Pharmacodynamic response profiles of anxiolytic and sedative drugs

被引:24
作者
Chen, Xia [1 ,2 ]
Broeyer, Freerk [1 ]
de Kam, Marieke [1 ]
Baas, Joke [3 ]
Cohen, Adam [1 ]
van Gerven, Joop [1 ]
机构
[1] Ctr Human Drug Res, Zernikedreef 8, NL-2333 CL Leiden, Netherlands
[2] Beijing Union Med Coll Hosp, Clin Pharmacol Res Ctr, Phase Unit 1, Beijing 100032, Peoples R China
[3] Univ Utrecht, Fac Social Sci, Dept Expt Psychol, Utrecht, Netherlands
关键词
biomarker; pharmacodynamics; pharmacokinetics; psychopharmacology; FEAR-POTENTIATED STARTLE; CENTRAL-NERVOUS-SYSTEM; SUBTYPE-SELECTIVE AGONIST; HEALTHY MALE-VOLUNTEERS; PHARMACOLOGY; 2015/16; CONCISE GUIDE; RECEPTOR MODULATOR; GABA(A) RECEPTORS; ION CHANNELS; BENZODIAZEPINES;
D O I
10.1111/bcp.13204
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
AIM Centrally-acting acutely anxiolytic drugs, such as benzodiazepines, barbiturates and gabapentinoids, affect various central nervous system (CNS) functions, which reflects not only their anxiolytic effects but also neuropsychological side-effects. To validate the pharmacodynamic biomarkers for GABA-ergic anxiolytics, this study determined the pharmacodynamics of two anxiolytics and a nonanxiolytic control, and linked them to their anxiolytic and sedative effects, during an anxiety-challenge study day. METHODS Twenty healthy volunteers were randomized in this placebo-controlled, double-blind, four-way cross-over study with single-dose alprazolam (1 mg), diphenhydramine (50 mg), pregabalin (200 mg) or placebo. The Neurocart was used between repeated fearpotentiated startle assessments. Thus, the potential influence of anxiety on CNS pharmacodynamic markers could be examined. RESULTS Compared to placebo, VAS(calmness) increased with alprazolam (2.0 mm) and pregabalin (2.5 mm) but not with diphenhydramine. Saccadic peak velocity (SPV) declined after alprazolam (-57 degrees s(-1)) and pregabalin (-28 degrees s(-1)), more than with diphenhydramine (-14 degrees s(-1)); so did smooth pursuit. The average responses of SPV and smooth pursuit were significantly correlated with the druginduced increases in VAScalmness. The SPV-relative responses of VA(Salertness), body-sway and adaptive-tracking also differed among alprazolam, pregabalin and diphenhydramine. CONCLUSIONS Compared with the antihistaminergic sedative diphenhydramine, alprazolam and pregabalin caused larger SPV reduction, which was correlated with simultaneous improvement of subjective calmness, during a study day in which anxiety was stimulated repeatedly. The different effect profiles of the three drugs are in line with their pharmacological distinctions. These findings corroborate the profiling of CNS effects to demonstrate pharmacological selectivity, and further support SPV as biomarker for anxiolysis involving GABA-ergic neurons. The study also supports the use of prolonged mild threat to demonstrate anxiolytic effects in healthy volunteers.
引用
收藏
页码:1028 / 1038
页数:11
相关论文
共 44 条
[1]   THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: G protein-coupled receptors [J].
Alexander, Stephen P. H. ;
Davenport, Anthony P. ;
Kelly, Eamonn ;
Marrion, Neil ;
Peters, John A. ;
Benson, Helen E. ;
Faccenda, Elena ;
Pawson, Adam J. ;
Sharman, Joanna L. ;
Southan, Christopher ;
Davies, Jamie A. ;
Aldrich, R. ;
Attali, B. ;
Back, M. ;
Barnes, N. M. ;
Bathgate, R. ;
Beart, P. M. ;
Becirovic, E. ;
Biel, M. ;
Birdsall, N. J. ;
Boison, D. ;
Brauner-Osborne, H. ;
Broeer, S. ;
Bryant, C. ;
Burnstock, G. ;
Burris, T. ;
Cain, D. ;
Calo, G. ;
Chan, S. L. ;
Chandy, K. G. ;
Chiang, N. ;
Christakos, S. ;
Christopoulos, A. ;
Chun, J. J. ;
Chung, J. -J. ;
Clapham, D. E. ;
Connor, M. A. ;
Coons, L. ;
Cox, H. M. ;
Dautzenberg, F. M. ;
Dent, G. ;
Douglas, S. D. ;
Dubocovich, M. L. ;
Edwards, D. P. ;
Farndale, R. ;
Fong, T. M. ;
Forrest, D. ;
Fowler, C. J. ;
Fuller, P. ;
Gainetdinov, R. R. .
BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :5744-5869
[2]   THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Ligand-gated ion channels [J].
