Persistent patency of the ductus arteriosus (PDA) is less frequent among infants treated with caffeine for apnea of prematurity. Caffeine acts to inhibit A1, A2, and A3 adenosine receptors (ARs). Adenosine is typically vasodilatory, and serum adenosine levels are elevated in preterm newborns, suggesting a potential mechanism for caffeine-associated reduction in PDA. We hypothesized that caffeine has an indirect vasoconstrictive effect on the ductus by antagonizing specific ARs. The expression of AR subtypes in the mouse ductus was analyzed by RT-PCR on days 15, 17, 19 (full term) of gestation, and postnatal day 1. Pressure myography was used to examine responses of the isolated ductus to adenosine, caffeine (citrate or base), or preincubation with either caffeine or adenosine. AR immuno-localization and adenosine-mediated cyclic AMP (cAMP) generation were evaluated in human ductus smooth muscle cells (SMCs). A1AR, A2AAR, A2BAR, and A3AR were present and developmentally regulated in the mouse ductus. Adenosine promoted ductus dilation under fetal and newborn O2 conditions. Caffeine had little or no effect on ductus tone with concentrations spanning the therapeutic range and failed to augment O2-induced or cyclooxygenase inhibitor-stimulated ductus constriction. However, pretreatment with caffeine or selective A1AR and A2AAR antagonists prevented adenosine-induced ductus dilation. Caffeine also blocked adenosine-stimulated cAMP release in human ductus SMCs. In conclusion, caffeine did not induce direct ductus constriction ex vivo. However, caffeine exposure prevented adenosine-induced ductus relaxation, suggesting the inhibition of an endogenous vasodilator as a mechanism for the reduction in PDA.NEW & NOTEWORTHY Caffeine is a respiratory stimulant and one of the most commonly prescribed drugs in the NICU. Primarily used to reduce apnea of prematurity, additional therapeutic benefits have been noted, including decreasing the incidence of patent ductus arteriosus. Using mouse and human ductus models, we have identified a mechanism by which caffeine can promote ductus constriction by inhibiting adenosine-mediated vasodilation.

Mechanical ventilation (MV) is a cornerstone of supportive care in intensive care units (ICUs), but prolonged ventilation is associated with adverse outcomes. Several pharmacologic agents with respiratory stimulants have been investigated to facilitate weaning and improve clinical outcomes; yet no comprehensive comparison across available agents exists. This network meta-analysis (NMA) aimed to compare and rank available interventions in adult patients receiving MV. A systematic search of PubMed, Web of Science, and Scopus (up to November 10, 2023) identified 15 randomized controlled trials (1,528 participants) evaluating ten respiratory stimulants in mechanically ventilated critically ill adults: Almitrine Bismesylate (AB), Doxofylline (DX), Progesterone (PRG), Acetazolamide (ACZT), Growth Hormone (GH), Oxandrolone (OXA), Nandrolone (NA), Caffeine (CAF), Donepezil (DPZ), and a multi-agent adjuvant therapeutic (AT) regimen containing anisodamine. Data were analyzed using a frequentist network meta-analysis with treatment rankings based on SUCRA values. Risk of bias was assessed using the modified Cochrane RoB 2 tool. No pharmacologic intervention significantly reduced hospital or ICU mortality, duration of mechanical ventilation, or time to successful weaning compared with placebo. According to SUCRA rankings, NA, OXA, and PRG had the highest probabilities of reducing hospital mortality, with NA also associated with shorter ICU and hospital stays. DPZ and PRG significantly shortened weaning duration, while GH showed the greatest reduction in mechanical ventilation duration. GH, PRG, and DPZ had the highest likelihood of successful weaning. Heterogeneity and inconsistency were generally low, except for the duration of mechanical ventilation (I² = 86.2%, p < 0.001). No pharmacologic intervention significantly reduced hospital mortality. However, agents such as NA, GH, and DPZ may help shorten ICU stay, reduce duration of mechanical ventilation, or improve weaning efficiency. These findings underscore the potential value of multi-agent adjuvant approaches and highlight the need for larger, high-quality trials to confirm their clinical benefits.Trial registration: CRD42023454122 (18/10/2023).

