect costs including personnel time, work load and cycle time delays associated with...

  16. Relabeling the Medications We Call Antidepressants

    Directory of Open Access Journals (Sweden)

    David Antonuccio

    2012-01-01

    Full Text Available This paper raises the question about whether the data on the medications we call antidepressants justify the label of antidepressant. The authors argue that a true antidepressant should be clearly superior to placebo, should offer a risk/benefit balance that exceeds that of alternative treatments, should not increase suicidality, should not increase anxiety and agitation, should not interfere with sexual functioning, and should not increase depression chronicity. Unfortunately, these medications appear to fall short on all of these dimensions. Many of the “side effects” of these medications have larger effect sizes than the antidepressant effect size. To call these medications antidepressants may make sense from a marketing standpoint but may be misleading from a scientific perspective. Consumers deserve a label that more accurately reflects the data on the largest effects and helps them understand the range of effects from these medications. In other words, it may make just as much sense to call these medications antiaphrodisiacs as antidepressants because the negative effects on libido and sexual functioning are so common. It can be argued that a misleading label may interfere with our commitment to informed consent. Therefore, it may be time to stop calling these medications antidepressants.

  17. 75 FR 37818 - Issues in the Design and Conduct of Clinical Trials for Antibacterial Drug Development; Public...

    Science.gov (United States)

    2010-06-30

    ... HUMAN SERVICES Food and Drug Administration Issues in the Design and Conduct of Clinical Trials for... regarding scientific issues in the design and conduct of clinical trials for antibacterial drug development... clinical trials for antibacterial drugs. The workshop will focus on the design and conduct of...

  18. TRPV1: A Target for Rational Drug Design.

    Science.gov (United States)

    Carnevale, Vincenzo; Rohacs, Tibor

    2016-01-01

    Transient Receptor Potential Vanilloid 1 (TRPV1) is a non-selective, Ca(2+) 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. PMID:27563913

  19. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.;

    2008-01-01

    the diffusion of neutral and ionic molecules across biomembranes, protonation to mono- or bivalent ions, adsorption to lipids, and electrical attraction or repulsion. Based on simulation results, high and selective accumulation in lysosomes was found for weak mono- and bivalent bases with intermediate to high...... predicted by the model and three were close. Five of the antimalarial drugs were lipophilic weak dibasic compounds. The predicted optimum properties for a selective accumulation of weak bivalent bases in lysosomes are consistent with experimental values and are more accurate than any prior calculation...

  20. Acid-mediated Lipinski’s second rule: application to drug design and targeting in cancer

    OpenAIRE

    Omran, Ziad; Rauch, Cyril

    2014-01-01

    With a predicted 382.4 per 100,000 people expected to suffer from some form of malignant neoplasm by 2015, and a current death toll of 1 out of 8 deaths worldwide, improving treatment and/or drug design is an essential focus of cancer research. Multi-drug resistance is the leading cause of chemotherapeutic failure, and delivery of anticancer drugs to the inside of cancerous cells is another major challenge. Fifteen years ago, in a completely different field in which improving drug delivery is...

  1. Standardized Design and Application Analysis of Drug Consultation in Psychiatric Hospital%精神病专科医院药物咨询服务模式的规范化设计与应用分析

    Institute of Scientific and Technical Information of China (English)

    秦颖; 于浚玫; 王莹

    2013-01-01

    目的:指导精神病患者合理用药,提高患者的用药依从性.方法:介绍我院药物咨询服务模式的规范化设计,并对2011年1 200例门诊药物咨询服务记录进行分析.结果:患者及家属是药物咨询的主体;咨询问题所涉及的药品种类主要为抗精神病药、抗抑郁药、镇静催眠药等;咨询问题主要包括药品不良反应、特殊人群用药、药品作用机制等相关问题.结论:精神病专科医院开展药物咨询服务对促进患者合理用药和提高临床疗效具有积极的意义.%OBJECTIVE: To offering guidance for psychiatric patients about rational drug use and improve patient' s compliance. METHODS: The standardized design of drug consultation in our hospital was introduced. The drug consultation records of 1 200 cases in 2011 were analyzed statistically. RESULTS: Patients and patients' families were the main groups of the counseling. The type of drugs involved mainly were antipsychotics, antidepressants and sedative and hypnotics. The main contents of counseling included adverse drug reactions, drug use for special groups and pharmacological action. CONCLUSION: There is positive significance to promote rational drug use and improve clinical efficacy by developing the drug consultation service in psychiatric hospital.

  2. α1A- and α1B-Adrenergic Receptors Differentially Modulate Antidepressant-Like Behavior in the Mouse

    OpenAIRE

    Doze, Van A.; Handel, Evelyn M.; Jensen, Kelly A.; Darsie, Belle; Luger, Elizabeth J.; Haselton, James R.; Talbot, Jeffery N.; Rorabaugh, Boyd R.

    2009-01-01

    Tricyclic antidepressant (TCA) drugs are used for the treatment of chronic depression, obsessive compulsive disorder (OCD), and anxiety-related disorders. Chronic use of TCA drugs increases the expression of α1-adrenergic receptors (α1-ARs). Yet, it is unclear whether increased α1-AR expression contributes to the antidepressant effects of these drugs or if this effect is unrelated to their therapeutic benefit. In this study, mice expressing constitutively active mutant α1A-ARs (CAM α1A-AR) or...

  3. Sildenafil, a phosphodiesterase type 5 inhibitor, enhances the antidepressant activity of amitriptyline but not desipramine, in the forced swim test in mice.

    Science.gov (United States)

    Socała, Katarzyna; Nieoczym, Dorota; Wyska, Elżbieta; Poleszak, Ewa; Wlaź, Piotr

    2012-06-01

    The cholinergic theory of depression highlights the involvement of muscarinic acetylcholine receptors in the neurobiology of mood disorders. The present study was designed to investigate the effect of sildenafil, a phosphodiesterase type 5 inhibitor which exhibits cholinomimetic properties, alone and in combination with scopolamine in the forced swim test in mice. Moreover, we assessed the ability of sildenafil to modify the antidepressant activity of two tricyclic antidepressants with distinct cholinolytic activity, amitriptyline and desipramine. Swim sessions were conducted by placing mice in glass cylinders filled with water for 6 min and the duration of behavioral immobility during the last 4 min of the test was evaluated. Locomotor activity was measured with photoresistor actimeters. To evaluate the potential pharmacokinetic interaction between amitriptyline and sildenafil, brain and serum concentrations of amitriptyline were determined by HPLC. Sildenafil (1.25-20 mg/kg) as well as scopolamine (0.5 mg/kg) and its combination with sildenafil (1.25 mg/kg) did not affect the total immobility time duration. However, joint administration of scopolamine with sildenafil at doses of 2.5 and 5 mg/kg significantly reduced immobility time as compared to control group. Moreover, co-administration of scopolamine with sildenafil at the highest dose (5 mg/kg) significantly decreased immobility time as compared to scopolamine-treated group. Sildenafil (1.25, 2.5 and 5 mg/kg) significantly enhanced the antidepressant activity of amitriptyline (5 mg/kg). No changes in anti-immobility action of desipramine (20 mg/kg) in combination with sildenafil (5, 10 and 20 mg/kg) were observed. Sildenafil did not affect amitriptyline level in both brain and serum. In conclusion, the present study suggests that sildenafil may enhance the activity of antidepressant drugs which exhibit cholinolytic activity.

  4. Improving protocol design feasibility to drive drug development economics and performance.

    Science.gov (United States)

    Getz, Kenneth

    2014-05-01

    Protocol design complexity has increased substantially during the past decade and this in turn has adversely impacted drug development economics and performance. This article reviews the results of two major Tufts Center for the Study of Drug Development studies quantifying the direct cost of conducting less essential and unnecessary protocol procedures and of implementing amendments to protocol designs. Indirect costs including personnel time, work load and cycle time delays associated with complex protocol designs are also discussed. The author concludes with an overview of steps that research sponsors are taking to improve protocol design feasibility. PMID:24823665

  5. Computer-Aided Drug Design of Bioactive Natural Products.

    Science.gov (United States)

    Prachayasittikul, Veda; Worachartcheewan, Apilak; Shoombuatong, Watshara; Songtawee, Napat; Simeon, Saw; Prachayasittikul, Virapong; Nantasenamat, Chanin

    2015-01-01

    Natural products have been an integral part of sustaining civilizations because of their medicinal properties. Past discoveries of bioactive natural products have relied on serendipity, and these compounds serve as inspiration for the generation of analogs with desired physicochemical properties. Bioactive natural products with therapeutic potential are abundantly available in nature and some of them are beyond exploration by conventional methods. The effectiveness of computational approaches as versatile tools for facilitating drug discovery and development has been recognized for decades, without exception, in the case of natural products. In the post-genomic era, scientists are bombarded with data produced by advanced technologies. Thus, rendering these data into knowledge that is interpretable and meaningful becomes an essential issue. In this regard, computational approaches utilize the existing data to generate knowledge that provides valuable understanding for addressing current problems and guiding the further research and development of new natural-derived drugs. Furthermore, several medicinal plants have been continuously used in many traditional medicine systems since antiquity throughout the world, and their mechanisms have not yet been elucidated. Therefore, the utilization of computational approaches and advanced synthetic techniques would yield great benefit to improving the world's health population and well-being.

  6. [Comparative study of discriminative stimulus properties of antidepressants].

    Science.gov (United States)

    Korolev, A O; Kalinina, T S; Volkova, A V; Mokrov, G V; Kudriashov, N V; Voronina, T A

    2014-01-01

    Interoceptive stimulus properties of amitriptyline (54 mg/kg body weight), fluoxetine (10 mg/kg), and pyrrolo[1,2-a][1,4]diazepine derivative GMAL-24 (10 mg/kg) were studied in a standard operant model with liquid reinforcement of drug discrimination (DD) in male Wistar rats. A new experimental schedule that includes subchronic (7-day) administration of a training drug was used to perform DD learning. For the first time, it was found that amitriptyline has a discriminative interoceptive stimulus properties. Neither fluoxetine nor GMAL-24 did exhibit interoceptive properties. Imipramine (15 mg/kg, i.p.) fully substitutes for amitriptyline stimulus in substitution test. Fluoxetine (5 - 20 mg/kg, i.p.) failed to substitute with amitriptyline. Thus, amitriptyline/saline drug discrimination should be used for a comparative analysis of the central mechanisms of action of psychotropic substances, rather than for screening specific antidepressant activity. PMID:25322645

  7. 去甲肾上腺素转运体基因多态性与环境对抗抑郁药物疗效的影响%Influence and interaction of genetic polymorphisms in norepinephrine transporter and enviroment on antidepressant drug response

    Institute of Scientific and Technical Information of China (English)

    徐治; 张志珺; 袁勇贵; 李磊; 汪天宇

    2015-01-01

    Objective To determine how genetic polymorphisms in norepinephrine transporter (NET) gene influence the response of antidepressant treatment and how they interact with childhood trauma and recent life stress in a Chinese depressive patients.Methods 281 Chinese Han depressive patients received single antidepressant drugs for 6 weeks.Hamilton Depression Scale-17 (HAMD-17),the Childhood Trauma Questionnaire short term (CTQ-SF) and the Life Events Scale (LES) were used to evaluate severity of depressive symptoms and the occurrence of stressful life events respectively.Three single nucleotide polymorphisms (SNPs) in norepinephrine transporter were genotyped.Associations of single locus and haplotypes with antidepressant treatment response were analyzed using UNPHASED 3.0.13.The interaction of gene and life stress was analyzed by SPSS13.0 software.Results One NET SNP rs2242446 was significantly associated with antidepressant response in this Chinese male sample(0.4118vs0.2375,x2=7.046,P=0.0079,OR=0.445,95% CI (0.243-0.815)),as was the haplotype CG(rs2242446 and rs5569;x2 =5.886,P=0.0153,OR=0.457,95% CI (0.198-1.054)) and another haplotype CG-G(rs2242446,rs1532701 and rs5569;x2=5.360,P=0.0206,OR=0.530,95% CI (0.202-1.386)) of NET in male samples.The NET SNPs rs5569 demonstrated interaction with childhood trauma to influence antidepressant response(β=-2.727,SE =1.195,P=0.023,OR=0.065,95% CI (0.006-0.681)).Conclusion Antidepressant drug response was influenced by not only NET genetic polymorphisms in norepinephrine transporter gene but also interaction between the NET genetic polymorphisms and early life stress.%目的 探讨去甲肾上腺素转运体(NET)基因多态性与抗抑郁剂疗效的相关性,以及基因和环境相互作用对抗抑郁药物疗效的影响.方法 281例符合入组标准的抑郁症患者给予抗抑郁剂治疗,随访6周,采用17项汉密尔顿抑郁量表(HAMD-17)评定抗抑郁疗效,采用Illumina Golden Gate定制芯片测定

  8. Antidepressant or Antipsychotic Overdose in the Intensive Care Unit - Identification of Patients at Risk

    DEFF Research Database (Denmark)

    Borg, Linda; Julkunen, Anna; Madsen, Kristian Rørbaek;

    2016-01-01

    adverse signs at hospital admission that turned out to need intensive care treatment. The effect of the antidepressants overdose risk assessment (ADORA) system was evaluated in patients with antidepressant as well as antipsychotic overdose. Our hypothesis was that patients with low ADORA do not need...... obvious need of intensive care. Of the 157 patients included, 12 patients (8%) developed events during the ICU stay. Only 3 patients received intubation, vasoactive drugs and/or dialysis. None developed ventricular dysrhythmias. There were no fatalities. All the patients with low-risk assessment by ADORA...

  9. Unsteady jet in designing innovative drug delivery system

    Science.gov (United States)

    Wang, Cong; Mazur, Paul; Cosse, Julia; Rider, Stephanie; Gharib, Morteza

    2014-11-01

    Micro-needle injections, a promising pain-free drug delivery method, is constrained by its limited penetration depth. This deficiency can be overcome by implementing fast unsteady jet that can penetrate sub-dermally. The development of a faster liquid jet would increase the penetration depth and delivery volume of micro-needles. In this preliminary work, the nonlinear transient behavior of an elastic tube balloon in providing fast discharge is analyzed. A physical model that combines the Mooney Rivlin Material model and Young-Lapalce's Law was developed and used to investigate the fast discharging dynamic phenomenon. A proof of concept prototype was constructed to demonstrate the feasibility of a simple thumb-sized delivery system to generate liquid jet with desired speed in the range of 5-10 m/s. This work is supported by ZCUBE Corporation.

  10. Design of Drug Delivery Methods for the Brain and Central Nervous System

    Science.gov (United States)

    Lueshen, Eric

    Due to the impermeability of the blood-brain barrier (BBB) to macromolecules delivered systemically, drug delivery to the brain and central nervous system (CNS) is quite difficult and has become an area of intense research. Techniques such as convection-enhanced intraparenchymal delivery and intrathecal magnetic drug targeting offer a means of circumventing the blood-brain barrier for targeted delivery of therapeutics. This dissertation focuses on three aspects of drug delivery: pharmacokinetics, convection-enhanced delivery, and intrathecal magnetic drug targeting. Classical pharmacokinetics mainly uses black-box curve fitting techniques without biochemical or biological basis. This dissertation advances the state-of-the-art of pharmacokinetics and pharmacodynamics by incorporating first principles and biochemical/biotransport mechanisms in the prediction of drug fate in vivo. A whole body physiologically-based pharmacokinetics (PBPK) modeling framework is engineered which creates multiscale mathematical models for entire organisms composed of organs, tissues, and a detailed vasculature network to predict drug bioaccumulation and to rigorously determine kinetic parameters. These models can be specialized to account for species, weight, gender, age, and pathology. Systematic individual therapy design using the proposed mechanistic PBPK modeling framework is also a possibility. Biochemical, anatomical, and physiological scaling laws are also developed to accurately project drug kinetics in humans from small animal experiments. Our promising results demonstrate that the whole-body mechanistic PBPK modeling approach not only elucidates drug mechanisms from a biochemical standpoint, but offers better scaling precision. Better models can substantially accelerate the introduction of drug leads to clinical trials and eventually to the market by offering more understanding of the drug mechanisms, aiding in therapy design, and serving as an accurate dosing tool. Convection

  11. Second-tier natural antidepressants: review and critique.

    Science.gov (United States)

    Iovieno, Nadia; Dalton, Elizabeth D; Fava, Maurizio; Mischoulon, David

    2011-05-01

    The use of Complementary and Alternative Medicine (CAM) for physical and mental problems has increased significantly in the US over the past two decades, and depression is one of the leading indications for the use of CAM. This article reviews some of the lesser-known natural products with potential psychiatric applications that are starting to emerge with some scientific and clinical evidence and may constitute a next wave of natural antidepressants: Rhodiola rosea, chromium, 5-Hydroxytryptophan (5-HTP) and inositol. Background information, efficacy data, proposed mechanisms of action, recommended doses, side effects, and precautions are reviewed. We found some encouraging data for the use of these natural products in specific populations of depressed patients. R. rosea is an adaptogen plant that can be especially helpful in treating asthenic or lethargic depression, and may be combined with conventional antidepressants to alleviate some of their common side effects. Chromium has a beneficial effect on eating-related atypical symptoms of depression, and may be a valuable agent in treating atypical depression and seasonal affective disorder. Inositol may be useful in the treatment of bipolar depression when combined with mood stabilizers. Evidence for the clinical efficacy of 5-HTP is also promising but still preliminary. Although more well-designed and larger controlled studies are needed before any substantive conclusions can be drawn, the available evidence is compelling and these natural products deserve further investigation as a possibly significant addition to the antidepressant armamentarium. PMID:20579741

