Phil Skolnick, Philip Krieter, Joseph Tizzano, Anthony Basile, Piotr Popik, Pal Czobor, Arnold Lippa
{"title":"“三重”再摄取抑制剂DOV 216,303的临床前和临床药理学研究","authors":"Phil Skolnick, Philip Krieter, Joseph Tizzano, Anthony Basile, Piotr Popik, Pal Czobor, Arnold Lippa","doi":"10.1111/j.1527-3458.2006.00123.x","DOIUrl":null,"url":null,"abstract":"<div>\n \n <p>DOV 216,303 [(±)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as “triple” reuptake inhibitors. Such compounds inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. DOV 216,303 inhibits [<sup>3</sup>H]NE, [<sup>3</sup>H]5-HT, and [<sup>3</sup>H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC<sub>50</sub> values of ∼20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine-induced ptosis and locomotor depression. The pharmacodynamic, pharmacokinetic, and toxicological profile of DOV 216,303 in animals prompted us to initiate clinical studies. In both single and multiple dose studies using normal volunteers, DOV 216,303 was safe and well-tolerated. Furthermore, both C<sub>max</sub> and AUC values were dose-proportional between 5–150 mg. The plasma concentrations of DOV 216,303 at doses >10 mg were in excess of the IC<sub>50</sub> values for inhibition of biogenic amine reuptake. In a Phase II study designed to explore the safety and tolerability of DOV 216,303 in depressed individuals, patients received either 100 mg DOV 216,303 (50 mg b.i.d.) or 40 mg citalopram (20 mg, b.i.d.) for two weeks. A placebo arm was not employed in this study because several institutional review boards required administration of an active control to severely depressed individuals. Time dependent reductions in HAM-D scores (the primary outcome measure) were observed in both the DOV 216,303 and citalopram groups compared to baseline scores (p < 0.0001). The side effect profile was not remarkably different between treatment arms. These findings provide preliminary evidence of a clinically meaningful antidepressant action with a molecule capable of inhibiting the three transmitters most closely linked to major depressive disorder.</p>\n </div>","PeriodicalId":94307,"journal":{"name":"CNS drug reviews","volume":"12 2","pages":"123-134"},"PeriodicalIF":0.0000,"publicationDate":"2006-08-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://sci-hub-pdf.com/10.1111/j.1527-3458.2006.00123.x","citationCount":"102","resultStr":"{\"title\":\"Preclinical and Clinical Pharmacology of DOV 216,303, a “Triple” Reuptake Inhibitor\",\"authors\":\"Phil Skolnick, Philip Krieter, Joseph Tizzano, Anthony Basile, Piotr Popik, Pal Czobor, Arnold Lippa\",\"doi\":\"10.1111/j.1527-3458.2006.00123.x\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n <p>DOV 216,303 [(±)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as “triple” reuptake inhibitors. Such compounds inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. DOV 216,303 inhibits [<sup>3</sup>H]NE, [<sup>3</sup>H]5-HT, and [<sup>3</sup>H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC<sub>50</sub> values of ∼20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine-induced ptosis and locomotor depression. The pharmacodynamic, pharmacokinetic, and toxicological profile of DOV 216,303 in animals prompted us to initiate clinical studies. In both single and multiple dose studies using normal volunteers, DOV 216,303 was safe and well-tolerated. Furthermore, both C<sub>max</sub> and AUC values were dose-proportional between 5–150 mg. The plasma concentrations of DOV 216,303 at doses >10 mg were in excess of the IC<sub>50</sub> values for inhibition of biogenic amine reuptake. In a Phase II study designed to explore the safety and tolerability of DOV 216,303 in depressed individuals, patients received either 100 mg DOV 216,303 (50 mg b.i.d.) or 40 mg citalopram (20 mg, b.i.d.) for two weeks. A placebo arm was not employed in this study because several institutional review boards required administration of an active control to severely depressed individuals. Time dependent reductions in HAM-D scores (the primary outcome measure) were observed in both the DOV 216,303 and citalopram groups compared to baseline scores (p < 0.0001). The side effect profile was not remarkably different between treatment arms. These findings provide preliminary evidence of a clinically meaningful antidepressant action with a molecule capable of inhibiting the three transmitters most closely linked to major depressive disorder.</p>\\n </div>\",\"PeriodicalId\":94307,\"journal\":{\"name\":\"CNS drug reviews\",\"volume\":\"12 2\",\"pages\":\"123-134\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2006-08-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://sci-hub-pdf.com/10.1111/j.1527-3458.2006.00123.x\",\"citationCount\":\"102\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"CNS drug reviews\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2006.00123.x\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"CNS drug reviews","FirstCategoryId":"1085","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1111/j.1527-3458.2006.00123.x","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Preclinical and Clinical Pharmacology of DOV 216,303, a “Triple” Reuptake Inhibitor
DOV 216,303 [(±)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] is the prototype of a class of compounds referred to as “triple” reuptake inhibitors. Such compounds inhibit the reuptake of norepinephrine (NE), serotonin (5-HT), and dopamine (DA), the three neurotransmitters most closely linked to major depressive disorder. DOV 216,303 inhibits [3H]NE, [3H]5-HT, and [3H]DA uptake to the corresponding human recombinant transporters (expressed in HEK 293 cells) with IC50 values of ∼20, 14, and 78 nM, respectively. DOV 216,303 is active in tests predictive of antidepressant activity including the mouse forced swim test and reversal of tetrabenazine-induced ptosis and locomotor depression. The pharmacodynamic, pharmacokinetic, and toxicological profile of DOV 216,303 in animals prompted us to initiate clinical studies. In both single and multiple dose studies using normal volunteers, DOV 216,303 was safe and well-tolerated. Furthermore, both Cmax and AUC values were dose-proportional between 5–150 mg. The plasma concentrations of DOV 216,303 at doses >10 mg were in excess of the IC50 values for inhibition of biogenic amine reuptake. In a Phase II study designed to explore the safety and tolerability of DOV 216,303 in depressed individuals, patients received either 100 mg DOV 216,303 (50 mg b.i.d.) or 40 mg citalopram (20 mg, b.i.d.) for two weeks. A placebo arm was not employed in this study because several institutional review boards required administration of an active control to severely depressed individuals. Time dependent reductions in HAM-D scores (the primary outcome measure) were observed in both the DOV 216,303 and citalopram groups compared to baseline scores (p < 0.0001). The side effect profile was not remarkably different between treatment arms. These findings provide preliminary evidence of a clinically meaningful antidepressant action with a molecule capable of inhibiting the three transmitters most closely linked to major depressive disorder.