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Sample records for antidepressant drug design

  1. Cost variation study of antidepressant drugs

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    Ajay Kumar Shukla

    2016-10-01

    Conclusions: There is wide price variation of different brands of the same generic antidepressant drug in Indian market. Cost of a drug plays an important role in treatment of depression as it follows a long course and adherence to the treatment is related with drug cost. To decrease the wide cost variation among different brands of antidepressant drugs; it is high time to generate physician awareness about impact of cost effectiveness of drug regimen and for regulation of drug prices by the concerned agencies. [Int J Basic Clin Pharmacol 2016; 5(5.000: 1816-1821

  2. 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

  3. Cost variation study of antidepressant drugs

    OpenAIRE

    Ajay Kumar Shukla; Parag Sharma

    2016-01-01

    Background: Depression and anxiety disorders are the most common mental illnesses, each affecting in excess of 10-15% of the population at some time in their lives. Approximately 10-15% of those with severe depression attempt suicide at some point of time. Thus, it is important that symptoms of depression be recognized and treated appropriately. Methods: The prices of 15 antidepressant drugs, available in 43 different formulations were analyzed. Costs of different brands of a particular ge...

  4. [Drug dependence on benzodiazepines and antidepressants].

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    Verbanck, P

    2009-09-01

    Since years, the concepts of drug abuse and drug dependence changed, due to new knowledge coming from the neurosciences. Specifically, the role of a brain structure called "reward circuit" was emphasized. Therefore, the diagnosis criteria for abuse and dependence on drugs are presently defined mostly from a behavioral point of view: both in animal models and in clinical situations, it was stressed the importance of drug-seeking behavior and of the loss of control of the consumption. The occurrence of a pharmacological dependence is in fact of concern for only some of addictive drugs. According to these new criteria, dependence on benzodiazepines or antidepressants is certainly not frequent, even if withdrawal manifestations can occur after a long-term exposition. Furthermore, it is important to keep in mind the risk for non-medical use of benzodiazepines in persons with illicit drug use.

  5. Risk of drug interaction: combination of antidepressants and other drugs

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    Miyasaka Lincoln Sakiara

    2003-01-01

    Full Text Available OBJECTIVE: To assess the frequency of combination of antidepressants with other drugs and risk of drug interactions in the setting public hospital units in Brazil. METHODS: Prescriptions of all patients admitted to a public hospital from November 1996 to February 1997 were surveyed from the hospital's data processing center in São Paulo, Brazil. A manual search of case notes of all patients admitted to the psychiatric unit from January 1993 to December 1995 and all patients registered in the affective disorders outpatient clinic in December 1996 was carried out. Patients taking any antidepressant were identified and concomitant use of drugs was checked. By means of a software program (Micromedex® drug interactions were identified. RESULTS: Out of 6,844 patients admitted to the hospital, 63 (0.9% used antidepressants and 16 (25.3% were at risk of drug interaction. Out of 311 patients in the psychiatric unit, 63 (20.2% used antidepressants and 13 of them (20.6% were at risk. Out of 87 patients in the affective disorders outpatient clinic, 43 (49.4% took antidepressants and 7 (16.2% were at risk. In general, the use of antidepressants was recorded in 169 patients and 36 (21.3% were at risk of drug interactions. Twenty different forms of combinations at risk of drug interactions were identified: four were classified as mild, 15 moderate and one severe interaction. CONCLUSION: In the hospital general units the number of drug interactions per patient was higher than in the psychiatric unit; and prescription for depression was lower than expected.

  6. Antidepressant drug discovery in the postgenomic era.

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    Holsboer, F

    2001-10-01

    The progress made in genome research raises the question whether the new knowledge bases that have emerged may also lead to better antidepressants. The past has seen many remarkable improvements over traditional drugs, but not a real breakthrough. More recently hypothesis-driven research in depression has focussed upon stress-hormone regulation as a possible target, but validation of new drugs is not yet in sight. In parallel, we see an upsurge of systematic unbiased research in a biotechnology-driven drug discovery effort. This research can only lead to results if clinical research adapts to these new demands by phenotyping depressed patients not only according to psychopathological characteristics but also by utilising functional (e.g. neuroendocrine, neuropsychological, neurophysiological, neuroimaging and clinical drug response) data that are to be correlated with data from genotyping. To achieve the goal of genotype/phenotype-based differential therapy, large-scale efforts with regards to both patient samples and genotyping capacities are needed. In the long term, increasingly detailed patient information, if translated into specific pharmacological treatments, will lead to customized drugs and thus to a partial fragmentation of the antidepressant market. Concurrently, the improved genotyping/phenotyping efforts will also lead to more widely applicable drugs that promise to avoid side effects and refractoriness and also to hasten the time to onset of action. Once these goals are achieved notorious undertreatment of depression may come to an end.

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

    OpenAIRE

    Bosch, O G; Quednow, B. B.; Seifritz, E.; Wetter, T C

    2012-01-01

    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) syste...

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

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    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

  9. Neuroplasticity and major depression, the role of modern antidepressant drugs

    OpenAIRE

    Serafini, Gianluca

    2012-01-01

    The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to pro...

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

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    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.

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

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    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.

  12. 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.

  13. Sudden cardiac death secondary to antidepressant and antipsychotic drugs.

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    Sicouri, Serge; Antzelevitch, Charles

    2008-03-01

    A number of antipsychotic and antidepressant drugs are known to increase the risk of ventricular arrhythmias and sudden cardiac death. Based largely on a concern over QT prolongation and the development of life-threatening arrhythmias, a number of antipsychotic drugs have been temporarily or permanently withdrawn from the market or their use restricted. Some antidepressants and antipsychotics have been linked to QT prolongation and the development of Torsade de pointes arrhythmias, whereas others have been associated with a Brugada syndrome phenotype and the development of polymorphic ventricular arrhythmias. This review examines the mechanisms and predisposing factors underlying the development of cardiac arrhythmias, and sudden cardiac death, associated with antidepressant and antipsychotic drugs in clinical use.

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

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    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.

  15. Acute antidepressant drug administration and autobiographical memory recall

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    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...... of the antidepressant reboxetine on emotional autobiographical retrieval in healthy volunteers (14 men, 10 women). Functional magnetic resonance imaging was used in a double-blind between-groups investigation with reboxetine (4 mg) and placebo. Consistent with previous reports using lab-based stimuli, neural activation...... of reboxetine on emotional memory extends to recall of personally experienced events. Such effects may be relevant to the cognitive improvements found with recovery from depression and with the mechanism of action of contemporary antidepressant drugs. (PsycINFO Database Record (c) 2012 APA, all rights reserved)....

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

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    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.

  17. Neuroplasticity and major depression, the role of modern antidepressant drugs.

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    Serafini, Gianluca

    2012-06-22

    The pathophysiology of depression has been traditionally attributed to a chemical imbalance and critical interactions between genetic and environmental risk factors, and antidepressant drugs suggested to act predominantly amplifying monoaminergic neurotransmission. This conceptualization may be currently considered reductive. The current literature about the pathophysiological mechanisms underlying depression, stress-related disorders and antidepressant treatment was examined. In order to provide a critical overview about neuroplasticity, depression and antidepressant drugs, a detailed Pubmed/Medline, Scopus, PsycLit, and PsycInfo search to identify all papers and book chapters during the period between 1980 and 2011 was performed. Pathological stress and depression determine relevant brain changes such as loss of dendritic spines and synapses, dendritic atrophy as well as reduction of glial cells (both in number and size) in specific areas such as the hippocampus and prefrontal cortex. An increased dendritic arborisation and synaptogenesis may instead be observed in the amygdala as a consequence of depression and stress-related disorders. While hippocampal and prefrontal functioning was impaired, amygdala functioning was abnormally amplified. Most of molecular abnormalities and biological changes of aberrant neuroplasticity may be explained by the action of glutamate. Antidepressant treatment is associated with neurogenesis, gliogenesis, dendritic arborisation, new synapse formation and cell survival both in the hippocampus and prefrontal cortex. Antidepressants (ADs) induce neuroplasticity mechanisms reversing the pathological effects of depression and stress-related disorders. The neuroplasticity hypothesis may explain the therapeutic and prophylactic action of ADs representing a new innovative approach to the pathophysiology of depression and stress-related disorders.

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

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    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.

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

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    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.

  20. Antidepressant drugs and breastfeeding: a review of the literature.

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    Davanzo, Riccardo; Copertino, Marco; De Cunto, Angela; Minen, Federico; Amaddeo, Alessandro

    2011-04-01

    The use of antidepressants in breastfeeding mothers is controversial: Manufacters often routinely discourage breastfeeding for the nursing mother despite the well-known positive impact that breastfeeding carries on the health of the nursing infant and on his or her family and society. We conducted a systematic review of drugs commonly used in the treatment of postpartum depression. For every single drug two sets of data were provided: (1) selected pharmacokinetic characteristics such as half-life, milk-to-plasma ratio, protein binding, and oral bioavailability and (2) information about lactational risk, according to some authoritative sources of the literature: Drugs in Pregnancy and Lactation edited by Briggs et al. (Lippincott Williams, Philadelphia, 2008), Medications and Mothers' Milk by Hale (Hale Publishing, Amarillo, TX, 2010), and the LactMed database of TOXNET ( www.pubmed.gov ; accessed June 2010). Notwithstanding a certain variability of advice, we found that (1) knowledge of pharmacokinetic characteristics are scarcely useful to assess safety and (2) the majority of antidepressants are not usually contraindicated: (a) Selective serotinin reuptake inhibitors and nortryptiline have a better safety profile during lactation, (b) fluoxetine must be used carefully, (c) the tricyclic doxepine and the atypical nefazodone should better be avoided, and (d) lithium, usually considered as contraindicated, has been recently rehabilitated.

  1. Electrochemical Synthesis and Kinetic Evaluation of Electrooxidation of Acetaminophen in the Presence of Antidepressant Drugs

    OpenAIRE

    Nematollahi, Davood; Feyzi Barnaji, Bahareh; Amani, Ameneh

    2015-01-01

    With the aim of obtaining information about drug-drug interaction (DDI) between acetaminophen and some of antidepressant drugs (fluoxetine, sertraline and nortriptyline), in the present work we studied the electrochemical oxidation of acetaminophen (paracetamol) in the presence of these drugs by means of cyclic voltammetry and Controlled-potential coulometry. The reaction between N-acetyl-p-benzoquinone-imine (NAPQI) produced from electrooxidation of acetaminophen and antidepressant drugs (se...

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

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    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.

  3. 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

  4. Association between antidepressant drug use and hyponatremia. A case control study

    NARCIS (Netherlands)

    Movig, K.L.L.; Egberts, A.C.G.; Lenderink, A.W.; van den Akker, V.G.A.; Hodiamont, P.P.G.; Goldschmidt, H.M.J.; Leufkens, H.G.M.

    2002-01-01

    Conclusions SSRIs are more frequently associated with hyponatraemia than other classes of antidepressant drugs. This adverse drug reaction was more common in older patients (65 years) and in those using diuretics.

  5. 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.

  6. 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.

  7. 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.

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

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    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

  9. Clinical implications of antidepressant drug effects on sexual function.

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    Harvey, K V; Balon, R

    1995-12-01

    Sexual dysfunction in a patient being treated with antidepressant medications may be due to the underlying depression, a coexisting medical illness, disruption of interpersonal relationships, or it may be a side effect of the medication. Almost all antidepressants are associated with sexual side effects that go above and beyond any symptoms that can be explained by the disease process itself. The incidence of such sexual side effects can be as high as 92% for some antidepressants. Some of the newer antidepressants currently on the market seem to have a lower incidence of sexual dysfunction as a side effect. In view of the fairly common occurrence of these unwanted effects, and their potential contribution to noncompliance, careful selection of antidepressant medications is necessary. A variety of treatment options is available, including decreasing the dosage of medication to the lowest-effective level, adjunctive medications (such as cyproheptadine, bethanechol, yohimbine, and amantadine, as well as other antidepressants) to counteract the adverse sexual effects, or switching to another antidepressant. The treatment of antidepressant-induced sexual dysfunction requires a creative approach on the part of the treating psychiatrist, and must be individualized to the patient.

  10. 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 ...

  11. Adsorptive stripping voltammetric determination of the antidepressant drug sulpiride.

    Science.gov (United States)

    Farghaly, O A

    2000-10-01

    The electrochemical behaviour of the antidepressant drug sulpiride (SP) at a hanging mercury drop electrode (HMDE) is investigated. Linear sweep cathodic stripping voltammetry (LSCSV) was used to determine sulpiride in the presence of 0.01 M sodium acetate medium pH 10.5 and 25 +/- 1 degrees C. Different parameters such as, supporting electrolyte, pH, accumulation potential, scan rate, accumulation time and ionic strength, were tested to optimize the conditions for the determination of SP. The adsorbed form is reduced irreversibly. The linear concentration range is from 2 x 10(-9) to 5 x 10(-8) M SP. Experimentally, 2 x 10(-9) M (0.68 ppb) with accumulation time 60 s can be determined successfully. Furthermore, a theoretical detection limit of 2 x 10(-10) M (0.068 ppb) Sp was calculated. The interferences of some metal ions, ascorbic acid and some amino acids were studied. The method was applied to the analysis of tablets and spiked urine, with recoveries of 104 +/- 3 and 101 + 3, and the relative standard deviation of 3.3 and 3.4%, respectively.

  12. [Threshold of Application of Antidepressant Drugs for Treatment of Depressive Disorder].

    Science.gov (United States)

    Kuroki, Toshihide; Tanaka, Teppei

    2015-01-01

    In recent years, along with the expansion of medical care for depressive disorder, there has been much controversy regarding the application of antidepressant drugs for its treatment. The aim of this paper is to consider critical issues concerning the threshold of application of antidepressant drugs for the treatment of depression. It was formerly important to diagnose the 'quality' of depression (melancholia or non-melancholia) in order to choose antidepressant treatment, whereas an assessment of the 'quantity' of depression (severity of symptoms) is crucial today to decide on the threshold. Recent guidelines for the treatment of major depressive disorder do not positively recommend the use of medication for the treatment of mild depression. The guidelines published by the Japanese Society of Mood Disorders also state that doctors have to give priority to treatments avoiding medication, although the effectiveness of antidepressant drugs for mild depression is controversial. Actually, in a clinical setting, doctors have to understand the conditions of individual cases and cope with many issues, such as a risk of suicide, comorbidity of other psychiatric disorders, target symptoms of pharmacotherapy, and choices of classes and doses of antidepressant drugs. The threshold of application of antidepressant drugs for the treatment of depression may vary according to the doctor-patient relationship and surrounding conditions. Doctors are required to provide treatment options other than pharmacotherapy.

  13. Differences in reporting serious adverse events in industry sponsored clinical trial registries and journal articles on antidepressant and antipsychotic drugs: a cross-sectional study

    OpenAIRE

    Hughes, S; Cohen, D.; Jaggi, R

    2014-01-01

    Objective: To examine the degree of concordance in reporting serious adverse events (SAEs) from antidepressant and antipsychotic drug trials among journal articles and clinical trial summaries, and to categorise types of discrepancies. Design: Cross-sectional study of summaries of all antidepressant and antipsychotic trials included in an online trial registry and their first associated stand-alone journal articles. Setting: Clinicalstudyresults.org, sponsored by Pharmaceutical Research and M...

  14. Antidepressant Withdrawal

    Science.gov (United States)

    Diseases and Conditions Depression (major depressive disorder) If you stop taking antidepressants, could you experience antidepressant withdrawal? Do withdrawal symptoms mean you were addicted to the drug? Answers from Daniel K. Hall-Flavin, M.D. Antidepressant withdrawal is possible if you ...

  15. 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

  16. 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.

  17. Drugs on the Internet, part II: antidepressant medication web sites.

    Science.gov (United States)

    Morgan, Melissa; Montagne, Michael

    2011-01-01

    Antidepressant medications have been the fastest growing category of use of pharmaceutical products over the past decade. Selected Internet web sites providing information on antidepressant medications were identified and assessed using code of conduct criteria for posting health information on the Internet as developed by the Health on the Internet Foundation. Thirteen representative web sites were evaluated. Degree of compliance with each of the eight criterion varied by site, though all 13 sites met the criterion for legality of content and conduct on their web site. WebMD and FamilyDoctor.org met most of the criteria, while pharmaceutical company sites tended to meet the fewest criteria.

  18. 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.

  19. 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

  20. Recent developments in the design of anti-depressive therapies: targeting the serotonin transporter.

    Science.gov (United States)

    Butler, S G; Meegan, M J

    2008-01-01

    The serotonin transporter protein (SERT) has been the target for the development of several modern antidepressants with an objective of achieving selectivity over other monoamine transporters, thereby minimising side effects observed in the older generation of tricyclic antidepressants. The clinical selective serotonin reuptake inhibitors (SSRIs) have been shown to be among the most effective therapies in the treatment of depression. However they have clinical disadvantages over other classes of antidepressant drugs such as slow onset of action nausea and sleep disruption. The negative feedback loop attributed to the presynaptic 5-HT(1A) receptors has been implicated in the "time lag" observed in many patients between the administration of the SSRI and its observed therapeutic action. In recent years the focus has been on developing compounds with dual affinity for serotonergic auto-receptors along with an inhibitory activity at SERT. These structurally diverse products promise to be the next generation of anti-depressant medicines. This review presents an analysis of the recently reported structural classes with SSRI activity and rationalises the unique relationship between their molecular properties and biological activities. Specific emphasis is placed on the development of molecular structures with dual serotonergic activity. Recent advances in the design and synthesis of single molecular entities possessing 5-HT reuptake inhibition together with 5-HT(1A), 5-HT(1B), 5-HT(1D), 5-HT(2A), DAT, NET, alpha (2)-adrenoceptor and acetylcholinesterase antagonism are reviewed. The structural studies to identify proposed SERT binding sites together with the role of structure and ligand based design in the development of more effective SSRIs are summarised.

  1. 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.

  2. 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.

  3. 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.

  4. Transcriptomic profiling of human hippocampal progenitor cells treated with antidepressants and its application in drug repositioning

    Science.gov (United States)

    Powell, Timothy R; Murphy, Tytus; Lee, Sang H; Price, Jack; Thuret, Sandrine; Breen, Gerome

    2017-01-01

    Current pharmacological treatments for major depressive disorder (MDD) are ineffective in a significant proportion of patients, and the identification of new antidepressant compounds has been difficult. ‘Connectivity mapping’ is a method that can be used to identify drugs that elicit similar downstream effects on mRNA levels when compared to current treatments, and thus may point towards possible repositioning opportunities. We investigated genome-wide transcriptomic changes to human hippocampal progenitor cells treated with therapeutically relevant concentrations of a tricyclic antidepressant (nortriptyline) and a selective serotonin reuptake inhibitor (escitalopram). We identified mRNA changes common to both drugs to create an ‘antidepressant mRNA signature’. We used this signature to probe the Library of Integrated Network-based Cellular Signatures (LINCS) and to identify other compounds that elicit similar changes to mRNA in neural progenitor cells. Results from LINCS revealed that the tricyclic antidepressant clomipramine elicited mRNA changes most similar to our mRNA signature, and we identified W-7 and vorinostat as functionally relevant drug candidates, which may have repositioning potential. Our results are encouraging and represent the first attempt to use connectivity mapping for drug repositioning in MDD. PMID:28208023

  5. 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

  6. Antidepressant drugs and the risk of suicide in children and adolescents.

    Science.gov (United States)

    Isacsson, Göran; Rich, Charles L

    2014-04-01

    Government agencies have issued warnings about the use of antidepressant medications in children, adolescents, and young adults since 2003. The statements warn that such medications may cause de novo 'suicidality' in some people. This review explores the data on the treatment of depression that led to these warnings and subsequent data that are relevant to the warnings. It also addresses the effectiveness of antidepressant treatment in general and the relationship of suicide rates to antidepressant treatment. It concludes that the decisions for the 'black box' warnings were based on biased data and invalid assumptions. Furthermore, the decisions were unsupported by the observational data regarding suicide in young people that existed in 2003. The following recommendations would seem to follow from these observations. First, drug authorities should re-evaluate the basis for their imposed warnings on antidepressant medicines, and analyze the actual public health consequences the warnings have had. In the absence of substantial evidence supporting the warnings, they should be removed. Second, physicians and other providers with prescription privileges should continue to be educated regarding the importance of aggressively treating depression in young people, using antidepressants when indicated. Third, physicians and other professionals who treat depressed young people must always be aware of the risk of suicide (albeit quite low) and observe them closely for any signs of increased risk of suicide. This is necessary regardless of the type of treatment being provided.

  7. 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.

  8. Molecular analysis of the interaction of the four histamine receptor subtypes with antidepressant and antipsychotic drugs

    OpenAIRE

    Appl, Heidrun

    2010-01-01

    Antidepressant and antipsychotic drugs are known to affect multiple molecular targets. Beside their determinant effects on the neurotransmission of serotonin, norepinephrine and dopamine via several transporters and receptors, they may also modulate muscarinic acetylcholine receptors and the histamine H1 receptor (H1R). Consequently, these drugs do not only yield unique profiles of desired effects but also several unwanted side effects that may impact therapy. In addition to the H1R, the hist...

  9. 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...

  10. 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.

  11. 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.

  12. Indole Alkaloids from Plants as Potential Leads for Antidepressant Drugs: A Mini Review

    Science.gov (United States)

    Hamid, Hazrulrizawati A.; Ramli, Aizi N. M.; Yusoff, Mashitah M.

    2017-01-01

    Depression is the most common illness observed in the elderly, adults, and children. Antidepressants prescribed are usually synthetic drugs and these can sometimes cause a wide range of unpleasant side effects. Current research is focussed on natural products from plants as they are a rich source of potent new drug leads. Besides Hypericum perforatum (St. John’s wort), the plants studied include Passiflora incarnata L. (passion flower), Mitragyna speciosa (kratom), Piper methysticum G. Forst (kava) and Valeriana officinalis L. Harman, harmol, harmine, harmalol and harmaline are indole alkaloids isolated from P. incarnata, while mitragynine is isolated from M. speciosa. The structure of isolated compounds from P. methysticum G. Forst and V. officinalis L. contains an indole moiety. The indole moiety is related to the neurotransmitter serotonin which is widely implicated for brain function and cognition as the endogenous receptor agonist. An imbalance in serotonin levels may influence mood in a way that leads to depression. The moiety is present in a number of antidepressants already on the market. Hence, the objective of this review is to discuss bioactive compounds containing the indole moiety from plants that can serve as potent antidepressants. PMID:28293192

  13. [Treatment for irritable bowel syndrome--psychotropic drugs, antidepressants and so on].

    Science.gov (United States)

    Sato, Mitsuko; Murakami, Masato

    2006-08-01

    Irritable bowel syndrome (IBS) is a functional disease with good prognosis, which is diagnosed by exclusion of possible causative organic diseases. However, since the patients tend to have strong psychotic symptoms including anxiety, tension, depression, irritation and insomnia, this syndrome has to be elucidated as a psychosomatic disease. Although the symptoms are usually limited to gastrointestinal symptoms such as abdominal pain and abnormal bowel movements, many patients also manifest some kinds of psychiatric abnormalities such as hypochondria, depression, hysteria, panic disorder and posttraumatic stress disorder. Especially, the prevalence of depression is high. Therefore, use of psychotropic drugs is efficient in treating IBS. Antidepressant agents including tricyclic agents such as amitriptyline, trimipramine, imipramine, clomipramine, amoxapine and nortriptyline; tetracyclic antidepressant; antidepressants such as SSRI and SNRI; sulpiride; benzodiazepine class anxiolytic agents; tandospirone; and Chinese herbal medicine are being used. IBS is a stress-related disease. Therefore, in spite of the importance of pharmacotherapy, patients should also be instructed to avoid the stress that aggravates the symptoms in all aspects of daily life.

  14. 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.

  15. Rational drug design.

    Science.gov (United States)

    Mandal, Soma; Moudgil, Mee'nal; Mandal, Sanat K

    2009-12-25

    In this article, current knowledge of drug design is reviewed and an approach of rational drug design is presented. The process of drug development is challenging, expensive, and time consuming, although this process has been accelerated due to the development of computational tools and methodologies. The current target based drug design approach is incomplete because most of the drugs developed by structure guided approaches have been shown to have serious toxic side effects. Otherwise these drugs would have been an ideal choice for the treatment of diseases. Hence, rational drug design would require a multidisciplinary approach. In this regard, incorporation of gene expression technology and bioinformatics tools would be indispensable in the structure based drug design. Global gene expression data and analysis of such data using bioinformatics tools will have numerous benefits such as efficiency, cost effectiveness, time saving, and will provide strategies for combination therapy in addition to overcoming toxic side effects. As a result of incorporation of gene expression data, partial benefit of the structure based drug design is slowly emerging and rapidly changing the approach of the drug development process. To achieve the full benefit of developing a successful drug, multidisciplinary approaches (approaches such as computational chemistry and gene expression analysis, as discussed in this article) would be necessary. In the future, there is adequate room for the development of more sophisticated methodologies.

  16. Invited review: the evolution of antidepressant mechanisms.

    Science.gov (United States)

    Slattery, D A; Hudson, A L; Nutt, D J

    2004-02-01

    Present antidepressants are all descendents of the serendipitous findings in the 1950s that the monoamine oxidase inhibitor iproniazid and the tricyclic antidepressant imipramine were effective antidepressants. The identification of their mechanism of action, and those of reserpine and amphetamine, in the 1960s, led to the monoamine theories of depression being postulated; first, with noradrenaline then 5-hydroxytryptamine being considered the more important amine. These monoamine theories of depression predominated both industrial and academic research for four decades. Recently, in attempts to design new drugs with faster onsets of action and more universal therapeutic action, downstream alterations common to current antidepressants are being examined as potential antidepressants. Additionally, the use of animal models has identified a number of novel targets some of which have been subjected to clinical trials in humans. However, monoamine antidepressants remain the best current medications and it may be some time before they are dislodged as the market leaders.

  17. 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.

  18. From antidepressant drugs to beta-mimetics: preclinical insights on potential new treatments for neuropathic pain.

    Science.gov (United States)

    Barrot, Michel; Yalcin, Ipek; Choucair-Jaafar, Nada; Benbouzid, Malika; Freund-Mercier, Marie-José

    2009-11-01

    The market for pain treatment is a major segment of nervous system pathologies. Despite this dynamism, the management of some pain conditions remains a clinical challenge. Neuropathic pain arises as a direct consequence of a lesion or disease affecting the somatosensory system. It is generally a chronic and disabling condition which is difficult to treat. Antidepressant drugs are recommended as one of the first line treatments, but they display noticeable side effects and are not effective on all patients. Using a murine model of neuropathy, we demonstrated that the stimulation of beta2-adrenergic receptors (beta2-AR) is not only necessary for antidepressant drugs to exert their antiallodynic action but that it is in fact sufficient to alleviate neuropathic allodynia. Chronic, but not acute, treatment with beta-mimetics such as terbutaline, salbutamol, fenoterol, salmeterol, ritodrine, isoprenaline (isoproterenol), metaproterenol (orciprenaline), procaterol, formoterol, clenbuterol or bambuterol, relieves allodynia. Agonists of beta2-ARs, and more generally any molecule stimulating beta2-ARs such as beta-mimetics, are thus proposed as potential new treatments for neuropathic pain. Clinical studies are now in preparation to confirm this potential in patients with neuropathic pain. This article reviews the findings leading to propose beta-mimetics for neuropathic pain treatment and other recent patents on the topic.

  19. Genetically encoded photocrosslinkers locate the high-affinity binding site of antidepressant drugs in the human serotonin transporter

    DEFF Research Database (Denmark)

    Rannversson, Hafsteinn; Andersen, Jacob; Hall, Lena Sørensen;

    2016-01-01

    Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode photocrosslin......Despite the well-established role of the human serotonin transporter (hSERT) in the treatment of depression, the molecular details of antidepressant drug binding are still not fully understood. Here we utilize amber codon suppression in a membrane-bound transporter protein to encode...

  20. Effects of some new antidepressant drugs on the glucocorticoid receptor-mediated gene transcription in fibroblast cells.

    Science.gov (United States)

    Augustyn, Matylda; Otczyk, Magdalena; Budziszewska, Bogusława; Jagła, Grzegorz; Nowak, Wojciech; Basta-Kaim, Agnieszka; Jaworska-Feil, Lucylla; Kubera, Marta; Tetich, Magdalena; Leśkiewicz, Monika; Lasoń, Władysław

    2005-01-01

    Antidepressant drugs are thought to counteract effects of hypercortisolemia, frequently associated with depression, by lowering cortisol level and by modifying the function of glucocorticoid receptors (GR). Indeed, classical antidepressants inhibit corticosteroid-induced gene transcription in cell cultures. The aim of the present study was to investigate effects of new generation antidepressant drugs on GR function in mouse fibroblast cells (L929), stably transfected with mouse mammary tumor virus-chloramphenicol acetyltransferase (MMTV-CAT) plasmid (LMCAT cells). It has been found that reboxetine (at 10 and 30 microM), venlafaxine, citalopram and mirtazapine (at 30 microM), but not milnacipran, in statistically significant manner inhibited corticosterone-induced gene transcription. However, the effects of new generation antidepressant drugs were weaker than those evoked by imipramine, which was active already at 3 microM concentration. Further studies on the mechanism of antidepressant action on GR function revealed that protein kinase C, but not mitogen-activated protein kinases (MAPK), glycogen synthase kinase (GSK-3) and protein kinase B (PKB, Akt) play a role in this phenomenon.

  1. 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.

  2. Skeletal effects of central nervous system active drugs: anxiolytics, sedatives, antidepressants, lithium and neuroleptics.

    Science.gov (United States)

    Vestergaard, Peter

    2008-09-01

    Many central nervous system active drugs can alter postural balance, increasing the risk of fractures. Anxiolytics and sedatives include the benzodiazepines, and these have been associated with a limited increase in the risk of fractures, even at low doses, probably from an increased risk of falls. No systematic differences have been shown between benzodiazepines with long and short half-lives. Although the increase in risk of fractures was limited, care must still be taken when prescribing for older fall-prone subjects at risk of osteoporosis. Neuroleptics may be associated with a decrease in bone mineral density and a very limited increase in fracture risk. Antidepressants are associated with a dose-dependent increase in the risk of fractures. The increase in relative risk of fractures seems to be larger with selective serotonin reuptake inhibitors (SSRIs) than with tricyclic antidepressants. The reason for this is not known but may be linked to serotonin effects on bone cells and the risk of falls. With the wide use of SSRIs, more research is needed. Lithium is associated with a decrease in the risk of fractures. This may be linked to its effects on the Wnt glycoprotein family, which is a specialised signalling system for certain cell types.

  3. Drug interactions between antineoplastic and antidepressant agents: analysis of patients seen at an oncology clinic at a general hospital

    Directory of Open Access Journals (Sweden)

    Camila de Araújo Reinert

    2015-06-01

    Full Text Available Objectives: To determine the prevalence of depressive symptoms among oncology patients and identify simultaneous use of antineoplastic and antidepressant agents.Methods: This was a cross-sectional study that interviewed 56 oncology patients using two data collection instruments: a questionnaire covering clinical and sociodemographic data and the Beck Depression Inventory-II (BDI-II, for assessment of depressive symptoms. For data analysis, descriptive statistics were used to determine the prevalence of depressive symptoms and the chi-square test was used to evaluate associations between sociodemographic and clinical variables and depressive symptoms.Results: A 26.7% (15 patients prevalence of depression was detected. Just eight of these 15 patients (53.3% were receiving treatment for depression. In the sample as a whole, 13 of the patients interviewed (23.2% were taking antidepressants and 11 of these 13 patients (19.6% were taking antidepressive and antineoplastic agents simultaneously. A total of five (8.9% of the sample contraindicated drug interactions were detected.Conclusions:Depressive symptoms are more prevalent among cancer patients than in the general population, but they are generally under-diagnosed and under-treated. Simultaneous use of antidepressant and antineoplastic agents is common and so, in order to reduce the number of harmful adverse effects, possible drug interactions must be identified before antidepressants are prescribed to cancer patients.

  4. 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.

  5. Miracle drug, poison, or placebo: patients' experiences with antidepressant medications as described in postings on an online message board.

    Science.gov (United States)

    Montagne, Michael

    2011-01-01

    Messages posted on the MSN Health message board in response to a news story reporting that antidepressant medications are placebos were examined. Over 37 days, 1,624 messages were posted by 1,238 unique authors. The sampling unit consisted of 960 authors who were users. Users' messages were gathered in real time and content analyzed. Few users explicitly responded to the question posed in the article: 2.5% of the users stated their antidepressant was a miracle drug, 2.0% stated it was a poison, and only 0.2% stated it was a placebo. Users reported positive experiences with antidepressants more than twice as often as they reported negative experiences.

  6. 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

  7. The relationship between pupil diameter and pain by the administration of morphine and antidepressant drugs in mice.

    Science.gov (United States)

    Onal, A; Tuğlular, I

    1999-07-01

    Because the pain sensation is subjective, it is difficult to evaluate the responses to analgesic drugs. Some analgesics that affect the central nervous system are known to change the pupil diameter. The pupil diameter is a more objective criterion that shows the drug effect. We studied the relation between the pupil diameter and analgesia responses to morphine and antidepressants by using the selective micro-receptor agonist morphine (2 and 4 mg/kg), the noradrenaline reuptake inhibitor desipramine (7.5 and 10 mg/kg), the mixed serotonergic and noradrenergic uptake inhibitor and cholinergic receptor antagonist amitriptyline (2.5 and 5 mg/kg), and the selective serotonin reuptake inhibitor sertraline (2.5 and 5 mg/kg) in mice. Both monocular microscopy to assess pupil measurement and the hot-plate test to assess nociceptive thresholds were used in the same animals. We found that morphine played an important role in both mydriasis and analgesia, whereas amitriptyline and desipramine had a greater effect on pupil response than on nociception. Sertraline produced antinociception without causing a change in pupil diameter. As a result, although the pupil response is an important criterion in evaluating the analgesic effect of morphine, it is not possible to put forward the same criterion for the antidepressant drugs. Because different neurotransmitters are involved in pupil and pain mechanisms of antidepressant drugs, it is difficult to evaluate the analgesic response with the pupil diameter.