The use of kratom as an alternative to conventional opioids has surged, driven largely by anecdotal reports of its efficacy for pain relief and opioid withdrawal management. The growing prevalence of kratom products enriched with 7-hydroxymitragynine (7-HMG), an active metabolite of mitragynine (MG), necessitates evaluating the respiratory effects of these alkaloids and determining whether naloxone reverses their potential respiratory depressant effects. Respiratory parameters were measured in awake, freely moving female and male Sprague-Dawley rats using whole body plethysmography. To minimize handling-induced artifacts and ensure precise respiratory recordings, drugs were administered intravenously. Morphine and 7-HMG induced significant respiratory depression, evidenced by reductions in breathing frequency, tidal volume, and minute volume. The potency of 7-HMG to decrease minute volume by 50% was 4.5-fold greater than that of morphine. In contrast, MG administration unexpectedly increased respiratory frequency. Naloxone fully reversed the respiratory depression induced by both morphine and 7-HMG but did not alter the respiratory stimulant effects produced by MG. These findings demonstrate that 7-HMG exhibits significant respiratory depressant properties similar to classical opioids, and importantly, such depressant effects are effectively antagonized by naloxone. Conversely, MG exerts respiratory stimulant effects through mechanisms independent of opioid receptor pathways. Collectively, these data highlight crucial pharmacological distinctions between kratom alkaloids, underscoring the risk associated with high 7-HMG-containing kratom products and suggesting that the predominant alkaloid MG may offer a safer respiratory profile. SIGNIFICANCE STATEMENT: The prevalence of kratom products containing 7-hydroxymitragynine (7-HMG), a μ-opioid receptor agonist, underscores the need to evaluate respiratory effects of kratom-related alkaloids and their reversal by naloxone. 7-HMG induced significant respiratory depression comparable with morphine, which was reversed by naloxone. Conversely, mitragynine, kratom's most abundant alkaloid, unexpectedly increased respiratory frequency unaffected by naloxone. These findings highlight critical pharmacological differences between kratom-related alkaloids, emphasizing potential risks associated with products containing high concentrations of 7-HMG.

Introduction: Episodes of apnoea are common in extremely preterm infants (EPIs) and usually treated with caffeine and respiratory support. Understanding differences in apnoea definitions, monitoring practices, and use of respiratory stimulants is essential to improve future treatment. Methods: Between March and July 2024, one lead consultant at European tertiary neonatal intensive care units (NICUs) was invited to complete a web-based survey on respiratory practices in EPIs. We sought information how they defined apnoea and monitored for it, and how they treated it with caffeine, doxapram, and non-invasive respiratory support. Results: We received replies from 447/721 (62%) NICUs across 24 European countries. Most NICUs (74%) use both electrocardiogram electrodes and pulse oximetry for apnoea monitoring. All NICUs reported using caffeine citrate, with 102 centres (23%) starting it in the delivery room. The median loading, maintenance and maximum maintenance doses used are 20 mg/kg, 5 and 10 mg/kg/day, respectively. Caffeine is occasionally given twice daily in some NICUs (30%) and stopped at 34–35 weeks of postmenstrual age at most of them (74%). Doxapram is used at 111 (25%) NICUs, with geographical differences. Strategies for the use and escalation of non-invasive respiratory support in case of persistent apnoea are not clearly defined. Automatic closed-loop oxygen delivery is used at 25% of NICUs. Conclusion: Despite consistency in the dosing and weaning of caffeine, there is much variation in the management of apnoea in preterm infants across Europe. Future research should focus on timing and dosage of caffeine, the use of doxapram, and strategies for optimising non-invasive respiratory support.

TASK-1 is a two-pore K+ leak channel. The name, TASK-1, stands for TWIK-related acid-sensitive potassium channel 1, and this channel is encoded by the KCNK3 gene. TASK-1 channels are expressed in humans and modulate cell excitability in excitable cells such as neurons, cardiomyocytes, and vascular smooth muscle cells. TASK-1 inhibition is a mechanism of action for some respiratory stimulants, such as doxapram. TASK-1 channels have also been suggested to play a role in circumventing cell apoptosis in a population of non-small-cell lung cancer cells. We propose that the inner vestibule of the TASK-1 channel, a known binding site of known TASK-1 inhibitors, BAY10000493 and BAY2341237, can be exploited via virtual screening to find other novel TASK-1 inhibitors. Our results show that by targeting the inner vestibule site, we found an active TASK-1 inhibitor. We suspect that this region of interest can be further exploited to discover additional TASK-1 inhibitors. Our initial success lends validity to our virtual screening methodology and parameters. In this study, we identified a novel TASK-1 inhibitor, KU124, which we verified using an in vitro assay.

