RESUMO
This was a double-blind, randomized, phase 2 study of adults (18-64 years) with DSM-5 diagnosis of major depressive disorder (MDD), with moderate-to-severe episode severity (Montgomery-Åsberg Depression Rating Scale [MADRS] ≥25) despite an adequate course with ongoing antidepressant for ≥6 weeks to ≤12 months. Following a double-blind placebo lead-in period (up to 3 weeks), participants were randomized to receive once daily aticaprant 10 mg or continue placebo, added to their ongoing treatment, for 6 weeks. Of 184 participants enrolled, 169 were included in safety analyses (aticaprant n = 85, placebo n = 84) and 166 in full intent-to-treat (fITT) efficacy analyses; 121 placebo lead-in non-responders (<30% reduction in MADRS total score) in fITT were included in enriched ITT (eITT) analyses. Improvement (least squares mean difference [upper limit 1-sided 80% CI] versus placebo) in MADRS total score at week 6 for aticaprant was significant versus placebo (eITT: -2.1 [-1.09], 1-sided p = 0.044; effect size (ES) 0.23; fITT -3.1 [2.21], 1-sided p = 0.002; ES 0.36). The between-group difference was larger among participants with Snaith-Hamilton Pleasure Scale (SHAPS) score greater/equal to versus less than baseline median SHAPS. The most common treatment-emergent adverse events reported for aticaprant (versus placebo) were headache (11.8% versus 7.1%), diarrhea (8.2% versus 2.4%), nasopharyngitis (5.9% versus 2.4%), and pruritus (5.9% versus 0%). One participant (1.2%) in each arm discontinued treatment due to an adverse event. In this study of participants with MDD and inadequate response to SSRI/SNRI, adjunctive treatment with aticaprant significantly reduced depressive symptoms versus placebo, without resulting in significant safety signals, supporting further investigation in larger trials.
Assuntos
Transtorno Depressivo Maior , Quimioterapia Combinada , Inibidores Seletivos de Recaptação de Serotonina , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Método Duplo-Cego , Adulto , Masculino , Feminino , Pessoa de Meia-Idade , Adulto Jovem , Inibidores Seletivos de Recaptação de Serotonina/administração & dosagem , Inibidores Seletivos de Recaptação de Serotonina/efeitos adversos , Inibidores Seletivos de Recaptação de Serotonina/uso terapêutico , Resultado do Tratamento , Adolescente , Receptores Opioides kappa/antagonistas & inibidores , Antidepressivos/administração & dosagem , Antidepressivos/efeitos adversos , Antidepressivos/uso terapêutico , Inibidores da Recaptação de Serotonina e Norepinefrina/administração & dosagem , Inibidores da Recaptação de Serotonina e Norepinefrina/efeitos adversos , Inibidores da Recaptação de Serotonina e Norepinefrina/farmacologia , Inibidores da Recaptação de Serotonina e Norepinefrina/uso terapêutico , Administração OralRESUMO
BACKGROUND: Alzheimer's disease cerebrospinal fluid (CSF) biomarkers amyloid-ß 1-42 (Aß42), total tau (T-tau), and phosphorylated tau 181 (P-tau181) are widely used. However, concentration gradient of these biomarkers between intraventricular (V-CSF) and lumbar CSF (L-CSF) has been demonstrated in idiopathic normal pressure hydrocephalus (iNPH), potentially affecting clinical utility. OBJECTIVE: Here we aim to provide conversion factors for clinical and research use between V-CSF and L-CSF. METHODS: Altogether 138 iNPH patients participated. L-CSF samples were obtained prior to shunt surgery. Intraoperative V-CSF samples were obtained from 97 patients. Post-operative follow-up L- and V-CSF (shunt reservoir) samples of 41 patients were obtained 1-73 months after surgery and