Dose selection for aztreonam-avibactam, including adjustments for renal impairment, for Phase IIa and Phase III evaluation.

PURPOSE: A series of iterative population pharmacokinetic (PK) modeling and probability of target attainment (PTA) analyses based on emerging data supported dose selection for aztreonam-avibactam, an investigational combination antibiotic for serious Gram-negative bacterial infections. METHODS: Two iterations of PK models built from avibactam data in infected patients and aztreonam data in healthy subjects with "patient-like" assumptions were used in joint PTA analyses (primary target: aztreonam 60% fT > 8 mg/L, avibactam 50% fT > 2.5 mg/L) exploring patient variability, infusion durations, and adjustments for moderate (estimated creatinine clearance [CrCL] > 30 to ≤ 50 mL/min) and severe renal impairment (> 15 to ≤ 30 mL/min). Achievement of > 90% joint PTA and the impact of differential renal clearance were considerations in dose selection. RESULTS: Iteration 1 simulations for Phase I/IIa dose selection/modification demonstrated that 3-h and continuous infusions provide comparable PTA; avibactam dose drives joint PTA within clinically relevant exposure targets; and loading doses support more rapid joint target attainment. An aztreonam/avibactam 500/137 mg 30-min loading dose and 1500/410 mg 3-h maintenance infusions q6h were selected for further evaluation. Iteration 2 simulations using expanded PK models supported an alteration to the regimen (500/167 mg loading; 1500/500 mg q6h maintenance 3-h infusions for CrCL > 50 mL/min) and selection of doses for renal impairment for Phase IIa/III clinical studies. CONCLUSION: A loading dose plus 3-h maintenance infusions of aztreonam-avibactam in a 3:1 fixed ratio q6h optimizes joint PTA. These analyses supported dose selection for the aztreonam-avibactam Phase III clinical program. CLINICAL TRIAL REGISTRATION: NCT01689207; NCT02655419; NCT03329092; NCT03580044.

Making memories last using the peripheral effect of direct current stimulation.

Most memories that are formed are forgotten, while others are retained longer and are subject to memory stabilization. We show that non-invasive transcutaneous electrical stimulation of the greater occipital nerve (NITESGON) using direct current during learning elicited a long-term memory effect. However, it did not trigger an immediate effect on learning. A neurobiological model of long-term memory proposes a mechanism by which memories that are initially unstable can be strengthened through subsequent novel experiences. In a series of studies, we demonstrate NITESGON's capability to boost the retention of memories when applied shortly before, during, or shortly after the time of learning by enhancing memory consolidation via activation and communication in and between the locus coeruleus pathway and hippocampus by plausibly modulating dopaminergic input. These findings may have a significant impact for neurocognitive disorders that inhibit memory consolidation such as Alzheimer's disease.

Peripheral nerve stimulation: A neuromodulation-based approach.

Recent technological improvements have positioned us at the threshold of innovative discoveries that will assist in new perspectives and avenues of research. Increased attention has been directed towards peripheral nerve stimulation, particularly of the vagus, trigeminal, or greater occipital nerve, due to their unique pathway that engages neural circuits within networks involved in higher cognitive processes. Here, we question whether the effects of transcutaneous electrical stimulation are mediated by synergistic interactions of multiple neuromodulatory networks, considering this pathway is shared by more than one neuromodulatory system. By spotlighting this attractive transcutaneous pathway, this opinion piece aims to acknowledge the contributions of four vital neuromodulators and prompt researchers to consider them in future investigations or explanations.

Effect of food on the pharmacokinetics of zoliflodacin granules for oral suspension: Phase I open-label randomized cross-over study in healthy subjects.

