The Important Role of Contextual Information in Speech Perception in Cochlear Implant Users and Its Consequences in Speech Tests.

This study investigated the role of contextual information in speech intelligibility, the influence of verbal working memory on the use of contextual information, and the suitability of an ecologically valid sentence test containing contextual information, compared with a CNC (Consonant-Nucleus-Consonant) word test, in cochlear implant (CI) users. Speech intelligibility performance was assessed in 50 postlingual adult CI users on sentence lists and on CNC word lists. Results were compared with a normal-hearing (NH) group. The influence of contextual information was calculated from three different context models. Working memory capacity was measured with a Reading Span Test. CI recipients made significantly more use of contextual information in recognition of CNC words and sentences than NH listeners. Their use of contextual information in sentences was related to verbal working memory capacity but not to age, indicating that the ability to use context is dependent on cognitive abilities, regardless of age. The presence of context in sentences enhanced the sensitivity to differences in sensory bottom-up information but also increased the risk of a ceiling effect. A sentence test appeared to be suitable in CI users if word scoring is used and noise is added for the best performers.

Comparing the Effect of Different Hearing Aid Fitting Methods in Bimodal Cochlear Implant Users.

Purpose The aim of the study was to investigate the effect of 3 hearing aid fitting procedures on provided gain of the hearing aid in bimodal cochlear implant users and their effect on bimodal benefit. Method This prospective study measured hearing aid gain and auditory performance in a cross-over design in which 3 hearing aid fitting methods were compared. Hearing aid fitting methods differed in initial gain prescription rule (NAL-NL2 and Audiogram+) and loudness balancing method (broadband vs. narrowband loudness balancing). Auditory functioning was evaluated by a speech-in-quiet test, a speech-in-noise test, and a sound localization test. Fourteen postlingually deafened adult bimodal cochlear implant users participated in the study. Results No differences in provided gain and in bimodal performance were found for the different hearing aid fittings. For all hearing aid fittings, a bimodal benefit was found for speech in noise and sound localization. Conclusion Our results confirm that cochlear implant users with residual hearing in the contralateral ear substantially benefit from bimodal stimulation. However, on average, no differences were found between different types of fitting methods, varying in prescription rule and loudness balancing method.

The Effect of Binaural Beamforming Technology on Speech Intelligibility in Bimodal Cochlear Implant Recipients.

Although the benefit of bimodal listening in cochlear implant users has been agreed on, speech comprehension remains a challenge in acoustically complex real-life environments due to reverberation and disturbing background noises. One way to additionally improve bimodal auditory performance is the use of directional microphones. The objective of this study was to investigate the effect of a binaural beamformer for bimodal cochlear implant (CI) users. This prospective study measured speech reception thresholds (SRT) in noise in a repeated-measures design that varied in listening modality for static and dynamic listening conditions. A significant improvement in SRT of 4.7 dB was found with the binaural beamformer switched on in the bimodal static listening condition. No significant improvement was found in the dynamic listening condition. We conclude that there is a clear additional advantage of the binaural beamformer in bimodal CI users for predictable/static listening conditions with frontal target speech and spatially separated noise sources.

Effects of a transient noise reduction algorithm on speech intelligibility in noise, noise tolerance and perceived annoyance in cochlear implant users.

OBJECTIVE: To evaluate the validity and efficacy of a transient noise reduction algorithm (TNR) in cochlear implant processing and the interaction of TNR with a continuous noise reduction algorithm (CNR). DESIGN: We studied the effects of TNR and CNR on the perception of realistic sound samples with transients, using subjective ratings of annoyance, a speech-in-noise test and a noise tolerance test. STUDY SAMPLE: Participants were 16 experienced cochlear implant recipients wearing an Advanced Bionics Naida Q70 processor. RESULTS: CI users rated sounds with transients as moderately annoying. Annoyance was slightly, but significantly reduced by TNR. Transients caused a large decrease in speech intelligibility in noise and a moderate decrease in noise tolerance, measured on the Acceptable Noise Level test. The TNR had no significant effect on noise tolerance or on speech intelligibility in noise. The combined application of TNR and CNR did not result in interactions. CONCLUSIONS: The TNR algorithm was effective in reducing annoyance from transient sounds, but was not able to prevent a decreasing effect of transients on speech understanding in noise and noise tolerance. TNR did not reduce the beneficial effect of CNR on speech intelligibility in noise, but no cumulated improvement was found either.