Monoamine receptors targeted by methamphetamine differentially modulate basal and fentanyl-depressed respiration in mice.

The use of kratom as an alternative to conventional opioids has surged, driven largely by anecdotal reports of its efficacy for pain relief and opioid withdrawal management. The growing prevalence of kratom products enriched with 7-hydroxymitragynine (7-HMG), an active metabolite of mitragynine (MG), necessitates evaluating the respiratory effects of these alkaloids and determining if naloxone reverses their potential respiratory depressant effects. Respiratory parameters were measured in awake, freely moving female and male Sprague-Dawley rats using whole body plethysmography. To minimize handling-induced artifacts and ensure precise respiratory recordings, drugs were administered intravenously. Morphine and 7-HMG induced significant respiratory depression, evidenced by reductions in breathing frequency, tidal volume, and minute volume. In contrast, MG administration unexpectedly increased respiratory frequency. Naloxone fully reversed the respiratory depression induced by both morphine and 7-HMG but did not alter the respiratory stimulant effects produced by MG. These findings demonstrate that 7-HMG exhibits significant respiratory depressant properties similar to classical opioids, and importantly, such depressant effects are effectively antagonized by naloxone. Conversely, MG exerts respiratory stimulant effects through mechanisms independent of opioid receptor pathways. Collectively, these data highlight crucial pharmacological distinctions between kratom alkaloids, underscoring the risk associated with high 7-HMG-containing kratom products and suggesting that the predominant alkaloid MG may offer a safer respiratory profile.

Background: We have previously shown that respiratory depression from intravenous (IV) remifentanil could be partially reversed with naloxone injection into the preBötzinger complex (preBötC) during moderate hypercapnia (PCO2 50 mmHg). We also showed that PCO2 significantly affected phase timing and neuronal discharge frequency ( Fn ) between PCO2 30-50 mmHg, but that there was little additional effect above ~50 mmHg. This study investigated the effects of “analgesic” remifentanil concentrations on Fn of individual preBötC neurons and whether an increase in chemodrive, i.e., hypercapnia and hypoxia, reversed the remifentanil effect on phase timing and Fn. Methods: The study was approved by the local Animal Care Committee and conformed to NIH standards. Adult New Zealand White rabbits (3-4 kg) of either sex were anesthetized, tracheotomized, ventilated, decerebrated and vagotomized. Phrenic nerve activity was recorded from the C5 rootlet, time averaged and used to calculate inspiratory (TI) and expiratory durations (TE) and peak phrenic activity (PPA). We extracellularly recorded individual neurons in the functionally identified preBötC using multichannel electrodes (Neuronexus, Ann Arbor, MI). Fn was continuously displayed and recorded and averaged posthoc using cycle-triggered histograms (30-40 cycles, Spike2, CED, Cambridge, MA). Neurons were identified at PCO2 50 mmHg. Remifentanil was infused IV to achieve a steady-state 50% depression in respiratory rate and continued until the end of the protocol. Parameters were sampled at PCO2 50 mmHg, PCO2 50mmHg with remifentanil, PCO2 60mmHg with remifentanil, and PCO2 60 mmHg with hypoxia (hyp, FiO2 0.15) with remifentanil. Complete reversal was achieved with IV naloxone. Statistical analysis with Mann-Whitney-U test for differences between states, values are median (25-75% range), p&lt;0.05. Results: In 17 animals, remifentanil increased TI from 0.8 (0.7-0.9) sec to 1.3 (1.1-1.4) sec (p&lt;0.05) and TE from 0.8 (0.6-0.9) sec to 1.9 (1.5-2.2) sec (p&lt;0.05). PPA did not change significantly. Additional hypercapnia and hypoxia did not reverse the effect on TI and TE, however, hypoxia increased PPA (p&lt;0.05). Remifentanil significantly decreased the Fn of inspiratory augmenting neurons from 56.7 (31.8-76.1) Hz to 40.4 (23.6-67.4) Hz (n=62, p&lt;0.05) and inspiratory parabolic neurons from 29.4 (19.3-50.0) Hz to 14.9 (9.2-28.3) Hz (n=18, p&lt;0.05). Hypercapnia and hypoxia did not alter that effect. The effect of remifentanil on inspiratory (n=10) and expiratory decrementing (n=6) neurons was not statistically significant, and there was again no effect of additional hypercapnia and hypoxia. Conclusion: Although hypercapnia and hypoxia increase chemodrive to the respiratory rhythm generator and have substantial effects on phase timing and tidal volume in normoxic, normocapnic individuals, the effect during remifentanil-induced respiratory depression is very limited. This matches the lack of effect on individual respiratory neuronal discharge. The increase in PPA during hypoxia may be due to a direct effect on respiratory premotor and motoneurons. The results reflect the clinical experience that even the significant hypercapnia and hypoxia that is experienced by victims of opioid overdose does not overcome the respiratory depression, leading to death. It is important to test whether similar limitations exist for respiratory stimulant drugs. NIH R01-HL159546 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Respiratory support is frequently needed for babies admitted to the neonatal intensive care unit. Among them, preterm babies are most likely to have issues of respiratory distress, and they may need invasive or non-invasive breathing support. Providing respiratory support, keeping the oxygen saturation (SpO2) in the target range (TR) and preventing abnormal high and low oxygen levels should be the aim of providing respiratory therapy. Usually, this control is achieved by manual adjustment of FiO2 (fraction of inspired oxygen) by bedside staff nurses to keep SpO2 in TR. However, the latest ventilators have automated oxygen control devices that adjust the FiO2 to keep SpO2 in TR. This study protocol is prepared to assess the effectiveness of automated versus manual oxygen control in keeping SpO2 in TR. This is a single-centre, non-blinded, randomised crossover trial that aims to recruit 26 preterm babies who may need invasive or non-invasive respiratory support. The 12-hour periods of automated oxygen control by ventilator will be compared with 12 hours of manual oxygen control by bedside staff nurse. The primary outcome will compare both interventions and will assess their efficacy to keep SpO2 in TR. Secondary outcomes will compare abnormal high and low SpO2 levels, and number and duration of fluctuations in both interventions. Median FiO2 values and median number of manual adjustments of FiO2 will also be compared. Secondary outcomes will also look for the impact of sedative and respiratory stimulant medications on target oxygen saturation. The ethics review committee at Aga Khan University Hospital Karachi has given ethical approval for this trial (approval number: 2024-10189-30775). Results from this trial will be published in journals. NCT06622161.

