CX717 / RespireRx - LARVOL DELTA

Amplification of the therapeutic potential of AMPA receptor potentiators from the nootropic era to today. (PubMed, Pharmacol Biochem Behav) - "AMPAkines are being investigated in patients with diverse neurological and psychiatric disorders including spinal cord injury (breathing and bladder function), cognition, attention-deficit-hyperactivity disorder, and major depressive disorder. The present discussion of this class of compounds focuses on their general value as therapeutics through their impact on synaptic plasticity."

Journal • Review • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Cognitive Disorders • Depression • Major Depressive Disorder • Mental Retardation • Orthopedics • Psychiatry

Safety, Tolerability and Pharmacokinetic Profile of the Low-Impact Ampakine CX717 in Young Healthy Male Subjects and Elderly Healthy Male and Female Subjects. (PubMed, Eur J Pharmacol) - "The half-life of CX717 was 8-12 h, and Tmax was 3-5 h. Cmax and AUC were dose-proportional. These findings provide key dosing and safety pharmacology data that can be used to inform further investigations of CX717 in subsequent clinical studies such as ADHD, opiate-induced respiratory depression and spinal cord injury."

Journal • PK/PD data • ADHD (Impulsive Aggression) • Attention Deficit Hyperactivity Disorder • CNS Disorders • Depression • Epilepsy • Mental Retardation • Orthopedics • Pain • Psychiatry

High Impact AMPAkines Induce a Gq-Protein Coupled Endoplasmic Calcium Release in Cortical Neurons: A Possible Mechanism for Explaining the Toxicity of High Impact AMPAkines. (PubMed, Synapse) - "The same linkage was not observed using high concentrations of the low impact AMPAkines, CX516 (Ampalex), and CX717. We also demonstrate that CX614 produces neuronal hyper-excitability at therapeutic doses, whereas the newer generation low impact AMPAkine CX1739 is safe at exceedingly high doses. Although earlier studies have demonstrated a functional linkage between AMPAR and G-proteins, this report demonstrates that in the presence of high impact AMPAkines, AMPAR also couple to a Gq-protein, which triggers a secondary calcium release from the ER and provides insight into the disparate actions of high and low impact AMPAkines."

Journal • CNS Disorders • Epilepsy

Ampakines increase diaphragm activation following mid-cervical contusion injury in rats. (PubMed, Exp Neurol) - "At 4- and 14-days following C4Ct, rats were given an intravenous bolus of ampakine CX717 (5 mg/kg, n = 10) or vehicle (2-hydroxypropyl-beta-cyclodextrin; HPCD; n = 10)...Direct recordings from the phrenic nerve at 21-24 days following C4Ct confirmed that ampakines stimulated bilateral phrenic neural output in injured rats. We conclude that low-dose i.v. treatment with a low-impact ampakine can enhance diaphragm activation shortly following mid-cervical contusion injury, when deficits in diaphragm activation are prominent."

Journal • Preclinical • CNS Disorders • Orthopedics

Pattern sensitivity of ampakine-hypoxia interactions for evoking phrenic motor facilitation in anesthetized rat. (PubMed, J Neurophysiol) - "Ampakine CX717 (15 mg/kg, iv) was given immediately prior to- (n=8), during (n=8), or immediately following (n=8) a 5-min hypoxic episode (arterial oxygen partial pressure 40-45 mmHg)...We conclude that the presentation order of ampakine and hypoxia impacts the magnitude of pMF, with ampakine pretreatment evoking the strongest response. Ampakine pretreatment may have value in the context of hypoxia-based neurorehabilitation strategies."

Journal • Preclinical • Anesthesia

Ampakine-Hypoxia Induced Phrenic Motor Facilitation is Not Prevented by Intrathecal Methysergide. (PubMed, FASEB J) - "After a stable baseline (BL) was established, intravenous (i.v.) ampakine (CX717, 15mg/kg) was followed by a single episode of hypoxia (arterial partial pressure of O = 42±9mmHg)...Intrathecal methysergide blocked pLTF (60 min post-AIH, phrenic burst amplitude = -2±31% BL, n=3), but intrathecal delivery of the DMSO vehicle did not (60 min: 94±28% BL, n=3). Collectively, these results do not support our hypothesis that phrenic motor facilitation induced by the pairing of ampakine with a single bout of hypoxia is dependent on serotonin receptor activation."

Journal • Anesthesia

The Pattern of Ampakine and Hypoxia Exposure Determines Phrenic Motor Facilitation. (PubMed, FASEB J) - "The ampakine used was CX717, given intravenously (i.v.) at 15 mg/kg...The presentation of ampakine followed by a single brief hypoxic episode appears to be ideal for producing pMF. These findings could have significant implications in planning hypoxia-based neurorehabilitation strategies with ampakines as an adjunct therapy."

Journal • Anesthesia

Ampakine CX717 Stimulates Diaphragm Activity following Mid-cervical Spinal Contusion Injury. (PubMed, FASEB J) - "In summary, our data indicate that low dose, low impact ampakine treatment can increase diaphragm muscle output at an acute timepoint following mid-cervical contusion type injuries. These studies pave the path for future experiments to test if ampakine treatment can be combined with rehabilitation techniques to further enhance the therapeutic effect of ampakines in this injury model."

