Supplementation with a ß-glucan tablet has no effect on hyperlipidemia: a randomized, placebo-controlled clinical trial.

BACKGROUND: Clinical evidence has suggested that the oat-soluble fiber ß-glucan might have lipid-lowering effects. OBJECTIVES: The present clinical trial was conducted to evaluate the efficacy and safety of high-medium molecular weight ß-glucan on serum low-density lipoprotein (LDL) cholesterol and other lipid subfractions in subjects with hyperlipidemia. METHODS: A randomized double-blinded trial was performed to assess the efficacy and safety of ß-glucan supplementation in reducing lipid levels. Subjects with LDL cholesterol levels of >3.37 mmol/L when treated or not with a statin were randomly assigned to receive 1 of 3 daily doses of a tableted formulation of ß-glucan (1.5, 3, or 6 g) or placebo. The primary efficacy end point was the change from baseline to 12 wk in LDL cholesterol. Secondary end points of lipid subfractions and safety were also assessed. RESULTS: A total of 263 subjects were enrolled; 66 subjects were assigned to each of the 3 ß-glucan groups, and 65 subjects were assigned to the placebo group. The mean change from baseline to 12 wk in serum LDL cholesterol level was 0.08, 0.11, and -0.04 mmol/L in the 3 ß-glucan groups (P = 0.23, 0.18, and 0.72 compared with the placebo group, respectively) and -0.10 mmol/L in the placebo group. The changes in total cholesterol, small LDL cholesterol subclass particle concentration, non-high-density lipoprotein cholesterol, apolipoprotein B, very low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein were also not significant in the ß-glucan groups when compared with the placebo group. Gastrointestinal adverse events were reported in 23.4%, 34.8%, and 66.7% of patients in the ß-glucan groups and in 36.9% of patients in the placebo group (P < 0.0001 for the overall comparison across the 4 groups). CONCLUSIONS: In subjects with LDL cholesterol levels of >3.37 mmol/L, a tablet formulation of ß-glucan was not effective in reducing LDL cholesterol concentration or other lipid subfractions when compared with a placebo. This trial was registered at clinicaltrials.gov as NCT03857256.

Effects of common cold and concomitant administration of nasal decongestant on the pharmacokinetics and pharmacodynamics of nasal glucagon in otherwise healthy participants: A randomized clinical trial.

AIMS: Nasal glucagon (NG) is a nasally-administered glucagon powder, absorbed through the nasal mucosa, designed for treatment of severe hypoglycaemia. This study evaluated the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of NG in otherwise healthy participants with common colds and after recovery from cold symptoms, with and without concomitant nasal decongestant. MATERIALS AND METHODS: This was a single-centre, open-label study. Cohort 1 participants (N = 18) received 2 doses of NG: one while experiencing nasal congestion and another after recovery from cold symptoms. Cohort 2 participants (N = 18), who also had colds with nasal congestion, received a single dose of NG 2 hours after treatment with the decongestant oxymetazoline. Total symptoms score and other safety measures were assessed before and after NG administration. RESULTS: NG was well tolerated, without serious adverse events. Common adverse events (transient lacrimation, nasal discomfort, rhinorrhea and nausea) were more frequent in both Cohorts 1 and 2 during nasal congestion. Glucagon levels peaked 18 minutes post-dose and glucose levels peaked 30 to 42 minutes post-dose in all groups. Nasal congestion, with or without concomitant nasal decongestant, did not significantly affect PK of NG. Although glucose AUECs0-t was different between Cohort 1 with nasal congestion and Cohort 2, glucose concentrations at 30 minutes appeared similar in all groups. CONCLUSIONS: There were no clinically relevant differences in safety or PK/PD of NG associated with nasal congestion or concomitant administration of nasal decongestant, suggesting that NG can be used to treat severe hypoglycaemia in individuals experiencing nasal congestion.

The Oral ß-Lactamase SYN-004 (Ribaxamase) Degrades Ceftriaxone Excreted into the Intestine in Phase 2a Clinical Studies.

SYN-004 (ribaxamase) is a ß-lactamase designed to be orally administered concurrently with intravenous ß-lactam antibiotics, including most penicillins and cephalosporins. Ribaxamase's anticipated mechanism of action is to degrade excess ß-lactam antibiotic that is excreted into the small intestine. This enzymatic inactivation of excreted antibiotic is expected to protect the gut microbiome from disruption and thus prevent undesirable side effects, including secondary infections such as Clostridium difficile infections, as well as other antibiotic-associated diarrheas. In phase 1 clinical studies, ribaxamase was well tolerated compared to a placebo group and displayed negligible systemic absorption. The two phase 2a clinical studies described here were performed to confirm the mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine, and were therefore conducted in subjects with functioning ileostomies to allow serial sampling of their intestinal chyme. Ribaxamase fully degraded ceftriaxone to below the level of quantitation in the intestines of all subjects in both studies. Coadministration of oral ribaxamase with intravenous ceftriaxone was also well tolerated, and the plasma pharmacokinetics of ceftriaxone were unchanged by ribaxamase administration. Since ribaxamase is formulated as a pH-dependent, delayed-release formulation, the activity of ribaxamase in the presence of the proton pump inhibitor esomeprazole was examined in the second study; coadministration of these drugs did not adversely affect ribaxamase's ability to degrade ceftriaxone excreted into the intestine. These studies have confirmed the in vivo mechanism of action of ribaxamase, degradation of ß-lactam antibiotics in the human intestine (registered at ClinicalTrials.gov under NCT02419001 and NCT02473640).

