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6.06.6.2 Amphetamine-Like Stimulants
Amphetamines including mixed salts have long been first line therapy of hypersomnolence and narcolepsy.64 Amphetamine is a central stimulant that promotes the release of DA, NE, and 5HT. Their primary effects are mediated through reverse efflux of DA via inhibition of the DAT. At higher doses, inhibition of vesicular monoamine transporter (VMAT) which is involved in amine storage enhances stimulant pharmacology, increasing amine quantities available for efflux. Dexamphetamine, the D-isomer, is more active than the racemate. Methamphetamine, the N-methyl analog of amphetamine, is also a potent CNS stimulant showing higher brain permeability due to increased lipophilicity. Various slow-release formulations of these drugs are available with extended efficacy. Amphetamine-like compounds are potent CNS stimulants with high abuse potential and are scheduled substances. Typical side effects for the amphetamines include headache, nausea, anxiety, and appetite suppression in addition to cardiovascular and pulmonary side effects. Stimulant efficacy is dependent on the route of administration, an effect related to pharmacokinetics.65 The effects of amphetamine are dependent on an intact DAT since amphetamine is without wake promoting activity in DAT knockout mice.66 A characteristic of CNS stimulants like amphetamine is that their positive effects on wake promotion are accompanied by rebound hypersomnolence following withdrawal, a more profound sleepiness than that which led to the use of stimulants.
Methylphenidate, 8, and its D-isomer dexmethylphenidate, are stimulants structurally different from amphetamine, that are used for the treatment of ADHD. Mechanistically, the methylphenidates block monoamine uptake (DA>NE»5HT) but have less effect on reverse amine efflux or VMAT function than amphetamine64 and the primary pharmacological stimulant effect is dopaminergic.65 Methylphenidate was introduced for the treatment of narcolepsy in 1959 and is the most widely prescribed psychostimulant.64 The more potent D-isomer has a half-life of 6h contributing to its greater usage compared to amphetamine. Various slow-release formulations of these drugs are also available. Side effects for methylphenidate include increased blood pressure, palpitations, appetite suppression (less than observed with amphetamine), tremor, and insomnia.
Pemoline, 9, is similar in its pharmacology to amphetamine but is a milder stimulant with less potent sympathomimetic properties, a slower onset of action, and a long half-life (12-16 h). Its primary mechanism of action is DAT inhibition. Pemoline was approved for the treatment of attention deficit/hyperactivity disorder (ADHD) but it and related generic products have been withdrawn (2005) from the market due to the risk of fatal hepatotoxicity. The MAO-B inhibitor selegiline (L-deprenyl, 10), which prolongs extracellular monoamine effects, has been largely replaced by other firstline agents for the treatment of hypersomnolence. It is metabolized to L-amphetamine and L-methamphetamine which likely accounts for its efficacy.64
Fencamfamine, 20, a phenethylamine derived stimulant, is not currently available for use in the USA. Bupropion, 21, originally developed as an antidepressant, is a selective DA uptake blocker with weak activity for inhibiting NE uptake ( > 60-fold less potent than imiprimine) and 5HT that may have utility in treating EDS.64 Insomnia has been observed in some patients in depression trials. Mazindol, 22, also blocks uptake of NE and is a weak DA releaser. Despite high affinity for DAT, it has low abuse potential. Mazindol has shown efficacy in treating cataplexy and EDS in humans but is rarely used in the USA and appears to have been recently discontinued.
6.06.6.3 Atypical Stimulants
Modafinil, 11, a novel, racemic sulfoxide derivative, is the only drug approved for the treatment of EDS associated with narcolepsy, and is first-line therapy for this indication. It is also approved for the treatment of EDS associated with obstructive sleep apnea/hypopnea syndrome and shift work sleep disorder. It is without effect against cataplexy. The mechanism of action of modafinil is controversial,64 its weak inhibition (IC50 ~3.7 ^M) of DAT67 being the only reported pharmacological effect of the compound. Despite the low affinity for DAT, there is considerable focus on an enhancement of dopaminergic transmission in its mechanism of action as modafinil lacks wake-promoting activity in DAT knockout mice.6,66 The wake-promoting activity of modafinil has also been attributed to: (1) stimulation of central ^-adrenoceptors; (2) inhibition of the transporter for NE (NET); (3) a selective activation of the hypothalamocortical pathways involved in sleep-wake regulation; (4) effects on GABAergic systems; and (5) effects on histamine release.64'68-70 Despite the DAT inhibiting effects of modafinil, the compound differs from the central stimulants amphetamine and methylphenidate in that it does not produce rebound hypersomno-lence.71 Armodafinil, the longer-acting R-enantiomer of modafinil, like the racemate does not produce rebound hypersomnolence.72
Sodium oxybate (g-hydroxybutyric acid, GHB, 12) is approved for the treatment of cataplexy associated with narcolepsy.73 GHB is a weak agonist of the GABAb receptor and also effects DA transmission.10 At therapeutically effective doses for cataplexy narcolepsy, GHB is well tolerated; however, like amphetamine and other central stimulants, it is abusable. The CNS effects of GHB are sedating at lower doses and it has also been investigated as an anesthetic agent. No structural analogs of this drug have been disclosed.
Ampakines like CX-516, 23, and CX-717 are modulators of the AMPA receptor. CX-516 is in phase I trials for Alzheimer's disease and mild cognitive impairment (MCI) and in a recent clinical study showed positive effects in wake promotion. A clinical study in shift work with the CX-717 is planned.74
Modulation of the histamine (H3) receptor represents another approach to treating sleep-wake disorders and H3 receptor antagonists have been shown to enhance wakefulness in rats and cats.18 The first H3 antagonist advanced to the clinic was GT-2331, 24, an imidazole derivative that reached phase II trials for ADHD but was subsequently withdrawn.74,75 The benzofuran, ABT-239, 25, was rumored to be in trials for cognitive dysfunction but was not actually advanced. ABT-834 (structure unknown) is in phase I trials for ADHD. The benzazepine, GSK-189254, 26, is in phase I trials for the treatment of dementias. JNJ-17216498 is an orally active and selective H3 antagonist of undisclosed structure that reduces cataplectic episodes in preclinical narcolepsy models and reported to be in phase I trials for narcolepsy.74 JNJ-5207852, 27, is another NCE antagonizing the H3 receptor.
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