Diagram showing position of the head-mount implant head-mount the of position showing Diagram EC50, Emax and keo. EC50, Emaxand determination of linkPK/PD model for to asigmoidalEmax were Predicted concentrations doses. PK across and120mg/kg fitted simultaneouslywas 30 modeling, the KetaminePK/PD For were LC/MS. bydetermined concentrations plasma Mouse methods PK/PD minutes 90 administration across was post-drug averagedpower a band specific to animals were averaged to obtain average maps shown. The series. time-frequencygenerate Fast-Fourier datainMATLABanalysisEEG was applied to to experiment, blood w plasma from administ drug following 90 minutes sub-cutaneously administered was intra-perito administered were administration. drug Testmin to prior compounds reference or 30 of period a for recorded electrophysiological was response Technology(Lawren system a Pinnacle with Continuous recordings performed were EEG recordings EEG used for upto4 mo allowed to recover from surgery for atleast 10 daysand were cemented onto theskull with de was assembly head-mount mm anteriortoBregma.The midline, with the along centered four screw electrode holes was Male C57BL/6 mice were anesthetized and a head-mountwith electrodes. EEG of implantation Surgical EXPERIMENTAL PROCEDURES translation. forward and back- compound potential for class, with a an overall aim to develop a study effectsofNMDA recepto both excitatory andinhibitory neuronal activity. Here we milliseconds the resolution in may beoftherapeutic inter Thus, to pharmacologicallyabilitygamma power the modulate and induced hallucinations, epilepsydisease. Alzheimer’s pathological stat also to function, but been toenhancedcognitive linked inhumans rangi frequencies defined as electroencephalogr Changes in drug various biomarker for pharmaco-dynamic, mechanistic provide a to opportunity an offers (qEEG) Quantitative EEG INTRODUCTION nths after surgery. es such as schizophrenia, such asschizophrenia, es drug- est. The EEG temporal EEG provides The est. disease states. -induced and useful biomarker for this ce, Kansas). Abaseline ce, Kansas). ng between have80 Hz, ng between 30 and neally, exceptTraxoprodil, which range, and the ability to detect to the abilityrange, and for Ketamine andTraxoprodil for r blockers on mouse EEG, with r blockersonmouseEEG, with then used to fitEEG responses am (EEG) gamma band power,am gammaband (EEG) placed on topofthe skull and ntal acrylic. Animalswere frontal screw screw positioned 1-1.5 frontal Z-score maps from individual mapsfrom Z-score and potentiallytranslatable as collected for bioanalysis. bioanalysis. for as collected to generate response curves. . EEG data was collected EEG datawas for . ration. Atthe end ofeach Maninder Chopra EEG GammaPowerChangesFollowing of NMDAAdministration Receptor Antagonists is slightly delayed in time. while onset of peak effect following 30 mg/kgdose decline rapidly peak and Ketamine concentrations
Frequency (Hz) Frequency (Hz) Frequency (Hz) 10 15 20 25 30 35 40 45 50 55 10 15 20 25 30 35 40 45 50 55 10 15 20 25 30 35 40 45 50 55 5 5 5 RESULTS 0 0 0
1 120 mg/kg 60 mg/kg 30 mg/kg , Michael Quirk , Michael 20 20 Ketamine 20 Neuroscience Biology 40 40 40 Time (minutes) Time (minutes) Time (minutes) Z-map Z-map Z-map 60 60 60 80 80 80 observed. was related indirecteffect mechanism or contribution metabolite activeprolonged (120 mg/kg) evidence of a ketamine Athigher dosesof 100 100 100
1 , Ray Rothstein , Ray 10 -2 0 2 4 6 8 10 12 14 -2 0 2 4 6 8 10 -2 0 2 4 6 8 of C function following as a drug administration minutes frequency 90 bandpower fold-change inthe Plots average showing from listed references. listed from or quoted simulated Clinical rangeswere max Frequency (Hz) Frequency (Hz) mg/kg). (Right column, 30,60 and 100 Traxoprodiland mg/kg) or 100 (middle Remacemide column, 30 and 120 mg/kg), column, 30,60 (left of administration ketamine changesfollowing spectrum power showing Heat maps 55 10 15 20 25 30 35 40 45 50 55 10 15 20 25 30 35 40 45 50 5 5 0 0