  8. Association between antipsychotic/antidepressant drug treatments and hospital admissions in schizophrenia assessed using a mental health case register

    Science.gov (United States)

    Cardinal, Rudolf N; Savulich, George; Mann, Louisa M; Fernández-Egea, Emilio

    2015-01-01

    Background: The impact of psychotropic drug choice upon admissions for schizophrenia is not well understood. Aims: To examine the association between antipsychotic/antidepressant use and time in hospital for patients with schizophrenia. Methods: We conducted an observational study, using 8 years’ admission records and electronically generated drug histories from an institution providing secondary mental health care in Cambridgeshire, UK, covering the period 2005–2012 inclusive. Patients with a coded ICD-10 diagnosis of schizophrenia were selected. The primary outcome measure was the time spent as an inpatient in a psychiatric unit. Antipsychotic and antidepressant drugs used by at least 5% of patients overall were examined for associations with admissions. Periods before and after drug commencement were compared for patients having pre-drug admissions, in mirror-image analyses correcting for overall admission rates. Drug use in one 6-month calendar period was used to predict admissions in the next period, across all patients, in a regression analysis accounting for the effects of all other drugs studied and for time. Results: In mirror-image analyses, sulpiride, aripiprazole, clozapine, and olanzapine were associated with fewer subsequent admission days. In regression analyses, sulpiride, mirtazapine, venlafaxine, and clozapine–aripiprazole and clozapine–amisulpride combinations were associated with fewer subsequent admission days. Conclusions: Use of these drugs was associated with fewer days in hospital. Causation is not implied and these findings require confirmation by randomized controlled trials. PMID:27336041

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

    OpenAIRE

    Mulinari, Shai

    2015-01-01

    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-dept...

  10. Association between antipsychotic/antidepressant drug treatments and hospital admissions in schizophrenia assessed using a mental health case register

    OpenAIRE

    2015-01-01

    This is the final version of the article. It first appeared from Nature Publishing Group via http://dx.doi.org/10.1038/npjschz.2015.35 Background: The impact of psychotropic drug choice upon admissions for schizophrenia is not well understood. Aims: To examine the association between antipsychotic/antidepressant use and time in hospital for patients with schizophrenia. Methods: We conducted an observational study, using 8 years? admission records and electronically gene...

  11. Evaluating early preventive antipsychotic and antidepressant drug treatment in an infection-based neurodevelopmental mouse model of schizophrenia.

    Science.gov (United States)

    Meyer, Urs; Spoerri, Erica; Yee, Benjamin K; Schwarz, Markus J; Feldon, Joram

    2010-05-01

    Current pharmacotherapy of schizophrenia remains unsatisfactory with little hope for complete functional restoration in patients once the disease has developed. A preventive approach based on intervention in the prodromal stage of the disease aiming to preserve functional integrity by halting the progress of the disease is therefore extremely attractive. Here, we investigated the effects of preventive antipsychotic or antidepressant drug treatment in a well-established neurodevelopmental mouse model of multiple schizophrenia-related abnormalities. Pregnant mice on gestation day 9 were exposed to the viral mimic polyriboinosinic-polyribocytidylic acid (2 mg/kg, intravenously) or corresponding vehicle treatment, and the resulting offspring from both prenatal treatment conditions were subjected to chronic antipsychotic (haloperidol or clozapine), antidepressant (fluoxetine), or placebo treatment during the periadolescent stage of development. The effects of the preventive pharmacotherapy on behavioral and pharmacological functions were then investigated in adulthood using paradigms relevant to schizophrenia, namely prepulse inhibition, latent inhibition, and sensitivity to psychostimulant drugs. We show that periadolescent treatment with the reference antipsychotic and antidepressant drugs can successfully block the emergence of multiple psychosis-related behavioral and pharmacological abnormalities in subjects predisposed to adult brain pathology by exposure to prenatal immune challenge. At the same time, however, our study reveals numerous negative influences of the early pharmacological intervention on normal behavioral development in control subjects. Hence, even though preventive pharmacotherapy may be beneficial in individuals with predisposition to psychosis-related brain dysfunctions, chronic antipsychotic or antidepressant drug treatment in false-positive subjects is associated with substantial risk for long-term behavioral disturbances in adulthood.

  12. Evaluating Early Preventive Antipsychotic and Antidepressant Drug Treatment in an Infection-Based Neurodevelopmental Mouse Model of Schizophrenia

    OpenAIRE

    Meyer, Urs; Spoerri, Erica; Yee, Benjamin K.; Schwarz, Markus J; Feldon, Joram

    2008-01-01

    Current pharmacotherapy of schizophrenia remains unsatisfactory with little hope for complete functional restoration in patients once the disease has developed. A preventive approach based on intervention in the prodromal stage of the disease aiming to preserve functional integrity by halting the progress of the disease is therefore extremely attractive. Here, we investigated the effects of preventive antipsychotic or antidepressant drug treatment in a well-established neurodevelopmental mous...

  13. Antidepressant Drugs Transactivate TrkB Neurotrophin Receptors in the Adult Rodent Brain Independently of BDNF and Monoamine Transporter Blockade

    OpenAIRE

    Tomi Rantamäki; Liisa Vesa; Hanna Antila; Antonio Di Lieto; Päivi Tammela; Angelika Schmitt; Klaus-Peter Lesch; Maribel Rios; Eero Castrén

    2011-01-01

    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 ne...

  14. The Responsiveness of TrkB to BDNF and Antidepressant Drugs Is Differentially Regulated during Mouse Development

    OpenAIRE

    Antonio Di Lieto; Tomi Rantamäki; Liisa Vesa; Sudhirkumar Yanpallewar; Hanna Antila; Jesse Lindholm; Maribel Rios; Lino Tessarollo; Eero Castrén

    2012-01-01

    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 respon...

  15. ANTIDEPRESSANT ACTIVITY OF HYDROALCOHOLIC EXTRACT OF ZINGIBER OFFICINALE

    Directory of Open Access Journals (Sweden)

    Singh Rudra Pratap

    2012-02-01

    Full Text Available The present study was design to evaluate the effect of Zingiber officinale hydro-alcoholic extract as well as its interaction with conventional anxiolytic and antidepressant drugs using tail suspension test and forced swim test (FST and to evaluate the possible mechanisms involved in its actions. The rhizomes of ginger were collected and authenticated. Extraction of dried rhizomes was carried out using soxhlet apparatus to obtain its Hydro alcoholic extract. The extract of Zingiber officinale showed the significant antidepressant activity comparable to the standard drug. The oral administration of Zingiber officinale extract at 150 mg/ kg and 300 mg/kg respectively as compared to the control treated group showed an antidepressant activity comparable to that of standard drug. The antidepressant effects of Zingiber officinale extract seem to be mainly associated with the activation of dopamineergic system and possess potential anxiolytic and antidepressant activities.

  16. The effect of anti-depressant and narcoleptic drugs on isopropyl iodoamphetamine biodistribution

    Energy Technology Data Exchange (ETDEWEB)

    Moretti, J.L.; Holman, B.L.; Delmon, L.; Carmel, A.; Johnson, D.; Moingeon, P.; Blau, M.; Chu, H.

    1985-05-01

    I-123 Nisopropyl p-iodoamphetamine (IMP) is a useful radiotracer for imaging regional cerebral perfursion in a wide variety of neurological and cerebrovascular diseases. The major route of amine metabolism in the lung is the mixed function oxidase (MFO) system. A number of antidepressants and narcoleptic agents have been shown to displace amphetamine from the lung. If these drugs release IMP before it is metabolized to lipophobic products, brain concentration will be affected. The authors investigated the effects of these drugs on IMP distribution in animals with high and low pulmonary concentrations of MFO. When 1 mg/kg imipramine (IM) was injected iv into Wistar rats 30 min before IMP and 50 min before sacrifice, lung activity was depressed (4 + 1% ID vs 12 + 4% ID). Brain activity was depressed only with 4 mg/kg IM (l.5 + .3% ID vs 2.7 + .7% ID). There was no significant difference in IMP brain activity without IM and when IM was given simultaneously with, 5 or 15 min after IMP. In New Zealand rabbits which have a low pulmonary MFO concentration, IM altered lung and brain uptake during simultaneous injection and as late as 15 min after IMP. Lung uptake was reduced 51% and brain uptake was increased 25%, 20%, and 19% when IM was injected 0, 5 and 15 min after IMP. The MAO inhibitors, phenelzine and L deprenyl, did not alter the brain, lung or liver IMP activity in rats at a dose of 5 mg/kg. These data are consistent with a model in which IMP is trapped and metabolized in the lung by the MFO system. Assuming an active MFO system in the human (unlike the rabbit), brain activity of IMP will not be altered by either IM or MAO inhibitors.

  17. 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'.

  18. 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.

  19. Anti-inflammatory drugs as moderators of antidepressant effects, especially those of the selective serotonin-reuptake inhibitor class.

    Science.gov (United States)

    Kronenberg, Sefi

    2011-09-01

    Large studies examining remission rates obtained by antidepressants have yielded somewhat dismal results. In the well-reported Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only 36.8% of patients exhibited remission with the selective serotonin-reuptake inhibitor (SSRI) citalopram and the cumulative remission rate was 67% after multiple treatments were attempted. Warner-Schmidt et al. recently published an interesting paper that suggests specific mechanisms by which anti-inflammatory drugs inhibit the antidepressant effects of SSRIs. They employed well-established mouse models of depression: the tail suspension test and the forced swim test. In their experiment, ibuprofen significantly attenuated the antidepressant-like effects of SSRIs in both tests. The authors also presented data from the STAR*D study itself. These data - demonstrating higher remission rates for depressed patients receiving citalopram without concomitant NSAIDs (55.2%) than those receiving citalopram with NSAIDs (44.5%) - serve to illustrate the potential hindering effects of anti-inflammatory drugs.

  20. Development of the first metabolite-based LC-MS(n) urine drug screening procedure-exemplified for antidepressants.

    Science.gov (United States)

    Wissenbach, Dirk K; Meyer, Markus R; Remane, Daniela; Weber, Armin A; Maurer, Hans H

    2011-04-01

    In contrast to GC-MS libraries, currently available LC-MS libraries for toxicological detection contain besides parent drugs only some main metabolites limiting their applicability for urine screening. Therefore, a metabolite-based LC-MS(n) screening procedure was developed and exemplified for antidepressants. The library was built up with MS(2) and MS(3) wideband spectra using an LXQ linear ion trap with electrospray ionization in the positive mode and full-scan information-dependent acquisition. Pure substance spectra were recorded in methanolic solution and metabolite spectra in urine from rats after administration of the corresponding drugs. After identification, the metabolite spectra were added to the library. Various drugs and metabolites could be sufficiently separated. Recovery, process efficiency, matrix effects, and limits of detection for selected drugs were determined using protein precipitation. Automatic data evaluation was performed using ToxID and SmileMS software. The library consists of over 700 parent compounds including 45 antidepressants, over 1,600 metabolites, and artifacts. Protein precipitation led to sufficient results for sample preparation. ToxID and SmileMS were both suitable for target screening with some pros and cons. In our study, only SmileMS was suitable for untargeted screening being not limited to precursor selection. The LC-MS(n) method was suitable for urine screening as exemplified for antidepressants. It also allowed detecting unknown compounds based on known fragment structures. As ion suppression can never be excluded, it is advantageous to have several targets per drug. Furthermore, the detection of metabolites confirms the body passage. The presented LC-MS(n) method complements established GC-MS or LC-MS procedures in the authors' lab.

  1. 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

  2. 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.

  3. Alterations in plasma prolyl endopeptidase activity in depression, mania, and schizophrenia: effects of antidepressants, mood stabilizers, and antipsychotic drugs.

    Science.gov (United States)

    Maes, M; Goossens, F; Scharpé, S; Calabrese, J; Desnyder, R; Meltzer, H Y

    1995-10-16

    The activity of prolyl endopeptidase (PEP), a serine proteinase, has been found to be significantly lower in the blood of patients with major depression than in normal volunteers. The present study investigates plasma PEP activity in 25 major depressed, 10 manic, and 14 schizophrenic subjects versus 30 normal volunteers. It also examines the effects of antidepressants, valproate, and neuroleptic drugs on plasma PEP activity. PEP activity was significantly lower in major depressed subjects than in normal volunteers and in patients with mania and schizophrenia. In depressed subjects, plasma PEP activity was significantly increased during treatment with antidepressant drugs, such as fluoxetine. Plasma PEP activity was significantly increased in manic and schizophrenic subjects compared with normal volunteers. In manic subjects, short-term treatment with valproate had a significant suppressive effect on PEP activity. No significant effects of neuroleptics on PEP activity could be found in the schizophrenic patients. The results support the hypothesis that lower PEP activity could play a role in the pathophysiology of major depression, while increased PEP activity may be related to psychotic conditions, such as mania and schizophrenia.

  4. Antidepressant drug exposure is associated with mRNA levels of tyrosine receptor kinase B in major depressive disorder.

    Science.gov (United States)

    Bayer, T A; Schramm, M; Feldmann, N; Knable, M B; Falkai, P

    2000-08-01

    1. Recent studies have provided support for the notion that the high affinity neurotrophin receptor tyrosine receptor kinase B (trk B) may be involved in the treatment of depression. 2. Using a quantitative RT-PCR approach trk B mRNA levels were determined in brain material from cerebellum, temporal cortex, and frontal cortex of control specimen and patients with major depressive disorder, schizophrenia and bipolar disorder (15 subjects each). 3. Interestingly, elevated trk B mRNA levels were found in cerebellum (3.6-fold) in patients with major depressive disorder, reaching statistical significance (p=0.03). 4. The major depressive disorder-on drugs group differed from controls (p=0.006) in the cerebellum. 5. Since only patients with major depressive disorder received antidepressants, elevated trk B mRNA levels are possibly related to drug treatment.

  5. 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.

  6. 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.

  7. Alterations in plasma dipeptidyl peptidase IV enzyme activity in depression and schizophrenia: effects of antidepressants and antipsychotic drugs.

    Science.gov (United States)

    Maes, M; De Meester, I; Scharpe, S; Desnyder, R; Ranjan, R; Meltzer, H Y

    1996-01-01

    Recently, our laboratory reported that the activity of dipeptidyl-peptidase IV (DPP IV) was significantly lower in the peripheral blood of major depressed patients than in normal controls. The present study examines plasma DPP IV activity in 43 major depressed and 13 schizophrenic subjects versus 21 normal controls and the effects of antidepressants and antipsychotic drugs on plasma DPP IV activity. DPP IV activity was significantly lower in major depressed subjects than in normal controls and schizophrenic subjects. There was a trend towards higher DPP IV activity in schizophrenic patients than in normal controls. There were no significant effects of antidepressants or neuroleptics on plasma DPP IV activity in depressed and schizophrenic patients, respectively. There were no significant relationships between plasma DPP IV activity and plasma cortisol or immune-inflammatory markers, such as serum interleukin-6 (IL-6) or soluble IL-2 receptor. A significant and positive correlation was found between plasma DPP IV and prolyl endopeptidase (PEP) enzyme activity in the study group as a whole and in schizophrenic subjects. The results support the hypothesis that lower and higher plasma DPP IV activities are trait markers of major depression and schizophrenia, respectively. It is concluded that alterations in the enzyme activity of peptidases, such as DPP IV and PEP, play a role in the pathophysiology of major depression and schizophrenia.

  8. 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

    2016-09-02

    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.

  9. 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…

  10. Tricyclic Antidepressants and Tetracyclic Antidepressants

    Science.gov (United States)

    Diseases and Conditions Depression (major depressive disorder) Tricyclic and tetracyclic antidepressants affect brain chemicals to ease depression symptoms. Explore their possible side effects and whether one of these antidepressants may be a good option for you. By Mayo Clinic ...

  11. Seasonal changes in antibiotics, antidepressants/psychiatric drugs, antihistamines and lipid regulators in a wastewater treatment plant.

    Science.gov (United States)

    Golovko, Oksana; Kumar, Vimal; Fedorova, Ganna; Randak, Tomas; Grabic, Roman

    2014-09-01

    Seasonal changes in the concentration of 21 pharmaceuticals in a wastewater treatment plant (WWTP) in České Budějovice were investigated over 12months. The target compounds were 10 antibiotics, 4 antidepressants, 3 psychiatric drugs, 2 antihistamines and 2 lipid regulators. 272 Wastewater samples (136 influents and 136 effluents) were collected from March 2011 to February 2012 and analyzed using two-dimensional liquid chromatography coupled with tandem mass spectrometry. All studied pharmaceuticals were frequently detected in both the influent and the effluent wastewater samples, except for meclozine, which was only found in the influent. The mean concentration of pharmaceuticals varied from 0.006μgL(-1) to 1.48μgL(-1) in the influent and from 0.003μgL(-1) to 0.93μgL(-1) in the effluent. The concentration of most pharmaceuticals was higher during winter.

  12. Obtained effect size as a function of sample size in approved antidepressants: a real-world illustration in support of better trial design.

    Science.gov (United States)

    Gibertini, Michael; Nations, Kari R; Whitaker, John A

    2012-03-01

    The high failure rate of antidepressant trials has spurred exploration of the factors that affect trial sensitivity. In the current analysis, Food and Drug Administration antidepressant drug registration trial data compiled by Turner et al. is extended to include the most recently approved antidepressants. The expanded dataset is examined to further establish the likely population effect size (ES) for monoaminergic antidepressants and to demonstrate the relationship between observed ES and sample size in trials on compounds with proven efficacy. Results indicate that the overall underlying ES for antidepressants is approximately 0.30, and that the variability in observed ES across trials is related to the sample size of the trial. The current data provide a unique real-world illustration of an often underappreciated statistical truism: that small N trials are more likely to mislead than to inform, and that by aligning sample size to the population ES, risks of both erroneously high and low effects are minimized. The results in the current study make this abstract concept concrete and will help drug developers arrive at informed gate decisions with greater confidence and fewer risks, improving the odds of success for future antidepressant trials.

  13. 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.

  14. 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

  15. 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

  16. Impact of brand-name drug worship and expectation psychology on antidepressant efficacy.

    Science.gov (United States)

    Cai, Jian; Ye, Meirong; Fei, Chunhua; Xu, Feng

    2013-01-01

    The choice of the generic drug is reasonable if there is evidence for its therapeutic equivalence with the brand-name drug. However, the reduced effectiveness of switching from brand-name drug to generic drug is not rare. The impact of brand-name worship and expectation psychology on drug efficacy is noteworthy to report. A 45-year-old woman suffered from depression mood disorder. She experienced profound improvement in her depressive symptoms after a switch from domestic generic venlafaxine to imported brand-name counterpart. The interview showed that the woman has a strong brand-name drug worship and expectation psychology, which is representative, typical and popular in China especially in vast rural areas. Medication education does not work too much. The brand-name drug worship and expectation psychology might improve drug efficacy when patient is switched from generic drug to branded medication.

  17. The relationship between rational drug design and drug side effects.

    Science.gov (United States)

    Wang, Juan; Li, Zhi-xin; Qiu, Cheng-xiang; Wang, Dong; Cui, Qing-hua

    2012-05-01

    Previous analysis of systems pharmacology has revealed a tendency of rational drug design in the pharmaceutical industry. The targets of new drugs tend to be close with the corresponding disease genes in the biological networks. However, it remains unclear whether the rational drug design introduces disadvantages, i.e. side effects. Therefore, it is important to dissect the relationship between rational drug design and drug side effects. Based on a recently released drug side effect database, SIDER, here we analyzed the relationship between drug side effects and the rational drug design. We revealed that the incidence drug side effect is significantly associated with the network distance of drug targets and diseases genes. Drugs with the distances of three or four have the smallest incidence of side effects, whereas drugs with the distances of more than four or smaller than three show significantly greater incidence of side effects. Furthermore, protein drugs and small molecule drugs show significant differences. Drugs hitting membrane targets and drugs hitting cytoplasm targets also show differences. Failure drugs because of severe side effects show smaller network distances than approved drugs. These results suggest that researchers should be prudent on rationalizing the drug design. Too small distances between drug targets and diseases genes may not always be advantageous for rational design for drug discovery.

  18. 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.

  19. Regulation of BDNF and trkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments.

    Science.gov (United States)

    Nibuya, M; Morinobu, S; Duman, R S

    1995-11-01

    The influence of chronic electroconvulsive seizure (ECS) or antidepressant drug treatments on expression of brain-derived neurotrophic factor (BDNF) and its receptor, trkB, was examined by in situ hybridization and Northern blot. In frontal cortex, acute ECS increased BDNF mRNA approximately twofold, an effect significantly augmented by a prior course of chronic ECS treatment (10 d). In the hippocampus, the influence of chronic ECS varied between the major subfields. In the dentate gyrus granule cell layer, chronic ECS decreased the acute induction of BDNF and trkB mRNA by approximately 50%, but prolonged their expression: levels remained elevated two- to threefold 18 hr later after the last chronic ECS treatment, but returned to control 18 hr after acute ECS. In CA3 and CA1 pyramidal cell layers, chronic ECS significantly elevated the acute induction of BDNF, and tended to prolong the expression of BDNF and trkB mRNA. A similar effect was observed in layer 2 of the piriform cortex, where chronic ECS significantly increased the acute induction and prolonged the expression of BDNF and trkB mRNA. Chronic (21 d), but not acute (1 d), administration of several different antidepressant drugs, including tranylcypromine, sertraline, desipramine, or mianserin, significantly increased BDNF mRNA and all but mianserin increased trkB mRNA in hippocampus. In contrast, chronic administration of nonantidepressant psychotropic drugs, including morphine, cocaine, or haloperidol, did not increase levels of BDNF mRNA. Furthermore, chronic administration of ECS or antidepressant drugs completely blocked the down-regulation of BDNF mRNA in the hippocampus in response to restraint stress. The enhanced induction and prolonged expression of BDNF in response to chronic ECS and antidepressant drug treatments could promote neuronal survival, and protect neurons from the damaging effects of stress.

  20. Boron-Based Drug Design.

    Science.gov (United States)

    Ban, Hyun Seung; Nakamura, Hiroyuki

    2015-06-01

    The use of the element boron, which is not generally observed in a living body, possesses a high potential for the discovery of new biological activity in pharmaceutical drug design. In this account, we describe our recent developments in boron-based drug design, including boronic acid containing protein tyrosine kinase inhibitors, proteasome inhibitors, and tubulin polymerization inhibitors, and ortho-carborane-containing proteasome activators, hypoxia-inducible factor 1 inhibitors, and topoisomerase inhibitors. Furthermore, we applied a closo-dodecaborate as a water-soluble moiety as well as a boron-10 source for the design of boron carriers in boron neutron capture therapy, such as boronated porphyrins and boron lipids for a liposomal boron delivery system.

  1. Active metabolites as antidepressant drugs: The role of norquetiapine in the mechanism of action of quetiapine in the treatment of mood disorders

    Directory of Open Access Journals (Sweden)

    Francisco eLopez-Munoz

    2013-09-01

    Full Text Available Active metabolites of some antipsychotic drugs exhibit pharmacodynamic and pharmacokinetic properties that may be similar to or differ from the original compound and that can be translated by a different profile of responses and interactions to clinical level. Some of these antipsychotics’ active metabolites might participate in mechanisms of antidepressant activity, as m-chlorophenylpiperazine (aripiprazole, 9-OH-risperidone and norquetiapine. Norquetiapine exhibits distinct pharmacological activity from quetiapine and plays a fundamental role in its antidepressant efficacy. In this review, we analyze the differential pharmacological aspects between quetiapine and norquetiapine, both from the pharmacokinetic and pharmacodynamic perspectives (affinity for dopaminergic, noradrenegic and/or serotonergic receptors, etc., as well as differential neuroprotective role. The pharmacological differences between the two drugs could explain the differential clinical effect, as well as some differences in tolerability profile and drug interactions. The available data are sufficient to arrive at the conclusion that antidepressant activity of quetiapine is mediated, at least in part, by the active metabolite norquetiapine, which selectively inhibits noradrenaline reuptake, is a partial 5-HT1A receptor agonist, and acts as an antagonist at presynaptic α2, 5-HT2C and 5-HT7 receptors.

  2. [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.

  3. 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.

  4. 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.

  5. 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.

  6. Effect of the Anti-depressant Sertraline, the Novel Anti-seizure Drug Vinpocetine and Several Conventional Antiepileptic Drugs on the Epileptiform EEG Activity Induced by 4-Aminopyridine.

    Science.gov (United States)

    Sitges, Maria; Aldana, Blanca Irene; Reed, Ronald Charles

    2016-06-01

    Seizures are accompanied by an exacerbated activation of cerebral ion channels. 4-aminopyridine (4-AP) is a pro-convulsive agent which mechanism of action involves activation of Na(+) and Ca(2+) channels, and several antiepileptic drugs control seizures by reducing these channels permeability. The antidepressant, sertraline, and the anti-seizure drug vinpocetine are effective inhibitors of cerebral presynaptic Na(+) channels. Here the effectiveness of these compounds to prevent the epileptiform EEG activity induced by 4-AP was compared with the effectiveness of seven conventional antiepileptic drugs. For this purpose, EEG recordings before and at three intervals within the next 30 min following 4-AP (2.5 mg/kg, i.p.) were taken in anesthetized animals; and the EEG-highest peak amplitude values (HPAV) calculated. In control animals, the marked increase in the EEG-HPAV observed near 20 min following 4-AP reached its maximum at 30 min. Results show that this epileptiform EEG activity induced by 4-AP is prevented by sertraline and vinpocetine at a dose of 2.5 mg/kg, and by carbamazepine, phenytoin, lamotrigine and oxcarbazepine at a higher dose (25 mg/kg). In contrast, topiramate (25 mg/kg), valproate (100 mg/kg) and levetiracetam (100 mg/kg) failed to prevent the epileptiform EEG activity induced by 4-AP. It is concluded that 4-AP is a useful tool to elicit the mechanism of action of anti-seizure drugs at clinical meaningful doses. The particular efficacy of sertraline and vinpocetine to prevent seizures induced by 4-AP is explained by their high effectiveness to reduce brain presynaptic Na(+) and Ca(2+) channels permeability.

  7. Proliferation rates and gene expression profiles in human lymphoblastoid cell lines from patients with depression characterized in response to antidepressant drug therapy.

    Science.gov (United States)

    Breitfeld, J; Scholl, C; Steffens, M; Brandenburg, K; Probst-Schendzielorz, K; Efimkina, O; Gurwitz, D; Ising, M; Holsboer, F; Lucae, S; Stingl, J C

    2016-11-15

    The current therapy success of depressive disorders remains in need of improvement due to low response rates and a delay in symptomatic improvement. Reliable functional biomarkers would be necessary to predict the individual treatment outcome. On the basis of the neurotrophic hypothesis of antidepressant's action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy. We studied individual differences in antidepressant drug effects on cell proliferation and gene expression in lymphoblastoid cell lines (LCLs) derived from patients treated for depression with documented clinical treatment outcome. Cell proliferation was characterized by EdU (5-ethynyl-2'-deoxyuridine) incorporation assays following a 3-week incubation with therapeutic concentrations of fluoxetine. Genome-wide expression profiling was conducted by microarrays, and candidate genes such as betacellulin-a gene involved in neuronal stem cell regeneration-were validated by quantitative real-time PCR. Ex vivo assessment of proliferation revealed large differences in fluoxetine-induced proliferation inhibition between donor LCLs, but no association with clinical response was observed. Genome-wide expression analyses followed by pathway and gene ontology analyses identified genes with different expression before vs after 21-day incubation with fluoxetine. Significant correlations between proliferation and gene expression of WNT2B, FZD7, TCF7L2, SULT4A1 and ABCB1 (all involved in neurogenesis or brain protection) were also found. Basal gene expression of SULT4A1 (P=0.029), and gene expression fold changes of WNT2B by ex vivo fluoxetine (P=0.025) correlated with clinical response and clinical remission, respectively. Thus, we identified potential gene expression biomarkers eventually being useful as baseline predictors or as longitudinal targets in antidepressant therapy.

  8. Proliferation rates and gene expression profiles in human lymphoblastoid cell lines from patients with depression characterized in response to antidepressant drug therapy

    Science.gov (United States)

    Breitfeld, J; Scholl, C; Steffens, M; Brandenburg, K; Probst-Schendzielorz, K; Efimkina, O; Gurwitz, D; Ising, M; Holsboer, F; Lucae, S; Stingl, J C

    2016-01-01

    The current therapy success of depressive disorders remains in need of improvement due to low response rates and a delay in symptomatic improvement. Reliable functional biomarkers would be necessary to predict the individual treatment outcome. On the basis of the neurotrophic hypothesis of antidepressant's action, effects of antidepressant drugs on proliferation may serve as tentative individual markers for treatment efficacy. We studied individual differences in antidepressant drug effects on cell proliferation and gene expression in lymphoblastoid cell lines (LCLs) derived from patients treated for depression with documented clinical treatment outcome. Cell proliferation was characterized by EdU (5-ethynyl-2'-deoxyuridine) incorporation assays following a 3-week incubation with therapeutic concentrations of fluoxetine. Genome-wide expression profiling was conducted by microarrays, and candidate genes such as betacellulin—a gene involved in neuronal stem cell regeneration—were validated by quantitative real-time PCR. Ex vivo assessment of proliferation revealed large differences in fluoxetine-induced proliferation inhibition between donor LCLs, but no association with clinical response was observed. Genome-wide expression analyses followed by pathway and gene ontology analyses identified genes with different expression before vs after 21-day incubation with fluoxetine. Significant correlations between proliferation and gene expression of WNT2B, FZD7, TCF7L2, SULT4A1 and ABCB1 (all involved in neurogenesis or brain protection) were also found. Basal gene expression of SULT4A1 (P=0.029), and gene expression fold changes of WNT2B by ex vivo fluoxetine (P=0.025) correlated with clinical response and clinical remission, respectively. Thus, we identified potential gene expression biomarkers eventually being useful as baseline predictors or as longitudinal targets in antidepressant therapy. PMID:27845776

  9. 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.

  10. 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.

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

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    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

  12. Is there a placebo problem in antidepressant trials?

    Science.gov (United States)

    Yang, Huaiyu; Cusin, Cristina; Fava, Maurizio

    2005-01-01

    In psychiatry, particularly in antidepressant clinical studies, placebo-controlled trials often yield results that are very difficult to interpret because of robust placebo responses. Meta-analyses of trials in major depressive disorder (MDD) suggest that drug-placebo differences in response rates range from 11% to 18%. However, in trials of marketed antidepressants present in the FDA databases, antidepressant drugs were superior to placebo in only 45 out of 93 RCTs (48%), and the placebo response overall appears to have increased over time. This gradual increase in placebo response rates may lead to delays in bringing new antidepressant treatments to the market, increased costs of antidepressant drug development and, in some cases, decisions to stop the development of certain compounds, or FDA decisions to not approve new treatments. A number of possible contributing factors to this significant placebo response in MDD have been identified, but further studies are needed. Many of the remedies used by researchers to minimize the placebo response, such as lead-in periods or shortening the duration of study visits, have failed to show consistent benefits. From our analysis of published studies, it appears that expectations about the speed of response may be shaped by the duration of the trial and that most of the placebo response occurs in the first half of the trial, regardless of its duration. These observations have led us to develop a novel approach to the placebo response problem called the Sequential Parallel Comparison Design.

  13. A model of placebo response in antidepressant clinical trials.

    Science.gov (United States)

    Rutherford, Bret R; Roose, Steven P

    2013-07-01

    Placebo response in clinical trials of antidepressant medications is substantial and has been increasing. High placebo response rates hamper efforts to detect signals of efficacy for new antidepressant medications, contributing to trial failures and delaying the delivery of new treatments to market. Media reports seize upon increasing placebo response and modest advantages for active drugs as reasons to question the value of antidepressant medication, which may further stigmatize treatments for depression and dissuade patients from accessing mental health care. Conversely, enhancing the factors responsible for placebo response may represent a strategy for improving available treatments for major depressive disorder. A conceptual framework describing the causes of placebo response is needed in order to develop strategies for minimizing placebo response in clinical trials, maximizing placebo response in clinical practice, and talking with depressed patients about the risks and benefits of antidepressant medications. In this review, the authors examine contributors to placebo response in antidepressant clinical trials and propose an explanatory model. Research aimed at reducing placebo response should focus on limiting patient expectancy and the intensity of therapeutic contact in antidepressant clinical trials, while the optimal strategy in clinical practice may be to combine active medication with a presentation and level of therapeutic contact designed to enhance treatment response.

  14. 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...

  15. 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....

  16. 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....

  17. 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

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

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    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

  19. Adherence to antidepressants

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    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.

  20. Computer Aided Drug Design: Success and Limitations.

    Science.gov (United States)

    Baig, Mohammad Hassan; Ahmad, Khurshid; Roy, Sudeep; Ashraf, Jalaluddin Mohammad; Adil, Mohd; Siddiqui, Mohammad Haris; Khan, Saif; Kamal, Mohammad Amjad; Provazník, Ivo; Choi, Inho

    2016-01-01

    Over the last few decades, computer-aided drug design has emerged as a powerful technique playing a crucial role in the development of new drug molecules. Structure-based drug design and ligand-based drug design are two methods commonly used in computer-aided drug design. In this article, we discuss the theory behind both methods, as well as their successful applications and limitations. To accomplish this, we reviewed structure based and ligand based virtual screening processes. Molecular dynamics simulation, which has become one of the most influential tool for prediction of the conformation of small molecules and changes in their conformation within the biological target, has also been taken into account. Finally, we discuss the principles and concepts of molecular docking, pharmacophores and other methods used in computer-aided drug design.

  1. 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.

  2. Towards structure-based protein drug design.

    Science.gov (United States)

    Zhang, Changsheng; Lai, Luhua

    2011-10-01

    Structure-based drug design for chemical molecules has been widely used in drug discovery in the last 30 years. Many successful applications have been reported, especially in the field of virtual screening based on molecular docking. Recently, there has been much progress in fragment-based as well as de novo drug discovery. As many protein-protein interactions can be used as key targets for drug design, one of the solutions is to design protein drugs based directly on the protein complexes or the target structure. Compared with protein-ligand interactions, protein-protein interactions are more complicated and present more challenges for design. Over the last decade, both sampling efficiency and scoring accuracy of protein-protein docking have increased significantly. We have developed several strategies for structure-based protein drug design. A grafting strategy for key interaction residues has been developed and successfully applied in designing erythropoietin receptor-binding proteins. Similarly to small-molecule design, we also tested de novo protein-binder design and a virtual screen of protein binders using protein-protein docking calculations. In comparison with the development of structure-based small-molecule drug design, we believe that structure-based protein drug design has come of age.