Gonorrhea is a sexually transmitted infection for which antibiotic treatment options have declined due to increasing antibiotic resistance. Zoliflodacin, an investigational oral spiropyrimidinetrione antibiotic with activity against Neisseria gonorrhoeae strains that are multidrug-resistant, including to third-generation cephalosporins, is in phase III development for uncomplicated gonorrhea. This phase I, parallel, open-label, randomized, crossover study in healthy adults evaluated the effect of food on the pharmacokinetics of single 3 or 4 g doses of zoliflodacin administered as granules for oral suspension in the fasted state or after consumption of a standardized high-fat meal. Forty-seven out of 48 randomized subjects completed the study. Oral administration of zoliflodacin with food delayed the absorption rate, compared with fasted state, with time to maximum concentration (Tmax ) increasing from 3 to 6 h for the 3 g dose, and 2.5 to 4 h for the 4 g dose, but had no impact on the elimination of zoliflodacin. The maximum concentration (Cmax ) and area under the plasma concentration-time curve from time 0 to 24 h (AUC(0-24) ) significantly increased with food by 52% and 94% for the 3 g dose, and by 89% and 108% for the 4 g dose. Forty-two percent of participants reported a total of 34 treatment-emergent adverse events (TEAEs), which were all considered mild in severity. Headache was the most common TEAE (22/48 subjects, 45.8%) and the only TEAE reported in more than one subject. In conclusion, administration of single 3 and 4 g doses of zoliflodacin as granules for oral suspension, with a high-fat meal was well-tolerated and resulted in statistically significant increases in peak and overall systemic exposure to zoliflodacin.

Potential role for peripheral nerve stimulation on learning and long-term memory: A comparison of alternating and direct current stimulations.

BACKGROUND: In the past decade, a rising interest in transcranial electrical stimulation has emerged owing to its advantageous capacity to facilitate the extraction of casual links between neuromodulation and the obtained behavioral effects in cognitive performance. However, an insufficient number of direct comparative studies between transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) effects on associative memory have caused optimal parameters and procedural application to remain undefined. OBJECTIVE: The current study aimed to comparatively investigate the effects of tDCS and tACS applied to the occipital nerve (ON), targeting the locus coeruleus, on associative memory performance. METHODS: We employed a randomized, double-blind, two-visit, active-controlled study design. 85 cognitively normal adults were assigned to receive either active ON-tDCS, 40 Hz ON-tACS, sham ON-tDCS, or 1 Hz ON-tACS during encoding of a 50-word Swahili-English associative memory recall task. To evaluate the effects of electrical stimulation, we measured the cumulative rate of learning on Day 1 and to assess possible long-term effects, we measured the number of words recalled on Day 7. RESULTS: Results presented two notable findings: (1) participants who received 40 Hz ON-tACS learned significantly more words on Day 1 (F3,81 = 4.37, p = .007, η2 = 0.14), and (2) participants who received 40 Hz ON-tACS or active ON-tDCS recalled significantly more words on Day 7 (F3,81 = 11.08, p < .001, η2 = 0.29). CONCLUSIONS: The evidence from this study alludes to 40 Hz ON-tACS and active ON-tDCS inducing distinct behavioral effects, whereby 40 Hz ON-tACS generated an effect during memory encoding via enhanced attention, however, active ON-tDCS elicited an offline effect transpiring during consolidation. Further neuroimaging studies are needed to validate these findings and proposed mechanisms of action.

Factors associated with recruitment success in the phase 2a study of aztreonam-avibactam development programme: a descriptive qualitative analysis among sites in Spain.

OBJECTIVE: Successful clinical trials are subject to recruitment. Recently, the REJUVENATE trial, a prospective phase 2a open-label, single-arm interventional clinical trial conducted within the Innovative Medicines Initiative-supported Combatting Bacterial Resistance in Europe-Carbapenem Resistance project, was published, with 85% of the recruitment performed in Spain. We analysed the recruitment success in this trial by establishing a model of recruitment practice. METHODS: A descriptive qualitative study was performed from May 2016 to October 2017 at 10 participating Spanish centres. Data were extracted from: (1) feasibility questionnaires to assess the centre's potential for patient enrolment; (2) delegation of responsibility records; (3) pre-screening records including an anonymised list of potentially eligible and (4) screening and enrolment records. A descriptive analysis of the features was performed by the participating centre. Pearson's and Spearman's correlation coefficients were calculated to determine factors of recruitment success. RESULTS: The highest recruitment rate was observed in Hospitals 3 and 6 (58.8 and 47.0 patients per month, respectively). All the study teams were multidisciplinary with a median of 15 members (range: 7-22). Only Hospitals 3, 5 and 6 had dedicated nursing staff appointed exclusively to this study. Moreover, in those three hospitals and in Hospital 9, the study coordinator performed exclusive functions as a research planner, and did not assume these functions for the other hospitals. The univariate analysis showed a significant association between recruitment success and months of recruitment (p=0.024), number of staff (p<0.001), higher number of pharmacists (p=0.005), infectious disease specialists (p<0.001), the presence of microbiologist in the research team (p=0.018) and specifically dedicated nursing staff (p=0.036). CONCLUSIONS: The existence of broad multidisciplinary teams with staff dedicated exclusively to the study as well as the implementation of a well-designed local patient assessment strategy were the essential optimisation factors for recruitment success in Spain. TRIAL REGISTRATION NUMBER: NCT02655419; EudraCT 2015-002726-39; analysis of pre-screened patients.