BackgroundIn acute exacerbation periods of chronic obstructive pulmonary disease (COPD), patients may experience hypoxemia or hypercapnia. Noninvasive ventilation (NIV) and respiratory stimulant drugs are used to treat this condition. Medroxyprogesterone acetate (MPA) can cross the blood-brain barrier and cause breathing stimulation and hyperventilation. This study was conducted to investigate the effectiveness of MPA in hypercapnic exacerbated COPD patients and the possibility of faster weaning of patients from NIV.Materials and methodsThis double-blind clinical trial was conducted on consecutive exacerbated COD patients referred to Shahid Rahnemoun Hospital, Yazd, Iran, from February 2022 to August 2022. Through a block randomized sampling method with a 1:1 allocation ratio, 58 eligible patients with hypercapnic exacerbated COPD on NIV were divided into two study groups: the intervention (treated with MPA 10 mg every 8 h) and the control (treated with placebo). The clinical and arterial blood gas (ABG) parameters were investigated in both groups.ResultsOut of 50 patients, 27 and 23 intervention and control arms cases were analyzed. Although there was a significant difference in the amount of ABG parameters during the study in each group, there was no statistically significant difference between the two groups. Also, There was no significant difference in the total weaning rate of the patients in the two groups. Despite the higher number of early weaning in the MPA group, no significant difference was reported between the two groups in this regard. In addition, there was no difference between the two groups in the rate of ICU hospitalization, the length of stay of hospitalization and ICU, and the mortality rate.ConclusionThe administration of MPA has not improved clinical and laboratory results, and MPA is not superior to placebo in the weaning process of patients undergoing NIV.Trial registrationIRCT20190810044500N21 (01/02/2022), (https//irct.behdasht.gov.ir/user/trial/59402/view)