Optimising the effect of noise reduction algorithm ClearVoice in cochlear implant users by increasing the maximum comfort levels.

OBJECTIVE: ClearVoice is a single-microphone noise reduction algorithm in Advanced Bionics cochlear implant(CI) systems with the aim to improve performance in background noise. The present study investigated a hypothesised increased effect of ClearVoice if combined with a structural increase of maximum comfort stimulation levels (M-levels) in the CI fitting. DESIGN: We tested performance with ClearVoice (Medium) in four conditions, defined by combined settings of ClearVoice off/on and with/without 5% increase of M-levels. The main outcome measures were the Acceptable Noise Level (ANL) and the speech reception threshold in continuous background noise (SRTn). STUDY SAMPLE: Participants were 16 experienced cochlear implant recipients with Advanced Bionics implants and a Naida Q70 processor. RESULTS: The ANL significantly improved by using either ClearVoice or an increase of M-levels. Combining both settings gave the largest improvement in ANL. For the SRTn, we found a small, but significant interaction between ClearVoice and an increase of M-levels, implying that ClearVoice improved speech understanding slightly, but only if combined with a 5% increase of M-levels. CONCLUSIONS: Optimal profit from ClearVoice is obtained if combined with a structural 5% increase of M-levels.

Population Modeling of Selexipag Pharmacokinetics and Clinical Response Parameters in Patients With Pulmonary Arterial Hypertension.

Selexipag (Uptravi) is an oral selective IP prostacyclin receptor agonist approved for the treatment of pulmonary arterial hypertension (PAH). The pivotal GRIPHON study was the largest clinical study ever conducted in PAH patients, providing long-term data from 1,156 patients. PAH comedication did not affect exposure to selexipag, while exposure to its active metabolite ACT-333679 was reduced by 30% when taken in combination, clinically not relevant in the context of individual dose up-titration. Using log-linear regression models linking model-predicted steady-state exposure to pharmacodynamics (PD), exposure to selexipag and ACT-333679 showed some statistically significant, albeit not clinically relevant, effects on exercise capacity, laboratory values, and the occurrence of prostacyclin-related adverse events, but not on vital signs or adverse events denoting hemorrhage. Using suitable modeling techniques, the GRIPHON study yielded clinically relevant data with limited burden of pharmacokinetics (PK) blood sampling, demonstrating that PK/PD modeling enables firm conclusions even with sparse PK and PD sampling.

Evaluation of a wireless remote microphone in bimodal cochlear implant recipients.

OBJECTIVE: To evaluate the benefit of a wireless remote microphone (MM) for speech recognition in noise in bimodal adult cochlear implant (CI) users both in a test setting and in daily life. DESIGN: This prospective study measured speech reception thresholds in noise in a repeated measures design with factors including bimodal hearing and MM use. The participants also had a 3-week trial period at home with the MM. STUDY SAMPLE: Thirteen post-lingually deafened adult bimodal CI users. RESULTS: A significant improvement in SRT of 5.4 dB was found between the use of the CI with the MM and the use of the CI without the MM. By also pairing the MM to the hearing aid (HA) another improvement in SRT of 2.2 dB was found compared to the situation with the MM paired to the CI alone. In daily life, participants reported better speech perception for various challenging listening situations, when using the MM in the bimodal condition. CONCLUSION: There is a clear advantage of bimodal listening (CI and HA) compared to CI alone when applying advanced wireless remote microphone techniques to improve speech understanding in adult bimodal CI users.

Self-Adjustment of Upper Electrical Stimulation Levels in CI Programming and the Effect on Auditory Functioning.

