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Home , Gabazine, Lorediplon, Sleep induction

Index

A C Acetylcholine anticholinergic , 49 GHB, 37 cholinergic wake-promoting system, 48 type 1, 215 cholinesterase inhibitors, 48–49 narcolepsy type 2, 215 milameline, 49 -promoting orexinergic inhibitors, 46 nicotine, 49 SXB, 238–240 receptors, 48 tricyclic , 253 sleep-promoting cholinergic Cell replacement therapy, 253 inhibitors, 49 Central (CSA) syndrome, 76 Adenosine Cheyne–Stokes breathing (CSB), 76 adenosine-mediated sleep-promoting Cholinesterase inhibitors system, 41 donepezil, 49 receptors, 42 physostigmine, 48 sleep-promoting adenosine Chronic agonists, 42 dose discrimination, lack of, 168 wake-promoting adenosine receptor psychiatric comorbidities, 169 antagonists, 42 short-term efficacy and long-term safety, , 77 167–168 Armodafinil sleep induction and maintenance, 168–169 chemical structure, 212 Chronic multiple sclerosis, 222 (OSA), 178–179 narcolepsy, 218 Chronic primary insomnia obstructive sleep apnea, 219–221 adverse effects, 165, 167 pharmacokinetics, 214 comorbid psychiatric disorders, 164 R enantiomer, 213 double-blind trial, 164 safety, 224–225 efficacy, 165 shift work disorder, 223 long-term trial, 165 open-label extension phase, 165 post hoc analysis, 165–166 B psychomotor performance, 164–165 Withdrawal Symptom rebound insomnia, 164 Questionnaire (BWSQ), 183 WASO, 164–165

© Springer International Publishing Switzerland 2015 289 A. Guglietta (ed.), Treatment of Sleep Disorders, Milestones in Drug Therapy, DOI 10.1007/978-3-319-11514-6 290 Index

Chronic primary insomnia (cont.) re-profiling/extension, marketed drug, , 166 282–283 Chronobiotics, 78 subsets of patients, 283–284 sleep–wake disorder DST. See Digit span test (DST) (CRSWD), 73, 78 Dual antagonists (DORAs) Clinical Global Impression of Change (CGI) advantages, 199, 201–202 scores, 216–217, 241 , 198–199 , 81 SB-649868, 199–200 Comorbid insomnia , 199–201 cancer pain, 180–181 clinical trials, 170–173 GAD, 176–177 E MDD, 174–176 multiple sclerosis, 180 administration dosage, 181 OSA, 178–179 clinical efficacy and safety Parkinson’s disease, 179–180 chronic insomnia, 167–169 perimenopausal and postmenopausal chronic primary insomnia (see Chronic women, 170, 174 primary insomnia) PTSD, 177 clinical trials, 161–163 pulmonary disease, 178–179 improvements, 169–170 rheumatoid arthritis, 179 transient insomnia, 161, 164 comorbid insomnia cancer pain, 180–181 D clinical trials, 170–173 Digit span test (DST), 134 GAD, 176–177 Dopamine MDD, 174–176 dopaminergic wake-promoting multiple sclerosis, 180 system, 55–56 OSA, 178–179 PLMD, 81 Parkinson’s disease, 179–180 receptors, 56 perimenopausal and postmenopausal RLS, 80–81 women, 170, 174 sleep-promoting dopaminergic inhibitors PTSD, 177 monoamine depletors, 58 pulmonary disease, 178–179 postsynaptic D1 and D2 receptor rheumatoid arthritis, 179 antagonists, 58 drug interaction, 181 presynaptic D2 receptor agonists, 58 , 183–184 wake-promoting dopaminergic activators mechanism of action, 160 dopamine release promoters, 57 multicenter trials, 184–185 dopamine reuptake inhibitors, 56–57 pharmacokinetic parameters, 160–161 postsynaptic D1 and D2 dopamine pharmacology, 160 receptor agonists, 57 placebo-controlled trials, 184–185 presynaptic D2 dopamine receptor randomized trials, 184–185 antagonists, 57 tolerability profile DORAs. See Dual orexin receptor antagonists adverse event profile, 182 (DORAs) BWSQ, 183 Dorsomedial hypothalamus (DMH), 32 cognitive/psychomotor function, . See Low-dose doxepin 182–183 Drug indications confusion rates, 182 design, 284–285 GABAA receptors, 182 pathophysiology, biochemistry, and memory impairment, 182 pharmacology, 283 treatment duration, 183 Index 291