Predisposition to domain-wide maladaptive changes in predictive coding in auditory phantom perception.

Tinnitus is hypothesised to be a predictive coding problem. Previous research indicates lower sensitivity to prediction errors (PEs) in tinnitus patients while processing auditory deviants corresponding to tinnitus-specific stimuli. However, based on research with patients with hallucinations and no psychosis we hypothesise tinnitus patients may be more sensitive to PEs produced by auditory stimuli that are not related to tinnitus characteristics. Specifically in patients with minimal to no hearing loss, we hypothesise a more top-down subtype of tinnitus that may be driven by maladaptive changes in an auditory predictive coding network. To test this, we use an auditory oddball paradigm with omission of global deviants, a measure that is previously shown to empirically characterise hierarchical prediction errors (PEs). We observe: (1) increased predictions characterised by increased pre-stimulus response and increased alpha connectivity between the parahippocampus, dorsal anterior cingulate cortex and parahippocampus, pregenual anterior cingulate cortex and posterior cingulate cortex; (2) increased PEs characterised by increased P300 amplitude and gamma activity and increased theta connectivity between auditory cortices, parahippocampus and dorsal anterior cingulate cortex in the tinnitus group; (3) increased overall feed-forward connectivity in theta from the auditory cortex and parahippocampus to the dorsal anterior cingulate cortex; (4) correlations of pre-stimulus theta activity to tinnitus loudness and alpha activity to tinnitus distress. These results provide empirical evidence of maladaptive changes in a hierarchical predictive coding network in a subgroup of tinnitus patients with minimal to no hearing loss. The changes in pre-stimulus activity and connectivity to non-tinnitus specific stimuli suggest that tinnitus patients not only produce strong predictions about upcoming stimuli but also may be predisposed to stimulus a-specific PEs in the auditory domain. Correlations with tinnitus-related characteristics may be a biomarker for maladaptive changes in auditory predictive coding.

Sex Differences in Locus Coeruleus: A Heuristic Approach That May Explain the Increased Risk of Alzheimer's Disease in Females.

This article aims to reevaluate our approach to female vulnerability to Alzheimer's disease (AD) and put forth a new hypothesis considering how sex differences in the locus coeruleus-noradrenaline (LC-NA) structure and function could account for why females are more likely to develop AD. We specifically focus our attention on locus coeruleus (LC) morphology, the paucity of estrogens, neuroinflammation, blood-brain barrier permeability, apolipoprotein ɛ4 polymorphism (APOEɛ4), and cognitive reserve. The role of the LC-NA system and sex differences are two of the most rapidly emerging topics in AD research. Current literature either investigates the LC due to it being one of the first brain areas to develop AD pathology or acknowledges the neuroprotective effects of estrogens and how the loss of these female hormones have the capacity to contribute to the sex differences seen in AD; however, existing research has neglected to concurrently examine these two rationales and therefore leaving our hypothesis undetermined. Collectively, this article should assist in alleviating current challenges surrounding female AD by providing thought-provoking connections into the interrelationship between the disruption of the female LC-NA system, the decline of estrogens, and AD vulnerability. It is therefore likely that treatment for this heterogeneous disease may need to be distinctly developed for females and males separately, and may require a precision medicine approach.

Polarity-specific high-definition transcranial direct current stimulation of the anterior and posterior default mode network improves remote memory retrieval.

