Downloaded from jpet.aspetjournals.org at ASPET Journals on September 24, 2021 379 397, May 2018 – https://doi.org/10.1124/jpet.117.247171 ve been used in most experiments ting its predictive efficacy. We iparkinsonian, and antipsychotic ug discovery and development parkinsonism, the macaque has a J Pharmacol Exp Ther 365:379 Materials and Methods We have therefore conducted a thorough and unbiased We believe this review comes at a critical time given that it Three nonhuman primate species ha primate when itdisability relates or to dopaminergic psychosis, the norbetween did effect different it primate of look species at when drugs differences itclinical on comes effectiveness to of parkinsonian predicting an the experimental molecule. review of the literature to compare theof predictive effectiveness different MPTP-lesionedeffectiveness primate of speciesand potential on antipsychotic the agents. antidyskinetic, clinical antiparkinsonian has recently been suggested thatbe some more primate species suited might thanlogic others to research conduct (Porras behavioralseveral pharmaco- et failures of al., high-profileet 2012); al., drugs 2014; Bespalov also, et in al., 2016), clinical therethe emphasizing the trials have need best to (Cook use been animalmaximize chances model of success when possible translating to in the clinic. preclinical settings to hope our resultsiments will help and in willprocess the in design facilitate PD. of the pharmacologic dr exper- predictive value ofwhereas the marmoset 87.5% has a positive andafalse-positiverateof15.6%.For predictive value a of 76.9% and false-positivepositive rate predictive of value44.4%, whereas 38.1%, of the 68.2% marmoset86.9% and has and a a a false-positive positivepsychosis rate false-positive predictive in of value rate 41.7%. the of macaque, No of drug clinic whereas that the has alleviates value. marmoset shown The has efficacy smallmonkey 100% at precluded positive number us doing predictive of from so calcula studies in conducted the in the squirrel to determine the antidyskinetic, ant Université de Montréal (N.V.),Montreal Neurological Institute (A.H.,P.H.), and ’ Supplemental material to this article can be found at: HERAPEUTICS T the macaque, marmoset, and s rahydropyridine (MPTP)-lesioned — tiparkinsonian agents. A review http://jpet.aspetjournals.org/content/suppl/2018/03/09/jpet.117.247171.DC1 XPERIMENTAL -3,4-dihydroxyphenylalanine; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; PD, Parkinson disease. L E Introduction -DOPA, L the last much less so than the first two species; — 397$35.00 – HARMACOLOGY AND P 2018 by The American Society for Pharmacology and Experimental Therapeutics Santé, Natural Sciences and Engineering Research Council of ª – This article has supplemental material available at jpet.aspetjournals.org. OURNAL OF J s Since its accidental discovery (Davis et al., 1979; Langston et al., https://doi.org/10.1124/jpet.117.247171. P.H. holds research support from Parkinson Canada, Fonds de Recherche HE Department of Neurology and Neurosurgery, McGill University (P.H.), Montreal, Quebec, Canada Copyright 1983), 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been used extensivelybreadth to of model nonhumananatomic Parkinson primates, (Jan disease enabling(Pessiglione (PD) the et et in al., investigation al., 2004a,b), a 1994; of neurochemical 2000; Huot (Soghomonian et et ZengMPTP-lesioned al., al., primate 2008), has et also and been invaluableeffective other al., in the antidyskinetic aspects search 2008), for of and the an behavioral disease. The article previously examined thethe translational MPTP-lesioned predictive primate for value the of drugs, development of but antidyskinetic it was2006a), published and more than manyprimate a decade drugs and ago have in (Foxexamine et clinical since the al., translational settings. been predictive This value tested of previous the both MPTP-lesioned review in did the not Canada, and the Weston Brain Institute. Québec ABBREVIATIONS: primate is the(PD) gold-standard and has animal been used model todrugs assess of the on effectiveness Parkinson dyskinesia, of experimental disease parkinsonism,have and been psychosis. Three used species in most studies T ABSTRACT The 1-methyl-4-phenyl-1,2,3,6-tet squirrel monkey however, the predictive value ofefficacy, each species or at forecasting lack clinical reviewed all thereof, the published is literature detailingthat pharmacologic poorly studies assessed documented. the Here,parkinsonism, effects and we psychosis of have calculated in experimental their each predictive value drugs of of successlevel. on these and We failure species dyskinesia, at found the and clinical that, have for dyskinesia, the macaque has a positive Received