unpleasant and bitter taste, 182 wake-promoting glutamatergic Excessive daytime sleepiness (EDS). See activators, 47 Modafinil G protein-regulated inward rectifier (EHS), 73, 79–80 (GIRK), 193

G H GABA. See γ-aminobutyric acid (GABA) Histamine GABAA receptor modulators histaminergic wake-promoting system, 43 anaesthetic site, 36 receptors, 43 receptor, 36 sleep-promoting histaminergic inhibitors, benzodiazepine receptor, 36 44–45 site, 37 wake-promoting histaminergic , 37 activators, 44 Galanin Hypersomnolence galaninergic sleep-promoting system, idiopathic , 73, 77 39–40 insufficient sleep syndrome, 73, 78 sleep-promoting galanin receptor Kleine–Levin syndrome, 73, 77 agonists, 40 long sleeper, 73, 78 wake-promoting galanin receptor traumatic brain injury, 221–222 antagonists, 40 type 1 narcolepsy, 72, 77 γ-aminobutyric acid (GABA) type 2 narcolepsy, 73, 77 noradrenergic locus coeruleus, 29, 34, 51 drugs receptors, 34–35 , 124–125 sleep-promoting activators , 124–125 anaesthetic site, 36 infections/cancer, 183–184 , 37 non-benzodiazepines hypnotics, 125 barbiturate receptor, 36 Hypocretin. See Orexin benzodiazepine receptor, 36 Hypocretin-2/orexin-B (Hcrt-2), 250–251 ethanol site, 37 , 36 GHB, 37 I neurosteroids, 37 ICSD-3. See International Classification of tiagabine, 37 Sleep Disorders (ICSD-3) wake-promoting inhibitors Insomnia disorder benzodiazepine binding site, 38 alkaloids, 276 and gabazine, 38 biochemical characterization, 90 flumazenil, 38 chemical molecules, 276 GABAB and GABAC receptors, 38 classification, 72 GABA receptor autoantibodies, 38–39 clinical development phase Generalized anxiety disorder (GAD), 176–177 double-blind studies, 99, 100 Genome-wide association studies (GWAS), 12 efficacy and safety data, 88, 97 γ-hydroxybutyric acid (GHB), 37 parallel group studies, 99 GIRK. See G protein-regulated inward rectifier phase II studies, 98 (GIRK) phase I studies, 97–98 Glutamate phase 0 studies (exploratory IND glutamatergic wake-promoting system, studies), 97 46–47 placebo-controlled studies, 97, 100 receptors, 47 method, 99 REMS-suppressing glutamatergic proof-of-concept studies, 98 inhibitors, 48 psychometric method, 99 sleep-promoting glutamatergic randomized studies, 99, 100 inhibitors, 47 clinical features, 75 292 Index