then after 3, 6, and 18 months. CSF concentrations of Aß42, T-tau, and P-tau181 were analyzed using commercial ELISA assays. RESULTS: Preoperative L-CSF Aß42, T-tau, and P-tau181 correlated to intraoperative V-CSF (ρ=â0.34-0.55, pâ<â0.001). Strong correlations were seen between postoperative L- and V-CSF for all biomarkers in every follow-up sampling point (ρs Aß42: 0.77-0.88, T-tau: 0.91-0.94, P-tau181: 0.94-0.96, pâ<â0.0001). Regression equations were determined for intraoperative V- and preoperative L-CSF (Aß42: V-CSFâ=â185+0.34*L-CSF, T-tau: Ln(V-CSF)â=â3.11+0.49*Ln(L-CSF), P-tau181: V-CSFâ=â8.2+0.51*L-CSF), and for postoperative V- and L-CSF (Aß42: V-CSFâ=â86.7+0.75*L-CSF, T-tau: V-CSFâ=â86.9+0.62*L-CSF, P-tau181: V-CSFâ=â2.6+0.74*L-CSF). CONCLUSION: Aß42, T-tau, and P-tau181 correlate linearly in-between V- and L-CSF, even stronger after CSF shunt surgery. Equations presented here, provide a novel tool to use V-CSF for diagnostic and prognostic entities relying on the L-CSF concentrations and can be applicable to clinical use when L-CSF samples are not available or less invasively obtained shunt reservoir samples should be interpreted.
Assuntos
Doença de Alzheimer , Hidrocefalia de Pressão Normal , Humanos , Doença de Alzheimer/diagnóstico , Doença de Alzheimer/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Biomarcadores/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidianoRESUMO
JNJ-54175446 is a selective purine P2X7 receptor (P2X7R) antagonist that attenuates microglial IL-1ß/IL-18 release. In healthy volunteers, JNJ-54175446 suppressed peripheral interleukin (IL)-1ß release, and attenuated dexamphetamine-induced improvements of mood and (visuo)motor performance in a human dexamphetamine-challenge paradigm. In depression, P2X7R inhibition may dampen immune-related dysregulation of mood. These results suggest that the impact of P2X7R inhibition is most prominent in situations where mood regulation is disrupted. Total sleep deprivation (TSD) results in an acute emotional perturbation, which yields a transient antidepressant effect. In the current study, TSD was applied as a behavioral challenge to investigate whether such effects could be modulated by JNJ-54175446. This was a double-blind, placebo-controlled, randomized study to assess the safety and pharmacokinetics of JNJ-54175446 and explore its effects in patients with single episode and recurrent major depressive disorder (MDD) (N = 69) and baseline total Inventory of Depressive Symptomatology Clinician Rated (IDS-C) > 30. Patients were randomized to receive JNJ-54175446 throughout the 10-day treatment period, placebo for days 1-3 followed by JNJ-54175446 or placebo throughout. All patients underwent 36 h of TSD starting on day three until the evening of day four. The early start group was hypothesized to experience a reduced effect from TSD whilst the late starting group was hypothesized to experience prolonged effects from the TSD. JNJ-54175446 was well-tolerated and adverse events were mild to moderate. JNJ-54175446 reduced IL-1ß release by LPS-stimulated peripheral white blood cells in the presence of the P2X receptor agonist benzyl adenosine triphosphate (BzATP). JNJ-54175446 did not have a significant effect on mood as assessed using the Hamilton Depression Rating Scale, 17 items (HDRS17) and the Self-rated Quick Inventory of Depressive Symptoms (QIDS-SR). However, JNJ-54175446 blunted an acute reduction of anhedonia that occurred as a result of TSD, assessed by the Snaith-Hamilton Pleasure Scale (SHAPS) and the Probabilistic Instrumental Learning Task (PILT).