  12. Diverse antidepressants increase CDP-diacylglycerol production and phosphatidylinositide resynthesis in depression-relevant regions of the rat brain

    Directory of Open Access Journals (Sweden)

    Undieh Ashiwel S

    2008-01-01

    Full Text Available Abstract Background Major depression is a serious mood disorder affecting millions of adults and children worldwide. While the etiopathology of depression remains obscure, antidepressant medications increase synaptic levels of monoamine neurotransmitters in brain regions associated with the disease. Monoamine transmitters activate multiple signaling cascades some of which have been investigated as potential mediators of depression or antidepressant drug action. However, the diacylglycerol arm of phosphoinositide signaling cascades has not been systematically investigated, even though downstream targets of this cascade have been implicated in depression. With the ultimate goal of uncovering the primary postsynaptic actions that may initiate cellular antidepressive signaling, we have examined the antidepressant-induced production of CDP-diacylglycerol which is both a product of diacylglycerol phosphorylation and a precursor for the synthesis of physiologically critical glycerophospholipids such as the phosphatidylinositides. For this, drug effects on [3H]cytidine-labeled CDP-diacylglycerol and [3H]inositol-labeled phosphatidylinositides were measured in response to the tricyclics desipramine and imipramine, the selective serotonin reuptake inhibitors fluoxetine and paroxetine, the atypical antidepressants maprotiline and nomifensine, and several monoamine oxidase inhibitors. Results Multiple compounds from each antidepressant category significantly stimulated [3H]CDP-diacylglycerol accumulation in cerebrocortical, hippocampal, and striatal tissues, and also enhanced the resynthesis of inositol phospholipids. Conversely, various antipsychotics, anxiolytics, and non-antidepressant psychotropic agents failed to significantly induce CDP-diacylglycerol or phosphoinositide synthesis. Drug-induced CDP-diacylglycerol accumulation was independent of lithium and only partially dependent on phosphoinositide hydrolysis, thus indicating that antidepressants

  13. Breast cancer resistance protein (ABCG2) in clinical pharmacokinetics and drug interactions: practical recommendations for clinical victim and perpetrator drug-drug interaction study design.

    Science.gov (United States)

    Lee, Caroline A; O'Connor, Meeghan A; Ritchie, Tasha K; Galetin, Aleksandra; Cook, Jack A; Ragueneau-Majlessi, Isabelle; Ellens, Harma; Feng, Bo; Taub, Mitchell E; Paine, Mary F; Polli, Joseph W; Ware, Joseph A; Zamek-Gliszczynski, Maciej J

    2015-04-01

    Breast cancer resistance protein (BCRP; ABCG2) limits intestinal absorption of low-permeability substrate drugs and mediates biliary excretion of drugs and metabolites. Based on clinical evidence of BCRP-mediated drug-drug interactions (DDIs) and the c.421C>A functional polymorphism affecting drug efficacy and safety, both the US Food and Drug Administration and European Medicines Agency recommend preclinical evaluation and, when appropriate, clinical assessment of BCRP-mediated DDIs. Although many BCRP substrates and inhibitors have been identified in vitro, clinical translation has been confounded by overlap with other transporters and metabolic enzymes. Regulatory recommendations for BCRP-mediated clinical DDI studies are challenging, as consensus is lacking on the choice of the most robust and specific human BCRP substrates and inhibitors and optimal study design. This review proposes a path forward based on a comprehensive analysis of available data. Oral sulfasalazine (1000 mg, immediate-release tablet) is the best available clinical substrate for intestinal BCRP, oral rosuvastatin (20 mg) for both intestinal and hepatic BCRP, and intravenous rosuvastatin (4 mg) for hepatic BCRP. Oral curcumin (2000 mg) and lapatinib (250 mg) are the best available clinical BCRP inhibitors. To interrogate the worst-case clinical BCRP DDI scenario, study subjects harboring the BCRP c.421C/C reference genotype are recommended. In addition, if sulfasalazine is selected as the substrate, subjects having the rapid acetylator phenotype are recommended. In the case of rosuvastatin, subjects with the organic anion-transporting polypeptide 1B1 c.521T/T genotype are recommended, together with monitoring of rosuvastatin's cholesterol-lowering effect at baseline and DDI phase. A proof-of-concept clinical study is being planned by a collaborative consortium to evaluate the proposed BCRP DDI study design. PMID:25587128

  14. Extracorporeal treatment for tricyclic antidepressant poisoning

    DEFF Research Database (Denmark)

    Yates, Christopher; Galvao, Tais; Sowinski, Kevin M;

    2014-01-01

    The Extracorporeal Treatments In Poisoning (EXTRIP) workgroup was formed to provide recommendations on the use of extracorporeal treatments (ECTR) in poisoning. Here, the workgroup presents its results for tricyclic antidepressants (TCAs). After an extensive literature search, using a predefined ...

  15. Antidepressant potential of nitrogen-containing heterocyclic moieties: An updated review

    Directory of Open Access Journals (Sweden)

    Nadeem Siddiqui

    2011-01-01

    Full Text Available Depression is currently the fourth leading cause of disease or disability worldwide. Antidepressant is approved for the treatment of major depression (including paediatric depression, obsessive-compulsive disorder (in both adult and paediatric populations, bulimia nervosa, panic disorder and premenstrual dysphoric disorder. Antidepressant is a psychiatric medication used to alleviate mood disorders, such as major depression and dysthymia and anxiety disorders such as social anxiety disorder. Many drugs produce an antidepressant effect, but restrictions on their use have caused controversy and off-label prescription a risk, despite claims of superior efficacy. Our current understanding of its pathogenesis is limited and existing treatments are inadequate, providing relief to only a subset of people suffering from depression. Reviews of literature suggest that heterocyclic moieties and their derivatives has proven success in treating depression.

  16. Naturally surveilled space: the design of a male drug rehabilitation center

    Science.gov (United States)

    Permana, A. R.; Aryanti, T.; Rahmanullah, F.

    2016-04-01

    The increase of drug addicts in Indonesia has not been supported by adequate facilities, both quantitatively and qualitatively. Despite being treated in a rehabilitation center, drug addicts may still use drugs surreptitiously and put themselves in danger. Architectural design may contribute to this either positively or negatively. This article elaborates a therapeutic design of a male rehabilitation center in the borderland of Bandung city, Indonesia. Employing the notion of natural surveillance, the rehabilitation center is designed to allow continual control over attendees without them feeling suppressed. The center design uses the behavioral approach to consider both attendees’ physical and psychological comforts, as well as their security. Building masses are designed in a way that forms an inward orientation and are laid out circularly according to the therapy processes that attendees must undertake. Moreover, rooms are planned differently in response to attendees’ unique conditions and restrictive physical requirements, such as their restriction on lighting and requirement of water for treatment. The landscape uses shady trees and vegetations as natural borders to demarcate the private zone, where attendees live, from the public area, where visitors may enter. The design is intended to provide a model for a responsive drug rehabilitation center that facilitates drug addicts’ recovery.

  17. Modifying 5-HT1A receptor gene expression as a new target for antidepressant therapy

    Directory of Open Access Journals (Sweden)

    Paul R Albert

    2010-06-01

    Full Text Available Major depression is the most common form of mental illness, and is treated with antidepressant compounds that increase serotonin (5-HT neurotransmission. Increased 5-HT1A autoreceptor levels in the raphe nuclei act as a “brake” to inhibit the 5-HT system, leading to depression and resistance to antidepressants. Several 5-HT1A receptor agonists (buspirone, flesinoxan, ipsapirone that preferentially desensitize 5-HT1A autoreceptors have been tested for augmentation of antidepressant drugs with mixed results. One explanation could be the presence of the C(-1019G 5-HT1A promoter polymorphism that prevents gene repression of the 5-HT1A autoreceptor. Furthermore, down-regulation of 5-HT1A autoreceptor expression, not simply desensitization of receptor signaling, appears to be required to enhance and accelerate antidepressant action. The current review focuses on the transcriptional regulators of 5-HT1A autoreceptor expression, their roles in permitting response to 5-HT1A-targeted treatments and their potential as targets for new antidepressant compounds for treatment-resistant depression.

  18. [Antidepressant-resistant depression and bipolar spectrum - diagnostic and therapeutic considerations].

    Science.gov (United States)

    Rihmer, Zoltán; Gonda, Xénia; Rihmer, Annamária; Döme, Péter

    2016-01-01

    According to the results of epidemiological studies mood disorders with unipolar (major and minor depressive disorder; dysthymia) or bipolar features are among the most prevalent psychiatric disorders. These disorders with their frequent comorbidities (alcohol and/or drug use disorders, smoking, suicide, cardiovascular disorders) pose great public health challenge and cause substantial individual and familar burdens as well. Since SSRIs and other new antidepressant agents entered the market the possibilities to treat depression improved substantially but 25-35 percent of major depressives do not respond even to the second antidepressant trial but the rate of patients who are resistant after the third and fourth adequate antidepressant trial are around only 15-25 and 10 percent, respectively. Pharmacotherapy-resistant depression is a multicausal phenomenon. Along with its well-known risk-factors investigations of the past decade have revealed that unrecognised or hidden (subsyndromal or subthreshold) bipolarity is one of the most frequent causes of treatment resistance. In the case of bipolar depression (either as a part of syndromal bipolar I or II disorder or a subsyndromal manifestation) antidepressant monotherapy should be avoided and, instead of it, the administration of a mood stabilizer (primarily lithium and lamotrigine) or some atypical antipsychotics (preferably quetiapine) are recommended. If antidepressant is inevitably necessary in bipolar depression, we should use it always in combination with mood stabilizers or atypical antipsychotics. PMID:27244871

  19. Effects of BDNF Polymorphisms on Antidepressant Action

    OpenAIRE

    Tsai, Shih-Jen; Hong, Chen-Jee; Liou, Ying-Jay

    2010-01-01

    Evidence suggests that the down-regulation of the signaling pathway involving brain-derived neurotrophic factor (BDNF), a molecular element known to regulate neuronal plasticity and survival, plays an important role in the pathogenesis of major depression. The restoration of BDNF activity induced by antidepressant treatment has been implicated in the antidepressant therapeutic mechanism. Because there is variability among patients with major depressive disorder in terms of response to antidep...

  20. Rational Design of Proteasome Inhibitors as Antimalarial Drugs.

    Science.gov (United States)

    Le Chapelain, Camille; Groll, Michael

    2016-05-23

    One life, two strategies: Crucial structural differences between the human and the Plasmodium falciparum proteasomes were recently identified. A combination of cryo-EM and functional characterization enabled the design of a selective antimalarial proteasome inhibitor that shows low toxicity in the host. When used with artemisinin, this ligand offers a new approach for the efficient treatment of malaria at all stages of the parasite lifecycle.

  1. Interfacing materials science and biology for drug carrier design.

    Science.gov (United States)

    Such, Georgina K; Yan, Yan; Johnston, Angus P R; Gunawan, Sylvia T; Caruso, Frank

    2015-04-01

    Over the last ten years, there has been considerable research interest in the development of polymeric carriers for biomedicine. Such delivery systems have the potential to significantly reduce side effects and increase the bioavailability of poorly soluble therapeutics. The design of carriers has relied on harnessing specific variations in biological conditions, such as pH or redox potential, and more recently, by incorporating specific peptide cleavage sites for enzymatic hydrolysis. Although much progress has been made in this field, the specificity of polymeric carriers is still limited when compared with their biological counterparts. To synthesize the next generation of carriers, it is important to consider the biological rationale for materials design. This requires a detailed understanding of the cellular microenvironments and how these can be harnessed for specific applications. In this review, several important physiological cues in the cellular microenvironments are outlined, with a focus on changes in pH, redox potential, and the types of enzymes present in specific regions. Furthermore, recent studies that use such biologically inspired triggers to design polymeric carriers are highlighted, focusing on applications in the field of therapeutic delivery.

  2. Possible involvement of the JAK/STAT signaling pathway in N-acetylcysteine-mediated antidepressant-like effects.

    Science.gov (United States)

    Al-Samhari, Marwa M; Al-Rasheed, Nouf M; Al-Rejaie, Salim; Al-Rasheed, Nawal M; Hasan, Iman H; Mahmoud, Ayman M; Dzimiri, Nduna

    2016-03-01

    Advances in depression research have targeted inflammation and oxidative stress to develop novel types of treatment. The JAK/STAT signaling pathway plays pivotal roles in immune and inflammatory responses. The present study was designed to investigate the effects of N-acetylcysteine, a putative precursor of the antioxidant glutathione, in an animal model of depression, with an emphasis on the JAK/STAT signaling pathway. Fluoxetine, a classical antidepressant drug was also under investigation. Male Wistar rats were subjected to forced swimming test and given N-acetylcysteine and fluoxetine immediately after the pre-test session, 5 h later and 1 h before the test session of the forced swimming test. N-acetylcysteine decreased immobility time (P rats with N-acetylcysteine produced significant (P < 0.001) down-regulation of STAT3 mRNA expression and protein phosphorylation. On the other hand, N-acetylcysteine significantly (P < 0.001) increased SOCS3 gene expression; however, SOCS3 protein was not changed. In conclusion, our study suggests that modulation of the JAK/STAT pathway might mediate the antidepressant-like effects of N-acetylcysteine. Therefore, depression research may target the JAK/STAT signaling pathway to provide a novel effective therapy. PMID:26643864

  3. Chemical dampening of Ly6C(hi) monocytes in the periphery produces anti-depressant effects in mice.

    Science.gov (United States)

    Zheng, Xiao; Ma, Sijing; Kang, An; Wu, Mengqiu; Wang, Lin; Wang, Qiong; Wang, Guangji; Hao, Haiping

    2016-01-19

    The involvement of systemic immunity in depression pathogenesis promises a periphery-targeting paradigm in novel anti-depressant discovery. However, relatively little is known about druggable targets in the periphery for mental and behavioral control. Here we report that targeting Ly6C(hi) monocytes in blood can serve as a strategy for anti-depressant purpose. A natural compound, ginsenoside Rg1 (Rg1), was firstly validated as a periphery-restricted chemical probe. Rg1 selectively suppressed Ly6C(hi) monocytes recruitment to the inflamed mice brain. The proinflammatory potential of Ly6C(hi) monocytes to activate astrocytes was abrogated by Rg1, which led to a blunted feedback release of CCL2 to recruit the peripheral monocytes. In vitro study demonstrated that Rg1 pretreatment on activated THP-1 monocytes retarded their ability to trigger CCL2 secretion from co-cultured U251 MG astrocytes. CCL2-triggered p38/MAPK and PI3K/Akt activation were involved in the action of Rg1. Importantly, in mice models, we found that dampening Ly6C(hi) monocytes at the periphery ameliorated depression-like behavior induced by neuroinflammation or chronic social defeat stress. Together, our work unravels that blood Ly6C(hi) monocytes may serve as the target to enable remote intervention on the depressed brain, and identifies Rg1 as a lead compound for designing drugs targeting peripheral CCL2 signals.

  4. Cross-reactivity of designer drugs, including cathinone derivatives, in commercial enzyme-linked immunosorbent assays.

    Science.gov (United States)

    Swortwood, Madeleine J; Hearn, W Lee; DeCaprio, Anthony P

    2014-01-01

    Since the introduction of synthetic heroin, designer drugs have been increasing in prevalence in the United States drug market over the past few decades. Recently, 'legal highs' sold as 'bath salts' have become a household term for one such class of designer drugs. While a number of federal and state bans have been enacted, the abuse of these designer drugs still continues. Few assays have been developed for the comprehensive detection of such compounds, so it is important to investigate how they may or may not react in presumptive screens, i.e. pre-existing commercial immunoassays. In this experiment, 16 different ELISA reagents were evaluated to determine the cross-reactivity of 30 designer drugs, including 24 phenylethylamines (including 8 cathinone derivatives), 3 piperazines, and 3 tryptamines. Cross-reactivity towards most drugs was <4% in assays targeting amphetamine or methamphetamine. Compounds such as MDA, MDMA, ethylamphetamine, and α-methyltryptamine demonstrated cross-reactivities in the range of 30-250%, but data were consistent with both manufacturer's inserts and published literature. When tested against the Randox Mephedrone/Methcathinone kit, cathinone derivatives demonstrated cross-reactivity at concentrations as low as 150 ng/ml. Since this same reagent did not cross-react with other amphetamine-like compounds, it opens the possibility to screen post-mortem specimens without the interference of putrefactive amines. All other assays demonstrated essentially no cross-reactivity towards any of the analytes evaluated. Given these results, a great need exists for more broad-range screening techniques to be applied when analyzing biological specimens by immunoassays for drugs of abuse, specifically the more recent designer drugs. PMID:23677923

  5. Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

    Directory of Open Access Journals (Sweden)

    Charles H. Williams

    2011-04-01

    Full Text Available In this article we propose a systematic development method for rational drug design while reviewing paradigms in industry, emerging techniques and technologies in the field. Although the process of drug development today has been accelerated by emergence of computational methodologies, it is a herculean challenge requiring exorbitant resources; and often fails to yield clinically viable results. The current paradigm of target based drug design is often misguided and tends to yield compounds that have poor absorption, distribution, metabolism, and excretion, toxicology (ADMET properties. Therefore, an in vivo organism based approach allowing for a multidisciplinary inquiry into potent and selective molecules is an excellent place to begin rational drug design. We will review how organisms like the zebrafish and Caenorhabditis elegans can not only be starting points, but can be used at various steps of the drug development process from target identification to pre-clinical trial models. This systems biology based approach paired with the power of computational biology; genetics and developmental biology provide a methodological framework to avoid the pitfalls of traditional target based drug design.

