RESUMO
AIMS: To characterise the safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending doses of oxathridine, a first-in-class histamine-3 receptor partialagonist, in healthy male volunteers. METHODS: A randomised, double-blind, placebo-controlled study including the NeuroCart, consisting of a battery of drug sensitive neurophysiological tests, was performed. Oxathridine was administered orally as an aqueous solution. After dosing, safety and NeuroCart tests (adaptive tracking [AT], body sway [BS], saccadic peak velocity [SPV], smooth pursuit [SP] eye movements, VAS according to Bond and Lader, VAS according to Bowdle [VAS B&L, Bowdle], pharmaco-electroencephalogram [pEEG], Sustained Attention to Response Task [SART]) were performed at set times. RESULTS: Forty volunteers completed the study. Given doses were: 0.5, 2.5, 5, 0.25 and 1.5 mg. At 5 mg, unacceptable and unanticipated adverse events (AEs) of (orthostatic) hypotension and pseudo-hallucinations were reported. Statistically significant effects ([CI]; p-value) of 2.5 mg and 5 mg oxathridine were observed on AT ([-8.28, -1.60]; p = 0.0048), ([-8.10, -1.51]; p = 0.00530), BS ([0.6, 80.2]; p = 0.0455), ([5.9, 93.1]; p = 0.0205) and SPV ([-59.0, -15.9]; p = 0.0011), ([-43.9, -1.09]; p = 0.0399), respectively. Oxathridine 5 mg significantly increased all three VAS Bowdle subscale scores; VAS external ([0.183, 0.476]; p = <.0001), VAS internal ([0.127, 0.370]; p = 0.0001) and VAS feeling high ([0.263, 0.887]; p = 0.0006). CONCLUSION: NeuroCart tests indicated central nervous system (CNS) depressant effects. Oxathridine also unexpectedly caused pseudohallucinations. Although this led to the decision to stop further development of oxathridine, these observations suggest that the H3R system could be an interesting new target for the development of novel antipsychotics.
Assuntos
Depressão , Histamina , Humanos , Masculino , Eletroencefalografia , Sistema Nervoso Central , Alucinações , Método Duplo-Cego , Voluntários Saudáveis , Relação Dose-Resposta a DrogaRESUMO
AIMS: ALKS 7119 is a novel compound with in vitro affinity highest for the SERT, and for µ receptor, α1A -adrenoceptor, α1B -adrenoceptor, NMDA receptor and sigma non-opioid intracellular receptor 1. This first-in-human study evaluated safety and PK/PD effects of single ascending doses (SAD) of ALKS 7119 in healthy males and compared effects with neurotransmitter modulators with partially overlapping targets. METHODS: In 10 cohorts (n = 10 subjects each), PK, safety and PD (NeuroCart tests, measuring neurophysiologic effects [pupillometry, pharmaco-EEG (pEEG)], visuomotor coordination, alertness, [sustained] attention [saccadic peak velocity, adaptive tracking], subjective drug effects [VAS Bowdle and VAS Bond and Lader] and postural stability [body sway]) were evaluated. Neuroendocrine effects (cortisol, prolactin, growth hormone) were measured. Data were analysed over the 12-hour post-dose period using mixed-effects model for repeated measure (MMRM) with baseline as covariate. RESULTS: ALKS 7119 demonstrated linear PK and was generally well tolerated. QTcF interval increases of 30-60 ms compared to baseline were observed with ALKS 7119 doses of ≥50 mg without related adverse events. Significant increases in left and right pupil/iris ratio were observed at dose levels ≥50 mg (estimate of difference [95% CI], P-value) (0.04 [0.01; 0.07], P < .01) and (0.06 [0.03; 0.09], P = .01), respectively. From dose levels ≥50 mg significant increases (% change) of serum cortisol (51.7 [8.4; 112.3], P = .02) and prolactin (77.9 [34.2; 135.8], P < .01) were observed. CONCLUSION: In line with ALKS 7119's in vitro pharmacological profile, the clinical profile observed in this study is most comparable to SERT inhibition.
Assuntos
Hidrocortisona , Prolactina , Relação Dose-Resposta a Droga , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Receptores Adrenérgicos , Movimentos SacádicosRESUMO
During the outbreak of the COVID-19 pandemic many clinical trials were abruptly halted. Measures to contain the pandemic are currently taking effect and societies in general and healthcare systems in particular are considering how to return to normalcy. This opens up the discussion when and how clinical trials should be restarted while the COVID-19 pandemic has not yet resolved, and what should happen in case of a resurgence of the virus in the coming months. This article uses the four ethical principles framework as a structured approach to come to a set of practical, ethically grounded guidelines for halting and relaunching clinical trials during the COVID-19 pandemic. The framework applied provides a structured approach for all clinical trials stakeholders and thereby prevents unclear reasoning in a complex situation. While it is essential to prevent the virus from resurging and focus on developing a COVID-19 treatment as soon as possible, it is just as important to our society that we continue developing new drugs for other conditions. In this article we argue that the situation for clinical trials is not essentially different from the pre-COVID-19 era and that an overcautious approach will have negative consequences.