  3. Further evaluation of mechanisms associated with the antidepressant-like signature of scopolamine in mice.

    Science.gov (United States)

    Martin, Anna E; Schober, Douglas A; Nikolayev, Alexander; Tolstikov, Vladimir V; Anderson, Wesley H; Higgs, Richard E; Kuo, Ming-Shang; Laksmanan, Anastasia; Catlow, John T; Li, Xia; Felder, Christian C; Witkin, Jeffrey M

    2017-03-09

    Conventional antidepressants lack efficacy for many patients (treatment-resistant depression or TRD) and generally take weeks to produce full therapeutic response in others. Emerging data has identified certain drugs such as ketamine as rapidly-acting antidepressants for major depressive disorder and TRD. Scopolamine, a drug used to treat motion sickness and nausea, has also been demonstrated to function as a rapidly-acting antidepressant. The mechanisms associated with efficacy in TRD patients and rapid onset of action have been suggested to involve a-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mammalian target of rapamycin (mTOR) signaling. Since the work on these mechanisms with scopolamine has been limited, the present set of experiments was designed to further explore these mechanisms of action. Male, NIH Swiss mice demonstrated a robust and immediate antidepressant signature when studied under the forced-swim test. The AMPA receptor antagonist NBQX prevented this antidepressant-like effect of scopolamine and ketamine. An orally-bioavilable mTOR inhibitor (ADZ8055) also attenuated the antidepressant-like effects of scopolamine and ketamine. Scopolamine was also shown to augment the antidepressant-like effect of the selective serotonin reuptake inhibitor citalopram. When given in combination, scopolamine and ketamine acted synergistically to produce antidepressant-like effects. Although drug interaction data suggested that additional mechanisms might be at play, metabolomic analysis of frontal cortex and plasma from muscarinic M1+/+ and M1 -/- mice given scopolamine or vehicle did not reveal any hints as to the nature of these additional mechanisms of action. Overall, the data substantiate and extend the idea that AMPA and mTOR signaling pathways are necessary for the antidepressant-like effects of scopolamine and ketamine, mechanisms that appear to be of general significance for TRD therapeutic agents.

  4. Uliginosin B, a phloroglucinol derivative from Hypericum polyanthemum: a promising new molecular pattern for the development of antidepressant drugs.

    Science.gov (United States)

    Stein, Ana C; Viana, Alice F; Müller, Liz G; Nunes, Jéssica M; Stolz, Eveline D; Do Rego, Jean-Claude; Costentin, Jean; von Poser, Gilsane L; Rates, Stela M K

    2012-03-01

    In this study we have demonstrated that cyclohexane extract of Hypericum polyanthemum (POL) and its main phloroglucinol derivative uliginosin B (ULI) present antidepressant-like activity in rodent forced swimming test (FST). The involvement of monoaminergic neurotransmission on the antidepressant-like activity of ULI was evaluated in vivo and in vitro. POL 90 mg/kg (p.o.) and ULI 10 mg/kg (p.o.) reduced the immobility time in the mice FST without altering locomotion activity in the open-field test. The combination of sub-effective doses of POL (45 mg/kg, p.o.) and ULI (5 mg/kg, p.o.) with sub-effective doses of imipramine (10 mg/kg, p.o.), bupropion (3 mg/kg, p.o.) and fluoxetine (15 mg/kg, p.o.) induced a significant reduction on immobility time in FST. The pretreatment with SCH 23390 (15 μg/kg, s.c., dopamine D1 receptor antagonist), sulpiride (50 mg/kg, i.p., dopamine D2 receptor antagonist), prazosin (1mg/kg, i.p., α1-adrenoceptor antagonist), yohimbine (1mg/kg, i.p., α2-adrenoceptor antagonist) and pCPA (100 mg/kg/day, i.p., p-chlorophenilalanine methyl ester, inhibitor of serotonin synthesis, for four consecutive days) before ULI administration (10 mg/kg, p.o.) significantly prevented the anti-immobility effect in FST. ULI was able to inhibit synaptosomal uptake of dopamine (IC50 = 90 ± 38 nM), serotonin (IC50 = 252 ± 13 nM) and noradrenaline (280 ± 48 nM), but it did not bind to any of the monoamine transporters. These data firstly demonstrated the antidepressant-like effect of POL and ULI, which depends on the activation of the monoaminergic neurotransmission in a different manner from the most antidepressants.

  5. 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.

  6. IC Treatment: Antidepressants

    Science.gov (United States)

    ... restrictions than MAOIs. Studies Testing Antidepressants to Treat IC With the exception of the TCA called amitriptyline ( ... when you have IC). Antidepressants Used to Treat IC Some of the current antidepressants your physician may ...

  7. Risk of drug interaction: combination of antidepressants and other drugs Risco de interação de drogas: combinações de uso de antidepressivos e outras drogas

    Directory of Open Access Journals (Sweden)

    Lincoln Sakiara Miyasaka

    2003-04-01

    Full Text Available OBJECTIVE: To assess the frequency of combination of antidepressants with other drugs and risk of drug interactions in the setting public hospital units in Brazil. METHODS: Prescriptions of all patients admitted to a public hospital from November 1996 to February 1997 were surveyed from the hospital's data processing center in São Paulo, Brazil. A manual search of case notes of all patients admitted to the psychiatric unit from January 1993 to December 1995 and all patients registered in the affective disorders outpatient clinic in December 1996 was carried out. Patients taking any antidepressant were identified and concomitant use of drugs was checked. By means of a software program (Micromedex® drug interactions were identified. RESULTS: Out of 6,844 patients admitted to the hospital, 63 (0.9% used antidepressants and 16 (25.3% were at risk of drug interaction. Out of 311 patients in the psychiatric unit, 63 (20.2% used antidepressants and 13 of them (20.6% were at risk. Out of 87 patients in the affective disorders outpatient clinic, 43 (49.4% took antidepressants and 7 (16.2% were at risk. In general, the use of antidepressants was recorded in 169 patients and 36 (21.3% were at risk of drug interactions. Twenty different forms of combinations at risk of drug interactions were identified: four were classified as mild, 15 moderate and one severe interaction. CONCLUSION: In the hospital general units the number of drug interactions per patient was higher than in the psychiatric unit; and prescription for depression was lower than expected.OBJETIVO: Verificar a freqüência de combinações de antidepressivos com outros medicamentos e o risco de interações medicamentosas em um hospital público no Brasil. MÉTODOS: Prescrições de todos os pacientes internados em um hospital público, em São Paulo, SP, de novembro de 1996 a fevereiro de 1997 foram analisadas pelo centro de processamento de dados do hospital. Foi realizada busca manual de

  8. Computer-Aided Drug Design Methods.

    Science.gov (United States)

    Yu, Wenbo; MacKerell, Alexander D

    2017-01-01

    Computational approaches are useful tools to interpret and guide experiments to expedite the antibiotic drug design process. Structure-based drug design (SBDD) and ligand-based drug design (LBDD) are the two general types of computer-aided drug design (CADD) approaches in existence. SBDD methods analyze macromolecular target 3-dimensional structural information, typically of proteins or RNA, to identify key sites and interactions that are important for their respective biological functions. Such information can then be utilized to design antibiotic drugs that can compete with essential interactions involving the target and thus interrupt the biological pathways essential for survival of the microorganism(s). LBDD methods focus on known antibiotic ligands for a target to establish a relationship between their physiochemical properties and antibiotic activities, referred to as a structure-activity relationship (SAR), information that can be used for optimization of known drugs or guide the design of new drugs with improved activity. In this chapter, standard CADD protocols for both SBDD and LBDD will be presented with a special focus on methodologies and targets routinely studied in our laboratory for antibiotic drug discoveries.

  9. 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.

  10. 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

  11. Designer drugs: a medicinal chemistry perspective.

    Science.gov (United States)

    Carroll, F Ivy; Lewin, Anita H; Mascarella, S Wayne; Seltzman, Herbert H; Reddy, P Anantha

    2012-02-01

    There are numerous medicinal chemistry reports in the literature describing the pharmacological properties of thousands of narcotics, stimulants, hallucinogens, sedative-hypnotic drugs, cannabinoids, and other psychoactive substances as well as synthetic methods for their preparations. This information, while essential for the advancement of science, has been used by clandestine chemists to manufacture and market an endless variety of analogs of so-called designer drugs. In this review, we describe how clandestine chemists used the principles of medicinal chemistry to design molecules, referred to as designer drugs, that elicit the effects of opioids, amphetamine and analogs, cannabinoids, and phencyclidine analogs while circumventing the law.

  12. Strategies for Drug Design-A Review

    Directory of Open Access Journals (Sweden)

    Deepa Sreedhar

    2013-01-01

    Full Text Available Drugs are essential for human survival. Drug molecules can bind the active site of the target proteins and there by disrupt the action of the target protein. A number of approaches are currently available to design drugs which make use of optimization algorithms that give quick result. Optimization algorithms help to select the best solution (drug molecule from the set of alternatives. This article discusses and compares six approaches for designing drugs that can reduce the time and cost of the early drug discovery process. Each of these approaches uses different optimization techniques. The approaches discussed here are based on Genetic Algorithm, its variants, Particle Swarm Optimization and Multiobjective Simulated Annealing.

  13. Changes in antidepressant use by young people and suicidal behavior after FDA warnings and media coverage: quasi-experimental study

    OpenAIRE

    Lu, Christine Y; Zhang, Fang; Lakoma, Matthew D; Madden, Jeanne M; Rusinak, Donna; Penfold, Robert B; Simon, Gregory; Ahmedani, Brian K.; Clarke, Gregory; Hunkeler, Enid M; Waitzfelder, Beth; Owen-Smith, Ashli; Raebel, Marsha A.; Rossom, Rebecca; Coleman, Karen J

    2014-01-01

    Objective: To investigate if the widely publicized warnings in 2003 from the US Food and Drug Administration about a possible increased risk of suicidality with antidepressant use in young people were associated with changes in antidepressant use, suicide attempts, and completed suicides among young people. Design: Quasi-experimental study assessing changes in outcomes after the warnings, controlling for pre-existing trends. Setting: Automated healthcare claims data (2000-10) derived from the...

  14. Drug or tool, design or serendipity?

    NARCIS (Netherlands)

    Verlinde, Christophe L.M.J.; Dijkstra, Bauke W.

    1995-01-01

    Iterative protein structure-based ligand design has led to a 'selective' inhibitor of human non-pancreatic secretory phospholipase A2 which provides a new tool for probing metabolic pathways and may lead to a useful drug.

  15. DRUG OR TOOL, DESIGN OR SERENDIPITY

    NARCIS (Netherlands)

    VERLINDE, CLMJ; DIJKSTRA, BW

    1995-01-01

    Iterative protein structure-based ligand design has led to a 'selective' inhibitor of human nonpancreatic secretory phospholipase A(2) which provides a new tool for probing metabolic pathways and may lead to a useful drug.

  16. Designing hydrogels for controlled drug delivery

    Science.gov (United States)

    Li, Jianyu; Mooney, David J.

    2016-12-01

    Hydrogel delivery systems can leverage therapeutically beneficial outcomes of drug delivery and have found clinical use. Hydrogels can provide spatial and temporal control over the release of various therapeutic agents, including small-molecule drugs, macromolecular drugs and cells. Owing to their tunable physical properties, controllable degradability and capability to protect labile drugs from degradation, hydrogels serve as a platform on which various physiochemical interactions with the encapsulated drugs occur to control drug release. In this Review, we cover multiscale mechanisms underlying the design of hydrogel drug delivery systems, focusing on physical and chemical properties of the hydrogel network and the hydrogel-drug interactions across the network, mesh and molecular (or atomistic) scales. We discuss how different mechanisms interact and can be integrated to exert fine control in time and space over drug presentation. We also collect experimental release data from the literature, review clinical translation to date of these systems and present quantitative comparisons between different systems to provide guidelines for the rational design of hydrogel delivery systems.

  17. Special focus on antidepressants

    OpenAIRE

    Balk-Møller, Carl August; Mogensen, Sofia Lin; Raatræ Lundstein, Sarah; Haubroe Larsen, André; Lohse, Mayasarah; Reininger Ardilsø, Lisa; Henrysdóttir, Gu∂run; Sondergaard, Nikolai

    2014-01-01

    This study examines the developments of SSRIs and the presence of them in the market. Dr. Peter Gøtszche’s book “Deadly Medicines and Organized Crime”, claims that scientific fraud is a big part of the pharmaceutical industry and the whole healthcare system in general. Through analyzing Peter Gøtszche’s book and several of his sources, the study aims to create a roadmap in the project, that resembles the process of the antidepressant drugs have to go through, to go from an idea to a patient. ...

  18. 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.

  19. Designer Drugs: A Synthetic Catastrophe.

    Science.gov (United States)

    Fratantonio, James; Andrade, Lawrence; Febo, Marcelo

    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.

  20. 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.

  1. Antidepressants: MedlinePlus Health Topic

    Science.gov (United States)

    ... antidepressants in primary care: descriptive study of... Article: Comparison chart of drugs for migraine prevention. Article: Sixty ... the sharing features on this page, please enable JavaScript. About MedlinePlus Site Map FAQs Customer Support Get ...

  2. A simple dried blood spot method for therapeutic drug monitoring of the tricyclic antidepressants amitriptyline, nortriptyline, imipramine, clomipramine, and their active metabolites using LC-MS/MS.

    Science.gov (United States)

    Berm, E J J; Paardekooper, J; Brummel-Mulder, E; Hak, E; Wilffert, B; Maring, J G

    2015-03-01

    Therapeutic drug monitoring (TDM) of tricyclic antidepressants (TCAs) is considered useful in patients with major depressive disorder, since these drugs display large individual differences in clearance, and the therapeutic windows of these drugs are relatively small. We developed an assay for determination of amitriptyline (ATP), nortriptyline (NTP), imipramine (IMP), desipramine (DSP) clomipramine (CMP) and desmethyl-clomipramine (DCMP) in dried blood spots (DBS). A fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of ATP, NTP, IMP, DSP, CMP, and DCMP in DBS. Six mm circles were punched out from DBS collected on Whatman DMPK-C paper and mixed with acetonitrile: methanol 1:3 containing the internal standard. The extract was analyzed by LC-MS/MS. Total LC-MS/MS runtime was 4.8 min. The assay was linear in the range 20-500 µg/L for all compounds. Overall-assay accuracy and precision were15% negative bias for all compounds. Punching at the perimeter of the blood spot instead of the center was associated with a positive bias. A good correlation was found between patients plasma and DBS samples of ATP, NTP and DMCP, but not for CMP. In addition, proportional differences were found. This LC-MS/MS method was analytically validated for determination of TCAs in DBS. Future validation will focus on the clinical application of the method.

  3. Protein Structure Network-based Drug Design.

    Science.gov (United States)

    Liang, Zhongjie; Hu, Guang

    2016-01-01

    Although structure-based drug design (SBDD) has become an indispensable tool in drug discovery for a long time, it continues to pose major challenges to date. With the advancement of "omics" techniques, systems biology has enriched SBDD into a new era, called polypharmacology, in which multi-targets drug or drug combination is designed to fight complex diseases. As a preliminary tool in systems biology, protein structure networks (PSNs) treat a protein as a set of residues linked by edges corresponding to the intramolecular interactions existing in folded structures between the residues. The PSN offers a computationally efficient tool to study the structure and function of proteins, and thus may facilitate structurebased drug design. Herein, we provide an overview of recent advances in PSNs, from predicting functionally important residues, to charactering protein-protein interactions and allosteric communication paths. Furthermore, we discuss potential pharmacological applications of PSN concepts and tools, and highlight the application to two families of drug targets, GPCRs and Hsp90. Although the application of PSNs as a framework for computer-aided drug discovery has been limited to date, we put forward the potential utility value in the near future and propose the PSNs could also serve as a new tool for polypharmacology research.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. Mass fragmentographic assay of nanogram amounts of the antidepressant drug mianserin hydrochloride (Org GB 94) in human plasma.

    Science.gov (United States)

    de Ridder, J J; Koppens, P C; van Hal, H J

    1977-05-01

    For the assay of the antidepressant compound mianserin hydrochloride (Org GB 94) in human plasma, a mass fragmentographic method, using the deuterated analogue as internal standard and a high-performance liquid chromatographie sample clean-up procedure has been developed. The assay specifications obtained are a lower limit for reliable measurements of 1 ng/ml, and accuracy of ca. 0.01 ng/ml, a precision of 6--7% and a capacity of about 60 samples per day. The applicability of the assay method is illustrated by measurements of single-dose and steady-state plasma levels in clinical experiments, demonstrating the possibility of monitoring plasma levels during at least 24 h after a single dose of 15 mg of Org GB 94. The mean steady-state plasma levels after a daily dose of 3 X 20 mg of Org GB 94 appeared to be remarkably constant with time: 38, 36 and 34 ng/ml after 2, 4, and 6 weeks of treatment of 18 depressed patients.

  9. Montmorillonite/Poly (L-Lactide microcomposite spheres as reservoirs of antidepressant drugs and their controlled release property

    Directory of Open Access Journals (Sweden)

    Shalini Rajkumar

    2015-10-01

    Full Text Available This work evaluates intercalation of Nortriptyline (NT and Venlafaxine (VFX in an interlayer gallery of Na+-MMT (Montmorillonite, which was further compounded with Poly (L-Lactide (PLLA to form microcomposite spheres (MPs for oral controlled drug delivery. The XRD patterns, thermal and spectroscopic analyses indicated intercalation of drugs into the MMT interlayer that was stabilized by electrostatic interaction. No significant changes in structural and functional properties of drugs were found in the MMT layers. In vitro drug release studies showed controlled release pattern.

  10. Drug: D08511 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08511 Drug Setiptiline (INN) C19H19N 261.1518 261.3609 D08511.gif Antidepressant tetracyclic antidepress...47+148) Salivary secretion map07027 Antidepressants Target-based classification o

  11. Drug: D07591 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07591 Drug Bupropion (INN) C13H18ClNO 239.1077 239.7411 D07591.gif Antidepressant ...SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06A...atment Agents Smoking Cessation Agents Bupropion D07591 Bupropion (INN) Antidepressants Antidepressants, Oth

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

    Science.gov (United States)

    Shelate, Pragna; 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

  13. 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

  14. Machine learning techniques and drug design.

    Science.gov (United States)

    Gertrudes, J C; Maltarollo, V G; Silva, R A; Oliveira, P R; Honório, K M; da Silva, A B F

    2012-01-01

    The interest in the application of machine learning techniques (MLT) as drug design tools is growing in the last decades. The reason for this is related to the fact that the drug design is very complex and requires the use of hybrid techniques. A brief review of some MLT such as self-organizing maps, multilayer perceptron, bayesian neural networks, counter-propagation neural network and support vector machines is described in this paper. A comparison between the performance of the described methods and some classical statistical methods (such as partial least squares and multiple linear regression) shows that MLT have significant advantages. Nowadays, the number of studies in medicinal chemistry that employ these techniques has considerably increased, in particular the use of support vector machines. The state of the art and the future trends of MLT applications encompass the use of these techniques to construct more reliable QSAR models. The models obtained from MLT can be used in virtual screening studies as well as filters to develop/discovery new chemicals. An important challenge in the drug design field is the prediction of pharmacokinetic and toxicity properties, which can avoid failures in the clinical phases. Therefore, this review provides a critical point of view on the main MLT and shows their potential ability as a valuable tool in drug design.

  15. 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.

  16. The Beneficial Impact of Antidepressant Drugs on Prenatal Stress-Evoked Malfunction of the Insulin-Like Growth Factor-1 (IGF-1) Protein Family in the Olfactory Bulbs of Adult Rats.

    Science.gov (United States)

    Trojan, Ewa; Głombik, Katarzyna; Ślusarczyk, Joanna; Budziszewska, Bogusława; Kubera, Marta; Roman, Adam; Lasoń, Władysław; Basta-Kaim, Agnieszka

    2016-02-01

    Insulin-like growth factor-1 (IGF-1) promotes the growth, differentiation, and survival of both neurons and glial cells, and it is believed to exert antidepressant-like activity. Thus, disturbances in the IGF-1 system could be responsible for the course of depression. To date, there have been no papers showing the impact of chronic antidepressant treatment on the IGF-1 network in the olfactory bulb (OB) in an animal model of depression. Prenatal stress was used as model of depression. Twenty-four 3-month-old male offspring of control and stressed mothers were subjected to behavioral testing (forced swim test). The mRNA expression of IGF-1 and IGF-1 receptor (IGF-1R) and the protein level of IGF-1 and its phosphorylation, as well as the concentrations of IGF-binding proteins (IGFBP-2, -4, -3, and -6), were measured in OBs before and after chronic imipramine, fluoxetine, or tianeptine administration. Adult rats exposed prenatally to stressful stimuli displayed not only depression-like behavior but also decreased IGF-1 expression, dysregulation in the IGFBP network, and diminished mRNA expression, as well as IGF-1R phosphorylation, in the OB. The administration of antidepressants normalized most of the changes in the IGF-1 system of the OB evoked by prenatal stress. These results suggested a beneficial effect of chronic antidepressant drug treatment in the alleviation of IGF-1 family malfunction in OBs in an animal model of depression.

  17. Antidepressants: update on new agents and indications.

    Science.gov (United States)

    Ables, Adrienne Z; Baughman, Otis L

    2003-02-01

    A number of antidepressants have emerged in the U.S. market in the past two decades. Selective serotonin reuptake inhibitors have become the drugs of choice in the treatment of depression, and they are also effective in the treatment of obsessive-compulsive disorder, panic disorder, and social phobia. New indications for selective serotonin reuptake inhibitors include post-traumatic stress disorder, premenstrual dysphoric disorder, and generalized anxiety disorder. Extended-release venlafaxine has recently been approved by the U.S. Food and Drug Administration for the treatment of generalized anxiety disorder. Mirtazapine, which is unrelated to the selective serotonin reuptake inhibitors, is unique in its action--stimulating the release of norepinephrine and serotonin. The choice of antidepressant drug depends on the agent's pharmacologic profile, secondary actions, and tolerability. Sexual dysfunction related to the use of antidepressants may be addressed by reducing the dosage, switching to another agent, or adding another drug to overcome the sexual side effects. Augmentation with lithium or triiodothyronine may be useful in patients who are partially or totally resistant to antidepressant treatment. Finally, tapering antidepressant medication may help to avoid discontinuation syndrome or antidepressant withdrawal.

  18. Rational drug design applied to myeloperoxidase inhibition.

    Science.gov (United States)

    Van Antwerpen, P; Zouaoui Boudjeltia, K

    2015-06-01

    Rational drug design is a general approach using protein-structure technique in which the discovery of a ligand can be driven either by chance, screening, or rational theory. Myeloperoxidase (MPO) was rapidly identified as a therapeutical target because of its involvement in chronic inflammatory syndromes. In this context, the research of MPO inhibitors was intensified and development of new chemical entities was rationally driven by the research of ligands that enter into the MPO catalytic pocket. Actually, as soon as crystallography data of MPO have become available and its structure was virtually designed, the rational drug design has been applied to this peroxidase. Pharmaceutical industries and academic laboratories apply rational drug design on MPO by either optimizing known inhibitors or searching new molecules by high-throughput virtual screening. By these ways, they were able to find efficient MPO inhibitors and understand their interactions with the enzyme. During this quest of MPO inhibition, it appears that Glu268 is a crucial residue in order to optimize ligand-target interaction. This amino acid should be carefully considered by medicinal chemist when they design inhibitors interfering with MPO activity.

  19. 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

  20. 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

  1. Application analysis on antidepressant drugs of 32 hospitals in Wuhan area during 2010-2012%2010-2012年武汉地区32家医院抗抑郁药物应用分析

    Institute of Scientific and Technical Information of China (English)

    贡雪芃; 何泉; 杜光

    2014-01-01

    Objective: To investigate the clinical application and the development tendency of antidepressant drugs in Wuhan area during 2010 - 2012. Methods:The utilization of antidepressant drugs was analyzed retrospectively in terms of consumption sum, DDDs, DDC, etc. Results:The consumption sum of antidepressant drugs increased by 29.7%and 11.4%year by year during 2010-2012. The consumption sum of SSRIs and SNRIs accounted for 50%and 30%among the total consumption sum of antidepressant drugs respectively. The top 3 drugs in consumption sum were venlafaxine, paroxetine and escitalopram. Flupentixol and melitracen tablets dominated the ifrst place over the 3 years in terms of DDDs. Conclusion:The utilization of antidepressant drugs increased remarkably in Wuhan area during 2010-2012, SSRIs and SNRIs occupied the dominant position of the market.%目的:了解2010-2012年武汉地区抗抑郁药物临床应用情况及用药趋势。方法:采用回顾性分析方法,对武汉地区32家医院2010-2012年抗抑郁药物的用药金额、用药频率、限定日费用等指标进行统计分析。结果:2010-2012年武汉地区抗抑郁药物用药总金额环比增长29.7%和11.4%。SSRIs及SNRIs类抗抑郁药物分别占用药总金额的50%和30%。用药总金额排序前3位的药物分别是:文拉法辛、帕罗西汀和艾司西酞普兰,复方制剂氟哌噻吨/美利曲辛的用药频度最高。结论:2010-2012年本地区抗抑郁药物应用显著增长,SSRIs及SNRIs类抗抑郁药占据市场主导地位。

  2. 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.

  3. Antidepressants triggering suicidal ideation: An area of concern

    Directory of Open Access Journals (Sweden)

    Himali Rajgadhi

    2016-01-01

    Full Text Available This is a report of four cases of possible suicidal ideation with the use of antidepressants in Indian population. The patients presented to emergency department of a tertiary care hospital with attempted suicide. All of them were prescribed at least one antidepressant. The association of increased suicidal attempts/ideation with antidepressant drugs themselves has been reported in the West, but data in the Indian population are lacking. Antidepressants are widely used not only for treatment of depression but also many other psychiatric illnesses; it is yet unclear whether suicidal ideation is because of these drugs or the progression of the disease. Hence, careful prescribing of these medicines is warranted.

  4. Application of Mice Humanized for CYP2D6 to the Study of Tamoxifen Metabolism and Drug–Drug Interaction with Antidepressants

    Science.gov (United States)

    MacLeod, A. Kenneth; McLaughlin, Lesley A.; Henderson, Colin J.

    2017-01-01

    Tamoxifen is an estrogen receptor antagonist used in the treatment of breast cancer. It is a prodrug that is converted by several cytochrome P450 enzymes to a primary metabolite, N-desmethyltamoxifen (NDT), which is then further modified by CYP2D6 to a pharmacologically potent secondary metabolite, 4-hydroxy-N-desmethyltamoxifen (endoxifen). Antidepressants (ADs), which are often coprescribed to patients receiving tamoxifen, are also metabolized by CYP2D6 and evidence suggests that a drug–drug interaction between these agents adversely affects the outcome of tamoxifen therapy by inhibiting endoxifen formation. We evaluated this potentially important drug–drug interaction in vivo in mice humanized for CYP2D6 (hCYP2D6). The rate of conversion of NDT to endoxifen by hCYP2D6 mouse liver microsomes (MLMs) in vitro was similar to that of the most active members of a panel of 13 individual human liver microsomes. Coincubation with quinidine, a CYP2D6 inhibitor, ablated endoxifen generation by hCYP2D6 MLMs. The NDT-hydroxylation activity of wild-type MLMs was 7.4 times higher than that of hCYP2D6, whereas MLMs from Cyp2d knockout animals were inactive. Hydroxylation of NDT correlated with that of bufuralol, a CYP2D6 probe substrate, in the human liver microsome panel. In vitro, ADs of the selective serotonin reuptake inhibitor class were, by an order of magnitude, more potent inhibitors of NDT hydroxylation by hCYP2D6 MLMs than were compounds of the tricyclic class. At a clinically relevant dose, paroxetine pretreatment inhibited the generation of endoxifen from NDT in hCYP2D6 mice in vivo. These data demonstrate the potential of ADs to affect endoxifen generation and, thereby, the outcome of tamoxifen therapy. PMID:27756789

  5. Patient and GP characteristics associated with antidepressant treatment in depressed patients: a multilevel analysis.

    NARCIS (Netherlands)

    Dijk, L. van; Volkers, A.; Bakker, D. de

    2007-01-01

    Background: Antidepressants are frequently prescribed drugs in Dutch general practice, but patients differ in the treatment they receive. Both patient and GP characteristics may explain this difference. Objectives: To identify patient and GP characteristics associated with antidepressant treatment i

  6. Drug design from the cryptic inhibitor envelope.

    Science.gov (United States)

    Lee, Chul-Jin; Liang, Xiaofei; Wu, Qinglin; Najeeb, Javaria; Zhao, Jinshi; Gopalaswamy, Ramesh; Titecat, Marie; Sebbane, Florent; Lemaitre, Nadine; Toone, Eric J; Zhou, Pei

    2016-02-25

    Conformational dynamics plays an important role in enzyme catalysis, allosteric regulation of protein functions and assembly of macromolecular complexes. Despite these well-established roles, such information has yet to be exploited for drug design. Here we show by nuclear magnetic resonance spectroscopy that inhibitors of LpxC--an essential enzyme of the lipid A biosynthetic pathway in Gram-negative bacteria and a validated novel antibiotic target--access alternative, minor population states in solution in addition to the ligand conformation observed in crystal structures. These conformations collectively delineate an inhibitor envelope that is invisible to crystallography, but is dynamically accessible by small molecules in solution. Drug design exploiting such a hidden inhibitor envelope has led to the development of potent antibiotics with inhibition constants in the single-digit picomolar range. The principle of the cryptic inhibitor envelope approach may be broadly applicable to other lead optimization campaigns to yield improved therapeutics.

  7. 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...

  8. Exploiting protein intrinsic flexibility in drug design.

    Science.gov (United States)

    Lukman, Suryani; Verma, Chandra S; Fuentes, Gloria

    2014-01-01

    Molecular recognition in biological systems relies on the existence of specific attractive interactions between two partner molecules. Structure-based drug design seeks to identify and optimize such interactions between ligands and their protein targets. The approach followed in medicinal chemistry follows a combination of careful analysis of structural data together with experimental and/or theoretical studies on the system. This chapter focuses on the fact that a protein is not fully characterized by a single structure, but by an ensemble of states, some of them represent "hidden conformations" with cryptic binding sites. We highlight case studies where both experimental and computational methods have been used to mutually drive each other in an attempt to improve the success of the drug design approaches.Advances in both experimental techniques and computational methods have greatly improved our physico-chemical understanding of the functional mechanisms in biomolecules and opened a debate about the interplay between molecular structure and biomolecular function. The beautiful static pictures of protein structures may have led to neglecting the intrinsic protein flexibility, however we are entering a new era where more sophisticated methods are used to exploit this ability of macromolecules, and this will definitely lead to the inclusion of the notion in the pharmaceutical field of drug design.

  9. Potentials of Curcumin as an Antidepressant

    Directory of Open Access Journals (Sweden)

    S.K. Kulkarni

    2009-01-01

    Full Text Available Major depression, a debilitating psychiatric disorder, is predicted to be the second most prevalent human illness by the year 2020. Various antidepressants, ranging from monoamine oxidase inhibitors to recently developed dual reuptake inhibitors, are prescribed for alleviating the symptoms of depression. Despite the availability of these blockbuster molecules, approximately 30% of depressed patients do not respond to the existing drug therapies and the remaining 70% fails to achieve complete remission. Moreover, antidepressants are associated with a plethora of side effects and drug-drug/drug-food interactions. In this context, novel approaches are being tried to find more efficacious and safer drugs for the treatment of major depression. Curcumin is one such molecule that has shown promising efficacy in various animal models of major depression. Although the mechanism of the antidepressant effect of curcumin is not fully understood, it is hypothesized to act through inhibiting the monoamine oxidase enzyme and modulating the release of serotonin and dopamine. Moreover, evidences have shown that curcumin enhances neurogenesis, notably in the frontal cortex and hippocampal regions of the brain. The use of curcumin in clinics for the treatment of major depression is limited due to its poor gastrointestinal absorption. The present review attempts to discuss the pharmacological profile along with molecular mechanisms of the antidepressant effect of curcumin in animal models of depression. A need for clinical trials in order to explore the antidepressant efficacy and safety profile of curcumin is emphasized.

  10. 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

  11. 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.

  12. Drug: D08222 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08222 Drug Milnacipran (INN) C15H22N2O 246.1732 246.348 D08222.gif Antidepressant ...rgic synapse map07027 Antidepressants map07234 Neurotransmitter transporter inhib...S N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX17 Milnacipran D08222 Milnacipran (INN) USP drug cla

  13. 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.

  14. 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

  15. Colleague interactions and new drug prescribing behavior: the case of the initial prescription of antidepressants in Taiwanese medical centers.

    Science.gov (United States)

    Lin, Shu-Jou; Jan, Kuan-An; Kao, Jen-Tse

    2011-10-01

    This research explores the social factors influencing hospital physicians' initial adoption of duloxetine hydrochloride, with a focus on colleague interactions. The study analyzes archival data compiled by the National Health Insurance Research Database of Taiwan to examine how the prescribing decisions made by psychiatrists' colleagues influence the likelihood of the psychiatrists' initial prescription. The results show that the adoption ratio of a physician's colleagues in a medical center is positively associated with the likelihood of a physician's adoption of the new drug. Specifically, colleague groups with similar and longer tenure as well as similar and older age have significantly positive effects. Colleague groups with the same and different gender also have positive effects. In summary, tenure and age, rather than gender, are vital sources of heterogeneous colleague interactions.

  16. 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

  17. 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.

  18. Ionic liquid based dispersive liquid-liquid microextraction coupled with micro-solid phase extraction of antidepressant drugs from environmental water samples.