Insomnia disorder (cont.) L diagnosis, 75 Lithium carbonate, 77 drug development failure, 86, 87 Lorediplon endogenous molecules replacement chemical structure, 125 approach, 89 GABAA receptor modulation eszopiclone (see Eszopiclone) biological effects, 123 herbal and natural products, 275–276 Cys loop receptors, 122 lorediplon (see Lorediplon) endogenous , 123 low-dose doxepin (see Low-dose doxepin) receptors, 122 molecule-based approach, 89 5-HT3A receptors, 122 nonclinical development phase hypnotic drugs, 124–125 analytical methods development, 91 nicotinic acetylcholine receptors, 122 efficacy and safety data, 88, 90 protein subunits, 122–124 formulation development, 95–96 sedation, 123, 124 manufacturing process, 90–91 pharmacokinetic profile, 133–136 nonclinical safety evaluation (see preclinical and clinical data, 141 Nonclinical safety evaluation) preclinical pharmacology pharmacokinetic and metabolism amnesic effects, 129–130 characterization, 95 GABAA subunits, 126–127 pharmacology development, 96–97 hypnotic and ethanol interactions, 130 orexin (see Orexin) Lorediplon EtOH Liability Index, 130 pharmacology and pharmacokinetic middle-of-the-night awakenings, characterization, 90 131–132 post-approval studies, 88 muscular tone inhibition, 127–129 formulation development, 101 Next-Day Hangover Liability indication, 101 Index, 130 miscellaneous studies, 103 physical dependence, 130, 131 regulatory agency, 101 polygraphic record, 131, 132 safety monitoring (pharmacovigilance), potency, 131 102–103 quality of sleep, 132 prevalence and impact of, 113–114 sedation, 127–128 target-based approach, 88–89 sleep fragmentation, 131 toxicology tests, 90 sleep–wake state, 131, 133 treatment, 75 safety, 139, 141 International Classification of Sleep Disorders vs. zolpidem (ICSD-3) advantages, 141, 142 circadian rhythm sleep–wake disorders, cortical and muscle electrodes, 130 73, 78 DST, 134 degree of standardization, 74–75 next-day residual drug effect, 139 hypersomnolence number of awakenings (W), 137, 139 , 73, 77 parameters, 131–133 insufficient sleep syndrome, 73, 78 PSQ, 139, 140 Kleine–Levin syndrome, 73, 77 PVT, 134 long sleeper, 73, 78 SEI, 137, 139 type 1 narcolepsy, 72, 77 , 135–137 type 2 narcolepsy, 73, 77 TST, 137, 139 insomnia disorders, 72, 75 VAS, 134 isolated symptoms and normal variants, WASO, 136, 138 74, 81 Lorediplon EtOH Liability Index, 130 Low-dose doxepin EHS, 73, 79–80 contraindications, 117 NREM-related parasomnias, 73, 79 dosing, 118 sleep-related hallucinations, 73, 79–80 efficacy, 115–116 sleep-related breathing disorders, 72, 76–77 mechanism of action, 115 SRMD, 74, 80–81 system Index 293