Assuntos
COVID-19 , Ensaios Clínicos como Assunto/ética , Ensaios Clínicos como Assunto/métodos , Análise Ética , Pandemias , Humanos , Projetos de PesquisaRESUMO
Disruption of cholinergic and serotonergic neurotransmitter systems is associated with cognitive, emotional and behavioural symptoms of Alzheimer's disease (AD). To investigate the responsiveness of these systems in AD we measured the effects of a single-dose of the selective serotonin reuptake inhibitor citalopram and acetylcholinesterase inhibitor galantamine in 12 patients with AD and 12 age-matched controls on functional brain connectivity with resting state functional magnetic resonance imaging. In this randomized, double blind, placebo-controlled crossover study, functional magnetic resonance images were repeatedly obtained before and after dosing, resulting in a dataset of 432 scans. Connectivity maps of ten functional networks were extracted using a dual regression method and drug vs. placebo effects were compared between groups with a multivariate analysis with signals coming from cerebrospinal fluid and white matter as covariates at the subject level, and baseline and heart rate measurements as confound regressors in the higher-level analysis (at pâ¯<â¯0.05, corrected). A galantamine induced difference between groups was observed for the cerebellar network. Connectivity within the cerebellar network and between this network and the thalamus decreased after galantamine vs. placebo in AD patients, but not in controls. For citalopram, voxelwise network connectivity did not show significant groupâ¯×â¯treatment interaction effects. However, we found default mode network connectivity with the precuneus and posterior cingulate cortex to be increased in AD patients, which could not be detected within the control group. Further, in contrast to the AD patients, control subjects showed a consistent reduction in mean connectivity with all networks after administration of citalopram. Since AD has previously been characterized by reduced connectivity between the default mode network and the precuneus and posterior cingulate cortex, the effects of citalopram on the default mode network suggest a restoring potential of selective serotonin reuptake inhibitors in AD. The results of this study also confirm a change in cerebellar connections in AD, which is possibly related to cholinergic decline.
Assuntos
Doença de Alzheimer , Cerebelo/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Conectoma , Rede Nervosa/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Tálamo/efeitos dos fármacos , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Cerebelo/diagnóstico por imagem , Cerebelo/fisiologia , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/fisiologia , Citalopram/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Galantamina/farmacologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Tálamo/diagnóstico por imagem , Tálamo/fisiologiaRESUMO
AIMS: In previous studies, the histamine-3 receptor antagonist CEP-26401 had a subtle effect on spatial working memory, with the best effect seen at the lowest dose tested (20 µg), and a dose-dependent disruption of sleep. In the current study, 3 low-dose levels of CEP-26401 were compared with modafinil and donepezil. METHODS: In this double-blind, placebo- and positive-controlled, randomized, partial 6-way cross-over study, 40 healthy subjects received single doses of placebo, CEP-26401 (5, 25 or 125 µg) or modafinil 200 mg or donepezil 10 mg. Pharmacokinetic and pharmacodynamic measurements were performed predose and at designated time points postdose. RESULTS: The main endpoint between-errors of the spatial working memory-10-boxes task only improved for the 125 µg dose of CEP-26401 with a difference of 2.92 (confidence interval [CI] -1.21 to 7.05), 3.24 (CI -1.57 to 8.04) and 7.45 (CI 2.72 to 12.19) for respectively the 5, 25 and 125 µg dose of CEP-26401, -1.65 (CI -0.572 to 1.96) for modafinil and - 3.55 (CI -7.13 to 0.03) for donepezil. CEP-26401 induced an improvement of adaptive tracking, saccadic peak velocity and reaction time during N-back, but a dose-related inhibition of sleep and slight worsening of several cognitive parameters at the highest dose. CEP-26401 significantly changed several subjective visual analogue scales, which was strongest at 25 µg, causing the same energizing and happy feeling as modafinil, but with a more relaxed undertone. DISCUSSION: Of the doses tested, the 25 µg dose of CEP-26401 had the most optimal balance between favourable subjective effects and sleep inhibition. Whether CEP-26401 can have beneficial effects in clinical practice remains to be studied.
Assuntos
Encéfalo/efeitos dos fármacos , Antagonistas dos Receptores Histamínicos/administração & dosagem , Piridazinas/administração & dosagem , Pirrolidinas/administração & dosagem , Adolescente , Adulto , Encéfalo/fisiologia , Cognição/efeitos dos fármacos , Cognição/fisiologia , Disfunção Cognitiva/tratamento farmacológico , Estudos de Coortes , Estudos Cross-Over , Donepezila/administração & dosagem , Donepezila/farmacocinética , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Voluntários Saudáveis , Antagonistas dos Receptores Histamínicos/farmacocinética , Humanos , Masculino , Memória/efeitos dos fármacos , Memória/fisiologia , Pessoa de Meia-Idade , Modafinila/administração & dosagem , Modafinila/farmacocinética , Piridazinas/farmacocinética , Pirrolidinas/farmacocinética , Tempo de Reação/efeitos dos fármacos , Tempo de Reação/fisiologia , Receptores Histamínicos H3/metabolismo , Sono/efeitos dos fármacos , Sono/fisiologia , Adulto JovemRESUMO
Aging is accompanied by changes in neurotransmission. To advance our understanding of how aging modifies specific neural circuitries, we examined serotonergic and cholinergic stimulation with resting state functional magnetic resonance imaging (RS-fMRI) in young and older adults. The instant response to the selective serotonin reuptake inhibitor citalopram (30â¯mg) and the acetylcholinesterase inhibitor galantamine (8â¯mg) was measured in 12 young and 17 older volunteers during a randomized, double blind, placebo-controlled, crossover study. A powerful dataset consisting of 522 RS-fMRI scans was obtained by acquiring multiple scans per subject before and after drug administration. Groupâ¯×â¯treatment interaction effects on voxelwise connectivity with ten functional networks were investigated (pâ¯<â¯.05, FWE-corrected) using a non-parametric multivariate analysis technique with cerebrospinal fluid, white matter, heart rate and baseline measurements as covariates. Both groups showed a decrease in sensorimotor network connectivity after citalopram administration. The comparable findings after citalopram intake are possibly due to relatively similar serotonergic systems in the young and older subjects. Galantamine altered connectivity between the occipital visual network and regions that are implicated in learning and memory in the young subjects. The lack of a cholinergic response in the elderly might relate to the well-known association between cognitive and cholinergic deterioration at older age.