OBJECTIVES: With current cochlear implants (CIs), CI recipients achieve good speech perception in quiet surroundings. However, in acoustically complex, real-life environments, speech comprehension remains difficult and sound quality often remains poor. It is, therefore, a challenge to program CIs for such environments in a clinic. The CI manufacturer Cochlear Ltd. recently introduced a remote control that enables CI recipients to alter the upper stimulation levels of their user programs themselves. In this concept, called remote assistant fitting (RAF), bass and treble controls can be adjusted by applying a tilt to emphasize either the low- or high-frequency C-levels, respectively. This concept of self-programming may be able to overcome limitations associated with fine-tuning the CI sound processor in a clinic. The aim of this study was to investigate to what extent CI recipients already accustomed to their clinically fitted program would adjust the settings in daily life if able to do so. Additionally, we studied the effects of these changes on auditory functioning in terms of speech intelligibility (in quiet and in noise), noise tolerance, and subjectively perceived speech perception and sound quality. DESIGN: Twenty-two experienced adult CI recipients (implant use >12 months) participated in this prospective clinical study, which used a within-subject repeated measures design. All participants had phoneme scores of ≥70% at 65 dB SPL in quiet conditions, and all used a Cochlear Nucleus CP810 sound processor. Auditory performance was tested by a speech-in-quiet test, a speech-in-noise test, an acceptable noise level test, and a questionnaire about perceived auditory functioning, that is, a speech and sound quality (SSQ-C) questionnaire. The first session consisted of a baseline test in which the participants used their own CI program and were instructed on how to use RAF. After the first session, participants used RAF for 3 weeks at home. After these 3 weeks, the participants returned to the clinic for auditory functioning tests with their self-adjusted programs and completed the SSQ-C. RESULTS: Fifteen participants (68%) adjusted their C-level frequency profile by more than 5 clinical levels for at least one electrode. Seven participants preferred a higher contribution of the high frequencies relative to the low frequencies, while five participants preferred more low-frequency stimulation. One-third of the participants adjusted the high and low frequencies equally, while some participants mainly used the overall volume to change their settings. Several parts of the SSQ-C questionnaire scores showed an improvement in perceived auditory functioning after the subjects used RAF. No significant change was found on the auditory functioning tests for speech-in-quiet, speech-in-noise, or acceptable noise level. CONCLUSIONS: In conclusion, the majority of experienced CI users made modest changes in the settings of their programs in various ways and were able to do so with the RAF. After altering the programs, the participants experienced an improvement in speech perception in quiet environments and improved perceived sound quality without compromising auditory performance. Therefore, it can be concluded that self-adjustment of CI settings is a useful and clinically applicable tool that may help CI recipients to improve perceived sound quality in their daily lives.

Lucerastat, an iminosugar with potential as substrate reduction therapy for glycolipid storage disorders: safety, tolerability, and pharmacokinetics in healthy subjects.

BACKGROUND: Lucerastat, an inhibitor of glucosylceramide synthase, has the potential to restore the balance between synthesis and degradation of glycosphingolipids in glycolipid storage disorders such as Gaucher disease and Fabry disease. The safety, tolerability, and pharmacokinetics of oral lucerastat were evaluated in two separate randomized, double-blind, placebo-controlled, single- and multiple-ascending dose studies (SAD and MAD, respectively) in healthy male subjects. METHODS: In the SAD study, 31 subjects received placebo or a single oral dose of 100, 300, 500, or 1000 mg lucerastat. Eight additional subjects received two doses of 1000 mg lucerastat or placebo separated by 12 h. In the MAD study, 37 subjects received placebo or 200, 500, or 1000 mg b.i.d. lucerastat for 7 consecutive days. Six subjects in the 500 mg cohort received lucerastat in both absence and presence of food. RESULTS: In the SAD study, 15 adverse events (AEs) were reported in ten subjects. Eighteen AEs were reported in 15 subjects in the MAD study, in which the 500 mg dose cohort was repeated because of elevated alanine aminotransferase (ALT) values in 4 subjects, not observed in other dose cohorts. No severe or serious AE was observed. No clinically relevant abnormalities regarding vital signs and 12-lead electrocardiograms were observed. Lucerastat Cmax values were comparable between studies, with geometric mean Cmax 10.5 (95% CI: 7.5, 14.7) and 11.1 (95% CI: 8.7, 14.2) µg/mL in the SAD and MAD study, respectively, after 1000 mg lucerastat b.i.d. tmax (0.5 - 4 h) and t1/2 (3.6 - 8.1 h) were also within the same range across dose groups in both studies. Using the Gough power model, dose proportionality was confirmed in the SAD study for Cmax and AUC0-∞, and for AUC0-12 in the MAD study. Fed-to-fasted geometric mean ratio for AUC0-12 was 0.93 (90% CI: 0.80, 1.07) and tmax was the same with or without food, indicating no food effect. CONCLUSIONS: Incidence of drug-related AEs did not increase with dose. No serious AEs were reported for any subject. Overall, lucerastat was well tolerated. These results warrant further investigation of substrate reduction therapy with lucerastat in patients with glycolipid storage disorders. SAD study was registered on clinicaltrials.gov under the identifier NCT02944487 on the 24th of October 2016 (retrospectively registered). MAD study was registered on clinicaltrials.gov under the identifier NCT02944474 on the 25th of October 2016 (retrospectively registered). TRIAL REGISTRATION: A Study to Assess the Safety and Tolerability of Lucerastat in Subjects With Fabry Disease. Clinicaltrials.gov: NCT02930655 .