Assuntos
Transtorno Depressivo Maior , Humanos , Transtorno Depressivo Maior/tratamento farmacológico , Transtorno Depressivo Maior/diagnóstico , Antagonistas do Receptor Purinérgico P2X/efeitos adversos , Receptores Purinérgicos P2X7 , Sistema Nervoso Central , Privação do Sono , DextroanfetaminaRESUMO
JNJ-42165279 is a selective inhibitor of fatty acid amide hydrolase (FAAH), the enzyme responsible for the degradation of fatty acid amides (FAA) including anandamide (AEA), palmitoylethanolamide (PEA), and N-oleoylethanolamide (OEA). We assessed the efficacy, safety, tolerability, pharmacokinetics, and pharmacodynamics of treatment with JNJ-42165279 in subjects with social anxiety disorder (SAD). This was a multicenter, double-blind, placebo-controlled study randomizing subjects to 12 weeks of treatment with either JNJ-42165279 (25 mg daily) or placebo (PBO). The primary endpoint was the change in the Liebowitz Social Anxiety Scale (LSAS) total score from baseline to end of study. Secondary endpoints included the Hamilton Anxiety Scale (HAM-A), Hamilton Depression Rating Scale (HDRS17), and the Clinical Global Impression-Improvement (CGI-I). Samples were collected for plasma concentration of AEA, PEA, OEA, and JNJ-42165279. A total of 149 subjects were enrolled with a mean baseline LSAS total score of 102.6 (SD 16.84). The mean change from baseline (SD) in LSAS total score at week 12 was numerically greater for JNJ-42165279: -29.4 (27.47) compared to PBO: -22.4 (23.57) but not significant. The percentage of subjects with ≥30% improvement from baseline in the LSAS total score was significantly higher for JNJ-42165279 (42.4%) compared to PBO (23.6%) (p value = 0.04). The percentage of subjects with a CGI-I score of much or very much improved was also significantly higher for JNJ-42165279 (44.1%) than for PBO (23.6%) (p value = 0.02). The drug was well tolerated. JNJ-42165279 appears to elicit an anxiolytic effect in subjects with SAD although trough concentrations with 25 mg once daily appeared to be insufficient to completely inhibit FAAH activity which may have led to suboptimal efficacy. ClinicalTrials.gov Identifier: NCT02432703.
Assuntos
Fobia Social , Amidoidrolases , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Piperazinas , Resultado do TratamentoRESUMO
BACKGROUND: Longitudinal changes in cerebrospinal fluid (CSF) biomarkers are seldom studied. Furthermore, data on biomarker gradient between lumbar (L-) and ventricular (V-) compartments seems to be discordant. OBJECTIVE: To examine alteration of CSF biomarkers reflecting Alzheimer's disease (AD)-related amyloid-ß (Aß) aggregation, tau pathology, neurodegeneration, and early synaptic degeneration by CSF shunt surgery in idiopathic normal pressure hydrocephalus (iNPH) in relation to AD-related changes in brain biopsy. In addition, biomarker levels in L- and V-CSF were compared. METHODS: L-CSF was collected prior to shunt placement and, together with V-CSF, 3-73 months after surgery. Thereafter, additional CSF sampling took place at 3, 6, and 18 months after the baseline sample from 26 iNPH patients with confirmed Aß plaques in frontal cortical brain biopsy and 13 iNPH patients without Aß pathology. CSF Amyloid-ß42 (Aß42), total tau (T-tau), phosphorylated tau (P-tau181), neurofilament light (NFL), and neurogranin (NRGN) were analyzed with customized ELISAs. RESULTS: All biomarkers but Aß42 increased notably by 140-810% in L-CSF after CSF diversion and then stabilized. Aß42 instead showed divergent longitudinal decrease between Aß-positive and -negative patients in L-CSF, and thereafter increase in Aß-negative iNPH patients in both L- and V-CSF. All five biomarkers correlated highly between V-CSF and L-CSF (Aß42 Râ=â0.87, T-tau Râ=â0.83, P-tau Râ=â0.92, NFL Râ=â0.94, NRGN Râ=â0.9; all pâ<â0.0001) but were systematically lower in V-CSF (Aß42 14 %, T-tau 22%, P-tau 20%, NFL 32%, NRGN 19%). With APOE genotype-grouping, only Aß42 showed higher concentration in non-carriers of allele É4. CONCLUSION: Longitudinal follow up shows that after an initial post-surgery increase, T-tau, P-tau, and NRGN are stable in iNPH patients regardless of brain biopsy Aß pathology, while NFL normalized toward its pre-shunt levels. Aß42 as biomarker seems to be the least affected by the surgical procedure or shunt and may be the best predictor of AD risk in iNPH patients. All biomarker concentrations were lower in V- than L-CSF yet showing strong correlations.