Assuntos
Envelhecimento/efeitos dos fármacos , Córtex Cerebral/efeitos dos fármacos , Inibidores da Colinesterase/farmacologia , Conectoma/métodos , Rede Nervosa/efeitos dos fármacos , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Adolescente , Adulto , Idoso , Córtex Cerebral/diagnóstico por imagem , Inibidores da Colinesterase/farmacocinética , Citalopram/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Galantamina/farmacologia , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Adulto JovemRESUMO
AIMS: Establishing a pharmacological challenge model could yield an important tool to understand the complex role of the nicotinic cholinergic system in cognition and to develop novel compounds acting on the nicotinic acetylcholine receptor. METHODS: This randomized, double-blind, double-dummy, placebo-controlled, four-way crossover study examined the effects of the nicotinic antagonist mecamylamine on a battery of cognitive and neurophysiological test with coadministration of a placebo, nicotine or galantamine in order to reverse the cognitive impairment caused by mecamylamine. RESULTS: Thirty-three healthy subjects received a single oral dose of 30 mg of mecamylamine (or placebo) in combination with either 16 mg of oral galantamine or 21 mg of transdermal nicotine (or its double-dummy). Mecamylamine 30 mg induced significant disturbances of cognitive functions. Attention and execution of visual (fine) motor tasks was decreased, short- and long-term memory was impaired and the reaction velocity during the test was slower when compared to placebo. Mecamylamine 30 mg produced a decrease in posterior α and ß power in the surface electroencephalogram, effects that were reversed by nicotine coadministration. Memory and motor coordination tests could be partially reversed by the coadministration of nicotine. CONCLUSIONS: Mecamylamine administration induced slowing of the electroencephalogram and produced decrease in performance of tests evaluating motor coordination, sustained attention and short- and long-term memory. These effects could be partially reversed by the coadministration of nicotine, and to a lesser extent by galantamine.
Assuntos
Cognição/efeitos dos fármacos , Eletroencefalografia/efeitos dos fármacos , Galantamina/farmacologia , Mecamilamina/antagonistas & inibidores , Nicotina/farmacologia , Adolescente , Adulto , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Voluntários Saudáveis , Humanos , Masculino , Mecamilamina/farmacologia , Pessoa de Meia-Idade , Agonistas Nicotínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Tempo de Reação/efeitos dos fármacos , Adulto JovemRESUMO
AIMS: Inflammation and organ failure have been reported to have an impact on cytochrome P450 (CYP) 3A-mediated clearance of midazolam in critically ill children. Our aim was to evaluate a previously developed population pharmacokinetic model both in critically ill children and other populations, in order to allow the model to be used to guide dosing in clinical practice. METHODS: The model was evaluated externally in 136 individuals, including (pre)term neonates, infants, children and adults (body weight 0.77-90 kg, C-reactive protein level 0.1-341 mg l-1 and 0-4 failing organs) using graphical and numerical diagnostics. RESULTS: The pharmacokinetic model predicted midazolam clearance and plasma concentrations without bias in postoperative or critically ill paediatric patients and term neonates [median prediction error (MPE) <30%]. Using the model for extrapolation resulted in well-predicted clearance values in critically ill and healthy adults (MPE <30%), while clearance in preterm neonates was over predicted (MPE >180%). CONCLUSION: The recently published pharmacokinetic model for midazolam, quantifying the influence of maturation, inflammation and organ failure in children, yields unbiased clearance predictions and can therefore be used for dosing instructions in term neonates, children and adults with varying levels of critical illness, including healthy adults, but not for extrapolation to preterm neonates.
