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Pediatric Pulmonology Oct 2022Though endogenous S-nitroso-l-cysteine (l-CSNO) signaling at the level of the carotid body increases minute ventilation (v̇ ), neither the background data nor the... (Review)
Review
Though endogenous S-nitroso-l-cysteine (l-CSNO) signaling at the level of the carotid body increases minute ventilation (v̇ ), neither the background data nor the potential clinical relevance are well-understood by pulmonologists in general, or by pediatric pulmonologists in particular. Here, we first review how regulation of the synthesis, activation, transmembrane transport, target interaction, and degradation of l-CSNO can affect the ventilatory drive. In particular, we review l-CSNO formation by hemoglobin R to T conformational change and by nitric oxide (NO) synthases (NOS), and the downstream effects on v̇ through interaction with voltage-gated K (Kv) channel proteins and other targets in the peripheral and central nervous systems. We will review how these effects are independent of-and, in fact may be opposite to-those of NO. Next, we will review evidence that specific elements of this pathway may underlie disorders of respiratory control in childhood. Finally, we will review the potential clinical implications of this pathway in the development of respiratory stimulants, with a particular focus on potential pediatric applications.
Topics: Child; Cysteine; Hemoglobins; Humans; Nitric Oxide; Nitric Oxide Synthase; Respiratory System Agents; S-Nitrosothiols
PubMed: 35785452
DOI: 10.1002/ppul.26036 -
Anesthesiology May 2018The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication... (Review)
Review
The ventilatory control system is highly vulnerable to exogenous administered opioid analgesics. Particularly respiratory depression is a potentially lethal complication that may occur when opioids are overdosed or consumed in combination with other depressants such as sleep medication or alcohol. Fatalities occur in acute and chronic pain patients on opioid therapy and individuals that abuse prescription or illicit opioids for their hedonistic pleasure. One important strategy to mitigate opioid-induced respiratory depression is cotreatment with nonopioid respiratory stimulants. Effective stimulants prevent respiratory depression without affecting the analgesic opioid response. Several pharmaceutical classes of nonopioid respiratory stimulants are currently under investigation. The majority acts at sites within the brainstem respiratory network including drugs that act at α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (ampakines), 5-hydroxytryptamine receptor agonists, phospodiesterase-4 inhibitors, D1-dopamine receptor agonists, the endogenous peptide glycyl-glutamine, and thyrotropin-releasing hormone. Others act peripherally at potassium channels expressed on oxygen-sensing cells of the carotid bodies, such as doxapram and GAL021 (Galleon Pharmaceuticals Corp., USA). In this review we critically appraise the efficacy of these agents. We conclude that none of the experimental drugs are adequate for therapeutic use in opioid-induced respiratory depression and all need further study of efficacy and toxicity. All discussed drugs, however, do highlight potential mechanisms of action and possible templates for further study and development.
Topics: Analgesia; Analgesics, Opioid; Animals; Carotid Body; Dipeptides; Humans; Phosphodiesterase 4 Inhibitors; Receptors, Dopamine D1; Respiratory Insufficiency; Respiratory System Agents
PubMed: 29553984
DOI: 10.1097/ALN.0000000000002184 -
Experimental Biology and Medicine... May 2021Assessment of respiratory mechanics extends from basic research and animal modeling to clinical applications in humans. However, to employ the applications in human... (Review)
Review
Assessment of respiratory mechanics extends from basic research and animal modeling to clinical applications in humans. However, to employ the applications in human models, it is desirable and sometimes mandatory to study non-human animals first. To acquire further precise and controlled signals and parameters, the animals studied must be further distant from their spontaneous ventilation. The majority of respiratory mechanics studies use positive pressure ventilation to model the respiratory system. In this scenario, a few drug categories become relevant: anesthetics, muscle blockers, bronchoconstrictors, and bronchodilators. Hence, the main objective of this study is to briefly review and discuss each drug category, and the impact of a drug on the assessment of respiratory mechanics. Before and during the positive pressure ventilation, the experimental animal must be appropriately sedated and anesthetized. The sedation will lower the pain and distress of the studied animal and the plane of anesthesia will prevent the pain. With those drugs, a more controlled procedure is carried out; further, because many anesthetics depress the respiratory system activity, a minimum interference of the animal's respiration efforts are achieved. The latter phenomenon is related to muscle blockers, which aim to minimize respiratory artifacts that may interfere with forced oscillation techniques. Generally, the respiratory mechanics are studied under appropriate anesthesia and muscle blockage. The application of bronchoconstrictors is prevalent in respiratory mechanics studies. To verify the differences among studied groups, it is often necessary to challenge the respiratory system, for example, by pharmacologically inducing bronchoconstriction. However, the selected bronchoconstrictor, doses, and administration can affect the evaluation of respiratory mechanics. Although not prevalent, studies have applied bronchodilators to return (airway resistance) to the basal state after bronchoconstriction. The drug categories can influence the mathematical modeling of the respiratory system, systemic conditions, and respiratory mechanics outcomes.
