Early Decision-Making in Drug Development: The Potential Role of Pharmaco-EEG and Pharmaco-Sleep.

The pharmaceutical industry has been suffering from low clinical success rates of new drugs for some time with particularly high attrition in early clinical development, especially for drugs aimed at central targets. Both pharmaco-electroencephalography (EEG) and pharmaco-sleep, along with other biomarker techniques, have significant potential to assist with this problem by enabling early decisions to be made about the likelihood of a compound proving successful in the clinic. This paper discusses the role and points of application of biomarker techniques in early drug development. It proposes a framework for the use of pharmaco-EEG and pharmaco-sleep in drug development that (i) relies on the combination of preclinical data and an understanding of translatability to generate robust hypotheses for testing in early clinical studies and (ii) is backed up by a clear decision-making process. The areas that need further development before this framework can be put fully into practice are discussed, along with some possible routes by which this could be achieved through precompetitive co-operation within the industry.

Effects of prolonged-release melatonin and zolpidem on postural stability in older adults.

OBJECTIVES: A prolonged-release formulation of melatonin (PR-M) is indicated for insomnia in patients aged 55 years and older. Because hypnotics result in impairments of body sway, it was important to evaluate the effect of 2 mg PR-M on postural stability in older adults at night. METHODS: Twenty-four healthy volunteers (12 women, 12 men, aged 55-64 years) completed a randomized, double-blind, single-dose, three-way crossover study of postural stability of PR-M 2 mg, zolpidem 10 mg (active control) or placebo. Subjects were tested for body sway 30 min before, 1.5 and 4 h after dosing. Parameters tested were the area of the 95% confidence ellipse enclosing the center of pressure (COP; [A95]) and COP path length. RESULTS: Zolpidem significantly increased the A95 (both eyes conditions at all time points) and path length of COP. PR-M had no effect on A95 (both "eyes closed" and "eyes open" conditions at all time points) compared with placebo and increased COP path length by 10% at 4 h post-dose in open but not closed eyes condition. No serious adverse events were observed. CONCLUSIONS: In older adults, evening PR-M intake did not impair postural stability during the night. The postural instability with zolpidem demonstrated assay sensitivity and validated the outcome.

Incidental discovery of a case of renal tuberculoma after intravesical BCG treatment.

Intravesical BCG treatment used in the management of NMIBC, usually presents as side effects: pollakiuria, hematuria, fever. Rarer complications may occur, affecting all organs of the urinary tract. Renal tuberculoma, a rare complication of intravesical BCG treatment, may be asymptomatic. It will be necessary to think about it, in front of the appearance of a tumoral lesion of renal localization post intravesical BCG treatment.

Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of the Positive Modulator of HGF/MET, Fosgonimeton, in Healthy Volunteers and Subjects with Alzheimer's Disease: Randomized, Placebo-Controlled, Double-Blind, Phase I Clinical Trial.

BACKGROUND: Fosgonimeton (ATH-1017) is being developed as a first-in-class regenerative therapy for people with Alzheimer's disease (AD) and dementia; potentially improving dementia symptoms and altering disease progression by reversing synaptic disconnection and neuronal loss. OBJECTIVE: This randomized, double-blind, placebo-controlled phase I trial (NCT03298672) evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of fosgonimeton. METHODS: Fosgonimeton was administered once daily via subcutaneous injection to 88 subjects. The single ascending dose study enrolled healthy young male subjects (n = 48; age, 33.4±6.3 years; dose, 2, 6, 20, 40, 60, or 90 mg); the multiple ascending dose study enrolled healthy elderly subjects (n = 29; age, 63.8±4.0 years; dose, 20, 40, 60, or 80 mg; 9-day duration); and the fixed-dose study enrolled AD subjects (n = 11; age, 69.2±7.1 years; dose, 40 mg; 9-day duration). Quantitative electroencephalogram (qEEG) and event-related potential (ERP) P300 measured neurophysiological signals following fosgonimeton treatment, supporting brain penetration and target engagement. RESULTS: Fosgonimeton and placebo were shown to be safe and well-tolerated across all doses. Pharmacokinetic results for fosgonimeton were dose-proportional, with no sex effect or accumulation over 9 days. The main effect of fosgonimeton on qEEG was acute and sustained gamma power induction. In AD subjects, there was a significant effect toward ERP P300 latency normalization compared with placebo (p = 0.027; n = 7 at 40 mg fosgonimeton versus n = 4 placebo). CONCLUSION: These results support the continued development of fosgonimeton as a novel therapeutic for people with AD and dementia. The fast-onset normalization of ERP P300 latency in AD subjects suggests enhancement of synaptic function and potential procognitive effects.

