Functional inhibition of orexin-a -induced intracellular calcium release in vitro. The
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1 Supplementary Methods Functional inhibition of orexin-a -induced intracellular calcium release in vitro. The cdnas for human and rat OX 1 and OX 2 were cloned, sequenced and stably over-expressed in a Chinese hamster ovary (CHO) cell background. Assays were performed on CHO cells in 96-well plates that were incubated overnight at 37 C in 5% CO 2 to reach confluency. On the day of the assay, cells were washed and test substance (in 0.5% DMSO final dilution buffer) was pipetted onto the plate. After a 20-min incubation, orexin-a was added to a final concentration of 10 nm. The intracellular calcium release induced by orexin-a was measured as real time fluorescence (488 nm input, around 560 nm output) using a Fluorometric Imaging Plate Reader (Molecular Devices). The peak height from each ACT treated sample was compared to the peak heights of the negative and positive controls, and IC 50 values were determined. The compound per se had no effect on basal intracellular Ca 2+ concentration in cells expressing orexin receptors or in wild-type CHO cells. Selectivity screen. ACT was tested at a concentration of 10 μm in 89 radioligand binding or enzymatic reaction assays (MDS Pharma Services). For those assays in which more than 50% inhibition or stimulation was observed, the IC 50 was determined. For details, see Supplementary Table 1 online. Drug substance and formulation. ACT was designed and synthesized at Actelion Pharmaceuticals Ltd, formulated in buffer containing 0.5% DMSO for in vitro experiments and in polyethylene glycol (PEG) 400 or 0.25% methylcellulose in water for in vivo oral gavage in rats. Large scale GMP-material was formulated in gelatin capsules for use in dogs and humans. Zolpidem was purchased commercially as powder (Apin Chemicals) or tablets (Stilnox ). For use in rats, it was formulated in PEG400 for oral gavage. Animal and human subjects. Healthy male Wistar rats (n = 66), weighing 250 to 320 g, had free access to normal rat chow and water and were maintained under standard housing conditions at Actelion Pharmaceuticals Ltd in Allschwil (temperature 20 ± 2 C, relative humidity 55 70%, on a 12 h light / 12 h dark cycle (5 am / 5 pm). They were acclimatized for 1
2 a week before surgery and the start of experiments. Several groups of eight rats, instrumented with radiotelemetric implants, were used in a semi-randomized partial-block crossover design, with at least 4-d washout periods separating two consecutive administrations. Compounds were administered in the evening at 5:00 pm or, for experiments during the quiet period, at 6:00 am (Supplementary Fig. 2 online). Experimental procedures were approved by the Basel-Landschaft cantonal veterinary office and followed international guidelines and Swiss federal regulations on animal experimentation. Healthy male Beagle dogs (n = 16) weighing between 10.9 and 14.5 kg were maintained in social groups under customary canine housing conditions at Actelion Pharmaceuticals facilities in the Shanghai Institute of Materia Medica of the Chinese Academy of Science. All dogs were allowed a 2-week total drug washout before behavioral observations were performed. Capsules were administered in the morning at 10:00 am. Groups of eight dogs per dose were used in a crossover design with at least 4-d washout periods. In a smaller group of dogs, the capsules were administered at 6:00 pm (Supplementary Fig.2 online). Experimental procedures were approved by the Actelion Animal Welfare Officer and followed international guidelines and Swiss federal regulations on animal experimentation. Healthy male human subjects (n = 70, age and body weight range years and kg, respectively), with no prior history of neurological, psychiatric, sleep disorders or drug or alcohol abuse, were randomized to receive a single dose of the compound (n = 6 per dose group), 10 mg zolpidem (n = 14 in total) or placebo (n = 14 in total) in a double blind, randomized, placebo-controlled, active-controlled, ascending single-dose design. Capsules were administered at approximately 10:00 am, after a normal night s sleep. Tablets of 10 mg zolpidem (Stilnox ) were formulated in capsules matching those containing the orexin receptor antagonist and placebo. Pharmacodynamic measures of sleep-wake states were incorporated into this entry-into-human trial. Experiments in humans followed the principles 2
3 of the Declaration of Helsinki and were approved by the Institutional Review Board of the Leiden University Medical Centre. Written informed consent was obtained from all subjects before start of study-related procedures. EEG, EMG and behavioral indices of alertness recorded by radiotelemetry in vivo in Wistar rats. EEG and EMG signals were measured by telemetry using TL11M2-F20-EET miniature radiotelemetric implants (Data Science Int.) with two pairs of differential leads. Surgical implantation was performed under general anesthesia with Ketamin/Xylazin, for cranial placement of one differential pair of EEG electrodes and one pair of EMG leads inserted in either side of the muscles of the neck. After surgery, rats recovered in a thermoregulated chamber and received analgesic treatment with subcutaneous buprenorphine twice a day for 2 d. They were then housed individually and allowed to recover for a minimum of 2 weeks. Thereafter, rats in their home cage were placed in a ventilated sound-attenuating box, on a 12-h light / 12-h dark cycle, for acclimatization before continuous EEG / EMG recordings started. The telemetric technology that we used in this study allows accurate and stress-free acquisition of biosignals in rats placed in their familiar home cage environment, with no recording leads restricting their movements. Variables analyzed included four different stages of vigilance and sleep, spontaneous activity in the home cage and body temperature. Sleep and wake stages were evaluated using a rodent scoring software (Somnologica Science) directly processing electrical biosignals on 10 s contiguous epochs. The scoring is based on frequency estimation for EEG and amplitude discrimination for EMG and locomotor activity. Using these measurements, the software determines the probability that all components within each epoch best represent active waking (AW), quiet waking (QW), non-rem-sleep (NREM) or REM-sleep (REM). The percentage of total time spent in AW, QW, NREM- and REM-sleep was calculated per 12 h light or dark period. The latency to the onset of the first significant NREM- and REM-sleep episodes and the frequency and duration of those episodes were also calculated. AW, QW, NREM- and REM-sleep, home cage activity and body temperature were measured at 3
