Info

Sanofi-Aventis

Phase IIb

5HT2A antagonist

It is a melatonin analog in which the indole nucleus has been replaced by an indane ring.80 TAK-375 has 15-fold greater affinity for the MT1 receptor than melatonin23 and in clinical studies was efficacious in reducing latency to persistent sleep and sleep onset as well as sleep maintenance.81 TAK-375 is the first nonscheduled drug in this area.

PD-6735 (Table 3) is an MT1 agonist and an analog of melatonin being developed for the treatment of sleep disorders, especially insomnia. It was granted orphan status in 2004 for the treatment of circadian sleep disorders in the blind and was efficacious in phase II trials.82

6.06.6.4.5.3 Miscellaneous NCEs acting at melatonin receptors

Agomelatine (S-20098), an NCE with MT1 agonist and 5HT2C antagonist activities, is reportedly in clinical evaluation for depression.23 BMS-214778 is a melatonin agonist of unknown structure.

6.06.6.4.6 GABAa receptor agonists/modulators

Gaboxadol is a direct-acting GABA receptor agonist and GABA mimetic, being developed for insomnia.82 It is a conformationally restricted analog of the GABA mimetic muscimol, where the hydroxyisoxazole moiety mimics the carboxyl group of GABA. Gaboxadol is relatively nonselective for GABA receptor subtypes and is less potent than muscimol in binding studies. Preclinical studies indicate that tolerance to gaboxadol does not develop quickly and that sleep patterns do not change dramatically following drug withdrawal. In the clinic, gaboxadol did not produce a hangover effect, a side effect characteristic of other hypnotic drugs.

6.06.6.4.6.2 Additional GABA agonists/modulators

NG-2-73 (structure undisclosed) is a GABAa receptor partial agonist reported to be in phase II development.83

6.06.6.4.7 Selective GABA reuptake inhibitors

6.06.6.4.7.1 Tiagabine

Tiagabine (Table 3) was originally developed as a novel anticonvulsant drug. It is a blocker of GABA reuptake selectively interacting with GAT-1, reducing GABA uptake, and potentiating the inhibitory effects of GABA. Tiagabine is a nipecotic acid analog. Tiagabine promoted slow wave sleep and delta EEG activity in normal elderly subjects84 supporting a role as a hypnotic agent.

6.06.6.4.8 Miscellaneous agents working through GABA

Like tiagabine, gabapentin, 38, was developed as an anticonvulsant although the mechanism of action is not completely defined despite its structural similarity to GABA. It is widely used for the treatment of neuropathic pain, bipolar disorder, and insomnia. Gabapentin does block GABA uptake but may interact with ligand gated ion channel subunits.23

6.06.6.4.9 5HT2A/2C receptor antagonists

6.06.6.4.9.1 Eplivanserin

The 5HT2A/2C receptor has been targeted as a new therapeutic approach for the treatment of insomnia.12 Eplivanserin, a potent 5HT2A receptor antagonist with 20-fold selectivity over the 5HT2C receptor, was originally developed as an antipsychotic but is currently in phase II trials for chronic insomnia and sleep apnea syndrome. Its sleep-inducing effects may be the result of its anxiogenic effects. This NCE may have reduced abuse potential.

S-( + )-Mirtazapine is the optically active isomer of the antidepressant mirtazapine. Mirtazapine is an antagonist at 5HT2C receptors as well as 5HT1, 5HT2, H1, a1, and a2 receptors. It is reported to be in phase II for insomnia.23'74

EMD-28104 (Table 3) is an indole derivative that is a potent and selective 5HT2A receptor antagonist.85 It advanced to phase I trials as an antipsychotic but is now being investigated for use in the treatment of sleep disorders.74,83

6.06.6.4.9.4 Miscellaneous 5HT receptor antagonists for insomnia

ORG-50081 is a 5HT2A receptor in phase II trials for insomnia. APD-125 is a 5HT2A inverse agonist in phase I trials for sleep disorders. M-100907 was an antipsychotic NCE that reached phase III trials but is now in phase II for sleep indications (Table 3).83

6.06.6.4.10 Miscellaneous drugs for insomnia

S0-101 is a low dose formulation of doxepine, 30, that has recently advanced to phase III trials.74 The mechanism of action of doxepine like other TCAs is complex with interactions at NE, 5HT, H1, and H2 receptors and sodium channels23; thus the use of a low dose formulation should improve the side effect profile. Unlike other insomnia drugs, doxepine is not a scheduled substance and if shown to have efficacy as a hypnotic agent will represent the first compound its class. Other H1 receptor-based hypnotics are in development.