    Science.gov (United States)

    Ge, Dandan; Lee, Hian Kee

    2013-11-22

    Ionic liquid-dispersive liquid-liquid microextraction combined with micro-solid phase extraction (IL-DLLME-μ-SPE), and high-performance liquid chromatography (HPLC) was developed for the determination of tricyclic antidepressants (TCAs) in water samples. Two hundred microliters of an organic solvent (as disperser solvent) and 20 μl of 1-hexyl-3-methylimidazolium tris(pentafluoroethyl)trifluorophosphate were injected into a 5.0 ml sample for sonication-assisted DLLME. After this, a μ-SPE device, containing a novel material zeolite imidazolate framework 4 (ZIF-4), was added into the sample solution and 1 min of vortex-assisted extraction was performed. After 5 min of sonication-assisted desorption, 10 μl of desorption solvent was injected into a HPLC system for analysis. A characteristic property of DLLME-VA-μ-SPE is that any organic solvent and solid sorbent immiscible with water can be used. Special apparatus, or conical-bottom test tubes, and tedious procedures conventionally associated with DLLME such as centrifugation, or refrigeration of solvent are not necessary in the present approach. A novel material, ZIF-4 was employed as μ-SPE sorbent. Under the optimized conditions, the calibration curves were linear in the range of 1-1000 μg/L. The relative standard deviations and the limits of detection were in the range of 1.5% and 7.8% and 0.3 and 1 μg/L, respectively. The relative recoveries of canal water samples, spiked with drugs, were in the range of 94.3% and 114.7%. The results showed that IL-DLLME-μ-SPE was suitable for the determination of TCAs in water samples.

  19. Drug: D00563 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 265.3529 D00563.gif Antidepressant Same as: C07570 Therapeutic category: 1179 ATC code: N06AX11 5-HT2-recep...6 [HSA:1565], CYP3A4 [HSA:1576] map07027 Antidepressants Therapeutic category of ...ANTIDEPRESSANTS N06AX Other antidepressants N06AX11 Mirtazapine D00563 Mirtazapine (JAN/USAN/INN) USP drug c...lassification [BR:br08302] Antidepressants Antidepressants, Other Mirtazapine D00563 Mirtazapine (JAN/USAN/I

  20. 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.

  1. 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.

  2. 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

  3. 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.

  4. Mechanisms of antidepressant resistance

    Science.gov (United States)

    El-Hage, Wissam; Leman, Samuel; Camus, Vincent; Belzung, Catherine

    2013-01-01

    Depression is one of the most frequent and severe mental disorder. Since the discovery of antidepressant (AD) 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 (MDD). However, there is a wide range of variability in response to ADs that might lead to non response or partial response or in increased rate of relapse or recurrence. The mechanisms of response to AD 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 (BBB) 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. PMID:24319431

  5. [Drug design ideas and methods of Chinese herb prescriptions].

    Science.gov (United States)

    Ren, Jun-guo; Liu, Jian-xun

    2015-09-01

    The new drug of Chinese herbal prescription, which is the best carrier for the syndrome differentiation and treatment of Chinese medicine and is the main form of the new drug research and development, plays a very important role in the new drug research and development. Although there are many sources of the prescriptions, whether it can become a new drug, the necessity, rationality and science of the prescriptions are the key to develop the new drug. In this article, aiming at the key issues in prescriptions design, the source, classification, composition design of new drug of Chinese herbal prescriptions are discussed, and provide a useful reference for research and development of new drugs.

  6. Structure-based drug design and modern medicine

    Directory of Open Access Journals (Sweden)

    Vijayakrishnan R

    2009-01-01

    Full Text Available Drug discovery has evolved through various stages into more rational and evidence-based drug designing. Compared to conventional methods which were time consuming and less logical, new drug designing based on structure is rational, evidence based, faster and more scientific in nature. In the era of modern medicine, where newer insights into molecular level of disease processes are available, it is very essential that drug designing be based on molecular mechanism of pathologic processes. Structure-based drug designing has made tremendous contributions in the field of cancer chemotherapy, drug resistant infections, neurological diseases, to mention a few. New drug discovery methods are furthered by developments in the technology especially computers, bioassay techniques and calibrated instruments. Computational structure-based drug designing opens the door to novel treatments in modern medicine.

  7. 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

  8. Drug: D08670 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08670 Drug Venlafaxine (INN); Efectin (TN) C17H27NO2 277.2042 277.4018 D08670.gif Antidepress...marker: CYP2D6 [HSA:1565] CYP inhibition: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurotransmitt... N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX16 Ve...nlafaxine D08670 Venlafaxine (INN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selecti

  9. Drug: D00394 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00394 Drug Trimipramine (USAN/INN) C20H26N2 294.2096 294.4338 D00394.gif Antidepress...ant ATC code: N06AA06 Tricyclic antidepressants noradrenalin transporter inhibitor [HSA:6530] [KO:K05035];...HSA:1565] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 ...06AA06 Trimipramine D00394 Trimipramine (USAN/INN) USP drug classification [BR:br08302] Antidepress

  10. Drug: D07880 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07880 Drug Duloxetine (INN); Yentreve (TN) C18H19NOS 297.1187 297.4146 D07880.gif Antidepress...A:1544], CYP2D6 [HSA:1565] CYP inhibition: CYP2D6 [HSA:1565] map07027 Antidepress...BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX21 D...uloxetine D07880 Duloxetine (INN) USP drug classification [BR:br08302] Antidepress

  11. Drug: D07793 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07793 Drug Desvenlafaxine (INN) C16H25NO2 263.1885 263.3752 D07793.gif Antidepress...ynapse CYP inhibition: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurot...S SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX23 Desvenlafaxine D07793... Desvenlafaxine (INN) USP drug classification [BR:br08302] Antidepressants SSRIs/

  12. Drug: D07448 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07448 Drug Amitriptyline (INN); Laroxyl (TN) C20H23N 277.1831 277.4033 D07448.gif Antidepress...ant, tricyclic Same as: C06824 ATC code: N06AA09 Tricyclic antidepressants serotonin transporter ...44], CYP3A4 [HSA:1576] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants map07048 Antimigraines ...USP drug classification [BR:br08302] Antidepressants Tricyclics Amitriptyline D07448 Amitriptyline (INN) Tar

  13. Drug: D07727 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07727 Drug Clomipramine (INN); Anafranil (TN) C19H23ClN2 314.155 314.8523 D07727.gif Antidepress...ant, tricyclic Same as: C06918 ATC code: N06AA04 Tricyclic antidepressants serotonin norepinep...YP inhibition: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurotransmitter transporter inhibitors A...amine D07727 Clomipramine (INN) USP drug classification [BR:br08302] Antidepressants Tricyclics Clomipramine

  14. Drug: D08288 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08288 Drug Nortriptyline (INN); Nortrilen (TN) C19H21N 263.1674 263.3767 D08288.gif Antidepress...ant, tricyclic Same as: C07274 ATC code: N06AA10 Tricyclic antidepressants serotonin transporte... Serotonergic synapse Enzyme: CYP2D6 [HSA:1565] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepress... D08288 Nortriptyline (INN) USP drug classification [BR:br08302] Antidepressants Tricyclics Nortriptyline D0

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

    NARCIS (Netherlands)

    Bockting, Claudi L H; Elgersma, Hermien J; van Rijsbergen, Gerard D; de Jonge, Peter; Ormel, Johan; Buskens, Erik; Stant, A Dennis; de Jong, Peter J; Peeters, Frenk P M L; Huibers, Marcus J H; Arntz, Arnoud; Muris, Peter; Nolen, Willem A; Schene, Aart H; Hollon, Steven D

    2011-01-01

    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

  16. SSRI antidepressants: altered psychomotor development following exposure in utero?

    Science.gov (United States)

    2013-02-01

    Selective serotonin reuptake inhibitor antidepressants (SSRIs) are sometimes prescribed to pregnant women. The potential consequences for the unborn child are gradually becoming clearer. In a case-control study of 298 children with autism and 1507 controls, 6.7% of mothers of autistic children had been prescribed an antidepressant during the year before delivery, compared to 3.3% of control mothers. The antidepressant was usually an SSRI. A dozen other small epidemiological studies of neurological development in children exposed to antidepressants in utero have provided mixed results. Two of these studies suggested a risk of psychomotor retardation. In practice, SSRI antidepressants should only be considered for pregnant women when non-drug measures fail and when symptoms are sufficiently serious to warrant drug therapy.

  17. Drug: D00812 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 55 302.8416 D00812.gif Antidepressant ATC code: N06AA01 Tricyclic antidepressants serotonin transporter inhi...1565] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neur...01 Desipramine D00812 Desipramine hydrochloride (JAN/USP) USP drug classification [BR:br08302] Antidepress

  18. Drug: D00815 [KEGG MEDICUS

    Lifescience Database Archive (English)

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

  19. Drug: D02408 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 06 410.506 D02408.gif Antidepressant Same as: C14029 Therapeutic category: 1174 ATC code: N06AA06 Tricyclic antidepress...5] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurotransmitter transporter inhib...6AA06 Trimipramine D02408 Trimipramine maleate (JAN/USAN) USP drug classification [BR:br08302] Antidepress

  20. Drug: D08472 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08472 Drug Reboxetine (INN); Edronax (TN) C19H23NO3 313.1678 313.3908 D08472.gif Antidepress...hibitor [HSA:6530] [KO:K05035] map07027 Antidepressants map07234 Neurotransmitter transporter inhibitors Ana...06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX18 Reboxetine D08472 Reboxetine (I

  1. Drug: D07872 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07872 Drug Dosulepin (INN); Dothiepin; Dothep (TN) C19H21NS 295.1395 295.4417 D07872.gif Antidepress...ant, trycyclic ATC code: N06AA16 Tricyclic antidepressants serotonin transporter inhibitor... [HSA:6532] [KO:K05037]; noradrenalin transporter inhibitor [HSA:6530] [KO:K05035] map07027 Antidepressants

  2. 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...

  3. 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...

  4. 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.

  5. Musical Hallucinations And Antidepressants: Case Report Involving Serotoninergic Ways

    OpenAIRE

    1998-01-01

    A case of musical hallucination (MII) triggered by different antidepressive drugs is described. This is an uncommon side effect, probably more related to individual factors than to high doses. Musical hallucinations seems to be a releasing phenomenon, associated to sensorial deficit and neuronal compensatory activation. The present case report suggests that not only classical tricyclic antidepressives (AD) can cause MH, but also more selective drugs such as the SSRIs and venlafaxine. Aminedip...

  6. Poisoining with Tricyclic Antidepressants and Current Treatment

    Directory of Open Access Journals (Sweden)

    Muge Gulen

    2016-12-01

    Full Text Available Poisoning with tricyclic antidepressants is one of the main causes of morbidity and mortality compared to all the antidepressants. Main toxic effects are on the cardiovascular system and central nervous system and manifests itself as anticholinergic symptoms. There is no antidote known to be used in the treatment. But sodium bicarbonate treatment is effective in preventing ventricular arrhythmias and hypotension, and resolving metabolic acidosis. There are some treatments that has been used for relief of symptoms and some of them still are in research stage. The drugs that are used can be customized according to the patients symptoms. [Archives Medical Review Journal 2016; 25(4.000: 608-621

  7. 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.

  8. Antidepressants: Safe during Pregnancy?

    Science.gov (United States)

    ... you need to know about antidepressants and pregnancy. Pregnancy hormones were once thought to protect women from depression, but researchers now say this isn't true. In addition, pregnancy can trigger a range of emotions that make ...

  9. An Educational Design To Teach Drug Information Across the Curriculum.

    Science.gov (United States)

    Gora-Harper, Mary Lea; Brandt, Barbara F.

    1997-01-01

    Describes design and implementation of a model for teaching drug information across the pharmacy curriculum. Program components include teaching/reinforcing drug information knowledge and skills; outlining practice-based outcomes for drug information; and impressing on students that such skills are routinely needed in pharmacy practice. Early…

  10. 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.

  11. 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.

  12. Organic carbamates in drug design and medicinal chemistry.

    Science.gov (United States)

    Ghosh, Arun K; Brindisi, Margherita

    2015-04-09

    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.

  13. 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.

  14. "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.

  15. Drug: D00821 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 809 313.8627 D00821.gif Antidepressant ATC code: N06AX16 selective serotonin norepinephrine reuptake inhibit...omic biomarker: CYP2D6 [HSA:1565] CYP inhibition: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurot...S SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N0...6AX16 Venlafaxine D00821 Venlafaxine hydrochloride (JAN/USAN) USP drug classification [BR:br08302] Antidepress

  16. 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....

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

    Energy Technology Data Exchange (ETDEWEB)

    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.

    2016-02-17

    A wide range of length and time scales are relevant to pharmacology, especially in drug development, drug design and drug delivery. Therefore, multi-scale computational modeling and simulation methods and paradigms that advance the linkage of phenomena occurring at these multiple scales have become increasingly important. Multi-scale 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 multi-scale modeling in drug design and development. We demonstrate the impact of multiple scales of modeling in this field. We indicate the common mathematical techniques employed for multi-scale modeling approaches used in pharmacology and present several examples illustrating the current state-of-the-art regarding drug development for: Excitable Systems (Heart); Cancer (Metastasis and Differentiation); Cancer (Angiogenesis and Drug Targeting); Metabolic Disorders; and Inflammation and Sepsis. We conclude with a focus on barriers to successful clinical translation of drug development, drug design and drug delivery multi-scale models.

  18. Target based drug design - a reality in virtual sphere.

    Science.gov (United States)

    Verma, Saroj; Prabhakar, Yenamandra S

    2015-01-01

    The target based drug design approaches are a series of computational procedures, including visualization tools, to support the decision systems of drug design/discovery process. In the essence of biological targets shaping the potential lead/drug molecules, this review presents a comprehensive position of different components of target based drug design which include target identification, protein modeling, molecular dynamics simulations, binding/catalytic sites identification, docking, virtual screening, fragment based strategies, substructure treatment of targets in tackling drug resistance, in silico ADMET, structural vaccinology, etc along with the key issues involved therein and some well investigated case studies. The concepts and working of these procedures are critically discussed to arouse interest and to advance the drug research.

  19. 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.

  20. 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

  1. 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.

  2. 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.

  3. [Depression and treatment. Apoptosis, neuroplasticity and antidepressants].

    Science.gov (United States)

    Arantes-Gonçalves, Filipe; Coelho, Rui

    2006-01-01

    Depression's neurobiology begins to be better understood. The last decade data considers neuroplasticity and stress as implicated factors on the pathophisiology of depression. Because antidepressants have a lag-time on their action it is possible that inhibition of neurotransmitters recaptation is not sufficient to explain long term changes. For that purpose, neurogenesis increase, nervous fibers sprouting, new synapses and stabilization of the old ones can be responsible for those changes. AMPc-MAPcinases-CREB-BDNF cellular cascade can play a significant role in the mechanisms of dendritic restructuration, hippocampal neurogenesis increase and nervous cells survival. The aim of this article is to discuss if apoptosis could play a key role as an ethiopathogenic factor on the patogenesis of depression. It was done a medline search for references with apoptosis, stress, neuroplasticity, depression and antidepressants key-words. It were found 101 original or review references about these subjects. Stress plays a key role in the etiopathogeny of depression. Its deletery effects on apoptosis and neuroplasticity can be changed by antidepressants. Neurogenesis' increase is necessary for their action. This increase is reached with chronic antidepressant treatment and not with other psychotropic drugs which means some pharmacological specificity of antidepressants. AMPc, CREB, BDNF and Bcl-2 can be considered as target genes in antidepressant synthesis. At the level of this neurotrophic factors apoptosis might be included in the neuroplastic model of depression and play a prominent role in etiopathogeny of depression. To confirm that, we need more research on the field to know which are the mechanisms that trigger apoptosis and its biological significance. In relation to the last one, we can say that is possible to be physiological apoptosis in deteriorated neurons death which cannot make strong connections and pathological apoptosis because of stress via, namely, HPA axis.

  4. Structure-based drug design to overcome drug resistance: challenges and opportunities.

    Science.gov (United States)

    Ferreira, Rafaela S; Andricopulo, Adriano D

    2014-01-01

    Drug resistance is a common concern for the development of novel antiviral, antimicrobial and anticancer therapies. To overcome this problem, several strategies have been developed, many of which involving the theme of this review, the use of structure-based drug design (SBDD) approaches. These include the successful design of new compounds that target resistant mutant proteins, as well as the development of drugs that target multiple proteins involved in specific biochemical pathways. Finally, drug resistance can also be considered in the early stages of drug discovery, through the use of strategies to delay the development of resistance. The purpose of this brief review is to underline the usefulness of SBDD approaches based on case studies, highlighting present challenges and opportunities in drug design.

  5. 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

  6. Hemozoin Formation as a Target for Antimalarial Drug Design

    Science.gov (United States)

    2005-02-01

    AD Award Number: DAMD17-03-1-0030 TITLE: Hemozoin Formation as a Target for Antimalarial Drug Design PRINCIPAL INVESTIGATOR: Michael K. Riscoe, Ph.D...Formation as a Target for Antimalarial Drug Design DAMD17-03-1-0030 6. A UTHOR(S) Michael K. Riscoe, Ph.D. 7. PERFORMING ORGANIZA TION NAME(S) AND ADDRESS...Report: by Principal Investigator - Michael K. Riscoe, Ph.D. DAMD1 7-03-1-0030: "Hemozoin Formation as a Target for Antimalarial Drug Design " INTRODUCTION

  7. Drug: D00505 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00505 Drug Phenelzine sulfate (USP); Nardil (TN) C8H12N2. H2SO4 234.0674 234.2728 D00505.gif Antidepress...129) Dopaminergic synapse map07027 Antidepressants map07216 Catecholamine transfe... Phenelzine sulfate (USP) USP drug classification [BR:br08302] Antidepressants Mo

  8. Drug: D08349 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08349 Drug Phenelzine (BAN) C8H12N2 136.1 136.1943 D08349.gif Antidepressant, MAO-... metabolism - cytochrome P450 hsa04726(4128+4129) Serotonergic synapse hsa04728(4128+4129) Dopaminergic synapse map07027 Antidepress...drug classification [BR:br08302] Antidepressants Monoamine Oxidase Inhibitors Phe

  9. Drug: D08625 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08625 Drug Tranylcypromine (INN); Parnate (TN) C9H11N 133.0891 133.1903 D08625.gif Antidepress...29) Dopaminergic synapse map07027 Antidepressants map07216 Catecholamine transfer...8625 Tranylcypromine (INN) USP drug classification [BR:br08302] Antidepressants M

  10. Drug Guru: a computer software program for drug design using medicinal chemistry rules.

    Science.gov (United States)

    Stewart, Kent D; Shiroda, Melisa; James, Craig A

    2006-10-15

    Drug Guru (drug generation using rules) is a new web-based computer software program for medicinal chemists that applies a set of transformations, that is, rules, to an input structure. The transformations correspond to medicinal chemistry design rules-of-thumb taken from the historical lore of drug discovery programs. The output of the program is a list of target analogs that can be evaluated for possible future synthesis. A discussion of the features of the program is followed by an example of the software applied to sildenafil (Viagra) in generating ideas for target analogs for phosphodiesterase inhibition. Comparison with other computer-assisted drug design software is given.

  11. 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

  12. Interactive evolutionary algorithms and data mining for drug design

    NARCIS (Netherlands)

    Lameijer, Eric Marcel Wubbo

    2010-01-01

    One of the main problems of drug design is that it is quite hard to discover compounds that have all the required properties to become a drug (efficacy against the disease, good biological availability, low toxicity). This thesis describes the use of data mining and interactive evolutionary algorith

  13. 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.

  14. 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...

  15. Increased use of antidepressants at the end of life

    DEFF Research Database (Denmark)

    Hansen, Dorte Gilså; Rosholm, Jens-Ulrik; Gichangi, Anthony

    2007-01-01

    BACKGROUND: The new antidepressants are generally effective and safe for older people, but may have serious side-effects. The use has been rapidly increasing, but focus on upper age groups has been limited. The pattern of antidepressant use as death approaches has never been analysed. OBJECTIVE......: To analyse the use of antidepressants among individuals aged 65 years and above with respect to time trends, age and proximity to death. DESIGN: Population-based prescription study. SETTING: The County of Funen, Denmark, 1992-2004 (approximately 470,000 inhabitants). RESULTS: The 1-year prevalence...... groups the use of antidepressants increases substantially with proximity to death in the last 3 years of life. In the last phase of life the use is independent of whether the patient dies at age 65 or 90 about 33% of females and 25% of males receive antidepressants in the last 6 months. CONCLUSIONS...

  16. 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.

  17. Interactive evolutionary algorithms and data mining for drug design

    OpenAIRE

    Lameijer, Eric Marcel Wubbo

    2010-01-01

    One of the main problems of drug design is that it is quite hard to discover compounds that have all the required properties to become a drug (efficacy against the disease, good biological availability, low toxicity). This thesis describes the use of data mining and interactive evolutionary algorithms to design novel classes of molecules. Using data mining, we split a 250,000 compound database into ring systems, substituents and linkers. We then counted the occurrence of the different fragmen...

  18. Evidence for shortening the duration of clinical trials of antidepressants and a proposed paradigm for such studies.

    Science.gov (United States)

    Katz, Martin M; Berman, Nancy; Bowden, Charles L; Frazer, Alan

    2015-06-01

    The model for the clinical trial of putative antidepressants is older than 50 years. Recent failures resulted in several drug companies, citing excessive costs of lengthy multiweek trials, abandoning new drug development. Collateral problems include patients being maintained on ineffective drugs for 6 to 8 weeks, increasing the pain associated with the disorder. This study proposes an alternative model for testing new drugs that both shortens the clinical trial and broadens its aims to include a profile of the new drug's specific clinical actions. This alternative model makes it possible to uncover the drug's application to treatment of other mental disorders. It is based on recent findings that onset of action and a large proportion of an effective drug's positive effects, contrary to early reports, occur within the first 2 weeks. It uses an index of the 2-week "early improvement" to predict a 6-week outcome. Measuring effects on the dimensions of the disorder determined that effective antidepressants act on mood and behavioral components and that the Hamilton and new "multivantaged" methods can provide a profile of specific drug actions distinguished from nonspecific placebo effects, at 2 weeks. This early improvement is predictive of positive outcome of 6-week trials. Because of the implications of successful 2-week trials for reducing costs, providing data on specific clinical drug actions, potentially stimulating new drug development, and reducing patient suffering from extended treatment with ineffective drugs, a large sample, prospective study designed in accord with this test trial is recommended.

  19. Editorial: in silico drug design and medicinal chemistry).

    Science.gov (United States)

    Singla, Rajeev K

    2015-01-01

    Medicinal chemistry is not limited to molecules, their structures and design but also highly cohesive to pharmacological activities. The potency of a molecule varies by its structure. Hence structural activity relationship is the sub-branch which deals with the estimation of ability of a molecule in depicting any pharmacological activity. In silico drug design is a novel technique which is employed in designing a molecule by using computer aided software’s and bringing a superior and potent molecule. In recent years, in silico drug design has been merged with medicinal chemistry especially by the techniques like ligand based strategy to isolate the required structures. By such strategic techniques, there are high chances of delivering high throughput screening which involves of screening large number of molecules in a very less time. Involvement of such techniques would be a boon for development of new drug entity as it can aid in development of newer, safe, effective and potent drug molecules. Hence, the present issue is aimed to emphasize the cohesion between in silico drug design and it significance in medicinal chemistry. The articles which would be published will mainly focus on the role of in silico drug design techniques in the development of molecules to target various disease and disorders. Molecules can from natural/ synthetic/semi synthetic origin. Articles will be a treasure box consisting of employment of computational methods for unprecedented molecules. The issue will be sure an endorsement for international readership and researchers.

  20. 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...

  1. PARP1 Inhibitors: antitumor drug design.

    Science.gov (United States)

    Malyuchenko, N V; Kotova, E Yu; Kulaeva, O I; Kirpichnikov, M P; Studitskiy, V M

    2015-01-01

    The poly (ADP-ribose) polymerase 1 (PARP1) enzyme is one of the promising molecular targets for the discovery of antitumor drugs. PARP1 is a common nuclear protein (1-2 million molecules per cell) serving as a "sensor" for DNA strand breaks. Increased PARP1 expression is sometimes observed in melanomas, breast cancer, lung cancer, and other neoplastic diseases. The PARP1 expression level is a prognostic indicator and is associated with a poor survival prognosis. There is evidence that high PARP1 expression and treatment-resistance of tumors are correlated. PARP1 inhibitors are promising antitumor agents, since they act as chemo- and radiosensitizers in the conventional therapy of malignant tumors. Furthermore, PARP1 inhibitors can be used as independent, effective drugs against tumors with broken DNA repair mechanisms. Currently, third-generation PARP1 inhibitors are being developed, many of which are undergoing Phase II clinical trials. In this review, we focus on the properties and features of the PARP1 inhibitors identified in preclinical and clinical trials. We also describe some problems associated with the application of PARP1 inhibitors. The possibility of developing new PARP1 inhibitors aimed at DNA binding and transcriptional activity rather than the catalytic domain of the protein is discussed.

  2. Membrane-Protein Crystallography and Potentiality for Drug Design

    Science.gov (United States)

    Yamashita, Atsuko

    Structure-based drug design for membrane proteins is far behind that for soluble proteins due to difficulty in crystallographic structure determination, despite the fact that about 60% of FDA-approved drugs target membrane proteins located at the cell surface. Stable homologs for a membrane protein of interest, such as prokaryotic neurotransmitter transporter homolog LeuT, might enable cooperative analyses by crystallography and functional assays, provide useful information for functional mechanisms, and thus serve as important probes for drug design based on mechanisms as well as structures.

  3. The mechanism of action of antidepressants revised.

    Science.gov (United States)

    Ackenheil, M

    1990-01-01

    The discovery of the clinical efficacy of imipramine and of the MAO-inhibitor iproniazid intensively stimulated biochemical-pharmacological research on the mechanism of action of antidepressants. Due to these investigations, until recently an enhanced activity of the central noradrenergic and/or serotonergic transmitter system was considered essential for the clinical antidepressive action. Such enhancement could be achieved either presynaptically by blocking alpha 2-adrenergic receptors, or in the synaptic cleft by inhibiting the transmitter reuptake or the main metabolic enzyme, MAO. The common final result, especially of chronic treatment, was the down-regulation of postsynaptic beta-receptors, modulated by interaction with the serotonergic system, neuropeptides, and hormones. The delay of clinical response corresponded better with such receptor alterations. However, the introduction of new, more selective antidepressants led to new reflections upon the mechanism of action. On the level of transmitters, alpha 1-upregulation, increased activity of the dopaminergic system, an alteration in the balance between the different transmitter systems, are reported and seem to be important. Most promising are recent investigations of the second messenger systems, the adenylate cyclase system and the phosphatidylinositol system. Both systems are modulated by antidepressant drugs including lithium and carbamazepine. These second messengers, in turn, modulate the phosphorylation status of neuronal proteins via protein kinase, which may lead to elevations of the above mentioned receptors and again their transduction systems.

  4. 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.

  5. Evaluating the tolerability of the newer antidepressants.

    Science.gov (United States)

    Dewan, M J; Anand, V S

    1999-02-01

    Given their equal efficacy, the choice of a specific antidepressant is largely influenced by side effect (SE) profiles. A number of new agents have recently become available. However, data directly comparing the side effects of these agents are scarce. As suggested by AHCPR guidelines, we used the 1998 Physicians' Desk Reference (PDR) to construct a comparison table using treatment emergent, placebo-adjusted incidence rates for the major (gastrointestinal, central nervous system, and sexual) side effects caused by nine antidepressants (fluoxetine, paroxetine, sertraline, fluvoxamine, nefazodone, bupropion SR, mirtazapine, venlafaxine XR, and citalopram). The results were tabulated to show the relative propensity of each drug to cause a particular side effect. Bupropion SR had the most favorable overall side-effect profile, and fluvoxamine the least favorable. However, there are several limitations in using the PDR to compare the newer antidepressants. Clinical studies directly comparing SEs of newer antidepressants are needed. Sexual SEs substantially affected total SE liability. A simplified summary table, with its advantages and some limitations, is not simple to construct. Pitfalls in this process are discussed.

  6. Drug: D07791 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07791 Drug Desipramine (INN) C18H22N2 266.1783 266.3807 D07791.gif Antidepressant,... tricyclic Same as: C06943 ATC code: N06AA01 Tricyclic antidepressants serotonin transporter inhibitor [HSA:...ic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurotransmitte...ine D07791 Desipramine (INN) USP drug classification [BR:br08302] Antidepressants

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. [Computational chemistry in structure-based drug design].

    Science.gov (United States)

    Cao, Ran; Li, Wei; Sun, Han-Zi; Zhou, Yu; Huang, Niu

    2013-07-01

    Today, the understanding of the sequence and structure of biologically relevant targets is growing rapidly and researchers from many disciplines, physics and computational science in particular, are making significant contributions to modern biology and drug discovery. However, it remains challenging to rationally design small molecular ligands with desired biological characteristics based on the structural information of the drug targets, which demands more accurate calculation of ligand binding free-energy. With the rapid advances in computer power and extensive efforts in algorithm development, physics-based computational chemistry approaches have played more important roles in structure-based drug design. Here we reviewed the newly developed computational chemistry methods in structure-based drug design as well as the elegant applications, including binding-site druggability assessment, large scale virtual screening of chemical database, and lead compound optimization. Importantly, here we address the current bottlenecks and propose practical solutions.

  12. 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.

  13. 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

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

    Science.gov (United States)

    Ioannidis, John P A

    2008-05-27

    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 reporting of results has built

  15. Design of an Implantable Device for Ocular Drug Delivery

    Directory of Open Access Journals (Sweden)

    Jae-Hwan Lee

    2012-01-01

    Full Text Available Ocular diseases, such as, glaucoma, age-related macular degeneration (AMD, diabetic retinopathy, and retinitis pigmentosa require drug management in order to prevent blindness and affecting million of adults in USA and worldwide. There is an increasing need to develop devices for drug delivery to address ocular diseases. This study focuses on the design, simulation, and development of an implantable ocular drug delivery device consisting of micro-/nanochannels embedded between top and bottom covers with a drug reservoir made from polydimethylsiloxane (PDMS which is silicon-based organic and biodegradable polymer. Several simulations were carried out with six different micro-channel configurations in order to see the feasibility for ocular drug delivery applications. Based on the results obtained, channel design of osmotic I and osmotic II satisfied the diffusion rates required for ocular drug delivery. Finally, a prototype illustrating the three components of the drug delivery design is presented. In the future, the device will be tested for its functionality and diffusion characteristics.

  16. Physics and Its Interfaces with Medicinal Chemistry and Drug Design

    Science.gov (United States)

    Santos, Ricardo N.; Andricopulo, Adriano D.

    2013-08-01

    Medicinal chemistry is a multidisciplinary subject that integrates knowledge from a variety of fields of science, including, but not limited to, chemistry, biology, and physics. The area of drug design involves the cooperative work of scientists with a diverse range of backgrounds and technical skills, trying to tackle complex problems using an integration of approaches and methods. One important contribution to this field comes from physics through studies that attempt to identify and quantify the molecular interactions between small molecules (drugs) and biological targets (receptors), such as the forces that govern the interactions, the thermodynamics of the drug-receptor interactions, and so on. In this context, the interfaces of physics, medicinal chemistry, and drug design are of vital importance for the development of drugs that not only have the right chemistry but also the right intermolecular properties to interact at the macromolecular level, providing useful information about the principles and molecular mechanisms underlying the therapeutic action of drugs. This article highlights some of the most important connections between physics and medicinal chemistry in the design of new drugs.

  17. Clonidine as a sensitizing agent in the forced swimming test for revealing antidepressant activity.

    OpenAIRE

    1991-01-01

    The forced swimming test (FST) in mice has failed to predict antidepressant activity for drugs having beta adrenoreceptor agonist activity and for serotonin uptake inhibitors. We investigated the potential for clonidine to render the FST sensitive to antidepressants by using a behaviorally inactive dose of this agent (0.1 mg/kg). All antidepressants studied (tricyclics, 5-HT uptake inhibitors, iprindole, mianserin, viloxazine, trazodone) showed either activity at lower doses or activity at pr...

  18. 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...

  19. Effect of educational outreach on general practice prescribing of antibiotics and antidepressants: A two-year randomised controlled trial

    Science.gov (United States)

    Enriquez-puga, Andres; Baker, Richard; Paul, Sanjoy; Villoro-Valdes, Renata

    2009-01-01

    Objective Prescribing of broad spectrum antibiotics and antidepressants in general practice often does not accord with guidelines. The aim was to determine the effectiveness of educational outreach in improving the prescribing of selected antibiotics and antidepressants, and whether the effect is sustained for two years. Design Single blind randomized trial. Setting Twenty-eight general practices in Leicestershire, England. Intervention Educational outreach visits were undertaken, tailored to barriers to change, 14 practices receiving visits for reducing selected antibiotics and 14 for improving antidepressant prescribing. Main outcome measures Number of items prescribed per 1000 registered patients for amoxicillin with clavulanic acid (co-amoxiclav) and quinolone antibiotics, and average daily quantities per 1000 patients for lofepramine and fluoxetine antidepressants, measured at the practice level for six-month periods over two years. Results There was no effect on the prescribing of co-amoxiclav, quinolones, or fluoxetine, but prescribing of lofepramine increased in accordance with the guidelines. The increase persisted throughout two years of follow-up. Conclusion A simple, group-level educational outreach intervention, designed to take account of identified barriers to change, can have a modest but sustained effect on prescribing levels. However, outreach is not always effective. The context in which change in prescribing practice is being sought, the views of prescribers concerning the value of the drug, or other unrecognised barriers to change may influence the effectiveness of outreach. PMID:19958063

  20. Voluntary exercise produces antidepressant and anxiolytic behavioral effects in mice.

    Science.gov (United States)

    Duman, Catharine H; Schlesinger, Lee; Russell, David S; Duman, Ronald S

    2008-03-14

    Reports of beneficial effects of exercise on psychological health in humans are increasingly supported by basic research studies. Exercise is hypothesized to regulate antidepressant-related mechanisms and we therefore characterized the effects of chronic exercise in mouse behavioral paradigms relevant to antidepressant actions. Mice given free access to running wheels showed antidepressant-like behavior in learned helplessness, forced-swim (FST) and tail suspension paradigms. These responses were similar to responses of antidepressant drug-treated animals. When tested under conditions where locomotor activity was not altered, exercising mice also showed reduced anxiety compared to sedentary control mice. In situ hybridization analysis showed that BDNF mRNA was increased in specific subfields of hippocampus after wheel running. We chose one paradigm, the FST, in which to investigate a functional role for brain-derived neurotrophic factor (BDNF) in the behavioral response to exercise. We tested mice heterozygous for a deletion of the BDNF gene in the FST after wheel-running. Exercising wild-type mice showed the expected antidepressant-like behavioral response in the FST but exercise was ineffective in improving FST performance in heterozygous BDNF knockout mice. A possible functional contribution of a BDNF signaling pathway to FST performance in exercising mice was investigated using the specific MEK inhibitor PD184161 to block the MAPK signaling pathway. Subchronic administration of PD184161 to exercising mice blocked the antidepressant-like behavioral response seen in vehicle-treated exercising mice in the FST. In summary, chronic wheel-running exercise in mice results in antidepressant-like behavioral changes that may involve a BDNF related mechanism similar to that hypothesized for antidepressant drug treatment.

