Stress assessment based on EEG univariate features and functional connectivity measures

The biological response to stress originates in the brain but involves different biochemical and physiological effects. Many common clinical methods to assess stress are based on the presence of specific hormones and on features extracted from different signals, including electrocardiogram, blood pressure, skin temperature, or galvanic skin response. The aim of this paper was to assess stress using EEG-based variables obtained from univariate analysis and functional connectivity evaluation. Two different stressors, the Stroop test and sleep deprivation, were applied to 30 volunteers to find common EEG patterns related to stress effects. Results showed a decrease of the high alpha power (11 to 12 Hz), an increase in the high beta band (23 to 36 Hz, considered a busy brain indicator), and a decrease in the approximate entropy. Moreover, connectivity showed that the high beta coherence and the interhemispheric nonlinear couplings, measured by the cross mutual information function, increased significantly for both stressors, suggesting that useful stress indexes may be obtained from EEG-based features.Peer ReviewedPostprint (author’s final draft

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150-200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective

Monitoring sleep depth: analysis of bispectral index (BIS) based on polysomnographic recordings and sleep deprivation

© 2015 Springer Science+Business Media Dordrecht The assessment and management of sleep are increasingly recommended in the clinical practice. Polysomnography (PSG) is considered the gold standard test to monitor sleep objectively, but some practical and technical constraints exist due to environmental and patient considerations. Bispectral index (BIS) monitoring is commonly used in clinical practice for guiding anesthetic administration and provides an index based on relationships between EEG components. Due to similarities in EEG synchronization between anesthesia and sleep, several studies have assessed BIS as a sleep monitor with contradictory results. The aim of this study was to evaluate objectively both the feasibility and reliability of BIS for sleep monitoring through a robust methodology, which included full PSG recordings at a baseline situation and after 40 h of sleep deprivation. Results confirmed that the BIS index was highly correlated with the hypnogram (0.89 ± 0.02), showing a progressive decrease as sleep deepened, and an increase during REM sleep (awake: 91.77 ± 8.42; stage N1: 83.95 ± 11.05; stage N2: 71.71 ± 11.99; stage N3: 42.41 ± 9.14; REM: 80.11 ± 8.73). Mean and median BIS values were lower in the post-deprivation night than in the baseline night, showing statistical differences for the slow wave sleep (baseline: 42.41 ± 9.14 vs. post-deprivation: 39.49 ± 10.27; p = 0.02). BIS scores were able to discriminate properly between deep (N3) and light (N1, N2) sleep. BIS values during REM overlapped those of other sleep stages, although EMG activity provided by the BIS monitor could help to identify REM sleep if needed. In conclusion, BIS monitors could provide a useful measure of sleep depth in especially particular situations such as intensive care units, and they could be used as an alternative for sleep monitoring in order to reduce PSG-derived costs and to increase capacity in ambulatory care.Postprint (author's final draft

Inhibition of alpha oscillations through serotonin-2A receptor activation underlies the visual effects of ayahuasca in humans

Ayahuasca is an Amazonian psychotropic plant tea typically obtained from two plants, Banisteriopsis caapi and Psychotria viridis. It contains the psychedelic 5-HT2A and sigma-1 agonist N,N-dimethyltryptamine (DMT) plus ß-carboline alkaloids with monoamine-oxidase (MAO)-inhibiting properties. Although the psychoactive effects of ayahuasca have commonly been attributed solely to agonism at the 5-HT2A receptor, the molecular target of classical psychedelics, this has not been tested experimentally. Here we wished to study the contribution of the 5-HT2A receptor to the neurophysiological and psychological effects of ayahuasca in humans. We measured drug-induced changes in spontaneous brain oscillations and subjective effects in a double-blind randomized placebo-controlled study involving the oral administration of ayahuasca (0.75 mg DMT/kg body weight) and the 5-HT2A antagonist ketanserin (40 mg). Twelve healthy, experienced psychedelic users (5 females) participated in four experimental sessions in which they received the following drug combinations: placebo+placebo, placebo+ayahuasca, ketanserin+placebo and ketanserin+ayahuasca. Ayahuasca induced EEG power decreases in the delta, theta and alpha frequency bands. Current density in alpha-band oscillations in parietal and occipital cortex was inversely correlated with the intensity of visual imagery induced by ayahuasca. Pretreatment with ketanserin inhibited neurophysiological modifications, reduced the correlation between alpha and visual effects, and attenuated the intensity of the subjective experience. These findings suggest that despite the chemical complexity of ayahuasca, 5-HT2A activation plays a key role in the neurophysiological and visual effects of ayahuasca in humans.Postprint (published version