Topics: Anesthetics; Animals; Bronchoconstrictor Agents; Bronchodilator Agents; Models, Animal; Neuromuscular Blocking Agents; Respiratory Mechanics
PubMed: 33601911
DOI: 10.1177/1535370221993095 -
Molecules (Basel, Switzerland) Sep 2020There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and... (Review)
Review
There is a vast practice of using antimalarial drugs, RAS inhibitors, serine protease inhibitors, inhibitors of the RNA-dependent RNA polymerase of the virus and immunosuppressants for the treatment of the severe form of COVID-19, which often occurs in patients with chronic diseases and older persons. Currently, the clinical efficacy of these drugs for COVID-19 has not been proven yet. Side effects of antimalarial drugs can worsen the condition of patients and increase the likelihood of death. Peptides, given their physiological mechanism of action, have virtually no side effects. Many of them are geroprotectors and can be used in patients with chronic diseases. Peptides may be able to prevent the development of the pathological process during COVID-19 by inhibiting SARS-CoV-2 virus proteins, thereby having immuno- and bronchoprotective effects on lung cells, and normalizing the state of the hemostasis system. Immunomodulators (RKDVY, EW, KE, AEDG), possessing a physiological mechanism of action at low concentrations, appear to be the most promising group among the peptides. They normalize the cytokines' synthesis and have an anti-inflammatory effect, thereby preventing the development of disseminated intravascular coagulation, acute respiratory distress syndrome and multiple organ failure.
Topics: Acute Disease; Anti-Inflammatory Agents; Antiviral Agents; Betacoronavirus; COVID-19; Coronavirus Infections; Cytokine Release Syndrome; Disseminated Intravascular Coagulation; Host-Pathogen Interactions; Humans; Immunologic Factors; Lung; Pandemics; Peptides; Pneumonia, Viral; Respiratory Insufficiency; Respiratory System Agents; SARS-CoV-2; Structure-Activity Relationship
PubMed: 32987757
DOI: 10.3390/molecules25194389 -
Chest Nov 2018Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA) pathway is implicated in IPF etiology. Safety... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Idiopathic pulmonary fibrosis (IPF) causes irreversible loss of lung function. The lysophosphatidic acid receptor 1 (LPA) pathway is implicated in IPF etiology. Safety and efficacy of BMS-986020, a high-affinity LPA antagonist, was assessed vs placebo in a phase 2 study in patients with IPF.
METHODS
IM136003 was a phase 2, parallel-arm, multicenter, randomized, double-blind, placebo-controlled trial. Adults with IPF (FVC, 45%-90%; diffusing capacity for carbon monoxide, 30%-80%) were randomized to receive placebo or 600 mg BMS-986020 (once daily [qd] or bid) for 26 weeks. The primary end point was rate of change in FVC from baseline to week 26.
RESULTS
Of 143 randomized patients, 108 completed the 26-week dosing phase. Thirty-five patients discontinued prematurely. Patient baseline characteristics were similar between treatment groups (placebo: n = 47; 600 mg qd: n = 48; 600 mg bid: n = 48). Patients treated with BMS-986020 bid experienced a significantly slower rate of decline in FVC vs placebo (-0.042 L; 95% CI, -0.106 to -0.022 vs -0.134 L; 95% CI, -0.201 to -0.068, respectively; P = .049). Dose-related elevations in hepatic enzymes were observed in both BMS-986020 treatment groups. The study was terminated early because of three cases of cholecystitis that were determined to be related to BMS-986020 after unblinding.
