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1.
J Headache Pain ; 22(1): 132, 2021 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-34742230

RESUMO

BACKGROUND: Lasmiditan (LTN) is a selective 5-HT1F receptor agonist for the acute treatment of migraine in adults. We present detailed safety findings from the placebo-controlled, double-blind Phase 3 study, of LTN treatment across 4 attacks (CENTURION). METHODS: Patients were randomized 1:1:1 to LTN 200 mg (LTN200), LTN100, or a control group that received placebo for 3 attacks and LTN50 for either the 3rd or 4th attack (1:1). Safety analyses were conducted for patients who took ≥1 dose of study drug and, in some cases, those who took all 4 doses. RESULTS: Overall, 1471 patients treated 4494 attacks. The incidences of treatment-emergent serious adverse events (SAEs) were - placebo, n=2 (0.4 %); LTN100, n=1 (0.2 %); LTN200, n=2 (0.4 %); no specific treatment-emergent SAE was reported in more than one patient. The most common treatment emergent adverse events (TEAEs) with lasmiditan were dizziness, paresthesia, fatigue, nausea, vertigo, and somnolence; the vast majority were mild or moderate in severity. The incidences of these TEAEs were highest during the first attack and decreased during subsequent attacks. For patients who experienced a common TEAE with the first attack, less than 45 % experienced the same event in subsequent attacks. Patients who did not experience an event in the 1st attack infrequently experienced the same event in subsequent attacks. The time of onset of the common TEAE ranged from ~40 min to 1 h (dependent upon TEAE) and, for individual TEAE, the onset was similar across attacks. Duration was dependent upon TEAE and attack. It was shortest for paresthesia (< 2 h for all attacks); it ranged from 1.8 to 5.5 h for other common TEAEs and was generally similar across attacks. Serotonin syndrome was reported for 2 patients post LTN dosing; there were no meaningful differences across treatment groups in suicidality; there was no evidence of an increase in motor vehicle accidents. CONCLUSION: In this blinded, controlled, multiple-attack study, LTN was associated with generally mild or moderate CNS-related TEAEs of short duration. TEAEs tended to decrease in frequency across the 4 attacks. TRIAL REGISTRATION: NCT03670810.


Assuntos
Transtornos de Enxaqueca , Agonistas do Receptor de Serotonina , Adulto , Benzamidas , Método Duplo-Cego , Humanos , Transtornos de Enxaqueca/tratamento farmacológico , Piperidinas , Piridinas , Resultado do Tratamento
2.
J Prev Alzheimers Dis ; 8(4): 414-424, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34585215