acetylcholine, 112 N adenosine, 112 Narcolepsy, 12 histamine, 113 amphetamines, 276–277 hypocretin, 113 cell replacement therapy, 253 norepinephrine, 112–113 experimental models serotonin, 112–113 day–night cycle, 252 pharmacokinetics, 115 embryonic day 19 E19, 252 tolerability, 117 end of sleep period (ZT12), 252 Hcrt-2/SAP, 250–251 peptide levels, 252 M prepro-Hcrt gene expression, 252 Maintenance of wakefulness test (MWT), method, 252 240–241 toxin, 250 Major depressive disorder (MDD), 174–176 wake-active period (ZT0), 252 Hcrt system, 250 idiopathic hypersomnia, 77 neural transplantation narcolepsy, 77 animal models, 253 Melanin beneficial effects, 253 MCHergic sleep-promoting system, 29, control rats, 255 31, 39 grafted dopaminergic neurons, 255 wake-promoting inhibitors, 39 hypocretin-immunoreactive somata, 254 chronobiotic melatoninergic activators, 41 inmunohistochemistry, 255 melatoninergic sleep-promoting system, 40 Parkinson’s disease, 253 sleep-promoting melatoninergic activators, (see Sodium oxybate 40–41 (SXB)) wake-promoting melatoninergic NARI. See Noradrenaline reuptake inhibitors inhibitors, 41 (NARI) Modafinil Neuronal network regulation chemical structure, 212 circadian network, 32–34 depression, 223 REM-sleep network idiopathic hypersomnia, 218–219 cortical activation, 30 mechanism of action, 214 dreaming, 29, 32 metabolism, 214 horizontal saccadic eye movements, 29 multiple sclerosis, 222 impairment, 30 myotonic dystrophy, 223 muscle atonia, 29, 30, 32 narcolepsy type 1 and type 2 penile erections, 29, 32 CGI-C, 216–217 PGO spikes, 29 double-blind crossover study, 217–218 promoting and inhibiting neurons, Epworth sleepiness scale, 216 30, 31 hypothalamic hypocretin, 215 sleep/arousal network, 28–29 maintenance of wakefulness test, 216 sleep-promoting systems (see Sleep- optimal dosing protocols, 217 promoting systems) placebo periods, 216 wake-promoting systems (see Wake- REM sleep, 215 promoting systems) U.S. modafinil trials, 217 Next-Day Hangover Liability Index, 130 nonmedical use, 225 Nonclinical safety evaluation obstructive sleep apnea, 219–221 addiction, 94 Parkinson’s disease, 221 drug–drug interactions, 95 pharmacokinetics, 214 next-day effects, 94–95 pharmacology, 213–214 physical dependence, 94 posttraumatic hypersomnia, 221–222 risk of falling, 94 safety, 224–225 tolerance, 93–94 shift work disorder, 222–223 Nonrapid eye movement (NREM) sleep latency, 212–213 homeostatic response, 10 294 Index

Nonrapid eye movement (NREM) (cont.) OX1R, 195–196 parasomnias, 73, 79 OX2R, 196–197 physiological regulation, 13 wake-promoting nuclei, 45 sleep architecture, 5–6 wake-promoting orexinergic sleep efficiency index, 139 activators, 46 total sleep time, 139 wake-promoting neurons, 7 Noradrenaline (NA) P α2-adrenoceptor agonists, 53–54 Paradoxical/active sleep. See Rapid eye α2-adrenoceptor antagonists, 53 movement (REM) arousal regulation, 50 Parasomnias autonomic regulation, 50 EHS, 73, 79–80 cellular targets, 52–53 NREM-related parasomnias, 73, 79 monoamine depletors, 54 sleep-related hallucinations, 73, 79–80 motor regulation, 51–52 Paraventricular nucleus (PVN), 196–197 μ receptor agonists, 54 Parkinson’s disease, 179–180 NARI, 53 Periodic limb movement disorder noradrenergic wake-promoting system, 50 (PLMD), 74, 80 photomodulation, 52 Pharmaceutical products Noradrenaline reuptake inhibitors (NARI), 53 benefit/risk ratio, 280 biochemical mechanisms, 280 biological products, 281 O combination products, 281 Obstructive sleep apnea (OSA) syndrome, 76 delivery system, 281–282 Orexin histamine H3 inverse agonists, 280 appetite/human metabolism, 204 innovative formulations, 281–282 benefit–risk ratio, 204 PLMD. See Periodic limb movement disorder benzodiazepines, 203–204 (PLMD) cataplexy, 203 Polysomnography method, 99 cerebral cortex, 45 Ponto-geniculo-occipital (PGO) spikes, 29 clinical study, 202 Post-Sleep Questionnaire (PSQ), 139, 140 DORAs Posttraumatic stress disorder (PTSD), 177 advantages, 199, 201–202 Psychometric method, 99 almorexant, 198–199 Psychomotor vigilance test (PVT), 134 SB-649868, 199–200 Pulmonary disease, 178–179 suvorexant, 199–201 GIRK, 193 hypnagogic hallucinations, 203 R mesolimbic pathways, 203 Randomized-withdrawal study of the efficacy morning/daytime sleepiness, 203 and safety of (RESET) narcoleptic symptoms, 202 study, 265–266 orexin-deficiency state, 45–46 Rapid eye movement (REM) orexinergic neurons, 45 sleep behavior disorder, 277 orthostasis, 202–203 sleep network overexpression, 194 cortical activation, 30 pharmacological treatment, 192 dreaming, 29, 32 potential side effects, 194 horizontal saccadic eye movements, 29 receptors, 193–194 impairment, 30 REM sleep behavior disorder, 203 muscle atonia, 29, 30, 32 sedating antidepressants, 204 penile erections, 29, 32 sleep and wakefulness, 192–193 PGO spikes, 29 , 203 promoting and inhibiting sleep-promoting orexinergic inhibitors, 46 neurons, 30, 31 SORA Restless legs syndrome (RLS), 12, 74, 80–81 Index 295