Safety, tolerability and pharmacokinetics of trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) in a randomized phase I integrated design study: single and multiple ascending doses and effect of food in healthy volunteers.

PURPOSE: Trimebutine 3-thiocarbamoylbenzenesulfonate (GIC-1001) is a new drug intended to be used for the management of visceral pain in patients undergoing sedation-free, full colonoscopy. The objectives of this Phase I, single-center, randomized, double-blinded, placebo-controlled, integrated study were to evaluate the safety and pharmacokinetics of GIC-1001 after single ascending doses (SAD) and multiple ascending doses (MAD) and to evaluate the influence of food on the pharmacokinetics in healthy volunteers. METHODS: GIC-1001 or placebo was orally administered to 80 healthy male and female subjects (non- or ex-smokers) aged 18 to 50 years with a body mass index between 18.5 and 30 kg/m(2). The SAD portion of the study consisted of 5 cohorts with dose levels of 125 to 1000 mg. The MAD portion included 4 cohorts in which subjects received TID doses of 125 to 500 mg over 7 days (19 consecutive doses). Subjects were randomized (6:2) to receive GIC-1001 or placebo. The third portion of the study included a single 375-mg dose of GIC-1001 in a randomized, 2-period, crossover design to assess the influence of food (n = 8 subjects). Safety was evaluated by using adverse events (AEs), vital signs, ECGs, physical examination, cardiac monitoring, and laboratory test results. The analytes were assayed by using validated HPLC-MS/MS methods. Pharmacokinetic parameters were evaluated by using a noncompartmental analysis, and regression models were used to assess dose linearity. To evaluate the effect of food, 90% CIs of the ratio of geometric least squares means from ln-transformed pharmacokinetic parameters were calculated. FINDINGS: The most frequently reported drug-related AEs were of nervous system and gastrointestinal origin. The most common AEs included headache, somnolence, and nausea. After single-dose administration, Tmax of trimebutine ranged from 1.0 to 1.5 hours. Cmax and AUCT were linear (nonlinearity P ≥ 0.05) and proportional (P < 0.05) over the studied dose range. Food increased the Cmax and AUC of trimebutine; the ratio of geometric least squares means (90% CI) were 140% (84-234) and 174% (138-221), respectively. In the MAD study portion, the Tmax of trimebutine ranged from 0.5 to 2 hours and AUCτ increased from 38 to 170 ng · h/mL. AUCτ and Cmax were linear and proportional over the studied dose range. IMPLICATIONS: GIC-1001 was well tolerated, and its safety profile was similar to that of placebo. Pharmacokinetics of GIC-1001 and its metabolites were mainly linear and proportional over the studied dose ranges. Steady state was generally considered to be reached after 3 days. Food consumption affected the pharmacokinetic profile of the analytes differently. (ClinicalTrials.gov identifier: NCT01738425.).

Determination of naproxen using DBS: evaluation & pharmacokinetic comparison of human plasma versus human blood DBS.

BACKGROUND: Dried blood spots (DBS) sampling is a well-known technology for qualitative determination such as DNA analysis and screening of newborn metabolic disorders. The scientific community has recently expressed interest in applying the DBS technique for quantitative determination of drugs in biological fluid. RESULTS: Two new bioanalytical assays were developed and validated for the determination of naproxen in human plasma and in DBS samples using liquid chromatography coupled with tandem MS. Furthermore, plasma and DBS clinical samples were collected from four subjects enrolled as part of a bioequivalence study. Concentration data for plasma and DBS samples were determined and pharmacokinetic (PK) profiles in plasma and in DBS samples were compared. CONCLUSIONS: A strong correlation between PK data obtained by the DBS and conventional plasma method was observed, which makes DBS a valuable technique for further naproxen bioavailability and PK investigations and studies.

Asymmetrical growth of the photopic hill during the light adaptation effect.