BACKGROUND: Previous studies show that activity in the posterior default mode network (pDMN), including the posterior cingulate cortex and the precuneus, is correlated with the success of long-term episodic memory retrieval. However, the role of the anterior DMN (aDMN) including the medial prefrontal cortex is still unclear. Some studies show that activating the medial prefrontal cortex improves memory retrieval while other studies show deactivation of the medial prefrontal cortex in successful retrieval of episodic memories, suggesting a possible functional dissociation between the aDMN and pDMN. OBJECTIVE: In the current study, we aim to causally explore this probable dissociation using high-definition transcranial direct current stimulation (HD-tDCS). METHODS: We perform a randomised double-blinded two-visit placebo-controlled study with 84 healthy young adults. During Visit 1 they learn 75 Swahili-English word-associations. Seven days later, they randomly receive either anodal, cathodal or sham HD-tDCS targeting the pDMN or aDMN while they recall what they have previously learned. RESULTS: We demonstrate that anodal stimulation of the pDMN and cathodal stimulation of the aDMN, equally improve the percentage of Swahili-English word-associations recalled 7 days after learning. CONCLUSIONS: Modulating the activity in the aDMN and pDMN causally affect memory retrieval performance. HD-tDCS of the aDMN and pDMN shows that anodal stimulation of the pDMN and cathodal stimulation of the aDMN increases memory retrieval performance one week after the learning phase. Given consistent evidence, it is highly likely that we are increasing the activity in the pDMN with anodal pDMN stimulation. However, it is not clear if cathodal HD-tDCS targetting aDMN works via decoupling from the pDMN or via indirectly disinhibit pDMN.

Impaired posterior cingulate cortex-parahippocampus connectivity is associated with episodic memory retrieval problems in amnestic mild cognitive impairment.

Episodic memory retention and retrieval decline are the most common impairments observed in amnestic mild cognitive impairment (aMCI) patients who progress to Alzheimer's disease (AD). Clinical electroencephalography research shows that patients with dementia due to AD exhibit a slowing of neural electrical activity in the parietal cortex. Memory research has further suggested that successful memory performance is associated with changes in a posterior cingulate-parahippocampal cortical network together with increased θ-γ oscillatory coupling, where θ oscillations act as carrier waves for γ oscillations, which contain the actual information. However, the neurophysiological link between the memory research and clinical studies investigating aMCI and AD is lacking. In this study, we look at brain activity in aMCI and how it relates to memory performance. We demonstrate decreased γ power in the posterior cingulate cortex and the left and right parahippocampus in aMCI patients in comparison to control participants. This goes together with reduced θ coherence between the posterior cingulate cortex and parahippocampus associated with altered memory performance aMCI patients in comparison to control participants. In addition, comparing patients with aMCI to control participants reveals an effect for θ-γ coupling for the posterior cingulate cortex, and the left and right parahippocampus. Taken together, our results show that parahippocampus and posterior cingulate cortex interact via θ-γ coupling, which is associated with memory recollection and is altered in aMCI patients, offering a potential candidate mechanism for memory decline in aMCI.

The peripheral effect of direct current stimulation on brain circuits involving memory.

An ongoing debate surrounding transcranial direct current stimulation (tDCS) of the scalp is whether it modulates brain activity both directly and in a regionally constrained manner enough to positively affect symptoms in patients with neurological disorders. One alternative explanation is that direct current stimulation affects neural circuits mainly indirectly, i.e., via peripheral nerves. Here, we report that noninvasive direct current stimulation indirectly affects neural circuits via peripheral nerves. In a series of studies, we show that direct current stimulation can cause activation of the greater occipital nerve (ON-tDCS) and augments memory via the ascending fibers of the occipital nerve to the locus coeruleus, promoting noradrenaline release. This noradrenergic pathway plays a key role in driving hippocampal activity by modifying functional connectivity supporting the consolidation of a memory event.

Greater Occipital Nerve Stimulation Boosts Associative Memory in Older Individuals: A Randomized Trial.