Assuntos
Citocromo P-450 CYP3A/metabolismo , Hipnóticos e Sedativos/farmacocinética , Midazolam/farmacocinética , Modelos Biológicos , Insuficiência de Múltiplos Órgãos/tratamento farmacológico , Síndrome de Resposta Inflamatória Sistêmica/tratamento farmacológico , Adulto , Proteína C-Reativa/análise , Criança , Estado Terminal , Humanos , Hipnóticos e Sedativos/sangue , Lactente , Recém-Nascido , Taxa de Depuração Metabólica , Midazolam/sangue , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/enzimologia , Valor Preditivo dos Testes , Síndrome de Resposta Inflamatória Sistêmica/sangue , Síndrome de Resposta Inflamatória Sistêmica/enzimologiaRESUMO
Psychopharmacological research, if properly designed, may offer insight into both timing and area of effect, increasing our understanding of the brain's neurotransmitter systems. For that purpose, the acute influence of the selective serotonin reuptake inhibitor citalopram (30 mg) and the acetylcholinesterase inhibitor galantamine (8 mg) was repeatedly measured in 12 healthy young volunteers with resting state functional magnetic resonance imaging (RS-fMRI). Eighteen RS-fMRI scans were acquired per subject during this randomized, double blind, placebo-controlled, crossover study. Within-group comparisons of voxelwise functional connectivity with 10 functional networks were examined (P < 0.05, FWE-corrected) using a non-parametric multivariate approach with cerebrospinal fluid, white matter, heart rate, and baseline measurements as covariates. Although both compounds did not change cognitive performance on several tests, significant effects were found on connectivity with multiple resting state networks. Serotonergic stimulation primarily reduced connectivity with the sensorimotor network and structures that are related to self-referential mechanisms, whereas galantamine affected networks and regions that are more involved in learning, memory, and visual perception and processing. These results are consistent with the serotonergic and cholinergic trajectories and their functional relevance. In addition, this study demonstrates the power of using repeated measures after drug administration, which offers the chance to explore both combined and time specific effects. Hum Brain Mapp 38:308-325, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Mapeamento Encefálico , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Colinérgicos/metabolismo , Serotonina/metabolismo , Adolescente , Adulto , Encéfalo/diagnóstico por imagem , Inibidores da Colinesterase/sangue , Inibidores da Colinesterase/farmacologia , Citalopram/sangue , Citalopram/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Feminino , Galantamina/sangue , Galantamina/farmacologia , Humanos , Hidrocortisona/sangue , Processamento de Imagem Assistida por Computador , Masculino , Modelos Neurológicos , Oxigênio/sangue , Prolactina/sangue , Inibidores Seletivos de Recaptação de Serotonina/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Adulto JovemRESUMO
AIMS: The aims of the present study were to investigate the role of pharmacology in the design of first-in-man (FIM) trials in the Netherlands, and to evaluate the change in design approaches between 2007 and 2015. METHODS: All FIM drug trials approved by all Dutch Institutional Review Boards (IRBs) in 2007 and in 2015 were selected. The original trial protocols, investigator's brochures and investigational medicinal product dossiers were the data sources. The following four design elements were assessed on the justification of the chosen approaches: preclinical information, dose calculation, endpoints, and dose escalation. RESULTS: In 2007, the Dutch IRBs approved 21 FIM trials, and in 2015 they approved 34 FIM trials (55 in total). Seven out of 21 (33%) of the FIM trials from 2007, and 14 out of the 34 (41%) FIM trials from 2015 discussed only the no-observed-adverse-effect level or no-observed-effect level as preclinical information. Furthermore, five of the 21 (24%) 2007 FIM trials and 12 of the 34 (35%) 2015 FIM trials used unexplained allometric scaling. Pharmacodynamic (PD) parameters were measured in 15 of the 21 (71%) 2007 FIM trials and in 31 of the 34 (91%) of the 2015 FIM trials, and allometric scaling was only guided by safety/tolerability in 11 of the 20 (55%) dose escalation trials in 2007 and in nine of the 33 (27%) dose escalation trials in 2015. CONCLUSIONS: Trial protocols and investigator's brochures commonly lack pharmacokinetic/PD approaches. Investigators, sponsors and IRBs should require an upfront consideration of pharmacology in these aspects for all FIM trials.
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Ensaios Clínicos como Assunto/métodos , Preparações Farmacêuticas/administração & dosagem , Projetos de Pesquisa/tendências , Bases de Dados Factuais , Relação Dose-Resposta a Droga , Cálculos da Dosagem de Medicamento , Avaliação Pré-Clínica de Medicamentos/tendências , Determinação de Ponto Final/tendências , Humanos , Países Baixos , Nível de Efeito Adverso não Observado , Farmacocinética , Fatores de TempoRESUMO
AIM: To evaluate the pharmacokinetics, pharmacodynamics, nasal tolerance and effects on sedation of a highly concentrated aqueous intranasal midazolam formulation (Nazolam) and to compare these to intravenous midazolam. METHODS: In this four-way crossover, double-blind, double-dummy, randomized, placebo-controlled study, 16 subjects received 2.5 mg Nazolam, 5.0 mg Nazolam, 2.5 mg intravenous midazolam or placebo on different occasions. Pharmacokinetics of midazolam and α-hydroxy-midazolam were characterized and related to outcome variables for sedation (saccadic peak velocity, the Bond and Lader visual analogue scale for sedation, the simple reaction time task and the observer's assessment of alertness/sedation). Nasal tolerance was evaluated through subject reporting, and ear, nose and throat examination. RESULTS: Nazolam bioavailability was 75%. Maximal plasma concentrations of 31 ng ml-1 (CV, 42.3%) were reached after 11 min (2.5 mg Nazolam), and of 66 ng ml-1 (coefficient of variability, 31.5%) after 14 min (5.0 mg Nazolam). Nazolam displayed a significant effect on OAA/S scores. Sedation onset (based on SPV change) occurred 1 ± 0.7 min after administration of 2.5 mg intravenous midazolam, 7 ± 4.4 min after 2.5 mg Nazolam, and 4 ± 1.8 min after 5 mg Nazolam. Sedation duration was 118 ± 95.6 min for 2.5 mg intravenous midazolam, 76 ± 80.4 min for 2.5 mg Nazolam, and 145 ± 104.9 min for 5.0 mg Nazolam. Nazolam did not lead to nasal mucosa damage. CONCLUSIONS: This study demonstrates the nasal tolerance, safety and efficacy of Nazolam. When considering the preparation time needed for obtaining venous access, conscious sedation can be achieved in the same time span as needed for intravenous midazolam. Nazolam may offer important advantages in conscious sedation.