Prevalence of age-related hearing loss, including sex differences, in older adults in a large cohort study.

OBJECTIVES/HYPOTHESIS: To obtain actual status of age-related hearing loss in a general unscreened population of older Dutch adults and to investigate whether the prevalence or degree has changed over time. STUDY DESIGN: To investigate the prevalence and degree of hearing loss, we conducted a large prospective cohort study of older adults between February 2011 and July 2015. METHODS: Pure-tone air- and bone-conduction thresholds were measured for 4,743 participants. Results were compared to previous cohort studies. RESULTS: As expected, hearing loss increased with age. We found a correlation of R2 = 0.317 for men and R2 = 0.354 for women (right ears). A prevalence of hearing loss greater than 35 dB hearing level the average of 0.5/1/2/4 kHz in the better ear, was found in 33% of the male and almost 29% of the female participants aged 65 years and older. Compared with previous studies, men had less hearing loss at the frequencies of 2 kHz and above. Hearing thresholds in women were significantly higher at 4 and 8 kHz. The difference in hearing loss between men and women is significantly less than in earlier studies. CONCLUSIONS: Our study confirms that hearing loss is highly prevalent in the general unscreened population of older adults. However, the difference in hearing between sexes was considerably less than previously reported. This is probably due to changing lifestyle and environmental circumstances, LEVEL OF EVIDENCE: 2b Laryngoscope, 127:725-730, 2017.

Clinical pharmacokinetics and pharmacodynamics of the endothelin receptor antagonist macitentan.

Pulmonary arterial hypertension (PAH) is a progressive disease of the lung vascular system, which leads to right-sided heart failure and ultimately death if untreated. Treatments to regulate the pulmonary vascular pressure target the prostacyclin, nitric oxide, and endothelin (ET) pathways. Macitentan, an oral, once-daily, dual ETA and ETB receptor antagonist with high affinity and sustained receptor binding is the first ET receptor antagonist to show significant reduction of the risk of morbidity and mortality in PAH patients in a large-scale phase III study with a long-term outcome. Here we present a review of the available clinical pharmacokinetic, pharmacodynamic, pharmacokinetic/pharmacodynamic relationship, and drug-drug interaction data of macitentan in healthy subjects, patients with PAH, and in special populations.

Efficacy and safety of the dual L- and T-type calcium channel blocker, ACT-280778: a proof-of-concept study in patients with mild-to-moderate essential hypertension.

ACT-280778 is an oral, non-dihydropyridine, dual L-/T-type calcium channel blocker. This phase 2a, double-blind, randomized, placebo- and active-controlled study investigated the efficacy and safety of 10 mg ACT-280778. Patients with mild-to-moderate essential hypertension received once-daily placebo (n=53), ACT-280778 10 mg (n=52) or amlodipine 10 mg (n=54) for 4 weeks. The primary end point was the change from baseline to week 4 in placebo-adjusted mean trough sitting diastolic blood pressure (SiDBP) with ACT-280778. Tolerability was assessed by recording treatment-emergent adverse events (TEAEs). Baseline clinical characteristics were similar across groups. No significant difference was observed at week 4 in mean trough SiDBP between placebo (-9.9 (95% confidence limit (CL) -12.7, -7.0) mm Hg) and ACT-280778 (-9.5 (-12.4, -6.5) mm Hg; P=0.86); amlodipine reduced mean trough SiDBP by -16.8 (-19.0, -14.5) mm Hg, confirming assay validity. Change in mean PR interval at week 4 (pre-dose) differed between placebo (-1.0 (95% CL -4.4, 2.3) ms) and ACT-280778 (6.5 (3.5, 9.6) ms); amlodipine did not increase PR interval (1.1 (-1.6, 3.9) ms).Treatment-emergent adverse events (TEAE) frequency was 32.1% (placebo), 32.7% (ACT-280778) and 33.3% (amlodipine). The most common TEAEs were headache, peripheral edema, hypertension and second-degree atrioventricular block. ACT-280778 (10 mg) did not lower blood pressure in mild-to-moderate hypertension.