Primary bladder amyloidosis: About a case of incidental discovery.

Primary bladder amyloidosis is rare. Hematuria is the most common form of it's revelation. There are no specific clinical and paraclinical signs to differentiate it from urothelial tumors. The diagnosis is histological. We are reporting you a case of incidental discovery.

Mismatch negativity as EEG biomarker supporting CNS drug development: a transnosographic and translational study.

The lack of translation from basic research into new medicines is a major challenge in CNS drug development. The need to use novel approaches relying on (i) patient clustering based on neurobiology irrespective to symptomatology and (ii) quantitative biomarkers focusing on evolutionarily preserved neurobiological systems allowing back-translation from clinical to nonclinical research has been highlighted. Here we sought to evaluate the mismatch negativity (MMN) response in schizophrenic (SZ) patients, Alzheimer's disease (AD) patients, and age-matched healthy controls. To evaluate back-translation of the MMN response, we developed EEG-based procedures allowing the measurement of MMN-like responses in a rat model of schizophrenia and a mouse model of AD. Our results indicate a significant MMN attenuation in SZ but not in AD patients. Consistently with the clinical findings, we observed a significant attenuation of deviance detection (~104.7%) in rats subchronically exposed to phencyclidine, while no change was observed in APP/PS1 transgenic mice when compared to wild type. This study provides new insight into the cross-disease evaluation of the MMN response. Our findings suggest further investigations to support the identification of neurobehavioral subtypes that may help patients clustering for precision medicine intervention. Furthermore, we provide evidence that MMN could be used as a quantitative/objective efficacy biomarker during both preclinical and clinical stages of SZ drug development.

Cholinergic modulation of disorder-relevant human defensive behaviour in generalised anxiety disorder.

Drugs that are clinically effective against anxiety disorders modulate the innate defensive behaviour of rodents, suggesting these illnesses reflect altered functioning in brain systems that process threat. This hypothesis is supported in humans by the discovery that the intensity of threat-avoidance behaviour is altered by the benzodiazepine anxiolytic lorazepam. However, these studies used healthy human participants, raising questions as to their validity in anxiety disorder patients, as well as their generalisability beyond GABAergic benzodiazepine drugs. BNC210 is a novel negative allosteric modulator of the alpha 7 nicotinic acetylcholine receptor and we recently used functional Magnetic Resonance Imaging to show it reduced amygdala responses to fearful faces in generalised anxiety disorder patients. Here we report the effect of BNC210 on the intensity of threat-avoidance behaviour in 21 female GAD patients from the same cohort. We used the Joystick Operated Runway Task as our behavioural measure, which is a computerised human translation of the Mouse Defense Test Battery, and the Spielberger state anxiety inventory as our measure of state affect. Using a repeated-measures, within-subjects design we assessed the effect of BNC210 at two dose levels versus placebo (300 mg and 2000 mg) upon two types of threat-avoidance behaviour (Flight Intensity and Risk Assessment Intensity). We also tested the effects of 1.5 mg of the benzodiazepine lorazepam as an active control. BNC210 significantly reduced Flight Intensity relative to placebo and the low dose of BNC210 also significantly reduced self-reported state anxiety. Risk Assessment Intensity was not significantly affected. Results show both human defensive behaviour and state anxiety are influenced by cholinergic neurotransmission and there provide converging evidence that this system has potential as a novel target for anxiolytic pharmacotherapy.

