clinicaltrials.gov identifier: NCT01998958.

Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

A rapid onset of robust antidepressant effects was observed in patients with TRD after a 40-minute IV infusion of either .20 mg/kg or .40 mg/kg of esketamine. The lower dose may allow for better tolerability while maintaining efficacy.

The P2X7 receptor (P2X7R) is an adenosine triphosphate-gated ion channel that is predominantly expressed on microglial cells in the central nervous system. We report the clinical qualification of P2X7specific PET ligand 18 F-JNJ-64413739 in healthy volunteers, including dosimetry, kinetic modeling, test-retest variability, and blocking by the P2X7 antagonist JNJ-54175446. Methods: Whole-body dosimetry was performed in 3 healthy male subjects by consecutive whole-body PET/CT scanning, estimation of the normalized cumulated activity, and calculation of the effective dose using OLINDA (v1.1). Next, 5 healthy male subjects underwent a 120-min dynamic 18 F-JNJ-64413739 PET/MRI scan with arterial blood sampling to determine the appropriate kinetic model. For this purpose, 1-and 2-tissue compartment models and Logan graphic analysis (LGA) were evaluated for estimating regional volumes of distribution (V T). PET/MRI scanning was repeated in 4 of these subjects to evaluate medium-term test-retest variability (interscan interval, 26-97 d). For the single-dose occupancy study, 8 healthy male subjects underwent baseline and postdose 18 F-JNJ-64413739 PET/MRI scans 4-6 h after the administration of a single oral dose of JNJ-54175446 (dose range, 5-300 mg). P2X7 occupancies were estimated using a Lassen plot and regional baseline and postdose V T. Results: The average (mean ± SD) effective dose was 22.0 ± 1.0 μSv/MBq. The 2tissue compartment model was the most appropriate kinetic model, with LGA showing very similar results. Regional 2-tissue compartment model V T values were about 3 and were rather homogeneous across all brain regions, with slightly higher estimates for the thalamus, striatum, and brain stem. Between-subject V T variability was relatively high, with cortical V T showing an approximate 3-fold range across subjects. As for time stability, the acquisition time could be reduced to 90 min. The average regional test-retest variability values were 10.7% ± 2.2% for 2-tissue compartment model V T and 11.9% ± 2.2% for LGA V T. P2X7 occupancy approached saturation for single doses of JNJ-54175446 higher than 50 mg, and no reference region could be identified. Conclusion: 18 F-JNJ-64413739 is a suitable PET ligand for the quantification of P2X7R expression in the human brain. It can be used to provide insight into P2X7R expression in health and disease, to evaluate target engagement by P2X7 antagonists, and to guide dose selection.

A double-blind, randomised, parallel-group trial was cant falls in heart rate. Both active drugs were well tolerconducted in patients with essential hypertension in ated, nebivolol marginally more so. Nebivolol, a longBritish general practices, of nebivolol 5 mg, atenolol acting, cardioselective, vasodilating beta-blocker which 50 mg, and placebo each given once daily. Both active acts partly via the l-arginine/nitric oxide mechanism, drugs, in comparison with placebo, caused highly sigappears potentially valuable for the treatment of hypernificant and similar reductions in systolic and diastolic tension. pressures without orthostatic effect, and small signifiKeywords: nitric oxide; quality of life; side effects daily were begun. After 4 weeks of this single-blind

ObjectivesSafety, tolerability, pharmacokinetics, and pharmacodynamics of a novel β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, JNJ-54861911, were assessed after single and multiple dosing in healthy participants.MethodsTwo randomized, placebo-controlled, double-blind studies were performed using single and multiple ascending JNJ-54861911 doses (up to 14 days) in young and elderly healthy participants. Regular blood samples and frequent CSF samples, up to 36 hours after last dose, were collected to assess the pharmacokinetic and pharmacodynamic (Aβ, sAPPα,β,total levels) profiles of JNJ-54861911.ResultsJNJ-54861911 was well-tolerated, adverse events were uncommon and unrelated to JNJ-54861911. JNJ-54861911 showed dose-proportional CSF and plasma pharmacokinetic profiles. Plasma- and CSF-Aβ and CSF-sAPPβ were reduced in a dose-dependent manner. Aβ reductions (up to 95%) outlasted exposure to JNJ-54861911. APOE ε4 carrier status and baseline Aβ levels did not influence Aβ/sAPPβ reductions.ConclusionJNJ-54861911, a potent brain-penetrant BACE1 inhibitor, achieved high and stable Aβ reductions after single and multiple dosing in healthy participants.