RESUMO

BACKGROUND: Donanemab (LY3002813) is an IgG1 antibody directed at an N­terminal pyroglutamate of amyloid beta epitope that is present only in brain amyloid plaques. OBJECTIVES: To assess effects of donanemab on brain amyloid plaque load after single and multiple intravenous doses, as well as pharmacokinetics, safety/tolerability, and immunogenicity. DESIGN: Phase 1b, investigator- and patient-blind, randomized, placebo-controlled study. SETTING: Patients recruited at clinical research sites in the United States and Japan. PARTICIPANTS: 61 amyloid plaque-positive patients with mild cognitive impairment due to Alzheimer's disease and mild-to-moderate Alzheimer's disease dementia. INTERVENTION: Six cohorts were dosed with donanemab: single dose 10-, 20- or 40- mg/kg (N = 18), multiple doses of 10-mg/kg every 2 weeks for 24 weeks (N = 10), and 10- or 20-mg/kg every 4 weeks for 72 weeks (N=18) or placebo (N = 15). MEASUREMENTS: Brain amyloid plaque load, using florbetapir positron emission tomography, was assessed up to 72 weeks. Safety was evaluated by occurrence of adverse events, magnetic resonance imaging, electrocardiogram, vital signs, laboratory testing, neurological monitoring, and immunogenicity. RESULTS: Treatment with donanemab resulted in rapid reduction of amyloid, even after a single dose. By 24 weeks, amyloid positron emission tomography mean changes from baseline for single donanemab doses in Centiloids were: -16.5 (standard error 11.22) 10-mg/kg intravenous; 40.0 (standard error 11.23) 20 mg/kg intravenous; and -49.6 (standard error 15.10) 40-mg/kg intravenous. Mean reduction of amyloid plaque in multiple dose cohorts by 24 weeks in Centiloids were: 55.8 (standard error 9.51) 10-mg/kg every 2 weeks; -50.2 (standard error 10.54) 10-mg/kg every 4 weeks; and -58.4 (standard error 9.66) 20-mg/kg every 4 weeks. Amyloid on average remained below baseline levels up to 72 weeks after a single dose of donanemab. Repeated dosing resulted in continued florbetapir positron emission tomography reductions over time compared to single dosing with 6 out of 28 patients attaining complete amyloid clearance within 24 weeks. Within these, 5 out of 10 patients in the 20 mg/kg every 4 weeks cohort attained complete amyloid clearance within 36 weeks. When dosing with donanemab was stopped after 24 weeks of repeat dosing in the 10 mg every 2 weeks cohort, florbetapir positron emission tomography reductions were sustained up to 72 weeks. For the single dose cohorts on day 1, dose proportional increases in donanemab pharmacokinetics were observed from 10 to 40 mg/kg. Dose proportional increases in pharmacokinetics were also observed at steady state with the multiple dose cohorts. Donanemab clearance was comparable across the dose levels. Mean donanemab elimination-half-life following 20 mg/kg single dose was 9.3 days with range of 5.6 to 16.2 days. Greater than 90% of patients had positive treatment-emergent antidrug antibodies with donanemab. However, overall, the treatment-emergent antidrug antibodies did not have a significant impact on pharmacokinetics. Donanemab was generally well tolerated. Amongst the 46 participants treated with donanemab, the following amyloid-related imaging abnormalities, common to the drug class, were observed: 12 vasogenic cerebral edema events (12 [19.7%] patients), 10 cerebral microhemorrhage events (6 [13.0%] patients), and 2 superficial siderosis events (2 [4.3%] patients). CONCLUSIONS: Single and multiple doses of donanemab demonstrated a rapid, robust, and sustained reduction up to 72 weeks in brain amyloid plaque despite treatment-emergent antidrug antibodies detected in most patients. Amyloid-related imaging abnormalities were the most common treatment-emergent event.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Amiloide/efeitos dos fármacos , Anticorpos Monoclonais/uso terapêutico , Tomografia por Emissão de Pósitrons , Idoso , Compostos de Anilina , Disfunção Cognitiva/tratamento farmacológico , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Etilenoglicóis , Feminino , Humanos , Japão , Masculino , Pessoa de Meia-Idade , Segurança do Paciente , Estados Unidos
3.
Regul Toxicol Pharmacol ; 89: 288-301, 2017 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-28757322

RESUMO

Given the serious nature of suicidal ideation and behavior (SIB) and the possibility of treatment-emergent SIB, pharmaceutical companies are now applying more proactive approaches in clinical trials and are considering the value of nonclinical models to predict SIB. The current review summarizes nonclinical approaches to modeling three common risk factors associated with SIB: aggression, impulsivity, and anhedonia. For each risk factor, a general description, advantages and disadvantages, species considerations, nonclinical to clinical translation, and pharmacological validation with respect to treatments associated with SIB are summarized. From this review, several gaps were identified that need to be addressed before use of these nonclinical models can be considered a viable option to predict the relative risk for SIB. Other future directions that may compliment these nonclinical approaches, including the use of selectively-bred or genetically-modified rodent models, transgenic models, gene expression profiling, and biomarker analysis, are discussed. This article was developed with the support of the DruSafe Leadership Group of the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ, www.iqconsortium.org).