Assuntos
Sedação Consciente/métodos , Hipnóticos e Sedativos/administração & dosagem , Midazolam/administração & dosagem , Administração Intranasal , Administração Intravenosa , Adulto , Disponibilidade Biológica , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hipnóticos e Sedativos/farmacocinética , Hipnóticos e Sedativos/farmacologia , Masculino , Midazolam/análogos & derivados , Midazolam/farmacocinética , Midazolam/farmacologia , Pessoa de Meia-Idade , Mucosa Nasal/efeitos dos fármacos , Mucosa Nasal/metabolismo , Tempo de Reação/efeitos dos fármacos , Adulto JovemRESUMO
AIMS: The muscarinic acetylcholine receptor antagonist scopolamine is often used for proof-of-pharmacology studies with pro-cognitive compounds. From a pharmacological point of view, it would seem more rational to use a nicotinic rather than a muscarinic anticholinergic challenge to prove pharmacology of a nicotinic acetylcholine receptor agonist. This study aims to characterize a nicotinic anticholinergic challenge model using mecamylamine and to compare it to the scopolamine model. METHODS: In this double-blind, placebo-controlled, four-way cross-over trial, 12 healthy male subjects received oral mecamylamine 10 and 20 mg, intravenous scopolamine 0.5 mg and placebo. Pharmacokinetics were analysed using non-compartmental analysis. Pharmacodynamic effects were measured with a multidimensional test battery that includes neurophysiological, subjective, (visuo)motor and cognitive measurements. RESULTS: All treatments were safe and well tolerated. Mecamylamine had a tmax of 2.5 h and a Cmax of 64.5 ng ml-1 for the 20 mg dose. Mecamylamine had a dose-dependent effect decreasing the adaptive tracking performance and VAS alertness, and increasing the finger tapping and visual verbal learning task performance time and errors. Scopolamine significantly affected almost all pharmacodynamic tests. CONCLUSION: This study demonstrated that mecamylamine causes nicotinic receptor specific temporary decline in cognitive functioning. Compared with the scopolamine model, pharmacodynamic effects were less pronounced at the dose levels tested; however, mecamylamine caused less sedation. The cognitive effects of scopolamine might at least partly be caused by sedation. Whether the mecamylamine model can be used for proof-of-pharmacology of nicotinic acetylcholine receptor agonists remains to be established.
Assuntos
Atenção/efeitos dos fármacos , Cognição/efeitos dos fármacos , Aprendizagem/efeitos dos fármacos , Antagonistas Muscarínicos/farmacologia , Antagonistas Nicotínicos/farmacologia , Adulto , Encéfalo/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Eletroencefalografia , Voluntários Saudáveis , Humanos , Hipnóticos e Sedativos/farmacologia , Masculino , Mecamilamina/farmacologia , Nicotina , Receptores Muscarínicos/metabolismo , Receptores Nicotínicos/metabolismo , Escopolamina/farmacologia , Fatores de Tempo , Adulto JovemRESUMO
AIM: The severe psychiatric side effects of cannabinoid receptor type 1 (CB1 ) antagonists hampered their wide development but this might be overcome by careful management of drug development with pharmacokinetic/pharmacodynamic (PK/PD) analyses. PK/PD models suitable for direct comparison of different CB1 antagonists in Δ(9) -tetrahydrocannabinol (THC) challenge tests in healthy volunteer were constructed. METHODS: The pharmacokinetic models of THC and four CB1 antagonists were built separately. THC-induced effects on heart rate and the visual analogue scale of feeling high in healthy volunteers and inhibitive effects of CB1 antagonists on THC-induced effects were modelled in PD models linked to the PK models. Simulations were then applied to evaluate the reduction rate of each antagonist on the reversal of the THC-induced effect in a unified simulation scenario. RESULTS: The final PK model of THC and antagonists was a two compartment model. An Emax model and logistic regression model were used for effect measures and the antagonist effect was added in these models in a competitive binding manner. t1/2ke0 ranged from 0.00462 to 63.7 h for heart rate and from 0.964 to 150 h for VAS. IC50 ranged from 6.42 to 202 ng ml(-1) for heart rate and from 12.1 to 376 ng ml(-1) for VAS. Benchmark simulation showed different dose-efficacy profiles of two efficacy measures for each CB1 antagonist. CONCLUSIONS: PK/PD modelling and simulation approach was suitable for describing and predicting heart rate and feeling high for CB1 antagonists in THC challenge tests. Direct comparison of four antagonists based on simulated efficacy profiles might be of benefit to guide future studies.
