Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine
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{"title"=>"Quantitative cross-species extrapolation between humans and fish: The case of the anti-depressant fluoxetine", "type"=>"journal", "authors"=>[{"first_name"=>"Luigi", "last_name"=>"Margiotta-Casaluci", "scopus_author_id"=>"36680216800"}, {"first_name"=>"Stewart F.", "last_name"=>"Owen", "scopus_author_id"=>"36808029000"}, {"first_name"=>"Rob I.", "last_name"=>"Cumming", "scopus_author_id"=>"26639218800"}, {"first_name"=>"Anna", "last_name"=>"De Polo", "scopus_author_id"=>"54894995400"}, {"first_name"=>"Matthew J.", "last_name"=>"Winter", "scopus_author_id"=>"7202444342"}, {"first_name"=>"Grace H.", "last_name"=>"Panter", "scopus_author_id"=>"6603157349"}, {"first_name"=>"Mariann", "last_name"=>"Rand-Weaver", "scopus_author_id"=>"6603807968"}, {"first_name"=>"John P.", "last_name"=>"Sumpter", "scopus_author_id"=>"7005149055"}], "year"=>2014, "source"=>"PLoS ONE", "identifiers"=>{"issn"=>"19326203", "pui"=>"600247513", "doi"=>"10.1371/journal.pone.0110467", "sgr"=>"84908541889", "scopus"=>"2-s2.0-84908541889", "isbn"=>"1932-6203", "pmid"=>"25338069"}, "id"=>"05199468-e417-306f-a501-644cc807e097", "abstract"=>"Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (Pimephales promelas) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 µg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (H(T)PCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the H(T)PC range, whereas no effects were observed at plasma concentrations below the H(T)PCs. In vivo metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation.", "link"=>"http://www.mendeley.com/research/quantitative-crossspecies-extrapolation-between-humans-fish-case-antidepressant-fluoxetine", "reader_count"=>58, "reader_count_by_academic_status"=>{"Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>2, "Student > Master"=>11, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_user_role"=>{"Professor > Associate Professor"=>4, "Librarian"=>1, "Researcher"=>9, "Student > Doctoral Student"=>1, "Student > Ph. D. Student"=>21, "Student > Postgraduate"=>2, "Student > Master"=>11, "Student > Bachelor"=>5, "Lecturer"=>1, "Professor"=>3}, "reader_count_by_subject_area"=>{"Environmental Science"=>14, "Biochemistry, Genetics and Molecular Biology"=>3, "Agricultural and Biological Sciences"=>15, "Medicine and Dentistry"=>3, "Neuroscience"=>2, "Pharmacology, Toxicology and Pharmaceutical Science"=>6, "Physics and Astronomy"=>1, "Chemical Engineering"=>1, "Psychology"=>3, "Chemistry"=>9, "Computer Science"=>1}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>3}, "Neuroscience"=>{"Neuroscience"=>2}, "Chemistry"=>{"Chemistry"=>9}, "Physics and Astronomy"=>{"Physics and Astronomy"=>1}, "Psychology"=>{"Psychology"=>3}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>15}, "Computer Science"=>{"Computer Science"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>3}, "Environmental Science"=>{"Environmental Science"=>14}, "Pharmacology, Toxicology and Pharmaceutical Science"=>{"Pharmacology, Toxicology and Pharmaceutical Science"=>6}, "Chemical Engineering"=>{"Chemical Engineering"=>1}}, "reader_count_by_country"=>{"Japan"=>1, "Brazil"=>1, "United Kingdom"=>1, "Spain"=>1}, "group_count"=>3}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1727789"], "description"=>"<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (<i>n</i> = 20). *: <i>p</i><0.05.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212734, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g004", "stats"=>{"downloads"=>3, "page_views"=>23, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationship_between_plasma_concentrations_of_fluoxetine_and_its_effects_on_fish_exploratory_behaviour_after_28_days_of_exposure_/1212734", "title"=>"Relationship between plasma concentrations of fluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727800"], "description"=>"<p>The unit of the values indicated in the columns Mean, Median, Min, Max, 25%, and 75% is ng/mL.</p><p>Inter-individual and intra-treatment variability of norfluoxetine plasma concentrations.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212745, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.t002", "stats"=>{"downloads"=>4, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inter_individual_and_intra_treatment_variability_of_norfluoxetine_plasma_concentrations_/1212745", "title"=>"Inter-individual and intra-treatment variability of norfluoxetine plasma concentrations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727798"], "description"=>"<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test after 28 days of exposure. The dose-response of behavioural endpoints appears to be visually more obvious when median values are used (in this figure) instead of mean values (<a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110467#pone-0110467-g004\" target=\"_blank\">Figure 4</a>). This highlights the important role of inter-individual variability in the interpretation of behavioural effects. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 91–302 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as medians (<i>n</i> = 20). *: <i>p</i><0.05.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212743, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g007", "stats"=>{"downloads"=>5, "page_views"=>34, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationship_between_plasma_concentrations_of_fluoxetine_and_behavioural_endpoints_expressed_as_median_values_/1212743", "title"=>"Relationship between plasma concentrations of fluoxetine and behavioural endpoints expressed as median values.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727799"], "description"=>"<p>The unit of the values indicated in the columns Mean, Median, Min, Max, 25%, and 75% is ng/mL.</p><p>Inter-individual and intra-treatment variability of fluoxetine plasma concentrations.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212744, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.t001", "stats"=>{"downloads"=>2, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Inter_individual_and_intra_treatment_variability_of_fluoxetine_plasma_concentrations_/1212744", "title"=>"Inter-individual and intra-treatment variability of fluoxetine plasma concentrations.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727771"], "description"=>"<p>A) Relationship between measured (red line; mean ± SD; n = 20) and predicted (dashed line) plasma concentrations of fluoxetine, based on concentrations quantified in the water. The predicted plasma concentrations were generated by using the Fish Plasma Model <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0110467#pone.0110467-Huggett1\" target=\"_blank\">[18]</a>. B) Relationship between measured plasma concentrations of fluoxetine (red line; mean ± SD; n = 20) and norfluoxetine:fluoxetine ratio (grey line, mean ± SD; n = 20). The change in the slope of the plasma concentration curve corresponds to the decrease of the norfluoxetine:fluoxetine ratio, indicating inhibitory and/or saturation effects on the metabolic enzymes that convert fluoxetine into norfluoxetine. C) Relationship between measured plasma concentrations of fluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 91–302 ng/mL). D) Relationship between measured plasma concentrations of norfluoxetine in fish plasma (mean ± SD; n = 20) and Human Therapeutic Plasma Concentration range (grey area, 72–258 ng/mL).</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212725, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g002", "stats"=>{"downloads"=>2, "page_views"=>21, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Fluoxetine_uptake_and_metabolism_in_fathead_minnow_following_a_28_d_study_/1212725", "title"=>"Fluoxetine uptake and metabolism in fathead minnow following a 28-d study.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727801", "https://ndownloader.figshare.com/files/1727802"], "description"=>"<div><p>Fish are an important model for the pharmacological and toxicological characterization of human pharmaceuticals in drug discovery, drug safety assessment and environmental toxicology. However, do fish respond to pharmaceuticals as humans do? To address this question, we provide a novel quantitative cross-species extrapolation approach (qCSE) based on the hypothesis that similar plasma concentrations of pharmaceuticals cause comparable target-mediated effects in both humans and fish at similar level of biological organization (Read-Across Hypothesis). To validate this hypothesis, the behavioural effects of the anti-depressant drug fluoxetine on the fish model fathead minnow (<i>Pimephales promelas</i>) were used as test case. Fish were exposed for 28 days to a range of measured water concentrations of fluoxetine (0.1, 1.0, 8.0, 16, 32, 64 µg/L) to produce plasma concentrations below, equal and above the range of Human Therapeutic Plasma Concentrations (H<sub>T</sub>PCs). Fluoxetine and its metabolite, norfluoxetine, were quantified in the plasma of individual fish and linked to behavioural anxiety-related endpoints. The minimum drug plasma concentrations that elicited anxiolytic responses in fish were above the upper value of the H<sub>T</sub>PC range, whereas no effects were observed at plasma concentrations below the H<sub>T</sub>PCs. <i>In vivo</i> metabolism of fluoxetine in humans and fish was similar, and displayed bi-phasic concentration-dependent kinetics driven by the auto-inhibitory dynamics and saturation of the enzymes that convert fluoxetine into norfluoxetine. The sensitivity of fish to fluoxetine was not so dissimilar from that of patients affected by general anxiety disorders. These results represent the first direct evidence of measured internal dose response effect of a pharmaceutical in fish, hence validating the Read-Across hypothesis applied to fluoxetine. Overall, this study demonstrates that the qCSE approach, anchored to internal drug concentrations, is a powerful tool to guide the assessment of the sensitivity of fish to pharmaceuticals, and strengthens the translational power of the cross-species extrapolation.