Effects of Vortioxetine and Escitalopram on Electroencephalographic Recordings - A Randomized, Crossover Trial in Healthy Males.

The antidepressant drug vortioxetine has a multimodal action modulating neurotransmission through inhibition of the serotonin transporter and modulation of serotonin receptors. Vortioxetine has also been shown to alleviate cognitive symptoms in preclinical studies and in patients with depression. However, it is largely unclear how vortioxetine affects the brain processing in humans. The present study was conducted in 32 healthy males in a randomized, double-blinded, placebo-controlled, active comparator, four-way crossover design. Treatments were 10 and 20 mg/day vortioxetine, 15 mg/day escitalopram, and placebo, administered orally once daily for three days. Results were compared to placebo. Treatment effect was assessed by recording spontaneous electroencephalography (EEG) and 40 Hz auditory steady state responses. For the spontaneous EEG, both vortioxetine and escitalopram decreased the frequency content in the theta band (4-8 Hz) and increased power in the beta (12-32 Hz) and gamma (32-45 Hz) bands. Vortioxetine and escitalopram decreased connectivity during rest in the theta band and increased connectivity in the gamma bands. Finally, both treatments caused decreased power in the evoked gamma band in response to 40 Hz auditory stimulation. Although the global EEG changes were comparable between vortioxetine and escitalopram, subtle differences between treatment effects on the EEG in terms of effect size and regional distribution of the EEG changes were apparent. To our knowledge, the current results are the first data on how vortioxetine affects EEG in humans. The present study calls for further investigations addressing the possible electrophysiological and cognitive effects of vortioxetine.

Cholinergic Modulation of Disorder-Relevant Neural Circuits in Generalized Anxiety Disorder.

BACKGROUND: Generalized anxiety disorder is associated with hyperactivity in the amygdala-prefrontal networks, and normalization of this aberrant function is thought to be critical for successful treatment. Preclinical evidence implicates cholinergic neurotransmission in the function of these systems and suggests that cholinergic modulation may have anxiolytic effects. However, the effects of cholinergic modulators on the function of anxiety-related networks in humans have not been investigated. METHODS: We administered a novel α7 nicotinic acetylcholine receptor-negative allosteric modulator, BNC210, to 24 individuals (3 male subjects) with generalized anxiety disorder and assessed its effects on neural responses to fearful face stimuli. RESULTS: BNC210 reduced amygdala reactivity to fearful faces relative to placebo and similarly to lorazepam and also reduced connectivity between the amygdala and the anterior cingulate cortex, a network involved in regulating anxious responses to aversive stimuli. CONCLUSIONS: These results demonstrate for the first time that the function of disorder-relevant neural circuits in generalized anxiety disorder can be beneficially altered through modulation of cholinergic neurotransmission and suggest potential for this system as a novel target for anxiolytic pharmacotherapy.