  6. 78 FR 51732 - The Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant...

    Science.gov (United States)

    2013-08-21

    ... HUMAN SERVICES Food and Drug Administration The Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant Public Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of public workshop. The Food and Drug Administration's (FDA) Office of Orphan Products...

  7. Pharmacogenetics of antidepressant response: An update

    Directory of Open Access Journals (Sweden)

    Drago Antonio

    2009-04-01

    Full Text Available Abstract The past few decades have witnessed much progress in the field of pharmacogenetics. The identification of the genetic background that regulates the antidepressant response has benefited from these advances. This review focuses on the pharmacogenetics of the antidepressant response through the analysis and discussion of the most compelling evidence in this line of research. Online databases (Medline and PsycINFO have been searched and the most replicated association findings relating to the genetics of the antidepressant response have been reported and discussed. Some replicated findings in the literature have suggested the serotonin transporter promoter (5-HTTLPR, serotonin receptor 1A (HTR1A, serotonin receptor 2A (HTR2A, brain derived neurotrophic factor (BDNF, corticotropin releasing hormone receptor 1 (CRHR1 and FK506 binding protein 5 (FKBP5 as putative regulators of the antidepressant response. A high rate of failure of replication has also been reported. Pharmacogenetics will hopefully provide the basis for personalised antidepressant treatment that is able to maximise the probability of a good response and to minimise side effects; however, this goal is not achievable at the moment. The extent of the validity of the replicated findings and the reasons for the poor results obtained from studies of the pharmacogenetics of the antidepressant response are discussed.

  8. Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons

    Directory of Open Access Journals (Sweden)

    Nadine eBeckmann

    2014-09-01

    Full Text Available Amitriptyline, a tricyclic antidepressant, has been used in the clinic to treat a number of disorders, in particular major depression and neuropathic pain. In the 1970s the ability of tricyclic antidepressants to inhibit acid sphingomyelinase (ASM was discovered. The enzyme ASM catalyzes the hydrolysis of sphingomyelin to ceramide. ASM and ceramide were shown to play a crucial role in a wide range of diseases, including cancer, cystic fibrosis, diabetes, Alzheimer’s disease and major depression, as well as viral (e.g. measles virus and bacterial (e.g. Staphylococcus aureus, Pseudomonas aeruginosa infections. Ceramide molecules may act in these diseases by the alteration of membrane biophysics, the self-association of ceramide molecules within the cell membrane and the ultimate formation of larger ceramide-enriched membrane domains/platforms. These domains were shown to serve the clustering of certain receptors such as CD95 and may also act in the above named diseases. The potential to block the generation of ceramide by inhibiting the ASM has opened up new therapeutic approaches for the treatment of these conditions. Since amitriptyline is one of the longest used clinical drugs and side effects are well studied, it could potentially become a cheap and easily accessible medication for patients suffering from these diseases. In this review, we aim to provide an overview of current in vitro and in vivo studies and clinical trials utilizing amitriptyline to inhibit ASM and contemplate possible future applications of the drug.

  9. How Commonly Used Inclusion and Exclusion Criteria in Antidepressant Registration Trials Affect Study Enrollment.

    Science.gov (United States)

    Preskorn, Sheldon H; Macaluso, Matthew; Trivedi, Madhukar

    2015-07-01

    In clinical trials, each specific inclusion and exclusion criterion eliminates a percentage of the potentially eligible population from trial participation and thus increases the time and effort needed for enrollment in a study. Drug developers often do not have data on how these criteria affect the pool of potentially eligible subjects for their trials and, hence, they cannot factor in the impact of these criteria when designing a study and planning the time needed to complete it. Consequently, drug developers often have ambitious timelines that are unrealistic and can lead to actions that may interfere with the ability to separate the efficacy of drug versus placebo. To investigate the effects of inclusion and exclusion criteria on study enrollment, the authors quantified the effects of the inclusion and exclusion criteria commonly used in antidepressant registration trials (ARTs) by applying these criteria to the population treated in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study. In essence, the STAR*D study population was used as a surrogate for the general population of individuals with major depressive disorder. The effect of each criterion commonly used in ARTs was assessed in terms of the percentage of the STAR*D population that would have been excluded individually and collectively (i.e., when all criteria were applied at once). For continuous criteria such as age and severity of depression, the resulting effects have been presented graphically. Collectively, the typical inclusion and exclusion criteria used in ARTs would have eliminated at least 82% of the STAR*D population. This result means that more than 5 times the number of subjects would have to be screened to find a population that would meet the typical inclusion and exclusion criteria for an ART, directly determining the screening effort required in terms of both resources and time. Thus, developers of antidepressant drugs can use the data from this study to plan the

  10. Secondary metabolites as DNA topoisomerase inhibitors: A new era towards designing of anticancer drugs

    Directory of Open Access Journals (Sweden)

    Supriya Baikar

    2010-01-01

    Full Text Available A large number of secondary metabolites like alkaloids, terpenoids, polyphenols and quinones are produced by the plants. These metabolites can be utilized as natural medicines for the reason that they inhibit the activity of DNA topoisomerase which are the clinical targets for anticancer drugs. DNA topoisomerases are the cellular enzymes that change the topological state of DNA through the breaking and rejoining of DNA strands. Synthetic drugs as inhibitors of topoisomerases have been developed and used in the clinical trials but severe side effects are a serious problem for them therefore, there is a need for the development of novel plant-derived natural drugs and their analogs which may serve as appropriate inhibitors with respect to drug designing. The theme for this review is how secondary metabolites or natural products inactivate the action of DNA topoisomerases and open new avenues towards isolation and characterization of compounds for the development of novel drugs with anticancer potential.

  11. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery

    Directory of Open Access Journals (Sweden)

    Md. Mirazul Islam

    2015-01-01

    Full Text Available The blood-brain barrier (BBB is a dynamic and highly selective permeable interface between central nervous system (CNS and periphery that regulates the brain homeostasis. Increasing evidences of neurological disorders and restricted drug delivery process in brain make BBB as special target for further study. At present, neurovascular unit (NVU is a great interest and highlighted topic of pharmaceutical companies for CNS drug design and delivery approaches. Some recent advancement of pharmacology and computational biology makes it convenient to develop drugs within limited time and affordable cost. In this review, we briefly introduce current understanding of the NVU, including molecular and cellular composition, physiology, and regulatory function. We also discuss the recent technology and interaction of pharmacogenomics and bioinformatics for drug design and step towards personalized medicine. Additionally, we develop gene network due to understand NVU associated transporter proteins interactions that might be effective for understanding aetiology of neurological disorders and new target base protective therapies development and delivery.

  12. Molecular docking as a popular tool in drug design, an in silico travel.

    Science.gov (United States)

    de Ruyck, Jerome; Brysbaert, Guillaume; Blossey, Ralf; Lensink, Marc F

    2016-01-01

    New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism-or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents' synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein-protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery.

  13. Molecular docking as a popular tool in drug design, an in silico travel

    Science.gov (United States)

    de Ruyck, Jerome; Brysbaert, Guillaume; Blossey, Ralf; Lensink, Marc F

    2016-01-01

    New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism-or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents’ synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery. PMID:27390530

  14. Does curcumin or pindolol potentiate fluoxetine′s antidepressant effect by a pharmacokinetic or pharmacodynamic interaction?

    Directory of Open Access Journals (Sweden)

    H.A.S. Murad

    2014-01-01

    Full Text Available This study was designed to study potentiation of fluoxetine′s antidepressant effect by curcumin or pindolol. Twenty eight groups of mice (n=8 were used in three sets of experiments. In the first set, 9 groups were subjected to the forced swimming test after being treated intraperitoneally with three vehicles, fluoxetine (5 and 20 mg/kg, curcumin (20 mg/kg, pindolol (32 mg/kg, curcumin+fluoxetine (5 mg/kg and pindolol+fluoxetine (5 mg/kg. One hour after the test, serum and brain fluoxetine and norfluoxetine levels were measured in mice receiving fluoxetine (5 and 20 mg/kg, curcumin+fluoxetine (5 mg/kg and pindolol+fluoxetine (5 mg/kg. In the second set, the test was done after pretreatment with p-chlorophenylalanine. In the third set, the locomotor activity was measured. The immobility duration was significantly decreased in fluoxetine (20 mg/kg, curcumin (20 mg/kg, curcumin+fluoxetine (5 mg/kg and pindolol+fluoxetine (5 mg/kg groups. These decreases were reversed with p-chlorophenylalanine. Fluoxetine and norfluoxetine levels were significantly higher in fluoxetine (20 mg/kg group with no differences in fluoxetine (5 mg/kg, curcumin+fluoxetine (5 mg/kg and pindolol+fluoxetine (5 mg/kg groups. Moreover, drugs failed to alter the locomotor activity indicating absence of central stimulation. In conclusion, curcumin, more than pindolol enhanced the antidepressant effect of a subeffective dose of fluoxetine in mice without increasing its serum or brain levels excluding any pharmacokinetic interaction. Reversal of this potentiation with p-chlorophenylalanine suggests a pharmacodynamic interaction through involvement of presynaptic 5-HT 1A receptors.

  15. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy

    OpenAIRE

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-01-01

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti...

  16. 75 FR 52780 - Designation of Nine Counties as High Intensity Drug Trafficking Areas

    Science.gov (United States)

    2010-08-27

    ...The Director of the Office of National Drug Control Policy designated nine additional counties as High Drug Trafficking Areas pursuant to 21 U.S.C. 1706. The new counties are (1) Shelby County in Tennessee as part of the Gulf Coast HIDTA, (2) Navajo County in Arizona as part of the Southwest Border HIDTA--Arizona Region, (3) Jefferson County in New York as part of the New York/New Jersey......

  17. 76 FR 44613 - Designation of Eight Counties as High Intensity Drug Trafficking Areas

    Science.gov (United States)

    2011-07-26

    ...The Director of the Office of National Drug Control Policy has designated eight additional counties as High Intensity Drug Trafficking Areas pursuant to 21 U.S.C. 1706. The new counties are (1) Orange County in New York as part of the New York/New Jersey HIDTA; (2) Medocino County in California as part of the Northern California HIDTA; (3) Porter County in Indiana as part of the Lake County......

  18. LIPOSOMAL ENCAPSULATION TECHNOLOGY A NOVEL DRUG DELIVERY SYSTEM DESIGNED FOR AYURVEDIC DRUG PREPARATION

    Directory of Open Access Journals (Sweden)

    M. Hemanth kumar

    2011-10-01

    Full Text Available Liposomal Encapsulation Technology (LET is the newest delivery method used by medical researchers to transfer drugs that act as healing promoters to the definite body organs. This form of delivery system offers targeted delivery of vital compounds to the body. It has been in existence since the early 70’s. Liposomal Encapsulation Technology is a state of the art method of producing sub-microscopic bubbles called liposomes, which encapsulate various substances. These phospholipids or “liposomes” form a barrier around their contents that is resistant to enzymes in the mouth and stomach, digestive juices, alkaline solutions, bile salts, and intestinal flora, found in the human body as well as free radicals. The contents of the liposomes are therefore shielded from degradation and oxidation. This protective phospholipid shield or barrier remains unharmed until the contents of the liposome are delivered right to the target organ, gland, or system where the contents will be utilized. Natural extracts are generally degraded because of oxidation and other chemical reactions before they delivered to the target site. Our research has shown liposomal encapsulated ayurvedic preparations have shown more stability and also more efficiency when compared to traditional preparations. Size of liposomes were measured around 85-200 nm.

  19. Drug-excipient compatibility testing using a high-throughput approach and statistical design.

    Science.gov (United States)

    Wyttenbach, Nicole; Birringer, Christian; Alsenz, Jochem; Kuentz, Martin

    2005-01-01

    The aim of our research was to develop a miniaturized high throughput drug-excipient compatibility test. Experiments were planned and evaluated using statistical experimental design. Binary mixtures of a drug, acetylsalicylic acid, or fluoxetine hydrochloride, and of excipients commonly used in solid dosage forms were prepared at a ratio of approximately 1:100 in 96-well microtiter plates. Samples were exposed to different temperature (40 degrees C/ 50 degrees C) and humidity (10%/75%) for different time (1 week/4 weeks), and chemical drug degradation was analyzed using a fast gradient high pressure liquid chromatography (HPLC). Categorical statistical design was applied to identify the effects and interactions of time, temperature, humidity, and excipient on drug degradation. Acetylsalicylic acid was least stable in the presence of magnesium stearate, dibasic calcium phosphate, or sodium starch glycolate. Fluoxetine hydrochloride exhibited a marked degradation only with lactose. Factor-interaction plots revealed that the relative humidity had the strongest effect on the drug excipient blends tested. In conclusion, the developed technique enables fast drug-excipient compatibility testing and identification of interactions. Since only 0.1 mg of drug is needed per data point, fast rational preselection of the pharmaceutical additives can be performed early in solid dosage form development.

  20. Prospects of Applying Enhanced Semi-Empirical QM Methods for 2101 Virtual Drug Design.

    Science.gov (United States)

    Yilmazer, Nusret Duygu; Korth, Martin

    2016-01-01

    The last five years have seen a renaissance of semiempirical quantum mechanical (SQM) methods in the field of virtual drug design, largely due to the increased accuracy of so-called enhanced SQM approaches. These methods make use of additional terms for treating dispersion (D) and hydrogen bond (H) interactions with an accuracy comparable to dispersion-corrected density functional theory (DFT-D). DFT-D in turn was shown to provide an accuracy comparable to the most sophisticated QM approaches when it comes to non-covalent intermolecular forces, which usually dominate the protein/ligand interactions that are central to virtual drug design. Enhanced SQM methods thus offer a very promising way to improve upon the current state of the art in the field of virtual drug design. PMID:27183985

  1. COMPUTATIONAL MODELING AND DRUG DESIGNING OF LIPOPROTEIN LIPASE (LPL INVOLVED IN ISCHEMIC STROKE

    Directory of Open Access Journals (Sweden)

    Maryam Torabizadeh

    2012-12-01

    Full Text Available Homology modeling and flexible docking of Lipoprotein Lipase has been studied in silico approach. Blast result was found to have similarity with Lipoprotein Lipase of 83% identity with 1LPA. Active site of LPL protein was identified by CASTP. Large potential drugs were designed for identifying molecules that can likely bind to protein target of interest. The different drug derivatives designed were used for docking with the generated structure, among the 10 derivatives designed, 3rd derivative showed highest docking result. The drug derivatives were docked to the protein by hydrogen bonding interactions and these interactions play an important role in the binding studies. Our investigations may be helpful for further studies.