Assuntos
Doença de Alzheimer/líquido cefalorraquidiano , Peptídeos beta-Amiloides/líquido cefalorraquidiano , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Fragmentos de Peptídeos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Idoso , Idoso de 80 Anos ou mais , Doença de Alzheimer/diagnóstico , Biomarcadores/líquido cefalorraquidiano , Derivações do Líquido Cefalorraquidiano , Feminino , Humanos , Hidrocefalia de Pressão Normal/patologia , Hidrocefalia de Pressão Normal/cirurgia , Masculino , Pessoa de Meia-Idade , Fosforilação , Análise de Regressão , Medição de RiscoRESUMO
In the original Article, Tables two and three had formatting issues which affected their clarity. This has been corrected in the PDF and HTML versions of this Article.
RESUMO
Excessive arousal has a role in the pathophysiology of major depressive disorder (MDD). Seltorexant (JNJ-42847922/MIN-202) is a selective antagonist of the human orexin-2 receptor (OX2R) that may normalize excessive arousal and thereby attenuate depressive symptoms. In this study, the effects of night-time arousal suppression on depressive symptoms were investigated. 47 MDD patients with a total Inventory of Depressive Symptomatology (IDS) score of ≥30 at screening were included in a randomized, double-blind, diphenhydramine-, and placebo-controlled multicentre study. Symptoms of depression were rated using the 17-item Hamilton Depression Rating Scale (HDRS17). Effects on sleep were evaluated by polysomnography and by the Leeds Sleep Evaluation Questionnaire (LSEQ). To investigate the safety and tolerability of seltorexant, vital signs, suicidal ideation and adverse events were monitored. At baseline the severity of depressive symptoms correlated with sleep efficiency (SE), wake after sleep onset (WASO), duration of stage 2 sleep, and ruminations. Ten days of treatment with seltorexant (and not diphenhydramine) resulted in a significant improvement of core depressive symptoms compared to placebo; the antidepressant efficacy of seltorexant was maintained with continued treatment up to 28 days. Compared to placebo, the antidepressant efficacy of seltorexant coincided with an overall increase in (left posterior) EEG power and a relative increase in delta- and decrease in theta-, alpha- and beta power during stage 2 sleep. Treatment with seltorexant was associated with mild, self-limiting adverse drug reactions. Seltorexant affected core symptoms of depression in the absence of overt changes in the hypnogram; in contrast, diphenhydramine was not efficacious.
Assuntos
Antidepressivos/uso terapêutico , Transtorno Depressivo Maior/tratamento farmacológico , Pirimidinas/uso terapêutico , Pirróis/uso terapêutico , Sono/efeitos dos fármacos , Triazóis/uso terapêutico , Adulto , Antidepressivos/farmacologia , Nível de Alerta/efeitos dos fármacos , Difenidramina/farmacologia , Difenidramina/uso terapêutico , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Escalas de Graduação Psiquiátrica , Pirimidinas/farmacologia , Pirróis/farmacologia , Resultado do Tratamento , Triazóis/farmacologiaRESUMO
BACKGROUND: Insomnia is common in patients with major depressive disorder. Although antidepressants improve mood, insomnia often persists as a result of physiological hyperarousal. The orexin-2 receptor is increasingly being recognized as a new target for the treatment of persistent insomnia in major depressive disorder . AIM: This exploratory study investigated the effects of seltorexant on objective sleep parameters and subjective depressive symptoms in antidepressant treated major depressive disorder patients with persistent insomnia. METHODS: Twenty male and female patients received a single dose of 10, 20, 40 mg seltorexant and placebo with a washout period of seven days in a double-blind four-way crossover study. Effects on latency to persistent sleep, total sleep time and sleep efficiency were assessed with polysomnography. Subjective changes in mood were explored by the Quick Inventory of Depressive Symptomatology Self-Report. Safety was recorded and suicidal ideation and behavior were assessed with the Columbia Suicide Severity Rating Scale. RESULTS: Latency to persistent sleep was significantly shorter for all doses of seltorexant compared to placebo. Placebo least square mean was 61.05 min with least square mean ratios treatment/placebo (80% confidence interval) of 0.32 (0.24-0.44), 0.15 (0.11-0.2) and 0.17 (0.12-0.23) 19.69, 9.2, 10.15 for 10, 20 and 40 mg seltorexant respectively, (all p<0.001). Total sleep time was significantly longer for all doses of seltorexant compared to placebo. Sleep efficiency was significantly improved. The Quick Inventory of Depressive Symptomatology Self-Report demonstrated a trend to mood-improvement for the 40 mg group. CONCLUSIONS: Seltorexant showed a statistically significant, dose-dependent decrease in latency to persistent sleep, and increase in total sleep time and sleep efficiency combined with a tendency toward subjectively improved mood.