Application of Noise Reduction Algorithm ClearVoice in Cochlear Implant Processing: Effects on Noise Tolerance and Speech Intelligibility in Noise in Relation to Spectral Resolution.

OBJECTIVES: Noise reduction algorithms have recently been introduced in the design of clinically available cochlear implants. This study was intended to (1) evaluate the effect of noise reduction algorithm "ClearVoice" on noise tolerance and on speech intelligibility in noisy conditions at different speech-in-noise ratios in cochlear implant users, and (2) test the hypothesis that CI recipients with low spectral resolution might benefit more from noise reduction algorithms than CI users with high spectral resolution. DESIGN: A double-blind crossover design was used to measure the effect of the noise reduction algorithm ClearVoice on noise tolerance with the acceptable noise level (ANL) test and on speech in noise for three performance levels: speech reception thresholds (SRT) at 50%, 70%, and at a speech to noise ratio of SRT50% + 11 dB. Furthermore, they tested speech intelligibility in quiet. The effective spectral resolution was measured with a spectral-ripple discrimination test. Twenty users of the Advanced Bionics Harmony processor with HiRes120-processing participated in this study. RESULTS: The noise reduction algorithm led to a significant improvement-a decrease of 3.6 dB-in the ANL test but had no significant effect on any of the three speech-in-noise performance levels. The improvement in ANL was not significantly correlated with any of the speech-in-noise measures, nor with the speech-in-noise ratio in the ANL test. However, higher maximum speech intelligibility in quiet conditions correlated significantly with higher noise tolerance. Spectral-ripple discrimination thresholds were not significantly correlated with the effect of noise reduction on ANL or on speech intelligibility in noise nor with the speech-in-noise ratios. The spectral-ripple discrimination thresholds did correlate significantly with maximum speech intelligibility in quiet but not with speech reception thresholds in noise. CONCLUSIONS: The noise reduction algorithm ClearVoice improves noise tolerance. However, this study shows no change in speech intelligibility in noise due to the algorithm. The improvement in noise tolerance is not significantly related to spectral-ripple discrimination thresholds, speech intelligibility measures, or signal to noise ratio. Our hypothesis that CI recipients with low spectral resolution have a greater benefit from noise reduction than CI users with high spectral resolution does not hold for noise tolerance or for speech intelligibility in noise.

Clinical pharmacology of ponesimod, a selective S1P1 receptor modulator, after uptitration to supratherapeutic doses in healthy subjects.

PURPOSE: The aim of this study was to assess in healthy subjects the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an oral selective sphingosine-1-phosphate receptor 1 (S1P1) modulator in development for multiple sclerosis, by using an uptitration scheme up to supratherapeutic doses. METHODS: This was a double-blind, placebo-controlled, randomised, parallel group, uptitration study. Male and female subjects received ascending oral doses of ponesimod (n=12) or placebo (n=4) once daily for 3 days at each dose level (10-20-40-60-80-100mg). RESULTS: The most frequent adverse events were chest discomfort, headache, dizziness, dyspnoea, abdominal pain, and night sweats. Chest discomfort and dyspnoea were considered dose-limiting. A transient decrease in heart rate was observed following the first 10-mg ponesimod dose (maximum mean decrease of 9 beats per minute (bpm) (placebo: 2 bpm)). After uptitration, effects on heart rate were indistinguishable from placebo. A dose-dependent effect on pulmonary function tests was observed and reached a plateau with 60-80 mg ponesimod (maximum mean decrease from baseline of 1.24l (-30.5%) in forced expiratory volume in 1s). A plateau in mean lymphocyte count reduction of approximately 70% from baseline was reached at the 40 mg dose level. Observed effects were fully reversible within 10days after treatment discontinuation. No relevant sex differences were observed. CONCLUSIONS: At supratherapeutic doses, symptoms of chest discomfort and dyspnoea were dose-limiting. An uptitration dosing scheme is to be preferred in clinical studies in patients in order to limit effects of ponesimod on heart rate and atrioventricular (AV) conduction.