  2. Orchiectomy modifies the antidepressant-like response of nicotine in the forced swimming test.

    Science.gov (United States)

    Bonilla-Jaime, H; Limón-Morales, O; Arteaga-Silva, M; Hernández-González, M; Guadarrama-Cruz, G; Alarcón-Aguilar, F; Vázquez-Palacios, G

    2010-11-01

    Several studies have demonstrated that nicotine (NIC) exhibits antidepressant-like effects. In addition, it has been suggested that sexual hormones participate in the antidepressant actions of antidepressives. The present study was designed to analyze the effect of orchiectomy and the supplementation of testosterone propionate (TP) or 17β-estradiol (E(2)) on the antidepressant properties of NIC using the forced swimming test (FST), as well as to determine possible changes in the FST during different time periods after orchiectomy. In order to evaluate the influences of orchiectomy on the effects of NIC, the study first evaluated the effects of different time periods on orchiectomized rats (15, 21, 30, 45 and 60 days) that were subjected to the FST. Then, different doses of NIC (0.2, 0.4, 0.8, 1.6 mg/kg, sc) were administered for 14 days to both intact and orchiectomized rats (after 21 day) which were then also subjected to the FST. Finally, the influence of the TP or E(2) supplementation on the antidepressant-like effect of NIC on orchiectomized rats (after 21 days) was also analyzed. Results reveal that orchiectomy significantly increased immobility behavior and decreased swimming and climbing up to 60 days after castration. In contrast, NIC decreased immobility behavior and increased swimming in intact rats; whereas orchiectomy suppressed this antidepressant effect of NIC. Only with E(2) supplementation was it possible to restore the sensitivity of the castrated rats to NIC. These results suggest that E(2) was able to facilitate the antidepressant response of NIC in orchiectomized rats. PMID:20709090

  3. Orchiectomy modifies the antidepressant-like response of nicotine in the forced swimming test.

    Science.gov (United States)

    Bonilla-Jaime, H; Limón-Morales, O; Arteaga-Silva, M; Hernández-González, M; Guadarrama-Cruz, G; Alarcón-Aguilar, F; Vázquez-Palacios, G

    2010-11-01

    Several studies have demonstrated that nicotine (NIC) exhibits antidepressant-like effects. In addition, it has been suggested that sexual hormones participate in the antidepressant actions of antidepressives. The present study was designed to analyze the effect of orchiectomy and the supplementation of testosterone propionate (TP) or 17β-estradiol (E(2)) on the antidepressant properties of NIC using the forced swimming test (FST), as well as to determine possible changes in the FST during different time periods after orchiectomy. In order to evaluate the influences of orchiectomy on the effects of NIC, the study first evaluated the effects of different time periods on orchiectomized rats (15, 21, 30, 45 and 60 days) that were subjected to the FST. Then, different doses of NIC (0.2, 0.4, 0.8, 1.6 mg/kg, sc) were administered for 14 days to both intact and orchiectomized rats (after 21 day) which were then also subjected to the FST. Finally, the influence of the TP or E(2) supplementation on the antidepressant-like effect of NIC on orchiectomized rats (after 21 days) was also analyzed. Results reveal that orchiectomy significantly increased immobility behavior and decreased swimming and climbing up to 60 days after castration. In contrast, NIC decreased immobility behavior and increased swimming in intact rats; whereas orchiectomy suppressed this antidepressant effect of NIC. Only with E(2) supplementation was it possible to restore the sensitivity of the castrated rats to NIC. These results suggest that E(2) was able to facilitate the antidepressant response of NIC in orchiectomized rats.

  4. A mega-analysis of fixed-dose trials reveals dose-dependency and a rapid onset of action for the antidepressant effect of three selective serotonin reuptake inhibitors.

    Science.gov (United States)

    Hieronymus, F; Nilsson, S; Eriksson, E

    2016-01-01

    The possible dose-dependency for the antidepressant effect of selective serotonin reuptake inhibitors (SSRIs) remains controversial. We believe we have conducted the first comprehensive patient-level mega-analysis exploring this issue, one incentive being to address the possibility that inclusion of low-dose arms in previous meta-analyses may have caused an underestimation of the efficacy of these drugs. All company-sponsored, acute-phase, placebo-controlled, fixed-dose trials using the Hamilton Depression Rating Scale (HDRS) and conducted to evaluate the effect of citalopram, paroxetine or sertraline in adult major depression were included (11 trials, n=2859 patients). The single-item depressed mood, which has proven a more sensitive measure to detect an antidepressant signal than the sum score of all HDRS items, was designated the primary effect parameter. Doses below or at the lower end of the usually recommended dose range (citalopram: 10-20 mg, paroxetine: 10 mg; sertraline: 50 mg) were superior to placebo but inferior to higher doses, hence confirming a dose-dependency to be at hand. In contrast, among doses above these, there was no indication of a dose-response relationship. The effect size (ES) after exclusion of suboptimal doses was of a more respectable magnitude (0.5) than that usually attributed to the antidepressant effect of the SSRIs. In conclusion, the observation that low doses are less effective than higher ones challenges the oft-cited view that the effect of the SSRIs is not dose-dependent and hence not caused by a specific, pharmacological antidepressant action. Moreover, we suggest that inclusion of suboptimal doses in previous meta-analyses has led to an underestimation of the efficacy of these drugs. PMID:27271860

  5. Comparison of the kinetic interactions of the neuroleptics perphenazine and zuclopenthixol with tricyclic antidepressives.

    Science.gov (United States)

    Linnet, K

    1995-06-01

    Using data from a therapeutic drug monitoring database, kinetic interactions between the neuroleptics zuclopenthixol and perphenazine and tricyclic antidepressives were studied. Out of 290 patients monitored for amitriptyline and 611 patients monitored for nortriptyline, 77 patients were comedicated with perphenazine and 50 patients with zuclopenthixol. Comedication with perphenazine increased the median steady-state serum concentration to daily dose ratio (C/D) of nortriptyline by 30-45%, whereas the median C/D of amitriptyline was unaffected. On the contrary, median C/D values of nortriptyline and amitriptyline were not significantly influenced by comedication with zuclopenthixol. Thus, in accordance with previous studies, perphenazine increases the concentration of tricyclic antidepressives to a moderate extent. Zuclopenthixol, on the other hand, does not exert any impact under routine therapeutic drug monitoring, even though the drug is known to partly depend on metabolism by the isozyme cytochrome P450 2D6. PMID:7624929

  6. Drug: D02567 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 91 414.4268 D02567.gif Antidepressant [selective serotonin reuptake inhibitor] Therapeutic category: 1179 ATC code: N06AB10 Selective...tic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective...ram oxalate (JAN/USAN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin...ate (JAN/USAN) Anxiolytics SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/Serotonin and Norepinephrine

  7. Drug: D02260 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available H2O 748.2494 749.668 D02260.gif Antidepressant Therapeutic category: 1179 ATC code: N06AB05 Selective seroto...tion [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective serotonin reupt...SP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/Ser...otonin and Norepinephrine Reuptake Inhibitors) Paroxetine D02260 Paroxetine hydrochloride hydrate (JAN) Anxiolytics SSRIs/SNRIs (Sele...ctive Serotonin Reuptake Inhibitors/Serotonin and Norepinephrine Reuptake Inhibitor

  8. Drug: D02362 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 62.gif Antidepressant Same as: C07415 ATC code: N06AB05 Selective serotonin reuptake inhibitor (SSRI) seroto...Therapeutic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective...oxetine (USP/INN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin Reup...ective Serotonin Reuptake Inhibitors/Serotonin and Norep...take Inhibitors/Serotonin and Norepinephrine Reuptake Inhibitors) Paroxetine D02362 Paroxetine (USP/INN) Anxiolytics SSRIs/SNRIs (Sel

  9. Determination of the tricyclic antidepressants amitriptyline, nortriptyline, imipramine, desipramine, clomipramine and desmethylclomipramine in dried blood spots using LC-MS/MS

    NARCIS (Netherlands)

    Berm, E.J.J.; Paardekooper, J.; Brummel-Mulder, E.; Hak, E.; Wilffert, B.; Maring, J.G.

    2013-01-01

    Background: Therapeutic Drug Monitoring (TDM) of Tricyclic Antidepressants (TADs) is considered useful in patients with major depressive disorders, since these drugs display large individual differences in clearance and therapeutic windows of these drugs are relatively small. We developed an assay f

  10. Antidepressant Effects of Resveratrol in an Animal Model of Depression

    Science.gov (United States)

    Akinfiresoye, Laura L. Hurley, Luli; Kalejaiye, Olubukola; Tizabi, Yousef

    2014-01-01

    Resveratrol (3,4’,5-trihydroxy-trans-stilbene) is a natural non-flavonoid polyphenol antioxidant extracted from red grapes in the processing of wine. Initially it was studied for its potential as anticancer drug, and later was found to reduce cardiovascular disease. More recently resveratrol was shown to alleviate depressive-like symptoms induced by stress or other means in mice and rats. The major purpose of this study was to investigate whether resveratrol would manifest an antidepressant effect in Wistar-Kyoto (WKY) rats, a putative and non-induced animal model of depression, and whether this effect might be associated with an increase in hippocampal and frontal cortical brain-derived neurotrophic factor (BDNF), a protein implicated in chronic effects of many antidepressants. Adult male WKY rats were injected with two doses of resveratrol (10 and 40 mg/kg, i.p.) and their behavior in the open field locomotor activity (LMA), forced swim test (FST: a measure of helplessness), and sucrose preference test (SPT: a measure of anhedonia) was evaluated after a single acute injection or following 7 days of daily treatment. Both acute and chronic administration of resveratrol resulted in a dose-dependent decrease in FST. However, only chronic resveratrol resulted in dose-dependent increase in sucrose consumption. LMA was not affected by any treatment. Parallel to the observed behavioral effects the level of hippocampal, but not frontal cortical, BDNF was also dose-dependently elevated after chronic resveratrol administration. These findings indicate an antidepressant-like effect of resveratrol in an animal model of depression possibly via activation of hippocampal BDNF, and suggest therapeutic potential of resveratrol in at least a subpopulation of depressed patients. PMID:24717328

  11. Drug Elucidation: Invertebrate Genetics Sheds New Light on the Molecular Targets of CNS Drugs

    Directory of Open Access Journals (Sweden)

    Donard S. Dwyer

    2014-07-01

    Full Text Available Many important drugs approved to treat common human diseases were discovered by serendipity, without a firm understanding of their modes of action. As a result, the side effects and interactions of these medications are often unpredictable, and there is limited guidance for improving the design of next-generation drugs. Here, we review the innovative use of simple model organisms, especially Caenorhabditis elegans, to gain fresh insights into the complex biological effects of approved CNS medications. Whereas drug discovery involves the identification of new drug targets and lead compounds/biologics, and drug development spans preclinical testing to FDA approval, drug elucidation refers to the process of understanding the mechanisms of action of marketed drugs by studying their novel effects in model organisms. Drug elucidation studies have revealed new pathways affected by antipsychotic drugs, e.g., the insulin signaling pathway, a trace amine receptor and a nicotinic acetylcholine receptor. Similarly, novel targets of antidepressant drugs and lithium have been identified in C. elegans, including lipid-binding/transport proteins and the SGK-1 signaling pathway, respectively. Elucidation of the mode of action of anesthetic agents has shown that anesthesia can involve mitochondrial targets, leak currents and gap junctions. The general approach reviewed in this article has advanced our knowledge about important drugs for CNS disorders and can guide future drug discovery efforts.

  12. Long-Term Weight Change after Initiating Second-Generation Antidepressants

    Directory of Open Access Journals (Sweden)

    David Arterburn

    2016-04-01

    Full Text Available (1 Objective: To examine the relationship between the choice of second-generation antidepressant drug treatment and long-term weight change; (2 Methods: We conducted a retrospective cohort study to investigate the relationship between choice of antidepressant medication and weight change at two years among adult patients with a new antidepressant treatment episode between January, 2006 and October, 2009 in a large health system in Washington State. Medication use, encounters, diagnoses, height, and weight were collected from electronic databases. We modeled change in weight and BMI at two years after initiation of treatment using inverse probability weighted linear regression models that adjusted for potential confounders. Fluoxetine was the reference treatment; (3 Results: In intent-to-treat analyses, non-smokers who initiated bupropion treatment on average lost 7.1 lbs compared to fluoxetine users who were non-smokers (95% CI: −11.3, −2.8; p-value < 0.01; smokers who initiated bupropion treatment gained on average 2.2 lbs compared to fluoxetine users who were smokers (95% CI: −2.3, 6.8; p-value = 0.33. Changes in weight associated with all other antidepressant medications were not significantly different than fluoxetine, except for sertraline users, who gained an average of 5.9 lbs compared to fluoxetine users (95% CI: 0.8, 10.9; p-value = 0.02; (4 Conclusion: Antidepressant drug therapy is significantly associated with long-term weight change at two years. Bupropion may be considered as the first-line drug of choice for overweight and obese patients unless there are other existing contraindications.

  13. Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods.

    Science.gov (United States)

    Moitessier, Nicolas; Pottel, Joshua; Therrien, Eric; Englebienne, Pablo; Liu, Zhaomin; Tomberg, Anna; Corbeil, Christopher R

    2016-09-20

    Computational methods for docking small molecules to proteins are prominent in drug discovery. There are hundreds, if not thousands, of documented examples-and several pertinent cases within our research program. Fifteen years ago, our first docking-guided drug design project yielded nanomolar metalloproteinase inhibitors and illustrated the potential of structure-based drug design. Subsequent applications of docking programs to the design of integrin antagonists, BACE-1 inhibitors, and aminoglycosides binding to bacterial RNA demonstrated that available docking programs needed significant improvement. At that time, docking programs primarily considered flexible ligands and rigid proteins. We demonstrated that accounting for protein flexibility, employing displaceable water molecules, and using ligand-based pharmacophores improved the docking accuracy of existing methods-enabling the design of bioactive molecules. The success prompted the development of our own program, Fitted, implementing all of these aspects. The primary motivation has always been to respond to the needs of drug design studies; the majority of the concepts behind the evolution of Fitted are rooted in medicinal chemistry projects and collaborations. Several examples follow: (1) Searching for HDAC inhibitors led us to develop methods considering drug-zinc coordination and its effect on the pKa of surrounding residues. (2) Targeting covalent prolyl oligopeptidase (POP) inhibitors prompted an update to Fitted to identify reactive groups and form bonds with a given residue (e.g., a catalytic residue) when the geometry allows it. Fitted-the first fully automated covalent docking program-was successfully applied to the discovery of four new classes of covalent POP inhibitors. As a result, efficient stereoselective syntheses of a few screening hits were prioritized rather than synthesizing large chemical libraries-yielding nanomolar inhibitors. (3) In order to study the metabolism of POP inhibitors by

  14. Medicinal Chemistry Projects Requiring Imaginative Structure-Based Drug Design Methods.

    Science.gov (United States)

    Moitessier, Nicolas; Pottel, Joshua; Therrien, Eric; Englebienne, Pablo; Liu, Zhaomin; Tomberg, Anna; Corbeil, Christopher R

    2016-09-20

    Computational methods for docking small molecules to proteins are prominent in drug discovery. There are hundreds, if not thousands, of documented examples-and several pertinent cases within our research program. Fifteen years ago, our first docking-guided drug design project yielded nanomolar metalloproteinase inhibitors and illustrated the potential of structure-based drug design. Subsequent applications of docking programs to the design of integrin antagonists, BACE-1 inhibitors, and aminoglycosides binding to bacterial RNA demonstrated that available docking programs needed significant improvement. At that time, docking programs primarily considered flexible ligands and rigid proteins. We demonstrated that accounting for protein flexibility, employing displaceable water molecules, and using ligand-based pharmacophores improved the docking accuracy of existing methods-enabling the design of bioactive molecules. The success prompted the development of our own program, Fitted, implementing all of these aspects. The primary motivation has always been to respond to the needs of drug design studies; the majority of the concepts behind the evolution of Fitted are rooted in medicinal chemistry projects and collaborations. Several examples follow: (1) Searching for HDAC inhibitors led us to develop methods considering drug-zinc coordination and its effect on the pKa of surrounding residues. (2) Targeting covalent prolyl oligopeptidase (POP) inhibitors prompted an update to Fitted to identify reactive groups and form bonds with a given residue (e.g., a catalytic residue) when the geometry allows it. Fitted-the first fully automated covalent docking program-was successfully applied to the discovery of four new classes of covalent POP inhibitors. As a result, efficient stereoselective syntheses of a few screening hits were prioritized rather than synthesizing large chemical libraries-yielding nanomolar inhibitors. (3) In order to study the metabolism of POP inhibitors by

  15. 77 FR 9946 - Draft Guidance for Industry on Drug Interaction Studies-Study Design, Data Analysis, Implications...

    Science.gov (United States)

    2012-02-21

    ... on Drug Interaction Studies--Study Design, Data Analysis, Implications for Dosing, and Labeling... entitled ``Drug Interaction Studies--Study Design, Data Analysis, Implications for Dosing, and Labeling... vivo studies, in vivo study design, and data analysis in the context of identifying potential...

  16. 76 FR 39883 - Design of Clinical Trials for Systemic Antibacterial Drugs for the Treatment of Acute Otitis...

    Science.gov (United States)

    2011-07-07

    ... HUMAN SERVICES Food and Drug Administration Design of Clinical Trials for Systemic Antibacterial Drugs... workshop regarding the design of Clinical Trials for Systemic Antibacterial Agents for the Treatment of... various aspects of the design of clinical trials. The input from this public workshop will help...

  17. 77 FR 49450 - Issues in the Design of Clinical Trials of Antibacterial Drugs for the Treatment of Non-Cystic...

    Science.gov (United States)

    2012-08-16

    ... HUMAN SERVICES Food and Drug Administration Issues in the Design of Clinical Trials of Antibacterial... announcing a public workshop focusing on the design of clinical trials of antibacterial drugs for the..., academia, and industry on various aspects of the design of clinical trials. The input from this...

  18. 75 FR 8968 - Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability

    Science.gov (United States)

    2010-02-26

    ... entitled ``Adaptive Design Clinical Trials for Drugs and Biologics.'' The draft guidance provides sponsors... Evaluation and Research (CBER) with information regarding adaptive design clinical trials when used in drug... design clinical trials (i.e., clinical, statistical, regulatory) call for special consideration, when...