Assuntos
Antagonistas de Receptores de Canabinoides/farmacocinética , Simulação por Computador , Dronabinol/farmacologia , Modelos Biológicos , Receptor CB1 de Canabinoide/antagonistas & inibidores , Antagonistas de Receptores de Canabinoides/administração & dosagem , Antagonistas de Receptores de Canabinoides/efeitos adversos , Antagonistas de Receptores de Canabinoides/farmacologia , Relação Dose-Resposta a Droga , Dronabinol/administração & dosagem , Dronabinol/efeitos adversos , Descoberta de Drogas , Voluntários Saudáveis , Frequência Cardíaca/efeitos dos fármacos , Humanos , Modelos Logísticos , Masculino , Valor Preditivo dos TestesRESUMO
AIM: Subjects with increasing age are more sensitive to the effects of the anti-muscarinic agent scopolamine, which is used (among other indications) to induce temporary cognitive dysfunction in early phase drug studies with cognition enhancing compounds. The enhanced sensitivity has always been attributed to incipient cholinergic neuronal dysfunction, as a part of the normal aging process. The aim of the study was to correlate age-dependent pharmacodynamic neuro-physiologic effects of scopolamine after correcting for differences in individual exposure. METHODS: We applied a pharmacokinetic and pharmacodynamic modelling approach to describe individual exposure and neurocognitive effects of intravenous scopolamine administration in healthy subjects. RESULTS: A two-compartment linear kinetics model best described the plasma concentrations of scopolamine. The estimated scopolamine population mean apparent central and peripheral volume of distribution was 2.66 ± 1.050 l and 62.10 ± 10.100 l, respectively and the clearance was 1.09 ± 0.096 l min(-1) . Age was not related to a decrease of performance in the tests following scopolamine administration in older subjects. Only the saccadic peak velocity showed a positive correlation between age and sensitivity to scopolamine. Age was, however, correlated at baseline with an estimated slower reaction time while performing the cognitive tests and to higher global δ and frontal θ frequency bands measured with the surface EEG. CONCLUSIONS: Most of the differences in response to scopolamine administration between young and older subjects could be explained by pharmacokinetic differences (lower clearance) and not to an enhanced sensitivity when corrected for exposure levels.
Assuntos
Envelhecimento/efeitos dos fármacos , Cognição/efeitos dos fármacos , Escopolamina/farmacologia , Escopolamina/farmacocinética , Adolescente , Adulto , Idoso , Relação Dose-Resposta a Droga , Eletroencefalografia/efeitos dos fármacos , Feminino , Voluntários Saudáveis , Humanos , Infusões Intravenosas , Masculino , Pessoa de Meia-Idade , Modelos Biológicos , Antagonistas Muscarínicos/farmacocinética , Antagonistas Muscarínicos/farmacologia , Testes Neuropsicológicos , Tempo de Reação/efeitos dos fármacos , Movimentos Sacádicos/efeitos dos fármacos , Escopolamina/sangue , Adulto JovemRESUMO
The serotonergic system is widely distributed throughout the central nervous system. It is well known as a mood regulating system, although it also contributes to many other functions. With resting state functional magnetic resonance imaging (RS-fMRI) it is possible to investigate whole brain functional connectivity. We used this non-invasive neuroimaging technique to measure acute pharmacological effects of the selective serotonin reuptake inhibitor sertraline (75 mg) in 12 healthy volunteers. In this randomized, double blind, placebo-controlled, crossover study, RS-fMRI scans were repeatedly acquired during both visits (at baseline and 3, 5, 7 and 9h after administering sertraline or placebo). Within-group comparisons of voxelwise functional connectivity with ten functional networks were examined (p<0.005, corrected) using a mixed effects model with cerebrospinal fluid, white matter, motion parameters, heart rate and respiration as covariates. Sertraline induced widespread effects on functional connectivity with multiple networks; the default mode network, the executive control network, visual networks, the sensorimotor network and the auditory network. A common factor among these networks was the involvement of the precuneus and posterior cingulate cortex. Cognitive and subjective measures were taken as well, but yielded no significant treatment effects, emphasizing the sensitivity of RS-fMRI to pharmacological challenges. The results are consistent with the existence of an extensive serotonergic system relating to multiple brain functions with a possible key role for the precuneus and cingulate.