Journal • Addiction (Opioid and Alcohol) • Anesthesia • CNS Disorders • Musculoskeletal Diseases • Orthopedics • Respiratory Diseases

Ampakines stimulate diaphragm activity after spinal cord injury. (PubMed, J Neurotrauma) - "Once a stable baseline recording was established, one of two different ampakines (CX717 or CX1739, 5 mg/kg, intravenous) or a vehicle (2-hydroxypropyl-beta-cyclodextrin; HPCD) was delivered. At 14-days post-injury, both ampakines produced sustained increases in ipsilateral diaphragm EMG output and enabled increased output during the respiratory challenge. We conclude that low dose ampakine treatment can increase diaphragm EMG activity after cervical SCI, and therefore may provide a pharmacologic strategy that could be useful in the context of respiratory rehabilitation."

Journal • CNS Disorders • Orthopedics

Spinally delivered ampakine CX717 increases phrenic motor output in adult rats. (PubMed, Respir Physiol Neurobiol) - "We conclude that intrathecally delivered ampakines can modulate phrenic motor output. This approach may have value for targeted induction of spinal neuroplasticity in the context of neurorehabiliation."

Journal • Preclinical • Anesthesia

Ampakine pretreatment enables a single hypoxic episode to produce phrenic motor facilitation with no added benefit of additional episodes. (PubMed, J Neurophysiol) - "Initial experiments demonstrated that ampakine CX717 (15 mg/kg, intravenous) caused an acute increase in phrenic nerve inspiratory burst amplitude reaching 70±48% baseline (BL) after 2 min (P=0.01...We conclude that pLTF is not enhanced when ampakine pretreatment is followed by repeated bouts of hypoxia. Rather, the combination of ampakine and a single hypoxic episode appears to be ideal for producing sustained increase in phrenic motor output."

Journal • Anesthesia

A comparison of breathing stimulants for reversal of synthetic opioid-induced respiratory depression in conscious rats. (PubMed, J Pharmacol Exp Ther) - "We studied taltirelin (1 mg/kg IV), PKTHPP (5 mg/kg IV), CX717 (30 mg/kg IV), BIMU8 (1 mg/kg IV), A85380 (30 mcg/kg IV), 8-OH-DPAT (150 mcg/kg IV/IM), and used sufentanil (10 mcg/kg IV)...Significance Statement Respiratory depression is an important cause of death following potent synthetic opioid overdose. 8-OH-DPAT or related compounds may be useful in treating respiratory depression as caused by potent synthetic opioids."

Journal • Preclinical • Addiction (Opioid and Alcohol) • CNS Disorders • Depression • Metabolic Disorders • Mood Disorders • Psychiatry

Ampakines stimulate phrenic motor output after cervical spinal cord injury. (PubMed, Exp Neurol) - "Two weeks after C2Hx, ampakine CX717 (15 mg/kg, i.v.) increased IL (61 ± 46% baseline, BL) and CL burst amplitude (47 ± 26%BL) in 8 of 8 rats...We conclude that ampakines effectively stimulate neural drive to the diaphragm after cervical SCI. Pairing ampakines with a single hypoxic exposure did not consistently enhance phrenic motor facilitation."

Journal • Review • Anesthesia • CNS Disorders • Complement-mediated Rare Disorders • Orthopedics

Antidepressant-Like Effects of CX717, a Positive Allosteric Modulator of AMPA Receptors. (PubMed, Mol Neurobiol) - "New glutamatergic drugs such as ketamine have shown promise as a rapid-acting antidepressant drugs although with adverse effects. CX717 also produced a rapid (up to 1 h) increase of brain-derived neurotrophic factor (BDNF) and a more sustained (up to 6 h) increase of p11. Overall, CX717 appears to possess a rapid but not sustained antidepressant action possibly caused by rapid increases of BDNF and p11."

Journal • BDNF

RespireRx Pharmaceuticals Inc. CEO issues progress and status report (GlobeNewswire) - "CX1739, have successfully completed multiple Phase 1 safety trials and Phase 2 efficacy trials demonstrating target engagement. CX717 has successfully completed a Phase 2 trial demonstrating the ability to significantly reduce the symptoms of adult ADHD. In an early Phase 2 study, CX1739 improved breathing in patients with central sleep apnea....We believe that we will be able to rapidly initiate...a human Phase 2B study in patients with ADHD with either CX717 or CX1739."

New P2b trial • P2 data • Trial completion

Ampakine pretreatment enables a single brief hypoxic episode to evoke phrenic motor facilitation. (PubMed, J Neurophysiol) - "When Cx717 was followed 2 minutes later by a 5-min exposure to hypoxia (n=8, PaO ~ 45 mmHg) a persistent increase in phrenic inspiratory burst amplitude (i.e., phrenic motor facilitation) was observed up to 60-min post-hypoxia (103±53% increase from baseline)...Additional experiments with another ampakine (Cx 1739, 15 mg/kg) produced comparable results. We conclude that pairing low dose ampakine treatment with a single, brief hypoxic exposure can evoke sustained phrenic motor facilitation. This targeted approach for enhancing respiratory neuroplasticity may have value in the context of hypoxia-based neurorehabilitation strategies."

Journal