  1. 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

  2. A Bright Future for Evolutionary Methods in Drug Design.

    Science.gov (United States)

    Le, Tu C; Winkler, David A

    2015-08-01

    Most medicinal chemists understand that chemical space is extremely large, essentially infinite. Although high-throughput experimental methods allow exploration of drug-like space more rapidly, they are still insufficient to fully exploit the opportunities that such large chemical space offers. Evolutionary methods can synergistically blend automated synthesis and characterization methods with computational design to identify promising regions of chemical space more efficiently. We describe how evolutionary methods are implemented, and provide examples of published drug development research in which these methods have generated molecules with increased efficacy. We anticipate that evolutionary methods will play an important role in future drug discovery.

  3. Choice of treatment with antidepressants: influencing factors.

    Science.gov (United States)

    Himmerich, Hubertus; Wranik, Dominika W

    2012-01-01

    Depressive disorders place a large burden on patients and on society. Although efficacious treatment options for unipolar depressive disorders exist, substantial gaps in care remain. In part, the challenge lies in the matching of individual patients with appropriate care. This is complicated by the steady increases in the variety of antidepressants available in the market. The goal of this study is to highlight the decision processes in the selection of antidepressants by clinicians, given that most treatments have similar clinical effectiveness profiles. We conducted a systematic literature review of studies that referred to the decisions surrounding treatment with antidepressants for the treatment of non-psychotic unipolar depression. Our analysis of the literature reveals that the choice of treatment is based on a variety of factors, of which clinical evidence is only one. These factors can be categorized into clinical factors such as illness and treatment characteristics, individual factors such as patient and physician characteristics, and contextual factors such as setting characteristics, decision supports and pharmacoeconomic aspects. Illness characteristics are defined by the type and severity of depression. Treatment characteristics include drug properties, efficacy, effectiveness and favorable as well as unintended adverse effects of the drug. Examples for patient characteristics are co-morbidities and individual preferences, and physician characteristics include knowledge, experience, values and beliefs, and the relationship with the patient. Treatment guidelines, algorithms, and most recently, computational supports and biological markers serve as decision supports.

  4. 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 designation. 316.30 Section 316.30 Food and Drugs FOOD AND DRUG ADMINISTRATION, DEPARTMENT OF HEALTH AND HUMAN... of holder of orphan-drug designation. Within 14 months after the date on which a drug was...

  5. Modulation of attention network activation under antidepressant agents in healthy subjects.

    Science.gov (United States)

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

    2013-07-01

    While antidepressants are supposed to exert similar effects on mood and drive via various mechanisms of action, diverging effects are observed regarding side-effects and accordingly on neural correlates of motivation, emotion, reward and salient stimuli processing as a function of the drugs impact on neurotransmission. In the context of erotic stimulation, a unidirectional modulation of attentional functioning despite opposite effects on sexual arousal has been suggested for the selective serotonin reuptake-inhibitor (SSRI) paroxetine and the selective dopamine and noradrenaline reuptake-inhibitor (SDNRI) bupropion. To further elucidate the effects of antidepressant-related alterations of neural attention networks, we investigated 18 healthy males under subchronic administration (7 d) of paroxetine (20 mg), bupropion (150 mg) and placebo within a randomized placebo-controlled cross-over double-blind functional magnetic resonance imaging (fMRI) design during an established preceding attention task. Neuropsychological effects beyond the fMRI-paradigm were assessed by measuring alertness and divided attention. Comparing preceding attention periods of salient vs. neutral pictures, we revealed congruent effects of both drugs vs. placebo within the anterior midcingulate cortex, dorsolateral prefrontal cortex, anterior prefrontal cortex, superior temporal gyrus, anterior insula and the thalamus. Relatively decreased activation in this network was paralleled by slower reaction times in the divided attention task in both verum conditions compared to placebo. Our results suggest similar effects of antidepressant treatments on behavioural and neural attentional functioning by diverging neurochemical pathways. Concurrent alterations of brain regions within a fronto-parietal and cingulo-opercular attention network for top-down control could point to basic neural mechanisms of antidepressant action irrespective of receptor profiles.

  6. 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.

  7. Drug: D00818 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 97 313.8643 D00818.gif Antidepressant Therapeutic category: 1179 ATC code: N06AA21 tetracyclic antidepressan...e: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurotransmitter transport...itors N06AA21 Maprotiline D00818 Maprotiline hydrochloride (JP16/USP) USP drug classification [BR:br08302] Antidepress

  8. Drug: D07339 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D07339 Drug Oxitriptan (INN); Levothym (TN) C11H12N2O3 220.0848 220.2246 D07339.gif Antidepress...r08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX01 Oxitr

  9. Drug: D02566 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ame as: C07107 ATC code: N06AA21 norepinephrine reuptake inhibitor Tetracyclic antidepressants noradrenalin ...transporter inhibitor [HSA:6530] [KO:K05035] Enzyme: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neu...ne reuptake inhibitors N06AA21 Maprotiline D02566 Maprotiline (USAN) USP drug classification [BR:br08302] Antidepress

  10. 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

  11. 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.

  12. Addressing metabolic activation as an integral component of drug design.

    Science.gov (United States)

    Doss, George A; Baillie, Thomas A

    2006-01-01

    Formation of reactive intermediates by metabolism of xenobiotics represents a potential liability in drug discovery and development. Although it is difficult, if not impossible, to predict toxicities of drug candidates accurately, it is prudent to try to minimize bioactivation liabilities as early as possible in the stage of drug discovery and lead optimization. Measurement of covalent binding to liver microsomal proteins in the presence and the absence of NADPH, as well as the use of trapping agents such as glutathione or cyanide ions to provide structural information on reactive intermediates, have been used routinely to screen drug candidates. These in vitro experiments are often supplemented with in vivo covalent binding data in rats. The resulting data are not only used to eliminate potentially risky compounds, but, more importantly, they provide invaluable information to direct the Medicinal Chemistry group efforts to design analogs with less propensity to undergo bioactivation. Select case histories are presented in which this approach was successfully applied at Merck.

  13. 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.

  14. The significance of chirality in drug design and development.

    Science.gov (United States)

    Brooks, W H; Guida, W C; Daniel, K G

    2011-01-01

    Proteins are often enantioselective towards their binding partners. When designing small molecules to interact with these targets, one should consider stereoselectivity. As considerations for exploring structure space evolve, chirality is increasingly important. Binding affinity for a chiral drug can differ for diastereomers and between enantiomers. For the virtual screening and computational design stage of drug development, this problem can be compounded by incomplete stereochemical information in structure libraries leading to a "coin toss" as to whether or not the "ideal" chiral structure is present. Creating every stereoisomer for each chiral compound in a structure library leads to an exponential increase in the number of structures resulting in potentially unmanageable file sizes and screening times. Therefore, only key chiral structures, enantiomeric pairs based on relative stereochemistry need be included, and lead to a compromise between exploration of chemical space and maintaining manageable libraries. In clinical environments, enantiomers of chiral drugs can have reduced, no, or even deleterious effects. This underscores the need to avoid mixtures of compounds and focus on chiral synthesis. Governmental regulations emphasizing the need to monitor chirality in drug development have increased. The United States Food and Drug Administration issued guidelines and policies in 1992 concerning the development of chiral compounds. These guidelines require that absolute stereochemistry be known for compounds with chiral centers and that this information should be established early in drug development in order that the analysis can be considered valid. From exploration of structure space to governmental regulations it is clear that the question of chirality in drug design is of vital importance.

  15. A Prospective Method to Guide Small Molecule Drug Design

    Science.gov (United States)

    Johnson, Alan T.

    2015-01-01

    At present, small molecule drug design follows a retrospective path when considering what analogs are to be made around a current hit or lead molecule with the focus often on identifying a compound with higher intrinsic potency. What this approach overlooks is the simultaneous need to also improve the physicochemical (PC) and pharmacokinetic (PK)…

  16. 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.…

  17. Pharmacology and clinical evaluation of the new antidepressant drug vilazodone%新型抗抑郁药维拉唑酮的药理与临床评价

    Institute of Scientific and Technical Information of China (English)

    王来海; 张瑞岭; 李焕芬

    2011-01-01

    Vilazodone, a new type of antidepressant, possesses dual mechanism of action. It was approved for the treatment of major depressive disorder by FDA in January 21, 2011. It is a selective serotonin (5-HT) re-uptake inhibitor and a partial 5-HT1A receptor agonist. The most common adverse reactions of vilazodone are diarrhea, nausea, vomiting and insomnia. The pharmacology, pharmacokinetics, clinical evaluation, safety and drug interactions of vilazodone were reviewed in this paper.%维拉唑酮为一种双重作用机制的新型抗抑郁药,即选择性5-羟色胺(5-HT)再摄取抑制剂和5-HT1A受体部分激动剂,2011年1月21日获得美国食品药品管理局(FDA)批准,用于成人重症抑郁症(major depressive disorder,MDD)的治疗.其常见不良反应包括腹泻、恶心、呕吐和失眠.文中对维拉唑酮的药理作用、药动学、临床评价、安全性以及药物相互作用等进行了综述.

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

    Science.gov (United States)

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

    2015-08-01

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

  19. 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.

  20. On p53 revival using system oriented drug dosage design.

    Science.gov (United States)

    Haseeb, Muhammad; Azam, Shumaila; Bhatti, A I; Azam, Rizwan; Ullah, Mukhtar; Fazal, Sahar

    2017-02-21

    We propose a new paradigm in the drug design for the revival of the p53 pathway in cancer cells. It is shown that the current strategy of using small molecule based Mdm2 inhibitors is not enough to adequately revive p53 in cancerous cells, especially when it comes to the extracting pulsating behavior of p53. This fact has come to notice when a novel method for the drug dosage design is introduced using system oriented concepts. As a test case, small molecule drug Mdm2 repressor Nutlin 3a is considered. The proposed method determines the dose of Nutlin to revive p53 pathway functionality. For this purpose, PBK dynamics of Nutlin have also been integrated with p53 pathway model. The p53 pathway is the focus of researchers for the last thirty years for its pivotal role as a frontline cancer suppressant protein due to its effect on cell cycle checkpoints and cell apoptosis in response to a DNA strand break. That is the reason for finding p53 being absent in more than 50% of tumor cancers. Various drugs have been proposed to revive p53 in cancer cells. Small molecule based drugs are at the foremost and are the subject of advanced clinical trials. The dosage design of these drugs is an important issue. We use control systems concepts to develop the drug dosage so that the cancer cells can be treated in appropriate time. We investigate by using a computational model how p53 protein responds to drug Nutlin 3a, an agent that interferes with the MDM2-mediated p53 regulation. The proposed integrated model describes in some detail the regulation network of p53 including the negative feedback loop mediated by MDM2 and the positive feedback loop mediated by Mdm2 mRNA as well as the reversible represses of MDM2 caused by Nutlin. The reported PBK dynamics of Nutlin 3a are also incorporated to see the full effect. It has been reported that p53 response to stresses in two ways. Either it has a sustained (constant) p53 response, or there are oscillations in p53 concentration. The

  1. Drug: D08673 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08673 Drug Viloxazine (INN) C13H19NO3 237.1365 237.2949 D08673.gif Antidepressant ...:6530] [KO:K05035]; serotonin transporter inhibitor [HSA:6532] [KO:K05037] hsa04726(6532) Serotonergic synapse map07027 Antidepress...[BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepressants N06AX09

  2. Drug: D02572 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available hsa04726(6532) Serotonergic synapse map07027 Antidepressants Anatomical Therapeu...tic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepress...73.7558 D02572.gif Antidepressant ATC code: N06AX09 serotonin norepinephrine reuptake inhibitor (SNRI) norad...D02572 Drug Viloxazine hydrochloride (USAN); Vivalan (TN) C13H19NO3. HCl 273.1132 2

  3. Drug: D00816 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 99.1441 299.8377 D00816.gif Antidepressant Therapeutic category: 1179 ATC code: N06AA10 norepinephrine reupt...ake inhibitor Tricyclic antidepressants serotonin transporter inhibitor [HSA:6532] [KO:K05037]; noradrenalin... Enzyme: CYP2D6 [HSA:1565] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants map07048 Antimigrai...ortriptyline hydrochloride (JP16/USP/INN) USP drug classification [BR:br08302] Antidepressants Tricyclics No

  4. Drug: D00811 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 50.1317 351.3133 D00811.gif Antidepressant Therapeutic category: 1174 ATC code: N06AA04 serotonin norepineph...rine reuptake inhibitor Tricyclic antidepressants serotonin transporter inhibitor [HSA:6532] [KO:K05037]; no...rker: CYP2D6 [HSA:1565] CYP inhibition: CYP2D6 [HSA:1565] map07027 Antidepressants map07234 Neurotransmitter...6/USP) USP drug classification [BR:br08302] Antidepressants Tricyclics Clomipramine D00811 Clomipramine hydr

  5. Drug: D00809 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 97 313.8643 D00809.gif Antidepressant Therapeutic category: 1179 ATC code: N06AA09 Tricyclic antidepressants...A:1557], CYP2D6 [HSA:1565], CYP3A4 [HSA:1576] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepressants ...tyline D00809 Amitriptyline hydrochloride (JP16/USP) USP drug classification [BR:br08302] Antidepressants Tr

  6. The evolution of drug design at Merck Research Laboratories

    Science.gov (United States)

    Brown, Frank K.; Sherer, Edward C.; Johnson, Scott A.; Holloway, M. Katharine; Sherborne, Bradley S.

    2016-11-01

    On October 5, 1981, Fortune magazine published a cover article entitled the "Next Industrial Revolution: Designing Drugs by Computer at Merck". With a 40+ year investment, we have been in the drug design business longer than most. During its history, the Merck drug design group has had several names, but it has always been in the "design" business, with the ultimate goal to provide an actionable hypothesis that could be tested experimentally. Often the result was a small molecule but it could just as easily be a peptide, biologic, predictive model, reaction, process, etc. To this end, the concept of design is now front and center in all aspects of discovery, safety assessment and early clinical development. At present, the Merck design group includes computational chemistry, protein structure determination, and cheminformatics. By bringing these groups together under one umbrella, we were able to align activities and capabilities across multiple research sites and departments. This alignment from 2010 to 2016 resulted in an 80% expansion in the size of the department, reflecting the increase in impact due to a significant emphasis across the organization to "design first" along the entire drug discovery path from lead identification (LID) to first in human (FIH) dosing. One of the major advantages of this alignment has been the ability to access all of the data and create an adaptive approach to the overall LID to FIH pathway for any modality, significantly increasing the quality of candidates and their probability of success. In this perspective, we will discuss how we crafted a new strategy, defined the appropriate phenotype for group members, developed the right skillsets, and identified metrics for success in order to drive continuous improvement. We will not focus on the tactical implementation, only giving specific examples as appropriate.

  7. A REVIEW ON HERBAL PLANTS SHOWING ANTIDEPRESSANT ACTIVITY

    Directory of Open Access Journals (Sweden)

    Talha Jawaid et al.

    2011-12-01

    Full Text Available Depression is a heterogenous mood disorder that has been classified and treated in variety of ways. Although a number of synthetic drugs are being used as standard treatment for clinically depressed patient, they have adverse effects that can compromise the therapeutic treatment .Thus, it is worthwhile to look for antidepressant from plants with proven advantage and favorable benefit to risk ratio. A number of medicinal plants and medicine derived from these plants have shown antidepressant properties by virtue of combined effect of their medicinal constituents. The causes of depression are decreased brain levels of monoamines like noradrenaline, dopamine and serotonin. Therefore, drugs restoring the reduced levels of these monoamines in the brain either by inhibiting monoamine oxidase or by inhibiting reuptake of these neurotransmitters might be fruitful in the treatment of depression. The present review is focused on the medicinal plants and plants based formulations having antidepressant activity in animal studies and in humans.

  8. Computer Aided Drug Design for Multi-Target Drug Design: SAR /QSAR, Molecular Docking and Pharmacophore Methods.

    Science.gov (United States)

    Abdolmaleki, Azizeh; Ghasemi, Jahan B; Ghasemi, Fatemeh

    2017-01-01

    Multi-target drugs against particular multiple targets get better protection, resistance profiles and curative influence by cooperative rules of a key beneficial target with resistance behavior and compensatory elements. Computational techniques can assist us in the efforts to design novel drugs (ligands) with a preferred bioactivity outline and alternative bioactive molecules at an early stage. A number of in silico methods have been explored extensively in order to facilitate the investigation of individual target agents and to propose a selective drug. A different, progressively more significant field which is used to predict the bioactivity of chemical compounds is the data mining method. Some of the previously mentioned methods have been investigated for multi-target drug design (MTDD) to find drug leads interact simultaneously with multiple targets. Several cheminformatics methods and structure-based approaches try to extract information from units working cooperatively in a biomolecular system to fulfill their task. To dominate the difficulties of the experimental specification of ligand-target structures, rational methods, namely molecular docking, SAR and QSAR are vital substitutes to obtain knowledge for each structure in atomic insight. These procedures are logically successful for the prediction of binding affinity and have shown promising potential in facilitating MTDD. Here, we review some of the important features of the multi-target therapeutics discoveries using the computational approach, highlighting the SAR, QSAR, docking and pharmacophore methods to discover interactions between drug-target that could be leveraged for curative benefits. A summary of each, followed by examples of its applications in drug design has been provided. Computational efficiency of each method has been represented according to its main strengths and limitations.

  9. Application of quality by design in the current drug development

    Directory of Open Access Journals (Sweden)

    Lan Zhang

    2017-01-01

    Full Text Available Quality by Test was the only way to guarantee quality of drug products before FDA launched current Good Manufacturing Practice. To clearly understand the manufacture processes, FDA generalized Quality by Design (QbD in the field of pharmacy, which is based on the thorough understanding of how materials and process parameters affect the quality profile of final products. The application of QbD in drug formulation and process design is based on a good understanding of the sources of variability and the manufacture process. In this paper, the basic knowledge of QbD, the elements of QbD, steps and tools for QbD implementation in pharmaceutics field, including risk assessment, design of experiment, and process analytical technology (PAT, are introduced briefly. Moreover, the concrete applications of QbD in various pharmaceutical related unit operations are summarized and presented.

  10. Prescription of antidepressants to patients on opioid maintenance therapy – a pharmacoepidemiological study

    Directory of Open Access Journals (Sweden)

    Ingeborg Hartz

    2011-12-01

    Full Text Available Background and aims: Depression and anxiety are commonly reported among patients in opioid maintenance treatment (OMT. The aim of the present study was to describe aspects of prescription of antidepresant drug therapy among patients on OMT. Our research questions were: 1 What is the prevalence of antidepressant use according to age and gender? 2 Which antidepressants are used? 3 How are antidepressants used in terms of reimbursement codes, dispensed dose and duration of therapy?Methods: Pharmacoepidemiological data were retrieved from the complete national Norwegian Prescription Database which contains information on all prescription drugs (such as Anatomical Theraputical Chemical (ATC-code, Defined Daily Dose (DDDs, dispensed at pharmacies to individual patients. Norwegian OMT-patients (N=4374, 3035 men and 1339 women who received methadone mixture, buprenorphine capsules or combined buprenorphine-naloxone capsules for at least 6 months in 2009 were included. Prevalence of antidepressant use in the studied patients was measured in terms of retrieval of prescriptions.Results: During 2009 21.7% of the studied patients filled at least one prescription for an antidepressant drugs (men: 21.2%; women: 22.9%. The subgroup of antidepressants most frequently dispensed was selective serotonin reuptake inhibitors (SSRIs (33%, followed by the sedative antidepressants mianserin and mirtazapin (22% and tricyclic antidepressants (TCAs (20%. Except for TCAs, prescriptions of all antidepressant subgroups were reimbursed for either anxiety or depression in 90% of the cases. Overall, 46.9% of the antidepressant users were prescribed antidepressants in the category < 1 DDD per day and/or treatment < 3 months, with no gender difference.Conclusions: About one out of five OMT-patients filled a prescription for an antidepressant drug in 2009. Above 90% had their prescriptions reimbursed for either depression or anxiety. Use at low doses and/or sporadic use among half

  11. Drug: D09699 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepress...ants N06AX24 Vilazodone D09699 Vilazodone hydrochloride (USAN) USP drug classification [BR:br08302] Antidepress...477.9858 D09699.gif Antidepressant ATC code: N06AX24 5-HT1A-receptor partial agonist [HSA:3350] [KO:K04153];...D09699 Drug Vilazodone hydrochloride (USAN); Viibryd (TN) C26H27N5O2. HCl 477.1932

  12. Drug: D00228 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D00228 Drug Amoxapine (JP16/USP/INN); Asendin (TN) C17H16ClN3O 313.0982 313.7814 D00228.gif Antidepress...ant Therapeutic category: 1179 ATC code: N06AA17 Tricyclic antidepressants serotonin tra... CYP2D6 [HSA:1565], CYP1A2 [HSA:1544], CYP2C19 [HSA:1557], CYP3A4 [HSA:1576] map07027 Antidepress... (JP16/USP/INN) USP drug classification [BR:br08302] Antidepressants Tricyclics A

  13. Drug: D08070 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08070 Drug Imipramine (INN); Tofranil (TN) C19H24N2 280.1939 280.4073 D08070.gif Antidepress...ant, tricyclic Same as: C07049 ATC code: N06AA02 Tricyclic antidepressant prodrug, active substanc...9 [HSA:1557], CYP2D6 [HSA:1565], CYP3A4 [HSA:1576] Genomic biomarker: CYP2D6 [HSA:1565] map07027 Antidepress...selective monoamine reuptake inhibitors N06AA02 Imipramine D08070 Imipramine (INN) USP drug classification [BR:br08302] Antidepress

  14. 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.

  15. 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

  16. 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

  17. 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.

  18. 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.

  19. From laptop to benchtop to bedside: Structure-based Drug Design on Protein Targets

    OpenAIRE

    Chen, Lu; Morrow, John K.; Tran, Hoang T.; Phatak, Sharangdhar S.; Du-Cuny, Lei; Zhang, Shuxing

    2012-01-01

    As an important aspect of computer-aided drug design, structure-based drug design brought a new horizon to pharmaceutical development. This in silico method permeates all aspects of drug discovery today, including lead identification, lead optimization, ADMET prediction and drug repurposing. Structure-based drug design has resulted in fruitful successes drug discovery targeting protein-ligand and protein-protein interactions. Meanwhile, challenges, noted by low accuracy and combinatoric issue...

  20. 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.

  1. 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.

  2. Molecular drug targets and structure based drug design: A holistic approach

    OpenAIRE

    Singh, Shailza; Malik, Balwant Kumar; Sharma, Durlabh Kumar

    2006-01-01

    Access to the complete human genome sequence as well as to the complete sequences of pathogenic organisms provides information that can result in an avalanche of therapeutic targets. Structure-based design is one of the first techniques to be used in drug design. Structure based design refers specifically to finding and complementing the 3D structure (binding and/or active site) of a target molecule such as a receptor protein. The aim of this review is to give an outline of studies in the fie...

  3. Computer-aided drug design at Boehringer Ingelheim

    Science.gov (United States)

    Muegge, Ingo; Bergner, Andreas; Kriegl, Jan M.

    2016-09-01

    Computer-Aided Drug Design (CADD) is an integral part of the drug discovery endeavor at Boehringer Ingelheim (BI). CADD contributes to the evaluation of new therapeutic concepts, identifies small molecule starting points for drug discovery, and develops strategies for optimizing hit and lead compounds. The CADD scientists at BI benefit from the global use and development of both software platforms and computational services. A number of computational techniques developed in-house have significantly changed the way early drug discovery is carried out at BI. In particular, virtual screening in vast chemical spaces, which can be accessed by combinatorial chemistry, has added a new option for the identification of hits in many projects. Recently, a new framework has been implemented allowing fast, interactive predictions of relevant on and off target endpoints and other optimization parameters. In addition to the introduction of this new framework at BI, CADD has been focusing on the enablement of medicinal chemists to independently perform an increasing amount of molecular modeling and design work. This is made possible through the deployment of MOE as a global modeling platform, allowing computational and medicinal chemists to freely share ideas and modeling results. Furthermore, a central communication layer called the computational chemistry framework provides broad access to predictive models and other computational services.

  4. Revisiting de novo drug design: receptor based pharmacophore screening.

    Science.gov (United States)

    Amaravadhi, Harikishore; Baek, Kwanghee; Yoon, Ho Sup

    2014-01-01

    De novo drug design methods such as receptor or protein based pharmacophore modeling present a unique opportunity to generate novel ligands by employing the potential binding sites even when no explicit ligand information is known for a particular target. Recent developments in molecular modeling programs have enhanced the ability of early programs such as LUDI or Pocket that not only identify the key interactions or hot spots at the suspected binding site, but also and convert these hot spots into three-dimensional search queries and virtual screening of the property filtered synthetic libraries. Together with molecular docking studies and consensus scoring schemes they would enrich the lead identification processes. In this review, we discuss the ligand and receptor based de novo drug design approaches with selected examples.

  5. What can we learn from consumer reports on psychiatric adverse drug reactions with antidepressant medication? : Experiences from reports to consumer association

    OpenAIRE

    2011-01-01

    Background According to the World Health Organization (WHO) the cost of adverse drug reactions   (ADRs) in the general population is high and under-reporting by health professionals   is a well-recognized problem. Another way to increase ADR reporting is to let the   consumers themselves report directly to the authorities. In Sweden it is mandatory   for prescribers to report serious ADRs to the Medical Products Agency (MPA), but there   are no such regulations for consumers. The non-profit a...

  6. Quantitative modeling of selective lysosomal targeting for drug design

    DEFF Research Database (Denmark)

    Trapp, Stefan; Rosania, G.; Horobin, R.W.;

    2008-01-01

    Lysosomes are acidic organelles and are involved in various diseases, the most prominent is malaria. Accumulation of molecules in the cell by diffusion from the external solution into cytosol, lysosome and mitochondrium was calculated with the Fick–Nernst–Planck equation. The cell model considers....... This demonstrates that the cell model can be a useful tool for the design of effective lysosome-targeting drugs with minimal off-target interactions....

  7. 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.

  8. 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.

  9. Emerging paradigms in anti-infective drug design.

    Science.gov (United States)

    Barrett, Michael P; Croft, Simon L

    2014-01-01

    The need for new drugs to treat microbial infections is pressing. The great progress made in the middle part of the twentieth Century was followed by a period of relative inactivity as the medical needs relating to infectious disease in the wealthier nations receded. Growing realisation that anti-infectives are needed in many parts of the world, to treat neglected diseases as well as to combat the burgeoning risk of resistance to existing drugs, has galvanised a new wave of research into anti-microbial drugs. The transfer of knowledge from the Pharmaceutical industry relating to the importance of understanding how to target drugs successfully within the body, and improved understanding of how pathogens interact with their hosts, is driving a series of new paradigms in anti-infective drug design. Here we provide an overview of those processes as an introduction to a series of articles from experts in this area that emerged from a meeting entitled "Emerging Paradigms in Anti-Infective Drug Design" held in London on the 17th and 18th September 2012. The symposium was organised jointly by British Society for Parasitology (BSP) and the Biological & Medicinal Chemistry sector of the Royal Society of Chemistry (RSC) and held at the London School of Hygiene & Tropical Medicine. The symposium set out to cover all aspects of the identification of new therapeutic modalities for the treatment of neglected and tropical diseases. We aimed to bring together leading scientists from all the disciplines working in this field and cover the pharmacology, medicinal chemistry and drug delivery of potential new medicines. Sessions were held on: "Target diseases and targets for drugs", "Target based medicinal chemistry", "Bioavailability and chemistry", "Targeting intracellular microbes", "Alternative approaches and models", and "New anti-infectives - how do we get there?" This symposium was organised by Simon Croft (LSHTM) and Mike Barrett (University of Glasgow) for the BSP, and David

  10. The hippocampus and dorsal raphe nucleus are key brain areas associated with the antidepressant effects of lithium augmentation of desipramine.

    Science.gov (United States)

    Cussotto, Sofia; Cryan, John F; O'Leary, Olivia F

    2017-03-27

    Approximately 50% of depressed individuals fail to achieve remission with first-line antidepressant drugs and a third remain treatment-resistant. When first-line antidepressant treatment is unsuccessful, second-line strategies include dose optimisation, switching to another antidepressant, combination with another antidepressant, or augmentation with a non-antidepressant medication. Much of the evidence for the efficacy of augmentation strategies comes from studies using lithium to augment the effects of tricyclic antidepressants. The neural circuitry underlying the therapeutic effects of lithium augmentation is not yet fully understood. Recently, we reported that chronic treatment with a combination of lithium and the antidepressant desipramine, exerted antidepressant-like behavioural effects in a mouse strain (BALB/cOLaHsd) that did not exhibit an antidepressant-like behavioural response to either drug alone. In the present study, we used this model in combination with ΔFosB/FosB immunohistochemistry to identify brain regions chronically affected by lithium augmentation of desipramine when compared to either treatment alone. The data suggest that the dorsal raphe nucleus and the CA3 regions of the dorsal hippocampus are key nodes in the neural circuitry underlying antidepressant action of lithium augmentation of desipramine. These data give new insight into the neurobiology underlying the mechanism of lithium augmentation in the context of treatment-resistant depression.

  11. Rising Trend of Use of Antidepressants Induced Non- Puerperal Lactation: A Case Report

    Science.gov (United States)

    Ali, Wazid; Jiloha, R.C.

    2016-01-01

    Non puerperal lactation or galactorrhea is a well known side effect of antipsychotic drugs but has been infrequently described with the use of antidepressants. In past few decades, there have been emerging trend of isolated case reports of selective serotonin reuptake inhibitors induced non puerperal lactation. We report a case of non puerperal lactation following usage of second generation tricyclic antidepressant, nortriptyline and resolution on withdrawing the drug. Literature review has been done for antidepressant induced galactorrhea to understand the current trends, putative mechanism as different from one implicated for antipsychotics and its clinical utility. PMID:27504388

  12. Towards novel 5-HT7versus 5-HT1A receptor ligands among LCAPs with cyclic amino acid amide fragments: design, synthesis, and antidepressant properties. Part II.

    Science.gov (United States)

    Canale, Vittorio; Kurczab, Rafał; Partyka, Anna; Satała, Grzegorz; Witek, Jagna; Jastrzębska-Więsek, Magdalena; Pawłowski, Maciej; Bojarski, Andrzej J; Wesołowska, Anna; Zajdel, Paweł

    2015-03-06

    A 26-membered library of novel long-chain arylpiperazines, which contained primary and tertiary amides of cyclic amino acids (proline and 1,2,3,4-tetrahydroisoquinoline-3-carboxamide) in the terminal fragment was synthesized and biologically evaluated for binding affinity for 5-HT7 and 5-HT1A receptors. Docking studies confirmed advantages of Tic-amide over Pro-amide fragment for interaction with 5-HT7 receptors. Selected compounds 32 and 28, which behaved as 5-HT7Rs antagonist and 5-HT1A partial agonist, respectively, produced antidepressant-like effects in the forced swim test in mice after acute treatment in doses of 10 mg/kg (32) and 1.25 mg/kg (28). Compound 32 reduced immobility in a manner similar to the selective 5-HT7 antagonist SB-269970.

  13. Design, synthesis, characterization and drug release kinetics of PAMAM dendrimer based drug formulations

    Science.gov (United States)

    Kurtoglu, Yunus Emre

    The drug release characteristics of G4-polyamidoamine (PAMAM) dendrimer-ibuprofen conjugates with ester, amide, and peptide linkers were investigated, in addition to a linear PEG-ibuprofen conjugate to understand the effect of architecture and linker on drug release. Ibuprofen was directly conjugated to NH2 -terminated dendrimer by an amide bond and OH-terminated dendrimer by an ester bond. A tetra-peptide linked dendrimer conjugate and a linear mPEG-ibuprofen conjugate were also studied for comparison to direct linked dendrimer conjugates. It is demonstrated that the 3-D nanoscale architecture of PAMAM dendrimer-drug conjugates, along with linking chemistry govern the drug release mechanisms as well as kinetics. Understanding these structural effects on their drug release characteristics is crucial for design of dendrimer conjugates with high efficacy such as poly(amidoamine) dendrimer-N-Acetylcysteine conjugates with disulfide linkages. N-Acetylcysteine (NAC) is an anti-inflammatory agent with significant potential for clinical use in the treatment of neuroinflammation, stroke and cerebral palsy. A poly(amidoamine) dendrimer-NAC conjugate that contains a disulfide linkage was synthesized and evaluated for its release kinetics in the presence of glutathione (GSH), Cysteine (Cys), and bovine serum albumin (BSA) at both physiological and lysosomal pH. FITC-labeled conjugates showed that they enter cells rapidly and localize in the cytoplasm of lipopolysaccharide (LPS)-activated microglial cells. The efficacy of the dendrimer-NAC conjugate was measured in activated microglial cells using reactive oxygen species (ROS) assays. The conjugates showed an order of magnitude increase in anti-oxidant activity compared to free drug. When combined with intrinsic and ligand-based targeting with dendrimers, these types of GSH sensitive nanodevices can lead to improved drug release profiles and in vivo efficacy.

  14. Cytisine-based nicotinic partial agonists as novel antidepressant compounds.

    Science.gov (United States)

    Mineur, Yann S; Eibl, Christoph; Young, Grace; Kochevar, Christopher; Papke, Roger L; Gündisch, Daniela; Picciotto, Marina R

    2009-04-01

    Nicotine and other nicotinic agents are thought to regulate mood in human subjects and have antidepressant-like properties in animal models. Recent studies have demonstrated that blockade of nicotinic acetylcholine receptors (nAChRs) including those containing the beta2 subunit (beta2(*)), results in antidepressant-like effects. Previous studies have shown that cytisine, a partial agonist at alpha4/beta2(*) nAChRs, and a full agonist at alpha3/beta4(*) and alpha7 nAChRs, has antidepressant-like properties in several rodent models of antidepressant efficacy; however, it is not clear whether more selective partial agonists will also be effective in these models. We tested cytisine and two derivatives, 5-bromo-cytisine (5-Br-Cyt) and 3-(pyridin-3'-yl)-cytisine (3-pyr-Cyt) for their ability to act as a partial agonist of different nAChR subtypes and to show antidepressant-like activity in C57/BL6 mice in the tail suspension, the forced-swim, and the novelty-suppressed feeding tests. 3-pyr-Cyt was a partial agonist with very low efficacy at alpha4/beta2(*) nAChRS but had no agonist effects at other nAChRs normally targeted by cytisine, and it was effective in mouse models of antidepressant efficacy. Animals showed dose-dependent antidepressant-like effects in all three behavioral paradigms. 5-Br-Cyt was not effective in behavioral tests when administered peripherally, probably because of its inability to penetrate the blood-brain barrier, because it efficiently reduced immobility in the tail suspension test when administered intraventricularly. These results suggest that novel nicotinic partial agonists may provide new possibilities for development of drugs to treat mood disorders.