  19. Molecular docking as a popular tool in drug design, an in silico travel

    Directory of Open Access Journals (Sweden)

    de Ruyck J

    2016-06-01

    Full Text Available Jerome de Ruyck, Guillaume Brysbaert, Ralf Blossey, Marc F Lensink University Lille, CNRS UMR8576 UGSF, Lille, FranceAbstract: New molecular modeling approaches, driven by rapidly improving computational platforms, have allowed many success stories for the use of computer-assisted drug design in the discovery of new mechanism- or structure-based drugs. In this overview, we highlight three aspects of the use of molecular docking. First, we discuss the combination of molecular and quantum mechanics to investigate an unusual enzymatic mechanism of a flavoprotein. Second, we present recent advances in anti-infectious agents' synthesis driven by structural insights. At the end, we focus on larger biological complexes made by protein–protein interactions and discuss their relevance in drug design. This review provides information on how these large systems, even in the presence of the solvent, can be investigated with the outlook of drug discovery.Keywords: structure-based drug design, protein–protein docking, quaternary structure prediction, residue interaction networks, RINs, water position

  20. Exposure / Ritual Prevention Therapy Boosts Antidepressant Treatment of OCD

    Science.gov (United States)

    ... NIMH (99 items) Exposure / Ritual Prevention Therapy Boosts Antidepressant Treatment of OCD CBT Trumps Antipsychotic for Augmentation, ... Update A form of behavioral therapy can augment antidepressant treatment of obsessive compulsive disorder (OCD) better than ...

  1. Antidepressant No Help to Heart Failure Patients: Study

    Science.gov (United States)

    ... page: https://medlineplus.gov/news/fullstory_159604.html Antidepressant No Help to Heart Failure Patients: Study Depression ... 2016 TUESDAY, June 28, 2016 (HealthDay News) -- The antidepressant Lexapro may not help heart failure patients suffering ...

  2. Drug: D05375 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available panic disorder [selective serotonin reuptake inhibitor] ATC code: N06AB05 Selective serotonin reuptake inhib...S SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective serotonin reuptake inhibitors N06AB05 Par...oxetine D05375 Paroxetine mesylate (USAN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective...ibitors) Paroxetine D05375 Paroxetine mesylate (USAN) Anxiolytics SSRIs/SNRIs (Selective Serotonin Reuptake

  3. Drug: D02360 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available Same as: C07246 ATC code: N06AB06 Selective serotonin reuptake inhibitor (SSRI) serotonin transporter inhib...YCHOANALEPTICS N06A ANTIDEPRESSANTS N06AB Selective serotonin reuptake inhibitors... N06AB06 Sertraline D02360 Sertraline (INN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective...0 Sertraline (INN) Anxiolytics SSRIs/SNRIs (Selective Serotonin Reuptake Inhibito

  4. Designing anti-cancer drugs and directing anti-cancer therapy

    OpenAIRE

    Velasquez, Elinor; Soto-Andrade, Jorge; Bongalon, Ben

    2014-01-01

    A prototype for a web application was designed and implemented as a guide to be used by clinicians when designing the best drug therapy for a specific cancer patient, given biological data derived from the patients tumor tissue biopsy. A representation of the patients metabolic pathways is displayed as a graph in the application, with nodes as substrates and products and edges as enzymes. The top metabolically active sub- paths in the pathway, ranked using an algorithm based on both the patie...

  5. Design and optimization of selfnanoemulsifying drug delivery systems for enhanced dissolution of gemfibrozil

    OpenAIRE

    Sierra Villar, Ana María; Clares Naveros, Beatriz; Calpena Campmany, Ana Cristina; Aróztegui Trenchs, Montserrat; Barbé Rocabert, Coloma; Halbaut, Lyda

    2012-01-01

    Self-nanoemulsifying drug delivery systems of gemfibrozil were developed under Quality by Design approach for improvement of dissolution and oral absorption. Preliminary screening was performed to select proper components combination. Box-Behnken experimental design was employed as statistical tool to optimize the formulation variables, X1 (Cremophor® EL), X2 (Capmul® MCM-C8), and X3 (lemon essential oil). Systems were assessed for visual characteristics (emulsification efficacy), turbidity, ...

  6. COMPARISON OF ANTIDEPRESSANT ACTIVITY OF LOSARTAN WITH IMIPRAMINE IN ALBINO MICE

    Directory of Open Access Journals (Sweden)

    Choppadandi

    2016-06-01

    Full Text Available OBJECTIVES Comparison of antidepressant activity of Losartan with Imipramine in albino mice. BACKGROUND Of all the afflictions that trouble the soul, depression is the commonest characterised by a state of low mood and aversion to activity that can affect a person's thoughts, behaviour, feelings and physical well-being. Similarly, hypertension is another condition which has emerged as a major public health problem in India and many other developing countries. There is compulsion that 35% of the population has to use the antihypertensives and antidepressants simultaneously for a long period of time to maintain their health. The present work is aimed at comparing antidepressant activity of losartan with imipramine which acts by raising brain BDNF (Brain derived neurotrophic factor levels so that a single agent can be used for both the conditions avoiding multiple medications. METHOD 18 Albino mice were taken, divided into 6 mice in each group and subjected to Forced swim test. All the drugs were administered orally. Drugs were administered and time of onset of immobility is measured 60 min. after the drug administration along with total duration of immobility. Animals are exposed to pretest of 15 min., 24 hrs. prior to the 6 min. swim test. Each animal is considered immobile when it ceased to struggle and swim and remained floating in the water, only moving to keep its head above water. Control group received distilled water (10 mL/kg. Standard group received Imipramine (5 mg/kg and test group was treated with Losartan (3 mg/kg. The Forced swim test for each mouse was video captured which was later analysed to count the time of onset of immobility and total duration of immobility. RESULTS Data was analysed using Analysis of Variance (ANOVA. Losartan showed significant antidepressant activity indicated by significant delay (P<0.05 in the time of onset of immobility and significant reduction (P<0.05 in the total duration of immobility compared to

  7. Molecular Docking of Enzyme Inhibitors: A Computational Tool for Structure-Based Drug Design

    Science.gov (United States)

    Rudnitskaya, Aleksandra; Torok, Bela; Torok, Marianna

    2010-01-01

    Molecular docking is a frequently used method in structure-based rational drug design. It is used for evaluating the complex formation of small ligands with large biomolecules, predicting the strength of the bonding forces and finding the best geometrical arrangements. The major goal of this advanced undergraduate biochemistry laboratory exercise…

  8. Using the [beta][subscript 2]-Adrenoceptor for Structure-Based Drug Design

    Science.gov (United States)

    Manallack, David T.; Chalmers, David K.; Yuriev, Elizabeth

    2010-01-01

    The topics of molecular modeling and drug design are studied in a medicinal chemistry course. The recently reported structures of several G protein-coupled receptors (GPCR) with bound ligands have been used to develop a simple computer-based experiment employing molecular-modeling software. Knowledge of the specific interactions between a ligand…

  9. Design and Evaluation of Stomach-Specific Drug Delivery of Domperidone using Floating Pectin Beads

    Directory of Open Access Journals (Sweden)

    K.Varun Kumar

    2013-03-01

    Full Text Available The objective of present study was to develop floating beads of Domperidone (DOM in order to increase its residence time in the stomach without contact with the mucosa, improve patient compliance and obtain improved therapeutic efficacy. They are prepared by extrusion congealing technique with pectin as a polymer. Floating beads were characterized by polymer compatibility by using FT-IR. The prepared beads were evaluated for particle size, surface morphology, buoyancy, actual drug content, entrapment efficiency and in vitro drug release. Nine formulations of DOM floating beads were formulated by using different percentage of both gas forming agent and pectin. Density of the formulated beads was found to be ranging between 0.101 and 0.182 g/cm3. The particle size was distributed between 0.6 to 1.6 mm. Buoyancy percentage was 71-87% and Drug entrapment efficiency was 54.4-64.48%. The micrometric properties were found to be good and scanning electron microscopy (SEM confirmed their hollow structure with smooth surface. The content of drug release was done by UV spectrophotometer at 284 nm. In vitro drug release of DOM, for F2 is 81.10% and for F6 is 82.6%. And the beads formulated using 0.3w/w (F2 and 0.4% w/w (F6 of pectin was more uniform in shape and exhibited maximum buoyancy. The drug content of the formulated beads was found to be satisfactory by this method. It remains in the gastric region for several hours and hence prolongs the gastric residence time of drug. From the study it was concluded that the gastro retentive drug delivery system designed as floating beads could be suitable drug delivery system for DOM.

  10. Combining clinical variables to optimize prediction of antidepressant treatment outcomes.

    Science.gov (United States)

    Iniesta, Raquel; Malki, Karim; Maier, Wolfgang; Rietschel, Marcella; Mors, Ole; Hauser, Joanna; Henigsberg, Neven; Dernovsek, Mojca Zvezdana; Souery, Daniel; Stahl, Daniel; Dobson, Richard; Aitchison, Katherine J; Farmer, Anne; Lewis, Cathryn M; McGuffin, Peter; Uher, Rudolf

    2016-07-01

    The outcome of treatment with antidepressants varies markedly across people with the same diagnosis. A clinically significant prediction of outcomes could spare the frustration of trial and error approach and improve the outcomes of major depressive disorder through individualized treatment selection. It is likely that a combination of multiple predictors is needed to achieve such prediction. We used elastic net regularized regression to optimize prediction of symptom improvement and remission during treatment with escitalopram or nortriptyline and to identify contributing predictors from a range of demographic and clinical variables in 793 adults with major depressive disorder. A combination of demographic and clinical variables, with strong contributions from symptoms of depressed mood, reduced interest, decreased activity, indecisiveness, pessimism and anxiety significantly predicted treatment outcomes, explaining 5-10% of variance in symptom improvement with escitalopram. Similar combinations of variables predicted remission with area under the curve 0.72, explaining approximately 15% of variance (pseudo R(2)) in who achieves remission, with strong contributions from body mass index, appetite, interest-activity symptom dimension and anxious-somatizing depression subtype. Escitalopram-specific outcome prediction was more accurate than generic outcome prediction, and reached effect sizes that were near or above a previously established benchmark for clinical significance. Outcome prediction on the nortriptyline arm did not significantly differ from chance. These results suggest that easily obtained demographic and clinical variables can predict therapeutic response to escitalopram with clinically meaningful accuracy, suggesting a potential for individualized prescription of this antidepressant drug. PMID:27089522

  11. Antidepressant treatment of the depressed patient with insomnia.

    Science.gov (United States)

    Thase, M E

    1999-01-01

    Sleep disturbances are an integral part of depressive disorder. As such, they are a part of all contemporary sets of diagnostic criteria for major depression and of all major symptom-based rating scales for depression. Insomnia is a particularly frequent complaint, and it is reported by more than 90% of depressed patients. Although the "kindling" or "illness transduction" model of depression remains hypothetical, there is evidence that people with recurrent depression have more pronounced abnormalities of sleep neurophysiology than those experiencing a single or initial episode. Therefore, early relief of insomnia in a depressed patient, in addition to alleviating other symptoms, may increase adherence to treatment and increase daytime performance and overall functioning, while complete relief of insomnia may improve prognosis. Stimulation of serotonin-2 (5-HT2) receptors is thought to underlie insomnia and changes in sleep architecture seen with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs). This is the reason why hypnotics or low-dose trazodone are commonly coprescribed at the initiation of the treatment with either the SSRIs or SNRIs. On the other hand, antidepressant drugs with 5-HT2 blocking properties, such as mirtazapine or nefazodone, alleviate insomnia and improve sleep architecture. In depressed patients, mirtazapine produces a significant shortening of sleep-onset latency, increases a total sleep time, and leads to a marked improvement in sleep efficiency. Antidepressants with preferential 5-HT2 blocking properties are therefore a good treatment option for depressed patients with marked insomnia. PMID:10446739

  12. Antidepressant Prescription and Suicide Rates: Effect of Age and Gender

    Science.gov (United States)

    Kalmar, Sandor; Szanto, Katalin; Rihmer, Zoltan; Mazumdar, Sati; Harrison, Katrin; Mann, J. John

    2008-01-01

    To determine whether the effect of antidepressant exposure on suicide rate is modified by age and gender in Hungary, annual antidepressant prescription rates and suicide rates of about 10 million inhabitants between 1999-2005 were analyzed by age and gender groups. The suicide rate was inversely related to the increased use of antidepressants in…

  13. GPs motivations of prescribing antidepressants and their practical relevance.

    NARCIS (Netherlands)

    Volkers, A.; Jong, A. de; Braspenning, J.C.C.; Bakker, D. de; Dijk, L. van

    2004-01-01

    Background: Insight in the motivations of prescribing antidepressants may contribute to advance the efficiency of the current, large antidepressant prescription rate. Less is known about why general practitioners (GPs) treat patients with antidepressants or not and choose modern SSRIs instead of the

  14. Ozone oxidation of antidepressants in wastewater –Treatment evaluation and characterization of new by-products by LC-QToFMS

    OpenAIRE

    Lajeunesse André; Blais Mireille; Barbeau Benoît; Sauvé Sébastien; Gagnon Christian

    2013-01-01

    Abstract Background The fate of 14 antidepressants along with their respective N-desmethyl metabolites and the anticonvulsive drug carbamazepine was examined in a primary sewage treatment plant (STP) and following advanced treatments with ozone (O3). The concentrations of each pharmaceutical compound were determined in raw sewage, effluent and sewage sludge samples by LC-MS/MS analysis. The occurrence of antidepressant by-products formed in treated effluent after ozonation was also investigat...

  15. 三环类抗抑郁药所致心肌损害的治疗%Treatment of myocardiac injury caused by tricyclic antidepressant

    Institute of Scientific and Technical Information of China (English)

    邢秀娟; 李美花; 吕伟

    2003-01-01

    @@ INTRODUCTION Tricyclic antidepressant has some toxic effect on heart, myocardicinjury is a common adverse effect which main characteristic areabnormality of EKG, change of T wave, deviation of ST segmentand prolongation of PR and Q-T interval. No self-conscious symp-toms is found in clinic. Compound Danshen dripping pill is thecommon drug in treatment of coronary heart disease and myocardiacinjury. We try to treat myocardiac injury caused by tricyclic an-tidepressant by compound Danshen dripping pill.

  16. HZI systems for EEG parametrization and classification of psychotropic drugs.

    Science.gov (United States)

    Itil, T M; Shapiro, D M; Herrmann, W M; Schulz, W; Morgan, V

    1979-01-01

    The EEG effects of twenty, clinically most frequently used psychotropic drugs and five placebos were studied in 75 male volunteers in five simultaneously designed basic studies. In each of the five studies single oral dosages of five drugs (well known representatives of neuroleptics, antidepressants, anxiolytics and psychostimulants, as well as placebos) were investigated in 15 subjects in a double-blind latin-square research design using the methods of the Quantitative Pharmaco-EEG. The results demonstrated that the therapeutically equivalent effective compounds also have similar effects on human EEG. With a classification rule, based on discriminant function 20, and with a classification rule, based on correlation statistics 19 of 25 compounds could be reclassified into correct clinical-therapeutic psychotropic drug groups. It is suggested that CEEG is an important tool in predicting and describing psychotropic properties of compounds, and should routinely be used in psychotropic drug development. PMID:419164

  17. Regioselective synthesis and evaluation of 3-alkylidene-1, 3-dihydroisobenzofurans as potential antidepressant agents

    Indian Academy of Sciences (India)

    C Praveen; C Iyyappan; K Girija; K Suresh Kumar; P T Perumal

    2012-03-01

    3-Alkylidene-1,3-dihydroisobenzofurans exhibited moderate antidepressant activity as evaluated by forced swim and tail suspension test methods. Virtual screening was carried out by docking the designed compounds into the serotonin binding sites of arabinase protein to predict the analogue binding mode of the compounds to the SSRIs.

  18. Nonconvulsive status epilepticus in the elderly associated with newer antidepressants used at therapeutic doses: A report of three cases

    Directory of Open Access Journals (Sweden)

    Go Taniguchi

    2015-01-01

    All three patients were male and were 73 years of age or older. One patient was recently diagnosed with temporal lobe epilepsy and treated with low-dose lamotrigine. In all patients, newer antidepressants were initiated because of depressive symptoms. After titrating to therapeutic doses (paroxetine 20 mg/day, sertraline 50 mg/day, and combination of sertraline 50 mg/day and mirtazapine 30 mg/day in one patient each, impaired consciousness appeared. Electroencephalography (EEG showed generalized slow waves with intermittent spike–slow-wave complexes. Intravenous injection of antiepileptic drugs improved EEG findings and clinical symptoms. After discontinuance of the abovementioned antidepressants, NCSE did not recur in any of patients. These reports raise the question of whether the newer antidepressants, like classic antidepressants, might also induce NCSE in the elderly, even when used at therapeutic doses. Physicians should consider monitoring for possible NCSE when using newer antidepressants in patients who may have low drug tolerability. Active continuous video-EEG monitoring is essential when behavioral and psychological symptoms or change in consciousness level is suspected.