Assuntos
Antidepressivos/administração & dosagem , Transtorno Depressivo Maior/tratamento farmacológico , Antagonistas dos Receptores de Orexina/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Triazóis/administração & dosagem , Adulto , Idoso , Antidepressivos/farmacologia , Estudos Cross-Over , Transtorno Depressivo Maior/complicações , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/farmacologia , Polissonografia , Pirimidinas/farmacologia , Pirróis/farmacologia , Distúrbios do Início e da Manutenção do Sono/etiologia , Resultado do Tratamento , Triazóis/farmacologia , Adulto JovemRESUMO
BACKGROUND: Pharmacokinetics, pharmacodynamics and general safety and tolerability of JNJ-42847922, a selective orexin-2 receptor antagonist, were assessed in healthy subjects. METHODS: Five consecutive cohorts of healthy subjects were enrolled and received doses of 5-60 mg orally once daily over 10 days of JNJ-42847922 ( n=6) or placebo ( n=2). Concentrations of drug in plasma and urine were measured over 24 h after dosing on Days 1, 5 and 10. Observed- and self-reported somnolence was used to evaluate the principal pharmacodynamic effect of JNJ-42847922. A test battery to assess vigilance state, sedation and alertness was assessed at 4, 6 and 8 h after dosing. Safety assessments included recording of adverse events, vital signs, electrocardiograms, clinical laboratory assessments and suicidality per Columbia Suicide Severity Rating Scale. RESULTS: JNJ-42847922 was rapidly absorbed after the morning dose administration. The median tmax ranged from 0.5-1.5 h and mean t1/2 values from 2-3 h. At JNJ-42847922 dose levels ⩾20 mg, mean Cmax and mean area under the curve, values increased less than dose proportionally. At doses ⩾20 mg, JNJ-42847922 consistently induced somnolence on all study days. At four hours post-dose administration, dose levels >5 mg JNJ-42847922 were identified as sedating by the Addiction Research Center Inventory-49. Except for a mild decrease in attention (Bond and Lader Visual Analogue Scale Factor 1) at dose levels >10 mg at four hours post-dose, no clinically relevant changes in other central measures have been observed. JNJ-42847922 was well tolerated.