Respiratory depression is a side effect of anesthetics. Treatment with specific antagonists or respiratory stimulants can reverse respiratory depression caused by anesthetics; however, they also interfere with the sedative effects of anesthetics. Previous studies have suggested that tandospirone may ameliorate respiratory depression without affecting the sedative effects of anesthetics. Therefore, we evaluated whether tandospirone (0.1–8 mg/kg) ameliorates respiratory depression in a rat model under anesthesia. The protein kinase A redistribution method was used to determine whether tandospirone activates α2a/2c and µ receptors. The effects of tandospirone (10 µM) on α1β2γ2 and α4β2δ GABA receptor current modulation were explored by two-electrode voltage clamping. Prophylactic tandospirone administration reduced respiratory depression caused by anesthetics in rats. Tandospirone (0.1–8 mg/kg) increased SaO2 in rats treated with fentanyl (80 µg/kg) or midazolam (80 mg/kg) (P < 0.05). The ability of tandospirone to prevent respiratory depression was inhibited by the 5-hydroxytryptamine (5-HT)1 A receptor antagonist WAY100635 (1 mg/kg) (P < 0.05). Co-administration of tandospirone with dexmedetomidine or fentanyl did not affect α2a/2c or µ receptors activation. Tandospirone (10 µM) did not affect α1β2γ2 and α4β2δ GABA receptor modulation (P < 0.05). Overall, tandospirone ameliorated respiratory depression caused by anesthetics in rats through 5-HT1A receptor activation.

BackgroundAcute mountain sickness (AMS) is a debilitating condition that individuals may develop on ascent to high altitude. It is characterized by headache, nausea, vomiting, dizziness, and fatigue with the potential to progress to fatal disease. Although the pathophysiology of AMS remains unclear, proposed mechanisms are hypothesized to be similar to migraine. Prochlorperazine, a first-line treatment for acute migraine, has been shown to abort migraine early and thus may be effective in preventing AMS. Its action as a respiratory stimulant additionally makes it a promising novel agent for AMS prevention.MethodsIn this randomized double-blinded trial, participants will be randomized to receive oral prochlorperazine maleate or placebo for 24 h of three times daily dosing on a rapid ascent to 4348 m. Participants will be adults, aged 18, and older who are unacclimatized. Participants will remain at this elevation overnight. The Lake Louise Questionnaire will be utilized to define the primary outcome and presence of AMS and will be assessed the evening of and morning after ascent to peak altitude.DiscussionCurrently, acetazolamide is the preferred option for the chemoprophylaxis of AMS, which has been studied and utilized since the 1970s and involves potential prohibitive side effects. Other more efficacious options with more tolerable side effects are needed. Preventing AMS has the potential to limit both the morbidity and mortality associated with developing AMS and more serious diseases (notably high-altitude cerebral edema). Additionally, there is a substantial economic and environmental impact of AMS that could be prevented.Trial registrationClinicaltrial.gov, NCT06450899. Registered on June 2024.

The article presents the results of a study of the amination reaction of nicotinic acid chlorohydride with amines morpholine, cytisine, and 1-aminoadamantane, which are often used in the search and creation of drugs for respiratory and circulatory stimulants. The study was conducted to search for new biologically active compounds with anti-inflammatory activity. The synthesis of new aminoamides was carried out by the interaction of nicotinic acid with molecules of morpholine, cytisine, and adamantane in anhydrous ethanol. As a result of the conducted studies, new amides of nicotinic acid with high yields (90.7–93.1%) were obtained. The structures of the new compounds were determined using NMR 1H and 13C spectroscopy methods, as well as data from two-dimensional spectra of COSY (1H-1H), HMQC (1H-13C), HMBC (1H-13C) and mass spectrometry. The results of an experimental study of the anti-inflammatory activity of synthesized new amides are presented. The anti-inflammatory effect of nicotinic acid N-adamantylamide was established, other new amides were ineffective compared with ibuprofen (p2 &lt; 0.05).

Obstructive sleep apnea (OSA) is a prevalent pathology with current modalities of treatment including continuous positive airway pressure (CPAP), surgery, weight loss, hypoglossal nerve stimulation, and pharmacotherapy. While CPAP is the current standard treatment for OSA, lack of tolerance and side effects necessitate alternative modalities of treatment. Various pharmacologic agents exist with mechanisms that may target OSA. Early trials have demonstrated efficacy of noradrenergic-antimuscarinic combinations to stimulate the airway, promote pharyngeal muscle tone, and prevent airway collapse. These agents, which we discuss in detail, have demonstrated significant reductions in apnea-hypopnea index (AHI) and lowest oxygen saturations based on preliminary studies. Glucagon-like peptide 1 receptor agonists (GLP-1RA), which stimulate endogenous insulin, reducing glucagon release, and decreasing gastric emptying, have shown positive results for OSA patients through weight loss with reductions in AHI. In this narrative review article, we highlight the mechanisms, current data, and future potential for multiple drug classes, including respiratory stimulants and GLP-1RAs.