Randomized, open-label, blinded-endpoint, crossover, single-dose study to compare the pharmacodynamics of torasemide-PR 10 mg, torasemide-IR 10 mg, and furosemide-IR 40 mg, in patients with chronic heart failure

Diuretics are the primary treatment for the management of chronic heart failure (HF) symptoms and for the improvement of acute HF symptoms. The rate of delivery to the site of action has been suggested to affect diuretic pharmacodynamics. The main objective of this clinical trial was to explore whether a prolonged release tablet formulation of torasemide (torasemide-PR) was more natriuretically efficient in patients with chronic HF compared to immediate-release furosemide (furosemide-IR) after a single-dose administration. Moreover, the pharmacokinetics of torasemide-PR, furosemide-IR, and torasemide-IR were assessed in chronic HF patients as well as urine pharmacodynamics. Randomized, open-label, blinded-endpoint, crossover, and single-dose Phase I clinical trial with three experimental periods. Torasemide-PR and furosemide-IR were administered as a single dose in a crossover fashion for the first two periods, and torasemide-IR 10 mg was administered for the third period. Blood and urine samples were collected at fixed timepoints. The primary endpoint was the natriuretic efficiency after administration of torasemide-PR and furosemide-IR, defined as the ratio between the average drug-induced natriuresis and the average drug recovered in urine over 24 hours. Ten patients were included and nine completed the study. Here, we present the results from nine patients. Torasemide-PR was more natriuretically efficient than furosemide-IR (0.096±0.03 mmol/μg vs 0.015±0.0007 mmol/μg; P <0.0001). Mictional urgency was lower and more delayed with torasemide-PR than with furosemide-IR. In a study with a limited sample size, our results suggest that 10 mg of torasemide-PR is more natriuretically efficient than 40 mg of furosemide-IR after single-dose administration in patients with chronic HF over a 24-hour collection period. Further studies are necessary to evaluate potential pharmacodynamic differences between torasemide formulations and to assess its impact on clinical therapeutics

Prevalence of sleep disorders in adults with down syndrome: a comparative study of subjective, actigraphic and polygraphic findings

STUDY OBJECTIVES:Sleep problems are often undetected in adults with Down syndrome (DS). Our objective was to determine the prevalence of sleep disorders in adults with DS through self-reported and objective sleep measures. METHODS:We performed a community-based cross-sectional study of 54 adults with DS not referred for sleep disorders. Two polysomnography (PSG) sleep studies were performed. Sleep quality was evaluated using the Pittsburgh Sleep Quality Index (PSQI); daytime sleepiness was evaluated using the Epworth Sleepiness Scale (ESS) and the risk for the sleep apnea syndrome (OSA) was identified using the Berlin Questionnaire (BQ). Participants' sleep/wake pattern was assessed from sleep diaries and by wrist actigraphy. PSQI, ESS, and PSG measures were compared with 35 sex-, age-, and body mass index-matched patients in the control groups. RESULTS:In PSG measures, adults with DS showed lower sleep efficiency (69 ± 17.7 versus 81.6 ± 11; P < .001), less rapid eye movement sleep (9.4 ± 5.8 versus 19.4 ± 5.1; P < .001), a higher prevalence of OSA (78% versus 14%; P < .001), and a higher apnea-hypopnea index (23.5 ± 24.5 versus 3.8 ± 10.5; P < .001) than patients in the control group. In the DS group, the questionnaires (mean PSQI 3.7 ± 2.9; mean ESS 6.3 ± 4.5 and mean BQ 1 ± 0) did not reflect the sleep disturbances detected on the PSG. Actigraphy data recorded daytime sleep that was not self-reported (118.2 ± 104.2 minutes). CONCLUSIONS:Adults with DS show severe sleep disruption and a high prevalence of OSA, undetected by self-reported sleep measures. Actigraphy, PSG, and validated simplified devices for screening OSA should be routinely recommended for this population because treatment of sleep disorders can contribute to healthy aging