4 baseline for at least one total circadian cycle (12 h-night, 12 h-day) before a test compound was administered. If baseline measurements indicated that animals were stable, test compound or vehicle was given in the evening by oral gavage at the end of the baseline 12- h day period, immediately before the nocturnal rise in orexin and activity in rats. All variables were subsequently recorded for 12 h following administration of the orexin receptor antagonist or zolpidem. Videorecording of wakefulness and sleep in Beagle dogs. Videorecording-based quantification of mobility and sleep postures was performed in dogs tested in the morning at the beginning of the active phase of their circadian cycle. Each dog was observed under undisturbed conditions by two videocameras (on top and side of cage) connected to a central recording unit located in an adjacent room. The recording system used videoscreens for on-line observations of dogs during the experiment and large disk storage capacity for subsequent off-line image digitalization and automated analysis of movements and micromovements (using VideoTrack TM, ViewPoint). Detailed behavioral analysis was performed on the videorecordings using LabWatcher TM (ViewPoint) for quantification of each dog s phases of behavioral activity, quiet wake states, sleep postures and evidence of distal muscle movements (usually on nose, lips, whiskers and limbs). Vital signs were measured in parallel via chronic subcutaneous telemetric probes previously implanted for recording hemodynamic variables and body temperature. Dogs were placed in the observation room immediately following morning administration of the test compound or vehicle and videorecording was started immediately for an undisturbed period of 6 h. Dogs underwent a neurological examination at the end of the experiment. In addition, they were carefully watched for any signs of emotion-induced loss of muscle tone (Supplementary Note online). Psychometric and EEG indices of alertness in humans. The main objective was to evaluate the tolerability and safety of ascending single doses of the orexin receptor antagonist in healthy male subjects. A new dose level was administered on the basis of the 4
5 tolerability and safety findings in the previous dose group. Adverse event monitoring, clinical laboratory testing, vital signs and ECG recording and physical examination evaluated tolerability. At regular time points for up to 12 h after drug administration, the subjects performed a validated psychomotor performance test battery 1 and filled out visual analog scales (VAS) assessing alertness 2. The VAS following each dose level investigated was expressed as absolute values in mm on a scale from mm. Baseline was defined as the mean of two assessments immediately before drug administration. The area-under-the curve (AUC) was calculated by the linear trapezoidal rule for the period 0 12 h after drug intake based on baseline-corrected data. Additional questionnaires rated the effects of ACT , zolpidem and placebo on sleep characteristics as well as possible narcoleptic effects. EEG recordings (according to the international 10/20 system) were performed 90 min and 6.5 h after study drug administration. EEGs were recorded for a period of 25 min. The subjects were sitting quietly in a reclining chair in a darkened room with their eyes closed. EEG signals were obtained from leads Fz-Cz and Pz-Oz. Fast Fourier transform analysis was performed to obtain the sum of amplitudes in the delta- ( Hz), theta ( Hz), alpha- ( Hz) and beta- ( Hz) frequency ranges. The square root of the total power (in μv) was analyzed. The 25-min EEGs were evaluated for the dose levels of mg by classifying each 30-s epoch automatically according to Rechtschaffen & Kales criteria 3 by means of a computer-assisted sleep analysis system, Somnolyzer 24x7 4. The system is based on the detection of sleep/wake-related features with subsequent classification according to a validated algorithm, followed by structured quality control procedures performed by an expert scorer. The main variable of interest was the latency to sleep stage 2, defined as the time from start of recording to the first occurrence of this stage (three consecutive epochs of 30 s). In addition, the following variables were derived: sleep efficiency, total sleep time, amount of time in sleep stage 1, amount of time in sleep stage 2 and deeper, latency to sleep stage 1, and sleep latency (time from start of recording to first occurrence of three consecutive 5
6 epochs of stage 1 or one epoch of stage 2). The test employed can be regarded as a variant of a multiple sleep latency test 5,6. Statistical analyses. A distribution-free, non-parametric Kruskal-Wallis test was used to analyze the effect of the antagonist versus vehicle/placebo, as the sample size in each dose group was limited (n < 20/group). The null hypothesis was that no difference exists between drug and vehicle/placebo and was tested at a 5% significance level. A Mann-Whitney test for two independent groups was used to assess differences between individual dose levels and vehicle/placebo (Statistica Software Inc.), at different times following administration, when applicable. An unpaired t-test was used to analyze the effect of the antagonist and zolpidem versus placebo with respect to AUC assessed in the VAS alertness test. References 1. van Steveninck, F. Methods of assessment of central nervous system effects of drugs in man (PhD Thesis). Leiden University; Bond, A. & Lader, M. The use of analogue scales in rating subjective feelings. Brit. J. Med. Psychol. 47, (1974). 3. Rechtschaffen, A. & Kales, A. A manual of standardized terminology, techniques and scoring systems for sleep stages of human subjects. US Department of Health, Education, and Welfare, Public Health Service, Anderer, P. et al. An E-health solution for automatic sleep classification according to Rechtschaffen and Kales: validation study of the Somnolyzer 24 x 7 utilizing the Siesta database. Neuropsychobiology 51, (2005). 5. Roehrs, T. & Roth, T. Multiple Sleep Latency Test: technical aspects and normal values. J. Clin. Neurophysiol. 9, (1992). 6. Thorpy, M.J. The clinical use of the Multiple Sleep Latency Test. The Standards of Practice Committee of the American Sleep Disorders Association. Sleep 15, (1992). 6
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