Assuntos
Agressão , Anedonia , Comportamento Impulsivo , Modelos Psicológicos , Ideação Suicida , Perfilação da Expressão Gênica , Humanos , Fatores de Risco
4.
Neuroscience ; 166(2): 391-6, 2010 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-20026251

RESUMO

The dorsal (A9) and ventral striatum (A10) of the midbrain mediate many of the effects of psychoactive drugs that alter emotion, cognition, and motor activity within the contexts of therapy or abuse. Although transgenic and knockout technologies have enabled development of genetic models to dissect contributions of specific dopamine (DA) receptor subtypes to psychoactive drug effects, few models exist that can distinguish contributions of A9 versus A10 circuits. Pitx3 is a transcription factor enriched in DA neurons. Aphakia (ak) mice deficient in Pitx3 show selective loss of nigrostriatal DA, while other DA pathways are relatively spared, and therefore could be a useful tool for investigating the role of this subclass of DA projections. We investigated the effects of stimulants amphetamine, apomorphine, and MK-801 and the antipsychotic drug haloperidol on behavior in ak mice. Whereas wild-type mice showed the characteristic locomotor hyperactivity in response to amphetamine (5 mg/kg) and apomorphine (4 mg/kg), these drugs caused a paradoxical suppression of locomotor hyperactivity in ak mice. MK-801 (0.2 mg/kg) induced hyperactivity was maintained in both wt and ak mice. Additionally, mutant but not wild-type mice were insensitive to the cataleptic effects of haloperidol (1 mg/kg). These studies indicate that the nigrostriatal DA circuit plays a critical role in maintaining normal responsiveness to psychotropic drugs that either stimulate or block DA neurotransmission. We propose that ak mice may represent a valuable genetic model not only to study Parkinson's disease, but also to dissect the pathophysiologic and pharmacotherapuetic mechanisms of other DA-mediated disorders such as attention-deficit hyperactivity disorder, drug abuse and schizophrenia.


Assuntos
Comportamento Animal/efeitos dos fármacos , Catalepsia/induzido quimicamente , Corpo Estriado/efeitos dos fármacos , Dopamina/metabolismo , Proteínas de Homeodomínio/genética , Atividade Motora/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Fatores de Transcrição/genética , Anfetamina/farmacologia , Análise de Variância , Animais , Afacia/genética , Afacia/metabolismo , Apomorfina/farmacologia , Comportamento Animal/fisiologia , Catalepsia/genética , Corpo Estriado/metabolismo , Maleato de Dizocilpina/farmacologia , Dopamina/genética , Dopaminérgicos/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Camundongos , Camundongos Knockout , Atividade Motora/genética , Neurônios/metabolismo , Fatores de Tempo
5.
Behav Pharmacol ; 12(6-7): 509-16, 2001 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-11742145

RESUMO

HDS and LDS rats are the result of selective breeding for differences in the hypothermic effects of the 5-hydroxytryptamine-1A (5-HT1A) agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT); HDS (high DPAT sensitivity) rats exhibit a much greater hypothermic response than do LDS (low DPAT sensitivity) rats. It is possible that this genetically-based difference in sensitivity to the hypothermic effects of the 5-HT1A agonist is associated with a change in other behaviours modulated by 5-HT neurotransmission. The present study examined the acoustic startle response, the classically conditioned enhancement of startle, and the effects of 8-OH-DPAT and buspirone treatments on these measures, in HDS and LDS rats. On four test sessions, HDS and LDS rats were exposed to 20 acoustic startle stimuli (115 dB; 40 ms in duration). For each test session, 10 trials were presented in the dark (Noise Alone trials) and 10 were presented at the end of a 3500 ms presentation of a 15 W signal light (Light + Noise trials). LDS rats exhibited greater startle amplitude than did HDS rats on Noise Alone trials. Initially, there was no difference in startle amplitude on the Light + Noise versus Noise Alone trials in either LDS or HDS rats. By the end of the first test session, however, and continuing throughout the remainder of the four test sessions, startle amplitude on the Light + Noise trials was significantly greater than in the Noise Alone trials. The magnitude of this startle-potentiated startle (SPS) effect did not differ in HDS versus LDS rats. SPS testing was continued for three additional sessions; in these sessions the effects of acute treatment with the 8-OH-DPAT (125 microg/kg, subcutaneously (s.c.)), the novel anxiolytic buspirone (4 mg/kg, intraperitoneally (i.p.)) or vehicle (distilled water) were determined. Both 8-OH-DPAT and buspirone treatment increased baseline (Noise Alone) startle amplitude in LDS rats but not in HDS rats. With respect to the conditioned enhancement of startle, buspirone reduced the SPS effect in both HDS and LDS rats, whereas 8-OH-DPAT did not change the conditioned enhancement effect in either rat line. These findings suggest that the selective breeding for differences in 8-OH-DPAT-induced hypothermia has resulted in changes in other behaviours and also changes in the response to 5-HT1A agonist treatment. Moreover, these findings are consistent with the hypotheses that: (a) 5-HT1A agonist actions underlie the buspirone-induced and 8-OH-DPAT-induced increases in Noise Alone startle amplitude; whereas (b) the buspirone-induced reduction in potentiated startle is not the result of 5-HT1A agonist actions of this compound.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Nível de Alerta/genética , Regulação da Temperatura Corporal/genética , Buspirona/farmacologia , Reflexo de Sobressalto/genética , Estimulação Acústica , Animais , Nível de Alerta/efeitos dos fármacos , Regulação da Temperatura Corporal/efeitos dos fármacos , Condicionamento Clássico/efeitos dos fármacos , Masculino , Ratos , Ratos Endogâmicos , Receptores de Serotonina/genética , Receptores 5-HT1 de Serotonina , Reflexo de Sobressalto/efeitos dos fármacos , Serotonina/fisiologia
6.
Physiol Behav ; 73(1-2): 9-17, 2001 May.
Artigo em Inglês | MEDLINE | ID: mdl-11399289