Tolerability, pharmacokinetics and night-time effects on postural sway and critical flicker fusion of gaboxadol and zolpidem in elderly subjects.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: Body sway increases in older adults and may lead to an increase in the risk of falling. The problem of impaired stability in the elderly may be compounded by the use of hypnotics, which have been associated with an increased risk of next-day falls as well as drowsiness. The potential adverse effects of hypnotic drugs on steadiness may be exacerbated during the night, in the event that an individual needs to get out of bed. WHAT THIS STUDY ADDS: This study examines the effects of gaboxadol (an investigational treatment for insomnia), zolpidem (a current hypnotic included as an active control) and placebo on body sway and attention/information processing ability following bedtime dosing in elderly subjects who were woken during the night for assessments. Zolpidem and gaboxadol increased body sway at various time points during the night relative to placebo; at 1.5 h post dose, the time of peak concentrations of both drugs, gaboxadol produced less impairment than zolpidem. Compared with placebo, neither gaboxadol nor zolpidem impaired attention/information-processing ability as assessed by critical flicker fusion. AIMS: To evaluate tolerability, pharmacokinetics and night-time effects on body sway and critical flicker fusion (CFF) of gaboxadol following bedtime dosing in healthy elderly subjects. METHODS: Subjects (17 women, seven men) aged 65-75 years received gaboxadol 10 mg, zolpidem 5 mg (active control) or placebo at 22.00 h in a three-period, randomized, double-blind crossover study. They were awakened during the night for evaluation of body sway and CFF. Pharmacokinetics of gaboxadol were assessed during a fourth single-blind treatment period. Adverse events were recorded throughout the study. RESULTS: The number of subjects with adverse events was 14 for gaboxadol 10 mg, seven for zolpidem and nine for placebo; most were mild or moderate in intensity. Two women discontinued the study following gaboxadol; one vomited and one experienced a severe vasovagal syncope after venepuncture. Mean gaboxadol t(max) was 2 h, t((1/2)) was 1.7 h, AUC(0-infinity) was 430 ng.h ml(-1) and C(max) was 139 ng ml(-1). At 1.5 h and 4 h post dose, zolpidem increased body sway relative to placebo (P < 0.01). Gaboxadol increased body sway at 4 h (P < 0.001) and 8 h (P < 0.05) relative to placebo. At 1.5 h, the time point closest to peak drug concentrations, zolpidem increased body sway compared with gaboxadol (P < 0.01). Gaboxadol and zolpidem had no effects on CFF vs. placebo. CONCLUSIONS: A bedtime dose of gaboxadol 10 mg was generally well tolerated. Changes in body sway at 1.5 h after bedtime dosing were smaller with gaboxadol 10 mg than with zolpidem 5 mg, whereas changes were similar at 4 h for both treatments and returned to near baseline at 8 h.

Rapid absorption of sumatriptan powder and effects on glyceryl trinitrate model of headache following intranasal delivery using a novel bi-directional device.

OBJECTIVES: The aim was to investigate the pharmacokinetics of intranasal sumatriptan (administered using a novel bi-directional powder delivery device) and study its effects on quantitative electroencephalography in patients with migraine. The safety profiles of the two formulations were also compared. METHODS: The pharmacokinetics of intranasal sumatriptan (10 mg and 20 mg) administered using a novel breath-actuated bi-directional powder delivery device were compared with subcutaneous sumatriptan (6 mg), along with an investigation of their effects on the electroencephalogram (EEG) following glyceryl trinitrate (GTN) challenge in 12 patients with migraine using a randomized, three-way cross-over design. KEY FINDINGS: Following intranasal delivery, median t(max) was 20 min with both doses compared with 10 min after the subcutaneous dose. Mean +/- SD values for C(max) were 96 +/- 25, 11 +/- 7 and 16 +/- 6 ng/ml for subcutaneous, intranasal 10 mg and intranasal 20 mg formulations, respectively. Values for area under the curve were also lower with the intranasal doses. Intranasal and subcutaneous sumatriptan induced similar EEG changes characterized by reduced theta-power and increased beta-power. The majority of study participants were free of pain according to the headache severity score with all treatments from 15 min through to 8 h post-dose. All treatments were well tolerated and there were no reports of bitter aftertaste after intranasal delivery. Sumatriptan was rapidly absorbed after intranasal administration using the new device. Using the GTN challenge, sumatriptan powder delivered intranasally at a dose of 20 mg by the new device had effects similar to those of subcutaneous sumatriptan on EEG and reported headache pain, despite much lower systemic exposure. CONCLUSIONS: Administration of sumatriptan intranasally at doses of 10 mg and 20 mg by the breath actuated bi-directional powder delivery device results in rapid absorption. Delivery to target sites beyond the nasal valve induced a similar EEG profile to subcutaneous sumatriptan 6 mg and prevented migraine attacks in patients following GTN challenge. Intranasal administration of sumatriptan powder with the breath actuated bi-directional powder delivery device was well tolerated.

Pre-intervention test-retest reliability of EEG and ERP over four recording intervals.