  15. 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

  16. Liposomal Drug Products: A Quality by Design Approach

    Science.gov (United States)

    Xu, Xiaoming

    Quality by Design (QbD) principles has been applied to the development of two liposomal formulations, containing a hydrophilic small molecule therapeutic (Tenofovir) and a protein therapeutic (superoxide dismutase). The goal of the research is to provide critical information on 1) how to reduce the preparation variability in liposome formulations, and 2) how to increase drug encapsulation inside liposomes to reduce manufacturing cost. Most notably, an improved liposome preparation method was developed which increased the encapsulation efficiency of hydrophilic molecules. In particular, this method allows for very high encapsulation efficiency. For example, encapsulation efficiencies of up to 50% have been achieved, whereas previously only 20% or less have been reported. Another significant outcome from this research is a first principle mathematical model to predict the encapsulation efficiency of hydrophilic drugs in unilamellar liposomes. This mathematical model will be useful in: formulation development to rapidly achieve optimized formulations; comparison of drug encapsulation efficiencies of liposomes prepared using different methods; and assisting in the development of suitable process analytical technologies to achieve real-time monitoring and control of drug encapsulation during manufacturing. A novel two-stage reverse dialysis in vitro release testing method has also been developed for passively targeted liposomes, which uses the first stage to mimic the circulation of liposomes in the body and the second stage to imitate the drug release process at the target. The developed in vitro release testing method can be used to distinguish formulations with varied compositions for quality control testing purposes. This developed method may pave the way to the development of more biorelevant quality control testing methods for liposomal drug products in the future. The QbD case studies performed in this research are examples of how this approach can be used to

  17. Antidepressants: Can They Lose Effectiveness?

    Science.gov (United States)

    ... be having the same effect. Can antidepressants lose effectiveness? Answers from Daniel K. Hall-Flavin, M.D. ... Policy Notice of Privacy Practices Notice of Nondiscrimination Advertising Mayo Clinic is a not-for-profit organization ...

  18. 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.

  19. Flexibility as a Strategy in Nucleoside Antiviral Drug Design.

    Science.gov (United States)

    Peters, H L; Ku, T C; Seley-Radtke, K L

    2015-01-01

    As far back as Melville Wolfrom's acyclic sugar synthesis in the 1960's, synthesis of flexible nucleoside analogues have been an area of interest. This concept, however, went against years of enzyme-substrate binding theory. Hence, acyclic methodology in antiviral drug design did not take off until the discovery and subsequent FDA approval of such analogues as Acyclovir and Tenofovir. More recently, the observation that flexible nucleosides could overcome drug resistance spawned a renewed interest in the field of nucleoside drug design. The next generation of flexible nucleosides shifted the focus from the sugar moiety to the nucleobase. With analogues such as Seley-Radtke "fleximers", and Herdewijn's C5 substituted 2'-deoxyuridines, the area of base flexibility has seen great expansion. More recently, the marriage of these methodologies with acyclic sugars has resulted in a series of acyclic flex-base nucleosides with a wide range of antiviral properties, including some of the first to exhibit anti-coronavirus activity. Various flexible nucleosides and their corresponding nucleobases will be compared in this review.

  20. Parasomnias and antidepressant therapy: a review of the literature.

    Science.gov (United States)

    Kierlin, Lara; Littner, Michael R

    2011-01-01

    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 REM sleep behavior disorder 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 selective serotonin reuptake inhibitors, tricyclic antidepressants, and serotonin-norepinephrine reuptake inhibitors to suppress REM, as well as the anticholinergic properties of the individual drugs to further disturb normal sleep architecture.

  1. Development of LC Method for the Simultaneous Determination of Antidepressant Drug Combination Melitracen Hydrochloride and Flupentixol Dihydrochloride in their Combined Dosage Form

    Directory of Open Access Journals (Sweden)

    Usmangani K. Chhalotiya

    2011-01-01

    Full Text Available A simple, specific and stability-indicating reversed-phase high-performance liquid chromatographic method was developed for the simultaneous determination of melitracen hydrochloride and flupentixol dihydrochloride in tablet dosage form. A Brownlee C-18, 5 μm column having 250×4.6 mm i.d. in isocratic mode, with mobile phase containing 0.025 M potassium dihydrogen phosphate: methanol (10 : 90, v/v; pH 7.3 was used. The flow rate was 1.0 mL/min, and effluents were monitored at 230 nm. The retention times of melitracen hydrochloride and flupentixol dihydrochloride were 7.75 min and 5.50 min, respectively. The linearity for melitracen hydrochloride and flupentixol dihydrochloride were in the range of 0.5–60 μg/mL. The recoveries obtained for melitracen hydrochloride and flupenthixol dihydrochloride was 99.81–100.77% and 99.42–100.12%, respectively. Both the drugs were subjected to acid and alkali hydrolysis, chemical oxidation, and dry heat degradation and photodegradation. The proposed method was validated and successfully applied to the estimation of melitracen hydrochloride and flupentixol dihydrochloride in combined tablet dosage form.

  2. Economic Effects of Anti-Depressant Usage on Elective Lumbar Fusion Surgery

    Directory of Open Access Journals (Sweden)

    Amirali Sayadipour

    2016-07-01

    Full Text Available Background: It has been suggested, although not proven, that presence of concomitant psychiatric disorders may increase the inpatient costs for patients undergoing elective surgery. This study was designed to test the hypothesis that elective lumbar fusion surgery is more costly in patients with under treatment for depression. Methods: This is a retrospective case-control study of 142 patients who underwent elective lumbar fusion. Of those 142 patients, 41 patients were chronically using an antidepressant medication that considered as a "study group", and 101 patients were not taking an antidepressant medication that considered as a "control group". Data was collected for this cohort regarding antidepressant usage patient demographics, length of stay (LOS, age-adjusted Charlson comorbidity index scores and cost. Costs were compared between those with a concomitant antidepressant usage and those without antidepressant usage using multivariate analysis. Results: Patients using antidepressants and those with no history of antidepressant usage were similar in terms of gender, age and number of operative levels. The LOS demonstrated a non-significant trend towards longer stays in those using anti-depressants. Total charges, payments, variable costs and fixed costs were all higher in the antidepressant group but none of the differences reached statistical significance. Using Total Charges as the dependent variable, gender and having psychiatric comorbidities were retained independent variables. Use of an antidepressant was independently predictive of a 36% increase in Total Charges . Antidepressant usage as an independent variable also conferred a 22% increase in cost and predictive of a 19% increase in Fixed Cost . Male gender was predictive of a 30% increase in Total Charges . Conclusion: This study suggests use of antidepressant in patients who undergo elective spine fusion compared with control group is associated with increasing total cost and

  3. Drug: D02570 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ; Pristiq (TN) C16H25NO2. C4H6O4. H2O 399.2257 399.4785 D02570.gif Treatment of major depressive disorder AT...Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepress...ate (JAN); Desvenlafaxine succinate (USAN) USP drug classification [BR:br08302] Antidepressants SSRIs/SNRIs ...[HSA:1565] map07027 Antidepressants map07234 Neurotransmitter transporter inhibitors Anatomical Therapeutic ...HSA:6530] [KO:K05035] hsa04726(6532) Serotonergic synapse CYP inhibition: CYP2D6

  4. Drug: D08216 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08216 Drug Mianserin (INN); Tolvon (TN) C18H20N2 264.1626 264.3648 D08216.gif Antidepress...ant, tetracyclic ATC code: N06AX03 tetracyclic antidepressants 5-HT1-receptor antagonist [HSA:3350 33...2 [HSA:1544], CYP2C19 [HSA:1557], CYP2D6 [HSA:1565] map07027 Antidepressants Anatomical Therapeutic Chemical...IDEPRESSANTS N06AX Other antidepressants N06AX03 Mianserin D08216 Mianserin (INN) Target-based classificatio

  5. GPCR structures in drug design, emerging opportunities with new structures.

    Science.gov (United States)

    Tautermann, Christofer S

    2014-09-01

    In recent years, GPCR targets from diverse regions of phylogenetic space have been determined. This effort has culminated this year in the determination of representatives of all major classes of GPCRs (A, B, C, and F). Although much of the now well established knowledge on GPCR structures has been known for some years, the new high-resolution structures allow structural insight into the causes of ligand efficacy, biased signaling, and allosteric modulation. In this digest the structural basis for GPCR signaling in the light of the new structures is reviewed and the use of the new non-class A GPCRs for drug design is discussed.

  6. Considerations of Protein Subpockets in Fragment-Based Drug Design.

    Science.gov (United States)

    Bartolowits, Matthew; Davisson, V Jo

    2016-01-01

    While the fragment-based drug design approach continues to gain importance, gaps in the tools and methods available in the identification and accurate utilization of protein subpockets have limited the scope. The importance of these features of small molecule-protein recognition is highlighted with several examples. A generalized solution for the identification of subpockets and corresponding chemical fragments remains elusive, but there are numerous advancements in methods that can be used in combination to address subpockets. Finally, additional examples of approaches that consider the relative importance of small-molecule co-dependence of protein conformations are highlighted to emphasize an increased significance of subpockets, especially at protein interfaces.

  7. Effects of Calcium Channel Blockers on Antidepressant Action of Alprazolam and Imipramine

    Directory of Open Access Journals (Sweden)

    Gorash ZM

    2007-01-01

    Full Text Available Alprazolam is effective as an anxiolytic and in the adjunct treatment of depression. In this study, the effects of calcium channel antagonists on the antidepressant action of alprazolam and imipramine were investigated. A forced swimming maze was used to study behavioral despair in albino mice. Mice were divided into nine groups (n = 7 per group. One group received a single dose of 1% Tween 80; two groups each received a single dose of the antidepressant alone (alprazolam or imipramine; two groups each received a single dose of the calcium channel blocker (nifedipine or verapamil; four groups each received a single dose of the calcium channel blocker followed by a single dose of the antidepressant (with same doses used for either in the previous four groups. Drug administration was performed concurrently on the nine groups. Our data confirmed the antidepressant action of alprazolam and imipramine. Both nifedipine and verapamil produced a significant antidepressant effect (delay the onset of immobility when administered separately. Verapamil augmented the antidepressant effects of alprazolam and imipramine (additive antidepressant effect. This may be due to the possibility that verapamil might have antidepressant-like effect through different mechanism. Nifedipine and imipramine combined led to a delay in the onset of immobility greater than their single use but less than the sum of their independent administration. This may be due to the fact that nifedipine on its own might act as an antidepressant but blocks one imipramine mechanism that depends on L-type calcium channel activation. Combining nifedipine with alprazolam produced additional antidepressant effects, which indicates that they exert antidepressant effects through different mechanisms.

  8. 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.

  9. Low energy nanoemulsification to design veterinary controlled drug delivery devices

    Directory of Open Access Journals (Sweden)

    Thierry F Vandamme

    2010-10-01

    Full Text Available Thierry F Vandamme, Nicolas Anton, University of Strasbourg, Faculty of Pharmacy, Illkirch Cedex, France; UMR CNRS 7199, Laboratoire de Conception et Application de Molécules Bioactives, équipe de Pharmacie Biogalénique, Illkirch Cedex, France,  This work is selected as Controlled Release Society Outstanding Veterinary Paper Award 2010Abstract: The unique properties of nanomaterials related to structural stability and quantum-scale reactive properties open up a world of possibilities that could be exploited to design and to target drug delivery or create truly microscale biological sensors for veterinary applications. We developed cost-saving and solvent-free nanoemulsions. Formulated with a low-energy method, these nanoemulsions can find application in the delivery of controlled amounts of drugs into the beverage of breeding animals (such as poultry, cattle, pigs or be used for the controlled release of injectable poorly water-soluble drugs.Keywords: nanoemulsion, nanomedicine, low-energy emulsification, veterinary, ketoprofen, sulfamethazine

  10. In silico ADME/T modelling for rational drug design.

    Science.gov (United States)

    Wang, Yulan; Xing, Jing; Xu, Yuan; Zhou, Nannan; Peng, Jianlong; Xiong, Zhaoping; Liu, Xian; Luo, Xiaomin; Luo, Cheng; Chen, Kaixian; Zheng, Mingyue; Jiang, Hualiang

    2015-11-01

    In recent decades, in silico absorption, distribution, metabolism, excretion (ADME), and toxicity (T) modelling as a tool for rational drug design has received considerable attention from pharmaceutical scientists, and various ADME/T-related prediction models have been reported. The high-throughput and low-cost nature of these models permits a more streamlined drug development process in which the identification of hits or their structural optimization can be guided based on a parallel investigation of bioavailability and safety, along with activity. However, the effectiveness of these tools is highly dependent on their capacity to cope with needs at different stages, e.g. their use in candidate selection has been limited due to their lack of the required predictability. For some events or endpoints involving more complex mechanisms, the current in silico approaches still need further improvement. In this review, we will briefly introduce the development of in silico models for some physicochemical parameters, ADME properties and toxicity evaluation, with an emphasis on the modelling approaches thereof, their application in drug discovery, and the potential merits or deficiencies of these models. Finally, the outlook for future ADME/T modelling based on big data analysis and systems sciences will be discussed.

  11. Targeting Plasmodium Metabolism to Improve Antimalarial Drug Design.

    Science.gov (United States)

    Avitia-Domínguez, Claudia; Sierra-Campos, Erick; Betancourt-Conde, Irene; Aguirre-Raudry, Miriam; Vázquez-Raygoza, Alejandra; Luevano-De la Cruz, Artemisa; Favela-Candia, Alejandro; Sarabia-Sanchez, Marie; Ríos-Soto, Lluvia; Méndez-Hernández, Edna; Cisneros-Martínez, Jorge; Palacio-Gastélum, Marcelo Gómez; Valdez-Solana, Mónica; Hernández-Rivera, Jessica; De Lira-Sánchez, Jaime; Campos-Almazán, Mara; Téllez-Valencia, Alfredo

    2016-01-01

    Malaria is one of the main infectious diseases in tropical developing countries and represents high morbidity and mortality rates nowadays. The principal etiological agent P. falciparum is transmitted through the bite of the female Anopheles mosquito. The issue has escalated due to the emergence of resistant strains to most of the antimalarials used for the treatment including Chloroquine, Sulfadoxine-Pyrimethamine, and recently Artemisinin derivatives, which has led to diminished effectiveness and by consequence increased the severity of epidemic outbreaks. Due to the lack of effective compounds to treat these drug-resistant strains, the discovery or development of novel anti-malaria drugs is important. In this context, one strategy has been to find inhibitors of enzymes, which play an important role for parasite survival. Today, promising results have been obtained in this regard, involving the entire P. falciparum metabolism. These inhibitors could serve as leads in the search of a new chemotherapy against malaria. This review focuses on the achievements in recent years with regard to inhibition of enzymes used as targets for drug design against malaria.

  12. Carboxylic acid (bio)isosteres in drug design.

    Science.gov (United States)

    Ballatore, Carlo; Huryn, Donna M; Smith, Amos B

    2013-03-01

    The carboxylic acid functional group can be an important constituent of a pharmacophore, however, the presence of this moiety can also be responsible for significant drawbacks, including metabolic instability, toxicity, as well as limited passive diffusion across biological membranes. To avoid some of these shortcomings while retaining the desired attributes of the carboxylic acid moiety, medicinal chemists often investigate the use of carboxylic acid (bio)isosteres. The same type of strategy can also be effective for a variety other purposes, for example, to increase the selectivity of a biologically active compound or to create new intellectual property. Several carboxylic acid isosteres have been reported, however, the outcome of any isosteric replacement cannot be readily predicted as this strategy is generally found to be dependent upon the particular context (i.e., the characteristic properties of the drug and the drug-target). As a result, screening of a panel of isosteres is typically required. In this context, the discovery and development of novel carboxylic acid surrogates that could complement the existing palette of isosteres remains an important area of research. The goal of this Minireview is to provide an overview of the most commonly employed carboxylic acid (bio)isosteres and to present representative examples demonstrating the use and utility of each isostere in drug design.

  13. 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.

  14. 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.

  15. 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.

  16. Combining docking and molecular dynamic simulations in drug design.

    Science.gov (United States)

    Alonso, Hernán; Bliznyuk, Andrey A; Gready, Jill E

    2006-09-01

    A rational approach is needed to maximize the chances of finding new drugs, and to exploit the opportunities of potential new drug targets emerging from genomic and proteomic initiatives, and from the large libraries of small compounds now readily available through combinatorial chemistry. Despite a shaky early history, computer-aided drug design techniques can now be effective in reducing costs and speeding up drug discovery. This happy outcome results from development of more accurate and reliable algorithms, use of more thoughtfully planned strategies to apply them, and greatly increased computer power to allow studies with the necessary reliability to be performed. Our review focuses on applications and protocols, with the main emphasis on critical analysis of recent studies where docking calculations and molecular dynamics (MD) simulations were combined to dock small molecules into protein receptors. We highlight successes to demonstrate what is possible now, but also point out drawbacks and future directions. The review is structured to lead the reader from the simpler to more compute-intensive methods. Thus, while inexpensive and fast docking algorithms can be used to scan large compound libraries and reduce their size, more accurate but expensive MD simulations can be applied when a few selected ligand candidates remain. MD simulations can be used: during the preparation of the protein receptor before docking, to optimize its structure and account for protein flexibility; for the refinement of docked complexes, to include solvent effects and account for induced fit; to calculate binding free energies, to provide an accurate ranking of the potential ligands; and in the latest developments, during the docking process itself to find the binding site and correctly dock the ligand a priori.

  17. Benzothiazoles: how relevant in cancer drug design strategy?

    Science.gov (United States)

    Singh, Meenakshi; Singh, Sushil K

    2014-01-01

    Heterocyclic compounds, analogs and derivatives have attracted attention due to their diverse biological and pharmacological properties. Benzoheterocycles such as benzothiazoles, benzimidazoles and benzoxazoles are constituents of many bioactive heterocyclic compounds, having wider range of applications. They have been extensively studied for their biological activities, and can serve as unique and versatile scaffolds for drug design. The benzothiazole, in the family of heterocyclic compounds has assumed special significance in synthetic chemistry, pharmaceutical chemistry as well as in clinical applications because of its anti-tumor properties. This review is organized in the following ways. It begins with brief introduction on the chemical diversity of synthetic analogs of benzothiazole. After this, drug design strategy and mechanisms of action through its diverse biological targets in which benzothiazole and its derivatives display their anticancer activity are discussed. It ends with the metabolism pattern of benzothiazole and its analogs. Analysis of the structure-activity relationships (SAR), quantitative structure-activity relationships (QSAR) as well as on docking studies of this family of compounds highlights the potential that may lead to the development of novel anticancer agents. Such relationships will definitely create lot of interest among the researchers to synthesize optimized variety of benzothiazole derivatives and to screen them for their anticancer activity.

  18. Drug design for ever, from hype to hope

    Science.gov (United States)

    Seddon, G.; Lounnas, V.; McGuire, R.; van den Bergh, T.; Bywater, R. P.; Oliveira, L.; Vriend, G.

    2012-01-01

    In its first 25 years JCAMD has been disseminating a large number of techniques aimed at finding better medicines faster. These include genetic algorithms, COMFA, QSAR, structure based techniques, homology modelling, high throughput screening, combichem, and dozens more that were a hype in their time and that now are just a useful addition to the drug-designers toolbox. Despite massive efforts throughout academic and industrial drug design research departments, the number of FDA-approved new molecular entities per year stagnates, and the pharmaceutical industry is reorganising accordingly. The recent spate of industrial consolidations and the concomitant move towards outsourcing of research activities requires better integration of all activities along the chain from bench to bedside. The next 25 years will undoubtedly show a series of translational science activities that are aimed at a better communication between all parties involved, from quantum chemistry to bedside and from academia to industry. This will above all include understanding the underlying biological problem and optimal use of all available data.

  19. 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

  20. 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

  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. 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.

  3. 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.

  4. 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.

  5. Antidepressant-resistant depression and antidepressant-associated suicidal behaviour: the role of underlying bipolarity.

    Science.gov (United States)

    Rihmer, Zoltan; Gonda, Xenia

    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 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 (hypo)manic switches and "suicide-inducing" potential of antidepressants seem to be related to the underlying bipolarity.

  6. 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

  7. Do patients initiate therapy? Primary non-adherence to statins and antidepressants in Iceland

    DEFF Research Database (Denmark)

    Thengilsdõttir, G.; Pottegård, A.; Halldõrsson, M.;

    2015-01-01

    Background Primary non-adherence occurs when a drug has been prescribed but the patient fails to have it dispensed at the pharmacy. Aims To assess primary non-adherence to statins and antidepressants in Iceland, the association of demographic factors with primary non-adherence, and the time from...... when a prescription is issued until it is dispensed. Methods Data on patients receiving a new prescription for a statin or an antidepressant from the Primary Health Care database were linked with dispensing histories from The Icelandic Prescription Database. The proportion of patients who did not have.......0% for statins and antidepressants, respectively. The majority of patients had their prescription dispensed within 7 days (85% for statins, 87% for antidepressants). Being disabled and receiving a prescription for an expensive drug was associated with higher rates of primary non-adherence. Conclusion The rate...

  8. 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...

  9. Click Chemistry in Peptide-Based Drug Design

    Directory of Open Access Journals (Sweden)

    Irwin Chaiken

    2013-08-01

    Full Text Available Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.

  10. Click chemistry in peptide-based drug design.

    Science.gov (United States)

    Li, Huiyuan; Aneja, Rachna; Chaiken, Irwin

    2013-08-16

    Click chemistry is an efficient and chemoselective synthetic method for coupling molecular fragments under mild reaction conditions. Since the advent in 2001 of methods to improve stereochemical conservation, the click chemistry approach has been broadly used to construct diverse chemotypes in both chemical and biological fields. In this review, we discuss the application of click chemistry in peptide-based drug design. We highlight how triazoles formed by click reactions have been used for mimicking peptide and disulfide bonds, building secondary structural components of peptides, linking functional groups together, and bioconjugation. The progress made in this field opens the way for synthetic approaches to convert peptides with promising functional leads into structure-minimized and more stable forms.

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

    Science.gov (United States)

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

    2009-11-01

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

  12. 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.

  13. 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.

  14. 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…

  15. What is an antidepressant binding site doing in a bacterial transporter?

    Science.gov (United States)

    Rudnick, Gary

    2007-09-21

    LeuT is a bacterial amino acid transporter belonging to a large family of membrane proteins, including the neurotransmitter transporters that are targets for antidepressant drugs. The high-resolution structure of LeuT has provided an important model for understanding structure and function in this family. Two recent papers found that LeuT can bind tricyclic antidepressants, raising the possibility that it may also serve as a model for the pharmacological properties of neurotransmitter transporters.

  16. [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.

  17. Evaluation of patient outcomes in an area where prescribing of anticholinergic antidepressants was influenced by academic detailing

    OpenAIRE

    Eijk, M.E.C. van; Belitser, S V; Porsius, A. J.; de Boer, A.

    2002-01-01

    OBJECTIVE: To evaluate, on a patient level, the effect of a "physician-level intervention" that successfully reduced the incidence of anticholinergic antidepressant prescribing. DESIGN: Cross-sectional surveys with questionnaires sent before and after intervention. SETTING: Additional study in an RCT to reduce the prescribing of highly anticholinergic antidepressants in the elderly in the South Holland Islands. PARTICIPANTS: Elderly patients (age 60-95 years) who used antidepressants in 1995 ...

  18. 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.

  19. 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

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

    Science.gov (United States)

    Zeng, Huahui; Wu, Xiangxiang

    2016-10-04

    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.

  1. 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

  2. Dopaminergic mechanism of antidepressant action in depressed patients.

    Science.gov (United States)

    Willner, Paul; Hale, Anthony S; Argyropoulos, Spilios

    2005-05-01

    Clinical studies have not yet determined a common mechanism of action for antidepressant drugs, which have primary sites of action on a variety of different neurotransmitter systems. However, a large body of evidence from animal studies demonstrates that sensitisation of D2-like dopamine receptors in the mesolimbic dopamine system may represent a 'final common pathway' in antidepressant action. The present study aimed to determine whether, consistent with data from animal studies, the clinical antidepressant action of selective serotonin reuptake inhibitors (SSRIs) is reversed by acute administration of a receptor antagonist selective for D2-like receptors in the mesolimbic dopamine system. The participants were patients diagnosed with major depressive disorder (n = 8) who had been treated successfully (Hamilton Depression Scale depressed, untreated volunteers (n = 10). They attended a psychiatric research ward on an out-patient basis, and received double-blind acute administration of either placebo, or a low dose of the selective dopamine D2/D3 receptor antagonist sulpiride (200 mg), in a counterbalanced order. Mood and psychomotor effects were assessed using visual analogue scales and the Fawcett-Clark Pleasure Capacity Scale. Sulpiride slightly improved subjective well-being in the control group, but in the antidepressant-treated patients, sulpiride caused a substantial reinstatement of depressed mood. These data are consistent with the hypothesis that sensitisation of D2-like receptors may be central to the clinical action of SSRIs.

  3. Minimizing the risk of chemically reactive metabolite formation of new drug candidates: implications for preclinical drug design.

    Science.gov (United States)

    Brink, Andreas; Pähler, Axel; Funk, Christoph; Schuler, Franz; Schadt, Simone

    2016-11-27

    Many pharmaceutical companies aim to reduce reactive metabolite formation by chemical modification at early stages of drug discovery. A practice often applied is the detection of stable trapping products of electrophilic intermediates with nucleophilic trapping reagents to guide rational structure-based drug design. This contribution delineates this strategy to minimize the potential for reactive metabolite formation of clinical candidates during preclinical drug optimization, exemplified by the experience at Roche over the past decade. For the majority of research programs it was possible to proceed with compounds optimized for reduced covalent binding potential. Such optimized candidates are expected to have a higher likelihood of succeeding throughout the development processes, resulting in safer drugs.

  4. 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.

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

    Directory of Open Access Journals (Sweden)

    Gayaprasad Upadhyay

    2016-01-01

    Full Text Available 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.

  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. Structural Studies on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design

    Science.gov (United States)

    2008-02-01

    Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design PRINCIPAL INVESTIGATOR: Subramanyam Swaminathan...Inhibitors Leading to Drug Design 5b. GRANT NUMBER DAMD17-02-2-0011 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Subramanyam Swaminathan, Ph.D. 5d...on Intact Clostridium botulinum Neurotoxins Complexed with Inhibitors Leading to Drug Design Annual Report for the Period ending January 2008

  9. Molecular Modeling in Drug Design for the Development of Organophosphorous Antidotes/Prophylactics

    Science.gov (United States)

    1986-05-01

    5012 61102A 1102BS11 EB 025 11. TITLE (Include Security Classification) Molecular Modeling in Drug Design for the Development of Organophosphorous...t ....................................., ’ i.° AD MOLECULAR MODELING IN DRUG DESIGN FOR THE DEVELOPMENT OF ORGANOPHOSPHOROUS ANTIDOTES...Reed, W.J. Murray, E.B. Roche and L.N. Donelsmith, Gen. Pharmac., 12, 177-185 (1981). 5. L.B.Kier, "Molecular Orbital Theory in Drug Design ", Academic

  10. 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

  11. 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

  12. 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

  13. 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

  14. 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

  15. 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

  16. 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.

  17. Peptide-based proteasome inhibitors in anticancer drug design.

    Science.gov (United States)

    Micale, Nicola; Scarbaci, Kety; Troiano, Valeria; Ettari, Roberta; Grasso, Silvana; Zappalà, Maria

    2014-09-01

    The identification of the key role of the eukaryotic 26S proteasome in regulated intracellular proteolysis and its importance as a target in many pathological conditions wherein the proteasomal activity is defective (e.g., malignancies, autoimmune diseases, neurodegenerative diseases, etc.) prompted several research groups to the development of specific inhibitors of this multicatalytic complex with the aim of obtaining valid drug candidates. In regard to the anticancer therapy, the peptide boronate bortezomib (Velcade®) represents the first molecule approved by FDA for the treatment of multiple myeloma in 2003 and mantle cell lymphoma in 2006. Since then, a plethora of molecules targeting the proteasome have been identified as potential anticancer agents and a few of them reached clinical trials or are already in the market (i.e., carfilzomib; Kyprolis®). In most cases, the design of new proteasome inhibitors (PIs) takes into account a proven peptide or pseudopeptide motif as a base structure and places other chemical entities throughout the peptide skeleton in such a way to create an efficacious network of interactions within the catalytic sites. The purpose of this review is to provide an in-depth look at the current state of the research in the field of peptide-based PIs, specifically those ones that might find an application as anticancer agents.

  18. Meta-analyses of comparative efficacy of antidepressant medications on peripheral BDNF concentration in patients with depression

    Science.gov (United States)

    Chen, Jianjun; Deng, Xiao; Zhang, Lin; Zhao, Xiang; Qu, Zehui; Lei, Yang; Lei, Ting

    2017-01-01

    Background Brain derived neurotrophic factor (BDNF) is one of the most important regulatory proteins in the pathophysiology of major depressive disorder (MDD). Increasing numbers of studies have reported the relationship between serum/plasma BDNF and antidepressants (ADs). However, the potential effects of several classes of antidepressants on BDNF concentrations are not well known. Hence, our meta-analyses aims to review the effects of differential antidepressant drugs on peripheral BDNF levels in MDD and make some recommendations for future research. Methods Electronic databases including PubMed, EMBASE, the Cochrane Library, Web of Science, and PsycINFO were searched from 1980 to June 2016. The change in BDNF levels were compared between baseline and post-antidepressants treatment by use of the standardized mean difference (SMD) with 95% confidence intervals (CIs). All statistical tests were two-sided. Results We identified 20 eligible trials of antidepressants treatments for BDNF in MDD. The overall effect size for all drug classes showed that BDNF levels were elevated following a course of antidepressants use. For between-study heterogeneity by stratification analyses, we detect that length of treatment and blood samples are significant effect modifiers for BDNF levels during antidepressants treatment. While both SSRIs and SNRIs could increase the BDNF levels after a period of antidepressant medication treatment, sertraline was superior to other three drugs (venlafaxine, paroxetine or escitalopram) in the early increase of BDNF concentrations with SMD 0.53(95% CI = 0.13–0.93; P = 0.009). Conclusions There is some evidence that treatment of antidepressants appears to be effective in the increase of peripheral BDNF levels. More robust evidence indicates that different types of antidepressants appear to induce differential effects on the BDNF levels. Since sertraline makes a particular effect on BDNF concentration within a short amount of time, there is

  19. User-centered design improves the usability of drug-drug interaction alerts: Experimental comparison of interfaces.

    Science.gov (United States)

    Luna, Daniel R; Rizzato Lede, Daniel A; Otero, Carlos M; Risk, Marcelo R; González Bernaldo de Quirós, Fernán

    2017-02-01

    Clinical Decision Support Systems can alert health professionals about drug interactions when they prescribe medications. The Hospital Italiano de Buenos Aires in Argentina developed an electronic health record with drug-drug interaction alerts, using traditional software engineering techniques and requirements. Despite enhancing the drug-drug interaction knowledge database, the alert override rate of this system was very high. We redesigned the alert system using user-centered design (UCD) and participatory design techniques to enhance the drug-drug interaction alert interface. This paper describes the methodology of our UCD. We used crossover method with realistic, clinical vignettes to compare usability of the standard and new software versions in terms of efficiency, effectiveness, and user satisfaction. Our study showed that, compared to the traditional alert system, the UCD alert system was more efficient (alerts faster resolution), more effective (tasks completed with fewer errors), and more satisfying. These results indicate that UCD techniques that follow ISO 9241-210 can generate more usable alerts than traditional design.

  20. 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

  1. Neuronal and immunological basis of action of antidepressants in chronic pain - clinical and experimental studies.

    Science.gov (United States)

    Mika, Joanna; Zychowska, Magdalena; Makuch, Wioletta; Rojewska, Ewelina; Przewlocka, Barbara

    2013-01-01

    The current knowledge of the pharmacological actions of the tricyclic antidepressants (TCAs) has slowly evolved through their over 40-year history. Chronic pain represents one of the most important public health problems, and antidepressants are an essential part of the therapeutic strategy in addition to classical analgesics. This article reviews the available evidence on the efficacy and safety of antidepressants in chronic pain conditions; namely, headaches, low back pain, fibromyalgia, cancer pain and especially neuropathic pain. TCAs are traditionally the main type of depression medication used to treat chronic pain. Recently, new antidepressants were introduced into clinical use, with a significant reduction in side effects and equivalent efficacy on mood disorders. These new drugs that are effective for chronic pain belong to the tetracyclic antidepressants (TeCAs) group (amoxapine, maprotiline), the serotonin and noradrenaline reuptake inhibitors (SNRIs) group (duloxetine, venlafaxine, milnacipran) and the atypical antidepressants group (bupropion, trazodone, mirtazapine, nefazodone). In this review, we present the available publications on TCAs (amitriptyline, doxepin, imipramine, desipramine, nortriptyline), TeCAs (amoxapine, maprotiline), selective serotonin reuptake inhibitors (SSRIs) (citalopram, fluoxetine, paroxetine), SNRIs (duloxetine, venlafaxine, milnacipran) and atypical antidepressants (bupropion) for the treatment of neuropathic pain. We also review analgesics acting as both opioid receptor agonists and also acting as aminergic reuptake inhibitors. Existing data are insufficient to conclude which of these new classes of antidepressants has the best clinical profile and will be the most effective in the treatment of neuropathic pain; in addition, a lower incidence of side effects should be considered. Increased experimental and translational research is a key for further improvement of the treatment of chronic pain with antidepressants. However

  2. Reduced treatment-emergent sexual dysfunction as a potential target in the development of new antidepressants.

    Science.gov (United States)

    Baldwin, David S; Palazzo, M Carlotta; Masdrakis, Vasilios G

    2013-01-01

    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.