Acute studies suggested a therapeutic benefit for fundus-relaxing drugs in functional dyspepsia (FD) with visceral hypersensitivity (VH) to gastric distention or impaired accommodation (IA), but long-term studies are lacking. R-137696 is a serotonin-1A (5-HT(1A)) receptor agonist which relaxes the proximal stomach in man. Our aim was to investigate the influence of R-137696 on symptoms in FD with VH or IA. Randomized, double-blind, placebo-controlled, parallel group study of 4 weeks R-137696 2 mg t.i.d. in FD with VH or IA. Symptoms were assessed using the patient assessment of upper gastrointestinal symptom severity index (PAGI-SYM) total score and individual symptom subscales. Barostat studies were performed before and after 4 weeks of treatment. Fifty-three patients (33 VH and 20 IA), 18 men, mean age 40 +/- 13 years were recruited. Twenty-four received placebo and 29 received R-137696. In VH patients, both placebo and R-137696 improved total symptom scores, with a tendency for superiority of placebo (-1.12 vs-0.51, P = 0.07). Placebo was superior for the subscales of early satiety, bloating, fullness and discomfort (all P < 0.05). In IA, both placebo and R-137696 had no significant influence on total or individual symptom scores (-0.08 and -0.27). In VH, both placebo and R-137696 increased the discomfort volume, without a statistical difference between both arms (+120 and +164 mL). In IA, both placebo and R-137696 enhanced accommodation, without a statistical difference between both (+77 and +159 mL). Adverse events were similar for drug and placebo. A 4-week administration of the fundus-relaxing 5-HT(1A) agonist R-137696 failed to significantly improve symptoms, VH or gastric accommodation compared to placebo.

Backgroundβ-Secretase enzyme (BACE) inhibition has been proposed as a priority treatment mechanism for Alzheimer’s disease (AD), but treatment initiation may need to be very early. We present proof of mechanism of atabecestat (also known as JNJ-54861911), an oral BACE inhibitor for the treatment of AD, in Caucasian and Japanese populations with early AD who do not show signs of dementia.MethodsIn two similarly designed phase I studies, a sample of amyloid-positive elderly patients comprising 45 Caucasian patients with early AD diagnosed as preclinical AD (n = 15, Clinical Dementia Rating [CDR] = 0) or with mild cognitive impairment due to AD (n = 30, CDR = 0.5) and 18 Japanese patients diagnosed as preclinical AD (CDR-J = 0) were randomized 1:1:1 to atabecestat 10 or 50 mg or placebo (n = 6–8/treatment) daily for 4 weeks. Safety, pharmacokinetics (PK), and pharmacodynamics (PD) (i.e., reduction of cerebrospinal fluid [CSF] amyloid beta 1–40 [Aβ1–40] levels [primary endpoint] and effect on other AD biomarkers) of atabecestat were evaluated.ResultsIn both populations, atabecestat was well tolerated and characterized by linear PK and high central nervous system penetrance of unbound drug. Atabecestat significantly reduced CSF Aβ1–40 levels from baseline at day 28 in both the 10-mg (67–68%) and 50-mg (87–90%) dose groups compared with placebo. For Caucasians with early AD, the least squares mean differences (95% CI) were − 69.37 (− 72.25; − 61.50) and − 92.74 (− 100.08; − 85.39), and for Japanese with preclinical AD, they were − 62.48 (− 78.32; − 46.64) and − 80.81 (− 96.13; − 65.49), respectively. PK/PD model simulations confirmed that once-daily 10 mg and 50 mg atabecestat can attain 60–70% and 90% Aβ1–40 reductions, respectively. The trend of the reduction was similar across the Aβ1–37, Aβ1–38, and Aβ1–42 fragments in both atabecestat dose groups, consistent with Aβ1–40. CSF amyloid precursor protein fragment (sAPPβ) levels declined from baseline, regardless of patient population, whereas CSF sAPPα levels increased compared with placebo. There were no relevant changes in either CSF total tau or phosphorylated tau 181P over a 4-week treatment period.ConclusionsJNJ-54861911 at 10 and 50 mg daily doses after 4 weeks resulted in mean CSF Aβ1–40 reductions of 67% and up to 90% in both Caucasian and Japanese patients with early stage AD, confirming results in healthy elderly adults.Trial registrationALZ1005: ClinicalTrials.gov, NCT01978548. Registered on 7 November 2013.ALZ1008: ClinicalTrials.gov, NCT02360657. Registered on 10 February 2015.Electronic supplementary materialThe online version of this article (10.1186/s13195-018-0415-6) contains supplementary material, which is available to authorized users.