</p></div>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212746, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0110467.s001", "https://dx.doi.org/10.1371/journal.pone.0110467.s002"], "stats"=>{"downloads"=>2, "page_views"=>19, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Quantitative_Cross_Species_Extrapolation_between_Humans_and_Fish_The_Case_of_the_Anti_Depressant_Fluoxetine_/1212746", "title"=>"Quantitative Cross-Species Extrapolation between Humans and Fish: The Case of the Anti-Depressant Fluoxetine", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727774"], "description"=>"<p>A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area. C1 and C2 indicate control group 1 and control group 2, respectively. Boxes represent medians (full line), with 5th and 95th percentiles (<i>n</i> = 20). *<i>p</i><0.05.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212727, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g003", "stats"=>{"downloads"=>3, "page_views"=>26, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Effect_of_fluoxetine_on_fish_exploratory_behaviour_quantified_during_a_Novel_Tank_Diving_Test_performed_after_14_days_of_exposure_/1212727", "title"=>"Effect of fluoxetine on fish exploratory behaviour quantified during a Novel Tank Diving Test performed after 14 days of exposure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727769"], "description"=>"<p>A) Experimental steps performed to quantify fish behavioural response to a new environment following 14-day and 28-day exposure to fluoxetine. Anxiety-related behavioural endpoints were quantified using a Novel Tank Diving Test. B) Example of different exploratory behaviours in a Novel Tank Diving Test. Inactive fish (left) <i>versus</i> active fish (right). The different tracking colours indicate different speeds (black, slow; green, medium; red, fast).</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212723, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g001", "stats"=>{"downloads"=>2, "page_views"=>14, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Methodological_procedure_for_the_quantification_of_fish_behaviour_/1212723", "title"=>"Methodological procedure for the quantification of fish behaviour.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727795"], "description"=>"<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine + norfluoxetine plotted in the graphs is 163–560 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (<i>n</i> = 20). *: <i>p</i><0.05.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212740, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g006", "stats"=>{"downloads"=>2, "page_views"=>11, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationship_between_plasma_concentrations_of_fluoxetine_plus_norfluoxetine_and_their_effects_on_fish_exploratory_behaviour_after_28_days_of_exposure_/1212740", "title"=>"Relationship between plasma concentrations of fluoxetine plus norfluoxetine and their effects on fish exploratory behaviour after 28 days of exposure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}
  • {"files"=>["https://ndownloader.figshare.com/files/1727790"], "description"=>"<p>Exploratory behaviour was quantified in individual fish using the Novel Tank Diving Test. A) Number of transitions into the Top Area; B) number of transitions into the Middle Area; C) time spent in the Top Area; D) time spent in the Middle Area; E) distance travelled in the Top Area; F) distance travelled in the Middle Area; G) speed. The Human Therapeutic Plasma Concentration range of fluoxetine plotted in the graphs is 72–258 ng/mL. C1 and C2 indicate control group 1 and control group 2, respectively. The X-axis has a Log2 scale, while the Y-axis has a linear scale. Values are plotted as mean ± SD (<i>n</i> = 20). *: <i>p</i><0.05.</p>", "links"=>[], "tags"=>["Human Therapeutic Plasma Concentrations", "fluoxetine", "drug safety assessment", "drug plasma concentrations", "pharmaceutical", "dose response effect", "HTPC", "fish model fathead minnow", "plasma concentrations"], "article_id"=>1212735, "categories"=>["Biological Sciences", "Science Policy"], "users"=>["Luigi Margiotta-Casaluci", "Stewart F. Owen", "Rob I. Cumming", "Anna de Polo", "Matthew J. Winter", "Grace H. Panter", "Mariann Rand-Weaver", "John P. Sumpter"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0110467.g005", "stats"=>{"downloads"=>2, "page_views"=>9, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Relationship_between_plasma_concentrations_of_norfluoxetine_and_its_effects_on_fish_exploratory_behaviour_after_28_days_of_exposure_/1212735", "title"=>"Relationship between plasma concentrations of norfluoxetine and its effects on fish exploratory behaviour after 28 days of exposure.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2014-10-22 03:25:01"}

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Relative Metric

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