In this study we present the test-retest reliability of pre-intervention EEG/ERP (electroencephalogram/event-related potentials) data across four recording intervals separated by a washout period (18-22 days). POz-recording-reference EEG/ERP (28 sites, average reference) were recorded from thirty-two healthy male participants. Participants were randomly allocated into different intervention sequences, each with four intervention regimens: 10 mg vortioxetine, 20 mg vortioxetine, 15 mg escitalopram and Placebo. We report classical EEG spectra: δ (1-4 Hz), θ (4-8 Hz), α (8-12 Hz), ß (12-30 Hz), γ1 (30-45 Hz) and γ2 (45-80 Hz) of resting state and vigilance-controlled, and of auditory steady state response, as well as ERP components N100, P200 and P300 in auditory oddball task and error related negativity (ERN) and error positivity (Pe) in hybrid flanker task. Reliability was quantified using intra-class correlation coefficient (ICC). We found that θ, α and ß of continuous EEG were highly reliable (ICCs ≥ 0.84). Evoked power of other tasks demonstrated larger variability and less reliability compared to the absolute power of continuous EEG. Furthermore, reliabilities of ERP measures were lower compared to those of the EEG spectra. We saw fair to excellent reliability of the amplitude of the components such as Pe (0.60-0.82) and P300 (0.55-0.80). Moreover, blood tests confirmed that there was no measurable drug carry-over from the previous intervention. The results support that EEG/ERP is reliable across four recording intervals, thus it can be used to assess the effect of different doses and types of drugs with CNS effects.

[Results of laparoscopic nephroureterectomy for transitional cell carcinoma]. / Résultats carcinologiques de la néphrourétérectomie laparoscopique pour tumeur urothéliale de la voie excrétrice.

OBJECTIVE: To report our experience of laparoscopic nephroureterectomy and to compare our results to those published in the literature. PATIENTS AND METHOD: Between 1997 and 2005, 15 laparoscopic nephroureterectomies were performed by 2 surgeons, in 12 men and 3 women for upper urinary tract transitional cell carcinoma. The mean age of the patients was 66 years. Three to five trocars were used depending on intraoperative findings in order to meet oncological imperatives: primary control of the renal pedicle before any contact with the tumour dissection in the plane of the radical nephrectomy. The operative specimen was extracted in a sealed bag via an infraumbilical mini-laparotomy that allowed pelvic ureterectomy and resection of the bladder cuff. RESULTS: The mean operating time was 210 min. The procedure was converted to open lumbar laparotomy in 3 patients. The mean hospital stay was 13 days. The final histological stage showed 8 invasive tumours (pT2-pT3), 4 superficial tumours (pTa-pT1), 2 CIS and a benign tumour. Two patients died from local progression of the disease. The mean follow-up was 41 months (range: 12-96 months). CONCLUSION: Laparoscopic nephroureterectomy for upper urinary tract transitional cell carcinoma, still under evaluation, is indicated in selected cases. Apart from patient selection, which remains difficult preoperatively, the cancer control results depend on compliance with the principles of this surgery.

A new sublingual formulation of zolpidem for the treatment of sleep-onset insomnia.

Insomnia is a very frequent complaint that periodically or permanently affects up to 60% of the general population. Valuable therapeutic options rely on pharmacological and nonpharmacological management of insomnia complaints. Zolpidem is one of the most popular hypnotic drugs used to treat insomnia. The drug was synthesized by Synthélabo Recherche in the early 1980s and has proved to be a suitable and well-tolerated drug, especially with regard to efficacy in sleep initiation. The present review focuses on an alternate delivery form of zolpidem, Edluar™, a new sublingual formulation of zolpidem that has been developed for the treatment of sleep-onset insomnia. Studies have shown that Edluar has a faster sleep-induction effect, whereas it did not differ from the oral formulation in terms of sleep maintenance or side effects. This review also discusses the mechanism of action of zolpidem and its pharmacokinetic profile in comparison to Edluar. Efficacy studies in specific settings (such as non-nightly use or use in combination with cognitive behavioral therapy) and particular safety issues encountered with zolpidem use are also discussed.

Noise-induced sleep maintenance insomnia: hypnotic and residual effects of zaleplon.