In response to progressively stronger flashes delivered against a rod saturating background light, the amplitude of the photopic ERG b-wave first increases, reaches a maximal value (V (max)) and then decreases gradually to a plateau where the amplitude of the b-wave equals that of the a-wave, a phenomenon known as the photopic hill (PH). The purpose of this study was to investigate how the PH grew during the course of the light adaptation (LA) process that follows a period of dark adaptation (DA): the so-called light adaptation effect (LAE). Photopic ERG (time-integrated) luminance-response (LR) functions were obtained prior to (control-fully light adapted) and at 0, 5 and 10 min of LA following a 30-min period of DA. A mathematical model combining a Gaussian and a logistic growth function, suggested to reflect the OFF and ON retinal contribution to the PH respectively, was fitted to the LR functions thus obtained. Our results indicate that the magnitude of the cone ERG LAE is modulated by the stimulus luminance, with b-wave enhancements being maximal for luminance levels that result in the descent of the PH. The Gaussian function grew significantly with LA while the logistic growth function remained basically unchanged. Our findings would therefore suggest that the LAE reflects primarily an increase in the retinal OFF response during LA.

Modulation of ERG retinal sensitivity parameters with light environment and photoperiod.

It has been reported that the sensitivity to light of the circadian system of animals and human subjects can be modulated following long-term exposure to a given light environment. Animal studies have also shown that long-term exposure to a light regimen, or light history, will have a significant impact on the retinal structure and function, the objective of which being to regulate the number of photons processed daily by the retina, a phenomenon referred to as photostasis. The existence of such a mechanism has never been explored in humans. In the present study, daily light exposure was continuously recorded in two populations of full-time workers: one group working indoors, in a relatively dim environment without access to natural light, and one group working mainly outdoors in natural bright light. The effect of seasonal changes in the length of the photoperiod was also examined. Retinal sensitivity, as determined with scotopic and photopic electroretinograms (ERG), was compared between these two groups. Indoor workers received less light than outdoor workers, the difference being significant only during work hours. A dim work environment was associated with greater retinal sensitivity in scotopic conditions and lower retinal sensitivity in photopic conditions when compared to a bright work environment. The above differences in retinal sensitivity were evidenced only in workers studied during the months with the shortest photoperiod (Fall-Winter). These results support the hypothesis that, similar to what was previously demonstrated with animal models, the human retina adapts its sensitivity to light according to previous chronic light history, suggesting the existence of a photostasis phenomenon in the human retina as well.

The photopic ERG of the albino guinea pig (Cavia porcellus): a model of the human photopic ERG.

Altricial rodents such as rats and mice are probably the most widely used animal model in the electroretinogram (ERG) literature. However, while the scotopic responses of these rodents share obvious similarities with that of humans, their photopic electroretinograms are strikingly different. For instance, the photopic ERGs of rats and mice include, when measurable, a minimal a-wave, while the b-wave is of much larger amplitude than that of humans. The purpose of this study is to present the albino guinea pig which is like humans, is a precocial animal, and is a better rodent model of the human photopic ERG. In order to investigate the above, photopic electroretinograms and oscillatory potentials, obtained from guinea pigs and human subjects, were compared. Furthermore, in a subset of animals we injected, intravitreally, selective blockers of the ON- (L-2-amino-4-phosphonobutyric acid: L-AP-4; 10 mM) or OFF- (kynurenic acid: KYN; 50 mM) retinal pathways in order to mimic similar retinal disorders found in human. Based on our results, we believe that, compared to rats and mice, the photopic (cone-mediated) ERG of the guinea pig clearly represents a superior rodent model of the human photopic ERG.

Modulation of the human photopic ERG luminance-response function with the use of chromatic stimuli.

In response to progressively brighter flashes, the amplitude of the photopic b-wave of the human electroretinogram (ERG) first increases, then saturates at a maximal value (V(max)) to finally decrease with the brightest flashes. The purpose of this study was to investigate if this "photopic hill" could be modulated with the use of stimuli of different wavelengths. ERGs were evoked to flashes of white, blue, green and red light presented against a white background in 30 normal subjects. Each chromatic stimulus produced a photopic hill. Findings indicate that the amplitude of V(max) was essentially identical except for that measured in response to the red stimuli, where it was 20% smaller than the others.

Comparing the photopic ERG i-wave in different species.

The i-wave, a post b-wave component of the human photopic electroretinogram (ERG), is claimed to originate at the level of the retinal ganglion cells (RGC) or more distally. We investigated whether this wave is a feature common to all species. Photopic ERGs were obtained from the following species: Beagle dog, European cat, New Zealand white rabbit, Göttingen minipig, Cynomolgus monkey, Sprague-Dawley and brown Norway rats, Hartley guinea pig, and CD1 and C57BL6 mice. Results were compared with those obtained from normal human subjects. Except for rats and mice, all species yielded a well-demarcated i-wave, easily identifiable and separated from the a-b-wave complex by approximately 20 ms. Our sample suggests that the i-wave is a feature common to the photopic ERG of most species including humans. In view of its suggested origin, the i-wave would offer a unique opportunity to test, with the flash ERG, the functional integrity of the retinal ganglion cells in animals where use of a pattern stimulus is not always easily obtained.