Assuntos
Encéfalo/fisiologia , Serotonina/fisiologia , Adulto , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Hidrocortisona/sangue , Imageamento por Ressonância Magnética , Masculino , Testes Neuropsicológicos , Prolactina/sangue , Inibidores Seletivos de Recaptação de Serotonina/farmacocinética , Inibidores Seletivos de Recaptação de Serotonina/farmacologia , Sertralina/farmacocinética , Sertralina/farmacologia , Adulto JovemRESUMO
Maladaptive dopaminergic mediation of reward processing in humans is thought to underlie multiple neuropsychiatric disorders, including addiction, Parkinson's disease, and schizophrenia. Mechanisms responsible for the development of such disorders may depend on individual differences in neural signaling within large-scale cortico-subcortical circuitry. Using a combination of functional neuroimaging and pharmacological challenges in healthy volunteers, we identified opposing dopamine agonistic and antagonistic neuromodulatory effects on distributed functional interactions between specific subcortical regions and corresponding neocortical "resting-state" networks, known to be involved in distinct aspects of cognition and reward processing. We found that, relative to a placebo, levodopa and haloperidol challenges, respectively, increased or decreased the functional connectivity between (1) the midbrain and a "default mode" network, (2) the right caudate and a right-lateralized frontoparietal network, and (3) the ventral striatum and a fronto-insular network. Further, we found drug-specific associations between brain circuitry reactivity to dopamine modulation and individual differences in trait impulsivity, revealing dissociable drug-personality interaction effects across distinct dopamine-dependent cortico-subcortical networks. Our findings identify possible systems underlying pathogenesis and treatment efficacy in disorders of dopamine deficiency.
Assuntos
Mapeamento Encefálico , Encéfalo/metabolismo , Dopamina/metabolismo , Rede Nervosa/fisiologia , Encéfalo/efeitos dos fármacos , Dopaminérgicos/farmacologia , Haloperidol/farmacologia , Humanos , Interpretação de Imagem Assistida por Computador , Comportamento Impulsivo/metabolismo , Comportamento Impulsivo/fisiopatologia , Levodopa/farmacologia , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/efeitos dos fármacos , Descanso/fisiologia , Recompensa , Adulto JovemRESUMO
Dopaminergic medications, used to treat neurochemical pathology and resultant symptoms in neuropsychiatric disorders, are of mixed efficacy and regularly associated with behavioural side effects. The possibility that dopamine exerts both linear and nonlinear ('inverted U-shaped') effects on cognitive neurocircuitry may explain this outcome variability. However, it has proven to be difficult to characterise neural manifestations of psychopharmacological effects in humans. We hypothesised that diverse effects of dopamine neuromodulation could be characterised using systems-level neuroimaging approaches. Using 'resting-state' functional magnetic resonance imaging (FMRI), combined with dopaminergic challenges, we examined the dopamine-dependent functional connectivity of brain 'resting-state networks' (RSNs). We compared RSN connectivity in 3 groups of healthy volunteers given dopamine antagonist (haloperidol; N=18) or agonistic (levodopa; N=16) drugs, or a placebo (N=15). As RSNs have been shown to be relevant for numerous psychological functions and dysfunctions, we investigated both linear and nonlinear effects on RSN connectivity of manipulating dopamine neurotransmission pharmacologically. A basal ganglia RSN displayed both linear and nonlinear effects of dopamine manipulation on functional connectivity, respectively, with lateral frontoparietal and medial frontal neocortical areas. Conversely, a cognitive 'default mode' network showed only linear dopaminergic effects on connectivity with lateral frontal and parietal cortices. Our findings highlight diverse functional effects of dopamine neuromodulations on systems-level neural interactions. The observation that dopamine modulates distinct large-scale network connectivity patterns differentially, in both linear and nonlinear fashions, provides support for the objective utility of RSN metrics in classifying the effects and efficacy of psychopharmacological medications.
Assuntos
Encéfalo/efeitos dos fármacos , Dopaminérgicos/farmacologia , Vias Neurais/efeitos dos fármacos , Encéfalo/metabolismo , Mapeamento Encefálico , Dopamina/metabolismo , Humanos , Interpretação de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Masculino , Vias Neurais/metabolismo , Neurotransmissores/farmacologia , Descanso , Adulto JovemRESUMO
Growing interest in pharmacological resting state fMRI (RSfMRI) necessitates developing standardized and robust analytical approaches that are insensitive to spurious correlated physiological signals. However, in pharmacological experiments physiological variations constitute an important aspect of the pharmacodynamic/pharmacokinetic profile of drug action; therefore retrospective corrective methods that discard physiological signals as noise may not be suitable. Previously, we have shown that template-based dual regression analysis is a sensitive method for model-free and objective detection of drug-specific effects on functional brain connectivity. In the current study, the robustness of this standard approach to physiological variations in a placebo controlled, repeated measures pharmacological RSfMRI study of morphine and alcohol in 12 healthy young men is tested. The impact of physiology-related variations on statistical inferences has been studied by: 1) modeling average physiological rates in higher level group analysis; 2) Regressing out the instantaneous respiration variation (RV); 3) applying retrospective image correction (RETROICOR) in the preprocessing stage; and 4) performing combined RV and heart rate correction (RVHRCOR) by regressing out physiological pulses convolved with canonical respiratory and cardiac hemodynamic response functions. Results indicate regional sensitivity of the BOLD signal to physiological variations, especially in the vicinity of large vessels, plus certain brain structures that are reported to be involved in physiological regulation, such as posterior cingulate, precuneus, medial prefrontal and insular cortices, as well as the thalamus, cerebellum and the brainstem. The largest impact of "correction" on final statistical test outcomes resulted from including the average respiration frequency and heart rate in the higher-level group analysis. Overall, the template-based dual regression method seems robust against physical noise that is corrected by RV regression or RETROICOR. However, convolving the RV and HR with canonical hemodynamic response functions caused a notable change in the BOLD signal variance, and in resting state connectivity estimates. The impact of RVHRCOR on statistical tests was limited to elimination of both morphine and alcohol effects related to the somatosensory network that consists of insula and cingulate cortex-important structures for autonomic regulation. Although our data do not warrant speculations about neuronal or vascular origins of these effects, these observations raise caution about the implications of physiological 'noise' and the risks of introducing false positives (e.g. increased white matter connectivity) by using generalized physiological correction methods in pharmacological studies. The obvious sensitivity of the posterior part of the default mode network to different correction schemes, underlines the importance of controlling for physiological fluctuations in seed-based functional connectivity analyses.