  3. 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.

  4. "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.

  5. 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.

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

    OpenAIRE

    Javad Safari; Zohre Zarnegar

    2014-01-01

    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 ...

  7. 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…

  8. Intriguing possibilities and beneficial aspects of transporter-conscious drug design.

    Science.gov (United States)

    Tashima, Toshihiko

    2015-08-01

    It has been revealed that many types of drugs interact with transporter proteins within an organism. Transporter proteins absorb or excrete materials, including drugs and nutrients, across the cell membrane. Some hydrophobic drugs are excreted from the cell as xenobiotics by ATP-binding cassette (ABC) transporters. However, solute carrier (SLC) transporters are tissue-specifically expressed and have substrate specificities. Thus, transporter-conscious drug design is an excellent method of delivering drugs to pharmaceutical target organs and provides advantages in absorption, distribution, excretion, and toxicity of drugs (ADMET) due to transport systems. In fact, based on this strategy, the bioavailability of prodrugs designed as peptide transporter 1 (PEPT1) substrates was better than that of the corresponding parent compounds due to the transport system in the small intestine. Furthermore, in central nervous system (CNS) drug developing, drug delivery into brain across the blood-brain barrier (BBB) is a serious problem. However, this problem can be also solved by the use of the transport systems at the BBB. Therefore, transporter-consciously designed drugs not only may effectively elicit activity but also may control adverse side effects caused by off-targets and drug-drug interactions and, consequently, may show good performance in clinical trials. In this review, I introduce possibilities and advantages of transporter-conscious drug designs.

  9. 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.

  10. Determination of designer drug cross-reactivity on five commercial immunoassay screening kits.

    Science.gov (United States)

    Regester, Laura E; Chmiel, Jeffrey D; Holler, Justin M; Vorce, Shawn P; Levine, Barry; Bosy, Thomas Z

    2015-03-01

    The detection of new designer drugs is often a difficult issue in forensic urine drug testing as immunoassays are the primary screening methodology for drugs of abuse in many of these laboratories. Cross-reactivity of compounds with immunoassay kits can either aid or complicate the detection of a variety of drug and drug metabolites. For instance, emerging designer drugs that share structural similarities to amphetamines and phencyclidine (PCP) have the potential to cross-react with assays designed to detect these compounds. This study evaluates the cross-reactivity of five commercially available immunoassay reagent kits for 94 designer drugs on a Roche/Hitachi Modular P automated screening instrument. The compounds used in this study are grouped by structural class as follows: 2,5-dimethoxyamphetamines, 2C (2,5-dimethoxyphenethylamines), β-keto amphetamines, substituted amphetamines, piperazines, α-pyrrolidinopropiophenones, tryptamines and PCP analogs. A drug concentration of 100 µg/mL was used to determine cross-reactivity for each assay and resulted in the following positive rates: Microgenics DRI(®) Ecstasy enzyme assay (19%), Microgenics DRI(®) Phencyclidine enzyme assay (20%), Lin-Zhi Methamphetamine enzyme immunoassay (39%), Siemens/Syva(®) EMIT(®)II Plus Amphetamines assay (43%) and CEDIA(®) DAU Amphetamine/Ecstasy assay (57%). Of the 94 designer drugs tested, 14% produced a negative response for all five kits. No designer drug used in this study generated a positive result for all five immunoassay kits.

  11. Rational drug design approach for overcoming drug resistance: application to pyrimethamine resistance in malaria.

    Science.gov (United States)

    McKie, J H; Douglas, K T; Chan, C; Roser, S A; Yates, R; Read, M; Hyde, J E; Dascombe, M J; Yuthavong, Y; Sirawaraporn, W

    1998-04-23

    Pyrimethamine acts by selectively inhibiting malarial dihydrofolate reductase-thymidylate synthase (DHFR-TS). Resistance in the most important human parasite, Plasmodium falciparum, initially results from an S108N mutation in the DHFR domain, with additional mutation (most commonly C59R or N51I or both) imparting much greater resistance. From a homology model of the 3-D structure of DHFR-TS, rational drug design techniques have been used to design and subsequently synthesize inhibitors able to overcome malarial pyrimethamine resistance. Compared to pyrimethamine (Ki 1.5 nM) with purified recombinant DHFR fromP. falciparum, the Ki value of the m-methoxy analogue of pyrimethamine was 1.07 nM, but against the DHFR bearing the double mutation (C59R + S108N), the Ki values for pyrimethamine and the m-methoxy analogue were 71.7 and 14.0 nM, respectively. The m-chloro analogue of pyrimethamine was a stronger inhibitor of both wild-type DHFR (with Ki 0.30 nM) and the doubly mutant (C59R +S108N) purified enzyme (with Ki 2.40 nM). Growth of parasite cultures of P. falciparum in vitro was also strongly inhibited by these compounds with 50% inhibition of growth occurring at 3.7 microM for the m-methoxy and 0.6 microM for the m-chloro compounds with the K1 parasite line bearing the double mutation (S108N + C59R), compared to 10.2 microM for pyrimethamine. These inhibitors were also found in preliminary studies to retain antimalarial activity in vivo in P. berghei-infected mice.

  12. Paediatric Drug Development and Formulation Design-a European Perspective

    NARCIS (Netherlands)

    Nales, D.A.; Kozarewicz, Piotr; Aylward, Brian; de Vries, Rutger; Egberts, Toine C G; Rademaker, Carin M A; Schobben, Alfred F A M

    2016-01-01

    The availability of licensed paediatric drugs is lagging behind those for adults, and there is a lack of safe formulations in suitable doses that children are able and willing to take. As a consequence, children are commonly treated with off-label or unlicensed drugs. As off-label and unlicensed dru

  13. Marine Antibody–Drug Conjugates: Design Strategies and Research Progress

    Science.gov (United States)

    Wang, Yu-Jie; Li, Yu-Yan; Liu, Xiao-Yu; Lu, Xiao-Ling; Cao, Xin; Jiao, Bing-Hua

    2017-01-01

    Antibody–drug conjugates (ADCs), constructed with monoclonal antibodies (mAbs), linkers, and natural cytotoxins, are innovative drugs developed for oncotherapy. Owing to the distinctive advantages of both chemotherapy drugs and antibody drugs, ADCs have obtained enormous success during the past several years. The development of highly specific antibodies, novel marine toxins’ applications, and innovative linker technologies all accelerate the rapid R&D of ADCs. Meanwhile, some challenges remain to be solved for future ADCs. For instance, varieties of site-specific conjugation have been proposed for solving the inhomogeneity of DARs (Drug Antibody Ratios). In this review, the usages of various natural toxins, especially marine cytotoxins, and the development strategies for ADCs in the past decade are summarized. Representative ADCs with marine cytotoxins in the pipeline are introduced and characterized with their new features, while perspective comments for future ADCs are proposed. PMID:28098746

  14. The effect size, study design, and development experience in commercially sponsored studies for new drug applications in approved drugs

    OpenAIRE

    Fukunaga, Satoshi; Kusama, Makiko; Ono, Shunsuke

    2014-01-01

    Pharmaceutical companies incorporate different features into the trials for new drug applications (NDAs) to render them efficient, making use of their experience. The objective of this analysis was to examine the associations between outcome and features related to study design and clinical development experience in commercially sponsored clinical trials. We collected data of phase 2 and phase 3 trials of all the drugs that obtained approval for depression, schizophrenia, asthma, hypertension...

  15. Mining the Information for Structure Based Drug Designing by Relational Database Management Notion

    OpenAIRE

    R. Balajee; Dhanarajan, M. S.

    2009-01-01

    Structure based drug design is a technique that is used in the initial stages of a drug discovery program. The role of various computational methods in the characterization of the chemical properties and behavior of molecular systems is discussed. The field of bioinformatics has become a major part of the drug discovery pipeline playing a key role for validating drug targets. By integrating data from many inter-related yet heterogeneous resources, informatics can help in our understanding of ...

  16. Effect of antidepressants on spatial memory deficit induced by dizocilpine.

    Science.gov (United States)

    Tao, Chenjuan; Yan, Weiwei; Li, Yuan; Lu, Xiaodong

    2016-10-30

    Cognitive deficits are a core symptom of schizophrenia. It is controversial whether antidepressants could improve cognitive symptoms in schizophrenia patients. The present study was designed to identify the therapeutic effect of antidepressants on cognitive deficits in schizophrenia. In the present study, adolescent rats were repeatedly exposed to dizocilpine, which can induce cognitive deficits associated with schizophrenia. Then these rats were treated by six antidepressants (fluvoxamine, sertraline, paroxetine, escitalopram, venlafaxine, mirtazapine) or vehicle. The rats in the control group were exposed to vehicle during the study. Lastly, all rats' spatial memory (a major part of cognition) was assessed using the Morris water maze (MWM) test, and the density of hippocampal parvalbumin (PV) interneurons was evaluated to explore possible mechanisms underlying spatial memory change in schizophrenia. The results of the present study supported the hypothesis of a therapeutic effect of fluvoxamine and escitalopram on spatial memory deficit induced by dizocilpine. Additionally, the data of the present study suggested that fluvoxamine and escitalopram remitted hippocampal PV interneuron reduction induced by dizocilpine. The neuroprotective effect of fluvoxamine and escitalopram may partly explain the therapeutic effect of antidepressants on spatial memory deficit in schizophrenia patients.

  17. 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.

  18. 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

  19. Antidepressants alleviate the impact of reinforcer downshift.

    Science.gov (United States)

    Nikiforuk, Agnieszka; Popik, Piotr

    2009-01-01

    Depressive disorder is associated with problems of coping with life's difficulties, including episodes of frustration and disappointment, operationally defined as an unexpected reinforcer omission or a reduction of reinforcer magnitude. In a novel model aimed at detecting potential antidepressants, rats were trained in the operant task under progressive ratio schedule of reinforcement with the break point (BP, the value of the last completed response ratio) as a behavioral endpoint. In the main experiment, a 32% sucrose solution was initially used as the reinforcer. Once the stable responding was achieved, for the following 5 days animals were treated once daily with the experimental drugs, and were offered a 4% sucrose solution instead. In vehicle-treated controls, the reduction of sucrose concentration resulted in a decrease in responding from a BP of about 40 (totaling 166 responses) to a BP of about 9 (totaling 22 responses). Chlordiazepoxide (4 and 8 mg/kg), fluoxetine (3 mg/kg), citalopram (6 mg/kg) and cocaine (2.5 and 5 mg/kg) markedly inhibited this response decrement, while fluoxetine (6 mg/kg) augmented it. Neither desipramine (1-6 mg/kg) nor morphine (1-5 mg/kg) affected responding under the reduced sucrose concentration condition. In the control experiment, the rats have never been offered 32% sucrose solution but their responding was always maintained by 4% sucrose. Under these unchanged conditions, only cocaine (5 mg/kg) affected (increased) responding. The present results suggest that the antidepressants selectively inhibiting serotonin reuptake and a benzodiazepine anxiolytic but not psychostimulant cocaine may specifically protect animals from the effects of a reinforcer downshift.

  20. Design Project on Controlled-Release Drug Delivery Devices: Implementation, Management, and Learning Experiences

    Science.gov (United States)

    Xu, Qingxing; Liang, Youyun; Tong, Yen Wah; Wang, Chi-Hwa

    2010-01-01

    A design project that focuses on the subject of controlled-release drug delivery devices is presented for use in an undergraduate course on mass transfer. The purpose of the project is to introduce students to the various technologies used in the fabrication of drug delivery systems and provide a practical design exercise for understanding the…

  1. Multi-Step Usage of in Vivo Models During Rational Drug Design and Discovery

    OpenAIRE

    Williams, Charles H.; Hong, Charles C.

    2011-01-01

    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 t...

  2. Design and Evaluation of Gastro retentive Drug Delivery System of Anti Ulcer Drug

    OpenAIRE

    Patil, J. S.

    2014-01-01

    Floating matrix tablets of Lansoprezol were developed to prolong gastric residence time, leading to sustained action of the drug. Tablets were prepared by wet granulation technique, using hydroxypropylmethyl-cellulose as a polymer in two different grades, HPMC K4M and HPMC K15M. Tablets were evaluated for their physical characteristics, viz., hardness, thickness, friability, mass variation, drug content and floating properties. Further, tablets were studied for in vitro drug release character...

  3. Drug: D08257 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08257 Drug Nefazodone (INN) C25H32ClN5O2 469.2245 470.0069 D08257.gif Antidepressa...arker: CYP2D6 [HSA:1565] CYP inhibition: CYP3A [HSA:1576 1577 1551] map07027 Antidepressants Anatomical Ther...apeutic Chemical (ATC) classification [BR:br08303] N NERVOUS SYSTEM N06 PSYCHOANALEPTICS N06A ANTIDEPRESSANTS N06AX Other antidepress... classification [BR:br08302] Antidepressants SSRIs/SNRIs (Selective Serotonin Reuptake Inhibitors/Serotonin

  4. 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.

  5. A review on antidepressant effect of medicinal plants

    Directory of Open Access Journals (Sweden)

    Zahra Rabiei

    2017-03-01

    Full Text Available Depression is a life-threatening, debilitating, and common disease affecting different segments of community. Chemical and synthetic drugs available to treat this disease cause many adverse effects and may lead to complete recovery in only 50% of patients. At the same time, medicinal plants have been reported to exert optimal pharmacological effects in treating depression in different models. In this review, the relevant articles indexed in the reliable databases PubMed, PubMed central, Scopus and Web of Science were review-ed. The review indicated that most medicinal plants exerted antidepressant effects through synaptic regulation of serotonin, noradrenaline, and dopamine, regulating activity of hypothalamic-pituitary-adrenal axis, reinfor-cing anti-oxidant defense system, and decreasing inflammatory mediators. The medicinal plants and their active compounds can relieve depression through different pathways and hence are considered a new source to produce antidepressants.

  6. Crystallization processes in pharmaceutical technology and drug delivery design

    Science.gov (United States)

    Shekunov, B. Yu; York, P.

    2000-04-01

    Crystallization is a major technological process for particle formation in pharmaceutical industry and, in addition, plays an important role in defining the stability and drug release properties of the final dosage forms. Industrial and regulatory aspects of crystallization are briefly reviewed with reference to solid-state properties of pharmaceuticals. Crystallization, incorporating wider definition to include precipitation and solid-state transitions, is considered in terms of preparation of materials for direct compression, formation of amorphous, solvated and polymorphic forms, chiral separation of drugs, production of materials for inhalation drug delivery and injections. Finally, recent developments in supercritical fluid particle technology is considered in relationship to the areas discussed.

  7. 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

  8. 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

  9. 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

    2015-11-02

    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

  10. 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.

  11. Design and evaluation of transdermal drug delivery system of gliclazide

    Directory of Open Access Journals (Sweden)

    Shinde Anilkumar

    2010-01-01

    Full Text Available Transdermal systems are ideally suited for diseases that demand chronic treatment. Hence, an anti-diabetic agent of both therapeutic and prophylactic usage has been subjected to transdermal investigation. Gliclazide, a second-generation hypoglycemic agent, faces problems like its poor solubility, poor oral bioavailability with large individual variation and extensive metabolism. In the present work, transdermal matrix-type patches were prepared by film casting techniques on mercury using polymers like HPMC, Eudragit RL-100, and chitosan. Also an attempt was made to increase the permeation rate of drug by preparing an inclusion complex with hydroxypropyl β-cyclodextrin (HP β-CD. The possibility of a synergistic effect of chemical penetration enhancers (CPE (propylene glycol and oleic acid on the transdermal transport of the drug was also studied. Folding endurance was found to be high in patches containing higher amount of the Eudragit. There was increase in tensile strength with an increase in Eudragit in the polymer blend. In vitro drug release profile indicates that the drug release is sustained with increasing the amount of Eudragit in patches. The patches containing inclusion complex of drug showed higher permeation flux compared with patches containing plain drug. The result of the synergistic effect indicates that the HP β- CD in conjunction with other CPE showed a higher permeation flux.

  12. Comparing episodes of antidepressants use with intermittent episodes of no use : A higher relative risk of suicide attempts but not of suicide at young age

    NARCIS (Netherlands)

    Termorshuizen, Fabian; Smeets, Hugo M.; Boks, Marco P M; Heerdink, Eibert R.

    2016-01-01

    The Food and Drug Administration has issued a number of advisories regarding a possible causal link between antidepressants and suicide behaviour among young persons. We investigated the age dependency of (fatal) suicide attempts associated with antidepressants (N=232,561). By linking insurance clai

  13. 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.

  14. 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.

  15. 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.

  16. 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.

  17. New tuberculostatic agents targeting nucleic acid biosynthesis: drug design using QSAR approaches.

    Science.gov (United States)

    Bueno, Renata V; Braga, Rodolpho C; Segretti, Natanael D; Ferreira, Elizabeth I; Trossini, Gustavo H G; Andrade, Carolina H

    2014-01-01

    Worldwide, tuberculosis (TB) is the leading cause of death among curable infectious diseases. The emergence of multidrug resistant (MDR) and extensively drug resistant (XDR) TB is a growing global health concern and there is an urgent need for new anti-TB drugs. Enzymes involved in DNA and ATP biosynthesis are potential targets for tuberculostatic drug design, since these enzymes are essential for Mycobacterium tuberculosis growth. This review presents the current progress and applications of structure-activity relationship analysis for the discovery of innovative tuberculostatic agents as inhibitors of ribonucleotide reductase, DNA gyrase, ATP synthase, and thymidylate kinase enzymes, highlighting present challenges and new opportunities in TB drug design.

  18. The effect size, study design, and development experience in commercially sponsored studies for new drug applications in approved drugs.

    Science.gov (United States)

    Fukunaga, Satoshi; Kusama, Makiko; Ono, Shunsuke

    2014-01-01

    Pharmaceutical companies incorporate different features into the trials for new drug applications (NDAs) to render them efficient, making use of their experience. The objective of this analysis was to examine the associations between outcome and features related to study design and clinical development experience in commercially sponsored clinical trials. We collected data of phase 2 and phase 3 trials of all the drugs that obtained approval for depression, schizophrenia, asthma, hypertension, and diabetes in Japan from 1970 to 2011. In total, 145 trials from 90 test drugs were eligible for our study. We calculated the effect size, the standard mean of differences between test drug and comparator therapeutic effects, as the objective variable for use in our analysis. A linear mixed effect model with nested and crossed random effects was used in the analysis including variety of therapeutic area, test drugs and clinical trials. The analysis showed that trial features including sample size, subjective endpoints and active comparator of the same mode of action were negatively associated with effect size. In addition, sponsors' domestic clinical development experience with similar drugs seemed to have a positive association, but prior development experience in foreign countries did not. The accumulation of skills and knowledge within sponsors, and accumulated experience in domestic professionals who implement clinical trials under study contracts with sponsors would be of great importance for yielding clear outcomes. This study provides additional evidence with respect to possible sizes and directions of the influence of study design features that must be considered when planning and implementing trials for new drug applications, and when retrospectively comparing outcomes from trials with different designs and environments.

  19. 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

  20. 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.

  1. Platinum anticancer drugs. From serendipity to rational design.

    Science.gov (United States)

    Monneret, C

    2011-11-01

    The discovery of cis-platin was serendipitous. In 1965, Rosenberg was looking into the effects of an electric field on the growth of Escherichia coli bacteria. He noticed that bacteria ceased to divide when placed in an electric field but what Rosenberg also observed was a 300-fold increase in the size of the bacteria. He attributed this to the fact that somehow the platinum-conducting plates were inducing cell growth but inhibiting cell division. It was later deduced that the platinum species responsible for this was cis-platin. Rosenberg hypothesized that if cis-platin could inhibit bacterial cell division it could also stop tumor cell growth. This conjecture has proven correct and has led to the introduction of cis-platin in cancer therapy. Indeed, in 1978, six years after clinical trials conducted by the NCI and Bristol-Myers-Squibb, the U.S. Food and Drug Administration (FDA) approved cis-platin under the name of Platinol(®) for treating patients with metastatic testicular or ovarian cancer in combination with other drugs but also for treating bladder cancer. Bristol-Myers Squibb also licensed carboplatin, a second-generation platinum drug with fewer side effects, in 1979. Carboplatin entered the U.S. market as Paraplatin(®) in 1989 for initial treatment of advanced ovarian cancer in established combination with other approved chemotherapeutic agents. Numerous platin derivatives have been further developed with more or less success and the third derivative to be approved in 1994 was oxaliplatin under the name of Eloxatin(®). It was the first platin-based drug to be active against metastatic colorectal cancer in combination with fluorouracil and folinic acid. The two others platin-based drugs to be approved were nedaplatin (Aqupla(®)) in Japan and lobaplatin in China, respectively. More recently, a strategy to overcome resistance due to interaction with thiol-containing molecules led to the synthesis of picoplatin in which one of the amines linked to Pt

  2. 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...

  3. Pharmaceutical equivalence by design for generic drugs: modified-release products.

    Science.gov (United States)

    Raw, André Sirota; Lionberger, Robert; Yu, Lawrence X

    2011-07-01

    The Office of Generic Drugs has ensured the high quality of generic products based upon two requirements: pharmaceutical equivalence and bioequivalence to the reference listed drug (RLD). This paradigm has been used with success toward ensuring quality generic drug products that provide the same therapeutic benefit as the RLD. Drug products have increased in design complexity; as a result, approaches to ensure therapeutic equivalence must evolve to provide assurance of quality generic drug products. The Food and Drug Administration quality by design initiative (QbD) provides an enhanced evaluation approach by introducing the concept of a quality target product profile (QTPP). The QTPP introduces, within the context of the current regulatory framework, the quality concept of "pharmaceutical equivalence by design." This article illustrates through several examples how this QbD element in the evaluation of modified-release drug products enhances the current framework to ensure generic drug product equivalence. It achieves this by complementing the traditional paradigm, "equivalence by testing," where product equivalence is based upon inferences from a limited bioequivalence study, to one that also considers whether the drug product was developed to be an equivalent to the RLD, using appropriate quality surrogates that target "pharmaceutical equivalence by design."

  4. 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.

  5. How do antidepressants work? New perspectives for refining future treatment approaches.

    Science.gov (United States)

    Harmer, Catherine J; Duman, Ronald S; Cowen, Philip J

    2017-01-30

    Most currently available antidepressants target monoamine neurotransmitter function. However, a purely neurotransmitter-based explanation for antidepressant drug action is challenged by the delayed clinical onset of most agents and the need to explain how neurochemical changes reverse the many different symptoms of depression. Novel approaches to understanding of antidepressant drug action include a focus on early changes in emotional and social processing and the role of neural plasticity. In this Review, we discuss the ways in which these two different theories reflect different or complementary approaches, and how they might be integrated to offer novel solutions for people with depression. We consider the predictions made by these mechanistic approaches for the stratification and development of new therapeutics for depression, and the next steps that need to be made to facilitate this translation of science to the clinic.

  6. 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.

  7. Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A

    Science.gov (United States)

    2008-09-26

    Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A Desigan Kumaran1, Richa Rawat1, S. Ashraf Ahmed2, Subramanyam...Swaminathan S (2008) Substrate Binding Mode and Its Implication on Drug Design for Botulinum Neurotoxin A. PLoS Pathog 4(9): e1000165. doi:10.1371/journal.ppat...COVERED - 4. TITLE AND SUBTITLE Substrate binding mode and its implication on drug design for botulinum neurotoxin A. PLoS Pathogen 4:e100165 5a

  8. 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.

  9. Newer antidepressants in pregnancy: prospective outcome of a case series.

    Science.gov (United States)

    Yaris, Fusun; Kadioglu, Mine; Kesim, Murat; Ulku, Cunay; Yaris, Ersin; Kalyoncu, Nuri Ihsan; Unsal, Mesut

    2004-12-01

    Antidepressant drug choice in pregnancy is a complex problem especially for new drugs. Among 590 cases exposed to drugs during pregnancy who were followed by our center, 21 cases used newer antidepressants, i.e., venlafaxine, mirtazapine, nefazodone. We present the gestational findings and fetal outcomes of these cases. Ten cases had used venlafaxine, one case had used both venlafaxine and mirtazapine, eight had used mirtazapine alone or with some other drugs and two had used nefazodone, in the first trimester. Of the 21 cases, 17 (80.9%) had healthy babies, 3 (14.3%) decided to terminate the pregnancy, and 1 (4.8%) spontaneous abortion was observed in a case exposed to mirtazapine, alprazolam, diazepam and trifluoperazine. All obstetrical findings were normal during the pregnancy of each case. No congenital abnormality and developmental problem was observed in the babies followed up for 12 months. The aim of the present study is to contribute the data to the limited knowledge available in the literature regarding human pregnancy.

  10. From G Protein-coupled Receptor Structure Resolution to Rational Drug Design.

    Science.gov (United States)

    Jazayeri, Ali; Dias, Joao M; Marshall, Fiona H

    2015-08-07

    A number of recent technical solutions have led to significant advances in G protein-coupled receptor (GPCR) structural biology. Apart from a detailed mechanistic view of receptor activation, the new structures have revealed novel ligand binding sites. Together, these insights provide avenues for rational drug design to modulate the activities of these important drug targets. The application of structural data to GPCR drug discovery ushers in an exciting era with the potential to improve existing drugs and discover new ones. In this review, we focus on technical solutions that have accelerated GPCR crystallography as well as some of the salient findings from structures that are relevant to drug discovery. Finally, we outline some of the approaches used in GPCR structure based drug design.

  11. [Antidepressive pharmacotherapy. In slight and severe disease, young and old].

    Science.gov (United States)

    Baghai, T C; Volz, H P; Möller, H J

    2009-02-01

    During the past decade a variety of promising new compounds launched onto the market not only enhancing serotonergic and noradrenergic neurotransmission, but also influencing the dopamine and the melatonergic receptor system. In spite of misleading discussions both in the specialized and in the lay press the clinical effectiveness of antidepressants still is indisputable. The main advantages of the newer drugs are the broadening of the spectrum treatments and a far better tolerability profile in comparison to older compounds. Predominantly depression of medium to high severity should be treated pharmacologically. Especially severe depression seems to respond better to dually acting antidepressants. In children effectiveness of Omega3-fatty acids has been shown, in adolescents SSRI treatment was efficacious. Older patients respond to all antidepressant mechanisms, but more selective substances should be preferred due to a better tolerability. The study of new treatment options is of major importance to provide better strategies for the clinical management of depression in the future, and is thus also of great socio-economic importance.

  12. 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.

  13. 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.

  14. 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.

  15. Rational, computer-enabled peptide drug design: principles, methods, applications and future directions.

    Science.gov (United States)

    Diller, David J; Swanson, Jon; Bayden, Alexander S; Jarosinski, Mark; Audie, Joseph

    2015-01-01

    Peptides provide promising templates for developing drugs to occupy a middle space between small molecules and antibodies and for targeting 'undruggable' intracellular protein-protein interactions. Importantly, rational or in cerebro design, especially when coupled with validated in silico tools, can be used to efficiently explore chemical space and identify islands of 'drug-like' peptides to satisfy diverse drug discovery program objectives. Here, we consider the underlying principles of and recent advances in rational, computer-enabled peptide drug design. In particular, we consider the impact of basic physicochemical properties, potency and ADME/Tox opportunities and challenges, and recently developed computational tools for enabling rational peptide drug design. Key principles and practices are spotlighted by recent case studies. We close with a hypothetical future case study.

  16. Evaluation of commercial multi-drug oral fluid devices to identify 39 new amphetamine-designer drugs.

    Science.gov (United States)

    Nieddu, Maria; Burrai, Lucia; Trignano, Claudia; Boatto, Gianpiero

    2014-03-01

    Recently, the diffusion on the black market of new psychoactive substances not controlled and often sold as 'legal highs', is exponentially increasing in Europe. Generally, the first analysis for these drugs involves an immunoassay screening in urine or plasma. Actually, there is growing interest in the use of oral fluid (OF) as alternative specimen over conventional biological fluids for drug testing, because of the significant advantages, as a non-invasive collection under direct observation without undue embarrassment or invasion of privacy, and a good correlation with plasma analytical data. Few assays have been developed for detection of new psychoactive compounds in biological samples, so it is important to investigate how they may or may not react in pre-existing commercial immunoassays. In this paper, two different multi-drugs oral fluid screen devices (OFDs) (Screen® Multi-Drug OFD and GIMA One Step Multi-Line Screen Test OFD) were evaluated to determine the cross-reactivity of thirty-nine new amphetamine designer drugs, including twelve substances officially recognized as illicit by italian legislation. Cross-reactivity towards most drugs analyzed was <1 in assays targeting amphetamine (AMP) or methamphetamine (MET). Only two (p-methoxyamphetamine and p-methoxymethamphetamine) of all tested amphetamines gave a positive result.

  17. 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.

  18. Antidepressant effect of Melissa officinalis in the forced swimming test

    Directory of Open Access Journals (Sweden)

    M Emamghoreishi

    2009-03-01

    Full Text Available ABSTRACT Background: In Iranian and other traditional medicines, an antidepressant effect has been indicated for Melissa officinalis (Lamiaceae. However, studies showing its antidepressant effect is lacking. Therefore, the present study was undertaken to examine whether the aqueous extract and essential oil from leaves of Melissa officinalis have an antidepressant-like activity in mice.  Materials and Methods: The effect of subchronic administration of different doses of the aqueous extract (25, 75, 150, 300 mg/kg or water; n=9-10 and the essential oil (10, 25, 75, 150, 300 mg/kg or almond oil; n=9-10 on immobility, climbing, and swimming behaviors were evaluated in the forced swimming test. Fluoxetine (20mg/kg and imipramine (15 mg/kg were used as reference drugs. Additionally, the effect of both plant preparations on spontaneous activity was examined. Results: All doses of the aqueous extract, used in this study, produced a significant reduction in immobility along with an increase in climbing behavior which is similar to those which have been observed with imipramine. Essential oil caused a dose-dependent reduction in immobility and an increase in climbing at all studied doses, compared to control group. Only the highest dose (300mg/kg of essential oil showed a significant increase in swimming behavior. The aqueous extract, but not the essential oil, decreased spontaneous activity in a dose dependent manner. Conclusion: The results of this study suggests that the Melissa officinalis possess an antidepressant-like activity similar to imipramine which may have a potential clinical value for treatment of depression.

  19. Computational drug designing of fungal pigments as potential aromatase inhibitors

    Directory of Open Access Journals (Sweden)

    Nighat Fatima

    2014-12-01

    Full Text Available The existing aromatase inhibitors produced unwelcome effects impose the discovery of novel drugs with privileged selectivity, a reduced amount of toxicity and humanizing potency. In this study, we illuminate the binding mode of polyketide azaphilanoid pigments monascin, ankaflavin, monascorubrin and monascorubramine isolated from Monascus fungus to the aromatase by molecular docking. The 3-dimensional structure of aromatase enzyme (PDB: 4KQ8 was obtained from the Protein Data Bank. PatchDock docking software was used to analyze structural complexes of the aromatase with monascus pigments. Comparatively, the AutoGrid model presented the most briskly constructive binding mode of monascin to aromatase. Docked energies in kcal/mol are: monascin;-13.2; monascorubramine:-12.8, monascorubrin:-12.3; ankaflavin: -10.5. These outcomes exposed these ligands could be potential drugs to treat hormone dependent breast cancer.

  20. Bioequivalence study designs for generic solid oral anticancer drug products: scientific and regulatory considerations.

    Science.gov (United States)

    Kaur, Paramjeet; Chaurasia, Chandra S; Davit, Barbara M; Conner, Dale P

    2013-12-01

    The demonstration of bioequivalence (BE) between the test and reference products is an integral part of generic drug approval process. A sound BE study design is pivotal to the successful demonstration of BE of generic drugs to their corresponding reference listed drug product. Generally, BE of systemically acting oral dosage forms is demonstrated in a crossover, single-dose in vivo study in healthy subjects. The determination of BE of solid oral anticancer drug products is associated with its own unique challenges due to the serious safety risks involved. Unlike typical BE study in healthy subjects, the safety issues often necessitate conducting BE studies in cancer patients. Such BE studies of an anticancer drug should be conducted without disturbing the patients' therapeutic dosing regimen. Attributes such as drug permeability and solubility, pharmacokinetics, dosing regimen, and approved therapeutic indication(s) are considered in the BE study design of solid anticancer drug products. To streamline the drug approval process, the Division of Bioequivalence posts the Bioequivalence Recommendations for Specific Products guidances on the FDA public website. The objective of this article is to illustrate the scientific and regulatory considerations in the design of BE studies for generic solid oral anticancer drug products through examples.

  1. A Statistical Perspective on the Design of Drug-Court Studies

    Science.gov (United States)

    Merrall, Elizabeth L. C.; Bird, Sheila M.

    2009-01-01

    Recent meta-analyses of drug-court studies recognized the poor methodological quality of the evaluations, with only a few being randomized. This article critiques the design of the randomized studies from a statistical perspective. Learning points are identified for future drug-court studies and are applicable to evaluations both of other…

  2. Drug treatments for subjective tinnitus: serendipitous discovery versus rational drug design.

    Science.gov (United States)

    Smith, Paul F; Darlington, Cynthia L

    2005-07-01

    Progress has been made in understanding the neural basis of subjective tinnitus (ST); however, this has not, as yet, translated into many new drug treatments. One reason for this is that realistic behavioral models of ST in animals have been developed only recently, and are still not widely used. Nonetheless, some significant pharmacological advances have been made. At present, there is evidence to support the efficacy of transtympanic gentamicin administration in the treatment of tinnitus associated with Meniere's disease; there is also some evidence to support the efficacy of intratympanic steroid and lidocaine application in the management of ST. Although benzodiazepines and anti-epileptic drugs appear to be effective in many cases of this condition, there is concern about their adverse side effect profile. Based on well-controlled clinical trials, vasodilators such as misoprostol, and histamine receptor ligands should be further investigated. Finally, given the evidence that ST is a form of sensory epilepsy, new antiepileptic drugs should be tested for potential efficacy as they are developed; such drugs may include novel N-methyl-D-aspartate receptor antagonists, as well as cannabinoids.

  3. Improving Protocol Design Feasibility to Drive Drug Development Economics and Performance

    OpenAIRE

    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 ...

  4. Improving Protocol Design Feasibility to Drive Drug Development Economics and Performance

    OpenAIRE

    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...