S monozygotic and dizygotic human Safety and Efficacy of Tasimelteon (SET) twins, 12 study, 265 negative feedback loops, 12 Saporin (SAP), 250–251 Per2 gene, 12 SCN. See Suprachiasmatic nucleus (SCN) restless leg syndrome, 12 Serotonin upregulates transcription, 12–13 receptors, 59 Sleep centers, 277–278 REMS-suppressing serotonergic Sleep Efficiency Index (SEI), 137, 139 activators, 60 Sleep-promoting systems serotonergic wake-promoting system, adenosine 58–59 adenosine-mediated sleep-promoting serotonin receptor agonists, 59 system, 41 serotonin reuptake inhibitors, 59–60 receptors, 42 sleep-promoting serotonergic inhibitors, 60 sleep-promoting adenosine receptor Single orexin receptor antagonists (SORAs) agonists, 42 OX1R, 195–196 wake-promoting adenosine receptor OX2R, 196–197 antagonists, 42 Sleep GABA (see γ-aminobutyric acid (GABA)) architecture, 5–6 galanin definition, 4–5 galaninergic sleep-promoting system, evolution 39–40 deprivation, 19–20 sleep-promoting galanin receptor long-existing theory, 21 agonists, 40 memory, 20 wake-promoting galanin receptor phylogenesis, 18 antagonists, 40 synaptic homeostasis theory, 21 melanin mechanisms MCHergic sleep-promoting system, 29, dorsal pathway, 7 31, 39 GABAergic nonorexinergic/non-MCH wake-promoting inhibitors, 39 neurons, 8 melatonin glutamatergic projection, 8 chronobiotic melatoninergic MCH/REM-on neurons, 8 activators, 41 orexinergic neurons, 8 melatoninergic sleep-promoting REM-on and REM-off neurons, 7 system, 40 rostral cholinergic system, 8 sleep-promoting melatoninergic ventral pathway, 7 activators, 40–41 physiological functions wake-promoting melatoninergic autonomic and cardiovascular inhibitors, 41 functions, 16–17 Sleep-related breathing disorders endocrine functions, 15–16 central sleep apnea, 76 hypothalamus, 13 cheyne–stokes breathing, 76 respiratory functions, 14–15 classification, 72 sensory and motor functions, 13–14 obstructive sleep apnea syndrome, 76 thermoregulation and metabolism, treatment, 76–77 17–18 Sleep-related movement disorders (SRMD), regulation 72, 76–77 chronobiology, 8–9 Sleep-related rhythmic disorder (RMD), 74, circadian and homeostatic sleep control, 80–81 10–11 Sodium oxybate (SXB) CLOCK and BMAL1, 11, 12 adverse events, 237–238 CRY and PER proteins, 11 deaths, 243–244 GWAS, 12 effects, 244 homeostasis, 9–10 efficacy Homer1 gene, 12 cataplexy, 238–240 microarray studies, 12–13 CGI scores, 241 296 Index