Assuntos
Antagonistas dos Receptores de Orexina/administração & dosagem , Receptores de Orexina/efeitos dos fármacos , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Sonolência , Triazóis/administração & dosagem , Administração Oral , Adolescente , Adulto , Área Sob a Curva , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Meia-Vida , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/farmacocinética , Antagonistas dos Receptores de Orexina/farmacologia , Receptores de Orexina/metabolismo , Pirimidinas/farmacocinética , Pirimidinas/farmacologia , Pirróis/farmacocinética , Pirróis/farmacologia , Fatores de Tempo , Triazóis/farmacocinética , Triazóis/farmacologia , Adulto JovemRESUMO
BACKGROUND: The effect of intranasal esketamine on cognitive functioning in healthy participants is assessed in this study. METHODS: Twenty-four participants (19-49 years) were randomized to one of two treatment sequences in which either esketamine 84 mg or placebo was intranasally administered in a double-blind, two-period crossover design. Primary measures included five tests of Cogstate® computerized test battery assessed at 1 h predose and 40 min, 2, 4, and 6 h postdose. Secondary measures included the Mental Effort Scale, Karolinska Sleepiness Scale (KSS), and safety. RESULTS: Esketamine was associated with significant cognitive performance impairment at 40 min postdose for all five Cogstate® tests (Detection p = 0.0011, Identification p = 0.0006, One-Card Learning p = 0.0040, One Back p = 0.0017, and Groton Maze Learning Test p < 0.0001) versus placebo. In contrast, performance on these tests did not differ significantly between esketamine and placebo at 2, 4, or 6 h postdose. Secondary outcomes indicated a significant, transient increase from baseline under esketamine versus placebo at 40 min postdose on the Mental Effort Scale and at 40 min and 2 h postdose on KSS (p < 0.0001 for both); however, no significant difference was observed on these outcomes between esketamine and placebo at later timepoints. The most commonly reported adverse events were dizziness (67%), nausea (37.5%), disturbance in attention (29.2%), and fatigue (29.2%); the majority were considered mild in severity. CONCLUSIONS: Esketamine was associated with cognitive performance decline, and greater effort was required to complete the test battery versus placebo at 40 min postdose, which returned to placebo-comparable levels by 2 h postdose. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02094378.
Assuntos
Cognição/efeitos dos fármacos , Antagonistas de Aminoácidos Excitatórios/administração & dosagem , Ketamina/análogos & derivados , Ketamina/administração & dosagem , Desempenho Psicomotor/efeitos dos fármacos , Administração Intranasal , Adulto , Cognição/fisiologia , Disfunção Cognitiva/induzido quimicamente , Estudos Cross-Over , Tontura/induzido quimicamente , Método Duplo-Cego , Antagonistas de Aminoácidos Excitatórios/química , Fadiga/induzido quimicamente , Feminino , Seguimentos , Voluntários Saudáveis , Humanos , Ketamina/efeitos adversos , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Aprendizagem em Labirinto/fisiologia , Pessoa de Meia-Idade , Desempenho Psicomotor/fisiologia , Resultado do Tratamento , Adulto JovemRESUMO
BACKGROUND: Seltorexant is a potent and selective antagonist of the orexin-2 receptor that is being developed for the treatment of insomnia and major depressive disorder. AIMS: The primary objective was to investigate the effect of seltorexant on sleep efficiency after single and multiple dose administration in subjects with insomnia disorder without psychiatric comorbidity. Secondary objectives included evaluation of total sleep time, latency to persistent sleep, and wake after sleep onset. Subjects received 40 mg of seltorexant for five days during Period 1 and placebo during Period 2 or vice versa in this randomized, two-way crossover study. Objective sleep parameters were evaluated by polysomnography over 8 h on Day 1/2 (single dose) and on Day 5/6 (multiple doses). Subjective sleep parameters were assessed by questionnaires. RESULTS: Twenty-seven subjects completed the study. The mean changes in sleep efficiency (% (SD)) of seltorexant from placebo at Day 1/2 were 5.8 (9.2), and 7.9 (9.8) at Day 5/6 ( p < 0.001 at both time points); in total sleep time (min (SD)) 27.7 (44.3) and 37.9 (47.1), respectively; in latency to persistent sleep (min (SD)) -18.8 (21.3) and -29.9 (27.7), respectively; and in wake after sleep onset (min (SD)) -11.1 (36.4) and -11.3 (46.5). The most common adverse events were headache and somnolence. CONCLUSIONS: Sleep efficiency was increased with seltorexant treatment compared with placebo. Treatment with seltorexant resulted in a prolonged total sleep time, shorter latency to persistent sleep and wake after sleep onset. There were no unexpected safety findings.