  19. Antidepressant-like effects of BCEF0083 in the chronic unpredictable stress models in mice

    Institute of Scientific and Technical Information of China (English)

    ZHOU Lan-lan; MING Liang; MA Chuan-geng; CHENG Yan; JIANG Qin

    2005-01-01

    Background Up to now there have been no satisfactory drugs to treat psychiatric disorders, and now bioactive compound from entomagenous fungi (BCEF0083) is a new type of bioactive compound from entomopathogenic fungi. Our previous investigations have shown that BCEF has an inhibition effect on monoamine oxidase. So, BCEF may be a latent antidepressant. This study aimed at observing the antidepressant effects and its mechanism of BCEF in the chronic unpredictable stress models in mice. Methods The antidepressant effects of BCEF were examined on the chronic unpredictable stress models in mice. Sixty mice were randomly divided to six groups. Animals were housed and isolated except saline group. Mice were exposed to different stressors per day randomly from day 1 to day 21. Body weight were weighed on day 1,day 10 and on day 21 during the 21-day stress procedure. Awarding response was detected by using method of calculating the 24-hour consumption of saccharum water. Step through test was used to evaluate the behavioral response. AVP contents in plasma were also detected by using radioimmunoassays. Results Chronic unpredictable stress resulted in a significant decrease of the body weight and could apparently cause escape behavior disturbance and gradual reduction of sensitivity to reward in animal models. Drug treatment (BCEF 25, 50, 100 mg/kg) could significantly ameliorate the decreased body weight and effectively reverse the escape behavior disturbance. The gradual reduction of sensitivity to reward, the anhedonic state, was also effectively reversed by BCEF. BCEF (50, 100 mg/kg) could also effectively restore the AVP content in the plasma.Conclusions This evidence suggests that BCEF can effectively inhibit the depression behavior and show strong antidepressant effect. BCEF can effectively restore the plasma AVP release and this may be an important mechanism of its antidepressant effect.

  20. In vivo studies of effects of antidepressants on parotid salivary secretion in the rat.

    Science.gov (United States)

    Johnsson, Martin; Winder, Michael; Zawia, Hana; Lödöen, Ida; Tobin, Gunnar; Götrick, Bengt

    2016-07-01

    Tricyclic antidepressants (TCA) are well-known xerogenic drugs, while antidepressants such as selective serotonin reuptake inhibitors (SSRI) are considered less xerogenic. The antimuscarinic effect of the TCAs has been considered to be the principal mechanism causing a dry mouth. Although the muscarinic receptor is commonly targeted by xerogenic pharmaceuticals, the salivation reflex arc may be affected at other levels as well. We currently wondered whether or not antidepressants exert an inhibition of the salivary reflex not only at the glandular level but at a central level as well. In this study, the effects of a TCA (clomipramine), a SSRI (citalopram) and a serotonin-noradrenaline reuptake inhibitor (SNRI; venlafaxine) were examined on reflex- (0.5M citric acid applied on the tongue) and methacholine-evoked salivary secretion. While all three compounds inhibited citric acid-evoked secretion (-40 to -60% at 5mg/kg i.v. of the antidepressants), only clomipramine inhibited methacholine-evoked secretion (-30% at 5mg/kg i.v.). On the contrary, both citalopram and venlafaxine increased the methacholine-evoked secretion (+44 to 49%). This was particularly obvious for the salivary protein output (>200%). In the presence of α- and β-adrenoceptor antagonists, the citalopram- and venlafaxine-induced increases were reduced. Thus, antidepressants irrespective of type may exert xerogenic effects by inhibiting the salivary reflex in the central nervous system. However, while TCAs may also hamper the secretory response by antimuscarinic effects, the SSRI and the SNRI groups of pharmaceuticals seem to lack this additional xerogenic mechanism indicating a better therapeutic profile and better opportunities for pharmacological treatment of drug-induced xerostomia. PMID:27023402

  1. Antidepressant stimulation of CDP-diacylglycerol synthesis does not require monoamine reuptake inhibition

    Directory of Open Access Journals (Sweden)

    Aboukhatwa Marwa A

    2010-01-01

    Full Text Available Abstract Background Recent studies demonstrate that diverse antidepressant agents increase the cellular production of the nucleolipid CDP-diacylglycerol and its synthetic derivative, phosphatidylinositol, in depression-relevant brain regions. Pharmacological blockade of downstream phosphatidylinositide signaling disrupted the behavioral antidepressant effects in rats. However, the nucleolipid responses were resistant to inhibition by serotonin receptor antagonists, even though antidepressant-facilitated inositol phosphate accumulation was blocked. Could the neurochemical effects be additional to the known effects of the drugs on monoamine transmitter transporters? To examine this question, we tested selected agents in serotonin-depleted brain tissues, in PC12 cells devoid of serotonin transporters, and on the enzymatic activity of brain CDP-diacylglycerol synthase - the enzyme that catalyzes the physiological synthesis of CDP-diacylglycerol. Results Imipramine, paroxetine, and maprotiline concentration-dependently increased the levels of CDP-diacylglycerol and phosphatidylinositides in PC12 cells. Rat forebrain tissues depleted of serotonin by pretreatment with p-chlorophenylalanine showed responses to imipramine or maprotiline that were comparable to respective responses from saline-injected controls. With fluoxetine, nucleolipid responses in the serotonin-depleted cortex or hippocampus were significantly reduced, but not abolished. Each drug significantly increased the enzymatic activity of CDP-diacylglycerol synthase following incubations with cortical or hippocampal brain tissues. Conclusion Antidepressants probably induce the activity of CDP-diacylglycerol synthase leading to increased production of CDP-diacylglycerol and facilitation of downstream phosphatidylinositol synthesis. Phosphatidylinositol-dependent signaling cascades exert diverse salutary effects in neural cells, including facilitation of BDNF signaling and neurogenesis. Hence

  2. Recent insights in nanotechnology-based drugs and formulations designed for effective anti-cancer therapy.

    Science.gov (United States)

    Piktel, Ewelina; Niemirowicz, Katarzyna; Wątek, Marzena; Wollny, Tomasz; Deptuła, Piotr; Bucki, Robert

    2016-01-01

    The rapid development of nanotechnology provides alternative approaches to overcome several limitations of conventional anti-cancer therapy. Drug targeting using functionalized nanoparticles to advance their transport to the dedicated site, became a new standard in novel anti-cancer methods. In effect, the employment of nanoparticles during design of antineoplastic drugs helps to improve pharmacokinetic properties, with subsequent development of high specific, non-toxic and biocompatible anti-cancer agents. However, the physicochemical and biological diversity of nanomaterials and a broad spectrum of unique features influencing their biological action requires continuous research to assess their activity. Among numerous nanosystems designed to eradicate cancer cells, only a limited number of them entered the clinical trials. It is anticipated that progress in development of nanotechnology-based anti-cancer materials will provide modern, individualized anti-cancer therapies assuring decrease in morbidity and mortality from cancer diseases. In this review we discussed the implication of nanomaterials in design of new drugs for effective antineoplastic therapy and describe a variety of mechanisms and challenges for selective tumor targeting. We emphasized the recent advantages in the field of nanotechnology-based strategies to fight cancer and discussed their part in effective anti-cancer therapy and successful drug delivery. PMID:27229857

  3. Crystals of Human Serum Albumin for Use in Genetic Engineering and Rational Drug Design

    Science.gov (United States)

    Carter, Daniel C. (Inventor)

    1994-01-01

    This invention pertains to crystals of serum albumin and processes for growing them. The purpose of the invention is to provide crystals of serum albumin which can be studied to determine binding sites for drugs. Form 2 crystals grow in the monoclinic space P2(sub 1), and possesses the following unit cell constraints: a = 58.9 +/- 7, b = 88.3 +/- 7, c = 60.7 +/- 7, Beta = 101.0 +/- 2 degrees. One advantage of the invention is that it will allow rational drug design

  4. Is the antidepressive effect of second-generation antidepressants a myth?

    DEFF Research Database (Denmark)

    Bech, P

    2010-01-01

    Two recent meta-analyses on second-generation antidepressants versus placebo in mild to moderate forms of major depression, based on data on all randomized clinical trials using the Hamilton Depression Scale (HAMD) submitted to FDA, have shown an effect size of approximately 0.30 in favour of...... antidepressants in the acute therapy of major depression. The clinical significance of an effect size at this level was found to be so poor that these meta-analyses have subscribed to the myth of an exclusively placebo-like effect of second-generation antidepressants. A re-allocation of HAMD items focusing on...... those items measuring severity of clinical depression, the HAMD6, has identified effect sizes of >or=0.40 for second-generation antidepressants in placebo-controlled trials for which even a dose-response relationship can be demonstrated. In the relapse-prevention phase during continuation therapy of...

  5. Inflammatory Biomarkers as Differential Predictors of Antidepressant Response

    Directory of Open Access Journals (Sweden)

    Kenji Hashimoto

    2015-04-01

    Full Text Available Although antidepressants are generally effective in the treatment of major depressive disorder (MDD, it can still take weeks before patients feel the full antidepressant effects. Despite the efficacy of standard treatments, approximately two-thirds of patients with MDD fail to respond to pharmacotherapy. Therefore, the identification of blood biomarkers that can predict the treatment response to antidepressants would be highly useful in order to improve this situation. This article discusses inflammatory molecules as predictive biomarkers for antidepressant responses to several classes of antidepressants, including the N-methyl-d-aspartate (NMDA receptor antagonist ketamine.

  6. Design and characterisation of matrix tablets of highly water soluble drug

    Directory of Open Access Journals (Sweden)

    Vijayalakshmi Prakya

    2012-04-01

    Full Text Available Tramadol HCL is a centrally acting opioid analgesic. Although the drug has a higher plasma half life, the steady state plasma concentration is not achieved with frequent dosing of q.i.d at 6 hour intervals. Therefore, the objective of the present work was to formulate a 100mg strength Tramadol matrix tablets to extend the drug release and thus decrease the dosing frequency and achieve steady state plasma concentration. Initially, preformulation studies were carried out to rule out any incompatibility between the drug and the chosen polymer(s after exposing physical mixtures of the drug and the polymer(s to 40 and deg;C/75% RH for three months. A suitable method was developed for drug estimation at 271nm by a UV double beam spectrophotometer. Next, various batches of tablets were designed using different polymers such as Ethylcellulose, Carnauba wax, HPMC-K100M, Carbopol-974P and Kollidon-SR. Direct compression technique was used except for the formulation containing carnauba wax for which melt granulation was done followed by compression. Formulations F-1 to F-15 contained single polymers in increasing concentrations in drug:polymer ratios of 1:1, 1:2 and 1:3 where it was observed that the drug release extended with increasing polymer concentrations. Carbopol-974P extended drug release better followed by HPMC-K100M and Carnauba wax compared to other polymers. A combination of these polymers was also used at various ratios to get formulations F-16 to F-20 and observed that the polymer combinations controlled drug release better. The type of fillers like lactose and microcrystalline cellulose had no effect on the physiochemical characters as well as on the drug release profiles. The in vitro release data from the best formulation fitted well in Higuchi as well as Peppas model, the and #8216;n and #8217; value, which confirmed that the release mechanism shifted from initial dissolution to later extended diffusion in which both diffusion and erosion

  7. Antidepressant-like effects of methanol extract of Hibiscus tiliaceus flowers in mice

    Directory of Open Access Journals (Sweden)

    Vanzella Cláudia

    2012-04-01

    Full Text Available Abstract Background Hibiscus tiliaceus L. (Malvaceae is used in postpartum disorders. Our purpose was to examine the antidepressant, anxiolytic and sedative actions of the methanol extract of H. tiliaceus flowers using animal models. Methods Adult male Swiss albino mice were treated with saline, standard drugs or methanol extract of H. tiliaceus and then subjected to behavioral tests. The forced swimming and tail suspension tests were used as predictive animal models of antidepressant activity, where the time of immobility was considered. The animals were submitted to the elevated plus-maze and ketamine-induced sleeping time to assess anxiolytic and sedative activities, respectively. Results Methanol extract of H. tiliaceus significantly decreased the duration of immobility in both animal models of antidepressant activity, forced swimming and tail suspension tests. This extract did not potentiate the effect of ketamine-induced hypnosis, as determined by the time to onset and duration of sleeping time. Conclusion Our results indicate an antidepressant-like profile of action for the extract of Hibiscus tiliaceus without sedative side effect.

  8. Evidences for the agmatine involvement in antidepressant like effect of bupropion in mouse forced swim test.

    Science.gov (United States)

    Kotagale, Nandkishor R; Tripathi, Sunil J; Aglawe, Manish M; Chopde, Chandrabhan T; Umekar, Milind J; Taksande, Brijesh G

    2013-06-01

    Although bupropion has been widely used in the treatment of depression, the precise mechanism of its therapeutic actions is not fully understood. The present study investigated the role of agmatine in an antidepressant like effect of bupropion in mouse forced swim test. The antidepressant like effect of bupropion was potentiated by pretreatment with agmatine (10-20mg/kg, ip) and by the drugs known to increase endogenous agmatine levels in brain viz., l-arginine (40 μg/mouse, icv), an agmatine biosynthetic precursor, ornithine decarboxylase inhibitor, dl-α-difluoromethyl ornithine hydrochloride, DFMO (12.5 μg/mouse, icv), diamine oxidase inhibitor, aminoguanidine (6.5 μg/mouse, icv) and agmatinase inhibitor, arcaine (50 μg/mouse, icv) as well as imidazoline I1 receptor agonists, moxonidine (0.25mg/kg, ip) and clonidine (0.015 mg/kg, ip) and imidazoline I2 receptor agonist, 2-(2-benzofuranyl)-2-imidazoline hydrochloride, 2-BFI (5mg/kg, ip). Conversely, prior administration of I1 receptor antagonist, efaroxan (1mg/kg, ip) and I2 receptor antagonist, idazoxan (0.25mg/kg, ip) blocked the antidepressant like effect of bupropion and its synergistic combination with agmatine. These results demonstrate involvement of agmatine in the antidepressant like effect of bupropion and suggest agmatine and imidazoline receptors as a potential therapeutic target for the treatment of depressive disorders.

  9. Potential antidepressant properties of cysteamine on hippocampal BDNF levels and behavioral despair in mice.

    Science.gov (United States)

    Shieh, Chu-Hsin; Hong, Chen-Jee; Huang, Yn-Ho; Tsai, Shih-Jen

    2008-08-01

    Several studies have demonstrated that antidepressants increase central brain-derived neurotrophic factor (BDNF) levels, suggesting that BDNF signaling is important for the therapeutic mechanism of antidepressants. Recent work has found that cysteamine and its related agent, cystamine, are neuroprotective in Huntington's disease mice, and act by enhancing the secretion of central BDNF. In the present study, the potential antidepressant effects of cysteamine were examined by behavioral paradigms and biochemical assay. Male BALB/CByJ mice were given a single dose of normal saline, 10 mg/kg of imipramine or either 50, 100 or 200 mg/kg of cysteamine (i.p.) 30 min before undergoing the forced-swimming test (FST) or the tail suspension test (TST). Other groups of mice treated with the same drugs and doses, without behavioral tests, were sacrificed for hippocampal BDNF measurements. We found that, compared with the control group, the cysteamine 200-mg/kg group showed a significant reduction in immobility time in the FST (Pcysteamine 200-mg/kg group (Pcysteamine may possess an antidepressant-like effect, which may be mediated by increasing central BDNF levels. PMID:18582526

  10. Antidepressant and neurocognitive effects of isoflurane anesthesia versus electroconvulsive therapy in refractory depression.

    Directory of Open Access Journals (Sweden)

    Howard R Weeks

    Full Text Available BACKGROUND: Many patients have serious depression that is nonresponsive to medications, but refuse electroconvulsive therapy (ECT. Early research suggested that isoflurane anesthesia may be an effective alternative to ECT. Subsequent studies altered drug, dose or number of treatments, and failed to replicate this success, halting research on isoflurane's antidepressant effects for a decade. Our aim was to re-examine whether isoflurane has antidepressant effects comparable to ECT, with less adverse effects on cognition. METHOD: Patients with medication-refractory depression received an average of 10 treatments of bifrontal ECT (n = 20 or isoflurane (n = 8 over 3 weeks. Depression severity (Hamilton Rating Scale for Depression-24 and neurocognitive responses (anterograde and retrograde memory, processing speed and verbal fluency were assessed at Pretreatment, Post all treatments and 4-week Follow-up. RESULTS: Both treatments produced significant reductions in depression scores at Post-treatment and 4-week Follow-up; however, ECT had modestly better antidepressant effect at follow-up in severity-matched patients. Immediately Post-treatment, ECT (but not isoflurane patients showed declines in memory, fluency, and processing speed. At Follow-up, only autobiographical memory remained below Pretreatment level for ECT patients, but isoflurane patients had greater test-retest neurocognitive score improvement. CONCLUSIONS: Our data reconfirm that isoflurane has an antidepressant effect approaching ECT with less adverse neurocognitive effects, and reinforce the need for a larger clinical trial.

  11. [Therapy of dementia with antipsychotics and antidepressives].