Sodium oxybate (SXB) (cont.) V characteristics, 238–239 Vanda performed clinical trials with EDS, 240–241 tasimelteon (VEC-162), 266 hypnagogic hallucinations, 241–242 Visual analogue scale (VAS), 134 sleep architecture, 241 sleep paralysis, 241–242 high sodium load, 242 W history, 234 Wakefulness after sleep onset (WASO), 136, human leukocyte antigen, 232 138, 164–165 hypocretin/orexin neurons, 232–233 Wake-promoting systems idiopathic hypersomnia, 77 acetylcholine indications, 235 anticholinergic drugs, 49 mechanism of action, 235–236 cholinergic wake-promoting system, 48 pharmacology, 233–234 cholinesterase inhibitors, 48–49 precautions, 236 milameline, 49 psychiatric complications, 244 nicotine, 49 respiratory depression, 242–243 receptors, 48 sleep-disordered breathing, 242–243 sleep-promoting cholinergic weight loss, 242 inhibitors, 49 SORAs. See Single orexin receptor antagonists dopamine (see Dopamine) (SORAs) glutamate SRMD. See Sleep-related movement disorders glutamatergic wake-promoting system, (SRMD) 46–47 Subparaventricular zone (SPZ), 32 receptors, 47 Suprachiasmatic nucleus (SCN) REMS-suppressing glutamatergic DMH, 32 inhibitors, 48 GABAergic output neurons, 33 sleep-promoting glutamatergic melatonin/light stimulation, 33–34 inhibitors, 47 SPZ, 32 wake-promoting glutamatergic activators, 47 histamine T histaminergic wake-promoting Tasimelteon system, 43 advantages, 267 receptors, 43 chemical designation, 263–264 sleep-promoting histaminergic guidelines, 267 inhibitors, 44–45 non-24 h sleep–wake disorder, 263 wake-promoting histaminergic pharmacodynamics, 264 activators, 44 pharmacokinetics, 264–265 noradrenaline regulatory issues, 266 α2-adrenoceptor agonists, 53–54 RESET study, 265–266 α2-adrenoceptor antagonists, 53 safety, 266 arousal regulation, 50 SET study, 265 autonomic regulation, 50 VEC-162, 266 cellular targets, 52–53 Tegmentopontine reticular nucleus monoamine depletors, 54 (TPR), 30 motor regulation, 51–52 Time to maximum concentration (Tmax), μ opioid receptor agonists, 54 149–150 NARI, 53 Total Sleep Time (TST), 137, 139 noradrenergic wake-promoting Transient insomnia, 161, 164 system, 50 Tuberomamillary nucleus (TMN), 196–197 photomodulation, 52 Type 1 orexin receptors (OX1R), 195–196 orexin Type 2 orexin receptors (OX2R), 196–197 cerebral cortex, 45 orexin-deficiency state, 45–46 Index 297

orexinergic neurons, 45 vs. lorediplon sleep-promoting orexinergic advantages, 141, 142 inhibitors, 46 cortical and muscle electrodes, 130 wake-promoting nuclei, 45 DST, 134 wake-promoting orexinergic next-day residual drug effect, 139 activators, 46 number of awakenings (W), 137, 139 serotonin parameters, 131–133 receptors, 59 PSQ, 139, 140 REMS-suppressing serotonergic PVT, 134 activators, 60 SEI, 137, 139 serotonergic wake-promoting system, sleep onset, 135–137 58–59 TST, 137, 139 serotonin receptor agonists, 59 VAS, 134 serotonin reuptake inhibitors, 59–60 WASO, 136, 138 sleep-promoting serotonergic orexinergic system, 278–279 inhibitors, 60 sublingual formulations Willis–Ekbom disease, 74, 80 CYP3A4 inhibitors, 150 efficacy/balance profile, 149 low dose, 154 X mechanism of action, 149 Xyrem®. See Sodium oxybate (SXB) oral bioavailability, 150 pharmacokinetic parameter, 150–151 safety, 154–155 Z standard dose, 151–153 Zolpidem Tmax, 149–150 chronic primary insomnia, 166