Vigilance levels during and after bright light exposure in the first half of the night.

Fourteen healthy subjects (8 women, 6 men, aged 22-35 yr) were recruited. Each subject was exposed, in a counterbalanced order, to bright white light (BWL: 3000 lux) and to dim red light (DRL: <15 lux) at a 1-week interval. Light treatments were administered from 00:30 to 04:30 h during sleep deprivation. Salivary melatonin and urinary cortisol concentrations were measured as was core body temperature. Vigilance levels were evaluated by subjective estimates, maintenance of wakefulness tests (MWT), waking EEG recordings, and three performance tests. Under BWL melatonin secretion was suppressed and core body temperature was significantly higher than under DRL. The BWL and DRL conditions produced no difference in cortisol secretion. Significant effects of BWL treatment were found for the MWT and theta-alpha and beta-1 frequency bands of the waking EEG. There was no significant effect of BWL on subjective alertness and performance. Vigilance measures were similar under the two conditions for the tests performed 1.5 h after the end of light treatments. Overall, the findings suggest that bright light (BL) exposure in the first half of the night decreases EEG-defined sleep propensity but has only modest effects on other aspects of vigilance.

The photopic ERG luminance-response function (photopic hill): method of analysis and clinical application.

With progressively brighter stimuli, the amplitude of the photopic b-wave first increases, briefly saturates and then decreases gradually to reach a plateau, where the amplitude of the b-wave equals that of the a-wave; a phenomenon previously presented as the photopic hill. The unique presentation of this luminance-response function seriously complicates its analysis with curve fitting equations such as that of Naka-Rushton used for scotopic electroretinogram. We report a method of analysis of the photopic hill based on easily identifiable and reproducible features of the ascending and descending limbs of this function. The clinical usefulness of these parameters is illustrated with selected cases of retinal disorders.

Correlating retinal function with melatonin secretion in subjects with an early or late circadian phase.

PURPOSE: Evaluate the diurnal variation of retinal function, as measured with the electroretinogram (ERG), in subjects with an early (morning type: M-type) or a late (evening type: E-type) circadian phase. METHODS: Subjects (n = 24) were recruited according to their scores on a Morningness-Eveningness Questionnaire assessing preferences in, e.g., bedtime, waketime, and timing of performance. ERG testing was performed twice on each subject, at 22:30 and at 08:00. Luminance-response functions were obtained in scotopic (blue flashes) and in photopic conditions (white, blue, green, and red flashes). Salivary melatonin samples were taken every half-hour from 20:30 to 00:00 and from 06:30 to 09:30. RESULTS: In scotopic conditions, both groups had lower ERG amplitudes and retinal sensitivity at 08:00. In photopic conditions, the two groups showed an opposite pattern of diurnal variations. The E-types demonstrated a significant reduction in ERG amplitudes at 08:00, whereas the M-types showed an increase in amplitude at the same time. In addition, negative correlations were found between both the cone ERG and mixed rod-cone ERG and the concentration of salivary melatonin, indicating that the ERG amplitude is lowest when melatonin concentration is highest. CONCLUSIONS: The reduction in scotopic ERG responses at 08:00 seen in both groups might be due to the peak of rod disc shedding that takes place, in some mammals, at around light onset. The strong correlation between the cone ERG and salivary melatonin could be attributable to a direct effect of retinal melatonin on the physiology of cones or of the circadian phase of the subjects.

Cone-dominated ERG luminance-response function: the Photopic Hill revisited.

PURPOSE: In response to progressively brighter stimuli, the b-wave of the photopic ERG gradually augments in amplitude, reaches a plateau for a narrow range of intensities and then rapidly decreases with further increments in the luminance of the flash. This unique luminance-response function was originally introduced as the Photopic Hill. The purpose of this study was to further characterize this unique feature of the cone ERG, investigate if it was only limited to b-wave measurements and if it could be obtained under different photopic background luminances. METHODS: Photopic ERGs and oscillatory potentials were generated in response to flashes of light ranging from 0.5 to 16 cd m(-2) s in intensity and presented against photopic backgrounds varying from 18 to 525 cd m(-2) in luminance. RESULTS: All but the brightest background yielded a clear Photopic Hill like luminance-response function which could only be evidenced with the b-wave, the i-wave and OP4 amplitude measurements. Interestingly, the maximal amplitude reached remained almost identical irrespective of the background luminance. CONCLUSIONS: Our results suggest that the retinal mechanisms at the origin of the Photopic Hill effect could represent a voltage limitation mechanism, intimately tied to the OFF pathway. The latter would however be intrinsic to the cone system only and not to the entire retinal network since significantly higher peak amplitudes are reached with dark adaptation.