    Science.gov (United States)

    Frölich, L; Hausner, L

    2015-04-01

    In dementia depressive symptoms, anxiety, hallucinations and delusions often occur and are accompanied by unspecific behavioral changes. A targeted pharmacotherapy is complicated by the underlying cognitive impairment and physical comorbidities. The current review focusses on recent evidence on the use of antidepressives and antipsychotics for psychotic disturbances, agitation and depression in dementia and analyzes currently published randomized controlled clinical trials and meta-analyses. The evidence on the use of antipsychotics for different indications favors risperidone, with lower evidence levels for quetiapine and aripiprazole, whereas haloperidol should be avoided. Increased mortality and the risk of cerebrovascular events due to antipsychotics are of major concern. With respect to antidepressives, the benefit of antidepressive pharmacotherapy in dementia is critically discussed because of limited efficacy and increased side effects; however, selective serotonin reuptake inhibitors (SSRI), such as citalopram and sertraline have demonstrated efficacy on neuropsychiatric behavioral symptoms in general. These conclusions on the risk-benefit ratio of antidepressives and antipsychotics in dementia are in accordance with the recommendations of the German Society of Neurology and German Association for Psychiatry, Psychotherapy and Psychosomatics (DGN/DGPPN) S3 guidelines on the treatment of dementia. PMID:25787724

  12. Physiological Bases of Bulimia, and Antidepressant Treatment.

    Science.gov (United States)

    Getzfeld, Andrew R.

    This paper reviews the literature on the physiological causes of bulimia and investigates the rationale behind the usage of antidepressant medication in the treatment of bulimia nervosa. No definite conclusions can be stated regarding the physiology of bulimia, but a number of hypotheses are suggested. It appears that the hypothalamus is involved…

  13. Application of CellDesigner to the Selection of Anticancer Drug Targets: Test Case using P53

    OpenAIRE

    Isea, Raul; Hoebeke, Johan; Mayo, Rafael; Alvarez, Fernando; Holmes, David S.

    2013-01-01

    Cancer is a disease involving many genes, consequently it has been difficult to design anticancer drugs that are efficacious over a broad range of cancers. The robustness of cellular responses to gene knockout and the need to reduce undesirable side effects also contribute to the problem of effective anti-cancer drug design. To promote the successful selection of drug targets, each potential target should be subjected to a systems biology scrutiny to locate effective and specific targets whil...

  14. Functionalized Benzimidazole Scaffolds: Privileged Heterocycle for Drug Design in Therapeutic Medicine.

    Science.gov (United States)

    Ajani, Olayinka O; Aderohunmu, Damilola V; Ikpo, Chinwe O; Adedapo, Adebusayo E; Olanrewaju, Ifedolapo O

    2016-07-01

    Benzimidazole derivatives are crucial structural scaffolds found in diverse libraries of biologically active compounds which are therapeutically useful agents in drug discovery and medicinal research. They are structural isosteres of naturally occurring nucleotides, which allows them to interact with the biopolymers of living systems. Hence, there is a need to couple the latest information with the earlier documentations to understand the current status of the benzimidazole nucleus in medicinal chemistry research. This present work unveils the benzimidazole core as a multifunctional nucleus that serves as a resourceful tool of information for synthetic modifications of old existing candidates in order to tackle drug resistance bottlenecks in therapeutic medicine. This manuscript deals with the recent advances in the synthesis of benzimidazole derivatives, the widespread biological activities as well as pharmacokinetic reports. These present them as a toolbox for fighting infectious diseases and also make them excellent candidates for future drug design. PMID:27213292

  15. Antidepressant prescribing in five European countries: application of common definitions to assess the prevalence, clinical observations, and methodological implications.

    NARCIS (Netherlands)

    Abbing-Karahagopian, V.; Huerta, C.; Souverein, P.C.; Abajo, F. de; Leufkens, H.G.M.; Slattery, J.; Alvarez, Y.; Miret, M.; Gil, M.; Oliva, B.; Hesse, U.; Requena, G.; Vries, F. de; Rottenkolber, M.; Schmiedl, S.; Reynolds, R.; Schlienger, R.G.; Groot, M.C.H. de; Klungel, O.H.; Staa, T.P. van; Dijk, L. van; Egberts, A.C.G.; Gardarsdottir, H.; Bruin, M.L. de

    2014-01-01

    Purpose: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence,

  16. Antidepressant prescribing in five European countries : Application of common definitions to assess the prevalence, clinical observations, and methodological implications

    NARCIS (Netherlands)

    Abbing-Karahagopian, V; Huerta, C; Souverein, P C; de Abajo, F; Leufkens, H G M; Slattery, J; Alvarez, Y; Miret, M; Gil, M; Oliva, B; Hesse, U; Requena, G; de Vries, F; Rottenkolber, M; Schmiedl, S; Reynolds, R; Schlienger, R G; de Groot, M C H; Klungel, O H; van Staa, T P; van Dijk, L; Egberts, A C G; Gardarsdottir, H; De Bruin, M L

    2014-01-01

    PURPOSE: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence,

  17. Antidepressant prescribing in five European countries: Application of common definitions to assess the prevalence, clinical observations, and methodological implications

    NARCIS (Netherlands)

    Abbing-Karahagopian, V.; Huerta, C.; Souverein, P.C.; De Abajo, F.; Leufkens, H.G.M.; Slattery, J.; Alvarez, Y.; Miret, M.; Gil, M.; Oliva, B.; Hesse, U.; Requena, G.; De Vries, F.; Rottenkolber, M.; Schmiedl, S.; Reynolds, R.; Schlienger, R.G.; De Groot, M.C.H.; Klungel, O.H.; Van Staa, T.P.; Van Dijk, L.; Egberts, A.C.G.; Gardarsdottir, H.; De Bruin, M.L.

    2014-01-01

    Purpose: Drug utilization studies have applied different methods to various data types to describe medication use, which hampers comparisons across populations. The aim of this study was to describe the time trends in antidepressant prescribing in the last decade and the variation in the prevalence,

  18. Prevalence and factors associated with off-label antidepressant prescriptions for insomnia

    OpenAIRE

    Lai, Leanne

    2011-01-01

    L Leanne Lai¹, Mooi Heong Tan¹, Yen Chi Lai²¹Department of Sociobehavioral and Administrative Pharmacy, College of Pharmacy, Nova Southeastern University, Fort Lauderdale, FL, USA; ²Department of Internal Medicine, Golen Hospital, Pintong City, TaiwanBackground: The primary objective of our study was to investigate the prevalence of off-label antidepressant drug use in insomnia. The secondary objective was to compare prescribing patterns between of...

  19. Aquatic blues: modeling depression and antidepressant action in zebrafish.

    Science.gov (United States)

    Nguyen, Michael; Stewart, Adam Michael; Kalueff, Allan V

    2014-12-01

    Depression is a serious psychiatric condition affecting millions of patients worldwide. Unipolar depression is characterized by low mood, anhedonia, social withdrawal and other severely debilitating psychiatric symptoms. Bipolar disorder manifests in alternating depressed mood and 'hyperactive' manic/hypomanic states. Animal experimental models are an invaluable tool for research into the pathogenesis of bipolar/unipolar depression, and for the development of potential treatments. Due to their high throughput value, genetic tractability, low cost and quick reproductive cycle, zebrafish (Danio rerio) have emerged as a promising new model species for studying brain disorders. Here, we discuss the developing utility of zebrafish for studying depression disorders, and outline future areas of research in this field. We argue that zebrafish represent a useful model organism for studying depression and its behavioral, genetic and physiological mechanisms, as well as for anti-depressant drug discovery.

  20. Computation-based virtual screening for designing novel antimalarial drugs by targeting falcipain-III: A structure-based drug designing approach

    Directory of Open Access Journals (Sweden)

    Rajesh Kumar Kesharwani

    2013-04-01

    Full Text Available Background & objectives: Cysteine proteases (falcipains, a papain-family of enzymes of Plasmodium falciparum, are responsible for haemoglobin degradation and thus necessary for its survival during asexual life cycle phase inside the human red blood cells while remaining non-functional for the human body. Therefore, these can act as potential targets for designing antimalarial drugs. The P. falciparum cysteine proteases, falcipain-II and falcipain- III are the enzymes which initiate the haemoglobin degradation, therefore, have been selected as targets. In the present study, we have designed new leupeptin analogues and subjected to virtual screening using Glide at the active site cavity of falcipain-II and falcipain-III to select the best docked analogues on the basis of Glide score and also compare with the result of AutoDock. The proposed analogues can be synthesized and tested in vivo as future potent antimalarial drugs. Methods: Protein falcipain-II and falcipain-III together with bounds inhibitors epoxysuccinate E64 (E64 and leupeptin respectively were retrieved from protein data bank (PDB and latter leupeptin was used as lead molecule to design new analogues by using Ligbuilder software and refined the molecules on the basis of Lipinski rule of five and fitness score parameters. All the designed leupeptin analogues were screened via docking simulation at the active site cavity of falcipain-II and falcipain-III by using Glide software and AutoDock. Results: The 104 new leupeptin-based antimalarial ligands were designed using structure-based drug designing approach with the help of Ligbuilder and subjected for virtual screening via docking simulation method against falcipain-II and falcipain-III receptor proteins. The Glide docking results suggest that the ligands namely result_037 shows good binding and other two, result_044 and result_042 show nearly similar binding than naturally occurring PDB bound ligand E64 against falcipain-II and in

  1. Antidepressant-Like Activity of the Ethanolic Extract from Uncaria lanosa Wallich var. appendiculata Ridsd in the Forced Swimming Test and in the Tail Suspension Test in Mice

    Directory of Open Access Journals (Sweden)

    Lieh-Ching Hsu

    2012-01-01

    Full Text Available This study investigated the antidepressant activity of ethanolic extract of U. lanosa Wallich var. appendiculata Ridsd (ULEtOH for two-weeks administrations by using FST and TST on mice. In order to understand the probable mechanism of antidepressant-like activity of ULEtOH in FST and TST, the researchers measured the levels of monoamines and monoamine oxidase activities in mice brain, and combined the antidepressant drugs (fluoxetine, imipramine, maprotiline, clorgyline, bupropion and ketanserin. Lastly, the researchers analyzed the content of RHY in the ULEtOH. The results showed that ULEtOH exhibited antidepressant-like activity in FST and TST in mice. ULEtOH increased the levels of 5-HT and 5-HIAA in cortex, striatum, hippocampus, and hypothalamus, the levels of NE and MHPG in cortex and hippocampus, the level of NE in striatum, and the level of DOPAC in striatum. Two-week injection of IMI, CLO, FLU and KET enhanced the antidepressant-like activity of ULEtOH. ULEtOH inhibited the activity of MAO-A. The amount of RHY in ULEtOH was 17.12 mg/g extract. Our findings support the view that ULEtOH exerts antidepressant-like activity. The antidepressant-like mechanism of ULEtOH may be related to the increase in monoamines levels in the hippocampus, cortex, striatum, and hypothalamus of mice.

  2. Analysis of the utilization of antidepressant drugs in our hospital from the year 2008 to 2010%我院2008~2010年抗抑郁药使用分析

    Institute of Scientific and Technical Information of China (English)

    杨佳艳; 李煌; 奚啸风

    2012-01-01

    Objective To evaluate and analyze the utilization of antideprcssant drugs in our hospital. Methods The amount of DDDs, average daily costs (DDC) and other data were analyzed. Results The amount of the annual sales of antideprcssants increased year by year,and the amount of sales ranked top 3 was paroxctinc,flupcntixol/mclitraccn and scrtralinc. DDDs ranked top 3 was flu-pcntixol/mclitraccn, paroxctinc,and scrtralinc. Conclusion Selective serotonin (5-HT) re-uptake inhibitors (SSRIs) class of antideprcssant drugs dominated the consumption and compound preparation-antideprcssant has broad application prospects.%目的 评价医院抗抑郁药的应用情况和发展趋势,为临床合理用药提供参考.方法 对医院2008~2010年抗抑郁药的销售金额、用药频度(DDDs)、日均费用(DDC)等数据进行统计、分析.结果 各年度抗抑郁药销售金额呈逐年上升趋势,销售金额排序前3位的是分别是帕罗西汀、氟哌噻吨/美利曲辛、舍曲林,用药频度排序前3位的是氟哌噻吨/美利曲辛、帕罗西汀、舍曲林.结论 选择性5-羟色胺(5-HT)再摄取抑制剂(SSRIs)类抗抑郁药的应用占主导地位,复合制剂型抗抑郁药应用前景广阔.

  3. A genome-wide association study points to multiple loci predicting antidepressant treatment outcome in depression

    Science.gov (United States)

    Binder, Elisabeth B.; Bettecken, Thomas; Uhr, Manfred; Ripke, Stephan; Kohli, Martin A.; Hennings, Johannes M.; Horstmann, Sonja; Kloiber, Stefan; Menke, Andreas; Bondy, Brigitta; Rupprecht, Rainer; Domschke, Katharina; Baune, Bernhard T.; Arolt, Volker; Rush, A. John; Holsboer, Florian; Müller-Myhsok, Bertram

    2015-01-01

    Context Efficacy of antidepressant treatment in depression is unsatisfactory as one in three patients does not fully recover even after several treatment trials. Genetic factors and clinical characteristics contribute to the failure of a favorable treatment outcome. Objective To identify genetic and clinical determinants of antidepressant treatment outcome in depression. Design Genome-wide pharmacogenetic association study with two independent replication samples. Setting We performed a genome-wide association (GWA) study in patients from the Munich-Antidepressant-Response-Signature (MARS) project and in pooled DNA from an independent German replication sample. A set of 328 single nucleotide polymorphisms (SNPs) highly related to outcome in both GWA studies was genotyped in a sample of the Sequenced-Treatment-Alternatives-to-Relieve-Depression (STAR*D) study. Participants 339 inpatients suffering from a depressive episode (MARS sample), further 361 depressed inpatients (German replication sample), and 832 outpatients with major depression (STAR*D sample). Main Outcome Measures We generated a multi-locus genetic variable describing the individual number of alleles of the selected SNPs associated with beneficial treatment outcome in the MARS sample (“response” alleles) to evaluate additive genetic effects on antidepressant treatment outcome. Results Multi-locus analysis revealed a significant contribution of a binary variable categorizing patients as carriers of a high vs. low number of response alleles in predicting antidepressant treatment outcome in both samples, MARS and STAR*D. In addition, we observed that patients with a comorbid anxiety disorder in combination with a low number of response alleles showed the least favorable outcome. Conclusion Our results demonstrate the importance of multiple genetic factors in combination with clinical features to predict antidepressant treatment outcome underscoring the multifactorial nature of this trait. PMID

  4. Preterm birth and antidepressant medication use during pregnancy: a systematic review and meta-analysis.

    Directory of Open Access Journals (Sweden)

    Krista F Huybrechts

    Full Text Available Preterm birth is a major contributor to neonatal morbidity and mortality and its rate has been increasing over the past two decades. Antidepressant medication use during pregnancy has also been rising, with rates up to 7.5% in the US. The objective was to systematically review the literature to determine the strength of the available evidence relating to a possible association between antidepressant use during pregnancy and preterm birth.We conducted a computerized search in PUBMED, MEDLINE and PsycINFO through September 2012, supplemented with a manual search of reference lists, to identify original published research on preterm birth rates in women taking antidepressants during pregnancy. Data were independently extracted by two reviewers, and absolute and relative risks abstracted or calculated. Our a priori design was to group studies by level of confounding adjustment and by timing of antidepressant use during pregnancy; we used random-effects models to calculate summary measures of effect.Forty-one studies met inclusion criteria. Pooled adjusted odds ratios (95% CI were 1.53 (1.40-1.66 for antidepressant use at any time and 1.96 (1.62-2.38 for 3rd trimester use. Controlling for a diagnosis of depression did not eliminate the effect. There was no increased risk [1.16 (0.92-1.45] in studies that identified patients based on 1st trimester exposure. Sensitivity analyses demonstrated unmeasured confounding would have to be strong to account for the observed association.Published evidence is consistent with an increased risk of preterm birth in women taking antidepressants during the 2nd and 3rd trimesters, although the possibility of residual confounding cannot be completely ruled out.

  5. [Drug therapy and the most common drugs for childhood psychiatric disorders].

    Science.gov (United States)

    Puustjärvi, Anita; Raunio, Hannu; Lecklin, Anne; Kumpulainen, Kirsti

    2016-01-01

    Psychotropic drugs are more commonly prescribed for children, although scientific evidence about psychotrophic medication and long-term effects thereof in children is scarce. The drugs are often used off-label. ADHD drugs, antipsychotics and antidepressants and melatonin are the most commonly used drugs. ADHD medication possesses the most established status. Antipsychotic drugs are utilized for the treatment of psychoses, bipolar disorder, and conduct disorder symptoms in particular. Antidepressants are utilized for the treatment of childhood depression and anxiety disorders, melatonin for the treatment of children's sleep problems. Drug therapy should always be carried out as part of other psychiatric therapy. PMID:27382830

  6. Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study.