Setipiprant, a selective CRTH2 antagonist, reduces allergen-induced airway responses in allergic asthmatics.

BACKGROUND: CRTH2 is a G-protein-coupled receptor on T helper2 cells that mediates pro-inflammatory effects of prostaglandin D2 in allergic responses. OBJECTIVE: To investigate the tolerability and pharmacokinetics of setipiprant (ACT-129968), a selective orally active CRTH2 antagonist, in allergic asthmatics and to assess the protective effects of multiple doses of this drug against allergen-induced airway responses. METHODS: In this 3-centre, double-blinded, placebo-controlled, cross-over study, 18 allergic asthmatic males were randomized to setipiprant 1000 mg or matching placebo b.i.d. for 5 consecutive days. Study periods were separated by a washout of ≥ 3 weeks. On study day 4, subjects underwent a standardized allergen challenge and airway response was recorded by FEV1 until 10 h post-allergen. Airway responsiveness to methacholine and exhaled nitric oxide (eNO) were measured pre- and post-dosing. The effects of both treatments on the allergen-induced airway responses were compared by a paired Student's t-test. RESULTS: Fifteen subjects completed the study per-protocol and were included in the analysis. Overall, setipiprant was well tolerated and no clinically relevant adverse events occurred. Trough plasma concentrations showed a high inter-subject variability. Compared with placebo, setipiprant significantly reduced the allergen-induced late asthmatic response (LAR), inhibiting the area under the response vs. time curve (AUC(3-10 h) ) by on average 25.6% (P = 0.006) and significantly protected against the allergen-induced airway hyperresponsiveness (AHR) to methacholine (P = 0.0029). There was no difference in the early asthmatic response (EAR) or in allergen-induced changes in eNO between treatments. CONCLUSION AND CLINICAL RELEVANCE: Setipiprant at multiple oral doses was well tolerated and reduced both the allergen-induced LAR and the associated AHR in allergic asthmatics. Our findings confirm that CRTH2 may be a promising target for the treatment of allergic disorders.

Multiple-dose tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator: favorable impact of dose up-titration.

This multiple-ascending-dose study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of ponesimod, an S1P1 receptor modulator and a potential new treatment for autoimmune diseases. In part A, 10 healthy male and female subjects received once daily oral doses of ponesimod (5, 10, or 20 mg) or placebo for 7 days. Sinus bradycardia and, in some subjects, atrioventricular (AV) block occurred primarily on the first day of dosing, as desensitization developed to ponesimod-induced heart rate (HR) reduction and PR-prolongation. This elicited the design of an up-titration schedule in 17 subjects to a dose of 40 mg in part B. The up-titration regimen reduced HR and PQ/PR effects. Reported adverse events were mainly related to the cardiac and respiratory systems. Respiratory effects increased with higher doses. Ponesimod multiple-dose pharmacokinetics were slightly more than dose-proportional and characterized by a time to maximum concentration and an elimination half-life varying from 2.5 to 4.0 hours and 30.9 to 33.5 hours, respectively, and an accumulation of about 2.3-fold. Ponesimod caused a dose-dependent sustained decrease in total lymphocyte count, reversible within 7 days of discontinuation. A pharmacokinetic-pharmacodynamic model enabled comparing day 1 and steady-state conditions. These results warrant further investigation of ponesimod in patients.

Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial.

The orexin system is a key regulator of sleep and wakefulness. In a multicenter, double-blind, randomized, placebo-controlled, two-way crossover study, 161 primary insomnia patients received either the dual orexin receptor antagonist almorexant, at 400, 200, 100, or 50 mg in consecutive stages, or placebo on treatment nights at 1-week intervals. The primary end point was sleep efficiency (SE) measured by polysomnography; secondary end points were objective latency to persistent sleep (LPS), wake after sleep onset (WASO), safety, and tolerability. Dose-dependent almorexant effects were observed on SE , LPS , and WASO . SE improved significantly after almorexant 400 mg vs. placebo (mean treatment effect 14.4%; P < 0.001). LPS (­18 min (P = 0.02)) and WASO (­54 min (P < 0.001)) decreased significantly at 400 mg vs. placebo. Adverse-event incidence was dose-related. Almorexant consistently and dose-dependently improved sleep variables. The orexin system may offer a new treatment approach for primary insomnia.

Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant.

Almorexant, a dual orexin receptor antagonist potentially representing a new class of sleep-promoting compounds, was administered in an ascending single-dose study to evaluate tolerability, pharmacokinetics, and pharmacodynamics. Seventy healthy male subjects were enrolled in this double-blind, placebo- and active-controlled study. Each dose level (1-1,000 mg) was investigated in a separate group of 10 subjects (6 on almorexant, 2 on placebo, 2 on zolpidem 10 mg). Almorexant was well tolerated with no signs of cataplexy. Peak plasma concentration (C(max)) was quickly attained (median time to maximum concentration (t(max)) ranged from 0.7 to 2.3 h), and plasma concentrations subsequently decreased quickly to ~20% of C(max) over the course of 8 h. Vigilance, alertness, and visuomotor and motor coordination were reduced following daytime administration of zolpidem or almorexant at doses of > or =400 mg. Population pharmacokinetic/pharmacodynamic modeling suggested that doses of ~500 mg almorexant and 10 mg zolpidem are equivalent with respect to subjectively assessed alertness.

Pharmacokinetics, pharmacodynamics and the pharmacokinetic/ pharmacodynamic relationship of zolpidem in healthy subjects.

Zolpidem is one of the most frequently prescribed hypnotics, as it is a very short-acting compound with relatively few side effects. Zolpidem's short duration of action is partly related to its short elimination half-life, but the associations between plasma levels and pharmacodynamic (PD) effects are not precisely known. In this study, the concentration-effect relationships for zolpidem were modelled. Zolpidem (10 mg) was administered in a double-blind, randomised, placebo-controlled trial to determine PD and pharmacokinetics (PK) in 14 healthy volunteers. Zolpidem was absorbed and eliminated quickly, with a median T(max) of 0.78 h (range: 0.33-2.50) and t(1/2) of 2.2 h. Zolpidem reduced saccadic peak velocity (SPV), adaptive tracking performance, electroencephalogram (EEG) alpha power and visual analogue scale (VAS) alertness score and increased body sway, EEG beta power and VAS 'feeling high'. Short- and long-term memory was not affected. Central nervous system effects normalised more rapidly than the decrease of plasma concentrations. For most effects, zolpidem's short duration of action could be adequately described by both a sigmoid E(max) model and a transit tolerance model. For SPV and EEG alpha power, the tolerance model seemed less suitable. These PK/PD models have different implications for the mechanism underlying zolpidem's short duration of action. A sigmoid E(max) model (which is based on ligand binding theory) would imply a threshold value for the drug's effective concentrations. A transit tolerance model (in which a hypothetical factor builds up with time that antagonises the effects of the parent compound) is compatible with a rapid reversible desensitisation of GABAergic subunits.

In vitro and in vivo pharmacokinetic characteristics of clazosentan, an intravenous endothelin receptor antagonist, in humans.

OBJECTIVE: In this study, the distribution, metabolism and excretion of the endothelin receptor antagonist clazosentan were investigated. SUBJECTS AND METHODS: 4 healthy male subjects received an intravenous 3-h infusion at a rate of 0.2 mg/kg/h of 14C-labeled clazosentan and blood, urine and feces samples were collected for a period of 8 days. Experiments were performed to investigate the plasma protein binding, the binding to red blood cells and the inhibition potential of cytochrome P450 isoenzymes of clazosentan. RESULTS: Clazosentan was mainly excreted unchanged into feces whereas about 15% of the radioactive dose was recovered in urine. No metabolites representing more than 5% of total radioactivity were identified. No relevant inhibition of the human cytochrome P450 isoenzymes, 1A2, 2A6, 2B6, 2C9, 2C19, 2D6, 2E1 and 3A4, was observed in vitro at clazosentan concentrations largely exceeding those observed in clinical trials. In human blood, clazosentan was highly bound to plasma proteins and did hardly penetrate into red blood cells. CONCLUSION: The primary route of excretion of clazosentan was via the feces, mainly as unchanged drug.