Index A C Acetylcholine Cataplexy anticholinergic drugs, 49 GHB, 37 cholinergic wake-promoting system, 48 narcolepsy type 1, 215 cholinesterase inhibitors, 48–49 narcolepsy type 2, 215 milameline, 49 sleep-promoting orexinergic inhibitors, 46 nicotine, 49 SXB, 238–240 receptors, 48 tricyclic antidepressants, 253 sleep-promoting cholinergic Cell replacement therapy, 253 inhibitors, 49 Central sleep apnea (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 receptor Chronic insomnia agonists, 42 dose discrimination, lack of, 168 wake-promoting adenosine receptor psychiatric comorbidities, 169 antagonists, 42 short-term efficacy and long-term safety, Amantadine, 77 167–168 Armodafinil sleep induction and maintenance, 168–169 chemical structure, 212 Chronic obstructive sleep apnea 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 Benzodiazepine Withdrawal Symptom rebound insomnia, 164 Questionnaire (BWSQ), 183 WASO, 164–165 © Springer International Publishing Switzerland 2015 289 A. Guglietta (ed.), Drug 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, zolpidem, 166 282–283 Chronobiotics, 78 subsets of patients, 283–284 Circadian rhythm sleep–wake disorder DST. See Digit span test (DST) (CRSWD), 73, 78 Dual orexin receptor antagonists (DORAs) Clinical Global Impression of Change (CGI) advantages, 199, 201–202 scores, 216–217, 241 almorexant, 198–199 Clonazepam, 81 SB-649868, 199–200 Comorbid insomnia suvorexant, 199–201 cancer pain, 180–181 clinical trials, 170–173 GAD, 176–177 E MDD, 174–176 Eszopiclone 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 hypnotics, 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, Doxepin. 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 Exploding head syndrome (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 barbiturate receptor, 36 sleep-promoting histaminergic inhibitors, benzodiazepine receptor, 36 44–45 ethanol site, 37 wake-promoting histaminergic neurosteroids, 37 activators, 44 Galanin Hypersomnolence galaninergic sleep-promoting system, idiopathic hypersomnia, 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 Hypnotic drugs receptors, 34–35 barbiturates, 124–125 sleep-promoting activators benzodiazepines, 124–125 anaesthetic site, 36 infections/cancer, 183–184 baclofen, 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 gaboxadol, 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 bicuculline 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 polysomnography 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 ligand, 123 low-dose doxepin (see Low-dose doxepin) glycine 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 idiopathic hypersomnia, 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 sleep onset, 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 parasomnias 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 neurotransmitters 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), sleep deprivation method, 252 240–241 toxin, 250 Major depressive disorder (MDD), 174–176 wake-active period (ZT0),