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What is the easiest and safest way to increase the drive to breathe? Although we have therapeutic agents that can modulate airway tone and compliance to make breathing easier, drugs that have a direct and relatively selective effect on the respiratory rhythm-generating circuitry of the brainstem are rare. In this issue of the Journal, Ren and colleagues (pp. 704-710) describe experiments in perinatal rats that demonstrate increased inspiratory drive in response to the ampakine CX1739 (1). The authors compare the efficacy of caffeine and CX1739 at stimulating respiration (in vitro, in vivo, and under hypoxic conditions) and show that CX1739 reduces apneas and improves ventilation in perinatal rats. Of particular interest from a clinical perspective is that CX1739 did not significantly alter respiratory parameters when breathing was already robust, showing that the ampakine selectively improved respiratory drive that was depressed.
Ampakines are a class of allosteric modulators of a-amino- 3-hydroxy-5-methyl-4-isoxazole-propionic acid (AMPA)-type glutamate receptors. These compounds alter the kinetics of deactivation of AMPA receptor-gated inward currents to increase depolarization. They have been used to treat a variety of disorders including schizophrenia and neurodegeneration and to enhance memory. Because AMPA receptors are ubiquitous in the central nervous system, it is surprising that ampakines have selective effects to mitigate these conditions (2). An explanation for this selectivity lies in the cell-type-specific variations of the four subunits that make up the glutamate receptors and subunit preferences inherent to many of the ampakines (3). This may be key to the specificity of the respiratory-related improvements observed by Ren and colleagues.
Ampakines are known to enhance cognitive performance, probably by their enhancement of long-term potentiation and trophic factors beneficial for synapse growth and retention (2, 3).
This particular ampakine, CX1739 (Cortex Pharmaceuticals, Irvine, CA), has been shown by the authors to be more effective than caffeine or other ampakines at improving inspiratory drive in rats. It is also more potent than CX717, an ampakine previously used by these investigators (4).
Premature infants exhibit frequent apneic events that are one of the most persistent and troubling problems in neonatal intensive care (5, 6). Frequent apneas are associated with...