    Science.gov (United States)

    Zafar, Ayesha; Reynisson, Jóhannes

    2016-05-01

    In this work the idea was investigated whether calculated hydration energy (ΔGhyd ) can be used as a molecular descriptor in defining promising regions of chemical space for drug design. Calculating ΔGhyd using the Density Solvation Model (SMD) in conjunction with the density functional theory (DFT) gave an excellent correlation with experimental values. Furthermore, calculated ΔGhyd correlates reasonably well with experimental water solubility (r(2) =0.545) and also log P (r(2) =0.530). Three compound collections were used: Known drugs (n=150), drug-like compounds (n=100) and simple organic compounds (n=140). As an approximation only molecules, which do not de/protonate at physiological pH were considered. A relatively broad distribution was seen for the known drugs with an average at -15.3 kcal/mol and a standard deviation of 7.5 kcal/mol. Interestingly, much lower averages were found for the drug-like compounds (-7.5 kcal/mol) and the simple organic compounds (-3.1 kcal/mol) with tighter distributions; 4.3 and 3.2 kcal/mol, respectively. This trend was not observed for these collections when calculated log P and log S values were used. The considerable greater exothermic ΔGhyd average for the known drugs clearly indicates in order to develop a successful drug candidate value of ΔGhyd <-5 kcal/mol or less is preferable. PMID:27492087

  7. Hydration Free Energy as a Molecular Descriptor in Drug Design: A Feasibility Study.

    Science.gov (United States)

    Zafar, Ayesha; Reynisson, Jóhannes

    2016-05-01

    In this work the idea was investigated whether calculated hydration energy (ΔGhyd ) can be used as a molecular descriptor in defining promising regions of chemical space for drug design. Calculating ΔGhyd using the Density Solvation Model (SMD) in conjunction with the density functional theory (DFT) gave an excellent correlation with experimental values. Furthermore, calculated ΔGhyd correlates reasonably well with experimental water solubility (r(2) =0.545) and also log P (r(2) =0.530). Three compound collections were used: Known drugs (n=150), drug-like compounds (n=100) and simple organic compounds (n=140). As an approximation only molecules, which do not de/protonate at physiological pH were considered. A relatively broad distribution was seen for the known drugs with an average at -15.3 kcal/mol and a standard deviation of 7.5 kcal/mol. Interestingly, much lower averages were found for the drug-like compounds (-7.5 kcal/mol) and the simple organic compounds (-3.1 kcal/mol) with tighter distributions; 4.3 and 3.2 kcal/mol, respectively. This trend was not observed for these collections when calculated log P and log S values were used. The considerable greater exothermic ΔGhyd average for the known drugs clearly indicates in order to develop a successful drug candidate value of ΔGhyd <-5 kcal/mol or less is preferable.

  8. Design or screening of drugs for the treatment of Chagas disease: what shows the most promise?

    Science.gov (United States)

    Lepesheva, Galina I.

    2013-01-01

    Introduction Endemic in Latin America, Chagas disease is now becoming a serious global health problem, and yet has no financial viability for the pharmaceutical industry and remains incurable. In 2012, two antimycotic drugs inhibitors of fungal sterol 14α-demethylase (CYP51) – posaconazole and ravuconazole – entered clinical trials. Availability of the X-ray structure of the orthologous enzyme from the causative agent of the disease, protozoan parasite Trypanosoma cruzi, determined in complexes with posaconazole as well as with several experimental protozoa-specific CYP51 inhibitors opens an excellent opportunity to improve the situation. Areas covered This article summarizes the information available in PubMed and Google on the outcomes of treatment of the chronic Chagas disease. It also outlines the major features of the T. cruzi CYP51 structure and the possible structure-based strategies for rational design of novel T. cruzi specific drugs. Expert opinion There is no doubt that screenings for alternative drug-like molecules as well as mining the T. cruzi genome for novel drug targets are of great value and might eventually lead to groundbreaking discoveries. However, all newly identified molecules must proceed through the long, expensive and low-yielding drug optimization process, and all novel potential drug targets must be validated in terms of their essentiality and druggability. CYP51 is already a well-validated and highly successful target for clinical and agricultural antifungals. With minimal investments into the final stages of their development/trials, T. cruzi-specific CYP51 inhibitors can provide an immediate treatment for Chagas disease, either on their own or in combination with the currently available drugs. PMID:24079515

  9. Structures of HIV Protease Guide Inhibitor Design to Overcome Drug Resistance

    Energy Technology Data Exchange (ETDEWEB)

    Weber, Irene T.; Kovalevsky, Andrey Y.; Harrison, Robert W. (GSU)

    2008-06-03

    The HIV/AIDS infection continues to be a major epidemic worldwide despite the initial promise of antiviral drugs. Current therapy includes a combination of drugs that inhibit two of the virally-encoded enzymes, the reverse transcriptase and the protease. The first generation of HIV protease inhibitors that have been in clinical use for treatment of AIDS since 1995 was developed with the aid of structural analysis of protease-inhibitor complexes. These drugs were successful in improving the life span of HIV-infected people. Subsequently, the rapid emergence of drug resistance has necessitated the design of new inhibitors that target mutant proteases. This second generation of antiviral protease inhibitors has been developed with the aid of data from medicinal chemistry, kinetics, and X-ray crystallographic analysis. Traditional computational methods such as molecular mechanics and dynamics can be supplemented with intelligent data mining approaches. One approach, based on similarities to the protease interactions with substrates, is to incorporate additional interactions with main chain atoms that cannot easily be eliminated by mutations. Our structural and inhibition data for darunavir have helped to understand its antiviral activity and effectiveness on drug resistant HIV and demonstrate the success of this approach.

  10. Self nano-emulsifying drug delivery system for Embelin: Design, characterization and in-vitro studies

    Directory of Open Access Journals (Sweden)

    Komal Parmar

    2015-10-01

    Full Text Available CThe objective of the present study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS containing Capryol-90 as oil phase for the delivery of Embelin, a poorly water soluble herbal active ingredient. Box-Behnken experimental design was employed to optimise the formulation variables, X1 (amount of oil; Capryol 90, X2 (amount of surfactant; Acrysol EL 135 and X3 (amount of co-surfactant; PEG 400. Systems were appraised for visual characteristics for self emulsifying time, globule size and drug release. Optimised liquid formulations were formulated into free flowing granules (S-SNEDDS by adsorption on the porous materials like Aerosil 200 and Neusilin and thereby compressed into tablet. In vitro dissolution studies of SNEDDS revealed increased in the dissolution rate of the drug. FT-IR data revealed no physicochemical interaction between drug and excipients. Solid state characterization of S-SNEDDS by DSC and Powder XRD confirmed reduction in drug crystallinity which further supports the results of dissolution studies. TEM analysis exhibited spherical globules. Further, the accelerated stability studies for 6 months revealed that S-SNEDDS of Embelin are found to be stable without any significant change in physicochemical properties. Thus, the present studies demonstrated dissolution enhancement potential of porous carrier based S-SNEDDS for poorly water soluble herbal active ingredient, Embelin.

  11. Design of a RESTful web information system for drug prescription and administration.

    Science.gov (United States)

    Bianchi, Lorenzo; Paganelli, Federica; Pettenati, Maria Chiara; Turchi, Stefano; Ciofi, Lucia; Iadanza, Ernesto; Giuli, Dino

    2014-05-01

    Drug prescription and administration processes strongly impact on the occurrence of risks in medical settings for they can be sources of adverse drug events (ADEs). A properly engineered use of information and communication technologies has proven to be a promising approach to reduce these risks. In this study, we propose PHARMA, a web information system which supports healthcare staff in the secure cooperative execution of drug prescription, transcription and registration tasks. PHARMA allows the easy sharing and management of documents containing drug-related information (i.e., drug prescriptions, medical reports, screening), which is often inconsistent and scattered across different information systems and heterogeneous organization domains (e.g., departments, other hospital facilities). PHARMA enables users to access such information in a consistent and secure way, through the adoption of REST and web-oriented design paradigms and protocols. We describe the implementation of the PHARMA prototype, and we discuss the results of the usability evaluation that we carried out with the staff of a hospital in Florence, Italy.

  12. A designed amphiphilic peptide containing the silk fibroin motif as a potential carrier of hydrophobic drugs

    Institute of Scientific and Technical Information of China (English)

    Qinghan Zhou; Juan Lin; Jing Wang; Feng Li; Fushan Tang; Xiaojun Zhao

    2009-01-01

    The amphiphilic peptide is becoming attractive as a potential drug carder to improve the dissolvability of hydrophobic drugs in an aqueous system; thus, facilitating drug uptake by target cells. Here, we report a novel designed amphiphilic peptide, Ac-RADAGAGA-RADAGAGA-NH_2, which was able to stabilize pyrene, a hydrophobic model drug we chose to study in aqueous solution. This designed peptide formed a colloidal suspension by encapsulating pyrene inside the peptide-pyrene complex. Egg phosphatidylcholine (EPC) ves-icles were used to mimic cell bilayer membranes. We found that pyrene was released from the peptide coating into the EPC vesicles by mixing the colloidal suspension with EPC vesicles, which was followed by steady fluorescence spectra as a function of time. A calibration curve for the amount of pyrene released into the EPC vesicles at a given time was used to determine the final concentration of pyrene released into the lipid vesicles from the peptide-pyrene complex. The release rate of the peptide pyrene complex was calculated to quan-tify the transfer of pyrene into EPC vesicles.

  13. [The use of saliva for exposure assessments on designer drugs among adolescents].

    Science.gov (United States)

    Napierała, Marta; Tezyk, Artur; Piznal, Małgorzata; Bogusiewicz, Joanna; Florek, Ewa

    2015-01-01

    Drug use is one of the fundamental problems of the contemporary world. Due to the debilitating effects on physical and mental health and the possibility of impaired social functions, it is extremely important to assess exposure to psychoactive substances among high-risk groups. Taking into account characteristics of adolescence, one of them includes young people. To assess the exposure of young people to drugs, survey research is the most commonly use. To establish reliability of the information indicated by the students, toxicological studies could be a good manner. High-performance liquid chromatography coupled with mass spectrometry (LC-MS) is currently one of the most common techniques use for the detection and determination of psychoactive substances in biological material. In practice, an important issue in toxicological studies is the selection of a suitable biological material. Taking into account economic considerations and the method of sampling, the saliva is an increasingly used alternative material. The aim of this study was to assess the exposure of junior high school students on psychoactive substances--designer drugs, through the analysis of surveys and qualitative analysis of saliva taken from teenagers. It has been shown that surveys are a relatively quick and easy form of assessing the exposure of young people to psychoactive substances, but require verification through toxicological analysis of biological material for the presence of psychoactive substances for their reliability. Poznan secondary school students experimented with designer drugs at a similar level as respondents of nationwide survey from 2013. PMID:26946561

  14. Factorial design studies of antiretroviral drug-loaded stealth liposomal injectable: PEGylation, lyophilization and pharmacokinetic studies

    Science.gov (United States)

    Sudhakar, Beeravelli; Krishna, Mylangam Chaitanya; Murthy, Kolapalli Venkata Ramana

    2016-01-01

    The aim of the present study was to formulate and evaluate the ritonavir-loaded stealth liposomes by using 32 factorial design and intended to delivered by parenteral delivery. Liposomes were prepared by ethanol injection method using 32 factorial designs and characterized for various physicochemical parameters such as drug content, size, zeta potential, entrapment efficiency and in vitro drug release. The optimization process was carried out using desirability and overlay plots. The selected formulation was subjected to PEGylation using 10 % PEG-10000 solution. Stealth liposomes were characterized for the above-mentioned parameters along with surface morphology, Fourier transform infrared spectrophotometer, differential scanning calorimeter, stability and in vivo pharmacokinetic studies in rats. Stealth liposomes showed better result compared to conventional liposomes due to effect of PEG-10000. The in vivo studies revealed that stealth liposomes showed better residence time compared to conventional liposomes and pure drug solution. The conventional liposomes and pure drug showed dose-dependent pharmacokinetics, whereas stealth liposomes showed long circulation half-life compared to conventional liposomes and pure ritonavir solution. The results of statistical analysis showed significance difference as the p value is (<0.05) by one-way ANOVA. The result of the present study revealed that stealth liposomes are promising tool in antiretroviral therapy.

  15. Drug: D01888 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D01888 Drug Safrazine hydrochloride (JAN) C11H16N2O2. HCl 244.0979 244.7179 D01888.gif Antidepressant withdr...awal drug monoamine oxidase (MAO) inhibitor [HSA:4128 4129] [KO:K00274] hsa00260(41

  16. Drug: D05575 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D05575 Drug Pramipexole (USAN/INN) C10H17N3S 211.1143 211.3271 D05575.gif Antidepressant; Antiparkins...:6582] Transporter inhibition: SCL47A2 [HSA:146802] map07057 Antiparkinsonian agents map07213 Dopamine recep... Pramipexole D05575 Pramipexole (USAN/INN) USP drug classification [BR:br08302] Antiparkinson Agents Dopamin

  17. When ageing meets the blues: Are current antidepressants effective in depressed aged patients?

    Science.gov (United States)

    Felice, Daniela; O'Leary, Olivia F; Cryan, John F; Dinan, Timothy G; Gardier, Alain M; Sánchez, Connie; David, Denis J

    2015-08-01

    "I had to wait 110 years to become famous. I wanted to enjoy it as long as possible.", Jeanne Louise Calment (1875-1997). This review summarizes current knowledge of the effects of antidepressant drugs in elderly patients (double-blind placebo (n=27) or active comparator-controlled clinical trials (n=21) indexed in Pubmed in depressed patients aged ≥60) and in aged mice (≥9 months) and middle-aged rats (≥14 months) on depression-related symptoms and cognitive performances. Finally, other potential therapeutic targets for treating depression-related disorders in elderly patients are also addressed (neurogenesis, GABAB receptor, 5-HT4 receptor, mTOR signaling). Overall, the very few published preclinical studies (n=12 in total) in middle-aged and aged rodents seem to suggest that selective serotonin reuptake inhibitors (SSRIs) may be less effective than tricyclic antidepressant drugs (TCAs) in ameliorating depression-like behavior and cognitive functions. On the other hand, results from clinical trials suggest that there is not a marked difference in efficacy and safety profiles of current marketed classes of antidepressant drugs.

  18. Impact of Antidepressants on Cytokine Production of Depressed Patients in Vitro

    Directory of Open Access Journals (Sweden)

    Alexander Munzer

    2013-11-01

    Full Text Available The interplay between immune and nervous systems plays a pivotal role in the pathophysiology of depression. In depressive episodes, patients show increased production of pro-inflammatory cytokines such as interleukin (IL-1β and tumor necrosis factor (TNF-α. There is limited information on the effect of antidepressant drugs on cytokines, most studies report on a limited sample of cytokines and none have reported effects on IL-22. We systematically investigated the effect of three antidepressant drugs, citalopram, escitalopram and mirtazapine, on secretion of cytokines IL-1β, IL-2, IL-4, IL-6, IL-17, IL-22 and TNF-α in a whole blood assay in vitro, using murine anti-human CD3 monoclonal antibody OKT3, and 5C3 monoclonal antibody against CD40, to stimulate T and B cells respectively. Citalopram increased production of IL-1β, IL-6, TNF-α and IL-22. Mirtazapine increased IL-1β, TNF-α and IL-22. Escitalopram decreased IL-17 levels. The influence of antidepressants on IL-2 and IL-4 levels was not significant for all three drugs. Compared to escitalopram, citalopram led to higher levels of IL-1β, IL-6, IL-17 and IL-22; and mirtazapine to higher levels of IL-1β, IL-17, IL-22 and TNF-α. Mirtazapine and citalopram increased IL-22 production. The differing profile of cytokine production may relate to differences in therapeutic effects, risk of relapse and side effects.

  19. Designing of Anti Dengue Drug Molecule against Insilico Modeled Target DC-Sign (CD-209

    Directory of Open Access Journals (Sweden)

    Prashantha C.N

    2013-09-01

    Full Text Available The C-type lectin DC-SIGN (CD209 plays a major role in receptor on human dendritic cells, it binds to several glycoproteins of viruses that facilitate disease progression. In dengue fever, the disease targets of arbovirus infection, show dendritic and reticuloendothelial cells that may affect immune system. The phytochemical extracts of Bosenbergia rotunda (BR have been effectively used as potential small molecular inhibitors to inhibit DC-SIGN (CD209 function. Using rational drug designing the training sets include Panduratin-A and 4-hydroxypanduratin is designed from BR derivatives could be an effective inhibitor of a DC-SIGN (CD209 binding towards the drug discovery/ therapy against dengue fever.

  20. Design and optimization of self-nanoemulsifying drug delivery systems for improved bioavailability of cyclovirobuxine D

    OpenAIRE

    Ke, Zhongcheng

    2016-01-01

    Zhongcheng Ke,1–3 Xuefeng Hou,4 Xiao-bin Jia31Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 2Huangshan University, Huangshan, Anhui, 3Third Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, 4Anhui University of Chinese Medicine, Hefei, Anhui, People’s Republic of ChinaBackground: The main purpose of this research was to design a self-nanoemulsifying drug delivery system (SNEDDS) for improving the bioavailability of cyclovirobux...