CONCLUSIONS
BMS-986020 600 mg bid treatment for 26 weeks vs placebo significantly slowed the rate of FVC decline. Both regimens of BMS-986020 were associated with elevations in hepatic enzymes.
TRIAL REGISTRY
ClinicalTrials.gov; No.: NCT01766817; URL: www.clinicaltrials.gov.
Topics: Aged; Aged, 80 and over; Cholecystitis; Dose-Response Relationship, Drug; Double-Blind Method; Early Termination of Clinical Trials; Female; Humans; Idiopathic Pulmonary Fibrosis; Liver Function Tests; Male; Middle Aged; Outcome and Process Assessment, Health Care; Receptors, Lysophosphatidic Acid; Respiratory Function Tests; Respiratory System Agents; Vital Capacity
PubMed: 30201408
DOI: 10.1016/j.chest.2018.08.1058 -
International Journal of Chronic... 2017COPD, for which cigarette smoking is the major risk factor, remains a worldwide burden. Current therapies provide only limited short-term benefit and fail to halt... (Review)
Review
COPD, for which cigarette smoking is the major risk factor, remains a worldwide burden. Current therapies provide only limited short-term benefit and fail to halt progression. A variety of potential therapeutic targets are currently being investigated, including COPD-related proinflammatory mediators and signaling pathways. Other investigational compounds target specific aspects or complications of COPD such as mucus hypersecretion and pulmonary hypertension. Although many candidate therapies have shown no significant effects, other emerging therapies have improved lung function, pulmonary hypertension, glucocorticoid sensitivity, and/or the frequency of exacerbations. Among these are compounds that inhibit the CXCR2 receptor, mitogen-activated protein kinase/Src kinase, myristoylated alanine-rich C kinase substrate, selectins, and the endothelin receptor. Activation of certain transcription factors may also be relevant, as a large retrospective cohort study of COPD patients with diabetes found that the peroxisome proliferator-activated receptor γ (PPARγ) agonists rosiglitazone and pioglitazone were associated with reduced COPD exacerbation rate. Notably, several therapies have shown efficacy only in identifiable subgroups of COPD patients, suggesting that subgroup identification may become more important in future treatment strategies. This review summarizes the status of emerging therapeutic pharmaceuticals for COPD and highlights those that appear most promising.
Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Bronchodilator Agents; Drug Design; Drug Resistance; Humans; Inflammation Mediators; Lung; Molecular Targeted Therapy; PPAR gamma; Phosphodiesterase Inhibitors; Protein Kinase Inhibitors; Pulmonary Disease, Chronic Obstructive; Respiratory System Agents; Signal Transduction
PubMed: 28790817
DOI: 10.2147/COPD.S121416 -
Molecular Medicine (Cambridge, Mass.) Jun 2020In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap... (Review)
Review
In light of the present therapeutic situation in COVID-19, any measure to improve course and outcome of seriously affected individuals is of utmost importance. We recap here evidence that supports the use of human recombinant erythropoietin (EPO) for ameliorating course and outcome of seriously ill COVID-19 patients. This brief expert review grounds on available subject-relevant literature searched until May 14, 2020, including Medline, Google Scholar, and preprint servers. We delineate in brief sections, each introduced by a summary of respective COVID-19 references, how EPO may target a number of the gravest sequelae of these patients. EPO is expected to: (1) improve respiration at several levels including lung, brainstem, spinal cord and respiratory muscles; (2) counteract overshooting inflammation caused by cytokine storm/ inflammasome; (3) act neuroprotective and neuroregenerative in brain and peripheral nervous system. Based on this accumulating experimental and clinical evidence, we finally provide the research design for a double-blind placebo-controlled randomized clinical trial including severely affected patients, which is planned to start shortly.