Alexander, Stephen P. H. ;
Peters, John A. ;
Kelly, Eamonn ;
Marrion, Neil ;
Benson, Helen E. ;
Faccenda, Elena ;
Pawson, Adam J. ;
Sharman, Joanna L. ;
Southan, Christopher ;
Davies, Jamie A. ;
Aldrich, R. ;
Attali, B. ;
Back, M. ;
Barnes, N. M. ;
Bathgate, R. ;
Beart, P. M. ;
Becirovic, E. ;
Biel, M. ;
Birdsall, N. J. ;
Boison, D. ;
Brauner-Osborne, H. ;
Broeer, S. ;
Bryant, C. ;
Burnstock, G. ;
Burris, T. ;
Cain, D. ;
Calo, G. ;
Chan, S. L. ;
Chandy, K. G. ;
Chiang, N. ;
Christakos, S. ;
Christopoulos, A. ;
Chun, J. J. ;
Chung, J. -J. ;
Clapham, D. E. ;
Connor, M. A. ;
Coons, L. ;
Cox, H. M. ;
Dautzenberg, F. M. ;
Dent, G. ;
Douglas, S. D. ;
Dubocovich, M. L. ;
Edwards, D. P. ;
Farndale, R. ;
Fong, T. M. ;
Forrest, D. ;
Fowler, C. J. ;
Fuller, P. ;
Gainetdinov, R. R. ;
Gershengorn, M. A. .
BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :5870-5903
[3]   THE CONCISE GUIDE TO PHARMACOLOGY 2015/16: Other ion channels [J].
Alexander, Stephen P. H. ;
Kelly, Eamonn ;
Marrion, Neil ;
Peters, John A. ;
Benson, Helen E. ;
Faccenda, Elena ;
Pawson, Adam J. ;
Sharman, Joanna L. ;
Southan, Christopher ;
Davies, Jamie A. ;
Aldrich, R. ;
Attali, B. ;
Back, M. ;
Barnes, N. M. ;
Bathgate, R. ;
Beart, P. M. ;
Becirovic, E. ;
Biel, M. ;
Birdsall, N. J. ;
Boison, D. ;
Brauner-Osborne, H. ;
Broeer, S. ;
Bryant, C. ;
Burnstock, G. ;
Burris, T. ;
Cain, D. ;
Calo, G. ;
Chan, S. L. ;
Chandy, K. G. ;
Chiang, N. ;
Christakos, S. ;
Christopoulos, A. ;
Chun, J. J. ;
Chung, J. -J. ;
Clapham, D. E. ;
Connor, M. A. ;
Coons, L. ;
Cox, H. M. ;
Dautzenberg, F. M. ;
Dent, G. ;
Douglas, S. D. ;
Dubocovich, M. L. ;
Edwards, D. P. ;
Farndale, R. ;
Fong, T. M. ;
Forrest, D. ;
Fowler, C. J. ;
Fuller, P. ;
Gainetdinov, R. R. ;
Gershengorn, M. A. .
BRITISH JOURNAL OF PHARMACOLOGY, 2015, 172 (24) :5942-5955
[4]  
Atack JR, 2010, CURR TOP BEHAV NEURO, V2, P331, DOI 10.1007/7854_2009_30
[5]   Validating a human model for anxiety using startle potentiated by cue and context: the effects of alprazolam, pregabalin, and diphenhydramine [J].
Baas, J. M. P. ;
Mol, N. ;
Kenemans, J. L. ;
Prinssen, E. P. ;
Niklson, I. ;
Xia-Chen, C. ;
Broeyer, F. ;
van Gerven, J. .
PSYCHOPHARMACOLOGY, 2009, 205 (01) :73-84
[6]   Benzodiazepines have no effect on fear-potentiated startle in humans [J].
Baas, JMP ;
Grillon, C ;
Böcker, KBE ;
Brack, AA ;
Morgan, CA ;
Kenemans, JL ;
Verbaten, MN .
PSYCHOPHARMACOLOGY, 2002, 161 (03) :233-247
[7]   QUANTITATIVE MEASUREMENT OF SACCADE AMPLITUDE, DURATION, AND VELOCITY [J].
BALOH, RW ;
SILLS, AW ;
KUMLEY, WE ;
HONRUBIA, V .
NEUROLOGY, 1975, 25 (11) :1065-1070
[8]   GABAergic modulation in central sensitization in humans: a randomized placebo-controlled pharmacokinetic-pharmacodynamic study comparing clobazam with clonazepam in healthy volunteers [J].
Besson, Marie ;
Matthey, Alain ;
Daali, Youssef ;
Poncet, Antoine ;
Vuillemier, Pascal ;
Curatolo, Michele ;
Zeilhofer, Hanns Ulrich ;
Desmeules, Jules .
PAIN, 2015, 156 (03) :397-404
[9]   THE RELATIONSHIP BETWEEN PEAK VELOCITY OF SACCADIC EYE-MOVEMENTS AND SERUM BENZODIAZEPINE CONCENTRATION [J].
BITTENCOURT, PRM ;
WADE, P ;
SMITH, AT ;
RICHENS, A .
BRITISH JOURNAL OF CLINICAL PHARMACOLOGY, 1981, 12 (04) :523-533
[10]   A double-blind, placebo- and flurazepam-control led investigation of the residual psychomotor and cognitive effects of modified release zolpidem in young healthy volunteers [J].
Blin, O ;
Micallef, J ;
Audebert, C ;
Legangneux, E .
JOURNAL OF CLINICAL PSYCHOPHARMACOLOGY, 2006, 26 (03) :284-289