RESUMO

In the Fear-Potentiated Startle (FPS) paradigm, the reflexive response to a noise burst is enhanced when it is presented with a stimulus (typically a light) that previously had been paired with the presentation of an aversive stimulus, usually an electric shock. In the FPS paradigm, the conditioned effect is demonstrated under conditions of extinction, i.e., the light is not paired with the shock during FPS testing. Because of this, the FPS paradigm is of somewhat limited value as a longitudinal measure for studying classically conditioned enhancement of acoustic startle. The present studies report a simple and reliable nonshock procedure for studying classically conditioned potentiation of acoustic startle in the rat that does not utilize testing under conditions of extinction. Naive rats were exposed to 5-or 3-days/week startle test sessions for up to 20 weeks. Twenty (20) startle stimuli (115 dB noise bursts; 40 ms in duration) were presented during each session. Half of these startle stimuli were presented in darkness and half were immediately preceded by a 3500-ms presentation of a 15-W light. With this paradigm, the effects of pairing the light with the startle noise burst could be studied across many test sessions in the absence of extinction training. The light did not increase startle amplitude on the first few startle trials of the first test session. By the end of the first session, however, and continuing for many weeks of testing, startle responses in the presence of the light were significantly greater (by 30-40%) than in the absence of the light. The finding that the startle stimulus itself can serve as an unconditioned stimulus (UCS) to enhance subsequent startle responses replicates an earlier finding. The persistence of this Startle-Potentiated Startle (SPS) effect across multiple weeks of testing is in contrast to that earlier report.


Assuntos
Condicionamento Clássico , Extinção Psicológica , Medo , Reflexo de Sobressalto , Estimulação Acústica , Animais , Feminino , Habituação Psicofisiológica , Masculino , Aprendizagem por Associação de Pares , Estimulação Luminosa , Ratos , Ratos Sprague-Dawley
7.
J Biol Chem ; 276(27): 24797-805, 2001 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-11333263