Direct venous inoculation of Plasmodium falciparum sporozoites for controlled human malaria infection: a dose-finding trial in two centres

BACKGROUND: Controlled human malaria infection (CHMI) accelerates development of anti-malarial interventions. So far, CHMI is done by exposure of volunteers to bites of five mosquitoes carrying Plasmodium falciparum sporozoites (PfSPZ), a technique available in only a few centres worldwide. Mosquito-mediated CHMI is logistically complex, exact PfSPZ dosage is impossible and live mosquito-based interventions are not suitable for further clinical development. METHODS: An open-labelled, randomized, dose-finding study in 18-45 year old, healthy, malaria-naive volunteers was performed to assess if intravenous (IV) injection of 50 to 3,200 aseptic, purified, cryopreserved PfSPZ is safe and achieves infection kinetics comparable to published data of mosquito-mediated CHMI. An independent study site verified the fully infectious dose using direct venous inoculation of PfSPZ. Parasite kinetics were assessed by thick blood smear microscopy and quantitative real time PCR. RESULTS: IV inoculation with 50, 200, 800, or 3,200 PfSPZ led to parasitaemia in 1/3, 1/3, 7/9, and 9/9 volunteers, respectively. The geometric mean pre-patent period (GMPPP) was 11.2 days (range 10.5-12.5) in the 3,200 PfSPZ IV group. Subsequently, six volunteers received 3,200 PfSPZ by direct venous inoculation at an independent investigational site. All six developed parasitaemia (GMPPP: 11.4 days, range: 10.4-12.3). Inoculation of PfSPZ was safe. Infection rate and pre-patent period depended on dose, and injection of 3,200 PfSPZ led to a GMPPP similar to CHMI with five PfSPZ-infected mosquitoes. The infectious dose of PfSPZ predicted dosage of radiation-attenuated PfSPZ required for successful vaccination. CONCLUSIONS: IV inoculation of PfSPZ is safe, well tolerated and highly reproducible. It shall further accelerate development of anti-malarial interventions through standardization and facilitation of CHMI. Beyond this, rational dose selection for whole PfSPZ-based immunization and complex study designs are now possible. TRIAL REGISTRATION: ClinicalTrials.gov NCT01624961 and NCT01771848

Stress assessment based on EEG univariate features and functional connectivity measures

The biological response to stress originates in the brain but involves different biochemical and physiological effects. Many common clinical methods to assess stress are based on the presence of specific hormones and on features extracted from different signals, including electrocardiogram, blood pressure, skin temperature, or galvanic skin response. The aim of this paper was to assess stress using EEG-based variables obtained from univariate analysis and functional connectivity evaluation. Two different stressors, the Stroop test and sleep deprivation, were applied to 30 volunteers to find common EEG patterns related to stress effects. Results showed a decrease of the high alpha power (11 to 12 Hz), an increase in the high beta band (23 to 36 Hz, considered a busy brain indicator), and a decrease in the approximate entropy. Moreover, connectivity showed that the high beta coherence and the interhemispheric nonlinear couplings, measured by the cross mutual information function, increased significantly for both stressors, suggesting that useful stress indexes may be obtained from EEG-based features.Peer Reviewe

Randomized, open-label, blinded-endpoint, crossover, single-dose study to compare the pharmacodynamics of torasemide-PR 10 mg, torasemide-IR 10 mg, and furosemide-IR 40 mg, in patients with chronic heart failure