Transcutaneous electrical stimulation (tES) is a new approach that aims to stimulate the brain. Recently, we have developed tES approaches to enhance plasticity that modulate cortical activity via the greater occipital nerve (ON) in a "bottom-up" way. Thirty subjects between the ages of 55 and 70 years were enrolled and tested using a double-blind, sham-controlled, and randomized design. Half of the participants received active stimulation, while the other half received sham stimulation. Our results demonstrate that ON-tES can enhance memory in older individuals after one session, with effects persisting up to 28 days after stimulation. The hypothesized mechanism by which ON-tES enhances memory is activation of the locus coeruleus-noradrenaline (LC-NA) pathway. It is likely that this pathway was activated after ON-tES, as supported by observed changes in α-amylase concentrations, a biomarker for noradrenaline. There were no significant or long-lasting side effects observed during stimulation. Clinicaltrial.gov (NCT03467698).

Pharmacokinetics and safety of aztreonam/avibactam for the treatment of complicated intra-abdominal infections in hospitalized adults: results from the REJUVENATE study.

OBJECTIVES: To investigate pharmacokinetics (PK) and safety (primary objectives) and efficacy (secondary objective) of the investigational monobactam/ß-lactamase inhibitor combination aztreonam/avibactam in patients with complicated intra-abdominal infection (cIAI). METHODS: This Phase 2a open-label, multicentre study (NCT02655419; EudraCT 2015-002726-39) enrolled adults with cIAI into sequential cohorts for 5-14 days treatment. Cohort 1 patients received an aztreonam/avibactam loading dose of 500/137 mg (30 min infusion), followed by maintenance doses of 1500/410 mg (3 h infusions) q6h; Cohort 2 received 500/167 mg (30 min infusion), followed by 1500/500 mg (3 h infusions) q6h. Cohort 3 was an extension of exposure at the higher dose regimen. Doses were adjusted for creatinine clearance of 31-50 mL/min (Cohorts 2 + 3). All patients received IV metronidazole 500 mg q8h. PK, safety and efficacy were assessed. RESULTS: Thirty-four patients (Cohort 1, n = 16; Cohorts 2 + 3, n = 18) comprised the modified ITT (MITT) population. Mean exposures of aztreonam and avibactam in Cohorts 2 + 3 were consistent with those predicted to achieve joint PK/pharmacodynamic target attainment in >90% patients. Adverse events (AEs) were similar between cohorts. The most common AEs were hepatic enzyme increases [n = 9 (26.5%)] and diarrhoea [n = 5 (14.7%)]. Clinical cure rates at the test-of-cure visit overall were 20/34 (58.8%) (MITT) and 14/23 (60.9%) (microbiological-MITT population). CONCLUSIONS: Observed AEs were consistent with the known safety profile of aztreonam monotherapy, with no new safety concerns identified. These data support selection of the aztreonam/avibactam 500/167 mg (30 min infusion) loading dose and 1500/500 mg (3 h infusions) maintenance dose q6h regimen, in patients with creatinine clearance >50 mL/min, for the Phase 3 development programme.

Safety, tolerability and pharmacodynamics of a novel immunomodulator, MIS416, in patients with chronic progressive multiple sclerosis.

BACKGROUND: Preclinical studies have demonstrated that MIS416, a bacterially derived immune modulator, targets myeloid cells following systemic delivery. MIS416 stimulated myeloid cells have the capacity to regulate innate inflammation, a potential therapeutic target for progressive multiple sclerosis. OBJECTIVES: To determine the safety, tolerability, pharmacodynamics and maximum tolerated dose and/or recommended Phase 2 dose of MIS416. METHODS: An open-label, non-randomized, phase II, dose-escalation study, in patients with progressive multiple sclerosis: dose-escalation phase, with MIS416 administered once weekly for four weeks to determine maximum tolerated dose; and dose-confirmation phase, administered once weekly for up to 12 weeks. RESULTS: The safety profile indicates the majority of adverse events were mild or moderate, tolerable, self-limiting and consistent with the known bioactivity of MIS416 (acute flu-like symptoms). Maximum tolerated dose was not reached. A dose of 500 µg/week was recommended for the Phase 2 dose. CONCLUSION: MIS416 is well tolerated at a dose of 500 µg/week. The adverse event profile is consistent with the mechanism of action of MIS416, indicating bioactivity within the signal transduction pathways and supported by induction of a known MIS416 pharmacodynamic marker. It is recommended that safety and efficacy of MIS416 is investigated further in a larger randomized controlled trial. http://clinicaltrials.gov reference NCT01191996.