RESUMO

The norepinephrine transporter (NET) is responsible for the rapid NaCl-dependent uptake of norepinephrine into presynaptic noradrenergic nerve endings. Recently, we have characterized the structural organization of the 5' upstream promoter region of the human NET (hNET) gene. A new intron of 476 base pairs was found in the middle of the 5'-untranslated leader sequence and was shown to robustly enhance the promoter activity. Here, we show that the first hNET intron enhances both the homologous hNET and the heterologous thymidine kinase promoter activities in an orientation- and position-dependent manner. The first hNET intron exhibited a similar promoter-enhancing effect in both SK-N-BE(2)C (NET-positive) and HeLa (NET-negative) cell lines, showing that its function is not cell-specific. Transient transfection assays of a series of deletional constructs show that the first hNET intron contains subdomains with either positive or negative regulatory functions. Furthermore, DNase I footprinting analysis demonstrated that the 5' side of the intron, encompassing the splice donor site, is prominently protected by nuclear proteins isolated from both SK-N-BE(2)C and HeLa cells. The protected nucleotide sequence contains a consensus E-box motif, known to regulate diverse eukaryotic genes, which overlaps with the splice donor site of the first intron. We demonstrate that two basic helix-loop-helix proteins, upstream stimulatory factors 1 and 2, are major proteins interacting at this site and that the E-box is at least in part responsible for the promoter-enhancing activity of the first intron. Furthermore, site-directed mutagenesis of the splice donor site of the first intron affects both correct splicing and transcriptional activity. Taken together, our results indicate that a cis-element residing at the first exon/intron junction, encompassing an E-box motif, has a unique dual role in basal transcriptional activation and splicing of hNET mRNA.


Assuntos
Proteínas de Transporte/genética , Éxons , Íntrons , Splicing de RNA , Simportadores , Ativação Transcricional , Sequência de Bases , Sequência Consenso , Pegada de DNA , Células HeLa , Sequências Hélice-Alça-Hélice , Humanos , Dados de Sequência Molecular , Mutagênese Sítio-Dirigida , Norepinefrina , Proteínas da Membrana Plasmática de Transporte de Norepinefrina , Regiões Promotoras Genéticas , RNA Mensageiro/metabolismo , Timidina Quinase/genética , Timidina Quinase/metabolismo
8.
Pharmacol Biochem Behav ; 67(1): 199-205, 2000 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-11113501

RESUMO

The high DPAT sensitivity (HDS) and low DPAT sensitivity (LDS) rat lines are the result of selective breeding for differences in the hypothermic response to acute treatment with the 5-HT(1A) receptor agonist 8-hydroxydipropylaminotetralin (8-OHDPAT). The HDS rats exhibit a much greater hypothermic response than do the LDS rats. The present study examined conflict anxiety-like behavior and the effects of acute challenges with 8-OHDPAT and phenobarbital (PhB) on conflict behavior in HDS and LDS rats. Water-restricted (24-h deprivation) HDS and LDS rats were trained to drink from a tube that was occasionally electrified. The 5-s bouts of drinking tube electrification occurred on a fixed interval (FI) 30-s schedule and were signaled by the presence of a tone. Under this schedule, responding is suppressed approximately 10-fold during the tone-on periods compared to the no-tone periods. After two weeks of training in this repeated measures drink suppression conflict paradigm, the effects of acute challenges with 8-OHDPAT (30-500 microg/kg, SC, +10 min) or PhB (20 mg/kg, IP, +10 min) were determined. In control (i.e. , non-drug) conflict test sessions, rats of the HDS line accepted significantly fewer shocks than did rats of the LDS line. Acute treatment with 8-OHDPAT resulted in a modest increase in punished responding (maximum increase: +30-40 shocks/session) in both lines at doses of 60 and 125 microg/kg. Higher doses produced significant general behavioral disruption and substantial reductions in water intake (unpunished responding) in both HDS and LDS rats. Neither the increase in shocks received nor the decrease in water intake produced by these 8-OHDPAT challenges differed between HDS and LDS rats. In both lines, acute PhB treatment resulted in a more dramatic increase in punished responding than did 8-OHDPAT (+55-65 shocks/session) and an increase in water intake. The effects of PhB also did not differ between HDS and LDS rats. These data suggest that the HDS and LDS rats exhibit differences in baseline anxiety-like behavior in the conflict task, but do not differ in their response to acute challenges with PhB or 8-OHDPAT.


Assuntos
8-Hidroxi-2-(di-n-propilamino)tetralina/farmacologia , Conflito Psicológico , Hipotermia/induzido quimicamente , Receptores de Serotonina/fisiologia , Animais , Ansiolíticos/farmacologia , Relação Dose-Resposta a Droga , Ingestão de Líquidos/efeitos dos fármacos , Masculino , Fenobarbital/farmacologia , Proibitinas , Ratos , Receptores 5-HT1 de Serotonina
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