Diuretics are the primary treatment for the management of chronic heart failure (HF) symptoms and for the improvement of acute HF symptoms. The rate of delivery to the site of action has been suggested to affect diuretic pharmacodynamics. The main objective of this clinical trial was to explore whether a prolonged release tablet formulation of torasemide (torasemide-PR) was more natriuretically efficient in patients with chronic HF compared to immediate-release furosemide (furosemide-IR) after a single-dose administration. Moreover, the pharmacokinetics of torasemide-PR, furosemide-IR, and torasemide-IR were assessed in chronic HF patients as well as urine pharmacodynamics. Randomized, open-label, blinded-endpoint, crossover, and single-dose Phase I clinical trial with three experimental periods. Torasemide-PR and furosemide-IR were administered as a single dose in a crossover fashion for the first two periods, and torasemide-IR 10 mg was administered for the third period. Blood and urine samples were collected at fixed timepoints. The primary endpoint was the natriuretic efficiency after administration of torasemide-PR and furosemide-IR, defined as the ratio between the average drug-induced natriuresis and the average drug recovered in urine over 24 hours. Ten patients were included and nine completed the study. Here, we present the results from nine patients. Torasemide-PR was more natriuretically efficient than furosemide-IR (0.096±0.03 mmol/μg vs 0.015±0.0007 mmol/μg; P <0.0001). Mictional urgency was lower and more delayed with torasemide-PR than with furosemide-IR. In a study with a limited sample size, our results suggest that 10 mg of torasemide-PR is more natriuretically efficient than 40 mg of furosemide-IR after single-dose administration in patients with chronic HF over a 24-hour collection period. Further studies are necessary to evaluate potential pharmacodynamic differences between torasemide formulations and to assess its impact on clinical therapeutics

Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers.

Ivermectin is a pivotal drug for the control of onchocerciasis and lymphatic filariasis, which is increasingly identified as a useful drug for the control of other Neglected Tropical Diseases. Its role in the treatment of soil transmitted helminthiasis through improved efficacy against Trichuris trichiura in combination with other anthelmintics might accelerate the progress towards breaking transmission. Ivermectin is a derivative of Avermectin B1, and consists of an 80:20 mixture of the equipotent homologous 22,23 dehydro B1a and B1b. Pharmacokinetic characteristics and safety profile of ivermectin allow to explore innovative uses to further expand its utilization through mass drug administration campaigns to improve coverage rates. We conducted a phase I clinical trial with 54 healthy adult volunteers who sequentially received 2 experimental treatments using a new 18 mg ivermectin tablet in a fixed-dose strategy of 18 and 36 mg single dose regimens, compared to the standard, weight based 150–200 μg/kg, regimen. Volunteers were recruited in 3 groups based on body weight. Plasma concentrations of ivermectin were measured through HPLC up to 168 hours post treatment. Safety data showed no significant differences between groups and no serious adverse events: headache was the most frequent adverse event in all treatment groups, none of them severe. Pharmacokinetic parameters showed a half-life between 81 and 91 h in the different treatment groups. When comparing the systemic bioavailability (AUC0t and Cmax) of the reference product (WA-ref) with the other two study groups using fixed doses, we observed an overall increase in AUC0t and Cmax for the two experimental treatments of 18 mg and 36 mg. Body mass index (BMI) and weight were associated with t1/2 and V/F, probably reflecting the high liposolubility of IVM with longer retention times proportional to the presence of more adipose tissue. Systemic exposure to ivermectin (AUC0t or Cmax) was not associated with BMI or weight in our study. These findings contribute to further understand the pharmacokinetic characteristics of ivermectin, highlighting its safety across different dosing regimens. They also correlate with known pharmacokinetic parameters showing stable levels of AUC and Cmax across a wide range of body weights, which justifies the strategy of fix dosing from a pharmacokinetic perspective.ClinicalTrials.gov NCT03173742