AIMS: The primary objective of the study was to assess the residual effects of zaleplon in the morning, 4 h after a middle-of-the-night administration. The secondary objective was to investigate the effectiveness of zaleplon in promoting sleep in healthy volunteers with noise-induced sleep maintenance insomnia. METHODS: Thirteen healthy male and female volunteers (aged 20-30 years) with normal hearing, who were sensitive to the sleep-disrupting effects of noise, participated in a double-blind, placebo- and active-drug controlled, four-period cross-over study. The subjects were permitted to sleep for 5 h (22.45-03.45 h) in a quiet environment before they were awoken. At 04.00 h they ingested 10 mg zaleplon, 20 mg zaleplon, 7.5 mg zopiclone (active control), or placebo before a second period of sleep (04.00-08.00 h), during which they were exposed to an 80 dB(A) 1 kHz pure tone pulse with an inter-tone interval of 1 s and a duration of 50 ms. The sound stimulus was stopped after 10 min of persistent sleep or after 2 h if the subject had not fallen asleep. Residual effects were assessed at 08.00 h (4 h after drug administration) using the digit symbol substitution test (DSST), choice reaction time (CRT), critical flicker fusion (CFF), and immediate and delayed free recall of a 20 word list. The data were analysed by analysis of variance. A Bonferroni adjustment was made for the three active treatments compared with placebo. RESULTS: There were no residual effects of zaleplon (10 and 20 mg) compared with placebo. Zopiclone impaired memory by delaying the free recall of words (P = 0.001) and attenuated performance on DSST (P = 0.004) and CRT (P = 0.001), compared with placebo. Zaleplon reduced the latency to persistent sleep (10 mg, P = 0.001; 20 mg, P = 0.014) and the 20 mg dose reduced stage 1 sleep (P = 0.012) compared with placebo. Zopiclone reduced stage 1 sleep (P = 0.001), increased stage 3 sleep (P = 0.0001) and increased total sleep time (P = 0.003), compared with placebo. CONCLUSIONS: Zaleplon (10 mg and 20 mg), administered in the middle of the night 4 h before arising, shortens sleep onset without impairing next-day performance.

Residual effects of middle-of-the-night administration of zaleplon and zolpidem on driving ability, memory functions, and psychomotor performance.

Thirty healthy volunteers participated in this two-part study. Part 1 was a single-blind, two-period crossover design to determine the effects of a single dose of ethanol (0.03% < BAC < 0.05%) or ethanol-placebo on driving ability, memory, and psychomotor performance. Part 2 was a double-blind, five-period crossover design to measure the effects of a middle-of-the-night administration of zaleplon 10 or 20 mg, zolpidem 10 or 20 mg, or placebo on driving ability 4 hours after administration and memory and psychomotor performance 6 hours after administration. The on-the-road driving test consisted of operating an instrumented automobile over a 100-km highway circuit at a constant speed (95 km/h) while maintaining a steady lateral position between the right lane boundaries. The standard deviation of lateral position (SDLP) was the primary performance parameter of the driving test. The psychomotor and memory test battery consisted of the Word Learning Test, the Critical Tracking Test, the Divided Attention Test, and the Digit Symbol Substitution Test. Data for each part were analyzed separately using ANOVA for crossover designs. Zaleplon 10 and 20 mg did not significantly impair driving ability 4 hours after middle-of-the-night administration. Relative to placebo, after zolpidem 10 mg, SDLP was significantly elevated, but the magnitude of the difference was small and not likely to be of clinical importance. Memory and psychomotor test performance was unaffected after both doses of zaleplon and zolpidem 10 mg. In contrast, zolpidem 20 mg significantly increased SDLP and speed variability. Further, zolpidem 20 mg significantly impaired performance on all psychomotor and memory tests. Finally, driving performance, Digit Symbol Substitution Test, Divided Attention Test, and immediate and delayed free recall of the Word Learning Test were significantly impaired after ethanol. The results show that zaleplon (10 and 20 mg) is a safe hypnotic devoid of next-morning residual impairment when used in the middle of the night.