CX1739 / RespireRx - LARVOL DELTA

Acute Administration of Ampakine CX1739 after Cervical Spinal Cord Injury. (PubMed, J Neurotrauma) - "Ampakine treatment should be reserved for the subacute and chronic SCI conditions, beyond the acute period of glutamate-related neurotoxicity. These results will be particularly important in determining the optimal timing of ampakine administration as CX1739 progresses in clinical trials."

Journal • CNS Disorders • Orthopedics

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

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

Safety, Tolerability, and Pharmacokinetic Profile of the Low-Impact Ampakine CX1739 in Young Healthy Volunteers. (PubMed, Clin Pharmacol Drug Dev) - "CX1739 Cmax and AUC were dose-proportional. These findings thus set the stage for further explorations of this drug candidate in phase 2 clinical studies."

Journal • PK/PD data • CNS Disorders • Depression • Mental Retardation • Pain • Psychiatry

AMPA receptors play an important role in the biological consequences of spinal cord injury: Implications for AMPA receptor modulators for therapeutic benefit. (PubMed, Biochem Pharmacol) - "The data summarized and discussed in this paper document proof of principle and strongly encourage additional studies on AMPARs as novel gateways to therapeutic benefit for patients suffering from SCI. The availability of both AMPAR antagonists such as perampanel and AMPAR allosteric modulators (i.e., ampakines) such as CX1739, that have been safely administered to humans, provides an expedited means of clinical inquiry for possible therapeutic advances."

Journal • Review • CNS Disorders • Inflammation • Orthopedics • Pain • Sexual Disorders

Acute ampakines increase voiding function and coordination in a rat model of SCI. (PubMed, Elife) - "The 'low-impact' ampakine CX1739 (5, 10, or 15 mg/kg) or vehicle (2-hydroxypropyl-beta-cyclodextrin [HPCD]) was administered intravenously...We conclude that modulating AMPA receptor function using ampakines can rapidly improve bladder-voiding capability at subacute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI."

Journal • Preclinical • Anesthesia • CNS Disorders • Orthopedics • Urology

Cisplatin induces BDNF downregulation in middle-aged female rat model while BDNF enhancement attenuates cisplatin neurotoxicity. (PubMed, Exp Neurol) - "In cultured hippocampal neurons, we screened three neuroprotective agents, riluzole (an approved treatment for amyotrophic lateral sclerosis), as well as the ampakines CX546 and CX1739. In conclusion, we established the first middle-aged rat model of cisplatin-induced CRCI, assessing the contribution of medical stress and longitudinal changes in BDNF levels with cognitive function, although future studies are warranted to assess the efficacy of BDNF enhancement in vivo on synaptic plasticity. Collectively, our results indicate that cancer treatment exerts long-lasting changes in BDNF levels, and support BDNF enhancement as a potential preventative approach to target CRCI with therapeutics that are FDA approved and/or in clinical study for other indications."

Journal • Preclinical • Alzheimer's Disease • Amyotrophic Lateral Sclerosis • CNS Disorders • Cognitive Disorders • Oncology • Ovarian Cancer • Solid Tumor • BDNF

Ampakines therapy improves voiding function and coordination following acute spinal cord injury (Neuroscience 2023) - "Then we assessed the effects of vehicle (HPCD) and low impact ampakine (CX1739) over 30 minutes to investigate whether it could restore the voiding functions in SCI...Our findings suggest that modulating AMPA receptor function using ampakines can rapidly improve voiding capability at sub-acute time points following contusion SCI. These results may provide a new and translatable method for therapeutic targeting of bladder dysfunction acutely after SCI."

CNS Disorders

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

The impact and mechanism of ampakine CX1739 on protection against respiratory depression in rats. (PubMed, Future Med Chem) - "Second, CX1739 rapidly crossed the blood-brain barrier (T = 2 min), which meets the requirement of rapid onset of action in vivo. Our work provides preliminarily confirmation that high-dose intravenous administration of CX1739 can immediately reverse respiratory depression in animal models of respiratory depression caused by opioid agonist 030418, pentobarbital sodium and ethanol."

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

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