The hazardous material release has frequently occurred worldwide. As a respiratory stimulant and a toxic substance, ammonia has numerous adverse effects on human health. The purpose of this study was to evaluate the human vulnerability and toxic effects of both chronic and acute respiratory exposure to ammonia. This study was conducted in an ice factory. Ammonia reservoirs were selected as the danger center. The scenarios were evaluated from the perspective of the worst-case. The Emergency Response Planning Guidelines 1-3 was used to predict the dangerous concentrations in acute exposure. The probability of human vulnerability was estimated using the Probit model. PHAST 7.2 software was used to model consequences. As a measure of chronic exposure to ammonia, NMAM 6016 was used. A respiratory symptom questionnaire developed by the American Thoracic Society was used for collecting respiratory symptom histories. The ERPG3 level or concentration of 750 ppm was found at a distance of 617.71 and 411.01 meters from tanks, respectively, as a result of a rupture in reservoir 1 over a period of two halves of the year. It was found that the highest probit values for tank 2 at distances of zero, 25, 50, 75, 100, 125, and 150 meters were 9.55, 5.92, 5.47, 4.82, 4.23, 3.56 and 2.96, respectively. The prevalence of pulmonary symptoms, which include coughing, dyspnea, phlegm, and wheezing, was 28%, 19%, 15%, and 26% in the chronic exposure group. In the event that an ammonia reservoir ruptures catastrophically, it may cause human injury at ERPG-2 or ERPG-3 levels. Results revealed that exposure to this substance can impose many pulmonary symptoms on the respiratory system of workers in industries. In order to reduce the vulnerability of humans to potential release scenarios, control measures must be implemented. Also, preventive and mitigation measures can be designed to enhance safety and resilience against the release of hazardous materials.

Medicinal plants are a pool of organically active compounds. In texts, there are various allusions to the use of vishdraya as a medicine. Kuchala (Strychnos nux-vomica Linn), an evergreen tree, commonly known as poison nut is attributed with both poisonous and medicinal values. Alkaloids are the main bioactive ingredients in S. nux-vomica Linn, 80% of which are strychnine and brucine, as well as their derivatives such as brucine N-oxide or isostrychnine. In Ayurveda, it has been used for curing various ailments including paralysis, dyspepsia, itching, joint pain, dysentery, emotional disorders, epilepsy, insomnia, etc. after proper shodhana process. Different studies reported safety and toxicity aspects while other studies reported antimicrobial, antidiabetic, hepatoprotective, immunomodulatory, antipyretic, etc. activities of the plant. In this review, an attempt has been made to understand its therapeutic potential by assimilating traditional medicinal knowledge and modern scientific findings about nux vomica. Strychnos nux-vomica Linn (Family: Loganiaceae), a medicinally important toxic plant, commonly known as nux vomica, poison nut, has manifold therapeutic and clinical implementation. This plant is commercially cultivated in different parts of the world such as the United States, the European Union, Fujian, Guangdong, Guangxi, Hainan, North Australia, Taiwan, and throughout tropical Asia.[1] Different parts of this plant, especially seeds and bark, own an ample variety of indications in long-established traditional and folklore medicines of different countries. At present, nux vomica is utilized in more than 60 formulations of Indian systems of medicine of which 30 formulations are used in the disorders of vata dosha.[2] The indole alkaloids, strychnine, and brucine, are richly present in different parts of this plant. These alkaloids pose a wide range of therapeutic potential. It is used as an appetite suppressant, purgative, and as a constituent of nerve toxin along with its uses as rodenticide, respiratory stimulants, and killing stray dogs.[1]

S119 - Safety and Tolerability of Ascending Doses of ENA-001: A Novel Respiratory Stimulant, for the Intended Management of Pharmacologically-Induced Respiratory Depression