Topics: Betacoronavirus; Brain Stem; COVID-19; Coronavirus Infections; Cytokine Release Syndrome; Double-Blind Method; Erythropoietin; Humans; Lung; Neuroprotective Agents; Pandemics; Phrenic Nerve; Pneumonia, Viral; Proof of Concept Study; Randomized Controlled Trials as Topic; Recombinant Proteins; Respiratory Muscles; Respiratory System Agents; SARS-CoV-2; Severity of Illness Index; Spinal Cord
PubMed: 32546125
DOI: 10.1186/s10020-020-00186-y -
Cells Nov 2022Bitter taste receptors (TAS2Rs) have recently arisen as a potential drug target for asthma due to their localization in airway cells. These receptors are expressed in... (Review)
Review
Bitter taste receptors (TAS2Rs) have recently arisen as a potential drug target for asthma due to their localization in airway cells. These receptors are expressed in all cell types of the respiratory system comprising epithelial, smooth muscle and immune cells; however, the expression pattern of the subtypes is different in each cell type and, accordingly, so is their role, for example, anti-inflammatory or bronchodilator. The most challenging aspect in studying TAS2Rs has been the identification of the downstream signaling cascades. Indeed, TAS2R activation leads to canonical IP3-dependent calcium release from the ER, but, alongside, there are other mechanisms that differ according to the histological localization. In this review, we summarize the current knowledge on the cytosolic calcium modulation downstream of TAS2R activation in the epithelial, smooth muscle and immune cells of the airway system.
Topics: Calcium; Cytosol; Muscle, Smooth; Taste Buds; Bronchodilator Agents
PubMed: 36429066
DOI: 10.3390/cells11223638 -
F1000Research 2020Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major... (Review)
Review
Strong opioid analgesics are the mainstay of therapy for the relief of moderate to severe acute nociceptive pain that may occur post-operatively or following major trauma, as well as for the management of chronic cancer-related pain. Opioid-related adverse effects include nausea and vomiting, sedation, respiratory depression, constipation, tolerance, and addiction/abuse liability. Of these, respiratory depression is of the most concern to clinicians owing to the potential for fatal consequences. In the broader community, opioid overdose due to either prescription or illicit opioids or co-administration with central nervous system depressants may evoke respiratory depression. To address this problem, there is ongoing interest in the identification of non-opioid respiratory stimulants to reverse opioid-induced respiratory depression but without reversing opioid analgesia. Promising compound classes evaluated to date include those that act on a diverse array of receptors including 5-hydroxytryptamine, D -dopamine, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), N-methyl-D-aspartate (NMDA) receptor antagonists, and nicotinic acetylcholine as well as phosphodiesterase inhibitors and molecules that act on potassium channels on oxygen-sensing cells in the carotid body. The aim of this article is to review recent advances in the development potential of these compounds for countering opioid-induced respiratory depression.
Topics: Analgesics, Opioid; Anesthesia; Humans; Pain; Respiratory Insufficiency; Respiratory System Agents
PubMed: 32089833
DOI: 10.12688/f1000research.21738.1 -
Respiratory Physiology & Neurobiology Nov 2013Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict... (Review)
Review
Drug-induced respiratory depression (DIRD) is a common problem encountered post-operatively and can persist for days after surgery. It is not always possible to predict the timing or severity of DIRD due to the number of contributing factors. A safe and effective respiratory stimulant could improve patient care by avoiding the use of reversal agents (e.g., naloxone, which reverses analgesia as well as respiratory depression) thereby permitting better pain management by enabling the use of higher doses of analgesics, facilitate weaning from prolonged ventilation, and ameliorate sleep-disordered breathing peri-operatively. The purpose of this review is to discuss the current pharmaceutical armamentarium of drugs (doxapram and almitrine) that are licensed for use in humans as respiratory stimulants and that could be used to reverse drug-induced respiratory depression in the post-operative period. We also discuss new chemical entities (AMPAkines and GAL-021) that have been recently evaluated in Phase 1 clinical trials and where the initial regulatory registration would be as a respiratory stimulant.
Topics: Humans; Postoperative Complications; Pulmonary Ventilation; Respiratory Insufficiency; Respiratory System Agents
PubMed: 23791825
DOI: 10.1016/j.resp.2013.06.010