(Left, ketamine;Right;traxoprodil) 30 mg/kg 100 mg/kg Remacemide 1 20 20 , Safety , Assessment 40 40 Time (minutes) Time Time (minutes) Time
using a link model. link using a ketamine gamma EEGPK/PD to fits predicted and actual showing Plot Gamma EEG Power Spectrogram Z-map 60 60 2 , JohnRoberts 80 80 100 100 Time (min) Time
10 -2 0 2 4 6 8 0 5 10 15 20 25 30 35 40 45 50 γ
Frequency (Hz) Frequency (Hz) Frequency (Hz) 55 10 15 20 25 30 35 40 45 50 55 10 15 20 25 30 35 40 45 50 55 10 15 20 25 30 35 40 45 50 5 5 5 0 3 0 0
2 100 mg/kg 60 mg/kg , MaryJ Bock 30 mg/kg , DMPK Traxoprodil 120 mg/kg 60 mg/kg 30 mg/kg 15 mg/kg 20 20 20 40 40 40 Time (minutes) Time (minutes) Time (minutes) WinNonlin 4.1. using obtained ketamine were PK/PD parameter estimatesfor Spectrogram Spectrogram Keo (min EC50 ( EC50 Hill slope Emax Parameter Z-map 60 60 60 μ 3 M) -1 , Astrazeneca R&D, Wilmington, DE. Wilmington, R&D, , Astrazeneca ) 80 80 80 4.15 Value 1.48 0.61 28 100 100 100 3 , Ed Christian
7 19 18 23 %CV -2 -1 0 1 2 3 4 5 -2 0 2 4 6 8 10 -2 -1 0 1 2 3 4 5 1 SUMMARY TaylorK,T, RussellDiringer TJ, Venkatakrishnan K, CrownoverP,K, Wilner Gibbs Benincosa LJ, PreskornLanden JW(2008) SH,KramsMenniti Baker B,FS,S, KolluriM, design innovative to An Zarate CAJr, JB,PJ,Singh CarlsonNE, Brutche R, LuckenbaughDA,DS,Ameli ManjiCharney Yanagihara Y, OhtaniM, Kariya S, Uchino K, HiraishiT, AshizawaN, AoyamaT, Yamamura Y, White PF, Ham J, Way WL, Trevor AJ(1980) Pharmacologyof ketamineisomers in surgical Pinnault D (2008) N-methylreceptord-aspartateand antagonistsketamine MK-801 induce wake- IdvallJ, Ahlgren I,and AronsenKR, Stenberg P infusions:pharmacokineticsKetamine (1979) Zhang SL, Wu QX, Lin ZL, CY,Zhou Deng WM, Yu F,Qian Rao XY, ZX, SJ, Shan Yang Kuang M, REFERENCES We wish to thank Mark Eisman and Bernie Lanoue for DMPK support,Weand for DMPKand Markto thankLanoue wish Bernie Eisman ACKNOWLEDGEMENTS , Russell Bialecki , Russell antagonist, traxoprodil. allosteric and NR2b-selective remacemide) anatgonists (ketamine, selective NMDAR the Plot comparing and/or unexplored polypharmacology.a yet allosteric antagonist)s vs blocker (open-channel pore mechanism may be explained by in differences blocking bytypesof NMDA thetwo receptor antagonists and increased and remacemide ketamine blockers, NMDANon-selective open channel receptor antagonist showed in γ decrease antagonist a small showed In contrast, traxoprodil,an manner Differences in the effects on EEG the effectsonEEG Differences in Poor Metabolisers. Mof (2006) Traxoprodil BioavailabilityOralAbsolute Extensiveand P450 2D6 Cytochromein depressive disorder. methyl-D-aspartateantagonist,CP-101,606, in patients with major treatment-refractory N- NR2B subunitofselectiveestablish theeffectsof ofproof the concept antidepressant major depression. HK (2006) A randomized trial of an N-methyl-D-aspartateantagonist in treatment-resistant Drug Dispos. Administrationof Various Ketamine Preparations to Healthy Yamada Y, Iga T. (2003) Plasma Concentration Profiles of Ketamine and Norketamine after patients. patients. neocortex. the rat in oscillations gamma aberrant related clinical effects. Physiology therapeutically relevant concentrations YY,myocytesaton human of atrial ketamine effects SG.ElectrophysiologicalLin Frank McGrath and Lisa Leon for surgery support. for surgery Leon Lisa and McGrath Frank γ pwri oe andexposure-dependent -power in adose- Anesthesiology (2008) 35, 1465–1470. 24: 37. Br J Anaesth Arch Gen Psychiatry Clin Pharmacokinet. Clin J ClinPsychopharmacol. 52:231. 51:1167. γ Clinical and Experimental Pharmacology and 63: 856. band power changes fornon- band power 45: 989. ubtype-selective effects, 28: 631. NR2b specific allosteric 2 Biol. Psychiatry Biol. and CarlosFonck Japanese VolunteersBiopharm. γ -power caused -power 63:730. -power. 750.1/V36 β 2