Respiratory changes are often associated with anxiety disorders, particularly panic disorder (PD). Individuals experiencing PD are subjected to unexpected panic attacks, marked by overwhelming anxiety and fear, leading to a variety of autonomic and respiratory symptoms. PD patients have increased sensitivity to carbon dioxide (CO2). In response to respiratory stimulants like CO2, patients with PD tend to hyperventilate and panic, triggering the activation of an excessively reactive fear network. While their respiratory physiology may appear normal, the presence of subtle breathing abnormalities and other functions related to bodily homeostasis. This fear network, comprising the hippocampus, medial prefrontal cortex, amygdala, and its connections to the brainstem, seems to be hypersensitive in PD’s patients. This review aims to present a comprehensive overview of the current landscape on the link between PD and respiratory disorders. In July 2023 a literature search was undertaken for articles examining the relationship between PD, respiratory disorders, and psychological implications. Multiple databases were searched: PubMed, PubMed Central, PsycINFO, Web of Science, Elsevier Journal, Health &amp; Medical Collection, and Springer. The analysis of six studies focused on the correlation between PD and asthma revealed important links between these two disorders. Anxiety and panic can have significant impacts on the manifestation and aggravation of asthma. Furthermore, the review indicates that psychological therapeutic approaches, in particular cognitive-behavioral therapy, may represent a valid intervention to improve clinical outcomes in patients suffering from both disorders. Future investigations in this field may help highlight new intervention strategies in the psychological area to help individuals with PD decrease concomitant asthma, significantly improving their quality of life.

Background ENA-001 (formerly known as GAL-021) is a novel, first-in-class respiratory stimulant. Pharmacokinetic and pharmacodynamic properties, plus safety and tolerability, were assessed in a randomized, single-center study of healthy volunteers. Methodology This four-period study was designed to test continuous two-hour intravenous infusion regimens of ENA-001 at doses of 0.96, 1.44, and 1.92 mg/kg/hour versus placebo. Each participant received four infusions with a seven-day minimum washout between them: one infusion each of the three doses of ENA-001 and one placebo. Pharmacokinetic and pharmacodynamic parameters were assessed and adverse events were recorded. Results A total of 17 participants completed the study. ENA-001 was generally safe and well tolerated over the dose range studied (0.96 to 1.92 mg/kg/hour). ENA-001 was able to drive hyperventilation in a dose-dependent manner in healthy participants. Increases in ventilation due to ENA-001 were not associated with like-magnitude blood pressure response. ENA-001-stimulated decreases in ETCO2 were associated with small, statistically significant, increases in SpO2 levels. Hyperventilation occurred in two participants at the highest dose level, leading to study discontinuation. The terminal half-life of ENA-001 was 6.33 hours. Conclusions The respiratory stimulant ENA-001 demonstrated well-behaved pharmacokinetics following the two-hour infusion. Mean peak plasma concentrations and the mean total systemic exposure values were approximately dose-proportional in the dose range studied.

The central CO2 chemoreflex is a vital component of respiratory control networks, providing excitatory drive during resting conditions and challenges to blood gas homeostasis. The retrotrapezoid nucleus is a crucial hub for CO2 chemosensitivity; its ablation or inhibition attenuates CO2 chemoreflexes and diminishes restful breathing. Similar phenotypes characterize certain hypoventilation syndromes, suggesting underlying retrotrapezoid nucleus impairment in these disorders. Progesterone stimulates restful breathing and CO2 chemoreflexes. However, its mechanisms and sites of actions remain unknown and the experimental use of synthetic progestins in patients and animal models have been met with mixed respiratory outcomes. We investigated whether acute or chronic administration of the progestinic drug, etonogestrel, could rescue respiratory chemoreflexes following selective lesion of the retrotrapezoid nucleus with saporin toxin. Adult female Sprague Dawley rats were grouped based on lesion size determined by the number of surviving chemosensitive neurons, and ventilatory responses were measured by whole body plethysmography. Ventilatory responses to hypercapnia (but not hypoxia) were compromised in a lesion-dependent manner. Chronic etonogestrel treatment improved CO2 chemosensitivity selectively in rats with moderate lesion, suggesting that a residual number of chemosensitive neurons are required for etonogestrel-induced CO2 chemoreflex recovery. This study provides new evidence for the use of progestins as respiratory stimulants under conditions of central hypoventilation and provides a new testable model for assessing the mechanism of action of progestins in the respiratory network.