December 13, 2017; accepted March 6, 2018 Nicolas Veyres, AdjiaCentre de Hamadjida, Recherche du and Centre Hospitalier de Philippe l Huot Squirrel Monkey Studies: A Comparison between the Macaque, Marmoset, and Predictive Value of Parkinsonian Primates in Pharmacologic Minireviews 1521-0103/365/2/379 380 Veyres et al. Downloaded from Fig. 1. A total of 98 experimental drugs were tested in the MPTP-lesioned Fig. 2. A total of 44 drugs that are either clinically approved or that macaque, 97 in the MPTP-lesioned marmoset, and nine in the MPTP- underwent clinical testing in PD were tested in the MPTP-lesioned lesioned squirrel monkey. macaque, 38 in the MPTP-lesioned marmoset, and one in the MPTP- lesioned squirrel monkey. effect of experimental drugs: the macaque [both cynomolgus (Di Paolo et al., 1986) and rhesus (Burns et al., 1983), Macaca fascicularis and Macaca considered. A drug was considered to have antiparkinsonian benefit jpet.aspetjournals.org mulatta, respectively], the common marmoset (Jenner et al., 1984) if it alleviated parkinsonism as monotherapy or as an adjunct to (Callithrix jacchus), and the common squirrel monkey (Langston et al., L-DOPA. Impulse-control disorders (Weintraub et al., 2010) were not 1984) (Saimiri sciureus). For each of these three primate species, we have considered a psychotic manifestation. reviewed all the studies that reported their effect, or lack thereof, on Several studies, especially in the macaque, were performed that dyskinesia, parkinsonism, and psychosis. We then sought which of these administered drugs (e.g., cabergoline) to reduce the development of drugs tested in the nonhuman primate underwent clinical testing and dyskinesia and then conducted postmortem experiments; we have compared their preclinical and clinical effects and calculated different included these studies in our analysis, even if their primary endpoint at ASPET Journals on September 24, 2021 predictive values (see Endpoints). was not determination of pharmacologic efficacy. Studies reporting the Inclusion Criteria. The literature search spans from 1983, when effects of experimental drugs on rotational behavior in the hemi-MPTP- the first MPTP-lesioned nonhuman primate was engineered (Burns lesioned primate (e.g., Vermeulen et al., 1995) were not included. et al., 1983), until December 10, 2017. Studies published after this In some instances, conflicting results were obtained with some drugs date, either online or in print format, are not included. (e.g., studies encountered a therapeutic benefit), whereas others did not Only drugs whose preclinical and clinicalefficacy,orlackthereof,were reach similar conclusions; whenever this happened, we calculated the reported in peer-reviewed articles are included in this article. Results predictive values using “best result” (i.e., the one that showed a disseminated solely through abstracts or conference proceedings are therapeutic effect), weighing in the methods used in the studies (Gad, therefore not reported here. We are aware that not all studies conducted 2009), if applicable. For instance, in the case of preladenant, phase on parkinsonian primates have been published and that the results of 2 studies have found antiparkinsonian efficacy (Hauser et al., 2011; some clinical trials have not been disseminated through peer-reviewed Factor et al., 2013), whereas phase 3 studies did not (Hauser et al., 2015; journals; by choosing to include only studies and reports that were Stocchi et al., 2017); but in one instance, the active comparator, rasagiline published in peer-reviewed journals, we may be introducing a selection (Hauser et al., 2015), was also ineffective, despite proven antiparkinso- bias in our analysis. For instance, although it has been studied in humans nian benefit in randomized-controlled trials (Parkinson Study Group, (NCT00034814, NCT00108667), the clinical effectiveness of talampanel 2005; Rascol et al., 2005), somewhat casting doubt on study conclusion. In will not be discussed here, as the results of the clinical trials where it was this case, we considered that preladenant exerted antiparkinsonian assessed were not published in peer-reviewed scientific journals. In benefit. addition, we have excluded L-3,4-dihydroxyphenylalanine (L-DOPA) and Endpoints. By comparing the outcomes of the primate studies on inhibitors of L-aromatic amino acid decarboxylase [e.g., benserazide dyskinesia, parkinsonism, and psychosis, we have calculated, for each (Rinne et al., 1975) and carbidopa (Marsden et al., 1973)] from our species, the positive predictive value, the negative predictive value, analysis, as these were used in almost all studies cited here to reverse and the false-positive rate. parkinsonism and induce dyskinesia. Here, we define the positive