Assuntos
Antagonistas dos Receptores de Orexina/administração & dosagem , Pirimidinas/administração & dosagem , Pirróis/administração & dosagem , Distúrbios do Início e da Manutenção do Sono/tratamento farmacológico , Sono/efeitos dos fármacos , Triazóis/administração & dosagem , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Cefaleia/induzido quimicamente , Humanos , Masculino , Pessoa de Meia-Idade , Antagonistas dos Receptores de Orexina/efeitos adversos , Antagonistas dos Receptores de Orexina/uso terapêutico , Receptores de Orexina/efeitos dos fármacos , Receptores de Orexina/metabolismo , Polissonografia , Pirimidinas/efeitos adversos , Pirimidinas/uso terapêutico , Pirróis/efeitos adversos , Pirróis/uso terapêutico , Sonolência , Inquéritos e Questionários , Fatores de Tempo , Resultado do Tratamento , Triazóis/efeitos adversos , Triazóis/uso terapêutico , Adulto JovemRESUMO
Inhibition of fatty acid amide hydrolase (FAAH) potentiates endocannabinoid activity and is hypothesized to have therapeutic potential for mood and anxiety disorders and pain. The clinical profile of JNJ-42165279, an oral selective FAAH inhibitor, was assessed by investigating the pharmacokinetics, pharmacodynamics, safety, and binding to FAAH in the brain of healthy human volunteers. Concentrations of JNJ-42165279 (plasma, cerebrospinal fluid (CSF), urine) and fatty acid amides (FAA; plasma, CSF), and FAAH activity in leukocytes was determined in a phase I multiple ascending dose study. A positron emission tomography study with the FAAH tracer [11 C]MK3168 was conducted to determine brain FAAH occupancy after single and multiple doses of JNJ-42165279. JNJ-42165279 administration resulted in an increase in plasma and CSF FAA. Significant blocking of brain FAAH binding of [11 C]MK3168 was observed after pretreatment with JNJ-42165279. JNJ-42165279 produces potent central and peripheral FAAH inhibition. Saturation of brain FAAH occupancy occurred with doses ≥10 mg of JNJ-42165279. No safety concerns were identified.
Assuntos
Amidoidrolases/antagonistas & inibidores , Encéfalo/metabolismo , Endocanabinoides/metabolismo , Inibidores Enzimáticos/farmacologia , Piperazinas/farmacologia , Administração Oral , Adulto , Idoso , Idoso de 80 Anos ou mais , Amidoidrolases/metabolismo , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Relação Dose-Resposta a Droga , Endocanabinoides/sangue , Endocanabinoides/líquido cefalorraquidiano , Feminino , Voluntários Saudáveis , Humanos , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Imagem Molecular/métodos , Tomografia por Emissão de Pósitrons/métodos , Traçadores Radioativos , Adulto JovemRESUMO
BACKGROUND: Detection of pathological tau aggregates could facilitate clinical diagnosis of Alzheimer's disease (AD) and monitor drug effects in clinical trials. S-[18F]THK-5117 could be a potential tracer to detect pathological tau deposits in brain. However, no previous study have correlated S-[18F]THK-5117 uptake in PET with brain biopsy verified tau pathology in vivo. OBJECTIVE: Here we aim to evaluate the association between cerebrospinal fluid (CSF) AD biomarkers, S-[18F]THK-5117, and [11C]PIB PET against tau and amyloid lesions in brain biopsy. METHODS: Fourteen patients with idiopathic normal pressure hydrocephalus (iNPH) with previous shunt surgery including right frontal cortical brain biopsy and CSF Aß1 - 42, total tau, and P-tau181 measures, underwent brain MRI, [11C]PIB PET, and S-[18F]THK-5117 PET imaging. RESULTS: Seven patients had amyloid-ß (Aß, 4G8) plaques, two both Aß and phosphorylated tau (Pτ, AT8) and one only Pτ in biopsy. As expected, increased brain biopsy Aß was well associated with higher [11C]PIB uptake in PET. However, S-[18F]THK-5117 uptake did not show any statistically significant correlation with either brain biopsy Pτ or CSF P-tau181 or total tau. CONCLUSIONS: S-[18F]THK-5117 lacked clear association with neuropathologically verified tau pathology in brain biopsy probably, at least partially, due to off-target binding. Further studies with larger samples of patients with different tau tracers are urgently needed. The detection of simultaneous Aß and tau pathology in iNPH is important since that may indicate poorer and especially shorter response for CSF shunt surgery compared with no pathology.