  5. 75 FR 8968 - Draft Guidance for Industry on Adaptive Design Clinical Trials for Drugs and Biologics; Availability

    Science.gov (United States)

    2010-02-26

    ... current thinking on adaptive design clinical trials for drugs and biologics. It does not create or confer... HUMAN SERVICES Food and Drug Administration Draft Guidance for Industry on Adaptive Design Clinical... entitled ``Adaptive Design Clinical Trials for Drugs and Biologics.'' The draft guidance provides...

  6. Drug: D07938 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ation [BR:br08302] Anti-Addiction/Substance Abuse Treatment Agents Smoking Cessation Agents Bupropion D07938...SSANTS N06AX Other antidepressants N06AX12 Bupropion D07938 Bupropion hydrobromide (USAN) USP drug classific

  7. Drug: D02571 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available rexic; Antidepressant ATC code: A08AA10 Serotonin norepinephrine reuptake inhibitor (SNRI) noradrenalin tran... Target-based classification of drugs [BR:br08310] Transporters Solute carrier family SLC6 SLC6A2 (nora

  8. Drug: D07334 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available ant, tricyclic Tricyclic antidepressants serotonin transporter inhibitor [HSA:6532] [KO:K05037]; noradrenali... classification of drugs [BR:br08310] Transporters Solute carrier family SLC6 SLC6A2 (nora

  9. Drug: D10133 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available 10133.gif Antidepressant serotonin transporter inhibitor [HSA:6532] [KO:K05037]; noradrenalin transporter in...lassification of drugs [BR:br08310] Transporters Solute carrier family SLC6 SLC6A2 (noradrenalin transporter

  10. 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] Antiparkinso

  11. TRPV1: A Target for Rational Drug Design

    Directory of Open Access Journals (Sweden)

    Vincenzo Carnevale

    2016-08-01

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

  12. Improving Protocol Design Feasibility to Drive Drug Development Economics and Performance

    Directory of Open Access Journals (Sweden)

    Kenneth Getz

    2014-05-01

    Full Text Available 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.

  13. Cytisine, a partial agonist of high-affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice.

    Science.gov (United States)

    Mineur, Yann S; Somenzi, Oli; Picciotto, Marina R

    2007-04-01

    The nicotine in tobacco is thought to modulate neuronal systems regulating mood. Moreover, it appears possible that blockade rather than activation of beta2-containing (beta2*) nicotinic acetylcholine receptors (nAChRs) may lead to antidepressant-like effects. We used cytisine, a partial agonist of alpha4/beta2*nAChRs and a full agonist at alpha3/beta4*nAChRs, in several tests of antidepressant efficacy. Further, we used c-fos expression to identify potential neurobiological correlates of the antidepressant-like effects of cytisine. Cytisine had antidepressant-like effects in several animal models of antidepressant efficacy. In addition, immunohistochemical analyses indicated that cytisine could reduce c-fos immunoreactivity in the basolateral amygdala by approximately 50%. These data show that cytisine acts like classical antidepressants in rodent models of antidepressant efficacy. In addition, cytisine's ability to block alpha4/beta2*nAChRs may be responsible for its antidepressant-like properties, and these may be mediated through a reduction of neuronal activity in the basolateral amygdala. These studies also suggest that both antagonists and partial agonists of alpha4/beta2*nAChRs would be interesting targets for the development of novel antidepressant drugs.

  14. Cytisine, a partial agonist of high affinity nicotinic acetylcholine receptors, has antidepressant-like properties in male C57BL/6J mice

    Science.gov (United States)

    Mineur, Yann S.; Somenzi, Oli; Picciotto, Marina R.

    2007-01-01

    The nicotine in tobacco is thought to modulate neuronal systems regulating mood. Moreover, it appears possible that blockade rather than activation of β2-containing (β2*) nicotinic acetylcholine receptors (nAChRs) may lead to antidepressant-like effects. We used cytisine, a partial agonist of α4/β2* nAChRs and a full agonist at α3/β4* nAChRs, in several tests of antidepressant efficacy. Further, we used c-fos expression to identify potential neurobiological correlates of the antidepressant-like effects of cytisine. Cytisine had antidepressant-like effects in several animal models of antidepressant efficacy. In addition, immunohistochemical analyses indicated that cytisine could reduce c-fos immunoreactivity in the basolateral amygdala by ~ 50%. These data show that cytisine acts like classical antidepressants in rodent models of antidepressant efficacy. In addition, cytisine’s ability to block α4/β2* nAChRs may be responsible for its antidepressant-like properties, and these may be mediated through a reduction of neuronal activity in the basolateral amygdala. These studies also suggest that both antagonists and partial agonists of α4/β2* nAChRs would be interesting targets for the development of novel antidepressant drugs. PMID:17320916

  15. Screening of a novel furan compound for its antidepressant activity in albino mice

    Directory of Open Access Journals (Sweden)

    Jayakumar JK

    2016-12-01

    Conclusions: It can be concluded that the test drug has produced significant inhibition in duration of immobility by FST and also had significant protection against passive behavior. Hence substituted furan had potential antidepressant activity. [Int J Basic Clin Pharmacol 2016; 5(6.000: 2389-2392

  16. Continuation and maintenance therapy with antidepressive agents. Meta-analysis of research

    NARCIS (Netherlands)

    Loonen, A.J.M.; Peer, P.G.M.; Zwanikken, G.J.

    1991-01-01

    The purpose of this study was to ascertain the clinical benefits of long-term antidepressant drug treatment in patients with recurrent major depression. Bibliographic reviews of four textbooks and five review articles, literature searches using MEDLINE (1977-1987) and EXCERPTA MEDICA (1974-1987), ha

  17. 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

  18. Application of the design of experiments in optimization of drug layering of pellets with an insight into drug polymer interactions.

    Science.gov (United States)

    Kovacevic, Jovana; Ibric, Svetlana; Djuris, Jelena; Kleinebudde, Peter

    2016-06-15

    This study consists of two experimental designs. Within the first one, suitable technique for application of model drug onto inactive pellets was evaluated and formulation and process parameters with greatest impact to process efficency and useful yield were determined. Results of experiments showed that formulation characteristics were the ones with the greatest impact on coating efficiency and that suspension layering technique was significantly better for drug application onto inactive pellets in comparison to solution layering during which pronounced agglomeration of pellets occurred. Analysis of drug-polymer interactions by differential scanning calorimetry was performed to explain the results of experiments. The reason for agglomeration of pellets during solution layering was formation of low Tg amorphous form of model drug. The second set of experiments was performed according to central composite design experimental plan in order to optimize level of binder and concentration of solids in the coating liquid which were found to have greatest positive impact on process efficiency and useful yield in the screening study. Statistically significant models were obtained by response surface methodology and it was possible to use them to define optimal levels of excipients in the formulation.

  19. Pleiotropic effects of statins: new therapeutic targets in drug design.

    Science.gov (United States)

    Bedi, Onkar; Dhawan, Veena; Sharma, P L; Kumar, Puneet

    2016-07-01

    The HMG Co-enzyme inhibitors and new lipid-modifying agents expand their new therapeutic target options in the field of medical profession. Statins have been described as the most effective class of drugs to reduce serum cholesterol levels. Since the discovery of the first statin nearly 30 years ago, these drugs have become the main therapeutic approach to lower cholesterol levels. The present scientific research demonstrates numerous non-lipid modifiable effects of statins termed as pleiotropic effects of statins, which could be beneficial for the treatment of various devastating disorders. The most important positive effects of statins are anti-inflammatory, anti-proliferative, antioxidant, immunomodulatory, neuroprotective, anti-diabetes, and antithrombotic, improving endothelial dysfunction and attenuating vascular remodeling besides many others which are discussed under the scope of this review. In particular, inhibition of Rho and its downstream target, Rho-associated coiled-coil-containing protein kinase (ROCK), and their agonistic action on peroxisome proliferator-activated receptors (PPARs) can be viewed as the principle mechanisms underlying the pleiotropic effects of statins. With gradually increasing knowledge of new therapeutic targets of statins, their use has also been advocated in chronic inflammatory disorders for example rheumatoid arthritis (RA) and in systemic lupus erythematosus (SLE). In the scope of review, we highlight statins and their pleiotropic effects with reference to their harmful and beneficial effects as a novel approach for their use in the treatment of devastating disorders. Graphical abstract Pleiotropic effect of statins.

  20. 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.

  1. General issues and precautions in the design for clinical trials of investigational new drugs.

    Science.gov (United States)

    Hu, Liang-ping; Bao, Xiao-lei

    2011-02-01

    The general problems existing in the clinical trials of investigational new drugs involve some key aspects such as the guiding principles, research designs, quality controls and statistical analyses. This paper explores the eight general issues in the clinical trials of investigational new drugs and presents precautionary measures with high operability. Research on the clinical trials of investigational new drugs is a complex project, which should be carried out strictly according to the policies, laws, criteria and operating rules set by related agencies. The neglect of research designs and data analyses will lead clinical trials to failure.

  2. Drug: D08626 [KEGG MEDICUS

    Lifescience Database Archive (English)

    Full Text Available D08626 Drug Trazodone (INN); Trittico (TN) C19H22ClN5O 371.1513 371.8639 D08626.gif Tranquilizer; Antidepres...+6532) Serotonergic synapse Enzyme: CYP3A4 [HSA:1576], CYP3A5 [HSA:1577], CYP3A7 [HSA:1551], CYP2D6 [HSA:1565] map07027 Antidepress...IDEPRESSANTS N06AX Other antidepressants N06AX05 Trazodone D08626 Trazodone (INN) USP drug classification [BR:br08302] Antidepress

  3. Rational use of plasma protein and tissue binding data in drug design.

    Science.gov (United States)

    Liu, Xingrong; Wright, Matthew; Hop, Cornelis E C A

    2014-10-23

    It is a commonly accepted assumption that only unbound drug molecules are available to interact with their targets. Therefore, one of the objectives in drug design is to optimize the compound structure to increase in vivo unbound drug concentration. In this review, theoretical analyses and experimental observations are presented to illustrate that low plasma protein binding does not necessarily lead to high in vivo unbound plasma concentration. Similarly, low brain tissue binding does not lead to high in vivo unbound brain tissue concentration. Instead, low intrinsic clearance leads to high in vivo unbound plasma concentration, and low efflux transport activity at the blood-brain barrier leads to high unbound brain concentration. Plasma protein and brain tissue binding are very important parameters in understanding pharmacokinetics, pharmacodynamics, and toxicities of drugs, but these parameters should not be targeted for optimization in drug design.

  4. Diffusion-Based Design of Multi-Layered Ophthalmic Lenses for Controlled Drug Release.

    Science.gov (United States)

    Pimenta, Andreia F R; Serro, Ana Paula; Paradiso, Patrizia; Saramago, Benilde; Colaço, Rogério

    2016-01-01

    The study of ocular drug delivery systems has been one of the most covered topics in drug delivery research. One potential drug carrier solution is the use of materials that are already commercially available in ophthalmic lenses for the correction of refractive errors. In this study, we present a diffusion-based mathematical model in which the parameters can be adjusted based on experimental results obtained under controlled conditions. The model allows for the design of multi-layered therapeutic ophthalmic lenses for controlled drug delivery. We show that the proper combination of materials with adequate drug diffusion coefficients, thicknesses and interfacial transport characteristics allows for the control of the delivery of drugs from multi-layered ophthalmic lenses, such that drug bursts can be minimized, and the release time can be maximized. As far as we know, this combination of a mathematical modelling approach with experimental validation of non-constant activity source lamellar structures, made of layers of different materials, accounting for the interface resistance to the drug diffusion, is a novel approach to the design of drug loaded multi-layered contact lenses.

  5. 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.

  6. 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.

  7. The impact of direct-to-consumer television and magazine advertising on antidepressant use.

    Science.gov (United States)

    Avery, Rosemary J; Eisenberg, Matthew D; Simon, Kosali I

    2012-09-01

    We examine whether exposure to direct-to-consumer advertising (DTCA) for antidepressant drugs affects individual use of these medications among those suffering from depression. Prior studies have almost exclusively relied on making connections between national or market-level advertising volume/expenditures and national or individual-level usage of medications. This is the first study to: estimate the impact of individual-level exposure to DTCA on individual-level use of antidepressants; estimate the impact of individual-level exposure to television DTCA on individual-level use in any drug class; consider the relative and interactive impact of DTCA in two different media in any drug class; and, consider the heterogeneity of impact among different populations in an econometric framework in the antidepressant market. There are also important limitations to note. Unlike prior market level studies that use monthly data, we are limited to aggregated annual data. Our measures of potential advertising exposure are constructed assuming that media consumption patterns are stable during the year. We are also not able to study the impact of advertising on use of antidepressants for conditions other than depression, such as anxiety disorders. We find that: DTCA impacts antidepressant use in a statistically and economically significant manner; that these effects are present in both television and magazine advertising exposure but do not appear to have interactive effects; are stronger for women than for men in the magazine medium, but are about equally strong for men and women in the TV medium; and, are somewhat stronger for groups suffering from more severe forms of depression. The overall size of the effect is a 6-10 percentage point increase in antidepressant use from being exposed to television advertising; the corresponding magazine effects are between 3 and 4 percentage points.

  8. 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

  9. The Development of CK2 Inhibitors: From Traditional Pharmacology to in Silico Rational Drug Design.

    Science.gov (United States)

    Cozza, Giorgio

    2017-02-20

    Casein kinase II (CK2) is an ubiquitous and pleiotropic serine/threonine protein kinase able to phosphorylate hundreds of substrates. Being implicated in several human diseases, from neurodegeneration to cancer, the biological roles of CK2 have been intensively studied. Upregulation of CK2 has been shown to be critical to tumor progression, making this kinase an attractive target for cancer therapy. Several CK2 inhibitors have been developed so far, the first being discovered by "trial and error testing". In the last decade, the development of in silico rational drug design has prompted the discovery, de novo design and optimization of several CK2 inhibitors, active in the low nanomolar range. The screening of big chemical libraries and the optimization of hit compounds by Structure Based Drug Design (SBDD) provide telling examples of a fruitful application of rational drug design to the development of CK2 inhibitors. Ligand Based Drug Design (LBDD) models have been also applied to CK2 drug discovery, however they were mainly focused on methodology improvements rather than being critical for de novo design and optimization. This manuscript provides detailed description of in silico methodologies whose applications to the design and development of CK2 inhibitors proved successful and promising.

  10. [In Silico Drug Design Using an Evolutionary Algorithm and Compound Database].

    Science.gov (United States)

    Kawai, Kentaro; Takahashi, Yoshimasa

    2016-01-01

      Computational drug design plays an important role in the discovery of new drugs. Recently, we proposed an algorithm for designing new drug-like molecules utilizing the structure of a known active molecule. To design molecules, three types of fragments (ring, linker, and side-chain fragments) were defined as building blocks, and a fragment library was prepared from molecules listed in G protein-coupled receptor (GPCR)-SARfari database. An evolutionary algorithm which executes evolutionary operations, such as crossover, mutation, and selection, was implemented to evolve the molecules. As a case study, some GPCRs were selected for computational experiments in which we tried to design ligands from simple seed fragments using the Tanimoto coefficient as a fitness function. The results showed that the algorithm could be used successfully to design new molecules with structural similarity, scaffold variety, and chemical validity. In addition, a docking study revealed that these designed molecules also exhibited shape complementarity with the binding site of the target protein. Therefore, this is expected to become a powerful tool for designing new drug-like molecules in drug discovery projects.

  11. 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.

  12. The Open Form Inducer Approach for Structure-Based Drug Design

    Science.gov (United States)

    Inaoka, Daniel Ken; Iida, Maiko; Tabuchi, Toshiyuki; Honma, Teruki; Lee, Nayoung; Hashimoto, Satoshi; Matsuoka, Shigeru; Kuranaga, Takefumi; Sato, Kazuhito; Shiba, Tomoo; Sakamoto, Kimitoshi; Balogun, Emmanuel Oluwadare; Suzuki, Shigeo; Nara, Takeshi; da Rocha, Josmar Rodrigues; Montanari, Carlos Alberto; Tanaka, Akiko; Inoue, Masayuki; Kita, Kiyoshi; Harada, Shigeharu

    2016-01-01

    Many open form (OF) structures of drug targets were obtained a posteriori by analysis of co-crystals with inhibitors. Therefore, obtaining the OF structure of a drug target a priori will accelerate development of potent inhibitors. In addition to its small active site, Trypanosoma cruzi dihydroorotate dehydrogenase (TcDHODH) is fully functional in its monomeric form, making drug design approaches targeting the active site and protein-protein interactions unrealistic. Therefore, a novel a priori approach was developed to determination the TcDHODH active site in OF. This approach consists of generating an "OF inducer" (predicted in silico) to bind the target and cause steric repulsion with flexible regions proximal to the active site that force it open. We provide the first proof-of-concept of this approach by predicting and crystallizing TcDHODH in complex with an OF inducer, thereby obtaining the OF a priori with its subsequent use in designing potent and selective inhibitors. Fourteen co-crystal structures of TcDHODH with the designed inhibitors are presented herein. This approach has potential to encourage drug design against diseases where the molecular targets are such difficult proteins possessing small AS volume. This approach can be extended to study open/close conformation of proteins in general, the identification of allosteric pockets and inhibitors for other drug targets where conventional drug design approaches are not applicable, as well as the effective exploitation of the increasing number of protein structures deposited in Protein Data Bank. PMID:27893848

  13. Hepatotoxicity of piperazine designer drugs: up-regulation of key enzymes of cholesterol and lipid biosynthesis.

    Science.gov (United States)

    Arbo, Marcelo Dutra; Melega, Simone; Stöber, Regina; Schug, Markus; Rempel, Eugen; Rahnenführer, Jörg; Godoy, Patricio; Reif, Raymond; Cadenas, Cristina; de Lourdes Bastos, Maria; Carmo, Helena; Hengstler, Jan G

    2016-12-01

    The piperazine derivatives most frequently consumed for recreational purposes are 1-benzylpiperazine, 1-(3,4-methylenedioxybenzyl) piperazine, 1-(3-trifluoromethylphenyl) piperazine and 1-(4-methoxyphenyl) piperazine. Generally, they are consumed as capsules, tablets or pills but also in powder or liquid forms. Currently, the precise mechanism by which piperazine designer drugs induce hepatotoxicity and whether they act by a common pathway is unclear. To answer this question, we performed a gene array study with rat hepatocytes incubated with the four designer drugs. Non-cytotoxic concentrations were chosen that neither induce a decrease in reduced glutathione or ATP depletion. Analysis of the gene array data showed a large overlap of gene expression alterations induced by the four drugs. This 'piperazine designer drug consensus signature' included 101 up-regulated and 309 down-regulated probe sets (p cholesterol biosynthesis represented a dominant overrepresented motif. Key enzymes of cholesterol biosynthesis up-regulated by all four piperazine drugs include sterol C4-methyloxidase, isopentyl-diphosphate-Δ-isomerase, Cyp51A1, squalene epoxidase and farnesyl diphosphate synthase. Additionally, glycoprotein transmembrane nmb, which participates in cell adhesion processes, and fatty acid desaturase 1, an enzyme that regulates unsaturation of fatty acids, were also up-regulated by the four piperazine designer drugs. Regarding the down-regulated probe sets, only one gene was common to all four piperazine derivatives, the betaine-homocysteine-S-methyltransferase 2. Analysis of transcription factor binding sites of the 'piperazine designer drug consensus signature' identified the sterol regulatory element binding protein (SREBP-1) as strongly overrepresented in the up-regulated genes. SREBP transcription factors are known to regulate multiple genes of cholesterol metabolism. In conclusion, the present study shows that piperazine designer drugs act by up-regulating key

  14. The 5-HT7 receptor as a mediator and modulator of antidepressant-like behavior

    OpenAIRE

    Sarkisyan, Gor; Roberts, Amanda J.; Hedlund, Peter B.

    2010-01-01

    The 5-HT7 receptor has been suggested as a target for treating depression since inactivation or blockade of the receptor has an antidepressant-like behavioral effect. The present study investigated possible interactions between various classes of drugs with antidepressant properties and blockade or inactivation of the 5-HT7 receptor. Immobility despair in the tail suspension test and the forced swim test was evaluated in mice lacking the 5-HT7 receptor (5-HT7−/−) and in wild-type controls (5-...

  15. 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.

  16. Adherence to anti-depressant medication

    DEFF Research Database (Denmark)

    Buus, Niels

    2014-01-01

    The study of medicine taking is controversial as it often reveals a discrepancy between healthcare professionals' advice and patients' actual behaviour. Qualitative researchers have examined depressed people's adherence to prescriptions of antidepressants by exploring the meaning they impute to t...

  17. 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.

  18. 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

    2015-04-08

    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.

  19. "New drug" designations for new therapeutic entities: new active substance, new chemical entity, new biological entity, new molecular entity.

    Science.gov (United States)

    Branch, Sarah K; Agranat, Israel

    2014-11-13

    This Perspective addresses ambiguities in designations of "new drugs" intended as new therapeutic entities (NTEs). Designation of an NTE as a new drug is significant, as it may confer regulatory exclusivity, an important incentive for development of novel compounds. Such designations differ between jurisdictions according to their drug laws and drug regulations. Chemical, biological, and innovative drugs are addressed in turn. The terms new chemical entity (NCE), new molecular entity (NME), new active substance (NAS), and new biological entity (NBE) as applied in worldwide jurisdictions are clarified. Differences between them are explored through case studies showing why new drugs have different periods of exclusivity in different jurisdictions or none at all. Finally, this Perspective recommends that in future, for the purpose of new drug compilations, NME is used for a new chemical drug, NBE for a new biological drug, and the combined designation NTE should refer to either an NME or an NBE.

  20. A study on evalution of antidepressant effect of imipramine adjunct with Aswagandha and Bramhi.

    Science.gov (United States)

    Maity, T; Adhikari, A; Bhattacharya, K; Biswas, S; Debnath, P K; Maharana, C S

    2011-12-01

    Depressive disorders increase the risks of self-harm or even suicide in patients. Indigenous drugs are being tried to treat such patient along with conventional antidepressant drugs. This study was planned to investigate the antidepressant action of Ashwagandha and Bramhi and also to confirm its efficacy in the behavioural despair animal model of depression. Normal saline as control (5 ml/kg), Imipramine as standard (16, 32, 64 mg/ kg) and Ashwagandha (50, 100, 150 mg/kg), Bramhi (20, 40, 80 mg/kg) as test drugs were introduced to the albino rats weighing between 200-250 gm for 2 weeks, 1 hr before electric shock in Learned helplessness test (LHT) and swimming in Forced swimming test (FST). Effects of individual drugs as well as their combination were evaluated. Avoidance response, escape failure and immobility period in case of Imipramine and Ashwagandha showed highly significant (p Imipramine gave a highly significant result (p Imipramine showed high efficacy in animal model.

  1. 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

  2. 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.

  3. Multi-step usage of in vivo models during rational drug design and discovery.

    Science.gov (United States)

    Williams, Charles H; Hong, Charles C

    2011-01-01

    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.

  4. Effects of antidepressants and antihistaminics on catalepsy induced by intracerebroventricular administration of histamine in mice.

    Science.gov (United States)

    Onodera, K

    1991-01-01

    The intracerebroventricular (icv) administration of histamine but not N-telemethylhistamine and 1-methyl-4-imidazole acetic acid induced catalepsy in mice. Histamine H1-receptor blockers such as cyproheptadine, mepyramine and diphenhydramine reduced histamine-induced catalepsy. However, astemizole which is known to be without central effects, did not reduce histamine-induced catalepsy. The icv pretreatment with histamine H2-receptor blockers, such as metiamide and cimetidine, also had no effect. Moreover, various antidepressants, both imipramine- and atypical-type drugs antagonized histamine-induced catalepsy to various degrees in this experiment. Thus, the induction of catalepsy by icv administration of histamine was mediated through histamine H1-receptors, and suggested that antidepressants reduced histamine-induced catalepsy via this mechanism. Histamine-induced catalepsy is a possible new animal model of depression which can also be used for evaluation of atypical antidepressants.

  5. 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.

  6. Synthesis of Chlorinated Tetracyclic Compounds and Testing for Their Potential Antidepressant Effect in Mice

    Directory of Open Access Journals (Sweden)

    Usama Karama

    2016-01-01

    Full Text Available The synthesis of the tetracyclic compounds 1-(4,5-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl-N-methylmethanamine (5 and 1-(1,8-dichloro-9,10-dihydro-9,10-ethanoanthracen-11-yl-N-methylmethanamine (6 as a homologue of the anxiolytic and antidepressant drugs benzoctamine and maprotiline were described. The key intermediate aldehydes (3 and (4 were successfully synthesized via a [4 + 2] cycloaddition between acrolein and 1,8-dichloroanthracene. The synthesized compounds were investigated for antidepressant activity using the forced swimming test. Compounds (5, (6 and (3 showed significant reduction in the mice immobility indicating significant antidepressant effects. These compounds significantly reduced the immobility times at a dose 80 mg/kg by 84.0%, 86.7% and 71.1% respectively.

  7. Effort-reward imbalance at work and the risk of antidepressant treatment in the Danish workforce

    DEFF Research Database (Denmark)

    Nielsen, Maj Britt D.; Madsen, Ida E. H.; Aust, Birgit;

    2016-01-01

    Background: Previous studies have shown that high effort-reward imbalance (ERI) at work is a risk factor for the onset of self-reported depressive symptoms. In this study, we examined whether ERI predicts risk of treatment with antidepressant medication in a representative sample of the Danish...... workforce. Methods: We linked survey data on ERI and covariates of 4541 participants from the Danish Work Environment Cohort Study 2000 with the Danish National Prescription Registry that includes all legally purchased prescription drugs at pharmacies in Denmark since 1995. Participants with a history...... of antidepressant treatment or with self-reported depressive symptoms at baseline were excluded. Using Cox proportional hazard analyses we examined the prospective association between ERI at baseline and incident antidepressant treatment while adjusting for potential confounders. Time of follow-up was 5 years...

  8. 77 FR 52744 - Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant Workshop

    Science.gov (United States)

    2012-08-30

    ... From the Federal Register Online via the Government Publishing Office DEPARTMENT OF HEALTH AND HUMAN SERVICES Food and Drug Administration Food and Drug Administration/European Medicines Agency Orphan Product Designation and Grant Workshop AGENCY: Food and Drug Administration, HHS. ACTION: Notice of meeting. The Food and Drug Administration's...

  9. 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.

  10. [Antidepressant-resistant depression and the 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.

  11. Behavioral and Biochemical Evidences for Antidepressant-Like Activity of Celastrus Paniculatus Seed Oil in Mice

    Science.gov (United States)

    Valecha, Rekha; Dhingra, Dinesh

    2016-01-01

    Introduction: Celastrus paniculatus seed oil, commonly known as Malkangni or Jyotishmati, was in use from time immemorial to treat brain related disorders. Celastrus paniculatus seed oil has significant antidepressant-like activity in chronic unpredictable stressed mice. The present study was undertaken to evaluate the antidepressant-like effect of Celastrus paniculatus seed oil in unstressed mice and to explore its mechanism of action. Methods: The seed oil (50, 100, and 200 mg/kg, PO) and fluoxetine per se were administered for 14 successive days to Swiss young albino mice. On the 14th day, 60 min after drug administration, animals were subjected to Tail Suspension Test (TST) and Forced Swim Test (FST). The mechanism of action was also studied. Results: The oil significantly decreased immobility period of mice in both tail suspension test and forced swim test, indicating its significant antidepressant-like activity. The efficacy was found to be comparable to fluoxetine (PSulpiride (selective D2-receptor antagonist), p-CPA (tryptophan hydroxylase inhibitor), and baclofen (GABAB agonist) significantly attenuated the oil-induced antidepressant-like effect, when assessed during TST. Discussion: Celastrus paniculatus seed oil produced significant antidepressant-like effect in mice possibly through interaction with dopamine D2, serotonergic, and GABAB receptors; as well as inhibition of MAO–A activity and decrease in plasma corticosterone levels. PMID:27303599

  12. 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.

  13. Treatment patterns in major depressive disorder after an inadequate response to first-line antidepressant treatment

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    Garcia-Toro Mauro

    2012-09-01

    Full Text Available Abstract Background The aim of the study was to determine the most common pharmacological strategies used in the management of major depressive disorder (MDD after an inadequate response to first-line antidepressant treatment in clinical practice. Methods Multicenter, non-interventional study in adult outpatients with a DSM-IV-TR diagnosis of MDD and inadequate response to first-line antidepressant medication. Multiple logistic regression analyses were performed to identify independent factors associated with the adoption of a specific second-line strategy. Results A total of 273 patients were analyzed (mean age: 46.8 years, 67.8% female. Baseline mean Montgomery-Asberg Depression Rating Scale total score was 32.1 (95%CI 31.2-32.9. The most common strategies were: switching antidepressant medication (39.6%, augmentation (18.8%, and combination therapy (17.9%. Atypical antipsychotic drugs were the most commonly used agent for augmenting antidepressant effect. The presence of psychotic symptoms and the number of previous major depressive episodes were associated with the adoption of augmenting strategy (OR = 3.2 and 1.2, respectively. Conclusion The switch to another antidepressant agent was the most common second-line therapeutic approach. Psychiatrists chose augmentation based on a worse patients’ clinical profile (number of previous episodes and presence of psychotic symptoms.

  14. Time-dependent biphasic modulation of human BDNF by antidepressants in neuroblastoma cells

    Directory of Open Access Journals (Sweden)

    Musazzi Laura

    2008-07-01

    Full Text Available Abstract Background Recent rodent studies reported that antidepressant treatments affect the expression of brain-derived neurotrophic factor (BDNF mRNA in a way that is dependent on treatment duration, by selective modulation of different BDNF transcripts. However, no data are available for the human BDNF gene. We studied the effect of different antidepressants on BDNF mRNA expression in human neuroblastoma SH-SY5Y cells. Results Cultured cells were treated with the antidepressants fluoxetine, reboxetine and desipramine for different time lengths (6, 24, 48 hours. Expression of total BDNF mRNA was analyzed by reverse transcription PCR and levels of different BDNF transcripts were detected by hemi-nested PCR with specific primers. Short-term treatment (6 hours with reboxetine or desipramine reduced total BDNF, whereas long-term treatment (48 hours significantly increased total BDNF mRNA levels. These changes were accounted for by differential regulation of BDNF IV and VIa/b transcripts. Fluoxetine showed no significant effects. Conclusion This is the first study showing biphasic changes in the expression of total and specific BDNF transcripts in human cells following antidepressant treatments. These findings suggest that biphasic induction of BDNF by antidepressants could be a feature common to rodents and humans and encourage the use of SH-SY5Y cells as a tool for investigation of drug effects on human genes.

  15. Recent Advances in Drug Design and Drug Discovery for Androgen- Dependent Diseases.

    Science.gov (United States)

    Cabeza, Marisa; Sánchez-Márquez, Araceli; Garrido, Mariana; Silva, Aylín; Bratoeff, Eugene

    2016-01-01

    This article summarizes the importance of different targets such as 5α-reductase, 17β-HSD, CYP17A, androgen receptor and protein kinase A for the treatment of prostate cancer and benign prostatic hyperplasia. It is a well known fact that dihydrotestosterone (DHT) is associated with the development of androgen-dependent afflictions. At the present time, several research groups are attempting to develop new steroidal and non-steroidal molecules with the purpose of inhibiting the synthesis and biological response of DHT. This review also discusses the most recent studies reported in the literature that describe the therapeutic potential of novel compounds, as well as the new drugs, principally inhibitors of 5α-reductase.

  16. Transiently increased glutamate cycling in rat PFC is associated with rapid onset of antidepressant-like effects

    Science.gov (United States)

    Chowdhury, Golam M. I.; Zhang, Jie; Thomas, Monique; Banasr, Mounira; Ma, Xiaoxian; Pittman, Brian; Bristow, Linda; Schaeffer, Eric; Duman, Ronald; Rothman, Douglas; Behar, Kevin; Sanacora, Gerard

    2017-01-01

    Several drugs have recently been reported to induce rapid antidepressant effects in clinical trials and rodent models. Although the cellular mechanisms involved remain unclear, reports suggest that increased glutamate transmission contributes to these effects. Here, we demonstrate that the antidepressant-like efficacy of three unique drugs, with reported rapid onset antidepressant properties, is coupled with a rapid transient rise in glutamate cycling in medial prefronal cortex (mPFC) of awake rats as measured by ex vivo 1H-[13C]-nuclear magnetic resonance spectroscopy. Rats were acutely pre-treated by intraperitoneal injection with a single dose of ketamine (1,3,10,30,80mg/kg), Ro 25-6981 (1,3,10mg/kg), scopolamine (5,25,100μg/kg) or vehicle (controls). At fixed times after drug injection animals received an intravenous infusion of [1,6-13C2]glucose for 8 min to enrich brain amino acid pools with 13C, followed by rapid euthanasia. The mPFC was dissected, extracted with ethanol and metabolite 13C enrichments measured. We found a clear dose dependent effect of ketamine and Ro 25-6981 on behavior and the percent of 13C-enrichment of glutamate, glutamine and GABA. Further, we also found an effect of scopolamine on both cycling and behavior. These studies demonstrate that three pharmacologically distinct classes of drugs, clinically related through their reported rapid antidepressant actions, share the common ability to rapidly stimulate glutamate cycling at doses pertinent for their antidepressant-like efficacy. We conclude that increased cycling precedes the antidepressant action at behaviorally effective doses and suggests the rapid change in cycling could be used to predict efficacy of novel agents or identify doses with antidepressant activity. PMID:27067013

  17. 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.

  18. Computational and Pharmacological Target of Neurovascular Unit for Drug Design and Delivery.

    Science.gov (United States)

    Islam, Md Mirazul; Mohamed, Zahurin

    2015-01-01

    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.

  19. 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.

  20. State-of-the-art technology in modern computer-aided drug design.

    Science.gov (United States)

    Dalkas, Georgios A; Vlachakis, Dimitrios; Tsagkrasoulis, Dimosthenis; Kastania, Anastasia; Kossida, Sophia

    2013-11-01

    The quest for small drug-like compounds that selectively inhibit the function of biological targets has always been a major focus in the pharmaceutical industry and in academia as well. High-throughput screening of compound libraries requires time, cost and resources. Therefore, the use of alternative methods is necessary for facilitating lead discovery. Computational techniques that dock small molecules into macromolecular targets and predict the affinity and activity of the small molecule are widely used in drug design and discovery, and have become an integral part of the industrial and academic research. In this review, we present an overview of some state-of-the-art technologies in modern drug design that have been developed for expediting the search for novel drug candidates.