CX717 for ADHD

CX717 is a weakly active ampakine.

Ampakines are synthetic positive allosteric modulators of AMPA receptors (α-amino-3-hydro-5-methyl-4-isoxazolepropionic acid receptors).¹ Ampakines may thereby enhance excitatory glutamatergic transmission. Ampakines do not appear to be direct AMPA receptor agonists, nor do they appear to act on other glutamatergic receptors such as NMDAR or kainitR. Ampakines enhance synaptic transmission and promote plasticity without altering the fundamental aspects of AMPA receptor activation.²

Studies have shown changes in glutamate, its metabolites and receptors³

• for bipolar Disorder
• for severe depression
• in animal models for stress

Ampakines can stimulate respiration by acting on premotor “rhythm-generating” neurons and motor neurons of the respiratory tract. Ampakines are particularly effective in stimulating respiration in cases of reduced or impaired respiratory motor activity, such as opioid overdose, spinal cord injury or neuromuscular disease. Ampakines can also increase the expression of respiratory neuroplasticity after hypoxia. ⁴⁵⁶² The latter implies that the number of hypoxic episodes required for the induction of respiratory neuroplasticity is reduced.⁷
A single dose of CX717 transiently increases the efferent motor output of the phrenic nerve, peaking ∼2 minutes after infusion and then gradually returning to baseline levels.⁸
CX717 reduces respiratory depression and fatal apnea when administered with propofol⁹, alcohol and barbiturates¹⁰ or opioids¹¹¹² . For opioid-induced respiratory problems, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) (150 μg/kg i.v./i.m.) was significantly more effective than CX717 (30 mg/kg i.v.).¹³
Hypoxia is one of the pathways leading to ADHD.

Other ampakines are¹⁴

• CX614: Class I ampakine
• CX1739: Class II ampakine (like CX717)

• 1. CX717 for ADHD
• 2. CX717 for depression
• 3. Neurophysiological effects of CX717
• 4. Pharmacological data of CX717
• 5. Compatibility CX717

1. CX717 for ADHD¶

CX717 was effective at 800 mg (200 mg was ineffective) in a randomized, double-blind, placebo-controlled, multicenter crossover study of 68 adult males (18 to 50 years) with moderate to severe DSM-IV ADHD, 17 of whom discontinued the study:¹⁵

• significant improvement
  • on the ADHD-RS total values
  • on the inattentive subscales
  • on the hyperactive subscales
• good compatibility
  • no significant change in cardiovascular and other safety parameters
  • the most common side effects were
    • Sleep disorders
    • Headache

CX717 (20 mg/kg s.c.) induced cognitive deficits in bilateral vestibular deafferentation (BVD)-induced rats (Alzheimer’s disease model) in a 5-choice serial reaction time task (5CSRTT) and an object recognition memory task:¹⁶

• improved inhibitory control
• reduced number of incorrect answers
• shorter exploration time and poorer performance in the object recognition memory task

From 45mg/kg reduced CX717 amphetamine-induced hyperactivity³

In adult young men, CX717 did not initially improve performance or objective vigilance after sleep deprivation. An exploratory repeated measures analysis, accounting for the influence of individual differences, showed an improvement in performance on attention-based tasks at 1000 mg, but not at 100 or 300 mg. CX717 1000 mg significantly reduced sleep stage 4 and slow-wave sleep, which correlated with reduced slow-wave and spindle activity in the electroencephalogram (EEG). CX717 may impair recovery sleep.¹⁷
In a study on monkeys, CX717 eliminated the adverse effects of 30 to 36 hours of sleep deprivation.¹⁸

A review on ampakines, which we have not yet been able to view, deals with their effect on ADHD, among other things.¹⁹

2. CX717 for depression¶

CX717 showed a rapid onset (30 minutes) but short-lasting (up to 24 hours) antidepressant-like effect in the forced swim test in rats.¹

From 30 mg/kg, CX717 had a calming effect in a rat model of mania.³
From 45mg/kg, CX717 reduced the aggressive reactions in the resident intruder test³

3. Neurophysiological effects of CX717¶

An intracortical infusion of CX717 caused¹

• acute
  • Increased release of noradrenaline, dopamine and serotonin
  • Glutamate unchanged
• systemic
  • Noradrenaline, dopamine, serotonin and glutamate unchanged
• rapid (up to 1 hour) increase in BDNF
• sustained increase (up to 6 hours) in p11

CX717 significantly increased regional cerebral metabolic rates for glucose (CMRglc) during a delayed match-to-sample task compared to normal alert conditions¹⁸

• in the PFC
• in the dorsal striatum
• in the medial temporal lobe including the hippocampus

4. Pharmacological data of CX717¶

Half-life: 8 to 12 hours²⁰
Tmax when taken orally after 3 to 5 hours.²⁰
Cmax and AUC were dose-proportional.²⁰

5. Compatibility CX717¶

CX717 was well tolerated up to 1600 mg and 800 mg BID. CX717 was also well tolerated when fed or taken on an empty stomach and was also well tolerated in the elderly.
The most common side effects were headaches, dizziness and nausea.²⁰