Assuntos
Artefatos , Encéfalo/fisiologia , Interpretação de Imagem Assistida por Computador/métodos , Imageamento por Ressonância Magnética/métodos , Vias Neurais/fisiologia , Adolescente , Adulto , Encéfalo/efeitos dos fármacos , Mapeamento Encefálico/métodos , Depressores do Sistema Nervoso Central/farmacocinética , Depressores do Sistema Nervoso Central/farmacologia , Método Duplo-Cego , Etanol/farmacocinética , Etanol/farmacologia , Humanos , Masculino , Morfina/farmacocinética , Morfina/farmacologia , Entorpecentes/farmacocinética , Entorpecentes/farmacologia , Vias Neurais/efeitos dos fármacos , Respiração/efeitos dos fármacos , Descanso , Adulto JovemRESUMO
AIMS: Antagonism of both NK1 and NK3 receptors may be an effective strategy in the pharmacotherapy of schizophrenia, drug addiction or depression. GSK1144814 is a novel selective dual NK1 /NK3 receptor antagonist. The potential influence of GSK1144814 on the effects of alcohol was investigated. METHODS: In a blinded, randomized, placebo-controlled, two period crossover study, the pharmacokinetics and central nervous system (CNS) effects of single oral doses of 200 mg GSK1144814 were evaluated in 20 healthy volunteers, using a controlled alcohol infusion paradigm to maintain stable alcohol concentrations with subsequent analysis of eye movements, adaptive tracking, body sway, visual analogue scales, Epworth sleepiness scale and the verbal visual learning test. RESULTS: Frequent adverse effects were mild somnolence, fatigue and headache. Plasma concentration of GSK1144814 in the presence of alcohol was maximal 1.5 h after dose administration. GSK1144814 did not affect alcohol pharmacokinetics. Co-administration of GSK1144814 and alcohol impaired saccadic reaction time and peak velocity, adaptive tracking, alertness, sleepiness, word recognition and recognition reaction time compared with administration of alcohol alone, but the size of the interaction was small. CONCLUSIONS: Administration of GSK1144814 in the presence of alcohol was generally well tolerated and not likely to produce clinically relevant additional impairments after alcohol consumption.
Assuntos
Intoxicação Alcoólica/metabolismo , Sistema Nervoso Central/efeitos dos fármacos , Etanol/farmacologia , Antagonistas dos Receptores de Neurocinina-1 , Desempenho Psicomotor/efeitos dos fármacos , Receptores da Neurocinina-3/antagonistas & inibidores , Adolescente , Adulto , Idoso , Estudos Cross-Over , Método Duplo-Cego , Interações Medicamentosas , Humanos , Masculino , Pessoa de Meia-Idade , Receptores da Neurocinina-1/metabolismo , Receptores da Neurocinina-3/metabolismo , Taquicininas/metabolismo , Adulto JovemRESUMO
AIM: Cannabinoid receptor type 1 (CB1 ) antagonists have been developed for the treatment of obesity and associated risk factors. Surinabant is a high affinity CB1 antagonist in vitro. The aim of this study was to assess the magnitude of inhibition by surinabant of CNS effects and heart rate induced by Δ(9) -tetrahydrocannabinol (THC) in humans. METHODS: This was a double-blind, placebo-controlled, randomized, four period six sequence crossover study. Thirty healthy young male occasional cannabis users (<1 per week) were included. A single oral dose of surinabant (5, 20 or 60 mg) or placebo was administered followed 1.5 h later by four intrapulmonary THC doses (2, 4, 6 and 6 mg) or vehicle, administered at 1 h intervals. The wash-out period was 14-21 days. Subjective and objective pharmacodynamic (PD) measurements were performed. A population PK-PD model for THC and surinabant quantified PK and PD effects. RESULTS: Surinabant 20 and 60 mg inhibited all THC-induced PD effects in a similar range for both doses with inhibition ratios ranging from 68.3% (95% CI = 32.5, 104.2; heart rate) to 91.1% (95% CI = 30.3, 151.8; body sway). IC50 ranged from 22.0 ng ml(-1) [relative standard error (RSE) = 45.2%; body sway] to 58.8 ng ml(-1) (RSE = 44.2%; internal perception). Surinabant 5 mg demonstrated no significant effects. CONCLUSIONS: The dose-related inhibition by surinabant, without any effect of its own, suggests that this compound behaves as a CB1 receptor antagonist in humans at these concentrations. A single surinabant dose between 5 to 20 mg and above was able to antagonize THC-induced effects in humans.