TH-9507 is a growth hormone-releasing hormone (GHRH) agonist.83 GHRH is located in hypothalamic and ventromedial neurons and promotes sleep in mice, rats, rabbits, and humans and is thought to be one of the key components of the sleep-promoting system.86

6.06.6.5 Circadian Rhythm Sleep Disorder

6.06.6.5.1 Shift work sleep disorder

The primary approach to treating shift work sleep disorder is the adoption of a schedule to allow for 1 week of consecutive sleep at a consistent time, either daytime or night-time, in concert with adjunctive light treatment; however, this is often difficult to accommodate in practice due to the shift work schedule. Stimulation by bright light results in inhibition of melatonin secretion via the retinohypothalamic pathways. Melatonin, which is released in a circadian manner with peak levels at night, has been used to resynchronize circadian rhythms. Hypnotics like Zolpidem and zopiclone (Table 3) have been used to treat sleep disorders related to shift work as has modafinil.87

6.06.6.5.2 Jet lag syndrome

Managing jet lag syndrome is generally accomplished via nonpharmacological measures, with the approach depending on how many time zones have been traveled. The duration of symptoms can be reduced by light exposure but the effectiveness of this approach is highly dependent on body temperature cycling. The maximum effect of bright light on phase-shifting generally occurs several hours prior to or following the endogenous temperature minimum, which occurs approximately during the midpoint of the usual sleep cycle. Light intensity is also an important factor as ambient indoor lighting is generally not of sufficient intensity to promote proper phase shifting. Short-acting hypnotics are used for the insomnia resulting from jet lag syndrome but tend to exacerbate insomnia on subsequent nights.88 Melatonin reduces the symptoms of jet lag syndrome but has phase cyclic effects opposite to those produced by bright light exposure.89

6.06.6.5.3 Delayed sleep phase syndrome

Several treatment options exist to manage delayed sleep phase syndrome. Generally, treatment is predicated upon simple phase-shifting of the sleep cycle. This can be accomplished by chronotherapy-resetting of the clock through progressively delayed sleeping times, timed exposure to bright light, and pharmacological intervention with BZ hypnotics or melatonin.29

6.06.6.5.4 Advanced sleep phase syndrome

Treatment for advanced sleep phase syndrome is similar to that for delayed sleep phase syndrome and includes chronotherapy, light exposure, and pharmacotherapy. The most effective treatment has been shown to be 2 h of bright light therapy in the evenings and a shift in the sleep schedule by short (15-30 min) daily intervals. Melatonin therapy has limited utility.29

6.06.6.5.5 Non 24-hour sleep-wake syndrome

This syndrome is particularly challenging from the perspective of treatment, and rigorous scheduling of the individual's activities is critical. In patients with ocular disorder but where retinal signaling pathways are intact, treatment with high-intensity light can be used to reset the circadian rhythm.

6.06.6.5.6 Irregular sleep-wake pattern

Irregular sleep-wake pattern is treated through management of patient activities and increased exposure to light. Hypnotics, stimulants, and neuroleptics are of little value and are contraindicated.

6.06.6.6 Breathing-Related Sleep Disorders

6.06.6.6.1 Obstructive sleep apnea-hypopnea syndrome

In moderate to severe cases obstructive sleep apnea-hypopnea syndrome (OSAHS) is treated with continuous positive airway pressure (CPAP) therapy, a highly effective technique in the control of apnea. Automatic CPAP devices that continually adjust airway pressure have been developed. Patient compliance can be a limiting factor in treatment outcomes, and initial or early patient rejection rates as high as 50% occur.90 Treatment approaches include agents that reduce REM sleep which improve symptomatology, such as antidepressants, e.g., fluoxetine91 and mirtazapine92 and adenosine A1 agonists, e.g., GR79236.93

6.06.6.6.2 Central sleep apnea

Therapeutic treatment of central sleep apnea (CSA) is based on the presumed causative factor, i.e., if cardiac insufficiency or congestive heart failure is suspected treatment of the underlying pathology would be the primary course. Nasal CPAP, oxygen, and carbon dioxide therapy may be useful based on the underlying etiology. The carbonic anhydrase inhibitor acetazolamide, 39, is useful for treating CSA in some patients by facilitating bicarbonate diuresis, reducing respiratory acidosis and hypocapnea which may precipitate episodes of apnea. Acetazolamide is used prophylactically by high-altitude (> 5000 m) climbers prior to ascending, to prevent apnea brought on by acute mountain sickness and associated sleep disruption and high-altitude respiratory sequelae such as pulmonary edema.94

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