Assuntos
Compostos de Anilina/farmacocinética , Encéfalo , Hidrocefalia de Pressão Normal/diagnóstico por imagem , Placa Amiloide/metabolismo , Quinolinas/farmacocinética , Tiazóis/farmacocinética , Proteínas tau/metabolismo , Idoso , Idoso de 80 Anos ou mais , Encéfalo/diagnóstico por imagem , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Mapeamento Encefálico , Feminino , Humanos , Hidrocefalia de Pressão Normal/líquido cefalorraquidiano , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tomografia por Emissão de PósitronsRESUMO
BACKGROUND: Corticotropin-releasing factor receptor type 1 (CRF(1)) antagonists have been proposed as therapeutic agents in the treatment of mood and anxiety disorders although clinical evidence supporting their development and understanding of a dose-response relationship has been lacking. METHODS: We tested two doses of the CRF(1) antagonist R317573 for effects on regional cerebral glucose metabolism (rCMglu) using [(18)F] fluoro-2-deoxy-D: -glucose (FDG) positron emission tomography (PET) following single-dose challenges in a double-blind, placebo-controlled, cross-over design, in 12 healthy male volunteers. RESULTS: Single 30- and 200-mg doses of R317573 resulted in dose-related changes in rCMglu. Relative increases in rCMglu were observed in frontal cortical regions while relative decreases occurred in the putamen and right amygdala after both doses. Relative decreases occurred in cerebellum and right parahippocampal gyrus following the higher dose. CONCLUSIONS: R317573 appears to produce acute dose-dependent changes in rCMglu. Effects occurred in regions that may be behaviorally relevant to mood and anxiety disorders. In some regions, these effects may be related to the receptor (target) density. Measuring acute effects on rCMglu with FDG-PET may offer a method for defining pharmacologically active doses for central nervous system targets for which selective radiotracers are lacking.
Assuntos
Encéfalo/efeitos dos fármacos , Glucose/metabolismo , Receptores de Hormônio Liberador da Corticotropina/antagonistas & inibidores , Adulto , Encéfalo/metabolismo , Estudos Cross-Over , Relação Dose-Resposta à Radiação , Método Duplo-Cego , Fluordesoxiglucose F18 , Humanos , Masculino , Tomografia por Emissão de Pósitrons , Adulto JovemRESUMO
BACKGROUND: Preoperative epoetin-alpha administration is said to have a limited effect in patients with chronic inflammatory diseases such as rheumatoid arthritis (RA), due to lower iron availability. We studied the effects of preoperative epoetin-alpha treatment in orthopedic surgery patients in a daily life setting in which iron supplementation was assured, and compared the effects in RA and non-RA patients. METHODS: In an open, naturalistic, randomized controlled trial, 695 orthopedic surgery patients with preoperative hemoglobin (Hb) values of 10-13 g/dL, either with RA (113) or without RA (582), received either preoperative epoetin-alpha treatment added to standard care, or standard care alone. Hb values and transfusions were evaluated from entry into the study until 4-6 weeks after surgery. RESULTS: Both in RA and non-RA patients, perioperative Hb values were significantly higher and transfusion requirements were significantly lower in epoetin-alpha treated patients than in control patients (p < 0.001). In RA patients, the outcomes regarding Hb values were not significantly or relevantly different from non-RA patients. INTERPRETATION: Just as with orthopedic patients in general, RA patients benefit from preoperative epoetin-alpha treatment in combination with iron supplementation. We postulate that iron supplementation during epoetin-alpha therapy in RA patients is important for optimal efficacy.